Redox regulation of antioxidant enzymes: post-translational modulation of catalase and glutathione peroxidase activity by resveratrol in diabetic rat liver.

PubMed

Sadi, Gökhan; Bozan, Davut; Yildiz, Huseyin Bekir

2014-08-01

Resveratrol is a strong antioxidant that exhibits blood glucose-lowering effects, which might contribute to its usefulness in preventing complications associated with diabetes. The present study aimed to investigate resveratrol effects on catalase (CAT) and glutathione peroxidase (GPx) gene and protein expression, their phosphorylation states and activities in rat liver of STZ-induced diabetes. Diabetes increased the levels of total protein phosphorylation and p-CAT, while mRNA expression, protein levels, and activity were reduced. Although diabetes induced transcriptional repression over GPx, it did not affect the protein levels and activity. When resveratrol was administered to diabetic rats, an increase in activity was associated with an increase in p-GPx levels. Decrease in Sirtuin1 (SIRT1) and nuclear factor erythroid 2-related factor (Nrf2) and increase in nuclear factor kappa B (NFκB) gene expression in diabetes were associated with a decrease in CAT and GPx mRNA expression. A possible compensatory mechanism for reduced gene expression of antioxidant enzymes is proved to be nuclear translocation of redox-sensitive Nrf2 and NFκB in diabetes which is confirmed by the increase in nuclear and decrease in cytoplasmic protein levels of Nrf2 and NFκB. Taken together, these findings revealed that an increase in the oxidized state in diabetes intricately modified the cellular phosphorylation status and regulation of antioxidant enzymes. Gene regulation of antioxidant enzymes was accompanied by nuclear translocation of Nrf2 and NFκB. Resveratrol administration also activated a coordinated cytoprotective response against diabetes-induced changes in liver tissues.

The influence of some environmental factors on cytological and biometric parameters and chlorophyll content of Deschampsia antarctica Desv. in the maritime Antarctic.

PubMed

Parnikoza, I Yu; Loro, P; Miryuta, N Yu; Kunakh, V A; Kozeretska, I A

2011-01-01

Under the environmental conditions of the Point Thomas Oasis (King George Island, the South Shetland Islands), we studied the influence of month-long artificial treatment with fresh water, salt water, and guano solution on the biometric characteristics, chlorophyll content, as well as the nuclear area of leaf parenchymal cells and nuclear DNA content, in a maritime Antarctic aboriginal plant Deschampsia antarctica. The modeled factors induced an increase in the generative shoot height and the length of the largest leaf, but did not influence the number of flowers. Treatment with guano caused an increase in the chlorophyll a and b contents, while fresh water treatment only led to some increase in chlorophyll a. Fluctuations of physiologically significant traits, such as the nuclear area and DNA content in the leaf parenchyma cells of D. antarctica, have been traced under the influence of the studied factors. Understanding of the hierarchy of influence of these factors as well as and sensitivity of plants of this species to external agents require further investigation.

FTS is responsible for radiation-induced nuclear phosphorylation of EGFR and repair of DNA damage in cervical cancer cells.

PubMed

Muthusami, Sridhar; Prabakaran, D S; Yu, Jae-Ran; Park, Woo-Yoon

2015-02-01

Radiation-induced nuclear stabilization and phosphorylation of epidermal growth factor receptor (EGFR) confers radioresistance. Understanding of the factor(s) regulating the nuclear stabilization and phosphorylation of EGFR is important for the modulation of radioresistance. Present study was designed to delineate the regulation of EGFR nuclear stabilization and phosphorylation by fused toes homolog (FTS), an oncoprotein, which is responsible for the radioresistance in cervical cancer cells. A cervical cancer cell line, ME180 was used. Radiation-induced change in the levels of EGFR, p-EGFR and FTS were evaluated in the cytoplasm and nucleus using Western blot analyses. FTS was silenced using siRNA-based approach. Interaction between EGFR and FTS was assessed using immunofluorescence and immunoprecipitation analyses. Double-strand breaks (DSB) of DNA were assessed using γ H2AX. Radiation increased the levels of EGFR and FTS in the cytoplasm and nucleus. EGFR and FTS are in physical association with each other and are co-localized in the cells. FTS silencing largely reduced the nuclear stabilization and phosphorylation of EGFR and DNA-protein kinase along with increased initial and residual DSBs. EGFR and FTS physically associate with each other and FTS silencing radiosensitizes ME180 cells through impaired nuclear EGFR signaling.

Prothymosin α overexpression contributes to the development of pulmonary emphysema.

PubMed

Su, Bing-Hua; Tseng, Yau-Lin; Shieh, Gia-Shing; Chen, Yi-Cheng; Shiang, Ya-Chieh; Wu, Pensee; Li, Kuo-Jung; Yen, Te-Hsin; Shiau, Ai-Li; Wu, Chao-Liang

2013-01-01

Emphysema is one of the disease conditions that comprise chronic obstructive pulmonary disease. Prothymosin α transgenic mice exhibit an emphysema phenotype, but the pathophysiological role of prothymosin α in emphysema remains unclear. Here we show that prothymosin α contributes to the pathogenesis of emphysema by increasing acetylation of histones and nuclear factor-kappaB, particularly upon cigarette smoke exposure. We find a positive correlation between prothymosin α levels and the severity of emphysema in prothymosin α transgenic mice and emphysema patients. Prothymosin α overexpression increases susceptibility to cigarette smoke-induced emphysema, and cigarette smoke exposure further enhances prothymosin α expression. We show that prothymosin α inhibits the association of histone deacetylases with histones and nuclear factor-kappaB, and that prothymosin α overexpression increases expression of nuclear factor-kappaB-dependent matrix metalloproteinase 2 and matrix metalloproteinase 9, which are found in the lungs of patients with chronic obstructive pulmonary disease. These results demonstrate the clinical relevance of prothymosin α in regulating acetylation events during the pathogenesis of emphysema.

Prothymosin α overexpression contributes to the development of pulmonary emphysema

PubMed Central

Su, Bing-Hua; Tseng, Yau-Lin; Shieh, Gia-Shing; Chen, Yi-Cheng; Shiang, Ya-Chieh; Wu, Pensee; Li, Kuo-Jung; Yen, Te-Hsin; Shiau, Ai-Li; Wu, Chao-Liang

2013-01-01

Emphysema is one of the disease conditions that comprise chronic obstructive pulmonary disease. Prothymosin α transgenic mice exhibit an emphysema phenotype, but the pathophysiological role of prothymosin α in emphysema remains unclear. Here we show that prothymosin α contributes to the pathogenesis of emphysema by increasing acetylation of histones and nuclear factor-kappaB, particularly upon cigarette smoke exposure. We find a positive correlation between prothymosin α levels and the severity of emphysema in prothymosin α transgenic mice and emphysema patients. Prothymosin α overexpression increases susceptibility to cigarette smoke-induced emphysema, and cigarette smoke exposure further enhances prothymosin α expression. We show that prothymosin α inhibits the association of histone deacetylases with histones and nuclear factor-kappaB, and that prothymosin α overexpression increases expression of nuclear factor-kappaB-dependent matrix metalloproteinase 2 and matrix metalloproteinase 9, which are found in the lungs of patients with chronic obstructive pulmonary disease. These results demonstrate the clinical relevance of prothymosin α in regulating acetylation events during the pathogenesis of emphysema. PMID:23695700

The future of nuclear power: A world-wide perspective

NASA Astrophysics Data System (ADS)

Aktar, Ismail

This study analyzes the future of commercial nuclear electric generation worldwide using the Environmental Kuznets Curve (EKC) concept. The Tobit panel data estimation technique is applied to analyze the data between 1980 and 1998 for 105 countries. EKC assumes that low-income countries increase their nuclear reliance in total electric production whereas high-income countries decrease their nuclear reliance. Hence, we expect that high-income countries should shut down existing nuclear reactors and/or not build any new ones. We encounter two reasons for shutdowns: economic or political/environmental concerns. To distinguish these two effects, reasons for shut down are also investigated by using the Hazard Model technique. Hence, the load factor of a reactor is used as an approximation for economic reason to shut down the reactor. If a shut downed reactor had high load factor, this could be attributable to political/environmental concern or else economic concern. The only countries with nuclear power are considered in this model. The two data sets are created. In the first data set, the single entry for each reactor is created as of 1998 whereas in the second data set, the multiple entries are created for each reactor beginning from 1980 to 1998. The dependent variable takes 1 if operational or zero if shut downed. The empirical findings provide strong evidence for EKC relationship for commercial nuclear electric generation. Furthermore, higher natural resources suggest alternative electric generation methods rather than nuclear power. Economic index as an institutional variable suggests higher the economic freedom, lower the nuclear electric generation as expected. This model does not support the idea to cut the carbon dioxide emission via increasing nuclear share. The Hazard Model findings suggest that higher the load factor is, less likely the reactor will shut down. However, if it is still permanently closed downed, then this could be attributable to political hostility against nuclear power. There are also some projections indicating which reactors are most/least likely to be shut downed from the logit model. We also project which countries are most likely to increase/decrease their nuclear reliance from the residuals of EKC model.

[Baicalin increases the antioxidant capacity via promoting the nuclear translocation of NF-E2-related factor 2 (Nrf2) in N2a/APPswe cells].

PubMed

Cao, Huimin; Chen, Beibei; Deng, Yushuang; Lu, Xi; Yu, Gang

2015-12-01

To investigate the protective effect and related mechanism of baicalin in murine neuroblastoma N2a cells stably expressing human Swedish mutant amyloid precursor protein (APP) (N2a/APPswe cells), a cellular model of Alzheimer' s disease (AD). MTT assay was performed to observe the effect of baicalin (0.1, 0.5, 1, 5, 10, 20) μmol/L on the viability of N2a/APPswe cells. After N2a/APPswe cells were incubated with (1, 5, 10) μmol/L baicalin for 48 hours, xanthine oxidase assay was used to test superoxide dismutase (SOD) activity and thiobarbituric acid method to detect malondialdehyde (MDA) content in each group. Real-time quantitative PCR was applied to determine nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA, and Western blotting to examine protein levels of total Nrf2, nuclear Nrf2 and nuclear factor κB (NF-κB) in N2a/APPswe cells exposed to different doses of baicalin. Immunofluorescence staining was also used to observe the distribution of Nrf2. We found that baicalin pretreatment increased cell viability. Compared with the control group (N2a/wt cells), SOD activity in N2a/APPswe cells significantly decreased, and MDA content significantly increased; but SOD activity was improved and MDA production was inhibited after pretreatment with baicalin, especially with 10 μmol/L bacalin. Both mRNA and total protein expression of Nrf2 were not significantly changed in baicalin treatment group compared with N2a/APPswe group, but the nuclear protein of Nrf2 distinctly increased after treatment with baicalin. In addition, baicalin decreased the level of nuclear NF-κB protein. Furthermore, immunofluorescence staining revealed that baicalin promoted the translocation of Nrf2 to the nucleus. Baicalin has the protection against oxidative stress via activation of Nrf2 in N2a/APPswe cells.

DNA damage induces nuclear actin filament assembly by Formin -2 and Spire-½ that promotes efficient DNA repair. [corrected].

PubMed

Belin, Brittany J; Lee, Terri; Mullins, R Dyche

2015-08-19

Actin filaments assemble inside the nucleus in response to multiple cellular perturbations, including heat shock, protein misfolding, integrin engagement, and serum stimulation. We find that DNA damage also generates nuclear actin filaments-detectable by phalloidin and live-cell actin probes-with three characteristic morphologies: (i) long, nucleoplasmic filaments; (ii) short, nucleolus-associated filaments; and (iii) dense, nucleoplasmic clusters. This DNA damage-induced nuclear actin assembly requires two biologically and physically linked nucleation factors: Formin-2 and Spire-1/Spire-2. Formin-2 accumulates in the nucleus after DNA damage, and depletion of either Formin-2 or actin's nuclear import factor, importin-9, increases the number of DNA double-strand breaks (DSBs), linking nuclear actin filaments to efficient DSB clearance. Nuclear actin filaments are also required for nuclear oxidation induced by acute genotoxic stress. Our results reveal a previously unknown role for nuclear actin filaments in DNA repair and identify the molecular mechanisms creating these nuclear filaments.

Prognostic significance of anaplasia and angiogenesis in childhood medulloblastoma: a pediatric oncology group study.

PubMed

Ozer, Erdener; Sarialioglu, Faik; Cetingoz, Riza; Yüceer, Nurullah; Cakmakci, Handan; Ozkal, Sermin; Olgun, Nur; Uysal, Kamer; Corapcioglu, Funda; Canda, Serefettin

2004-01-01

The purpose of this study was to investigate whether quantitative assessment of cytologic anaplasia and angiogenesis may predict the clinical prognosis in medulloblastoma and stratify the patients to avoid both undertreatment and overtreatment. Medulloblastomas from 23 patients belonging to the Pediatric Oncology Group were evaluated with respect to some prognostic variables, including histologic assessment of nodularity and desmoplasia, grading of anaplasia, measurement of nuclear size, mitotic cell count, quantification of angiogenesis, including vascular surface density (VSD) and microvessel number (NVES), and immunohistochemical scoring of vascular endothelial growth factor (VEGF) expression. Univariate and multivariate analyses for prognostic indicators for survival were performed. Univariate analysis revealed that extensive nodularity was a significant favorable prognostic factor, whereas the presence of anaplasia, increased nuclear size, mitotic rate, VSD, and NVES were significant unfavorable prognostic factors. Using multivariate analysis, increased nuclear size was found to be an independent unfavorable prognostic factor for survival. Neither the presence of desmoplasia nor VEGF expression was significantly related to patient survival. Although care must be taken not to overstate the importance of the results of this single-institution preliminary report, pathologic grading of medulloblastomas with respect to grading of anaplasia and quantification of nodularity, nuclear size, and microvessel profiles may be clinically useful for the treatment of medulloblastomas. Further validation of the independent prognostic significance of nuclear size in stratifying patients is required.

Bortezomib reverses the proliferative and antiapoptotic effect of neuropeptides on prostate cancer cells.

PubMed

Tsapakidis, Konstantinos; Vlachostergios, Panagiotis J; Voutsadakis, Ioannis A; Befani, Christina D; Patrikidou, Anna; Hatzidaki, Eleana; Daliani, Danai D; Moutzouris, George; Liakos, Panagiotis; Papandreou, Christos N

2012-06-01

Neuropeptides are important signal initiators in advanced prostate cancer, partially acting through activation of nuclear factor kappa B. Central to nuclear factor kappa B regulation is the ubiquitin-proteasome system, pharmacological inhibition of which has been proposed as an anticancer strategy. We investigated the putative role of the proteasome inhibitor bortezomib in neuropeptides signaling effects on prostate cancer cells. Human prostate cancer cell lines, LNCaP and PC-3, were used to examine cell proliferation, levels of proapoptotic (caspase-3, Bad) and cell cycle regulatory proteins (p53, p27, p21), as well as total and phosphorylated Akt and p44/42 mitogen-activated protein kinase proteins. Furthermore, 20S proteasome activity, subcellular localization of nuclear factor kappa B and transcription of nuclear factor kappa B target genes, interleukin-8 and vascular endothelial growth factor, were assessed. Neuropeptides (endothelin-1, bombesin) increased cell proliferation, whereas bortezomib decreased proliferation and induced apoptosis, an effect maintained after cotreatment with neuropeptides. Bad, p53, p21 and p27 were downregulated by neuropeptides in PC-3, and these effects were reversed with the addition of bortezomib. Neuropeptides increased proteasomal activity and nuclear factor kappa B levels in PC-3, and these effects were prevented by bortezomib. Interleukin-8 and vascular endothelial growth factor transcripts were induced after neuropeptides treatment, but downregulated by bortezomib. These results coincided with the ability of bortezomib to reduce mitogen-activated protein kinase signaling in both cell lines. These findings are consistent with bortezomib-mediated abrogation of neuropeptides-induced proliferative and antiapoptotic signaling. Thus, the effect of the drug on the neuropeptides axis needs to be further investigated, as neuropeptide action in prostate cancer might entail involvement of the proteasome. © 2012 The Japanese Urological Association.

Assessment of nuclear anxiety among American students: Stability over time, secular trends, and emotional correlates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Newcomb, M.D.

1989-10-01

Studies of reactions and attitudes toward nuclear war have progressed from the use of anecdotal evidence to multi-item psychological measures. Additional psychometric data and substantive results of the Nuclear Attitudes Questionnaire (NAQ; Newcomb, 1986) are reported here. Data from three independent samples of students from the United States collected in 1984, 1986, and 1987 were compared and contrasted. The 1986 data were obtained immediately following the Chernobyl nuclear power plant accident. Test-retest reliability of the NAQ items and subscales was quite high and comparable among samples and established the across-time stability of the measure. There were several secular trends acrossmore » years on items and subscales, indicating some increased concern about nuclear power (particularly in 1986), but also a general increase in nuclear concerns, fears, and anxiety. Anticipated sex differences were found on many of the NAQ items and subscales. Correlations between the NAQ subscales and the nine SCL-90-R scales (Derogatis, 1977) were consistent for the 1986 and 1987 samples. In latent variable analyses, a general factor of Emotional Distress was significantly correlated with a general factor of Nuclear Anxiety, as well as specifically with nuclear concern and fear for the future.« less

Ultraviolet B Radiation Stimulates the Interaction between Nuclear Factor of Activated T Cells 5 (NFAT5) and Nuclear Factor-Kappa B (NF-κB) in Human Lens Epithelial Cells.

PubMed

Chung, Inyoung; Hah, Young-Sool; Ju, SunMi; Kim, Ji-Hye; Yoo, Woong-Sun; Cho, Hee-Young; Yoo, Ji-Myong; Seo, Seong-Wook; Choi, Wan-Sung; Kim, Seong-Jae

2017-07-01

Nuclear factor-kappa B (NF-κB) has been proposed as a therapeutic target for the treatment of cataracts. The authors investigated the relationship between nuclear factor of activated T cells 5 (NFAT5) and NF-κB in ultraviolet B (UVB)-irradiated human lens epithelial (HLE) cells. Human lens epithelial B-3 (HLE-B3) cells were exposed to UVB light at a dose of 10 mJ/cm 2 and then incubated for 24 h. Cell viability was assessed by using the Cell Counting Kit-8 (CCK-8) assay. Gene expression level of NFAT5 was determined using real-time quantitative polymerase chain reaction (qPCR). Protein expression levels of NFAT5, NF-κB p65, and α-smooth muscle actin (α-SMA) and the association of NFAT5 with the NF-κB p65 subunit were measured by Western blot analysis and a co-immunoprecipitation assay, respectively. The cellular distribution of NFAT5 and NF-κB p65 was examined by triple immunofluorescence staining. At 24 h after UVB exposure, cell viability significantly decreased in a dose-dependent manner, and UVB light (15 and 20 mJ/cm 2 ) significantly increased the ROS generation. UVB irradiation increased NFAT5 mRNA and protein levels and increased phosphorylation of NF-κB in HLE-B3 cells. α-SMA protein levels were increased in the irradiated cells. In addition, NFAT5 and NF-κB translocated from the cytoplasm to the nucleus, and binding between the p65 subunit and NFAT5 was increased. Exposure to UVB radiation induces nuclear translocation and stimulates binding between NFAT5 and NF-κB proteins in HLE-B3 cells. These interactions may form part of the biochemical mechanism of cataractogenesis in UVB-irradiated HLECs.

Exploring Students' Ideas about Risks and Benefits of Nuclear Power Using Risk Perception Theories

ERIC Educational Resources Information Center

Kilinc, Ahmet; Boyes, Edward; Stanisstreet, Martin

2013-01-01

Due to increased energy demand, Turkey is continuing to explore the possibilities of introducing nuclear power. Gaining acceptance from local populations, however, may be problematic because nuclear power has a negative image and risk perceptions are complicated by a range of psychological and cultural factors. In this study, we explore the views…

4-Phenylbutyrate Benefits Traumatic Hemorrhagic Shock in Rats by Attenuating Oxidative Stress, Not by Attenuating Endoplasmic Reticulum Stress.

PubMed

Yang, Guangming; Peng, Xiaoyong; Hu, Yi; Lan, Dan; Wu, Yue; Li, Tao; Liu, Liangming

2016-07-01

Vascular dysfunction such as vascular hyporeactivity following severe trauma and shock is a major cause of death in injured patients. Oxidative stress and endoplasmic reticulum stress play an important role in vascular dysfunction. The objective of the present study was to determine whether or not 4-phenylbutyrate can improve vascular dysfunction and elicit antishock effects by inhibiting oxidative and endoplasmic reticulum stress. Prospective, randomized, controlled laboratory experiment. State key laboratory of trauma, burns, and combined injury. Five hundred and fifty-two Sprague-Dawley rats. Rats were anesthetized, and a model of traumatic hemorrhagic shock was established by left femur fracture and hemorrhage. The effects of 4-phenylbutyrate (5, 20, 50, 100, 200, and 300 mg/kg) on vascular reactivity, animal survival, hemodynamics, and vital organ function in traumatic hemorrhagic shock rats and cultured vascular smooth muscle cells, and the relationship to oxidative stress and endoplasmic reticulum stress was observed. Lower doses of 4-phenylbutyrate significantly improved the vascular function, stabilized the hemodynamics, and increased the tissue blood flow and vital organ function in traumatic hemorrhagic shock rats, and markedly improved the survival outcomes. Among all dosages observed in the present study, 20 mg/kg of 4-phenylbutyrate had the best effect. Further results indicated that 4-phenylbutyrate significantly inhibited the oxidative stress, decreased shock-induced oxidative stress index such as the production of reactive oxygen species, increased the antioxidant enzyme levels such as superoxide dismutase, catalase, and glutathione, and improved the mitochondrial function by inhibiting the opening of the mitochondrial permeability transition pore in rat artery and vascular smooth muscle cells. In contrast, 4-phenylbutyrate did not affect the changes of endoplasmic reticulum stress markers following traumatic hemorrhagic shock. Furthermore, 4-phenylbutyrate increased the nuclear levels of nuclear factor-E2-related factor 2, and decreased the nuclear levels of nuclear factor κB in hypoxic vascular smooth muscle cells. 4-phenylbutyrate has beneficial effects for traumatic hemorrhagic shock including improving animal survival and protecting organ function. These beneficial effects of 4-phenylbutyrate in traumatic hemorrhagic shock result from its vascular function protection via attenuation of the oxidative stress and mitochondrial permeability transition pore opening. Nuclear factor-E2-related factor 2 and nuclear factor-κB may be involved in 4-phenylbutyrate-mediated inhibition of oxidative stress.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kaur, Gurpreet; Ly-Huynh, Jennifer D.; Jans, David A., E-mail: David.Jans@monash.edu

Highlights: • High intracellular calcium inhibits Impα/β1- or Impβ1-dependent nuclear protein import. • The effect of Ca{sup 2+} on nuclear import does not relate to changes in the nuclear pore. • High intracellular calcium can result in mislocalisation of Impβ1, Ran and RCC1. - Abstract: We previously showed that increased intracellular calcium can modulate Importin (Imp)β1-dependent nuclear import of SRY-related chromatin remodeling proteins. Here we extend this work to show for the first time that high intracellular calcium inhibits Impα/β1- or Impβ1-dependent nuclear protein import generally. The basis of this relates to the mislocalisation of the transport factors Impβ1 andmore » Ran, which show significantly higher nuclear localization in contrast to various other factors, and RCC1, which shows altered subnuclear localisation. The results here establish for the first time that intracellular calcium modulates conventional nuclear import through direct effects on the nuclear transport machinery.« less

Neuronal injury-induced expression and release of apolipoprotein E in mixed neuron/glia co-cultures: nuclear factor kappaB inhibitors reduce basal and lesion-induced secretion of apolipoprotein E.

PubMed

Petegnief, V; Saura, J; de Gregorio-Rocasolano, N; Paul, S M

2001-01-01

In order to better delineate the intracellular signaling pathways underlying glial apolipoprotein E (apoE) expression and release, we have characterized an in vitro model of induction of glial apoE production induced by neuronal death. Exposure of mixed fetal cortical neuron/glia co-cultures to the neurotoxin N-methyl-D-aspartate results in increased apoE expression and release in a time- and concentration-dependent manner. Increased expression of apoE messenger RNA precedes the increase in intracellular apoE, followed by accumulation of the holoprotein in the culture medium. Neuronal injury induced by N-methyl-D-aspartate is accompanied by a reactive astrogliosis as measured by an increase in glial fibrillary acidic protein messenger RNA and protein at 48 and 72h post-lesion, respectively. A similar microgliosis was observed using the microglial marker ED-1. Neuronal injury-induced glial apoE secretion is attenuated by the nuclear factor kappaB inhibitors, aspirin, Bay 11-7082 and MG-132, suggesting that this transcription factor is involved in both constitutive and induced glial apoE expression. The present data show that up-regulation of apoE is an early event in the glial activation triggered by neurodegeneration in vitro and that activation of nuclear factor kappaB directly or indirectly mediates the increase in apoE expression.

Effect of the Fukushima nuclear accident on the risk perception of residents near a nuclear power plant in China

PubMed Central

Huang, Lei; Zhou, Ying; Han, Yuting; Hammitt, James K.; Bi, Jun; Liu, Yang

2013-01-01

We assessed the influence of the Fukushima nuclear accident (FNA) on the Chinese public’s attitude and acceptance of nuclear power plants in China. Two surveys (before and after the FNA) were administered to separate subsamples of residents near the Tianwan nuclear power plant in Lianyungang, China. A structural equation model was constructed to describe the public acceptance of nuclear power and four risk perception factors: knowledge, perceived risk, benefit, and trust. Regression analysis was conducted to estimate the relationship between acceptance of nuclear power and the risk perception factors while controlling for demographic variables. Meanwhile, we assessed the median public acceptable frequencies for three levels of nuclear events. The FNA had a significant impact on risk perception of the Chinese public, especially on the factor of perceived risk, which increased from limited risk to great risk. Public acceptance of nuclear power decreased significantly after the FNA. The most sensitive groups include females, those not in public service, those with lower income, and those living close to the Tianwan nuclear power plant. Fifty percent of the survey respondents considered it acceptable to have a nuclear anomaly no more than once in 50 y. For nuclear incidents and serious incidents, the frequencies are once in 100 y and 150 y, respectively. The change in risk perception and acceptance may be attributed to the FNA. Decreased acceptance of nuclear power after the FNA among the Chinese public creates additional obstacles to further development of nuclear power in China and require effective communication strategies. PMID:24248341

Natural antioxidants exhibit chemopreventive characteristics through the regulation of CNC b-Zip transcription factors in estrogen-induced breast carcinogenesis.

PubMed

Chatterjee, Anwesha; Ronghe, Amruta; Singh, Bhupendra; Bhat, Nimee K; Chen, Jie; Bhat, Hari K

2014-12-01

The objective of the present study was to characterize the role of resveratrol (Res) and vitamin C (VC) in prevention of estrogen-induced breast cancer through regulation of cap "n"collar (CNC) b-zip transcription factors. Human breast epithelial cell line MCF-10A was treated with 17β-estradiol (E2) and VC or Res with or without E2. mRNA and protein expression levels of CNC b-zip transcription factors nuclear factor erythroid 2-related factor 1 (Nrf1), nuclear factor erythroid 2 related factor 2 (Nrf2), nuclear factor erythroid 2 related factor 3 (Nrf3), and Nrf2-regulated antioxidant enzymes superoxide dismutase 3 (SOD3) and quinone oxidoreductase 1 (NQO1) were quantified. The treatment with E2 suppressed, whereas VC and Res prevented E2-mediated decrease in the expression levels of SOD3, NQO1, Nrf2 mRNA, and protein in MCF-10A cells. The treatment with E2, Res, or VC significantly increased mRNA and protein expression levels of Nrf1. 17β-Estradiol treatment significantly increased but VC or Res decreased Nrf3 mRNA and protein expression levels. Our studies demonstrate that estrogen-induced breast cancer might be prevented through upregulation of antioxidant enzymes via Nrf-dependent pathways. © 2014 Wiley Periodicals, Inc.

Retinoblastoma-binding Protein 4-regulated Classical Nuclear Transport Is Involved in Cellular Senescence*

PubMed Central

Tsujii, Akira; Miyamoto, Yoichi; Moriyama, Tetsuji; Tsuchiya, Yuko; Obuse, Chikashi; Mizuguchi, Kenji; Oka, Masahiro; Yoneda, Yoshihiro

2015-01-01

Nucleocytoplasmic trafficking is a fundamental cellular process in eukaryotic cells. Here, we demonstrated that retinoblastoma-binding protein 4 (RBBP4) functions as a novel regulatory factor to increase the efficiency of importin α/β-mediated nuclear import. RBBP4 accelerates the release of importin β1 from importin α via competitive binding to the importin β-binding domain of importin α in the presence of RanGTP. Therefore, it facilitates importin α/β-mediated nuclear import. We showed that the importin α/β pathway is down-regulated in replicative senescent cells, concomitant with a decrease in RBBP4 level. Knockdown of RBBP4 caused both suppression of nuclear transport and induction of cellular senescence. This is the first report to identify a factor that competes with importin β1 to bind to importin α, and it demonstrates that the loss of this factor can trigger cellular senescence. PMID:26491019

Expression of pERK and pAKT in human astrocytomas: correlation with IDH1-R132H presence, vascular endothelial growth factor, microvascular characteristics and clinical outcome.

PubMed

Saetta, Angelica A; Levidou, Georgia; El-Habr, Elias A; Panayotidis, Ioannis; Samaras, Vassilis; Thymara, Irene; Sakellariou, Stratigoula; Boviatsis, Efstathios; Patsouris, Efstratios; Korkolopoulou, Penelope

2011-06-01

Although pERK and pAKT are reportedly activated in various neoplasms, little information is available about their significance in astrocytomas. Paraffin-embedded tissue from 82 patients with diffuse infiltrating astrocytomas (grades II to IV) was investigated for the association of pERK and pAKT activation with clinicopathological features, vascular endothelial growth factor (VEGF), isocitrate dehydrogenase 1 and microvascular parameters. Nuclear pERK labelling index (LI) increased with increasing cytoplasmic pERK LI and nuclear and cytoplasmic pAKT LI (p = 0.0019, p = 0.0260 and p = 0.0012, respectively). Accordingly, cytoplasmic pERK increased with increasing levels of nuclear (p = 0.0001) and marginally with cytoplasmic pAKT LI (p = 0.0526). Nuclear and cytoplasmic pERK LI and nuclear pAKT LI were positively correlated with tumour histological grade (p = 0.0040, p = 0.0238 for pERK and p = 0.0004 for pAKT, respectively). VEGF expression was correlated with nuclear pERK (p = 0.0099) and nuclear pAKT LI (p = 0.0002). Interestingly, pERK cytoplasmic LI increased with microvessel calibre (p = 0.0287), whereas pAKT nuclear LI was marginally related to microvessel density (p = 0.0685). The presence of IDH1-R132H was related only to histological grade and lower microvessel calibre. Multivariate survival analysis in the entire cohort selected cytoplasmic pAKT LI (p = 0.045), histological grade, microvessel calibre (p = 0.028), patients' age, gender and surgical excision as independent predictors of survival. Moreover, in glioblastomas, pERK nuclear LI emerged as a favourable prognosticator in the presence of IDH1-R132H. pERK and pAKT in astrocytomas are interrelated and associated with tumour grade and angiogenesis. Moreover, the importance of cytoplasmic pAKT immunoexpression in patients' prognosis and nuclear pERK immunoexpression in glioblastomas is confirmed.

Reactive oxygen species mediate liver injury through parenchymal nuclear factor-kappaB inactivation in prolonged ischemia/reperfusion.

PubMed

Llacuna, Laura; Marí, Montserrat; Lluis, Josep M; García-Ruiz, Carmen; Fernández-Checa, José C; Morales, Albert

2009-05-01

Nuclear factor (NF)-kappaB participates in ischemia/reperfusion (I/R) hepatic signaling, stimulating both protective mechanisms and the generation of inflammatory cytokines. After analyzing NF-kappaB activation during increasing times of ischemia in murine I/R, we observed that the nuclear translocation of p65 paralleled Src and IkappaB tyrosine phosphorylation, which peaked after 60 minutes of ischemia. After extended ischemic periods (90 to 120 minutes) however, nuclear p65 levels were inversely correlated with the progressive induction of oxidative stress. Despite this profile of NF-kappaB activation, inflammatory genes, such as tumor necrosis factor (TNF) and interleukin (IL)-1beta, predominantly induced by Kupffer cells, increased throughout time during ischemia (30 to 120 minutes), whereas protective NF-kappaB-dependent genes, such as manganese superoxide dismutase (Mn-SOD), expressed in parenchymal cells, decreased. Consistent with this behavior, gadolinium chloride pretreatment abolished TNF/IL-1beta up-regulation during ischemia without affecting Mn-SOD levels. Interestingly, specific glutathione (GSH) up-regulation in hepatocytes by S-adenosylmethionine increased Mn-SOD expression and protected against I/R-mediated liver injury despite TNF/IL-1beta induction. Similar protection was achieved by administration of the SOD mimetic MnTBAP. In contrast, indiscriminate hepatic GSH depletion by buthionine-sulfoximine before I/R potentiated oxidative stress and decreased both nuclear p65 and Mn-SOD expression levels, increasing TNF/IL-1beta up-regulation and I/R-induced liver damage. Thus, the divergent role of NF-kappaB activation in selective liver cell populations underlies the dichotomy of NF-kappaB in hepatic I/R injury, illustrating the relevance of specifically maintaining NF-kappaB activation in parenchymal cells.

The nuclear-factor kappaB pathway is activated in pterygium.

PubMed

Siak, Jay Jyh Kuen; Ng, See Liang; Seet, Li-Fong; Beuerman, Roger W; Tong, Louis

2011-01-05

Pterygium is a prevalent ocular surface disease with unknown pathogenesis. The authors investigated the role of nuclear factor kappa B (NF-κB) transcription factors in pterygium. Surgically excised primary pterygia were studied compared with uninvolved conjunctiva tissues. NF-κB activation was evaluated using Western blot analysis, ELISA, and DNA-binding assays. Primary pterygium fibroblasts were treated with TNF-α (20 ng/mL), and NF-κB activation was evaluated using immunocytochemistry, Western blot analysis, phospho-IκBα ELISA, and DNA-binding assays. TNF-α stimulation of NF-κB target genes RelB, NFKB2, RANTES, MCP-1, ENA-78, MMP-1, MMP-2, and MMP-3 in pterygium fibroblasts was compared with that in primary tenon fibroblasts by real-time PCR. Phosphorylation of IκBα (Ser32) was increased in pterygia tissues compared with uninvolved conjunctiva tissues, as determined by Western blot analysis and ELISA. IκBα expression was decreased, whereas nuclear RelA and p50 DNA-binding capacities were increased. Within 30 minutes of treatment with TNF-α, pterygium fibroblasts showed increased IκBα phosphorylation and nuclear translocation of RelA and p50. Treatment with TNF-α beyond 12 hours resulted in increased nuclear expression of RelB, p100, and p52. Furthermore, the upregulation of RANTES, MCP-1, ENA-78, MMP-1, MMP-2, and MMP-3 expression was more pronounced in TNF-α-treated pterygium fibroblasts than in tenon fibroblasts. The NF-κB pathway is shown for the first time to be activated in pterygia tissues compared with normal conjunctiva tissues. Stimulation by the inflammatory cytokine TNF-α can activate both canonical and noncanonical NF-κB pathways in pterygium fibroblasts with concomitant upregulation of NF-κB target genes.

Nuclear size is sensitive to NTF2 protein levels in a manner dependent on Ran binding

PubMed Central

Vuković, Lidija D.; Jevtić, Predrag; Zhang, Zhaojie; Stohr, Bradley A.; Levy, Daniel L.

2016-01-01

ABSTRACT Altered nuclear size is associated with many cancers, and determining whether cancer-associated changes in nuclear size contribute to carcinogenesis necessitates an understanding of mechanisms of nuclear size regulation. Although nuclear import rates generally positively correlate with nuclear size, NTF2 levels negatively affect nuclear size, despite the role of NTF2 (also known as NUTF2) in nuclear recycling of the import factor Ran. We show that binding of Ran to NTF2 is required for NTF2 to inhibit nuclear expansion and import of large cargo molecules in Xenopus laevis egg and embryo extracts, consistent with our observation that NTF2 reduces the diameter of the nuclear pore complex (NPC) in a Ran-binding-dependent manner. Furthermore, we demonstrate that ectopic NTF2 expression in Xenopus embryos and mammalian tissue culture cells alters nuclear size. Finally, we show that increases in nuclear size during melanoma progression correlate with reduced NTF2 expression, and increasing NTF2 levels in melanoma cells is sufficient to reduce nuclear size. These results show a conserved capacity for NTF2 to impact on nuclear size, and we propose that NTF2 might be a new cancer biomarker. PMID:26823604

Improvements in cloning efficiencies may be possible by increasing uniformity in recipient oocytes and donor cells.

PubMed

Miyoshi, Kazuchika; Rzucidlo, S Jacek; Pratt, Scott L; Stice, Steven L

2003-04-01

The low efficiency of somatic cell cloning is the major obstacle to widespread use of this technology. Incomplete nuclear reprogramming following the transfer of donor nuclei into recipient oocytes has been implicated as a primary reason for the low efficiency of the cloning procedure. The mechanisms and factors that affect the progression of the nuclear reprogramming process have not been completely elucidated, but the identification of these factors and their subsequent manipulation would increase cloning efficiency. At present, many groups are studying donor nucleus reprogramming. Here, we present an approach in which the efficiency of producing viable offspring is improved by selecting recipient oocytes and donor cells that will produce cloned embryos with functionally reprogrammed nuclei. This approach will produce information useful in future studies aimed at further deciphering the nuclear reprogramming process.

A Role for the NF-kb/Rel Transcription Factors in Human Breast Cancer

DTIC Science & Technology

1998-07-01

binding proteins present in a series of nuclear extracts from cell lines and from breast tumor tissues as well as normal mammary epithelium. Finally, we...RelA is nuclear in several examples. Our recent data on nuclear extracts of breast tumors shows that there is a significant increase in NF-KB binding...Figure 2 in the appendix). Additionally, immunoblotting of nuclear extracts versus adjacent tissue controls showed that NF-KB p50, p52 and c-Rel were

Endothelin-1 Expression Associated with Lipid Peroxidation and Nuclear Factor-κB Activation in Type 2 Diabetes Mellitus Patients with Angiopathy and Limb Amputation.

PubMed

Kuo, Yur-Ren; Chien, Ching-Ming; Kuo, Ming-Jen; Wang, Feng-Sheng; Huang, Eng-Yen; Wang, Ching-Jen

2016-01-01

It is unclear whether diabetic angiopathy is related to oxidative stress-associated endothelial dysfunction. The authors investigated whether alteration of endothelin-1 and lipid peroxide production and activation of nuclear factor-κB expression were involved in lower limb amputation in type 2 diabetes mellitus patients. A total of 135 subjects including 51 type 2 diabetes mellitus patients with major lower extremity amputations and 36 diabetes mellitus patients without limb and vascular complication and 48 normal controls were recruited for this study. The authors measured the plasma soluble endothelin-1 concentrations by a sandwich enzyme immunoassay, and measured oxidative stress as determined by the lipid peroxide byproduct malondialdehyde. Histologic staining and nuclear factor-κB activation determined by electrophoretic mobility shift assay of the amputated vessels were examined. Histologic staining revealed that severe arteriosclerosis with atheroma formation in the amputated diabetic arteries was significantly prominent compared with normal controls. Soluble endothelin-1 concentrations and malondialdehyde levels were increased significantly in diabetic amputation patients compared with other groups (p < 0.001). The nuclear factor-κB binding activity in amputated diabetic stump vessels was more prominent compared with healthy vessels without diabetes mellitus. There was a positive correlation between endothelin-1 and malondialdehyde in patients with diabetic amputation (r = 0.46, p = 0.001). These results suggest that elevation of endothelin-1 and lipid peroxide levels is involved in the pathogenesis of diabetic foot amputation. An increase of lipid peroxide and endothelin-1 associated with nuclear factor-κB activation plays an important role in the development of diabetic angiopathies.

Adaptive and regulatory mechanisms in aged rats with postoperative cognitive dysfunction

PubMed Central

Bi, Yanlin; Liu, Shuyun; Yu, Xinjuan; Wang, Mingshan; Wang, Yuelan

2014-01-01

Inflammation may play a role in postoperative cognitive dysfunction. 5′ Adenosine monophosphate-activated protein kinase, nuclear factor-kappa B, interleukin-1β, and tumor necrosis factor-α are involved in inflammation. Therefore, these inflammatory mediators may be involved in postoperative cognitive dysfunction. Western immunoblot analysis revealed 5′ adenosine monophosphate-activated protein kinase and nuclear factor-kappa B in the hippocampus of aged rats were increased 1–7 days after splenectomy. Moreover, interleukin-1β and tumor necrosis factor-α were upregulated and gradually decreased. Therefore, these inflammatory mediators may participate in the splenectomy model of postoperative cognitive dysfunction in aged rats. PMID:25206851

Type 1 IGF Receptor Localization in Paediatric Gliomas: Significant Association with WHO Grading and Clinical Outcome.

PubMed

Clément, Florencia; Martin, Ayelen; Venara, Marcela; de Luján Calcagno, Maria; Mathó, Cecilia; Maglio, Silvana; Lombardi, Mercedes García; Bergadá, Ignacio; Pennisi, Patricia A

2018-06-01

Nuclear localization of insulin-like growth factor receptor type 1 (IGF-1R) has been described as adverse prognostic factor in some cancers. We studied the expression and localization of IGF-1R in paediatric patients with gliomas, as well as its association with World Health Organization (WHO) grading and survival. We conducted a single cohort, prospective study of paediatric patients with gliomas. Samples were taken at the time of the initial surgery; IGF-1R expression and localization were characterized by immunohistochemistry (IHC), subcellular fractionation and western blotting. Tumours (47/53) showed positive staining for IGF-1R by IHC. IGF-1R nuclear labelling was observed in 10/47 cases. IGF-1R staining was mostly non-nuclear in low-grade tumours, while IGF-1R nuclear labelling was predominant in high-grade gliomas (p = 0.0001). Survival was significantly longer in patients with gliomas having non-nuclear IGF-1R localization than in patients with nuclear IGF-1R tumours (p = 0.016). In gliomas, IGF-1R nuclear localization was significantly associated with both high-grade tumours and increased risk of death. Based on a prospective design, we provide evidence of a potential usefulness of intracellular localization of IGF-1R as prognostic factor in paediatric patients with gliomas.

Application of an in silico liver model to determine nuclear receptor mediated pathways in liver cancer

EPA Science Inventory

Nuclear receptors (NRs) are ligand-activated transcription factors that control diverse cellular processes. Chronic stimulation of some NRs in rodents can result in increased incidence of liver tumors. These are generally thought to develop through a non-genotoxic mechanism with...

Morris Water Maze Training in Mice Elevates Hippocampal Levels of Transcription Factors Nuclear Factor (Erythroid-derived 2)-like 2 and Nuclear Factor Kappa B p65

PubMed Central

Snow, Wanda M.; Pahlavan, Payam S.; Djordjevic, Jelena; McAllister, Danielle; Platt, Eric E.; Alashmali, Shoug; Bernstein, Michael J.; Suh, Miyoung; Albensi, Benedict C.

2015-01-01

Research has identified several transcription factors that regulate activity-dependent plasticity and memory, with cAMP-response element binding protein (CREB) being the most well-studied. In neurons, CREB activation is influenced by the transcription factor nuclear factor kappa B (NF-κB), considered central to immunity but more recently implicated in memory. The transcription factor early growth response-2 (Egr-2), an NF-κB gene target, is also associated with learning and memory. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an antioxidant transcription factor linked to NF-κB in pathological conditions, has not been studied in normal memory. Given that numerous transcription factors implicated in activity-dependent plasticity demonstrate connections to NF-κB, this study simultaneously evaluated protein levels of NF-κB, CREB, Egr-2, Nrf2, and actin in hippocampi from young (1 month-old) weanling CD1 mice after training in the Morris water maze, a hippocampal-dependent spatial memory task. After a 6-day acquisition period, time to locate the hidden platform decreased in the Morris water maze. Mice spent more time in the target vs. non-target quadrants of the maze, suggestive of recall of the platform location. Western blot data revealed a decrease in NF-κB p50 protein after training relative to controls, whereas NF-κB p65, Nrf2 and actin increased. Nrf2 levels were correlated with platform crosses in nearly all tested animals. These data demonstrate that training in a spatial memory task results in alterations in and associations with particular transcription factors in the hippocampus, including upregulation of NF-κB p65 and Nrf2. Training-induced increases in actin protein levels caution against its use as a loading control in immunoblot studies examining activity-dependent plasticity, learning, and memory. PMID:26635523

Aptamer-Mediated Codelivery of Doxorubicin and NF-κB Decoy Enhances Chemosensitivity of Pancreatic Tumor Cells

PubMed Central

Porciani, David; Tedeschi, Lorena; Marchetti, Laura; Citti, Lorenzo; Piazza, Vincenzo; Beltram, Fabio; Signore, Giovanni

2015-01-01

Aptamers able to bind efficiently cell-surface receptors differentially expressed in tumor and in healthy cells are emerging as powerful tools to perform targeted anticancer therapy. Here, we present a novel oligonucleotide chimera, composed by an RNA aptamer and a DNA decoy. Our assembly is able to (i) target tumor cells via an antitransferrin receptor RNA aptamer and (ii) perform selective codelivery of a chemotherapeutic drug (Doxorubicin) and of an inhibitor of a cell-survival factor, the nuclear factor κB decoy oligonucleotide. Both payloads are released under conditions found in endolysosomal compartments (low pH and reductive environment). Targeting and cytotoxicity of the oligonucleotidic chimera were assessed by confocal microscopy, cell viability, and Western blot analysis. These data indicated that the nuclear factor κB decoy does inhibit nuclear factor κB activity and ultimately leads to an increased therapeutic efficacy of Doxorubicin selectively in tumor cells. PMID:25919089

Effects of Nuclear Factor-E2-related factor 2/Heme Oxygenase 1 on splanchnic hemodynamics in experimental cirrhosis with portal hypertension.

PubMed

Qin, Jun; He, Yue; Duan, Ming; Luo, Meng

2017-05-01

We explored the effects of Nuclear Factor-E2-related factor 2 (Nrf2) and Heme Oxygenase 1 (HO-1) on splanchnic hemodynamics in portal hypertensive rats. Experimental cirrhosis with portal hypertension was induced by intraperitoneal injection of carbon tetrachloride. The expression of proteins was examined by immunoblotting. Hemodynamic studies were performed by radioactive microspheres. The vascular perfusion system was used to measure the contractile response of mesentery arterioles in rats. Nrf2 expression in the nucleus and HO-1 expression in cytoplasm was significantly enhanced in portal hypertensive rats. Portal pressure, as well as regional blood flow, increased significantly in portal hypertension and can be blocked by tin protoporphyrin IX. The expression of endogenous nitric oxide synthase and vascular endothelial growth factors increased significantly compared to normal rats, while HO-1 inhibition decreased the expression of these proteins significantly. The contractile response of mesenteric arteries decreased in portal hypertension, but can be partially recovered through tin protoporphyrin IX treatment. The expression of Nrf2/HO-1 increased in mesenteric arteries of portal hypertensive rats, which was related to oxidative stress. HO-1was involved in increased portal pressure and anomaly splanchnic hemodynamics in portal hypertensive rats. Copyright © 2016 Elsevier Inc. All rights reserved.

Mangiferin inhibits tumor necrosis factor-α-induced matrix metalloproteinase-9 expression and cellular invasion by suppressing nuclear factor-κB activity

PubMed Central

Dilshara, Matharage Gayani; Kang, Chang-Hee; Choi, Yung Hyun; Kim, Gi-Young

2015-01-01

We investigated the effects of mangiferin on the expression and activity of metalloproteinase (MMP)-9 and the invasion of tumor necrosis factor (TNF)-α-stimulated human LNCaP prostate carcinoma cells. Reverse-transcription polymerase chain reaction (RT-PCR) and western blot analysis showed that mangiferin significantly reversed TNF-α-induced mRNA and protein expression of MMP-9 expression. Zymography data confirmed that stimulation of cells with TNF-α significantly increased MMP-9 activity. However, mangiferin substantially reduced the TNF-α-induced activity of MMP-9. Additionally, a matrigel invasion assay showed that mangiferin significantly reduced TNF-α-induced invasion of LNCaP cells. Compared to untreated controls, TNF-α-stimulated LNCaP cells showed a significant increase in nuclear factor-κB (NF-κB) luciferase activity. However, mangiferin treatment markedly decreased TNF-α-induced NF-κB luciferase activity. Furthermore, mangiferin suppressed nuclear translocation of the NF-κB subunits p65 and p50. Collectively, our results indicate that mangiferin is a potential anti-invasive agent that acts by suppressing NF-κB-mediated MMP-9 expression. [BMB Reports 2015; 48(10): 559-564] PMID:25739392

Mangiferin inhibits tumor necrosis factor-α-induced matrix metalloproteinase-9 expression and cellular invasion by suppressing nuclear factor-κB activity.

PubMed

Dilshara, Matharage Gayani; Kang, Chang-Hee; Choi, Yung Hyun; Kim, Gi-Young

2015-10-01

We investigated the effects of mangiferin on the expression and activity of metalloproteinase (MMP)-9 and the invasion of tumor necrosis factor (TNF)-α-stimulated human LNCaP prostate carcinoma cells. Reverse-transcription polymerase chain reaction (RT-PCR) and western blot analysis showed that mangiferin significantly reversed TNF-α-induced mRNA and protein expression of MMP-9 expression. Zymography data confirmed that stimulation of cells with TNF-α significantly increased MMP-9 activity. However, mangiferin substantially reduced the TNF-α-induced activity of MMP-9. Additionally, a matrigel invasion assay showed that mangiferin significantly reduced TNF-α-induced invasion of LNCaP cells. Compared to untreated controls, TNF-α-stimulated LNCaP cells showed a significant increase in nuclear factor-κB (NF-κB) luciferase activity. However, mangiferin treatment markedly decreased TNF-α-induced NF-κB luciferase activity. Furthermore, mangiferin suppressed nuclear translocation of the NF-κB subunits p65 and p50. Collectively, our results indicate that mangiferin is a potential anti-invasive agent that acts by suppressing NF-κB-mediated MMP-9 expression.

Monomeric cocoa catechins enhance β-cell function by increasing mitochondrial respiration.

PubMed

Rowley, Thomas J; Bitner, Benjamin F; Ray, Jason D; Lathen, Daniel R; Smithson, Andrew T; Dallon, Blake W; Plowman, Chase J; Bikman, Benjamin T; Hansen, Jason M; Dorenkott, Melanie R; Goodrich, Katheryn M; Ye, Liyun; O'Keefe, Sean F; Neilson, Andrew P; Tessem, Jeffery S

2017-11-01

A hallmark of type 2 diabetes (T2D) is β-cell dysfunction and the eventual loss of functional β-cell mass. Therefore, mechanisms that improve or preserve β-cell function could be used to improve the quality of life of individuals with T2D. Studies have shown that monomeric, oligomeric and polymeric cocoa flavanols have different effects on obesity, insulin resistance and glucose tolerance. We hypothesized that these cocoa flavanols may have beneficial effects on β-cell function. INS-1 832/13-derived β-cells and primary rat islets cultured with a monomeric catechin-rich cocoa flavanol fraction demonstrated enhanced glucose-stimulated insulin secretion, while cells cultured with total cocoa extract and with oligomeric or polymeric procyanidin-rich fraction demonstrated no improvement. The increased glucose-stimulated insulin secretion in the presence of the monomeric catechin-rich fraction corresponded with enhanced mitochondrial respiration, suggesting improvements in β-cell fuel utilization. Mitochondrial complex III, IV and V components are up-regulated after culture with the monomer-rich fraction, corresponding with increased cellular ATP production. The monomer-rich fraction improved cellular redox state and increased glutathione concentration, which corresponds with nuclear factor, erythroid 2 like 2 (Nrf2) nuclear localization and expression of Nrf2 target genes including nuclear respiratory factor 1 (Nrf1) and GA binding protein transcription factor alpha subunit (GABPA), essential genes for increasing mitochondrial function. We propose a model by which monomeric cocoa catechins improve the cellular redox state, resulting in Nrf2 nuclear migration and up-regulation of genes critical for mitochondrial respiration, glucose-stimulated insulin secretion and ultimately improved β-cell function. These results suggest a mechanism by which monomeric cocoa catechins exert their effects as an effective complementary strategy to benefit T2D patients. Copyright © 2017 Elsevier Inc. All rights reserved.

Nuclear size is sensitive to NTF2 protein levels in a manner dependent on Ran binding.

PubMed

Vuković, Lidija D; Jevtić, Predrag; Zhang, Zhaojie; Stohr, Bradley A; Levy, Daniel L

2016-03-15

Altered nuclear size is associated with many cancers, and determining whether cancer-associated changes in nuclear size contribute to carcinogenesis necessitates an understanding of mechanisms of nuclear size regulation. Although nuclear import rates generally positively correlate with nuclear size, NTF2 levels negatively affect nuclear size, despite the role of NTF2 (also known as NUTF2) in nuclear recycling of the import factor Ran. We show that binding of Ran to NTF2 is required for NTF2 to inhibit nuclear expansion and import of large cargo molecules in Xenopus laevis egg and embryo extracts, consistent with our observation that NTF2 reduces the diameter of the nuclear pore complex (NPC) in a Ran-binding-dependent manner. Furthermore, we demonstrate that ectopic NTF2 expression in Xenopus embryos and mammalian tissue culture cells alters nuclear size. Finally, we show that increases in nuclear size during melanoma progression correlate with reduced NTF2 expression, and increasing NTF2 levels in melanoma cells is sufficient to reduce nuclear size. These results show a conserved capacity for NTF2 to impact on nuclear size, and we propose that NTF2 might be a new cancer biomarker. © 2016. Published by The Company of Biologists Ltd.

Study of the in-medium nucleon electromagnetic form factors using a light-front nucleon wave function combined with the quark-meson coupling model

NASA Astrophysics Data System (ADS)

de Araújo, W. R. B.; de Melo, J. P. B. C.; Tsushima, K.

2018-02-01

We study the nucleon electromagnetic (EM) form factors in symmetric nuclear matter as well as in vacuum within a light-front approach using the in-medium inputs calculated by the quark-meson coupling model. The same in-medium quark properties are used as those used for the study of in-medium pion properties. The zero of the proton EM form factor ratio in vacuum, the electric to magnetic form factor ratio μpGEp (Q2) /GMp (Q2) (Q2 = -q2 > 0 with q being the four-momentum transfer), is determined including the latest experimental data by implementing a hard constituent quark component in the nucleon wave function. A reasonable fit is achieved for the ratio μpGEp (Q2) /GMp (Q2) in vacuum, and we predict that the Q02 value to cross the zero of the ratio to be about 15 GeV2. In addition the double ratio data of the proton EM form factors in 4He and H nuclei, [GEp4He (Q2) /G4HeMp (Q2) ] / [GEp1H (Q2) /GMp1H (Q2) ], extracted by the polarized (e → ,e‧ p →) scattering experiment on 4He at JLab, are well described. We also predict that the Q02 value satisfying μpGEp (Q02) /GMp (Q0 2) = 0 in symmetric nuclear matter, shifts to a smaller value as increasing nuclear matter density, which reflects the facts that the faster falloff of GEp (Q2) as increasing Q2 and the increase of the proton mean-square charge radius. Furthermore, we calculate the neutron EM form factor double ratio in symmetric nuclear matter for 0.1

Epigenetic regulation of the expression of genes involved in steroid hormone biosynthesis and action

PubMed Central

Martinez-Arguelles, Daniel B.; Papadopoulos, Vassilios

2010-01-01

Steroid hormones participate in organ development, reproduction, body homeostasis, and stress responses. The steroid machinery is expressed in a development- and tissue-specific manner, with the expression of these factors being tightly regulated by an array of transcription factors (TFs). Epigenetics provides an additional layer of gene regulation through DNA methylation and histone tail modifications. Evidence of epigenetic regulation of key steroidogenic enzymes is increasing, though this does not seem to be a predominant regulatory pathway. Steroid hormones exert their action in target tissues through steroid nuclear receptors belonging to the NR3A and NR3C families. Nuclear receptor expression levels and post-translational modifications regulate their function and dictate their sensitivity to steroid ligands. Nuclear receptors and TFs are more likely to be epigenetically regulated than proteins involved in steroidogenesis and have secondary impact on the expression of these steroidogenic enzymes. Here we review evidence for epigenetic regulation of enzymes, transcription factors, and nuclear receptors related to steroid biogenesis and action. PMID:20156469

Nuclear translocation of the cytoplasmic domain of HB-EGF induces gastric cancer invasion.

PubMed

Shimura, Takaya; Yoshida, Michihiro; Fukuda, Shinji; Ebi, Masahide; Hirata, Yoshikazu; Mizoshita, Tsutomu; Tanida, Satoshi; Kataoka, Hiromi; Kamiya, Takeshi; Higashiyama, Shigeki; Joh, Takashi

2012-05-30

Membrane-anchored heparin-binding epidermal growth factor-like growth factor (proHB-EGF) yields soluble HB-EGF, which is an epidermal growth factor receptor (EGFR) ligand, and a carboxy-terminal fragment of HB-EGF (HB-EGF-CTF) after ectodomain shedding. We previously reported that HB-EGF-CTF and unshed proHB-EGF which has the cytoplasmic domain of proHB-EGF (HB-EGF-C), translocate from the plasma membrane to the nucleus and regulate cell cycle after shedding stimuli. However, the significance of nuclear exported HB-EGF-C in human gastric cancer is unclear. We investigated the relationship between intracellular localization of HB-EGF-C and clinical outcome in 96 gastric cancer patients treated with gastrectomy. Moreover, we established stable gastric cancer cell lines overexpressing wild-type HB-EGF (wt-HB-EGF) and mutated HB-EGF (HB-EGF-mC), which prevented HB-EGF-C nuclear translocation after shedding. Cell motility between these 2 gastric cancer cell lines was investigated using a transwell invasion assay and a wound healing assay. Of the 96 gastric cancer cases, HB-EGF-C immunoreactivity was detected in both the nucleus and cytoplasm in 19 cases (19.8 %) and in the cytoplasm only in 25 cases (26.0 %). The nuclear immunoreactivity of HB-EGF-C was significantly increased in stage pT3/4 tumors compared with pT1/2 tumors (T1/2 vs. T3/4: 11.1 % vs. 36.4 %, P < 0.01). The growth of wt-HB-EGF- and HB-EGF-mC-expressing cells significantly increased compared with control cells, but the growth of HB-EGF-mC-expressing cells was significantly decreased compared with wt-HB-EGF-expressing cells. Gastric cancer cell invasion obviously increased in wt-HB-EGF-expressing cells, but invasion in HB-EGF-mC-expressing cells showed a slight increase compared with control cells. Moreover, wt-HB-EGF overexpression increased the effectiveness of wound healing, but had no significant effect in HB-EGF-mC-expressing cells. Both the function of HB-EGF as an EGFR ligand and a novel signal for HB-EGF-C nuclear translocation induce gastric cancer growth, whereas HB-EGF-C nuclear translocation independently plays a critical role in gastric cancer invasion. The present study demonstrated that HB-EGF-C nuclear translocation might be crucial in gastric cancer invasion. HB-EGF-C nuclear translocation may offer a prognostic marker and a new molecular target for gastric cancer therapy.

Clonorchis sinensis excretory-secretory products regulate migration and invasion in cholangiocarcinoma cells via extracellular signal-regulated kinase 1/2/nuclear factor-κB-dependent matrix metalloproteinase-9 expression.

PubMed

Pak, Jhang Ho; Shin, Jimin; Song, In-Sung; Shim, Sungbo; Jang, Sung-Wuk

2017-01-01

Matrix metalloproteinase-9 plays an important role in the invasion and metastasis of various types of cancer cells. We have previously reported that excretory-secretory products from Clonorchis sinensis increases matrix metalloproteinase-9 expression. However, the regulatory mechanisms through which matrix metalloproteinase-9 expression affects cholangiocarcinoma development remain unclear. In the current study, we examined the potential role of excretory-secretory products in regulating the migration and invasion of various cholangiocarcinoma cell lines. We demonstrated that excretory-secretory products significantly induced matrix metalloproteinase-9 expression and activity in a concentration-dependent manner. Reporter gene and chromatin immunoprecipitation assays showed that excretory-secretory products induced matrix metalloproteinase-9 expression by enhancing the activity of nuclear factor-kappa B. Moreover, excretory-secretory products induced the degradation and phosphorylation of IκBα and stimulated nuclear factor-kappa B p65 nuclear translocation, which was regulated by extracellular signal-regulated kinase 1/2. Taken together, our findings indicated that the excretory-secretory product-dependent enhancement of matrix metalloproteinase-9 activity and subsequent induction of IκBα and nuclear factor-kappa B activities may contribute to the progression of cholangiocarcinoma. Copyright © 2016 Australian Society for Parasitology. Published by Elsevier Ltd. All rights reserved.

Inhibition of human T cell leukemia virus type 2 replication by the suppressive action of class II transactivator and nuclear factor Y.

PubMed

Tosi, Giovanna; Pilotti, Elisabetta; Mortara, Lorenzo; De Lerma Barbaro, Andrea; Casoli, Claudio; Accolla, Roberto S

2006-08-22

The master regulator of MHC-II gene transcription, class II transactivator (CIITA), acts as a potent inhibitor of human T cell leukemia virus type 2 (HTLV-2) replication by blocking the activity of the viral Tax-2 transactivator. Here, we show that this inhibitory effect takes place at the nuclear level and maps to the N-terminal 1-321 region of CIITA, where we identified a minimal domain, from positions 64-144, that is strictly required to suppress Tax-2 function. Furthermore, we show that Tax-2 specifically cooperates with cAMP response element binding protein-binding protein (CBP) and p300, but not with p300/CBP-associated factor, to enhance transcription from the viral promoter. This finding represents a unique difference with respect to Tax-1, which uses all three coactivators to transactivate the human T cell leukemia virus type 1 LTR. Direct sequestering of CBP or p300 is not the primary mechanism by which CIITA causes suppression of Tax-2. Interestingly, we found that the transcription factor nuclear factor Y, which interacts with CIITA to increase transcription of MHC-II genes, exerts a negative regulatory action on the Tax-2-mediated HTLV-2 LTR transactivation. Thus, CIITA may inhibit Tax-2 function, at least in part, through nuclear factor Y. These findings demonstrate the dual defensive role of CIITA against pathogens: it increases the antigen-presenting function for viral determinants and suppresses HTLV-2 replication in infected cells.

Macrophages control vascular stem/progenitor cell plasticity through tumor necrosis factor-α-mediated nuclear factor-κB activation.

PubMed

Wong, Mei Mei; Chen, Yikuan; Margariti, Andriani; Winkler, Bernhard; Campagnolo, Paola; Potter, Claire; Hu, Yanhua; Xu, Qingbo

2014-03-01

Vascular lineage differentiation of stem/progenitor cells can contribute to both tissue repair and exacerbation of vascular diseases such as in vein grafts. The role of macrophages in controlling vascular progenitor differentiation is largely unknown and may play an important role in graft development. This study aims to identify the role of macrophages in vascular stem/progenitor cell differentiation and thereafter elucidate the mechanisms that are involved in the macrophage- mediated process. We provide in vitro evidence that macrophages can induce endothelial cell (EC) differentiation of the stem/progenitor cells while simultaneously inhibiting their smooth muscle cell differentiation. Mechanistically, both effects were mediated by macrophage-derived tumor necrosis factor-α (TNF-α) via TNF-α receptor 1 and canonical nuclear factor-κB activation. Although the overexpression of p65 enhanced EC (or attenuated smooth muscle cell) differentiation, p65 or TNF-α receptor 1 knockdown using lentiviral short hairpin RNA inhibited EC (or rescued smooth muscle cell) differentiation in response to TNF-α. Furthermore, TNF-α-mediated EC differentiation was driven by direct binding of nuclear factor-κB (p65) to specific VE-cadherin promoter sequences. Subsequent experiments using an ex vivo decellularized vessel scaffold confirmed an increase in the number of ECs and reduction in smooth muscle cell marker expression in the presence of TNF-α. The lack of TNF-α in a knockout mouse model of vein graft decreased endothelialization and significantly increased thrombosis formation. Our study highlights the role of macrophages in directing vascular stem/progenitor cell lineage commitment through TNF-α-mediated TNF-α receptor 1 and nuclear factor-κB activation that is likely required for endothelial repair in vascular diseases such as vein graft.

Tissue factor transcription driven by Egr-1 is a critical mechanism of murine pulmonary fibrin deposition in hypoxia

PubMed Central

Yan, Shi-Fang; Zou, Yu Shan; Gao, Yun; Zhai, Chao; Mackman, Nigel; Lee, Stephen L.; Milbrandt, Jeffrey; Pinsky, David; Kisiel, Walter; Stern, David

1998-01-01

Local hypoxemia and stasis trigger thrombosis. We have demonstrated previously that in a murine model of normobaric hypoxia pulmonary fibrin deposition is a result of expression of tissue factor, especially in oxygen-deprived mononuclear phagocytes (MPs). We now show that transcription factor early-growth-response gene product (Egr-1) is rapidly activated in hypoxia, both in vitro and in vivo, and is responsible for transcription and expression of tissue factor in hypoxic lung. MPs and HeLa cells subjected to hypoxia (pO2 ≈13 torr) had increased levels of tissue factor transcripts (≈18-fold) and an increased rate of transcription (≈15-fold), based on nuclear run-on analysis. Gel-shift analysis of nuclear extracts from hypoxic MPs and HeLa cells demonstrated increased DNA-binding activity at the serum response region (SRR; −111/+14 bp) of the tissue factor promoter at Egr-1 motifs. Using 32P-labeled Egr consensus oligonucleotide, we observed induction of DNA-binding activity in nuclear extracts from hypoxic lung and HeLa cells because of activation of Egr-1, by means of supershift analysis. Transient transfection of HeLa cells with chimeric plasmids containing wild-type or mutant SRR from the tissue factor promoter showed that intact Sp1 sites are necessary for basal promoter activity, whereas the integrity of Egr-1 sites was required for hypoxia-enhanced expression. A central role for Egr-1 in hypoxia-mediated tissue factor expression was confirmed by experiments with homozygous Egr-1 null mice; wild-type mice subjected to oxygen deprivation expressed tissue factor and showed fibrin deposition, but hypoxic homozygous Egr-1 null mice displayed neither tissue factor nor fibrin. These data delineate a novel biology for hypoxia-induced fibrin deposition, in which oxygen deprivation-induced activation of Egr-1, resulting in expression of tissue factor, has an unexpected and central role. PMID:9653181

Curcumin attenuates insulin resistance in hepatocytes by inducing Nrf2 nuclear translocation.

PubMed

Zhao, Shu-Guang; Li, Qiang; Liu, Zhen-Xiong; Wang, Jing-Jie; Wang, Xv-Xia; Qin, Ming; Wen, Qin-Sheng

2011-01-01

NF-E2-Related Factor-2 (Nrf2) is a transcription factor that plays a crucial role in the cellular protection against oxidative stress. Curcumin has been reported to induce Nrf2 nuclear translocation and upregulate the expression of numerous reactive oxygen species (ROS) detoxifying and antioxidant genes in hepatocytes. This study was designed to investigate whether curcumin-induced Nrf2 nuclear translocation could reduce ROS-mediated insulin resistance in cultured LO2 hepatocytes. Human LO2 hepatocytes were incubated with curcumine and glucose oxidase (GO) in the presence/absence of wortmannin (a phosphatidyinositol 3-kinase (PI3K) inhibitor), oxidative stress, cellular damage, Nrf2 nuclear translocation and insulin resistance were measured. GO exposure significantly increased intracellular ROS, glutathione (GSH) depletion, malondialdehyde (MDA) formation, and increased activities of cellular lactate dehydrogenase (LDH) and aspartate amino transferase (AST), as well as causing insulin resistance. Curcumin pretreatment significantly attenuated these disturbances in intracellular ROS, liver enzyme activity and significantly antagonized the lipid peroxidation, GSH depletion and insulin resistance induced by GO in LO2 hepatocytes. These effects paralleled Nrf2 nuclear translocation induced by curcumin. Wortmannin partially blocked curcumin-induced Nrf2 nuclear translocation. In addition, wortmannin prevented curcumin-induced improvements in intracellular ROS, MDA formation, GSH depletion, liver enzyme activity and insulin resistance in cultured LO2 hepatocytes. These findings suggest that curcumin could reduce ROS-mediated insulin resistance in hepatocytes, at least in part through nuclear translocation of Nrf2.

Forsythia suspensa extract attenuates lipopolysaccharide-induced inflammatory liver injury in rats via promoting antioxidant defense mechanisms.

PubMed

Zhao, Panfeng; Piao, Xiangshu; Pan, Long; Zeng, Zhikai; Li, Qingyun; Xu, Xiao; Wang, Hongliang

2017-06-01

Reactive oxygen species (ROS) have been shown to have a role in inflammation. We investigated whether Forsythia suspensa extract (FSE) could exert its antioxidant potential against lipopolysaccharide (LPS)-induced inflammatory liver injury in rats. Rats were orally fed FSE once daily for 7 consecutive days prior to LPS (Escherichia coli, serotype O55:B5) injection. LPS treatment caused liver dysfunction as evidenced by massive histopathological changes and increased serum alanine aminotransferase and aspartate aminotransferase activities which were ameliorated by FSE pretreatment. FSE attenuated LPS-induced depletion of cytosolic nuclear factor-erythroid 2-related factor 2 (Nrf2) and suppression of Nrf2 nuclear translocation in liver, and the generation of ROS and malondialdehyde in serum and liver. FSE increased the Nrf2-mediated induction of heme oxygenase-1 in liver, as well as superoxide dismutase and glutathione peroxidase activities in serum and liver. Importantly, FSE attenuated LPS-induced nuclear factor-кB (NF-кB) nuclear translocation in liver, and subsequently decreased tumor necrosis factor-α, interleukin (IL)-1β and IL-6 levels in serum and liver, which were associated with FSE-induced activation of Nrf2 in liver. These results indicate that the protective mechanisms of FSE may be involved in the attenuation of oxidative stress and the inhibition of the NF-кB-mediated inflammatory response by modulating the Nrf2-mediated antioxidant response against LPS-induced inflammatory liver injury. © 2016 Japanese Society of Animal Science.

Continuous application of compressive force induces fusion of osteoclast-like RAW264.7 cells via upregulation of RANK and downregulation of LGR4.

PubMed

Matsuike, Rieko; Tanaka, Hideki; Nakai, Kumiko; Kanda, Mai; Nagasaki, Maki; Murakami, Fumiko; Shibata, Chika; Mayahara, Kotoe; Nakajima, Akira; Tanabe, Natsuko; Kawato, Takayuki; Maeno, Masao; Shimizu, Noriyoshi

2018-05-15

During orthodontic treatment, facilitating osteoclastic bone resorption in the alveolar bone exposed to the compressive force (CF) is an important factor for tooth movement. The present study investigated the effect of CF stimulation on the differentiation of RAW264.7 cells from precursors to mature osteoclasts. The cells were continuously stimulated with 0.3, 0.6, or 1.1 g/cm 2 CF-which was generated by increasing the volume of culture medium in the wells of a 96-well plate-in the presence or absence of receptor activator of nuclear factor κB (RANK) ligand (RANKL) for 4 days. In the presence of RANKL, the number of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells and the mRNA levels of dendritic cell-specific transmembrane protein (DC-STAMP) and osteoclast-stimulatory transmembrane protein (OC-STAMP) were increased by application of 0.6 and 1.1 g/cm 2 CF as compared to 0.3 g/cm 2 CF. The mRNA level of RANK was upregulated whereas that of leucine-rich repeat-containing G-protein-coupled receptor (LGR)4-another RANKL receptor was downregulated by 0.6 and 1.1 g/cm 2 CF as compared to 0.3 g/cm 2 CF in the absence of RANKL. The proportion of cells with nuclear translocation of the nuclear translocation of nuclear factor of activated T cells (NFAT)c1 was increased by 0.6 and 1.1 g/cm 2 CF in the presence of RANKL. Continuous application of CF induced the differentiation of RAW264.7 cells into TRAP-positive multinuclear cells by enhancing the expression of DC- and OC-STAMP and the nuclear translocation of NFATc1. This may result from the CF-induced increase in RANK and decrease in LGR4 expression. Copyright © 2018 Elsevier Inc. All rights reserved.

Rare sugar D-allose strongly induces thioredoxin-interacting protein and inhibits osteoclast differentiation in Raw264 cells.

PubMed

Yamada, Kana; Noguchi, Chisato; Kamitori, Kazuyo; Dong, Youyi; Hirata, Yuko; Hossain, Mohammad A; Tsukamoto, Ikuko; Tokuda, Masaaki; Yamaguchi, Fuminori

2012-02-01

Oxidative stress modulates the osteoclast differentiation via redox systems, and thioredoxin 1 (Trx) promotes the osteoclast formation by regulating the activity of transcription factors. The function of Trx is known to be regulated by its binding partner, thioredoxin-interacting protein (TXNIP). We previously reported that the expression of TXNIP gene is strongly induced by a rare sugar D-allose. In this study, we tested the hypothesis that D-allose could inhibit the osteoclast differentiation by regulating the Trx function. We used a murine Raw264 cell line that differentiates to the osteoclast by the receptor activator of nuclear factor-κB ligand (RANKL) treatment. The effect of sugars was evaluated by tartrate-resistant acid phosphatase staining. The expression and localization of TXNIP and Trx protein were examined by Western blotting and immunohistochemisty. The activity of the nuclear factor-κB, nuclear factor of activated T cells, and activator protein 1 transcription factors was measured by the luciferase reporter assay. The addition of D-allose (25 mmol/L) inhibited the osteoclast differentiation down to 9.53% ± 1.27% of a receptor activator of nuclear factor-κB ligand-only treatment. During the osteoclast differentiation, a significant increase of TNXIP was observed by D-allose treatment. The immunohistochemical analysis showed that both Trx and TXNIP existed in the nucleus in preosteoclasts and osteoclasts. Overexpression of TXNIP by plasmid transfection also inhibited the osteoclast formation, indicating the functional importance of TXNIP for the osteoclast differentiation. Transcriptional activity of the activator protein 1, nuclear factor-κB, and nuclear factor of activated T cells, known to be modulated by Trx, were inhibited by D-allose. In conclusion, our data indicate that D-allose is a strong inhibitor of the osteoclast differentiation, and this effect could be caused by TXNIP induction and a resulting inhibition of the Trx function. Copyright © 2012 Elsevier Inc. All rights reserved.

FBI-1 enhances transcription of the nuclear factor-kappaB (NF-kappaB)-responsive E-selectin gene by nuclear localization of the p65 subunit of NF-kappaB.

PubMed

Lee, Dong-Kee; Kang, Jae-Eun; Park, Hye-Jin; Kim, Myung-Hwa; Yim, Tae-Hee; Kim, Jung-Min; Heo, Min-Kyu; Kim, Kyu-Yeun; Kwon, Ho Jeong; Hur, Man-Wook

2005-07-29

The POZ domain is a highly conserved protein-protein interaction motif found in many regulatory proteins. Nuclear factor-kappaB (NF-kappaB) plays a key role in the expression of a variety of genes in response to infection, inflammation, and stressful conditions. We found that the POZ domain of FBI-1 (factor that binds to the inducer of short transcripts of human immunodeficiency virus-1) interacted with the Rel homology domain of the p65 subunit of NF-kappaB in both in vivo and in vitro protein-protein interaction assays. FBI-1 enhanced NF-kappaB-mediated transcription of E-selectin genes in HeLa cells upon phorbol 12-myristate 13-acetate stimulation and overcame gene repression by IkappaB alpha or IkappaB beta. In contrast, the POZ domain of FBI-1, which is a dominant-negative form of FBI-1, repressed NF-kappaB-mediated transcription, and the repression was cooperative with IkappaB alpha or IkappaB beta. In contrast, the POZ domain tagged with a nuclear localization sequence polypeptide of FBI-1 enhanced NF-kappaB-responsive gene transcription, suggesting that the molecular interaction between the POZ domain and the Rel homology domain of p65 and the nuclear localization by the nuclear localization sequence are important in the transcription enhancement mediated by FBI-1. Confocal microscopy showed that FBI-1 increased NF-kappaB movement into the nucleus and increased the stability of NF-kappaB in the nucleus, which enhanced NF-kappaB-mediated transcription of the E-selectin gene. FBI-1 also interacted with IkappaB alpha and IkappaB beta.

NUCLEAR FACTOR-Y: still complex after all these years?

PubMed

Myers, Zachary A; Holt, Ben F

2018-06-11

The NUCLEAR FACTOR-Y (NF-Y) families of transcription factors are important regulators of plant development and physiology. Though NF-Y regulatory roles have recently been suggested for numerous aspects of plant biology, their roles in flowering time, early seedling development, stress responses, hormone signaling, and nodulation are the best characterized. The past few years have also seen significant advances in our understanding of the mechanistic function of the NF-Y, and as such, increasingly complex and interesting questions are now more approachable. This review will primarily focus on these developmental, physiological, and mechanistic roles of the NF-Y in recent research. Copyright © 2018 Elsevier Ltd. All rights reserved.

RNA helicase MOV10 functions as a co-factor of HIV-1 Rev to facilitate Rev/RRE-dependent nuclear export of viral mRNAs.

PubMed

Huang, Feng; Zhang, Junsong; Zhang, Yijun; Geng, Guannan; Liang, Juanran; Li, Yingniang; Chen, Jingliang; Liu, Chao; Zhang, Hui

2015-12-01

Human immunodeficiency virus type 1 (HIV-1) exploits multiple host factors during its replication. The REV/RRE-dependent nuclear export of unspliced/partially spliced viral transcripts needs the assistance of host proteins. Recent studies have shown that MOV10 overexpression inhibited HIV-1 replication at various steps. However, the endogenous MOV10 was required in certain step(s) of HIV-1 replication. In this report, we found that MOV10 potently enhances the nuclear export of viral mRNAs and subsequently increases the expression of Gag protein and other late products through affecting the Rev/RRE axis. The co-immunoprecipitation analysis indicated that MOV10 interacts with Rev in an RNA-independent manner. The DEAG-box of MOV10 was required for the enhancement of Rev/RRE-dependent nuclear export and the DEAG-box mutant showed a dominant-negative activity. Our data propose that HIV-1 utilizes the anti-viral factor MOV10 to function as a co-factor of Rev and demonstrate the complicated effects of MOV10 on HIV-1 life cycle. Copyright © 2015 Elsevier Inc. All rights reserved.

Nuclear DNA as Predictor of Acute Kidney Injury in Patients Undergoing Coronary Artery Bypass Graft: A Pilot Study.

PubMed

Likhvantsev, Valery V; Landoni, Giovanni; Grebenchikov, Oleg A; Skripkin, Yuri V; Zabelina, Tatiana S; Zinovkina, Liudmila A; Prikhodko, Anastasia S; Lomivorotov, Vladimir V; Zinovkin, Roman A

2017-12-01

To measure the release of plasma nuclear deoxyribonucleic acid (DNA) and to assess the relationship between nuclear DNA level and acute kidney injury occurrence in patients undergoing cardiac surgery. Cardiovascular anesthesiology and intensive care unit of a large tertiary-care university hospital. Prospective observational study. Fifty adult patients undergoing cardiac surgery. Nuclear DNA concentration was measured in the plasma. The relationship between the level of nuclear DNA and the incidence of acute kidney injury after coronary artery bypass grafting was investigated. Cardiac surgery leads to significant increase in plasma nuclear DNA with peak levels 12 hours after surgery (median [interquartile range] 7.0 [9.6-22.5] µg/mL). No difference was observed between off-pump and on-pump surgical techniques. Nuclear DNA was the only predictor of acute kidney injury between baseline and early postoperative risk factors. The authors found an increase of nuclear DNA in the plasma of patients who had undergone coronary artery bypass grafting, with a peak after 12 hours and an association of nuclear DNA with postoperative acute kidney injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of transactivation-responsive DNA-binding protein 43 (TARDBP43; TDP-43) as a novel factor for TNF-α expression upon lipopolysaccharide stimulation in human monocytes.

PubMed

Murata, H; Hattori, T; Maeda, H; Takashiba, S; Takigawa, M; Kido, J; Nagata, T

2015-08-01

Tumor necrosis factor alpha (TNF-α) is a major cytokine implicated in various inflammatory diseases. The nature of the nuclear factors associated with human TNF-α gene regulation is not well elucidated. We previously identified a novel region located from -550 to -487 in human TNF-α promoter that did not contain the reported binding sites for nuclear factor kappa B (NF-κB) but showed lipopolysaccharide (LPS)-induced transcriptional activity. The purpose of this study is to identify novel factors that bind to the promoter region and regulate TNF-α expression. To identify DNA-binding proteins that bound to the target region of TNF-α promoter, a cDNA library from LPS-stimulated human monocytic cell line THP-1 was screened using a yeast one-hybrid system. Cellular localizations of the DNA-binding protein in the cells were examined by subcellular immunocytochemistry. Nuclear amounts of the protein in LPS-stimulated THP-1 cells were identified by western blot analysis. Expression of mRNA of the protein in the cells was quantified by real-time polymerase chain reaction. Electrophoretic mobility shift assays were performed to confirm the DNA-binding profile. Overexpression of the protein and knockdown of the gene were also performed to investigate the role for TNF-α expression. Several candidates were identified from the cDNA library and transactivation-responsive DNA-binding protein 43 (TARDBP43; TDP-43) was focused on. Western blot analysis revealed that nuclear TDP-43 protein was increased in the LPS-stimulated THP-1 cells. Expression of TDP-43 mRNA was already enhanced before TNF-α induction by LPS. Electrophoretic mobility shift assay analysis showed that nuclear extracts obtained by overexpressing FLAG-tagged TDP-43 bound to the -550 to -487 TNF-α promoter fragments. Overexpression of TDP-43 in THP-1 cells resulted in an increase of TNF-α expression. Knockdown of TDP-43 in THP-1 cells downregulated TNF-α expression. We identified TDP-43 as one of the novel TNF-α factors and found that it bound to the LPS-responsive element in the TNF-α promoter to increase TNF-α expression. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Direct Estimation of Power Distribution in Reactors for Nuclear Thermal Space Propulsion

NASA Astrophysics Data System (ADS)

Aldemir, Tunc; Miller, Don W.; Burghelea, Andrei

2004-02-01

A recently proposed constant temperature power sensor (CTPS) has the capability to directly measure the local power deposition rate in nuclear reactor cores proposed for space thermal propulsion. Such a capability reduces the uncertainties in the estimated power peaking factors and hence increases the reliability of the nuclear engine. The CTPS operation is sensitive to the changes in the local thermal conditions. A procedure is described for the automatic on-line calibration of the sensor through estimation of changes in thermal .conditions.

Effect of lifestyle interventions with or without metformin therapy on serum levels of osteoprotegerin and receptor activator of nuclear factor kappa B ligand in patients with prediabetes.

PubMed

Arslan, Muyesser Sayki; Tutal, Esra; Sahin, Mustafa; Karakose, Melia; Ucan, Bekir; Ozturk, Gulfer; Cakal, Erman; Biyikli Gencturk, Zeynep; Ozbek, Mustafa; Delibasi, Tuncay

2017-02-01

Osteoprotegerin has been shown to be increased in cardiovascular disorders and type 2 diabetes mellitus. Prediabetes represents a high risk condition for diabetes and diabetic complications. Therefore, we aimed to find the relationship between prediabetes and osteoprotegerin with nuclear factor-B ligand, carotid intima media thickness, and metabolic markers. A total of 54 participants with prediabetes including impaired fasting glucose (n = 21), impaired glucose tolerance (n = 8), impaired fasting glucose and impaired glucose tolerance (n = 25), and 60 healthy individuals as a control were admitted to the study. Metabolic and anthropometric parameters, insulin resistance variables, osteoprotegerin, and nuclear factor-B ligand markers, carotid intima media thickness were examined at baseline for all participants. To evaluate the effect of therapy we determined the same parameters after the end of the study. Measurements of waist circumference, body mass index, body fat percentage and levels of fasting blood glucose, fasting insulin, homeostatic model assessment of insulin resistance, triglyceride levels and hsCRP and carotid intima media thickness were significantly higher in patients with prediabetes (p < 0.05). We also found higher osteoprotegerin and lower nuclear factor-B ligand levels in patients than in controls however, the value was non-significant (p > 0.05). Patients with prediabetes were under lifestyle interventions with (group 1, n = 33) or without metformin (group 2, n = 21) therapy. Baseline anthropometric and metabolic characteristics were not found statistically different in group 1 and group 2. Mean follow up period of the patients were 7.9 ± 2.2 month (min-max: 6-12 months). After the follow up period we evaluated the same parameters and found significant differences between waist circumference, body mass index, body fat percentage, fasting insulin, homeostatic model assessment of insulin resistance, and osteoprotegerin levels (p < 0.05). However, carotid intima media thickness, and nuclear factor-B ligand levels significantly different only in the group treated with metformin (p < 0.05). We also compared the variables after the treatment period with the control group and found significantly lower levels in terms of fasting insulin, homeostatic model assessment of insulin resistance, waist circumference, body mass index, body fat percentage, carotid intima media thickness, osteoprotegerin, and nuclear factor-B ligand values (p < 0.05). Correlation analysis revealed a negative relationship between nuclear factor-B ligand and body mass index, and body fat percentage in group 1 (p = 0.05, r = -0.646, p = 0.01, r = -0.585). Therapy of prediabetes was associated with a significant decrease in osteoprotegerin and certain metabolic variables together with an increase in nuclear factor-B ligand levels particularly in patients with under metformin therapy.

Berry Phenolic Compounds Increase Expression of Hepatocyte Nuclear Factor-1α (HNF-1α) in Caco-2 and Normal Colon Cells Due to High Affinities with Transcription and Dimerization Domains of HNF-1α

PubMed Central

Real Hernandez, Luis M.; Fan, Junfeng; Johnson, Michelle H.; Gonzalez de Mejia, Elvira

2015-01-01

Hepatocyte nuclear factor-1α (HNF-1α) is found in the kidneys, spleen, thymus, testis, skin, and throughout the digestive organs. It has been found to promote the transcription of various proteins involved in the management of type II diabetes, including dipeptidyl peptidase-IV (DPP-IV). Phenolic compounds from berries and citrus fruits are known to inhibit DPP-IV, but have not been tested for their interactions with wild-type HNF-1α. By studying the interactions of compounds from berries and citrus fruits have with HNF-1α, pre-transcriptional mechanisms that inhibit the expression of proteins such as DPP-IV may be elucidated. In this study, the interactions of berry phenolic compounds and citrus flavonoids with the dimerization and transcriptional domains of HNF-1α were characterized using the molecular docking program AutoDock Vina. The anthocyanin delphinidin-3-O-arabinoside had the highest binding affinity for the dimerization domain as a homodimer (-7.2 kcal/mol) and transcription domain (-8.3 kcal/mol) of HNF-1α. Anthocyanins and anthocyanidins had relatively higher affinities than resveratrol and citrus flavonoids for both, the transcription domain and the dimerization domain as a homodimer. The flavonoid flavone had the highest affinity for a single unit of the dimerization domain (-6.5 kcal/mol). Nuclear expression of HNF-1α was measured in Caco-2 and human normal colon cells treated with blueberry and blackberry anthocyanin extracts. All extracts tested increased significantly (P < 0.05) the nuclear expression of HNF-1α in Caco-2 cells by 85.2 to 260% compared to a control. The extracts tested increased significantly (P < 0.02) the nuclear expression of HNF-1α in normal colon cells by 48.6 to 243%. It was confirmed that delphinidin-3-O-glucoside increased by 3-fold nuclear HNF-1α expression in Caco-2 cells (P < 0.05). Anthocyanins significantly increased nuclear HNF-1α expression, suggesting that these compounds might regulate the genes HNF-1α promotes. PMID:26413797

Effects of pentachlorophenol on the quail (Coturnix japonica) liver detoxification pathway.

PubMed

Jiang, Peng; Wang, Jianshe; Sheng, Nan; Wei, Dongbing; Dai, Jiayin

2017-06-01

Pentachlorophenol (PCP), an extensively used pesticide and biocide, is of critical environmental concern due to its toxicity and recalcitrance to degradation. In this study, the effect of PCP on induction of transcription factors, cytochrome P450 (CYP450) genes, and the antioxidative enzyme system were investigated in the quail liver. A total of 60 (4- to 6-week-old) male quails (Coturnix japonica) were administered 0, 0.05, 0.5, and 5 mg/kg/d PCP orally for 42 d. Following exposure, both absolute and relative liver weights were significantly lower than those of the control. Using gas chromatography-mass spectrometry, PCP accumulation was, from highest to lowest, kidney > liver > muscle for all exposure groups. The expressions of CYP1A5, CYP1B1, CYP2C18, nuclear translocator 1 (ARNT1), and aryl hydrocarbon receptor 1 (AHR1) were induced after PCP treatment, and increases were found in the activities of hepatic superoxide dismutase (SOD) and catalase (CAT), and the content of hepatic malondialdehyde (MDA). In addition, exposure to PCP induced an increase in liver 8-hydroxydeoxyguanosine (8-OHdG) and significantly elevated ethoxyresorufin O-deethylase (EROD), methoxyresorufin O-demethylase (MROD), and 7-ethoxycoumarin-O-deethylase (ECOD) activity, but decreased that of glutathione peroxidase (GSH-Px), benzyloxyresorufin O-debenzylase (BROD), pentoxyresorufin O-depentylase (PROD), and erythromycin N-demethylase (END). No significant responses were observed for benzyloxy-trifluoromethyl-coumarin (BFC). The protein level of liver nuclear factor κB (NF-κB) was higher, whereas that of nuclear factor E2-related factor 2 (Nrf2) was lower for exposed quail. These results suggest that PCP affects quail oxidative stress by modulating CYP450 enzymes and nuclear transcription factors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Epigallocatechin-3-gallate prevents lipid peroxidation and enhances antioxidant defense system via modulating hepatic nuclear transcription factors in heat-stressed quails.

PubMed

Sahin, K; Orhan, C; Tuzcu, M; Ali, S; Sahin, N; Hayirli, A

2010-10-01

Epigallocatechin-3-gallate (EGCG), a polyphenol derived from green tea, exerts antioxidant effects. Oxidative stress is one of the consequences of heat stress (HS), which also depresses performance in poultry. This experiment was conducted to elucidate the action mode of EGCG in alleviation of oxidative stress in heat-stressed quail (Coturnix coturnix japonica). A total of 180 five-week-old female Japanese quails were reared either at 22°C for 24 h/d (thermoneutral, TN) or 34°C for 8 h/d (HS) for 12 wk. Birds in both environments were randomly fed 1 of 3 diets: basal diet and basal diet added with 200 or 400 mg of EGCG/kg of diet. Each of the 2×3 factorially arranged groups was replicated in 10 cages, each containing 3 quails. Performance variables [feed intake (FI) and egg production (EP)], oxidative stress biomarkers [malondialdehyde (MDA), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px)] and hepatic transcription factors [nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)] were analyzed using 2-way ANOVA. Exposure to HS caused reductions in FI by 9.7% and EP by 14.4%, increased hepatic MDA level by 84.8%, and decreased hepatic SOD, CAT, and GSH-Px activities by 25.8, 52.3, and 45.5%, respectively (P<0.0001 for all). The hepatic NF-κB expression was greater (156 vs. 82%) and Nrf2 expression was lower (84 vs. 118%) for quails reared under the HS environment than for those reared under the TN environment (P<0.0001 for both). In response to increasing supplemental EGCG level, there were linear increases in FI from 29.6 to 30.9 g/d and EP from 84.3 to 90.1%/d, linear decreases in hepatic MDA level from 2.82 to 1.72 nmol/g and Nrf2 expression from 77.5 to 123.3%, and linear increases in hepatic SOD (146.4 to 182.2), CAT (36.2 to 47.1), and GSH-Px (13.5 to 18.5) activities (U/mg of protein) and NF-κB expression (149.7 to 87.3%) (P<0.0001 for all). Two-way treatment interactions revealed that the degree of restorations in all response variables was more notable under the HS environment than under the TN environment as supplemental EGCG level was increased. Moreover, levels of oxidative biomarkers were strongly correlated with expressions of hepatic nuclear transcription factors. In conclusion, supplemental EGCG alleviates oxidative stress through modulating the hepatic nuclear transcription factors in heat-stressed quails.

Promoter- and RNA polymerase II–dependent hsp-16 gene association with nuclear pores in Caenorhabditis elegans

PubMed Central

Rohner, Sabine; Kalck, Veronique; Wang, Xuefei; Ikegami, Kohta; Lieb, Jason D.; Meister, Peter

2013-01-01

Some inducible yeast genes relocate to nuclear pores upon activation, but the general relevance of this phenomenon has remained largely unexplored. Here we show that the bidirectional hsp-16.2/41 promoter interacts with the nuclear pore complex upon activation by heat shock in the nematode Caenorhabditis elegans. Direct pore association was confirmed by both super-resolution microscopy and chromatin immunoprecipitation. The hsp-16.2 promoter was sufficient to mediate perinuclear positioning under basal level conditions of expression, both in integrated transgenes carrying from 1 to 74 copies of the promoter and in a single-copy genomic insertion. Perinuclear localization of the uninduced gene depended on promoter elements essential for induction and required the heat-shock transcription factor HSF-1, RNA polymerase II, and ENY-2, a factor that binds both SAGA and the THO/TREX mRNA export complex. After induction, colocalization with nuclear pores increased significantly at the promoter and along the coding sequence, dependent on the same promoter-associated factors, including active RNA polymerase II, and correlated with nascent transcripts. PMID:23460676

Effects of different ligands on epidermal growth factor receptor (EGFR) nuclear translocation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Faria, Jerusa A.Q.A.; Andrade, Carolina de; Goes, Alfredo M.

The epidermal growth factor receptor (EGFR) is activated through binding to specific ligands and generates signals for proliferation, differentiation, migration, and cell survival. Recent data show the role of nuclear EGFR in tumors. Although many EGFR ligands are upregulated in cancers, little is known about their effects on EGFR nuclear translocation. We have compared the effects of six EGFR ligands (EGF, HB-EGF, TGF-α, β-Cellulin, amphiregulin, and epiregulin) on nuclear translocation of EGFR, receptor phosphorylation, migration, and proliferation. Cell fractionation and confocal immunofluorescence detected EGFR in the nucleus after EGF, HB-EGF, TGF-α and β-Cellulin stimulation in a dose-dependent manner. In contrast,more » amphiregulin and epiregulin did not generate nuclear translocation of EGFR. EGF, HB-EGF, TGF-α and β-Cellulin showed correlations between a higher rate of wound closure and increased phosphorylation of residues in the carboxy-terminus of EGFR, compared to amphiregulin and epiregulin. The data indicate that EGFR is translocated to the nucleus after stimulation with EGF, HB-EGF, TGF-α and β-Cellulin, and that these ligands are related to increased phosphorylation of EGFR tyrosine residues, inducing migration of SkHep-1 cells. - Highlights: • EGF, HB-EGF, TGF-α, β-Cellulin are involved in the EGFR nuclear translocation. • Amphiregulin and epiregulin did not promote nuclear translocation of EGFR. • EGF, HB-EGF, TGF-α and β-Cellulin have a role in SkHep-1 cells migration. • EGFR ligands associated with better prognosis don't stimulate EGFR translocation.« less

Modulatory effect of silymarin on nuclear factor-erythroid-2-related factor 2 regulated redox status, nuclear factor-κB mediated inflammation and apoptosis in experimental gastric ulcer.

PubMed

Arafa Keshk, Walaa; Zahran, Samer Mahmoud; Katary, Mohamed Alaa; Abd-Elaziz Ali, Darin

2017-08-01

Non-steroidal anti-inflammatory drugs (NSAIDs) consumption has been commonly associated with gastric mucosal lesions including gastric ulcer. Silymarin (SM) is a flavonoid mixture with anti-oxidant and anti-inflammatory activities which explain its protective role against hepatic and renal injuries. However, its impact on gastric ulcer has not yet been elucidated. Thus we went further to investigate the potential protective effects of SM against indomethacin-induced gastric injury in rats. Pretreatment with SM (50 mg/kg orally) attenuated the severity of gastric mucosal damage as evidenced by decreasing ulcer index (UI) and ulcer score, improvement of disturbed histopathologicl features to be insignificant with those induced by the reference anti-ulcer drug. Pretreatment with SM also suppressed gastric inflammation by decreasing myeloperoxidase activity, tumer necrosis factor-α (TNF- α) and interleukin 6 (IL6) levels along with nuclear factor kappa B p65 (NF-κB) expression. Meanwhile, SM prevent gastric oxidative stress via inhibition of lipid peroxides formation, enhancement of glutathione peroxidase, superoxide dismutase activities and up-regulation of nuclear factor-erythroid-2-related factor 2 (Nrf2), the redox-sensitive master regulator of oxidative stress signaling. In conclusion, the results herein revealed that SM has a gastro-protective effect which is mediated via suppression of gastric inflammation, oxidative stress, increased the anti-oxidant and the cyto-protective defense mechanisms. Copyright © 2017 Elsevier B.V. All rights reserved.

Improved efficacy of soluble human receptor activator of nuclear factor kappa B (RANK) fusion protein by site-directed mutagenesis.

PubMed

Son, Young Jun; Han, Jihye; Lee, Jae Yeon; Kim, HaHyung; Chun, Taehoon

2015-06-01

Soluble human receptor activator of nuclear factor kappa B fusion immunoglobulin (hRANK-Ig) has been considered as one of the therapeutic agents to treat osteoporosis or diseases associated with bone destruction by blocking the interaction between RANK and the receptor activator of nuclear factor kappa B ligand (RANKL). However, no scientific record showing critical amino acid residues within the structural interface between the human RANKL and RANK complex is yet available. In this study, we produced several mutants of hRANK-Ig by replacement of amino acid residue(s) and tested whether the mutants had increased binding affinity to human RANKL. Based on the results from flow cytometry and surface plasmon resonance analyses, the replacement of E(125) with D(125), or E(125) and C(127) with D(125) and F(127) within loop 3 of cysteine-rich domain 3 of hRANK-Ig increases binding affinity to human RANKL over the wild-type hRANK-Ig. This result may provide the first example of improvement in the efficacy of hRANK-Ig by protein engineering and may give additional information to understand a more defined structural interface between hRANK and RANKL.

CORTICOSTEROIDS AND MUSCLE WASTING ROLE OF TRANSCRIPTION FACTORS, NUCLEAR COFACTORS, AND HYPERACETYLATION

PubMed Central

Hasselgren, Per-Olof; Alamdari, Nima; Aversa, Zaira; Gonnella, Patricia; Smith, Ira J; Tizio, Steven

2010-01-01

Purpose of review The purpose of this review is to discuss novel insight into mechanisms of glucocorticoid-regulated muscle wasting, in particular the role of transcription factors and nuclear cofactors. In addition, novel strategies that may become useful in the treatment or prevention of glucocorticoid-induced muscle wasting are reviewed. Recent findings Studies suggest that glucocorticoid-induced upregulation of the transcription factors FOXO1 and C/EBPβ and downregulation of MyoD and myogenin are involved in glucocorticoid-induced muscle wasting. In addition, glucocorticoid-induced hyperacetylation caused by increased expression of the nuclear cofactor p300 and its histone acetyl transferase activity and decreased expression and activity of histone deacetylases (HDACs) plays an important role in glucocorticoid-induced muscle proteolysis and wasting. Other mechanisms may also be involved in glucocorticoid-induced muscle wasting, including insulin resistance and store-operated calcium entry. Novel potential strategies to prevent or treat glucocorticoid-induced muscle wasting include the use of small molecule HDAC activators, dissociated glucocorticoid receptor agonists, and 11β-hydroxysteroid dehydrogenase type 1 inhibitors. Summary An increased understanding of molecular mechanisms regulating glucocorticoid-induced muscle wasting will help develop new strategies to prevent and treat this debilitating condition. PMID:20473154

Tangeretin Inhibits IL-12 Expression and NF-κB Activation in Dendritic Cells and Attenuates Colitis in Mice.

PubMed

Eun, Su-Hyeon; Woo, Je-Te; Kim, Dong-Hyun

2017-04-01

In the preliminary study, tangeretin (5,6,7,8,4'-pentamethoxy flavone), a major constituent of the pericarp of Citrus sp., inhibited TNF- α , IL-12, and IL-23 expression and nuclear factor kappa-B activation in lipopolysaccharide-stimulated dendritic cells; however, it did not affect IL-10 expression. Furthermore, tangeretin (5, 10, and 20 µM) suppressed the activation and translocation of nuclear factor kappa-B (p65) into the nuclei in vitro by inhibiting the binding of lipopolysaccharide on dendritic cells. Oral administration of tangeretin (10 and 20 mg/kg) suppressed the inflammatory responses, such as nuclear factor kappa-B and mitogen-activated protein kinase activation and myeloperoxidase activity, in the colon of mice with 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Tangeretin increased 2,4,6-trinitrobenzene sulfonic acid-suppressed expression of tight junction proteins occludin, claudin-1, and ZO-1. Tangeretin also inhibited 2,4,6-trinitrobenzene sulfonic acid-induced differentiation of Th1 and Th17 cells as well as the expression of T-bet, ROR γ t, interferon- γ , IL-12, IL-17, and TNF- α . However, tangeretin increased 2,4,6-trinitrobenzene sulfonic acid-suppressed differentiation of regulatory T cells as well as the expression of Foxp3 and IL-10. These results suggest that oral administration of tangeretin may attenuate colitis by suppressing IL-12 and TNF- α expression and nuclear factor kappa-B activation through the inhibition of lipopolysaccharide binding on immune cells such as dendritic cells. Georg Thieme Verlag KG Stuttgart · New York.

The canonical nuclear factor-κB pathway regulates cell survival in a developmental model of spinal cord motoneurons.

PubMed

Mincheva, Stefka; Garcera, Ana; Gou-Fabregas, Myriam; Encinas, Mario; Dolcet, Xavier; Soler, Rosa M

2011-04-27

In vivo and in vitro motoneuron survival depends on the support of neurotrophic factors. These factors activate signaling pathways related to cell survival or inactivate proteins involved in neuronal death. In the present work, we analyzed the involvement of the nuclear factor-κB (NF-κB) pathway in mediating mouse spinal cord motoneuron survival promoted by neurotrophic factors. This pathway comprises ubiquitously expressed transcription factors that could be activated by two different routes: the canonical pathway, associated with IKKα/IKKβ kinase phosphorylation and nuclear translocation RelA (p65)/p50 transcription factors; and the noncanonical pathway, related to IKKα kinase homodimer phosphorylation and RelB/p52 transcription factor activation. In our system, we show that neurotrophic factors treatment induced IKKα and IKKβ phosphorylation and RelA nuclear translocation, suggesting NF-κB pathway activation. Protein levels of different members of the canonical or noncanonical pathways were reduced in a primary culture of isolated embryonic motoneurons using an interference RNA approach. Even in the presence of neurotrophic factors, selective reduction of IKKα, IKKβ, or RelA proteins induced cell death. In contrast, RelB protein reduction did not have a negative effect on motoneuron survival. Together these results demonstrated that the canonical NF-κB pathway mediates motoneuron survival induced by neurotrophic factors, and the noncanonical pathway is not related to this survival effect. Canonical NF-κB blockade induced an increase of Bim protein level and apoptotic cell death. Bcl-x(L) overexpression or Bax reduction counteracted this apoptotic effect. Finally, RelA knockdown causes changes of CREB and Smn protein levels.

Nuclear Calcium Buffering Capacity Shapes Neuronal Architecture*

PubMed Central

Mauceri, Daniela; Hagenston, Anna M.; Schramm, Kathrin; Weiss, Ursula; Bading, Hilmar

2015-01-01

Calcium-binding proteins (CaBPs) such as parvalbumin are part of the cellular calcium buffering system that determines intracellular calcium diffusion and influences the spatiotemporal dynamics of calcium signals. In neurons, CaBPs are primarily localized to the cytosol and function, for example, in nerve terminals in short-term synaptic plasticity. However, CaBPs are also expressed in the cell nucleus, suggesting that they modulate nuclear calcium signals, which are key regulators of neuronal gene expression. Here we show that the calcium buffering capacity of the cell nucleus in mouse hippocampal neurons regulates neuronal architecture by modulating the expression levels of VEGFD and the complement factor C1q-c, two nuclear calcium-regulated genes that control dendrite geometry and spine density, respectively. Increasing the levels of nuclear calcium buffers by means of expression of a nuclearly targeted form of parvalbumin fused to mCherry (PV.NLS-mC) led to a reduction in VEGFD expression and, as a result, to a decrease in total dendritic length and complexity. In contrast, mRNA levels of the synapse pruning factor C1q-c were increased in neurons expressing PV.NLS-mC, causing a reduction in the density and size of dendritic spines. Our results establish a close link between nuclear calcium buffering capacity and the transcription of genes that determine neuronal structure. They suggest that the development of cognitive deficits observed in neurological conditions associated with CaBP deregulation may reflect the loss of necessary structural features of dendrites and spines. PMID:26231212

Nuclear Cataract Shows Significant Familial Aggregation in an Older Population after Adjustment for Possible Shared Environmental Factors

PubMed Central

Congdon, Nathan; Broman, Karl W.; Lai, Hong; Munoz, Beatriz; Bowie, Heidi; Gilber, Donna; Wojciechowski, Robert; Alston, Christine; West, Sheila K.

2011-01-01

Purpose To quantify the association between siblings in age-related nuclear cataract, after adjusting for known environmental and personal risk factors. Methods All participants (probands) in the Salisbury Eye Evaluation (SEE) project and their locally resident siblings underwent digital slit lamp photography and were administered a questionnaire to assess risk factors for cataract including: age, gender, lifetime sun exposure, smoking and diabetes history, and use of alcohol and medications such as estrogens and steroids. In addition, blood pressure, body mass index, and serum antioxidants were measured in all participants. Lens photographs were graded by trained observers masked to the subjects' identity, using the Wilmer Cataract Grading System. The odds ratio for siblings for affectedness with nuclear cataract and the sibling correlation of nuclear cataract grade, after adjusting for covariates, were estimated with generalized estimating equations. Results Among 307 probands (mean age, 77.6 ± 4.5 years) and 434 full siblings (mean age, 72.4 ± 7.4 years), the average sibship size was 2.7 per family. After adjustment for covariates, the probability of development of nuclear cataract was significantly increased (odds ratio [OR] = 2.07, 95% confidence interval [CI], 1.30–3.30) among individuals with a sibling with nuclear cataract (nuclear grade ≥ 3.0). The final fitted model indicated a magnitude of heritability for nuclear cataract of 35.6% (95% CI: 21.0%–50.3%) after adjustment for the covariates. Conclusions Findings in this study are consistent with a genetic effect for age-related nuclear cataract, a common and clinically significant form of lens opacity. PMID:15223793

Disruption of both nesprin 1 and desmin results in nuclear anchorage defects and fibrosis in skeletal muscle

PubMed Central

Chapman, Mark A.; Zhang, Jianlin; Banerjee, Indroneal; Guo, Ling T.; Zhang, Zhiwei; Shelton, G. Diane; Ouyang, Kunfu; Lieber, Richard L.; Chen, Ju

2014-01-01

Proper localization and anchorage of nuclei within skeletal muscle is critical for cellular function. Alterations in nuclear anchoring proteins modify a number of cellular functions including mechanotransduction, nuclear localization, chromatin positioning/compaction and overall organ function. In skeletal muscle, nesprin 1 and desmin are thought to link the nucleus to the cytoskeletal network. Thus, we hypothesize that both of these factors play a key role in skeletal muscle function. To examine this question, we utilized global ablation murine models of nesprin 1, desmin or both nesprin 1 and desmin. Herein, we have created the nesprin-desmin double-knockout (DKO) mouse, eliminating a major fraction of nuclear-cytoskeletal connections and enabling understanding of the importance of nuclear anchorage in skeletal muscle. Globally, DKO mice are marked by decreased lifespan, body weight and muscle strength. With regard to skeletal muscle, DKO myonuclear anchorage was dramatically decreased compared with wild-type, nesprin 1−/− and desmin−/− mice. Additionally, nuclear-cytoskeletal strain transmission was decreased in DKO skeletal muscle. Finally, loss of nuclear anchorage in DKO mice coincided with a fibrotic response as indicated by increased collagen and extracellular matrix deposition and increased passive mechanical properties of muscle bundles. Overall, our data demonstrate that nesprin 1 and desmin serve redundant roles in nuclear anchorage and that the loss of nuclear anchorage in skeletal muscle results in a pathological response characterized by increased tissue fibrosis and mechanical stiffness. PMID:24943590

Increased occupational radiation doses: nuclear fuel cycle.

PubMed

Bouville, André; Kryuchkov, Victor

2014-02-01

The increased occupational doses resulting from the Chernobyl nuclear reactor accident that occurred in Ukraine in April 1986, the reactor accident of Fukushima that took place in Japan in March 2011, and the early operations of the Mayak Production Association in Russia in the 1940s and 1950s are presented and discussed. For comparison purposes, the occupational doses due to the other two major reactor accidents (Windscale in the United Kingdom in 1957 and Three Mile Island in the United States in 1979) and to the main plutonium-producing facility in the United States (Hanford Works) are also covered but in less detail. Both for the Chernobyl nuclear reactor accident and the routine operations at Mayak, the considerable efforts made to reconstruct individual doses from external irradiation to a large number of workers revealed that the recorded doses had been overestimated by a factor of about two.Introduction of Increased Occupational Exposures: Nuclear Industry Workers. (Video 1:32, http://links.lww.com/HP/A21).

Hemistepsin A ameliorates acute inflammation in macrophages via inhibition of nuclear factor-κB and activation of nuclear factor erythroid 2-related factor 2.

PubMed

Kim, Jae Kwang; Lee, Ji Eun; Jung, Eun Hye; Jung, Ji Yun; Jung, Dae Hwa; Ku, Sae Kwang; Cho, Il Je; Kim, Sang Chan

2018-01-01

Hemistepsin A (HsA) is a sesquiterpene lactone isolated from Hemistepta lyrata (Bunge) Bunge. We investigated the anti-inflammatory effects of HsA and sought to determine its mechanisms of action in macrophages. HsA pretreatment inhibited nitric oxide production, and reduced the expression of iNOS and COX-2 in Toll-like receptor ligand-stimulated RAW 264.7 cells. Additionally, HsA decreased the secretion of proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated Kupffer cells as well as in RAW 264.7 cells. HsA inhibited phosphorylation of IKKα/β and degradation of IκBα, resulting in decreased nuclear translocation of nuclear factor-κB (NF-κB) and its transcriptional activity. Moreover, HsA phosphorylated nuclear factor erythroid 2-related factor 2 (Nrf2), increased expression levels of antioxidant genes, and attenuated LPS-stimulated H 2 O 2 production. Phosphorylation of p38 and c-Jun N-terminal kinase was required for HsA-mediated Nrf2 phosphorylation. In a D-galactosamine/LPS-induced liver injury model, HsA ameliorated D-galactosamine/LPS-induced hepatocyte degeneration and inflammatory cells infiltration. Moreover, immunohistochemical analyses using nitrotyrosine, 4-hydroxynonenal, and cleaved poly (ADP-ribose) polymerase antibodies revealed that HsA protected the liver from oxidative stress. Furthermore, HsA reduced the numbers of proinflammatory cytokine-positive cells in hepatic tissues. Thus, these results suggest HsA may be a promising natural product to manage inflammation-mediated tissue injuries through inhibition of NF-κB and activation of Nrf2. Copyright © 2017 Elsevier Ltd. All rights reserved.

Role of Nuclear Factor Erythroid 2-Related Factor 2 in Diabetic Nephropathy

PubMed Central

Min, Xu; Xu, Xiaohong

2017-01-01

Diabetic nephropathy (DN) is manifested as increased urinary protein level, decreased glomerular filtration rate, and final renal dysfunction. DN is the leading cause of end-stage renal disease worldwide and causes a huge societal healthcare burden. Since satisfied treatments are still limited, exploring new strategies for the treatment of this disease is urgently needed. Oxidative stress takes part in the initiation and development of DN. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) plays a key role in the cellular response to oxidative stress. Thus, activation of Nrf2 seems to be a new choice for the treatment of DN. In current review, we discussed and summarized the therapeutic effects of Nrf2 activation on DN from both basic and clinical studies. PMID:28512642

Role of osteoprotegerin/receptor activator of nuclear factor kappa B/receptor activator of nuclear factor kappa B ligand axis in nonalcoholic fatty liver disease.

PubMed

Pacifico, Lucia; Andreoli, Gian Marco; D'Avanzo, Miriam; De Mitri, Delia; Pierimarchi, Pasquale

2018-05-21

Concomitantly with the increase in the prevalences of overweight/obesity, nonalcoholic fatty liver disease (NAFLD) has worldwide become the main cause of chronic liver disease in both adults and children. Patients with fatty liver display features of metabolic syndrome (MetS), like insulin resistance (IR), glucose intolerance, hypertension and dyslipidemia. Recently, epidemiological studies have linked obesity, MetS, and NAFLD to decreased bone mineral density and osteoporosis, highlighting an intricate interplay among bone, adipose tissue, and liver. Osteoprotegerin (OPG), an important symbol of the receptor activator of nuclear factor-B ligand/receptor activator of nuclear factor kappa B/OPG system activation, typically considered for its role in bone metabolism, may also play critical roles in the initiation and perpetuation of obesity-related comorbidities. Clinical data have indicated that OPG concentrations are associated with hypertension, left ventricular hypertrophy, vascular calcification, endothelial dysfunction, and severity of liver damage in chronic hepatitis C. Nonetheless, the relationship between circulating OPG and IR as a key feature of MetS as well as between OPG and NAFLD remains uncertain. Thus, the aims of the present review are to provide the existent knowledge on these associations and to discuss briefly the underlying mechanisms linking OPG and NAFLD.

COPPER-DEPENDENT INFLAMMATION AND NUCLEAR FACTOR-KB ACTIVATION BY PARTICULATE AIR POLLUTION

EPA Science Inventory

Particulate air pollution causes increased cardiopulmonary morbidity and mortality, but the chemical determinants responsible for its biologic effects are not understood. We studied the effect of total suspended particulates collected in Provo, Utah, an area where an increase in ...

APE/Ref-1 is increased in nuclear fractions of human thyroid hyperfunctioning nodules.

PubMed

Russo, D; Celano, M; Bulotta, S; Bruno, R; Arturi, F; Giannasio, P; Filetti, S; Damante, G; Tell, G

2002-08-30

Apurinic/apyrimidinic endonuclease APE/Ref-1 is a multifunctional protein provided with DNA repair, transcription-factor regulation and anti-apoptotic activities. We have previously reported that, in thyroid cells, TSH regulates both the synthesis and nuclear translocation of APE/Ref-1. We have also shown that nuclear levels of this protein are reduced both in thyroid carcinoma tissues and cell lines. In the present study, APE/Ref-1 expression and cellular localization were analysed by Western blot in hyperfunctioning thyroid nodules from patients with toxic adenoma and/or toxic multinodular goiter. The total content of APE/Ref-1 protein was increased in the majority of the hyperfunctioning tissues with respect to normal adjacent tissue. There was also an increase in the nuclear levels of APE/Ref-1, suggesting enhanced cytoplasm-to-nucleus translocation of the protein in addition to its increased rate of synthesis. These results demonstrate that the phenomenon of nuclear translocation of APE/Ref-1 hypothesized on the basis of cell culture experiments does actually occur in vivo. Together with previous observations in thyroid carcinomas and tumoral cell lines, our findings suggest a two-stage model of APE/Ref-1 behaviour during malignant thyrocyte transformation: an early stage characterized by simple hyperplasia and upregulation of APE/Ref-1 in the nuclear compartment of the cell and a later stage in which nuclear levels of the protein drop to below-normal levels as the cell becomes progressively undifferentiated.

Signal-mediated nuclear transport in the amoeba.

PubMed

Feldherr, C M; Akin, D

1999-06-01

The evolutionary changes that occur in signal-mediated nuclear transport would be expected to reflect an increasing need to regulate nucleocytoplasmic exchanges as the complexity of organisms increases. This could involve changes in both the composition and structure of the pore complex, as well as the cytosolic factors that mediate transport. In this regard, we investigated the transport process in amoebae (Amoeba proteus and Chaos carolinensis), primitive cells that would be expected to have less stringent regulatory requirements than more complex organisms. Colloidal gold particles, coated with bovine serum albumin (BSA) conjugated with simple (large T) nuclear localization signals (NLSs), bipartite (nucleoplasmin) NLSs or mutant NLSs, were used to assay nuclear import. It was found that in amoebae (1) the diameter of the particles that are able to enter the nucleoplasm is significantly less than in vertebrate cells, (2) the simple NLS is more effective in mediating nuclear import than the bipartite NLS, and (3) the nucleoporins do not appear to be glycosylated. Evidence was also obtained suggesting that, in amoebae, the simple NLS can mediate nuclear export.

Indoxyl Sulfate Affects Glial Function Increasing Oxidative Stress and Neuroinflammation in Chronic Kidney Disease: Interaction between Astrocytes and Microglia.

PubMed

Adesso, Simona; Magnus, Tim; Cuzzocrea, Salvatore; Campolo, Michela; Rissiek, Björn; Paciello, Orlando; Autore, Giuseppina; Pinto, Aldo; Marzocco, Stefania

2017-01-01

Indoxyl sulfate (IS) is a protein-bound uremic toxin resulting from the metabolism of dietary tryptophan which accumulates in patients with impaired renal function, such as chronic kidney disease (CKD). IS is a well-known nephrovascular toxin but little is known about its effects on central nervous system (CNS) cells. Considering the growing interest in the field of CNS comorbidities in CKD, we studied the effect of IS on CNS cells. IS (15-60 μM) treatment in C6 astrocyte cells increased reactive oxygen species release and decreased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation, and heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 expression. Moreover, IS increased Aryl hydrocarbon Receptor (AhR) and Nuclear Factor-kB (NF-kB) activation in these cells. Similiar observations were made in primary mouse astrocytes and mixed glial cells. Inducible nitric oxide synthase and cyclooxygenase-2 (COX-2) expression, tumor necrosis factor-α and interleukin-6 release and nitrotyrosine formation were increased by IS (15-60 μM) in primary mouse astrocytes and mixed glial cells. IS increased AhR and NF-kB nuclear translocation and reduced Nrf2 translocation and HO-1 expression in primary glial cells. In addition, IS induced cell death in neurons in a dose dependent fashion. Injection of IS (800 mg/kg, i.p.) into mice induced histological changes and increased COX-2 expression and nitrotyrosine formation in thebrain tissue. Taken together, our results show a significant contribution of IS in generating a neurotoxic enviroment and it could also have a potential role in neurodegeneration. IS could be considered also a potential therapeutical target for CKD-associated neurodegenerative complications.

Antithrombotic Effects of Nur77 and Nor1 Are Mediated Through Upregulating Thrombomodulin Expression in Endothelial Cells.

PubMed

Yang, Ping; Wei, Xin; Zhang, Jian; Yi, Bing; Zhang, Guan-Xin; Yin, Litian; Yang, Xiao-Feng; Sun, Jianxin

2016-02-01

Thrombomodulin is highly expressed on the lumenal surface of vascular endothelial cells (ECs) and possesses potent anticoagulant, antifibrinolytic, and anti-inflammatory activities in the vessel wall. However, the regulation of thrombomodulin expression in ECs remains largely unknown. In this study, we characterized nuclear receptor 4A family as a novel regulator of thrombomodulin expression in vascular ECs. We demonstrated that both nuclear receptors 4A, Nur77 and Nor1, robustly increase thrombomodulin mRNA and protein levels in human vascular ECs and in mouse liver tissues after adenovirus-mediated transduction of Nur77 and Nor1 cDNAs. Moreover, Nur77 deficiency and knockdown of Nur77 and Nor1 expression markedly attenuated the basal and vascular endothelial growth factor165-stimulated thrombomodulin expression. Mechanistically, we found that Nur77 and Nor1 increase thrombomodulin expression by acting through 2 different mechanisms. We showed that Nur77 barely affects thrombomodulin promoter activity, but significantly increases thrombomodulin mRNA stability, whereas Nor1 enhances thrombomodulin expression mainly through induction of Kruppel-like factors 2 and 4 in vascular ECs. Furthermore, we demonstrated that both Nur77 and Nor1 significantly increase protein C activity and inhibit tumor necrosis factor α-induced prothrombotic effects in human ECs. Deficiency of Nur77 increases susceptibility to arterial thrombosis, whereas enhanced expression of Nur77 and Nor1 protects mice from arterial thrombus formation. Our results identified nuclear receptors 4A as novel regulators of thrombomodulin expression and function in vascular ECs and provided a proof-of-concept demonstration that targeted increasing expression of Nur77 and Nor1 in the vascular endothelium might represent a novel therapeutic approach for the treatment of thrombotic disorders. © 2015 American Heart Association, Inc.

Nuclear import of proinflammatory transcription factors is required for massive liver apoptosis induced by bacterial lipopolysaccharide.

PubMed

Liu, Danya; Li, Chunsheng; Chen, Yiliu; Burnett, Christie; Liu, Xue Yan; Downs, Sheila; Collins, Robert D; Hawiger, Jacek

2004-11-12

Stimulation of macrophages with lipopolysaccharide (LPS) leads to the production of cytokines that elicit massive liver apoptosis. We investigated the in vivo role of stress-responsive transcription factors (SRTFs) in this process focusing on the precipitating events that are sensitive to a cell-permeant peptide inhibitor of SRTF nuclear import (cSN50). In the absence of cSN50, mice challenged with LPS displayed very early bursts of inflammatory cytokines/chemokines, tumor necrosis factor alpha (1 h), interleukin 6 (2 h), interleukin 1 beta (2 h), and monocyte chemoattractant protein 1 (2 h). Activation of both initiator caspases 8 and 9 and effector caspase 3 was noted 4 h later when full-blown DNA fragmentation and chromatin condensation were first observed (6 h). At this time an increase of pro-apoptotic Bax gene expression was observed. It was preceded by a decrease of anti-apoptotic Bcl2 and BclX(L) gene transcripts. Massive apoptosis was accompanied by microvascular injury manifested by hemorrhagic necrosis and a precipitous drop in blood platelets observed at 6 h. An increase in fibrinogen/fibrin degradation products and a rise in plasminogen activator inhibitor 1 occurred between 4 and 6 h. Inhibition of SRTFs nuclear import with the cSN50 peptide abrogated all these changes and increased survival from 7 to 71%. Thus, the nuclear import of SRTFs induced by LPS is a prerequisite for activation of the genetic program that governs cytokines/chemokines production, liver apoptosis, microvascular injury, and death. These results should facilitate the rational design of drugs that protect the liver from inflammation-driven apoptosis.

Protection against dexamethasone-induced muscle atrophy is related to modulation by testosterone of FOXO1 and PGC-1{alpha}

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qin, Weiping, E-mail: weiping.qin@mssm.edu; Department of Medicine, Mount Sinai School of Medicine, NY; Pan, Jiangping

Research highlights: {yields} In rat gastrocnemius muscle, dexamethasone reduced PGC-1{alpha} cellular and nuclear levels without altering mRNA levels for this factor. {yields} Dexamethasone reduced phosphorylating of p38 MAPK, which stabilizes PGC-1{alpha} and promotes its nuclear entry. {yields} Co-administration of testosterone with dexamethasone increased cellular and nuclear levels of PGC-1{alpha} protein without changing its mRNA levels. {yields} Co-administration of testosterone restored p38 MAPK levels to those of controls. -- Abstract: Glucocorticoid-induced muscle atrophy results from muscle protein catabolism and reduced protein synthesis, associated with increased expression of two muscle-specific ubiquitin ligases (MAFbx and MuRF1), and of two inhibitors of protein synthesis,more » REDD1 and 4EBP1. MAFbx, MuRF1, REDD1 and 4EBP1 are up-regulated by the transcription factors FOXO1 and FOXO3A. The transcriptional co-activator PGC-1{alpha} has been shown to attenuate many forms of muscle atrophy and to repress FOXO3A-mediated transcription of atrophy-specific genes. Dexamethasone-induced muscle atrophy can be prevented by testosterone, which blocks up-regulation by dexamethasone of FOXO1. Here, an animal model of dexamethasone-induced muscle atrophy was used to further characterize effects of testosterone to abrogate adverse actions of dexamethasone on FOXO1 levels and nuclear localization, and to determine how these agents affect PGC-1{alpha}, and its upstream activators, p38 MAPK and AMPK. In rat gastrocnemius muscle, testosterone blunted the dexamethasone-mediated increase in levels of FOXO1 mRNA, and FOXO1 total and nuclear protein. Dexamethasone reduced total and nuclear PGC-1{alpha} protein levels in the gastrocnemius; co-administration of testosterone with dexamethasone increased total and nuclear PGC-1{alpha} levels above those present in untreated controls. Testosterone blocked dexamethasone-induced decreases in activity of p38 MAPK in the gastrocnemius muscle. Regulation of FOXO1, PGC-1{alpha} and p38 MAPK by testosterone may represent a novel mechanism by which this agent protects against dexamethasone-induced muscle atrophy.« less

Subnuclear organization and trafficking of regulatory proteins: implications for biological control and cancer.

PubMed

Stein, G S; van Wijnen, A J; Stein, J L; Lian, J B; Montecino, M; Zaidi, K; Javed, A

2000-01-01

The regulated and regulatory components that interrelate nuclear structure and function must be experimentally established. A formidable challenge is to define further the control of transcription factor targeting to acceptor sites associated with the nuclear matrix. It will be important to determine whether acceptor proteins are associated with a pre-existing core-filament structural lattice or whether a compositely organized scaffold of regulatory factors is dynamically assembled. An inclusive model for all steps in the targeting of proteins to subnuclear sites cannot yet be proposed. However, this model must account for the apparent diversity of intranuclear targeting signals. It is also important to assess the extent to which regulatory discrimination is mediated by subnuclear domain-specific trafficking signals. Furthermore, the checkpoints that monitor subnuclear distribution of regulatory factors and the sorting steps that ensure both structural and functional fidelity of nuclear domains in which replication and expression of genes occur must be biochemically and mechanistically defined. There is emerging recognition that placement of regulatory components of gene expression must be temporally and spatially coordinated to facilitate biological control. The consequences of breaches in nuclear structure-function relationships are observed in an expanding series of diseases that include cancer [Weis et al., 1994; Rogaia et al., 1997; Yano et al., 1997; Rowley, 1998; Zeng et al., 1998; McNeil et al., 1999; Tao and Levine, 1999a] and neurological disorders [Skinner et al., 1997]. As the repertoire of architecture-associated regulatory factors and cofactors expands, workers in the field are becoming increasingly confident that nuclear organization contributes significantly to control of transcription. To gain increased appreciation for the complexities of subnuclear organization and gene regulation, we must continue to characterize mechanisms that direct regulatory proteins to specific transcription sites within the nucleus so that these proteins are in the right place at the right time. J. Cell. Biochem. Suppl. 35:84-92, 2000. Copyright 2001 Wiley-Liss, Inc.

NR4A nuclear receptors support memory enhancement by histone deacetylase inhibitors

PubMed Central

Hawk, Joshua D.; Bookout, Angie L.; Poplawski, Shane G.; Bridi, Morgan; Rao, Allison J.; Sulewski, Michael E.; Kroener, Brian T.; Manglesdorf, David J.; Abel, Ted

2012-01-01

The formation of a long-lasting memory requires a transcription-dependent consolidation period that converts a short-term memory into a long-term memory. Nuclear receptors compose a class of transcription factors that regulate diverse biological processes, and several nuclear receptors have been implicated in memory formation. Here, we examined the potential contribution of nuclear receptors to memory consolidation by measuring the expression of all 49 murine nuclear receptors after learning. We identified 13 nuclear receptors with increased expression after learning, including all 3 members of the Nr4a subfamily. These CREB-regulated Nr4a genes encode ligand-independent “orphan” nuclear receptors. We found that blocking NR4A activity in memory-supporting brain regions impaired long-term memory but did not impact short-term memory in mice. Further, expression of Nr4a genes increased following the memory-enhancing effects of histone deacetylase (HDAC) inhibitors. Blocking NR4A signaling interfered with the ability of HDAC inhibitors to enhance memory. These results demonstrate that the Nr4a gene family contributes to memory formation and is a promising target for improving cognitive function. PMID:22996661

Economic and Market Challenges Facing the U.S. Nuclear Commercial Fleet

DOE Office of Scientific and Technical Information (OSTI.GOV)

Szilard, Ronaldo; Sharpe, Phil; Kee, Edward

This report identifies underlying economic and electricity market factors that have led to early retirements of U.S. operating nuclear power plants, assesses the Gap between operating revenues and operating costs for selected nuclear power plants, and discusses a range of actions that might be taken to stop early retirement of operating nuclear power plants. The Kewaunee and Vermont Yankee nuclear power plants were retired early for economic and financial reasons. Early retirement has been announced or proposed for Clinton and Quad Cities in Illinois, Fitzpatrick and Ginna in New York, Fort Calhoun in Nebraska. Other nuclear power plants, including Palisades,more » Davis-Besse, Prairie Island, and Three Mile Island Unit 1, have been identified as facing financial stress that might lead to early retirement. The early retirement of operating nuclear power plants will mean the loss of a large amount of zero-emission electricity, inconsistent with the goal of reducing carbon emissions in the electricity sector. This report provides a high-level view of the major factors driving early retirement: • The U.S. market and private ownership approach to the electricity sector; • Low electricity market prices resulting from low natural gas prices, low demand growth, increased penetration of renewable generation, and negative electricity market prices; and • No compensation to nuclear power plants for public benefits including zero-emission electricity.« less

Steady-state nuclear actin levels are determined by export competent actin pool.

PubMed

Skarp, Kari-Pekka; Huet, Guillaume; Vartiainen, Maria K

2013-10-01

A number of studies in the last decade have irrevocably promoted actin into a fully fledged member of the nuclear compartment, where it, among other crucial tasks, facilitates transcription and chromatin remodeling. Changes in nuclear actin levels have been linked to different cellular processes: decreased nuclear actin to quiescence and increased nuclear actin to differentiation. Importin 9 and exportin 6 transport factors are responsible for the continuous nucleocytoplasmic shuttling of actin, but the mechanisms, which result in modulated actin levels, have not been characterized. We find that in cells growing under normal growth conditions, the levels of nuclear actin vary considerably from cell to cell. To understand the basis for this, we have extensively quantified several cellular parameters while at the same time recording the import and export rates of green fluorescent protein (GFP)-tagged actin. Surprisingly, our dataset shows that the ratio of nuclear to cytoplasmic fluorescence intensity, but not nuclear shape, size, cytoplasm size, or their ratio, correlates negatively with both import and export rate of actin. This suggests that high-nuclear actin content is maintained by both diminished import and export. The high nuclear actin containing cells still show high mobility of actin, but it is not export competent, suggesting increased binding of actin to nuclear complexes. Creation of such export incompetent actin pool would ensure enough actin is retained in the nucleus and make it available for the various nuclear functions described for actin. Copyright © 2013 Wiley Periodicals, Inc.

Perturbation of nucleo-cytoplasmic transport affects size of nucleus and nucleolus in human cells.

PubMed

Ganguly, Abira; Bhattacharjee, Chumki; Bhave, Madhura; Kailaje, Vaishali; Jain, Bhawik K; Sengupta, Isha; Rangarajan, Annapoorni; Bhattacharyya, Dibyendu

2016-03-01

Size regulation of human cell nucleus and nucleolus are poorly understood subjects. 3D reconstruction of live image shows that the karyoplasmic ratio (KR) increases by 30-80% in transformed cell lines compared to their immortalized counterpart. The attenuation of nucleo-cytoplasmic transport causes the KR value to increase by 30-50% in immortalized cell lines. Nucleolus volumes are significantly increased in transformed cell lines and the attenuation of nucleo-cytoplasmic transport causes a significant increase in the nucleolus volume of immortalized cell lines. A cytosol and nuclear fraction swapping experiment emphasizes the potential role of unknown cytosolic factors in nuclear and nucleolar size regulation. © 2016 Federation of European Biochemical Societies.

Activation of nuclear transcription factor-kappaB in mouse brain induced by a simulated microgravity environment

NASA Technical Reports Server (NTRS)

Wise, Kimberly C.; Manna, Sunil K.; Yamauchi, Keiko; Ramesh, Vani; Wilson, Bobby L.; Thomas, Renard L.; Sarkar, Shubhashish; Kulkarni, Anil D.; Pellis, Neil R.; Ramesh, Govindarajan T.

2005-01-01

Microgravity induces inflammatory responses and modulates immune functions that may increase oxidative stress. Exposure to a microgravity environment induces adverse neurological effects; however, there is little research exploring the etiology of these effects resulting from exposure to such an environment. It is also known that spaceflight is associated with increase in oxidative stress; however, this phenomenon has not been reproduced in land-based simulated microgravity models. In this study, an attempt has been made to show the induction of reactive oxygen species (ROS) in mice brain, using ground-based microgravity simulator. Increased ROS was observed in brain stem and frontal cortex with concomitant decrease in glutathione, on exposing mice to simulated microgravity for 7 d. Oxidative stress-induced activation of nuclear factor-kappaB was observed in all the regions of the brain. Moreover, mitogen-activated protein kinase kinase was phosphorylated equally in all regions of the brain exposed to simulated microgravity. These results suggest that exposure of brain to simulated microgravity can induce expression of certain transcription factors, and these have been earlier argued to be oxidative stress dependent.

Severe Psychological Distress of Evacuees in Evacuation Zone Caused by the Fukushima Daiichi Nuclear Power Plant Accident: The Fukushima Health Management Survey.

PubMed

Kunii, Yasuto; Suzuki, Yuriko; Shiga, Tetsuya; Yabe, Hirooki; Yasumura, Seiji; Maeda, Masaharu; Niwa, Shin-Ichi; Otsuru, Akira; Mashiko, Hirobumi; Abe, Masafumi

2016-01-01

Following the Great East Japan Earthquake on March 11, 2011, the nuclear disaster at the Fukushima Daiichi Nuclear Power Plant has continued to affect the mental health status of residents in the evacuation zone. To examine the mental health status of evacuee after the nuclear accident, we conducted the Mental Health and Lifestyle Survey as part of the ongoing Fukushima Health Management Survey. We measured mental health status using the Kessler 6-item psychological distress scale (K6) in a total of 73,569 (response rate: 40.7%) evacuees aged 15 and over who lived in the evacuation zone in Fukushima Prefecture. We then dichotomized responders using a 12/13 cutoff on the K6, and compared the proportion of K6 scores ≥13 and ≤12 in each risk factor including demographic information, socioeconomic variables, and disaster-related variables. We also performed bivariate analyses between mental health status and possible risk factors using the chi-square test. Furthermore, we performed multivariate regression analysis using modified Poisson regression models. The median K6 score was 5 (interquartile range: 1-10). The number of psychological distress was 8,717 (14.6%). We found that significant differences in the prevalence of psychological distress by almost all survey items, including disaster-related risk factors, most of which were also associated with increased Prevalence ratios (PRs). Additionally, we found that psychological distress in each evacuation zone was significantly positively associated with the radiation levels in their environment (r = 0.768, p = 0.002). The earthquake, tsunami and subsequent nuclear accident likely caused severe psychological distress among residents in the evacuation zone in Fukushima Prefecture. The close association between psychological distress and the radiation levels shows that the nuclear accident seriously influenced the mental health of the residents, which might be exacerbated by increased risk perception. To provide prompt and appropriate support, continued psychosocial intervention for evacuees is strongly recommended.

Nuclear Calcium Buffering Capacity Shapes Neuronal Architecture.

PubMed

Mauceri, Daniela; Hagenston, Anna M; Schramm, Kathrin; Weiss, Ursula; Bading, Hilmar

2015-09-18

Calcium-binding proteins (CaBPs) such as parvalbumin are part of the cellular calcium buffering system that determines intracellular calcium diffusion and influences the spatiotemporal dynamics of calcium signals. In neurons, CaBPs are primarily localized to the cytosol and function, for example, in nerve terminals in short-term synaptic plasticity. However, CaBPs are also expressed in the cell nucleus, suggesting that they modulate nuclear calcium signals, which are key regulators of neuronal gene expression. Here we show that the calcium buffering capacity of the cell nucleus in mouse hippocampal neurons regulates neuronal architecture by modulating the expression levels of VEGFD and the complement factor C1q-c, two nuclear calcium-regulated genes that control dendrite geometry and spine density, respectively. Increasing the levels of nuclear calcium buffers by means of expression of a nuclearly targeted form of parvalbumin fused to mCherry (PV.NLS-mC) led to a reduction in VEGFD expression and, as a result, to a decrease in total dendritic length and complexity. In contrast, mRNA levels of the synapse pruning factor C1q-c were increased in neurons expressing PV.NLS-mC, causing a reduction in the density and size of dendritic spines. Our results establish a close link between nuclear calcium buffering capacity and the transcription of genes that determine neuronal structure. They suggest that the development of cognitive deficits observed in neurological conditions associated with CaBP deregulation may reflect the loss of necessary structural features of dendrites and spines. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Antioxidants for Healthy Skin: The Emerging Role of Aryl Hydrocarbon Receptors and Nuclear Factor-Erythroid 2-Related Factor-2

PubMed Central

Furue, Masutaka; Uchi, Hiroshi; Mitoma, Chikage; Hashimoto-Hachiya, Akiko; Chiba, Takahito; Ito, Takamichi; Nakahara, Takeshi; Tsuji, Gaku

2017-01-01

Skin is the outermost part of the body and is, thus, inevitably exposed to UV rays and environmental pollutants. Oxidative stress by these hazardous factors accelerates skin aging and induces skin inflammation and carcinogenesis. Aryl hydrocarbon receptors (AHRs) are chemical sensors that are abundantly expressed in epidermal keratinocytes and mediate the production of reactive oxygen species. To neutralize or minimize oxidative stress, the keratinocytes also express nuclear factor-erythroid 2-related factor-2 (NRF2), which is a master switch for antioxidant signaling. Notably, there is fine-tuned crosstalk between AHR and NRF2, which mutually increase or decrease their activation states. Many NRF2-mediated antioxidant phytochemicals are capable of up- and downmodulating AHR signaling. The precise mechanisms by which these phytochemicals differentially affect the AHR and NRF2 system remain largely unknown and warrant future investigation. PMID:28273792

Antioxidants for Healthy Skin: The Emerging Role of Aryl Hydrocarbon Receptors and Nuclear Factor-Erythroid 2-Related Factor-2.

PubMed

Furue, Masutaka; Uchi, Hiroshi; Mitoma, Chikage; Hashimoto-Hachiya, Akiko; Chiba, Takahito; Ito, Takamichi; Nakahara, Takeshi; Tsuji, Gaku

2017-03-03

Skin is the outermost part of the body and is, thus, inevitably exposed to UV rays and environmental pollutants. Oxidative stress by these hazardous factors accelerates skin aging and induces skin inflammation and carcinogenesis. Aryl hydrocarbon receptors (AHRs) are chemical sensors that are abundantly expressed in epidermal keratinocytes and mediate the production of reactive oxygen species. To neutralize or minimize oxidative stress, the keratinocytes also express nuclear factor-erythroid 2-related factor-2 (NRF2), which is a master switch for antioxidant signaling. Notably, there is fine-tuned crosstalk between AHR and NRF2, which mutually increase or decrease their activation states. Many NRF2-mediated antioxidant phytochemicals are capable of up- and downmodulating AHR signaling. The precise mechanisms by which these phytochemicals differentially affect the AHR and NRF2 system remain largely unknown and warrant future investigation.

Functional mechanism of neuroprotection by inhibitors of type B monoamine oxidase in Parkinson's disease.

PubMed

Naoi, Makoto; Maruyama, Wakako

2009-08-01

Neuroprotective therapy has been proposed for age-related neurodegenerative disorders, including Parkinson's disease. Inhibitors of type B monoamine oxidase (MAOB-Is), rasagiline and (-)deprenyl, are the most promising candidate neuroprotective drugs. Clinical trials of rasagiline in patients with Parkinson's disease suggest that rasagiline may have some disease-modifying effects. Results using animal and cellular models have proved that the MAOB-Is protect neurons by the intervention of 'intrinsic' mitochondrial apoptotic cascade and the induction of prosurvival antiapoptotic Bcl-2 and neurotrophic factors. Rasagiline-related MAOB-Is prevent mitochondrial permeability transition induced by various insults and activation of subsequent apoptotic cascades: cytochrome c release, casapase activation, and condensation and fragmentation of nuclear DNA. MAOB-Is increase transcription of prosurvival genes through activating the nuclear transcription factor-(NF) system. Rasagiline increases the protein and mRNA levels of GDNF in dopaminergic SH-SY5Y cells, whereas (-)deprenyl increases those of BDNF. Systemic administration of (-)deprenyl and rasagiline increases these neurotrophic factors in the cerebrospinal fluid from patients with Parkinson's disease and nonhuman primates. This review presents recent advances in our understanding of the neuroprotection offered by MAOB-Is and possible evaluation of neuroprotective efficacy in clinical samples is discussed.

Nuclear IL-33 is a transcriptional regulator of NF-{kappa}B p65 and induces endothelial cell activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Yeon-Sook; Park, Jeong Ae; Kim, Jihye

2012-05-04

Highlights: Black-Right-Pointing-Pointer IL-33 as nuclear factor regulated expression of ICAM-1 and VCAM-1. Black-Right-Pointing-Pointer Nuclear IL-33 increased the transcription of NF-{kappa}B p65 by binding to the p65 promoter. Black-Right-Pointing-Pointer Nuclear IL-33 controls NF-{kappa}B-dependent inflammatory responses. -- Abstract: Interleukin (IL)-33, an IL-1 family member, acts as an extracellular cytokine by binding its cognate receptor, ST2. IL-33 is also a chromatin-binding transcriptional regulator highly expressed in the nuclei of endothelial cells. However, the function of IL-33 as a nuclear factor is poorly defined. Here, we show that IL-33 is a novel transcriptional regulator of the p65 subunit of the NF-{kappa}B complex and ismore » involved in endothelial cell activation. Quantitative reverse transcriptase PCR and Western blot analyses indicated that IL-33 mediates the expression of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in endothelial cells basally and in response to tumor necrosis factor-{alpha}-treatment. IL-33-induced ICAM-1/VCAM-1 expression was dependent on the regulatory effect of IL-33 on the nuclear factor (NF)-{kappa}B pathway; NF-{kappa}B p65 expression was enhanced by IL-33 overexpression and, conversely, reduced by IL-33 knockdown. Moreover, NF-{kappa}B p65 promoter activity and chromatin immunoprecipitation analysis revealed that IL-33 binds to the p65 promoter region in the nucleus. Our data provide the first evidence that IL-33 in the nucleus of endothelial cells participates in inflammatory reactions as a transcriptional regulator of NF-{kappa}B p65.« less

Nuclear Transcription Factors in the Mitochondria: A New Paradigm in Fine-Tuning Mitochondrial Metabolism.

PubMed

Sepuri, Naresh Babu V; Tammineni, Prasad; Mohammed, Fareed; Paripati, Arunkumar

2017-01-01

Noncanonical functions of several nuclear transcription factors in the mitochondria have been gaining exceptional traction over the years. These transcription factors include nuclear hormone receptors like estrogen, glucocorticoid, and thyroid hormone receptors: p53, IRF3, STAT3, STAT5, CREB, NF-kB, and MEF-2D. Mitochondria-localized nuclear transcription factors regulate mitochondrial processes like apoptosis, respiration and mitochondrial transcription albeit being nuclear in origin and having nuclear functions. Hence, the cell permits these multi-stationed transcription factors to orchestrate and fine-tune cellular metabolism at various levels of operation. Despite their ubiquitous distribution in different subcompartments of mitochondria, their targeting mechanism is poorly understood. Here, we review the current status of mitochondria-localized transcription factors and discuss the possible targeting mechanism besides the functional interplay between these factors.

PDE4 and mAKAPβ are nodal organizers of β2-ARs nuclear PKA signaling in cardiac myocytes.

PubMed

Bedioune, Ibrahim; Lefebvre, Florence; Lechêne, Patrick; Varin, Audrey; Domergue, Valérie; Kapiloff, Michael S; Fischmeister, Rodolphe; Vandecasteele, Grégoire

2018-05-03

β1- and β2-adrenergic receptors (β-ARs) produce different acute contractile effects on the heart partly because they impact on different cytosolic pools of cAMP-dependent protein kinase (PKA). They also exert different effects on gene expression but the underlying mechanisms remain unknown. The aim of this study was to understand the mechanisms by which β1- and β2-ARs regulate nuclear PKA activity in cardiomyocytes. We used cytoplasmic and nuclear targeted biosensors to examine cAMP signals and PKA activity in adult rat ventricular myocytes upon selective β1- or β2-ARs stimulation. Both β1- and β2-AR stimulation increased cAMP and activated PKA in the cytoplasm. While the two receptors also increased cAMP in the nucleus, only β1-ARs increased nuclear PKA activity and up-regulated the PKA target gene and pro-apoptotic factor, inducible cAMP element repressor (ICER). Inhibition of PDE4, but not Gi, PDE3, GRK2 nor caveolae disruption disclosed nuclear PKA activation and ICER induction by β2-ARs. Both nuclear and cytoplasmic PKI prevented nuclear PKA activation and ICER induction by β1-ARs, indicating that PKA activation outside the nucleus is required for subsequent nuclear PKA activation and ICER mRNA expression. Cytoplasmic PKI also blocked ICER induction by β2-AR stimulation (with concomitant PDE4 inhibition). However, in this case nuclear PKI decreased ICER up-regulation by only 30%, indicating that other mechanisms are involved. Down-regulation of mAKAPβ partially inhibited nuclear PKA activation upon β1-AR stimulation, and drastically decreased nuclear PKA activation upon β2-AR stimulation in the presence of PDE4 inhibition. β1- and β2-ARs differentially regulate nuclear PKA activity and ICER expression in cardiomyocytes. PDE4 insulates a mAKAPβ-targeted PKA pool at the nuclear envelope that prevents nuclear PKA activation upon β2-AR stimulation.

Disruption of both nesprin 1 and desmin results in nuclear anchorage defects and fibrosis in skeletal muscle.

PubMed

Chapman, Mark A; Zhang, Jianlin; Banerjee, Indroneal; Guo, Ling T; Zhang, Zhiwei; Shelton, G Diane; Ouyang, Kunfu; Lieber, Richard L; Chen, Ju

2014-11-15

Proper localization and anchorage of nuclei within skeletal muscle is critical for cellular function. Alterations in nuclear anchoring proteins modify a number of cellular functions including mechanotransduction, nuclear localization, chromatin positioning/compaction and overall organ function. In skeletal muscle, nesprin 1 and desmin are thought to link the nucleus to the cytoskeletal network. Thus, we hypothesize that both of these factors play a key role in skeletal muscle function. To examine this question, we utilized global ablation murine models of nesprin 1, desmin or both nesprin 1 and desmin. Herein, we have created the nesprin-desmin double-knockout (DKO) mouse, eliminating a major fraction of nuclear-cytoskeletal connections and enabling understanding of the importance of nuclear anchorage in skeletal muscle. Globally, DKO mice are marked by decreased lifespan, body weight and muscle strength. With regard to skeletal muscle, DKO myonuclear anchorage was dramatically decreased compared with wild-type, nesprin 1(-/-) and desmin(-/-) mice. Additionally, nuclear-cytoskeletal strain transmission was decreased in DKO skeletal muscle. Finally, loss of nuclear anchorage in DKO mice coincided with a fibrotic response as indicated by increased collagen and extracellular matrix deposition and increased passive mechanical properties of muscle bundles. Overall, our data demonstrate that nesprin 1 and desmin serve redundant roles in nuclear anchorage and that the loss of nuclear anchorage in skeletal muscle results in a pathological response characterized by increased tissue fibrosis and mechanical stiffness. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Gastroprotective effects of sulforaphane and thymoquinone against acetylsalicylic acid-induced gastric ulcer in rats.

PubMed

Zeren, Sezgin; Bayhan, Zulfu; Kocak, Fatma Emel; Kocak, Cengiz; Akcılar, Raziye; Bayat, Zeynep; Simsek, Hasan; Duzgun, Sukru Aydin

2016-06-15

Nonsteroidal anti-inflammatory drugs (NSAIDs) commonly cause gastric ulcers (GUs). We investigated the effects of sulforaphane (SF) and thymoquinone (TQ) in rats with acetylsalicylic acid (ASA)-induced GUs. Thirty-five male Wistar-Albino rats were divided into five groups: control; ASA; ASA with vehicle; ASA + SF; and ASA + TQ. Compounds were administered by oral gavage before GU induction. GUs were induced by intragastric administration of ASA. Four hours after GU induction, rats were killed and stomachs excised. Total oxidant status, total antioxidant status, total thiol, nitric oxide, asymmetric dimethylarginine, tumor necrosis factor-alpha levels, superoxide dismutase activity, and glutathione peroxidase activity in tissue were measured. Messenger RNA expression of dimethylarginine dimethylaminohydrolases, heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2, and nuclear factor kappa-light-chain-enhancer of activated B cells were analyzed. Renal tissues were evaluated by histopathologic and immunohistochemical means. SF and TQ reduced GU indices, apoptosis, total oxidant status, asymmetric dimethylarginine, and tumor necrosis factor-alpha levels, nuclear factor kappa-light-chain-enhancer of activated B cells, and inducible nitric oxide synthase expressions (P < 0.001, P = 0.001). Both examined compounds increased superoxide dismutase activity, glutathione peroxidase activity, total antioxidant status, total thiol, nitric oxide levels, endothelial nitric oxide synthase, dimethylarginine dimethylaminohydrolases, HO-1, nuclear factor erythroid 2-related factor 2, and HO-1 expressions (P < 0.001). These results suggest that pretreatment with SF or TQ can reduce ASA-induced GUs via anti-inflammatory, antioxidant, and antiapoptotic effects. These compounds may be useful therapeutic strategies to prevent the gastrointestinal adverse effects that limit nonsteroidal anti-inflammatory drugs use. Copyright © 2016 Elsevier Inc. All rights reserved.

A Pro-Inflammatory Role for Nuclear Factor Kappa B in Childhood Obstructive Sleep Apnea Syndrome

PubMed Central

Israel, Lee P.; Benharoch, Daniel; Gopas, Jacob; Goldbart, Aviv D.

2013-01-01

Study Objectives: Childhood obstructive sleep apnea syndrome (OSAS) is associated with an elevation of inflammatory markers such as C-reactive protein (CRP) that correlates with specific morbidities and subsides following intervention. In adults, OSAS is associated with activation of the transcription factor nuclear factor kappa B (NF-kB). We explored the mechanisms underlying NF-kB activation, based on the hypothesis that specific NF-kB signaling is activated in children with OSAS. Design: Adenoid and tonsillar tissues from children with OSAS and matched controls were immunostained against NF-kB classical (p65 and p50) and alternative (RelB and p52) pathway subunits, and NF-kB-dependent cytokines: interleukin (IL)- 1α, IL-1β, tumor necrosis factor-α, and IL-8). Serum CRP levels were measured in all subjects. NF-kB induction was evaluated by a luciferase-NF-kB reporter assay in L428 cells constitutively expressing NF-kB and in Jurkat cells with inducible NF-kB expression. p65 translocation to the nucleus, reflecting NF-kB activation, was measured in cells expressing fluorescent NF-kB-p65-GFP (green fluorescent protein). Setting: Sleep research laboratory. Patients or Participants: Twenty-five children with OSAS and 24 without OSAS. Interventions: N/A. Measurements and Results: Higher expression of IL-1α and classical NF-kB subunits p65 and p50 was observed in adenoids and tonsils of children with OSAS. Patient serum induced NF-kB activity, as measured by a luciferase-NF-kB reporter assay and by induction of p65 nuclear translocation in cells permanently transfected with GFP-p65 plasmid. IL-1β showed increased epithelial expression in OSAS tissues. Conclusions: Nuclear factor kappa B is locally and systemically activated in children with obstructive sleep apnea syndrome. This observation may motivate the search for new anti-inflammatory strategies for controlling nuclear factor kappa B activation in obstructive sleep apnea syndrome. Citation: Israel LP; Benharoch D; Gopas J; Goldbart AD. A pro-inflammatory role for nuclear factor kappa B in childhood obstructive sleep apnea syndrome. SLEEP 2013;36(12):1947-1955. PMID:24293770

Interactions of trans-acting factor(s) with the estradiol response element and nuclear factor 1 of the vitellogenin II gene of Japanese quail.

PubMed

Gupta, S; Upadhayay, R; Kanungo, M S

1996-08-01

This study was directed at achieving an understanding of the mechanisms by which steroid hormones control the synthesis of vitellogenin (VTG) protein in the liver of the Japanese quail. Northern hybridization shows that administration of estradiol alone or with progesterone stimulates the synthesis of VTG mRNA. Gel mobility shift assay of DNA fragments containing the ERE and NF 1 shows that estradiol alone or with progesterone increases the levels of nuclear proteins that bind to these cis-acting elements of the promoter of the VTG gene. The cooperative effect of the two hormones seen at the level of expression of the VTG gene may be due to protein-protein interactions of trans-acting factors that bind to ERE and NF 1.

Influence of various factors on individual radiation exposure from the Chernobyl disaster.

PubMed

Zamostian, Pavlo; Moysich, Kirsten B; Mahoney, Martin C; McCarthy, Philip; Bondar, Alexandra; Noschenko, Andrey G; Michalek, Arthur M

2002-10-29

The explosion at the Chernobyl Nuclear Power Plant was one of the greatest known nuclear disasters of the 20th century. To reduce individual exposure to ionizing radiation the Soviet Union government introduced a number of counter-measures. This article presents a description of how historical events conspired to disrupt these efforts and affect residents in exposed areas. This study employed an extensive review of data on radionuclide deposition, contamination patterns and lifestyle characteristics. Data were obtained from the Ukraine Ministry of Health and the Ukraine Research Center for Radiation Medicine. Data are presented on annual contamination rates in selected locales as well as data on local food consumption patterns. Historical factors including economic and political circumstances are also highlighted. Results show the diminution of individual doses between 1987 and 1991 and then an increase between 1991 and 1994 and the relationship between this increase and changes in the lifestyle of the local population. A number of factors played direct and indirect roles in contributing to the populace's cumulative radiation exposure. Future post-contamination studies need to consider these factors when estimating individual exposures.

Confidence in Nuclear Weapons as Numbers Decrease and Time Since Testing Increases

NASA Astrophysics Data System (ADS)

Adams, Marvin

2011-04-01

As numbers and types of nuclear weapons are reduced, the U.S. objective is to maintain a safe, secure and effective nuclear deterrent without nuclear-explosive testing. A host of issues combine to make this a challenge. An evolving threat environment may prompt changes to security systems. Aging of weapons has led to ``life extension programs'' that produce weapons that differ in some ways from the originals. Outdated and changing facilities pose difficulties for life-extension, surveillance, and dismantlement efforts. A variety of factors can make it a challenge to recruit, develop, and retain outstanding people with the skills and experience that are needed to form the foundation of a credible deterrent. These and other issues will be discussed in the framework of proposals to reduce and perhaps eliminate nuclear weapons.

Population morbidity in the Zaporizhzhia Nuclear Power Plant observation zone as an integral part of public health.

PubMed

Khomenko, I M; Zakladna, N V; Orlova, N M

2017-12-01

To evaluate the health status of adult population living in the Ukrainian nuclear power industry obser vation zone on the example of Zaporizhzhia Nuclear Power Plant. System review, analytic, sociological survey and statistical methods. There was established an increase in the incidence of digestive diseases among adult population in Nikopol of Dnipropetrovsk region, which is included in the Zaporizhzhia NPP observation zone. The highest increase was observed in the incidence of peptic ulcer, gastritis and duodenitis, cholecystitis and cholangitis by 340 %, 305 % and 83 %, respectively. In connection with the residence in industrially developed region and NPP life extension in Ukraine, the possible influence of harmful factors on health status of the population of observation zones, an increase in the incidence of digestive diseases among adult population, there is required continuous monitoring and detailed study of public health. I. M. Khomenko, N. V. Zakladna, N. M. Orlova.

Changes at the nuclear lamina alter binding of pioneer factor Foxa2 in aged liver.

PubMed

Whitton, Holly; Singh, Larry N; Patrick, Marissa A; Price, Andrew J; Osorio, Fernando G; López-Otín, Carlos; Bochkis, Irina M

2018-06-01

Increasing evidence suggests that regulation of heterochromatin at the nuclear envelope underlies metabolic disease susceptibility and age-dependent metabolic changes, but the mechanism is unknown. Here, we profile lamina-associated domains (LADs) using lamin B1 ChIP-Seq in young and old hepatocytes and find that, although lamin B1 resides at a large fraction of domains at both ages, a third of lamin B1-associated regions are bound exclusively at each age in vivo. Regions occupied by lamin B1 solely in young livers are enriched for the forkhead motif, bound by Foxa pioneer factors. We also show that Foxa2 binds more sites in Zmpste24 mutant mice, a progeroid laminopathy model, similar to increased Foxa2 occupancy in old livers. Aged and Zmpste24-deficient livers share several features, including nuclear lamina abnormalities, increased Foxa2 binding, de-repression of PPAR- and LXR-dependent gene expression, and fatty liver. In old livers, additional Foxa2 binding is correlated to loss of lamin B1 and heterochromatin (H3K9me3 occupancy) at these loci. Our observations suggest that changes at the nuclear lamina are linked to altered Foxa2 binding, enabling opening of chromatin and de-repression of genes encoding lipid synthesis and storage targets that contribute to etiology of hepatic steatosis. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

STEF/TIAM2-mediated Rac1 activity at the nuclear envelope regulates the perinuclear actin cap.

PubMed

Woroniuk, Anna; Porter, Andrew; White, Gavin; Newman, Daniel T; Diamantopoulou, Zoi; Waring, Thomas; Rooney, Claire; Strathdee, Douglas; Marston, Daniel J; Hahn, Klaus M; Sansom, Owen J; Zech, Tobias; Malliri, Angeliki

2018-05-29

The perinuclear actin cap is an important cytoskeletal structure that regulates nuclear morphology and re-orientation during front-rear polarisation. The mechanisms regulating the actin cap are currently poorly understood. Here, we demonstrate that STEF/TIAM2, a Rac1 selective guanine nucleotide exchange factor, localises at the nuclear envelope, co-localising with the key perinuclear proteins Nesprin-2G and Non-muscle myosin IIB (NMMIIB), where it regulates perinuclear Rac1 activity. We show that STEF depletion reduces apical perinuclear actin cables (a phenotype rescued by targeting active Rac1 to the nuclear envelope), increases nuclear height and impairs nuclear re-orientation. STEF down-regulation also reduces perinuclear pMLC and decreases myosin-generated tension at the nuclear envelope, suggesting that STEF-mediated Rac1 activity regulates NMMIIB activity to promote stabilisation of the perinuclear actin cap. Finally, STEF depletion decreases nuclear stiffness and reduces expression of TAZ-regulated genes, indicating an alteration in mechanosensing pathways as a consequence of disruption of the actin cap.

Effects of inhalational anaesthetics in experimental allergic asthma.

PubMed

Burburan, S M; Silva, J D; Abreu, S C; Samary, C S; Guimarães, I H L; Xisto, D G; Morales, M M; Rocco, P R M

2014-06-01

We evaluated whether isoflurane, halothane and sevoflurane attenuate the inflammatory response and improve lung morphofunction in experimental asthma. Fifty-six BALB/c mice were sensitised and challenged with ovalbumin and anaesthetised with isoflurane, halothane, sevoflurane or pentobarbital sodium for one hour. Lung mechanics and histology were evaluated. Gene expression of pro-inflammatory (tumour necrosis factor-α), pro-fibrogenic (transforming growth factor-β) and pro-angiogenic (vascular endothelial growth factor) mediators, as well as oxidative process modulators, were analysed. These modulators included nuclear factor erythroid-2 related factor 2, sirtuin, catalase and glutathione peroxidase. Isoflurane, halothane and sevoflurane reduced airway resistance, static lung elastance and atelectasis when compared with pentobarbital sodium. Sevoflurane minimised bronchoconstriction and cell infiltration, and decreased tumour necrosis factor-α, transforming growth factor-β, vascular endothelial growth factor, sirtuin, catalase and glutathione peroxidase, while increasing nuclear factor erythroid-2-related factor 2 expression. Sevoflurane down-regulated inflammatory, fibrogenic and angiogenic mediators, and modulated oxidant-antioxidant imbalance, improving lung function in this model of asthma. © 2014 The Association of Anaesthetists of Great Britain and Ireland.

MicroRNA-194 promotes osteoblast differentiation via downregulating STAT1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Jun; He, Xijing; Wei, Wenzhi

Osteoblast differentiation is a vital process in maintaining bone homeostasis in which various transcriptional factors, signaling molecules, and microRNAs (miRNAs) are involved. Recently, signal transducer and activator of transcription 1 (STAT1) has been found to play an important role in regulating osteoblast differentiation. Here, we identified that STAT1 expression was regulated by miR-194. Using mouse bone mesenchymal stem cells (BMSCs), we found that miR-194 expression was significantly increased following osteoblast differentiation induction. Overexpression of miR-194 by lentivirus-mediated gene transfer markedly increased osteoblast differentiation, whereas inhibition of miR-194 significantly suppressed osteoblast differentiation of BMSCs. Using a dual-luciferase reporter assay, a directmore » interaction between miR-194 and the 3′-untranslated region (UTR) of STAT1 was confirmed. Additionally, miR-194 regulated mRNA and protein expression of STAT1 in BMSCs. Further analysis showed that miR-194 overexpression promoted the nuclear translocation of runt-related transcription factor 2 (Runx2), which is critical for osteoblast differentiation. In contrast, inhibition of miR-194 blocked the nuclear translocation of Runx2. Moreover, overexpression of STAT1 significantly blocked Runx2 nuclear translocation and osteoblast differentiation mediated by miR-194 overexpression. Taken together, our data suggest that miR-194 regulates osteoblast differentiation through modulating STAT1-mediated Runx2 nuclear translocation. - Highlights: • Overexpression of miR-194 significantly increased osteoblast differentiation. • miR-194 directly targeted the 3′- UTR of STAT1. • miR-194 regulated the expression of STAT1. • Overexpression of miR-194 promoted the nuclear translocation of Runx2.« less

Role of RANKL in bone diseases.

PubMed

Anandarajah, Allen P

2009-03-01

Bone remodeling is a tightly regulated process of osteoclast-mediated bone resorption, balanced by osteoblast-mediated bone formation. Disruption of this balance can lead to increased bone turnover, resulting in excessive bone loss or extra bone formation and consequent skeletal disease. The receptor activator of nuclear factor kappaB ligand (RANKL) (along with its receptor), the receptor activator of nuclear factor kappaB and its natural decoy receptor, osteoprotegerin, are the final effector proteins of osteoclastic bone resorption. Here, I provide an overview of recent studies that highlight the key role of RANKL in the pathophysiology of several bone diseases and discuss the novel therapeutic approaches afforded by the modulation of RANKL.

RNA helicase MOV10 functions as a co-factor of HIV-1 Rev to facilitate Rev/RRE-dependent nuclear export of viral mRNAs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Huang, Feng; Zhang, Junsong; Zhang, Yijun

Human immunodeficiency virus type 1 (HIV-1) exploits multiple host factors during its replication. The REV/RRE-dependent nuclear export of unspliced/partially spliced viral transcripts needs the assistance of host proteins. Recent studies have shown that MOV10 overexpression inhibited HIV-1 replication at various steps. However, the endogenous MOV10 was required in certain step(s) of HIV-1 replication. In this report, we found that MOV10 potently enhances the nuclear export of viral mRNAs and subsequently increases the expression of Gag protein and other late products through affecting the Rev/RRE axis. The co-immunoprecipitation analysis indicated that MOV10 interacts with Rev in an RNA-independent manner. The DEAG-boxmore » of MOV10 was required for the enhancement of Rev/RRE-dependent nuclear export and the DEAG-box mutant showed a dominant-negative activity. Our data propose that HIV-1 utilizes the anti-viral factor MOV10 to function as a co-factor of Rev and demonstrate the complicated effects of MOV10 on HIV-1 life cycle. - Highlights: • MOV10 can function as a co-factor of HIV-1 Rev. • MOV10 facilitates Rev/RRE-dependent transport of viral mRNAs. • MOV10 interacts with Rev in an RNA-independent manner. • The DEAG-box of MOV10 is required for the enhancement of Rev/RRE-dependent export.« less

Elevated Muscle TLR4 Expression and Metabolic Endotoxemia in Human Aging

PubMed Central

Ghosh, Sangeeta; Lertwattanarak, Raweewan; Garduño, Jose de Jesus; Galeana, Joaquin Joya; Li, Jinqi; Zamarripa, Frank; Lancaster, Jack L.; Mohan, Sumathy; Hussey, Sophie

2015-01-01

Aging is associated with alterations in glucose metabolism and sarcopenia that jointly contribute to a higher risk of developing type 2 diabetes. Because aging is considered as a state of low-grade inflammation, in this study we examined whether older, healthy (lean, community-dwelling) participants have altered signaling flux through toll-like receptor 4 (TLR4), a key mediator of innate and adaptive immune responses. We also examined whether a 4-month aerobic exercise program would have an anti-inflammatory effect by reducing TLR4 expression and signaling. At baseline, muscle TLR4, nuclear factor κB p50 and nuclear factor κB p65 protein content, and c-Jun N-terminal kinase phosphorylation were significantly elevated in older versus young participants. The plasma concentration of the TLR4 agonist lipopolysaccharide and its binding protein also were significantly elevated in older participants, indicative of metabolic endotoxemia, which is a recently described phenomenon of increased plasma endotoxin level in metabolic disease. These alterations in older participants were accompanied by decreased insulin sensitivity, quadriceps muscle volume, and muscle strength. The exercise training program increased insulin sensitivity, without affecting quadriceps muscle volume or strength. Muscle TLR4, nuclear factor κB, and c-Jun N-terminal kinase, and plasma lipopolysaccharide and lipopolysaccharide binding protein were not changed by exercise. In conclusion, insulin resistance and sarcopenia of aging are associated with increased TLR4 expression/signaling, which may be secondary to metabolic endotoxemia. PMID:24846769

Diesel Exhaust Particulate Extracts Inhibit Transcription of Nuclear Respiratory Factor-1 and Cell Viability in Human Umbilical Vein Endothelial Cells

PubMed Central

Mattingly, Kathleen A.; Klinge, Carolyn M.

2011-01-01

Endothelial dysfunction precedes cardiovascular disease and is accompanied by mitochondrial dysfunction. Here we tested the hypothesis that diesel exhaust particulate extracts (DEPEs), prepared from a truck run at different speeds and engine loads, would inhibit genomic estrogen receptor activation of nuclear respiratory factor-1 (NRF-1) transcription in human umbilical vein endothelial cells (HUVECs). Additionally, we examined how DEPEs affect NRF-1 regulated TFAM expression and, in turn, Tfam-regulated mtDNA-encoded cytochrome c oxidase subunit I (COI, MTCO1) and NADH dehydrogenase subunit I (NDI) expression as well as cell proliferation and viability. We report that 17β-estradiol (E2), 4-hydroxytamoxifen (4-OHT), and raloxifene increased NRF-1 transcription in HUVECs in an ER-dependent manner. DEPEs inhibited NRF-1 transcription and this suppression was not ablated by concomitant treatment with E2, 4-OHT, or raloxifene, indicating that the effect was not due to inhibition of ER activity. While E2 increased HUVEC proliferation and viability, DEPEs inhibited viability but not proliferation. Resveratrol increased NRF-1 transcription in an ER-dependent manner in HUVECs, and ablated DEPE inhibition of basal NRF-1 expression. Given that NRF-1 is a key nuclear transcription factor regulating genes involved in mitochondrial activity and biogenesis, these data suggest that DEPEs may adversely affect mitochondrial function leading to endothelial dysfunction and resveratrol may block these effects. PMID:22105178

Protective effect of nuclear factor E2-related factor 2 on inflammatory cytokine response to brominated diphenyl ether-47 in the HTR-8/SVneo human first trimester extravillous trophoblast cell line.

PubMed

Park, Hae-Ryung; Loch-Caruso, Rita

2014-11-15

Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants, and BDE-47 is a prevalent PBDE congener detected in human tissues. Exposure to PBDEs has been linked to adverse pregnancy outcomes in humans. Although the underlying mechanisms of adverse birth outcomes are poorly understood, critical roles for oxidative stress and inflammation are implicated. The present study investigated antioxidant responses in a human extravillous trophoblast cell line, HTR-8/SVneo, and examined the role of nuclear factor E2-related factor 2 (Nrf2), an antioxidative transcription factor, in BDE-47-induced inflammatory responses in the cells. Treatment of HTR-8/SVneo cells with 5, 10, 15, and 20μM BDE-47 for 24h increased intracellular glutathione (GSH) levels compared to solvent control. Treatment of HTR-8/SVneo cells with 20μM BDE-47 for 24h induced the antioxidant response element (ARE) activity, indicating Nrf2 transactivation by BDE-47 treatment, and resulted in differential expression of redox-sensitive genes compared to solvent control. Pretreatment with tert-butyl hydroquinone (tBHQ) or sulforaphane, known Nrf2 inducers, reduced BDE-47-stimulated IL-6 release with increased ARE reporter activity, reduced nuclear factor kappa B (NF-κB) reporter activity, increased GSH production, and stimulated expression of antioxidant genes compared to non-Nrf2 inducer pretreated groups, suggesting that Nrf2 may play a protective role against BDE-47-mediated inflammatory responses in HTR-8/SVneo cells. These results suggest that Nrf2 activation significantly attenuated BDE-47-induced IL-6 release by augmentation of cellular antioxidative system via upregulation of Nrf2 signaling pathways, and that Nrf2 induction may be a potential therapeutic target to reduce adverse pregnancy outcomes associated with toxicant-induced oxidative stress and inflammation. Copyright © 2014 Elsevier Inc. All rights reserved.

Amomum tsao-ko suppresses lipopolysaccharide-induced inflammatory responses in RAW264.7 macrophages via Nrf2-dependent heme oxygenase-1 expression.

PubMed

Li, Bin; Choi, Hee-Jin; Lee, Dong-Sung; Oh, Hyuncheol; Kim, Youn-Chul; Moon, Jin-Young; Park, Won-Hwan; Park, Sun-Dong; Kim, Jai-Eun

2014-01-01

Amomum tsao-ko Crevost et Lemaire, used as a spice in Asia, is an important source of Chinese cuisine and traditional Chinese medicines. A. tsao-ko is reported to exert a variety of biological and pharmacological activities, including anti-proliferative, anti-oxidative and neuroprotective effects. In this study, NNMBS227, consisting of the ethanol extract of A. tsao-ko, exhibited potent anti-inflammatory activities in RAW264.7 macrophages. We investigated the effect of NNMBS227 in the suppression of pro-inflammatory mediators, including pro-inflammatory enzymes (inducible nitric oxide synthase and cyclooxygenase-2) and cytokines (tumor necrosis factor-α and interleukin-1β) in LPS stimulated macrophages. NNMBS227 also inhibited the phosphorylation and degradation of IκB-α, as well as the nuclear translocation of nuclear factor kappa B (NF-κB) p65 caused by stimulation with LPS. In addition, NNMBS227 induced heme oxygenase (HO)-1 expression through the nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) in macrophages. Using tin protoporphyrin (SnPP), an HO activity inhibitor, we confirmed an association between the anti-inflammatory effects of NNMBS227 and the up-regulation of HO-1. These findings suggest that Nrf2-dependent increases in the expression of HO-1 induced by NNMBS227 conferred anti-inflammatory activities in LPS stimulated RAW264.7 macrophages.

Suppression of nuclear factor erythroid‑2‑related factor 2‑mediated antioxidative defense in the lung injury induced by chronic exposure to methamphetamine in rats.

PubMed

Bai, Yang; Wang, Yun; Liu, Ming; Gu, Yu-Han; Jiang, Bin; Wu, Xu; Wang, Huai-Liang

2017-05-01

The imbalance between oxidative stress and antioxidant defense is important in the pathogenesis of lung diseases. Nuclear factor erythroid‑2‑related factor 2 (Nrf2) is a key transcriptional factor that regulates the antioxidant response. The purpose of the present study was to investigate whether Nrf2‑mediated antioxidative defense is involved in methamphetamine (MA)‑induced lung injury in rats. Following establishment of chronic MA toxicity in rats, Doppler ultrasonic detection was used to measure the changes of physiological indexes, followed by hematoxylin and eosin staining, ELISA and western blot analysis. MA was demonstrated to increase the heart rate and peak blood flow velocity of pulmonary arterial valves and to decrease the survival rate of rats, and resulted in lung injury characterized by perivascular exudates, airspace edema, slight hemorrhage and inflammatory cell infiltration. MA significantly inhibited the expression of nuclear Nrf2 protein and its target genes (glutamate‑cysteine ligase catalytic subunit C and heme oxygenase‑1), and dose‑dependently reduced glutathione (GSH) levels and the ratio of GSH/oxidized glutathione, accompanied by increases in reactive oxygen species (ROS) levels in rat lungs. Linear regression analysis revealed that there was a positive correlation between lung ROS level and lung injury indexes. These findings suggested that chronic exposure to MA led to lung injury by suppression of Nrf2‑mediated antioxidative defense, suggesting that Nrf2 may be an important therapeutic target for MA‑induced chronic lung toxicity.

Protein–energy malnutrition increases activation of the transcription factor, nuclear factor κB, in the gerbil hippocampus following global ischemia☆

PubMed Central

Ji, Liang; Nazarali, Adil J.; Paterson, Phyllis G.

2013-01-01

Protein–energy malnutrition (PEM) exacerbates functional impairment caused by brain ischemia. This is correlated with reactive gliosis, which suggests an increased inflammatory response. The objective of the current study was to investigate if PEM increases hippocampal activation of nuclear factor κB (NFκB), a transcription factor that amplifies the inflammatory response involved in ischemic brain injury. Mongolian gerbils (11–12 weeks old) were randomly assigned to control diet (12.5% protein) or protein-deficient diet (2%) for 4 weeks. The 2% protein group had a 15% decrease in voluntary food intake (P<.001; unpaired t test), resulting in PEM. Body weight after 4 weeks was 20% lower in the PEM group (P<.001). Gerbils were then exposed to sham surgery or global ischemia induced by 5-min bilateral common carotid artery occlusion. PEM independently increased hippocampal NFκB activation detected by electrophoretic mobility shift assay at 6 h after surgery (P=.014; 2-factor ANOVA). Ischemia did not significantly affect NFκB activation nor was there interaction between diet and ischemia. Serum glucose and cortisol concentrations at 6 h postischemia were unaltered by diet or ischemia. A second experiment using gerbils of the same age and feeding paradigm demonstrated that PEM also increases hippocampal NFκB activation in the absence of surgery. These findings suggest that PEM, which exists in 16% of elderly patients at admission for stroke, may worsen outcome by increasing activation of NFκB. Since PEM increased NFκB activation independent of ischemia or surgery, the data also have implications for the inflammatory response of the many individuals affected globally by PEM. PMID:18430555

Nuclear factor I-C reciprocally regulates adipocyte and osteoblast differentiation via control of canonical Wnt signaling.

PubMed

Zhou, Jie; Wang, Shan; Qi, Qi; Yang, Xiaoyue; Zhu, Endong; Yuan, Hairui; Li, Xuemei; Liu, Ying; Li, Xiaoxia; Wang, Baoli

2017-05-01

Nuclear factor I-C (NFIC) has recently been identified as an important player in osteogenesis and bone homeostasis in vivo However, the molecular mechanisms involved have yet to be defined. In the current study, Nfic expression was altered in primary marrow stromal cells and established progenitor lines after adipogenic and osteogenic treatment. Overexpression of Nfic in stromal cells ST2, mesenchymal cells C3H10T1/2, and primary marrow stromal cells inhibited adipogenic differentiation, whereas it promoted osteogenic differentiation. Conversely, silencing of endogenous Nfic in the cell lines enhanced adipogenic differentiation, whereas it blocked osteogenic differentiation. Mechanism investigations revealed that Nfic overexpression promoted nuclear translocation of β-catenin and increased nuclear protein levels of β-catenin and transcription factor 7-like 2 (TCF7L2). Promoter studies and the chromatin immunoprecipitation (ChIP) assay revealed that NFIC directly binds to the promoter of low-density lipoprotein receptor-related protein 5 (Lrp5) and thereafter transactivates the promoter. Finally, inactivation of canonical Wnt signaling in ST2 attenuated the inhibition of adipogenic differentiation and stimulation of osteogenic differentiation by NFIC. Our study suggests that NFIC balances adipogenic and osteogenic differentiation from progenitor cells through controlling canonical Wnt signaling and highlights the potential of NFIC as a target for new therapies to control metabolic disorders like osteoporosis and obesity.-Zhou, J., Wang, S., Qi, Q., Yang, X., Zhu, E., Yuan, H., Li, X., Liu, Y., Li, X., Wang, B. Nuclear factor I-C reciprocally regulates adipocyte and osteoblast differentiation via control of canonical Wnt signaling. © FASEB.

Human Factors Research and Nuclear Safety.

ERIC Educational Resources Information Center

Moray, Neville P., Ed.; Huey, Beverly M., Ed.

The Panel on Human Factors Research Needs in Nuclear Regulatory Research was formed by the National Research Council in response to a request from the Nuclear Regulatory Commission (NRC). The NRC asked the research council to conduct an 18-month study of human factors research needs for the safe operation of nuclear power plants. This report…

Importin α1 is required for nuclear import of herpes simplex virus proteins and capsid assembly in fibroblasts and neurons

PubMed Central

Anderson, Fenja; Rother, Franziska; Rudolph, Kathrin; Prank, Ute; Binz, Anne; Hügel, Stefanie; Hartmann, Enno; Bader, Michael; Bauerfeind, Rudolf; Sodeik, Beate

2018-01-01

Herpesviruses are large DNA viruses which depend on many nuclear functions, and therefore on host transport factors to ensure specific nuclear import of viral and host components. While some import cargoes bind directly to certain transport factors, most recruit importin β1 via importin α. We identified importin α1 in a small targeted siRNA screen to be important for herpes simplex virus (HSV-1) gene expression. Production of infectious virions was delayed in the absence of importin α1, but not in cells lacking importin α3 or importin α4. While nuclear targeting of the incoming capsids, of the HSV-1 transcription activator VP16, and of the viral genomes were not affected, the nuclear import of the HSV-1 proteins ICP4 and ICP0, required for efficient viral transcription, and of ICP8 and pUL42, necessary for DNA replication, were reduced. Furthermore, quantitative electron microscopy showed that fibroblasts lacking importin α1 contained overall fewer nuclear capsids, but an increased proportion of mature nuclear capsids indicating that capsid formation and capsid egress into the cytoplasm were impaired. In neurons, importin α1 was also not required for nuclear targeting of incoming capsids, but for nuclear import of ICP4 and for the formation of nuclear capsid assembly compartments. Our data suggest that importin α1 is specifically required for the nuclear localization of several important HSV1 proteins, capsid assembly, and capsid egress into the cytoplasm, and may become rate limiting in situ upon infection at low multiplicity or in terminally differentiated cells such as neurons. PMID:29304174

Nuclear translocation of HIF-1α induced by influenza A (H1N1) infection is critical to the production of proinflammatory cytokines.

PubMed

Guo, Xinkun; Zhu, Zhaoqin; Zhang, Wanju; Meng, Xiaoxiao; Zhu, Yong; Han, Peng; Zhou, Xiaohui; Hu, Yunwen; Wang, Ruilan

2017-05-24

Infection with the influenza A (H1N1) virus is a major challenge for public health because it can cause severe morbidity and even mortality in humans. The over-secretion of inflammatory cytokines (cytokine storm) is considered to be a key contributor to the severe pneumonia caused by H1N1 infection. It has been reported that hypoxia-inducible factor 1-alpha (HIF-1α) is associated with the production of proinflammatory molecules, but whether HIF-1α participates in the acute inflammatory responses against H1N1 infection is still unclear. To investigate the role of HIF-1α in H1N1 infection, the expression and nuclear translocation of HIF-1α in A549 and THP-1 cell lines infected with H1N1 virus were observed. The results showed that without altering the intracellular mRNA or protein expression of HIF-1α, H1N1 infection only induced nuclear translocation of HIF-1α under normal oxygen concentrations. The use of 2-methoxyestradiol (2ME2), a HIF-1α inhibitor that blocks HIF-1α nuclear accumulation, in H1N1-infected cells decreased the mRNA and protein expression of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6 and increased the levels of IL-10. In contrast, H1N1-infected cells under hypoxic conditions had increased HIF-1α nuclear accumulation, increased expression of TNF-α and IL-6 and decreased levels of IL-10. In conclusion, our data implied that in vitro H1N1 infection induced nuclear translocation of HIF-1α without altering the expression of HIF-1α, which may promote the secretion of proinflammatory cytokines during H1N1 infection.

Developing Si(Li) nuclear radiation detectors by pulsed electric field treatment

NASA Astrophysics Data System (ADS)

Muminov, R. A.; Radzhapov, S. A.; Saimbetov, A. K.

2009-08-01

Fabrication of Si(Li) nuclear radiation detectors using lithium ion drift under the action of a pulsed electric field is considered. Optimum treatment regime parameters are determined, including the pulse amplitude, duration, and repetition rate. Experimental data are presented, which show that the ion drift in a pulsed electric field decreases the semiconductor bulk compensation time by a factor of two to four and significantly increases the efficiency of detectors.

Clinical validation of nuclear factor kappa B expression in invasive breast cancer.

PubMed

Agrawal, Anil Kumar; Pielka, Ewa; Lipinski, Artur; Jelen, Michal; Kielan, Wojciech; Agrawal, Siddarth

2018-01-01

Breast cancer is the most commonly diagnosed cancer in Polish women. The expression of transcription nuclear factor kappa B, a key inducer of inflammatory response promoting carcinogenesis and cancer progression in breast cancer, is not well-established. We assessed the nuclear factor kappa B expression in a total of 119 invasive breast carcinomas and 25 healthy control samples and correlated this expression pattern with several clinical and pathologic parameters including histologic type and grade, tumor size, lymph node status, estrogen receptor status, and progesterone receptor status. The data used for the analysis were derived from medical records. An immunohistochemical analysis of nuclear factor kappa B, estrogen receptor, and progesterone receptor was carried out and evaluation of stainings was performed. The expression of nuclear factor kappa B was significantly higher than that in the corresponding healthy control samples. No statistical difference was demonstrated in nuclear factor kappa B expression in relation to age, menopausal status, lymph node status, tumor size and location, grade and histologic type of tumor, and hormonal status (estrogen receptor and progesterone receptor). Nuclear factor kappa B is significantly overexpressed in invasive breast cancer tissues. Although nuclear factor kappa B status does not correlate with clinicopathological findings, it might provide important additional information on prognosis and become a promising object for targeted therapy.

Tau regulates the subcellular localization of calmodulin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Barreda, Elena Gomez de; Avila, Jesus, E-mail: javila@cbm.uam.es; CIBER de Enfermedades Neurodegenerativas, 28031 Madrid

Highlights: {yields} In this work we have tried to explain how a cytoplasmic protein could regulate a cell nuclear function. We have tested the role of a cytoplasmic protein (tau) in regulating the expression of calbindin gene. We found that calmodulin, a tau-binding protein with nuclear and cytoplasmic localization, increases its nuclear localization in the absence of tau. Since nuclear calmodulin regulates calbindin expression, a decrease in nuclear calmodulin, due to the presence of tau that retains it at the cytoplasm, results in a change in calbindin expression. -- Abstract: Lack of tau expression in neuronal cells results in amore » change in the expression of few genes. However, little is known about how tau regulates gene expression. Here we show that the presence of tau could alter the subcellular localization of calmodulin, a protein that could be located at the cytoplasm or in the nucleus. Nuclear calmodulin binds to co-transcription factors, regulating the expression of genes like calbindin. In this work, we have found that in neurons containing tau, a higher proportion of calmodulin is present in the cytoplasm compared with neurons lacking tau and that an increase in cytoplasmic calmodulin correlates with a higher expression of calbindin.« less

Exploring Students' Ideas About Risks and Benefits of Nuclear Power Using Risk Perception Theories

NASA Astrophysics Data System (ADS)

Kılınç, Ahmet; Boyes, Edward; Stanisstreet, Martin

2013-06-01

Due to increased energy demand, Turkey is continuing to explore the possibilities of introducing nuclear power. Gaining acceptance from local populations, however, may be problematic because nuclear power has a negative image and risk perceptions are complicated by a range of psychological and cultural factors. In this study, we explore the views about nuclear power of school students from three locations in Turkey, two of which have been proposed as sites suitable for nuclear power plants. About half of the student cohort believed that nuclear power can supply continuous and sufficient electricity, but approximately three quarters thought that nuclear power stations could harm organisms, including humans, living nearby. Rather few students realized that adoption of nuclear power would help to reduce global warming and thereby limit climate change; indeed, three quarters thought that nuclear power would make global warming worse. There was a tendency for more students from the location most likely to have a nuclear power plant to believe negative characteristics of nuclear power, and for fewer students to believe positive characteristics. Exploration of the possible nuclear power programmes by Turkey offers an educational opportunity to understand the risk perceptions of students that affect their decision-making processes.

Augmentation of poly(ADP-ribose) polymerase-dependent neuronal cell death by acidosis.

PubMed

Zhang, Jian; Li, Xiaoling; Kwansa, Herman; Kim, Yun Tai; Yi, Liye; Hong, Gina; Andrabi, Shaida A; Dawson, Valina L; Dawson, Ted M; Koehler, Raymond C; Yang, Zeng-Jin

2017-06-01

Tissue acidosis is a key component of cerebral ischemic injury, but its influence on cell death signaling pathways is not well defined. One such pathway is parthanatos, in which oxidative damage to DNA results in activation of poly(ADP-ribose) polymerase and generation of poly(ADP-ribose) polymers that trigger release of mitochondrial apoptosis-inducing factor. In primary neuronal cultures, we first investigated whether acidosis per sé is capable of augmenting parthanatos signaling initiated pharmacologically with the DNA alkylating agent, N-methyl- N'-nitro- N-nitrosoguanidine. Exposure of neurons to medium at pH 6.2 for 4 h after N-methyl- N'-nitro- N-nitrosoguanidine washout increased intracellular calcium and augmented the N-methyl- N'-nitro- N-nitrosoguanidine-evoked increase in poly(ADP-ribose) polymers, nuclear apoptosis-inducing factor , and cell death. The augmented nuclear apoptosis-inducing factor and cell death were blocked by the acid-sensitive ion channel-1a inhibitor, psalmotoxin. In vivo, acute hyperglycemia during transient focal cerebral ischemia augmented tissue acidosis, poly(ADP-ribose) polymers formation, and nuclear apoptosis-inducing factor , which was attenuated by a poly(ADP-ribose) polymerase inhibitor. Infarct volume from hyperglycemic ischemia was decreased in poly(ADP-ribose) polymerase 1-null mice. Collectively, these results demonstrate that acidosis can directly amplify neuronal parthanatos in the absence of ischemia through acid-sensitive ion channel-1a . The results further support parthanatos as one of the mechanisms by which ischemia-associated tissue acidosis augments cell death.

Acute glucose starvation activates the nuclear localization signal of a stress-specific yeast transcription factor

PubMed Central

Görner, Wolfram; Durchschlag, Erich; Wolf, Julia; Brown, Elizabeth L.; Ammerer, Gustav; Ruis, Helmut; Schüller, Christoph

2002-01-01

In yeast, environmental conditions control the transcription factor Msn2, the nuclear accumulation and function of which serve as a sensitive indicator of nutrient availablity and environmental stress load. We show here that the nuclear localization signal (NLS) of Msn2 is a direct target of cAMP-dependent protein kinase (cAPK). Genetic analysis suggests that Msn2-NLS function is inhibited by phosphorylation and activated by dephosphorylation. Msn2-NLS function is unaffected by many stress conditions that normally induce nuclear accumulation of full-length Msn2. The Msn2-NLS phosphorylation status is, however, highly sensitive to carbohydrate fluctuations during fermentative growth. Dephosphorylation occurs in >2 min after glucose withdrawal but the effect is reversed rapidly by refeeding with glucose. This response to glucose depletion is due to changes in cAPK activity rather than an increase in protein phosphatase activity. Surprisingly, the classical glucose-sensing systems are not connected to this rapid response system. Our results further imply that generic stress signals do not cause short-term depressions in cAPK activity. They operate on Msn2 by affecting an Msn5-dependent nuclear export and/or retention mechanism. PMID:11782433

Genetics Home Reference: familial cylindromatosis

MedlinePlus

... instructions for making a protein that helps regulate nuclear factor-kappa-B. Nuclear factor-kappa-B is a group of related ... to certain signals. In regulating the action of nuclear factor-kappa-B, the CYLD protein allows cells ...

Comparative analysis of proton- and neutron-halo breakups

NASA Astrophysics Data System (ADS)

Mukeru, B.

2018-06-01

A detailed analysis of the proton- and neutron-halo breakup cross sections is presented. Larger neutron-halo breakup cross sections than proton-halo breakup cross sections are obtained. This is found to be mainly due to the projectile structure, namely the ground state wave function and the dipole electric response function. It is also found that the continuum–continuum couplings are stronger in the proton-halo breakup than in the neutron-halo breakup. The increase of proton- and neutron-halo ground state separation energy slightly strengthens these couplings in the proton- and neutron-halo total and nuclear breakups, while they are weakened in the proton- and neutron-halo Coulomb breakups. The Coulomb-nuclear interference remains strongly destructive in both proton- and neutron-halo breakups and this is independent of the ground state separation energy. The results also show that the increase of the neutron-halo ground state separation energy decreases significantly the agreement between the proton- and neutron-halo breakup cross sections, both qualitatively and quantitatively. It is obtained that when the proton-halo ground state separation energy is increased by a factor of 4.380, the proton-halo breakup cross section is reduced by a factor of 4.392, indicating a clear proportionality. However, when the neutron-halo ground state separation energy is increased by the same factor, the neutron-halo total breakup cross section is reduced by a factor of 8.522.

The contribution of hypothalamic neuroendocrine, neuroplastic and neuroinflammatory processes to lipopolysaccharide-induced depressive-like behaviour in female and male rats: Involvement of glucocorticoid receptor and C/EBP-β.

PubMed

Adzic, Miroslav; Djordjevic, Jelena; Mitic, Milos; Brkic, Zeljka; Lukic, Iva; Radojcic, Marija

2015-09-15

Peripheral inflammation induced by lipopolysaccharide (LPS) causes behavioural changes indicative for depression. The possible mechanisms involve the interference with neuroinflammatory, neuroendocrine, and neurotrophic processes. Apart from heterogeneity in the molecular background, sexual context may be another factor relevant to the manifestation of mood disturbances upon an immune challenge. We investigated sex-dependent effects of a 7-day LPS treatment of adult Wistar rats on depressive-like behaviour and their relation with hypothalamic neuroendocrine factor, corticotrophin-releasing hormone (CRH), proplastic brain-derived neurotropic factor (BDNF), pro-inflammatory cyclooxygenase-2 (COX-2) and nuclear factor kappa beta (NFkB). Also, their regulators, the glucocorticoid receptor (GR) and CCAAT enhancer-binding protein (C/EBP) β were followed. LPS induced depressive-like behaviour in females was associated with the increased hypothalamic CRH and decreased BDNF, but not with COX-2. These changes were paralleled by an increase in nuclear GR, NFkB and 20 kDa C/EBPβ. LPS also altered behaviour in males and increased CRH expression, but in contrast to females, this was accompanied with the elevated COX-2, accumulation of cytosolic GR and elevated nuclear 38 kDa C/EBPβ and NFkB. In conclusion, depressive-like phenotype induced by LPS in both sexes emerges from similar HPA axis activation and sex-specific alterations of hypothalamic molecular signalling: in males it is related to compromised control of neuroinflamation connected with cytoplasmic GR retention, while in females it is related to diminished proplastic capacity of BDNF. Sex-dependent mechanisms by which inflammation alters hypothalamic processes and cause pathological behaviour in animals, could be operative in the treatment of depression-related brain inflammation. Copyright © 2015 Elsevier B.V. All rights reserved.

Effect of nuclear power on CO₂ emission from power plant sector in Iran.

PubMed

Kargari, Nargess; Mastouri, Reza

2011-01-01

It is predicted that demand for electricity in Islamic Republic of Iran will continue to increase dramatically in the future due to the rapid pace of economic development leading to construction of new power plants. At the present time, most of electricity is generated by burning fossil fuels which result in emission of great deal of pollutants and greenhouse gases (GHG) such as SO₂, NOx, and CO₂. The power industry is the largest contributor to these emissions. Due to minimal emission of GHG by renewable and nuclear power plants, they are most suitable replacements for the fossil-fueled power plants. However, the nuclear power plants are more suitable than renewable power plants in providing baseload electricity. The Bushehr Nuclear Power Plant, the only nuclear power plant of Iran, is expected to start operation in 2010. This paper attempts to interpret the role of Bushehr nuclear power plant (BNPP) in CO₂ emission trend of power plant sector in Iran. In order to calculate CO₂ emissions from power plants, National CO₂ coefficients have been used. The National CO₂ emission coefficients are according to different fuels (natural gas, fuels gas, fuel oil). By operating Bushehr Nuclear Power Plant in 2010, nominal capacity of electricity generation in Iran will increase by about 1,000 MW, which increases the electricity generation by almost 7,000 MWh/year (it is calculated according to availability factor and nominal capacity of BNPP). Bushehr Nuclear Power Plant will decrease the CO₂ emission in Iran power sector, by about 3% in 2010.

Karyopherin alpha 1 regulates satellite cell proliferation and survival by modulating nuclear import

PubMed Central

Choo, Hyo-Jung; Cutler, Alicia; Rother, Franziska; Bader, Michael; Pavlath, Grace K.

2016-01-01

Satellite cells are stem cells with an essential role in skeletal muscle repair. Precise regulation of gene expression is critical for proper satellite cell quiescence, proliferation, differentiation and self -renewal. Nuclear proteins required for gene expression are dependent on the nucleocytoplasmic transport machinery to access to nucleus, however little is known about regulation of nuclear transport in satellite cells. The best characterized nuclear import pathway is classical nuclear import which depends on a classical nuclear localization signal (cNLS) in a cargo protein and the heterodimeric import receptors, karyopherin alpha (KPNA) and beta (KPNB). Multiple KPNA1 paralogs exist and can differ in importing specific cNLS proteins required for cell differentiation and function. We show that transcripts for six Kpna paralogs underwent distinct changes in mouse satellite cells during muscle regeneration accompanied by changes in cNLS proteins in nuclei. Depletion of KPNA1, the most dramatically altered KPNA, caused satellite cells in uninjured muscle to prematurely activate, proliferate and undergo apoptosis leading to satellite cell exhaustion with age. Increased proliferation of satellite cells led to enhanced muscle regeneration at early stages of regeneration. In addition, we observed impaired nuclear localization of two key KPNA1 cargo proteins: p27, a cyclin-dependent kinase inhibitor associated with cell cycle control and lymphoid enhancer factor 1, a critical co-transcription factor for β-catenin. These results indicate that regulated nuclear import of proteins by KPNA1 is critical for satellite cell proliferation and survival and establish classical nuclear import as a novel regulatory mechanism for controlling satellite cell fate. PMID:27434733

L-2-Oxothiazolidine-4-Carboxylic Acid or α-Lipoic Acid Attenuates Airway Remodeling: Involvement of Nuclear Factor-κB (NF-κB), Nuclear Factor Erythroid 2p45-Related Factor-2 (Nrf2), and Hypoxia-Inducible Factor (HIF)

PubMed Central

Park, Seoung Ju; Lee, Kyung Sun; Lee, Su Jeong; Kim, So Ri; Park, Seung Yong; Jeon, Myoung Shin; Lee, Heung Bum; Lee, Yong Chul

2012-01-01

Reactive oxygen species (ROS) play a crucial role in the pathogenesis of acute and chronic respiratory diseases. Antioxidants have been found to ameliorate airway inflammation and hyperresponsiveness in animal models employing short-term exposure to allergen. However, little data are available on the effect of antioxidants on airway remodeling and signaling pathways in chronic asthma. In the present study, we used a long-term exposure murine model of allergic airway disease to evaluate the effects of an antioxidant, L-2-oxothiazolidine-4-carboxylic acid (OTC) or α-lipoic acid (LA) on airway remodeling, focusing on the ROS-related hypoxia-inducible signaling. Long-term challenge of ovalbumin (OVA) increased ROS production, airway inflammation, and airway hyperresponsiveness, and developed features of airway remodeling such as excessive mucus secretion, subepithelial fibrosis, and thickening of the peribronchial smooth muscle layer. Administration of OTC or LA reduced these features of asthma, including airway remodeling, which was accompanied by suppression of transforming growth factor-β1, vascular endothelial growth factor, and T-helper 2 cytokines. In addition, OVA-induced activation of nuclear factor-κB (NF-κB), nuclear factor erythroid 2p45-related factor-2 (Nrf2), hypoxia-inducible factor (HIF)-1α, and HIF-2α was reduced by OTC or LA. Our results also showed that OTC or LA down-regulated phosphoinositide 3-kinase activity and decreased phosphorylation of p38 mitogen-activated protein kinase but not extracellular signal-regulated kinase 1/2 or c-Jun N-terminal kinase. These findings demonstrate that OTC and LA can inhibit activation of NF-κB, Nrf2, and HIF, leading to attenuate allergen-induced airway remodeling. PMID:22942681

Skeletal muscle and nuclear hormone receptors: implications for cardiovascular and metabolic disease.

PubMed

Smith, Aaron G; Muscat, George E O

2005-10-01

Skeletal muscle is a major mass peripheral tissue that accounts for approximately 40% of the total body mass and a major player in energy balance. It accounts for >30% of energy expenditure, is the primary tissue of insulin stimulated glucose uptake, disposal, and storage. Furthermore, it influences metabolism via modulation of circulating and stored lipid (and cholesterol) flux. Lipid catabolism supplies up to 70% of the energy requirements for resting muscle. However, initial aerobic exercise utilizes stored muscle glycogen but as exercise continues, glucose and stored muscle triglycerides become important energy substrates. Endurance exercise increasingly depends on fatty acid oxidation (and lipid mobilization from other tissues). This underscores the importance of lipid and glucose utilization as an energy source in muscle. Consequently skeletal muscle has a significant role in insulin sensitivity, the blood lipid profile, and obesity. Moreover, caloric excess, obesity and physical inactivity lead to skeletal muscle insulin resistance, a risk factor for the development of type II diabetes. In this context skeletal muscle is an important therapeutic target in the battle against cardiovascular disease, the worlds most serious public health threat. Major risk factors for cardiovascular disease include dyslipidemia, hypertension, obesity, sedentary lifestyle, and diabetes. These risk factors are directly influenced by diet, metabolism and physical activity. Metabolism is largely regulated by nuclear hormone receptors which function as hormone regulated transcription factors that bind DNA and mediate the patho-physiological regulation of gene expression. Metabolism and activity, which directly influence cardiovascular disease risk factors, are primarily driven by skeletal muscle. Recently, many nuclear receptors expressed in skeletal muscle have been shown to improve glucose tolerance, insulin resistance, and dyslipidemia. Skeletal muscle and nuclear receptors are rapidly emerging as critical targets in the battle against cardiovascular disease risk factors. Understanding the function of nuclear receptors in skeletal muscle has enormous pharmacological utility for the treatment of cardiovascular disease. This review focuses on the molecular regulation of metabolism by nuclear receptors in skeletal muscle in the context of dyslipidemia and cardiovascular disease.

Data feature: 1996 world nuclear electricity production

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

1997-12-01

Detailed data on electricity supplied by nuclear power reactors in 1996 are provided. Figures from the International Atomic Energy Agency indicate that a total of 32 countries worldwide were operating 441 nuclear power plants with an installed capacity of 350,411 GWe, and that 36 commercial nuclear power plant units in 14 different countries with an aggregate installed capacity of 27,928 GWe were under construction. Worldwide nuclear generated electricity increased by 3.6% from 1995 to 1996, providing 17.3% of the world`s electricity production. Data for individual countries and regional totals, including generation and consumption data by source, are provided for Westernmore » Europe, Eastern Europe, the Commonwealth of Independent States, the Far East, Canada, and the United States. Other information provided includes 1996 commercial startups, decommissioning, reactor load factors, imports and exports, and gross electricity production.« less

Reversal of ethanol-induced hepatotoxicity by cinnamic and syringic acids in mice.

PubMed

Yan, Sheng-Lei; Wang, Zhi-Hong; Yen, Hsiu-Fang; Lee, Yi-Ju; Yin, Mei-Chin

2016-12-01

Ethanol was used to induce acute hepatotoxicity in mice. Effects of cinnamic acid (CA) and syringic acid (SA) post-intake for hepatic recovery from alcoholic injury was investigated. Ethanol treated mice were supplied by CA or SA at 40 or 80 mg/kg BW/day for 5 days. Results showed that ethanol stimulated protein expression of CYP2E1, p47 phox , gp91 phox , cyclooxygenase-2 and nuclear factor kappa B in liver. CA or SA post-intake restricted hepatic expression of these molecules. Ethanol suppressed nuclear factor erythroid 2-related factor (Nrf2) expression, and CA or SA enhanced Nrf2 expression in cytosolic and nuclear fractions. Ethanol increased the release of reactive oxygen species, oxidized glutathione, interleukin-6, tumor necrosis factor-alpha, nitric acid and prostaglandin E 2 . CA or SA lowered hepatic production of these oxidative and inflammatory factors. Histological data revealed that ethanol administration caused obvious foci of inflammatory cell infiltration, and CA or SA post-intake improved hepatic inflammatory infiltration. These findings support that cinnamic acid and syringic acid are potent nutraceutical agents for acute alcoholic liver disease therapy. However, potential additive or synergistic benefits of cinnamic and syringic acids against ethanol-induced hepatotoxicity need to be investigated. Copyright © 2016 Elsevier Ltd. All rights reserved.

Prenatal exposure of mice to diethylstilbestrol disrupts T-cell differentiation by regulating Fas/Fas ligand expression through estrogen receptor element and nuclear factor-κB motifs.

PubMed

Singh, Narendra P; Singh, Udai P; Nagarkatti, Prakash S; Nagarkatti, Mitzi

2012-11-01

Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effect of prenatal exposure to DES on thymocyte differentiation involving apoptotic pathways. Prenatal DES exposure caused thymic atrophy, apoptosis, and up-regulation of Fas and Fas ligand (FasL) expression in thymocytes. To examine the mechanism underlying DES-mediated regulation of Fas and FasL, we performed luciferase assays using T cells transfected with luciferase reporter constructs containing full-length Fas or FasL promoters. There was significant luciferase induction in the presence of Fas or FasL promoters after DES exposure. Further analysis demonstrated the presence of several cis-regulatory motifs on both Fas and FasL promoters. When DES-induced transcription factors were analyzed, estrogen receptor element (ERE), nuclear factor κB (NF-κB), nuclear factor of activated T cells (NF-AT), and activator protein-1 motifs on the Fas promoter, as well as ERE, NF-κB, and NF-AT motifs on the FasL promoter, showed binding affinity with the transcription factors. Electrophoretic mobility-shift assays were performed to verify the binding affinity of cis-regulatory motifs of Fas or FasL promoters with transcription factors. There was shift in mobility of probes (ERE or NF-κB2) of both Fas and FasL in the presence of nuclear proteins from DES-treated cells, and the shift was specific to DES because these probes failed to shift their mobility in the presence of nuclear proteins from vehicle-treated cells. Together, the current study demonstrates that prenatal exposure to DES triggers significant alterations in apoptotic molecules expressed on thymocytes, which may affect T-cell differentiation and cause long-term effects on the immune functions.

Prenatal Exposure of Mice to Diethylstilbestrol Disrupts T-Cell Differentiation by Regulating Fas/Fas Ligand Expression through Estrogen Receptor Element and Nuclear Factor-κB Motifs

PubMed Central

Singh, Narendra P.; Singh, Udai P.; Nagarkatti, Prakash S.

2012-01-01

Prenatal exposure to diethylstilbestrol (DES) is known to cause altered immune functions and increased susceptibility to autoimmune disease in humans. In the current study, we investigated the effect of prenatal exposure to DES on thymocyte differentiation involving apoptotic pathways. Prenatal DES exposure caused thymic atrophy, apoptosis, and up-regulation of Fas and Fas ligand (FasL) expression in thymocytes. To examine the mechanism underlying DES-mediated regulation of Fas and FasL, we performed luciferase assays using T cells transfected with luciferase reporter constructs containing full-length Fas or FasL promoters. There was significant luciferase induction in the presence of Fas or FasL promoters after DES exposure. Further analysis demonstrated the presence of several cis-regulatory motifs on both Fas and FasL promoters. When DES-induced transcription factors were analyzed, estrogen receptor element (ERE), nuclear factor κB (NF-κB), nuclear factor of activated T cells (NF-AT), and activator protein-1 motifs on the Fas promoter, as well as ERE, NF-κB, and NF-AT motifs on the FasL promoter, showed binding affinity with the transcription factors. Electrophoretic mobility-shift assays were performed to verify the binding affinity of cis-regulatory motifs of Fas or FasL promoters with transcription factors. There was shift in mobility of probes (ERE or NF-κB2) of both Fas and FasL in the presence of nuclear proteins from DES-treated cells, and the shift was specific to DES because these probes failed to shift their mobility in the presence of nuclear proteins from vehicle-treated cells. Together, the current study demonstrates that prenatal exposure to DES triggers significant alterations in apoptotic molecules expressed on thymocytes, which may affect T-cell differentiation and cause long-term effects on the immune functions. PMID:22888145

Fascin regulates nuclear actin during Drosophila oogenesis

PubMed Central

Kelpsch, Daniel J.; Groen, Christopher M.; Fagan, Tiffany N.; Sudhir, Sweta; Tootle, Tina L.

2016-01-01

Drosophila oogenesis provides a developmental system with which to study nuclear actin. During Stages 5–9, nuclear actin levels are high in the oocyte and exhibit variation within the nurse cells. Cofilin and Profilin, which regulate the nuclear import and export of actin, also localize to the nuclei. Expression of GFP-tagged Actin results in nuclear actin rod formation. These findings indicate that nuclear actin must be tightly regulated during oogenesis. One factor mediating this regulation is Fascin. Overexpression of Fascin enhances nuclear GFP-Actin rod formation, and Fascin colocalizes with the rods. Loss of Fascin reduces, whereas overexpression of Fascin increases, the frequency of nurse cells with high levels of nuclear actin, but neither alters the overall nuclear level of actin within the ovary. These data suggest that Fascin regulates the ability of specific cells to accumulate nuclear actin. Evidence indicates that Fascin positively regulates nuclear actin through Cofilin. Loss of Fascin results in decreased nuclear Cofilin. In addition, Fascin and Cofilin genetically interact, as double heterozygotes exhibit a reduction in the number of nurse cells with high nuclear actin levels. These findings are likely applicable beyond Drosophila follicle development, as the localization and functions of Fascin and the mechanisms regulating nuclear actin are widely conserved. PMID:27535426

Genetics Home Reference: anhidrotic ectodermal dysplasia with immune deficiency

MedlinePlus

... The proteins produced from these two genes regulate nuclear factor-kappa-B. Nuclear factor-kappa-B is a group of related ... proteins with impaired function, which reduces activation of nuclear factor-kappa-B. These changes disrupt certain signaling ...

Influence of the Great East Japan Earthquake and the Fukushima Daiichi nuclear disaster on the birth weight of newborns in Fukushima Prefecture: Fukushima Health Management Survey.

PubMed

Yasuda, Shun; Kyozuka, Hyo; Nomura, Yasuhisa; Fujimori, Keiya; Goto, Aya; Yasumura, Seiji; Hata, Kennichi; Ohira, Tetsuya; Abe, Masafumi

2017-12-01

The Great East Japan Earthquake and Fukushima Daiichi nuclear disaster occurred on 11 March 2011. We investigated the incidence of SGA (small for gestational age) in the Fukushima Prefecture in newborns delivered by women who were pregnant at the time of the disasters and identified any risk factors for SGA. Subjects were women who were pregnant at the time of the disasters. Questionnaires were sent to the women who lived in the Hamadori area (seaside and near to the nuclear power plant) at the time of the disasters as well as to a control group of women who lived outside the Hamadori area. The incidence of SGA was compared. Logistic regression analysis was performed to identify the risk factors for SGA. In total, 325(5.6%) women had infants with SGA. Neither area nor the trimester of pregnancy at the time of the disasters influenced the incidence of SGA. Pregnancy-induced hypertension (PIH) was higher in the SGA group. PIH was found to be an independent risk factor for SGA. We found no evidence that the Great East Japan Earthquake and the Fukushima Daiichi nuclear disaster increased the incidence of SGA in the Fukushima Prefecture.

Automated work packages architecture: An initial set of human factors and instrumentation and controls requirements

DOE Office of Scientific and Technical Information (OSTI.GOV)

Agarwal, Vivek; Oxstrand, Johanna H.; Le Blanc, Katya L.

The work management process in current fleets of national nuclear power plants is so highly dependent on large technical staffs and quality of work instruction, i.e., paper-based, that this puts nuclear energy at somewhat of a long-term economic disadvantage and increase the possibility of human errors. Technologies like mobile portable devices and computer-based procedures can play a key role in improving the plant work management process, thereby increasing productivity and decreasing cost. Automated work packages are a fundamentally an enabling technology for improving worker productivity and human performance in nuclear power plants work activities because virtually every plant work activitymore » is accomplished using some form of a work package. As part of this year’s research effort, automated work packages architecture is identified and an initial set of requirements identified, that are essential and necessary for implementation of automated work packages in nuclear power plants.« less

Up-regulation of Toll-like receptor 4/nuclear factor-kappaB signaling is associated with enhanced adipogenesis and insulin resistance in fetal skeletal muscle of obese sheep at late gestation.

PubMed

Yan, Xu; Zhu, Mei J; Xu, Wei; Tong, Jun F; Ford, Stephen P; Nathanielsz, Peter W; Du, Min

2010-01-01

Maternal obesity is increasing at an alarming rate. We previously showed that maternal obesity induces an inflammatory response and enhances adipogenesis in fetal skeletal muscle at midgestation. The objective of this study was to evaluate effects of maternal obesity on adipogenesis, inflammatory signaling, and insulin pathways at late gestation when ovine fetal skeletal muscle matures. Nonpregnant ewes were assigned to a control diet (Con, fed 100% of National Research Council nutrient recommendations, n = 6) or obesogenic diet (OB, fed 150% of National Research Council recommendations, n = 6) from 60 d before to 135 d after conception (term 148 d) when the fetal semitendenosus skeletal muscle was sampled. Expression of the adipogenic marker, peroxisome proliferator-activated receptor-gamma, was increased in OB compared with Con fetal semitendenosus muscle, indicating up-regulation of adipogenesis. More intramuscular adipocytes were observed in OB muscle. Phosphorylation of inhibitor-kappaB kinase-alpha/beta and nuclear factor-kappaB RelA/p65 were both increased in OB fetal muscle, indicating activation of nuclear factor-kappaB pathway. Phosphorylation of c-Jun N-terminal kinase and c-Jun (at Ser 63 and Ser 73) was also elevated. Toll-like receptor 4 expression was higher in OB than Con fetal muscle. Moreover, despite higher insulin concentrations in OB vs. Con fetal plasma (2.89 +/- 0.53 vs. 1.06 +/- 0.52 ng/ml; P < 0.05), phosphorylation of protein kinase B at Ser 473 was reduced, indicating insulin resistance. In conclusion, our data show maternal obesity-induced inflammatory signaling in late gestation fetal muscle, which correlates with increased im adipogenesis and insulin resistance, which may predispose offspring to later-life obesity and diabetes.

The effects of chromium picolinate and chromium histidinate administration on NF-κB and Nrf2/HO-1 pathway in the brain of diabetic rats.

PubMed

Sahin, Kazim; Tuzcu, Mehmet; Orhan, Cemal; Gencoglu, Hasan; Ulas, Mustafa; Atalay, Mustafa; Sahin, Nurhan; Hayirli, Armagan; Komorowski, James R

2012-12-01

The objective of this experiment was to investigate the effects of supplemental chromium picolinate (CrPic) and chromium histidinate (CrHis) on nuclear factor-kappa B (NF-κB p65) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathway in diabetic rat brain. Nondiabetic (n = 45) and diabetic (n = 45) male Wistar rats were either not supplemented or supplemented with CrPic or CrHis via drinking water to consume 8 μg elemental chromium (Cr) per day for 12 weeks. Diabetes was induced by streptozotocin injection (40 mg/kg i.p., for 2 weeks) and maintained by high-fat feeding (40 %). Diabetes was associated with increases in cerebral NF-κB and 4-hydroxynonenal (4-HNE) protein adducts and decreased in cerebral nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (IκBα) and Nrf2 levels. Both Cr chelates were effective to decrease levels of NF-κB and 4-HNE protein adducts and to increase levels of IκBα and Nrf2 in the brain of diabetic rats. However, responses of these increases and decreases were more notable when Cr was supplemented as CrHis than as CrPic. In conclusion, Cr may play a protective role in cerebral antioxidant defense system in diabetic subjects via the Nrf2 pathway by reducing inflammation through NF-κB p65 inhibition. Histidinate form of Cr was superior to picolinate form of Cr in reducing NF-κB expression and increasing Nrf2 expression in the brain of diabetic rats.

The nuclear lamina promotes telomere aggregation and centromere peripheral localization during senescence of human mesenchymal stem cells.

PubMed

Raz, Vered; Vermolen, Bart J; Garini, Yuval; Onderwater, Jos J M; Mommaas-Kienhuis, Mieke A; Koster, Abraham J; Young, Ian T; Tanke, Hans; Dirks, Roeland W

2008-12-15

Ex vivo, human mesenchymal stem cells (hMSCs) undergo spontaneous cellular senescence after a limited number of cell divisions. Intranuclear structures of the nuclear lamina were formed in senescent hMSCs, which are identified by the presence of Hayflick-senescence-associated factors. Notably, spatial changes in lamina shape were observed before the Hayflick senescence-associated factors, suggesting that the lamina morphology can be used as an early marker to identify senescent cells. Here, we applied quantitative image-processing tools to study the changes in nuclear architecture during cell senescence. We found that centromeres and telomeres colocalised with lamina intranuclear structures, which resulted in a preferred peripheral distribution in senescent cells. In addition, telomere aggregates were progressively formed during cell senescence. Once formed, telomere aggregates showed colocalization with gamma-H2AX but not with TERT, suggesting that telomere aggregates are sites of DNA damage. We also show that telomere aggregation is associated with lamina intranuclear structures, and increased telomere binding to lamina proteins is found in cells expressing lamina mutants that lead to increases in lamina intranuclear structures. Moreover, three-dimensional image processing revealed spatial overlap between telomere aggregates and lamina intranuclear structures. Altogether, our data suggest a mechanical link between changes in lamina spatial organization and the formation of telomere aggregates during senescence of hMSCs, which can possibly contribute to changes in nuclear activity during cell senescence.

Geographic variation in U.S. thyroid cancer incidence and a cluster near nuclear reactors in New Jersey, New York, and Pennsylvania.

PubMed

Mangano, Joseph J

2009-01-01

In the United States, thyroid cancer incidence (along with liver cancer) is increasing more rapidly than any other malignancy, rising nearly threefold from 1980 to 2006. Improved diagnosis has been proposed by some as the major reason for this change, while others contend that additional factors also account for the increase. Among U.S. states, 2001-2005 age-adjusted thyroid cancer incidence rates vary from 5.4 to 12.8 per 100,000. County-specific incidence data, available for the first time, document that most U.S. counties with the highest thyroid cancer incidence are in a contiguous area of eastern Pennsylvania, New Jersey, and southern New York State. Exposures to radioactive iodine emissions from 16 nuclear power reactors within a 90-mile radius in this area indicate that these emissions are a likely etiological factor in rising thyroid cancer incidence rates.

Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER).

PubMed

Ma, Shao; Yin, Ning; Qi, Xiaomei; Pfister, Sandra L; Zhang, Mei-Jie; Ma, Rong; Chen, Guan

2015-05-30

Protein-protein interactions can increase or decrease its therapeutic target activity and the determining factors involved, however, are largely unknown. Here, we report that tyrosine-dephosphorylation of epidermal growth factor receptor (EGFR) increases its therapeutic target activity by disrupting its interaction with estrogen receptor (ER). Protein tyrosine phosphatase H1 (PTPH1) dephosphorylates the tyrosine kinase EGFR, disrupts its interaction with the nuclear receptor ER, and increases breast cancer sensitivity to small molecule tyrosine kinase inhibitors (TKIs). These effects require PTPH1 catalytic activity and its interaction with EGFR, suggesting that the phosphatase may increase the sensitivity by dephosphorylating EGFR leading to its dissociation with ER. Consistent with this notion, a nuclear-localization defective ER has a higher EGFR-binding activity and confers the resistance to TKI-induced growth inhibition. Additional analysis show that PTPH1 stabilizes EGFR, stimulates the membranous EGFR accumulation, and enhances the growth-inhibitory activity of a combination therapy of TKIs with an anti-estrogen. Since EGFR and ER both are substrates for PTPH1 in vitro and in intact cells, these results indicate that an inhibitory EGFR-ER protein complex can be switched off through a competitive enzyme-substrate binding. Our results would have important implications for the treatment of breast cancer with targeted therapeutics.

Respiratory syncytial virus M2-1 protein induces the activation of nuclear factor kappa B

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reimers, Kerstin; Buchholz, Katja; Werchau, Hermann

2005-01-20

Respiratory syncytial virus (RSV) induces the production of a number of cytokines and chemokines by activation of nuclear factor kappa B (NF-{kappa}B). The activation of NF-{kappa}B has been shown to depend on viral replication in the infected cells. In this study, we demonstrate that expression of RSV M2-1 protein, a transcriptional processivity and anti-termination factor, is sufficient to activate NF-{kappa}B in A549 cells. Electromobility shift assays show increased NF-{kappa}B complexes in the nuclei of M2-1-expressing cells. M2-1 protein is found in nuclei of M2-1-expressing cells and in RSV-infected cells. Co-immunoprecipitations of nuclear extracts of M2-1-expressing cells and of RSV-infected cellsmore » revealed an association of M2-1 with Rel A protein. Furthermore, the activation of NF-{kappa}B depends on the C-terminus of the RSV M2-1 protein, as shown by NF-{kappa}B-induced gene expression of a reporter gene construct.« less

The small-x gluon distribution in centrality biased pA and pp collisions

NASA Astrophysics Data System (ADS)

Dumitru, Adrian; Kapilevich, Gary; Skokov, Vladimir

2018-06-01

The nuclear modification factor RpA (pT) provides information on the small-x gluon distribution of a nucleus at hadron colliders. Several experiments have recently measured the nuclear modification factor not only in minimum bias but also for central pA collisions. In this paper we analyze the bias on the configurations of soft gluon fields introduced by a centrality selection via the number of hard particles. Such bias can be viewed as reweighting of configurations of small-x gluons. We find that the biased nuclear modification factor QpA (pT) for central collisions is above RpA (pT) for minimum bias events, and that it may redevelop a "Cronin peak" even at small x. The magnitude of the peak is predicted to increase approximately like 1 /A⊥ ν, ν ∼ 0.6 ± 0.1, if one is able to select more compact configurations of the projectile proton where its gluons occupy a smaller transverse area A⊥. We predict an enhanced Qpp (pT) - 1 ∼ 1 /(pT2) ν and a Cronin peak even for central pp collisions.

Imaging analysis of nuclear antiviral factors through direct detection of incoming adenovirus genome complexes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Komatsu, Tetsuro; Department of Infection Biology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575; Will, Hans

2016-04-22

Recent studies involving several viral systems have highlighted the importance of cellular intrinsic defense mechanisms through nuclear antiviral proteins that restrict viral propagation. These factors include among others components of PML nuclear bodies, the nuclear DNA sensor IFI16, and a potential restriction factor PHF13/SPOC1. For several nuclear replicating DNA viruses, it was shown that these factors sense and target viral genomes immediately upon nuclear import. In contrast to the anticipated view, we recently found that incoming adenoviral genomes are not targeted by PML nuclear bodies. Here we further explored cellular responses against adenoviral infection by focusing on specific conditions asmore » well as additional nuclear antiviral factors. In line with our previous findings, we show that neither interferon treatment nor the use of specific isoforms of PML nuclear body components results in co-localization between incoming adenoviral genomes and the subnuclear domains. Furthermore, our imaging analyses indicated that neither IFI16 nor PHF13/SPOC1 are likely to target incoming adenoviral genomes. Thus our findings suggest that incoming adenoviral genomes may be able to escape from a large repertoire of nuclear antiviral mechanisms, providing a rationale for the efficient initiation of lytic replication cycle. - Highlights: • Host nuclear antiviral factors were analyzed upon adenovirus genome delivery. • Interferon treatments fail to permit PML nuclear bodies to target adenoviral genomes. • Neither Sp100A nor B targets adenoviral genomes despite potentially opposite roles. • The nuclear DNA sensor IFI16 does not target incoming adenoviral genomes. • PHF13/SPOC1 targets neither incoming adenoviral genomes nor genome-bound protein VII.« less

Quercetin Reduces Tumor Necrosis Factor Alpha-Induced Muscle Atrophy by Upregulation of Heme Oxygenase-1.

PubMed

Kim, Yeji; Kim, Chu-Sook; Joe, Yeonsoo; Chung, Hun Taeg; Ha, Tae Youl; Yu, Rina

2018-06-01

The inflammatory cytokine tumor necrosis factor α (TNFα), upregulated in the obese condition, promotes protein degradation and is implicated in obesity-related skeletal muscle atrophy and age-related sarcopenia. Quercetin, a flavonoid, elicits antioxidative and anti-inflammatory activities. In this study, we investigated the effect of quercetin on TNFα-induced skeletal muscle atrophy as well as its potential mechanism of action. In this study, we observed that quercetin suppressed expression of TNFα-induced atrophic factors such as MAFbx/atrogin-1 and MuRF1 in myotubes, and it enhanced heme oxygenase-1 (HO-1) protein level accompanied by increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in myotubes. The HO-1 inhibitor ZnPP suppressed the inhibitory actions of quercetin on TNFα-induced atrophic responses and degradation of IκB-α in myotubes. Moreover, quercetin supplementation to high-fat diet-fed obese mice inhibited obesity-induced atrophic responses in skeletal muscle, accompanied by upregulation of HO-1 and inactivation of nuclear factor-kappa B (NF-κB), and the quercetin actions were attenuated in Nrf2-deficient mice. These findings suggest that quercetin protects against TNFα-induced muscle atrophy under obese conditions through Nrf2-mediated HO-1 induction accompanied by inactivation of NF-κB. Quercetin may be used as a dietary supplement to protect against obesity-induced skeletal muscle atrophy.

An Abnormal Nitric Oxide Metabolism Contributes to Brain Oxidative Stress in the Mouse Model for the Fragile X Syndrome, a Possible Role in Intellectual Disability

PubMed Central

Lima-Cabello, Elena; Garcia-Guirado, Francisco; Calvo-Medina, Rocio; el Bekay, Rajaa; Perez-Costillas, Lucia; Quintero-Navarro, Carolina; Sanchez-Salido, Lourdes

2016-01-01

Background. Fragile X syndrome is the most common genetic cause of mental disability. Although many research has been performed, the mechanism underlying the pathogenesis is unclear and needs further investigation. Oxidative stress played major roles in the syndrome. The aim was to investigate the nitric oxide metabolism, protein nitration level, the expression of NOS isoforms, and furthermore the activation of the nuclear factor NF-κB-p65 subunit in different brain areas on the fragile X mouse model. Methods. This study involved adult male Fmr1-knockout and wild-type mice as controls. We detected nitric oxide metabolism and the activation of the nuclear factor NF-κBp65 subunit, comparing the mRNA expression and protein content of the three NOS isoforms in different brain areas. Results. Fmr1-KO mice showed an abnormal nitric oxide metabolism and increased levels of protein tyrosine nitrosylation. Besides that, nuclear factor NF-κB-p65 and inducible nitric oxide synthase appeared significantly increased in the Fmr1-knockout mice. mRNA and protein levels of the neuronal nitric oxide synthase appeared significantly decreased in the knockout mice. However, the epithelial nitric oxide synthase isoform displayed no significant changes. Conclusions. These data suggest the potential involvement of an abnormal nitric oxide metabolism in the pathogenesis of the fragile X syndrome. PMID:26788253

Regulation of Rat Hepatic L-Pyruvate Kinase Promoter Composition and Activity by Glucose, n-3 Polyunsaturated Fatty Acids, and Peroxisome Proliferator-activated Receptor-α Agonist*S

PubMed Central

Xu, Jinghua; Christian, Barbara; Jump, Donald B.

2009-01-01

Carbohydrate regulatory element-binding protein (ChREBP), MAX-like factor X(MLX), and hepatic nuclear factor-4α (HNF-4α)are key transcription factors involved in the glucose-mediated induction of hepatic L-type pyruvate kinase (L-PK) gene transcription. n-3 polyunsaturated fatty acids (PUFA) and WY14643 (peroxisome proliferator-activated receptor α (PPARα) agonist) interfere with glucose-stimulated L-PK gene transcription in vivo and in rat primary hepatocytes. Feeding rats a diet containing n-3 PUFA or WY14643 suppressed hepatic mRNAL-PK but did not suppress hepatic ChREBP or HNF-4α nuclear abundance. Hepatic MLX nuclear abundance, however, was suppressed by n-3 PUFA but not WY14643. In rat primary hepatocytes, glucose-stimulated accumulation of mRNALPK and L-PK promoter activity correlated with increased ChREBP nuclear abundance. This treatment also increased L-PK promoter occupancy by RNA polymerase II (RNA pol II), acetylated histone H3 (Ac-H3), and acetylated histone H4 (Ac-H4) but did not significantly impact L-PK promoter occupancy by ChREBP or HNF-4α. Inhibition of L-PK promoter activity by n-3 PUFA correlated with suppressed RNA pol II, Ac-H3, and Ac-H4 occupancy on the L-PK promoter. Although n-3 PUFA transiently suppressed ChREBP and MLX nuclear abundance, this treatment did not impact ChREBP-LPK promoter interaction. HNF4α-LPK promoter interaction was transiently suppressed by n-3 PUFA. Inhibition of L-PK promoter activity by WY14643 correlated with a transient decline in ChREBP nuclear abundance and decreased Ac-H4 interaction with the L-PK promoter. WY14643, however, had no impact on MLX nuclear abundance or HNF4α-LPK promoter interaction. Although overexpressed ChREBP or HNF-4α did not relieve n-3 PUFA suppression of L-PK gene expression, overexpressed MLX fully abrogated n-3 PUFA suppression of L-PK promoter activity and mRNAL-PK abundance. Overexpressed ChREBP, but not MLX, relieved the WY14643 inhibition of L-PK. In conclusion, n-3 PUFA and WY14643/PPARα target different transcription factors to control L-PK gene transcription. MLX, the heterodimer partner for ChREBP, has emerged as a novel target for n-3 PUFA regulation. PMID:16644726

Cordyceps sinensis increases hypoxia tolerance by inducing heme oxygenase-1 and metallothionein via Nrf2 activation in human lung epithelial cells.

PubMed

Singh, Mrinalini; Tulsawani, Rajkumar; Koganti, Praveen; Chauhan, Amitabh; Manickam, Manimaran; Misra, Kshipra

2013-01-01

Cordyceps sinensis, an edible mushroom growing in Himalayan regions, is widely recognized in traditional system of medicine. In the present study, we report the efficacy of Cordyceps sinensis in facilitating tolerance to hypoxia using A549 cell line as a model system. Treatment with aqueous extract of Cordyceps sinensis appreciably attenuated hypoxia induced ROS generation, oxidation of lipids and proteins and maintained antioxidant status similar to that of controls via induction of antioxidant gene HO1 (heme oxygenase-1), MT (metallothionein) and Nrf2 (nuclear factor erythroid-derived 2-like 2). In contrast, lower level of NF κ B (nuclear factor kappaB) and tumor necrosis factor- α observed which might be due to higher levels of HO1, MT and transforming growth factor- β . Further, increase in HIF1 (hypoxia inducible factor-1) and its regulated genes; erythropoietin, vascular endothelial growth factor, and glucose transporter-1 was observed. Interestingly, Cordyceps sinensis treatment under normoxia did not regulate the expression HIF1, NF κ B and their regulated genes evidencing that Cordyceps sinensis per se did not have an effect on these transcription factors. Overall, Cordyceps sinensis treatment inhibited hypoxia induced oxidative stress by maintaining higher cellular Nrf2, HIF1 and lowering NF κ B levels. These findings provide a basis for possible use of Cordyceps sinensis in tolerating hypoxia.

Cordyceps sinensis Increases Hypoxia Tolerance by Inducing Heme Oxygenase-1 and Metallothionein via Nrf2 Activation in Human Lung Epithelial Cells

PubMed Central

Manickam, Manimaran; Misra, Kshipra

2013-01-01

Cordyceps sinensis, an edible mushroom growing in Himalayan regions, is widely recognized in traditional system of medicine. In the present study, we report the efficacy of Cordyceps sinensis in facilitating tolerance to hypoxia using A549 cell line as a model system. Treatment with aqueous extract of Cordyceps sinensis appreciably attenuated hypoxia induced ROS generation, oxidation of lipids and proteins and maintained antioxidant status similar to that of controls via induction of antioxidant gene HO1 (heme oxygenase-1), MT (metallothionein) and Nrf2 (nuclear factor erythroid-derived 2-like 2). In contrast, lower level of NFκB (nuclear factor kappaB) and tumor necrosis factor-α observed which might be due to higher levels of HO1, MT and transforming growth factor-β. Further, increase in HIF1 (hypoxia inducible factor-1) and its regulated genes; erythropoietin, vascular endothelial growth factor, and glucose transporter-1 was observed. Interestingly, Cordyceps sinensis treatment under normoxia did not regulate the expression HIF1, NFκB and their regulated genes evidencing that Cordyceps sinensis per se did not have an effect on these transcription factors. Overall, Cordyceps sinensis treatment inhibited hypoxia induced oxidative stress by maintaining higher cellular Nrf2, HIF1 and lowering NFκB levels. These findings provide a basis for possible use of Cordyceps sinensis in tolerating hypoxia. PMID:24063008

Effects of alkaloids from Sophora flavescens on osteoblasts infected with Staphylococcus aureus and osteoclasts.

PubMed

Wang, Xuping; Zheng, Rongzong; Huang, Xiaowen; Mao, Zhujun; Wang, Nani; Li, Hongyu; Wen, Chengping; Shou, Dan

2018-03-25

Chronic osteomyelitis is primarily caused by infection with Staphylococcus aureus (S. aureus). Antibiotics are commonly administered; however, it is a challenge to promote bone healing. The aim of this study was to investigate the in vitro effects of alkaloids from the herbal remedy Sophora flavescens (ASF) on rat calvarial osteoblasts (ROBs) infected with S. aureus and healthy osteoclasts. Cell proliferation and alkaline phosphatase, interleukin-6, and tumour necrosis factor-α activity was measured in infected ROBs; tartrate-resistant acid phosphatase was evaluated in osteoclasts via enzyme-linked immunosorbent assay. The mRNA and protein expression levels of bone morphogenetic protein 2, runt-related transcription factor 2, osteoprotegerin, and receptor activator of nuclear factor kappa-B ligand were assessed in infected ROBs through reverse transcription-polymerase chain reaction and western blotting analysis, respectively. Results indicated that ASF increased the viability of uninfected ROBs and infected ROBs treated with vancomycin via regulation of bone morphogenetic protein 2, runt-related transcription factor, osteoprotegerin, and receptor activator of nuclear factor kappa-B ligand mRNA and protein expression levels. In addition, the secretion of the inflammatory factor tumour necrosis factor-α was decreased and alkaline phosphatase activity was increased, inhibiting the viability of osteoclasts and tartrate-resistant acid phosphatase activity. Therefore, the herbal remedy ASF has potential as a new treatment for chronic osteomyelitis. Copyright © 2018 John Wiley & Sons, Ltd.

Thoracic vagal efferent nerve stimulation evokes substance P-induced early airway bronchonstriction and late proinflammatory and oxidative injury in the rat respiratory tract.

PubMed

Li, Ping-Chia; Li, Sheng-Chung; Lin, Yuan-Ju; Liang, Jin-Tung; Chien, Chiang-Ting; Shaw, Chen-Fu

2005-01-01

Electrical stimulation of efferent thoracic vagus nerve (TVN) evoked neurogenic inflammation in respiratory tract of atropine-treated rats by an undefined mechanism. We explored whether efferent TVN stimulation via substance P facilitates neurogenic inflammation via action of nuclear factor-kappaB (NF-kappaB) activation and reactive oxygen species (ROS) production. Our results showed that increased frequency of TVN stimulation concomitantly increased substance P-enhanced hypotension, and bronchoconstriction (increases in smooth muscle electromyographic activity and total pulmonary resistance). The enhanced SP release evoked the appearance of endothelial gap in silver-stained leaky venules, India-ink labeled extravasation, and accumulations of inflammatory cells in the respiratory tract, contributing to trachea plasma extravasation as well as increases in blood O (2)(-) and H(2)O(2) ROS amount. L-732138 (NK(1) receptor antagonist), SR-48968 (NK(2) receptor antagonist), dimethylthiourea (H(2)O(2) scavenger) or catechins (O (2)(-) and H(2)O(2) scavenger) pretreatment reduced efferent TVN stimulation-enhanced hypotension, bronchoconstriction, and plasma extravasation. Increased frequency of TVN stimulation significantly upregulated the expression of nuclear factor-kappaB (NF-kappaB) in nuclear protein and intercellular adhesion molecule-1 (ICAM-1) in total protein of the lower respiratory tract tissue. The upregulation of NF-kappaB and ICAM-1 was attenuated by NK receptor antagonist and antioxidants. In conclusion, TVN efferent stimulation increases substance P release to trigger NF-kappaB mediated ICAM-1 expression and O (2)(-) and H(2)O(2) ROS production in the respiratory tract.

Hepatocyte Nuclear Factor 4α (HNF4α) Is a Transcription Factor of Vertebrate Fatty Acyl Desaturase Gene as Identified in Marine Teleost Siganus canaliculatus

PubMed Central

Dong, Yewei; Wang, Shuqi; Chen, Junliang; Zhang, Qinghao; Liu, Yang; You, Cuihong; Monroig, Óscar; Tocher, Douglas R.; Li, Yuanyou

2016-01-01

Rabbitfish Siganus canaliculatus was the first marine teleost demonstrated to have the capability of biosynthesizing long-chain polyunsaturated fatty acids (LC-PUFA) from C18 precursors, and to possess a Δ4 fatty acyl desaturase (Δ4 Fad) which was the first report in vertebrates, and is a good model for studying the regulatory mechanisms of LC-PUFA biosynthesis in teleosts. In order to understand regulatory mechanisms of transcription of Δ4 Fad, the gene promoter was cloned and characterized in the present study. An upstream sequence of 1859 bp from the initiation codon ATG was cloned as the promoter candidate. On the basis of bioinformatic analysis, several binding sites of transcription factors (TF) including GATA binding protein 2 (GATA-2), CCAAT enhancer binding protein (C/EBP), nuclear factor 1 (NF-1), nuclear factor Y (NF-Y), hepatocyte nuclear factor 4α (HNF4α) and sterol regulatory element (SRE), were identified in the promoter by site-directed mutation and functional assays. HNF4α and NF-1 were confirmed to interact with the core promoter of Δ4 Fad by gel shift assay and mass spectrometry. Moreover, over-expression of HNF4α increased promoter activity in HEK 293T cells and mRNA level of Δ4 Fad in rabbitfish primary hepatocytes, respectively. The results indicated that HNF4α is a TF of rabbitfish Δ4 Fad. To our knowledge, this is the first report on promoter structure of a Δ4 Fad, and also the first demonstration of HNF4α as a TF of vertebrate Fad gene involved in transcription regulation of LC-PUFA biosynthesis. PMID:27472219

Dietary moderately oxidized oil activates the Nrf2 signaling pathway in the liver of pigs.

PubMed

Varady, Juliane; Gessner, Denise K; Most, Erika; Eder, Klaus; Ringseis, Robert

2012-02-24

Previous studies have shown that administration of oxidized oils increases gene expression and activities of various enzymes involved in xenobiotic metabolism and stress response in the liver of rats and guinea pigs. As these genes are controlled by nuclear factor erythroid-derived 2-like 2 (Nrf2), we investigated the hypothesis that feeding of oxidized fats causes an activation of that transcription factor in the liver which in turn activates the expression of antioxidant, cytoprotective and detoxifying genes. Twenty four crossbred pigs were allocated to two groups of 12 pigs each and fed nutritionally adequate diets with either fresh rapeseed oil (fresh fat group) or oxidized rapeseed oil prepared by heating at a temperature of 175°C for 72 h (oxidized fat group). After 29 days of feeding, pigs of the oxidized fat group had a markedly increased nuclear concentration of the transcription factor Nrf2 and a higher activity of cellular superoxide dismutase and T4-UDP glucuronosyltransferase in liver than the fresh fat group (P < 0.05). In addition, transcript levels of antioxidant and phase II genes in liver, like superoxide dismutase 1, heme oxygenase 1, glutathione peroxidase 1, thioredoxin reductase 1, microsomal glutathione-S-transferase 1, UDP glucuronosyltransferase 1A1 and NAD(P)H:quinone oxidoreductase 1 in the liver were higher in the oxidized fat group than in the fresh fat group (P < 0.05). Moreover, pigs of the oxidized fat group had an increased hepatic nuclear concentration of the transcription factor NF-κB which is also an important transcription factor mediating cellular stress response. The present study shows for the first time that administration of an oxidized fat activates the Nrf2 in the liver of pigs which likely reflects an adaptive mechanism to prevent cellular oxidative damage. Activation of the NF-κB pathway might also contribute to this effect of oxidized fat.

The transcription factor Prep1 controls hepatic insulin sensitivity and gluconeogenesis by targeting nuclear localization of FOXO1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kulebyakin, Konstantin; Penkov, Dmitry; IFOM – the FIRC Institute of Molecular Oncology, Via Adamello 16, Milan, 20139

Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to searchmore » new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability. - Highlights: • A novel model of liver-specific Prep1 knockout is established. • Ablation of Prep1 in hepatocytes increases insulin sensitivity. • Prep1 controls hepatic insulin sensitivity by regulating localization of FOXO1. • Prep1 regulates localization of FOXO1 via Wnt/β-catenin signaling pathway.« less

Imaging analysis of nuclear antiviral factors through direct detection of incoming adenovirus genome complexes.

PubMed

Komatsu, Tetsuro; Will, Hans; Nagata, Kyosuke; Wodrich, Harald

2016-04-22

Recent studies involving several viral systems have highlighted the importance of cellular intrinsic defense mechanisms through nuclear antiviral proteins that restrict viral propagation. These factors include among others components of PML nuclear bodies, the nuclear DNA sensor IFI16, and a potential restriction factor PHF13/SPOC1. For several nuclear replicating DNA viruses, it was shown that these factors sense and target viral genomes immediately upon nuclear import. In contrast to the anticipated view, we recently found that incoming adenoviral genomes are not targeted by PML nuclear bodies. Here we further explored cellular responses against adenoviral infection by focusing on specific conditions as well as additional nuclear antiviral factors. In line with our previous findings, we show that neither interferon treatment nor the use of specific isoforms of PML nuclear body components results in co-localization between incoming adenoviral genomes and the subnuclear domains. Furthermore, our imaging analyses indicated that neither IFI16 nor PHF13/SPOC1 are likely to target incoming adenoviral genomes. Thus our findings suggest that incoming adenoviral genomes may be able to escape from a large repertoire of nuclear antiviral mechanisms, providing a rationale for the efficient initiation of lytic replication cycle. Copyright © 2016 Elsevier Inc. All rights reserved.

Interactions between IGFBP-3 and Nuclear Receptors in Prostate Cancer Apoptosis

DTIC Science & Technology

2008-01-01

manner. Tumor necrosis factor (TNF)- treatment also inhibited glucose transport to the same degree as IGFBP-3 and, in addition, increased IGFBP-3...mechanisms involved in its actions. In addition, we show here that the insulin-antagonistic effects of tumor necrosis factor (TNF)- are mediated in...adipocytes. J Biol Chem 265:12434–12443 14. Ranganathan S, Davidson MB 1996 Effect of tumor necrosis factor-a on basal and insulin-stimulated glucose

Protective effects of nuclear factor erythroid 2-related factor 2 on whole body heat stress-induced oxidative damage in the mouse testis.

PubMed

Li, Yansen; Huang, Yi; Piao, Yuanguo; Nagaoka, Kentaro; Watanabe, Gen; Taya, Kazuyoshi; Li, ChunMei

2013-03-21

Whole body heat stress had detrimental effect on male reproductive function. It's known that the nuclear factor erythroid 2-related factor 2 (Nrf2) activates expression of cytoprotective genes to enable cell adaptation to protect against oxidative stress. However, it's still unclear about the exactly effects of Nrf2 on the testis. Here, we investigate the protective effect of Nrf2 on whole body heat stress-induced oxidative damage in mouse testis. Male mice were exposed to the elevated ambient temperature (42°C) daily for 2 h. During the period of twelve consecutive days, mice were sacrificed on days 1, 2, 4, 8 and 12 immediately following heat exposure. Testes weight, enzymatic antioxidant activities and concentrations of malondialdehyde (MDA) and glutathione (GSH) in the testes were determined and immunohistochemical detection of Nrf2 protein and mRNA expression of Nrf2-regulated genes were analyzed to assess the status of Nrf2-antioxidant system. Heat-exposed mice presented significant increases in rectal, scrotal surface and body surface temperature. The concentrations of cortisol and testosterone in serum fluctuated with the number of exposed days. There were significant decrease in testes weight and relative testes weight on day 12 compared with those on other days, but significant increases in catalase (CAT) activity on day 1 and GSH level on day 4 compared with control group. The activities of total superoxide dismutase (T-SOD) and copper-zinc SOD (CuZn-SOD) increased significantly on days 8 and 12. Moreover, prominent nuclear accumulation of Nrf2 protein was observed in Leydig cells on day 2, accompanying with up-regulated mRNA levels of Nrf2-regulated genes such as Nrf2, heme oxygenase 1 (HO-1), γ-Glutamylcysteine synthetase (GCLC) and NAD (P) H: quinone oxidoreductase 1 (NQO1)) in heat-treated groups. These results suggest that Nrf2 displayed nuclear accumulation and protective activity in the process of heat treated-induced oxidative stress in mouse testes, indicating that Nrf2 might be a potential target for new drugs designed to protect germ cell and Leydig cell from oxidative stress.

Thrombosis and systemic and cardiac oxidative stress and DNA damage induced by pulmonary exposure to diesel exhaust particles and the effect of nootkatone thereon.

PubMed

Nemmar, Abderrahim; Al-Salam, Suhail; Beegam, Sumaya; Yuvaraju, Priya; Ali, Badreldin H

2018-05-01

Adverse cardiovascular effects of particulate air pollution persist even at lower concentrations than those of the current air quality limit. Therefore, identification of safe and effective measures against particle-induced cardiovascular toxicity is needed. Nootkatone is a sesquiterpenoid in grapefruit with diverse bioactivities including anti-inflammatory and antioxidant effects. However, its protective effect on the cardiovascular injury induced by diesel exhaust particles (DEPs) has not been studied before. We assessed the possible protective effect of nootkatone (90 mg/kg) administered by gavage 1 h before intratracheal instillation of DEPs (30 μg/mouse). Twenty-four hours after the intratracheal administration of DEPs, various thrombotic and cardiac parameters were assessed. Nootkatone inhibited the prothrombotic effect induced by DEPs in pial arterioles and venules in vivo and platelet aggregation in whole blood in vitro. Also, nootkatone prevented the shortening of activated partial thromboplastin time and prothrombin time induced by DEPs. Nootkatone inhibited the increase of plasma concentration of fibrinogen, plasminogen activator inhibitor-1, interleukin-6, and lipid peroxidation induced by DEPs. Immunohistochemically, hearts showed an analogous increase in glutathione and nuclear factor erythroid-derived 2-like 2 expression by cardiac myocytes and endothelial cells after DEP exposure, and these effects were enhanced in mice treated with nootkatone + DEPs. Likewise, heme oxygenase-1 was increased in mice treated with nootkatone + DEPs compared with those treated with DEPs or nootkatone + saline. The DNA damage caused by DEPs was prevented by nootkatoone pretreatment. In conclusion, nootkatoone alleviates DEP-induced thrombogenicity and systemic and cardiac oxidative stress and DNA damage, at least partly, through nuclear factor erythroid-derived 2-like 2 and heme oxygenase-1 activation. NEW & NOTEWORTHY Nootkatoone, a sesquiterpenoid found in grapefruit, alleviates the thrombogenicity and systemic and cardiac oxidative stress and DNA damage in mice exposed to diesel exhaust particles. Nootkatone-induced boosting of nuclear factor erythroid-derived 2-like 2 and heme oxygenase-1 levels in the heart of mice exposed to diesel exhaust particles suggests that its protective effect is, at least partly, mediated through nuclear factor erythroid-derived 2-like 2 and heme oxygenase-1 activation.

Plant nuclear factor Y (NF-Y) B subunits confer drought tolerance and lead to improved corn yields on water-limited acres.

PubMed

Nelson, Donald E; Repetti, Peter P; Adams, Tom R; Creelman, Robert A; Wu, Jingrui; Warner, David C; Anstrom, Don C; Bensen, Robert J; Castiglioni, Paolo P; Donnarummo, Meghan G; Hinchey, Brendan S; Kumimoto, Roderick W; Maszle, Don R; Canales, Roger D; Krolikowski, Katherine A; Dotson, Stanton B; Gutterson, Neal; Ratcliffe, Oliver J; Heard, Jacqueline E

2007-10-16

Commercially improved crop performance under drought conditions has been challenging because of the complexity of the trait and the multitude of factors that influence yield. Here we report the results of a functional genomics approach that identified a transcription factor from the nuclear factor Y (NF-Y) family, AtNF-YB1, which acts through a previously undescribed mechanism to confer improved performance in Arabidopsis under drought conditions. An orthologous maize transcription factor, ZmNF-YB2, is shown to have an equivalent activity. Under water-limited conditions, transgenic maize plants with increased ZmNF-YB2 expression show tolerance to drought based on the responses of a number of stress-related parameters, including chlorophyll content, stomatal conductance, leaf temperature, reduced wilting, and maintenance of photosynthesis. These stress adaptations contribute to a grain yield advantage to maize under water-limited environments. The application of this technology has the potential to significantly impact maize production systems that experience drought.

Plant nuclear factor Y (NF-Y) B subunits confer drought tolerance and lead to improved corn yields on water-limited acres

PubMed Central

Nelson, Donald E.; Repetti, Peter P.; Adams, Tom R.; Creelman, Robert A.; Wu, Jingrui; Warner, David C.; Anstrom, Don C.; Bensen, Robert J.; Castiglioni, Paolo P.; Donnarummo, Meghan G.; Hinchey, Brendan S.; Kumimoto, Roderick W.; Maszle, Don R.; Canales, Roger D.; Krolikowski, Katherine A.; Dotson, Stanton B.; Gutterson, Neal; Ratcliffe, Oliver J.; Heard, Jacqueline E.

2007-01-01

Commercially improved crop performance under drought conditions has been challenging because of the complexity of the trait and the multitude of factors that influence yield. Here we report the results of a functional genomics approach that identified a transcription factor from the nuclear factor Y (NF-Y) family, AtNF-YB1, which acts through a previously undescribed mechanism to confer improved performance in Arabidopsis under drought conditions. An orthologous maize transcription factor, ZmNF-YB2, is shown to have an equivalent activity. Under water-limited conditions, transgenic maize plants with increased ZmNF-YB2 expression show tolerance to drought based on the responses of a number of stress-related parameters, including chlorophyll content, stomatal conductance, leaf temperature, reduced wilting, and maintenance of photosynthesis. These stress adaptations contribute to a grain yield advantage to maize under water-limited environments. The application of this technology has the potential to significantly impact maize production systems that experience drought. PMID:17923671

Epidermal growth factor-like growth factors prevent apoptosis of alcohol-exposed human placental cytotrophoblast cells.

PubMed

Wolff, Garen S; Chiang, Po Jen; Smith, Susan M; Romero, Roberto; Armant, D Randall

2007-07-01

Maternal alcohol abuse during pregnancy can produce an array of birth defects comprising fetal alcohol syndrome. A hallmark of fetal alcohol syndrome is intrauterine growth retardation, which is associated with elevated apoptosis of placental cytotrophoblast cells. Using a human first trimester cytotrophoblast cell line, we examined the relationship between exposure to ethanol and cytotrophoblast survival, as well as the ameliorating effects of epidermal growth factor (EGF)-like growth factors produced by human cytotrophoblast cells. After exposure to 0-100 mM ethanol, cell death was quantified by the TUNEL method, and expression of the nuclear proliferation marker, Ki67, was measured by immunohistochemistry. The mode of cell death was determined by assessing annexin V binding, caspase 3 activation, pyknotic nuclear morphology, reduction of TUNEL by caspase inhibition, and cellular release of lactate dehydrogenase. Ethanol significantly reduced proliferation and increased cell death approximately 2.5-fold through the apoptotic pathway within 1-2 h of exposure to 50 mM alcohol. Exposure to 25-50 mM ethanol significantly increased transforming growth factor alpha (TGFA) and heparin-binding EGF-like growth factor (HBEGF), but not EGF or amphiregulin (AREG). When cytotrophoblasts were exposed concurrently to 100 mM ethanol and 1 nM HBEGF or TGFA, the increase in apoptosis was prevented, while EGF ameliorated at 10 nM and AREG was weakly effective. HBEGF survival-promoting activity required ligation of either of its cognate receptors, HER1 or HER4. These findings reveal the potential for ethanol to rapidly induce cytotrophoblast apoptosis. However, survival factor induction could provide cytotrophoblasts with an endogenous cytoprotective mechanism.

Friedelane-type triterpenoids as selective anti-inflammatory agents by regulation of differential signaling pathways in LPS-stimulated macrophages

DOE Office of Scientific and Technical Information (OSTI.GOV)

Villar-Lorenzo, Andrea, E-mail: avillar@iib.uam.es

A series of 31 pentacyclic triterpenoids isolated from the root barks of Celastrus vulcanicola and Maytenus jelskii were tested for cytotoxicity and inhibitory activity against lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compounds 18 (C18) and 25 (C25) exhibited significant inhibition of LPS-induced NO release at 50 and 25 μM concentrations, respectively, and decreased mRNAs of pro-inflammatory cytokines. At the molecular level, C18 neither inhibited LPS-mediated phosphorylation of mitogen activated protein kinases (MAPKs) nor nuclear translocation of nuclear factor kappa beta (NFκB). Instead, C18 enhanced and prolonged nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2) andmore » increased the expression of its target genes including hemeoxigenase 1 (HO1). C25 efficiently inhibited LPS-mediated phosphorylation of JNK, p38 and ERK, without affecting NFκB or Nrf2 signaling pathways. Both compounds reduced LPS-mediated processing of caspase-1 and the cleavage of interleukin 1β (IL1β) proform, reflecting their ability to target the inflammasome. C25 also counteracted LPS effects on iNOS expression and pro-inflammatory cytokines mRNA levels in Bv-2 microglial cells. The anti-inflammatory effect of both compounds was also assessed in human macrophages. Our results suggest that triterpenoids C18 and C25 possess anti-inflammatory effects, which may be therapeutically relevant for diseases linked to inflammation. - Highlights: • Compounds 18 (C18) and 25 (C25) exert anti-inflammatory effects in macrophages. • C18 enhanced nuclear translocation of Nrf2 and increased HO1 expression. • C25 inhibited the phosphorylation of JNK, p38 and ERK, members of the MAPKs family. • C25 reduced LPS-mediated processing of caspase-1 and the cleavage of interleukin 1β. • C18 and C25 may be therapeutic agents for diseases linked to inflammation.« less

Construction of two novel reciprocal conplastic rat strains and characterization of cardiac mitochondria

PubMed Central

Kumarasamy, Sivarajan; Gopalakrishnan, Kathirvel; Abdul-Majeed, Shakila; Partow-Navid, Rod; Farms, Phyllis

2013-01-01

Because of the lack of appropriate animal models, the potentially causal contributions of inherited mitochondrial genomic factors to complex traits are less well studied compared with inherited nuclear genomic factors. We previously detected variations between the mitochondrial DNA (mtDNA) of the Dahl salt-sensitive (S) rat and the spontaneously hypertensive rat (SHR). Specifically, multiple variations were detected in mitochondrial genes coding for subunits of proteins essential for electron transport, in mitochondrial reactive oxygen species production, and within the D-loop region. To evaluate the effects of these mtDNA variations in the absence of the corresponding nuclear genomic factors as confounding variables, novel reciprocal strains of S and SHR were constructed and characterized. When compared with that of the S rat, the heart tissue from the S.SHRmt conplastic strain wherein the mtDNA of the S rat was substituted with that of the SHR had a significant increase in mtDNA copy number and decrease in mitochondrial reactive oxygen species production. A corresponding increase in aerobic treadmill running capacity and a significant increase in survival that was not related to changes in blood pressure were observed in the S.SHRmt rats compared with the S rat. The reciprocal SHR.Smt rats did not differ from the SHR in any phenotype tested, suggesting lower penetrance of the S mtDNA on the nuclear genomic background of the SHR. These novel conplastic strains serve as invaluable tools to further dissect the relationship between heart function, aerobic fitness, cardiovascular disease progression, and mortality. PMID:23125210

Postprandial endothelial dysfunction: role of glucose, lipids and insulin.

PubMed

Nitenberg, A; Cosson, E; Pham, I

2006-09-01

Endothelium plays a key role in the regulation of vascular tone and development of atherosclerosis. Endothelial function is impaired early in patients with risk factors and endothelial dysfunction is a strong and independent predictor of cardiovascular events. Because in normal subjects blood concentrations of glucose, lipids and insulin are increased after each meals, and postprandial changes last a long time after the meals, these changes might be of importance in the process of atherosclerosis initiation and development. Experimental and human studies have shown that a transient increase of blood concentrations of glucose, triglycerides and fatty acids, and insulin are able to depress endothelium-dependent vasodilation in healthy subjects and that hyperglycemia, hypertriglyceridemia and hyperinsulinemia are generator of reactive oxygen species at the origin of a cascade of pathophysiological events resulting in the activation of nuclear factor-kappaB. Nuclear factor-kappaB is an ubiquitous transcription factor controlling the expression of numerous genes and is involved in immunity, inflammation, regulation of cell proliferation and growth and apoptosis. These mechanisms may be involved in the development of atherosclerosis in normal subjects when food intake is chronically modified towards glucids and lipids with cumulative effects both on depression of endothelium dependent dilation and oxidative stress.

The Role of Free Radicals in the Aging Brain and Parkinson’s Disease: Convergence and Parallelism

PubMed Central

Kumar, Hemant; Lim, Hyung-Woo; More, Sandeep Vasant; Kim, Byung-Wook; Koppula, Sushruta; Kim, In Su; Choi, Dong-Kug

2012-01-01

Free radical production and their targeted action on biomolecules have roles in aging and age-related disorders such as Parkinson’s disease (PD). There is an age-associated increase in oxidative damage to the brain, and aging is considered a risk factor for PD. Dopaminergic neurons show linear fallout of 5–10% per decade with aging; however, the rate and intensity of neuronal loss in patients with PD is more marked than that of aging. Here, we enumerate the common link between aging and PD at the cellular level with special reference to oxidative damage caused by free radicals. Oxidative damage includes mitochondrial dysfunction, dopamine auto-oxidation, α-synuclein aggregation, glial cell activation, alterations in calcium signaling, and excess free iron. Moreover, neurons encounter more oxidative stress as a counteracting mechanism with advancing age does not function properly. Alterations in transcriptional activity of various pathways, including nuclear factor erythroid 2-related factor 2, glycogen synthase kinase 3β, mitogen activated protein kinase, nuclear factor kappa B, and reduced activity of superoxide dismutase, catalase and glutathione with aging might be correlated with the increased incidence of PD. PMID:22949875

Influence of various factors on individual radiation exposure from the chernobyl disaster

PubMed Central

Zamostian, Pavlo; Moysich, Kirsten B; Mahoney, Martin C; McCarthy, Philip; Bondar, Alexandra; Noschenko, Andrey G; Michalek, Arthur M

2002-01-01

Background The explosion at the Chernobyl Nuclear Power Plant was one of the greatest known nuclear disasters of the 20th century. To reduce individual exposure to ionizing radiation the Soviet Union government introduced a number of counter-measures. This article presents a description of how historical events conspired to disrupt these efforts and affect residents in exposed areas. Methods This study employed an extensive review of data on radionuclide deposition, contamination patterns and lifestyle characteristics. Data were obtained from the Ukraine Ministry of Health and the Ukraine Research Center for Radiation Medicine. Results Data are presented on annual contamination rates in selected locales as well as data on local food consumption patterns. Historical factors including economic and political circumstances are also highlighted. Results show the diminution of individual doses between 1987 and 1991 and then an increase between 1991 and 1994 and the relationship between this increase and changes in the lifestyle of the local population. Conclusion A number of factors played direct and indirect roles in contributing to the populace's cumulative radiation exposure. Future post-contamination studies need to consider these factors when estimating individual exposures. PMID:12495449

Regulation of RE1 Protein Silencing Transcription Factor (REST) Expression by HIP1 Protein Interactor (HIPPI)*

PubMed Central

Datta, Moumita; Bhattacharyya, Nitai P.

2011-01-01

Earlier we have shown that the proapoptotic protein HIPPI (huntingtin interacting protein 1 (HIP1) protein interactor) along with its molecular partner HIP1 could regulate transcription of the caspase-1 gene. Here we report that RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a new transcriptional target of HIPPI. HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). The ability of HIPPI to activate REST gene transcription was dependent on HIP1, the nuclear transporter of HIPPI. Using a Huntington disease cell model, we have demonstrated that feeble interaction of HIP1 with mutant huntingtin protein resulted in increased nuclear accumulation of HIPPI and HIP1, leading to higher occupancy of HIPPI at the REST promoter, triggering its transcriptional activation and consequent repression of REST target genes. This novel transcription regulatory mechanism of REST by HIPPI may contribute to the deregulation of transcription observed in the cell model of Huntington disease. PMID:21832040

Regulation of RE1 protein silencing transcription factor (REST) expression by HIP1 protein interactor (HIPPI).

PubMed

Datta, Moumita; Bhattacharyya, Nitai P

2011-09-30

Earlier we have shown that the proapoptotic protein HIPPI (huntingtin interacting protein 1 (HIP1) protein interactor) along with its molecular partner HIP1 could regulate transcription of the caspase-1 gene. Here we report that RE1-silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is a new transcriptional target of HIPPI. HIPPI could bind to the promoter of REST and increased its expression in neuronal as well as non-neuronal cells. Such activation of REST down-regulated expression of REST target genes, such as brain-derived neurotrophic factor (BDNF) or proenkephalin (PENK). The ability of HIPPI to activate REST gene transcription was dependent on HIP1, the nuclear transporter of HIPPI. Using a Huntington disease cell model, we have demonstrated that feeble interaction of HIP1 with mutant huntingtin protein resulted in increased nuclear accumulation of HIPPI and HIP1, leading to higher occupancy of HIPPI at the REST promoter, triggering its transcriptional activation and consequent repression of REST target genes. This novel transcription regulatory mechanism of REST by HIPPI may contribute to the deregulation of transcription observed in the cell model of Huntington disease.

Tumor necrosis factor-{alpha} enhances IL-15-induced natural killer cell differentiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Jiwon; Lee, Suk Hyung; Korea University of Science and Technology, Yusong, Daejeon 305-333

2009-09-04

The differentiation of natural killer (NK) cells is regulated by various factors including soluble growth factors and transcription factors. Here, we have demonstrated that tumor necrosis factor-{alpha} (TNF-{alpha}) is a positive regulator of NK cell differentiation. TNF-{alpha} augmented the IL-15-induced expression of NK1.1 and CD122 in mature NK cells, and TNF-{alpha} alone also induced NK cell maturation as well as IL-15. TNF-{alpha} also increased IFN-{gamma} production in NK cells in the presence of IL-15. Meanwhile, mRNA expression of several transcription factors, including T-bet and GATA-3, was increased by the addition of TNF-{alpha} and IL-15. In addition, TNF-{alpha} increased nuclear factor-kappamore » B (NF-{kappa}B) activity in NK cells and inhibition of NF-{kappa}B impeded TNF-{alpha}-enhanced NK cell maturation. Overall, these data suggest that TNF-{alpha} significantly increased IL-15-driven NK cell differentiation by increasing the expression of transcription factors that play crucial roles in NK cell maturation and inducing the NF-{kappa}B activity.« less

Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1)

PubMed Central

Vaeth, Martin; Gogishvili, Tea; Bopp, Tobias; Klein, Matthias; Berberich-Siebelt, Friederike; Gattenloehner, Stefan; Avots, Andris; Sparwasser, Tim; Grebe, Nadine; Schmitt, Edgar; Hünig, Thomas; Serfling, Edgar; Bodor, Josef

2011-01-01

Inducible cAMP early repressor (ICER) is a transcriptional repressor, which, because of alternate promoter use, is generated from the 3′ region of the cAMP response modulator (Crem) gene. Its expression and nuclear occurrence are elevated by high cAMP levels in naturally occurring regulatory T cells (nTregs). Using two mouse models, we demonstrate that nTregs control the cellular localization of ICER/CREM, and thereby inhibit IL-2 synthesis in conventional CD4+ T cells. Ablation of nTregs in depletion of regulatory T-cell (DEREG) mice resulted in cytosolic localization of ICER/CREM and increased IL-2 synthesis upon stimulation. Direct contacts between nTregs and conventional CD4+ T cells led to nuclear accumulation of ICER/CREM and suppression of IL-2 synthesis on administration of CD28 superagonistic (CD28SA) Ab. In a similar way, nTregs communicated with B cells and induced the cAMP-driven nuclear localization of ICER/CREM. High levels of ICER suppressed the induction of nuclear factor of activated T cell c1 (Nfatc1) gene in T cells whose inducible Nfatc1 P1 promoter bears two highly conserved cAMP-responsive elements to which ICER/CREM can bind. These findings suggest that nTregs suppress T-cell responses by the cAMP-dependent nuclear accumulation of ICER/CREM and inhibition of NFATc1 and IL-2 induction. PMID:21262800

The transcription factor Prep1 controls hepatic insulin sensitivity and gluconeogenesis by targeting nuclear localization of FOXO1.

PubMed

Kulebyakin, Konstantin; Penkov, Dmitry; Blasi, Francesco; Akopyan, Zhanna; Tkachuk, Vsevolod

2016-12-02

Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to search new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability. Copyright © 2016 Elsevier Inc. All rights reserved.

Relationship between socioeconomic and lifestyle factors and cataracts in Koreans: the Korea National Health and Nutrition Examination Survey 2008-2011.

PubMed

Nam, G E; Han, K; Ha, S G; Han, B-D; Kim, D H; Kim, Y-H; Cho, K H; Park, Y G; Ko, B-J

2015-07-01

Cataracts are the leading cause of visual impairment and blindness, and therefore early identification and modification of the risk factors for cataracts are meaningful. This study aimed to investigate the relationship between socioeconomic status (SES) and lifestyle factors, and age-related cataracts in South Korea. This cross-sectional study was based on data collected in the 2008-2011 Korea National Health and Nutrition Examination Survey. A total of 15 866 subjects, aged ≥40 years, were included. SES was defined using household income and education level. Sociodemographic, lifestyle, and other associated factors were assessed by health interviews and examinations. Cataracts were diagnosed via slit-lamp examination using the Lens Opacities Classification System III. The prevalence of any cataract was 38.9% in men and 42.3% in women (P<0.001). In women, the risk of cataracts increased with decreases in household income (P-value for trend=0.016 and 0.041 in any, and cortical cataract, respectively) and education level (P-value for trend=0.009, 0.027, and 0.016 in any, nuclear, and cortical cataract, respectively) after adjusting for confounding factors. Current smoking was correlated with nuclear cataracts in men (OR 1.21; 95% CI: 1.00, 1.46 in age-adjusted analysis) and cataract surgery in women (OR 2.25; 95% CI: 1.00, 5.04 in multivariate-adjusted analysis). Socioeconomic disparities in cataract prevalence were observed in women; current smoking increased the risk of nuclear cataracts in men and surgery in women. Public health interventions focusing on gender differences are warranted to prevent and treat cataracts.

Severe Psychological Distress of Evacuees in Evacuation Zone Caused by the Fukushima Daiichi Nuclear Power Plant Accident: The Fukushima Health Management Survey

PubMed Central

Kunii, Yasuto; Suzuki, Yuriko; Shiga, Tetsuya; Yabe, Hirooki; Yasumura, Seiji; Maeda, Masaharu; Niwa, Shin-ichi; Otsuru, Akira; Mashiko, Hirobumi; Abe, Masafumi

2016-01-01

Background Following the Great East Japan Earthquake on March 11, 2011, the nuclear disaster at the Fukushima Daiichi Nuclear Power Plant has continued to affect the mental health status of residents in the evacuation zone. To examine the mental health status of evacuee after the nuclear accident, we conducted the Mental Health and Lifestyle Survey as part of the ongoing Fukushima Health Management Survey. Methods We measured mental health status using the Kessler 6-item psychological distress scale (K6) in a total of 73,569 (response rate: 40.7%) evacuees aged 15 and over who lived in the evacuation zone in Fukushima Prefecture. We then dichotomized responders using a 12/13 cutoff on the K6, and compared the proportion of K6 scores ≥13 and ≤12 in each risk factor including demographic information, socioeconomic variables, and disaster-related variables. We also performed bivariate analyses between mental health status and possible risk factors using the chi-square test. Furthermore, we performed multivariate regression analysis using modified Poisson regression models. Results The median K6 score was 5 (interquartile range: 1–10). The number of psychological distress was 8,717 (14.6%). We found that significant differences in the prevalence of psychological distress by almost all survey items, including disaster-related risk factors, most of which were also associated with increased Prevalence ratios (PRs). Additionally, we found that psychological distress in each evacuation zone was significantly positively associated with the radiation levels in their environment (r = 0.768, p = 0.002). Conclusion The earthquake, tsunami and subsequent nuclear accident likely caused severe psychological distress among residents in the evacuation zone in Fukushima Prefecture. The close association between psychological distress and the radiation levels shows that the nuclear accident seriously influenced the mental health of the residents, which might be exacerbated by increased risk perception. To provide prompt and appropriate support, continued psychosocial intervention for evacuees is strongly recommended. PMID:27391446

The ZO-1–associated Y-box factor ZONAB regulates epithelial cell proliferation and cell density

PubMed Central

Balda, Maria S.; Garrett, Michelle D.; Matter, Karl

2003-01-01

Epithelial tight junctions regulate paracellular permeability, restrict apical/basolateral intramembrane diffusion of lipids, and have been proposed to participate in the control of epithelial cell proliferation and differentiation. Previously, we have identified ZO-1–associated nucleic acid binding proteins (ZONAB), a Y-box transcription factor whose nuclear localization and transcriptional activity is regulated by the tight junction–associated candidate tumor suppressor ZO-1. Now, we found that reduction of ZONAB expression using an antisense approach or by RNA interference strongly reduced proliferation of MDCK cells. Transfection of wild-type or ZONAB-binding fragments of ZO-1 reduced proliferation as well as nuclear ZONAB pools, indicating that promotion of proliferation by ZONAB requires its nuclear accumulation. Overexpression of ZONAB resulted in increased cell density in mature monolayers, and depletion of ZONAB or overexpression of ZO-1 reduced cell density. ZONAB was found to associate with cell division kinase (CDK) 4, and reduction of nuclear ZONAB levels resulted in reduced nuclear CDK4. Thus, our data indicate that tight junctions can regulate epithelial cell proliferation and cell density via a ZONAB/ZO-1–based pathway. Although this regulatory process may also involve regulation of transcription by ZONAB, our data suggest that one mechanism by which ZONAB and ZO-1 influence proliferation is by regulating the nuclear accumulation of CDK4. PMID:12566432

Mineral trioxide aggregate promotes the odonto/osteogenic differentiation and dentinogenesis of stem cells from apical papilla via nuclear factor kappa B signaling pathway.

PubMed

Yan, Ming; Wu, Jintao; Yu, Yan; Wang, Yanping; Xie, Lizhe; Zhang, Guangdong; Yu, Jinhua; Zhang, Chengfei

2014-05-01

Mineral trioxide aggregate (MTA) has been widely used in clinical apexification and apexogenesis. However, the effects of MTA on the stem cells from apical papilla (SCAPs) and the precise mechanism of apexogenesis have not been elucidated in detail. Multiple colony-derived stem cells were isolated from the apical papillae, and the effects of MTA on the proliferation and differentiation of SCAPs were investigated both in vitro and in vivo. Activation of nuclear factor kappa B (NFκB) pathway in MTA-treated SCAPs was analyzed by immunofluorescence assay and Western blot. MTA at the concentration of 2 mg/mL did not affect the proliferation activity of SCAPs. However, 2 mg/mL MTA-treated SCAPs presented the ultrastructural changes, up-regulated alkaline phosphatase, increased calcium deposition, up-regulated expression of odontoblast markers (dentin sialoprotein and dentin sialophosphoprotein) and odonto/osteoblast markers (runt-related transcription factor 2 and osteocalcin), suggesting that MTA enhanced the odonto/osteoblastic differentiation of SCAPs in vitro. In vivo results confirmed that MTA can promote the regular dentinogenesis of SCAPs. Moreover, MTA-treated SCAPs exhibited the up-regulated cytoplasmic phos-IκBα and phos-P65, enhanced nuclear P65, and increased nuclear translocation of P65. When co-treated with BMS345541 (the specific NFκB inhibitor), MTA-mediated odonto/osteoblastic differentiation was significantly attenuated. MTA at the concentration of 2 mg/mL can improve the odonto/osteogenic capacity of SCAPs via the activation of NFκB pathway. Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Somatic cell cloning: the ultimate form of nuclear reprogramming?

PubMed

Piedrahita, Jorge A; Mir, Bashir; Dindot, Scott; Walker, Shawn

2004-05-01

With the increasing difficulties associated with meeting the required needs for organs used in transplantation, alternative approaches need to be considered. These include the use of stem cells as potential sources of specialized cells, the ability to transdifferentiate cell types in culture, and the development of complete organs that can be used in humans. All of the above goals will require a complete understanding of the factors affecting cell differentiation and nuclear reprogramming. To make this a reality, however, techniques associated with cloning and genetic modifications in somatic cells need to be continued to be developed and optimized. This includes not only an enhancement of the rate of homologous recombination in somatic cells, but also a thorough understanding of the nuclear reprogramming process taking place during nuclear transfer. The understanding of this process is likely to have an effect beyond the area of nuclear transfer and assist with better methods for transdifferentiation of mammalian cells.

Keap1 silencing boosts lipopolysaccharide-induced transcription of interleukin 6 via activation of nuclear factor κB in macrophages

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lv, Peng; Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709; Xue, Peng

2013-11-01

Interleukin-6 (IL6) is a multifunctional cytokine that regulates immune and inflammatory responses. Multiple transcription factors, including nuclear factor κB (NF-κB) and nuclear factor E2-related factor 2 (Nrf2), regulate IL6 transcription. Kelch-like ECH-associated protein 1 (Keap1) is a substrate adaptor protein for the Cullin 3-dependent E3 ubiquitin ligase complex, which regulates the degradation of many proteins, including Nrf2 and IκB kinase β (IKKβ). Here, we found that stable knockdown of Keap1 (Keap1-KD) in RAW 264.7 (RAW) mouse macrophages and human monocyte THP-1 cells significantly increased expression of Il6, and Nrf2-target genes, under basal and lipopolysaccharide (LPS, 0.001–0.1 μg/ml)-challenged conditions. However, Nrf2more » activation alone, by tert-butylhydroquinone treatment of RAW cells, did not increase expression of Il6. Compared to cells transduced with scrambled non-target negative control shRNA, Keap1-KD RAW cells showed enhanced protein levels of IKKβ and increased expression and phosphorylation of NF-κB p65 under non-stressed and LPS-treated conditions. Because the expression of Il6 in Keap1-KD RAW cells was significantly attenuated by silencing of Ikkβ, but not Nrf2, it appears that stabilized IKKβ is responsible for the enhanced transactivation of Il6 in Keap1-KD cells. This study demonstrated that silencing of Keap1 in macrophages boosts LPS-induced transcription of Il6 via NF-κB activation. Given the importance of IL6 in the inflammatory response, the Keap1–IKKβ–NF-κB pathway may be a novel target for treatment and prevention of inflammation and associated disorders. - Highlights: • Knockdown of Keap1 increases expression of Il6 in macrophages. • Silencing of Keap1 results in protein accumulation of IKKβ and NF-κB p65. • Induction of Il6 resulting from Keap1 silencing is attributed to NF-κB activation.« less

Lycopene inhibits NF-κB activation and adhesion molecule expression through Nrf2-mediated heme oxygenase-1 in endothelial cells.

PubMed

Yang, Po-Min; Chen, Huang-Zhi; Huang, Yu-Ting; Hsieh, Chia-Wen; Wung, Being-Sun

2017-06-01

The endothelial expression of cell adhesion molecules plays a leading role in atherosclerosis. Lycopene, a carotenoid with 11 conjugated double bonds, has been shown to have anti-inflammatory properties. In the present study, we demonstrate a putative mechanism for the anti-inflammatory effects of lycopene. We demonstrate that lycopene inhibits the adhesion of tumor necrosis factor α (TNFα)-stimulated monocytes to endothelial cells and suppresses the expression of intercellular cell adhesion molecule-1 (ICAM-1) at the transcriptional level. Moreover, lycopene was found to exert its inhibitory effects by blocking the degradation of the inhibitory protein, IκBα, following 6 h of pre-treatment. In TNFα-stimulated endothelial cells, nuclear factor-κB (NF-κB) nuclear translocation and transcriptional activity were abolished by up to 12 h of lycopene pre-treatment. We also found that lycopene increased the intracellular glutathione (GSH) level and glutamate-cysteine ligase expression. Subsequently, lycopene induced nuclear factor-erythroid 2 related factor 2 (Nrf2) activation, leading to the increased expression of downstream of heme oxygenase-1 (HO-1). The use of siRNA targeting HO-1 blocked the inhibitory effects of lycopene on IκB degradation and ICAM-1 expression. The inhibitory effects of lycopene thus appear to be mediated through its induction of Nrf2-mediated HO-1 expression. Therefore, the findings of the present study indicate that lycopene suppresses the activation of TNFα-induced signaling pathways through the upregulation of Nrf2-mediated HO-1 expression.

Low-Temperature Dynamic Nuclear Polarization at 9.4 Tesla With a 30 Milliwatt Microwave Source

PubMed Central

Thurber, Kent R.; Yau, Wai-Ming; Tycko, Robert

2010-01-01

Dynamic nuclear polarization (DNP) can provide large signal enhancements in nuclear magnetic resonance (NMR) by transfer of polarization from electron spins to nuclear spins. We discuss several aspects of DNP experiments at 9.4 Tesla (400 MHz resonant frequency for 1H, 264 GHz for electron spins in organic radicals) in the 7–80 K temperature range, using a 30 mW, frequency-tunable microwave source and a quasi-optical microwave bridge for polarization control and low-loss microwave transmission. In experiments on frozen glycerol/water doped with nitroxide radicals, DNP signal enhancements up to a factor of 80 are observed (relative to 1H NMR signals with thermal equilibrium spin polarization). The largest sensitivity enhancements are observed with a new triradical dopant, DOTOPA-TEMPO. Field modulation with a 10 G root-mean-squared amplitude during DNP increases the nuclear spin polarizations by up to 135%. Dependencies of 1H NMR signal amplitudes, nuclear spin relaxation times, and DNP build-up times on the dopant and its concentration, temperature, microwave power, and modulation frequency are reported and discussed. The benefits of low-temperature DNP can be dramatic: the 1H spin polarization is increased approximately 1000-fold at 7 K with DNP, relative to thermal polarization at 80 K. PMID:20392658

A muscle-specific knockout implicates nuclear receptor coactivator MED1 in the regulation of glucose and energy metabolism.

PubMed

Chen, Wei; Zhang, Xiaoting; Birsoy, Kivanc; Roeder, Robert G

2010-06-01

As conventional transcriptional factors that are activated in diverse signaling pathways, nuclear receptors play important roles in many physiological processes that include energy homeostasis. The MED1 subunit of the Mediator coactivator complex plays a broad role in nuclear receptor-mediated transcription by anchoring the Mediator complex to diverse promoter-bound nuclear receptors. Given the significant role of skeletal muscle, in part through the action of nuclear receptors, in glucose and fatty acid metabolism, we generated skeletal muscle-specific Med1 knockout mice. Importantly, these mice show enhanced insulin sensitivity and improved glucose tolerance as well as resistance to high-fat diet-induced obesity. Furthermore, the white muscle of these mice exhibits increased mitochondrial density and expression of genes specific to type I and type IIA fibers, indicating a fast-to-slow fiber switch, as well as markedly increased expression of the brown adipose tissue-specific UCP-1 and Cidea genes that are involved in respiratory uncoupling. These dramatic results implicate MED1 as a powerful suppressor in skeletal muscle of genetic programs implicated in energy expenditure and raise the significant possibility of therapeutical approaches for metabolic syndromes and muscle diseases through modulation of MED1-nuclear receptor interactions.

Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

PubMed Central

Nafi, Siti Norasikin Mohd; Generali, Daniele; Kramer-Marek, Gabriela; Gijsen, Merel; Strina, Carla; Cappelletti, Mariarosa; Andreis, Daniele; Haider, Syed; Li, Ji-Liang; Bridges, Esther; Capala, Jacek; Ioannis, Roxanis; Harris, Adrian L; Kong, Anthony

2014-01-01

The role of HER4 in breast cancer is controversial and its role in relation to trastuzumab resistance remains unclear. We showed that trastuzumab treatment and its acquired resistance induced HER4 upregulation, cleavage and nuclear translocation. However, knockdown of HER4 by specific siRNAs increased trastuzumab sensitivity and reversed its resistance in HER2 positive breast cancer cells. Preventing HER4 cleavage by a γ-secretase inhibitor and inhibiting HER4 tyrosine kinase activity by neratinib decreased trastuzumab-induced HER4 nuclear translocation and enhanced trastuzumab response. There was also increased nuclear HER4 staining in the tumours from BT474 xenograft mice and human patients treated with trastuzumab. Furthermore, nuclear HER4 predicted poor clinical response to trastuzumab monotherapy in patients undergoing a window study and was shown to be an independent poor prognostic factor in HER2 positive breast cancer. Our data suggest that HER4 plays a key role in relation to trastuzumab resistance in HER2 positive breast cancer. Therefore, our study provides novel findings that HER4 activation, cleavage and nuclear translocation influence trastuzumab sensitivity and resistance in HER2 positive breast cancer. Nuclear HER4 could be a potential prognostic and predictive biomarker and understanding the role of HER4 may provide strategies to overcome trastuzumab resistance in HER2 positive breast cancer. PMID:25153719

Increased Temperature and Protein Oxidation Signal HSP72 mRNA and Protein Accumulation in the In Vivo Exercised Rat Heart

PubMed Central

Staib, Jessica L.; Tümer, Nihal; Powers, Scott K.

2010-01-01

Myocardial heat shock protein 72 (HSP72) expression, mediated by its transcription factor heat shock factor 1 (HSF1), increases following exercise. However, the up-stream stimuli governing exercise-induced HSF1 activation and subsequent HSP72 gene expression in the whole animal remain unclear. Exercise-induced increases in body temperature may promote myocardial radical production leading to protein oxidation. Conceivably, myocardial protein oxidation during exercise may serve as an important signal promoting nuclear HSF1 migration and activation of HSP72 expression. Therefore, these experiments tested the hypothesis that preventing exercise-induced increases in body temperature attenuates cardiac protein oxidation, diminishes HSF1 activation and decreases HSP72 expression in vivo. To test this hypothesis, in vivo exercise-induced body temperature was manipulated by exercising male rats in either cold (4°C) or warm (22°C) ambient conditions. Warm exercise increased both body temperature (+ 3°C) and myocardial protein oxidation whereas these changes were attenuated by cold exercise. Interestingly, exercise in both conditions did not significantly increase myocardial nuclear localized phosphorylated HSF1. Nonetheless, warm exercise elevated left-ventricular HSP72 mRNA by 9-fold and increased myocardial HSP72 protein levels by 3-fold compared to cold-exercised animals. Collectively, these data indicate that elevated body temperature and myocardial protein oxidation promoted exercise-induced cardiac HSP72 mRNA expression and protein accumulation following in vivo exercise. However, these results suggest that exercise-induced myocardial HSP72 protein accumulation is not a result of nuclear-localized, phosphorylated HSF1 indicating that other transcriptional or posttranscriptional regulatory mechanisms are involved in exercise-induced HSP72 expression. PMID:18931043

Brain Science and International Nuclear Safeguards: Implications from Cognitive Science and Human Factors Research on the Provision and Use of Safeguards-Relevant Information in the Field

DOE PAGES

Gastelum, Zoe Nellie; Matzen, Laura E.; Smartt, Heidi A.; ...

2017-06-01

Today’s international nuclear safeguards inspectors have access to an increasing volume of supplemental information about the facilities under their purview, including commercial satellite imagery, nuclear trade data, open source information, and results from previous safeguards activities. In addition to completing traditional in-field safeguards activities, inspectors are now responsible for being able to act upon this growing corpus of supplemental safeguards-relevant data and for maintaining situational awareness of unusual activities taking place in their environment. However, cognitive science research suggests that maintaining too much information can be detrimental to a user’s understanding, and externalizing information (for example, to a mobile device)more » to reduce cognitive burden can decrease cognitive function related to memory, navigation, and attention. Given this dichotomy, how can international nuclear safeguards inspectors better synthesize information to enhance situational awareness, decision making, and performance in the field? This paper examines literature from the fields of cognitive science and human factors in the areas of wayfinding, situational awareness, equipment and technical assistance, and knowledge transfer, and describes the implications for the provision of, and interaction with, safeguards-relevant information for international nuclear safeguards inspectors working in the field.« less

Brain Science and International Nuclear Safeguards: Implications from Cognitive Science and Human Factors Research on the Provision and Use of Safeguards-Relevant Information in the Field

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gastelum, Zoe Nellie; Matzen, Laura E.; Smartt, Heidi A.

Today’s international nuclear safeguards inspectors have access to an increasing volume of supplemental information about the facilities under their purview, including commercial satellite imagery, nuclear trade data, open source information, and results from previous safeguards activities. In addition to completing traditional in-field safeguards activities, inspectors are now responsible for being able to act upon this growing corpus of supplemental safeguards-relevant data and for maintaining situational awareness of unusual activities taking place in their environment. However, cognitive science research suggests that maintaining too much information can be detrimental to a user’s understanding, and externalizing information (for example, to a mobile device)more » to reduce cognitive burden can decrease cognitive function related to memory, navigation, and attention. Given this dichotomy, how can international nuclear safeguards inspectors better synthesize information to enhance situational awareness, decision making, and performance in the field? This paper examines literature from the fields of cognitive science and human factors in the areas of wayfinding, situational awareness, equipment and technical assistance, and knowledge transfer, and describes the implications for the provision of, and interaction with, safeguards-relevant information for international nuclear safeguards inspectors working in the field.« less

Perception of Radiation Risk as a Predictor of Mid-Term Mental Health after a Nuclear Disaster: The Fukushima Health Management Survey

PubMed Central

Miura, Itaru; Nagai, Masato; Maeda, Masaharu; Harigane, Mayumi; Fujii, Senta; Takahashi, Hideto; Ohira, Tetsuya; Yasumura, Seiji; Abe, Masafumi

2017-01-01

Predictive factors including risk perception for mid-term mental health after a nuclear disaster remain unknown. The purpose of this study was to examine the association between perceived radiation risk and other factors at baseline and mid-term mental health after the Fukushima Daiichi nuclear disaster of 2011 in Japan. A mail-based questionnaire survey was conducted in January 2012 and January 2013. Mental health status was assessed using the K6 scale. Psychological distress over the 2-year period was categorized into the following four groups: chronic, recovered, resistant, or worsened. Most participants (80.3%) were resistant to the disaster. A positive association was found between the radiation risk perception regarding immediate effects and the worsened group in women. Baseline post-traumatic stress disorder (PTSD) or a history of psychiatric disease predicted being in the chronic or worsened group in mid-term course. These results suggest that evacuees who believed that their health was substantially affected by the nuclear disaster were at an increased risk of having poor mid-term mental health in women. Careful assessment of risk perception after a nuclear disaster, including the presence of PTSD or a history of psychiatric disease, is needed for appropriate interventions. PMID:28914809

Perception of Radiation Risk as a Predictor of Mid-Term Mental Health after a Nuclear Disaster: The Fukushima Health Management Survey.

PubMed

Miura, Itaru; Nagai, Masato; Maeda, Masaharu; Harigane, Mayumi; Fujii, Senta; Oe, Misari; Yabe, Hirooki; Suzuki, Yuriko; Takahashi, Hideto; Ohira, Tetsuya; Yasumura, Seiji; Abe, Masafumi

2017-09-15

Predictive factors including risk perception for mid-term mental health after a nuclear disaster remain unknown. The purpose of this study was to examine the association between perceived radiation risk and other factors at baseline and mid-term mental health after the Fukushima Daiichi nuclear disaster of 2011 in Japan. A mail-based questionnaire survey was conducted in January 2012 and January 2013. Mental health status was assessed using the K6 scale. Psychological distress over the 2-year period was categorized into the following four groups: chronic, recovered, resistant, or worsened. Most participants (80.3%) were resistant to the disaster. A positive association was found between the radiation risk perception regarding immediate effects and the worsened group in women. Baseline post-traumatic stress disorder (PTSD) or a history of psychiatric disease predicted being in the chronic or worsened group in mid-term course. These results suggest that evacuees who believed that their health was substantially affected by the nuclear disaster were at an increased risk of having poor mid-term mental health in women. Careful assessment of risk perception after a nuclear disaster, including the presence of PTSD or a history of psychiatric disease, is needed for appropriate interventions.

Anaplasia is rare and does not influence prognosis in adult medulloblastoma.

PubMed

Giordana, Maria Teresa; D'Agostino, Carla; Pollo, Bianca; Silvani, Antonio; Ferracini, Romano; Paiolo, Anna; Ghiglione, Paolo; Chiò, Adriano

2005-10-01

Histopathologic grading based on increasing anaplasia predicts clinical behavior of pediatric medulloblastomas. The present study was aimed at grading 86 medulloblastomas of adult patients (aged 18 and older) by anaplasia and analyzing the predictive power. Nodularity, desmoplasia, nuclear size, nuclear pleomorphism, necrosis, and endothelial proliferations have been evaluated. Morphometric analysis of nuclear size was performed using the Eclipse Net program. Patients treated with standard postoperative radiotherapy (35 Gy to craniospinal axis and 50 Gy to posterior fossa) were considered for correlation with survival. Pathologic data and total survival were compared by Kaplan-Meier and logrank analysis. No correlation was found between total survival duration and individual pathologic features. Cooccurrence of nuclear pleomorphism, large nuclear diameter, microvascular proliferations, and necroses did not predict outcome. Severe nuclear pleomorphism was found in 4 of 86 cases; the only large-cell medulloblastoma was from an 18-year-old patient. Histopathologic factors have no clinical use for stratification of patients in risk groups. The histologic spectrum of medulloblastoma in adults is different from that in children.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walpen, Thomas; Kalus, Ina; Schwaller, Juerg

Highlights: Black-Right-Pointing-Pointer Pim1{sup -/-} endothelial cell proliferation displays increased sensitivity to rapamycin. Black-Right-Pointing-Pointer mTOR inhibition by rapamycin enhances PIM1 cytosolic and nuclear protein levels. Black-Right-Pointing-Pointer Truncation of Pim1 beyond serine 276 results in nuclear localization of the kinase. Black-Right-Pointing-Pointer Nuclear PIM1 increases endothelial proliferation independent of rapamycin. -- Abstract: The PIM serine/threonine kinases and the mTOR/AKT pathway integrate growth factor signaling and promote cell proliferation and survival. They both share phosphorylation targets and have overlapping functions, which can partially substitute for each other. In cancer cells PIM kinases have been reported to produce resistance to mTOR inhibition by rapamycin. Tumormore » growth depends highly on blood vessel infiltration into the malignant tissue and therefore on endothelial cell proliferation. We therefore investigated how the PIM1 kinase modulates growth inhibitory effects of rapamycin in mouse aortic endothelial cells (MAEC). We found that proliferation of MAEC lacking Pim1 was significantly more sensitive to rapamycin inhibition, compared to wildtype cells. Inhibition of mTOR and AKT in normal MAEC resulted in significantly elevated PIM1 protein levels in the cytosol and in the nucleus. We observed that truncation of the C-terminal part of Pim1 beyond Ser 276 resulted in almost exclusive nuclear localization of the protein. Re-expression of this Pim1 deletion mutant significantly increased the proliferation of Pim1{sup -/-} cells when compared to expression of the wildtype Pim1 cDNA. Finally, overexpression of the nuclear localization mutant and the wildtype Pim1 resulted in complete resistance to growth inhibition by rapamycin. Thus, mTOR inhibition-induced nuclear accumulation of PIM1 or expression of a nuclear C-terminal PIM1 truncation mutant is sufficient to increase endothelial cell proliferation, suggesting that nuclear localization of PIM1 is important for resistance of MAEC to rapamycin-mediated inhibition of proliferation.« less

Regulation of subcellular localization of the Aryl Hydrocarbon Receptor (AhR)

USGS Publications Warehouse

Richter, Catherine A.; Tillitt, Donald E.; Hannink, Mark

2001-01-01

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity of dioxin and other xenobiotics. In the absence of exogenous ligand, AhR is cytosolic. We investigated how AhR is retained in the cytosol and how dioxin induces AhR to move to the nucleus. Disruption of nuclear export of AhR by the nuclear export inhibitor leptomycin B (LMB) or by mutation of the AhR nuclear export signal resulted in nuclear accumulation of AhR in the absence of exogenous ligand. Mutation of the AhR nuclear localization signal resulted in defects in nuclear import of AhR in both the presence and the absence of exogenous ligand. Dioxin treatment caused a more rapid accumulation of AhR in the nucleus than LMB treatment. In the presence of both dioxin and LMB, nuclear accumulation of AhR was more rapid than in the presence of dioxin alone. Our results show that AhR shuttles between the nucleus and the cytosol in the absence of exogenous ligand. Binding of ligand induces an increase in the rate of nuclear import of AhR but does not eliminate nuclear export of AhR.

Oxaloacetate activates brain mitochondrial biogenesis, enhances the insulin pathway, reduces inflammation and stimulates neurogenesis.

PubMed

Wilkins, Heather M; Harris, Janna L; Carl, Steven M; E, Lezi; Lu, Jianghua; Eva Selfridge, J; Roy, Nairita; Hutfles, Lewis; Koppel, Scott; Morris, Jill; Burns, Jeffrey M; Michaelis, Mary L; Michaelis, Elias K; Brooks, William M; Swerdlow, Russell H

2014-12-15

Brain bioenergetic function declines in some neurodegenerative diseases, this may influence other pathologies and administering bioenergetic intermediates could have therapeutic value. To test how one intermediate, oxaloacetate (OAA) affects brain bioenergetics, insulin signaling, inflammation and neurogenesis, we administered intraperitoneal OAA, 1-2 g/kg once per day for 1-2 weeks, to C57Bl/6 mice. OAA altered levels, distributions or post-translational modifications of mRNA and proteins (proliferator-activated receptor-gamma coactivator 1α, PGC1 related co-activator, nuclear respiratory factor 1, transcription factor A of the mitochondria, cytochrome oxidase subunit 4 isoform 1, cAMP-response element binding, p38 MAPK and adenosine monophosphate-activated protein kinase) in ways that should promote mitochondrial biogenesis. OAA increased Akt, mammalian target of rapamycin and P70S6K phosphorylation. OAA lowered nuclear factor κB nucleus-to-cytoplasm ratios and CCL11 mRNA. Hippocampal vascular endothelial growth factor mRNA, doublecortin mRNA, doublecortin protein, doublecortin-positive neuron counts and neurite length increased in OAA-treated mice. (1)H-MRS showed OAA increased brain lactate, GABA and glutathione thereby demonstrating metabolic changes are detectable in vivo. In mice, OAA promotes brain mitochondrial biogenesis, activates the insulin signaling pathway, reduces neuroinflammation and activates hippocampal neurogenesis. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

β-Adrenergic Stimulation Induces Histone Deacetylase 5 (HDAC5) Nuclear Accumulation in Cardiomyocytes by B55α-PP2A-Mediated Dephosphorylation.

PubMed

Weeks, Kate L; Ranieri, Antonella; Karaś, Agnieszka; Bernardo, Bianca C; Ashcroft, Alexandra S; Molenaar, Chris; McMullen, Julie R; Avkiran, Metin

2017-03-25

Class IIa histone deacetylase (HDAC) isoforms such as HDAC5 are critical signal-responsive repressors of maladaptive cardiomyocyte hypertrophy, through nuclear interactions with transcription factors including myocyte enhancer factor-2. β-Adrenoceptor (β-AR) stimulation, a signal of fundamental importance in regulating cardiac function, has been proposed to induce both phosphorylation-independent nuclear export and phosphorylation-dependent nuclear accumulation of cardiomyocyte HDAC5. The relative importance of phosphorylation at Ser259/Ser498 versus Ser279 in HDAC5 regulation is also controversial. We aimed to determine the impact of β-AR stimulation on the phosphorylation, localization, and function of cardiomyocyte HDAC5 and delineate underlying molecular mechanisms. A novel 3-dimensional confocal microscopy method that objectively quantifies the whole-cell nuclear/cytoplasmic distribution of green fluorescent protein tagged HDAC5 revealed the β-AR agonist isoproterenol to induce β 1 -AR-mediated and protein kinase A-dependent HDAC5 nuclear accumulation in adult rat cardiomyocytes, which was accompanied by dephosphorylation at Ser259/279/498. Mutation of Ser259/Ser498 to Ala promoted HDAC5 nuclear accumulation and myocyte enhancer factor-2 inhibition, whereas Ser279 ablation had no such effect and did not block isoproterenol-induced nuclear accumulation. Inhibition of the Ser/Thr phosphatase PP2A blocked isoproterenol-induced HDAC5 dephosphorylation. Co-immunoprecipitation revealed a specific interaction of HDAC5 with the PP2A targeting subunit B55α, as well as catalytic and scaffolding subunits, which increased >3-fold with isoproterenol. Knockdown of B55α in neonatal cardiomyocytes attenuated isoproterenol-induced HDAC5 dephosphorylation. β-AR stimulation induces HDAC5 nuclear accumulation in cardiomyocytes by a mechanism that is protein kinase A-dependent but requires B55α-PP2A-mediated dephosphorylation of Ser259/Ser498 rather than protein kinase A-mediated phosphorylation of Ser279. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

The effects of Mucuna pruriens on the renal oxidative stress and transcription factors in high-fructose-fed rats.

PubMed

Ulu, Ramazan; Gozel, Nevzat; Tuzcu, Mehmet; Orhan, Cemal; Yiğit, İrem Pembegül; Dogukan, Ayhan; Telceken, Hafize; Üçer, Özlem; Kemeç, Zeki; Kaman, Dilara; Juturu, Vijaya; Sahin, Kazim

2018-05-31

In the present study, we evaluated the effects of M. pruriens administration on metabolic parameters, oxidative stress and kidney nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathways in high-fructose fed rats. Male rats (n = 28) were divided into 4 groups as control, M. pruriens, fructose, and M. pruriens plus fructose. All rats were fed a standard diet supplemented or no supplemented with M. pruriens (200 mg/kg/d by gavage). Fructose was given in drinking water for 8 weeks. High fructose consumption led to an increase in the serum level of glucose, triglyceride, urea and renal malondialdehyde (MDA) levels. Although M. pruriens treatment reduced triglyceride and MDA levels, it did not affect other parameters. M. pruriens supplementation significantly decreased the expression of NF-ҡB and decreased expression of Nrf2 and HO-1 proteins in the kidney. This study showed that the adverse effects of high fructose were alleviated by M. pruriens supplementation via modulation of the expression of kidney nuclear transcription factors in rats fed high fructose diet. Copyright © 2018 Elsevier Ltd. All rights reserved.

Flow Accelerated Erosion-Corrosion (FAC) considerations for secondary side piping in the AP1000{sup R} nuclear power plant design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vanderhoff, J. F.; Rao, G. V.; Stein, A.

2012-07-01

The issue of Flow Accelerated Erosion-Corrosion (FAC) in power plant piping is a known phenomenon that has resulted in material replacements and plant accidents in operating power plants. Therefore, it is important for FAC resistance to be considered in the design of new nuclear power plants. This paper describes the design considerations related to FAC that were used to develop a safe and robust AP1000{sup R} plant secondary side piping design. The primary FAC influencing factors include: - Fluid Temperature - Pipe Geometry/layout - Fluid Chemistry - Fluid Velocity - Pipe Material Composition - Moisture Content (in steam lines) Duemore » to the unknowns related to the relative impact of the influencing factors and the complexities of the interactions between these factors, it is difficult to accurately predict the expected wear rate in a given piping segment in a new plant. This paper provides: - a description of FAC and the factors that influence the FAC degradation rate, - an assessment of the level of FAC resistance of AP1000{sup R} secondary side system piping, - an explanation of options to increase FAC resistance and associated benefits/cost, - discussion of development of a tool for predicting FAC degradation rate in new nuclear power plants. (authors)« less

Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-1-/-) attenuates ex vivo myocardial ischemia/reperfusion injury through hypoxia-inducible factor-1α transcription factor and its target genes in mice.

PubMed

Adluri, Ram Sudheer; Thirunavukkarasu, Mahesh; Dunna, Nageswara Rao; Zhan, Lijun; Oriowo, Babatunde; Takeda, Kotaro; Sanchez, Juan A; Otani, Hajime; Maulik, Gautam; Fong, Guo-Hua; Maulik, Nilanjana

2011-10-01

Hypoxia-inducible transcription factor (HIF)-prolyl hydroxylases domain (PHD-1-3) are oxygen sensors that regulate the stability of the HIFs in an oxygen-dependent manner. Suppression of PHD enzymes leads to stabilization of HIFs and offers a potential treatment option for many ischemic disorders, such as peripheral artery occlusive disease, myocardial infarction, and stroke. Here, we show that homozygous disruption of PHD-1 (PHD-1(-/-)) could facilitate HIF-1α-mediated cardioprotection in ischemia/reperfused (I/R) myocardium. Wild-type (WT) and PHD-1(-/-) mice were randomized into WT time-matched control (TMC), PHD-1(-/-) TMC (PHD1TMC), WT I/R, and PHD-1(-/-) I/R (PHD1IR). Isolated hearts from each group were subjected to 30 min of global ischemia followed by 2 h of reperfusion. TMC hearts were perfused for 2 h 30 min without ischemia. Decreased infarct size (35%±0.6% vs. 49%±0.4%) and apoptotic cardiomyocytes (106±13 vs. 233±21 counts/100 high-power field) were observed in PHD1IR compared to wild-type ischemia/reperfusion (WTIR). Protein expression of HIF-1α was significantly increased in PHD1IR compared to WTIR. mRNA expression of β-catenin (1.9-fold), endothelial nitric oxide synthase (1.9-fold), p65 (1.9-fold), and Bcl-2 (2.7-fold) were upregulated in the PHD1IR compared with WTIR, which was studied by real-time quantitative polymerase chain reaction. Further, gel-shift analysis showed increased DNA binding activity of HIF-1α and nuclear factor-kappaB in PHD1IR compared to WTIR. In addition, nuclear translocation of β-catenin was increased in PHD1IR compared with WTIR. These findings indicated that silencing of PHD-1 attenuates myocardial I/R injury probably by enhancing HIF-1α/β-catenin/endothelial nitric oxide synthase/nuclear factor-kappaB and Bcl-2 signaling pathway.

Low Oxygen Modulates Multiple Signaling Pathways, Increasing Self-Renewal, While Decreasing Differentiation, Senescence, and Apoptosis in Stromal MIAMI Cells

PubMed Central

Rios, Carmen; D'Ippolito, Gianluca; Curtis, Kevin M.; Delcroix, Gaëtan J.-R.; Gomez, Lourdes A.; El Hokayem, Jimmy; Rieger, Megan; Parrondo, Ricardo; de las Pozas, Alicia; Perez-Stable, Carlos; Howard, Guy A.

2016-01-01

Human bone marrow multipotent mesenchymal stromal cell (hMSC) number decreases with aging. Subpopulations of hMSCs can differentiate into cells found in bone, vasculature, cartilage, gut, and other tissues and participate in their repair. Maintaining throughout adult life such cell subpopulations should help prevent or delay the onset of age-related degenerative conditions. Low oxygen tension, the physiological environment in progenitor cell-rich regions of the bone marrow microarchitecture, stimulates the self-renewal of marrow-isolated adult multilineage inducible (MIAMI) cells and expression of Sox2, Nanog, Oct4a nuclear accumulation, Notch intracellular domain, notch target genes, neuronal transcriptional repressor element 1 (RE1)-silencing transcription factor (REST), and hypoxia-inducible factor-1 alpha (HIF-1α), and additionally, by decreasing the expression of (i) the proapoptotic proteins, apoptosis-inducing factor (AIF) and Bak, and (ii) senescence-associated p53 expression and β-galactosidase activity. Furthermore, low oxygen increases canonical Wnt pathway signaling coreceptor Lrp5 expression, and PI3K/Akt pathway activation. Lrp5 inhibition decreases self-renewal marker Sox2 mRNA, Oct4a nuclear accumulation, and cell numbers. Wortmannin-mediated PI3K/Akt pathway inhibition leads to increased osteoblastic differentiation at both low and high oxygen tension. We demonstrate that low oxygen stimulates a complex signaling network involving PI3K/Akt, Notch, and canonical Wnt pathways, which mediate the observed increase in nuclear Oct4a and REST, with simultaneous decrease in p53, AIF, and Bak. Collectively, these pathway activations contribute to increased self-renewal with concomitant decreased differentiation, cell cycle arrest, apoptosis, and/or senescence in MIAMI cells. Importantly, the PI3K/Akt pathway plays a central mechanistic role in the oxygen tension-regulated self-renewal versus osteoblastic differentiation of progenitor cells. PMID:27059084

Methamphetamine toxicity-induced calcineurin activation, nuclear translocation of nuclear factor of activated T-cells and elevation of cyclooxygenase 2 levels are averted by calpastatin overexpression in neuroblastoma SH-SY5Y cells.

PubMed

Chetsawang, Jirapa; Nudmamud-Thanoi, Sutisa; Phonchai, Ruchee; Abubakar, Zuroida; Govitrapong, Piyarat; Chetsawang, Banthit

2018-06-23

Methamphetamine (METH) is an addictive stimulant drug that has many negative consequences, including toxic effects to the brain. Recently, the induction of inflammatory processes has been identified as a potential contributing factor to induce neuronal cell degeneration. It has been demonstrated that the expression of inflammatory agents, such as cyclooxygenase 2 (COX-2), depends on the activation of calcineurin (CaN) and nuclear factor of activated T-cells (NFAT). Moreover, the excessive elevation in cytosolic Ca 2+ levels activates the cell death process, including calpain activation in neurons, which was diminished by the overexpression of the calpain inhibitor protein, calpastatin. However, it is unclear whether calpain mediates CaN-NFAT activation in the neurotoxic process. In the present study, we observed that the toxic high dose of METH-treated neuroblastoma SH-SY5Y cells significantly decreased cell viability but increased apoptotic cell death, the active cleaved form of calcineurin, the nuclear translocation of NFAT, and COX-2 levels. Nevertheless, these toxic effects were diminished in METH-treated calpastatin-overexpressing SH-SY5Y cells. These findings might emphasize the role of calpastatin against METH-induced toxicity by a mechanism related to calpain-dependent CaN-NFAT activation-induced COX-2 expression. Copyright © 2018. Published by Elsevier B.V.

Assessment of medium-term cardiovascular disease risk after Japan’s 2011 Fukushima Daiichi nuclear accident: a retrospective analysis

PubMed Central

Nomura, Shuhei; Gilmour, Stuart; Oikawa, Tomoyoshi; Lee, Kiwon; Kiyabu, Grace Y; Shibuya, Kenji

2017-01-01

Objective To assess the medium-term indirect impact of the 2011 Fukushima Daiichi nuclear accident on cardiovascular disease (CVD) risks and to identify whether risk factors for CVD changed after the accident. Participants Residents aged 40 years and over participating in annual public health check-ups from 2009 to 2012, administered by Minamisoma city, located about 10 to 40 km from the Fukushima Daiichi nuclear plant. Methods The sex-specific Framingham CVD risk score was considered as the outcome measure and was compared before (2009–2010) and after the accident (2011–2012). A multivariate regression analysis was employed to evaluate risk factors for CVD. Results Data from 563 individuals (60.2% women) aged 40 to 74 years who participated in the check-ups throughout the study period was analysed. After adjusting for covariates, no statistically significant change was identified in the CVD risk score postaccident in both sexes, which may suggest no obvious medium-term health impact of the Fukushima nuclear accident on CVD risk. The risk factors for CVD and their magnitude and direction (positive/negative) did not change after the accident. Conclusions There was no obvious increase in CVD risks in Minamisoma city, which may indicate successful management of health risks associated with CVD in the study sample. PMID:29275343

Gamma-tocopherol supplementation ameliorated hyper-inflammatory response during the early cutaneous wound healing in alloxan-induced diabetic mice

PubMed Central

Shin, Jihyun; Yang, Soo Jin

2016-01-01

Delayed wound healing is one of the major diabetic complications. During wound healing process, the early inflammatory stage is important for better prognosis. One of antioxidant nutrient, gamma-tocopherol (GT) is considered to regulate inflammatory conditions. This study investigated the effect of GT supplementation on mechanism associated with inflammation, oxidative stress, and apoptosis during early cutaneous wound healing in diabetic mice. Diabetes was induced by alloxan injection in ICR mice. All mice were divided into three groups: non-diabetic control mice (CON), diabetic control mice (DMC), and diabetic mice supplemented with GT (GT). After two weeks of GT supplementation, excisional wounds were made by biopsy punches (4 mm). Diabetic mice showed increases in fasting blood glucose (FBG) level, hyper-inflammatory response, oxidative stress, and delayed wound closure rate compared to non-diabetic mice. However, GT supplementation reduced FBG level and accelerated wound closure rate by regulation of inflammatory response-related proteins such as nuclear factor kappa B, interleukin-1β, tumor necrosis factor-α, and c-reactive protein, and oxidative stress-related markers including nuclear factor (erythroid derived 2)-like 2, NAD(P)H dehydrogenase quinone1, heme oxygenase-1, manganese superoxide dismutase, catalase and glutathione peroxidase and apoptosis-related markers such as sirtuin-1, peroxisome proliferator-activated receptor gamma coactivator 1-α, and p53 in diabetic mice. Taken together, GT would be a potential therapeutic to prevent diabetes-induced delayed wound healing by regulation of inflammatory response, apoptosis, and oxidative stress. Impact statement Gamma tocopherol has shown ameliorative effect on diabetic wound healing by regulation of inflammation, oxidative stress, and apoptosis demonstrated by nuclear factor kappa B, nuclear factor (erythroid derived 2)-like 2, and sirtuin-1. PMID:28211759

Gamma-tocopherol supplementation ameliorated hyper-inflammatory response during the early cutaneous wound healing in alloxan-induced diabetic mice.

PubMed

Shin, Jihyun; Yang, Soo Jin; Lim, Yunsook

2017-03-01

Delayed wound healing is one of the major diabetic complications. During wound healing process, the early inflammatory stage is important for better prognosis. One of antioxidant nutrient, gamma-tocopherol (GT) is considered to regulate inflammatory conditions. This study investigated the effect of GT supplementation on mechanism associated with inflammation, oxidative stress, and apoptosis during early cutaneous wound healing in diabetic mice. Diabetes was induced by alloxan injection in ICR mice. All mice were divided into three groups: non-diabetic control mice (CON), diabetic control mice (DMC), and diabetic mice supplemented with GT (GT). After two weeks of GT supplementation, excisional wounds were made by biopsy punches (4 mm). Diabetic mice showed increases in fasting blood glucose (FBG) level, hyper-inflammatory response, oxidative stress, and delayed wound closure rate compared to non-diabetic mice. However, GT supplementation reduced FBG level and accelerated wound closure rate by regulation of inflammatory response-related proteins such as nuclear factor kappa B, interleukin-1β, tumor necrosis factor-α, and c-reactive protein, and oxidative stress-related markers including nuclear factor (erythroid derived 2)-like 2, NAD(P)H dehydrogenase quinone1, heme oxygenase-1, manganese superoxide dismutase, catalase and glutathione peroxidase and apoptosis-related markers such as sirtuin-1, peroxisome proliferator-activated receptor gamma coactivator 1- α, and p53 in diabetic mice. Taken together, GT would be a potential therapeutic to prevent diabetes-induced delayed wound healing by regulation of inflammatory response, apoptosis, and oxidative stress. Impact statement Gamma tocopherol has shown ameliorative effect on diabetic wound healing by regulation of inflammation, oxidative stress, and apoptosis demonstrated by nuclear factor kappa B, nuclear factor (erythroid derived 2)-like 2, and sirtuin-1.

Identification and characterization of an oocyte factor required for development of porcine nuclear transfer embryos

PubMed Central

Miyamoto, Kei; Nagai, Kouhei; Kitamura, Naoya; Nishikawa, Tomoaki; Ikegami, Haruka; Binh, Nguyen T.; Tsukamoto, Satoshi; Matsumoto, Mai; Tsukiyama, Tomoyuki; Minami, Naojiro; Yamada, Masayasu; Ariga, Hiroyoshi; Miyake, Masashi; Kawarasaki, Tatsuo; Matsumoto, Kazuya; Imai, Hiroshi

2011-01-01

Nuclear reprogramming of differentiated cells can be induced by oocyte factors. Despite numerous attempts, these factors and mechanisms responsible for successful reprogramming remain elusive. Here, we identify one such factor, necessary for the development of nuclear transfer embryos, using porcine oocyte extracts in which some reprogramming events are recapitulated. After incubating somatic nuclei in oocyte extracts from the metaphase II stage, the oocyte proteins that were specifically and abundantly incorporated into the nuclei were identified by mass spectrometry. Among 25 identified proteins, we especially focused on a multifunctional protein, DJ-1. DJ-1 is present at a high concentration in oocytes from the germinal vesicle stage until embryos at the four-cell stage. Inhibition of DJ-1 function compromises the development of nuclear transfer embryos but not that of fertilized embryos. Microarray analysis of nuclear transfer embryos in which DJ-1 function is inhibited shows perturbed expression of P53 pathway components. In addition, embryonic arrest of nuclear transfer embryos injected with anti–DJ-1 antibody is rescued by P53 inhibition. We conclude that DJ-1 is an oocyte factor that is required for development of nuclear transfer embryos. This study presents a means for identifying natural reprogramming factors in mammalian oocytes and a unique insight into the mechanisms underlying reprogramming by nuclear transfer. PMID:21482765

Importin 8 mediates m7G cap-sensitive nuclear import of the eukaryotic translation initiation factor eIF4E

PubMed Central

Volpon, Laurent; Culjkovic-Kraljacic, Biljana; Osborne, Michael J.; Ramteke, Anup; Sun, Qingxiang; Niesman, Ashley; Chook, Yuh Min; Borden, Katherine L. B.

2016-01-01

Regulation of nuclear-cytoplasmic trafficking of oncoproteins is critical for growth homeostasis. Dysregulated trafficking contributes to malignancy, whereas understanding the process can reveal unique therapeutic opportunities. Here, we focus on eukaryotic translation initiation factor 4E (eIF4E), a prooncogenic protein highly elevated in many cancers, including acute myeloid leukemia (AML). Typically, eIF4E is localized to both the nucleus and cytoplasm, where it acts in export and translation of specific methyl 7-guanosine (m7G)–capped mRNAs, respectively. Nuclear accumulation of eIF4E in patients who have AML is correlated with increased eIF4E-dependent export of transcripts encoding oncoproteins. The subcellular localization of eIF4E closely correlates with patients’ responses. During clinical responses to the m7G-cap competitor ribavirin, eIF4E is mainly cytoplasmic. At relapse, eIF4E reaccumulates in the nucleus, leading to elevated eIF4E-dependent mRNA export. We have identified importin 8 as a factor that directly imports eIF4E into the nucleus. We found that importin 8 is highly elevated in untreated patients with AML, leading to eIF4E nuclear accumulation. Importin 8 only imports cap-free eIF4E. Cap-dependent changes to the structure of eIF4E underpin this selectivity. Indeed, m7G cap analogs or ribavirin prevents nuclear entry of eIF4E, which mirrors the trafficking phenotypes observed in patients with AML. Our studies also suggest that nuclear entry is important for the prooncogenic activity of eIF4E, at least in this context. These findings position nuclear trafficking of eIF4E as a critical step in its regulation and position the importin 8–eIF4E complex as a novel therapeutic target. PMID:27114554

Factors affecting the development of somatic cell nuclear transfer embryos in Cattle.

PubMed

Akagi, Satoshi; Matsukawa, Kazutsugu; Takahashi, Seiya

2014-01-01

Nuclear transfer is a complex multistep procedure that includes oocyte maturation, cell cycle synchronization of donor cells, enucleation, cell fusion, oocyte activation and embryo culture. Therefore, many factors are believed to contribute to the success of embryo development following nuclear transfer. Numerous attempts to improve cloning efficiency have been conducted since the birth of the first sheep by somatic cell nuclear transfer. However, the efficiency of somatic cell cloning has remained low, and applications have been limited. In this review, we discuss some of the factors that affect the developmental ability of somatic cell nuclear transfer embryos in cattle.

Molecular pathways mediating differential responses to lipopolysaccharide between human and baboon arterial endothelial cells.

PubMed

Shi, Qiang; Cox, Laura A; Glenn, Jeremy; Tejero, Maria E; Hondara, Vida; Vandeberg, John L; Wang, Xing Li

2010-02-01

1. Vascular inflammation plays a critical role in atherogenesis. Previously, we showed that baboon arterial endothelial cells (BAEC) were hyporesponsive to lipopolysaccharide (LPS) compared with human arterial endothelial cells (HAEC). 2. In the present study, we investigated mechanisms underlying differential responses between HAEC and BAEC to tumour necrosis factor (TNF)-alpha and LPS. 3. Both HAEC and BAEC responded similarly to TNF-alpha. However, BAEC showed retarded responses to LPS in expression of E-selectin, intercellular adhesion molecule-1, monocyte chemotactic protein-1 and interleukin-8 (P < 0.05). These changes were confirmed at the mRNA level. Tumour necrosis factor-alpha activated nuclear factor-kappaB members such as p50, p52, p65, c-rel and RelB in both HAEC and BAEC. In contrast, LPS activated p50 and p65 only in HAEC. Using microarray assays, we found that TNF receptor-associated factor 2 (TRAF-2), TNF receptor superfamily, member 1A-associated via death domain (TRADD) and nuclear factors such as nuclear factor of kappa in B-cells inhibitor, alpha (NFKBIA) and nuclear factor of kappa in B-cells inhibitor, beta (NFKBIB) were upregulated by LPS only in HAEC. Although the baseline expression of Toll-like receptor (TLR) 4 was low in both HAEC and BAEC, TNF-alpha activated TLR4 expression in both cell types. Although LPS increased TLR4 expression only in HAEC, human and baboon peripheral blood mononuclear cells exhibited similar TLR4 expression and response to LPS. Transfecting BAEC with TLR4/myeloid differentiation protein-2 overexpression vector conferred BAEC responsiveness to LPS. 4. The findings of the present study indicate that an altered TLR4 system may be responsible for the resistance of baboon endothelial cells to LPS. Given the importance of TLR4 in human immune responses and vascular diseases, the natural resistance of baboons to LPS/TLR4-initiated inflammation could make the baboon a valuable animal model in which to study how inflammation affects atherogenesis.

Measurements of the nuclear modification factor for jets in Pb + Pb collisions at s NN = 2.76 TeV with the ATLAS detector

DOE PAGES

Aad, G.

2015-02-20

The measurements of inclusive jet production are performed in pp and Pb+Pb collisions at √ sNN = 2.76 TeV with the ATLAS detector at the LHC, corresponding to integrated luminosities of 4.0 and 0.14 nb -1, respectively. The jets are identified with the anti-kt algorithm with R = 0.4, and the spectra are measured over the kinematic range of jet transverse momentum 32T<500 GeV and absolute rapidity |y|<2.1 and as a function of collision centrality. The nuclear modification factor R AA is evaluated, and jets are found to be suppressed by approximately a factor of 2 in central collisions comparedmore » to pp collisions. The R AA shows a slight increase with p T and no significant variation with rapidity.« less

Anti-Inflammatory Effects of Water Chestnut Extract on Cytokine Responses via Nuclear Factor-κB-signaling Pathway

PubMed Central

Kim, Bora; Kim, Jin Eun; Choi, Byung-Kook; Kim, Hyun-Soo

2015-01-01

Water chestnut (Trapa japonica Flerov.) is an annual aquatic plant. In the present study, we showed that the treatment of water chestnut extracted with boiling water resulted in a significant increase 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activity and decrease the intracellular H2O2-induced accumulation of reactive oxygen species. In addition, water chestnut extract (WCE) inhibited lipopolysaccharide (LPS)-induced nitric oxide production and suppressed mRNA and protein expression of the inducible nitric oxide synthase gene. The cytokine array results showed that WCE inhibited inflammatory cytokine secretion. Also, WCE reduced tumor necrosis factor-α-and interleukin-6-induced nuclear factor-αB activity. Furthermore, during sodium lauryl sulfate (SLS)-induced irritation of human skin, WCE reduced SLS-induced skin erythema and improved barrier regeneration. These results indicate that WCE may be a promising topical anti-inflammatory agent. PMID:25593649

Receptor activator of nuclear factor kappa β ligand (RANKL) and its relationship to coronary atherosclerosis in HIV patients

PubMed Central

Hwang, Janice J.; Wei, Jeffrey; Abbara, Suhny; Grinspoon, Steven K.; Lo, Janet

2013-01-01

HIV-infected individuals have an increased prevalence of coronary artery disease (CAD). Receptor activator of nuclear factor kappa β ligand (RANKL) and osteoprotegerin (OPG) have been postulated as mediators of vascular calcification. 78 HIV-infected men and 32 healthy controls without history of CAD were prospectively recruited to undergo cardiac computed tomography (CT) and CT angiography to assess coronary artery calcium and plaque burden. sRANKL was lower in HIV-infected individuals than controls (2.52 [1.08, 3.98] vs. 3.33 [2.44, 4.64] pg/ml, P=0.01, median [IQR] respectively). sRANKL was negatively associated with the number of coronary segments with plaque (Spearman ρ=−0.41, P<0.001) and Agatston calcium score (ρ=−0.30, P<0.01) in HIV-infected individuals even after adjusting for traditional cardiovascular risk factors. PMID:22842843

Measurements of the Nuclear Modification Factor for Jets in Pb +Pb Collisions at √{sNN}=2.76 TeV with the ATLAS Detector

NASA Astrophysics Data System (ADS)

Aad, G.; Abbott, B.; Abdallah, J.; Abdel Khalek, S.; Abdinov, O.; Aben, R.; Abi, B.; Abolins, M.; Abouzeid, O. S.; Abramowicz, H.; Abreu, H.; Abreu, R.; Abulaiti, Y.; Acharya, B. S.; Adamczyk, L.; Adams, D. L.; Adelman, J.; Adomeit, S.; Adye, T.; Agatonovic-Jovin, T.; Aguilar-Saavedra, J. A.; Agustoni, M.; Ahlen, S. P.; Ahmadov, F.; Aielli, G.; Akerstedt, H. Å.; Kesson, T. P. A.; Akimoto, G.; Akimov, A. V.; Alberghi, G. L.; Albert, J.; Albrand, S.; Alconada Verzini, M. J.; Aleksa, M.; Aleksandrov, I. N.; Alexa, C.; Alexander, G.; Alexandre, G.; Alexopoulos, T.; Alhroob, M.; Alimonti, G.; Alio, L.; Alison, J.; Allbrooke, B. M. M.; Allison, L. J.; Allport, P. P.; Almond, J.; Aloisio, A.; Alonso, A.; Alonso, F.; Alpigiani, C.; Altheimer, A.; Alvarez Gonzalez, B.; Alviggi, M. G.; Amako, K.; Amaral Coutinho, Y.; Amelung, C.; Amidei, D.; Amor Dos Santos, S. P.; Amorim, A.; Amoroso, S.; Amram, N.; Amundsen, G.; Anastopoulos, C.; Ancu, L. S.; Andari, N.; Andeen, T.; Anders, C. F.; Anders, G.; Anderson, K. J.; Andreazza, A.; Andrei, V.; Anduaga, X. S.; Angelidakis, S.; Angelozzi, I.; Anger, P.; Angerami, A.; Anghinolfi, F.; Anisenkov, A. V.; Anjos, N.; Annovi, A.; Antonaki, A.; Antonelli, M.; Antonov, A.; Antos, J.; Anulli, F.; Aoki, M.; Aperio Bella, L.; Apolle, R.; Arabidze, G.; Aracena, I.; Arai, Y.; Araque, J. P.; Arce, A. T. H.; Arguin, J.-F.; Argyropoulos, S.; Arik, M.; Armbruster, A. J.; Arnaez, O.; Arnal, V.; Arnold, H.; Arratia, M.; Arslan, O.; Artamonov, A.; Artoni, G.; Asai, S.; Asbah, N.; Ashkenazi, A.; Åsman, B.; Asquith, L.; Assamagan, K.; Astalos, R.; Atkinson, M.; Atlay, N. B.; Auerbach, B.; Augsten, K.; Aurousseau, M.; Avolio, G.; Azuelos, G.; Azuma, Y.; Baak, M. A.; Baas, A. E.; Bacci, C.; Bachacou, H.; Bachas, K.; Backes, M.; Backhaus, M.; Backus Mayes, J.; Badescu, E.; Bagiacchi, P.; Bagnaia, P.; Bai, Y.; Bain, T.; Baines, J. T.; Baker, O. K.; Balek, P.; Balli, F.; Banas, E.; Banerjee, Sw.; Bannoura, A. A. E.; Bansal, V.; Bansil, H. S.; Barak, L.; Baranov, S. P.; Barberio, E. L.; Barberis, D.; Barbero, M.; Barillari, T.; Barisonzi, M.; Barklow, T.; Barlow, N.; Barnett, B. M.; Barnett, R. M.; Barnovska, Z.; Baroncelli, A.; Barone, G.; Barr, A. J.; Barreiro, F.; Barreiro Guimarães da Costa, J.; Bartoldus, R.; Barton, A. E.; Bartos, P.; Bartsch, V.; Bassalat, A.; Basye, A.; Bates, R. L.; Batley, J. R.; Battaglia, M.; Battistin, M.; Bauer, F.; Bawa, H. S.; Beattie, M. D.; Beau, T.; Beauchemin, P. H.; Beccherle, R.; Bechtle, P.; Beck, H. P.; Becker, K.; Becker, S.; Beckingham, M.; Becot, C.; Beddall, A. J.; Beddall, A.; Bedikian, S.; Bednyakov, V. A.; Bee, C. P.; Beemster, L. J.; Beermann, T. A.; Begel, M.; Behr, K.; Belanger-Champagne, C.; Bell, P. J.; Bell, W. H.; Bella, G.; Bellagamba, L.; Bellerive, A.; Bellomo, M.; Belotskiy, K.; Beltramello, O.; Benary, O.; Benchekroun, D.; Bendtz, K.; Benekos, N.; Benhammou, Y.; Benhar Noccioli, E.; Benitez Garcia, J. A.; Benjamin, D. P.; Bensinger, J. R.; Benslama, K.; Bentvelsen, S.; Berge, D.; Bergeaas Kuutmann, E.; Berger, N.; Berghaus, F.; Beringer, J.; Bernard, C.; Bernat, P.; Bernius, C.; Bernlochner, F. U.; Berry, T.; Berta, P.; Bertella, C.; Bertoli, G.; Bertolucci, F.; Bertsche, C.; Bertsche, D.; Besana, M. I.; Besjes, G. J.; Bessidskaia Bylund, O.; Bessner, M.; Besson, N.; Betancourt, C.; Bethke, S.; Bhimji, W.; Bianchi, R. M.; Bianchini, L.; Bianco, M.; Biebel, O.; Bieniek, S. P.; Bierwagen, K.; Biesiada, J.; Biglietti, M.; Bilbao de Mendizabal, J.; Bilokon, H.; Bindi, M.; Binet, S.; Bingul, A.; Bini, C.; Black, C. W.; Black, J. E.; Black, K. M.; Blackburn, D.; Blair, R. E.; Blanchard, J.-B.; Blazek, T.; Bloch, I.; Blocker, C.; Blum, W.; Blumenschein, U.; Bobbink, G. J.; Bobrovnikov, V. S.; Bocchetta, S. S.; Bocci, A.; Bock, C.; Boddy, C. R.; Boehler, M.; Boek, T. T.; Bogaerts, J. A.; Bogdanchikov, A. G.; Bogouch, A.; Bohm, C.; Bohm, J.; Boisvert, V.; Bold, T.; Boldea, V.; Boldyrev, A. S.; Bomben, M.; Bona, M.; Boonekamp, M.; Borisov, A.; Borissov, G.; Borri, M.; Borroni, S.; Bortfeldt, J.; Bortolotto, V.; Bos, K.; Boscherini, D.; Bosman, M.; Boterenbrood, H.; Boudreau, J.; Bouffard, J.; Bouhova-Thacker, E. V.; Boumediene, D.; Bourdarios, C.; Bousson, N.; Boutouil, S.; Boveia, A.; Boyd, J.; Boyko, I. R.; Bracinik, J.; Brandt, A.; Brandt, G.; Brandt, O.; Bratzler, U.; Brau, B.; Brau, J. E.; Braun, H. M.; Brazzale, S. F.; Brelier, B.; Brendlinger, K.; Brennan, A. J.; Brenner, R.; Bressler, S.; Bristow, K.; Bristow, T. M.; Britton, D.; Brochu, F. M.; Brock, I.; Brock, R.; Bromberg, C.; Bronner, J.; Brooijmans, G.; Brooks, T.; Brooks, W. K.; Brosamer, J.; Brost, E.; Brown, J.; Bruckman de Renstrom, P. A.; Bruncko, D.; Bruneliere, R.; Brunet, S.; Bruni, A.; Bruni, G.; Bruschi, M.; Bryngemark, L.; Buanes, T.; Buat, Q.; Bucci, F.; Buchholz, P.; Buckingham, R. M.; Buckley, A. G.; Buda, S. I.; Budagov, I. A.; Buehrer, F.; Bugge, L.; Bugge, M. K.; Bulekov, O.; Bundock, A. C.; Burckhart, H.; Burdin, S.; Burghgrave, B.; Burke, S.; Burmeister, I.; Busato, E.; Büscher, D.; Büscher, V.; Bussey, P.; Buszello, C. P.; Butler, B.; Butler, J. M.; Butt, A. I.; Buttar, C. M.; Butterworth, J. M.; Butti, P.; Buttinger, W.; Buzatu, A.; Byszewski, M.; Cabrera Urbán, S.; Caforio, D.; Cakir, O.; Calafiura, P.; Calandri, A.; Calderini, G.; Calfayan, P.; Calkins, R.; Caloba, L. P.; Calvet, D.; Calvet, S.; Camacho Toro, R.; Camarda, S.; Cameron, D.; Caminada, L. M.; Caminal Armadans, R.; Campana, S.; Campanelli, M.; Campoverde, A.; Canale, V.; Canepa, A.; Cano Bret, M.; Cantero, J.; Cantrill, R.; Cao, T.; Capeans Garrido, M. D. M.; Caprini, I.; Caprini, M.; Capua, M.; Caputo, R.; Cardarelli, R.; Carli, T.; Carlino, G.; Carminati, L.; Caron, S.; Carquin, E.; Carrillo-Montoya, G. D.; Carter, J. R.; Carvalho, J.; Casadei, D.; Casado, M. P.; Casolino, M.; Castaneda-Miranda, E.; Castelli, A.; Castillo Gimenez, V.; Castro, N. F.; Catastini, P.; Catinaccio, A.; Catmore, J. R.; Cattai, A.; Cattani, G.; Caughron, S.; Cavaliere, V.; Cavalli, D.; Cavalli-Sforza, M.; Cavasinni, V.; Ceradini, F.; Cerio, B. C.; Cerny, K.; Cerqueira, A. S.; Cerri, A.; Cerrito, L.; Cerutti, F.; Cerv, M.; Cervelli, A.; Cetin, S. A.; Chafaq, A.; Chakraborty, D.; Chalupkova, I.; Chang, P.; Chapleau, B.; Chapman, J. D.; Charfeddine, D.; Charlton, D. G.; Chau, C. C.; Chavez Barajas, C. A.; Cheatham, S.; Chegwidden, A.; Chekanov, S.; Chekulaev, S. V.; Chelkov, G. A.; Chelstowska, M. A.; Chen, C.; Chen, H.; Chen, K.; Chen, L.; Chen, S.; Chen, X.; Chen, Y.; Chen, Y.; Cheng, H. C.; Cheng, Y.; Cheplakov, A.; Cherkaoui El Moursli, R.; Chernyatin, V.; Cheu, E.; Chevalier, L.; Chiarella, V.; Chiefari, G.; Childers, J. T.; Chilingarov, A.; Chiodini, G.; Chisholm, A. S.; Chislett, R. T.; Chitan, A.; Chizhov, M. V.; Chouridou, S.; Chow, B. K. B.; Chromek-Burckhart, D.; Chu, M. L.; Chudoba, J.; Chwastowski, J. J.; Chytka, L.; Ciapetti, G.; Ciftci, A. K.; Ciftci, R.; Cinca, D.; Cindro, V.; Ciocio, A.; Cirkovic, P.; Citron, Z. H.; Citterio, M.; Ciubancan, M.; Clark, A.; Clark, P. J.; Clarke, R. N.; Cleland, W.; Clemens, J. C.; Clement, C.; Coadou, Y.; Cobal, M.; Coccaro, A.; Cochran, J.; Coffey, L.; Cogan, J. G.; Coggeshall, J.; Cole, B.; Cole, S.; Colijn, A. P.; Collot, J.; Colombo, T.; Colon, G.; Compostella, G.; Conde Muiño, P.; Coniavitis, E.; Conidi, M. C.; Connell, S. H.; Connelly, I. A.; Consonni, S. M.; Consorti, V.; Constantinescu, S.; Conta, C.; Conti, G.; Conventi, F.; Cooke, M.; Cooper, B. D.; Cooper-Sarkar, A. M.; Cooper-Smith, N. J.; Copic, K.; Cornelissen, T.; Corradi, M.; Corriveau, F.; Corso-Radu, A.; Cortes-Gonzalez, A.; Cortiana, G.; Costa, G.; Costa, M. J.; Costanzo, D.; Côté, D.; Cottin, G.; Cowan, G.; Cox, B. E.; Cranmer, K.; Cree, G.; Crépé-Renaudin, S.; Crescioli, F.; Cribbs, W. A.; Crispin Ortuzar, M.; Cristinziani, M.; Croft, V.; Crosetti, G.; Cuciuc, C.-M.; Cuhadar Donszelmann, T.; Cummings, J.; Curatolo, M.; Cuthbert, C.; Czirr, H.; Czodrowski, P.; Czyczula, Z.; D'Auria, S.; D'Onofrio, M.; da Cunha Sargedas de Sousa, M. J.; da Via, C.; Dabrowski, W.; Dafinca, A.; Dai, T.; Dale, O.; Dallaire, F.; Dallapiccola, C.; Dam, M.; Daniells, A. C.; Dano Hoffmann, M.; Dao, V.; Darbo, G.; Darmora, S.; Dassoulas, J. A.; Dattagupta, A.; Davey, W.; David, C.; Davidek, T.; Davies, E.; Davies, M.; Davignon, O.; Davison, A. R.; Davison, P.; Davygora, Y.; Dawe, E.; Dawson, I.; Daya-Ishmukhametova, R. K.; de, K.; de Asmundis, R.; de Castro, S.; de Cecco, S.; de Groot, N.; de Jong, P.; de la Torre, H.; de Lorenzi, F.; de Nooij, L.; de Pedis, D.; de Salvo, A.; de Sanctis, U.; de Santo, A.; de Vivie de Regie, J. B.; Dearnaley, W. J.; Debbe, R.; Debenedetti, C.; Dechenaux, B.; Dedovich, D. V.; Deigaard, I.; Del Peso, J.; Del Prete, T.; Deliot, F.; Delitzsch, C. M.; Deliyergiyev, M.; Dell'Acqua, A.; Dell'Asta, L.; Dell'Orso, M.; Della Pietra, M.; Della Volpe, D.; Delmastro, M.; Delsart, P. A.; Deluca, C.; Demers, S.; Demichev, M.; Demilly, A.; Denisov, S. P.; Derendarz, D.; Derkaoui, J. E.; Derue, F.; Dervan, P.; Desch, K.; Deterre, C.; Deviveiros, P. O.; Dewhurst, A.; Dhaliwal, S.; di Ciaccio, A.; di Ciaccio, L.; di Domenico, A.; di Donato, C.; di Girolamo, A.; di Girolamo, B.; di Mattia, A.; di Micco, B.; di Nardo, R.; di Simone, A.; di Sipio, R.; di Valentino, D.; Dias, F. A.; Diaz, M. A.; Diehl, E. B.; Dietrich, J.; Dietzsch, T. A.; Diglio, S.; Dimitrievska, A.; Dingfelder, J.; Dionisi, C.; Dita, P.; Dita, S.; Dittus, F.; Djama, F.; Djobava, T.; Do Vale, M. A. B.; Do Valle Wemans, A.; Doan, T. K. O.; Dobos, D.; Doglioni, C.; Doherty, T.; Dohmae, T.; Dolejsi, J.; Dolezal, Z.; Dolgoshein, B. A.; Donadelli, M.; Donati, S.; Dondero, P.; Donini, J.; Dopke, J.; Doria, A.; Dova, M. T.; Doyle, A. T.; Dris, M.; Dubbert, J.; Dube, S.; Dubreuil, E.; Duchovni, E.; Duckeck, G.; Ducu, O. A.; Duda, D.; Dudarev, A.; Dudziak, F.; Duflot, L.; Duguid, L.; Dührssen, M.; Dunford, M.; Duran Yildiz, H.; Düren, M.; Durglishvili, A.; Dwuznik, M.; Dyndal, M.; Ebke, J.; Edson, W.; Edwards, N. C.; Ehrenfeld, W.; Eifert, T.; Eigen, G.; Einsweiler, K.; Ekelof, T.; El Kacimi, M.; Ellert, M.; Elles, S.; Ellinghaus, F.; Ellis, N.; Elmsheuser, J.; Elsing, M.; Emeliyanov, D.; Enari, Y.; Endner, O. C.; Endo, M.; Engelmann, R.; Erdmann, J.; Ereditato, A.; Eriksson, D.; Ernis, G.; Ernst, J.; Ernst, M.; Ernwein, J.; Errede, D.; Errede, S.; Ertel, E.; Escalier, M.; Esch, H.; Escobar, C.; Esposito, B.; Etienvre, A. I.; Etzion, E.; Evans, H.; Ezhilov, A.; Fabbri, L.; Facini, G.; Fakhrutdinov, R. M.; Falciano, S.; Falla, R. J.; Faltova, J.; Fang, Y.; Fanti, M.; Farbin, A.; Farilla, A.; Farooque, T.; Farrell, S.; Farrington, S. M.; Farthouat, P.; Fassi, F.; Fassnacht, P.; Fassouliotis, D.; Favareto, A.; Fayard, L.; Federic, P.; Fedin, O. L.; Fedorko, W.; Fehling-Kaschek, M.; Feigl, S.; Feligioni, L.; Feng, C.; Feng, E. J.; Feng, H.; Fenyuk, A. B.; Fernandez Perez, S.; Ferrag, S.; Ferrando, J.; Ferrari, A.; Ferrari, P.; Ferrari, R.; Ferreira de Lima, D. E.; Ferrer, A.; Ferrere, D.; Ferretti, C.; Ferretto Parodi, A.; Fiascaris, M.; Fiedler, F.; Filipčič, A.; Filipuzzi, M.; Filthaut, F.; Fincke-Keeler, M.; Finelli, K. D.; Fiolhais, M. C. N.; Fiorini, L.; Firan, A.; Fischer, A.; Fischer, J.; Fisher, W. C.; Fitzgerald, E. A.; Flechl, M.; Fleck, I.; Fleischmann, P.; Fleischmann, S.; Fletcher, G. T.; Fletcher, G.; Flick, T.; Floderus, A.; Flores Castillo, L. R.; Florez Bustos, A. C.; Flowerdew, M. J.; Formica, A.; Forti, A.; Fortin, D.; Fournier, D.; Fox, H.; Fracchia, S.; Francavilla, P.; Franchini, M.; Franchino, S.; Francis, D.; Franconi, L.; Franklin, M.; Franz, S.; Fraternali, M.; French, S. T.; Friedrich, C.; Friedrich, F.; Froidevaux, D.; Frost, J. A.; Fukunaga, C.; Fullana Torregrosa, E.; Fulsom, B. G.; Fuster, J.; Gabaldon, C.; Gabizon, O.; Gabrielli, A.; Gabrielli, A.; Gadatsch, S.; Gadomski, S.; Gagliardi, G.; Gagnon, P.; Galea, C.; Galhardo, B.; Gallas, E. J.; Gallo, V.; Gallop, B. J.; Gallus, P.; Galster, G.; Gan, K. K.; Gandrajula, R. P.; Gao, J.; Gao, Y. S.; Garay Walls, F. M.; Garberson, F.; García, C.; García Navarro, J. E.; Garcia-Sciveres, M.; Gardner, R. W.; Garelli, N.; Garonne, V.; Gatti, C.; Gaudio, G.; Gaur, B.; Gauthier, L.; Gauzzi, P.; Gavrilenko, I. L.; Gay, C.; Gaycken, G.; Gazis, E. N.; Ge, P.; Gecse, Z.; Gee, C. N. P.; Geerts, D. A. A.; Geich-Gimbel, Ch.; Gellerstedt, K.; Gemme, C.; Gemmell, A.; Genest, M. H.; Gentile, S.; George, M.; George, S.; Gerbaudo, D.; Gershon, A.; Ghazlane, H.; Ghodbane, N.; Giacobbe, B.; Giagu, S.; Giangiobbe, V.; Giannetti, P.; Gianotti, F.; Gibbard, B.; Gibson, S. M.; Gilchriese, M.; Gillam, T. P. S.; Gillberg, D.; Gilles, G.; Gingrich, D. M.; Giokaris, N.; Giordani, M. P.; Giordano, R.; Giorgi, F. M.; Giorgi, F. M.; Giraud, P. F.; Giugni, D.; Giuliani, C.; Giulini, M.; Gjelsten, B. K.; Gkaitatzis, S.; Gkialas, I.; Gladilin, L. K.; Glasman, C.; Glatzer, J.; Glaysher, P. C. F.; Glazov, A.; Glonti, G. L.; Goblirsch-Kolb, M.; Goddard, J. R.; Godfrey, J.; Godlewski, J.; Goeringer, C.; Goldfarb, S.; Golling, T.; Golubkov, D.; Gomes, A.; Gomez Fajardo, L. S.; Gonçalo, R.; Goncalves Pinto Firmino da Costa, J.; Gonella, L.; González de La Hoz, S.; Gonzalez Parra, G.; Gonzalez-Sevilla, S.; Goossens, L.; Gorbounov, P. A.; Gordon, H. A.; Gorelov, I.; Gorini, B.; Gorini, E.; Gorišek, A.; Gornicki, E.; Goshaw, A. T.; Gössling, C.; Gostkin, M. I.; Gouighri, M.; Goujdami, D.; Goulette, M. P.; Goussiou, A. G.; Goy, C.; Gozpinar, S.; Grabas, H. M. X.; Graber, L.; Grabowska-Bold, I.; Grafström, P.; Grahn, K.-J.; Gramling, J.; Gramstad, E.; Grancagnolo, S.; Grassi, V.; Gratchev, V.; Gray, H. M.; Graziani, E.; Grebenyuk, O. G.; Greenwood, Z. D.; Gregersen, K.; Gregor, I. M.; Grenier, P.; Griffiths, J.; Grillo, A. A.; Grimm, K.; Grinstein, S.; Gris, Ph.; Grishkevich, Y. V.; Grivaz, J.-F.; Grohs, J. P.; Grohsjean, A.; Gross, E.; Grosse-Knetter, J.; Grossi, G. C.; Groth-Jensen, J.; Grout, Z. J.; Guan, L.; Guescini, F.; Guest, D.; Gueta, O.; Guicheney, C.; Guido, E.; Guillemin, T.; Guindon, S.; Gul, U.; Gumpert, C.; Gunther, J.; Guo, J.; Gupta, S.; Gutierrez, P.; Gutierrez Ortiz, N. G.; Gutschow, C.; Guttman, N.; Guyot, C.; Gwenlan, C.; Gwilliam, C. B.; Haas, A.; Haber, C.; Hadavand, H. K.; Haddad, N.; Haefner, P.; Hageböck, S.; Hajduk, Z.; Hakobyan, H.; Haleem, M.; Hall, D.; Halladjian, G.; Hamacher, K.; Hamal, P.; Hamano, K.; Hamer, M.; Hamilton, A.; Hamilton, S.; Hamity, G. N.; Hamnett, P. G.; Han, L.; Hanagaki, K.; Hanawa, K.; Hance, M.; Hanke, P.; Hanna, R.; Hansen, J. B.; Hansen, J. D.; Hansen, P. H.; Hara, K.; Hard, A. S.; Harenberg, T.; Hariri, F.; Harkusha, S.; Harper, D.; Harrington, R. D.; Harris, O. M.; Harrison, P. F.; Hartjes, F.; Hasegawa, M.; Hasegawa, S.; Hasegawa, Y.; Hasib, A.; Hassani, S.; Haug, S.; Hauschild, M.; Hauser, R.; Havranek, M.; Hawkes, C. M.; Hawkings, R. J.; Hawkins, A. D.; Hayashi, T.; Hayden, D.; Hays, C. P.; Hayward, H. S.; Haywood, S. J.; Head, S. J.; Heck, T.; Hedberg, V.; Heelan, L.; Heim, S.; Heim, T.; Heinemann, B.; Heinrich, L.; Hejbal, J.; Helary, L.; Heller, C.; Heller, M.; Hellman, S.; Hellmich, D.; Helsens, C.; Henderson, J.; Henderson, R. C. W.; Heng, Y.; Hengler, C.; Henrichs, A.; Henriques Correia, A. M.; Henrot-Versille, S.; Hensel, C.; Herbert, G. H.; Hernández Jiménez, Y.; Herrberg-Schubert, R.; Herten, G.; Hertenberger, R.; Hervas, L.; Hesketh, G. G.; Hessey, N. P.; Hickling, R.; Higón-Rodriguez, E.; Hill, E.; Hill, J. C.; Hiller, K. H.; Hillert, S.; Hillier, S. J.; Hinchliffe, I.; Hines, E.; Hirose, M.; Hirschbuehl, D.; Hobbs, J.; Hod, N.; Hodgkinson, M. C.; Hodgson, P.; Hoecker, A.; Hoeferkamp, M. R.; Hoenig, F.; Hoffman, J.; Hoffmann, D.; Hofmann, J. I.; Hohlfeld, M.; Holmes, T. R.; Hong, T. M.; Hooft van Huysduynen, L.; Hostachy, J.-Y.; Hou, S.; Hoummada, A.; Howard, J.; Howarth, J.; Hrabovsky, M.; Hristova, I.; Hrivnac, J.; Hryn'ova, T.; Hsu, C.; Hsu, P. J.; Hsu, S.-C.; Hu, D.; Hu, X.; Huang, Y.; Hubacek, Z.; Hubaut, F.; Huegging, F.; Huffman, T. B.; Hughes, E. W.; Hughes, G.; Huhtinen, M.; Hülsing, T. A.; Hurwitz, M.; Huseynov, N.; Huston, J.; Huth, J.; Iacobucci, G.; Iakovidis, G.; Ibragimov, I.; Iconomidou-Fayard, L.; Ideal, E.; Iengo, P.; Igonkina, O.; Iizawa, T.; Ikegami, Y.; Ikematsu, K.; Ikeno, M.; Ilchenko, Y.; Iliadis, D.; Ilic, N.; Inamaru, Y.; Ince, T.; Ioannou, P.; Iodice, M.; Iordanidou, K.; Ippolito, V.; Irles Quiles, A.; Isaksson, C.; Ishino, M.; Ishitsuka, M.; Ishmukhametov, R.; Issever, C.; Istin, S.; Iturbe Ponce, J. M.; Iuppa, R.; Ivarsson, J.; Iwanski, W.; Iwasaki, H.; Izen, J. M.; Izzo, V.; Jackson, B.; Jackson, M.; Jackson, P.; Jaekel, M. R.; Jain, V.; Jakobs, K.; Jakobsen, S.; Jakoubek, T.; Jakubek, J.; Jamin, D. O.; Jana, D. K.; Jansen, E.; Jansen, H.; Janssen, J.; Janus, M.; Jarlskog, G.; Javadov, N.; Javå¯Rek, T.; Jeanty, L.; Jejelava, J.; Jeng, G.-Y.; Jennens, D.; Jenni, P.; Jentzsch, J.; Jeske, C.; Jézéquel, S.; Ji, H.; Jia, J.; Jiang, Y.; Jimenez Belenguer, M.; Jin, S.; Jinaru, A.; Jinnouchi, O.; Joergensen, M. D.; Johansson, K. E.; Johansson, P.; Johns, K. A.; Jon-And, K.; Jones, G.; Jones, R. W. L.; Jones, T. J.; Jongmanns, J.; Jorge, P. M.; Joshi, K. D.; Jovicevic, J.; Ju, X.; Jung, C. A.; Jungst, R. M.; Jussel, P.; Juste Rozas, A.; Kaci, M.; Kaczmarska, A.; Kado, M.; Kagan, H.; Kagan, M.; Kajomovitz, E.; Kalderon, C. W.; Kama, S.; Kamenshchikov, A.; Kanaya, N.; Kaneda, M.; Kaneti, S.; Kantserov, V. A.; Kanzaki, J.; Kaplan, B.; Kapliy, A.; Kar, D.; Karakostas, K.; Karastathis, N.; Karnevskiy, M.; Karpov, S. N.; Karpova, Z. M.; Karthik, K.; Kartvelishvili, V.; Karyukhin, A. N.; Kashif, L.; Kasieczka, G.; Kass, R. D.; Kastanas, A.; Kataoka, Y.; Katre, A.; Katzy, J.; Kaushik, V.; Kawagoe, K.; Kawamoto, T.; Kawamura, G.; Kazama, S.; Kazanin, V. F.; Kazarinov, M. Y.; Keeler, R.; Kehoe, R.; Keil, M.; Keller, J. S.; Kempster, J. J.; Keoshkerian, H.; Kepka, O.; Kerševan, B. P.; Kersten, S.; Kessoku, K.; Keung, J.; Khalil-Zada, F.; Khandanyan, H.; Khanov, A.; Khodinov, A.; Khomich, A.; Khoo, T. J.; Khoriauli, G.; Khoroshilov, A.; Khovanskiy, V.; Khramov, E.; Khubua, J.; Kim, H. Y.; Kim, H.; Kim, S. H.; Kimura, N.; Kind, O.; King, B. T.; King, M.; King, R. S. B.; King, S. B.; Kirk, J.; Kiryunin, A. E.; Kishimoto, T.; Kisielewska, D.; Kiss, F.; Kittelmann, T.; Kiuchi, K.; Kladiva, E.; Klein, M.; Klein, U.; Kleinknecht, K.; Klimek, P.; Klimentov, A.; Klingenberg, R.; Klinger, J. A.; Klioutchnikova, T.; Klok, P. F.; Kluge, E.-E.; Kluit, P.; Kluth, S.; Kneringer, E.; Knoops, E. B. F. G.; Knue, A.; Kobayashi, D.; Kobayashi, T.; Kobel, M.; Kocian, M.; Kodys, P.; Koevesarki, P.; Koffas, T.; Koffeman, E.; Kogan, L. A.; Kohlmann, S.; Kohout, Z.; Kohriki, T.; Koi, T.; Kolanoski, H.; Koletsou, I.; Koll, J.; Komar, A. A.; Komori, Y.; Kondo, T.; Kondrashova, N.; Köneke, K.; König, A. C.; König, S.; Kono, T.; Konoplich, R.; Konstantinidis, N.; Kopeliansky, R.; Koperny, S.; Köpke, L.; Kopp, A. K.; Korcyl, K.; Kordas, K.; Korn, A.; Korol, A. A.; Korolkov, I.; Korolkova, E. V.; Korotkov, V. A.; Kortner, O.; Kortner, S.; Kostyukhin, V. V.; Kotov, V. M.; Kotwal, A.; Kourkoumelis, C.; Kouskoura, V.; Koutsman, A.; Kowalewski, R.; Kowalski, T. Z.; Kozanecki, W.; Kozhin, A. S.; Kral, V.; Kramarenko, V. A.; Kramberger, G.; Krasnopevtsev, D.; Krasny, M. W.; Krasznahorkay, A.; Kraus, J. K.; Kravchenko, A.; Kreiss, S.; Kretz, M.; Kretzschmar, J.; Kreutzfeldt, K.; Krieger, P.; Kroeninger, K.; Kroha, H.; Kroll, J.; Kroseberg, J.; Krstic, J.; Kruchonak, U.; Krüger, H.; Kruker, T.; Krumnack, N.; Krumshteyn, Z. V.; Kruse, A.; Kruse, M. C.; Kruskal, M.; Kubota, T.; Kuday, S.; Kuehn, S.; Kugel, A.; Kuhl, A.; Kuhl, T.; Kukhtin, V.; Kulchitsky, Y.; Kuleshov, S.; Kuna, M.; Kunkle, J.; Kupco, A.; Kurashige, H.; Kurochkin, Y. A.; Kurumida, R.; Kus, V.; Kuwertz, E. S.; Kuze, M.; Kvita, J.; La Rosa, A.; La Rotonda, L.; Lacasta, C.; Lacava, F.; Lacey, J.; Lacker, H.; Lacour, D.; Lacuesta, V. R.; Ladygin, E.; Lafaye, R.; Laforge, B.; Lagouri, T.; Lai, S.; Laier, H.; Lambourne, L.; Lammers, S.; Lampen, C. L.; Lampl, W.; Lançon, E.; Landgraf, U.; Landon, M. P. J.; Lang, V. S.; Lankford, A. J.; Lanni, F.; Lantzsch, K.; Laplace, S.; Lapoire, C.; Laporte, J. F.; Lari, T.; Lassnig, M.; Laurelli, P.; Lavrijsen, W.; Law, A. T.; Laycock, P.; Le Dortz, O.; Le Guirriec, E.; Le Menedeu, E.; Lecompte, T.; Ledroit-Guillon, F.; Lee, C. A.; Lee, H.; Lee, J. S. H.; Lee, S. C.; Lee, L.; Lefebvre, G.; Lefebvre, M.; Legger, F.; Leggett, C.; Lehan, A.; Lehmacher, M.; Lehmann Miotto, G.; Lei, X.; Leight, W. A.; Leisos, A.; Leister, A. G.; Leite, M. A. L.; Leitner, R.; Lellouch, D.; Lemmer, B.; Leney, K. J. C.; Lenz, T.; Lenzen, G.; Lenzi, B.; Leone, R.; Leone, S.; Leonhardt, K.; Leonidopoulos, C.; Leontsinis, S.; Leroy, C.; Lester, C. G.; Lester, C. M.; Levchenko, M.; Levêque, J.; Levin, D.; Levinson, L. J.; Levy, M.; Lewis, A.; Lewis, G. H.; Leyko, A. M.; Leyton, M.; Li, B.; Li, B.; Li, H.; Li, H. L.; Li, L.; Li, L.; Li, S.; Li, Y.; Liang, Z.; Liao, H.; Liberti, B.; Lichard, P.; Lie, K.; Liebal, J.; Liebig, W.; Limbach, C.; Limosani, A.; Lin, S. C.; Lin, T. H.; Linde, F.; Lindquist, B. E.; Linnemann, J. T.; Lipeles, E.; Lipniacka, A.; Lisovyi, M.; Liss, T. M.; Lissauer, D.; Lister, A.; Litke, A. M.; Liu, B.; Liu, D.; Liu, J. B.; Liu, K.; Liu, L.; Liu, M.; Liu, M.; Liu, Y.; Livan, M.; Livermore, S. S. A.; Lleres, A.; Llorente Merino, J.; Lloyd, S. L.; Lo Sterzo, F.; Lobodzinska, E.; Loch, P.; Lockman, W. S.; Loddenkoetter, T.; Loebinger, F. K.; Loevschall-Jensen, A. E.; Loginov, A.; Lohse, T.; Lohwasser, K.; Lokajicek, M.; Lombardo, V. P.; Long, B. A.; Long, J. D.; Long, R. E.; Lopes, L.; Lopez Mateos, D.; Lopez Paredes, B.; Lopez Paz, I.; Lorenz, J.; Lorenzo Martinez, N.; Losada, M.; Loscutoff, P.; Lou, X.; Lounis, A.; Love, J.; Love, P. A.; Lowe, A. J.; Lu, F.; Lu, N.; Lubatti, H. J.; Luci, C.; Lucotte, A.; Luehring, F.; Lukas, W.; Luminari, L.; Lundberg, O.; Lund-Jensen, B.; Lungwitz, M.; Lynn, D.; Lysak, R.; Lytken, E.; Ma, H.; Ma, L. L.; Maccarrone, G.; Macchiolo, A.; Machado Miguens, J.; Macina, D.; Madaffari, D.; Madar, R.; Maddocks, H. J.; Mader, W. F.; Madsen, A.; Maeno, M.; Maeno, T.; Magradze, E.; Mahboubi, K.; Mahlstedt, J.; Mahmoud, S.; Maiani, C.; Maidantchik, C.; Maier, A. A.; Maio, A.; Majewski, S.; Makida, Y.; Makovec, N.; Mal, P.; Malaescu, B.; Malecki, Pa.; Maleev, V. P.; Malek, F.; Mallik, U.; Malon, D.; Malone, C.; Maltezos, S.; Malyshev, V. M.; Malyukov, S.; Mamuzic, J.; Mandelli, B.; Mandelli, L.; Mandić, I.; Mandrysch, R.; Maneira, J.; Manfredini, A.; Manhaes de Andrade Filho, L.; Manjarres Ramos, J. A.; Mann, A.; Manning, P. M.; Manousakis-Katsikakis, A.; Mansoulie, B.; Mantifel, R.; Mapelli, L.; March, L.; Marchand, J. F.; Marchiori, G.; Marcisovsky, M.; Marino, C. P.; Marjanovic, M.; Marques, C. N.; Marroquim, F.; Marsden, S. P.; Marshall, Z.; Marti, L. F.; Marti-Garcia, S.; Martin, B.; Martin, B.; Martin, T. A.; Martin, V. J.; Martin Dit Latour, B.; Martinez, H.; Martinez, M.; Martin-Haugh, S.; Martyniuk, A. C.; Marx, M.; Marzano, F.; Marzin, A.; Masetti, L.; Mashimo, T.; Mashinistov, R.; Masik, J.; Maslennikov, A. L.; Massa, I.; Massa, L.; Massol, N.; Mastrandrea, P.; Mastroberardino, A.; Masubuchi, T.; Mättig, P.; Mattmann, J.; Maurer, J.; Maxfield, S. J.; Maximov, D. A.; Mazini, R.; Mazzaferro, L.; Mc Goldrick, G.; Mc Kee, S. P.; McCarn, A.; McCarthy, R. L.; McCarthy, T. G.; McCubbin, N. A.; McFarlane, K. W.; McFayden, J. A.; McHedlidze, G.; McMahon, S. J.; McPherson, R. A.; Meade, A.; Mechnich, J.; Medinnis, M.; Meehan, S.; Mehlhase, S.; Mehta, A.; Meier, K.; Meineck, C.; Meirose, B.; Melachrinos, C.; Mellado Garcia, B. R.; Meloni, F.; Mengarelli, A.; Menke, S.; Meoni, E.; Mercurio, K. M.; Mergelmeyer, S.; Meric, N.; Mermod, P.; Merola, L.; Meroni, C.; Merritt, F. S.; Merritt, H.; Messina, A.; Metcalfe, J.; Mete, A. S.; Meyer, C.; Meyer, C.; Meyer, J.-P.; Meyer, J.; Middleton, R. P.; Migas, S.; Mijović, L.; Mikenberg, G.; Mikestikova, M.; Mikuž, M.; Milic, A.; Miller, D. W.; Mills, C.; Milov, A.; Milstead, D. A.; Milstein, D.; Minaenko, A. A.; Minashvili, I. A.; Mincer, A. I.; Mindur, B.; Mineev, M.; Ming, Y.; Mir, L. M.; Mirabelli, G.; Mitani, T.; Mitrevski, J.; Mitsou, V. A.; Mitsui, S.; Miucci, A.; Miyagawa, P. S.; Mjörnmark, J. U.; Moa, T.; Mochizuki, K.; Mohapatra, S.; Mohr, W.; Molander, S.; Moles-Valls, R.; Mönig, K.; Monini, C.; Monk, J.; Monnier, E.; Montejo Berlingen, J.; Monticelli, F.; Monzani, S.; Moore, R. W.; Moraes, A.; Morange, N.; Moreno, D.; Moreno Llácer, M.; Morettini, P.; Morgenstern, M.; Morii, M.; Moritz, S.; Morley, A. K.; Mornacchi, G.; Morris, J. D.; Morvaj, L.; Moser, H. G.; Mosidze, M.; Moss, J.; Motohashi, K.; Mount, R.; Mountricha, E.; Mouraviev, S. V.; Moyse, E. J. W.; Muanza, S.; Mudd, R. D.; Mueller, F.; Mueller, J.; Mueller, K.; Mueller, T.; Mueller, T.; Muenstermann, D.; Munwes, Y.; Murillo Quijada, J. A.; Murray, W. J.; Musheghyan, H.; Musto, E.; Myagkov, A. G.; Myska, M.; Nackenhorst, O.; Nadal, J.; Nagai, K.; Nagai, R.; Nagai, Y.; Nagano, K.; Nagarkar, A.; Nagasaka, Y.; Nagel, M.; Nairz, A. M.; Nakahama, Y.; Nakamura, K.; Nakamura, T.; Nakano, I.; Namasivayam, H.; Nanava, G.; Narayan, R.; Nattermann, T.; Naumann, T.; Navarro, G.; Nayyar, R.; Neal, H. A.; Nechaeva, P. Yu.; Neep, T. J.; Nef, P. D.; Negri, A.; Negri, G.; Negrini, M.; Nektarijevic, S.; Nelson, A.; Nelson, T. K.; Nemecek, S.; Nemethy, P.; Nepomuceno, A. A.; Nessi, M.; Neubauer, M. S.; Neumann, M.; Neves, R. M.; Nevski, P.; Newman, P. R.; Nguyen, D. H.; Nickerson, R. B.; Nicolaidou, R.; Nicquevert, B.; Nielsen, J.; Nikiforou, N.; Nikiforov, A.; Nikolaenko, V.; Nikolic-Audit, I.; Nikolics, K.; Nikolopoulos, K.; Nilsson, P.; Ninomiya, Y.; Nisati, A.; Nisius, R.; Nobe, T.; Nodulman, L.; Nomachi, M.; Nomidis, I.; Norberg, S.; Nordberg, M.; Novgorodova, O.; Nowak, S.; Nozaki, M.; Nozka, L.; Ntekas, K.; Nunes Hanninger, G.; Nunnemann, T.; Nurse, E.; Nuti, F.; O'Brien, B. J.; O'Grady, F.; O'Neil, D. C.; O'Shea, V.; Oakham, F. G.; Oberlack, H.; Obermann, T.; Ocariz, J.; Ochi, A.; Ochoa, M. I.; Oda, S.; Odaka, S.; Ogren, H.; Oh, A.; Oh, S. H.; Ohm, C. C.; Ohman, H.; Okamura, W.; Okawa, H.; Okumura, Y.; Okuyama, T.; Olariu, A.; Olchevski, A. G.; Olivares Pino, S. A.; Oliveira Damazio, D.; Oliver Garcia, E.; Olszewski, A.; Olszowska, J.; Onofre, A.; Onyisi, P. U. E.; Oram, C. J.; Oreglia, M. J.; Oren, Y.; Orestano, D.; Orlando, N.; Oropeza Barrera, C.; Orr, R. S.; Osculati, B.; Ospanov, R.; Otero Y Garzon, G.; Otono, H.; Ouchrif, M.; Ouellette, E. A.; Ould-Saada, F.; Ouraou, A.; Oussoren, K. P.; Ouyang, Q.; Ovcharova, A.; Owen, M.; Ozcan, V. E.; Ozturk, N.; Pachal, K.; Pacheco Pages, A.; Padilla Aranda, C.; Pagáčová, M.; Pagan Griso, S.; Paganis, E.; Pahl, C.; Paige, F.; Pais, P.; Pajchel, K.; Palacino, G.; Palestini, S.; Palka, M.; Pallin, D.; Palma, A.; Palmer, J. D.; Pan, Y. B.; Panagiotopoulou, E.; Panduro Vazquez, J. G.; Pani, P.; Panikashvili, N.; Panitkin, S.; Pantea, D.; Paolozzi, L.; Papadopoulou, Th. D.; Papageorgiou, K.; Paramonov, A.; Paredes Hernandez, D.; Parker, M. A.; Parodi, F.; Parsons, J. A.; Parzefall, U.; Pasqualucci, E.; Passaggio, S.; Passeri, A.; Pastore, F.; Pastore, Fr.; Pásztor, G.; Pataraia, S.; Patel, N. D.; Pater, J. R.; Patricelli, S.; Pauly, T.; Pearce, J.; Pedersen, M.; Pedraza Lopez, S.; Pedro, R.; Peleganchuk, S. V.; Pelikan, D.; Peng, H.; Penning, B.; Penwell, J.; Perepelitsa, D. V.; Perez Codina, E.; Pérez García-Estañ, M. T.; Perez Reale, V.; Perini, L.; Pernegger, H.; Perrino, R.; Peschke, R.; Peshekhonov, V. D.; Peters, K.; Peters, R. F. Y.; Petersen, B. A.; Petersen, T. C.; Petit, E.; Petridis, A.; Petridou, C.; Petrolo, E.; Petrucci, F.; Pettersson, N. E.; Pezoa, R.; Phillips, P. W.; Piacquadio, G.; Pianori, E.; Picazio, A.; Piccaro, E.; Piccinini, M.; Piegaia, R.; Pignotti, D. T.; Pilcher, J. E.; Pilkington, A. D.; Pina, J.; Pinamonti, M.; Pinder, A.; Pinfold, J. L.; Pingel, A.; Pinto, B.; Pires, S.; Pitt, M.; Pizio, C.; Plazak, L.; Pleier, M.-A.; Pleskot, V.; Plotnikova, E.; Plucinski, P.; Poddar, S.; Podlyski, F.; Poettgen, R.; Poggioli, L.; Pohl, D.; Pohl, M.; Polesello, G.; Policicchio, A.; Polifka, R.; Polini, A.; Pollard, C. S.; Polychronakos, V.; Pommès, K.; Pontecorvo, L.; Pope, B. G.; Popeneciu, G. A.; Popovic, D. S.; Poppleton, A.; Portell Bueso, X.; Pospisil, S.; Potamianos, K.; Potrap, I. N.; Potter, C. J.; Potter, C. T.; Poulard, G.; Poveda, J.; Pozdnyakov, V.; Pralavorio, P.; Pranko, A.; Prasad, S.; Pravahan, R.; Prell, S.; Price, D.; Price, J.; Price, L. E.; Prieur, D.; Primavera, M.; Proissl, M.; Prokofiev, K.; Prokoshin, F.; Protopapadaki, E.; Protopopescu, S.; Proudfoot, J.; Przybycien, M.; Przysiezniak, H.; Ptacek, E.; Puddu, D.; Pueschel, E.; Puldon, D.; Purohit, M.; Puzo, P.; Qian, J.; Qin, G.; Qin, Y.; Quadt, A.; Quarrie, D. R.; Quayle, W. B.; Queitsch-Maitland, M.; Quilty, D.; Qureshi, A.; Radeka, V.; Radescu, V.; Radhakrishnan, S. K.; Radloff, P.; Rados, P.; Ragusa, F.; Rahal, G.; Rajagopalan, S.; Rammensee, M.; Randle-Conde, A. S.; Rangel-Smith, C.; Rao, K.; Rauscher, F.; Rave, T. C.; Ravenscroft, T.; Raymond, M.; Read, A. L.; Readioff, N. P.; Rebuzzi, D. M.; Redelbach, A.; Redlinger, G.; Reece, R.; Reeves, K.; Rehnisch, L.; Reisin, H.; Relich, M.; Rembser, C.; Ren, H.; Ren, Z. L.; Renaud, A.; Rescigno, M.; Resconi, S.; Rezanova, O. L.; Reznicek, P.; Rezvani, R.; Richter, R.; Ridel, M.; Rieck, P.; Rieger, J.; Rijssenbeek, M.; Rimoldi, A.; Rinaldi, L.; Ritsch, E.; Riu, I.; Rizatdinova, F.; Rizvi, E.; Robertson, S. H.; Robichaud-Veronneau, A.; Robinson, D.; Robinson, J. E. M.; Robson, A.; Roda, C.; Rodrigues, L.; Roe, S.; Røhne, O.; Rolli, S.; Romaniouk, A.; Romano, M.; Romero Adam, E.; Rompotis, N.; Ronzani, M.; Roos, L.; Ros, E.; Rosati, S.; Rosbach, K.; Rose, M.; Rose, P.; Rosendahl, P. L.; Rosenthal, O.; Rossetti, V.; Rossi, E.; Rossi, L. P.; Rosten, R.; Rotaru, M.; Roth, I.; Rothberg, J.; Rousseau, D.; Royon, C. R.; Rozanov, A.; Rozen, Y.; Ruan, X.; Rubbo, F.; Rubinskiy, I.; Rud, V. I.; Rudolph, C.; Rudolph, M. S.; Rühr, F.; Ruiz-Martinez, A.; Rurikova, Z.; Rusakovich, N. A.; Ruschke, A.; Rutherfoord, J. P.; Ruthmann, N.; Ryabov, Y. F.; Rybar, M.; Rybkin, G.; Ryder, N. C.; Saavedra, A. F.; Sacerdoti, S.; Saddique, A.; Sadeh, I.; Sadrozinski, H. F.-W.; Sadykov, R.; Safai Tehrani, F.; Sakamoto, H.; Sakurai, Y.; Salamanna, G.; Salamon, A.; Saleem, M.; Salek, D.; Sales de Bruin, P. H.; Salihagic, D.; Salnikov, A.; Salt, J.; Salvatore, D.; Salvatore, F.; Salvucci, A.; Salzburger, A.; Sampsonidis, D.; Sanchez, A.; Sánchez, J.; Sanchez Martinez, V.; Sandaker, H.; Sandbach, R. L.; Sander, H. G.; Sanders, M. P.; Sandhoff, M.; Sandoval, T.; Sandoval, C.; Sandstroem, R.; Sankey, D. P. C.; Sansoni, A.; Santoni, C.; Santonico, R.; Santos, H.; Santoyo Castillo, I.; Sapp, K.; Sapronov, A.; Saraiva, J. G.; Sarrazin, B.; Sartisohn, G.; Sasaki, O.; Sasaki, Y.; Sauvage, G.; Sauvan, E.; Savard, P.; Savu, D. O.; Sawyer, C.; Sawyer, L.; Saxon, D. H.; Saxon, J.; Sbarra, C.; Sbrizzi, A.; Scanlon, T.; Scannicchio, D. A.; Scarcella, M.; Scarfone, V.; Schaarschmidt, J.; Schacht, P.; Schaefer, D.; Schaefer, R.; Schaepe, S.; Schaetzel, S.; Schäfer, U.; Schaffer, A. C.; Schaile, D.; Schamberger, R. D.; Scharf, V.; Schegelsky, V. A.; Scheirich, D.; Schernau, M.; Scherzer, M. I.; Schiavi, C.; Schieck, J.; Schillo, C.; Schioppa, M.; Schlenker, S.; Schmidt, E.; Schmieden, K.; Schmitt, C.; Schmitt, S.; Schneider, B.; Schnellbach, Y. J.; Schnoor, U.; Schoeffel, L.; Schoening, A.; Schoenrock, B. D.; Schorlemmer, A. L. S.; Schott, M.; Schouten, D.; Schovancova, J.; Schramm, S.; Schreyer, M.; Schroeder, C.; Schuh, N.; Schultens, M. J.; Schultz-Coulon, H.-C.; Schulz, H.; Schumacher, M.; Schumm, B. A.; Schune, Ph.; Schwanenberger, C.; Schwartzman, A.; Schwegler, Ph.; Schwemling, Ph.; Schwienhorst, R.; Schwindling, J.; Schwindt, T.; Schwoerer, M.; Sciacca, F. G.; Scifo, E.; Sciolla, G.; Scott, W. G.; Scuri, F.; Scutti, F.; Searcy, J.; Sedov, G.; Sedykh, E.; Seidel, S. C.; Seiden, A.; Seifert, F.; Seixas, J. M.; Sekhniaidze, G.; Sekula, S. J.; Selbach, K. E.; Seliverstov, D. M.; Sellers, G.; Semprini-Cesari, N.; Serfon, C.; Serin, L.; Serkin, L.; Serre, T.; Seuster, R.; Severini, H.; Sfiligoj, T.; Sforza, F.; Sfyrla, A.; Shabalina, E.; Shamim, M.; Shan, L. Y.; Shang, R.; Shank, J. T.; Shapiro, M.; Shatalov, P. B.; Shaw, K.; Shehu, C. Y.; Sherwood, P.; Shi, L.; Shimizu, S.; Shimmin, C. O.; Shimojima, M.; Shiyakova, M.; Shmeleva, A.; Shochet, M. J.; Short, D.; Shrestha, S.; Shulga, E.; Shupe, M. A.; Shushkevich, S.; Sicho, P.; Sidiropoulou, O.; Sidorov, D.; Sidoti, A.; Siegert, F.; Sijacki, Dj.; Silva, J.; Silver, Y.; Silverstein, D.; Silverstein, S. B.; Simak, V.; Simard, O.; Simic, Lj.; Simion, S.; Simioni, E.; Simmons, B.; Simoniello, R.; Simonyan, M.; Sinervo, P.; Sinev, N. B.; Sipica, V.; Siragusa, G.; Sircar, A.; Sisakyan, A. N.; Sivoklokov, S. Yu.; Sjölin, J.; Sjursen, T. B.; Skottowe, H. P.; Skovpen, K. Yu.; Skubic, P.; Slater, M.; Slavicek, T.; Sliwa, K.; Smakhtin, V.; Smart, B. H.; Smestad, L.; Smirnov, S. Yu.; Smirnov, Y.; Smirnova, L. N.; Smirnova, O.; Smith, K. M.; Smizanska, M.; Smolek, K.; Snesarev, A. A.; Snidero, G.; Snyder, S.; Sobie, R.; Socher, F.; Soffer, A.; Soh, D. A.; Solans, C. A.; Solar, M.; Solc, J.; Soldatov, E. Yu.; Soldevila, U.; Solodkov, A. A.; Soloshenko, A.; Solovyanov, O. V.; Solovyev, V.; Sommer, P.; Song, H. Y.; Soni, N.; Sood, A.; Sopczak, A.; Sopko, B.; Sopko, V.; Sorin, V.; Sosebee, M.; Soualah, R.; Soueid, P.; Soukharev, A. M.; South, D.; Spagnolo, S.; Spanò, F.; Spearman, W. R.; Spettel, F.; Spighi, R.; Spigo, G.; Spiller, L. A.; Spousta, M.; Spreitzer, T.; Spurlock, B.; St. Denis, R. D.; Staerz, S.; Stahlman, J.; Stamen, R.; Stamm, S.; Stanecka, E.; Stanek, R. W.; Stanescu, C.; Stanescu-Bellu, M.; Stanitzki, M. M.; Stapnes, S.; Starchenko, E. A.; Stark, J.; Staroba, P.; Starovoitov, P.; Staszewski, R.; Stavina, P.; Steinberg, P.; Stelzer, B.; Stelzer, H. J.; Stelzer-Chilton, O.; Stenzel, H.; Stern, S.; Stewart, G. A.; Stillings, J. A.; Stockton, M. C.; Stoebe, M.; Stoicea, G.; Stolte, P.; Stonjek, S.; Stradling, A. R.; Straessner, A.; Stramaglia, M. E.; Strandberg, J.; Strandberg, S.; Strandlie, A.; Strauss, E.; Strauss, M.; Strizenec, P.; Ströhmer, R.; Strom, D. M.; Stroynowski, R.; Stucci, S. A.; Stugu, B.; Styles, N. A.; Su, D.; Su, J.; Subramaniam, R.; Succurro, A.; Sugaya, Y.; Suhr, C.; Suk, M.; Sulin, V. V.; Sultansoy, S.; Sumida, T.; Sun, S.; Sun, X.; Sundermann, J. E.; Suruliz, K.; Susinno, G.; Sutton, M. R.; Suzuki, Y.; Svatos, M.; Swedish, S.; Swiatlowski, M.; Sykora, I.; Sykora, T.; Ta, D.; Taccini, C.; Tackmann, K.; Taenzer, J.; Taffard, A.; Tafirout, R.; Taiblum, N.; Takai, H.; Takashima, R.; Takeda, H.; Takeshita, T.; Takubo, Y.; Talby, M.; Talyshev, A. A.; Tam, J. Y. C.; Tan, K. G.; Tanaka, J.; Tanaka, R.; Tanaka, S.; Tanaka, S.; Tanasijczuk, A. J.; Tannenwald, B. B.; Tannoury, N.; Tapprogge, S.; Tarem, S.; Tarrade, F.; Tartarelli, G. F.; Tas, P.; Tasevsky, M.; Tashiro, T.; Tassi, E.; Tavares Delgado, A.; Tayalati, Y.; Taylor, F. E.; Taylor, G. N.; Taylor, W.; Teischinger, F. A.; Teixeira Dias Castanheira, M.; Teixeira-Dias, P.; Temming, K. K.; Ten Kate, H.; Teng, P. K.; Teoh, J. J.; Terada, S.; Terashi, K.; Terron, J.; Terzo, S.; Testa, M.; Teuscher, R. J.; Therhaag, J.; Theveneaux-Pelzer, T.; Thomas, J. P.; Thomas-Wilsker, J.; Thompson, E. N.; Thompson, P. D.; Thompson, P. D.; Thompson, R. J.; Thompson, A. S.; Thomsen, L. A.; Thomson, E.; Thomson, M.; Thong, W. M.; Thun, R. P.; Tian, F.; Tibbetts, M. J.; Tikhomirov, V. O.; Tikhonov, Yu. A.; Timoshenko, S.; Tiouchichine, E.; Tipton, P.; Tisserant, S.; Todorov, T.; Todorova-Nova, S.; Toggerson, B.; Tojo, J.; Tokár, S.; Tokushuku, K.; Tollefson, K.; Tomlinson, L.; Tomoto, M.; Tompkins, L.; Toms, K.; Topilin, N. D.; Torrence, E.; Torres, H.; Torró Pastor, E.; Toth, J.; Touchard, F.; Tovey, D. R.; Tran, H. L.; Trefzger, T.; Tremblet, L.; Tricoli, A.; Trigger, I. M.; Trincaz-Duvoid, S.; Tripiana, M. F.; Trischuk, W.; Trocmé, B.; Troncon, C.; Trottier-McDonald, M.; Trovatelli, M.; True, P.; Trzebinski, M.; Trzupek, A.; Tsarouchas, C.; Tseng, J. C.-L.; Tsiareshka, P. V.; Tsionou, D.; Tsipolitis, G.; Tsirintanis, N.; Tsiskaridze, S.; Tsiskaridze, V.; Tskhadadze, E. G.; Tsukerman, I. I.; Tsulaia, V.; Tsuno, S.; Tsybychev, D.; Tudorache, A.; Tudorache, V.; Tuna, A. N.; Tupputi, S. A.; Turchikhin, S.; Turecek, D.; Turk Cakir, I.; Turra, R.; Tuts, P. M.; Tykhonov, A.; Tylmad, M.; Tyndel, M.; Uchida, K.; Ueda, I.; Ueno, R.; Ughetto, M.; Ugland, M.; Uhlenbrock, M.; Ukegawa, F.; Unal, G.; Undrus, A.; Unel, G.; Ungaro, F. C.; Unno, Y.; Unverdorben, C.; Urbaniec, D.; Urquijo, P.; Usai, G.; Usanova, A.; Vacavant, L.; Vacek, V.; Vachon, B.; Valencic, N.; Valentinetti, S.; Valero, A.; Valery, L.; Valkar, S.; Valladolid Gallego, E.; Vallecorsa, S.; Valls Ferrer, J. A.; van den Wollenberg, W.; van der Deijl, P. C.; van der Geer, R.; van der Graaf, H.; van der Leeuw, R.; van der Ster, D.; van Eldik, N.; van Gemmeren, P.; van Nieuwkoop, J.; van Vulpen, I.; van Woerden, M. C.; Vanadia, M.; Vandelli, W.; Vanguri, R.; Vaniachine, A.; Vankov, P.; Vannucci, F.; Vardanyan, G.; Vari, R.; Varnes, E. W.; Varol, T.; Varouchas, D.; Vartapetian, A.; Varvell, K. E.; Vazeille, F.; Vazquez Schroeder, T.; Veatch, J.; Veloso, F.; Veneziano, S.; Ventura, A.; Ventura, D.; Venturi, M.; Venturi, N.; Venturini, A.; Vercesi, V.; Verducci, M.; Verkerke, W.; Vermeulen, J. C.; Vest, A.; Vetterli, M. C.; Viazlo, O.; Vichou, I.; Vickey, T.; Vickey Boeriu, O. E.; Viehhauser, G. H. A.; Viel, S.; Vigne, R.; Villa, M.; Villaplana Perez, M.; Vilucchi, E.; Vincter, M. G.; Vinogradov, V. B.; Virzi, J.; Vivarelli, I.; Vives Vaque, F.; Vlachos, S.; Vladoiu, D.; Vlasak, M.; Vogel, A.; Vogel, M.; Vokac, P.; Volpi, G.; Volpi, M.; von der Schmitt, H.; von Radziewski, H.; von Toerne, E.; Vorobel, V.; Vorobev, K.; Vos, M.; Voss, R.; Vossebeld, J. H.; Vranjes, N.; Vranjes Milosavljevic, M.; Vrba, V.; Vreeswijk, M.; Vu Anh, T.; Vuillermet, R.; Vukotic, I.; Vykydal, Z.; Wagner, P.; Wagner, W.; Wahlberg, H.; Wahrmund, S.; Wakabayashi, J.; Walder, J.; Walker, R.; Walkowiak, W.; Wall, R.; Waller, P.; Walsh, B.; Wang, C.; Wang, C.; Wang, F.; Wang, H.; Wang, H.; Wang, J.; Wang, J.; Wang, K.; Wang, R.; Wang, S. M.; Wang, T.; Wang, X.; Wanotayaroj, C.; Warburton, A.; Ward, C. P.; Wardrope, D. R.; Warsinsky, M.; Washbrook, A.; Wasicki, C.; Watkins, P. M.; Watson, A. T.; Watson, I. J.; Watson, M. F.; Watts, G.; Watts, S.; Waugh, B. M.; Webb, S.; Weber, M. S.; Weber, S. W.; Webster, J. S.; Weidberg, A. R.; Weigell, P.; Weinert, B.; Weingarten, J.; Weiser, C.; Weits, H.; Wells, P. S.; Wenaus, T.; Wendland, D.; Weng, Z.; Wengler, T.; Wenig, S.; Wermes, N.; Werner, M.; Werner, P.; Wessels, M.; Wetter, J.; Whalen, K.; White, A.; White, M. J.; White, R.; White, S.; Whiteson, D.; Wicke, D.; Wickens, F. J.; Wiedenmann, W.; Wielers, M.; Wienemann, P.; Wiglesworth, C.; Wiik-Fuchs, L. A. M.; Wijeratne, P. A.; Wildauer, A.; Wildt, M. A.; Wilkens, H. G.; Will, J. Z.; Williams, H. H.; Williams, S.; Willis, C.; Willocq, S.; Wilson, A.; Wilson, J. A.; Wingerter-Seez, I.; Winklmeier, F.; Winter, B. T.; Wittgen, M.; Wittig, T.; Wittkowski, J.; Wollstadt, S. J.; Wolter, M. W.; Wolters, H.; Wosiek, B. K.; Wotschack, J.; Woudstra, M. J.; Wozniak, K. W.; Wright, M.; Wu, M.; Wu, S. L.; Wu, X.; Wu, Y.; Wulf, E.; Wyatt, T. R.; Wynne, B. M.; Xella, S.; Xiao, M.; Xu, D.; Xu, L.; Yabsley, B.; Yacoob, S.; Yakabe, R.; Yamada, M.; Yamaguchi, H.; Yamaguchi, Y.; Yamamoto, A.; Yamamoto, K.; Yamamoto, S.; Yamamura, T.; Yamanaka, T.; Yamauchi, K.; Yamazaki, Y.; Yan, Z.; Yang, H.; Yang, H.; Yang, U. K.; Yang, Y.; Yanush, S.; Yao, L.; Yao, W.-M.; Yasu, Y.; Yatsenko, E.; Yau Wong, K. H.; Ye, J.; Ye, S.; Yeletskikh, I.; Yen, A. L.; Yildirim, E.; Yilmaz, M.; Yoosoofmiya, R.; Yorita, K.; Yoshida, R.; Yoshihara, K.; Young, C.; Young, C. J. S.; Youssef, S.; Yu, D. R.; Yu, J.; Yu, J. M.; Yu, J.; Yuan, L.; Yurkewicz, A.; Yusuff, I.; Zabinski, B.; Zaidan, R.; Zaitsev, A. M.; Zaman, A.; Zambito, S.; Zanello, L.; Zanzi, D.; Zeitnitz, C.; Zeman, M.; Zemla, A.; Zengel, K.; Zenin, O.; Ženiš, T.; Zerwas, D.; Zevi Della Porta, G.; Zhang, D.; Zhang, F.; Zhang, H.; Zhang, J.; Zhang, L.; Zhang, X.; Zhang, Z.; Zhao, Z.; Zhemchugov, A.; Zhong, J.; Zhou, B.; Zhou, L.; Zhou, N.; Zhu, C. G.; Zhu, H.; Zhu, J.; Zhu, Y.; Zhuang, X.; Zhukov, K.; Zibell, A.; Zieminska, D.; Zimine, N. I.; Zimmermann, C.; Zimmermann, R.; Zimmermann, S.; Zimmermann, S.; Zinonos, Z.; Ziolkowski, M.; Zobernig, G.; Zoccoli, A.; Zur Nedden, M.; Zurzolo, G.; Zutshi, V.; Zwalinski, L.; Atlas Collaboration

2015-02-01

Measurements of inclusive jet production are performed in p p and Pb +Pb collisions at √{sNN}=2.76 TeV with the ATLAS detector at the LHC, corresponding to integrated luminosities of 4.0 and 0.14 nb-1 , respectively. The jets are identified with the anti-kt algorithm with R =0.4 , and the spectra are measured over the kinematic range of jet transverse momentum 32

Expression, fermentation and purification of a predicted intrinsically disordered region of the transcription factor, NFAT5.

PubMed

DuMond, Jenna F; He, Yi; Burg, Maurice B; Ferraris, Joan D

2015-11-01

Hypertonicity stimulates Nuclear Factor of Activated T-cells 5 (NFAT5) nuclear localization and transactivating activity. Many transcription factors are known to contain intrinsically disordered regions (IDRs) which become more structured with local environmental changes such as osmolality, temperature and tonicity. The transactivating domain of NFAT5 is predicted to be intrinsically disordered under normal tonicity, and under high NaCl, the activity of this domain is increased. To study the binding of co-regulatory proteins at IDRs a cDNA construct expressing the NFAT5 TAD was created and transformed into Escherichia coli cells. Transformed E. coli cells were mass produced by fermentation and extracted by cell lysis to release the NFAT5 TAD. The NFAT5 TAD was subsequently purified using a His-tag column, cation exchange chromatography as well as hydrophobic interaction chromatography and then characterized by mass spectrometry (MS). Published by Elsevier Inc.

Measurements of the Nuclear Modification Factor for Jets in Pb+Pb Collisions at √(s)NN]=2.76  TeV with the ATLAS detector.

PubMed

Aad, G; Abbott, B; Abdallah, J; Abdel Khalek, S; Abdinov, O; Aben, R; Abi, B; Abolins, M; AbouZeid, O S; Abramowicz, H; Abreu, H; Abreu, R; Abulaiti, Y; Acharya, B S; Adamczyk, L; Adams, D L; Adelman, J; Adomeit, S; Adye, T; Agatonovic-Jovin, T; Aguilar-Saavedra, J A; Agustoni, M; Ahlen, S P; Ahmadov, F; Aielli, G; Akerstedt, H; Åkesson, T P A; Akimoto, G; Akimov, A V; Alberghi, G L; Albert, J; Albrand, S; Alconada Verzini, M J; Aleksa, M; Aleksandrov, I N; Alexa, C; Alexander, G; Alexandre, G; Alexopoulos, T; Alhroob, M; Alimonti, G; Alio, L; Alison, J; Allbrooke, B M M; Allison, L J; Allport, P P; Almond, J; Aloisio, A; Alonso, A; Alonso, F; Alpigiani, C; Altheimer, A; Alvarez Gonzalez, B; Alviggi, M G; Amako, K; Amaral Coutinho, Y; Amelung, C; Amidei, D; Amor Dos Santos, S P; Amorim, A; Amoroso, S; Amram, N; Amundsen, G; Anastopoulos, C; Ancu, L S; Andari, N; Andeen, T; Anders, C F; Anders, G; Anderson, K J; Andreazza, A; Andrei, V; Anduaga, X S; Angelidakis, S; Angelozzi, I; Anger, P; Angerami, A; Anghinolfi, F; Anisenkov, A V; Anjos, N; Annovi, A; Antonaki, A; Antonelli, M; Antonov, A; Antos, J; Anulli, F; Aoki, M; Aperio Bella, L; Apolle, R; Arabidze, G; Aracena, I; Arai, Y; Araque, J P; Arce, A T H; Arguin, J-F; Argyropoulos, S; Arik, M; Armbruster, A J; Arnaez, O; Arnal, V; Arnold, H; Arratia, M; Arslan, O; Artamonov, A; Artoni, G; Asai, S; Asbah, N; Ashkenazi, A; Åsman, B; Asquith, L; Assamagan, K; Astalos, R; Atkinson, M; Atlay, N B; Auerbach, B; Augsten, K; Aurousseau, M; Avolio, G; Azuelos, G; Azuma, Y; Baak, M A; Baas, A E; Bacci, C; Bachacou, H; Bachas, K; Backes, M; Backhaus, M; Backus Mayes, J; Badescu, E; Bagiacchi, P; Bagnaia, P; Bai, Y; Bain, T; Baines, J T; Baker, O K; Balek, P; Balli, F; Banas, E; Banerjee, Sw; Bannoura, A A E; Bansal, V; Bansil, H S; Barak, L; Baranov, S P; Barberio, E L; Barberis, D; Barbero, M; Barillari, T; Barisonzi, M; Barklow, T; Barlow, N; Barnett, B M; Barnett, R M; Barnovska, Z; Baroncelli, A; Barone, G; Barr, A J; Barreiro, F; Barreiro Guimarães da Costa, J; Bartoldus, R; Barton, A E; Bartos, P; Bartsch, V; Bassalat, A; Basye, A; Bates, R L; Batley, J R; Battaglia, M; Battistin, M; Bauer, F; Bawa, H S; Beattie, M D; Beau, T; Beauchemin, P H; Beccherle, R; Bechtle, P; Beck, H P; Becker, K; Becker, S; Beckingham, M; Becot, C; Beddall, A J; Beddall, A; Bedikian, S; Bednyakov, V A; Bee, C P; Beemster, L J; Beermann, T A; Begel, M; Behr, K; Belanger-Champagne, C; Bell, P J; Bell, W H; Bella, G; Bellagamba, L; Bellerive, A; Bellomo, M; Belotskiy, K; Beltramello, O; Benary, O; Benchekroun, D; Bendtz, K; Benekos, N; Benhammou, Y; Benhar Noccioli, E; Benitez Garcia, J A; Benjamin, D P; Bensinger, J R; Benslama, K; Bentvelsen, S; Berge, D; Bergeaas Kuutmann, E; Berger, N; Berghaus, F; Beringer, J; Bernard, C; Bernat, P; Bernius, C; Bernlochner, F U; Berry, T; Berta, P; Bertella, C; Bertoli, G; Bertolucci, F; Bertsche, C; Bertsche, D; Besana, M I; Besjes, G J; Bessidskaia Bylund, O; Bessner, M; Besson, N; Betancourt, C; Bethke, S; Bhimji, W; Bianchi, R M; Bianchini, L; Bianco, M; Biebel, O; Bieniek, S P; Bierwagen, K; Biesiada, J; Biglietti, M; Bilbao De Mendizabal, J; Bilokon, H; Bindi, M; Binet, S; Bingul, A; Bini, C; Black, C W; Black, J E; Black, K M; Blackburn, D; Blair, R E; Blanchard, J-B; Blazek, T; Bloch, I; Blocker, C; Blum, W; Blumenschein, U; Bobbink, G J; Bobrovnikov, V S; Bocchetta, S S; Bocci, A; Bock, C; Boddy, C R; Boehler, M; Boek, T T; Bogaerts, J A; Bogdanchikov, A G; Bogouch, A; Bohm, C; Bohm, J; Boisvert, V; Bold, T; Boldea, V; Boldyrev, A S; Bomben, M; Bona, M; Boonekamp, M; Borisov, A; Borissov, G; Borri, M; Borroni, S; Bortfeldt, J; Bortolotto, V; Bos, K; Boscherini, D; Bosman, M; Boterenbrood, H; Boudreau, J; Bouffard, J; Bouhova-Thacker, E V; Boumediene, D; Bourdarios, C; Bousson, N; Boutouil, S; Boveia, A; Boyd, J; Boyko, I R; Bracinik, J; Brandt, A; Brandt, G; Brandt, O; Bratzler, U; Brau, B; Brau, J E; Braun, H M; Brazzale, S F; Brelier, B; Brendlinger, K; Brennan, A J; Brenner, R; Bressler, S; Bristow, K; Bristow, T M; Britton, D; Brochu, F M; Brock, I; Brock, R; Bromberg, C; Bronner, J; Brooijmans, G; Brooks, T; Brooks, W K; Brosamer, J; Brost, E; Brown, J; Bruckman de Renstrom, P A; Bruncko, D; Bruneliere, R; Brunet, S; Bruni, A; Bruni, G; Bruschi, M; Bryngemark, L; Buanes, T; Buat, Q; Bucci, F; Buchholz, P; Buckingham, R M; Buckley, A G; Buda, S I; Budagov, I A; Buehrer, F; Bugge, L; Bugge, M K; Bulekov, O; Bundock, A C; Burckhart, H; Burdin, S; Burghgrave, B; Burke, S; Burmeister, I; Busato, E; Büscher, D; Büscher, V; Bussey, P; Buszello, C P; Butler, B; Butler, J M; Butt, A I; Buttar, C M; Butterworth, J M; Butti, P; Buttinger, W; Buzatu, A; Byszewski, M; Cabrera Urbán, S; Caforio, D; Cakir, O; Calafiura, P; Calandri, A; Calderini, G; Calfayan, P; Calkins, R; Caloba, L P; Calvet, D; Calvet, S; Camacho Toro, R; Camarda, S; Cameron, D; Caminada, L M; Caminal Armadans, R; Campana, S; Campanelli, M; Campoverde, A; Canale, V; Canepa, A; Cano Bret, M; Cantero, J; Cantrill, R; Cao, T; Capeans Garrido, M D M; Caprini, I; Caprini, M; Capua, M; Caputo, R; Cardarelli, R; Carli, T; Carlino, G; Carminati, L; Caron, S; Carquin, E; Carrillo-Montoya, G D; Carter, J R; Carvalho, J; Casadei, D; Casado, M P; Casolino, M; Castaneda-Miranda, E; Castelli, A; Castillo Gimenez, V; Castro, N F; Catastini, P; Catinaccio, A; Catmore, J R; Cattai, A; Cattani, G; Caughron, S; Cavaliere, V; Cavalli, D; Cavalli-Sforza, M; Cavasinni, V; Ceradini, F; Cerio, B C; Cerny, K; Cerqueira, A S; Cerri, A; Cerrito, L; Cerutti, F; Cerv, M; Cervelli, A; Cetin, S A; Chafaq, A; Chakraborty, D; Chalupkova, I; Chang, P; Chapleau, B; Chapman, J D; Charfeddine, D; Charlton, D G; Chau, C C; Chavez Barajas, C A; Cheatham, S; Chegwidden, A; Chekanov, S; Chekulaev, S V; Chelkov, G A; Chelstowska, M A; Chen, C; Chen, H; Chen, K; Chen, L; Chen, S; Chen, X; Chen, Y; Chen, Y; Cheng, H C; Cheng, Y; Cheplakov, A; Cherkaoui El Moursli, R; Chernyatin, V; Cheu, E; Chevalier, L; Chiarella, V; Chiefari, G; Childers, J T; Chilingarov, A; Chiodini, G; Chisholm, A S; Chislett, R T; Chitan, A; Chizhov, M V; Chouridou, S; Chow, B K B; Chromek-Burckhart, D; Chu, M L; Chudoba, J; Chwastowski, J J; Chytka, L; Ciapetti, G; Ciftci, A K; Ciftci, R; Cinca, D; Cindro, V; Ciocio, A; Cirkovic, P; Citron, Z H; Citterio, M; Ciubancan, M; Clark, A; Clark, P J; Clarke, R N; Cleland, W; Clemens, J C; Clement, C; Coadou, Y; Cobal, M; Coccaro, A; Cochran, J; Coffey, L; Cogan, J G; Coggeshall, J; Cole, B; Cole, S; Colijn, A P; Collot, J; Colombo, T; Colon, G; Compostella, G; Conde Muiño, P; Coniavitis, E; Conidi, M C; Connell, S H; Connelly, I A; Consonni, S M; Consorti, V; Constantinescu, S; Conta, C; Conti, G; Conventi, F; Cooke, M; Cooper, B D; Cooper-Sarkar, A M; Cooper-Smith, N J; Copic, K; Cornelissen, T; Corradi, M; Corriveau, F; Corso-Radu, A; Cortes-Gonzalez, A; Cortiana, G; Costa, G; Costa, M J; Costanzo, D; Côté, D; Cottin, G; Cowan, G; Cox, B E; Cranmer, K; Cree, G; Crépé-Renaudin, S; Crescioli, F; Cribbs, W A; Crispin Ortuzar, M; Cristinziani, M; Croft, V; Crosetti, G; Cuciuc, C-M; Cuhadar Donszelmann, T; Cummings, J; Curatolo, M; Cuthbert, C; Czirr, H; Czodrowski, P; Czyczula, Z; D'Auria, S; D'Onofrio, M; Da Cunha Sargedas De Sousa, M J; Da Via, C; Dabrowski, W; Dafinca, A; Dai, T; Dale, O; Dallaire, F; Dallapiccola, C; Dam, M; Daniells, A C; Dano Hoffmann, M; Dao, V; Darbo, G; Darmora, S; Dassoulas, J A; Dattagupta, A; Davey, W; David, C; Davidek, T; Davies, E; Davies, M; Davignon, O; Davison, A R; Davison, P; Davygora, Y; Dawe, E; Dawson, I; Daya-Ishmukhametova, R K; De, K; de Asmundis, R; De Castro, S; De Cecco, S; De Groot, N; de Jong, P; De la Torre, H; De Lorenzi, F; De Nooij, L; De Pedis, D; De Salvo, A; De Sanctis, U; De Santo, A; De Vivie De Regie, J B; Dearnaley, W J; Debbe, R; Debenedetti, C; Dechenaux, B; Dedovich, D V; Deigaard, I; Del Peso, J; Del Prete, T; Deliot, F; Delitzsch, C M; Deliyergiyev, M; Dell'Acqua, A; Dell'Asta, L; Dell'Orso, M; Della Pietra, M; Della Volpe, D; Delmastro, M; Delsart, P A; Deluca, C; Demers, S; Demichev, M; Demilly, A; Denisov, S P; Derendarz, D; Derkaoui, J E; Derue, F; Dervan, P; Desch, K; Deterre, C; Deviveiros, P O; Dewhurst, A; Dhaliwal, S; Di Ciaccio, A; Di Ciaccio, L; Di Domenico, A; Di Donato, C; Di Girolamo, A; Di Girolamo, B; Di Mattia, A; Di Micco, B; Di Nardo, R; Di Simone, A; Di Sipio, R; Di Valentino, D; Dias, F A; Diaz, M A; Diehl, E B; Dietrich, J; Dietzsch, T A; Diglio, S; Dimitrievska, A; Dingfelder, J; Dionisi, C; Dita, P; Dita, S; Dittus, F; Djama, F; Djobava, T; do Vale, M A B; Do Valle Wemans, A; Doan, T K O; Dobos, D; Doglioni, C; Doherty, T; Dohmae, T; Dolejsi, J; Dolezal, Z; Dolgoshein, B A; Donadelli, M; Donati, S; Dondero, P; Donini, J; Dopke, J; Doria, A; Dova, M T; Doyle, A T; Dris, M; Dubbert, J; Dube, S; Dubreuil, E; Duchovni, E; Duckeck, G; Ducu, O A; Duda, D; Dudarev, A; Dudziak, F; Duflot, L; Duguid, L; Dührssen, M; Dunford, M; Duran Yildiz, H; Düren, M; Durglishvili, A; Dwuznik, M; Dyndal, M; Ebke, J; Edson, W; Edwards, N C; Ehrenfeld, W; Eifert, T; Eigen, G; Einsweiler, K; Ekelof, T; El Kacimi, M; Ellert, M; Elles, S; Ellinghaus, F; Ellis, N; Elmsheuser, J; Elsing, M; Emeliyanov, D; Enari, Y; Endner, O C; Endo, M; Engelmann, R; Erdmann, J; Ereditato, A; Eriksson, D; Ernis, G; Ernst, J; Ernst, M; Ernwein, J; Errede, D; Errede, S; Ertel, E; Escalier, M; Esch, H; Escobar, C; Esposito, B; Etienvre, A I; Etzion, E; Evans, H; Ezhilov, A; Fabbri, L; Facini, G; Fakhrutdinov, R M; Falciano, S; Falla, R J; Faltova, J; Fang, Y; Fanti, M; Farbin, A; Farilla, A; Farooque, T; Farrell, S; Farrington, S M; Farthouat, P; Fassi, F; Fassnacht, P; Fassouliotis, D; Favareto, A; Fayard, L; Federic, P; Fedin, O L; Fedorko, W; Fehling-Kaschek, M; Feigl, S; Feligioni, L; Feng, C; Feng, E J; Feng, H; Fenyuk, A B; Fernandez Perez, S; Ferrag, S; Ferrando, J; Ferrari, A; Ferrari, P; Ferrari, R; Ferreira de Lima, D E; Ferrer, A; Ferrere, D; Ferretti, C; Ferretto Parodi, A; Fiascaris, M; Fiedler, F; Filipčič, A; Filipuzzi, M; Filthaut, F; Fincke-Keeler, M; Finelli, K D; Fiolhais, M C N; Fiorini, L; Firan, A; Fischer, A; Fischer, J; Fisher, W C; Fitzgerald, E A; Flechl, M; Fleck, I; Fleischmann, P; Fleischmann, S; Fletcher, G T; Fletcher, G; Flick, T; Floderus, A; Flores Castillo, L R; Florez Bustos, A C; Flowerdew, M J; Formica, A; Forti, A; Fortin, D; Fournier, D; Fox, H; Fracchia, S; Francavilla, P; Franchini, M; Franchino, S; Francis, D; Franconi, L; Franklin, M; Franz, S; Fraternali, M; French, S T; Friedrich, C; Friedrich, F; Froidevaux, D; Frost, J A; Fukunaga, C; Fullana Torregrosa, E; Fulsom, B G; Fuster, J; Gabaldon, C; Gabizon, O; Gabrielli, A; Gabrielli, A; Gadatsch, S; Gadomski, S; Gagliardi, G; Gagnon, P; Galea, C; Galhardo, B; Gallas, E J; Gallo, V; Gallop, B J; Gallus, P; Galster, G; Gan, K K; Gandrajula, R P; Gao, J; Gao, Y S; Garay Walls, F M; Garberson, F; García, C; García Navarro, J E; Garcia-Sciveres, M; Gardner, R W; Garelli, N; Garonne, V; Gatti, C; Gaudio, G; Gaur, B; Gauthier, L; Gauzzi, P; Gavrilenko, I L; Gay, C; Gaycken, G; Gazis, E N; Ge, P; Gecse, Z; Gee, C N P; Geerts, D A A; Geich-Gimbel, Ch; Gellerstedt, K; Gemme, C; Gemmell, A; Genest, M H; Gentile, S; George, M; George, S; Gerbaudo, D; Gershon, A; Ghazlane, H; Ghodbane, N; Giacobbe, B; Giagu, S; Giangiobbe, V; Giannetti, P; Gianotti, F; Gibbard, B; Gibson, S M; Gilchriese, M; Gillam, T P S; Gillberg, D; Gilles, G; Gingrich, D M; Giokaris, N; Giordani, M P; Giordano, R; Giorgi, F M; Giorgi, F M; Giraud, P F; Giugni, D; Giuliani, C; Giulini, M; Gjelsten, B K; Gkaitatzis, S; Gkialas, I; Gladilin, L K; Glasman, C; Glatzer, J; Glaysher, P C F; Glazov, A; Glonti, G L; Goblirsch-Kolb, M; Goddard, J R; Godfrey, J; Godlewski, J; Goeringer, C; Goldfarb, S; Golling, T; Golubkov, D; Gomes, A; Gomez Fajardo, L S; Gonçalo, R; Goncalves Pinto Firmino Da Costa, J; Gonella, L; González de la Hoz, S; Gonzalez Parra, G; Gonzalez-Sevilla, S; Goossens, L; Gorbounov, P A; Gordon, H A; Gorelov, I; Gorini, B; Gorini, E; Gorišek, A; Gornicki, E; Goshaw, A T; Gössling, C; Gostkin, M I; Gouighri, M; Goujdami, D; Goulette, M P; Goussiou, A G; Goy, C; Gozpinar, S; Grabas, H M X; Graber, L; Grabowska-Bold, I; Grafström, P; Grahn, K-J; Gramling, J; Gramstad, E; Grancagnolo, S; Grassi, V; Gratchev, V; Gray, H M; Graziani, E; Grebenyuk, O G; Greenwood, Z D; Gregersen, K; Gregor, I M; Grenier, P; Griffiths, J; Grillo, A A; Grimm, K; Grinstein, S; Gris, Ph; Grishkevich, Y V; Grivaz, J-F; Grohs, J P; Grohsjean, A; Gross, E; Grosse-Knetter, J; Grossi, G C; Groth-Jensen, J; Grout, Z J; Guan, L; Guescini, F; Guest, D; Gueta, O; Guicheney, C; Guido, E; Guillemin, T; Guindon, S; Gul, U; Gumpert, C; Gunther, J; Guo, J; Gupta, S; Gutierrez, P; Gutierrez Ortiz, N G; Gutschow, C; Guttman, N; Guyot, C; Gwenlan, C; Gwilliam, C B; Haas, A; Haber, C; Hadavand, H K; Haddad, N; Haefner, P; Hageböck, S; Hajduk, Z; Hakobyan, H; Haleem, M; Hall, D; Halladjian, G; Hamacher, K; Hamal, P; Hamano, K; Hamer, M; Hamilton, A; Hamilton, S; Hamity, G N; Hamnett, P G; Han, L; Hanagaki, K; Hanawa, K; Hance, M; Hanke, P; Hanna, R; Hansen, J B; Hansen, J D; Hansen, P H; Hara, K; Hard, A S; Harenberg, T; Hariri, F; Harkusha, S; Harper, D; Harrington, R D; Harris, O M; Harrison, P F; Hartjes, F; Hasegawa, M; Hasegawa, S; Hasegawa, Y; Hasib, A; Hassani, S; Haug, S; Hauschild, M; Hauser, R; Havranek, M; Hawkes, C M; Hawkings, R J; Hawkins, A D; Hayashi, T; Hayden, D; Hays, C P; Hayward, H S; Haywood, S J; Head, S J; Heck, T; Hedberg, V; Heelan, L; Heim, S; Heim, T; Heinemann, B; Heinrich, L; Hejbal, J; Helary, L; Heller, C; Heller, M; Hellman, S; Hellmich, D; Helsens, C; Henderson, J; Henderson, R C W; Heng, Y; Hengler, C; Henrichs, A; Henriques Correia, A M; Henrot-Versille, S; Hensel, C; Herbert, G H; Hernández Jiménez, Y; Herrberg-Schubert, R; Herten, G; Hertenberger, R; Hervas, L; Hesketh, G G; Hessey, N P; Hickling, R; Higón-Rodriguez, E; Hill, E; Hill, J C; Hiller, K H; Hillert, S; Hillier, S J; Hinchliffe, I; Hines, E; Hirose, M; Hirschbuehl, D; Hobbs, J; Hod, N; Hodgkinson, M C; Hodgson, P; Hoecker, A; Hoeferkamp, M R; Hoenig, F; Hoffman, J; Hoffmann, D; Hofmann, J I; Hohlfeld, M; Holmes, T R; Hong, T M; Hooft van Huysduynen, L; Hostachy, J-Y; Hou, S; Hoummada, A; Howard, J; Howarth, J; Hrabovsky, M; Hristova, I; Hrivnac, J; Hryn'ova, T; Hsu, C; Hsu, P J; Hsu, S-C; Hu, D; Hu, X; Huang, Y; Hubacek, Z; Hubaut, F; Huegging, F; Huffman, T B; Hughes, E W; Hughes, G; Huhtinen, M; Hülsing, T A; Hurwitz, M; Huseynov, N; Huston, J; Huth, J; Iacobucci, G; Iakovidis, G; Ibragimov, I; Iconomidou-Fayard, L; Ideal, E; Iengo, P; Igonkina, O; Iizawa, T; Ikegami, Y; Ikematsu, K; Ikeno, M; Ilchenko, Y; Iliadis, D; Ilic, N; Inamaru, Y; Ince, T; Ioannou, P; Iodice, M; Iordanidou, K; Ippolito, V; Irles Quiles, A; Isaksson, C; Ishino, M; Ishitsuka, M; Ishmukhametov, R; Issever, C; Istin, S; Iturbe Ponce, J M; Iuppa, R; Ivarsson, J; Iwanski, W; Iwasaki, H; Izen, J M; Izzo, V; Jackson, B; Jackson, M; Jackson, P; Jaekel, M R; Jain, V; Jakobs, K; Jakobsen, S; Jakoubek, T; Jakubek, J; Jamin, D O; Jana, D K; Jansen, E; Jansen, H; Janssen, J; Janus, M; Jarlskog, G; Javadov, N; Javůrek, T; Jeanty, L; Jejelava, J; Jeng, G-Y; Jennens, D; Jenni, P; Jentzsch, J; Jeske, C; Jézéquel, S; Ji, H; Jia, J; Jiang, Y; Jimenez Belenguer, M; Jin, S; Jinaru, A; Jinnouchi, O; Joergensen, M D; Johansson, K E; Johansson, P; Johns, K A; Jon-And, K; Jones, G; Jones, R W L; Jones, T J; Jongmanns, J; Jorge, P M; Joshi, K D; Jovicevic, J; Ju, X; Jung, C A; Jungst, R M; Jussel, P; Juste Rozas, A; Kaci, M; Kaczmarska, A; Kado, M; Kagan, H; Kagan, M; Kajomovitz, E; Kalderon, C W; Kama, S; Kamenshchikov, A; Kanaya, N; Kaneda, M; Kaneti, S; Kantserov, V A; Kanzaki, J; Kaplan, B; Kapliy, A; Kar, D; Karakostas, K; Karastathis, N; Karnevskiy, M; Karpov, S N; Karpova, Z M; Karthik, K; Kartvelishvili, V; Karyukhin, A N; Kashif, L; Kasieczka, G; Kass, R D; Kastanas, A; Kataoka, Y; Katre, A; Katzy, J; Kaushik, V; Kawagoe, K; Kawamoto, T; Kawamura, G; Kazama, S; Kazanin, V F; Kazarinov, M Y; Keeler, R; Kehoe, R; Keil, M; Keller, J S; Kempster, J J; Keoshkerian, H; Kepka, O; Kerševan, B P; Kersten, S; Kessoku, K; Keung, J; Khalil-Zada, F; Khandanyan, H; Khanov, A; Khodinov, A; Khomich, A; Khoo, T J; Khoriauli, G; Khoroshilov, A; Khovanskiy, V; Khramov, E; Khubua, J; Kim, H Y; Kim, H; Kim, S H; Kimura, N; Kind, O; King, B T; King, M; King, R S B; King, S B; Kirk, J; Kiryunin, A E; Kishimoto, T; Kisielewska, D; Kiss, F; Kittelmann, T; Kiuchi, K; Kladiva, E; Klein, M; Klein, U; Kleinknecht, K; Klimek, P; Klimentov, A; Klingenberg, R; Klinger, J A; Klioutchnikova, T; Klok, P F; Kluge, E-E; Kluit, P; Kluth, S; Kneringer, E; Knoops, E B F G; Knue, A; Kobayashi, D; Kobayashi, T; Kobel, M; Kocian, M; Kodys, P; Koevesarki, P; Koffas, T; Koffeman, E; Kogan, L A; Kohlmann, S; Kohout, Z; Kohriki, T; Koi, T; Kolanoski, H; Koletsou, I; Koll, J; Komar, A A; Komori, Y; Kondo, T; Kondrashova, N; Köneke, K; König, A C; König, S; Kono, T; Konoplich, R; Konstantinidis, N; Kopeliansky, R; Koperny, S; Köpke, L; Kopp, A K; Korcyl, K; Kordas, K; Korn, A; Korol, A A; Korolkov, I; Korolkova, E V; Korotkov, V A; Kortner, O; Kortner, S; Kostyukhin, V V; Kotov, V M; Kotwal, A; Kourkoumelis, C; Kouskoura, V; Koutsman, A; Kowalewski, R; Kowalski, T Z; Kozanecki, W; Kozhin, A S; Kral, V; Kramarenko, V A; Kramberger, G; Krasnopevtsev, D; Krasny, M W; Krasznahorkay, A; Kraus, J K; Kravchenko, A; Kreiss, S; Kretz, M; Kretzschmar, J; Kreutzfeldt, K; Krieger, P; Kroeninger, K; Kroha, H; Kroll, J; Kroseberg, J; Krstic, J; Kruchonak, U; Krüger, H; Kruker, T; Krumnack, N; Krumshteyn, Z V; Kruse, A; Kruse, M C; Kruskal, M; Kubota, T; Kuday, S; Kuehn, S; Kugel, A; Kuhl, A; Kuhl, T; Kukhtin, V; Kulchitsky, Y; Kuleshov, S; Kuna, M; Kunkle, J; Kupco, A; Kurashige, H; Kurochkin, Y A; Kurumida, R; Kus, V; Kuwertz, E S; Kuze, M; Kvita, J; La Rosa, A; La Rotonda, L; Lacasta, C; Lacava, F; Lacey, J; Lacker, H; Lacour, D; Lacuesta, V R; Ladygin, E; Lafaye, R; Laforge, B; Lagouri, T; Lai, S; Laier, H; Lambourne, L; Lammers, S; Lampen, C L; Lampl, W; Lançon, E; Landgraf, U; Landon, M P J; Lang, V S; Lankford, A J; Lanni, F; Lantzsch, K; Laplace, S; Lapoire, C; Laporte, J F; Lari, T; Lassnig, M; Laurelli, P; Lavrijsen, W; Law, A T; Laycock, P; Le Dortz, O; Le Guirriec, E; Le Menedeu, E; LeCompte, T; Ledroit-Guillon, F; Lee, C A; Lee, H; Lee, J S H; Lee, S C; Lee, L; Lefebvre, G; Lefebvre, M; Legger, F; Leggett, C; Lehan, A; Lehmacher, M; Lehmann Miotto, G; Lei, X; Leight, W A; Leisos, A; Leister, A G; Leite, M A L; Leitner, R; Lellouch, D; Lemmer, B; Leney, K J C; Lenz, T; Lenzen, G; Lenzi, B; Leone, R; Leone, S; Leonhardt, K; Leonidopoulos, C; Leontsinis, S; Leroy, C; Lester, C G; Lester, C M; Levchenko, M; Levêque, J; Levin, D; Levinson, L J; Levy, M; Lewis, A; Lewis, G H; Leyko, A M; Leyton, M; Li, B; Li, B; Li, H; Li, H L; Li, L; Li, L; Li, S; Li, Y; Liang, Z; Liao, H; Liberti, B; Lichard, P; Lie, K; Liebal, J; Liebig, W; Limbach, C; Limosani, A; Lin, S C; Lin, T H; Linde, F; Lindquist, B E; Linnemann, J T; Lipeles, E; Lipniacka, A; Lisovyi, M; Liss, T M; Lissauer, D; Lister, A; Litke, A M; Liu, B; Liu, D; Liu, J B; Liu, K; Liu, L; Liu, M; Liu, M; Liu, Y; Livan, M; Livermore, S S A; Lleres, A; Llorente Merino, J; Lloyd, S L; Lo Sterzo, F; Lobodzinska, E; Loch, P; Lockman, W S; Loddenkoetter, T; Loebinger, F K; Loevschall-Jensen, A E; Loginov, A; Lohse, T; Lohwasser, K; Lokajicek, M; Lombardo, V P; Long, B A; Long, J D; Long, R E; Lopes, L; Lopez Mateos, D; Lopez Paredes, B; Lopez Paz, I; Lorenz, J; Lorenzo Martinez, N; Losada, M; Loscutoff, P; Lou, X; Lounis, A; Love, J; Love, P A; Lowe, A J; Lu, F; Lu, N; Lubatti, H J; Luci, C; Lucotte, A; Luehring, F; Lukas, W; Luminari, L; Lundberg, O; Lund-Jensen, B; Lungwitz, M; Lynn, D; Lysak, R; Lytken, E; Ma, H; Ma, L L; Maccarrone, G; Macchiolo, A; Machado Miguens, J; Macina, D; Madaffari, D; Madar, R; Maddocks, H J; Mader, W F; Madsen, A; Maeno, M; Maeno, T; Magradze, E; Mahboubi, K; Mahlstedt, J; Mahmoud, S; Maiani, C; Maidantchik, C; Maier, A A; Maio, A; Majewski, S; Makida, Y; Makovec, N; Mal, P; Malaescu, B; Malecki, Pa; Maleev, V P; Malek, F; Mallik, U; Malon, D; Malone, C; Maltezos, S; Malyshev, V M; Malyukov, S; Mamuzic, J; Mandelli, B; Mandelli, L; Mandić, I; Mandrysch, R; Maneira, J; Manfredini, A; Manhaes de Andrade Filho, L; Manjarres Ramos, J A; Mann, A; Manning, P M; Manousakis-Katsikakis, A; Mansoulie, B; Mantifel, R; Mapelli, L; March, L; Marchand, J F; Marchiori, G; Marcisovsky, M; Marino, C P; Marjanovic, M; Marques, C N; Marroquim, F; Marsden, S P; Marshall, Z; Marti, L F; Marti-Garcia, S; Martin, B; Martin, B; Martin, T A; Martin, V J; Martin Dit Latour, B; Martinez, H; Martinez, M; Martin-Haugh, S; Martyniuk, A C; Marx, M; Marzano, F; Marzin, A; Masetti, L; Mashimo, T; Mashinistov, R; Masik, J; Maslennikov, A L; Massa, I; Massa, L; Massol, N; Mastrandrea, P; Mastroberardino, A; Masubuchi, T; Mättig, P; Mattmann, J; Maurer, J; Maxfield, S J; Maximov, D A; Mazini, R; Mazzaferro, L; Mc Goldrick, G; Mc Kee, S P; McCarn, A; McCarthy, R L; McCarthy, T G; McCubbin, N A; McFarlane, K W; Mcfayden, J A; Mchedlidze, G; McMahon, S J; McPherson, R A; Meade, A; Mechnich, J; Medinnis, M; Meehan, S; Mehlhase, S; Mehta, A; Meier, K; Meineck, C; Meirose, B; Melachrinos, C; Mellado Garcia, B R; Meloni, F; Mengarelli, A; Menke, S; Meoni, E; Mercurio, K M; Mergelmeyer, S; Meric, N; Mermod, P; Merola, L; Meroni, C; Merritt, F S; Merritt, H; Messina, A; Metcalfe, J; Mete, A S; Meyer, C; Meyer, C; Meyer, J-P; Meyer, J; Middleton, R P; Migas, S; Mijović, L; Mikenberg, G; Mikestikova, M; Mikuž, M; Milic, A; Miller, D W; Mills, C; Milov, A; Milstead, D A; Milstein, D; Minaenko, A A; Minashvili, I A; Mincer, A I; Mindur, B; Mineev, M; Ming, Y; Mir, L M; Mirabelli, G; Mitani, T; Mitrevski, J; Mitsou, V A; Mitsui, S; Miucci, A; Miyagawa, P S; Mjörnmark, J U; Moa, T; Mochizuki, K; Mohapatra, S; Mohr, W; Molander, S; Moles-Valls, R; Mönig, K; Monini, C; Monk, J; Monnier, E; Montejo Berlingen, J; Monticelli, F; Monzani, S; Moore, R W; Moraes, A; Morange, N; Moreno, D; Moreno Llácer, M; Morettini, P; Morgenstern, M; Morii, M; Moritz, S; Morley, A K; Mornacchi, G; Morris, J D; Morvaj, L; Moser, H G; Mosidze, M; Moss, J; Motohashi, K; Mount, R; Mountricha, E; Mouraviev, S V; Moyse, E J W; Muanza, S; Mudd, R D; Mueller, F; Mueller, J; Mueller, K; Mueller, T; Mueller, T; Muenstermann, D; Munwes, Y; Murillo Quijada, J A; Murray, W J; Musheghyan, H; Musto, E; Myagkov, A G; Myska, M; Nackenhorst, O; Nadal, J; Nagai, K; Nagai, R; Nagai, Y; Nagano, K; Nagarkar, A; Nagasaka, Y; Nagel, M; Nairz, A M; Nakahama, Y; Nakamura, K; Nakamura, T; Nakano, I; Namasivayam, H; Nanava, G; Narayan, R; Nattermann, T; Naumann, T; Navarro, G; Nayyar, R; Neal, H A; Nechaeva, P Yu; Neep, T J; Nef, P D; Negri, A; Negri, G; Negrini, M; Nektarijevic, S; Nelson, A; Nelson, T K; Nemecek, S; Nemethy, P; Nepomuceno, A A; Nessi, M; Neubauer, M S; Neumann, M; Neves, R M; Nevski, P; Newman, P R; Nguyen, D H; Nickerson, R B; Nicolaidou, R; Nicquevert, B; Nielsen, J; Nikiforou, N; Nikiforov, A; Nikolaenko, V; Nikolic-Audit, I; Nikolics, K; Nikolopoulos, K; Nilsson, P; Ninomiya, Y; Nisati, A; Nisius, R; Nobe, T; Nodulman, L; Nomachi, M; Nomidis, I; Norberg, S; Nordberg, M; Novgorodova, O; Nowak, S; Nozaki, M; Nozka, L; Ntekas, K; Nunes Hanninger, G; Nunnemann, T; Nurse, E; Nuti, F; O'Brien, B J; O'grady, F; O'Neil, D C; O'Shea, V; Oakham, F G; Oberlack, H; Obermann, T; Ocariz, J; Ochi, A; Ochoa, M I; Oda, S; Odaka, S; Ogren, H; Oh, A; Oh, S H; Ohm, C C; Ohman, H; Okamura, W; Okawa, H; Okumura, Y; Okuyama, T; Olariu, A; Olchevski, A G; Olivares Pino, S A; Oliveira Damazio, D; Oliver Garcia, E; Olszewski, A; Olszowska, J; Onofre, A; Onyisi, P U E; Oram, C J; Oreglia, M J; Oren, Y; Orestano, D; Orlando, N; Oropeza Barrera, C; Orr, R S; Osculati, B; Ospanov, R; Otero Y Garzon, G; Otono, H; Ouchrif, M; Ouellette, E A; Ould-Saada, F; Ouraou, A; Oussoren, K P; Ouyang, Q; Ovcharova, A; Owen, M; Ozcan, V E; Ozturk, N; Pachal, K; Pacheco Pages, A; Padilla Aranda, C; Pagáčová, M; Pagan Griso, S; Paganis, E; Pahl, C; Paige, F; Pais, P; Pajchel, K; Palacino, G; Palestini, S; Palka, M; Pallin, D; Palma, A; Palmer, J D; Pan, Y B; Panagiotopoulou, E; Panduro Vazquez, J G; Pani, P; Panikashvili, N; Panitkin, S; Pantea, D; Paolozzi, L; Papadopoulou, Th D; Papageorgiou, K; Paramonov, A; Paredes Hernandez, D; Parker, M A; Parodi, F; Parsons, J A; Parzefall, U; Pasqualucci, E; Passaggio, S; Passeri, A; Pastore, F; Pastore, Fr; Pásztor, G; Pataraia, S; Patel, N D; Pater, J R; Patricelli, S; Pauly, T; Pearce, J; Pedersen, M; Pedraza Lopez, S; Pedro, R; Peleganchuk, S V; Pelikan, D; Peng, H; Penning, B; Penwell, J; Perepelitsa, D V; Perez Codina, E; Pérez García-Estañ, M T; Perez Reale, V; Perini, L; Pernegger, H; Perrino, R; Peschke, R; Peshekhonov, V D; Peters, K; Peters, R F Y; Petersen, B A; Petersen, T C; Petit, E; Petridis, A; Petridou, C; Petrolo, E; Petrucci, F; Pettersson, N E; Pezoa, R; Phillips, P W; Piacquadio, G; Pianori, E; Picazio, A; Piccaro, E; Piccinini, M; Piegaia, R; Pignotti, D T; Pilcher, J E; Pilkington, A D; Pina, J; Pinamonti, M; Pinder, A; Pinfold, J L; Pingel, A; Pinto, B; Pires, S; Pitt, M; Pizio, C; Plazak, L; Pleier, M-A; Pleskot, V; Plotnikova, E; Plucinski, P; Poddar, S; Podlyski, F; Poettgen, R; Poggioli, L; Pohl, D; Pohl, M; Polesello, G; Policicchio, A; Polifka, R; Polini, A; Pollard, C S; Polychronakos, V; Pommès, K; Pontecorvo, L; Pope, B G; Popeneciu, G A; Popovic, D S; Poppleton, A; Portell Bueso, X; Pospisil, S; Potamianos, K; Potrap, I N; Potter, C J; Potter, C T; Poulard, G; Poveda, J; Pozdnyakov, V; Pralavorio, P; Pranko, A; Prasad, S; Pravahan, R; Prell, S; Price, D; Price, J; Price, L E; Prieur, D; Primavera, M; Proissl, M; Prokofiev, K; Prokoshin, F; Protopapadaki, E; Protopopescu, S; Proudfoot, J; Przybycien, M; Przysiezniak, H; Ptacek, E; Puddu, D; Pueschel, E; Puldon, D; Purohit, M; Puzo, P; Qian, J; Qin, G; Qin, Y; Quadt, A; Quarrie, D R; Quayle, W B; Queitsch-Maitland, M; Quilty, D; Qureshi, A; Radeka, V; Radescu, V; Radhakrishnan, S K; Radloff, P; Rados, P; Ragusa, F; Rahal, G; Rajagopalan, S; Rammensee, M; Randle-Conde, A S; Rangel-Smith, C; Rao, K; Rauscher, F; Rave, T C; Ravenscroft, T; Raymond, M; Read, A L; Readioff, N P; Rebuzzi, D M; Redelbach, A; Redlinger, G; Reece, R; Reeves, K; Rehnisch, L; Reisin, H; Relich, M; Rembser, C; Ren, H; Ren, Z L; Renaud, A; Rescigno, M; Resconi, S; Rezanova, O L; Reznicek, P; Rezvani, R; Richter, R; Ridel, M; Rieck, P; Rieger, J; Rijssenbeek, M; Rimoldi, A; Rinaldi, L; Ritsch, E; Riu, I; Rizatdinova, F; Rizvi, E; Robertson, S H; Robichaud-Veronneau, A; Robinson, D; Robinson, J E M; Robson, A; Roda, C; Rodrigues, L; Roe, S; Røhne, O; Rolli, S; Romaniouk, A; Romano, M; Romero Adam, E; Rompotis, N; Ronzani, M; Roos, L; Ros, E; Rosati, S; Rosbach, K; Rose, M; Rose, P; Rosendahl, P L; Rosenthal, O; Rossetti, V; Rossi, E; Rossi, L P; Rosten, R; Rotaru, M; Roth, I; Rothberg, J; Rousseau, D; Royon, C R; Rozanov, A; Rozen, Y; Ruan, X; Rubbo, F; Rubinskiy, I; Rud, V I; Rudolph, C; Rudolph, M S; Rühr, F; Ruiz-Martinez, A; Rurikova, Z; Rusakovich, N A; Ruschke, A; Rutherfoord, J P; Ruthmann, N; Ryabov, Y F; Rybar, M; Rybkin, G; Ryder, N C; Saavedra, A F; Sacerdoti, S; Saddique, A; Sadeh, I; Sadrozinski, H F-W; Sadykov, R; Safai Tehrani, F; Sakamoto, H; Sakurai, Y; Salamanna, G; Salamon, A; Saleem, M; Salek, D; Sales De Bruin, P H; Salihagic, D; Salnikov, A; Salt, J; Salvatore, D; Salvatore, F; Salvucci, A; Salzburger, A; Sampsonidis, D; Sanchez, A; Sánchez, J; Sanchez Martinez, V; Sandaker, H; Sandbach, R L; Sander, H G; Sanders, M P; Sandhoff, M; Sandoval, T; Sandoval, C; Sandstroem, R; Sankey, D P C; Sansoni, A; Santoni, C; Santonico, R; Santos, H; Santoyo Castillo, I; Sapp, K; Sapronov, A; Saraiva, J G; Sarrazin, B; Sartisohn, G; Sasaki, O; Sasaki, Y; Sauvage, G; Sauvan, E; Savard, P; Savu, D O; Sawyer, C; Sawyer, L; Saxon, D H; Saxon, J; Sbarra, C; Sbrizzi, A; Scanlon, T; Scannicchio, D A; Scarcella, M; Scarfone, V; Schaarschmidt, J; Schacht, P; Schaefer, D; Schaefer, R; Schaepe, S; Schaetzel, S; Schäfer, U; Schaffer, A C; Schaile, D; Schamberger, R D; Scharf, V; Schegelsky, V A; Scheirich, D; Schernau, M; Scherzer, M I; Schiavi, C; Schieck, J; Schillo, C; Schioppa, M; Schlenker, S; Schmidt, E; Schmieden, K; Schmitt, C; Schmitt, S; Schneider, B; Schnellbach, Y J; Schnoor, U; Schoeffel, L; Schoening, A; Schoenrock, B D; Schorlemmer, A L S; Schott, M; Schouten, D; Schovancova, J; Schramm, S; Schreyer, M; Schroeder, C; Schuh, N; Schultens, M J; Schultz-Coulon, H-C; Schulz, H; Schumacher, M; Schumm, B A; Schune, Ph; Schwanenberger, C; Schwartzman, A; Schwegler, Ph; Schwemling, Ph; Schwienhorst, R; Schwindling, J; Schwindt, T; Schwoerer, M; Sciacca, F G; Scifo, E; Sciolla, G; Scott, W G; Scuri, F; Scutti, F; Searcy, J; Sedov, G; Sedykh, E; Seidel, S C; Seiden, A; Seifert, F; Seixas, J M; Sekhniaidze, G; Sekula, S J; Selbach, K E; Seliverstov, D M; Sellers, G; Semprini-Cesari, N; Serfon, C; Serin, L; Serkin, L; Serre, T; Seuster, R; Severini, H; Sfiligoj, T; Sforza, F; Sfyrla, A; Shabalina, E; Shamim, M; Shan, L Y; Shang, R; Shank, J T; Shapiro, M; Shatalov, P B; Shaw, K; Shehu, C Y; Sherwood, P; Shi, L; Shimizu, S; Shimmin, C O; Shimojima, M; Shiyakova, M; Shmeleva, A; Shochet, M J; Short, D; Shrestha, S; Shulga, E; Shupe, M A; Shushkevich, S; Sicho, P; Sidiropoulou, O; Sidorov, D; Sidoti, A; Siegert, F; Sijacki, Dj; Silva, J; Silver, Y; Silverstein, D; Silverstein, S B; Simak, V; Simard, O; Simic, Lj; Simion, S; Simioni, E; Simmons, B; Simoniello, R; Simonyan, M; Sinervo, P; Sinev, N B; Sipica, V; Siragusa, G; Sircar, A; Sisakyan, A N; Sivoklokov, S Yu; Sjölin, J; Sjursen, T B; Skottowe, H P; Skovpen, K Yu; Skubic, P; Slater, M; Slavicek, T; Sliwa, K; Smakhtin, V; Smart, B H; Smestad, L; Smirnov, S Yu; Smirnov, Y; Smirnova, L N; Smirnova, O; Smith, K M; Smizanska, M; Smolek, K; Snesarev, A A; Snidero, G; Snyder, S; Sobie, R; Socher, F; Soffer, A; Soh, D A; Solans, C A; Solar, M; Solc, J; Soldatov, E Yu; Soldevila, U; Solodkov, A A; Soloshenko, A; Solovyanov, O V; Solovyev, V; Sommer, P; Song, H Y; Soni, N; Sood, A; Sopczak, A; Sopko, B; Sopko, V; Sorin, V; Sosebee, M; Soualah, R; Soueid, P; Soukharev, A M; South, D; Spagnolo, S; Spanò, F; Spearman, W R; Spettel, F; Spighi, R; Spigo, G; Spiller, L A; Spousta, M; Spreitzer, T; Spurlock, B; St Denis, R D; Staerz, S; Stahlman, J; Stamen, R; Stamm, S; Stanecka, E; Stanek, R W; Stanescu, C; Stanescu-Bellu, M; Stanitzki, M M; Stapnes, S; Starchenko, E A; Stark, J; Staroba, P; Starovoitov, P; Staszewski, R; Stavina, P; Steinberg, P; Stelzer, B; Stelzer, H J; Stelzer-Chilton, O; Stenzel, H; Stern, S; Stewart, G A; Stillings, J A; Stockton, M C; Stoebe, M; Stoicea, G; Stolte, P; Stonjek, S; Stradling, A R; Straessner, A; Stramaglia, M E; Strandberg, J; Strandberg, S; Strandlie, A; Strauss, E; Strauss, M; Strizenec, P; Ströhmer, R; Strom, D M; Stroynowski, R; Stucci, S A; Stugu, B; Styles, N A; Su, D; Su, J; Subramaniam, R; Succurro, A; Sugaya, Y; Suhr, C; Suk, M; Sulin, V V; Sultansoy, S; Sumida, T; Sun, S; Sun, X; Sundermann, J E; Suruliz, K; Susinno, G; Sutton, M R; Suzuki, Y; Svatos, M; Swedish, S; Swiatlowski, M; Sykora, I; Sykora, T; Ta, D; Taccini, C; Tackmann, K; Taenzer, J; Taffard, A; Tafirout, R; Taiblum, N; Takai, H; Takashima, R; Takeda, H; Takeshita, T; Takubo, Y; Talby, M; Talyshev, A A; Tam, J Y C; Tan, K G; Tanaka, J; Tanaka, R; Tanaka, S; Tanaka, S; Tanasijczuk, A J; Tannenwald, B B; Tannoury, N; Tapprogge, S; Tarem, S; Tarrade, F; Tartarelli, G F; Tas, P; Tasevsky, M; Tashiro, T; Tassi, E; Tavares Delgado, A; Tayalati, Y; Taylor, F E; Taylor, G N; Taylor, W; Teischinger, F A; Teixeira Dias Castanheira, M; Teixeira-Dias, P; Temming, K K; Ten Kate, H; Teng, P K; Teoh, J J; Terada, S; Terashi, K; Terron, J; Terzo, S; Testa, M; Teuscher, R J; Therhaag, J; Theveneaux-Pelzer, T; Thomas, J P; Thomas-Wilsker, J; Thompson, E N; Thompson, P D; Thompson, P D; Thompson, R J; Thompson, A S; Thomsen, L A; Thomson, E; Thomson, M; Thong, W M; Thun, R P; Tian, F; Tibbetts, M J; Tikhomirov, V O; Tikhonov, Yu A; Timoshenko, S; Tiouchichine, E; Tipton, P; Tisserant, S; Todorov, T; Todorova-Nova, S; Toggerson, B; Tojo, J; Tokár, S; Tokushuku, K; Tollefson, K; Tomlinson, L; Tomoto, M; Tompkins, L; Toms, K; Topilin, N D; Torrence, E; Torres, H; Torró Pastor, E; Toth, J; Touchard, F; Tovey, D R; Tran, H L; Trefzger, T; Tremblet, L; Tricoli, A; Trigger, I M; Trincaz-Duvoid, S; Tripiana, M F; Trischuk, W; Trocmé, B; Troncon, C; Trottier-McDonald, M; Trovatelli, M; True, P; Trzebinski, M; Trzupek, A; Tsarouchas, C; Tseng, J C-L; Tsiareshka, P V; Tsionou, D; Tsipolitis, G; Tsirintanis, N; Tsiskaridze, S; Tsiskaridze, V; Tskhadadze, E G; Tsukerman, I I; Tsulaia, V; Tsuno, S; Tsybychev, D; Tudorache, A; Tudorache, V; Tuna, A N; Tupputi, S A; Turchikhin, S; Turecek, D; Turk Cakir, I; Turra, R; Tuts, P M; Tykhonov, A; Tylmad, M; Tyndel, M; Uchida, K; Ueda, I; Ueno, R; Ughetto, M; Ugland, M; Uhlenbrock, M; Ukegawa, F; Unal, G; Undrus, A; Unel, G; Ungaro, F C; Unno, Y; Unverdorben, C; Urbaniec, D; Urquijo, P; Usai, G; Usanova, A; Vacavant, L; Vacek, V; Vachon, B; Valencic, N; Valentinetti, S; Valero, A; Valery, L; Valkar, S; Valladolid Gallego, E; Vallecorsa, S; Valls Ferrer, J A; Van Den Wollenberg, W; Van Der Deijl, P C; van der Geer, R; van der Graaf, H; Van Der Leeuw, R; van der Ster, D; van Eldik, N; van Gemmeren, P; Van Nieuwkoop, J; van Vulpen, I; van Woerden, M C; Vanadia, M; Vandelli, W; Vanguri, R; Vaniachine, A; Vankov, P; Vannucci, F; Vardanyan, G; Vari, R; Varnes, E W; Varol, T; Varouchas, D; Vartapetian, A; Varvell, K E; Vazeille, F; Vazquez Schroeder, T; Veatch, J; Veloso, F; Veneziano, S; Ventura, A; Ventura, D; Venturi, M; Venturi, N; Venturini, A; Vercesi, V; Verducci, M; Verkerke, W; Vermeulen, J C; Vest, A; Vetterli, M C; Viazlo, O; Vichou, I; Vickey, T; Vickey Boeriu, O E; Viehhauser, G H A; Viel, S; Vigne, R; Villa, M; Villaplana Perez, M; Vilucchi, E; Vincter, M G; Vinogradov, V B; Virzi, J; Vivarelli, I; Vives Vaque, F; Vlachos, S; Vladoiu, D; Vlasak, M; Vogel, A; Vogel, M; Vokac, P; Volpi, G; Volpi, M; von der Schmitt, H; von Radziewski, H; von Toerne, E; Vorobel, V; Vorobev, K; Vos, M; Voss, R; Vossebeld, J H; Vranjes, N; Vranjes Milosavljevic, M; Vrba, V; Vreeswijk, M; Vu Anh, T; Vuillermet, R; Vukotic, I; Vykydal, Z; Wagner, P; Wagner, W; Wahlberg, H; Wahrmund, S; Wakabayashi, J; Walder, J; Walker, R; Walkowiak, W; Wall, R; Waller, P; Walsh, B; Wang, C; Wang, C; Wang, F; Wang, H; Wang, H; Wang, J; Wang, J; Wang, K; Wang, R; Wang, S M; Wang, T; Wang, X; Wanotayaroj, C; Warburton, A; Ward, C P; Wardrope, D R; Warsinsky, M; Washbrook, A; Wasicki, C; Watkins, P M; Watson, A T; Watson, I J; Watson, M F; Watts, G; Watts, S; Waugh, B M; Webb, S; Weber, M S; Weber, S W; Webster, J S; Weidberg, A R; Weigell, P; Weinert, B; Weingarten, J; Weiser, C; Weits, H; Wells, P S; Wenaus, T; Wendland, D; Weng, Z; Wengler, T; Wenig, S; Wermes, N; Werner, M; Werner, P; Wessels, M; Wetter, J; Whalen, K; White, A; White, M J; White, R; White, S; Whiteson, D; Wicke, D; Wickens, F J; Wiedenmann, W; Wielers, M; Wienemann, P; Wiglesworth, C; Wiik-Fuchs, L A M; Wijeratne, P A; Wildauer, A; Wildt, M A; Wilkens, H G; Will, J Z; Williams, H H; Williams, S; Willis, C; Willocq, S; Wilson, A; Wilson, J A; Wingerter-Seez, I; Winklmeier, F; Winter, B T; Wittgen, M; Wittig, T; Wittkowski, J; Wollstadt, S J; Wolter, M W; Wolters, H; Wosiek, B K; Wotschack, J; Woudstra, M J; Wozniak, K W; Wright, M; Wu, M; Wu, S L; Wu, X; Wu, Y; Wulf, E; Wyatt, T R; Wynne, B M; Xella, S; Xiao, M; Xu, D; Xu, L; Yabsley, B; Yacoob, S; Yakabe, R; Yamada, M; Yamaguchi, H; Yamaguchi, Y; Yamamoto, A; Yamamoto, K; Yamamoto, S; Yamamura, T; Yamanaka, T; Yamauchi, K; Yamazaki, Y; Yan, Z; Yang, H; Yang, H; Yang, U K; Yang, Y; Yanush, S; Yao, L; Yao, W-M; Yasu, Y; Yatsenko, E; Yau Wong, K H; Ye, J; Ye, S; Yeletskikh, I; Yen, A L; Yildirim, E; Yilmaz, M; Yoosoofmiya, R; Yorita, K; Yoshida, R; Yoshihara, K; Young, C; Young, C J S; Youssef, S; Yu, D R; Yu, J; Yu, J M; Yu, J; Yuan, L; Yurkewicz, A; Yusuff, I; Zabinski, B; Zaidan, R; Zaitsev, A M; Zaman, A; Zambito, S; Zanello, L; Zanzi, D; Zeitnitz, C; Zeman, M; Zemla, A; Zengel, K; Zenin, O; Ženiš, T; Zerwas, D; Zevi Della Porta, G; Zhang, D; Zhang, F; Zhang, H; Zhang, J; Zhang, L; Zhang, X; Zhang, Z; Zhao, Z; Zhemchugov, A; Zhong, J; Zhou, B; Zhou, L; Zhou, N; Zhu, C G; Zhu, H; Zhu, J; Zhu, Y; Zhuang, X; Zhukov, K; Zibell, A; Zieminska, D; Zimine, N I; Zimmermann, C; Zimmermann, R; Zimmermann, S; Zimmermann, S; Zinonos, Z; Ziolkowski, M; Zobernig, G; Zoccoli, A; Zur Nedden, M; Zurzolo, G; Zutshi, V; Zwalinski, L

2015-02-20

Measurements of inclusive jet production are performed in pp and Pb+Pb collisions at √(s)NN=2.76  TeV with the ATLAS detector at the LHC, corresponding to integrated luminosities of 4.0 and 0.14  nb(-1), respectively. The jets are identified with the anti-k(t) algorithm with R=0.4, and the spectra are measured over the kinematic range of jet transverse momentum 32

Diabetes-induced hepatic pathogenic damage, inflammation, oxidative stress, and insulin resistance was exacerbated in zinc deficient mouse model.

PubMed

Zhang, Chi; Lu, Xuemian; Tan, Yi; Li, Bing; Miao, Xiao; Jin, Litai; Shi, Xue; Zhang, Xiang; Miao, Lining; Li, Xiaokun; Cai, Lu

2012-01-01

Zinc (Zn) deficiency often occurs in the patients with diabetes. Effects of Zn deficiency on diabetes-induced hepatic injury were investigated. Type 1 diabetes was induced in FVB mice with multiple low-dose streptozotocin. Hyperglycemic and age-matched control mice were treated with and without Zn chelator, N,N,N',N'-tetrakis (2-pyridylemethyl) ethylenediamine (TPEN), at 5 mg/kg body-weight daily for 4 months. Hepatic injury was examined by serum alanine aminotransferase (ALT) level and liver histopathological and biochemical changes. Hepatic Zn deficiency (lower than control level, p<0.05) was seen in the mice with either diabetes or TPEN treatment and more evident in the mice with both diabetes and TPEN. Zn deficiency exacerbated hepatic injuries, shown by further increased serum ALT, hepatic lipid accumulation, inflammation, oxidative damage, and endoplasmic reticulum stress-related cell death in Diabetes/TPEN group compared to Diabetes alone. Diabetes/TPEN group also showed a significant decrease in nuclear factor-erythroid 2-related factor 2 (Nrf2) expression and transcription action along with significant increases in Akt negative regulators, decrease in Akt and GSK-3β phosphorylation, and increase in nuclear accumulation of Fyn (a Nrf2 negative regulator). In vitro study with HepG2 cells showed that apoptotic effect of TPEN at 0.5-1.0 µM could be completely prevented by simultaneous Zn supplementation at the dose range of 30-50 µM. Zn is required for maintaining Akt activation by inhibiting the expression of Akt negative regulators; Akt activation can inhibit Fyn nuclear translocation to export nuclear Nrf2 to cytoplasm for degradation. Zn deficiency significantly enhanced diabetes-induced hepatic injury likely through down-regulation of Nrf2 function.

Future electricity production methods. Part 1: Nuclear energy

NASA Astrophysics Data System (ADS)

Nifenecker, Hervé

2011-02-01

The global warming challenge aims at stabilizing the concentrations of Green House Gas (GHG) in the atmosphere. Carbon dioxide is the most effective of the anthropogenic GHG and is essentially produced by consumption of fossil fuels. Electricity production is the dominant cause of CO2 emissions. It is, therefore, crucial that the share of 'carbon less' electricity production techniques increases at a fast pace. This is the more so, that 'clean' electricity would be useful to displace 'dirty' techniques in other fields such as heat production and transportation. Here we examine the extent to which nuclear energy could be operational in providing 'clean' electricity. A nuclear intensive scenario is shown to give the possibility to divide CO2 emissions by a factor of 2 worldwide, within 50 years. However, the corresponding sharp increase in nuclear power will put a heavy burden on uranium reserves and will necessitate the development of breeding reactors as soon as possible. A review of present and future reactors is given with special attention to the safety issues. The delicate question of nuclear fuel cycle is discussed concerning uranium reserves and management of used fuels. It is shown that dealing with nuclear wastes is more a socio-political problem than a technical one. The third difficult question associated with the development of nuclear energy is the proliferation risk. It is advocated that, while this is, indeed, a very important question, it is only weakly related to nuclear power development. Finally, the possibilities of nuclear fusion are discussed and it is asserted that, under no circumstances, could nuclear fusion give a significant contribution to the solution of the energy problem before 50 years, too late for dealing with the global warming challenge.

Nuclear accumulation of SHIP1 mutants derived from AML patients leads to increased proliferation of leukemic cells.

PubMed

Nalaskowski, Marcus M; Ehm, Patrick; Rehbach, Christoph; Nelson, Nina; Täger, Maike; Modest, Kathrin; Jücker, Manfred

2018-05-28

The inositol 5-phosphatase SHIP1 acts as negative regulator of intracellular signaling in myeloid cells and is a tumor suppressor in myeloid leukemogenesis. After relocalization from the cytoplasm to the plasma membrane SHIP1 terminates PI3-kinase mediated signaling processes. Furthermore, SHIP1 is also found in distinct puncta in the cell nucleus and nuclear SHIP1 has a pro-proliferative function. Here we report the identification of five nuclear export signals (NESs) which regulate together with the two known nuclear localization signals (NLSs) the nucleocytoplasmic shuttling of SHIP1. Mutation of NLSs reduced the nuclear import and mutation of NESs decreased the nuclear export of SHIP1 in the acute myeloid leukemia (AML) cell line UKE-1. Interestingly, four SHIP1 mutants (K210R, N508D, V684E, Q1153L) derived from AML patients showed a nuclear accumulation after expression in UKE-1 cells. In addition, overexpression of the AML patient-derived mutation N508D caused an increased proliferation rate of UKE-1 cells in comparison to wild type SHIP1. Furthermore, we identified serine and tyrosine phosphorylation as a molecular mechanism for the regulation of nucleocytoplasmic shuttling of SHIP1 where tyrosine phosphorylation of distinct residues i.e. Y864, Y914, Y1021 reduces nuclear localization, whereas serine phosphorylation at S933 enhances nuclear localization of SHIP1. In summary, our data further implicate nuclear SHIP1 in cellular signaling and suggest that enhanced accumulation of SHIP1 mutants in the nucleus may be a contributory factor of abnormally high proliferation of AML cells. Copyright © 2018 Elsevier Inc. All rights reserved.

Nuclear factor-E2-related factor 2 is a major determinant of bile acid homeostasis in the liver and intestine

PubMed Central

Weerachayaphorn, Jittima; Mennone, Albert; Soroka, Carol J.; Harry, Kathy; Hagey, Lee R.; Kensler, Thomas W.

2012-01-01

The transcription factor nuclear factor-E2-related factor 2 (Nrf2) is a key regulator for induction of hepatic detoxification and antioxidant mechanisms, as well as for certain hepatobiliary transporters. To examine the role of Nrf2 in bile acid homeostasis and cholestasis, we assessed the determinants of bile secretion and bile acid synthesis and transport before and after bile duct ligation (BDL) in Nrf2−/− mice. Our findings indicate reduced rates of biliary bile acid and GSH excretion, higher levels of intrahepatic bile acids, and decreased expression of regulators of bile acid synthesis, Cyp7a1 and Cyp8b1, in Nrf2−/− compared with wild-type control mice. The mRNA expression of the bile acid transporters bile salt export pump (Bsep) and organic solute transporter (Ostα) were increased in the face of impaired expression of the multidrug resistance-associated proteins Mrp3 and Mrp4. Deletion of Nrf2 also decreased ileal apical sodium-dependent bile acid transporter (Asbt) expression, leading to reduced bile acid reabsorption and increased loss of bile acid in feces. Finally, when cholestasis is induced by BDL, liver injury was not different from that in wild-type BDL mice. These Nrf2−/− mice also had increased pregnane X receptor (Pxr) and Cyp3a11 mRNA expression in association with enhanced hepatic bile acid hydroxylation. In conclusion, this study finds that Nrf2 plays a major role in the regulation of bile acid homeostasis in the liver and intestine. Deletion of Nrf2 results in a cholestatic phenotype but does not augment liver injury following BDL. PMID:22345550

Hypericin-mediated sonodynamic therapy induces autophagy and decreases lipids in THP-1 macrophage by promoting ROS-dependent nuclear translocation of TFEB.

PubMed

Li, Xuesong; Zhang, Xin; Zheng, Longbin; Kou, Jiayuan; Zhong, Zhaoyu; Jiang, Yueqing; Wang, Wei; Dong, Zengxiang; Liu, Zhongni; Han, Xiaobo; Li, Jing; Tian, Ye; Zhao, Yajun; Yang, Liming

2016-12-22

Lipid catabolism disorder is the primary cause of atherosclerosis. Transcription factor EB (TFEB) prevents atherosclerosis by activating macrophage autophagy to promote lipid degradation. Hypericin-mediated sonodynamic therapy (HY-SDT) has been proved non-invasively inducing THP-1-derived macrophage apoptosis; however, it is unknown whether macrophage autophagy could be triggered by HY-SDT to influence cellular lipid catabolism via regulating TFEB. Here, we report that HY-SDT resulted in the time-dependent THP-1-derived macrophage autophagy activation through AMPK/AKT/mTOR pathway. Besides, TFEB nuclear translocation in macrophage was triggered by HY-SDT to promote autophagy activation and lysosome regeneration which enhanced lipid degradation in response to atherogenic lipid stressors. Moreover, following HY-SDT, the ABCA1 expression level was increased to promote lipid efflux in macrophage, and the expression levels of CD36 and SR-A were decreased to inhibit lipid uptake, both of which were prevented by TFEB knockdown. These results indicated that TFEB nuclear translocation activated by HY-SDT was not only the key regulator of autophagy activation and lysosome regeneration in macrophage to promote lipolysis, but also had a crucial role in reverse cholesterol transporters to decrease lipid uptake and increase lipid efflux. Reactive oxygen species (ROS) were adequately generated in macrophage by HY-SDT. Further, ROS scavenger N-acetyl-l-cysteine abolished HY-SDT-induced TFEB nuclear translocation and autophagy activation, implying that ROS were the primary upstream factors responsible for these effects during HY-SDT. In summary, our data indicate that HY-SDT decreases lipid content in macrophage by promoting ROS-dependent nuclear translocation of TFEB to influence consequent autophagy activation and cholesterol transporters. Thus, HY-SDT may be beneficial for atherosclerosis via TFEB regulation to ameliorate lipid overload in atherosclerotic plaques.

Mangiferin induces apoptosis in multiple myeloma cell lines by suppressing the activation of nuclear factor kappa B-inducing kinase.

PubMed

Takeda, Tomoya; Tsubaki, Masanobu; Kino, Toshiki; Yamagishi, Misa; Iida, Megumi; Itoh, Tatsuki; Imano, Motohiro; Tanabe, Genzoh; Muraoka, Osamu; Satou, Takao; Nishida, Shozo

2016-05-05

Mangiferin is a naturally occurring glucosyl xanthone, which induces apoptosis in various cancer cells. However, the molecular mechanism underlying mangiferin-induced apoptosis has not been clarified thus far. Therefore, we examined the molecular mechanism underlying mangiferin-induced apoptosis in multiple myeloma (MM) cell lines. We found that mangiferin decreased the viability of MM cell lines in a concentration-dependent manner. We also observed an increased number of apoptotic cells, caspase-3 activation, and a decrease in the mitochondrial membrane potential. In addition, mangiferin inhibited the nuclear translocation of nuclear factor kappa B (NF-κB) and expression of phosphorylated inhibitor kappa B (IκB) and increased the expression of IκB protein, whereas no changes were observed in the phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal protein kinase 1/2 (JNK1/2), and mammalian target of rapamycin (mTOR). The molecular mechanism responsible for mangiferin-induced inhibition of nuclear translocation of NF-κB was a decrease in the expression of phosphorylated NF-κB-inducing kinase (NIK). Moreover, mangiferin decreased the expression of X-linked inhibitor of apoptosis protein (XIAP), survivin, and Bcl-xL proteins. Knockdown of NIK expression showed results similar to those observed with mangiferin treatment. Our results suggest that mangiferin induces apoptosis through the inhibition of nuclear translocation of NF-κB by suppressing NIK activation in MM cell lines. Our results provide a new insight into the molecular mechanism of mangiferin-induced apoptosis. Importantly, since the number of reported NIK inhibitors is limited, mangiferin, which targets NIK, may be a potential anticancer agent for the treatment of MM. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Inactivation of p27kip1 Promoted Nonspecific Inflammation by Enhancing Macrophage Proliferation in Islet Transplantation.

PubMed

Li, Yang; Ding, Xiaoming; Fan, Ping; Guo, Jian; Tian, Xiaohui; Feng, Xinshun; Zheng, Jin; Tian, Puxun; Ding, Chenguang; Xue, Wujun

2016-11-01

Islet transplantation suffers from low efficiency caused by nonspecific inflammation-induced graft loss after transplantation. This study reports increased islet loss and enhanced inflammatory response in p27-deficient mice (p27-/-) and proposes a possible mechanism. Compared with wild type, p27-/- mice showed more severe functional injury of islet, with increased serum levels of inflammatory cytokines IL-1 and TNF-α, inducing macrophage proliferation. Furthermore, the increased number, proapoptotic proteins, and nuclear factor-kappa b (NF-κB) phosphorylation status of the infiltrating macrophages were accompanied by increased TNF-α mRNA level of islet graft site in p27-/- mice. Moreover, in vitro, we found that macrophages were still activated and cocultured with islet and promoted islet loss even blocking the direct effect of TNF-α on islets. Malondialdehyde (MDA, an end product of lipid peroxidation) in islet and media were increased after cocultured with macrophages. p27 deficiency also increased macrophage proliferation and islet injury. Therefore, p27 inactivation promotes injury islet graft loss via the elevation of proliferation and inflammatory cytokines secretion in infiltrating macrophages which induced nonspecific inflammation independent of TNF-α/nuclear factor-kappa b pathway. This potentially represents a promising therapeutic target in improving islet graft survival.

Canonical and non-canonical mechanisms of Nrf2 activation.

PubMed

Silva-Islas, Carlos Alfredo; Maldonado, Perla D

2018-06-15

Nuclear Factor Erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates the expression of genes involved in the metabolism, immune response, cellular proliferation, and other processes; however, the attention has been focused on the study of its ability to induce the expression of proteins involved in the antioxidant defense. Nrf2 is mainly regulated by Kelch-like ECH-associated protein 1 (Keap1), an adapter substrate of Cullin 3 (Cul3) ubiquitin E3 ligase complex. Keap1 represses Nrf2 activity in the cytoplasm by its sequestering, ubiquitination and proteosomal degradation. Nrf2 activation, through the canonical mechanism, is carried out by electrophilic compounds and oxidative stress where some cysteine residues in Keap1 are oxidized, resulting in a decrease in Nrf2 ubiquitination and an increase in its nuclear translocation and activation. In the nucleus, Nrf2 induces a variety of genes involved in the antioxidant defense. Recently a new mechanism of Nrf2 activation has been described, called the non-canonical pathway, where proteins such as p62, p21, dipeptidyl peptidase III (DPP3), wilms tumor gene on X chromosome (WTX) and others are able to disrupt the Nrf2-Keap1 complex, by direct interaction with Keap1 decreasing Nrf2 ubiquitination and increasing its nuclear translocation and activation. In this review, the regulatory mechanisms involved in both canonical and non-canonical Nrf2 activation are discussed. Copyright © 2018. Published by Elsevier Ltd.

Hydrogen gas attenuates sevoflurane neurotoxicity through inhibiting nuclear factor κ-light-chain-enhancer of activated B cells signaling and proinflammatory cytokine release in neonatal rats.

PubMed

Shi, Yiwei; Wang, Gang; Li, Jinyuan; Yu, Wenli

2017-12-06

Anesthesia neurotoxicity in developing brain has gained increasing attention. However, knowledge regarding its mitigating strategies remains scant. Sevoflurane, a commonly used anesthetic, is responsible for learning and memory deficits in neonates. Molecular hydrogen is reported to be a potential neuroprotective agent because of its antioxidative and anti-inflammatory activities. This study aimed to investigate the effect of hydrogen gas on sevoflurane neurotoxicity. The newborn rats were treated with sevoflurane and/or hydrogen gas for 2 h. Spatial recognition memory and fear memory were determined by Y-maze and fear conditioning tests at 10 weeks of age. Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and proinflammatory cytokine levels were detected using western blot analysis. The data showed that the spatial recognition memory and fear memory of the rats treated with sevoflurane decreased compared with the control, and the cognitive function of the rats treated with sevoflurane and hydrogen gas significantly increased in comparison with treatment with sevoflurane alone. Moreover, hydrogen gas suppressed NF-κB phosphorylation and nuclear translocation and reduced the production of interleukin-1β, interleukin-6, and tumor necrosis factor-α following sevoflurane administration. Thus, the results proposed that hydrogen gas might protect against sevoflurane neurotoxicity by inhibiting NF-κB activation and proinflammatory cytokine release, providing a novel therapeutic strategy for anesthesia neurotoxicity.

THz Dynamic Nuclear Polarization NMR

PubMed Central

Nanni, Emilio A.; Barnes, Alexander B.; Griffin, Robert G.; Temkin, Richard J.

2013-01-01

Dynamic nuclear polarization (DNP) increases the sensitivity of nuclear magnetic resonance (NMR) spectroscopy by using high frequency microwaves to transfer the polarization of the electrons to the nuclear spins. The enhancement in NMR sensitivity can amount to a factor of well above 100, enabling faster data acquisition and greatly improved NMR measurements. With the increasing magnetic fields (up to 23 T) used in NMR research, the required frequency for DNP falls into the THz band (140–600 GHz). Gyrotrons have been developed to meet the demanding specifications for DNP NMR, including power levels of tens of watts; frequency stability of a few megahertz; and power stability of 1% over runs that last for several days to weeks. Continuous gyrotron frequency tuning of over 1 GHz has also been demonstrated. The complete DNP NMR system must include a low loss transmission line; an optimized antenna; and a holder for efficient coupling of the THz radiation to the sample. This paper describes the DNP NMR process and illustrates the THz systems needed for this demanding spectroscopic application. THz DNP NMR is a rapidly developing, exciting area of THz science and technology. PMID:24639915

Shade-induced nuclear localization of PIF7 is regulated by phosphorylation and 14-3-3 proteins in Arabidopsis.

PubMed

Huang, Xu; Zhang, Qian; Jiang, Yupei; Yang, Chuanwei; Wang, Qianyue; Li, Lin

2018-06-21

Shade avoidance syndrome enables shaded plants to grow and compete effectively against their neighbors. In Arabidopsis , the shade-induced de-phosphorylation of the transcription factor PIF7 (PHYTOCHROME-INTERACTING FACTOR 7) is the key event linking light perception to stem elongation. However, the mechanism through which phosphorylation regulates the activity of PIF7 is unclear. Here, we show that shade light induces the de-phosphorylation and nuclear accumulation of PIF7. Phosphorylation-resistant site mutations in PIF7 result in increased nuclear localization and shade-induced gene expression, and consequently augment hypocotyl elongation. PIF7 interacts with 14-3-3 proteins. Blocking the interaction between PIF7 and 14-3-3 proteins or reducing the expression of 14-3-3 proteins accelerates shade-induced nuclear localization and de-phosphorylation of PIF7, and enhances the shade phenotype. By contrast, the 14-3-3 overexpressing line displays an attenuated shade phenotype. These studies demonstrate a phosphorylation-dependent translocation of PIF7 when plants are in shade and a novel mechanism involving 14-3-3 proteins, mediated by the retention of PIF7 in the cytoplasm that suppresses the shade response. © 2018, Huang et al.

The small-x gluon distribution in centrality biased pA and pp collisions

DOE PAGES

Dumitru, Adrian; Kapilevich, Gary; Skokov, Vladimir

2018-04-04

Here, the nuclear modification factor R pA(p T) provides information on the small- x gluon distribution of a nucleus at hadron colliders. Several experiments have recently measured the nuclear modification factor not only in minimum bias but also for central pA collisions. In this paper we analyze the bias on the configurations of soft gluon fields introduced by a centrality selection via the number of hard particles. Such bias can be viewed as reweighting of configurations of small- x gluons. We find that the biased nuclear modification factor Q pA(p T) for central collisions is above R pA(p T) formore » minimum bias events, and that it may redevelop a “Cronin peak” even at small x . The magnitude of the peak is predicted to increase approximately like 1/A ⊥ ν, ν~0.6±0.1 , if one is able to select more compact configurations of the projectile proton where its gluons occupy a smaller transverse area A ⊥. We predict an enhanced Q pp(p T)–1~1/(p T 2) ν and a Cronin peak even for central pp collisions.« less

The small-x gluon distribution in centrality biased pA and pp collisions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dumitru, Adrian; Kapilevich, Gary; Skokov, Vladimir

Here, the nuclear modification factor R pA(p T) provides information on the small- x gluon distribution of a nucleus at hadron colliders. Several experiments have recently measured the nuclear modification factor not only in minimum bias but also for central pA collisions. In this paper we analyze the bias on the configurations of soft gluon fields introduced by a centrality selection via the number of hard particles. Such bias can be viewed as reweighting of configurations of small- x gluons. We find that the biased nuclear modification factor Q pA(p T) for central collisions is above R pA(p T) formore » minimum bias events, and that it may redevelop a “Cronin peak” even at small x . The magnitude of the peak is predicted to increase approximately like 1/A ⊥ ν, ν~0.6±0.1 , if one is able to select more compact configurations of the projectile proton where its gluons occupy a smaller transverse area A ⊥. We predict an enhanced Q pp(p T)–1~1/(p T 2) ν and a Cronin peak even for central pp collisions.« less

Quartetting in Nuclear Matter and α Particle Condensation in Nuclear Systems

NASA Astrophysics Data System (ADS)

Röpke, G.; Schuck, P.; Horiuchi, H.; Tohsaki, A.; Funaki, Y.; Yamada, T.

2008-02-01

Alternatively to pairing, four-particle correlations may become of importance for the formation of quantum condensates in nuclear matter. With increasing density, four-particle correlations are suppressed because of Pauli blocking. Signatures of α-like clusters are expected to occur in low-density nuclear systems. The famous Hoyle state (02+ at 7.654 MeV in 12C) is identified as being an almost ideal condensate of three α-particles, hold together only by the Coulomb barrier. It, therefore, has a 8Be-α structure of low density. Transition probability and inelastic form factor together with position and other physical quantities are correctly reproduced without any adjustable parameter from our two parameter wave function of α-particle condensate type. The possibility of the existence of α-particle condensed states in heavier nα nuclei is also discussed.

Elevated muscle TLR4 expression and metabolic endotoxemia in human aging.

PubMed

Ghosh, Sangeeta; Lertwattanarak, Raweewan; Garduño, Jose de Jesus; Galeana, Joaquin Joya; Li, Jinqi; Zamarripa, Frank; Lancaster, Jack L; Mohan, Sumathy; Hussey, Sophie; Musi, Nicolas

2015-02-01

Aging is associated with alterations in glucose metabolism and sarcopenia that jointly contribute to a higher risk of developing type 2 diabetes. Because aging is considered as a state of low-grade inflammation, in this study we examined whether older, healthy (lean, community-dwelling) participants have altered signaling flux through toll-like receptor 4 (TLR4), a key mediator of innate and adaptive immune responses. We also examined whether a 4-month aerobic exercise program would have an anti-inflammatory effect by reducing TLR4 expression and signaling. At baseline, muscle TLR4, nuclear factor κB p50 and nuclear factor κB p65 protein content, and c-Jun N-terminal kinase phosphorylation were significantly elevated in older versus young participants. The plasma concentration of the TLR4 agonist lipopolysaccharide and its binding protein also were significantly elevated in older participants, indicative of metabolic endotoxemia, which is a recently described phenomenon of increased plasma endotoxin level in metabolic disease. These alterations in older participants were accompanied by decreased insulin sensitivity, quadriceps muscle volume, and muscle strength. The exercise training program increased insulin sensitivity, without affecting quadriceps muscle volume or strength. Muscle TLR4, nuclear factor κB, and c-Jun N-terminal kinase, and plasma lipopolysaccharide and lipopolysaccharide binding protein were not changed by exercise. In conclusion, insulin resistance and sarcopenia of aging are associated with increased TLR4 expression/signaling, which may be secondary to metabolic endotoxemia. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Valproic acid attenuates acute lung injury induced by ischemia-reperfusion in rats.

PubMed

Wu, Shu-Yu; Tang, Shih-En; Ko, Fu-Chang; Wu, Geng-Chin; Huang, Kun-Lun; Chu, Shi-Jye

2015-06-01

Evidence reveals that histone deacetylase (HDAC) inhibition has potential for the treatment of inflammatory diseases. The protective effect of HDAC inhibition involves multiple mechanisms. Heme oxygenase-1 (HO-1) is protective in lung injury as a key regulator of antioxidant response. The authors examined whether HDAC inhibition provided protection against ischemia-reperfusion (I/R) lung injury in rats by up-regulating HO-1 activity. Acute lung injury was induced by producing 40 min of ischemia followed by 60 min of reperfusion in isolated perfused rat lungs. The rats were randomly allotted to control group, I/R group, or I/R + valproic acid (VPA) group with or without an HO-1 activity inhibitor (zinc protoporphyrin IX) (n = 6 per group). I/R caused significant increases in the lung edema, pulmonary arterial pressure, lung injury scores, tumor necrosis factor-α, and cytokine-induced neutrophil chemoattractant-1 concentrations in bronchoalveolar lavage fluid. Malondialdehyde levels, carbonyl contents, and myeloperoxidase-positive cells in lung tissue were also significantly increased. I/R stimulated the degradation of inhibitor of nuclear factor-κB-α, nuclear translocation of nuclear factor-κB, and up-regulation of HO-1 activity. Furthermore, I/R decreased B-cell lymphoma-2, heat shock protein 70, acetylated histone H3 protein expression, and increased the caspase-3 activity in the rat lungs. In contrast, VPA treatment significantly attenuated all the parameters of lung injury, oxidative stress, apoptosis, and inflammation. In addition, VPA treatment also enhanced HO-1 activity. Treatment with zinc protoporphyrin IX blocked the protective effect of VPA. VPA protected against I/R-induced lung injury. The protective mechanism may be partly due to enhanced HO-1 activity following HDAC inhibition.

Nuclear respiratory factor-1 and bioenergetics in tamoxifen-resistant breast cancer cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Radde, Brandie N.; Ivanova, Margarita M.; Mai, Huy Xuan

Acquired tamoxifen (TAM) resistance is a significant clinical problem in treating patients with estrogen receptor α (ERα)+ breast cancer. We reported that ERα increases nuclear respiratory factor-1 (NRF-1), which regulates nuclear-encoded mitochondrial gene transcription, in MCF-7 breast cancer cells and NRF-1 knockdown stimulates apoptosis. Whether NRF-1 and target gene expression is altered in endocrine resistant breast cancer cells is unknown. We measured NRF-1and metabolic features in a cell model of progressive TAM-resistance. NRF-1 and its target mitochondrial transcription factor A (TFAM) were higher in TAM-resistant LCC2 and LCC9 cells than TAM-sensitive MCF-7 cells. Using extracellular flux assays we observed thatmore » LCC1, LCC2, and LCC9 cells showed similar oxygen consumption rate (OCR), but lower mitochondrial reserve capacity which was correlated with lower Succinate Dehydrogenase Complex, Subunit B in LCC1 and LCC2 cells. Complex III activity was lower in LCC9 than MCF-7 cells. LCC1, LCC2, and LCC9 cells had higher basal extracellular acidification (ECAR), indicating higher aerobic glycolysis, relative to MCF-7 cells. Mitochondrial bioenergetic responses to estradiol and 4-hydroxytamoxifen were reduced in the endocrine-resistant cells compared to MCF-7 cells. These results suggest the acquisition of altered metabolic phenotypes in response to long term antiestrogen treatment may increase vulnerability to metabolic stress. - Highlights: • NRF-1 and TFAM expression are higher in endocrine-resistant breast cancer cells. • Oxygen consumption rate is similar in endocrine-sensitive and resistant cells. • Mitochondrial reserve capacity is lower in endocrine-resistant cells. • Endocrine-resistant breast cancer cells have increased glycolysis. • Bioenergetic responses to E2 and tamoxifen are lower in endocrine-resistant cells.« less

Structural and calorimetric studies demonstrate that the hepatocyte nuclear factor 1β (HNF1β) transcription factor is imported into the nucleus via a monopartite NLS sequence.

PubMed

Wiedmann, Mareike M; Aibara, Shintaro; Spring, David R; Stewart, Murray; Brenton, James D

2016-09-01

The transcription factor hepatocyte nuclear factor 1β (HNF1β) is ubiquitously overexpressed in ovarian clear cell carcinoma (CCC) and is a potential therapeutic target. To explore potential approaches that block HNF1β transcription we have identified and characterised extensively the nuclear localisation signal (NLS) for HNF1β and its interactions with the nuclear protein import receptor, Importin-α. Pull-down assays demonstrated that the DNA binding domain of HNF1β interacted with a spectrum of Importin-α isoforms and deletion constructs tagged with eGFP confirmed that the HNF1β (229)KKMRRNR(235) sequence was essential for nuclear localisation. We further characterised the interaction between the NLS and Importin-α using complementary biophysical techniques and have determined the 2.4Å resolution crystal structure of the HNF1β NLS peptide bound to Importin-α. The functional, biochemical, and structural characterisation of the nuclear localisation signal present on HNF1β and its interaction with the nuclear import protein Importin-α provide the basis for the development of compounds targeting transcription factor HNF1β via its nuclear import pathway. Copyright © 2016. Published by Elsevier Inc.

Fascin Overexpression Promotes Cholangiocarcinoma RBE Cell Proliferation, Migration, and Invasion.

PubMed

Zhao, Haiying; Yang, Fuquan; Zhao, Wenyan; Zhang, Chunjv; Liu, Jingang

2016-04-01

Fascin is overexpressed in various tumor tissues and is closely related to tumor metastasis and invasion. However, the role of fascin in cholangiocarcinoma RBE cells has not been clearly reported. This study aimed to establish a cholangiocarcinoma cell line with stable and high expression of fascin to observe the effect of fascin on cell proliferation, migration, and invasion. A fascin overexpression vector, pcDNA3.1-Fascin, was constructed and transfected into the human cholangiocarcinoma RBE cell line. The results of real-time polymerase chain reaction, Western blot, and immunofluorescence indicated that fascin was steadily and highly expressed in RBE cells. The results of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide and colony formation assay indicated that upregulated fascin expression could enhance cholangiocarcinoma cell proliferation. The results of wound healing assay and transwell assay indicated that fascin could promote cholangiocarcinoma cell migration and invasion, and a further study found that the nuclear factor-κB signaling pathway was activated after upregulation of fascin, whereas E-cadherin expression in these cells was significantly decreased. Additionally, E-cadherin expression was significantly increased after inhibiting nuclear factor-κB activity using inhibitor or small interfering RNA, and E-cadherin expression was decreased by fascin overexpression after nuclear factor-κB inhibition, suggesting that nuclear factor-κB signaling pathway was not involved in the regulation of E-cadherin by fascin. In summary, the results of this study demonstrated that fascin effectively promoted cholangiocarcinoma RBE cell proliferation, migration, and invasion. This study provides evidence for fascin as a potential target in the treatment of cholangiocarcinoma. © The Author(s) 2015.

Bortezomib as a new therapeutic approach for blastic plasmacytoid dendritic cell neoplasm

PubMed Central

Philippe, Laure; Ceroi, Adam; Bôle-Richard, Elodie; Jenvrin, Alizée; Biichle, Sabeha; Perrin, Sophie; Limat, Samuel; Bonnefoy, Francis; Deconinck, Eric; Saas, Philippe; Garnache-Ottou, Francine; Angelot-Delettre, Fanny

2017-01-01

Blastic plasmacytoid dendritic cell neoplasm is an aggressive hematologic malignancy with a poor prognosis. No consensus regarding optimal treatment modalities is currently available. Targeting the nuclear factor-kappa B pathway is considered a promising approach since blastic plasmacytoid dendritic cell neoplasm has been reported to exhibit constitutive activation of this pathway. Moreover, nuclear factor-kappa B inhibition in blastic plasmacytoid dendritic cell neoplasm cell lines, achieved using either an experimental specific inhibitor JSH23 or the clinical drug bortezomib, interferes in vitro with leukemic cell proliferation and survival. Here we extended these data by showing that primary blastic plasmacytoid dendritic cell neoplasm cells from seven patients were sensitive to bortezomib-induced cell death. We confirmed that bortezomib efficiently inhibits the phosphorylation of the RelA nuclear factor-kappa B subunit in blastic plasmacytoid dendritic cell neoplasm cell lines and primary cells from patients in vitro and in vivo in a mouse model. We then demonstrated that bortezomib can be associated with other drugs used in different chemotherapy regimens to improve its impact on leukemic cell death. Indeed, when primary blastic plasmacytoid dendritic cell neoplasm cells from a patient were grafted into mice, bortezomib treatment significantly increased the animals’ survival, and was associated with a significant decrease of circulating leukemic cells and RelA nuclear factor-kappa B subunit expression. Overall, our results provide a rationale for the use of bortezomib in combination with other chemotherapy for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm. Based on our data, a prospective clinical trial combining proteasome inhibitor with classical drugs could be envisaged. PMID:28798071

Protective effects of glutamine on human melanocyte oxidative stress model.

PubMed

Jiang, Liya; Guo, Zhen; Kong, Yulong; Liang, Jianhua; Wang, Yi; Wang, Keyu

2018-01-01

Vitiligo is a disorder caused by the loss of the melanocyte activity on melanin pigment generation. Studies show that oxidative-stress induced apoptosis in melanocytes is closely related to the pathogenesis of vitiligo. Glutamine is a well known antioxidant with anti-apoptotic effects, and is used in a variety of diseases. However, it is unclear whether glutamine has an antioxidant or anti-apoptotic effect on melanocytes. The aim of this study was to investigate the protective effects of glutamine on a human melanocyte oxidative stress model. The oxidative stress model was established on human melanocytes using hydrogen peroxide. The morphology and viability of melanocytes, levels of oxidants [reactive oxygen species and malondialdehyde], levels of antioxidants [superoxide dismutase and glutathione-S-transferase], and apoptosis-related indicators (caspase-3, bax and bcl-2) were examined after glutamine exposure at various concentrations. Expressions of nuclear factor-E2-related factor 2, heme oxygenase-1, and heat shock protein 70 were detected using western blot technique after glutamine exposure at various concentrations. Our results demonstrate that pre-treatment and post-treatment with glutamine promoted melanocyte viability, increased levels of superoxide dismutase, glutathione-S-transferase and bcl-2, decreased levels of reactive oxygen species, malondialdehyde, bax and caspase-3, and enhanced nuclear factor-E2-related factor 2, heme oxygenase-1, and heat shock protein 70 expression in a dose dependent manner. The effect of pre-treatment was more significant than post-treatment, at the same concentration. The mechanisms of glutamine activated nuclear factor-E2-related factor 2 antioxidant responsive element signaling pathway need further investigation. Glutamine enhances the antioxidant and anti-apoptotic capabilities of melanocytes and protects them against oxidative stress.

Exopolyphosphatases in nuclear and mitochondrial fractions during embryogenesis of the hard tick Rhipicephalus (Boophilus) microplus.

PubMed

Campos, Eldo; Façanha, Arnoldo R; Costa, Evenilton P; da Silva Vaz, Itabajara; Masuda, Aoi; Logullo, Carlos

2008-11-01

The present work evaluated polyphosphate (poly P) metabolism in nuclear and mitochondrial fractions during Rhipicephalus microplus embryogenesis. Nuclear poly P decreased and activity of exopolyphosphatase (PPX - polyphosphate-phosphohydrolases; EC 3.6.1.11) increased after embryo cellularization until the end of embryogenesis. The utilization of mitochondrial poly P content occurred between embryo cellularization and segmentation stages. Increasing amounts of total RNA extracted from eggs progressively enhanced nuclear PPX activity, whereas it exerted no effect on mitochondrial PPX activity. The decline in total poly P content after the 7th day of embryogenesis does not reflect the free P(i) increase and the total poly P chain length decrease after embryo cellularization. The Km(app) utilizing poly P(3), poly P(15) and poly P(65) as substrate was almost the same for the nuclear fraction (around 1muM), while the affinity for substrate in mitochondrial fraction was around 10 times higher for poly P(3) (Km(app) = 0.2muM) than for poly P(15) (Km(app) = 2.8muM) and poly P(65) (Km(app) = 3.6muM). PPX activity was stimulated by a factor of two by Mg2+ and Co2+ in the nuclear fraction and only by Mg2+ in the mitochondrial fraction. Heparin (20microg/mL) inhibited nuclear and mitochondrial PPX activity in about 90 and 95% respectively. Together, these data are consistent with the existence of two different PPX isoforms operating in the nuclei and mitochondria of the hard tick R. microplus with distinct metal dependence, inhibitor and activator sensitivities. The data also shed new light on poly P biochemistry during arthropod embryogenesis, opening new routes for future comparative studies on the physiological roles of different poly P pools distributed over cell compartments.

Andrographolide stimulates p38 mitogen-activated protein kinase-nuclear factor erythroid-2-related factor 2-heme oxygenase 1 signaling in primary cerebral endothelial cells for definite protection against ischemic stroke in rats.

PubMed

Yen, Ting-Lin; Chen, Ray-Jade; Jayakumar, Thanasekaran; Lu, Wan-Jung; Hsieh, Cheng-Ying; Hsu, Ming-Jen; Yang, Chih-Hao; Chang, Chao-Chien; Lin, Yen-Kuang; Lin, Kuan-Hung; Sheu, Joen-Rong

2016-04-01

Stroke pathogenesis involves complex oxidative stress-related pathways. The nuclear factor erythroid-2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) pathways have been considered molecular targets in pharmacologic intervention for ischemic diseases. Andrographolide, a labdane diterpene, has received increasing attention in recent years because of its various pharmacologic activities. We determined that andrographolide modulates the mitogen-activated protein kinase (MAPK)-Nrf2-HO-1 signaling cascade in primary cerebral endothelial cells (CECs) to provide positive protection against middle cerebral artery occlusion (MCAO)-induced ischemic stroke in rats. In the present study, andrographolide (10 μM) increased HO-1 protein and messenger RNA expressions, Nrf2 phosphorylation, and nuclear translocation in CECs, and these activities were disrupted by a p38 MAPK inhibitor, SB203580, but not by the extracellular signal-regulated kinase inhibitor PD98059 or c-Jun amino-terminal kinase inhibitor SP600125. Similar results were observed in confocal microscopy analysis. Moreover, andrographolide-induced Nrf2 and HO-1 protein expressions were significantly inhibited by Nrf2 small interfering RNA. Moreover, HO-1 knockdown attenuated the protective effect of andrographolide against oxygen-glucose deprivation-induced CEC death. Andrographolide (0.1 mg/kg) significantly suppressed free radical formation, blood-brain barrier disruption, and brain infarction in MCAO-insulted rats, and these effects were reversed by the HO-1 inhibitor zinc protoporphyrin IX. The mechanism is attributable to HO-1 activation, as directly evidenced by andrographolide-induced pronounced HO-1 expression in brain tissues, which was highly localized in the cerebral capillary. In conclusion, andrographolide increased Nrf2-HO-1 expression through p38 MAPK regulation, confirming that it provides protection against MCAO-induced brain injury. These findings provide strong evidence that andrographolide could be a therapeutic agent for treating ischemic stroke or neurodegenerative diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

Experimental realization of Shor's quantum factoring algorithm using nuclear magnetic resonance.

PubMed

Vandersypen, L M; Steffen, M; Breyta, G; Yannoni, C S; Sherwood, M H; Chuang, I L

The number of steps any classical computer requires in order to find the prime factors of an l-digit integer N increases exponentially with l, at least using algorithms known at present. Factoring large integers is therefore conjectured to be intractable classically, an observation underlying the security of widely used cryptographic codes. Quantum computers, however, could factor integers in only polynomial time, using Shor's quantum factoring algorithm. Although important for the study of quantum computers, experimental demonstration of this algorithm has proved elusive. Here we report an implementation of the simplest instance of Shor's algorithm: factorization of N = 15 (whose prime factors are 3 and 5). We use seven spin-1/2 nuclei in a molecule as quantum bits, which can be manipulated with room temperature liquid-state nuclear magnetic resonance techniques. This method of using nuclei to store quantum information is in principle scalable to systems containing many quantum bits, but such scalability is not implied by the present work. The significance of our work lies in the demonstration of experimental and theoretical techniques for precise control and modelling of complex quantum computers. In particular, we present a simple, parameter-free but predictive model of decoherence effects in our system.

Rac-mediated Stimulation of Phospholipase Cγ2 Amplifies B Cell Receptor-induced Calcium Signaling*♦

PubMed Central

Walliser, Claudia; Tron, Kyrylo; Clauss, Karen; Gutman, Orit; Kobitski, Andrei Yu.; Retlich, Michael; Schade, Anja; Röcker, Carlheinz; Henis, Yoav I.; Nienhaus, G. Ulrich; Gierschik, Peter

2015-01-01

The Rho GTPase Rac is crucially involved in controlling multiple B cell functions, including those regulated by the B cell receptor (BCR) through increased cytosolic Ca2+. The underlying molecular mechanisms and their relevance to the functions of intact B cells have thus far remained unknown. We have previously shown that the activity of phospholipase Cγ2 (PLCγ2), a key constituent of the BCR signalosome, is stimulated by activated Rac through direct protein-protein interaction. Here, we use a Rac-resistant mutant of PLCγ2 to functionally reconstitute cultured PLCγ2-deficient DT40 B cells and to examine the effects of the Rac-PLCγ2 interaction on BCR-mediated changes of intracellular Ca2+ and regulation of Ca2+-regulated and nuclear-factor-of-activated-T-cell-regulated gene transcription at the level of single, intact B cells. The results show that the functional Rac-PLCγ2 interaction causes marked increases in the following: (i) sensitivity of B cells to BCR ligation; (ii) BCR-mediated Ca2+ release from intracellular stores; (iii) Ca2+ entry from the extracellular compartment; and (iv) nuclear translocation of the Ca2+-regulated nuclear factor of activated T cells. Hence, Rac-mediated stimulation of PLCγ2 activity serves to amplify B cell receptor-induced Ca2+ signaling. PMID:25903139

Obstructive sleep apnea as an independent stroke risk factor: possible mechanisms.

PubMed

Godoy, Jaime; Mellado, Patricio; Tapia, Jorge; Santín, Julia

2009-03-01

Obstructive Sleep Apnea (OSA) is a prevalent disease that has emerged as a new cerebrovascular disease (CVD) risk factor, which is independent of its association to hypertension, age and other known conditions that increase CVD. The mechanisms involved in this relation are most likely induced by the periodic hypoxia/reoxygenation that characteristically occurs in OSA, which results in oxidative stress, endothelial dysfunction and activation of the inflammatory cascade, all of which favor atherogenesis. Numerous markers of these changes have been reported in OSA patients, including increased circulating free radicals, increased lipid peroxidation, decreased antioxidant capacity, elevation of tumor necrosis factor and interleukines, increased levels of proinflammatory nuclear transcription factor kappa B, decreased circulating nitric oxide, elevation of vascular adhesion molecules and vascular endothelial growth factor. In addition, several authors have described that Continuous Positive Airway Pressure, the standard OSA therapy, reverts these abnormalities. Further research is needed in order to better clarify the complex mechanisms that underlie the relation between OSA, atherogenesis and CVD which most likely will have significant clinical impact.

Hydrogen use projections and supply options

NASA Technical Reports Server (NTRS)

Manvi, R.; Fujita, T.

1976-01-01

Two projections of future hydrogen demand, based on the Ford technical fix and the Westinghouse nuclear electric economy energy supply and demand scenarios, are analyzed. It is suggested that hydrogen use will increase during the remainder of this century by at least a factor of five, and perhaps by a factor of twenty. Primary energy sources for producing hydrogen are discussed in terms of the transition from low to high demand for hydrogen.

Nuclear recoil effect on g-factor of heavy ions: prospects for tests of quantum electrodynamics in a new region

NASA Astrophysics Data System (ADS)

Malyshev, A. V.; Shabaev, V. M.; Glazov, D. A.; Tupitsyn, I. I.

2017-12-01

The nuclear recoil effect on the g-factor of H- and Li-like heavy ions is evaluated to all orders in αZ. The calculations include an approximate treatment of the nuclear size and the electron-electron interaction corrections to the recoil effect. As the result, the second largest contribution to the theoretical uncertainty of the g-factor values of 208Pb79+ and 238U89+ is strongly reduced. Special attention is paid to tests of the QED recoil effect on the g-factor in experiments with heavy ions. It is found that, while the QED recoil effect on the g-factor value is masked by the uncertainties of the nuclear size and nuclear polarization contributions, it can be probed on a few-percent level in the specific difference of the g-factors of H- and Li-like heavy ions. This provides a unique opportunity to test QED in a new region-strong-coupling regime beyond the Furry picture.

Anti-fibrotic effects of L-2-oxothiazolidine-4-carboxylic acid via modulation of nuclear factor erythroid 2-related factor 2 in rats.

PubMed

Kim, In Hee; Kim, Dae-Ghon; Hao, Peipei; Wang, Yunpeng; Kim, Seong Hun; Kim, Sang Wook; Lee, Seung Ok; Lee, Soo Teik

2012-06-01

L-2-Oxothiazolidine-4-carboxylic acid (OTC) is a cysteine prodrug that maintains glutathione in tissues. The present study was designed to investigate anti-fibrotic and anti-oxidative effects of OTC via modulation of nuclear factor erythroid 2-related factor 2 (Nrf2) in an in vivo thioacetamide (TAA)-induced hepatic fibrosis model. Treatment with OTC (80 or 160 mg/kg) improved serum liver function parameters and significantly ameliorated liver fibrosis. The OTC treatment groups exhibited significantly lower expression of α-smooth muscle actin, transforming growth factor-β 1, and collagen α 1 mRNA than that in the TAA model group. Furthermore, the OTC treatment groups showed a significant decrease in hepatic malondialdehyde level compared to that in the TAA model group. Nrf2 and heme oxygenase-1 expression increased significantly in the OTC treatment groups compared with that in the TAA model group. Taken together, these results suggest that OTC restores the anti- oxidative system by upregulating Nrf2; thus, ameliorating liver injury and a fibrotic reaction.

Count-doubling time safety circuit

DOEpatents

Rusch, Gordon K.; Keefe, Donald J.; McDowell, William P.

1981-01-01

There is provided a nuclear reactor count-factor-increase time monitoring circuit which includes a pulse-type neutron detector, and means for counting the number of detected pulses during specific time periods. Counts are compared and the comparison is utilized to develop a reactor scram signal, if necessary.

Synergistic growth inhibition of squamous cell carcinoma of the head and neck by erlotinib and epigallocatechin-3-gallate: the role of p53-dependent inhibition of nuclear factor-kappaB.

PubMed

Amin, A R M Ruhul; Khuri, Fadlo R; Chen, Zhuo Georgia; Shin, Dong M

2009-06-01

We have previously reported that the green tea polyphenol epigallocatechin-3-gallate (EGCG) and the epidermal growth factor receptor-tyrosine kinase inhibitor erlotinib had synergistic growth-inhibitory effects in cell culture and a nude mouse xenograft model of squamous cell carcinoma of the head and neck. However, the mechanism of their antitumor synergism is not fully understood. In the current study, we investigate the mechanism of their synergistic growth-inhibitory effects. The treatment of squamous cell carcinoma of the head and neck cell lines with erlotinib time-dependently increased the expression of cell cycle regulatory proteins p21 and p27 and apoptosis regulatory protein Bim. EGCG alone had very little or no effect on the expression of these proteins among the cell lines. However, simultaneous treatment with EGCG and erlotinib strongly inhibited erlotinib-induced expression of p21 and p27 without affecting the expression of Bim. Moreover, erlotinib increased the expression of p53 protein, the ablation of which by short hairpin RNA strongly inhibited EGCG- and erlotinib-mediated growth inhibition and the expression of p21, p27, and Bim. In addition, combined treatment with erlotinib and EGCG inhibited the protein level of p65 subunit of nuclear factor-kappaB and its transcriptional target Bcl-2, but failed to do so in cells with ablated p53. Taken together, our results, for the first time, suggest that erlotinib treatment activates p53, which plays a critical role in synergistic growth inhibition by erlotinib and EGCG via inhibiting nuclear factor-kappaB signaling pathway. Characterizing the underlying mechanisms of EGCG and erlotinib synergism will provide an important rationale for chemoprevention or treatment trials using this combination.

Immunotoxicity of ochratoxin A and aflatoxin B1 in combination is associated with the nuclear factor kappa B signaling pathway in 3D4/21 cells.

PubMed

Hou, Lili; Gan, Fang; Zhou, Xuan; Zhou, Yajiao; Qian, Gang; Liu, Zixuan; Huang, Kehe

2018-05-01

The co-contamination of cereals, grains, crops, and animal feeds by mycotoxins is a universal problem. Humans and animals are exposed to several mycotoxins simultaneously as evidenced by extensive studies on this topic. Yet, most studies have addressed the effects of mycotoxins individually. Aflatoxin B1 and ochratoxin A can induce immunotoxicity. However, it remains unclear whether a combination of these mycotoxins aggravates immunotoxicity and the potential mechanism underlying this effect. In this study, we used the cell line 3D4/21, swine alveolus macrophages and innate immune cell. The results showed that the percentage of cell inhibition, annexin V/PI-positive rates, and the expression of pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin-6) significantly increased and the release of lactate dehydrogenase and phagocytotic index were significantly decreased at different concentrations of aflatoxin B1 and ochratoxin A combination when compared with control. The combination of aflatoxin B1 and ochratoxin A significantly decreased the production of GSH and increased reactive oxygen species level. However, N-acetylcysteine suppressed the oxidative stress and alleviated the immunotoxicity induced by the combination. The combination of aflatoxin B1 and ochratoxin A markedly enhanced the degradation of IκBa, the phosphorylation of nuclear factor kappa B (p65), and the translocation of activated nuclear factor kappa B (NF-κB) into the nuclei as demonstrated by western blotting and confocal laser scanning microscopy. These effects could be reversed by BAY 11-7082, a specific inhibitor of NF-κB. Taken together, a combination of aflatoxin B1 and ochratoxin A could aggravate immunotoxicity by activating the NF-κB signaling pathway. Copyright © 2018 Elsevier Ltd. All rights reserved.

Aging and oxidative stress reduce the response of human articular chondrocytes to insulin-like growth factor 1 and osteogenic protein 1.

PubMed

Loeser, Richard F; Gandhi, Uma; Long, David L; Yin, Weihong; Chubinskaya, Susan

2014-08-01

To determine the effects of aging and oxidative stress on the response of human articular chondrocytes to insulin-like growth factor 1 (IGF-1) and osteogenic protein 1 (OP-1). Chondrocytes isolated from normal articular cartilage obtained from tissue donors were cultured in alginate beads or monolayer. Cells were stimulated with 50-100 ng/ml of IGF-1, OP-1, or both. Oxidative stress was induced using tert-butyl hydroperoxide. Sulfate incorporation was used to measure proteoglycan synthesis, and immunoblotting of cell lysates was performed to analyze cell signaling. Confocal microscopy was performed to measure nuclear translocation of Smad4. Chondrocytes isolated from the articular cartilage of tissue donors ranging in age from 24 years to 81 years demonstrated an age-related decline in proteoglycan synthesis stimulated by IGF-1 and IGF-1 plus OP-1. Induction of oxidative stress inhibited both IGF-1- and OP-1-stimulated proteoglycan synthesis. Signaling studies showed that oxidative stress inhibited IGF-1-stimulated Akt phosphorylation while increasing phosphorylation of ERK, and that these effects were greater in cells from older donors. Oxidative stress also increased p38 phosphorylation, which resulted in phosphorylation of Smad1 at the Ser(206) inhibitory site and reduced nuclear accumulation of Smad1. Oxidative stress also modestly reduced OP-1-stimulated nuclear translocation of Smad4. These results demonstrate an age-related reduction in the response of human chondrocytes to IGF-1 and OP-1, which are 2 important anabolic factors in cartilage, and suggest that oxidative stress may be a contributing factor by altering IGF-1 and OP-1 signaling. Copyright © 2014 by the American College of Rheumatology.

Factors Affecting the Development of Somatic Cell Nuclear Transfer Embryos in Cattle

PubMed Central

AKAGI, Satoshi; MATSUKAWA, Kazutsugu; TAKAHASHI, Seiya

2014-01-01

Nuclear transfer is a complex multistep procedure that includes oocyte maturation, cell cycle synchronization of donor cells, enucleation, cell fusion, oocyte activation and embryo culture. Therefore, many factors are believed to contribute to the success of embryo development following nuclear transfer. Numerous attempts to improve cloning efficiency have been conducted since the birth of the first sheep by somatic cell nuclear transfer. However, the efficiency of somatic cell cloning has remained low, and applications have been limited. In this review, we discuss some of the factors that affect the developmental ability of somatic cell nuclear transfer embryos in cattle. PMID:25341701

Combined aliskiren and amlodipine reduce albuminuria via reduction in renal inflammation in diabetic rats.

PubMed

Matavelli, Luis C; Huang, Jiqian; Siragy, Helmy M

2012-03-01

We hypothesized that compared with hydrochlorothiazide (HCTZ), the renin inhibitor aliskiren (ALISK) or amlodipine (AMLO) and their combination reduce albuminuria via reduction in renal inflammation, independent of blood pressure (BP) changes. We studied normal and streptozotocin-induced diabetic (DM) Sprague-Dawley rats treated for 6 weeks with vehicle, ALISK, HCTZ, or AMLO individually and combined and evaluated the effects of treatments on BP, urine albumin to creatinine ratio, renal interstitial fluid levels of angiotensin II, tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) and renal expression of TNF-α, IL-6, transforming growth factor beta 1, and nuclear factor kappa B. There were no differences in BP between treatments. Only ALISK and its combinations reduced renal interstitial fluid angiotensin II. Urine albumin to creatinine ratio increased in DM rats and decreased with ALISK alone or combined with HCTZ or AMLO. HCTZ or AMLO individually and combined did not influence urine albumin to creatinine ratio. Renal interstitial fluid TNF-α and IL-6, and the renal expression of TNF-α, IL-6, transforming growth factor beta 1, and nuclear factor kappa B were increased in DM rats. These renal inflammatory markers were reduced only with ALISK or AMLO individually or combined with other treatments. We conclude that ALISK alone and combined with HCTZ or AMLO reduced albuminuria in diabetes via reduction in renal inflammation, independent of BP changes.

C/EBPβ and Nuclear Factor of Activated T Cells Differentially Regulate Adamts-1 Induction by Stimuli Associated with Vascular Remodeling

PubMed Central

Oller, Jorge; Alfranca, Arántzazu; Méndez-Barbero, Nerea; Villahoz, Silvia; Lozano-Vidal, Noelia; Martín-Alonso, Mara; Arroyo, Alicia G.; Escolano, Amelia; Armesilla, Angel Luis

2015-01-01

Emerging evidence indicates that the metalloproteinase Adamts-1 plays a significant role in the pathophysiology of vessel remodeling, but little is known about the signaling pathways that control Adamts-1 expression. We show that vascular endothelial growth factor (VEGF), angiotensin-II, interleukin-1β, and tumor necrosis factor α, stimuli implicated in pathological vascular remodeling, increase Adamts-1 expression in endothelial and vascular smooth muscle cells. Analysis of the intracellular signaling pathways implicated in this process revealed that VEGF and angiotensin-II upregulate Adamts-1 expression via activation of differential signaling pathways that ultimately promote functional binding of the NFAT or C/EBPβ transcription factors, respectively, to the Adamts-1 promoter. Infusion of mice with angiotensin-II triggered phosphorylation and nuclear translocation of C/EBPβ proteins in aortic cells concomitantly with an increase in the expression of Adamts-1, further underscoring the importance of C/EBPβ signaling in angiotensin-II-induced upregulation of Adamts-1. Similarly, VEGF promoted NFAT activation and subsequent Adamts-1 induction in aortic wall in a calcineurin-dependent manner. Our results demonstrate that Adamts-1 upregulation by inducers of pathological vascular remodeling is mediated by specific signal transduction pathways involving NFAT or C/EBPβ transcription factors. Targeting of these pathways may prove useful in the treatment of vascular disease. PMID:26217013

Low-temperature dynamic nuclear polarization at 9.4 T with a 30 mW microwave source.

PubMed

Thurber, Kent R; Yau, Wai-Ming; Tycko, Robert

2010-06-01

Dynamic nuclear polarization (DNP) can provide large signal enhancements in nuclear magnetic resonance (NMR) by transfer of polarization from electron spins to nuclear spins. We discuss several aspects of DNP experiments at 9.4 T (400 MHz resonant frequency for (1)H, 264 GHz for electron spins in organic radicals) in the 7-80K temperature range, using a 30 mW, frequency-tunable microwave source and a quasi-optical microwave bridge for polarization control and low-loss microwave transmission. In experiments on frozen glycerol/water doped with nitroxide radicals, DNP signal enhancements up to a factor of 80 are observed (relative to (1)H NMR signals with thermal equilibrium spin polarization). The largest sensitivity enhancements are observed with a new triradical dopant, DOTOPA-TEMPO. Field modulation with a 10 G root-mean-squared amplitude during DNP increases the nuclear spin polarizations by up to 135%. Dependencies of (1)H NMR signal amplitudes, nuclear spin relaxation times, and DNP build-up times on the dopant and its concentration, temperature, microwave power, and modulation frequency are reported and discussed. The benefits of low-temperature DNP can be dramatic: the (1)H spin polarization is increased approximately 1000-fold at 7 K with DNP, relative to thermal polarization at 80K. (c) 2010 Elsevier Inc. All rights reserved.

Nuclear-polarization correction to the bound-electron g factor in heavy hydrogenlike ions.

PubMed

Nefiodov, A V; Plunien, G; Soff, G

2002-08-19

The influence of nuclear polarization on the bound-electron g factor in heavy hydrogenlike ions is investigated. Numerical calculations are performed for the K- and L-shell electrons taking into account the dominant virtual nuclear excitations. This determines the ultimate limit for tests of QED utilizing measurements of the bound-electron g factor in highly charged ions.

Applications of Neutron Radiography for the Nuclear Power Industry

NASA Astrophysics Data System (ADS)

Craft, Aaron E.; Barton, John P.

The World Conference on Neutron Radiography (WCNR) and International Topical Meeting on Neutron Radiography (ITMNR) series have been running over 35 years. The most recent event, ITMNR-8, focused on industrial applications and was the first time this series was hosted in China. In China, more than twenty new nuclear power plants are under construction and plans have been announced to increase the nuclear capacity by a factor of three within fifteen years. There are additional prospects in many other nations. Neutron tests were vital during previous developments of materials and components for nuclear power applications, as reported in the WCNR and ITMNR conference series. For example a majority of the 140 papers in the Proceedings of the First WCNR are for the benefit of the nuclear power industry. Many of those techniques are being utilized and advanced to the present time. Neutron radiography of irradiated nuclear fuel provides more comprehensive information about the internal condition of irradiated nuclear fuel than any other non-destructive technique to date. Applications include examination of nuclear waste, nuclear fuels, cladding, control elements, and other critical components. In this paper, applications of neutron radiography techniques developed and applied internationally for the nuclear power industry since the earliest years are reviewed, and the question is asked whether neutron test techniques, in general, can be of value in development of the present and future generations of nuclear power plants world-wide.

Expression of Fibroblast Growth Factor 21 and β-Klotho Regulates Hepatic Fibrosis through the Nuclear Factor-κB and c-Jun N-Terminal Kinase Pathways.

PubMed

Lee, Kyong Joo; Jang, Yoon Ok; Cha, Seung-Kuy; Kim, Moon Young; Park, Kyu-Sang; Eom, Young Woo; Baik, Soon Koo

2018-04-27

Fibroblast growth factor (FGF) 21 is associated with hepatic inflammation and fibrosis. However, little is known regarding the effects of inflammation and fibrosis on the β-Klotho and FGF21 pathway in the liver. Enrolled patients had biopsy-confirmed viral or alcoholic hepatitis. FGF19, FGF21 and β-Klotho levels were evaluated using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and Western blotting. Furthermore, we explored the underlying mechanisms for this process by evaluating nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathway involvement in Huh-7 cells. We observed that the FGF19 and FGF21 serum and mRNA levels in the biopsied liver tissue gradually increased and were correlated with fibrosis stage. Inflammatory markers (interleukin 1β [IL-1β], IL-6, and tumor necrosis factor-α) were positively correlated, while β-Klotho expression was negatively correlated with the degree of fibrosis. In Huh-7 cells, IL-1β increased FGF21 levels and decreased β-Klotho levels. NF-κB and JNK inhibitors abolished the effect of IL-1β on both FGF21 and β-Klotho expression. FGF21 protected IL-1β-induced growth retardation in Huh-7 cells. These results indicate that the inflammatory response during fibrogenesis increases FGF21 levels and suppresses β-Klotho via the NF-κB and JNK pathway. In addition, FGF21 likely protects hepatocytes from hepatic inflammation and fibrosis.

Biochemical and histopathologic analysis of the effects of periodontitis on left ventricular heart tissues of rats.

PubMed

Köse, O; Arabacı, T; Gedikli, S; Eminoglu, D Ö; Kermen, E; Kızıldağ, A; Kara, A; Ozkanlar, S; Yemenoglu, H

2017-04-01

Current epidemiological works have suggested that chronic infections, such as periodontitis, are associated with an increased risk of cardiovascular diseases, including hypertrophy and heart failure. However, mechanisms behind the association are not known. The aim of this study was to evaluate the effects of periodontitis on the serum lipid levels, inflammatory marker levels and left ventricular heart muscle tissues of rats. Eighteen male Sprague-Dawley rats were randomly divided into two groups: control (without ligature) and experimental periodontitis (EP; ligatured). Periodontitis was induced by placing ligatures (3.0 silk) at a submarginal position of the lower first molar teeth for 5 wk. Serum samples were collected for biochemical studies (C-reactive protein, interleukin-1β, tumor necrosis factor-α and serum lipids), after which the rats were killed and heart tissue samples were obtained for histopathological and immunological studies (nuclear factor kappa B and β-myosin heavy chain). Significant increases in C-reactive protein and interleukin-1β levels and no statistically significant increase in tumor necrosis factor-α level were observed in the EP group compared to the control group. In addition, total cholesterol, low-density lipoprotein cholesterol and triglyceride levels were significantly higher in the EP group. Stereological and immunological findings showed that the number of nuclear factor kappa B-p65- and β-myosin heavy chain-positive cardiomyocytes increased significantly in the left ventricular tissue samples of the rats with periodontitis. Early chronic phase effects of periodontitis on heart tissue are in the form of degenerative and hypotrophic changes. Prolonging the exposure to systemic inflammatory stress may increase the risk of occurrence of hypertrophic changes. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Glutamine's protection against cellular injury is dependent on heat shock factor-1.

PubMed

Morrison, Angela L; Dinges, Martin; Singleton, Kristen D; Odoms, Kelli; Wong, Hector R; Wischmeyer, Paul E

2006-06-01

Glutamine (GLN) has been shown to protect cells, tissues, and whole organisms from stress and injury. Enhanced expression of heat shock protein (HSP) has been hypothesized to be responsible for this protection. To date, there are no clear mechanistic data confirming this relationship. This study tested the hypothesis that GLN-mediated activation of the HSP pathway via heat shock factor-1 (HSF-1) is responsible for cellular protection. Wild-type HSF-1 (HSF-1(+/+)) and knockout (HSF-1(-/-)) mouse fibroblasts were used in all experiments. Cells were treated with GLN concentrations ranging from 0 to 16 mM and exposed to heat stress injury in a concurrent treatment model. Cell viability was assayed with phenazine methosulfate plus tetrazolium salt, HSP-70, HSP-25, and nuclear HSF-1 expression via Western blot analysis, and HSF-1/heat shock element (HSE) binding via EMSA. GLN significantly attenuated heat-stress induced cell death in HSF-1(+/+) cells in a dose-dependent manner; however, the survival benefit of GLN was lost in HSF-1(-/-) cells. GLN led to a dose-dependent increase in HSP-70 and HSP-25 expression after heat stress. No inducible HSP expression was observed in HSF-1(-/-) cells. GLN increased unphosphorylated HSF-1 in the nucleus before heat stress. This was accompanied by a GLN-mediated increase in HSF-1/HSE binding and nuclear content of phosphorylated HSF-1 after heat stress. This is the first demonstration that GLN-mediated cellular protection after heat-stress injury is related to HSF-1 expression and cellular capacity to activate an HSP response. Furthermore, the mechanism of GLN-mediated protection against injury appears to involve an increase in nuclear HSF-1 content before stress and increased HSF-1 promoter binding and phosphorylation.

Protective effects of nuclear factor erythroid 2-related factor 2 on whole body heat stress-induced oxidative damage in the mouse testis

PubMed Central

2013-01-01

Background Whole body heat stress had detrimental effect on male reproductive function. It's known that the nuclear factor erythroid 2-related factor 2 (Nrf2) activates expression of cytoprotective genes to enable cell adaptation to protect against oxidative stress. However, it’s still unclear about the exactly effects of Nrf2 on the testis. Here, we investigate the protective effect of Nrf2 on whole body heat stress-induced oxidative damage in mouse testis. Methods Male mice were exposed to the elevated ambient temperature (42°C) daily for 2 h. During the period of twelve consecutive days, mice were sacrificed on days 1, 2, 4, 8 and 12 immediately following heat exposure. Testes weight, enzymatic antioxidant activities and concentrations of malondialdehyde (MDA) and glutathione (GSH) in the testes were determined and immunohistochemical detection of Nrf2 protein and mRNA expression of Nrf2-regulated genes were analyzed to assess the status of Nrf2-antioxidant system. Results Heat-exposed mice presented significant increases in rectal, scrotal surface and body surface temperature. The concentrations of cortisol and testosterone in serum fluctuated with the number of exposed days. There were significant decrease in testes weight and relative testes weight on day 12 compared with those on other days, but significant increases in catalase (CAT) activity on day 1 and GSH level on day 4 compared with control group. The activities of total superoxide dismutase (T-SOD) and copper-zinc SOD (CuZn-SOD) increased significantly on days 8 and 12. Moreover, prominent nuclear accumulation of Nrf2 protein was observed in Leydig cells on day 2, accompanying with up-regulated mRNA levels of Nrf2-regulated genes such as Nrf2, heme oxygenase 1 (HO-1), γ-Glutamylcysteine synthetase (GCLC) and NAD (P) H: quinone oxidoreductase 1 (NQO1)) in heat-treated groups. Conclusions These results suggest that Nrf2 displayed nuclear accumulation and protective activity in the process of heat treated-induced oxidative stress in mouse testes, indicating that Nrf2 might be a potential target for new drugs designed to protect germ cell and Leydig cell from oxidative stress. PMID:23514035

Development of Methodologies for Technology Deployment for Advanced Outage Control Centers that Improve Outage Coordination, Problem Resolution and Outage Risk Management

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shawn St. Germain; Ronald Farris; Heather Medeman

2013-09-01

This research effort is a part of the Light-Water Reactor Sustainability (LWRS) Program, which is a research and development (R&D) program sponsored by Department of Energy (DOE) and performed in close collaboration with industry R&D programs that provides the technical foundations for licensing and managing the long-term, safe, and economical operation of current nuclear power plants. The LWRS program serves to help the U.S. nuclear industry adopt new technologies and engineering solutions that facilitate the continued safe operation of the plants and extension of the current operating licenses. The long term viability of existing nuclear power plants in the U.S.more » will depend upon maintaining high capacity factors, avoiding nuclear safety issues and reducing operating costs. The slow progress in the construction on new nuclear power plants has placed in increased importance on maintaining the output of the current fleet of nuclear power plants. Recently expanded natural gas production has placed increased economic pressure on nuclear power plants due to lower cost competition. Until recently, power uprate projects had steadily increased the total output of the U.S. nuclear fleet. Errors made during power plant upgrade projects have now removed three nuclear power plants from the U.S. fleet and economic considerations have caused the permanent shutdown of a fourth plant. Additionally, several utilities have cancelled power uprate projects citing economic concerns. For the past several years net electrical generation from U.S. nuclear power plants has been declining. One of few remaining areas where significant improvements in plant capacity factors can be made is in minimizing the duration of refueling outages. Managing nuclear power plant outages is a complex and difficult task. Due to the large number of complex tasks and the uncertainty that accompanies them, outage durations routinely exceed the planned duration. The ability to complete an outage on or near schedule depends upon the performance of the outage management organization. During an outage, the outage control center (OCC) is the temporary command center for outage managers and provides several critical functions for the successful execution of the outage schedule. Essentially, the OCC functions to facilitate information inflow, assist outage management in processing information and to facilitate the dissemination of information to stakeholders. Currently, outage management activities primarily rely on telephone communication, face to face reports of status and periodic briefings in the OCC. Much of the information displayed in OCCs is static and out of date requiring an evaluation to determine if it is still valid. Several advanced communication and collaboration technologies have shown promise for facilitating the information flow into, across and out of the OCC. Additionally, advances in the areas of mobile worker technologies, computer based procedures and electronic work packages can be leveraged to improve the availability of real time status to outage managers.« less

YY1 Controls Immunoglobulin Class Switch Recombination and Nuclear Activation-Induced Deaminase Levels

PubMed Central

Zaprazna, Kristina

2012-01-01

Activation-induced deaminase (AID) is an enzyme required for class switch recombination (CSR) and somatic hypermutation (SHM), processes that ensure antibody maturation and expression of different immunoglobulin isotypes. AID function is tightly regulated by tissue- and stage-specific expression, nuclear localization, and protein stability. Transcription factor YY1 is crucial for early B cell development, but its function at late B cell stages is unknown. Here, we show that YY1 conditional knockout in activated splenic B cells interferes with CSR. Knockout of YY1 did not affect B cell proliferation, transcription of the AID and IgM genes, or levels of various switch region germ line transcripts. However, we show that YY1 physically interacts with AID and controls the accumulation of nuclear AID, at least in part, by increasing nuclear AID stability. We show for the first time that YY1 plays a novel role in CSR and controls nuclear AID protein levels. PMID:22290437

Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice.

PubMed

Dankbar, Berno; Fennen, Michelle; Brunert, Daniela; Hayer, Silvia; Frank, Svetlana; Wehmeyer, Corinna; Beckmann, Denise; Paruzel, Peter; Bertrand, Jessica; Redlich, Kurt; Koers-Wunrau, Christina; Stratis, Athanasios; Korb-Pap, Adelheid; Pap, Thomas

2015-09-01

Myostatin (also known as growth and differentiation factor 8) is a secreted member of the transforming growth factor-β (TGF-β) family that is mainly expressed in skeletal muscle, which is also its primary target tissue. Deletion of the myostatin gene (Mstn) in mice leads to muscle hypertrophy, and animal studies support the concept that myostatin is a negative regulator of muscle growth and regeneration. However, myostatin deficiency also increases bone formation, mainly through loading-associated effects on bone. Here we report a previously unknown direct role for myostatin in osteoclastogenesis and in the progressive loss of articular bone in rheumatoid arthritis (RA). We demonstrate that myostatin is highly expressed in the synovial tissues of RA subjects and of human tumor necrosis factor (TNF)-α transgenic (hTNFtg) mice, a model for human RA. Myostatin strongly accelerates receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclast formation in vitro through transcription factor SMAD2-dependent regulation of nuclear factor of activated T-cells (NFATC1). Myostatin deficiency or antibody-mediated inhibition leads to an amelioration of arthritis severity in hTNFtg mice, chiefly reflected by less bone destruction. Consistent with these effects in hTNFtg mice, the lack of myostatin leads to increased grip strength and less bone erosion in the K/BxN serum-induced arthritis model in mice. The results strongly suggest that myostatin is a potent therapeutic target for interfering with osteoclast formation and joint destruction in RA.

Microscopic study of spin cut-off factors of nuclear level densities

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gholami, M.; Kildir, M.; Behkami, A. N.

Level densities and spin cut-off factors have been investigated within the microscopic approach based on the BCS Hamiltonian. In particular, the spin cut-off parameters have been calculated at neutron binding energies over a large range of nuclear mass using the BCS theory. The spin cut-off parameters {sigma}{sup 2}(E) have also been obtained from the Gilbert and Cameron expression and from rigid body calculations. The results were compared with their corresponding macroscopic values. It was found that the values of {sigma}{sup 2}(E) did not increase smoothly with A as expected based on macroscopic theory. Instead, the values of {sigma}{sup 2}(E) showmore » structure reflecting the angular momentum of the shell model orbitals near the Fermi energy.« less

Human serum reduces mitomycin-C cytotoxicity in human tenon's fibroblasts.

PubMed

Crowston, Jonathan G; Wang, Xiao Y; Khaw, Peng T; Zoellner, Hans; Healey, Paul R

2006-03-01

To determine the effect of human serum factors on mitomycin-C (MMC) cytotoxicity in cultured human subconjunctival Tenon's capsule fibroblasts. Fibroblast monolayers were treated with 5-minute applications of mitomycin-C (0.4 mg/mL) and incubated in culture medium with or without additional human serum. Fibroblast apoptosis was quantified by direct cell counts based on nuclear morphology, flow cytometry with annexin-V/propidium iodide, and a lactate dehydrogenase release assay. The number of viable fibroblasts and fibroblast proliferation were measured with a colorimetric MTT assay and by bromodeoxyuridine (BrdU) labeling. Mitomycin-C induced significant levels of fibroblast apoptosis. The addition of human serum resulted in a 40% reduction in MMC-induced fibroblast apoptosis (range, 31.3%-55.3%; P = 0.021) as determined by nuclear morphology and a 32.4% reduction measured by annexin-V/PI. There was a corresponding dose-dependent increase in the number of viable fibroblasts. Serum did not restore proliferation in MMC-treated fibroblasts. Factors present in human serum reduce MMC cytotoxicity in cultured human Tenon's fibroblasts. Human serum increased the number of viable fibroblasts by inhibiting MMC-induced fibroblast apoptosis. Serum factors access aqueous humor after trabeculectomy and may therefore influence the clinical outcome of MMC treatment.

Zinc-induced Dnmt1 expression involves antagonism between MTF-1 and nuclear receptor SHP

PubMed Central

Zhang, Yuxia; Andrews, Glen K.; Wang, Li

2012-01-01

Dnmt1 is frequently overexpressed in cancers, which contributes significantly to cancer-associated epigenetic silencing of tumor suppressor genes. However, the mechanism of Dnmt1 overexpression remains elusive. Herein, we elucidate a pathway through which nuclear receptor SHP inhibits zinc-dependent induction of Dnmt1 by antagonizing metal-responsive transcription factor-1 (MTF-1). Zinc treatment induces Dnmt1 transcription by increasing the occupancy of MTF-1 on the Dnmt1 promoter while decreasing SHP expression. SHP in turn represses MTF-1 expression and abolishes zinc-mediated changes in the chromatin configuration of the Dnmt1 promoter. Dnmt1 expression is increased in SHP-knockout (sko) mice but decreased in SHP-transgenic (stg) mice. In human hepatocellular carcinoma (HCC), increased DNMT1 expression is negatively correlated with SHP levels. Our study provides a molecular explanation for increased Dnmt1 expression in HCC and highlights SHP as a potential therapeutic target. PMID:22362755

Dynamic nuclear polarization by frequency modulation of a tunable gyrotron of 260GHz.

PubMed

Yoon, Dongyoung; Soundararajan, Murari; Cuanillon, Philippe; Braunmueller, Falk; Alberti, Stefano; Ansermet, Jean-Philippe

2016-01-01

An increase in Dynamic Nuclear Polarization (DNP) signal intensity is obtained with a tunable gyrotron producing frequency modulation around 260GHz at power levels less than 1W. The sweep rate of frequency modulation can reach 14kHz, and its amplitude is fixed at 50MHz. In water/glycerol glassy ice doped with 40mM TEMPOL, the relative increase in the DNP enhancement was obtained as a function of frequency-sweep rate for several temperatures. A 68 % increase was obtained at 15K, thus giving a DNP enhancement of about 80. By employing λ/4 and λ/8 polarizer mirrors, we transformed the polarization of the microwave beam from linear to circular, and achieved an increase in the enhancement by a factor of about 66% for a given power. Copyright © 2015 Elsevier Inc. All rights reserved.

Post-fusion treatment with MG132 increases transcription factor expression in somatic cell nuclear transfer embryos in pigs.

PubMed

You, Jinyoung; Lee, Joohyeong; Kim, Jinyoung; Park, Junhong; Lee, Eunsong

2010-02-01

The objective of this study was to examine the effect of post-fusion treatment of somatic cell nuclear transfer (SCNT) oocytes with the proteasomal inhibitor MG132 on maturation promoting factor (MPF) activity, nuclear remodeling, embryonic development, and gene expression of cloned pig embryos. Immediately after electrofusion, SCNT oocytes were treated with MG132 and/or caffeine for 2 hr, vanadate for 0.5 hr, or vanadate for 0.5 hr followed by MG132 for 1.5 hr. Of the MG132 concentrations tested (0-5 microM), the 1 microM concentration showed a higher rate of blastocyst formation (25.9%) than 0 (14.2%), 0.5 (16.9%), and 5 microM (16.9%). Post-fusion treatment with MG132, caffeine, and both MG132 and caffeine improved blastocyst formation (22.1%, 21.4%, and 24.4%, respectively), whereas vanadate treatment inhibited blastocyst formation (6.5%) compared to the control (11.1%). When examined 2 hr after fusion and 1 hr after activation, MPF activity remained at a higher (P < 0.05) level in SCNT oocytes that were treated post-fusion with caffeine and/or MG132, but it was decreased by vanadate. The rate of oocytes showing premature chromosome condensation was not altered by MG132 but was decreased by vanadate treatment. In addition, formation of single pronuclei was increased by MG132 compared to control and vanadate treatment. MG132-treated embryos showed increased expression of POU5F1, DPPA2, DPPA3, DPPA5, and NDP52l1 genes compared to control embryos. Our results demonstrate that post-fusion treatment of SCNT oocytes with MG132 prevents MPF degradation and increases expression of transcription factors in SCNT embryos, which are necessary for normal development of SCNT embryos. (c) 2009 Wiley-Liss, Inc.

Pomegranate protects against arsenic-induced p53-dependent ROS-mediated inflammation and apoptosis in liver cells.

PubMed

Choudhury, Sreetama; Ghosh, Sayan; Mukherjee, Sudeshna; Gupta, Payal; Bhattacharya, Saurav; Adhikary, Arghya; Chattopadhyay, Sreya

2016-12-01

Molecular mechanisms involved in arsenic-induced toxicity are complex and elusive. Liver is one of the most favored organs for arsenic toxicity as methylation of arsenic occurs mostly in the liver. In this study, we have selected a range of environmentally relevant doses of arsenic to examine the basis of arsenic toxicity and the role of pomegranate fruit extract (PFE) in combating it. Male Swiss albino mice exposed to different doses of arsenic presented marked hepatic injury as evident from histological and electron microscopic studies. Increased activities of enzymes alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase corroborated extensive liver damage. It was further noted that arsenic exposure initiated reactive oxygen species (ROS)-dependent apoptosis in the hepatocytes involving loss of mitochondrial membrane potential. Arsenic significantly increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB), coupled with increase in phosphorylated Iκ-B, possibly as adaptive cellular survival strategies. Arsenic-induced oxidative DNA damage to liver cells culminated in p53 activation and increased expression of p53 targets like miR-34a and Bax. Pomegranate polyphenols are known to possess remarkable antioxidant properties and are capable of protecting normal cells from various stimuli-induced oxidative stress and toxicities. We explored the protective role of PFE in ameliorating arsenic-induced hepatic damage. PFE was shown to reduce ROS generation in hepatocytes, thereby reducing arsenic-induced Nrf2 activation. PFE also inhibited arsenic-induced NF-κB-inflammatory pathway. Data revealed that PFE reversed arsenic-induced hepatotoxicity and apoptosis by modulating the ROS/Nrf2/p53-miR-34a axis. For the first time, we have mapped the possible signaling pathways associated with arsenic-induced hepatotoxicity and its rescue by pomegranate polyphenols. Copyright © 2016 Elsevier Inc. All rights reserved.

Higher serum levels of rheumatoid factor and anti-nuclear antibodies in helicobacter pylori-infected peptic ulcer patients.

PubMed

Jafarzadeh, Abdollah; Nemati, Maryam; Rezayati, Mohammad Taghi; Nabizadeh, Mansooreh; Ebrahimi, Medhi

2013-07-01

H. pylori infection has been associated with some autoimmune disorders. The aim of this study was to evaluate the serum concentrations of rheumatoid factor and anti-nuclear antibodies in H. pylori-infected peptic ulcer patients, H. pylori-infected asymptomatic carriers and a healthy control group. A Total of 100 H. pylori-infected peptic ulcer patients, 65 asymptomatic carriers and 30 healthy H. pylori-negative subjects (as a control group) were enrolled into study. Serum samples of participants tested for the levels of rheumatoid factor and anti-nuclear antibodies by use of ELISA. The mean serum levels of rheumatoid factor and anti-nuclear antibodies in peptic ulcer group was significantly higher in comparison to the control group (p<0.05). Although, the mean serum levels of rheumatoid factor and anti-nuclear antibodies in the asymptomatic carriers group was higher than those in the control group, the difference was not statistically significant. No significant differences were observed between peptic ulcer patients and asymptomatic carriers groups regarding the mean serum levels of rheumatoid factor and anti-nuclear antibodies. The mean serum levels of rheumatoid factor in men with peptic ulcer was significantly higher compared to the group of healthy men (p<0.05). Although in female of peptic ulcer patients or asymptomatic carriers groups, the mean serum levels of rheumatoid factor was higher than that in healthy women, but the differences were not statistically significant. Also, no significant differences were observed between men and women with peptic ulcer, asymptomatic carriers control groups based on the serum levels of anti-nuclear antibodies. The results showed higher serum levels of rheumatoid factor and anti-nuclear antibodies in H. pylori-infected patients with peptic ulcer disease which represent the H. pylori-related immune disturbance in these patients. Additional follow-up studies are necessary to clarify the clinical significance of these autoantibodies in patients with H. pylori infection.

The influence of radiation shielding on reusable nuclear shuttle design

NASA Technical Reports Server (NTRS)

Littman, T. M.; Garcia, D.

1972-01-01

Alternate reusable nuclear shuttle configurations were synthesized and evaluated. Particular attention was given to design factors which reduced tank exposure to direct and scattered radiation, increased payload-engine separation, and improved self-shielding by the LH2 propellant. The most attractive RNS concept in terms of cost effectiveness consists of a single conical aft bulkhead tank with a high fineness ratio. Launch is accomplished by the INT-21 with the tank positioned in the inverted attitude. The NERVA engine is delivered to orbit separately where final stage assembly and checkout are accomplished. This approach is consistent with NERVA definition criteria and required operating procedures to support an economically viable nuclear shuttle transportation program in the post-1980 period.

Analysis of antimycin A by reversed-phase liquid chromatography/nuclear magnetic-resonance spectrometry

USGS Publications Warehouse

Ha, Steven T.K.; Wilkins, Charles L.; Abidi, Sharon L.

1989-01-01

A mixture of closely related streptomyces fermentation products, antimycin A, Is separated, and the components are identified by using reversed-phase high-performance liquid chromatography with directly linked 400-MHz proton nuclear magnetic resonance detection. Analyses of mixtures of three amino acids, alanine, glycine, and valine, are used to determine optimal measurement conditions. Sensitivity increases of as much as a factor of 3 are achieved, at the expense of some loss in chromatographic resolution, by use of an 80-μL NMR cell, Instead of a smaller 14-μL cell. Analysis of the antimycin A mixture, using the optimal analytical high performance liquid chromatography/nuclear magnetic resonance conditions, reveals it to consist of at least 10 closely related components.

Alpinia officinarum Stimulates Osteoblast Mineralization and Inhibits Osteoclast Differentiation.

PubMed

Shim, Ki-Shuk; Lee, Chung-Jo; Yim, Nam-Hui; Gu, Min Jung; Ma, Jin Yeul

2016-01-01

Alpinia officinarum rhizome has been used as a traditional herbal remedy to treat inflammatory and internal diseases. Based on the previously observed inhibitory effect of A. officinarum rhizome in an arthritis model, we evaluated whether a water extract of A. officinarum rhizome (WEAO) would enhance in vitro osteoblast mineralization using calvarial osteoblast precursor cells or would inhibit in vitro osteoclast differentiation and bone resorption using bone marrow derived macrophages. In osteoblasts, WEAO enhanced the mRNA levels of transcription factor (runt-related transcription factor 2, smad1, smad5, and junB) and marker (bone morphogenetic protein-2, collagen type 1alpha1, and osteocalcin) genes related to osteoblast mineralization, consistent with increased alizarin red S staining intensity. WEAO markedly inhibited osteoclast differentiation by suppressing the receptor activator for nuclear factor-[Formula: see text]B ligand-induced downregulation of inhibitor of DNA binding 2 and V-maf musculoaponeurotic fibrosarcoma oncogene homolog B and the phosphorylation of c-Jun N-terminal kinase, p38, nuclear factor-[Formula: see text]B, c-Src, and Bruton's tyrosine kinase to induce nuclear factor of activated T cells cytoplasmic 1 expression. WEAO also suppressed the resorbing activity of mature osteoclasts by altering actin ring formation. Therefore, the results of this study demonstrate that WEAO stimulates osteoblast mineralization and inhibits osteoclast differentiation. Thus, WEAO may be a promising herbal candidate to treat or prevent pathological bone diseases by regulating the balance between osteoclast and osteoblast activity.

Nuclear factor of activated T cells (NFAT) in pearl oyster Pinctada fucata: molecular cloning and functional characterization.

PubMed

Huang, Xian-De; Wei, Guo-jian; Zhang, Hua; He, Mao-Xian

2015-01-01

Nuclear factor of activated T cells (NFAT) plays an important role in nonimmune cells and also in T cells and many other cells of the immune system, by regulating the expression of a variety of genes involved in the immune response, organ development, developmental apoptosis and angiogenesis. In the present study, the NFAT homology gene, PfNFAT, from the pearl oyster Pinctada fucata was cloned and its genomic structure and promoter were analyzed. PfNFAT encodes a putative protein of 1226 amino acids, and contains a highly conserved Rel homology region (RHR) with DNA-binding specificity, and a regulatory domain (NFAT homology region, NHR) containing a potent transactivation domain (TAD). The PfNFAT gene consists of 12 exons and 11 introns, and its promoter contains potential binding sites for transcription factors such as NF-κB (Nuclear factor κB), STATx (signal transducer and activator of transcription), AP-1 (activator protein-1) and Sox-5/9 (SRY type HMG box-5/9), MyoD (Myogenic Differentiation Antigen) and IRF (Interferon regulatory factor). Comparison and phylogenetic analysis revealed that PfNFAT shows high identity with other invertebrate NFAT, and clusters with the NFAT5 subgroup. Furthermore, gene expression analysis revealed that PfNFAT is involved in the immune response to lipopolysaccharide (LPS) and Polyinosinic-polycytidylic acid (poly I:C) stimulation and in the nucleus inserting operation. The study of PfNFAT may increase understanding of molluscan innate immunity. Copyright © 2014 Elsevier Ltd. All rights reserved.

Charged-particle nuclear modification factors in PbPb and pPb collisions at √{s_{NN}}=5.02 TeV

NASA Astrophysics Data System (ADS)

Khachatryan, V.; Sirunyan, A. M.; Tumasyan, A.; Adam, W.; Asilar, E.; Bergauer, T.; Brandstetter, J.; Brondolin, E.; Dragicevic, M.; Erö, J.; Flechl, M.; Friedl, M.; Frühwirth, R.; Ghete, V. M.; Hartl, C.; Hörmann, N.; Hrubec, J.; Jeitler, M.; König, A.; Krätschmer, I.; Liko, D.; Matsushita, T.; Mikulec, I.; Rabady, D.; Rad, N.; Rahbaran, B.; Rohringer, H.; Schieck, J.; Strauss, J.; Waltenberger, W.; Wulz, C.-E.; Dvornikov, O.; Makarenko, V.; Zykunov, V.; Mossolov, V.; Shumeiko, N.; Gonzalez, J. Suarez; Alderweireldt, S.; De Wolf, E. A.; Janssen, X.; Lauwers, J.; Van De Klundert, M.; Van Haevermaet, H.; Van Mechelen, P.; Van Remortel, N.; Van Spilbeeck, A.; Zeid, S. Abu; Blekman, F.; D'Hondt, J.; Daci, N.; De Bruyn, I.; Deroover, K.; Lowette, S.; Moortgat, S.; Moreels, L.; Olbrechts, A.; Python, Q.; Tavernier, S.; Van Doninck, W.; Van Mulders, P.; Van Parijs, I.; Brun, H.; Clerbaux, B.; De Lentdecker, G.; Delannoy, H.; Fasanella, G.; Favart, L.; Goldouzian, R.; Grebenyuk, A.; Karapostoli, G.; Lenzi, T.; Léonard, A.; Luetic, J.; Maerschalk, T.; Marinov, A.; Randle-conde, A.; Seva, T.; Velde, C. Vander; Vanlaer, P.; Vannerom, D.; Yonamine, R.; Zenoni, F.; Zhang, F.; Cimmino, A.; Cornelis, T.; Dobur, D.; Fagot, A.; Garcia, G.; Gul, M.; Khvastunov, I.; Poyraz, D.; Salva, S.; Schöfbeck, R.; Tytgat, M.; Van Driessche, W.; Yazgan, E.; Zaganidis, N.; Bakhshiansohi, H.; Beluffi, C.; Bondu, O.; Brochet, S.; Bruno, G.; Caudron, A.; De Visscher, S.; Delaere, C.; Delcourt, M.; Francois, B.; Giammanco, A.; Jafari, A.; Jez, P.; Komm, M.; Krintiras, G.; Lemaitre, V.; Magitteri, A.; Mertens, A.; Musich, M.; Nuttens, C.; Piotrzkowski, K.; Quertenmont, L.; Selvaggi, M.; Marono, M. Vidal; Wertz, S.; Beliy, N.; Júnior, W. L. Aldá; Alves, F. L.; Alves, G. A.; Brito, L.; Hensel, C.; Moraes, A.; Pol, M. E.; Teles, P. Rebello; Chagas, E. Belchior Batista Das; Carvalho, W.; Chinellato, J.; Custódio, A.; Da Costa, E. M.; Da Silveira, G. G.; De Jesus Damiao, D.; De Oliveira Martins, C.; De Souza, S. Fonseca; Guativa, L. M. Huertas; Malbouisson, H.; Figueiredo, D. Matos; Herrera, C. Mora; Mundim, L.; Nogima, H.; Da Silva, W. L. Prado; Santoro, A.; Sznajder, A.; Manganote, E. J. Tonelli; Pereira, A. Vilela; Ahuja, S.; Bernardes, C. A.; Dogra, S.; Tomei, T. R. Fernandez Perez; Gregores, E. M.; Mercadante, P. G.; Moon, C. S.; Novaes, S. F.; Padula, Sandra S.; Abad, D. Romero; Vargas, J. C. Ruiz; Aleksandrov, A.; Hadjiiska, R.; Iaydjiev, P.; Rodozov, M.; Stoykova, S.; Sultanov, G.; Vutova, M.; Dimitrov, A.; Glushkov, I.; Litov, L.; Pavlov, B.; Petkov, P.; Fang, W.; Ahmad, M.; Bian, J. G.; Chen, G. M.; Chen, H. S.; Chen, M.; Chen, Y.; Cheng, T.; Jiang, C. H.; Leggat, D.; Liu, Z.; Romeo, F.; Shaheen, S. M.; Spiezia, A.; Tao, J.; Wang, C.; Wang, Z.; Zhang, H.; Zhao, J.; Ban, Y.; Chen, G.; Li, Q.; Liu, S.; Mao, Y.; Qian, S. J.; Wang, D.; Xu, Z.; Avila, C.; Cabrera, A.; Sierra, L. F. Chaparro; Florez, C.; Gomez, J. P.; Hernández, C. F. González; Alvarez, J. D. Ruiz; Sanabria, J. C.; Godinovic, N.; Lelas, D.; Puljak, I.; Cipriano, P. M. Ribeiro; Sculac, T.; Antunovic, Z.; Kovac, M.; Brigljevic, V.; Ferencek, D.; Kadija, K.; Mesic, B.; Micanovic, S.; Sudic, L.; Susa, T.; Attikis, A.; Mavromanolakis, G.; Mousa, J.; Nicolaou, C.; Ptochos, F.; Razis, P. A.; Rykaczewski, H.; Tsiakkouri, D.; Finger, M.; Finger, M.; Jarrin, E. Carrera; Abdelalim, A. A.; Mohammed, Y.; Salama, E.; Kadastik, M.; Perrini, L.; Raidal, M.; Tiko, A.; Veelken, C.; Eerola, P.; Pekkanen, J.; Voutilainen, M.; Härkönen, J.; Järvinen, T.; Karimäki, V.; Kinnunen, R.; Lampén, T.; Lassila-Perini, K.; Lehti, S.; Lindén, T.; Luukka, P.; Tuominiemi, J.; Tuovinen, E.; Wendland, L.; Talvitie, J.; Tuuva, T.; Besancon, M.; Couderc, F.; Dejardin, M.; Denegri, D.; Fabbro, B.; Faure, J. L.; Favaro, C.; Ferri, F.; Ganjour, S.; Ghosh, S.; Givernaud, A.; Gras, P.; de Monchenault, G. Hamel; Jarry, P.; Kucher, I.; Locci, E.; Machet, M.; Malcles, J.; Rander, J.; Rosowsky, A.; Titov, M.; Zghiche, A.; Abdulsalam, A.; Antropov, I.; Baffioni, S.; Beaudette, F.; Busson, P.; Cadamuro, L.; Chapon, E.; Charlot, C.; Davignon, O.; de Cassagnac, R. Granier; Jo, M.; Lisniak, S.; Miné, P.; Nguyen, M.; Ochando, C.; Ortona, G.; Paganini, P.; Pigard, P.; Regnard, S.; Salerno, R.; Sirois, Y.; Strebler, T.; Yilmaz, Y.; Zabi, A.; Agram, J.-L.; Andrea, J.; Aubin, A.; Bloch, D.; Brom, J.-M.; Buttignol, M.; Chabert, E. C.; Chanon, N.; Collard, C.; Conte, E.; Coubez, X.; Fontaine, J.-C.; Gelé, D.; Goerlach, U.; Le Bihan, A.-C.; Skovpen, K.; Van Hove, P.; Gadrat, S.; Beauceron, S.; Bernet, C.; Boudoul, G.; Montoya, C. A. Carrillo; Chierici, R.; Contardo, D.; Courbon, B.; Depasse, P.; El Mamouni, H.; Fan, J.; Fay, J.; Gascon, S.; Gouzevitch, M.; Grenier, G.; Ille, B.; Lagarde, F.; Laktineh, I. B.; Lethuillier, M.; Mirabito, L.; Pequegnot, A. L.; Perries, S.; Popov, A.; Sabes, D.; Sordini, V.; Donckt, M. Vander; Verdier, P.; Viret, S.; Toriashvili, T.; Tsamalaidze, Z.; Autermann, C.; Beranek, S.; Feld, L.; Heister, A.; Kiesel, M. K.; Klein, K.; Lipinski, M.; Ostapchuk, A.; Preuten, M.; Raupach, F.; Schael, S.; Schomakers, C.; Schulz, J.; Verlage, T.; Weber, H.; Zhukov, V.; Albert, A.; Brodski, M.; Dietz-Laursonn, E.; Duchardt, D.; Endres, M.; Erdmann, M.; Erdweg, S.; Esch, T.; Fischer, R.; Güth, A.; Hamer, M.; Hebbeker, T.; Heidemann, C.; Hoepfner, K.; Knutzen, S.; Merschmeyer, M.; Meyer, A.; Millet, P.; Mukherjee, S.; Olschewski, M.; Padeken, K.; Pook, T.; Radziej, M.; Reithler, H.; Rieger, M.; Scheuch, F.; Sonnenschein, L.; Teyssier, D.; Thüer, S.; Cherepanov, V.; Flügge, G.; Kargoll, B.; Kress, T.; Künsken, A.; Lingemann, J.; Müller, T.; Nehrkorn, A.; Nowack, A.; Pistone, C.; Pooth, O.; Stahl, A.; Martin, M. Aldaya; Arndt, T.; Asawatangtrakuldee, C.; Beernaert, K.; Behnke, O.; Behrens, U.; Anuar, A. A. Bin; Borras, K.; Campbell, A.; Connor, P.; Contreras-Campana, C.; Costanza, F.; Pardos, C. Diez; Dolinska, G.; Eckerlin, G.; Eckstein, D.; Eichhorn, T.; Eren, E.; Gallo, E.; Garcia, J. Garay; Geiser, A.; Gizhko, A.; Luyando, J. M. Grados; Gunnellini, P.; Harb, A.; Hauk, J.; Hempel, M.; Jung, H.; Kalogeropoulos, A.; Karacheban, O.; Kasemann, M.; Keaveney, J.; Kleinwort, C.; Korol, I.; Krücker, D.; Lange, W.; Lelek, A.; Leonard, J.; Lipka, K.; Lobanov, A.; Lohmann, W.; Mankel, R.; Melzer-Pellmann, I.-A.; Meyer, A. B.; Mittag, G.; Mnich, J.; Mussgiller, A.; Ntomari, E.; Pitzl, D.; Placakyte, R.; Raspereza, A.; Roland, B.; Sahin, M. Ö.; Saxena, P.; Schoerner-Sadenius, T.; Seitz, C.; Spannagel, S.; Stefaniuk, N.; Van Onsem, G. P.; Walsh, R.; Wissing, C.; Blobel, V.; Vignali, M. Centis; Draeger, A. R.; Dreyer, T.; Garutti, E.; Gonzalez, D.; Haller, J.; Hoffmann, M.; Junkes, A.; Klanner, R.; Kogler, R.; Kovalchuk, N.; Lapsien, T.; Lenz, T.; Marchesini, I.; Marconi, D.; Meyer, M.; Niedziela, M.; Nowatschin, D.; Pantaleo, F.; Peiffer, T.; Perieanu, A.; Poehlsen, J.; Sander, C.; Scharf, C.; Schleper, P.; Schmidt, A.; Schumann, S.; Schwandt, J.; Stadie, H.; Steinbrück, G.; Stober, F. M.; Stöver, M.; Tholen, H.; Troendle, D.; Usai, E.; Vanelderen, L.; Vanhoefer, A.; Vormwald, B.; Akbiyik, M.; Barth, C.; Baur, S.; Baus, C.; Berger, J.; Butz, E.; Caspart, R.; Chwalek, T.; Colombo, F.; De Boer, W.; Dierlamm, A.; Fink, S.; Freund, B.; Friese, R.; Giffels, M.; Gilbert, A.; Goldenzweig, P.; Haitz, D.; Hartmann, F.; Heindl, S. M.; Husemann, U.; Katkov, I.; Kudella, S.; Mildner, H.; Mozer, M. U.; Müller, Th.; Plagge, M.; Quast, G.; Rabbertz, K.; Röcker, S.; Roscher, F.; Schröder, M.; Shvetsov, I.; Sieber, G.; Simonis, H. J.; Ulrich, R.; Wayand, S.; Weber, M.; Weiler, T.; Williamson, S.; Wöhrmann, C.; Wolf, R.; Anagnostou, G.; Daskalakis, G.; Geralis, T.; Giakoumopoulou, V. A.; Kyriakis, A.; Loukas, D.; Topsis-Giotis, I.; Kesisoglou, S.; Panagiotou, A.; Saoulidou, N.; Tziaferi, E.; Evangelou, I.; Flouris, G.; Foudas, C.; Kokkas, P.; Loukas, N.; Manthos, N.; Papadopoulos, I.; Paradas, E.; Filipovic, N.; Bencze, G.; Hajdu, C.; Horvath, D.; Sikler, F.; Veszpremi, V.; Vesztergombi, G.; Zsigmond, A. J.; Beni, N.; Czellar, S.; Karancsi, J.; Makovec, A.; Molnar, J.; Szillasi, Z.; Bartók, M.; Raics, P.; Trocsanyi, Z. L.; Ujvari, B.; Bahinipati, S.; Choudhury, S.; Mal, P.; Mandal, K.; Nayak, A.; Sahoo, D. K.; Sahoo, N.; Swain, S. K.; Bansal, S.; Beri, S. B.; Bhatnagar, V.; Chawla, R.; Bhawandeep, U.; Kalsi, A. K.; Kaur, A.; Kaur, M.; Kumar, R.; Kumari, P.; Mehta, A.; Mittal, M.; Singh, J. B.; Walia, G.; Kumar, Ashok; Bhardwaj, A.; Choudhary, B. C.; Garg, R. B.; Keshri, S.; Malhotra, S.; Naimuddin, M.; Nishu, N.; Ranjan, K.; Sharma, R.; Sharma, V.; Bhattacharya, R.; Bhattacharya, S.; Chatterjee, K.; Dey, S.; Dutt, S.; Dutta, S.; Ghosh, S.; Majumdar, N.; Modak, A.; Mondal, K.; Mukhopadhyay, S.; Nandan, S.; Purohit, A.; Roy, A.; Roy, D.; Chowdhury, S. Roy; Sarkar, S.; Sharan, M.; Thakur, S.; Behera, P. K.; Chudasama, R.; Dutta, D.; Jha, V.; Kumar, V.; Mohanty, A. K.; Netrakanti, P. K.; Pant, L. M.; Shukla, P.; Topkar, A.; Aziz, T.; Dugad, S.; Kole, G.; Mahakud, B.; Mitra, S.; Mohanty, G. B.; Parida, B.; Sur, N.; Sutar, B.; Banerjee, S.; Bhowmik, S.; Dewanjee, R. K.; Ganguly, S.; Guchait, M.; Jain, Sa.; Kumar, S.; Maity, M.; Majumder, G.; Mazumdar, K.; Sarkar, T.; Wickramage, N.; Chauhan, S.; Dube, S.; Hegde, V.; Kapoor, A.; Kothekar, K.; Pandey, S.; Rane, A.; Sharma, S.; Chenarani, S.; Tadavani, E. Eskandari; Etesami, S. M.; Fahim, A.; Khakzad, M.; Najafabadi, M. Mohammadi; Naseri, M.; Mehdiabadi, S. Paktinat; Hosseinabadi, F. Rezaei; Safarzadeh, B.; Zeinali, M.; Felcini, M.; Grunewald, M.; Abbrescia, M.; Calabria, C.; Caputo, C.; Colaleo, A.; Creanza, D.; Cristella, L.; De Filippis, N.; De Palma, M.; Fiore, L.; Iaselli, G.; Maggi, G.; Maggi, M.; Miniello, G.; My, S.; Nuzzo, S.; Pompili, A.; Pugliese, G.; Radogna, R.; Ranieri, A.; Selvaggi, G.; Sharma, A.; Silvestris, L.; Venditti, R.; Verwilligen, P.; Abbiendi, G.; Battilana, C.; Bonacorsi, D.; Braibant-Giacomelli, S.; Brigliadori, L.; Campanini, R.; Capiluppi, P.; Castro, A.; Cavallo, F. R.; Chhibra, S. S.; Codispoti, G.; Cuffiani, M.; Dallavalle, G. M.; Fabbri, F.; Fanfani, A.; Fasanella, D.; Giacomelli, P.; Grandi, C.; Guiducci, L.; Marcellini, S.; Masetti, G.; Montanari, A.; Navarria, F. L.; Perrotta, A.; Rossi, A. M.; Rovelli, T.; Siroli, G. P.; Tosi, N.; Albergo, S.; Costa, S.; Di Mattia, A.; Giordano, F.; Potenza, R.; Tricomi, A.; Tuve, C.; Barbagli, G.; Ciulli, V.; Civinini, C.; D'Alessandro, R.; Focardi, E.; Lenzi, P.; Meschini, M.; Paoletti, S.; Sguazzoni, G.; Viliani, L.; Benussi, L.; Bianco, S.; Fabbri, F.; Piccolo, D.; Primavera, F.; Calvelli, V.; Ferro, F.; Vetere, M. Lo; Monge, M. R.; Robutti, E.; Tosi, S.; Brianza, L.; Brivio, F.; Dinardo, M. E.; Fiorendi, S.; Gennai, S.; Ghezzi, A.; Govoni, P.; Malberti, M.; Malvezzi, S.; Manzoni, R. A.; Menasce, D.; Moroni, L.; Paganoni, M.; Pedrini, D.; Pigazzini, S.; Ragazzi, S.; de Fatis, T. Tabarelli; Buontempo, S.; Cavallo, N.; De Nardo, G.; Di Guida, S.; Esposito, M.; Fabozzi, F.; Fienga, F.; Iorio, A. O. M.; Lanza, G.; Lista, L.; Meola, S.; Paolucci, P.; Sciacca, C.; Thyssen, F.; Azzi, P.; Bacchetta, N.; Benato, L.; Bisello, D.; Boletti, A.; Carlin, R.; Checchia, P.; Dall'Osso, M.; De Castro Manzano, P.; Dorigo, T.; Dosselli, U.; Gasparini, F.; Gasparini, U.; Gozzelino, A.; Lacaprara, S.; Margoni, M.; Meneguzzo, A. T.; Pazzini, J.; Pozzobon, N.; Ronchese, P.; Simonetto, F.; Torassa, E.; Ventura, S.; Zanetti, M.; Zotto, P.; Zumerle, G.; Braghieri, A.; Magnani, A.; Montagna, P.; Ratti, S. P.; Re, V.; Riccardi, C.; Salvini, P.; Vai, I.; Vitulo, P.; Solestizi, L. Alunni; Bilei, G. M.; Ciangottini, D.; Fanò, L.; Lariccia, P.; Leonardi, R.; Mantovani, G.; Menichelli, M.; Saha, A.; Santocchia, A.; Androsov, K.; Azzurri, P.; Bagliesi, G.; Bernardini, J.; Boccali, T.; Castaldi, R.; Ciocci, M. A.; Dell'Orso, R.; Donato, S.; Fedi, G.; Giassi, A.; Grippo, M. T.; Ligabue, F.; Lomtadze, T.; Martini, L.; Messineo, A.; Palla, F.; Rizzi, A.; SavoyNavarro, A.; Spagnolo, P.; Tenchini, R.; Tonelli, G.; Venturi, A.; Verdini, P. G.; Barone, L.; Cavallari, F.; Cipriani, M.; Del Re, D.; Diemoz, M.; Gelli, S.; Longo, E.; Margaroli, F.; Marzocchi, B.; Meridiani, P.; Organtini, G.; Paramatti, R.; Preiato, F.; Rahatlou, S.; Rovelli, C.; Santanastasio, F.; Amapane, N.; Arcidiacono, R.; Argiro, S.; Arneodo, M.; Bartosik, N.; Bellan, R.; Biino, C.; Cartiglia, N.; Cenna, F.; Costa, M.; Covarelli, R.; Degano, A.; Demaria, N.; Finco, L.; Kiani, B.; Mariotti, C.; Maselli, S.; Migliore, E.; Monaco, V.; Monteil, E.; Monteno, M.; Obertino, M. M.; Pacher, L.; Pastrone, N.; Pelliccioni, M.; Angioni, G. L. Pinna; Ravera, F.; Romero, A.; Ruspa, M.; Sacchi, R.; Shchelina, K.; Sola, V.; Solano, A.; Staiano, A.; Traczyk, P.; Belforte, S.; Casarsa, M.; Cossutti, F.; Ricca, G. Della; Zanetti, A.; Kim, D. H.; Kim, G. N.; Kim, M. S.; Lee, S.; Lee, S. W.; Oh, Y. D.; Sekmen, S.; Son, D. C.; Yang, Y. C.; Lee, A.; Kim, H.; Cifuentes, J. A. Brochero; Kim, T. J.; Cho, S.; Choi, S.; Go, Y.; Gyun, D.; Ha, S.; Hong, B.; Jo, Y.; Kim, Y.; Lee, B.; Lee, K.; Lee, K. S.; Lee, S.; Lim, J.; Park, S. K.; Roh, Y.; Almond, J.; Kim, J.; Lee, H.; Oh, S. B.; Radburn-Smith, B. C.; Seo, S. h.; Yang, U. K.; Yoo, H. D.; Yu, G. B.; Choi, M.; Kim, H.; Kim, J. H.; Lee, J. S. H.; Park, I. C.; Ryu, G.; Ryu, M. S.; Choi, Y.; Goh, J.; Hwang, C.; Lee, J.; Yu, I.; Dudenas, V.; Juodagalvis, A.; Vaitkus, J.; Ahmed, I.; Ibrahim, Z. A.; Komaragiri, J. R.; Ali, M. A. B. Md; Idris, F. Mohamad; Abdullah, W. A. T. Wan; Yusli, M. N.; Zolkapli, Z.; Castilla-Valdez, H.; De La Cruz-Burelo, E.; La Cruz, I. Heredia-De; Hernandez-Almada, A.; Lopez-Fernandez, R.; Villalba, R. Magaña; Guisao, J. Mejia; Sanchez-Hernandez, A.; Moreno, S. Carrillo; Barrera, C. Oropeza; Valencia, F. Vazquez; Carpinteyro, S.; Pedraza, I.; Ibarguen, H. A. Salazar; Estrada, C. Uribe; Pineda, A. Morelos; Krofcheck, D.; Butler, P. H.; Ahmad, A.; Ahmad, M.; Hassan, Q.; Hoorani, H. R.; Khan, W. A.; Saddique, A.; Shah, M. A.; Shoaib, M.; Waqas, M.; Bialkowska, H.; Bluj, M.; Boimska, B.; Frueboes, T.; Górski, M.; Kazana, M.; Nawrocki, K.; Romanowska-Rybinska, K.; Szleper, M.; Zalewski, P.; Bunkowski, K.; Byszuk, A.; Doroba, K.; Kalinowski, A.; Konecki, M.; Krolikowski, J.; Misiura, M.; Olszewski, M.; Walczak, M.; Bargassa, P.; Da Cruz E Silva, C. Beirão; Calpas, B.; Di Francesco, A.; Faccioli, P.; Parracho, P. G. Ferreira; Gallinaro, M.; Hollar, J.; Leonardo, N.; Iglesias, L. Lloret; Nemallapudi, M. V.; Antunes, J. Rodrigues; Seixas, J.; Toldaiev, O.; Vadruccio, D.; Varela, J.; Vischia, P.; Afanasiev, S.; Bunin, P.; Gavrilenko, M.; Golutvin, I.; Gorbunov, I.; Kamenev, A.; Karjavin, V.; Lanev, A.; Malakhov, A.; Matveev, V.; Palichik, V.; Perelygin, V.; Shmatov, S.; Shulha, S.; Skatchkov, N.; Smirnov, V.; Voytishin, N.; Zarubin, A.; Chtchipounov, L.; Golovtsov, V.; Ivanov, Y.; Kim, V.; Kuznetsova, E.; Murzin, V.; Oreshkin, V.; Sulimov, V.; Vorobyev, A.; Andreev, Yu.; Dermenev, A.; Gninenko, S.; Golubev, N.; Karneyeu, A.; Kirsanov, M.; Krasnikov, N.; Pashenkov, A.; Tlisov, D.; Toropin, A.; Epshteyn, V.; Gavrilov, V.; Lychkovskaya, N.; Popov, V.; Pozdnyakov, I.; Safronov, G.; Spiridonov, A.; Toms, M.; Vlasov, E.; Zhokin, A.; Bylinkin, A.; Chistov, R.; Markin, O.; Polikarpov, S.; Andreev, V.; Azarkin, M.; Dremin, I.; Kirakosyan, M.; Leonidov, A.; Terkulov, A.; Baskakov, A.; Belyaev, A.; Boos, E.; Ershov, A.; Gribushin, A.; Kaminskiy, A.; Kodolova, O.; Korotkikh, V.; Lokhtin, I.; Miagkov, I.; Obraztsov, S.; Petrushanko, S.; Savrin, V.; Snigirev, A.; Vardanyan, I.; Blinov, V.; Skovpen, Y.; Shtol, D.; Azhgirey, I.; Bayshev, I.; Bitioukov, S.; Elumakhov, D.; Kachanov, V.; Kalinin, A.; Konstantinov, D.; Krychkine, V.; Petrov, V.; Ryutin, R.; Sobol, A.; Troshin, S.; Tyurin, N.; Uzunian, A.; Volkov, A.; Adzic, P.; Cirkovic, P.; Devetak, D.; Dordevic, M.; Milosevic, J.; Rekovic, V.; Maestre, J. Alcaraz; Luna, M. Barrio; Calvo, E.; Cerrada, M.; Llatas, M. Chamizo; Colino, N.; De La Cruz, B.; Peris, A. Delgado; Del Valle, A. Escalante; Bedoya, C. Fernandez; Ramos, J. P. Fernández; Flix, J.; Fouz, M. C.; Garcia-Abia, P.; Lopez, O. Gonzalez; Lopez, S. Goy; Hernandez, J. M.; Josa, M. I.; De Martino, E. Navarro; Yzquierdo, A. Pérez-Calero; Pelayo, J. Puerta; Olmeda, A. Quintario; Redondo, I.; Romero, L.; Soares, M. S.; de Trocóniz, J. F.; Missiroli, M.; Moran, D.; Cuevas, J.; Menendez, J. Fernandez; Caballero, I. Gonzalez; Fernández, J. R. González; Cortezon, E. Palencia; Cruz, S. Sanchez; Andrés, I. Suárez; Garcia, J. M. Vizan; Cabrillo, I. J.; Calderon, A.; De Saa, J. R. Castiñeiras; Curras, E.; Fernandez, M.; Garcia-Ferrero, J.; Gomez, G.; Virto, A. Lopez; Marco, J.; Rivero, C. Martinez; Matorras, F.; Gomez, J. Piedra; Rodrigo, T.; Ruiz-Jimeno, A.; Scodellaro, L.; Trevisani, N.; Vila, I.; Vilar Cortabitarte, R.; Abbaneo, D.; Auffray, E.; Auzinger, G.; Bachtis, M.; Baillon, P.; Ball, A. H.; Barney, D.; Bloch, P.; Bocci, A.; Bonato, A.; Botta, C.; Camporesi, T.; Castello, R.; Cepeda, M.; Cerminara, G.; D'Alfonso, M.; d'Enterria, D.; Dabrowski, A.; Daponte, V.; David, A.; De Gruttola, M.; De Roeck, A.; Di Marco, E.; Dobson, M.; Dorney, B.; du Pree, T.; Duggan, D.; Dünser, M.; Dupont, N.; Elliott-Peisert, A.; Fartoukh, S.; Franzoni, G.; Fulcher, J.; Funk, W.; Gigi, D.; Gill, K.; Girone, M.; Glege, F.; Gulhan, D.; Gundacker, S.; Guthoff, M.; Hammer, J.; Harris, P.; Hegeman, J.; Innocente, V.; Janot, P.; Kieseler, J.; Kirschenmann, H.; Knünz, V.; Kornmayer, A.; Kortelainen, M. J.; Kousouris, K.; Krammer, M.; Lange, C.; Lecoq, P.; Lourenço, C.; Lucchini, M. T.; Malgeri, L.; Mannelli, M.; Martelli, A.; Meijers, F.; Merlin, J. A.; Mersi, S.; Meschi, E.; Milenovic, P.; Moortgat, F.; Morovic, S.; Mulders, M.; Neugebauer, H.; Orfanelli, S.; Orsini, L.; Pape, L.; Perez, E.; Peruzzi, M.; Petrilli, A.; Petrucciani, G.; Pfeiffer, A.; Pierini, M.; Racz, A.; Reis, T.; Rolandi, G.; Rovere, M.; Ruan, M.; Sakulin, H.; Sauvan, J. B.; Schäfer, C.; Schwick, C.; Seidel, M.; Sharma, A.; Silva, P.; Sphicas, P.; Steggemann, J.; Stoye, M.; Takahashi, Y.; Tosi, M.; Treille, D.; Triossi, A.; Tsirou, A.; Veckalns, V.; Veres, G. I.; Verweij, M.; Wardle, N.; Wöhri, H. K.; Zagozdzinska, A.; Zeuner, W. D.; Bertl, W.; Deiters, K.; Erdmann, W.; Horisberger, R.; Ingram, Q.; Kaestli, H. C.; Kotlinski, D.; Langenegger, U.; Rohe, T.; Bachmair, F.; Bäni, L.; Bianchini, L.; Casal, B.; Dissertori, G.; Dittmar, M.; Donegà, M.; Grab, C.; Heidegger, C.; Hits, D.; Hoss, J.; Kasieczka, G.; Lecomte, P.; Lustermann, W.; Mangano, B.; Marionneau, M.; del Arbol, P. Martinez Ruiz; Masciovecchio, M.; Meinhard, M. T.; Meister, D.; Micheli, F.; Musella, P.; Nessi-Tedaldi, F.; Pandolfi, F.; Pata, J.; Pauss, F.; Perrin, G.; Perrozzi, L.; Quittnat, M.; Rossini, M.; Schönenberger, M.; Starodumov, A.; Tavolaro, V. R.; Theofilatos, K.; Wallny, R.; Aarrestad, T. K.; Amsler, C.; Caminada, L.; Canelli, M. F.; De Cosa, A.; Galloni, C.; Hinzmann, A.; Hreus, T.; Kilminster, B.; Ngadiuba, J.; Pinna, D.; Rauco, G.; Robmann, P.; Salerno, D.; Yang, Y.; Zucchetta, A.; Candelise, V.; Doan, T. H.; Jain, Sh.; Khurana, R.; Konyushikhin, M.; Kuo, C. M.; Lin, W.; Lu, Y. J.; Pozdnyakov, A.; Yu, S. S.; Kumar, Arun; Chang, P.; Chang, Y. H.; Chang, Y. W.; Chao, Y.; Chen, K. F.; Chen, P. H.; Dietz, C.; Fiori, F.; Hou, W.-S.; Hsiung, Y.; Liu, Y. F.; Lu, R.-S.; Moya, M. Miñano; Paganis, E.; Psallidas, A.; Tsai, J. f.; Tzeng, Y. M.; Asavapibhop, B.; Singh, G.; Srimanobhas, N.; Suwonjandee, N.; Adiguzel, A.; Cerci, S.; Damarseckin, S.; Demiroglu, Z. S.; Dozen, C.; Dumanoglu, I.; Girgis, S.; Gokbulut, G.; Guler, Y.; Hos, I.; Kangal, E. E.; Kara, O.; Kiminsu, U.; Oglakci, M.; Onengut, G.; Ozdemir, K.; Cerci, D. Sunar; Tali, B.; Topakli, H.; Turkcapar, S.; Zorbakir, I. S.; Zorbilmez, C.; Bilin, B.; Bilmis, S.; Isildak, B.; Karapinar, G.; Yalvac, M.; Zeyrek, M.; Gülmez, E.; Kaya, M.; Kaya, O.; Yetkin, E. A.; Yetkin, T.; Cakir, A.; Cankocak, K.; Sen, S.; Grynyov, B.; Levchuk, L.; Sorokin, P.; Aggleton, R.; Ball, F.; Beck, L.; Brooke, J. J.; Burns, D.; Clement, E.; Cussans, D.; Flacher, H.; Goldstein, J.; Grimes, M.; Heath, G. P.; Heath, H. F.; Jacob, J.; Kreczko, L.; Lucas, C.; Newbold, D. M.; Paramesvaran, S.; Poll, A.; Sakuma, T.; El Nasr-storey, S. Seif; Smith, D.; Smith, V. J.; Belyaev, A.; Brew, C.; Brown, R. M.; Calligaris, L.; Cieri, D.; Cockerill, D. J. A.; Coughlan, J. A.; Harder, K.; Harper, S.; Olaiya, E.; Petyt, D.; Shepherd-Themistocleous, C. H.; Thea, A.; Tomalin, I. R.; Williams, T.; Baber, M.; Bainbridge, R.; Buchmuller, O.; Bundock, A.; Burton, D.; Casasso, S.; Citron, M.; Colling, D.; Corpe, L.; Dauncey, P.; Davies, G.; De Wit, A.; Negra, M. Della; Di Maria, R.; Dunne, P.; Elwood, A.; Futyan, D.; Haddad, Y.; Hall, G.; Iles, G.; James, T.; Lane, R.; Laner, C.; Lucas, R.; Lyons, L.; Magnan, A.-M.; Malik, S.; Mastrolorenzo, L.; Nash, J.; Nikitenko, A.; Pela, J.; Penning, B.; Pesaresi, M.; Raymond, D. M.; Richards, A.; Rose, A.; Seez, C.; Summers, S.; Tapper, A.; Uchida, K.; Acosta, M. Vazquez; Virdee, T.; Wright, J.; Zenz, S. C.; Cole, J. E.; Hobson, P. R.; Khan, A.; Kyberd, P.; Leslie, D.; Reid, I. D.; Symonds, P.; Teodorescu, L.; Turner, M.; Borzou, A.; Call, K.; Dittmann, J.; Hatakeyama, K.; Liu, H.; Pastika, N.; Cooper, S. I.; Henderson, C.; Rumerio, P.; West, C.; Arcaro, D.; Avetisyan, A.; Bose, T.; Gastler, D.; Rankin, D.; Richardson, C.; Rohlf, J.; Sulak, L.; Zou, D.; Benelli, G.; Berry, E.; Cutts, D.; Garabedian, A.; Hakala, J.; Heintz, U.; Hogan, J. M.; Jesus, O.; Kwok, K. H. M.; Laird, E.; Landsberg, G.; Mao, Z.; Narain, M.; Piperov, S.; Sagir, S.; Spencer, E.; Syarif, R.; Breedon, R.; Breto, G.; Burns, D.; De La Barca Sanchez, M. Calderon; Chauhan, S.; Chertok, M.; Conway, J.; Conway, R.; Cox, P. T.; Erbacher, R.; Flores, C.; Funk, G.; Gardner, M.; Ko, W.; Lander, R.; Mclean, C.; Mulhearn, M.; Pellett, D.; Pilot, J.; Shalhout, S.; Smith, J.; Squires, M.; Stolp, D.; Tripathi, M.; Bravo, C.; Cousins, R.; Dasgupta, A.; Everaerts, P.; Florent, A.; Hauser, J.; Ignatenko, M.; Mccoll, N.; Saltzberg, D.; Schnaible, C.; Takasugi, E.; Valuev, V.; Weber, M.; Bouvier, E.; Burt, K.; Clare, R.; Ellison, J.; Gary, J. W.; Shirazi, S. M. A. Ghiasi; Hanson, G.; Heilman, J.; Jandir, P.; Kennedy, E.; Lacroix, F.; Long, O. R.; Negrete, M. Olmedo; Paneva, M. I.; Shrinivas, A.; Si, W.; Wei, H.; Wimpenny, S.; Yates, B. R.; Branson, J. G.; Cerati, G. B.; Cittolin, S.; Derdzinski, M.; Gerosa, R.; Holzner, A.; Klein, D.; Krutelyov, V.; Letts, J.; Macneill, I.; Olivito, D.; Padhi, S.; Pieri, M.; Sani, M.; Sharma, V.; Simon, S.; Tadel, M.; Vartak, A.; Wasserbaech, S.; Welke, C.; Wood, J.; Würthwein, F.; Yagil, A.; Porta, G. Zevi Della; Amin, N.; Bhandari, R.; Bradmiller-Feld, J.; Campagnari, C.; Dishaw, A.; Dutta, V.; Sevilla, M. Franco; George, C.; Golf, F.; Gouskos, L.; Gran, J.; Heller, R.; Incandela, J.; Mullin, S. D.; Ovcharova, A.; Qu, H.; Richman, J.; Stuart, D.; Suarez, I.; Yoo, J.; Anderson, D.; Bendavid, J.; Bornheim, A.; Bunn, J.; Chen, Y.; Duarte, J.; Lawhorn, J. M.; Mott, A.; Newman, H. B.; Pena, C.; Spiropulu, M.; Vlimant, J. R.; Xie, S.; Zhu, R. Y.; Andrews, M. B.; Ferguson, T.; Paulini, M.; Russ, J.; Sun, M.; Vogel, H.; Vorobiev, I.; Weinberg, M.; Cumalat, J. P.; Ford, W. T.; Jensen, F.; Johnson, A.; Krohn, M.; Mulholland, T.; Stenson, K.; Wagner, S. R.; Alexander, J.; Chaves, J.; Chu, J.; Dittmer, S.; Mcdermott, K.; Mirman, N.; Kaufman, G. Nicolas; Patterson, J. R.; Rinkevicius, A.; Ryd, A.; Skinnari, L.; Soffi, L.; Tan, S. M.; Tao, Z.; Thom, J.; Tucker, J.; Wittich, P.; Zientek, M.; Winn, D.; Abdullin, S.; Albrow, M.; Apollinari, G.; Apresyan, A.; Banerjee, S.; Bauerdick, L. A. T.; Beretvas, A.; Berryhill, J.; Bhat, P. C.; Bolla, G.; Burkett, K.; Butler, J. N.; Cheung, H. W. K.; Chlebana, F.; Cihangir, S.; Cremonesi, M.; Elvira, V. D.; Fisk, I.; Freeman, J.; Gottschalk, E.; Gray, L.; Green, D.; Grünendahl, S.; Gutsche, O.; Hare, D.; Harris, R. M.; Hasegawa, S.; Hirschauer, J.; Hu, Z.; Jayatilaka, B.; Jindariani, S.; Johnson, M.; Joshi, U.; Klima, B.; Kreis, B.; Lammel, S.; Linacre, J.; Lincoln, D.; Lipton, R.; Liu, M.; Liu, T.; De Sá, R. Lopes; Lykken, J.; Maeshima, K.; Magini, N.; Marraffino, J. M.; Maruyama, S.; Mason, D.; McBride, P.; Merkel, P.; Mrenna, S.; Nahn, S.; O'Dell, V.; Pedro, K.; Prokofyev, O.; Rakness, G.; Ristori, L.; Sexton-Kennedy, E.; Soha, A.; Spalding, W. J.; Spiegel, L.; Stoynev, S.; Strait, J.; Strobbe, N.; Taylor, L.; Tkaczyk, S.; Tran, N. V.; Uplegger, L.; Vaandering, E. W.; Vernieri, C.; Verzocchi, M.; Vidal, R.; Wang, M.; Weber, H. A.; Whitbeck, A.; Wu, Y.; Acosta, D.; Avery, P.; Bortignon, P.; Bourilkov, D.; Brinkerhoff, A.; Carnes, A.; Carver, M.; Curry, D.; Das, S.; Field, R. D.; Furic, I. K.; Konigsberg, J.; Korytov, A.; Low, J. F.; Ma, P.; Matchev, K.; Mei, H.; Mitselmakher, G.; Rank, D.; Shchutska, L.; Sperka, D.; Thomas, L.; Wang, J.; Wang, S.; Yelton, J.; Linn, S.; Markowitz, P.; Martinez, G.; Rodriguez, J. L.; Ackert, A.; Adams, J. R.; Adams, T.; Askew, A.; Bein, S.; Diamond, B.; Hagopian, S.; Hagopian, V.; Johnson, K. F.; Prosper, H.; Santra, A.; Yohay, R.; Baarmand, M. M.; Bhopatkar, V.; Colafranceschi, S.; Hohlmann, M.; Noonan, D.; Roy, T.; Yumiceva, F.; Adams, M. R.; Apanasevich, L.; Berry, D.; Betts, R. R.; Bucinskaite, I.; Cavanaugh, R.; Evdokimov, O.; Gauthier, L.; Gerber, C. E.; Hofman, D. J.; Jung, K.; Kurt, P.; O'Brien, C.; Gonzalez, I. D. Sandoval; Turner, P.; Varelas, N.; Wang, H.; Wu, Z.; Zakaria, M.; Zhang, J.; Bilki, B.; Clarida, W.; Dilsiz, K.; Durgut, S.; Gandrajula, R. P.; Haytmyradov, M.; Khristenko, V.; Merlo, J.-P.; Mermerkaya, H.; Mestvirishvili, A.; Moeller, A.; Nachtman, J.; Ogul, H.; Onel, Y.; Ozok, F.; Penzo, A.; Snyder, C.; Tiras, E.; Wetzel, J.; Yi, K.; Anderson, I.; Blumenfeld, B.; Cocoros, A.; Eminizer, N.; Fehling, D.; Feng, L.; Gritsan, A. V.; Maksimovic, P.; Martin, C.; Osherson, M.; Roskes, J.; Sarica, U.; Swartz, M.; Xiao, M.; Xin, Y.; You, C.; Al-bataineh, A.; Baringer, P.; Bean, A.; Boren, S.; Bowen, J.; Bruner, C.; Castle, J.; Forthomme, L.; Kenny, R. P.; Khalil, S.; Kropivnitskaya, A.; Majumder, D.; Mcbrayer, W.; Murray, M.; Sanders, S.; Stringer, R.; Takaki, J. D. Tapia; Wang, Q.; Ivanov, A.; Kaadze, K.; Maravin, Y.; Mohammadi, A.; Saini, L. K.; Skhirtladze, N.; Toda, S.; Rebassoo, F.; Wright, D.; Anelli, C.; Baden, A.; Baron, O.; Belloni, A.; Calvert, B.; Eno, S. C.; Ferraioli, C.; Gomez, J. A.; Hadley, N. J.; Jabeen, S.; Kellogg, R. G.; Kolberg, T.; Kunkle, J.; Lu, Y.; Mignerey, A. C.; Ricci-Tam, F.; Shin, Y. H.; Skuja, A.; Tonjes, M. B.; Tonwar, S. C.; Abercrombie, D.; Allen, B.; Apyan, A.; Azzolini, V.; Barbieri, R.; Baty, A.; Bi, R.; Bierwagen, K.; Brandt, S.; Busza, W.; Cali, I. A.; Demiragli, Z.; Di Matteo, L.; Ceballos, G. Gomez; Goncharov, M.; Hsu, D.; Iiyama, Y.; Innocenti, G. M.; Klute, M.; Kovalskyi, D.; Krajczar, K.; Lai, Y. S.; Lee, Y.-J.; Levin, A.; Luckey, P. D.; Maier, B.; Marini, A. C.; Mcginn, C.; Mironov, C.; Narayanan, S.; Niu, X.; Paus, C.; Roland, C.; Roland, G.; Salfeld-Nebgen, J.; Stephans, G. S. F.; Sumorok, K.; Tatar, K.; Varma, M.; Velicanu, D.; Veverka, J.; Wang, J.; Wang, T. W.; Wyslouch, B.; Yang, M.; Zhukova, V.; Benvenuti, A. C.; Chatterjee, R. M.; Evans, A.; Finkel, A.; Gude, A.; Hansen, P.; Kalafut, S.; Kao, S. C.; Kubota, Y.; Lesko, Z.; Mans, J.; Nourbakhsh, S.; Ruckstuhl, N.; Rusack, R.; Tambe, N.; Turkewitz, J.; Acosta, J. G.; Oliveros, S.; Avdeeva, E.; Bartek, R.; Bloom, K.; Claes, D. R.; Dominguez, A.; Fangmeier, C.; Suarez, R. Gonzalez; Kamalieddin, R.; Kravchenko, I.; Rodrigues, A. Malta; Meier, F.; Monroy, J.; Siado, J. E.; Snow, G. R.; Stieger, B.; Alyari, M.; Dolen, J.; George, J.; Godshalk, A.; Harrington, C.; Iashvili, I.; Kaisen, J.; Kharchilava, A.; Kumar, A.; Parker, A.; Rappoccio, S.; Roozbahani, B.; Alverson, G.; Barberis, E.; Hortiangtham, A.; Massironi, A.; Morse, D. M.; Nash, D.; Orimoto, T.; De Lima, R. Teixeira; Trocino, D.; Wang, R.-J.; Wood, D.; Bhattacharya, S.; Charaf, O.; Hahn, K. A.; Kubik, A.; Kumar, A.; Mucia, N.; Odell, N.; Pollack, B.; Schmitt, M. H.; Sung, K.; Trovato, M.; Velasco, M.; Dev, N.; Hildreth, M.; Anampa, K. Hurtado; Jessop, C.; Karmgard, D. J.; Kellams, N.; Lannon, K.; Marinelli, N.; Meng, F.; Mueller, C.; Musienko, Y.; Planer, M.; Reinsvold, A.; Ruchti, R.; Smith, G.; Taroni, S.; Wayne, M.; Wolf, M.; Woodard, A.; Alimena, J.; Antonelli, L.; Bylsma, B.; Durkin, L. S.; Flowers, S.; Francis, B.; Hart, A.; Hill, C.; Hughes, R.; Ji, W.; Liu, B.; Luo, W.; Puigh, D.; Winer, B. L.; Wulsin, H. W.; Cooperstein, S.; Driga, O.; Elmer, P.; Hardenbrook, J.; Hebda, P.; Lange, D.; Luo, J.; Marlow, D.; Medvedeva, T.; Mei, K.; Mooney, M.; Olsen, J.; Palmer, C.; Piroué, P.; Stickland, D.; Svyatkovskiy, A.; Tully, C.; Zuranski, A.; Malik, S.; Barker, A.; Barnes, V. E.; Folgueras, S.; Gutay, L.; Jha, M. K.; Jones, M.; Jung, A. W.; Khatiwada, A.; Miller, D. H.; Neumeister, N.; Schulte, J. F.; Shi, X.; Sun, J.; Wang, F.; Xie, W.; Parashar, N.; Stupak, J.; Adair, A.; Akgun, B.; Chen, Z.; Ecklund, K. M.; Geurts, F. J. M.; Guilbaud, M.; Li, W.; Michlin, B.; Northup, M.; Padley, B. P.; Redjimi, R.; Roberts, J.; Rorie, J.; Tu, Z.; Zabel, J.; Betchart, B.; Bodek, A.; de Barbaro, P.; Demina, R.; Duh, Y. t.; Ferbel, T.; Galanti, M.; Garcia-Bellido, A.; Han, J.; Hindrichs, O.; Khukhunaishvili, A.; Lo, K. H.; Tan, P.; Verzetti, M.; Agapitos, A.; Chou, J. P.; Contreras-Campana, E.; Gershtein, Y.; Espinosa, T. A. Gómez; Halkiadakis, E.; Heindl, M.; Hidas, D.; Hughes, E.; Kaplan, S.; Elayavalli, R. Kunnawalkam; Kyriacou, S.; Lath, A.; Nash, K.; Saka, H.; Salur, S.; Schnetzer, S.; Sheffield, D.; Somalwar, S.; Stone, R.; Thomas, S.; Thomassen, P.; Walker, M.; Delannoy, A. G.; Foerster, M.; Heideman, J.; Riley, G.; Rose, K.; Spanier, S.; Thapa, K.; Bouhali, O.; Celik, A.; Dalchenko, M.; De Mattia, M.; Delgado, A.; Dildick, S.; Eusebi, R.; Gilmore, J.; Huang, T.; Juska, E.; Kamon, T.; Mueller, R.; Pakhotin, Y.; Patel, R.; Perloff, A.; Perniè, L.; Rathjens, D.; Rose, A.; Safonov, A.; Tatarinov, A.; Ulmer, K. A.; Akchurin, N.; Cowden, C.; Damgov, J.; De Guio, F.; Dragoiu, C.; Dudero, P. R.; Faulkner, J.; Gurpinar, E.; Kunori, S.; Lamichhane, K.; Lee, S. W.; Libeiro, T.; Peltola, T.; Undleeb, S.; Volobouev, I.; Wang, Z.; Greene, S.; Gurrola, A.; Janjam, R.; Johns, W.; Maguire, C.; Melo, A.; Ni, H.; Sheldon, P.; Tuo, S.; Velkovska, J.; Xu, Q.; Arenton, M. W.; Barria, P.; Cox, B.; Goodell, J.; Hirosky, R.; Ledovskoy, A.; Li, H.; Neu, C.; Sinthuprasith, T.; Sun, X.; Wang, Y.; Wolfe, E.; Xia, F.; Clarke, C.; Harr, R.; Karchin, P. E.; Sturdy, J.; Belknap, D. A.; Buchanan, J.; Caillol, C.; Dasu, S.; Dodd, L.; Duric, S.; Gomber, B.; Grothe, M.; Herndon, M.; Hervé, A.; Klabbers, P.; Lanaro, A.; Levine, A.; Long, K.; Loveless, R.; Ojalvo, I.; Perry, T.; Pierro, G. A.; Polese, G.; Ruggles, T.; Savin, A.; Smith, N.; Smith, W. H.; Taylor, D.; Woods, N.

2017-04-01

The spectra of charged particles produced within the pseudorapidity window | η| < 1 at √{s_{NN}}=5.02 TeV are measured using 404 μb-1 of PbPb and 27.4 pb-1 of pp data collected by the CMS detector at the LHC in 2015. The spectra are presented over the transverse momentum ranges spanning 0 .5 < p T < 400 GeV in pp and 0 .7 < p T < 400 GeV in PbPb collisions. The corresponding nuclear modification factor, R AA, is measured in bins of collision centrality. The R AA in the 5% most central collisions shows a maximal suppression by a factor of 7-8 in the p T region of 6-9 GeV. This dip is followed by an increase, which continues up to the highest p T measured, and approaches unity in the vicinity of p T = 200 GeV. The R AA is compared to theoretical predictions and earlier experimental results at lower collision energies. The newly measured pp spectrum is combined with the pPb spectrum previously published by the CMS collaboration to construct the pPb nuclear modification factor, R pA, up to 120 GeV. For p T > 20 GeV, R pA exhibits weak momentum dependence and shows a moderate enhancement above unity. [Figure not available: see fulltext.

Ribes nigrum L. Prevents UVB-mediated Photoaging in Human Dermal Fibroblasts: Potential Antioxidant and Antiinflammatory Activity.

PubMed

Li, Lu; Hwang, Eunson; Ngo, Hien T T; Seo, Seul A; Lin, Pei; Gao, Wei; Liu, Ying; Yi, Tae-Hoo

2018-05-16

Black currants (Ribes nigrum L, RN) are known as a "super fruit" to possess for their many potential health benefits such as the alleviation of oxidative stress-related disorders. However, little skin photoaging-related research has been done on the use of this agent. In the present study, we investigated the protective effects of RN in UVB-irradiated human dermal fibroblasts (NHDFs). RN treatment in UVB-irradiated skin models alleviated UVB-mediated photoaging through several mechanisms: Treatment with RN downregulated MAPK-related signaling models, such as those of activation protein 1 (AP-1) and nuclear factor kappa B (NF-κB). In addition, phase II gene heme oxygenase-1 (HO-1) was modulated by the increase in nuclear factor erythroid 2-related factor 2 (Nrf2) in the nuclear, and finally, transforming growth factor TGF-β was upregulated in vitro. Further study indicated that UVB-induced production of MMP-1 and IL-6 could be inhibited by PD 98059 (an inhibitor of ERK) and SP600125 (an inhibitor of JNK). Thus, RN improved the expression of type I procollagen and inhibited UVB-induced MMP-1 and IL-6 secretion through inactivating MAPK cascades. Therefore, RN is a suitable target for further investigation as an antiphotoaging agent and may have applications in the skincare industry. © 2018 The American Society of Photobiology.

The variations in the nuclear proteome reveal new transcription factors and mechanisms involved in UV stress response in Pinus radiata.

PubMed

Pascual, Jesús; Alegre, Sara; Nagler, Matthias; Escandón, Mónica; Annacondia, María Luz; Weckwerth, Wolfram; Valledor, Luis; Cañal, María Jesús

2016-06-30

The importance of UV stress and its side-effects over the loss of plant productivity in forest species demands a deeper understanding of how pine trees respond to UV irradiation. Although the response to UV stress has been characterized at system and cellular levels, the dynamics within the nuclear proteome triggered by UV is still unknown despite that they are essential for gene expression and regulation of plant physiology. To fill this gap this work aims to characterize the variations in the nuclear proteome as a response to UV irradiation by using state-of-the-art mass spectrometry-based methods combined with novel bioinformatics workflows. The combination of SEQUEST, de novo sequencing, and novel annotation pipelines allowed cover sensing and transduction pathways, endoplasmic reticulum-related mechanisms and the regulation of chromatin dynamism and gene expression by histones, histone-like NF-Ys, and other transcription factors previously unrelated to this stress source, as well as the role of alternative splicing and other mechanisms involved in RNA translation and protein synthesis. The determination of 33 transcription factors, including NF-YB13, Pp005698_3 (NF-YB) and Pr009668_2 (WD-40), which are correlated to stress responsive mechanisms like an increased accumulation of photoprotective pigments and reduced photosynthesis, pointing them as strong candidate biomarkers for breeding programs aimed to improve UV resistance of pine trees. The description of the nuclear proteome of Pinus radiata combining a classic approach based on the use of SEQUEST and the use of a mass accuracy precursor alignment (MAPA) allowed an unprecedented protein coverage. This workflow provided the methodological basis for characterizing the changes in the nuclear proteome triggered by UV irradiation, allowing the depiction of the nuclear events involved in stress response and adaption. The relevance of some of the discovered proteins will suppose a major advance in stress biology field, also providing a set of transcription factors that can be considered as strong biomarker candidates to select trees more tolerant to UV radiation in forest upgrade programs. Copyright © 2016 Elsevier B.V. All rights reserved.

Nuclear degradation of Wilms tumor 1-associating protein and survivin splice variant switching underlie IGF-1-mediated survival.

PubMed

Small, Theodore W; Pickering, J Geoffrey

2009-09-11

WTAP (Wilms tumor 1-associating protein) is a recently identified nuclear protein that is essential for mouse embryo development. The Drosophila homolog of WTAP, Fl(2)d, regulates pre-mRNA splicing; however, the role of WTAP in mammalian cells is uncertain. To elucidate a context for WTAP action, we screened growth and survival factors for their effects on WTAP expression in vascular smooth muscle cells (SMCs), a cell type previously found to express WTAP dynamically. This revealed that insulin-like growth factor-1 (IGF-1) uniquely reduced WTAP abundance. This decline in WTAP proved to be necessary for IGF-1 to confer its antiapoptotic properties, which were blocked by transducing the WTAP gene into SMCs. WTAP down-regulation by IGF-1 was mediated by an IGF-1 receptor-phosphatidylinositol 3-kinase-Akt signaling axis that directed WTAP degradation via a nuclear 26 S proteasome. Moreover, by promoting the degradation of WTAP, IGF-1 shifted the pre-mRNA splicing program for the survival factor, survivin, to reduce expression of survivin-2B, which is proapoptotic, and increase expression of survivin, which is antiapoptotic. Knockdown of survivin-2B rescued the ability of IGF-1 to promote survival when WTAP was overexpressed. These data uncover a novel regulatory cascade for human SMC survival based on adjusting the nuclear abundance of WTAP to define the splice variant balance among survivin isoforms.

Comments on the feasibility of developing gas core nuclear reactors. [for manned interplanetary spacecraft propulsion

NASA Technical Reports Server (NTRS)

Rom, F. E.

1969-01-01

Recent developments in the fields of gas core hydrodynamics, heat transfer, and neutronics indicate that gas core nuclear rockets may be feasible from the point of view of basic principles. Based on performance predictions using these results, mission analyses indicate that gas core nuclear rockets may have the potential for reducing the initial weight in orbit of manned interplanetary vehicles by a factor of 5 when compared to the best chemical rocket systems. In addition, there is a potential for reducing total trip times from 450 to 500 days for chemical systems to 250 to 300 days for gas core systems. The possibility of demonstrating the feasibility of gas core nuclear rocket engines by means of a logical series of experiments of increasing difficulty that ends with ground tests of full scale gas core reactors is considered.

Nuclear recoil measurements with the ARIS experiment

NASA Astrophysics Data System (ADS)

Fan, Alden; ARIS Collaboration

2017-01-01

As direct dark matter searches become increasingly sensitive, it is important to fully characterize the target of the search. The goal of the Argon Recoil Ionization and Scintillation (ARIS) experiment is to quantify information related to the scintillation and ionization energy scale, quenching factor, ion recombination probability, and scintillation time response of nuclear recoils, as expected from WIMPs, in liquid argon. A time projection chamber with an active mass of 0.5 kg of liquid argon and capable of full 3D position reconstruction was exposed to an inverse kinematic neutron beam at the Institut de Physique Nucleaire d'Orsay in France. A scan of nuclear recoil energies was performed through coincidence with a set of neutron detectors to quantify properties of nuclear recoils in liquid argon at various electric fields. The difference in ionization and scintillation response with differing recoil track angle to the electric field was also studied. The preliminary results of the experiment will be presented.

Nuclear insulin-like growth factor 1 receptor phosphorylates proliferating cell nuclear antigen and rescues stalled replication forks after DNA damage.

PubMed

Waraky, Ahmed; Lin, Yingbo; Warsito, Dudi; Haglund, Felix; Aleem, Eiman; Larsson, Olle

2017-11-03

We have previously shown that the insulin-like growth factor 1 receptor (IGF-1R) translocates to the cell nucleus, where it binds to enhancer-like regions and increases gene transcription. Further studies have demonstrated that nuclear IGF-1R (nIGF-1R) physically and functionally interacts with some nuclear proteins, i.e. the lymphoid enhancer-binding factor 1 (Lef1), histone H3, and Brahma-related gene-1 proteins. In this study, we identified the proliferating cell nuclear antigen (PCNA) as a nIGF-1R-binding partner. PCNA is a pivotal component of the replication fork machinery and a main regulator of the DNA damage tolerance (DDT) pathway. We found that IGF-1R interacts with and phosphorylates PCNA in human embryonic stem cells and other cell lines. In vitro MS analysis of PCNA co-incubated with the IGF-1R kinase indicated tyrosine residues 60, 133, and 250 in PCNA as IGF-1R targets, and PCNA phosphorylation was followed by mono- and polyubiquitination. Co-immunoprecipitation experiments suggested that these ubiquitination events may be mediated by DDT-dependent E2/E3 ligases ( e.g. RAD18 and SHPRH/HLTF). Absence of IGF-1R or mutation of Tyr-60, Tyr-133, or Tyr-250 in PCNA abrogated its ubiquitination. Unlike in cells expressing IGF-1R, externally induced DNA damage in IGF-1R-negative cells caused G 1 cell cycle arrest and S phase fork stalling. Taken together, our results suggest a role of IGF-1R in DDT. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Tracking STAT nuclear traffic.

PubMed

Reich, Nancy C; Liu, Ling

2006-08-01

Accurate cellular localization is crucial for the effective function of most signalling molecules and nuclear translocation is central to the function of transcription factors. The passage of large molecules between the cytoplasm and nucleus is restricted, and this restriction affords a mechanism to regulate transcription by controlling the access of transcription factors to the nucleus. In this Review, we focus on the signal transducer and activator of transcription (STAT) family of transcription factors. The regulation of the nuclear trafficking of STAT-family members is diverse. Some STAT proteins constitutively shuttle between the nucleus and cytoplasm, whereas others require tyrosine phosphorylation for nuclear localization. In either case, the regulation of nuclear trafficking can provide a target for therapeutic intervention.

GATA Factor Regulation in Excess Nitrogen Occurs Independently of Gtr-Ego Complex-Dependent TorC1 Activation.

PubMed

Tate, Jennifer J; Georis, Isabelle; Rai, Rajendra; Vierendeels, Fabienne; Dubois, Evelyne; Cooper, Terrance G

2015-05-29

The TorC1 protein kinase complex is a central component in a eukaryotic cell's response to varying nitrogen availability, with kinase activity being stimulated in nitrogen excess by increased intracellular leucine. This leucine-dependent TorC1 activation requires functional Gtr1/2 and Ego1/3 complexes. Rapamycin inhibition of TorC1 elicits nuclear localization of Gln3, a GATA-family transcription activator responsible for the expression of genes encoding proteins required to transport and degrade poor nitrogen sources, e.g., proline. In nitrogen-replete conditions, Gln3 is cytoplasmic and Gln3-mediated transcription minimal, whereas in nitrogen limiting or starvation conditions, or after rapamycin treatment, Gln3 is nuclear and transcription greatly increased. Increasing evidence supports the idea that TorC1 activation may not be as central to nitrogen-responsive intracellular Gln3 localization as envisioned previously. To test this idea directly, we determined whether Gtr1/2- and Ego1/3-dependent TorC1 activation also was required for cytoplasmic Gln3 sequestration and repressed GATA factor-mediated transcription by abolishing the Gtr-Ego complex proteins. We show that Gln3 is sequestered in the cytoplasm of gtr1Δ, gtr2Δ, ego1Δ, and ego3Δ strains either long term in logarithmically glutamine-grown cells or short term after refeeding glutamine to nitrogen-limited or -starved cells; GATA factor-dependent transcription also was minimal. However, in all but a gtr1Δ, nuclear Gln3 localization in response to nitrogen limitation or starvation was adversely affected. Our data demonstrate: (i) Gtr-Ego-dependent TorC1 activation is not required for cytoplasmic Gln3 sequestration in nitrogen-rich conditions; (ii) a novel Gtr-Ego-TorC1 activation-independent mechanism sequesters Gln3 in the cytoplasm; (iii) Gtr and Ego complex proteins participate in nuclear Gln3-Myc(13) localization, heretofore unrecognized functions for these proteins; and (iv) the importance of searching for new mechanisms associated with TorC1 activation and/or the regulation of Gln3 localization/function in response to changes in the cells' nitrogen environment. Copyright © 2015 Tate et al.

Rosmarinic acid counteracts activation of hepatic stellate cells via inhibiting the ROS-dependent MMP-2 activity: Involvement of Nrf2 antioxidant system

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, Changfang; Zou, Yu; Liu, Yuzhang

Recently, oxidative stress is involved in hepatofibrogenesis. Matrix metalloproteinase-2 (MMP-2) is required for activation of hepatic stellate cells (HSCs) in response to reactive oxygen species (ROS). This study was designed to explore the hypothesis that the inhibitory effect of rosmarinic acid (RA) on HSCs activation might mainly result from its antioxidant capability by increasing the synthesis of glutathione (GSH) involved in nuclear factor kappa B (NF-κB)-dependent inhibition of MMP-2 activity. Here, we demonstrate that RA reverses activated HSCs to quiescent cells. Concomitantly, RA inhibits MMP-2 activity. RNA interference-imposed knockdown of NF-κB abolished down-regulation of MMP-2 by RA. RA-mediated inactivation ofmore » NF-κB could be blocked by the diphenyleneiodonium chloride (DPI; a ROS inhibitor). Conversely, transfection of dominant-negative (DN) mutant of extracellular signal-regulated kinases 2 (ERK2), c-Jun N-terminal kinase 1 (JNK1), or p38α kinase had no such effect. Simultaneously, RA suppresses ROS generation and lipid peroxidation (LPO) whereas increases cellular GSH in HSC-T6 cells. Furthermore, RA significantly increased antioxidant response element (ARE)-mediated luciferase activity, nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and catalytic subunits from glutamate cysteine ligase (GCLc) expression, but not modulatory subunits from GCL (GCLm). RA-mediated up-regulation of GClc is inhibited by the shRNA-induced Nrf2 knockdown. The knocking down of Nrf2 or buthionine sulfoximine (a GCL inhibitor) abolished RA-mediated inhibition of ROS. Collectively, these results provide novel insights into the mechanisms of RA as an antifibrogenic candidate in the prevention and treatment of liver fibrosis. - Highlights: • RA reverses activated HSCs to quiescent cells. • RA suppresses MMP-2 activity through a NF-κB-dependent pathway. • Inhibition of oxidative stress by RA is dependent on nuclear translocation of Nrf2. • RA-mediated down-regulation of MMP-2 was ROS-dependent.« less

The transcription factor LEF-1 induces an epithelial–mesenchymal transition in MDCK cells independent of β-catenin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kobayashi, Wakako; Ozawa, Masayuki, E-mail: mozawa@m.kufm.kagoshima-u.ac.jp

2013-12-06

Highlights: •The transcription factor LEF-1 induces an EMT in MDCK cells. •A mutant LEF-1 that cannot interact with β-catenin retained the ability. •The nuclear function of β-catenin was not necessary for the LEF-1-induced EMT. •The mRNA levels of Slug, ZEB1, and ZEB2 increased significantly in these cells. -- Abstract: The epithelial–mesenchymal transition (EMT), a key process in the tumor metastatic cascade, is characterized by the loss of cell–cell junctions and cell polarity, as well as the acquisition of migratory and invasive properties. LEF-1 is a member of the lymphoid enhancer-binding factor/T-cell factor (LEF/TCF) family of DNA-binding transcription factors, which interactmore » with nuclear β-catenin and act as central transcriptional mediators of Wnt signaling. To investigate the role of LEF-1 in EMT, we generated stable LEF-1 transfectants using MDCK cells. The transfectants had a spindle-shaped mesenchymal morphology, and enhanced migration and invasiveness relative to control cells. These EMT changes were accompanied by the downregulation of an epithelial marker protein, E-cadherin, and the upregulation of mesenchymal marker proteins, vimentin and N-cadherin. Consistent with these observations, the mRNA levels of Slug, ZEB1, and ZEB2—EMT-related transcription factors—increased significantly. Although the N-terminally deleted mutant LEF-1 cannot interact with β-catenin, it retained the ability to induce EMT. Consistent with these observations, neither the expression of a dominant negative β-catenin/engrailed chimera, nor the expression of a cytoplasmic domain of E-cadherin that sequesters β-catenin from binding to LEF/TCF, reversed LEF-1-induced EMT. Together, these data indicated that the nuclear function of β-catenin was not necessary for the induction of Slug, ZEB1, and ZEB2 expression leading to EMT.« less

Nuclear Recoil Effect on the g-Factor of Heavy Ions: Prospects for Tests of Quantum Electrodynamics in a New Region

NASA Astrophysics Data System (ADS)

Malyshev, A. V.; Shabaev, V. M.; Glazov, D. A.; Tupitsyn, I. I.

2017-12-01

The nuclear recoil effect on the g-factor of H- and Li-like heavy ions is evaluated to all orders in αZ. The calculations include an approximate treatment of the nuclear size and the electron-electron interaction corrections to the recoil effect. As the result, the second largest contribution to the theoretical uncertainty of the g-factor values of 208Pb79+ and 238U89+ is strongly reduced. Special attention is paid to tests of the QED recoil effect on the g-factor in experiments with heavy ions. It is found that, while the QED recoil effect on the gfactor value is masked by the uncertainties of the nuclear size and nuclear polarization contributions, it can be probed on a few-percent level in the specific difference of the g-factors of H- and Li-like heavy ions. This provides a unique opportunity to test QED in a new region of the strong-coupling regime beyond the Furry picture.

10 CFR 63.305 - Required characteristics of the reference biosphere.

Code of Federal Regulations, 2011 CFR

2011-01-01

....305 Section 63.305 Energy NUCLEAR REGULATORY COMMISSION (CONTINUED) DISPOSAL OF HIGH-LEVEL RADIOACTIVE... biosphere (other than climate), human biology, or increases or decreases of human knowledge or technology... factors remain constant as they are at the time of submission of the license application. (c) DOE must...

The Nuclear Transcription Factor RAR Associates with Neuronal RNA Granules and Suppresses Translation

USDA-ARS?s Scientific Manuscript database

All-trans-retinoic acid stimulates dendritic growth in hippocampal neurons within minutes by activating mitogen-activated protein kinase and mTOR and increasing dendritic translation of calcium calmodulin-dependent protein kinase II alpha and the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole propionat...

Deciphering the Regulatory Logic of an Ancient, Ultraconserved Nuclear Receptor Enhancer Module

PubMed Central

Bagamasbad, Pia D.; Bonett, Ronald M.; Sachs, Laurent; Buisine, Nicolas; Raj, Samhitha; Knoedler, Joseph R.; Kyono, Yasuhiro; Ruan, Yijun; Ruan, Xiaoan

2015-01-01

Cooperative, synergistic gene regulation by nuclear hormone receptors can increase sensitivity and amplify cellular responses to hormones. We investigated thyroid hormone (TH) and glucocorticoid (GC) synergy on the Krüppel-like factor 9 (Klf9) gene, which codes for a zinc finger transcription factor involved in development and homeostasis of diverse tissues. We identified regions of the Xenopus and mouse Klf9 genes 5–6 kb upstream of the transcription start sites that supported synergistic transactivation by TH plus GC. Within these regions, we found an orthologous sequence of approximately 180 bp that is highly conserved among tetrapods, but absent in other chordates, and possesses chromatin marks characteristic of an enhancer element. The Xenopus and mouse approximately 180-bp DNA element conferred synergistic transactivation by hormones in transient transfection assays, so we designate this the Klf9 synergy module (KSM). We identified binding sites within the mouse KSM for TH receptor, GC receptor, and nuclear factor κB. TH strongly increased recruitment of liganded GC receptor and serine 5 phosphorylated (initiating) RNA polymerase II to chromatin at the KSM, suggesting a mechanism for transcriptional synergy. The KSM is transcribed to generate long noncoding RNAs, which are also synergistically induced by combined hormone treatment, and the KSM interacts with the Klf9 promoter and a far upstream region through chromosomal looping. Our findings support that the KSM plays a central role in hormone regulation of vertebrate Klf9 genes, it evolved in the tetrapod lineage, and has been maintained by strong stabilizing selection. PMID:25866873

Osthole protects against inflammation in a rat model of chronic kidney failure via suppression of nuclear factor-κB, transforming growth factor-β1 and activation of phosphoinositide 3-kinase/protein kinase B/nuclear factor (erythroid-derived 2)-like 2 signaling.

PubMed

Huang, Tao; Dong, Zhen

2017-10-01

Multiple pharmacological applications of osthole have been previously recognized, including antioxidant, anti-inflammatory, anti‑platelet and estrogenic effects, and resistance to pain. The present study investigated the protective effects of osthole against inflammation in a rat model of chronic kidney failure (CRF) and the underlying mechanisms. Osthole treatment with significantly reversed CRF‑induced changes in serum creatinine, calcium, phosphorus and blood urea nitrogen levels in CRF rats. Male Sprague‑Dawley rats (age, 8 weeks) received 200 mg/kg 2% adenine suspension to induce CRF in the model group. In the osthole‑treated group, rats received 200 mg/kg 2% adenine suspension + osthole (40 mg/kg, intravenously). The results revealed that treatment with osthole significantly inhibited CRF‑induced tumor necrosis factor‑α, interleukin (IL)‑8 and IL‑6 expression, and suppressed nuclear factor‑κB (NF‑κB) protein expression in CRF rats. Osthole treatment significantly attenuated the protein expression of transforming growth factor‑β1 (TGF‑β1), reduced monocyte chemoattractant protein‑1 activity and increased the phosphoinositide 3‑kinase (PI3K)/protein kinase B (Akt) ratio in CRF rats. These results suggested that osthole protects against inflammation in a rat model of CRF via suppression of NF‑κB and TGF‑β1, and activation of PI3K/Akt/nuclear factor (erythroid‑derived 2)‑like 2 signaling. Therefore, osthole may represent a potential therapeutic agent for the treatment of CRF.

Balance between fibroblast growth factor 10 and secreted frizzled-relate protein-1 controls the development of hair follicle by competitively regulating β-catenin signaling.

PubMed

Zhang, Haihua; Nan, Weixiao; Wang, Shiyong; Si, Huazhe; Li, Guangyu

2018-07-01

Growth of hairs depends on the regular development of hair follicles which are hypothesized to be regulated by fibroblast growth factor 10 (FGF10) and secreted frizzled-relate protein-1 (sFRP1). In the current study, the effect of FGF10 or sFRP1 on hair follicle cells was assessed and the possible mechanism mediating the interaction between FGF10 and sFRP1 in hair follicle cells was explored. Out root sheath (ORS) and dermal papilla (DP) cells were isolated from mink skin tissues and subjected to administrations of FGF10 (50 ng/ml) or sFRP1 (10 ng/ml). Then proliferation, cell cycle distribution, and migration potentials of both cell types were detected. Moreover, the nuclear translocation of β-catenin was determined. The results showed that the administration of FGF10 increased cell proliferation and migration potential in both cell types, which was associated with the up-regulated nuclear level of β-catenin. To the contrary, the administration of sFRP1 decreased cell proliferation and migration potentials while induced the G1 cell cycle arrest in both cell types by inhibiting nuclear translocation of β-catenin. Compared with the sole administrations, the co-treatment of FGF10 and sFRP1 had a medium effect on cell proliferation, cell cycle distribution, cell migration, and nuclear β-catenin level, representing an antagonistic interaction between the two factors, which was exerted by competitively regulating β-catenin pathway. Conclusively, the cycle of hair follicles was promoted by FGF10 while blocked by sFRP1 and the interplay between the two factors controlled the development of hair follicles by competitively regulating β-catenin signaling. Copyright © 2018. Published by Elsevier Masson SAS.

Deferasirox is a powerful NF-κB inhibitor in myelodysplastic cells and in leukemia cell lines acting independently from cell iron deprivation by chelation and reactive oxygen species scavenging

PubMed Central

Messa, Emanuela; Carturan, Sonia; Maffè, Chiara; Pautasso, Marisa; Bracco, Enrico; Roetto, Antonella; Messa, Francesca; Arruga, Francesca; Defilippi, Ilaria; Rosso, Valentina; Zanone, Chiara; Rotolo, Antonia; Greco, Elisabetta; Pellegrino, Rosa M.; Alberti, Daniele; Saglio, Giuseppe; Cilloni, Daniela

2010-01-01

Background Usefulness of iron chelation therapy in myelodysplastic patients is still under debate but many authors suggest its possible role in improving survival of low-risk myelodysplastic patients. Several reports have described an unexpected effect of iron chelators, such as an improvement in hemoglobin levels, in patients affected by myelodysplastic syndromes. Furthermore, the novel chelator deferasirox induces a similar improvement more rapidly. Nuclear factor-κB is a key regulator of many cellular processes and its impaired activity has been described in different myeloid malignancies including myelodysplastic syndromes. Design and Methods We evaluated deferasirox activity on nuclear factor-κB in myelodysplastic syndromes as a possible mechanism involved in hemoglobin improvement during in vivo treatment. Forty peripheral blood samples collected from myelodysplastic syndrome patients were incubated with 50 μM deferasirox for 18h. Results Nuclear factor-κB activity dramatically decreased in samples showing high basal activity as well as in cell lines, whereas no similar behavior was observed with other iron chelators despite a similar reduction in reactive oxygen species levels. Additionally, ferric hydroxyquinoline incubation did not decrease deferasirox activity in K562 cells suggesting the mechanism of action of the drug is independent from cell iron deprivation by chelation. Finally, incubation with both etoposide and deferasirox induced an increase in K562 apoptotic rate. Conclusions Nuclear factor-κB inhibition by deferasirox is not seen from other chelators and is iron and reactive oxygen species scavenging independent. This could explain the hemoglobin improvement after in vivo treatment, such that our hypothesis needs to be validated in further prospective studies. PMID:20534700

Bortezomib as a new therapeutic approach for blastic plasmacytoid dendritic cell neoplasm.

PubMed

Philippe, Laure; Ceroi, Adam; Bôle-Richard, Elodie; Jenvrin, Alizée; Biichle, Sabeha; Perrin, Sophie; Limat, Samuel; Bonnefoy, Francis; Deconinck, Eric; Saas, Philippe; Garnache-Ottou, Francine; Angelot-Delettre, Fanny

2017-11-01

Blastic plasmacytoid dendritic cell neoplasm is an aggressive hematologic malignancy with a poor prognosis. No consensus regarding optimal treatment modalities is currently available. Targeting the nuclear factor-kappa B pathway is considered a promising approach since blastic plasmacytoid dendritic cell neoplasm has been reported to exhibit constitutive activation of this pathway. Moreover, nuclear factor-kappa B inhibition in blastic plasmacytoid dendritic cell neoplasm cell lines, achieved using either an experimental specific inhibitor JSH23 or the clinical drug bortezomib, interferes in vitro with leukemic cell proliferation and survival. Here we extended these data by showing that primary blastic plasmacytoid dendritic cell neoplasm cells from seven patients were sensitive to bortezomib-induced cell death. We confirmed that bortezomib efficiently inhibits the phosphorylation of the RelA nuclear factor-kappa B subunit in blastic plasmacytoid dendritic cell neoplasm cell lines and primary cells from patients in vitro and in vivo in a mouse model. We then demonstrated that bortezomib can be associated with other drugs used in different chemotherapy regimens to improve its impact on leukemic cell death. Indeed, when primary blastic plasmacytoid dendritic cell neoplasm cells from a patient were grafted into mice, bortezomib treatment significantly increased the animals' survival, and was associated with a significant decrease of circulating leukemic cells and RelA nuclear factor-kappa B subunit expression. Overall, our results provide a rationale for the use of bortezomib in combination with other chemotherapy for the treatment of patients with blastic plasmacytoid dendritic cell neoplasm. Based on our data, a prospective clinical trial combining proteasome inhibitor with classical drugs could be envisaged. Copyright© Ferrata Storti Foundation.

Proceedings of the Human Factors Society 35th annual meeting

DOE Office of Scientific and Technical Information (OSTI.GOV)

Not Available

1991-01-01

These volumes cover the proceedings of the 35th annual meeting of the Human Factors Society. Topics include: designing for the future of nuclear power plants international perspectives on advanced control room design; human performance assessment in the nuclear power industry; validity of strength tests for predicting endurance of coal miners, psychosocial issues in hazard management and nuclear power plants; and human factors at the DOE's national laboratories.

Nationwide Increase in Cryptorchidism After the Fukushima Nuclear Accident.

PubMed

Murase, Kaori; Murase, Joe; Machidori, Koji; Mizuno, Kentaro; Hayashi, Yutaro; Kohri, Kenjiro

2018-05-08

To estimate the change of discharge rate after cryptorchidism surgery between pre- and postdisaster in Japan. Cryptorchidism cannot be diagnosed before birth and is not a factor that would influence a woman's decision to seek an abortion. Therefore, this disease is considered suitable for assessing how the Great East Japan Earthquake and the subsequent Fukushima Daiichi nuclear accident (2011) influenced congenital diseases. We obtained cryptorchidism discharge data collected over 6 years from hospitals that were included in an impact assessment survey of the Diagnosis Procedure Combination survey database in Japan and used these data to estimate the discharge rate after cryptorchidism surgery before and after the disaster. The 94 hospitals in Japan that participated in Diagnosis Procedure Combination system and had 10 or more discharges after cryptorchidism surgery within successive 6 years covering pre- and postdisaster period (FY2010-FY2015) were involved. The change in discharge rate between pre- and postdisaster was analyzed using a Bayesian generalized linear mixed model. Nationwide, a 13.4% (95% credible interval 4.7%-23.0%) increase in discharge rates was estimated. The results of all sensitivity analyses were similar to the reported main results. The discharge rate of cryptorchidism was increased nationwide. The rates of low-weight babies or preterm births, risk factors of cryptorchidism, were almost constant during the study period, and age distribution of the surgery was also not changed, which suggested that the other factors that associated with the disaster increased the incidence of cryptorchidism. Copyright © 2018 Elsevier Inc. All rights reserved.

Online Appointment Scheduling for a Nuclear Medicine Department in a Chinese Hospital

PubMed Central

Feng, Ya-bing

2018-01-01

Nuclear medicine, a subspecialty of radiology, plays an important role in proper diagnosis and timely treatment. Multiple resources, especially short-lived radiopharmaceuticals involved in the process of nuclear medical examination, constitute a unique problem in appointment scheduling. Aiming at achieving scientific and reasonable appointment scheduling in the West China Hospital (WCH), a typical class A tertiary hospital in China, we developed an online appointment scheduling algorithm based on an offline nonlinear integer programming model which considers multiresources allocation, the time window constraints imposed by short-lived radiopharmaceuticals, and the stochastic nature of the patient requests when scheduling patients. A series of experiments are conducted to show the effectiveness of the proposed strategy based on data provided by the WCH. The results show that the examination amount increases by 29.76% compared with the current one with a significant increase in the resource utilization and timely rate. Besides, it also has a high stability for stochastic factors and bears the advantage of convenient and economic operation. PMID:29849748

α-Naphthoflavone Increases Lipid Accumulation in Mature Adipocytes and Enhances Adipocyte-Stimulated Endothelial Tube Formation.

PubMed

Wang, Mei-Lin; Lin, Shyh-Hsiang; Hou, Yuan-Yu; Chen, Yue-Hwa

2015-04-30

The aryl hydrocarbon receptor (AhR) is a ligand-activated factor that regulates biological effects associated with obesity. The AhR agonists, such as environmental contaminants 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and β-naphthoflavone (BNF), inhibit preadipocyte differentiation and interfere with the functions of adipose tissue, whereas the antagonist may have opposite or protective effects in obesity. This study investigated the effects of α-naphthoflavone (α-NF), an AhR antagonist, on adipogenesis- and angiogenesis-associated factors in mature adipocytes and on cross-talk of mature adipocytes with endothelial cells (ECs). Besides, the roles of the AhR on lipid accumulation and on secretion of vascular endothelial growth factor were also determined by introducing siRNA of AhR. Differentiated 3T3-L1 cells were treated with α-naphthoflavone (α-NF) (1-5 μM) for 16 h. Lipid accumulation and the expressions of AhR-associated factors in the cells were determined. The interaction between adipocytes and ECs was investigated by cultivating ECs with conditioned medium (CM) from α-NF-treated mature adipocytes, followed by the determination of endothelial tube formation. The results showed that α-NF significantly increased triglyceride (TG) accumulation in mature adipocytes, which was associated with increased expression of hormone-sensitive lipase (HSL), estrogen receptor (ER), as well as decreased expression of AhR, AhR nuclear translocator (ARNT), cytochrome P4501B1 (CYP1B1), and nuclear factor erythroid-2-related factor (NRF-2) proteins. In addition, CM stimulated formation of tube-like structures in ECs, and α-NF further enhanced such stimulation in association with modulated the secretions of various angiogenic mediators by mature adipocytes. Similarly, increased TG accumulation and vascular endothelial growth factor (VEGF) secretion were observed in AhR-knockout cells. In conclusion, α-NF increased TG accumulation in mature adipocytes and enhanced mature adipocyte-stimulated tube formation in ECs, suggesting that the AhR may suppress obesity-induced adverse effects, and α-NF abolished the protective effects of the AhR.

Identification of a chemical inhibitor for nuclear speckle formation: Implications for the function of nuclear speckles in regulation of alternative pre-mRNA splicing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kurogi, Yutaro; Matsuo, Yota; Mihara, Yuki

2014-03-28

Highlights: • We identified tubercidin as a compound inducing aberrant formation of the speckles. • Tubercidin causes delocalization of poly (A){sup +}RNAs from nuclear speckles. • Tubercidin induces dispersion of splicing factors from nuclear speckles. • Tubercidin affects alternative pre-mRNA splicing. • Nuclear speckles play a role in regulation of alternative pre-mRNA splicing. - Abstract: Nuclear speckles are subnuclear structures enriched with RNA processing factors and poly (A){sup +} RNAs comprising mRNAs and poly (A){sup +} non-coding RNAs (ncRNAs). Nuclear speckles are thought to be involved in post-transcriptional regulation of gene expression, such as pre-mRNA splicing. By screening 3585 culturemore » extracts of actinomycetes with in situ hybridization using an oligo dT probe, we identified tubercidin, an analogue of adenosine, as an inhibitor of speckle formation, which induces the delocalization of poly (A){sup +} RNA and dispersion of splicing factor SRSF1/SF2 from nuclear speckles in HeLa cells. Treatment with tubercidin also decreased steady-state MALAT1 long ncRNA, thought to be involved in the retention of SRSF1/SF2 in nuclear speckles. In addition, we found that tubercidin treatment promoted exon skipping in the alternative splicing of Clk1 pre-mRNA. These results suggest that nuclear speckles play a role in modulating the concentration of splicing factors in the nucleoplasm to regulate alternative pre-mRNA splicing.« less

Nuclear translocation of Nrf2 and expression of antioxidant defence genes in THP-1 cells exposed to carbon nanotubes.

PubMed

Brown, David M; Donaldson, Kenneth; Stone, Vicki

2010-06-01

Carbon nanotubes have a wide range of applications in various industries and their use is likely to rise in the future. Currently, a major concern is that with the increasing use and production of these materials, there may be increased health risks to exposed workers. Long (> 15 microm) straight nanotubes may undergo frustrated phagocytosis which is likely to result in reduced clearance. We examine here the effects of multiwalled carbon nanotubes of different sizes on monocytic THP-1 cells, with regard to their ability to stimulate increased expression of the HO-1 and GST genes and their ability to produce nuclear translocation of the transcription factor, Nrf2, as well as the release of several pro-inflammatory cytokines and mediators of inflammation. Our results suggest that long (50 microm) carbon nanotubes (62.5 microg/ml for 4 hours) produce increased nuclear translocation of Nrf2 and increased HO-1 gene expression compared with shorter entangled nanotubes. There was no increased gene expression for GST. The long nanotubes (NT1) caused increased release of the proinflammatory cytokine IL-1beta, an effect which was diminished by the antioxidant trolox, suggesting a role of oxidative stress in the upregulation of this cytokine. Tentatively, our study suggests that long carbon nanotubes may exert their effect in THP-1 cells in part via an oxidative stress mechanism.

Enhancement of CD8+ T-cell memory by removal of a vaccinia virus nuclear factor-κB inhibitor

PubMed Central

Ren, Hongwei; Ferguson, Brian J; de Motes, Carlos Maluquer; Sumner, Rebecca P; Harman, Laura E R; Smith, Geoffrey L

2015-01-01

Factors influencing T-cell responses are important for vaccine development but are incompletely understood. Here, vaccinia virus (VACV) protein N1 is shown to impair the development of both effector and memory CD8+ T cells and this correlates with its inhibition of nuclear factor-κB (NF-κB) activation. Infection with VACVs that either have the N1L gene deleted (vΔN1) or contain a I6E mutation (vN1.I6E) that abrogates its inhibition of NF-κB resulted in increased central and memory CD8+ T-cell populations, increased CD8+ T-cell cytotoxicity and lower virus titres after challenge. Furthermore, CD8+ memory T-cell function was increased following infection with vN1.I6E, with more interferon-γ production and greater protection against VACV infection following passive transfer to naive mice, compared with CD8+ T cells from mice infected with wild-type virus (vN1.WT). This demonstrates the importance of NF-κB activation within infected cells for long-term CD8+ T-cell memory and vaccine efficacy. Further, it provides a rationale for deleting N1 from VACV vectors to enhance CD8+ T-cell immunogenicity, while simultaneously reducing virulence to improve vaccine safety. PMID:25382035

Kpna7 interacts with egg-specific nuclear factors in rainbow trout (Oncorhynchus mykiss)

USDA-ARS?s Scientific Manuscript database

Nuclear proteins are required for initiation of transcription in early embryos before embryonic genome activation. The regulation of transportation of nuclear proteins is mediated by transport factors known as importins (karyopherins). Kpna7 is a newly discovered member of the importin a family, whi...

Acute arsenic exposure induces inflammatory responses and CD4+ T cell subpopulations differentiation in spleen and thymus with the involvement of MAPK, NF-kB, and Nrf2.

PubMed

Duan, Xiaoxu; Gao, Shuang; Li, Jinlong; Wu, Liuzhong; Zhang, Yang; Li, Wei; Zhao, Lu; Chen, Jinli; Yang, Shan; Sun, Guifan; Li, Bing

2017-01-01

Increasing lines of evidence indicate that arsenic may be associated with immune related problems, but its detailed effects on immune organs are poorly understood. The objective of this study was to explore inflammatory responses and T cell differentiation of arsenic exposure in spleen and thymus. Female C57BL/6 mice were used as a model to systemically administration 2.5, 5 and 10mg/kg NaAsO 2 intra-gastrically for 24h. We found that arsenic significantly decreased the spleen and thymus weights and indices, and flow cytometry revealed that arsenic decreased the relative frequency of CD4 + T cell subpopulation and the ratios of CD4/CD8 in spleen. In contrast, serum concentration of tumor necrosis factor α (TNF-α), IL-1β and IL-6 as well as the mRNA of key inflammatory mediators in spleen and thymus, including transforming growth factor β (Tgf-β), Tnf-α, Il-12, Il-1β and Il-6 were significantly increased in arsenic-treated mice compared to the control as assayed by ELISA and real time PCR, respectively. In addition, arsenic increased the expression of T helper cell 1 (Th1), Th2 and regulatory T cell (Treg) -associated transcription factors and cytokines as well as decreased Th17-associated transcription factors and cytokines. Moreover, arsenic enhanced oxidative stress and induced the activation of extracellular-signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and p38 and their downstream transcription factors nuclear factor kappa B (NF-kB) and nuclear factor E2-related factor 2 (Nrf2), which comprise important mechanistic pathways involved in immune-inflammatory manifestations. Together, these results provide a novel strategy to block the arsenic-dependent impairments in immune responses. Copyright © 2016 Elsevier Ltd. All rights reserved.

The actin binding cytoskeletal protein Moesin is involved in nuclear mRNA export.

PubMed

Kristó, Ildikó; Bajusz, Csaba; Borsos, Barbara N; Pankotai, Tibor; Dopie, Joseph; Jankovics, Ferenc; Vartiainen, Maria K; Erdélyi, Miklós; Vilmos, Péter

2017-10-01

Current models imply that the evolutionarily conserved, actin-binding Ezrin-Radixin-Moesin (ERM) proteins perform their activities at the plasma membrane by anchoring membrane proteins to the cortical actin network. Here we show that beside its cytoplasmic functions, the single ERM protein of Drosophila, Moesin, has a novel role in the nucleus. The activation of transcription by heat shock or hormonal treatment increases the amount of nuclear Moesin, indicating biological function for the protein in the nucleus. The distribution of Moesin in the nucleus suggests a function in transcription and the depletion of mRNA export factors Nup98 or its interacting partner, Rae1, leads to the nuclear accumulation of Moesin, suggesting that the nuclear function of the protein is linked to mRNA export. Moesin localizes to mRNP particles through the interaction with the mRNA export factor PCID2 and knock down of Moesin leads to the accumulation of mRNA in the nucleus. Based on our results we propose that, beyond its well-known, manifold functions in the cytoplasm, the ERM protein of Drosophila is a new, functional component of the nucleus where it participates in mRNA export. Copyright © 2017 Elsevier B.V. All rights reserved.

The Mitochondrial Genome and a 60-kb Nuclear DNA Segment from Naegleria fowleri, the Causative Agent of Primary Amoebic Meningoencephalitis

PubMed Central

Herman, Emily K.; Greninger, Alexander L.; Visvesvara, Govinda S.; Marciano-Cabral, Francine; Dacks, Joel B.; Chiu, Charles Y.

2013-01-01

Naegleria fowleri is a unicellular eukaryote causing primary amoebic meningoencephalitis, a neuropathic disease killing 99% of those infected, usually within 7–14 days. N. fowleri is found globally in regions including the US and Australia. The genome of the related non-pathogenic species Naegleria gruberi has been sequenced, but the genetic basis for N. fowleri pathogenicity is unclear. To generate such insight, we sequenced and assembled the mitochondrial genome and a 60-kb segment of nuclear genome from N. fowleri. The mitochondrial genome is highly similar to its counterpart in N. gruberi in gene complement and organization, while distinct lack of synteny is observed for the nuclear segments. Even in this short (60-kb) segment, we identified examples of potential factors for pathogenesis, including ten novel N. fowleri-specific genes. We also identified a homologue of cathepsin B; proteases proposed to be involved in the pathogenesis of diverse eukaryotic pathogens, including N. fowleri. Finally, we demonstrate a likely case of horizontal gene transfer between N. fowleri and two unrelated amoebae, one of which causes granulomatous amoebic encephalitis. This initial look into the N. fowleri nuclear genome has revealed several examples of potential pathogenesis factors, improving our understanding of a neglected pathogen of increasing global importance. PMID:23360210

Dose equivalent near the bone-soft tissue interface from nuclear fragments produced by high-energy protons

NASA Technical Reports Server (NTRS)

Shavers, M. R.; Poston, J. W.; Cucinotta, F. A.; Wilson, J. W.

1996-01-01

During manned space missions, high-energy nucleons of cosmic and solar origin collide with atomic nuclei of the human body and produce a broad linear energy transfer spectrum of secondary particles, called target fragments. These nuclear fragments are often more biologically harmful than the direct ionization of the incident nucleon. That these secondary particles increase tissue absorbed dose in regions adjacent to the bone-soft tissue interface was demonstrated in a previous publication. To assess radiological risks to tissue near the bone-soft tissue interface, a computer transport model for nuclear fragments produced by high energy nucleons was used in this study to calculate integral linear energy transfer spectra and dose equivalents resulting from nuclear collisions of 1-GeV protons transversing bone and red bone marrow. In terms of dose equivalent averaged over trabecular bone marrow, target fragments emitted from interactions in both tissues are predicted to be at least as important as the direct ionization of the primary protons-twice as important, if recently recommended radiation weighting factors and "worst-case" geometry are used. The use of conventional dosimetry (absorbed dose weighted by aa linear energy transfer-dependent quality factor) as an appropriate framework for predicting risk from low fluences of high-linear energy transfer target fragments is discussed.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mehmood, Rashid; Yasuhara, Noriko; Oe, Souichi

The transition from undifferentiated pluripotent cells to terminally differentiated neurons is coordinated by a repertoire of transcription factors. NeuroD1 is a type II basic helix loop helix (bHLH) transcription factor that plays critical roles in neuronal differentiation and maintenance in the central nervous system. Its dimerization with E47, a type I bHLH transcription factor, leads to the transcriptional regulation of target genes. Mounting evidence suggests that regulating the localization of transcription factors contributes to the regulation of their activity during development as defects in their localization underlie a variety of developmental disorders. In this study, we attempted to understand themore » nuclear import mannerisms of NeuroD1 and E47. We found that the nuclear import of NeuroD1 and E47 is energy-dependent and involves the Ran-mediated pathway. Herein, we demonstrate that NeuroD1 and E47 can dimerize inside the cytoplasm before their nuclear import. Moreover, this dimerization promotes nuclear import as the nuclear accumulation of NeuroD1 was enhanced in the presence of E47 in an in vitro nuclear import assay, and NLS-deficient NeuroD1 was successfully imported into the nucleus upon E47 overexpression. NeuroD1 also had a similar effect on the nuclear accumulation of NLS-deficient E47. These findings suggest a novel role for dimerization that may promote, at least partially, the nuclear import of transcription factors allowing them to function efficiently in the nucleus.« less

Effects of age and sedentary lifestyle on skeletal muscle NF-kappaB signaling in men.

PubMed

Buford, Thomas W; Cooke, Matthew B; Manini, Todd M; Leeuwenburgh, Christiaan; Willoughby, Darryn S

2010-05-01

Nuclear factor kappa B (NF-kappaB) is a critical signaling molecule of disuse-induced skeletal muscle atrophy. However, few studies have carefully investigated whether similar pathways are modulated with physical activity and age. The present study examined lean mass, maximal force production, and skeletal muscle NF-kappaB signaling in 41 men categorized as sedentary (OS, N = 13, 63.85 +/- 6.59 year), physically active (OA, N = 14, 60.71 +/- 5.54 year), or young and sedentary (YS, N = 14, 21.35 +/- 3.84 year). Muscle tissue from the vastus lateralis was assayed for messenger RNA (mRNA) expression of the beta subunit of IkB kinase (IKKbeta), cytosolic protein content of phosphorylated inhibitor of kappa B alpha (pIKBalpha), and nuclear content of NF-kappaB subunits p50 and p65. When compared with YS, OS demonstrated age-related muscle atrophy and reduced isokinetic knee extension torque. Physical activity in older individuals preserved maximal isokinetic knee extension torque. OS muscle contained 50% more pIKBalpha than OA and 61% more pIKBalpha than YS. Furthermore, nuclear p65 was significantly elevated in OS compared with YS. OS muscle did not differ from either of the other two groups for nuclear p50 or for mRNA expression of IKKbeta. These results indicate that skeletal muscle content of nuclear-bound p65 is elevated by age in humans. The elevation in nuclear-bound p65 appears to be at least partially due to significant increases in pIKBalpha. A sedentary lifestyle appears to play some role in increased IKBalpha; however, further research is needed to identify downstream effects of this increase.

Effects of Age and Sedentary Lifestyle on Skeletal Muscle NF-κB Signaling in Men

PubMed Central

Buford, Thomas W.; Cooke, Matthew B.; Manini, Todd M.; Leeuwenburgh, Christiaan

2010-01-01

Background. Nuclear factor kappa B (NF-κB) is a critical signaling molecule of disuse-induced skeletal muscle atrophy. However, few studies have carefully investigated whether similar pathways are modulated with physical activity and age. Methods. The present study examined lean mass, maximal force production, and skeletal muscle NF-κB signaling in 41 men categorized as sedentary (OS, N = 13, 63.85 ± 6.59 year), physically active (OA, N = 14, 60.71 ± 5.54 year), or young and sedentary (YS, N = 14, 21.35 ± 3.84 year). Muscle tissue from the vastus lateralis was assayed for messenger RNA (mRNA) expression of the β subunit of IkB kinase (IKKβ), cytosolic protein content of phosphorylated inhibitor of kappa B alpha (pIKBα), and nuclear content of NF-κB subunits p50 and p65. Results. When compared with YS, OS demonstrated age-related muscle atrophy and reduced isokinetic knee extension torque. Physical activity in older individuals preserved maximal isokinetic knee extension torque. OS muscle contained 50% more pIKBα than OA and 61% more pIKBα than YS. Furthermore, nuclear p65 was significantly elevated in OS compared with YS. OS muscle did not differ from either of the other two groups for nuclear p50 or for mRNA expression of IKKβ. Conclusions. These results indicate that skeletal muscle content of nuclear-bound p65 is elevated by age in humans. The elevation in nuclear-bound p65 appears to be at least partially due to significant increases in pIKBα. A sedentary lifestyle appears to play some role in increased IKBα; however, further research is needed to identify downstream effects of this increase. PMID:20045871

Differential expression of upstream stimulatory factor (USF) 2 variants in eutopic endometria from women with endometriosis: estradiol regulation.

PubMed

Castro, Jazmin; Araya, Germán; Inostroza, Pamela; Hidalgo, Paulina; González-Ramos, Reinaldo; Sovino, Hugo; Boric, M Angélica; Fuentes, Ariel; Johnson, M Cecilia

2015-10-09

Endometriosis, pro-inflammatory and invasive benign disease estrogen dependent, abnormally express in endometria the enzyme P450Arom, positively regulated by steroid factor-1 (SF-1). Our objective was to study the nuclear protein contents of upstream stimulating factor 2 (USF2a and USF2b), a positive regulator of SF-1, throughout the menstrual cycle in eutopic endometria from women with and without (control) endometriosis and the involvement of nuclear estrogen receptors (ER) and G-coupled protein estrogen receptor (GPER)-1. Upstream stimulating factor 2 protein contents were higher in mid (USF2b) and late (USF2a and USF2b) secretory phase in eutopic endometria from endometriosis than control (p < 0.05). In isolated control epithelial cells incubated with E2 and PGE2, to resemble the endometriosis condition, the data showed: (a) significant increase of USF2a and USF2b nuclear protein contents when treated with E2, PPT (specific agonist for ERα) or G1 (specific agonist for GPER1); (b) no increase in USF2 binding to SF-1 E-Box/DNA consensus sequence in E2-treated cells; (c) USF2 variants protein contents were not modified by PGE2; (d) SF-1 nuclear protein content was significantly higher than basal when treated with PGE2, E2 or G1, stimulation unaffected by ICI (nuclear ER antagonist); and (e) increased (p < 0.05) cytosolic protein contents of P450Arom when treated with PGE2, E2, PPT or G1 compared to basal, effect that was additive with E2 + PGE2 together. Nevertheless, in endometriosis cells, the high USF2, SF-1 and P450Arom protein contents in basal condition were unmodified. These data strongly suggest that USF2 variants and P450Arom are regulated by E2 through ERα and GPER1, whereas SF-1 through GPER1, visualized by the response of the cells obtained from control endometria, being unaffected the endogenously stimulated cells from endometriosis origin. The lack of E2 stimulation on USF2/SF-1 E-Box/DNA-sequence binding and the absence of PGE2 effect on USF2 variants opposite to the strong induction that they exert on SF1 and P450 proteins suggest different mechanisms and indirect regulations. The sustained USF2 variants protein expression during the secretory phase in eutopic endometria from women with endometriosis may participate in the pathophysiology of this disease strongly associated with infertility and its characteristic endometrial invasion to ectopic sites in the pelvic cavity.

Strategies to regulate transcription factor-mediated gene positioning and interchromosomal clustering at the nuclear periphery.

PubMed

Randise-Hinchliff, Carlo; Coukos, Robert; Sood, Varun; Sumner, Michael Chas; Zdraljevic, Stefan; Meldi Sholl, Lauren; Garvey Brickner, Donna; Ahmed, Sara; Watchmaker, Lauren; Brickner, Jason H

2016-03-14

In budding yeast, targeting of active genes to the nuclear pore complex (NPC) and interchromosomal clustering is mediated by transcription factor (TF) binding sites in the gene promoters. For example, the binding sites for the TFs Put3, Ste12, and Gcn4 are necessary and sufficient to promote positioning at the nuclear periphery and interchromosomal clustering. However, in all three cases, gene positioning and interchromosomal clustering are regulated. Under uninducing conditions, local recruitment of the Rpd3(L) histone deacetylase by transcriptional repressors blocks Put3 DNA binding. This is a general function of yeast repressors: 16 of 21 repressors blocked Put3-mediated subnuclear positioning; 11 of these required Rpd3. In contrast, Ste12-mediated gene positioning is regulated independently of DNA binding by mitogen-activated protein kinase phosphorylation of the Dig2 inhibitor, and Gcn4-dependent targeting is up-regulated by increasing Gcn4 protein levels. These different regulatory strategies provide either qualitative switch-like control or quantitative control of gene positioning over different time scales. © 2016 Randise-Hinchliff et al.

Whole genome siRNA cell-based screen links mitochondria to Akt signaling network through uncoupling of electron transport chain

PubMed Central

Senapedis, William T.; Kennedy, Caleb J.; Boyle, Patrick M.; Silver, Pamela A.

2011-01-01

Forkhead transcription factors (FOXOs) alter a diverse array of cellular processes including the cell cycle, oxidative stress resistance, and aging. Insulin/Akt activation directs phosphorylation and cytoplasmic sequestration of FOXO away from its target genes and serves as an endpoint of a complex signaling network. Using a human genome small interfering RNA (siRNA) library in a cell-based assay, we identified an extensive network of proteins involved in nuclear export, focal adhesion, and mitochondrial respiration not previously implicated in FOXO localization. Furthermore, a detailed examination of mitochondrial factors revealed that loss of uncoupling protein 5 (UCP5) modifies the energy balance and increases free radicals through up-regulation of uncoupling protein 3 (UCP3). The increased superoxide content induces c-Jun N-terminal kinase 1 (JNK1) kinase activity, which in turn affects FOXO localization through a compensatory dephosphorylation of Akt. The resulting nuclear FOXO increases expression of target genes, including mitochondrial superoxide dismutase. By connecting free radical defense and mitochondrial uncoupling to Akt/FOXO signaling, these results have implications in obesity and type 2 diabetes development and the potential for therapeutic intervention. PMID:21460183

Whole genome siRNA cell-based screen links mitochondria to Akt signaling network through uncoupling of electron transport chain.

PubMed

Senapedis, William T; Kennedy, Caleb J; Boyle, Patrick M; Silver, Pamela A

2011-05-15

Forkhead transcription factors (FOXOs) alter a diverse array of cellular processes including the cell cycle, oxidative stress resistance, and aging. Insulin/Akt activation directs phosphorylation and cytoplasmic sequestration of FOXO away from its target genes and serves as an endpoint of a complex signaling network. Using a human genome small interfering RNA (siRNA) library in a cell-based assay, we identified an extensive network of proteins involved in nuclear export, focal adhesion, and mitochondrial respiration not previously implicated in FOXO localization. Furthermore, a detailed examination of mitochondrial factors revealed that loss of uncoupling protein 5 (UCP5) modifies the energy balance and increases free radicals through up-regulation of uncoupling protein 3 (UCP3). The increased superoxide content induces c-Jun N-terminal kinase 1 (JNK1) kinase activity, which in turn affects FOXO localization through a compensatory dephosphorylation of Akt. The resulting nuclear FOXO increases expression of target genes, including mitochondrial superoxide dismutase. By connecting free radical defense and mitochondrial uncoupling to Akt/FOXO signaling, these results have implications in obesity and type 2 diabetes development and the potential for therapeutic intervention.

Protective effect of nuclear factor E2-related factor 2 on inflammatory cytokine response to brominated diphenyl ether-47 in the HTR-8/SVneo human first trimester extravillous trophoblast cell line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, Hae-Ryung, E-mail: heaven@umich.edu; Loch-Caruso, Rita

Polybrominated diphenyl ethers (PBDEs) are widely used flame retardants, and BDE-47 is a prevalent PBDE congener detected in human tissues. Exposure to PBDEs has been linked to adverse pregnancy outcomes in humans. Although the underlying mechanisms of adverse birth outcomes are poorly understood, critical roles for oxidative stress and inflammation are implicated. The present study investigated antioxidant responses in a human extravillous trophoblast cell line, HTR-8/SVneo, and examined the role of nuclear factor E2-related factor 2 (Nrf2), an antioxidative transcription factor, in BDE-47-induced inflammatory responses in the cells. Treatment of HTR-8/SVneo cells with 5, 10, 15, and 20 μM BDE-47more » for 24 h increased intracellular glutathione (GSH) levels compared to solvent control. Treatment of HTR-8/SVneo cells with 20 μM BDE-47 for 24 h induced the antioxidant response element (ARE) activity, indicating Nrf2 transactivation by BDE-47 treatment, and resulted in differential expression of redox-sensitive genes compared to solvent control. Pretreatment with tert-butyl hydroquinone (tBHQ) or sulforaphane, known Nrf2 inducers, reduced BDE-47-stimulated IL-6 release with increased ARE reporter activity, reduced nuclear factor kappa B (NF-κB) reporter activity, increased GSH production, and stimulated expression of antioxidant genes compared to non-Nrf2 inducer pretreated groups, suggesting that Nrf2 may play a protective role against BDE-47-mediated inflammatory responses in HTR-8/SVneo cells. These results suggest that Nrf2 activation significantly attenuated BDE-47-induced IL-6 release by augmentation of cellular antioxidative system via upregulation of Nrf2 signaling pathways, and that Nrf2 induction may be a potential therapeutic target to reduce adverse pregnancy outcomes associated with toxicant-induced oxidative stress and inflammation. - Highlights: • BDE-47 stimulated ARE reporter activity and GSH production. • BDE-47 resulted in differential expression of redox-sensitive genes. • Nrf2 inducers upregulated Nrf2-mediated oxidative stress responses. • Nrf2 inducers reduced BDE-47-stimulated IL-6 release and NF-κB activity.« less

Role of platelet-released growth factors in detoxification of reactive oxygen species in osteoblasts.

PubMed

Tohidnezhad, Mersedeh; Wruck, Christoph-Jan; Slowik, Alexander; Kweider, Nisreen; Beckmann, Rainer; Bayer, Andreas; Houben, Astrid; Brandenburg, Lars-Ove; Varoga, Deike; Sönmez, Tolga-Taha; Stoffel, Marcus; Jahr, Holger; Lippross, Sebastian; Pufe, Thomas

2014-08-01

Oxidative stress can impair fracture healing. To protect against oxidative damage, a system of detoxifying and antioxidative enzymes works to reduce the cellular stress. The transcription of these enzymes is regulated by antioxidant response element (ARE). The nuclear factor (erythroid-derived 2)-like2 (Nrf2) plays a major role in transcriptional activation of ARE-driven genes. Recently it has been shown that vascular endothelial growth factor (VEGF) prevents oxidative damage via activation of the Nrf2 pathway in vitro. Platelet-released growth factor (PRGF) is a mixture of autologous proteins and growth factors, prepared from a determined volume of platelet-rich plasma (PRP). It has already used to enhance fracture healing in vitro. The aim of the present study was to elucidate if platelets can lead to upregulation of VEGF and if platelets can regulate the activity of Nrf2-ARE system in primary human osteoblast (hOB) and in osteoblast-like cell line (SAOS-2). Platelets and PRGF were obtained from healthy human donors. HOB and SAOS-2 osteosarcoma cell line were used. The ARE activity was analysed using a dual luciferase reporter assay system. We used Western blot to detect the nuclear accumulation of Nrf2 and the amount of cytosolic antioxidant Thioredoxin Reductase-1 (TXNRD-1), Heme Oxygenase-1 (HO-1) and NAD(P)H quinine oxidoreductase-1 (NQO1). Gene expression analysis was performed by real-time RT PCR. ELISA was used for the quantification of growth factors. The activity of ARE was increased in the presence of PRGF up to 50%. Western blotting demonstrated enhanced nuclear accumulation of Nrf2. This was followed by an increase in the protein expression of the aforementioned downstream targets of Nrf2. Real-time RT PCR data showed an upregulation in the gene expression of the VEGF after PRGF treatment. This was confirmed by ELISA, where the treatment with PRGF induced the protein level of VEGF in both cells. These results provide a new insight into PRGF's mode of action in osteoblasts. PRGF not only leads to increase the endogenous VEGF, but also it may be involved in preventing oxidative damage through the Nrf2-ARE signalling. Nrf2 activation via PRGF may have great potential as an effective therapeutic drug target in fracture healing. Copyright © 2014 Elsevier Inc. All rights reserved.

Disruption of Hypoxia-Inducible Transcription Factor-Prolyl Hydroxylase Domain-1 (PHD-1−/−) Attenuates Ex Vivo Myocardial Ischemia/Reperfusion Injury Through Hypoxia-Inducible Factor-1α Transcription Factor and Its Target Genes in Mice

PubMed Central

Adluri, Ram Sudheer; Thirunavukkarasu, Mahesh; Dunna, Nageswara Rao; Zhan, Lijun; Oriowo, Babatunde; Takeda, Kotaro; Sanchez, Juan A.; Otani, Hajime; Maulik, Gautam; Fong, Guo-Hua

2011-01-01

Abstract Hypoxia-inducible transcription factor (HIF)-prolyl hydroxylases domain (PHD-1–3) are oxygen sensors that regulate the stability of the HIFs in an oxygen-dependent manner. Suppression of PHD enzymes leads to stabilization of HIFs and offers a potential treatment option for many ischemic disorders, such as peripheral artery occlusive disease, myocardial infarction, and stroke. Here, we show that homozygous disruption of PHD-1 (PHD-1−/−) could facilitate HIF-1α-mediated cardioprotection in ischemia/reperfused (I/R) myocardium. Wild-type (WT) and PHD-1−/− mice were randomized into WT time-matched control (TMC), PHD-1−/− TMC (PHD1TMC), WT I/R, and PHD-1−/− I/R (PHD1IR). Isolated hearts from each group were subjected to 30 min of global ischemia followed by 2 h of reperfusion. TMC hearts were perfused for 2 h 30 min without ischemia. Decreased infarct size (35% ± 0.6% vs. 49% ± 0.4%) and apoptotic cardiomyocytes (106 ± 13 vs. 233 ± 21 counts/100 high-power field) were observed in PHD1IR compared to wild-type ischemia/reperfusion (WTIR). Protein expression of HIF-1α was significantly increased in PHD1IR compared to WTIR. mRNA expression of β-catenin (1.9-fold), endothelial nitric oxide synthase (1.9-fold), p65 (1.9-fold), and Bcl-2 (2.7-fold) were upregulated in the PHD1IR compared with WTIR, which was studied by real-time quantitative polymerase chain reaction. Further, gel-shift analysis showed increased DNA binding activity of HIF-1α and nuclear factor-kappaB in PHD1IR compared to WTIR. In addition, nuclear translocation of β-catenin was increased in PHD1IR compared with WTIR. These findings indicated that silencing of PHD-1 attenuates myocardial I/R injury probably by enhancing HIF-1α/β-catenin/endothelial nitric oxide synthase/nuclear factor-kappaB and Bcl-2 signaling pathway. Antioxid. Redox Signal. 15, 1789–1797. PMID:21083501

Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals

PubMed Central

Nakamura, Shuhei; Karalay, Özlem; Jäger, Philipp S.; Horikawa, Makoto; Klein, Corinna; Nakamura, Kayo; Latza, Christian; Templer, Sven E.; Dieterich, Christoph; Antebi, Adam

2016-01-01

Germline removal provokes longevity in several species and shifts resources towards survival and repair. Several Caenorhabditis elegans transcription factors regulate longevity arising from germline removal; yet, how they work together is unknown. Here we identify a Myc-like HLH transcription factor network comprised of Mondo/Max-like complex (MML-1/MXL-2) to be required for longevity induced by germline removal, as well as by reduced TOR, insulin/IGF signalling and mitochondrial function. Germline removal increases MML-1 nuclear accumulation and activity. Surprisingly, MML-1 regulates nuclear localization and activity of HLH-30/TFEB, a convergent regulator of autophagy, lysosome biogenesis and longevity, by downregulating TOR signalling via LARS-1/leucyl-transfer RNA synthase. HLH-30 also upregulates MML-1 upon germline removal. Mammalian MondoA/B and TFEB show similar mutual regulation. MML-1/MXL-2 and HLH-30 transcriptomes show both shared and preferential outputs including MDL-1/MAD-like HLH factor required for longevity. These studies reveal how an extensive interdependent HLH transcription factor network distributes responsibility and mutually enforces states geared towards reproduction or survival. PMID:27001890

Possible involvement of nuclear factor erythroid 2-related factor 2 in the gene expression of Cyp2b10 and Cyp2a5.

PubMed

Ashino, Takashi; Ohkubo-Morita, Haruyo; Yamamoto, Masayuki; Yoshida, Takemi; Numazawa, Satoshi

2014-01-01

Cytochrome P450 gene expression is altered by various chemical compounds. In this study, we used nuclear factor erythroid 2-related factor 2 (Nrf2)-deficient (Nrf2(-⧸-)) mice to investigate the involvement of Nrf2 in Cyp2b10 and Cyp2a5 gene expression. Phorone, an Nrf2 activator, strongly increased Cyp2b10 and Cyp2a5 mRNA as well as Nrf2 target genes, including NAD(P)H-quinone oxidoreductase-1 and heme oxygenase-1, in wild-type mouse livers 8 h after treatment. The phorone-induced mRNA levels in Nrf2(-⧸-) mouse livers were lower than that in wild-type mouse livers. Nrf2(-⧸-) mice showed attenuated Cyp2b10 and Cyp2a5 induction by phenobarbital, a classical Cyp2b inducer. These findings suggest that the Nrf2 pathway is involved in Cyp2b10 and Cyp2a5 gene expression.

Possible involvement of nuclear factor erythroid 2-related factor 2 in the gene expression of Cyp2b10 and Cyp2a5☆

PubMed Central

Ashino, Takashi; Ohkubo-Morita, Haruyo; Yamamoto, Masayuki; Yoshida, Takemi; Numazawa, Satoshi

2014-01-01

Cytochrome P450 gene expression is altered by various chemical compounds. In this study, we used nuclear factor erythroid 2-related factor 2 (Nrf2)–deficient (Nrf2−⧸−) mice to investigate the involvement of Nrf2 in Cyp2b10 and Cyp2a5 gene expression. Phorone, an Nrf2 activator, strongly increased Cyp2b10 and Cyp2a5 mRNA as well as Nrf2 target genes, including NAD(P)H-quinone oxidoreductase-1 and heme oxygenase-1, in wild-type mouse livers 8 h after treatment. The phorone-induced mRNA levels in Nrf2−⧸− mouse livers were lower than that in wild-type mouse livers. Nrf2−⧸− mice showed attenuated Cyp2b10 and Cyp2a5 induction by phenobarbital, a classical Cyp2b inducer. These findings suggest that the Nrf2 pathway is involved in Cyp2b10 and Cyp2a5 gene expression. PMID:24494203

Influence of collective nonideal shielding on fusion reaction in partially ionized classical nonideal plasmas

NASA Astrophysics Data System (ADS)

Lee, Myoung-Jae; Jung, Young-Dae

2017-04-01

The collective nonideal effects on the nuclear fusion reaction process are investigated in partially ionized classical nonideal hydrogen plasmas. The effective pseudopotential model taking into account the collective and plasma shielding effects is applied to describe the interaction potential in nonideal plasmas. The analytic expressions of the Sommerfeld parameter, the fusion penetration factor, and the cross section for the nuclear fusion reaction in nonideal plasmas are obtained as functions of the nonideality parameter, Debye length, and relative kinetic energy. It is found that the Sommerfeld parameter is suppressed due to the influence of collective nonideal shielding. However, the collective nonideal shielding is found to enhance the fusion penetration factor in partially ionized classical nonideal plasmas. It is also found that the fusion penetration factors in nonideal plasmas represented by the pseudopotential model are always greater than those in ideal plasmas represented by the Debye-Hückel model. In addition, it is shown that the collective nonideal shielding effect on the fusion penetration factor decreases with an increase of the kinetic energy.

[The effect of the intratracheal administration of americium-241 on rat alveolar macrophages].

PubMed

Shopova, V; Sŭlovski, P; Dancheva, V

1996-01-01

In experiments in rats it was found that 241Am transitory decreases the total cell number and alveolar macrophage's percentage in bronchoalveolar lavage fluid (BALF): increases the macrophages size and nuclear size; and increases acid phosphatase and lactate dehydrogenase activities in BALF. It was suggested that 241Am causes and activation in the alveolar macrophages which probably appears as one of factors provoking lung injuries.

Applications of neutron radiography for the nuclear power industry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Craft, Aaron E.; Barton, John P.

The World Conference on Neutron Radiography (WCNR) and International Topical Meeting on Neutron Radiography (ITMNR) series have been running over 35 years. The most recent event, ITMNR-8, focused on industrial applications and was the first time this series was hosted in China. In China, more than twenty new nuclear power plants are in construction and plans have been announced to increase the nuclear capacity further by a factor of three within fifteen years. There are additional prospects in many other nations. Neutron tests were vital during previous developments of materials and components for nuclear power applications, as reported in thismore » conference series. For example a majority of the 140 papers in the Proceedings of the First WCNR are for the benefit of the nuclear power industry. Included are reviews of the diverse techniques being applied in Europe, Japan, the United States, and at many other centers. Many of those techniques are being utilized and advanced to the present time. Neutron radiography of irradiated nuclear fuel provides more comprehensive information about the internal condition of irradiated nuclear fuel than any other non-destructive technique to date. Applications include examination of nuclear waste, nuclear fuels, cladding, control elements, and other critical components. In this paper, the techniques developed and applied internationally for the nuclear power industry since the earliest years are reviewed, and the question is asked whether neutron test techniques can be of value in development of the present and future generations of nuclear power plants world-wide.« less

Retention of prolyl hydroxylase PHD2 in the cytoplasm prevents PHD2-induced anchorage-independent carcinoma cell growth

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jokilehto, Terhi; Turku Graduate School of Biomedical Sciences, Turku; Hoegel, Heidi

2010-04-15

Cellular oxygen tension is sensed by a family of prolyl hydroxylases (PHD1-3) that regulate the degradation of hypoxia-inducible factors (HIF-1{alpha} and -2{alpha}). The PHD2 isoform is considered as the main downregulator of HIF in normoxia. Our previous results have shown that nuclear translocation of PHD2 associates with poorly differentiated tumor phenotype implying that nuclear PHD2 expression is advantageous for tumor growth. Here we show that a pool of PHD2 is shuttled between the nucleus and the cytoplasm. In line with this, accumulation of wild type PHD2 in the nucleus was detected in human colon adenocarcinomas and in cultured carcinoma cells.more » The PHD2 isoforms showing high nuclear expression increased anchorage-independent carcinoma cell growth. However, retention of PHD2 in the cytoplasm inhibited the anchorage-independent cell growth. A region that inhibits the nuclear localization of PHD2 was identified and the deletion of the region promoted anchorage-independent growth of carcinoma cells. Finally, the cytoplasmic PHD2, as compared with the nuclear PHD2, less efficiently downregulated HIF expression. Forced HIF-1{alpha} or -2{alpha} expression decreased and attenuation of HIF expression increased the anchorage-independent cell growth. However, hydroxylase-inactivating mutations in PHD2 had no effect on cell growth. The data imply that nuclear PHD2 localization promotes malignant cancer phenotype.« less

Chromium picolinate and chromium histidinate protects against renal dysfunction by modulation of NF-κB pathway in high-fat diet fed and Streptozotocin-induced diabetic rats.

PubMed

Selcuk, Mustafa Yavuz; Aygen, Bilge; Dogukan, Ayhan; Tuzcu, Zeynep; Akdemir, Fatih; Komorowski, James R; Atalay, Mustafa; Sahin, Kazim

2012-04-08

Diabetic nephropathy is one of major complications of diabetes mellitus. Although chromium is an essential element for carbohydrate and lipid metabolism, its effects on diabetic nephropathy are not well understood. The present study was conducted to investigate the effects of chromium picolinate (CrPic) and chromium histidinate (CrHis) on nuclear factor-kappa B (NF-κB) and nuclear factor-E2-related factor-2 (Nrf2) pathway in the rat kidney. Male Wistar rats were divided into six groups. Group I received a standard diet (8% fat) and served as a control; Group II was fed with a standard diet and received CrPic; Group III was fed with a standard diet and received CrHis; Group IV received a high fat diet (HFD, 40% fat) for 2 weeks and then were injected with streptozotocin (STZ) (HFD/STZ); Group V was treated as group IV (HFD/STZ) but supplemented with CrPic for 12 weeks. Group VI was treated as group IV (HFD/STZ) but supplemented with CrHis. The increased NF-κβ p65 in the HFD/STZ group was inhibited by CrPic and CrHis supplementation (P < 0.05). In STZ-treated rats, a significant decrease in levels of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) was found in kidney tissues when compared to control rats (P < 0.05). A significant increase in the levels of IκBα was observed in CrPic- and CrHis-treated rats when compared with STZ-treated rats. Renal Nrf2 levels were significantly decreased in diabetic rats compared with the control rats. There was a higher tendency for increase of kidney Nrf2 level and decrease in kidney NFκBp65 levels and 4- hydroxyl nonenal (4-HNE) protein adducts (P < 0.05) in diabetic rats. Our result show that in kidney tissue CrHis/CrPic increases Nrf2 level, parallelly decreases NF-κB and partially restores IκBα levels in HFD/STZ group, suggesting that CrPic and CrHis may play a role in antioxidant defense system via the Nrf2 pathway by reducing inflammation through NF-κβ p65 inhibition. Moreover, a greater reduction in NF-κB expression and greater increases in expressions of IκBα and Nrf2 in diabetic rats supplemented with CrHis than rats supplemented with CrPic suggest that CrHis has more favorable effects than CrPic.

β-DECAY Studies at Triumf and Future Opportunities with Griffin

NASA Astrophysics Data System (ADS)

Garnsworthy, A. B.; Ball, G. C.; Bender, P. C.; Churchman, R.; Close, A.; Glister, J.; Hackman, G.; Ketelhut, S.; Krücken, R.; Sjue, S. K. L.; Tardiff, E.; Garrett, P. E.; Demand, G. A.; Dunlop, R.; Finlay, P.; Hadinia, B.; Leach, K.; Michetti-Wilson, J.; Rand, E. T.; Svensson, C. E.; Andreoiu, C.; Ashley, R.; Chester, A.; Cross, D.; Starosta, K.; Wang, Z.; Zganjar, E. F.

2013-03-01

The 8π spectrometer at TRIUMF-ISAC-I and a powerful suite of ancillary detectors support a wide program of research in the fields of nuclear structure, nuclear astrophysics and fundamental symmetries with low-energy radioactive beams.Work is underway to upgrade the Ge detectors and DAQ aspects of the facility to a new state-of-the-art γ-ray spectrometer, GRIFFIN, which will become operational in 2014. GRIFFIN will constitute an increase in the γ-γ efficiency of close to a factor of 300 over the current setup and extend the capabilities for investigations of exotic nuclei produced at ISAC.

Adiponectin stimulates IL-8 production by rheumatoid synovial fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kitahara, Kanako; Department of Immunology, Toho University School of Medicine, Tokyo; Kusunoki, Natsuko

The adipokines are linked not only to metabolic regulation, but also to immune responses. Adiponectin, but not leptin or resistin induced interleukin-8 production from rheumatoid synovial fibroblasts (RSF). The culture supernatant of RSF treated with adiponectin induced chemotaxis, although adiponectin itself had no such effect. Addition of antibody against adiponectin, and inhibition of adiponectin receptor gene decreased adiponectin-induced IL-8 production. Nuclear translocation of nuclear factor-kappa B was increased by adiponectin. The induction of interleukin-8 was inhibited by mitogen-activated protein kinase inhibitors. These findings suggest that adiponectin contributes to the pathogenesis of rheumatoid arthritis.

Algorithmic cooling in liquid-state nuclear magnetic resonance

NASA Astrophysics Data System (ADS)

Atia, Yosi; Elias, Yuval; Mor, Tal; Weinstein, Yossi

2016-01-01

Algorithmic cooling is a method that employs thermalization to increase qubit purification level; namely, it reduces the qubit system's entropy. We utilized gradient ascent pulse engineering, an optimal control algorithm, to implement algorithmic cooling in liquid-state nuclear magnetic resonance. Various cooling algorithms were applied onto the three qubits of C132-trichloroethylene, cooling the system beyond Shannon's entropy bound in several different ways. In particular, in one experiment a carbon qubit was cooled by a factor of 4.61. This work is a step towards potentially integrating tools of NMR quantum computing into in vivo magnetic-resonance spectroscopy.

The RNA Exosome Adaptor ZFC3H1 Functionally Competes with Nuclear Export Activity to Retain Target Transcripts.

PubMed

Silla, Toomas; Karadoulama, Evdoxia; Mąkosa, Dawid; Lubas, Michal; Jensen, Torben Heick

2018-05-15

Mammalian genomes are promiscuously transcribed, yielding protein-coding and non-coding products. Many transcripts are short lived due to their nuclear degradation by the ribonucleolytic RNA exosome. Here, we show that abolished nuclear exosome function causes the formation of distinct nuclear foci, containing polyadenylated (pA + ) RNA secluded from nucleocytoplasmic export. We asked whether exosome co-factors could serve such nuclear retention. Co-localization studies revealed the enrichment of pA + RNA foci with "pA-tail exosome targeting (PAXT) connection" components MTR4, ZFC3H1, and PABPN1 but no overlap with known nuclear structures such as Cajal bodies, speckles, paraspeckles, or nucleoli. Interestingly, ZFC3H1 is required for foci formation, and in its absence, selected pA + RNAs, including coding and non-coding transcripts, are exported to the cytoplasm in a process dependent on the mRNA export factor AlyREF. Our results establish ZFC3H1 as a central nuclear pA + RNA retention factor, counteracting nuclear export activity. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Role of bardoxolone methyl, a nuclear factor erythroid 2-related factor 2 activator, in aldosterone- and salt-induced renal injury.

PubMed

Hisamichi, Mikako; Kamijo-Ikemori, Atsuko; Sugaya, Takeshi; Hoshino, Seiko; Kimura, Kenjiro; Shibagaki, Yugo

2018-01-01

The aim of this study was to investigate the renoprotective effect of bardoxolone methyl (BM), a nuclear factor erythroid 2-related factor 2 (Nrf2) activator with an antioxidant effect, in a salt-sensitive hypertension model induced by aldosterone (Ald) and salt. Tubulointerstitial damage with urinary liver-type fatty acid-binding protein (L-FABP) was evaluated using human L-FABP chromosomal transgenic (L-FABP +/- ) male mice. The mice in the Ald group (n=7) received systemic Ald infusions via an osmotic minipump and were given 1% NaCl water for 35 days. Those in the Ald-BM group (n=8) were administered BM intraperitoneally in addition to an injection of Ald and salt. The dose of BM was gradually increased every 7 days up to 10 mg kg -1 per day, which was maintained for 14 days. The administration of BM significantly increased renal expression of the Nrf2 target antioxidant gene. Tubulointerstitial damage was significantly ameliorated in the Ald-BM group compared to the Ald group. The increase in reactive oxygen species (ROS) and upregulation of angiotensinogen expression in the kidneys of the Ald group was significantly prevented in the Ald-BM group. The upregulation of human L-FABP expression induced in the kidneys and increase in urinary L-FABP in the Ald group were significantly suppressed by BM administration. In conclusion, BM ameliorated tubulointerstitial damage in the Ald- and salt-induced hypertension model through suppression of both ROS production and intrarenal renin-angiotensin system activation. Urinary L-FABP may be a useful marker reflecting the therapeutic efficacy of BM.

Advanced ceramic materials for next-generation nuclear applications

NASA Astrophysics Data System (ADS)

Marra, John

2011-10-01

The nuclear industry is at the eye of a 'perfect storm' with fuel oil and natural gas prices near record highs, worldwide energy demands increasing at an alarming rate, and increased concerns about greenhouse gas (GHG) emissions that have caused many to look negatively at long-term use of fossil fuels. This convergence of factors has led to a growing interest in revitalization of the nuclear power industry within the United States and across the globe. Many are surprised to learn that nuclear power provides approximately 20% of the electrical power in the US and approximately 16% of the world-wide electric power. With the above factors in mind, world-wide over 130 new reactor projects are being considered with approximately 25 new permit applications in the US. Materials have long played a very important role in the nuclear industry with applications throughout the entire fuel cycle; from fuel fabrication to waste stabilization. As the international community begins to look at advanced reactor systems and fuel cycles that minimize waste and increase proliferation resistance, materials will play an even larger role. Many of the advanced reactor concepts being evaluated operate at high-temperature requiring the use of durable, heat-resistant materials. Advanced metallic and ceramic fuels are being investigated for a variety of Generation IV reactor concepts. These include the traditional TRISO-coated particles, advanced alloy fuels for 'deep-burn' applications, as well as advanced inert-matrix fuels. In order to minimize wastes and legacy materials, a number of fuel reprocessing operations are being investigated. Advanced materials continue to provide a vital contribution in 'closing the fuel cycle' by stabilization of associated low-level and high-level wastes in highly durable cements, ceramics, and glasses. Beyond this fission energy application, fusion energy will demand advanced materials capable of withstanding the extreme environments of high-temperature plasma systems. Fusion reactors will likely depend on lithium-based ceramics to produce tritium that fuels the fusion plasma, while high-temperature alloys or ceramics will contain and control the hot plasma. All the while, alloys, ceramics, and ceramic-related processes continue to find applications in the management of wastes and byproducts produced by these processes.

Bergamottin Promotes Adipocyte Differentiation and Inhibits Tumor Necrosis Factor-α-induced Inflammatory Cytokines Induction in 3T3-L1 Cells.

PubMed

Mizuno, Hideya; Hatano, Tomoko; Taketomi, Ayako; Kawabata, Mami; Nakabayashi, Toshikatsu

2017-01-01

Nowadays, a lot of food ingredients are marketed as dietary supplements for health. Because the effectiveness and mechanisms of these compounds have not been fully characterized, they might have unknown functions. Therefore, we investigated the effect of several food ingredients (Bergamottin, Chrysin, L-Citrulline and β-Carotene) known as health foods on adipocyte differentiation by using 3T3-L1 preadipocytes. In this study, we found that Bergamottin, a furanocoumarin isolated from grapefruit juice, promotes adipocyte differentiation. In addition, Bergamottin increases the expression of adiponectin, an anti-inflammatory adipokine, and peroxisome proliferator activated receptor γ (PPARγ), a nuclear receptor regulating adipocyte differentiation. Furthermore, the anti-inflammatory activity of Bergamottin was demonstrated by its inhibition of the activation of nuclear factor-κB (NF-κB), an inflammatory transcription factor. Stimulation of mature 3T3-L1 adipocytes by tumor necrosis factor-α (TNF-α) decreased the expression of the endogeneous NF-κB inhibitor, IκBα. Treatment with Bergamottin further decreased the TNF-α-induced change in IκBα expression, suggesting that Bergamottin mediated the inhibition of NF-κB activation. In addition, Bergamottin decreased the TNF-α-induced increase in the mRNA levels of pro-inflammatory adipokines, monocyte chemoattractant protein-1 and interleukin-6. Taken together, our results show that Bergamottin treatment could inhibit inflammatory activity through promoting adipocyte differentiation, which in turn suggests that Bergamottin has the potential to minimize the risk factors of metabolic syndrome.

WTEC monograph on instrumentation, control and safety systems of Canadian nuclear facilities

NASA Technical Reports Server (NTRS)

Uhrig, Robert E.; Carter, Richard J.

1993-01-01

This report updates a 1989-90 survey of advanced instrumentation and controls (I&C) technologies and associated human factors issues in the U.S. and Canadian nuclear industries carried out by a team from Oak Ridge National Laboratory (Carter and Uhrig 1990). The authors found that the most advanced I&C systems are in the Canadian CANDU plants, where the newest plant (Darlington) has digital systems in almost 100 percent of its control systems and in over 70 percent of its plant protection system. Increased emphasis on human factors and cognitive science in modern control rooms has resulted in a reduced workload for the operators and the elimination of many human errors. Automation implemented through digital instrumentation and control is effectively changing the role of the operator to that of a systems manager. The hypothesis that properly introducing digital systems increases safety is supported by the Canadian experience. The performance of these digital systems has been achieved using appropriate quality assurance programs for both hardware and software development. Recent regulatory authority review of the development of safety-critical software has resulted in the creation of isolated software modules with well defined interfaces and more formal structure in the software generation. The ability of digital systems to detect impending failures and initiate a fail-safe action is a significant safety issue that should be of special interest to nuclear utilities and regulatory authorities around the world.

HTLV-1 Tax upregulates early growth response protein 1 through nuclear factor-κB signaling.

PubMed

Huang, Qingsong; Niu, Zhiguo; Han, Jingxian; Liu, Xihong; Lv, Zhuangwei; Li, Huanhuan; Yuan, Lixiang; Li, Xiangping; Sun, Shuming; Wang, Hui; Huang, Xinxiang

2017-08-01

Human T cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that causes adult T cell leukemia (ATL) in susceptible individuals. The HTLV-1-encoded oncoprotein Tax induces persistent activation of the nuclear factor-κB (NF-κB) pathway. Early growth response protein 1 (EGR1) is overexpressed in HTLV-1-infected T cell lines and ATL cells. Here, we showed that both Tax expression and HTLV-1 infection promoted EGR1 overexpression. Loss of the NF-κB binding site in the EGR1 promotor or inhibition of NF-κB activation reduced Tax-induced EGR1 upregulation. Tax mutants unable to activate NF-κB induced only slight EGR1 upregulation as compared with wild-type Tax, confirming NF-κB pathway involvement in EGR1 regulation. Tax also directly interacted with the EGR1 protein and increased endogenous EGR1 stability. Elevated EGR1 in turn promoted p65 nuclear translocation and increased NF-κB activation. These results demonstrate a positive feedback loop between EGR1 expression and NF-κB activation in HTLV-1-infected and Tax-expressing cells. Both NF-κB activation and Tax-induced EGR1 stability upregulated EGR1, which in turn enhanced constitutive NF-κB activation and facilitated ATL progression in HTLV-1-infected cells. These findings suggest EGR1 may be an effective anti-ATL therapeutic target.

Nuclear energy and radioactive waste disposal in the age of recycling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Conca, James L.; Apted, Michael

2007-07-01

The magnitude of humanity's energy needs requires that we embrace a multitude of various energy sources and applications. For a variety of reasons, nuclear energy must be a major portion of the distribution, at least one third. The often-cited strategic hurdle to this approach is nuclear waste disposal. Present strategies concerning disposal of nuclear waste need to be changed if the world is to achieve both a sustainable energy distribution by 2040 and solve the largest environmental issue of the 21. century - global warming. It is hoped that ambitious proposals to replace fossil fuel power generation by alternatives willmore » drop the percentage of fossil fuel use substantially, but the absolute amount of fossil fuel produced electricity must be kept at or below its present 10 trillion kW-hrs/year. Unfortunately, the rapid growth in consumption to over 30 trillion kW-hrs/year by 2040, means that 20 trillion kW-hrs/yr of non-fossil fuel generated power has to come from other sources. If half of that comes from alternative non-nuclear, non-hydroelectric sources (an increase of 3000%), then nuclear still needs to increase by a factor of four worldwide to compensate. Many of the reasons nuclear energy did not expand after 1970 in North America (proliferation, capital costs, operational risks, waste disposal, and public fear) are no longer a problem. The WIPP site in New Mexico, an example of a solution to the nuclear waste disposal issue, and also to public fear, is an operating deep geologic nuclear waste repository in the massive bedded salt of the Salado Formation. WIPP has been operating for eight years, and as of this writing, has disposed of over 50,000 m{sup 3} of transuranic waste (>100 nCi/g but <23 Curie/liter) including high activity waste. The Salado Formation is an ideal host for any type of nuclear waste, especially waste from recycled spent fuel. (authors)« less

Lycopene activates antioxidant enzymes and nuclear transcription factor systems in heat-stressed broilers.

PubMed

Sahin, K; Orhan, C; Tuzcu, M; Sahin, N; Hayirli, A; Bilgili, S; Kucuk, O

2016-05-01

This study was conducted to evaluate the effects of dietary lycopene supplementation on growth performance, antioxidant status, and muscle nuclear transcription factor [Kelch like-ECH-associated protein 1 (Keap1) and (erythroid-derived 2)-like 2 (Nrf2)] expressions in broiler chickens exposed to heat stress (HS). A total of 180 one-day-old male broiler chicks (Ross 308) were assigned randomly to one of 2×3 factorially arranged treatments: two housing temperatures (22°C for 24 h/d; thermoneutral, TN or 34°C for 8 h/d HS) and three dietary lycopene levels (0, 200, or 400 mg/kg). Each treatment consisted of three replicates of 10 birds. Birds were reared to 42 d of age. Heat stress caused reductions in feed intake and weight gain by 12.2 and 20.7% and increased feed efficiency by 10.8% (P<0.0001 for all). Increasing dietary lycopene level improved performance in both environments. Birds reared under the HS environment had lower serum and muscle lycopene concentration (0.34 vs. 0.50 μg/mL and 2.80 vs. 2.13 μg/g), activities of superoxide dismutase (151 vs. 126 U/mL and 131 vs. 155 U/mg protein), glutathione peroxidase (184 vs. 154 U/mL and 1.39 vs. 1.74 U/mg protein), and higher malondialdehyde (MDA) concentration (0.53 vs. 0.83 μg/mL and 0.78 vs. 0.45 μg/ mg protein) than birds reared under the TN environment. Changes in levels of lycopene and MDA and activities of enzymes in serum and muscle varied by the environmental temperature as dietary lycopene level increased. Moreover, increasing dietary lycopene level suppressed muscle Keap1 expression and enhanced muscle Nrf2 expression, which had increased by 150% and decreased by 40%, respectively in response to HS. In conclusion, lycopene supplementation alleviates adverse effects of HS on performance through modulating expressions of stress-related nuclear transcription factors. © 2016 Poultry Science Association Inc.

Effect of The Receptor Activator of Nuclear Factor кB and RANK Ligand on In Vitro Differentiation of Cord Blood CD133(+) Hematopoietic Stem Cells to Osteoclasts.

PubMed

Kalantari, Nasim; Abroun, Saeid; Soleimani, Masoud; Kaviani, Saeid; Azad, Mehdi; Eskandari, Fatemeh; Habibi, Hossein

2016-01-01

Receptor activator of nuclear factor-kappa B ligand (RANKL) appears to be an osteoclast-activating factor, bearing an important role in the pathogenesis of multiple myeloma. Some studies demonstrated that U-266 myeloma cell line and primary myeloma cells expressed RANK and RANKL. It had been reported that the expression of myeloid and monocytoid markers was increased by co-culturing myeloma cells with hematopoietic stem cells (HSCs). This study also attempted to show the molecular mechanism of RANK and RANKL on differentiation capability of human cord blood HSC to osteoclast, as well as expression of calcitonin receptor (CTR) on cord blood HSC surface. In this experimental study, CD133(+) hematopoietic stem cells were isolated from umbilical cord blood and cultured in the presence of macrophage colony-stimulating factor (M-CSF) and RANKL. Osteoclast differentiation was characterized by using tartrate-resistant acid phosphatase (TRAP) staining, giemsa staining, immunophenotyping, and reverse transcription-polymerase chain reaction (RT-PCR) assay for specific genes. Hematopoietic stem cells expressed RANK before and after differentiation into osteoclast. Compared to control group, flow cytometric results showed an increased expression of RANK after differentiation. Expression of CTR mRNA showed TRAP reaction was positive in some differentiated cells, including osteoclast cells. Presence of RANKL and M-CSF in bone marrow could induce HSCs differentiation into osteoclast.

Characterization factors for thermal pollution in freshwater aquatic environments.

PubMed

Verones, Francesca; Hanafiah, Marlia Mohd; Pfister, Stephan; Huijbregts, Mark A J; Pelletier, Gregory J; Koehler, Annette

2010-12-15

To date the impact of thermal emissions has not been addressed in life cycle assessment despite the narrow thermal tolerance of most aquatic species. A method to derive characterization factors for the impact of cooling water discharges on aquatic ecosystems was developed which uses space and time explicit integration of fate and effects of water temperature changes. The fate factor is calculated with a 1-dimensional steady-state model and reflects the residence time of heat emissions in the river. The effect factor specifies the loss of species diversity per unit of temperature increase and is based on a species sensitivity distribution of temperature tolerance intervals for various aquatic species. As an example, time explicit characterization factors were calculated for the cooling water discharge of a nuclear power plant in Switzerland, quantifying the impact on aquatic ecosystems of the rivers Aare and Rhine. The relative importance of the impact of these cooling water discharges was compared with other impacts in life cycle assessment. We found that thermal emissions are relevant for aquatic ecosystems compared to other stressors, such as chemicals and nutrients. For the case of nuclear electricity investigated, thermal emissions contribute between 3% and over 90% to Ecosystem Quality damage.

Resveratrol: Why Is It a Promising Therapy for Chronic Kidney Disease Patients?

PubMed Central

Saldanha, Juliana F.; Leal, Viviane de O.; Stenvinkel, Peter; Carraro-Eduardo, José Carlos

2013-01-01

Resveratrol, a phenolic compound found in various plants, including grapes, berries, and peanuts, shows promise for the treatment of cancer, aging, type 2 diabetes, and cardiovascular diseases. Resveratrol can promote transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) activation, increase the expression level of SIRT-1, which is a sirtuin family protein, and reduce mTOR pathway signaling. This compound has anti-inflammatory properties in that it inhibits or antagonizes the nuclear factor-κB (NF-κB) activity, which is a redox-sensitive transcription factor that coordinates the inflammatory response. Inflammation and oxidative stress, which are common features in patients with chronic kidney disease (CKD), are interrelated and associated with cardiovascular disease and the progression of CKD itself. Because of the modulation of the mechanisms involved in the inflammatory-oxidative stress cycle, resveratrol could play an important role in controlling CKD-related metabolic derangements. Although resveratrol supplementation in theory is a promising therapy in this patient group, there are no studies evaluating its effects. Thus, the present review aims to describe the role of resveratrol in inflammation and oxidative stress modulation and its possible benefits to patients with CKD. PMID:24489988

Hypercapnic acidosis attenuates ventilation-induced lung injury by a nuclear factor-κB-dependent mechanism.

PubMed

Contreras, Maya; Ansari, Bilal; Curley, Gerard; Higgins, Brendan D; Hassett, Patrick; O'Toole, Daniel; Laffey, John G

2012-09-01

Hypercapnic acidosis protects against ventilation-induced lung injury. We wished to determine whether the beneficial effects of hypercapnic acidosis in reducing stretch-induced injury were mediated via inhibition of nuclear factor-κB, a key transcriptional regulator in inflammation, injury, and repair. Prospective randomized animal study. University research laboratory. Adult male Sprague-Dawley rats. In separate experimental series, the potential for hypercapnic acidosis to attenuate moderate and severe ventilation-induced lung injury was determined. In each series, following induction of anesthesia and tracheostomy, Sprague-Dawley rats were randomized to (normocapnia; FICO2 0.00) or (hypercapnic acidosis; FICO2 0.05), subjected to high stretch ventilation, and the severity of lung injury and indices of activation of the nuclear factor-κB pathway were assessed. Subsequent in vitro experiments examined the potential for hypercapnic acidosis to reduce pulmonary epithelial inflammation and injury induced by cyclic mechanical stretch. The role of the nuclear factor-κB pathway in hypercapnic acidosis-mediated protection from stretch injury was then determined. Hypercapnic acidosis attenuated moderate and severe ventilation-induced lung injury, as evidenced by improved oxygenation, compliance, and reduced histologic injury compared to normocapnic conditions. Hypercapnic acidosis reduced indices of inflammation such as interleukin-6 and bronchoalveolar lavage neutrophil infiltration. Hypercapnic acidosis reduced the decrement of the nuclear factor-κB inhibitor IκBα and reduced the generation of cytokine-induced neutrophil chemoattractant-1. Hypercapnic acidosis reduced cyclic mechanical stretch-induced nuclear factor-κB activation, reduced interleukin-8 production, and decreased epithelial injury and cell death compared to normocapnia. Hypercapnic acidosis attenuated ventilation-induced lung injury independent of injury severity and decreased mechanical stretch-induced epithelial injury and death, via a nuclear factor-κB-dependent mechanism.

A novel NFIA-NFκB feed-forward loop contributes to glioblastoma cell survival

PubMed Central

Lee, JunSung; Hoxha, Edlira

2017-01-01

Abstract Background. The nuclear factor I-A (NFIA) transcription factor promotes glioma growth and inhibits apoptosis in glioblastoma (GBM) cells. Here we report that the NFIA pro-survival effect in GBM is mediated in part via a novel NFIA–nuclear factor-kappaB (NFκB) p65 feed-forward loop. Methods. We examined effects of gain- and loss-of-function manipulations of NFIA and NFκB p65 on each other’s transcription, cell growth, apoptosis and sensitivity to chemotherapy in patient-derived GBM cells and established GBM cell lines. Results. NFIA enhanced apoptosis evasion by activating NFκB p65 and its downstream anti-apoptotic factors tumor necrosis factor receptor-associated factor 1 (TRAF1) and cellular inhibitor of apoptosis proteins (cIAPs). Induction of NFκB by NFIA was required to protect cells from apoptosis, and inhibition of NFκB effectively reversed the NFIA anti-apoptotic effect. Conversely, NFIA knockdown decreased expression of NFκB and anti-apoptotic genes TRAF1 and cIAPs, and increased baseline apoptosis. NFIA positively regulated NFκB transcription and NFκB protein level. Interestingly, NFκB also activated the NFIA promoter and increased NFIA level, and knockdown of NFIA was sufficient to attenuate the NFκB pro-survival effect, suggesting a reciprocal regulation between NFIA and NFκB in governing GBM cell survival. Supporting this, NFIA and NFκB expression levels were highly correlated in human GBM and patient-derived GBM cells. Conclusions. These data define a previously unknown NFIA-NFκB feed-forward regulation that may contribute to GBM cell survival. PMID:27994064

NMR study of the transforming growth factor-alpha (TGF-alpha)-epidermal growth factor receptor complex. Visualization of human TGF-alpha binding determinants through nuclear Overhauser enhancement analysis.

PubMed

McInnes, C; Hoyt, D W; Harkins, R N; Pagila, R N; Debanne, M T; O'Connor-McCourt, M; Sykes, B D

1996-12-13

The study of human transforming growth factor-alpha (TGF-alpha) in complex with the epidermal growth factor (EGF) receptor extracellular domain has been undertaken in order to generate information on the interactions of these molecules. Analysis of 1H NMR transferred nuclear Overhauser enhancement data for titration of the ligand with the receptor has yielded specific data on the residues of the growth factor involved in contact with the larger protein. Significant increases and decreases in nuclear Overhauser enhancement cross-peak intensity occur upon complexation, and interpretation of these changes indicates that residues of the A- and C-loops of TGF-alpha form the major binding interface, while the B-loop provides a structural scaffold for this site. These results corroborate the conclusions from NMR relaxation studies (Hoyt, D. W., Harkins, R. N., Debanne, M. T., O'Connor-McCourt, M., and Sykes, B. D. (1994) Biochemistry 33, 15283-15292), which suggest that the C-terminal residues of the polypeptide are immobilized upon receptor binding, while the N terminus of the molecule retains considerable flexibility, and are consistent with structure-function studies of the TGF-alpha/EGF system indicating a multidomain binding model. These results give a visualization, for the first time, of native TGF-alpha in complex with the EGF receptor and generate a picture of the ligand-binding site based upon the intact molecule. This will undoubtedly be of utility in the structure-based design of TGF-alpha/EGF agonists and/or antagonists.

Variance Reduction Factor of Nuclear Data for Integral Neutronics Parameters

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chiba, G., E-mail: go_chiba@eng.hokudai.ac.jp; Tsuji, M.; Narabayashi, T.

We propose a new quantity, a variance reduction factor, to identify nuclear data for which further improvements are required to reduce uncertainties of target integral neutronics parameters. Important energy ranges can be also identified with this variance reduction factor. Variance reduction factors are calculated for several integral neutronics parameters. The usefulness of the variance reduction factors is demonstrated.

Nuclear Function of Subclass I Actin-Depolymerizing Factor Contributes to Susceptibility in Arabidopsis to an Adapted Powdery Mildew Fungus1[OPEN

PubMed Central

Inada, Noriko; Higaki, Takumi; Hasezawa, Seiichiro

2016-01-01

Actin-depolymerizing factors (ADFs) are conserved proteins that function in regulating the structure and dynamics of actin microfilaments in eukaryotes. In this study, we present evidence that Arabidopsis (Arabidopsis thaliana) subclass I ADFs, particularly ADF4, functions as a susceptibility factor for an adapted powdery mildew fungus. The null mutant of ADF4 significantly increased resistance against the adapted powdery mildew fungus Golovinomyces orontii. The degree of resistance was further enhanced in transgenic plants in which the expression of all subclass I ADFs (i.e. ADF1–ADF4) was suppressed. Microscopic observations revealed that the enhanced resistance of adf4 and ADF1-4 knockdown plants (ADF1-4Ri) was associated with the accumulation of hydrogen peroxide and cell death specific to G. orontii-infected cells. The increased resistance and accumulation of hydrogen peroxide in ADF1-4Ri were suppressed by the introduction of mutations in the salicylic acid- and jasmonic acid-signaling pathways but not by a mutation in the ethylene-signaling pathway. Quantification by microscopic images detected an increase in the level of actin microfilament bundling in ADF1-4Ri but not in adf4 at early G. orontii infection time points. Interestingly, complementation analysis revealed that nuclear localization of ADF4 was crucial for susceptibility to G. orontii. Based on its G. orontii-infected-cell-specific phenotype, we suggest that subclass I ADFs are susceptibility factors that function in a direct interaction between the host plant and the powdery mildew fungus. PMID:26747284

Extracellular HSP27 acts as a signaling molecule to activate NF-κB in macrophages.

PubMed

Salari, Samira; Seibert, Tara; Chen, Yong-Xiang; Hu, Tieqiang; Shi, Chunhua; Zhao, Xiaoling; Cuerrier, Charles M; Raizman, Joshua E; O'Brien, Edward R

2013-01-01

Heat shock protein 27 (HSP27) shows attenuated expression in human coronary arteries as the extent of atherosclerosis progresses. In mice, overexpression of HSP27 reduces atherogenesis, yet the precise mechanism(s) are incompletely understood. Inflammation plays a central role in atherogenesis, and of particular interest is the balance of pro- and anti-inflammatory factors produced by macrophages. As nuclear factor-kappa B (NF-κB) is a key immune signaling modulator in atherogenesis, and macrophages are known to secrete HSP27, we sought to determine if recombinant HSP27 (rHSP27) alters NF-κB signaling in macrophages. Treatment of THP-1 macrophages with rHSP27 resulted in the degradation of an inhibitor of NF-κB, IκBα, nuclear translocation of the NF-κB p65 subunit, and increased NF-κB transcriptional activity. Treatment of THP-1 macrophages with rHSP27 yielded increased expression of a variety of genes, including the pro-inflammatory factors, IL-1β, and TNF-α. However, rHSP27 also increased the expression of the anti-inflammatory factors IL-10 and GM-CSF both at the mRNA and protein levels. Our study suggests that in macrophages, activation of NF-κB signaling by rHSP27 is associated with upregulated expression and secretion of key pro- and anti-inflammatory cytokines. Moreover, we surmise that it is the balance in expression of these mediators and antagonists of inflammation, and hence atherogenesis, that yields a favorable net effect of HSP27 on the vessel wall.

Exercise Training Mitigates Water Pipe Smoke Exposure-Induced Pulmonary Impairment via Inhibiting NF-κB and Activating Nrf2 Signalling Pathways

PubMed Central

Yuvaraju, Priya; Beegam, Sumaya; Ali, Badreldin H.

2018-01-01

Water pipe smoking is a tobacco smoking method commonly used in Eastern countries and is gaining popularity in Europe and North America, in particular among adolescents and young adults. Several clinical and experimental studies have reported that exposure to water pipe smoke (WPS) induces lung inflammation and impairment of pulmonary function. However, the mechanisms of such effects are not understood, as are data on the possible palliative effect of exercise training. The present study evaluated the effects of regular aerobic exercise training (treadmill: 5 days/week, 40 min/day) on subchronic exposure to WPS (30 minutes/day, 5 days/week for 2 months). C57BL/6 mice were exposed to air or WPS with or without exercise training. Airway resistance measured using forced oscillation technique was significantly and dose-dependently increased in the WPS-exposed group when compared with the air-exposed one. Exercise training significantly prevented the effect of WPS on airway resistance. Histologically, the lungs of WPS-exposed mice had focal moderate interstitial inflammatory cell infiltration consisting of neutrophil polymorphs, plasma cells, and lymphocytes. There was a mild increase in intra-alveolar macrophages and a focal damage to alveolar septae in some foci. Exercise training significantly alleviated these effects and also decreased the WPS-induced increase of tumor necrosis factor α and interleukin 6 concentrations and attenuated the increase of 8-isoprostane in lung homogenates. Likewise, the lung DNA damage induced by WPS was significantly inhibited by exercise training. Moreover, exercise training inhibited nuclear factor kappa-B (NF-κB) expression induced by WPS and increased that of nuclear factor erythroid 2-related factor 2 (Nrf2). Our findings suggest that exercise training significantly mitigated WPS-induced increase in airway resistance, inflammation, oxidative stress, and DNA damage via mechanisms that include inhibiting NF-κB and activating Nrf2 signalling pathways. PMID:29692875

Nuclear factor of activated T-cells 5 increases intestinal goblet cell differentiation through an mTOR/Notch signaling pathway

PubMed Central

Zhou, Yuning; Wang, Qingding; Weiss, Heidi L.; Evers, B. Mark

2014-01-01

The intestinal mucosa undergoes a continual process of proliferation, differentiation, and apoptosis that is regulated by multiple signaling pathways. Previously, we have shown that the nuclear factor of activated T-cells 5 (NFAT5) is involved in the regulation of intestinal enterocyte differentiation. Here we show that treatment with sodium chloride (NaCl), which activates NFAT5 signaling, increased mTORC1 repressor regulated in development and DNA damage response 1 (REDD1) protein expression and inhibited mTOR signaling; these alterations were attenuated by knockdown of NFAT5. Knockdown of NFAT5 activated mammalian target of rapamycin (mTOR) signaling and significantly inhibited REDD1 mRNA expression and protein expression. Consistently, overexpression of NFAT5 increased REDD1 expression. In addition, knockdown of REDD1 activated mTOR and Notch signaling, whereas treatment with mTOR inhibitor rapamycin repressed Notch signaling and increased the expression of the goblet cell differentiation marker mucin 2 (MUC2). Moreover, knockdown of NFAT5 activated Notch signaling and decreased MUC2 expression, while overexpression of NFAT5 inhibited Notch signaling and increased MUC2 expression. Our results demonstrate a role for NFAT5 in the regulation of mTOR signaling in intestinal cells. Importantly, these data suggest that NFAT5 participates in the regulation of intestinal homeostasis via the suppression of mTORC1/Notch signaling pathway. PMID:25057011

Protein Kinase Inhibitor γ reciprocally regulates osteoblast and adipocyte differentiation by downregulating Leukemia Inhibitory Factor

PubMed Central

Chen, Xin; Hausman, Bryan S.; Luo, Guangbin; Zhou, Guang; Murakami, Shunichi; Rubin, Janet; Greenfield, Edward M.

2013-01-01

The Protein Kinase Inhibitor (Pki) gene family inactivates nuclear PKA and terminates PKA-induced gene expression. We previously showed that Pkig is the primary family member expressed in osteoblasts and that Pkig knockdown increases the effects of parathyroid hormone and isoproterenol on PKA activation, gene expression, and inhibition of apoptosis. Here, we determined whether endogenous levels of Pkig regulate osteoblast differentiation. Pkig is the primary family member in MEFs, murine marrow-derived mesenchymal stem cells, and human mesenchymal stem cells. Pkig deletion increased forskolin-dependent nuclear PKA activation and gene expression and Pkig deletion or knockdown increased osteoblast differentiation. PKA signaling is known to stimulate adipogenesis; however, adipogenesis and osteogenesis are often reciprocally regulated. We found that the reciprocal regulation predominates over the direct effects of PKA since adipogenesis was decreased by Pkig deletion or knockdown. Pkig deletion or knockdown simultaneously increased osteogenesis and decreased adipogenesis in mixed osteogenic/adipogenic medium. Pkig deletion increased PKA-induced expression of Leukemia Inhibitory Factor (Lif) mRNA and LIF protein. LIF neutralizing antibodies inhibited the effects on osteogenesis and adipogenesis of either Pkig deletion in MEFs or PKIγ knockdown in both murine and human mesenchymal stem cells. Collectively, our results show that endogenous levels of Pkig reciprocally regulate osteoblast and adipocyte differentiation and that this reciprocal regulation is mediated in part by LIF. PMID:23963683

Activation of Nrf2 is required for up-regulation of the π class of glutathione S-transferase in rat primary hepatocytes with L-methionine starvation.

PubMed

Lin, Ai-Hsuan; Chen, Haw-Wen; Liu, Cheng-Tze; Tsai, Chia-Wen; Lii, Chong-Kuei

2012-07-04

Numerous genes expression is regulated in response to amino acid shortage, which helps organisms adapt to amino acid limitation. The expression of the π class of glutathione (GSH) S-transferase (GSTP), a highly inducible phase II detoxification enzyme, is regulated mainly by activates activating protein 1 (AP-1) binding to the enhancer I of GSTP (GPEI). Here we show the critical role of nuclear factor erythroid-2-related factor 2 (Nrf2) in up-regulating GSTP gene transcription. Primary rat hepatocytes were cultured in a methionine-restricted medium, and immunoblotting and RT-PCR analyses showed that methionine restriction time-dependently increased GSTP protein and mRNA expression over a 48 h period. Nrf2 translocation to the nucleus, nuclear proteins binding to GPEI, and antioxidant response element (ARE) luciferase reporter activity were increased by methionine restriction as well as by l-buthionine sulfoximine (BSO), a GSH synthesis inhibitor. Transfection with Nrf2 siRNA knocked down Nrf2 expression and reversed the methionine-induced GSTP expression and GPEI binding activity. Chromatin immunoprecipitation assay confirmed the binding of Nrf2 to the GPEI. Phosphorylation of extracellular signal-regulated kinase 2 (ERK2) was increased in methionine-restricted and BSO-treated cells. ERK2 siRNA abolished methionine restriction-induced Nrf2 nuclear translocation, GPEI binding activity, ARE-luciferase reporter activity, and GSTP expression. Our results suggest that the up-regulation of GSTP gene transcription in response to methionine restriction likely occurs via the ERK-Nrf2-GPEI signaling pathway.

Impacts on Chinese Agriculture of Geoengineering and Smoke from Fires Ignited by Nuclear War

NASA Astrophysics Data System (ADS)

Xia, L.; Robock, A.

2013-12-01

Climate is one of the most important factors determining crop yields and world food supplies. To be well prepared for possible futures, it is necessary to study yield changes of major crops under different climate scenarios. Here we consider two situations: stratospheric sulfate geoengineering and nuclear war. Although we certainly do not advocate either scenario, we cannot exclude the possibilities: if global warming is getting worse, society might consider deliberately manipulating global temperature; if nuclear weapons still exist, we might face a nuclear war catastrophe. Since in both scenarios there would be reductions of temperature, precipitation, and insolation, which are three controlling factors on crop growth, it is important to study food supply changes under the two cases. We conducted our simulations for China, because it has the highest population and crop production in the world and it is under the strong influence of the summer monsoon, which would be altered in geoengineering and nuclear war scenarios. To examine the effects of climate changes induced by geoengineering and nuclear war on Chinese agriculture, we use the Decision Support System for Agrotechnology Transfer (DSSAT) crop model. We first evaluated the model by forcing it with daily weather data and management practices for the period 1978-2008 for 24 provinces in China, and compared the results to observations of the yields of major crops in China (middle season rice, winter wheat, and maize). Then we perturbed observed weather data using climate anomalies for geoengineering and nuclear war simulations. For geoengineering, we consider the G2 scenario of the Geoengineering Model Intercomparison Project (GeoMIP), which prescribes an insolation reduction to balance a 1% per year increase in CO2 concentration (1pctCO2). We used results from ten climate models participating in G2. For the nuclear war scenario, we consider the effects of 5 Tg of soot that could be injected into the upper troposphere by a war between India and Pakistan using only 100 Hiroshima-size atomic bombs dropped on cities. We used results from three climate models that did the same simulation. For the geoengineering scenario, without changes of agricultural technology, the combined effect of climate changes due to geoengineering and CO2 fertilization would change rice production in China by -4.6×6.0 Mt (4.5×5.9%) as compared with 1pctCO2 and would increase Chinese maize production by 20.9×6.9 Mt (14.8×4.9%) the period 46-50 years after the CO2 increase and compensating insolation reduction began. The CO2 fertilization effect compensates for the deleterious impacts of climate changes due to geoengineering on rice production, increasing rice production by 8.2 Mt and the elevated CO2 concentration enhances maize production in G2, contributing 35.5% to the total increase. While agricultural impacts may not be a serious problem for geoengineering, there are many other potential risks that need to be evaluated before geoengineering should be considered. Climate changes due to nuclear war would decrease Chinese rice production by 20×4.7%, maize production by 15×6.2% and winter wheat production by 35×19.3% for a five-year period after the soot injection, producing a major world food security crisis.

DNA-independent PARP-1 activation by phosphorylated ERK2 increases Elk1 activity: a link to histone acetylation.

PubMed

Cohen-Armon, Malka; Visochek, Leonid; Rozensal, Dana; Kalal, Adi; Geistrikh, Ilona; Klein, Rodika; Bendetz-Nezer, Sarit; Yao, Zhong; Seger, Rony

2007-01-26

PolyADP-ribose polymerases (PARPs) catalyze a posttranslational modification of nuclear proteins by polyADP-ribosylation. The catalytic activity of the abundant nuclear protein PARP-1 is stimulated by DNA strand breaks, and PARP-1 activation is required for initiation of DNA repair. Here we show that PARP-1 also acts within extracellular signal-regulated kinase (ERK) signaling cascade that mediates growth and differentiation. The findings reveal an alternative mode of PARP-1 activation, which does not involve binding to DNA or DNA damage. In a cell-free system, recombinant PARP-1 was intensively activated and thereby polyADP-ribosylated by a direct interaction with phosphorylated ERK2, and the activated PARP-1 dramatically increased ERK2-catalyzed phosphorylation of the transcription factor Elk1. In cortical neurons treated with nerve growth factors and in stimulated cardiomyocytes, PARP-1 activation enhanced ERK-induced Elk1-phosphorylation, core histone acetylation, and transcription of the Elk1-target gene c-fos. These findings constitute evidence for PARP-1 activity within the ERK signal-transduction pathway.

The nuclear factor-erythroid 2-related factor/heme oxygenase-1 axis is critical for the inflammatory features of type 2 diabetes-associated osteoarthritis.

PubMed

Vaamonde-Garcia, Carlos; Courties, Alice; Pigenet, Audrey; Laiguillon, Marie-Charlotte; Sautet, Alain; Houard, Xavier; Kerdine-Römer, Saadia; Meijide, Rosa; Berenbaum, Francis; Sellam, Jérémie

2017-09-01

Epidemiological findings support the hypothesis that type 2 diabetes mellitus (T2DM) is a risk factor for osteoarthritis (OA). Moreover, OA cartilage from patients with T2DM exhibits a greater response to inflammatory stress, but the molecular mechanism is unclear. To investigate whether the antioxidant defense system participates in this response, we examined here the expression of nuclear factor-erythroid 2-related factor (Nrf-2), a master antioxidant transcription factor, and of heme oxygenase-1 (HO-1), one of its main target genes, in OA cartilage from T2DM and non-T2DM patients as well as in murine chondrocytes exposed to high glucose (HG). Ex vivo experiments indicated that Nrf-2 and HO-1 expression is reduced in T2DM versus non-T2DM OA cartilage (0.57-fold Nrf-2 and 0.34-fold HO-1), and prostaglandin E 2 (PGE 2 ) release was increased in samples with low HO-1 expression. HG-exposed, IL-1β-stimulated chondrocytes had lower Nrf-2 levels in vitro , particularly in the nuclear fraction, than chondrocytes exposed to normal glucose (NG). Accordingly, HO-1 levels were also decreased (0.49-fold) in these cells. The HO-1 inducer cobalt protoporphyrin IX more efficiently attenuated PGE 2 and IL-6 release in HG+IL-1β-treated cells than in NG+IL-1β-treated cells. Greater reductions in HO-1 expression and increase in PGE 2 /IL-6 production were observed in HG+IL-1β-stimulated chondrocytes from Nrf-2 -/- mice than in chondrocytes from wild-type mice. We conclude that the Nrf-2/HO-1 axis is a critical pathway in the hyperglucidic-mediated dysregulation of chondrocytes. Impairments in this antioxidant system may explain the greater inflammatory responsiveness of OA cartilage from T2DM patients and may inform treatments of such patients. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Morphometric computer-assisted image analysis of epithelial cells in different grades of oral squamous cell carcinoma.

PubMed

Ananjan, Chatterjee; Jyothi, Mahadesh; Laxmidevi, B L; Gopinathan, Pillai Arun; Nazir, Salroo Humaira; Pradeep, L

2018-01-01

Oral squamous cell carcinoma (OSCC) accounts 94% of all malignant lesions in the oral cavity. In the assessment of OSCC, nowadays the WHO grading system has been followed widely but due to its subjectivity, investigators applied the sophisticated technique of computer-assisted image analysis in the grading of carcinoma in larynx, lungs, esophagus, and cervix to make it more objective. Access, analyze, and compare the cellular area (CA); cytoplasmic area (Cyt A); nuclear area (NA); nuclear perimeter (NP); nuclear form factor (NF); and nuclear-cytoplasmic ratio (N/C) of the cells in different grades of OSCC. Fifty OSCC cases were obtained and stained with hematoxylin and eosin which were graded according to the WHO classification. The sections were subjected to morphometric analysis to analyze all the morphometric parameters in different grades of OSCC and subjected to one-way ANOVA statistical analysis. CA and Cyt A decreased from normal mucosa with dedifferentiation of OSCC. The NA and NP increased in carcinoma group when compared to normal mucosa but decreased with dedifferentiation of OSCC (P < 0.05). NF had no significance with normal mucosa and different grades of OSCC (P > 0.05), while N/C ratio increased from normal mucosa through increasing grades of OSCC, reaching the highest value in poorly differentiated squamous cell carcinoma (P < 0.05). Both cellular and nuclear variables provide a more accurate indication of tumor aggressiveness than any single parameter. Morphometric analysis can be a reliable tool to determine objectively the degree of malignancy at the invasive tumor front.

Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-κB activation

PubMed Central

Tanaka, S; Nishiumi, S; Nishida, M; Mizushina, Y; Kobayashi, K; Masuda, A; Fujita, T; Morita, Y; Mizuno, S; Kutsumi, H; Azuma, T; Yoshida, M

2010-01-01

Vitamin K is a family of fat-soluble compounds including phylloquinone (vitamin K1), menaquinone (vitamin K2) and menadione (vitamin K3). Recently, it was reported that vitamin K, especially vitamins K1 and K2, exerts a variety of biological effects, and these compounds are expected to be candidates for therapeutic agents against various diseases. In this study, we investigated the anti-inflammatory effects of vitamin K3 in in vitro cultured cell experiments and in vivo animal experiments. In human embryonic kidney (HEK)293 cells, vitamin K3 inhibited the tumour necrosis factor (TNF)-α-evoked translocation of nuclear factor (NF)-κB into the nucleus, although vitamins K1 and K2 did not. Vitamin K3 also suppressed the lipopolysaccharide (LPS)-induced nuclear translocation of NF-κB and production of TNF-α in mouse macrophage RAW264·7 cells. Moreover, the addition of vitamin K3 before and after LPS administration attenuated the severity of lung injury in an animal model of acute lung injury/acute respiratory distress syndrome (ARDS), which occurs in the setting of acute severe illness complicated by systemic inflammation. In the ARDS model, vitamin K3 also suppressed the LPS-induced increase in the serum TNF-α level and inhibited the LPS-evoked nuclear translocation of NF-κB in lung tissue. Despite marked efforts, little therapeutic progress has been made, and the mortality rate of ARDS remains high. Vitamin K3 may be an effective therapeutic strategy against acute lung injury including ARDS. PMID:20030669

Vitamin K3 attenuates lipopolysaccharide-induced acute lung injury through inhibition of nuclear factor-kappaB activation.

PubMed

Tanaka, S; Nishiumi, S; Nishida, M; Mizushina, Y; Kobayashi, K; Masuda, A; Fujita, T; Morita, Y; Mizuno, S; Kutsumi, H; Azuma, T; Yoshida, M

2010-05-01

Vitamin K is a family of fat-soluble compounds including phylloquinone (vitamin K1), menaquinone (vitamin K2) and menadione (vitamin K3). Recently, it was reported that vitamin K, especially vitamins K1 and K2, exerts a variety of biological effects, and these compounds are expected to be candidates for therapeutic agents against various diseases. In this study, we investigated the anti-inflammatory effects of vitamin K3 in in vitro cultured cell experiments and in vivo animal experiments. In human embryonic kidney (HEK)293 cells, vitamin K3 inhibited the tumour necrosis factor (TNF)-alpha-evoked translocation of nuclear factor (NF)-kappaB into the nucleus, although vitamins K1 and K2 did not. Vitamin K3 also suppressed the lipopolysaccharide (LPS)-induced nuclear translocation of NF-kappaB and production of TNF-alpha in mouse macrophage RAW264.7 cells. Moreover, the addition of vitamin K3 before and after LPS administration attenuated the severity of lung injury in an animal model of acute lung injury/acute respiratory distress syndrome (ARDS), which occurs in the setting of acute severe illness complicated by systemic inflammation. In the ARDS model, vitamin K3 also suppressed the LPS-induced increase in the serum TNF-alpha level and inhibited the LPS-evoked nuclear translocation of NF-kappaB in lung tissue. Despite marked efforts, little therapeutic progress has been made, and the mortality rate of ARDS remains high. Vitamin K3 may be an effective therapeutic strategy against acute lung injury including ARDS.

70-kDa Heat Shock Cognate Protein hsc70 Mediates Calmodulin-dependent Nuclear Import of the Sex-determining Factor SRY*

PubMed Central

Kaur, Gurpreet; Lieu, Kim G.; Jans, David A.

2013-01-01

We recently showed that the developmentally important family of SOX (SRY (sex determining region on the Y chromosome)-related high mobility group (HMG) box) proteins require the calcium-binding protein calmodulin (CaM) for optimal nuclear accumulation, with clinical mutations in SRY that specifically impair nuclear accumulation via this pathway resulting in XY sex reversal. However, the mechanism by which CaM facilitates nuclear accumulation is unknown. Here, we show, for the first time, that the 70-kDa heat shock cognate protein hsc70 plays a key role in CaM-dependent nuclear import of SRY. Using a reconstituted nuclear import assay, we show that antibodies to hsc70 significantly reduce nuclear accumulation of wild type SRY and mutant derivatives thereof that retain CaM-dependent nuclear import, with an increased rate of nuclear accumulation upon addition of both CaM and hsc70, in contrast to an SRY mutant derivative with impaired CaM binding. siRNA knockdown of hsc70 in intact cells showed similar results, indicating clear dependence upon hsc70 for CaM-dependent nuclear import. Analysis using the technique of fluorescence recovery after photobleaching indicated that hsc70 is required for the maximal rate of SRY nuclear import in living cells but has no impact upon SRY nuclear retention/nuclear dynamics. Finally, we demonstrate direct binding of hsc70 to the SRY·CaM complex, with immunoprecipitation experiments from cell extracts showing association of hsc70 with wild type SRY, but not with a mutant derivative with impaired CaM binding, dependent on Ca2+. Our novel findings strongly implicate hsc70 in CaM-dependent nuclear import of SRY. PMID:23235156

Charged-particle nuclear modification factors in PbPb and pPb collisions at $$ \\sqrt{s_{\\mathrm{NN}}}=5.02 $$ TeV

DOE PAGES

Khachatryan, V.; Sirunyan, A. M.; Tumasyan, A.; ...

2016-04-07

The spectra of charged particles produced within the pseudorapidity windowmore » $$| \\eta | < $$ 1 at $$\\sqrt{s_{\\mathrm{NN}}}= $$ 5.02 TeV are measured using 404 $$ \\mu $$b$$^{-1}$$ of PbPb and 27.4 pb$$^{-1}$$ of pp data collected by the CMS detector at the LHC in 2015. The spectra are presented over the transverse momentum ranges spanning 0.5 $$ < p_{\\mathrm{T}} < $$ 400 GeV in pp and 0.7 $$ < p_{\\mathrm{T}} < $$ 400 GeV in PbPb collisions. The corresponding nuclear modification factor, $${R_\\mathrm{AA}} $$, is measured in bins of collision centrality. The $${R_\\mathrm{AA}} $$ in the 5% most central collisions shows a maximal suppression by a factor of 7-8 in the $$p_{\\mathrm{T}}$$ region of 6-9 GeV. This dip is followed by an increase, which continues up to the highest $$ p_{\\mathrm{T}}$$ measured, and approaches unity in the vicinity of $$p_{\\mathrm{T}}= $$ 200 GeV. The $${R_\\mathrm{AA}} $$ is compared to theoretical predictions and earlier experimental results at lower collision energies. Here, the newly measured pp spectrum is combined with the pPb spectrum previously published by the CMS Collaboration to construct the pPb nuclear modification factor, $${R_{\\mathrm{ p }\\mathrm{A}}} $$, up to 120 GeV. For $$ p_{\\mathrm{T}} > $$ 20 GeV, $${R_{\\mathrm{ p }\\mathrm{A}}} $$ exhibits weak momentum dependence and shows a moderate enhancement above unity.« less

Nuclear factor erythroid 2-related factor-2 activity controls 4-hydroxynonenal metabolism and activity in prostate cancer cells.

PubMed

Pettazzoni, Piergiorgio; Ciamporcero, Eric; Medana, Claudio; Pizzimenti, Stefania; Dal Bello, Federica; Minero, Valerio Giacomo; Toaldo, Cristina; Minelli, Rosalba; Uchida, Koji; Dianzani, Mario Umberto; Pili, Roberto; Barrera, Giuseppina

2011-10-15

4-Hydroxynonenal (HNE) is an end product of lipoperoxidation with antiproliferative and proapoptotic properties in various tumors. Here we report a greater sensitivity to HNE in PC3 and LNCaP cells compared to DU145 cells. In contrast to PC3 and LNCaP cells, HNE-treated DU145 cells showed a smaller reduction in growth and did not undergo apoptosis. In DU145 cells, HNE did not induce ROS production and DNA damage and generated a lower amount of HNE-protein adducts. DU145 cells had a greater GSH and GST A4 content and GSH/GST-mediated HNE detoxification. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a regulator of the antioxidant response. Nrf2 protein content and nuclear accumulation were higher in DU145 cells compared to PC3 and LNCaP cells, whereas the expression of KEAP1, the main negative regulator of Nrf2 activity, was lower. Inhibition of Nrf2 expression with specific siRNA resulted in a reduction in GST A4 expression and GS-HNE formation, indicating that Nrf2 controls HNE metabolism. In addition, Nrf2 knockdown sensitized DU145 cells to HNE-mediated antiproliferative and proapoptotic activity. In conclusion, we demonstrated that increased Nrf2 activity resulted in a reduction in HNE sensitivity in prostate cancer cells, suggesting a potential mechanism of resistance to pro-oxidant therapy. Copyright © 2011 Elsevier Inc. All rights reserved.

Targeting SMN to Cajal bodies and nuclear gems during neuritogenesis

PubMed Central

Navascues, Joaquin; Berciano, Maria T.; Tucker, Karen E.

2006-01-01

Neurite outgrowth is a central feature of neuronal differentiation. PC12 cells are a good model system for studying the peripheral nervous system and the outgrowth of neurites. In addition to the dramatic changes observed in the cytoplasm, neuronal differentiation is also accompanied by striking changes in nuclear morphology. The large and sustained increase in nuclear transcription during neuronal differentiation requires synthesis of a large number of factors involved in pre-mRNA processing. We show that the number and composition of the nuclear subdomains called Cajal bodies and gems changes during the course of N-ras-induced neuritogenesis in the PC12-derived cell line UR61. The Cajal bodies found in undifferentiated cells are largely devoid of the survival of motor neurons (SMN) protein product. As cells shift to a differentiated state, SMN is not only globally upregulated, but is progressively recruited to Cajal bodies. Additional SMN foci (also known as Gemini bodies, gems) can also be detected. Using dual-immunogold labeling electron microscopy and mouse embryonic fibroblasts lacking the coilin protein, we show that gems clearly represent a distinct category of nuclear body. PMID:15164213

Electronic Properties of DNA-Based Schottky Barrier Diodes in Response to Alpha Particles.

PubMed

Al-Ta'ii, Hassan Maktuff Jaber; Periasamy, Vengadesh; Amin, Yusoff Mohd

2015-05-21

Detection of nuclear radiation such as alpha particles has become an important field of research in recent history due to nuclear threats and accidents. In this context; deoxyribonucleic acid (DNA) acting as an organic semiconducting material could be utilized in a metal/semiconductor Schottky junction for detecting alpha particles. In this work we demonstrate for the first time the effect of alpha irradiation on an Al/DNA/p-Si/Al Schottky diode by investigating its current-voltage characteristics. The diodes were exposed for different periods (0-20 min) of irradiation. Various diode parameters such as ideality factor, barrier height, series resistance, Richardson constant and saturation current were then determined using conventional, Cheung and Cheung's and Norde methods. Generally, ideality factor or n values were observed to be greater than unity, which indicates the influence of some other current transport mechanism besides thermionic processes. Results indicated ideality factor variation between 9.97 and 9.57 for irradiation times between the ranges 0 to 20 min. Increase in the series resistance with increase in irradiation time was also observed when calculated using conventional and Cheung and Cheung's methods. These responses demonstrate that changes in the electrical characteristics of the metal-semiconductor-metal diode could be further utilized as sensing elements to detect alpha particles.

The Food Contaminants Nivalenol and Deoxynivalenol Induce Inflammation in Intestinal Epithelial Cells by Regulating Reactive Oxygen Species Release.

PubMed

Adesso, Simona; Autore, Giuseppina; Quaroni, Andrea; Popolo, Ada; Severino, Lorella; Marzocco, Stefania

2017-12-11

Fusarium mycotoxins are fungal metabolites whose ability to affect cereal grains as multi-contaminants is progressively increasing. The trichothecene mycotoxins nivalenol (NIV) and deoxynivalenol (DON) are often found in almost all agricultural commodities worldwide. They are able to affect animal and human health, including at the intestinal level. In this study, NIV, both alone and in combination with DON, induced inflammation and increased the inflammatory response induced by lipopolysaccharide (LPS) plus Interferon-γ (IFN) in the non-tumorigenic intestinal epithelial cell line (IEC-6). The inflammatory response induced by NIV and DON involves tumor necrosis factor-α (TNF-α) production, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, nitrotyrosine formation, reactive oxygen species (ROS) release, Nuclear Factor-κB (NF-κB), Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and inflammasome activation. The pro-inflammatory effect was strongly induced by NIV and by the mycotoxin mixture, when compared to DON alone. Mechanistic studies indicate a pivotal role for ROS in the observed pro-inflammatory effects induced by mycotoxins. In this study, the interactions between NIV and DON point out the importance of their food co-contamination, further highlighting the risk assessment process that is of growing concern.

Autoregulatory loop of nuclear corepressor 1 expression controls invasion, tumor growth, and metastasis

PubMed Central

Martínez-Iglesias, Olaia A.; Alonso-Merino, Elvira; Gómez-Rey, Sara; Velasco-Martín, Juan Pedro; Martín Orozco, Rosa; Luengo, Enrique; García Martín, Rosa; Ibáñez de Cáceres, Inmaculada; Fernández, Agustín F.; Fraga, Mario F.; González-Peramato, Pilar; Varona, Constantino; Palacios, José; Regadera, Javier; Aranda, Ana

2016-01-01

Nuclear corepressor 1 (NCoR) associates with nuclear receptors and other transcription factors leading to transcriptional repression. We show here that NCoR depletion enhances cancer cell invasion and increases tumor growth and metastatic potential in nude mice. These changes are related to repressed transcription of genes associated with increased metastasis and poor prognosis in patients. Strikingly, transient NCoR silencing leads to heterochromatinization and stable silencing of the NCoR gene, suggesting that NCoR loss can be propagated, contributing to tumor progression even in the absence of NCoR gene mutations. Down-regulation of the thyroid hormone receptor β1 (TRβ) appears to be associated with cancer onset and progression. We found that expression of TRβ increases NCoR levels and that this induction is essential in mediating inhibition of tumor growth and metastasis by this receptor. Moreover, NCoR is down-regulated in human hepatocarcinomas and in the more aggressive breast cancer tumors, and its expression correlates positively with that of TRβ. These data provide a molecular basis for the anticancer actions of this corepressor and identify NCoR as a potential molecular target for development of novel cancer therapies. PMID:26729869

Induction of apoptosis in cells expressing exogenous Hippi, a molecular partner of huntingtin-interacting protein Hip1.

PubMed

Majumder, Pritha; Chattopadhyay, Biswanath; Mazumder, Arindam; Das, Pradeep; Bhattacharyya, Nitai P

2006-05-01

To decipher the pathway of apoptosis induction downstream to caspase-8 activation by exogenous expression of Hippi, an interactor of huntingtin-interacting protein Hip1, we studied apoptosis in HeLa and Neuro2A cells expressing GFP-tagged Hippi. Nuclear fragmentation, caspase-1, caspase-8, caspase-9/caspase-6 and caspase-3 activation were increased significantly in Hippi expressing cells. Cleavage of Bid, release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria were also increased in GFP-Hippi expressing cells. It was observed that caspase-1 and caspase-8 activation was earlier than caspase-3 activation and nuclear fragmentation. Expression of caspase-1, caspase-3 and caspase-7 was increased while anti-apoptotic gene Bcl-2 and mitochondrial genes ND1 and ND4 were reduced in Hippi expressing cells. Besides, the expression SDHA and SDHB, nuclear genes, subunits of mitochondrial complex II were decreased in GFP-Hippi expressing cells. Taken together, we concluded that Hippi expression induced apoptosis by releasing AIF and cytochrome c from mitochondria, activation of caspase-1 and caspase-3, and altering the expression of apoptotic genes and genes involved in mitochondrial complex I and II.

Natural compounds regulate energy metabolism by the modulating the activity of lipid-sensing nuclear receptors.

PubMed

Goto, Tsuyoshi; Kim, Young-Il; Takahashi, Nobuyuki; Kawada, Teruo

2013-01-01

Obesity causes excess fat accumulation in various tissues, most notoriously in the adipose tissue, along with other insulin-responsive organs such as skeletal muscle and the liver, which predisposes an individual to the development of metabolic abnormalities. The molecular mechanisms underlying obesity-induced metabolic abnormalities have not been completely elucidated; however, in recent years, the search for therapies to prevent the development of obesity and obesity-associated metabolic disorders has increased. It is known that several nuclear receptors, when activated by specific ligands, regulate carbohydrate and lipid metabolism at the transcriptional level. The expression of lipid metabolism-related enzymes is directly regulated by the activity of various nuclear receptors via their interaction with specific response elements in promoters of those genes. Many natural compounds act as ligands of nuclear receptors and regulate carbohydrate and lipid metabolism by regulating the activities of these nuclear receptors. In this review, we describe our current knowledge of obesity, the role of lipid-sensing nuclear receptors in energy metabolism, and several examples of food factors that act as agonists or antagonists of nuclear receptors, which may be useful for the management of obesity and the accompanying energy metabolism abnormalities. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The effect of transverse flow on the nuclear modification factor at RHIC and LHC

DOE Office of Scientific and Technical Information (OSTI.GOV)

Betz, Barbara; Gyulassy, Miklos

2016-01-22

We determine the nuclear modification factor at RHIC and LHC energies using a generic jet-energy loss model that is expanded by an additional flow factor accounting for the impact of transverse flow. We consider a pQCD-based ansatz with and without jet-energy loss fluctuations that is coupled to a state-of-the-art hydrodynamic prescription and includes a running coupling effect. We show that the nuclear modification factor is a rather insensitive quantity that is barely affected by the flow dynamics of the medium created in a heavy-ion collision.

ADVANCED CERAMIC MATERIALS FOR NEXT-GENERATION NUCLEAR APPLICATIONS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Marra, J.

2010-09-29

Rising global energy demands coupled with increased environmental concerns point to one solution; they must reduce their dependence on fossil fuels that emit greenhouse gases. As the global community faces the challenge of maintaining sovereign nation security, reducing greenhouse gases, and addressing climate change nuclear power will play a significant and likely growing role. In the US, nuclear energy already provides approximately one-fifth of the electricity used to power factories, offices, homes, and schools with 104 operating nuclear power plants, located at 65 sites in 31 states. Additionally, 19 utilities have applied to the US Nuclear Regulatory Commission (NRC) formore » construction and operating licenses for 26 new reactors at 17 sites. This planned growth of nuclear power is occurring worldwide and has been termed the 'nuclear renaissance.' As major industrial nations craft their energy future, there are several important factors that must be considered about nuclear energy: (1) it has been proven over the last 40 years to be safe, reliable and affordable (good for Economic Security); (2) its technology and fuel can be domestically produced or obtained from allied nations (good for Energy Security); and (3) it is nearly free of greenhouse gas emissions (good for Environmental Security). Already an important part of worldwide energy security via electricity generation, nuclear energy can also potentially play an important role in industrial processes and supporting the nation's transportation sector. Coal-to-liquid processes, the generation of hydrogen and supporting the growing potential for a greatly increased electric transportation system (i.e. cars and trains) mean that nuclear energy could see dramatic growth in the near future as we seek to meet our growing demand for energy in cleaner, more secure ways. In order to address some of the prominent issues associated with nuclear power generation (i.e., high capital costs, waste management, and proliferation), the worldwide community is working to develop and deploy new nuclear energy systems and advanced fuel cycles. These new nuclear systems address the key challenges and include: (1) extracting the full energy value of the nuclear fuel; (2) creating waste solutions with improved long term safety; (3) minimizing the potential for the misuse of the technology and materials for weapons; (4) continually improving the safety of nuclear energy systems; and (5) keeping the cost of energy affordable.« less

Genetic factors in familial aggregation of blood pressure of Portuguese nuclear families.

PubMed

Fermino, Rogério César; Seabra, André; Garganta, Rui; Maia, José António Ribeiro

2009-03-01

Despite of the increase in the prevalence of hypertension in Portugal, the importance of genetic factors in blood pressure (BP) has not been studied extensively in our country. To verify the indirect presence of vertical transmission of genetic factors between parents and children in BP values, and to estimate the magnitude of genetic factors contributing for variation in BP values in the population. Sample size comprises 367 individuals (164 parents and 203 children) pertaining the 107 nuclear families participating in 'Familias Activas' project, proceeding from different regions of North Portugal. The BP was measured with Omron model M6 (HEM-7001-E) digital device. SPSS 15.0 was used for data analysis; PEDSTATS was used to verify the structure of each family data. Familial correlations and heritability estimates were computed in FCOR and ASSOC modules of S.A.G.E. version 5.3. For systolic BP (SBP), correlation values were low to moderate (0.21< or = r < or =0.35); for diastolic BP (DBP) values were found to be moderate (0.24< or = r < or =0. 50). Genetic factors explain 43 and 49% of the total variation in SBP and DBP, respectively. A moderate amount of the SBP and the DBP is accounted for by genetic factors.

Association of growth factors, HIF-1 and NF-κB expression with proteasomes in endometrial cancer.

PubMed

Spirina, Ludmila V; Yunusova, Nataliya V; Kondakova, Irina V; Kolomiets, Larisa A; Koval, Valeriya D; Chernyshova, Alena L; Shpileva, Olga V

2012-09-01

Insulin-like growth factors (IGFs), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1 (HIF-1), and nuclear factor kappa-B (NF-κB) are known to play an important role in endometrial cancer pathogenesis. However, the proteolytic regulation of these factors is still poorly understood. We studied the correlation between chymotrypsin-like activity of proteasomes and IGF-I, IGF-II, VEGF, HIF-1, and NF-κB levels in endometrial cancer tissues. It was shown that the total activity of proteasomes and the activity of the 20S and 26S proteasomes in malignant tumors were significantly higher than those observed in the normal endometrium. Negative relationships between the proteasome activity and IGF-I, HIF-1, and NF-κB p50 expressions were found. High 20S proteasome activity was associated with increase of HIF-1 level. Positive relationships between IGF-I expression and two classic forms of NF-κB p50 and p65 in endometrial cancer were revealed. The data obtained indicate the possible proteasomal regulation of growth and transcription factors. The major pool of IGF-I is located in the extracellular space, and it is likely that extracellular proteasomes also take part in the regulation of the IGF-I content. The present data show the evidence of proteasome regulation of growth and nuclear factors that can play an important role in cancer pathogenesis.

Mitochondrial reactive oxygen species mediate the lipopolysaccharide-induced pro-inflammatory response in human gingival fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Xue; Wang, Xiaoxuan; Zheng, Ming, E-mail: zhengm@bjmu.edu.cn

Although periodontal diseases are initiated by bacteria that colonize the tooth surface and gingival sulcus, the host response is believed to play an essential role in the breakdown of connective tissue and bone. Mitochondrial reactive oxygen species (mtROS) have been proposed to regulate the activation of the inflammatory response by the innate immune system. However, the role of mtROS in modulating the response of human gingival fibroblasts (HGFs) to immune stimulation by lipopolysaccharides (LPS) has yet to be fully elucidated. Here, we showed that LPS from Porphyromonas gingivalis stimulated HGFs to increase mtROS production, which could be inhibited by treatmentmore » with a mitochondrial-targeted exogenous antioxidant (mito-TEMPO) or transfection with manganese superoxide dismutase (MnSOD). A time-course study revealed that an increase in the concentration of mtROS preceded the expression of inflammatory cytokines in HGFs. Mito-TEMPO treatment or MnSOD transfection also significantly prevented the LPS-induced increase of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. Furthermore, suppressing LPS-induced mtROS generation inhibited the activation of p38, c-Jun N-terminal kinase, and inhibitor of nuclear factor-κB kinase, as well as the nuclear localization of nuclear factor-κB. These results demonstrate that mtROS generation is a key signaling event in the LPS-induced pro-inflammatory response of HGFs. - Highlights: • Inflammation is thought to promote pathogenic changes in periodontitis. • We investigated mtROS as a regulator of inflammation in gingival fibroblasts. • Targeted antioxidants were used to inhibit mtROS production after LPS challenge. • Inhibiting mtROS generation suppressed the secretion of pro-inflammatory cytokines. • JNK, p38, IKK, and NF-κB were shown to act as transducers of mtROS signaling.« less

Phosphorylation of a conserved serine in the deoxyribonucleic acid binding domain of nuclear receptors alters intracellular localization.

PubMed

Sun, Kai; Montana, Vedrana; Chellappa, Karthikeyani; Brelivet, Yann; Moras, Dino; Maeda, Yutaka; Parpura, Vladimir; Paschal, Bryce M; Sladek, Frances M

2007-06-01

Nuclear receptors (NRs) are a superfamily of transcription factors whose genomic functions are known to be activated by lipophilic ligands, but little is known about how to deactivate them or how to turn on their nongenomic functions. One obvious mechanism is to alter the nuclear localization of the receptors. Here, we show that protein kinase C (PKC) phosphorylates a highly conserved serine (Ser) between the two zinc fingers of the DNA binding domain of orphan receptor hepatocyte nuclear factor 4alpha (HNF4alpha). This Ser (S78) is adjacent to several positively charged residues (Arg or Lys), which we show here are involved in nuclear localization of HNF4alpha and are conserved in nearly all other NRs, along with the Ser/threonine (Thr). A phosphomimetic mutant of HNF4alpha (S78D) reduced DNA binding, transactivation ability, and protein stability. It also impaired nuclear localization, an effect that was greatly enhanced in the MODY1 mutant Q268X. Treatment of the hepatocellular carcinoma cell line HepG2 with PKC activator phorbol 12-myristate 13-acetate also resulted in increased cytoplasmic localization of HNF4alpha as well as decreased endogenous HNF4alpha protein levels in a proteasome-dependent fashion. We also show that PKC phosphorylates the DNA binding domain of other NRs (retinoic acid receptor alpha, retinoid X receptor alpha, and thyroid hormone receptor beta) and that phosphomimetic mutants of the same Ser/Thr result in cytoplasmic localization of retinoid X receptor alpha and peroxisome proliferator-activated receptor alpha. Thus, phosphorylation of this conserved Ser between the two zinc fingers may be a common mechanism for regulating the function of NRs.

Impacts of Geoengineering and Nuclear War on Chinese Agriculture

NASA Astrophysics Data System (ADS)

Xia, L.; Robock, A.

2011-12-01

Climate is one of the most important factors determining crop yields and world food supplies. To be well prepared for possible futures, it is necessary to study yield changes of major crops under different climate scenarios. Here we consider two situations: stratospheric sulfate geoengineering and nuclear war. Although we certainly do not advocate either scenario, we cannot exclude the possibilities: if global warming is getting worse, we might have to deliberately manipulate global temperature; if nuclear weapons still exist, we might face a nuclear war catastrophe. Since in both scenarios there would be reductions of temperature, precipitation, and insolation, which are three controlling factors on crop growth, it is important to study food supply changes under the two cases. We conducted our simulations for China, because it has the highest population and crop production in the world and it is under the strong influence of the summer monsoon, which would be altered in geoengineering and nuclear war scenarios. To examine the effects of climate changes induced by geoengineering and nuclear war on Chinese agriculture, we use the DSSAT crop model. We first evaluate the model by forcing it with daily weather data and management practices for the period 1978-2008 for all the provinces in China, and compare the results to observations of the yields of major crops in China (middle season rice, winter wheat, and maize). Then we perturbed observed weather data using climate anomalies for geoengineering and nuclear war simulations using NASA GISS ModelE. For stratospheric geoengineering, we consider the injection of 5 Tg SO2 per year into the tropical lower stratosphere. For the nuclear war scenario, we consider the effects of 5 Tg of soot that could be injected into the upper troposphere by a war between India and Pakistan using only 100 Hiroshima-size atomic bombs dropped on cities. We perturbed each year of the 31-year climate record with anomalies from each year of geoengineering and nuclear war simulations for different regions in China. Without changes of agricultural technology, we found that in both climate scenarios, the national crop production decreases, but different regions responded differently, indicating that the climate under which agriculture is conducted is a key factor to determine the impacts of geoengineering and nuclear war on agriculture. In southern China, the cooling helps the rice and maize grow. In northern China, the cooling makes the temperatures so cold that it hurts crop productivity, and in western China, the reduction of precipitation causes failed crop growth. To adapt to geoengineering and nuclear war scenarios, we could substitute crops that would grow better in the perturbed climate, increase fertilizer usage, irrigate agricultural land, change planting date, or change to seeds which are tolerant of cooler and drier climates.

The Protective Effect of Glycyrrhetinic Acid on Carbon Tetrachloride-Induced Chronic Liver Fibrosis in Mice via Upregulation of Nrf2

PubMed Central

Chen, Shaoru; Zou, Liyi; Li, Li; Wu, Tie

2013-01-01

This study was designed to investigate the potentially protective effects of glycyrrhetinic acid (GA) and the role of transcription factor nuclear factor-erythroid 2(NF-E2)-related factor 2 (Nrf2) signaling in the regulation of Carbon Tetrachloride (CCl4)-induced chronic liver fibrosis in mice. The potentially protective effects of GA on CCl4-induced chronic liver fibrosis in mice were depicted histologically and biochemically. Firstly, histopathological changes including regenerative nodules, inflammatory cell infiltration and fibrosis were induced by CCl4.Then, CCl4 administration caused a marked increase in the levels of serum aminotransferases (GOT, GPT), serum monoamine oxidase (MAO) and lipid peroxidation (MDA) as well as MAO in the mice liver homogenates. Also, decreased nuclear Nrf2 expression, mRNA levels of its target genes such as superoxide dismutase 3 (SOD3), catalase (CAT), glutathione peroxidase 2 (GPX2), and activity of cellular antioxidant enzymes were found after CCl4 exposure. All of these phenotypes were markedly reversed by the treatment of the mice with GA. In addition, GA exhibited the antioxidant effects in vitro by on FeCl2-ascorbate induced lipid peroxidation in mouse liver homogenates, and on DPPH scavenging activity. Taken together, these results suggested that GA can protect the liver from oxidative stress in mice, presumably through activating the nuclear translocation of Nrf2, enhancing the expression of its target genes and increasing the activity of the antioxidant enzymes. Therefore, GA may be an effective hepatoprotective agent and viable candidate for treating liver fibrosis and other oxidative stress-related diseases. PMID:23341968

Hericium erinaceus Inhibits TNF-α-Induced Angiogenesis and ROS Generation through Suppression of MMP-9/NF-κB Signaling and Activation of Nrf2-Mediated Antioxidant Genes in Human EA.hy926 Endothelial Cells.

PubMed

Chang, Hebron C; Yang, Hsin-Ling; Pan, Jih-Hao; Korivi, Mallikarjuna; Pan, Jian-You; Hsieh, Meng-Chang; Chao, Pei-Min; Huang, Pei-Jane; Tsai, Ching-Tsan; Hseu, You-Cheng

2016-01-01

Hericium erinaceus (HE) is an edible mushroom that has been shown to exhibit anticancer and anti-inflammatory activities. We investigated the antiangiogenic and antioxidant potentials of ethanol extracts of HE in human endothelial (EA.hy926) cells upon tumor necrosis factor-α- (TNF-α-) stimulation (10 ng/mL). The underlying molecular mechanisms behind the pharmacological efficacies were elucidated. We found that noncytotoxic concentrations of HE (50-200 μg/mL) significantly inhibited TNF-α-induced migration/invasion and capillary-like tube formation of endothelial cells. HE treatment suppressed TNF-α-induced activity and/or overexpression of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1). Furthermore, HE downregulated TNF-α-induced nuclear translocation and transcriptional activation of nuclear factor-κB (NF-κB) followed by suppression of I-κB (inhibitor-κB) degradation. Data from fluorescence microscopy illustrated that increased intracellular ROS production upon TNF-α-stimulation was remarkably inhibited by HE pretreatment in a dose-dependent manner. Notably, HE triggered antioxidant gene expressions of heme oxygenase-1 (HO-1), γ-glutamylcysteine synthetase (γ-GCLC), and glutathione levels, which may contribute to inhibition of ROS. Increased antioxidant status was associated with upregulated nuclear translocation and transcriptional activation of NF-E2 related factor-2 (Nrf2) in HE treated cells. Our findings conclude that antiangiogenic and anti-inflammatory activities of H. erinaceus may contribute to its anticancer property through modulation of MMP-9/NF-κB and Nrf2-antioxidant signaling pathways.

Hericium erinaceus Inhibits TNF-α-Induced Angiogenesis and ROS Generation through Suppression of MMP-9/NF-κB Signaling and Activation of Nrf2-Mediated Antioxidant Genes in Human EA.hy926 Endothelial Cells

PubMed Central

Chang, Hebron C.; Yang, Hsin-Ling; Pan, Jih-Hao; Korivi, Mallikarjuna; Pan, Jian-You; Hsieh, Meng-Chang; Chao, Pei-Min; Huang, Pei-Jane; Tsai, Ching-Tsan; Hseu, You-Cheng

2016-01-01

Hericium erinaceus (HE) is an edible mushroom that has been shown to exhibit anticancer and anti-inflammatory activities. We investigated the antiangiogenic and antioxidant potentials of ethanol extracts of HE in human endothelial (EA.hy926) cells upon tumor necrosis factor-α- (TNF-α-) stimulation (10 ng/mL). The underlying molecular mechanisms behind the pharmacological efficacies were elucidated. We found that noncytotoxic concentrations of HE (50–200 μg/mL) significantly inhibited TNF-α-induced migration/invasion and capillary-like tube formation of endothelial cells. HE treatment suppressed TNF-α-induced activity and/or overexpression of matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1). Furthermore, HE downregulated TNF-α-induced nuclear translocation and transcriptional activation of nuclear factor-κB (NF-κB) followed by suppression of I-κB (inhibitor-κB) degradation. Data from fluorescence microscopy illustrated that increased intracellular ROS production upon TNF-α-stimulation was remarkably inhibited by HE pretreatment in a dose-dependent manner. Notably, HE triggered antioxidant gene expressions of heme oxygenase-1 (HO-1), γ-glutamylcysteine synthetase (γ-GCLC), and glutathione levels, which may contribute to inhibition of ROS. Increased antioxidant status was associated with upregulated nuclear translocation and transcriptional activation of NF-E2 related factor-2 (Nrf2) in HE treated cells. Our findings conclude that antiangiogenic and anti-inflammatory activities of H. erinaceus may contribute to its anticancer property through modulation of MMP-9/NF-κB and Nrf2-antioxidant signaling pathways. PMID:26823953

Ginsenoside Rg3 improves cardiac mitochondrial population quality: Mimetic exercise training

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sun, Mengwei; Huang, Chenglin; Wang, Cheng

Highlights: •Rg3 is an ergogenic aid. •Rg3 improves mitochondrial antioxidant capacity. •Rg3 regulates mitochondria dynamic remodeling. •Rg3 alone matches some the benefits of aerobic exercise. -- Abstract: Emerging evidence indicates exercise training could mediate mitochondrial quality control through the improvement of mitochondrial dynamics. Ginsenoside Rg3 (Rg3), one of the active ingredients in Panax ginseng, is well known in herbal medicine as a tonic and restorative agent. However, the molecular mechanism underlying the beneficial effects of Rg3 has been elusive. In the present study, we compared the effects of Rg3 administration with aerobic exercise on mitochondrial adaptation in cardiac muscle tissuemore » of Sprague–Dawley (SD) rats. Three groups of SD rats were studied: (1) sedentary control, (2) Rg3-treated and (3) aerobic exercise trained. Both aerobic exercise training and Rg3 supplementation enhanced peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1α) and nuclear factor-E2-related factor 2 (Nrf2) protein levels in cardiac muscle. The activation of PGC-1α led to increased mRNA levels of mitochondrial transcription factor A (Tfam) and nuclear related factor 1(Nrf1), these changes were accompanied by increases in mitochondrial DNA copy number and complex protein levels, while activation of Nrf2 increased levels of phase II detoxifying enzymes, including nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1(NQO1), superoxide dismutase (MnSOD) and catalase. Aerobic exercise also enhanced mitochondrial autophagy pathway activity, including increased conversion of LC3-I to LC3-II and greater expression of beclin1 and autophagy-related protein 7 (ATG7), these effects of aerobic exercise are comparable to that of Rg3. These results demonstrate that Rg3 mimics improved cardiac adaptations to exercise by regulating mitochondria dynamic remodeling and enhancing the quantity and quality of mitochondria.« less

Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI.

PubMed

Guerard, Marie; Robin, Thomas; Perron, Pascal; Hatat, Anne-Sophie; David-Boudet, Laurence; Vanwonterghem, Laetitia; Busser, Benoit; Coll, Jean-Luc; Lantuejoul, Sylvie; Eymin, Beatrice; Hurbin, Amandine; Gazzeri, Sylvie

2018-04-28

Many Receptor Tyrosine Kinases translocate from the cell surface to the nucleus in normal and pathological conditions, including cancer. Here we report the nuclear expression of insulin-like growth factor-1 receptor (IGF1R) in primary human lung tumours. Using lung cancer cell lines and lung tumour xenografts, we demonstrate that the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib induces the nuclear accumulation of IGF1R in mucinous lung adenocarcinoma by a mechanism involving the intracellular re-localization of the growth factor amphiregulin. Amphiregulin allows the binding of IGF1R to importin-β1 and promotes its nuclear transport. The nuclear accumulation of IGF1R by amphiregulin induces cell cycle arrest through p21 WAF1/CIP1 upregulation, and prevents the induction of apoptosis in response to gefitinib. These results identify amphiregulin as the first nuclear localization signal-containing protein that interacts with IGF1R and allows its nuclear translocation. Furthermore they indicate that nuclear expression of IGF1R contributes to EGFR-TKI resistance in lung cancer. Copyright © 2018 Elsevier B.V. All rights reserved.

The effects of dexamethasone on rat brain cortical nuclear factor kappa B (NF-{kappa}B) in endotoxic shock

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang Zhi; Kang Jinsong; Li Yang

2006-08-01

To explore the molecular mechanism of brain tissue injury induced by lipopolysaccharide (LPS), we studied the effects of endotoxic shock on rat brain cortex NF-{kappa}B and the effects of dexamethasone on these changes. Rats were randomly divided into LPS, LPS + dexamethasone, and control groups. The DNA-binding activity of NF-{kappa}B was observed using electrophoretic mobility shift assay (EMSA). Protein expression in nuclear extracts was studied using Western blots, and nuclear translocation was observed using immunohistochemistry. These indices were assayed at 1 h and 4 h after intravenous injection of LPS (4 mg.kg{sup -1}). EMSA showed significantly increased NF-{kappa}B DNA-binding activitymore » in nuclear extracts from the LPS group at both 1 h and 4 h after LPS injection, compared with the control group (P < 0.01). For the LPS group, the NF-{kappa}B DNA-binding activity was greater at 1 h than at 4 h (P < 0.05). The expression of p65 and p50 protein in the nuclear extracts was also increased, as compared with the control group. However, the expression of p65 and p50 protein from cytosolic extracts did not show any significant change. Dexamethasone down-regulated not only NF-{kappa}B DNA-binding activity but also the expression of p65 protein in the nuclear extracts. From these data, we have concluded that NF-{kappa}B activation and nuclear translocation of NF-{kappa}B play a key role in the molecular mechanism of brain tissue injury in endotoxic shock. Dexamethasone may alleviate brain injury by inhibiting NF-{kappa}B activation.« less

Nuclear microscopy in biomedical analysis with special emphasis on clinical metal biology

NASA Astrophysics Data System (ADS)

Lindh, Ulf; Frisk, Peter; Nyström, Joakim; Danersund, Antero; Hudecek, Romuald; Lindvall, Anders; Thunell, Stig

1997-07-01

Nuclear microscopy based upon developments in high energy ion beam techniques is by now an accepted technique in many fields of research. The advancements into the biomedical field have, however, been slower than expected. A major factor explaining this tendency is the availability of nuclear microscopy. This paper reviews briefly the biomedical work using nuclear microscopy that has been carried out since the 4 th International Conference on Nuclear Microprobe Technology and Applications held in Shanghai. Nuclear microscopy of isolated individual blood cells from patients adversely affected by metal exposure from dental amalgam has been performed both before and after removal of the metallic fillings. The elemental profile of blood cells was more or less normalised after treatment. Some of these results will be presented to illustrate a medical application. Results from bulk analysis by ICP-MS of erythrocytes and plasma before and after treatment will also be presented to illustrate the difference in information content between these two approaches as well as the need for complementary information in solving biomedical problems. As part of a larger study of acute porphyria, nuclear microscopy of blood cells was included among the 78 laboratory tests. The approach in this study was unbiased in the sense that no hypothesis was formulated as to which laboratory parameters would be the most explanatory for health or disease. Multivariate discriminant analysis was applied to the large amounts of data acquired. This approach led to the hypothesis that oxidative stress increased the synthesis of manganese-dependent superoxide dismutase in the mitochondria of polymorphonuclear leukocytes, explaining the increase of manganese in these cells. Antioxidant therapy was therefore applied to a couple of patients with porphyria, however, without clinical success.

Utilization of nuclear medicine scintigraphy in Taiwan, 1997-2009.

PubMed

Hung, Mao-Chin; Hsieh, Wanhua Annie; Chang, Peter Wushou; Hwang, Jeng-Jong

2011-12-01

To analyze the utilization of nuclear medicine scintigraphy in the Taiwanese population within the national health-care system between 1997 and 2009. Based on the Taiwan's National Health Insurance Research Database of 1997-2009, a retrospective population-based analysis was conducted. Descriptive statistics and regression analysis were employed to analyze the frequencies and longitudinal trends in the utilization of diagnostic nuclear medicine procedures during the period. In addition, correlation analysis was applied to determine the correlated factors in the utility of nuclear medicine scintigraphy. The annual total nuclear medicine scintigraphy was estimated to be 256,389 on average in 1997-2009 and 11.7 per 1,000 population over the period. The frequency had increased by 67% over the years, from 8.2 per 1,000 population in 1997 to 13.7 per 1,000 population in 2009. The most frequently performed procedures were whole-body bone scans (33.4% of total) and myocardial perfusion scans (29.4% of total), with 4,615 and 5,620 increments per year, respectively. Most patients were in the age group of 41-65 years old when taking examinations. In addition, male subjects were slightly more than female patients (51.5 vs. 48.5%). Furthermore, the frequencies of whole-body bone scans and PET scans were proportional to the incidences of cancers (correlation coefficients were 0.96 and 0.94, respectively). The utilization of nuclear medicine scintigraphy with the National Health Insurance system in Taiwan has been changed considerably in the past 13 years. Both whole-body bone scan and myocardial perfusion scan were performed most often with significantly increases. The trend of nuclear medicine scintigraphy may have potential impact on making health-care policy in Taiwan.

Unusual Attenuation Recovery Process After Fiber Optic Cable Irradiation

NASA Astrophysics Data System (ADS)

Konečná, Z.; Plaček, V.; Havránek, P.

2017-11-01

At present, the number of optical cables in nuclear power plants has been increasing. Fiber optic cables are commonly used at nuclear power plants in instrumentation and control systems but they are usually used in environments without radiation. Nevertheless, currently, the number of applications in NPP containment with radiation is increasing. One of the most prevalent effects of radiation exposure is an increase of signal attenuation (signal loss). This is the result of fiber darkening due to radiation exposure and it is the main limitation factor in application of fiber optics in radiation environment. However, after the irradiation, the fiber optics go through a “recovery process” during which the optical properties improve again; i.e. attenuation decreases. However, we have found cable, where the expected healing process after few days changed its trend and the attenuation increased again to a value well above the attenuation just after the irradiation. This paper describes experiments that were carried out to explain this unusual recovery behaviour.

Effects of the Fukushima Daiichi nuclear accident on goshawk reproduction

PubMed Central

Murase, Kaori; Murase, Joe; Horie, Reiko; Endo, Koichi

2015-01-01

Although the influence of nuclear accidents on the reproduction of top predators has not been investigated, it is important that we identify the effects of such accidents because humans are also top predators. We conducted field observation for 22 years and analysed the reproductive performance of the goshawk (Accipiter gentilis fujiyamae), a top avian predator in the North Kanto area of Japan, before and after the accidents at the Fukushima Daiichi nuclear power plant that occurred in 2011. The reproductive performance declined markedly compared with the pre-accident years and progressively decreased for the three post-accident study years. Moreover, it was suggested that these declines were primarily caused by an increase in the air dose rate of radio-active contaminants measured under the nests caused by the nuclear accidents, rather than by other factors. We consider the trends in the changes of the reproductive success rates and suggest that internal exposure may play an important role in the reproductive performance of the goshawk, as well as external exposure. PMID:25802117

Non-senescent Hydra tolerates severe disturbances in the nuclear lamina.

PubMed

Klimovich, Alexander; Rehm, Arvid; Wittlieb, Jörg; Herbst, Eva-Maria; Benavente, Ricardo; Bosch, Thomas C G

2018-05-10

The cnidarian Hydra is known for its unlimited lifespan and non-senescence, due to the indefinite self-renewal capacity of its stem cells. While proteins of the Lamin family are recognized as critical factors affecting senescence and longevity in human and mice, their putative role in the extreme longevity and non-senescence in long-living animals remains unknown. Here we analyze the role of a single lamin protein in non-senescence of Hydra . We demonstrate that proliferation of stem cells in Hydra is robust against the disturbance of Lamin expression and localization. While Lamin is indispensable for Hydra , the stem cells tolerate overexpression, downregulation and mislocalization of Lamin, and disturbances in the nuclear envelope structure. This extraordinary robustness may underlie the indefinite self-renewal capacity of stem cells and the non-senescence of Hydra . A relatively low complexity of the nuclear envelope architecture in basal Metazoa might allow for their extreme lifespans, while an increasing complexity of the nuclear architecture in bilaterians resulted in restricted lifespans.

Effects of the Fukushima Daiichi nuclear accident on goshawk reproduction.

PubMed

Murase, Kaori; Murase, Joe; Horie, Reiko; Endo, Koichi

2015-03-24

Although the influence of nuclear accidents on the reproduction of top predators has not been investigated, it is important that we identify the effects of such accidents because humans are also top predators. We conducted field observation for 22 years and analysed the reproductive performance of the goshawk (Accipiter gentilis fujiyamae), a top avian predator in the North Kanto area of Japan, before and after the accidents at the Fukushima Daiichi nuclear power plant that occurred in 2011. The reproductive performance declined markedly compared with the pre-accident years and progressively decreased for the three post-accident study years. Moreover, it was suggested that these declines were primarily caused by an increase in the air dose rate of radio-active contaminants measured under the nests caused by the nuclear accidents, rather than by other factors. We consider the trends in the changes of the reproductive success rates and suggest that internal exposure may play an important role in the reproductive performance of the goshawk, as well as external exposure.

Accuracy and Precision of Radioactivity Quantification in Nuclear Medicine Images

PubMed Central

Frey, Eric C.; Humm, John L.; Ljungberg, Michael

2012-01-01

The ability to reliably quantify activity in nuclear medicine has a number of increasingly important applications. Dosimetry for targeted therapy treatment planning or for approval of new imaging agents requires accurate estimation of the activity in organs, tumors, or voxels at several imaging time points. Another important application is the use of quantitative metrics derived from images, such as the standard uptake value commonly used in positron emission tomography (PET), to diagnose and follow treatment of tumors. These measures require quantification of organ or tumor activities in nuclear medicine images. However, there are a number of physical, patient, and technical factors that limit the quantitative reliability of nuclear medicine images. There have been a large number of improvements in instrumentation, including the development of hybrid single-photon emission computed tomography/computed tomography and PET/computed tomography systems, and reconstruction methods, including the use of statistical iterative reconstruction methods, which have substantially improved the ability to obtain reliable quantitative information from planar, single-photon emission computed tomography, and PET images. PMID:22475429

Deciphering the origin of mito-nuclear discordance in two sibling caddisfly species.

PubMed

Weigand, Hannah; Weiss, Martina; Cai, Huimin; Li, Yongping; Yu, Lili; Zhang, Christine; Leese, Florian

2017-10-01

An increasing number of phylogenetic studies have reported discordances among nuclear and mitochondrial markers. These discrepancies are highly relevant to widely used biodiversity assessment approaches, such as DNA barcoding, that rely almost exclusively on mitochondrial markers. Although the theoretical causes of mito-nuclear discordances are well understood, it is often extremely challenging to determine the principal underlying factor in a given study system. In this study, we uncovered significant mito-nuclear discordances in a pair of sibling caddisfly species. Application of genome sequencing, ddRAD and DNA barcoding revealed ongoing hybridization, as well as historical hybridization in Pleistocene refugia, leading us to identify introgression as the ultimate cause of the observed discordance pattern. Our novel genomic data, the discovery of a European-wide hybrid zone and the availability of established techniques for laboratory breeding make this species pair an ideal model system for studying species boundaries with ongoing gene flow. © 2017 John Wiley & Sons Ltd.

Cyclophilin B enhances HIV-1 Infection

PubMed Central

DeBoer, Jason; Madson, Christian J.; Belshan, Michael

2016-01-01

Cyclophilin B (CypB) is a member of the immunophilin family and intracellular chaperone. It predominantly localizes to the ER, but also contains a nuclear localization signal and is secreted from cells. CypB has been shown to interact with the Gag protein of human immunodeficiency type 1 (HIV-1). Several proteomic and genetic studies identified it as a potential factor involved in HIV replication. Herein, we show that over-expression of CypB enhances HIV infection by increasing nuclear import of viral DNA. This enhancement was unaffected by cyclosporine treatment and requires the N-terminus of the protein. The N-terminus contains an ER leader sequence, putative nuclear localization signal, and is required for secretion. Deletion of the N-terminus resulted in mislocalization from the ER and suppression of HIV infection. Passive transfer experiments showed that secreted CypB did not impact HIV infection. Combined, these experiments show that intracellular CypB modulates a pathway of HIV nuclear import. PMID:26774171

Cyclophilin B enhances HIV-1 infection.

PubMed

DeBoer, Jason; Madson, Christian J; Belshan, Michael

2016-02-01

Cyclophilin B (CypB) is a member of the immunophilin family and intracellular chaperone. It predominantly localizes to the ER, but also contains a nuclear localization signal and is secreted from cells. CypB has been shown to interact with the Gag protein of human immunodeficiency type 1 (HIV-1). Several proteomic and genetic studies identified it as a potential factor involved in HIV replication. Herein, we show that over-expression of CypB enhances HIV infection by increasing nuclear import of viral DNA. This enhancement was unaffected by cyclosporine treatment and requires the N-terminus of the protein. The N-terminus contains an ER leader sequence, putative nuclear localization signal, and is required for secretion. Deletion of the N-terminus resulted in mislocalization from the ER and suppression of HIV infection. Passive transfer experiments showed that secreted CypB did not impact HIV infection. Combined, these experiments show that intracellular CypB modulates a pathway of HIV nuclear import. Copyright © 2015 Elsevier Inc. All rights reserved.

Non-senescent Hydra tolerates severe disturbances in the nuclear lamina

PubMed Central

Rehm, Arvid; Wittlieb, Jörg; Herbst, Eva-Maria; Benavente, Ricardo

2018-01-01

The cnidarian Hydra is known for its unlimited lifespan and non-senescence, due to the indefinite self-renewal capacity of its stem cells. While proteins of the Lamin family are recognized as critical factors affecting senescence and longevity in human and mice, their putative role in the extreme longevity and non-senescence in long-living animals remains unknown. Here we analyze the role of a single lamin protein in non-senescence of Hydra. We demonstrate that proliferation of stem cells in Hydra is robust against the disturbance of Lamin expression and localization. While Lamin is indispensable for Hydra, the stem cells tolerate overexpression, downregulation and mislocalization of Lamin, and disturbances in the nuclear envelope structure. This extraordinary robustness may underlie the indefinite self-renewal capacity of stem cells and the non-senescence of Hydra. A relatively low complexity of the nuclear envelope architecture in basal Metazoa might allow for their extreme lifespans, while an increasing complexity of the nuclear architecture in bilaterians resulted in restricted lifespans. PMID:29754147

Proceedings of the Symposium on Training of Nuclear Facility Personnel (7th, Orlando, Florida, April 27-30, 1987).

ERIC Educational Resources Information Center

Oak Ridge National Lab., TN.

These proceedings contain program highlights as well as 45 papers given during six sessions of the Symposium on Training of Nuclear Facility Personnel. The six sessions are entitled: (1) the training challenge; (2) influences on nuclear training; (3) the human factors--training partnership and factors affecting job performance; (4) current…

Is crisis stability still achievable?

NASA Astrophysics Data System (ADS)

Pollack, Joshua

During the Cold War, the idea of crisis stability concerned whether the United States and the Soviet Union would be faced with powerful incentives to strike each other first with their nuclear weapons during periods of tension. This idea influenced the design of nuclear forces and guided aspects of nuclear arms control. The United States and Russia continue to operate large, alert nuclear forces, but at least three new factors have emerged that add significantly greater complexity to this picture. The first new factor consists of the development and deployment of new strategic military technologies that are entangled with nuclear weapons. These include strategic ballistic missile defenses, counter-space weapons, and strategic conventional weapons. The second new factor consists of new dyads of interacting strategic forces beyond US-Russia. These include US-China, US-North Korea, India-Pakistan, and India-China. The third new factor consists of the emergence of three-actor crisis stability dynamics, where the third actor is not necessarily nuclear-armed. This paper illustrates the concept with the US-North Korea-South Korea triangle. It briefly discusses the implications of these developments and reflects on the broad policy options that may be available.

Using the Time-Correlated Induced Fission Method to Simultaneously Measure the 235U Content and the Burnable Poison Content in LWR Fuel Assemblies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Root, M. A.; Menlove, H. O.; Lanza, R. C.

The uranium neutron coincidence collar uses thermal neutron interrogation to verify the 235U mass in low-enriched uranium (LEU) fuel assemblies in fuel fabrication facilities. Burnable poisons are commonly added to nuclear fuel to increase the lifetime of the fuel. The high thermal neutron absorption by these poisons reduces the active neutron signal produced by the fuel. Burnable poison correction factors or fast-mode runs with Cd liners can help compensate for this effect, but the correction factors rely on operator declarations of burnable poison content, and fast-mode runs are time-consuming. Finally, this paper describes a new analysis method to measure themore » 235U mass and burnable poison content in LEU nuclear fuel simultaneously in a timely manner, without requiring additional hardware.« less

Using the Time-Correlated Induced Fission Method to Simultaneously Measure the 235U Content and the Burnable Poison Content in LWR Fuel Assemblies

DOE PAGES

Root, M. A.; Menlove, H. O.; Lanza, R. C.; ...

2018-03-21

The uranium neutron coincidence collar uses thermal neutron interrogation to verify the 235U mass in low-enriched uranium (LEU) fuel assemblies in fuel fabrication facilities. Burnable poisons are commonly added to nuclear fuel to increase the lifetime of the fuel. The high thermal neutron absorption by these poisons reduces the active neutron signal produced by the fuel. Burnable poison correction factors or fast-mode runs with Cd liners can help compensate for this effect, but the correction factors rely on operator declarations of burnable poison content, and fast-mode runs are time-consuming. Finally, this paper describes a new analysis method to measure themore » 235U mass and burnable poison content in LEU nuclear fuel simultaneously in a timely manner, without requiring additional hardware.« less

Enhanced Expression of WD Repeat-Containing Protein 35 via Nuclear Factor-Kappa B Activation in Bupivacaine-Treated Neuro2a Cells

PubMed Central

Huang, Lei; Kondo, Fumio; Harato, Misako; Feng, Guo-Gang; Ishikawa, Naoshisa; Fujiwara, Yoshihiro; Okada, Shoshiro

2014-01-01

The family of WD repeat proteins comprises a large number of proteins and is involved in a wide variety of cellular processes such as signal transduction, cell growth, proliferation, and apoptosis. Bupivacaine is a sodium channel blocker administered for local infiltration, nerve block, epidural, and intrathecal anesthesia. Recently, we reported that bupivacaine induces reactive oxygen species (ROS) generation and p38 mitogen-activated protein kinase (MAPK) activation, resulting in an increase in the expression of WD repeat-containing protein 35 (WDR35) in mouse neuroblastoma Neuro2a cells. It has been shown that ROS activate MAPK through phosphorylation, followed by activation of nuclear factor-kappa B (NF-κB) and activator protein 1 (AP-1). The present study was undertaken to test whether NF-κB and c-Jun/AP-1 are involved in bupivacaine-induced WDR35 expression in Neuro2a cells. Bupivacaine activated both NF-κB and c-Jun in Neuro2a cells. APDC, an NF-κB inhibitor, attenuated the increase in NF-κB activity and WDR35 protein expression in bupivacaine-treated Neuro2a cells. GW9662, a selective peroxisome proliferator-activated receptor-γ antagonist, enhanced the increase in NF-κB activity and WDR35 protein expression in bupivacaine-treated Neuro2a cells. In contrast, c-Jun siRNA did not inhibit the bupivacaine-induced increase in WDR35 mRNA expression. These results indicate that bupivacaine induces the activation of transcription factors NF-κB and c-Jun/AP-1 in Neuro2a cells, while activation of NF-κB is involved in bupivacaine-induced increases in WDR35 expression. PMID:24466034

Dual-energy precursor and nuclear erythroid-related factor 2 activator treatment additively improve redox glutathione levels and neuron survival in aging and Alzheimer mouse neurons upstream of reactive oxygen species.

PubMed

Ghosh, Debolina; LeVault, Kelsey R; Brewer, Gregory J

2014-01-01

To determine whether glutathione (GSH) loss or increased reactive oxygen species (ROS) are more important to neuron loss, aging, and Alzheimer's disease (AD), we stressed or boosted GSH levels in neurons isolated from aging 3xTg-AD neurons compared with those from age-matched nontransgenic (non-Tg) neurons. Here, using titrating with buthionine sulfoximine, an inhibitor of γ-glutamyl cysteine synthetase (GCL), we observed that GSH depletion increased neuronal death of 3xTg-AD cultured neurons at increasing rates across the age span, whereas non-Tg neurons were resistant to GSH depletion until old age. Remarkably, the rate of neuron loss with ROS did not increase in old age and was the same for both genotypes, which indicates that cognitive deficits in the AD model were not caused by ROS. Therefore, we targeted for neuroprotection activation of the redox sensitive transcription factor, nuclear erythroid-related factor 2 (Nrf2) by 18 alpha glycyrrhetinic acid to stimulate GSH synthesis through GCL. This balanced stimulation of a number of redox enzymes restored the lower levels of Nrf2 and GCL seen in 3xTg-AD neurons compared with those of non-Tg neurons and promoted translocation of Nrf2 to the nucleus. By combining the Nrf2 activator together with the NADH precursor, nicotinamide, we increased neuron survival against amyloid beta stress in an additive manner. These stress tests and neuroprotective treatments suggest that the redox environment is more important for neuron survival than ROS. The dual neuroprotective treatment with nicotinamide and an Nrf2 inducer indicates that these age-related and AD-related changes are reversible. Copyright © 2014 Elsevier Inc. All rights reserved.

Sofalcone, a gastric mucosa protective agent, increases vascular endothelial growth factor via the Nrf2-heme-oxygenase-1 dependent pathway in gastric epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shibuya, Akiko; Onda, Kenji, E-mail: knjond@toyaku.ac.jp; Kawahara, Hirofumi

2010-07-30

Research highlights: {yields} Sofalcone increases HO-1 in gastric epithelial cells. {yields} The induction of HO-1 by sofalcone treatment follows the activation of Nrf2. {yields} The production of VEGF by sofalcone treatment is mediated by HO-1 induction. -- Abstract: Sofalcone, 2'-carboxymethoxy-4,4-bis(3-methyl-2-butenyloxy)chalcone, is an anti-ulcer agent that is classified as a gastric mucosa protective agent. Recent studies indicate heat shock proteins such as HSP32, also known as heme-oxygenase-1(HO-1), play important roles in protecting gastrointestinal tissues from several stresses. We have previously reported that sofalcone increases the expression of HO-1 in adipocytes and pre-adipocytes, although the effect of sofalcone on HO-1 induction inmore » gastrointestinal tissues is not clear. In the current study, we investigated the effects of sofalcone on the expression of HO-1 and its functional role in rat gastric epithelial (RGM-1) cells. We found that sofalcone increased HO-1 expression in RGM-1 cells in both time- and concentration-dependent manners. The HO-1 induction was associated with the nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in RGM-1 cells. We also observed that sofalcone increased vascular endothelial growth factor (VEGF) production in the culture medium. Treatment of RGM-1 cells with an HO-1 inhibitor (tin-protoporphyrin), or HO-1 siRNA inhibited sofalcone-induced VEGF production, suggesting that the effect of sofalcone on VEGF expression is mediated by the HO-1 pathway. These results suggest that the gastroprotective effects of sofalcone are partly exerted via Nrf2-HO-1 activation followed by VEGF production.« less

The Yeast Nuclear Pore Complex and Transport Through It

PubMed Central

Aitchison, John D.; Rout, Michael P.

2012-01-01

Exchange of macromolecules between the nucleus and cytoplasm is a key regulatory event in the expression of a cell’s genome. This exchange requires a dedicated transport system: (1) nuclear pore complexes (NPCs), embedded in the nuclear envelope and composed of proteins termed nucleoporins (or “Nups”), and (2) nuclear transport factors that recognize the cargoes to be transported and ferry them across the NPCs. This transport is regulated at multiple levels, and the NPC itself also plays a key regulatory role in gene expression by influencing nuclear architecture and acting as a point of control for various nuclear processes. Here we summarize how the yeast Saccharomyces has been used extensively as a model system to understand the fundamental and highly conserved features of this transport system, revealing the structure and function of the NPC; the NPC’s role in the regulation of gene expression; and the interactions of transport factors with their cargoes, regulatory factors, and specific nucleoporins. PMID:22419078

Modulation of nuclear factor-κB signaling and reduction of neural tube defects by quercetin-3-glucoside in embryos of diabetic mice.

PubMed

Tan, Chengyu; Meng, Fantong; Reece, E Albert; Zhao, Zhiyong

2018-05-04

Diabetes mellitus in early pregnancy increases the risk of birth defects in infants. Maternal hyperglycemia stimulates the expression of nitric oxide (NO) synthase 2 (NOS2), which can be regulated by transcription factors of the nuclear factor-κB (NF-κB) family. Increases in reactive nitrogen species (RNS) generate intracellular stress conditions, including nitrosative, oxidative, and endoplasmic reticulum (ER) stresses, and trigger programmed cell death (or apoptosis) in the neural folds, resulting in neural tube defects (NTDs) in the embryo. Inhibiting NOS2 can reduce NTDs; however, the underlying mechanisms require further delineation. Targeting NOS2 and associated nitrosative stress using naturally occurring phytochemicals is a potential approach to preventing birth defects in diabetic pregnancies. This study aims to investigate the effect of quercetin-3-glucoside (Q3G), a polyphenol flavonoid found in fruit, in reducing maternal diabetes-induced NTDs in an animal model, and to delineate the molecular mechanisms underlying Q3G action in regulating NOS2 expression. Female mice (C57BL/6) were induced to develop diabetes using streptozotocin before pregnancy. Diabetic pregnant mice were administered Q3G (100 mg/kg) daily via gavage feeding, introduction of drug to the stomach directly via a feeding needle, during neurulation from embryonic (E) day 6.5 to E9.5. After treatment, E10.5 embryos were collected and examined for the presence of NTDs and apoptosis in the neural tube. Expression of Nos2 and superoxide dismutase 1 (Sod1; an antioxidative enzyme) was quantified using Western blot assay. Nitrosative, oxidative, and endoplasmic reticulum (ER) stress conditions were assessed using specific biomarkers. Expression and posttranslational modification of factors in the NF-κB system were investigated. Treatment with Q3G (suspended in water) significantly decreased NTD rate (24.7%) and apoptosis in the embryos of diabetic mice, compared with those in the water-treated diabetic group (3.1%; p<0.001). Q3G decreased the expression of Nos2 and nitrosative stress (p<0.05). It also increased the levels of Sod1 (p<0.05), further increasing the antioxidative capacity of the cells. Q3G treatment also alleviated of ER stress in the embryos of diabetic mice (p<0.05). Q3G reduced the levels of p65 (RelA; p<0.05), a member of the NF-κB transcription factor family, but augmented the levels of the inhibitor of κBα (IκBα; p<0.05), which suppresses p65 nuclear translocation. In association with these changes, the levels of IκB kinase α (Ikkα) and IκBα phosphorylation were elevated (p<0.05). Q3G reduces the NTD rate in the embryos of diabetic dams. Q3G suppresses Nos2 and increases Sod1 expression, leading to alleviation of nitrosative, oxidative, and ER stress conditions. Q3G may regulate the expression of Nos2 via modulating the NF-κB transcription regulation system. Q3G, a naturally occurring polyphenol that has high bioavailability and low toxicity, is a promising candidate agent to prevent birth defects in diabetic pregnancies. The phytochemical quercetin-3-glucoside prevents neural tube defects in embryos of diabetic mice by alleviating nitrosative stress via suppression of the nuclear factor κB-regulated nitric oxide synthase 2 expression. Copyright © 2018 Elsevier Inc. All rights reserved.

Aluminium induced oxidative stress results in decreased mitochondrial biogenesis via modulation of PGC-1α expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sharma, Deep Raj; Sunkaria, Aditya; Wani, Willayat Yousuf

The present investigation was carried out to elucidate a possible molecular mechanism related to the effects of aluminium-induced oxidative stress on various mitochondrial respiratory complex subunits with special emphasis on the role of Peroxisome proliferator activated receptor gamma co-activator 1α (PGC-1α) and its downstream targets i.e. Nuclear respiratory factor-1(NRF-1), Nuclear respiratory factor-2(NRF-2) and Mitochondrial transcription factor A (Tfam) in mitochondrial biogenesis. Aluminium lactate (10 mg/kg b.wt./day) was administered intragastrically to rats for 12 weeks. After 12 weeks of exposure, we found an increase in ROS levels, mitochondrial DNA oxidation and decrease in citrate synthase activity in the Hippocampus (HC) andmore » Corpus striatum (CS) regions of rat brain. On the other hand, there was a decrease in the mRNA levels of the mitochondrial encoded subunits–NADH dehydrogenase (ND) subunits i.e. ND1, ND2, ND3, Cytochrome b (Cytb), Cytochrome oxidase (COX) subunits i.e. COX1, COX3, ATP synthase (ATPase) subunit 6 along with reduced expression of nuclear encoded subunits COX4, COX5A, COX5B of Electron transport chain (ETC). Besides, a decrease in mitochondrial DNA copy number and mitochondrial content in both regions of rat brain was observed. The PGC-1α was down-regulated in aluminium treated rats along with NRF-1, NRF-2 and Tfam, which act downstream from PGC-1α in aluminium treated rats. Electron microscopy results revealed a significant increase in the mitochondrial swelling, loss of cristae, chromatin condensation and decreases in mitochondrial number in case of aluminium treated rats as compared to control. So, PGC-1α seems to be a potent target for aluminium neurotoxicity, which makes it an almost ideal target to control or limit the damage that has been associated with the defective mitochondrial function seen in neurodegenerative diseases. - Highlights: • Aluminium decreases the mRNA levels of mitochondrial and nuclear encoded subunits. • It decreases the mtDNA copy number and mitochondrial content in rat brain. • It down-regulates the mRNA and protein levels of PGC-1α, NRF-1, NRF-2 and Tfam. • It also disturbs the mitochondrial or nuclear architecture of neurons. • Finally it also decreases mitochondrial number in HC and CS regions of rat brain.« less

The mitochondrial genome and a 60-kb nuclear DNA segment from Naegleria fowleri, the causative agent of primary amoebic meningoencephalitis.

PubMed

Herman, Emily K; Greninger, Alexander L; Visvesvara, Govinda S; Marciano-Cabral, Francine; Dacks, Joel B; Chiu, Charles Y

2013-01-01

Naegleria fowleri is a unicellular eukaryote causing primary amoebic meningoencephalitis, a neuropathic disease killing 99% of those infected, usually within 7-14 days. Naegleria fowleri is found globally in regions including the US and Australia. The genome of the related nonpathogenic species Naegleria gruberi has been sequenced, but the genetic basis for N. fowleri pathogenicity is unclear. To generate such insight, we sequenced and assembled the mitochondrial genome and a 60-kb segment of nuclear genome from N. fowleri. The mitochondrial genome is highly similar to its counterpart in N. gruberi in gene complement and organization, while distinct lack of synteny is observed for the nuclear segments. Even in this short (60-kb) segment, we identified examples of potential factors for pathogenesis, including ten novel N. fowleri-specific genes. We also identified a homolog of cathepsin B; proteases proposed to be involved in the pathogenesis of diverse eukaryotic pathogens, including N. fowleri. Finally, we demonstrate a likely case of horizontal gene transfer between N. fowleri and two unrelated amoebae, one of which causes granulomatous amoebic encephalitis. This initial look into the N. fowleri nuclear genome has revealed several examples of potential pathogenesis factors, improving our understanding of a neglected pathogen of increasing global importance. © 2013 The Author(s) Journal of Eukaryotic Microbiology © 2013 International Society of Protistologists.

Impact of Leishmania Infection on Host Macrophage Nuclear Physiology and Nucleopore Complex Integrity

PubMed Central

Isnard, Amandine; Christian, Jan G.; Kodiha, Mohamed; Stochaj, Ursula; McMaster, W. Robert; Olivier, Martin

2015-01-01

The protease GP63 is an important virulence factor of Leishmania parasites. We previously showed that GP63 reaches the perinuclear area of host macrophages and that it directly modifies nuclear translocation of the transcription factors NF-κB and AP-1. Here we describe for the first time, using molecular biology and in-depth proteomic analyses, that GP63 alters the host macrophage nuclear envelope, and impacts on nuclear processes. Our results suggest that GP63 does not appear to use a classical nuclear localization signal common between Leishmania species for import, but degrades nucleoporins, and is responsible for nuclear transport alterations. In the nucleoplasm, GP63 activity accounts for the degradation and mislocalization of proteins involved amongst others in gene expression and in translation. Collectively, our data indicates that Leishmania infection strongly affects nuclear physiology, suggesting that targeting of nuclear physiology may be a strategy beneficial for virulent Leishmania parasites. PMID:25826301

Biological Effects of Orthodontic Tooth Movement Into the Grafted Alveolar Cleft.

PubMed

Sun, Jian; Zhang, Xiaoyue; Li, Renmei; Chen, Zhengxi; Huang, Yuanliang; Chen, Zhenqi

2018-03-01

Functional stimulus during orthodontic tooth movement into the grafted bone can lead to better alveolar bone grafting outcomes. The aim of this study was to analyze the biological effects of orthodontic tooth movement into the grafted alveolar cleft area with histologic staining, fluorescence staining, and real-time polymerase chain reaction (PCR). An animal model of orthodontic tooth movement into the grafted alveolar cleft area was established in 8-week-old Sprague-Dawley rats. The animals were divided into the experimental group and the control group. Four checkpoints were observed: before orthodontic stimuli, day 1 after orthodontic stimuli, day 3 after orthodontic stimuli, and day 5 after orthodontic stimuli. The cleft bone formation conditions, including the collagen fibers and the activities of the osteoclasts and osteoblasts, were evaluated by histologic staining. The expression of tartrate-resistant acid phosphatase (TRAP), receptor activator nuclear factor κB ligand, and Runt-related transcription factor 2 was detected by real-time PCR in both groups. Hematoxylin-eosin staining showed that the remodeling process of iliac autografts was completed when the orthodontic stress was applied, whereas the bone tissues first showed osteoclastogenesis and then osteogenesis. On the basis of TRAP staining, the osteoclasts increased to the maximal amount on day 3 and decreased thereafter. Evidence from tetracycline fluorescence staining indicated that no obvious changes in osteoblast activity were detected at the early stage; however, it gradually increased, especially in the region close to the root surface. According to real-time PCR, the expression of TRAP increased in both the early and middle stages, that of receptor activator nuclear factor κB ligand increased in the early stage, and that of Runt-related transcription factor 2 increased in the late stage. Moreover, the results showed significant differences between the experimental and control groups. Orthodontic tooth movement into the alveolar cleft bone graft area promoted bone remodeling of embedded bone, thus inducing bone resorption and subsequent deposition. Copyright © 2017. Published by Elsevier Inc.

Nuclear factor κB and cyclooxygenase-2 immunoexpression in oral dysplasia and oral squamous cell carcinoma.

PubMed

Pontes, Hélder Antônio Rebelo; Pontes, Flávia Sirotheau Corrêa; Fonseca, Felipe Paiva; de Carvalho, Pedro Luiz; Pereira, Erika Martins; de Abreu, Michelle Carvalho; de Freitas Silva, Brunno Santos; dos Santos Pinto, Décio

2013-02-01

Oral leukoplakia is the main potentially malignant oral lesion, and oral squamous cell carcinoma accounts for more than 95% of all malignant neoplasms in the oral cavity. Therefore, the aim of this study was to verify the immunoexpression of nuclear factor κB (NF-κB) and cyclooxygenase-2 (COX-2) proteins in dysplastic oral lesions and oral squamous cell carcinoma. Immunohistochemical reactions were performed on 6 inflammatory fibrous hyperplasia, 28 oral leukoplakia, and 15 oral squamous cell carcinoma paraffin-embedded samples. Immunoperoxidase reaction for NF-κB and COX-2 was applied on the specimens, and the positivity of the reactions was calculated for 1000 epithelial cells. Using the analysis of variance and the Tukey post hoc statistical analyses, a significantly increased immunoexpression for NF-κB was observed when oral squamous cell carcinoma samples were compared with the other groups studied. However, using the Kruskal-Wallis and the Dunn post hoc tests, a statistically significant result for COX-2 expression was obtained only when the moderate dysplasia group was compared with the inflammatory fibrous hyperplasia group. Nuclear factor κB may participate in the malignant phenotype acquisition process of the oral squamous cell carcinoma in its late stages, whereas COX-2 may be involved in the early stages of oral carcinogenesis process. Copyright © 2013 Elsevier Inc. All rights reserved.

Mechanistic study on the nuclear modifier gene MSS1 mutation suppressing neomycin sensitivity of the mitochondrial 15S rRNA C1477G mutation in Saccharomyces cerevisiae.

PubMed

Zhou, Qiyin; Wang, Wei; He, Xiangyu; Zhu, Xiaoyu; Shen, Yaoyao; Yu, Zhe; Wang, Xuexiang; Qi, Xuchen; Zhang, Xuan; Fan, Mingjie; Dai, Yu; Yang, Shuxu; Yan, Qingfeng

2014-01-01

The phenotypic manifestation of mitochondrial DNA (mtDNA) mutations can be modulated by nuclear genes and environmental factors. However, neither the interaction among these factors nor their underlying mechanisms are well understood. The yeast Saccharomyces cerevisiae mtDNA 15S rRNA C1477G mutation (PR) corresponds to the human 12S rRNA A1555G mutation. Here we report that a nuclear modifier gene mss1 mutation suppresses the neomycin-sensitivity phenotype of a yeast C1477G mutant in fermentable YPD medium. Functional assays show that the mitochondrial function of the yeast C1477G mutant was impaired severely in YPD medium with neomycin. Moreover, the mss1 mutation led to a significant increase in the steady-state level of HAP5 (heme activated protein), which greatly up-regulated the expression of glycolytic transcription factors RAP1, GCR1, and GCR2 and thus stimulated glycolysis. Furthermore, the high expression of the key glycolytic enzyme genes HXK2, PFK1 and PYK1 indicated that enhanced glycolysis not only compensated for the ATP reduction from oxidative phosphorylation (OXPHOS) in mitochondria, but also ensured the growth of the mss1(PR) mutant in YPD medium with neomycin. This study advances our understanding of the phenotypic manifestation of mtDNA mutations.

Implications of Recent Legislation and Strategy Developments in UK - Impact on regulation of radioactive waste management at nuclear installations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Griffiths, J.S.; Rutherford, J.; Boydon, F.M.D.

2007-07-01

Recently a number of factors are having a significant impact on the environment within which the UK nuclear industry operates. This presents a challenge for regulators and how they ensure delivery of proportionate regulation. The traditional organisations that made up the nuclear operators/ licensees that Health and Safety Executive (HSE) has regulated for over 30 years have changed radically with new company structures still being developed leading to the increased nuclear industry fragmentation. HSE already has some regulatory experience in this area but the pace of change is increasing as a result of competition for contracts to operate UK sitesmore » or facilities. This has already resulted in HSE undertaking a significant programme of work to regulate the re-licensing of such sites to new organisations. In response to this more dynamic environment we are examining our approach to regulation plus the safety assessment standards that need to be adopted within this changing environment. This paper will outline recent examples of how HSE has adapted its regulatory approach to specific case studies, along with discussion of how it intends to apply standards at a national and international level to illustrate the challenges that are faced in a changing operating environment. (authors)« less

Selenium antagonizes cadmium-induced apoptosis in chicken spleen but not involving Nrf2-regulated antioxidant response.

PubMed

Chen, Menghao; Li, Xiaojing; Fan, Ruifeng; Cao, Changyu; Yao, Haidong; Xu, Shiwen

2017-11-01

The nuclear transcription factor NF-E2-related factor 2 (Nrf2) binds to antioxidant response elements (AREs) and is involved in the regulation of genes participated in defending cells against oxidative damage, which have been confirmed in animal models. Selenium (Se), known as an important element in the regulation of antioxidant activity, can antagonize Cadmium (Cd) toxicity in birds. However, the role of Nrf2 in selenium-cadmium interaction has not been reported in birds. To further explore the mechanism of selenium attenuating spleen toxicity induced by cadmium in chickens, cadmium chloride (CdCl 2 , 150mg/kg) and sodium selenite (Na 2 SeO 3 , 2mg/kg) were co-administrated or individually administered in the diet of chickens for 90 days. The results showed that Cd exposure increased the level of hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA) and decreased the antioxidant enzyme activities, including superoxide dismutase (SOD), glutathione peroxidase (Gpx), total antioxidative capacity (T-AOC), catalase (CAT). Cd exposure increased obviously nuclear accumulation of Nrf2, and the expression of Nrf2 downstream heme oxygenase-1 (HO-1) and NAD(P)H: quinine oxidoreductase 1 (NQO1), reduced the expression of Kelch-like ECH-associated protein (keap1), Gpx-1 and thioredoxin reductase-1 (TrxR1). In addition, Cd induced the increase of bak, caspase9, p53, Cyt c mRNA levels, increased bax/bcl-2 ratio, increased caspase3 mRNA and protein levels. Selenium treatment reduced the accumulation of Cd in the spleen, attenuates Cd-induced Nrf2 nuclear accumulation, enhanced antioxidant enzyme activities, ameliorated Cd-induced oxidative stress and apoptosis in the spleen. In summary, our results demonstrate that Se ameliorated spleen toxicity induced by cadmium by modulating the antioxidant system, independently of Nrf2-regulated antioxidant response pathway. Copyright © 2017 Elsevier Inc. All rights reserved.

Nuclear Imprisonment: Viral Strategies to Arrest Host mRNA Nuclear Export

PubMed Central

Kuss, Sharon K.; Mata, Miguel A.; Zhang, Liang; Fontoura, Beatriz M. A.

2013-01-01

Viruses possess many strategies to impair host cellular responses to infection. Nuclear export of host messenger RNAs (mRNA) that encode antiviral factors is critical for antiviral protein production and control of viral infections. Several viruses have evolved sophisticated strategies to inhibit nuclear export of host mRNAs, including targeting mRNA export factors and nucleoporins to compromise their roles in nucleo-cytoplasmic trafficking of cellular mRNA. Here, we present a review of research focused on suppression of host mRNA nuclear export by viruses, including influenza A virus and vesicular stomatitis virus, and the impact of this viral suppression on host antiviral responses. PMID:23872491

Myosin-1C uses a novel phosphoinositide-dependent pathway for nuclear localization.

PubMed

Nevzorov, Ilja; Sidorenko, Ekaterina; Wang, Weihuan; Zhao, Hongxia; Vartiainen, Maria K

2018-02-01

Accurate control of macromolecule transport between nucleus and cytoplasm underlines several essential biological processes, including gene expression. According to the canonical model, nuclear import of soluble proteins is based on nuclear localization signals and transport factors. We challenge this view by showing that nuclear localization of the actin-dependent motor protein Myosin-1C (Myo1C) resembles the diffusion-retention mechanism utilized by inner nuclear membrane proteins. We show that Myo1C constantly shuttles in and out of the nucleus and that its nuclear localization does not require soluble factors, but is dependent on phosphoinositide binding. Nuclear import of Myo1C is preceded by its interaction with the endoplasmic reticulum, and phosphoinositide binding is specifically required for nuclear import, but not nuclear retention, of Myo1C. Our results therefore demonstrate, for the first time, that membrane association and binding to nuclear partners is sufficient to drive nuclear localization of also soluble proteins, opening new perspectives to evolution of cellular protein sorting mechanisms. © 2018 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Regulation of the heat shock response under anoxia in the turtle, Trachemys scripta elegans.

PubMed

Krivoruchko, Anastasia; Storey, Kenneth B

2010-03-01

The effects of 20 h of anoxic submergence in cold water and 5 h of aerobic recovery on the heat shock response were analyzed in four organs of the anoxia-tolerant turtle Trachemys scripta elegans. Immunoblotting was used to analyze levels of active and inactive forms of the heat shock transcription factor 1 (HSF1), nuclear translocation of HSF1, and the levels of six heat shock proteins (HSPs). PCR was also used to retrieve the turtle HSF1 nucleotide sequence; its deduced amino acid sequence showed 97% identity with chicken HSF1. White skeletal muscle showed a strong fivefold increase in the amount of active HSF1 under anoxic conditions as well as an 80% increase in nuclear localization. This was accompanied by upregulation of five HSPs by 1.8- to 2.9-fold: Hsp25, Hsp40, Hsp70, Hsc70, and Hsp90, the latter two remained elevated after 5 h of aerobic recovery. Kidney and liver showed little change in active HSF1 content during anoxia and recovery, but a significant increase in the nuclear localization of HSF1 during anoxia. This supported enhanced expression of three HSPs in kidney (Hsp40, Hsc70, and Hsp90) and four in liver (Hsp40, Hsp60, Hsp70, Hsc70). Heart displayed a strong increase in active HSF1 during anoxia and recovery (6.6- to 6.8-fold higher than control) and increased nuclear localization but heart HSP levels did not rise. The data demonstrate organ-specific regulation of HSPs during anoxia exposure and aerobic recovery in T. s. elegans and suggest that the heat shock response is an important aspect of cytoprotection during facultative anaerobiosis, particularly with regard to underwater hibernation of turtles in cold water.

The Selenocysteine-Specific Elongation Factor Contains Unique Sequences That Are Required for Both Nuclear Export and Selenocysteine Incorporation.

PubMed

Dubey, Aditi; Copeland, Paul R

2016-01-01

Selenocysteine (Sec) is a critical residue in at least 25 human proteins that are essential for antioxidant defense and redox signaling in cells. Sec is inserted into proteins cotranslationally by the recoding of an in-frame UGA termination codon to a Sec codon. In eukaryotes, this recoding event requires several specialized factors, including a dedicated, Sec-specific elongation factor called eEFSec, which binds Sec-tRNASec with high specificity and delivers it to the ribosome for selenoprotein production. Unlike most translation factors, including the canonical elongation factor eEF1A, eEFSec readily localizes to the nucleus of mammalian cells and shuttles between the cytoplasmic and nuclear compartments. The functional significance of eEFSec's nuclear localization has remained unclear. In this study, we have examined the subcellular localization of eEFSec in the context of altered Sec incorporation to demonstrate that reduced selenoprotein production does not correlate with changes in the nuclear localization of eEFSec. In addition, we identify several novel sequences of the protein that are essential for localization as well as Sec insertion activity, and show that eEFSec utilizes CRM1-mediated nuclear export pathway. Our findings argue for two distinct pools of eEFSec in the cell, where the cytoplasmic pool participates in Sec incorporation and the nuclear pool may be involved in an as yet unknown function.

Clinicopathological factors increased the risk of malignancy in thyroid nodules with atypical or follicular lesions of undetermined significance (AUS/FLUS) risk factor of malignancy in thyroid nodule with AUS/FLUS

PubMed Central

Hong, In Ki; Kim, Jun Ho; Cho, Young Up; Park, Shin-Young

2016-01-01

Purpose Ultrasound-guided fine needle aspiration (US-FNA) in thyroid nodules is presently most commonly used to identify whether these nodules are benign or malignant. However, atypical or follicular lesions of undetermined significance (AUS/FLUS), as categorized in the Bethesda System for reporting the results of FNA, cannot be classified as benign or malignant. Therefore, several clinical factors should be considered to assess the risk of malignancy in patients with AUS/FLUS. The purpose of the present study was to determine which clinical factor increased the risk of malignancy in patients with AUS/FLUS. Methods A retrospective study was done on 129 patients with fine needle aspiration categorized as AUS/FLUS from January 2011 through April 2015. Univariate and multivariate analyses were performed to assess the independent effect of risk factors such as age, sex, size of nodule, atypical descriptors, and ultrasonography criteria for malignancy. Results We identified that the presence of spiculated margin (odds ratio [OR], 5.655; 95% confidence interval [CI], 2.114-15.131; P = 0.001), nuclear grooving (OR, 3.697; 95% CI, 1.409-9.701; P = 0.008), irregular nuclei (OR, 3.903; 95% CI, 1.442-10.560; P = 0.001) were shown to be significantly related to malignancy on univariate and multivariate analyses. Conclusion We recommend that surgical resection of thyroid nodules be considered in patients with AUS/FLUS showing the histologic findings such as nuclear grooving, irregular nuclei along with spiculated margin of ultrasonographic finding. PMID:27073790

Nuclear deterrents: Intrinsic regulators of IL-1β-induced effects on hippocampal neurogenesis.

PubMed

O'Léime, Ciarán S; Cryan, John F; Nolan, Yvonne M

2017-11-01

Hippocampal neurogenesis, the process by which new neurons are born and develop into the host circuitry, begins during embryonic development and persists throughout adulthood. Over the last decade considerable insights have been made into the role of hippocampal neurogenesis in cognitive function and the cellular mechanisms behind this process. Additionally, an increasing amount of evidence exists on the impact of environmental factors, such as stress and neuroinflammation on hippocampal neurogenesis and subsequent impairments in cognition. Elevated expression of the pro-inflammatory cytokine interleukin-1β (IL-1β) in the hippocampus is established as a significant contributor to the neuronal demise evident in many neurological and psychiatric disorders and is now known to negatively regulate hippocampal neurogenesis. In order to prevent the deleterious effects of IL-1β on neurogenesis it is necessary to identify signalling pathways and regulators of neurogenesis within neural progenitor cells that can interact with IL-1β. Nuclear receptors are ligand regulated transcription factors that are involved in modulating a large number of cellular processes including neurogenesis. In this review we focus on the signalling mechanisms of specific nuclear receptors involved in regulating neurogenesis (glucocorticoid receptors, peroxisome proliferator activated receptors, estrogen receptors, and nuclear receptor subfamily 2 group E member 1 (NR2E1 or TLX)). We propose that these nuclear receptors could be targeted to inhibit neuroinflammatory signalling pathways associated with IL-1β. We discuss their potential to be therapeutic targets for neuroinflammatory disorders affecting hippocampal neurogenesis and associated cognitive function. Copyright © 2017 Elsevier Inc. All rights reserved.

Systems biology of lupus: mapping the impact of genomic and environmental factors on gene expression signatures, cellular signaling, metabolic pathways, hormonal and cytokine imbalance, and selecting targets for treatment.

PubMed

Perl, Andras

2010-02-01

Systemic lupus erythematosus (SLE) is characterized by the dysfunction of T cells, B cells, and dendritic cells, the release of pro-inflammatory nuclear materials from necrotic cells, and the formation of antinuclear antibodies (ANA) and immune complexes of ANA with DNA, RNA, and nuclear proteins. Activation of the mammalian target of rapamycin (mTOR) has recently emerged as a key factor in abnormal activation of T and B cells in SLE. In T cells, increased production of nitric oxide and mitochondrial hyperpolarization (MHP) were identified as metabolic checkpoints upstream of mTOR activation. mTOR controls the expression T-cell receptor-associated signaling proteins CD4 and CD3zeta through increased expression of the endosome recycling regulator Rab5 and HRES-1/Rab4 genes, enhances Ca2+ fluxing and skews the expression of tyrosine kinases both in T and B cells, and blocks the expression of Foxp3 and the generation of regulatory T cells. MHP, increased activity of mTOR, Rab GTPases, and Syk kinases, and enhanced Ca2+ flux have emerged as common T and B cell biomarkers and targets for treatment in SLE.

Distinct biological effects of low-dose radiation on normal and cancerous human lung cells are mediated by ATM signaling

PubMed Central

Li, Wei; Zhao, Yuguang; Wen, Xue; Liang, Xinyue; Zhang, Xiaoying; Zhou, Lei; Hu, Jifan; Niu, Chao; Tian, Huimin; Han, Fujun; Chen, Xiao; Dong, Lihua; Cai, Lu; Cui, Jiuwei

2016-01-01

Low-dose radiation (LDR) induces hormesis and adaptive response in normal cells but not in cancer cells, suggesting its potential protection of normal tissue against damage induced by conventional radiotherapy. However, the underlying mechanisms are not well established. We addressed this in the present study by examining the role of the ataxia telangiectasia mutated (ATM) signaling pathway in response to LDR using A549 human lung adenocarcinoma cells and HBE135-E6E7 (HBE) normal lung epithelial cells. We found that LDR-activated ATM was the initiating event in hormesis and adaptive response to LDR in HBE cells. ATM activation increased the expression of CDK4/CDK6/cyclin D1 by activating the AKT/glycogen synthase kinase (GSK)-3β signaling pathway, which stimulated HBE cell proliferation. Activation of ATM/AKT/GSK-3β signaling also increased nuclear accumulation of nuclear factor erythroid 2-related factor 2, leading to increased expression of antioxidants, which mitigated cellular damage from excessive reactive oxygen species production induced by high-dose radiation. However, these effects were not observed in A549 cells. Thus, the failure to activate these pathways in A549 cells likely explains the difference between normal and cancer cells in terms of hormesis and adaptive response to LDR. PMID:27708248

Elevated extracellular glucose and uncontrolled type 1 diabetes enhance NFAT5 signaling and disrupt the transverse tubular network in mouse skeletal muscle

PubMed Central

Hernández-Ochoa, Erick O; Robison, Patrick; Contreras, Minerva; Shen, Tiansheng; Zhao, Zhiyong; Schneider, Martin F

2012-01-01

The transcription factor nuclear factor of activated T-cells 5 (NFAT5) is a key protector from hypertonic stress in the kidney, but its role in skeletal muscle is unexamined. Here, we evaluate the effects of glucose hypertonicity and hyperglycemia on endogenous NFAT5 activity, transverse tubular system morphology and Ca2+ signaling in adult murine skeletal muscle fibers. We found that exposure to elevated glucose (25–50 mmol/L) increased NFAT5 expression and nuclear translocation, and NFAT-driven transcriptional activity. These effects were insensitive to the inhibition of calcineurin A, but sensitive to both p38a mitogen-activated protein kinases and phosphoinositide 3-kinase-related kinase inhibition. Fibers exposed to elevated glucose exhibited disrupted transverse tubular morphology, characterized by swollen transverse tubules and an increase in longitudinal connections between adjacent transverse tubules. Ca2+ transients elicited by a single, brief electric field stimuli were increased in amplitude in fibers challenged by elevated glucose. Muscle fibers from type 1 diabetic mice exhibited increased NFAT5 expression and transverse tubule disruptions, but no differences in electrically evoked Ca2+ transients. Our results suggest the hypothesis that these changes in skeletal muscle could play a role in the pathophysiology of acute and severe hyperglycemic episodes commonly observed in uncontrolled diabetes. PMID:22966145

Azilsartan increases levels of IL-10, down-regulates MMP-2, MMP-9, RANKL/RANK, Cathepsin K and up-regulates OPG in an experimental periodontitis model.

PubMed

Araújo, Aurigena Antunes de; Varela, Hugo; Brito, Gerly Anne de Castro; Medeiros, Caroline Addison Carvalho Xavier de; Araújo, Lorena de Souza; do Nascimento, José Heriberto Oliveira; de Araújo Júnior, Raimundo Fernandes

2014-01-01

The aim of this study was to evaluate the effects of azilsartan (AZT) on bone loss, inflammation, and the expression of matrix metallo proteinases (MMPs), receptor activator of nuclear factor κB ligand (RANKL), receptor activator of nuclear factor κB (RANK), osteoprotegerin (OPG), cyclooxygenase-2 (COX-2), and cathepsin K in periodontal tissue in a rat model of ligature-induced periodontitis. Male Wistar albino rats were randomly divided into 5 groups of 10 rats each: (1) nonligated, water; (2) ligated, water; (3) ligated, 1 mg/kg AZT; (4) ligated, 5 mg/kg AZT; and (5) ligated, 10 mg/kg AZT. All groups were treated with saline or AZT for 10 days. Periodontal tissues were analyzed by histopathology and immunohistochemical detection of MMP-2, MMP-9, COX-2, RANKL, RANK, OPG, and cathepsin K. Levels of IL-1β, IL-10, TNF-α, myeloperoxidase (MPO), and glutathione (GSH) were determined by ELISA. Treatment with 5 mg/kg AZT resulted in reduced MPO (p<0.05) and IL-1β (p<0.05), increased levels of IL-10 (p<0.05), and reduced expression of MMP-2, MMP-9, COX-2, RANK, RANKL, cathepsin K, and increased expression of OPG. These findings reveal that AZT increases anti-inflammatory cytokines and GSH and decreases bone loss in ligature-induced periodontitis in rats.

Target fragmentation in radiobiology

NASA Technical Reports Server (NTRS)

Wilson, John W.; Cucinotta, Francis A.; Shinn, Judy L.; Townsend, Lawrence W.

1993-01-01

Nuclear reactions in biological systems produce low-energy fragments of the target nuclei seen as local high events of linear energy transfer (LET). A nuclear-reaction formalism is used to evaluate the nuclear-induced fields within biosystems and their effects within several biological models. On the basis of direct ionization interaction, one anticipates high-energy protons to have a quality factor and relative biological effectiveness (RBE) of unity. Target fragmentation contributions raise the effective quality factor of 10 GeV protons to 3.3 in reasonable agreement with RBE values for induced micronuclei in bean sprouts. Application of the Katz model indicates that the relative increase in RBE with decreasing exposure observed in cell survival experiments with 160 MeV protons is related solely to target fragmentation events. Target fragment contributions to lens opacity given an RBE of 1.4 for 2 GeV protons in agreement with the work of Lett and Cox. Predictions are made for the effective RBE for Harderian gland tumors induced by high-energy protons. An exposure model for lifetime cancer risk is derived from NCRP 98 risk tables, and protraction effects are examined for proton and helium ion exposures. The implications of dose rate enhancement effects on space radiation protection are considered.

Expression of transcription factors during sodium phenylacetate induced erythroid differentiation in K562 cells.

PubMed

Rath, A V; Schmahl, G E; Niemeyer, C M

1997-01-01

During 15 days of treatment of K562 cells with sodium phenylacetate, we observed an increase in the cellular hemoglobin concentration with a similar increase in the expression of gamma-globin mRNA. Morphological studies demonstrated characteristic features of erythroid differentiation and maturation. At the same time there was no change in the level of expression of the cell surface antigenes CD33, CD34, CD45, CD71 and glycophorin A. Likewise, the level of expression of the erythroid transcription factors GATA-1, GATA-2, NF-E2, SCL and RBTN2, all expressed in untreated K562 cells, did not increase during sodium phenylacetate induced erythroid differentiation. The expression of the nuclear factors Evi-1 and c-myb, known to inhibit erythroid differentiation, did not decrease. We conclude that sodium phenylacetate treatment of K562 cells increases gamma-globin mRNA and induces cell maturation as judged by morphology without affecting the expression of the erythroid transcription factors, some of which are known to be involved in the regulation of beta-like globin genes.

Fourier transform ion cyclotron resonance mass spectrometry

NASA Astrophysics Data System (ADS)

Marshall, Alan G.

1998-06-01

As for Fourier transform infrared (FT-IR) interferometry and nuclear magnetic resonance (NMR) spectroscopy, the introduction of pulsed Fourier transform techniques revolutionized ion cyclotron resonance mass spectrometry: increased speed (factor of 10,000), increased sensitivity (factor of 100), increased mass resolution (factor of 10,000-an improvement not shared by the introduction of FT techniques to IR or NMR spectroscopy), increased mass range (factor of 500), and automated operation. FT-ICR mass spectrometry is the most versatile technique for unscrambling and quantifying ion-molecule reaction kinetics and equilibria in the absence of solvent (i.e., the gas phase). In addition, FT-ICR MS has the following analytically important features: speed (~1 second per spectrum); ultrahigh mass resolution and ultrahigh mass accuracy for analysis of mixtures and polymers; attomole sensitivity; MSn with one spectrometer, including two-dimensional FT/FT-ICR/MS; positive and/or negative ions; multiple ion sources (especially MALDI and electrospray); biomolecular molecular weight and sequencing; LC/MS; and single-molecule detection up to 108 Dalton. Here, some basic features and recent developments of FT-ICR mass spectrometry are reviewed, with applications ranging from crude oil to molecular biology.

Characterization of karyopherins in androgen receptor intracellular trafficking in the yeast model

PubMed Central

Nguyen, Minh M; Harmon, Robert M; Wang, Zhou

2014-01-01

Background: Mechanisms regulating androgen receptor (AR) subcellular localization represent an essential component of AR signaling. Karyopherins are a family of nucleocytoplasmic trafficking factors. In this paper, we used the yeast model to study the effects of karyopherins on the subcellular localization of the AR. Methods: Yeast mutants deficient in different nuclear transport factors were transformed with various AR based, GFP tagged constructs and their localization was monitored using microscopy. Results: We showed that yeast can mediate androgen-induced AR nuclear localization and that in addition to the import factor, Importinα/β, this process required the import karyopherin Sxm1. We also showed that a previously identified nuclear export sequence (NESAR) in the ligand binding domain of AR does not appear to rely on karyopherins for cytoplasmic localization. Conclusions: These results suggest that while AR nuclear import relies on karyopherin activity, AR nuclear export and/or cytoplasmic localization may require other undefined mechanisms. PMID:25031696

Signal Transduction Triggered by Iron to Induce the Nuclear Importation of a Myb3 Transcription Factor in the Parasitic Protozoan Trichomonas vaginalis*

PubMed Central

Hsu, Hong-Ming; Lee, Yu; Hsu, Pang-Hung; Liu, Hsing-Wei; Chu, Chien-Hsin; Chou, Ya-Wen; Chen, Yet-Ran; Chen, Shu-Hui; Tai, Jung-Hsiang

2014-01-01

Iron was previously shown to induce rapid nuclear translocation of a Myb3 transcription factor in the protozoan parasite, Trichomonas vaginalis. In the present study, iron was found to induce a transient increase in cellular cAMP, followed by the nuclear influx of Myb3, whereas the latter was also induced by 8-bromo-cyclic AMP. Iron-inducible cAMP production and nuclear influx of Myb3 were inhibited by suramin and SQ22536, respective inhibitors of the Gα subunit of heterotrimeric G proteins and adenylyl cyclases. In contrast, the nuclear influx of Myb3 induced by iron or 8-bromo-cAMP was delayed or inhibited, respectively, by H89, the inhibitor of protein kinase A. Using liquid chromatography-coupled tandem mass spectrometry, Thr156 and Lys143 in Myb3 were found to be phosphorylated and ubiquitinated, respectively. These modifications were induced by iron and inhibited by H89, as shown by immunoprecipitation-coupled Western blotting. Iron-inducible ubiquitination and nuclear influx were aborted in T156A and K143R, but T156D was constitutively ubiquitinated and persistently localized to the nucleus. Myb3 was phosphorylated in vitro by the catalytic subunit of a T. vaginalis protein kinase A, TvPKAc. A transient interaction between TvPKAc and Myb3 and the phosphorylation of both proteins were induced in the parasite shortly after iron or 8-bromo-cAMP treatment. Together, these observations suggest that iron may induce production of cAMP and activation of TvPKAc, which then induces the phosphorylation of Myb3 and subsequent ubiquitination for accelerated nuclear influx. It is conceivable that iron probably exerts a much broader impact on the physiology of the parasite than previously thought to encounter environmental changes. PMID:25183012

Self-Reliability and Motivation in a Nuclear Security Culture Enhancement Program

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rogers,E.; deBoer,G.; Crawford, C.

2009-10-19

The threat of nuclear terrorism has become a global concern. Many countries continue to make efforts to strengthen nuclear security by enhancing systems of nuclear material protection, control, and accounting (MPC&A). Though MPC&A systems can significantly upgrade nuclear security, they do not eliminate the "human factor." Gen. Eugene Habiger, a former "Assistant Secretary for Safeguards and Security" at the U.S. Department of Energy’s (DOE) nuclear-weapons complex and a former commander of U.S. strategic nuclear forces, has observed that "good security is 20% equipment and 80% people." Although eliminating the "human factor" is not possible, accounting for and mitigating the riskmore » of the insider threat is an essential element in establishing an effective nuclear security culture. This paper will consider the organizational role in mitigating the risk associated with the malicious insider through monitoring and enhancing human reliability and motivation as well as enhancing the nuclear security culture.« less

High glucose induces inflammatory cytokine through protein kinase C-induced toll-like receptor 2 pathway in gingival fibroblasts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jiang, Shao-Yun, E-mail: jiangshaoyun@yahoo.com; Wei, Cong-Cong; Shang, Ting-Ting

2012-10-26

Highlights: Black-Right-Pointing-Pointer High glucose significantly induced TLR2 expression in gingival fibroblasts. Black-Right-Pointing-Pointer High glucose increased NF-{kappa}B p65 nuclear activity, IL-1{beta} and TNF-{alpha} levels. Black-Right-Pointing-Pointer PKC-{alpha}/{delta}-TLR2 pathway is involved in periodontal inflammation under high glucose. -- Abstract: Toll-like receptors (TLRs) play a key role in innate immune response and inflammation, especially in periodontitis. Meanwhile, hyperglycemia can induce inflammation in diabetes complications. However, the activity of TLRs in periodontitis complicated with hyperglycemia is still unclear. In the present study, high glucose (25 mmol/l) significantly induced TLR2 expression in gingival fibroblasts (p < 0.05). Also, high glucose increased nuclear factor kappa B (NF-{kappa}B)more » p65 nuclear activity, tumor necrosis factor-{alpha} (TNF-{alpha}) and interleukin-l{beta} (IL-1{beta}) levels. Protein kinase C (PKC)-{alpha} and {delta} knockdown with siRNA significantly decreased TLR2 and NF-{kappa}B p65 expression (p < 0.05), whereas inhibition of PKC-{beta} had no effect on TLR2 and NF-{kappa}B p65 under high glucose (p < 0.05). Additional studies revealed that TLR2 knockdown significantly abrogated high-glucose-induced NF-{kappa}B expression and inflammatory cytokine secretion. Collectively, these data suggest that high glucose stimulates TNF-{alpha} and IL-1{beta} secretion via inducing TLR2 through PKC-{alpha} and PKC-{delta} in human gingival fibroblasts.« less

HTLV-1 Tax upregulates early growth response protein 1 through nuclear factor-κB signaling

PubMed Central

Han, Jingxian; Liu, Xihong; Lv, Zhuangwei; Li, Huanhuan; Yuan, Lixiang; Li, Xiangping; Sun, Shuming; Wang, Hui; Huang, Xinxiang

2017-01-01

Human T cell leukemia virus type 1 (HTLV-1) is a complex retrovirus that causes adult T cell leukemia (ATL) in susceptible individuals. The HTLV-1-encoded oncoprotein Tax induces persistent activation of the nuclear factor-κB (NF-κB) pathway. Early growth response protein 1 (EGR1) is overexpressed in HTLV-1-infected T cell lines and ATL cells. Here, we showed that both Tax expression and HTLV-1 infection promoted EGR1 overexpression. Loss of the NF-κB binding site in the EGR1 promotor or inhibition of NF-κB activation reduced Tax-induced EGR1 upregulation. Tax mutants unable to activate NF-κB induced only slight EGR1 upregulation as compared with wild-type Tax, confirming NF-κB pathway involvement in EGR1 regulation. Tax also directly interacted with the EGR1 protein and increased endogenous EGR1 stability. Elevated EGR1 in turn promoted p65 nuclear translocation and increased NF-κB activation. These results demonstrate a positive feedback loop between EGR1 expression and NF-κB activation in HTLV-1-infected and Tax-expressing cells. Both NF-κB activation and Tax-induced EGR1 stability upregulated EGR1, which in turn enhanced constitutive NF-κB activation and facilitated ATL progression in HTLV-1-infected cells. These findings suggest EGR1 may be an effective anti-ATL therapeutic target. PMID:28881635

Effects of the in-medium nucleon-nucleon cross section on collective flow and nuclear stopping in heavy-ion collisions in the Fermi-energy domain

NASA Astrophysics Data System (ADS)

Li, Pengcheng; Wang, Yongjia; Li, Qingfeng; Guo, Chenchen; Zhang, Hongfei

2018-04-01

With the newly updated version of the ultrarelativistic quantum molecular dynamics (UrQMD) model, a systematic investigation of the effects of in-medium nucleon-nucleon (NN ) elastic cross section on the collective flow and the stopping observables in 197Au+197Au collisions at beam energies from 40 to 150 MeV/nucleon is performed. Simulations with the medium correction factors F =σNN in -medium/σNN free=0.2 ,0.3 ,0.5 and the one obtained with the FU3FP1 parametrization which depends on both the density and the momentum are compared to the FOPI and INDRA experimental data. It is found that, to best fit the experimental data of the slope of the directed flow and the elliptic flow at midrapidity as well as the nuclear stopping, the correction factors of F =0.2 and 0.5 are required for reactions at beam energies of 40 and 150 MeV/nucleon, respectively. Whereas calculations with the FU3FP1 parametrization can simultaneously reproduce these experimental data reasonably well. And, the observed increasing nuclear stopping with increasing beam energy in experimental data can also be reproduced by using the FU3FP1 parametrization, whereas the calculated stopping power in Au + Au collisions with beam energies from 40 to 150 MeV /nucleon almost remains constant when taking F equal to a fixed value.

4-Methoxylonchocarpin attenuates inflammation by inhibiting lipopolysaccharide binding to Toll-like receptor of macrophages and M1 macrophage polarization.

PubMed

Jang, Hyo-Min; Kang, Geum-Dan; Van Le, Thi Kim; Lim, Su-Min; Jang, Dae-Sik; Kim, Dong-Hyun

2017-04-01

The roots of Abrus precatorius (AP, Fabaceae) have traditionally been used in Vietnam and China for the treatment of inflammatory diseases such as stomatitis, asthma, bronchitis, and hepatitis. Therefore, in this study, we isolated 4-methoxylonchocarpin (ML), an anti-inflammatory compound present in AP, and studied its anti-inflammatory effects in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. In lipopolysaccharide (LPS)-stimulated macrophages, ML was found to inhibit nuclear factor (NF)-κB activation and tumor necrosis factor (TNF) and interleukin (IL)-6 expression by inhibiting LPS binding to Toll-like receptor 4 (TLR4) in vitro. Oral administration of ML in mice with TNBS-induced colitis suppressed colon shortening and colonic myeloperoxidase activity. ML treatment significantly inhibited the activation of nuclear factor (NF)-κB and phosphorylation of transforming growth factor β-activated kinase 1 in the colon. Treatment with ML also inhibited TNBS-induced expression of IL-1β, IL-17A, and TNF. While ML reduced the TNBS-induced expression of M1 macrophage markers such as arginase-2 and TNF, it was found to increase the expression of M2 macrophage markers such as arginase-1 and IL-10. In conclusion, oral administration of ML attenuated colitis in mice by inhibiting the binding of LPS to TLR4 on immune cells and increasing the polarization of M1 macrophages to M2 macrophages. Copyright © 2017 Elsevier B.V. All rights reserved.

Role of tumour necrosis factor receptor-1 and nuclear factor-κB in production of TNF-α-induced pro-inflammatory microparticles in endothelial cells.

PubMed

Lee, S K; Yang, S-H; Kwon, I; Lee, O-H; Heo, J H

2014-09-02

Tumour necrosis factor-α (TNF-α) is upregulated in many inflammatory diseases and is also a potent agent for microparticle (MP) generation. Here, we describe an essential role of TNF-α in the production of endothelial cell-derived microparticles (EMPs) in vivo and the function of TNF-α-induced EMPs in endothelial cells. We found that TNF-α rapidly increased blood levels of EMPs in mice. Treatment of human umbilical vein endothelial cells (HUVECs) with TNF-α also induced EMP formation in a time-dependent manner. Silencing of TNF receptor (TNFR)-1 or inhibition of the nuclear factor-κB (NF-κB) in HUVECs impaired the production of TNF-α-induced EMP. Incubation of HUVECs with PKH-67-stained EMPs showed that endothelial cells readily engulfed EMPs, and the engulfed TNF-α-induced EMPs promoted the expression of pro-apoptotic molecules and upregulated intercellular adhesion molecule-1 level on the cell surface, which led to monocyte adhesion. Collectively, our findings indicate that the generation of TNF-α-induced EMPs was mediated by TNFR1 or NF-κB and that EMPs can contribute to apoptosis and inflammation of endothelial cells.

Apigenin inhibits d-galactosamine/LPS-induced liver injury through upregulation of hepatic Nrf-2 and PPARγ expressions in mice.

PubMed

Zhou, Rui-Jun; Ye, Hua; Wang, Feng; Wang, Jun-Long; Xie, Mei-Lin

2017-11-04

Apigenin is a natural flavonoid compound widely distributed in a variety of vegetables, medicinal plants and health foods. This study aimed to examine the protective effect of apigenin against d-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced mouse liver injury and to investigate the potential biochemical mechanisms. The results showed that after oral administration of apigenin 100-200 mg/kg for 7 days, the levels of serum alanine aminotransferase and aspartate aminotransferase were decreased, and the severity of liver injury was alleviated. Importantly, apigenin pretreatment increased the levels of hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) and peroxisome proliferator-activated receptor γ (PPARγ) protein expressions as well as superoxide dismutase, catalase, glutathione S-transferase and glutathione reductase activities, decreased the levels of hepatic nuclear factor-κB (NF-κB) protein expression and tumor necrosis factor-α. These findings demonstrated that apigenin could prevent the D-GalN/LPS-induced liver injury in mice, and its mechanisms might be associated with the increments of Nrf-2-mediated antioxidative enzymes and modulation of PPARγ/NF-κB-mediated inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

The Transcriptional Regulator CBP Has Defined Spatial Associations within Interphase Nuclei

PubMed Central

McManus, Kirk J; Stephens, David A; Adams, Niall M; Islam, Suhail A; Freemont, Paul S; Hendzel, Michael J

2006-01-01

It is becoming increasingly clear that nuclear macromolecules and macromolecular complexes are compartmentalized through binding interactions into an apparent three-dimensionally ordered structure. This ordering, however, does not appear to be deterministic to the extent that chromatin and nonchromatin structures maintain a strict 3-D arrangement. Rather, spatial ordering within the cell nucleus appears to conform to stochastic rather than deterministic spatial relationships. The stochastic nature of organization becomes particularly problematic when any attempt is made to describe the spatial relationship between proteins involved in the regulation of the genome. The CREB–binding protein (CBP) is one such transcriptional regulator that, when visualised by confocal microscopy, reveals a highly punctate staining pattern comprising several hundred individual foci distributed within the nuclear volume. Markers for euchromatic sequences have similar patterns. Surprisingly, in most cases, the predicted one-to-one relationship between transcription factor and chromatin sequence is not observed. Consequently, to understand whether spatial relationships that are not coincident are nonrandom and potentially biologically important, it is necessary to develop statistical approaches. In this study, we report on the development of such an approach and apply it to understanding the role of CBP in mediating chromatin modification and transcriptional regulation. We have used nearest-neighbor distance measurements and probability analyses to study the spatial relationship between CBP and other nuclear subcompartments enriched in transcription factors, chromatin, and splicing factors. Our results demonstrate that CBP has an order of spatial association with other nuclear subcompartments. We observe closer associations between CBP and RNA polymerase II–enriched foci and SC35 speckles than nascent RNA or specific acetylated histones. Furthermore, we find that CBP has a significantly higher probability of being close to its known in vivo substrate histone H4 lysine 5 compared with the closely related H4 lysine 12. This study demonstrates that complex relationships not described by colocalization exist in the interphase nucleus and can be characterized and quantified. The subnuclear distribution of CBP is difficult to reconcile with a model where chromatin organization is the sole determinant of the nuclear organization of proteins that regulate transcription but is consistent with a close link between spatial associations and nuclear functions. PMID:17054391

Competition of nuclear factor-erythroid 2 factors related transcription factor isoforms, Nrf1 and Nrf2, in antioxidant enzyme induction☆

PubMed Central

Chepelev, Nikolai L.; Zhang, Hongqiao; Liu, Honglei; McBride, Skye; Seal, Andrew J.; Morgan, Todd E.; Finch, Caleb E.; Willmore, William G.; Davies, Kelvin J.A.; Forman, Henry Jay

2013-01-01

Although the Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2) regulated expression of multiple antioxidant and cytoprotective genes through the electrophile responsive element (EpRE) is well established, interaction of Nrf2/EpRE with Nrf1, a closely-related transcription factor, is less well understood. Due to either proteolysis or alternative translation, Nrf1 has been found as proteins of varying size, p120, p95, and p65, which have been described as either activators of EpRE or competitive inhibitors of Nrf2. We investigated the effect of Nrf1 on EpRE-regulated gene expression using the catalytic and modifier subunits of glutamate cysteine ligase (GCLC and GCLM) as models and explored the potential role of Nrf1 in altering their expression in aging and upon chronic exposure to airborne nano-sized particulate matter (nPM). Nrf1 knockout resulted in the increased expression of GCLC and GCLM in human bronchial epithelial (HBE1) cells. Overexpression Nrf2 in combination with either p120 or p65 diminished or failed to further increase the GCLC- and GLCM-EpRE luciferase activity. All known forms of Nrf1 protein, remained unchanged in the lungs of mice with age or in response to nPM. Our study shows that Nrf1 could inhibit EpRE activity in vitro, whereas the precise role of Nrf1 in vivo requires further investigations. We conclude that Nrf1 may not be directly responsible for the loss of Nrf2-dependent inducibility of antioxidant and cytoprotective genes observed in aged animals. PMID:24024152

Protective protein/cathepsin A down-regulates osteoclastogenesis by associating with and degrading NF-kappaB p50/p65.

PubMed

Masuhara, Masaaki; Sato, Takuya; Hada, Naoto; Hakeda, Yoshiyuki

2009-01-01

Disruption of the cooperative function balance between osteoblasts and osteoclasts causes various bone disorders, some of which are attributed to abnormal osteoclast recruitment. Osteoclast differentiation is dependent on the receptor activator of nuclear factor (NF)-kappaB ligand (RANKL) as well as the macrophage colony-stimulating factor. The osteoclast formation induced by cytokines requires activation of NF-kappaB, AP-1 and nuclear factor of activated T cells c1. However, osteoclasts are not the only cell types that express these transcription factors, suggesting that some unknown molecules specific for osteoclasts may associate with the transcription factors. Here, we explored the possibility of molecules binding directly to NF-kappaB and cloned protective protein/cathepsin A (PPCA) by yeast two-hybrid screening using a cDNA library of osteoclast precursors. Forced expression of PPCA with p50/p65 in HEK293 cells decreased both the level of p50/p65 proteins and the transcriptional activity. Abundant PPCA was detected in the lysosomes of the transfected HEK293 cells, but a small amount of this enzyme was also present in the cytosolic fraction. In addition, over-expression of PPCA caused the disappearance of p50/p65 in both the lysosomal and cytosolic fractions. PPCA was expressed throughout osteoclastogenesis, and the expression was slightly up-regulated by RANKL signaling. Knockdown of PPCA in osteoclast precursors with PPCA siRNA stimulated binding of nuclear proteins to oligonucleotides containing an NF-kappaB binding motif and increased osteoclastogenesis. Our present results indicate a novel role for PPCA in osteoclastogenesis via down-regulation of NF-kappaB activity and suggest a new function for PPCA as an NF-kappaB-degrading enzyme in addition to its known multifunctional properties.

Nup100 regulates Saccharomyces cerevisiae replicative life span by mediating the nuclear export of specific tRNAs

PubMed Central

Lord, Christopher L.; Ospovat, Ophir; Wente, Susan R.

2017-01-01

Nuclear pore complexes (NPCs), which are composed of nucleoporins (Nups) and regulate transport between the nucleus and cytoplasm, significantly impact the replicative life span (RLS) of Saccharomyces cerevisiae. We previously reported that deletion of the nonessential gene NUP100 increases RLS, although the molecular basis for this effect was unknown. In this study, we find that nuclear tRNA accumulation contributes to increased longevity in nup100Δ cells. Fluorescence in situ hybridization (FISH) experiments demonstrate that several specific tRNAs accumulate in the nuclei of nup100Δ mutants. Protein levels of the transcription factor Gcn4 are increased when NUP100 is deleted, and GCN4 is required for the elevated life spans of nup100Δ mutants, similar to other previously described tRNA export and ribosomal mutants. Northern blots indicate that tRNA splicing and aminoacylation are not significantly affected in nup100Δ cells, suggesting that Nup100 is largely required for nuclear export of mature, processed tRNAs. Distinct tRNAs accumulate in the nuclei of nup100Δ and msn5Δ mutants, while Los1-GFP nucleocytoplasmic shuttling is unaffected by Nup100. Thus, we conclude that Nup100 regulates tRNA export in a manner distinct from Los1 or Msn5. Together, these experiments reveal a novel Nup100 role in the tRNA life cycle that impacts the S. cerevisiae life span. PMID:27932586

Oral Application of Magnesium-L-Threonate Attenuates Vincristine-induced Allodynia and Hyperalgesia by Normalization of Tumor Necrosis Factor-α/Nuclear Factor-κB Signaling.

PubMed

Xu, Ting; Li, Dai; Zhou, Xin; Ouyang, Han-Dong; Zhou, Li-Jun; Zhou, Hang; Zhang, Hong-Mei; Wei, Xu-Hong; Liu, Guosong; Liu, Xian-Guo

2017-06-01

Antineoplastic agents, including vincristine, often induce neuropathic pain and magnesium deficiency clinically, but the causal link between them has not been determined. No drug is available for treating this form of neuropathic pain. Injection of vincristine (0.1 mg · kg · day, intraperitoneally, for 10 days) was used to induce nociceptive sensitization, which was accessed with von Frey hairs and the plantar tester in adult male Sprague-Dawley rats. Magnesium-L- threonate was administered through drinking water (604 mg · kg · day). Extracellular and intracellular free Mg were measured by Calmagite chromometry and flow cytometry. Molecular biologic and electrophysiologic experiments were performed to expose the underlying mechanisms. Vincristine injection induced allodynia and hyperalgesia (n = 12), activated tumor necrosis factor-α/nuclear factor-κB signaling, and reduced free Mg in cerebrospinal fluid by 21.7 ± 6.3% (mean ± SD; n = 13) and in dorsal root ganglion neurons by 27 ± 6% (n = 11). Reducing Mg activated tumor necrosis factor-α/nuclear factor-κB signaling in cultured dorsal root ganglion neurons. Oral application of magnesium-L-threonate prevented magnesium deficiency and attenuated both activation of tumor necrosis factor-α/nuclear factor-κB signaling and nociceptive sensitization (n = 12). Mechanistically, vincristine induced long-term potentiation at C-fiber synapses, up-regulated N-methyl-D-aspartate receptor type 2B subunit of N-methyl-D-aspartate receptor, and led to peptidergic C-fiber sprouting in spinal dorsal horn (n = 6 each). The vincristine-induced pathologic plasticity was blocked by intrathecal injection of nuclear factor-κB inhibitor (n = 6), mimicked by tumor necrosis factor-α, and substantially prevented by oral magnesium-L-threonate (n = 5). Vincristine may activate tumor necrosis factor-α/nuclear factor-κB pathway by reduction of intracellular magnesium, leading to spinal pathologic plasticity and nociceptive sensitization. Oral magnesium-L-threonate that prevents the magnesium deficiency is a novel approach to prevent neuropathic pain induced by chemotherapy.

Anoxia-responsive regulation of the FoxO transcription factors in freshwater turtles, Trachemys scripta elegans.

PubMed

Krivoruchko, Anastasia; Storey, Kenneth B

2013-11-01

The forkhead class O (FoxO) transcription factors are important regulators of multiple aspects of cellular metabolism. We hypothesized that activation of these transcription factors could play crucial roles in low oxygen survival in the anoxia-tolerant turtle, Trachemys scripta elegans. Two FoxOs, FoxO1 and FoxO3, were examined in turtle tissues in response to 5 and 20h of anoxic submergence using techniques of RT-PCR, western immunoblotting and DNA-binding assays to assess activation. Transcript levels of FoxO-responsive genes were also quantified using RT-PCR. FoxO1 was anoxia-responsive in the liver, with increases in transcript levels, protein levels, nuclear levels and DNA-binding of 1.7-4.8fold in response to anoxia. Levels of phosphorylated FoxO1 also decreased to 57% of control values in response to 5h of anoxia, indicating activation. FoxO3 was activated in the heart, kidney and liver in response to anoxia, with nuclear levels increasing by 1.5-3.7fold and DNA-binding activity increasing by 1.3-2.9fold. Transcript levels of two FoxO-target genes, p27kip1 and catalase, also rose by 2.4-2.5fold in the turtle liver under anoxia. The results suggest that the FoxO transcription factors are activated in response to anoxia in T. scripta elegans, potentially contributing to the regulation of stress resistance and metabolic depression. This study provides the first demonstration of activation of FoxOs in a natural model for vertebrate anoxia tolerance, further improving understanding of how tissues can survive without oxygen. © 2013.

KLF5 regulates infection- and inflammation-induced pro-labour mediators in human myometrium.

PubMed

Lappas, Martha

2015-05-01

The transcription factor Kruppel-like factor 5 (KLF5) has been shown to associate with nuclear factor kappa B (NFκB) to regulate genes involved in inflammation. However, there are no studies on the expression and regulation of KLF5 in the processes of human labour and delivery. Thus, the aims of this study were to determine the effect of i) human labour on KLF5 expression in both foetal membranes and myometrium; ii) the pro-inflammatory cytokine interleukin 1 beta (IL1β), bacterial product flagellin and the viral dsRNA analogue poly(I:C) on KLF5 expression and iii) KLF5 knockdown by siRNA in human myometrial primary cells on pro-inflammatory and pro-labour mediators. In foetal membranes, there was no effect of term or preterm labour on KLF5 expression. In myometrium, the term labour was associated with an increase in nuclear KLF5 protein expression. Moreover, KLF5 expression was also increased in myometrial cells treated with IL1β, flagellin or poly(IC), likely factors contributing to preterm birth. KLF5 silencing in myometrial cells significantly decreased IL1β-induced cytokine expression (IL6 and IL8 mRNA expression and release), COX2 mRNA expression, and subsequent release of prostaglandins PGE2 and PGF2 α. KLF5 silencing also significantly reduced flagellin- and poly(I:C)-induced IL6 and IL8 mRNA expression. Lastly, IL1β-, flagellin- and poly(I:C)-stimulated NFκB transcriptional activity was significantly suppressed in KLF5-knockout myometrial cells. In conclusion, this study describes novel data in which KLF5 is increased in labouring myometrium, and KLF5 silencing decreased inflammation- and infection-induced pro-labour mediators. © 2015 Society for Reproduction and Fertility.

Principles of Exercise Prescription, and How They Influence Exercise-Induced Changes of Transcription Factors and Other Regulators of Mitochondrial Biogenesis.

PubMed

Granata, Cesare; Jamnick, Nicholas A; Bishop, David J

2018-04-19

Physical inactivity represents the fourth leading risk factor for mortality, and it has been linked with a series of chronic disorders, the treatment of which absorbs ~ 85% of healthcare costs in developed countries. Conversely, physical activity promotes many health benefits; endurance exercise in particular represents a powerful stimulus to induce mitochondrial biogenesis, and it is routinely used to prevent and treat chronic metabolic disorders linked with sub-optimal mitochondrial characteristics. Given the importance of maintaining a healthy mitochondrial pool, it is vital to better characterize how manipulating the endurance exercise dose affects cellular mechanisms of exercise-induced mitochondrial biogenesis. Herein, we propose a definition of mitochondrial biogenesis and the techniques available to assess it, and we emphasize the importance of standardizing biopsy timing and the determination of relative exercise intensity when comparing different studies. We report an intensity-dependent regulation of exercise-induced increases in nuclear peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) protein content, nuclear phosphorylation of p53 (serine 15), and PGC-1α messenger RNA (mRNA), as well as training-induced increases in PGC-1α and p53 protein content. Despite evidence that PGC-1α protein content plateaus within a few exercise sessions, we demonstrate that greater training volumes induce further increases in PGC-1α (and p53) protein content, and that short-term reductions in training volume decrease the content of both proteins, suggesting training volume is still a factor affecting training-induced mitochondrial biogenesis. Finally, training-induced changes in mitochondrial transcription factor A (TFAM) protein content are regulated in a training volume-dependent manner and have been linked with training-induced changes in mitochondrial content.

Emerin plays a crucial role in nuclear invagination and in the nuclear calcium transient

PubMed Central

Shimojima, Masaya; Yuasa, Shinsuke; Motoda, Chikaaki; Yozu, Gakuto; Nagai, Toshihiro; Ito, Shogo; Lachmann, Mark; Kashimura, Shin; Takei, Makoto; Kusumoto, Dai; Kunitomi, Akira; Hayashiji, Nozomi; Seki, Tomohisa; Tohyama, Shugo; Hashimoto, Hisayuki; Kodaira, Masaki; Egashira, Toru; Hayashi, Kenshi; Nakanishi, Chiaki; Sakata, Kenji; Yamagishi, Masakazu; Fukuda, Keiichi

2017-01-01

Alteration of the nuclear Ca2+ transient is an early event in cardiac remodeling. Regulation of the nuclear Ca2+ transient is partly independent of the cytosolic Ca2+ transient in cardiomyocytes. One nuclear membrane protein, emerin, is encoded by EMD, and an EMD mutation causes Emery-Dreifuss muscular dystrophy (EDMD). It remains unclear whether emerin is involved in nuclear Ca2+ homeostasis. The aim of this study is to elucidate the role of emerin in rat cardiomyocytes by means of hypertrophic stimuli and in EDMD induced pluripotent stem (iPS) cell-derived cardiomyocytes in terms of nuclear structure and the Ca2+ transient. The cardiac hypertrophic stimuli increased the nuclear area, decreased nuclear invagination, and increased the half-decay time of the nuclear Ca2+ transient in cardiomyocytes. Emd knockdown cardiomyocytes showed similar properties after hypertrophic stimuli. The EDMD-iPS cell-derived cardiomyocytes showed increased nuclear area, decreased nuclear invagination, and increased half-decay time of the nuclear Ca2+ transient. An autopsied heart from a patient with EDMD also showed increased nuclear area and decreased nuclear invagination. These data suggest that Emerin plays a crucial role in nuclear structure and in the nuclear Ca2+ transient. Thus, emerin and the nuclear Ca2+ transient are possible therapeutic targets in heart failure and EDMD. PMID:28290476

Effect of estetrol, a selective nuclear estrogen receptor modulator, in mouse models of arterial and venous thrombosis.

PubMed

Valéra, Marie-Cécile; Noirrit-Esclassan, Emmanuelle; Dupuis, Marion; Fontaine, Coralie; Lenfant, Françoise; Briaux, Anne; Cabou, Cendrine; Garcia, Cedric; Lairez, Olivier; Foidart, Jean-Michel; Payrastre, Bernard; Arnal, Jean-François

2018-06-19

Estetrol (E4) is a natural estrogen synthesized exclusively during pregnancy by the human fetal liver, and the physiological role of this hormone is unknown. Interestingly, E4 was recently evaluated in preclinical and phase II-III clinical studies in combination with a progestin, with the advantage to not increase the circulating level of coagulation factors, at variance to oral estradiol or ethinylestradiol. Here, we evaluated the effect of E4 on hemostasis and thrombosis in mouse. Following chronic E4 treatment, mice exhibited a prolonged tail-bleeding time and were protected from arterial and also venous thrombosis in vivo. In addition, E4 treatment decreased ex vivo thrombus growth on collagen under arterial flow conditions. We recently showed that E4 activates uterine epithelial proliferation through nuclear estrogen receptor (ER) α. To analyze the impact of nuclear ERα actions on hemostasis and thrombosis, we generated hematopoietic chimera with bone marrow cells deficient for nuclear ERα. E4-induced protection against thromboembolism was significantly reduced in the absence of hematopoietic nuclear ERα activation, while the increased tail-bleeding time was not impacted by this deletion. In addition to its "liver friendly" profile described in women, our data shows that E4 has anti-thrombotic properties in various mouse models. Altogether, the natural fetal estrogen E4 could represent an attractive alternative to classic estrogens in oral contraception and treatment of menopause. Copyright © 2018. Published by Elsevier B.V.

Glycogen synthase kinase 3 regulates expression of nuclear factor-erythroid-2 related transcription factor-1 (Nrf1) and inhibits pro-survival function of Nrf1

PubMed Central

Biswas, Madhurima; Kwong, Erick K.; Park, Eujean; Nagra, Parminder; Chan, Jefferson Y.

2013-01-01

Nuclear factor E2-related factor-1 (Nrf1) is a basic leucine zipper transcription factor that is known to regulate antioxidant and cytoprotective gene expression. It was recently shown that Nrf1 is regulated by SCF-Fbw7 ubiquitin ligase. However our knowledge of upstream signals that targets Nrf1 for degradation by the UPS is not known. We report here that Nrf1 expression is negatively regulated by glycogen synthase kinase 3 (GSK3) in Fbw7-dependent manner. We show that GSK3 interacts with Nrf1 and phosphorylates the Cdc4 phosphodegron domain (CPD) in Nrf1. Mutation of serine residue in the CPD of Nrf1 to alanine (S350A), blocks Nrf1 from phosphorylation by GSK3, and stabilizes Nrf1. Knockdown of Nrf1 and expression of a constitutively active form of GSK3 results in increased apoptosis in neuronal cells in response to ER stress, while expression of the GSK3 phosphorylation resistant S350A–Nrfl attenuates apoptotic cell death. Together these data suggest that GSK3 regulates Nrf1 expression and cell survival function in response to stress activation. PMID:23623971

Nup124p Is a Nuclear Pore Factor of Schizosaccharomyces pombe That Is Important for Nuclear Import and Activity of Retrotransposon Tf1

PubMed Central

Balasundaram, David; Benedik, Michael J.; Morphew, Mary; Dang, Van-Dinh; Levin, Henry L.

1999-01-01

The long terminal repeat (LTR)-containing retrotransposon Tf1 propagates within the fission yeast Schizosaccharomyces pombe as the result of several mechanisms that are typical of both retrotransposons and retroviruses. To identify host factors that contribute to the transposition process, we mutagenized cultures of S. pombe and screened them for strains that were unable to support Tf1 transposition. One such strain contained a mutation in a gene we named nup124. The product of this gene contains 11 FXFG repeats and is a component of the nuclear pore complex. In addition to the reduced levels of Tf1 transposition, the nup124-1 allele caused a significant reduction in the nuclear localization of Tf1 Gag. Surprisingly, the mutation in nup124-1 did not cause any reduction in the growth rate, the nuclear localization of specific nuclear localization signal-containing proteins, or the cytoplasmic localization of poly(A) mRNA. A two-hybrid analysis and an in vitro precipitation assay both identified an interaction between Tf1 Gag and the N terminus of Nup124p. These results provide evidence for an unusual mechanism of nuclear import that relies on a direct interaction between a nuclear pore factor and Tf1 Gag. PMID:10409764

Nup124p is a nuclear pore factor of Schizosaccharomyces pombe that is important for nuclear import and activity of retrotransposon Tf1.

PubMed

Balasundaram, D; Benedik, M J; Morphew, M; Dang, V D; Levin, H L

1999-08-01

The long terminal repeat (LTR)-containing retrotransposon Tf1 propagates within the fission yeast Schizosaccharomyces pombe as the result of several mechanisms that are typical of both retrotransposons and retroviruses. To identify host factors that contribute to the transposition process, we mutagenized cultures of S. pombe and screened them for strains that were unable to support Tf1 transposition. One such strain contained a mutation in a gene we named nup124. The product of this gene contains 11 FXFG repeats and is a component of the nuclear pore complex. In addition to the reduced levels of Tf1 transposition, the nup124-1 allele caused a significant reduction in the nuclear localization of Tf1 Gag. Surprisingly, the mutation in nup124-1 did not cause any reduction in the growth rate, the nuclear localization of specific nuclear localization signal-containing proteins, or the cytoplasmic localization of poly(A) mRNA. A two-hybrid analysis and an in vitro precipitation assay both identified an interaction between Tf1 Gag and the N terminus of Nup124p. These results provide evidence for an unusual mechanism of nuclear import that relies on a direct interaction between a nuclear pore factor and Tf1 Gag.

Quercetin attenuates zymosan-induced arthritis in mice.

PubMed

Guazelli, Carla F S; Staurengo-Ferrari, Larissa; Zarpelon, Ana C; Pinho-Ribeiro, Felipe A; Ruiz-Miyazawa, Kenji W; Vicentini, Fabiana T M C; Vignoli, Josiane A; Camilios-Neto, Doumit; Georgetti, Sandra R; Baracat, Marcela M; Casagrande, Rubia; Verri, Waldiceu A

2018-06-01

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by articular lesions, recruitment of inflammatory cells and increased levels of pro-inflammatory cytokine. The intra-articular administration of zymosan is an experimental model that promotes inflammatory parameters resembling RA. Therefore, this model was used to investigate the efficacy of quercetin as a treatment of articular inflammation. Treatment with quercetin dose-dependently reduced zymosan-induced hyperalgesia, articular edema and the recruitment of neutrophils to the knee joint cavity. Histological analysis confirmed that quercetin inhibited zymosan-induced arthritis. The treatment with quercetin also inhibited zymosan-induced depletion of reduced glutathione (GSH) levels, TNFα and IL-1β production, and gp91 phox , prepro-endothelin-1 (preproET-1), and cyclooxygenase-2 mRNA expression. These molecular effects of quercetin were related to the inhibition of the nuclear factor kappa-B and induction of Nuclear factor erythroid 2- related factor (Nrf2)/home oxygenase (HO-1) pathway. Thus, quercetin exerted anti-inflammatory, analgesic and antioxidant effects in experimental arthritis, suggesting quercetin is a possible candidate for arthritis treatment. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Icotinib inhibits the invasion of Tca8113 cells via downregulation of nuclear factor κB-mediated matrix metalloproteinase expression

PubMed Central

YANG, CAILING; YAN, JIANGUO; YUAN, GUOYAN; ZHANG, YINGHUA; LU, DERONG; REN, MINGXIN; CUI, WEIGANG

2014-01-01

Icotinib is an epidermal growth factor receptor tyrosine kinase inhibitor, which has been revealed to inhibit proliferation in tumor cells. However, the effect of icotinib on cancer cell metastasis remains to be explained. This study examines the effect of icotinib on the migration and invasion of squamous cells of tongue carcinoma (Tca8113 cells) in vitro. The results of the Boyden chamber invasion assay demonstrated that icotinib reduced cell invasion, suppressed the protein levels of matrix metalloproteinases (MMPs), MMP-2 and MMP-9, and increased the expression of tissue inhibitor of metalloproteinase-1. In addition, icotinib was found to significantly decrease the protein levels of nuclear factor κB (NF-κB) p65, which suggested that icotinib inhibits NF-κB activity. Furthermore, treatment with the NF-κB inhibitor, pyrrolidine dithiocarbamate, suppressed cell invasion and MMP-2 expression. These results suggested that icotinib inhibits the invasion of Tca8113 cells by downregulating MMP via the inactivation of the NF-κB signaling pathways. PMID:25120710

Icotinib inhibits the invasion of Tca8113 cells via downregulation of nuclear factor κB-mediated matrix metalloproteinase expression.

PubMed

Yang, Cailing; Yan, Jianguo; Yuan, Guoyan; Zhang, Yinghua; Lu, Derong; Ren, Mingxin; Cui, Weigang

2014-09-01

Icotinib is an epidermal growth factor receptor tyrosine kinase inhibitor, which has been revealed to inhibit proliferation in tumor cells. However, the effect of icotinib on cancer cell metastasis remains to be explained. This study examines the effect of icotinib on the migration and invasion of squamous cells of tongue carcinoma (Tca8113 cells) in vitro . The results of the Boyden chamber invasion assay demonstrated that icotinib reduced cell invasion, suppressed the protein levels of matrix metalloproteinases (MMPs), MMP-2 and MMP-9, and increased the expression of tissue inhibitor of metalloproteinase-1. In addition, icotinib was found to significantly decrease the protein levels of nuclear factor κB (NF-κB) p65, which suggested that icotinib inhibits NF-κB activity. Furthermore, treatment with the NF-κB inhibitor, pyrrolidine dithiocarbamate, suppressed cell invasion and MMP-2 expression. These results suggested that icotinib inhibits the invasion of Tca8113 cells by downregulating MMP via the inactivation of the NF-κB signaling pathways.

Activation of the nuclear factor E2-related factor 2/anitioxidant response element alleviates the nitroglycerin-induced hyperalgesia in rats.

PubMed

Di, Wei; Shi, Xiaolei; Lv, Hua; Liu, Jun; Zhang, Hong; Li, Zhiwei; Fang, Yannan

2016-12-01

Antioxidants have been proven to weaken hyperalgesia in neuropathic pain. Endogenous antioxidant defense system may have a role in the prevention of hyperalgesia in migraine. In this study, we aimed to evaluate the role of nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) pathway in regulating the activation of the trigeminovascular system (TGVS) and hypersensitivity in nitroglycerin (NTG)-induced hyperalgesia rats. The expression levels of Nrf2, HO, HO1, and NQO1 in the trigeminal nucleus caudalis (TNC) were detected by western blot. Immunofluorescence was used to demonstrate the cell-specific localization of Nrf2 in TNC. Sulforaphane, a Nrf2 activator, was administered to NTG-induced rats. Then, the number of c-Fos- and nNOS-immunoreactive neurons in TNC was evaluated using immunofluorescence, and c-Fos and nNOS protein levels were quantified using western blot. Von Frey hair testing was used to evaluate the tactile thresholds of rats at different time points in different groups. Total cellular and nuclear levels of the proteins Nrf2, HO1, and NQO1 were elevated in TNC after NTG injection, and Nrf2 was found to be located in the nucleus and cytoplasm of the neurons. Sulforaphane pretreatment significantly increased the nuclear Nrf2, HO1, and NQO1 levels in TNC. In addition, sulforaphane exposure effectively inhibited the expression of nNOS and c-Fos, reduced the number of nNOS and c-Fos immunoreactive neurons in TNC, and attenuated the tactile thresholds induced by NTG injection. Oxidative stress was involved in nitroglycerin-induced hyperalgesia. Activation of the Nrf2/ARE pathway inhibited the activation of TGVS and prevented the induction of hyperalgesia. Sulforaphane might therefore be an effective agent for hyperalgesia. Further studies are needed to discover the underlying mechanisms of the process.

Induction of Lung GSH and Glutamate Cysteine Ligase by 1,4-phenylenebis(methylene)selenocyanate and its Glutathione Conjugate: Role of Nuclear factor-erythroid 2-Related Factor 2

PubMed Central

Emmert, Sans W.; El-Bayoumy, Karam; Das, Arunangshu; Sun, Yuan-Wan; Amin, Shantu; Desai, Dhimant; Aliaga, Cesar; Richie, John P.

2012-01-01

The synthetic organoselenium agent 1,4- phenylenebis(methylene)selenocyanate (p-XSC) and its glutathione (GSH) conjugate (p-XSeSG), are potent chemopreventive agents in several preclinical models. p-XSC is also an effective inducer of GSH in mouse lung. Our objectives were to test the hypothesis that GSH induction by p-XSC occurs through upregulation of the rate-limiting GSH biosynthetic enzyme glutamate cysteine ligase (GCL), through activation of antioxidant response elements (ARE) in GCL genes via activation of nuclear factor-erythroid 2-related factor 2 (Nrf2). p-XSC feeding (10 ppm Se) increased GSH (230%) and upregulated the catalytic subunit of GCL (GCLc) (55%), extracellular related kinase (ERK) (220%) and nuclear Nrf2 (610%) in lung but not liver after 14 days in the rat (P<0.05). Similarly, p-XSeSG feeding (10 ppm) induced lung GCLc (88%) and GSH (200%) (P<0.05), while the naturally-occurring selenomethionine had no effect. Both p-XSC and p-XSeSG activated a luciferase reporter in HepG2 ARE reporter cells up to 3-fold for p-XSC and ≥5-fold for p-XSeSG. Luciferase activation by p-XSeSG was associated with enhanced levels of GSH, GCLc and nuclear Nrf2, which were significantly reduced by co-incubation with short interfering RNA targeting Nrf2 (siNrf2). The dependence of GCL induction on Nrf2 was confirmed in Nrf2 deficient mouse embryonic fibroblasts (MEF) where p-XSeSG induced GCL subunits in wildtype, but not Nrf2 deficient cells (p<0.05). These results indicate that p-XSC may act through the Nrf2 pathway in vivo, and that p-XSeSG is the putative metabolite responsible for such activation, thus offering p-XSeSG as a less toxic, yet highly efficacious inducer of GSH. PMID:22542796

Gestational Diabetes Mellitus Impairs Nrf2-Mediated Adaptive Antioxidant Defenses and Redox Signaling in Fetal Endothelial Cells In Utero

PubMed Central

Cheng, Xinghua; Chapple, Sarah J.; Patel, Bijal; Puszyk, William; Sugden, David; Yin, Xiaoke; Mayr, Manuel; Siow, Richard C.M.; Mann, Giovanni E.

2013-01-01

In utero exposure to gestational diabetes mellitus (GDM) is associated with an increased risk of type 2 diabetes and cardiovascular disease in later life, yet the underlying mechanisms remain to be elucidated. We examined the effects of GDM on the proteome, redox status, and nuclear factor erythroid 2–related factor 2 (Nrf2)-mediated antioxidant gene expression in human fetal endothelial cells. Proteomic analysis revealed that proteins involved in redox homeostasis were significantly altered in GDM and associated with increased mitochondrial superoxide generation, protein oxidation, DNA damage, and diminished glutathione (GSH) synthesis. In GDM cells, the lipid peroxidation product 4-hydroxynonenal (HNE) failed to induce nuclear Nrf2 accumulation and mRNA and/or protein expression of Nrf2 and its target genes NAD(P)H:quinone oxidoreductase 1 (NQO1), Bach1, cystine/glutamate transporter, and glutamate cysteine ligase. Although methylation of CpG islands in Nrf2 or NQO1 promoters was unaltered by GDM, decreased DJ-1 and increased phosphorylated glycogen synthase kinase 3β levels may account for impaired Nrf2 signaling. HNE-induced increases in GSH and NQO1 levels were abrogated by Nrf2 small interfering RNA in normal cells, and overexpression of Nrf2 in GDM cells partially restored NQO1 induction. Dysregulation of Nrf2 in fetal endothelium may contribute to the increased risk of type 2 diabetes and cardiovascular disease in offspring. PMID:23974919

Gestational diabetes mellitus impairs Nrf2-mediated adaptive antioxidant defenses and redox signaling in fetal endothelial cells in utero.

PubMed

Cheng, Xinghua; Chapple, Sarah J; Patel, Bijal; Puszyk, William; Sugden, David; Yin, Xiaoke; Mayr, Manuel; Siow, Richard C M; Mann, Giovanni E

2013-12-01

In utero exposure to gestational diabetes mellitus (GDM) is associated with an increased risk of type 2 diabetes and cardiovascular disease in later life, yet the underlying mechanisms remain to be elucidated. We examined the effects of GDM on the proteome, redox status, and nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant gene expression in human fetal endothelial cells. Proteomic analysis revealed that proteins involved in redox homeostasis were significantly altered in GDM and associated with increased mitochondrial superoxide generation, protein oxidation, DNA damage, and diminished glutathione (GSH) synthesis. In GDM cells, the lipid peroxidation product 4-hydroxynonenal (HNE) failed to induce nuclear Nrf2 accumulation and mRNA and/or protein expression of Nrf2 and its target genes NAD(P)H:quinone oxidoreductase 1 (NQO1), Bach1, cystine/glutamate transporter, and glutamate cysteine ligase. Although methylation of CpG islands in Nrf2 or NQO1 promoters was unaltered by GDM, decreased DJ-1 and increased phosphorylated glycogen synthase kinase 3β levels may account for impaired Nrf2 signaling. HNE-induced increases in GSH and NQO1 levels were abrogated by Nrf2 small interfering RNA in normal cells, and overexpression of Nrf2 in GDM cells partially restored NQO1 induction. Dysregulation of Nrf2 in fetal endothelium may contribute to the increased risk of type 2 diabetes and cardiovascular disease in offspring.

Changes in the Factors Influencing Public Acceptance of Nuclear Power Generation in Japan Since the 2011 Fukushima Daiichi Nuclear Disaster.

PubMed

Tsujikawa, Norifumi; Tsuchida, Shoji; Shiotani, Takamasa

2016-01-01

Public support for nuclear power generation has decreased in Japan since the Fukushima Daiichi nuclear accident in March 2011. This study examines how the factors influencing public acceptance of nuclear power changed after this event. The influence factors examined are perceived benefit, perceived risk, trust in the managing bodies, and pro-environmental orientation (i.e., new ecological paradigm). This study is based on cross-sectional data collected from two online nationwide surveys: one conducted in November 2009, before the nuclear accident, and the other in October 2011, after the accident. This study's target respondents were residents of Aomori, Miyagi, and Fukushima prefectures in the Tohoku region of Japan, as these areas were the epicenters of the Great East Japan Earthquake and the locations of nuclear power stations. After the accident, trust in the managing bodies was found to have a stronger influence on perceived risk, and pro-environmental orientation was found to have a stronger influence on trust in the managing bodies; however, perceived benefit had a weaker positive influence on public acceptance. We also discuss the theoretical and practical implications of these findings. © 2015 Society for Risk Analysis.

RAGE-Specific Inhibitor FPS-ZM1 Attenuates AGEs-Induced Neuroinflammation and Oxidative Stress in Rat Primary Microglia.

PubMed

Shen, Chao; Ma, Yingjuan; Zeng, Ziling; Yin, Qingqing; Hong, Yan; Hou, Xunyao; Liu, Xueping

2017-10-01

Advanced glycation end products (AGEs) enhance microglial activation and intensify the inflammatory response and oxidative stress in the brain. This process may occur due to direct cytotoxicity or interacting with AGEs receptors (RAGE), which are expressed on the surface of microglia. FPS-ZM1 is a high-affinity but nontoxic RAGE-specific inhibitor that has been recently shown to attenuate the Aβ-induced inflammatory response by blocking the ligation of Aβ to RAGE. In this study, we further investigated the effect of FPS-ZM1 on the AGEs/RAGE interaction and downstream elevation of neuroinflammation and oxidative stress in primary microglia cells. The results suggested that FPS-ZM1 significantly suppressed AGEs-induced RAGE overexpression, RAGE-dependent microglial activation, nuclear translocation of nuclear factor kappaB p65 (NF-κB p65), and the expression of downstream inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) and inducible nitric oxide synthase (iNOS)/nitric oxide (NO). Furthermore, FPS-ZM1 attenuated AGEs-stimulated NADPH oxidase (NOX) activation and reactive oxygen species (ROS) expression. Finally, FPS-ZM1 elevated the levels of transcription factors nuclear-factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1 (HO-1), as well as decreased antioxidant capacity and increased production of oxidative species. Our results suggest that FPS-ZM1 may be neuroprotective through attenuating microglial activation, oxidative stress and inflammation by blocking RAGE.

Oncoprotein p28 GANK binds to RelA and retains NF-kappaB in the cytoplasm through nuclear export.

PubMed

Chen, Yao; Li, Hong Hai; Fu, Jing; Wang, Xue Feng; Ren, Yi Bin; Dong, Li Wei; Tang, Shan Hua; Liu, Shu Qing; Wu, Meng Chao; Wang, Hong Yang

2007-12-01

p28(GANK) (also known as PSMD10, p28 and gankyrin) is an ankyrin repeat anti-apoptotic oncoprotein that is commonly overexpressed in hepatocellular carcinomas and increases the degradation of p53 and Rb. NF-kappaB (nuclear factor-kappaB) is known to be sequestered in the cytoplasm by I kappaB (inhibitor of NF-kappaB) proteins, but much less is known about the cytoplasmic retention of NF-kappaB by other cellular proteins. Here we show that p28(GANK) inhibits NF-kappaB activity. As a nuclear-cytoplasmic shuttling protein, p28(GANK) directly binds to NF-kappaB/RelA and exports RelA from nucleus through a chromosomal region maintenance-1 (CRM-1) dependent pathway, which results in the cytoplasmic retention of NF-kappaB/RelA. We demonstrate that all the ankyrin repeats of p28(GANK) are required for the interaction with RelA and that the N terminus of p28(GANK), which contains the nuclear export sequence (NES), is responsible for suppressing NF-kappaB/RelA nuclear translocation. These results suggest that overexpression of p28(GANK) prevents the nuclear localization and inhibits the activity of NF-kappaB/RelA.

NATO (North Atlantic Treaty Organization) deterrence and defense after the INF (Intermediate-Range Nuclear Forces) treaty. Final report, June 1988-June 1989

DOE Office of Scientific and Technical Information (OSTI.GOV)

Garrett, S.A.

1989-06-21

The treaty between the Soviet Union and the United States eliminating a whole class of intermediate-range nuclear forces (INF) in Europe raises a number of questions about NATO's future ability to deter Warsaw Pact aggression. Future choices on Alliance strategy and doctrine will be influenced by a variety of factors, including the image of new thinking in Soviet security policy enunciated by General Secretary Gorbachev, changing West European opinion toward the use of nuclear weapons for NATO deterrence, the complications inherent in further nuclear and conventional arms-control negotiations, assessments of the current conventional arms balance in Europe, and ongoing questionsmore » about NATO cohesion as well as the continued coupling of American security with that of her European allies. In the post-INF environment it may well be that U.S. Navy nuclear assets will assume an increasingly important role, particularly the Tomahawk Land Attack Missile/Nuclear (TLAM/N). The TLAM/N has many attractive attributes that can be supportive of NATO deterrence of the WTO, but there are also a number of unresolved questions to be addressed concerning this particular weapons system. Modernization of NATO's land-based short-range nuclear forces (SNF), such as the Lance missile, is also seen by many as critical to the maintenance of Alliance security in the aftermath of INF.« less

Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS).

PubMed

Morris, Gerwyn; Maes, Michael

2012-11-01

Fukuda's criteria are adequate to make a distinction between Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) and chronic fatigue (CF), but ME/CFS patients should be subdivided into those with (termed ME) and without (termed CFS) post exertional malaise [Maes et al. 2012]. ME/CFS is considered to be a neuro-immune disease. ME/CFS is characterized by activated immuno-inflammatory pathways, including increased levels of pro-inflammatory cytokines, nuclear factor κB (NF-κB) and aberrations in mitochondrial functions, including lowered ATP. These processes may explain typical symptoms of ME/CFS, e.g. fatigue, malaise, hyperalgesia, and neurologic and autonomic symptoms. Here we hypothesize that increased NF-κB together with a loss of p53 are key phenomena in ME/CFS that further explain ME/CFS symptoms, such as fatigue and neurocognitive dysfunction, and explain ME symptoms, such as post-exertional malaise following mental and physical activities. Inactivation of p53 impairs aerobic mitochondrial functions and causes greater dependence on anaerobic glycolysis, elevates lactate levels, reduces mitochondrial density in skeletal muscle and reduces endurance during physical exercise. Lowered p53 and increased NF-κB are associated with elevated reactive oxygen species. Increased NF-κB induces the production of pro-inflammatory cytokines, which increase glycolysis and further compromise mitochondrial functions. All these factors together may contribute to mitochondrial exhaustion and indicate that the demand for extra ATP upon the commencement of increased activity cannot be met. In conditions of chronic inflammation and oxidative stress, high NF-κB and low p53 may conspire to promote neuron and glial cell survival at a price of severely compromised metabolic brain function. Future research should examine p53 signaling in ME/CFS. Copyright © 2012. Published by Elsevier Ltd.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Eich, F. G.; Agostini, Federica, E-mail: agostini@mpi-halle.mpg.de

We propose a procedure to analyze the relation between the exact factorization of the electron-nuclear wave function and the Born-Oppenheimer approximation. We define the adiabatic limit as the limit of infinite nuclear mass. To this end, we introduce a unit system that singles out the dependence on the electron-nuclear mass ratio of each term appearing in the equations of the exact factorization. We observe how non-adiabatic effects induced by the coupling to the nuclear motion affect electronic properties and we analyze the leading term, connecting it to the classical nuclear momentum. Its dependence on the mass ratio is tested numericallymore » on a model of proton-coupled electron transfer in different non-adiabatic regimes.« less

[Induction of uridine 5'-diphosphate-glucuronosyltransferase gene expression by sulforaphane and its mechanism: experimental study in human colon cancel cells].

PubMed

Wang, Min; Li, Yan-Qing; Zhong, Ning; Chen, Jian; Xu, Xiao-Qun; Yuan, Meng-Biao

2005-03-30

To study the induction of expression of uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) 1A in colon cancer cells by sulforaphane (SFN) and its possible mechanism. Human colon cancer cells of the line Caco-2 were cultured and added with SFN of different terminal concentrations, all below the concentration of IC(50). RT-PCR was used to examine the expression of UGT1A mRNA induced by SFN. Western blotting was used to detect the expression of UGT1A protein. The glucuronidation rate of N-hydroxy-PhIP was measured by high performance liquid chromatography (HPLC). The nuclear localization of transcription factor Nrf2 was observed by confocal laser microscopy. (1) Expression of UGT1A mRNA was observed in the Cac0-2 cells induced by SFN of the concentrations of 10 micromol/L approximately 35 micromol/L in a dose-independent manner (P < 0.05). Sulforaphane of the concentration of 25 micromol/L induced the UGT1A mRNA expression time-dependently. The levels of UGT1A1, UGT1A8, and UGT1A10 mRNA expression were significantly increased in the cells treated with 25 micromol/L sulforaphane compared to that in the controls (P = 0.006, P = 0.017, and P = 0.008 respectively). (2) The UGT1A protein band intensity increased significantly in the Coco-2 cells treated with sulforaphane of the concentrations 10 micromol/L approximately 30 micromol/L for 24 h in comparison with the control cells. (3) When the microsomes from the untreated Caco-2 cells were incubated with N-hydroxy-PhIP there was a minor HPLC peak at the expected retention time for N-hydroxy-PhIP-N2-glucuronide. This peak was dramatically increased in the sulforaphane-treated cells, suggesting higher activities of glucuronidation of N-hydroxy-PhIP. (4) Cytoplasmic labeling of NF-E2-related factor 2 (Nrf2), a transcription factor, with no nuclear staining was observed in the non-stimulated cells, whereas an intense nuclear labeling was observed in the sulforaphane-treated cells, indicating the induction of nuclear translocation of Nrf2 by sulforaphane. (1) Low dose sulforaphane induces the expression of UGT1A, UGT1A1, UGT1A A8, and UGT1A A10 mRNA significantly. These changes are accompanied by an increase in UGT1A1 protein and increase in heterocyclic aromatic amine glucuronidation. (2) The induction of the phase II enzyme activity by SFN occurs at the transcriptional level and is regulated by Nrf2.

Examining Factors Affecting Attitudes toward Nuclear Power in Taiwan

NASA Astrophysics Data System (ADS)

Chan, Tzu-Jen

Nuclear power has become a major issue in Taiwan for several decades. The objective of the present study is to obtain evidence about the major determinants contributing to attitudes toward nuclear power, by investigating socioeconomic factors, environmental attitudes, knowledge of issues, trust, and risk perception, in shaping nuclear attitudes. A face-to-face survey was conducted using paper-based questionnaires from July 2014 to September 2014. Finally, 364 surveys were collected, of which 356 met validation requirements. The findings showed (1) knowledge of issues, trust in university scientists, trust in environmental groups, and risk perception directly influence attitudes toward nuclear power. (2) Risk perception is directly influenced by trust in nuclear authorities, trust in environmental groups, environmental attitudes, and party preference. (3) Gender, age, and party preference directly influence knowledge, trust in nuclear authorities, or trust in university scientists. The potential explanations and implications of findings are discussed.

Heat Shock Protein 70 Prevents Hyperoxia-Induced Disruption of Lung Endothelial Barrier via Caspase-Dependent and AIF-Dependent Pathways

PubMed Central

Kondrikov, Dmitry; Fulton, David; Dong, Zheng; Su, Yunchao

2015-01-01

Exposure of pulmonary artery endothelial cells (PAECs) to hyperoxia results in a compromise in endothelial monolayer integrity, an increase in caspase-3 activity, and nuclear translocation of apoptosis-inducing factor (AIF), a marker of caspase-independent apoptosis. In an endeavor to identify proteins involved in hyperoxic endothelial injury, we found that the protein expression of heat-shock protein 70 (Hsp70) was increased in hyperoxic PAECs. The hyperoxia-induced Hsp70 protein expression is from hspA1B gene. Neither inhibition nor overexpression of Hsp70 affected the first phase barrier disruption of endothelial monolayer. Nevertheless, inhibition of Hsp70 by using the Hsp70 inhibitor KNK437 or knock down Hsp70 using siRNA exaggerated and overexpression of Hsp70 prevented the second phase disruption of lung endothelial integrity. Moreover, inhibition of Hsp70 exacerbated and overexpression of Hsp70 prevented hyperoxia-induced apoptosis, caspase-3 activation, and increase in nuclear AIF protein level in PAECs. Furthermore, we found that Hsp70 interacted with AIF in the cytosol in hyperoxic PAECs. Inhibition of Hsp70/AIF association by KNK437 correlated with increased nuclear AIF level and apoptosis in KNK437-treated PAECs. Finally, the ROS scavenger NAC prevented the hyperoxia-induced increase in Hsp70 expression and reduced the interaction of Hsp70 with AIF in hyperoxic PAECs. Together, these data indicate that increased expression of Hsp70 plays a protective role against hyperoxia-induced lung endothelial barrier disruption through caspase-dependent and AIF-dependent apoptotic pathways. Association of Hsp70 with AIF prevents AIF nuclear translocation, contributing to the protective effect of Hsp70 on hyperoxia-induced endothelial apoptosis. The hyperoxia-induced increase in Hsp70 expression and Hsp70/AIF interaction is contributed to ROS formation. PMID:26066050

STATs get their move on.

PubMed

Reich, Nancy C

2013-10-01

Understanding the mechanisms that regulate dynamic localization of a protein within a cell can provide critical insight to its functional molecular interactions. Signal transducers and activators of transcription (STATs) play essential roles in development, proliferation, and immune defense. However the consequences of STAT hyperactivity can predispose to diseases including autoimmunity and cancer. To function as transcription factors STATs must gain access to the nucleus, and knowledge of the mechanisms that regulate STAT nuclear trafficking can provide a means to control STAT action. This review presents a synopsis of some of the studies that address the nuclear dynamics of the STAT proteins. Evidence suggests that not all STATs are the same. Nuclear import of STAT1 and STAT4 appears linked to their tyrosine phosphorylation and the formation of parallel dimers via reciprocal phosphotyrosine and Src homology 2 domain interactions. This dimer arrangement generates a conformational nuclear localization signal. STAT2 is imported continually to the nucleus in an unphosphorylated state due to its association with IRF9, but the dominant nuclear export signal of STAT2 shuttles the complex back to the cytoplasm. Following STAT2 tyrosine phosphorylation, it can form dimers with STAT1 to affect nuclear import as the trimeric complex (ISGF3). Distinctly, STAT3, STAT5, and STAT6 are continually imported to the nucleus independent of tyrosine phosphorylation. Mutational studies indicate the nuclear localization signals in these STATs require the conformational structure of their coiled-coil domains. Increases in STAT nuclear accumulation following cytokine stimulation appear coordinate with their ability to bind DNA.

Nuclear fluxes during coherent tunnelling in asymmetric double well potentials

NASA Astrophysics Data System (ADS)

Liu, ChunMei; Manz, Jörn; Yang, Yonggang

2015-08-01

Previous results for nuclear fluxes during coherent tunnelling of molecules with symmetric double well potentials are extended to fluxes in asymmetric double well potentials. The theory is derived using the two-state approximation (TSA). The symmetric system serves as a reference. As an example, we consider the one-dimensional model of the tunnelling inversion of oriented ammonia, with semiclassical dipole coupling to an electric field. The tunnelling splitting increases with the dipole coupling by a factor f≥slant 1. The tunnelling time decreases by 1/f. The nuclear density appears as the sum of two parts: The tunnelling part decreases as {1/f}2 times the density of the symmetric reference, whereas the non-tunnelling part is the initial density times ≤ft({{1-1}/f}2\\right). Likewise, the nuclear flux decreases by 1/f, with essentially the same shape as for the symmetric reference, with maximum value at the potential barrier. Coherent nuclear tunnellings starting from the upper or lower wells of the asymmetric potential are equivalent. The results are universal, in the frame of the TSA, hence they allow straightforward extrapolations from one system to others. This is demonstrated by the prediction of isotope effects for five isotopomers of ammonia.

Saponarin activates AMPK in a calcium-dependent manner and suppresses gluconeogenesis and increases glucose uptake via phosphorylation of CRTC2 and HDAC5.

PubMed

Seo, Woo-Duck; Lee, Ji Hae; Jia, Yaoyao; Wu, Chunyan; Lee, Sung-Joon

2015-11-15

This study investigated the molecular mechanism of saponarin, a flavone glucoside, in the regulation of insulin sensitivity. Saponarin suppressed the rate of gluconeogenesis and increased cellular glucose uptake in HepG2 and TE671 cells by regulating AMPK. Using an in vitro kinase assay, we showed that saponarin did not directly interact with the AMPK protein. Instead, saponarin increased intracellular calcium levels and induced AMPK phosphorylation, which was diminished by co-stimulation with STO-609, an inhibitor of CAMKKβ. Transcription of hepatic gluconeogenesis genes was upregulated by nuclear translocation of CRTC2 and HDAC5, coactivators of CREB and FoxO1 transcription factors, respectively. This nuclear translocation was inhibited by increased phosphorylation of CRTC2 and HDAC5 by saponarin-induced AMPK in HepG2 cells and suppression of CREB and FoxO1 transactivation activities in cells stimulated by saponarin. The results from a chromatin immunoprecipitation assay confirmed the reduced binding of CRTC2 on the PEPCK and G6Pase promoters. In TE671 cells, AMPK phosphorylated HDAC5, which suppressed nuclear penetration and upregulated GLUT4 transcription, leading to enhanced glucose uptake. Collectively, these results suggest that saponarin activates AMPK in a calcium-dependent manner, thus regulating gluconeogenesis and glucose uptake. Copyright © 2015 Elsevier Ltd. All rights reserved.

Highly selective detection of individual nuclear spins with rotary echo on an electron spin probe

PubMed Central

Mkhitaryan, V. V.; Jelezko, F.; Dobrovitski, V. V.

2015-01-01

We consider an electronic spin, such as a nitrogen-vacancy center in diamond, weakly coupled to a large number of nuclear spins, and subjected to the Rabi driving with a periodically alternating phase. We show that by switching the driving phase synchronously with the precession of a given nuclear spin, the interaction to this spin is selectively enhanced, while the rest of the bath remains decoupled. The enhancement is of resonant character. The key feature of the suggested scheme is that the width of the resonance is adjustable, and can be greatly decreased by increasing the driving strength. Thus, the resonance can be significantly narrowed, by a factor of 10–100 in comparison with the existing detection methods. Significant improvement in selectivity is explained analytically and confirmed by direct numerical many-spin simulations. The method can be applied to a wide range of solid-state systems. PMID:26497777

Statistical methods for thermonuclear reaction rates and nucleosynthesis simulations

NASA Astrophysics Data System (ADS)

Iliadis, Christian; Longland, Richard; Coc, Alain; Timmes, F. X.; Champagne, Art E.

2015-03-01

Rigorous statistical methods for estimating thermonuclear reaction rates and nucleosynthesis are becoming increasingly established in nuclear astrophysics. The main challenge being faced is that experimental reaction rates are highly complex quantities derived from a multitude of different measured nuclear parameters (e.g., astrophysical S-factors, resonance energies and strengths, particle and γ-ray partial widths). We discuss the application of the Monte Carlo method to two distinct, but related, questions. First, given a set of measured nuclear parameters, how can one best estimate the resulting thermonuclear reaction rates and associated uncertainties? Second, given a set of appropriate reaction rates, how can one best estimate the abundances from nucleosynthesis (i.e., reaction network) calculations? The techniques described here provide probability density functions that can be used to derive statistically meaningful reaction rates and final abundances for any desired coverage probability. Examples are given for applications to s-process neutron sources, core-collapse supernovae, classical novae, and Big Bang nucleosynthesis.

Mutations in Ran system affected telomere silencing in Saccharomyces cerevisiae

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hayashi, Naoyuki; Department of Molecular Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934; Kobayashi, Masahiko

The Ran GTPase system regulates the direction and timing of several cellular events, such as nuclear-cytosolic transport, centrosome formation, and nuclear envelope assembly in telophase. To gain insight into the Ran system's involvement in chromatin formation, we investigated gene silencing at the telomere in several mutants of the budding yeast Saccharomyces cerevisiae, which had defects in genes involved in the Ran system. A mutation of the RanGAP gene, rna1-1, caused reduced silencing at the telomere, and partial disruption of the nuclear Ran binding factor, yrb2-{delta}2, increased this silencing. The reduced telomere silencing in rna1-1 cells was suppressed by a highmore » dosage of the SIR3 gene or the SIT4 gene. Furthermore, hyperphosphorylated Sir3 protein accumulated in the rna1-1 mutant. These results suggest that RanGAP is required for the heterochromatin structure at the telomere in budding yeast.« less

Impaired redox signaling and antioxidant gene expression in endothelial cells in diabetes: a role for mitochondria and the nuclear factor-E2-related factor 2-Kelch-like ECH-associated protein 1 defense pathway.

PubMed

Cheng, Xinghua; Siow, Richard C M; Mann, Giovanni E

2011-02-01

Type 2 diabetes is an age-related disease associated with vascular pathologies, including severe blindness, renal failure, atherosclerosis, and stroke. Reactive oxygen species (ROS), especially mitochondrial ROS, play a key role in regulating the cellular redox status, and an overproduction of ROS may in part underlie the pathogenesis of diabetes and other age-related diseases. Cells have evolved endogenous defense mechanisms against sustained oxidative stress such as the redox-sensitive transcription factor nuclear factor E2-related factor 2 (Nrf2), which regulates antioxidant response element (ARE/electrophile response element)-mediated expression of detoxifying and antioxidant enzymes and the cystine/glutamate transporter involved in glutathione biosynthesis. We hypothesize that diminished Nrf2/ARE activity contributes to increased oxidative stress and mitochondrial dysfunction in the vasculature leading to endothelial dysfunction, insulin resistance, and abnormal angiogenesis observed in diabetes. Sustained hyperglycemia further exacerbates redox dysregulation, thereby providing a positive feedback loop for severe diabetic complications. This review focuses on the role that Nrf2/ARE-linked gene expression plays in regulating endothelial redox homeostasis in health and type 2 diabetes, highlighting recent evidence that Nrf2 may provide a therapeutic target for countering oxidative stress associated with vascular disease and aging.

Atmospheric effects and societal consequences of regional scale nuclear conflicts and acts of individual nuclear terrorism

NASA Astrophysics Data System (ADS)

Toon, O. B.; Turco, R. P.; Robock, A.; Bardeen, C.; Oman, L.; Stenchikov, G. L.

2006-11-01

We assess the potential damage and smoke production associated with the detonation of small nuclear weapons in modern megacities. While the number of nuclear warheads in the world has fallen by about a factor of three since its peak in 1986, the number of nuclear weapons states is increasing and the potential exists for numerous regional nuclear arms races. Eight countries are known to have nuclear weapons, 2 are constructing them, and an additional 32 nations already have the fissile material needed to build substantial arsenals of low-yield (Hiroshima-sized) explosives. Population and economic activity worldwide are congregated to an increasing extent in megacities, which might be targeted in a nuclear conflict. Our analysis shows that, per kiloton of yield, low yield weapons can produce 100 times as many fatalities and 100 times as much smoke from fires as high-yield weapons, if they are targeted at city centers. A single "small'' nuclear detonation in an urban center could lead to more fatalities, in some cases by orders of magnitude, than have occurred in the major historical conflicts of many countries. We analyze the likely outcome of a regional nuclear exchange involving 100 15-kt explosions (less than 0.1% of the explosive yield of the current global nuclear arsenal). We find that such an exchange could produce direct fatalities comparable to all of those worldwide in World War II, or to those once estimated for a "counterforce'' nuclear war between the superpowers. Megacities exposed to atmospheric fallout of long-lived radionuclides would likely be abandoned indefinitely, with severe national and international implications. Our analysis shows that smoke from urban firestorms in a regional war would rise into the upper troposphere due to pyro-convection. Robock et al. (2006) show that the smoke would subsequently rise deep into the stratosphere due to atmospheric heating, and then might induce significant climatic anomalies on global scales.We also anticipate substantial perturbations of global ozone. While there are many uncertainties in the predictions we make here, the principal unknowns are the type and scale of conflict that might occur. The scope and severity of the hazards identified pose a significant threat to the global community. They deserve careful analysis by governments worldwide advised by a broad section of the world scientific community, as well as widespread public debate.

Inflammatory mediator mRNA expression by adenovirus E1A-transfected bronchial epithelial cells.

PubMed

Higashimoto, Yuji; Elliott, W Mark; Behzad, Ali R; Sedgwick, Edward G; Takei, Tatsuo; Hogg, James C; Hayashi, Shizu

2002-07-15

Lung tissue from patients with emphysema and airway obstruction carries excess adenoviral E1A DNA that is expressed as protein in airway surface epithelium and is associated with an increased inflammatory response. To examine mechanisms by which latent adenoviral infection might amplify the inflammatory process, we transfected primary human bronchial epithelial (HBE) cells from three separate patients undergoing lung resection so that they stably expressed adenovirus E1A. Lipopolysaccharide stimulation of the E1A-transfected HBE cells increased intercellular adhesion molecule-1 and interleukin-8 mRNA and protein expression compared with control cells from the same patient. It also induced greater intercellular adhesion molecule-1 promoter activity and greater nuclear factor-kappa B binding activity of nuclear extracts in E1A transfectants than controls. E1A-positive transfectants constitutively expressed transforming growth factor-beta 1 mRNA and protein, whereas this expression was either very low or not detected in control cells. We conclude that adenoviral E1A transfection transforms primary HBE cells and upregulates their production of mediators that are clinically relevant to the pathogenesis of chronic obstructive pulmonary disease.

TGF-β-induced IκB-ζ controls Foxp3 gene expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

MaruYama, Takashi, E-mail: ta-maru@umin.ac.jp; School of Medicine, Gifu University, Gifu 501-1194

2015-08-21

Inhibitor of kappa B (IκB)-ζ, a member of the nuclear IκB family of proteins, is induced by the transforming growth factor (TGF)-β signaling pathway and plays a pivotal role in maintaining the balance of T helper (Th) cell subsets. IκB-ζ deficiency results in reduced percentages of Th17 cells and increased percentages of Th1 cells. In this study, the effects of IκB-ζ deficiency on T-cell subsets were examined further. The data showed that IκB-ζ-deficient T cells had a high capacity for generation of regulatory T cells (Tregs) when T cells were cultured under TGF-β stimulation in the presence of cytokine-neutralizing antibodies.more » Mechanistically, IκB-ζ itself negatively regulated activation of the Foxp3 promoter in a nuclear factor of kappaB-dependent manner. Thus, this study showed that IκB-ζ controlled Treg differentiation. - Highlights: • IκB-ζ-deficient T cells exhibited increased generation of Foxp3{sup +} Tregs. • IκB-ζ played a key role in Foxp3 gene expression. • Retroviral overexpression of IκB-ζ was achieved in T cells.« less

Nuclear Fuels.

ERIC Educational Resources Information Center

Nash, J. Thomas

1983-01-01

Trends in and factors related to the nuclear industry and nuclear fuel production are discussed. Topics addressed include nuclear reactors, survival of the U.S. uranium industry, production costs, budget cuts by the Department of Energy and U.S. Geological survey for resource studies, mining, and research/development activities. (JN)

Developmental expression of STATs, nuclear factor-κB and inflammatory genes in the jejunum of piglets during weaning.

PubMed

Yi, Hongbo; Jiang, Denghu; Zhang, Lin; Xiong, Haitao; Han, Feifei; Wang, Yizhen

2016-07-01

The signal transducer and activator of transcription (STAT) proteins play essential roles in apoptosis, proliferation and survival. However, the role of STATs in intestinal inflammation during weaning is unclear. This study aimed to investigate developmental expression of STATs, nuclear factor-κB (NF-κB) and inflammatory genes in the jejunum of piglets during weaning. Thirty-two piglets were weaned at 21d and sacrificed at 0, 1, 7, or 14d (n=8) after weaning. Villus height and the villus height/crypt depth ratio were decreased, whereas crypt depth was increased in the jejunum at 7 and 14d after weaning. In addition, the mRNA levels of interferon-γ (IFN-γ), inducible nitric oxide synthase (iNOS), IL-6, IL-8, IL-12 and IL-22 were increased in the jejunum at 7 and 14d after weaning, whereas transforming growth factor-β (TGF-β), suppressor of cytokine signaling 3 (SCOS3) and arginase-1 was decreased. Neutrophil infiltration was increased in the mucosa of the jejunum after weaning. Moreover, phosphorylation of IκB-α, NF-κB, AKT and STAT-3 was increased. However, the phosphorylation of STAT-1 (at 7 and 14d) and STAT-6 (at 1 and 7d) was suppressed in the jejunum after weaning. Treatment of porcine jejunal epithelial (IPEC-J2) cells with the STAT inhibitors fludarabine, niclosamide and teriflunomide, which inhibit the phosphorylation of STAT-1, STAT-3 and STAT-6, respectively, weakened the defense capacity of these cells against bacterial infection. In conclusion, weaning caused severe inflammation associated with activation of the NF-κB and STAT-3 pathways and suppression of STAT-1 and STAT-6 in the jejunum of piglets. Copyright © 2016 Elsevier B.V. All rights reserved.

Histiocyte-like cells expressing factor XIIIa do not belong to the neoplastic cell population in malignant fibrous histiocytoma.

PubMed

Szollosi, Zoltan; Nemeth, Tamas; Egervari, Kristof; Nemes, Zoltan

2005-01-01

The term malignant fibrous histiocytoma (MFH) is widely used for pleomorphic soft tissue sarcomas without a specific line of differentiation. MFH is included in the category of fibrohistiocytic soft tissue tumors. MFH has a broad range of histological appearances, and it has several subtypes. All of these subtypes are composed of spindled fibroblast-like cells, undifferentiated cells, and histiocytic or histiocyte-like cells. A large number of fibroblast-like and pleomorphic cells express factor XIIIa in MFH. The cytological pleomorphism of factor XIIIa cells suggests that these cells may belong to the neoplastic population. It is equally possible that the factor XIIIa-positive cells are only activated stromal cells. The relation of factor XIIIa-positive cells to the neoplastic cell population in MFH is addressed in the present study. A morphometric approach compares the measure of nuclear pleomorphism of the factor XIIIa-positive cells with that of the factor XIIIa-negative tumor cells in high-grade MFH. The immunohistochemical approach compares the factor XIIIa-positive and -negative cell populations with regard to mutations of p53 tumor suppressor gene in p53-positive MFH cases. We selected 58 cases of soft tissue pleomorphic or storiform-pleomorphic MFH on the basis of histopathological examinations. A combination of incident light immunofluorescence for factor XIIIa and transmitted light examination for nuclear staining was used for morphometrical analysis. We found cytoplasmic factor XIIIa positivity in at least 2% of cells in 39 cases; the number of factor XIIIa-positive cells was under 0.5% in two cases, and the number of factor-positive cells ranged between 0.5% and 2% in 13 cases. Eighteen cases were analyzed with nuclear morphometry. We found that mean nuclear area and mean nuclear Ferret diameter in factor XIIIa-positive cells differed significantly from those of the tumor cells in all cases. The mean nuclear roundness factor differed significantly only in four cases. The latter finding showed that the microscopic polymorphism of factor XIIIa cells is measurable and is not merely a suspicion. The immunohistochemical positivity for p53 positivity can be accepted as the manifestation of a missense mutation of TP53 gene and as a marker of neoplastic cells. The simultaneous immunohistochemical detection of factor XIIIa and p53 in the same section revealed that factor XIIIa-positive cells were invariably p53 negative in MFH. This finding implies that the factor XIIIa cell population is non-neoplastic and belongs to the stromal component of MFH.

c-Jun localizes to the nucleus independent of its phosphorylation by and interaction with JNK and vice versa promotes nuclear accumulation of JNK

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schreck, Ilona; Al-Rawi, Marco; Mingot, Jose-Manuel

2011-04-22

Highlights: {yields} HSP70, Ku70 and 80 as well as importin 8 are novel interactors of c-Jun. {yields} Nuclear accumulation of c-Jun does not require its functions as a transcription factor. {yields} Nuclear accumulation of c-Jun does not require the interaction with its kinase JNK. {yields} Nuclear accumulation of JNK is regulated by interaction with c-Jun. -- Abstract: In order to activate gene expression, transcription factors such as c-Jun have to reside in the nucleus. The abundance of c-Jun in the nucleus correlates with the activity of its target genes. As a consequence of excessive c-Jun activation, cells undergo apoptosis ormore » changes in differentiation whereas decreased c-Jun function can reduce proliferation. In the present study we addressed how nuclear accumulation of the transcription factor c-Jun is regulated. First, we analyzed which functions of c-Jun are required for efficient nuclear accumulation. Mutants of c-Jun deficient in dimerization or DNA-binding show no defect in nuclear transport. Furthermore, c-Jun import into the nucleus of living cells occurred when the c-Jun phosphorylation sites were mutated as well in cells that lack the major c-Jun kinase, JNK, suggesting that c-Jun transport into the nucleus does not require JNK signaling. Conversely, however, binding of c-Jun seemed to enhance nuclear accumulation of JNK. In order to identify proteins that might be relevant for the nuclear translocation of c-Jun we searched for novel binding partners by a proteomic approach. In addition to the heat shock protein HSP70 and the DNA damage repair factors Ku70 and 80, we isolated human importin 8 as a novel interactor of c-Jun. Interaction of Imp 8 with c-Jun in human cells was confirmed by co-immunoprecipitation experiments. Nuclear accumulation of c-Jun does not require its functions as a transcription factor or the interaction with its kinase JNK. Interestingly, nuclear accumulation of JNK is regulated by interaction with c-Jun. Unraveling the mechanisms of c-Jun and JNK transport to the nucleus and its regulation will improve our understanding of their role in biological and pathophysiological processes.« less

(-)-7(S)-hydroxymatairesinol protects against tumor necrosis factor-α-mediated inflammation response in endothelial cells by blocking the MAPK/NF-κB and activating Nrf2/HO-1.

PubMed

Yang, Di; Xiao, Chen-Xi; Su, Zheng-Hua; Huang, Meng-Wei; Qin, Ming; Wu, Wei-Jun; Jia, Wan-Wan; Zhu, Yi-Zhun; Hu, Jin-Feng; Liu, Xin-Hua

2017-08-15

Endothelial inflammation is an increasingly prevalent condition in the pathogenesis of many cardiovascular diseases. (-)-7(S)-hydroxymatairesinol (7-HMR), a naturally occurring plant lignan, possesses both antioxidant and anti-cancer properties and therefore would be a good strategy to suppress tumor necrosis factor-α (TNF-α)-mediated inflammation in vascular endothelial cells (VECs). The objective of this study is to evaluate for its anti-inflammatory effect on TNF-α-stimulated VECs and underling mechanisms. The effect of the 7-HMR on suppression of TNF-α-induced inflammation mediators in VECs were determined by qRT-PCR and Western blot. MAPKs and phosphorylation of Akt, HO-1 and NF-κB p65 were examined using Western blot. Nuclear localisation of NF-κB was also examined using Western blot and immunofluorescence. Here we found that 7-HMR could suppress TNF-α-induced inflammatory mediators, such as vascularcelladhesion molecule-1, interleukin-6 and inducible nitric oxide synthase expression both in mRNA and protein levels, and concentration-dependently attenuated reactive oxidase species generation. We further identified that 7-HMR remarkably induced superoxide dismutase and heme oxygenase-1 expression associated with degradation of Kelch-like ECH-associated protein 1 (keap1) and up-regulated nuclear factor erythroid 2-related factor 2 (Nrf2). In addition, 7-HMR time- and concentration-dependently attenuated TNF-α-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK) and Akt, but not p38, or c-Jun N-terminal kinase 1/2. Moreover, 7-HMR significantly suppressed TNF-α-mediated nuclear factor-κB (NF-κB) activation by inhibiting phosphorylation and nuclear translocation of NF-κB p65. Our results demonstrated that 7-HMR inhibited TNF-α-stimulated endothelial inflammation, at least in part, through inhibition of NF-κB activation and upregulation of Nrf2-antioxidant response element signaling pathway, suggesting 7-HMR might be used as a promising vascular protective drug. Copyright © 2017. Published by Elsevier GmbH.

Risk Factors for Cortical, Nuclear, Posterior Subcapsular, and Mixed Lens Opacities: The Los Angeles Latino Eye Study

PubMed Central

Richter, Grace M.; Torres, Mina; Choudhury, Farzana; Azen, Stanley P.; Varma, Rohit

2012-01-01

Purpose To identify socio-demographic and biological risk factors associated with having cortical, nuclear, posterior sub-capsular (PSC), and mixed lens opacities. Design Population-based, cross-sectional study Participants Five thousand nine hundred forty-five Latinos 40 years and older from 6 census tracts in Los Angeles, California. Methods Participants underwent an interview and detailed eye examination, including best-corrected visual acuity and slit-lamp assessment of lens opacities using the Lens Opacities Classification System II. Univariate and stepwise logistic regression analyses were used to identify independent risk factors associated with each type of lens opacity. Main Outcome Measures Odds ratios for socio-demographic and biological risk factors associated with cortical only, nuclear only, PSC only, and mixed lens opacities. Results Of the 5945 participants with gradable lenses, 468 had cortical only lens opacities, 217 had nuclear only lens opacities, 27 had PSC only opacities, and 364 had mixed lens opacities. Older age, higher hemoglobin A1c, and history of diabetes mellitus were independent risk factors for cortical only lens opacities. Older age, smoking, and myopic refractive error were independent risk factors for nuclear only lens opacities. Higher systolic blood pressure and history of diabetes were independent risk factors for posterior sub-capsular lens opacities. Older age, myopic refractive error, history of diabetes, higher systolic blood pressure, female gender, and presence of large drusen were independent risk factors for mixed lens opacities. Conclusions The modifiable and non-modifiable risk factors identified in this study provide insight into the mechanisms related to the development of lens opacification. Improved glycemic control, smoking cessation and prevention, and blood pressure control may help to reduce the risk of having lens opacities and their associated vision loss. PMID:22197433

IL-1β promotes the nuclear translocaiton of S100A4 protein in gastric cancer cells MGC803 and the cell's stem-like properties through PI3K pathway.

PubMed

Yu, Aiwen; Wang, Yu; Bian, Yue; Chen, Lisha; Guo, Junfu; Shen, Wei; Chen, Danqi; Liu, Shanshan; Sun, Xiuju

2018-06-22

It has been shown that nuclear expression of S100A4 is significantly correlated with increased metastasis and reduced survival in patients with gastric cancer and many other cancers. However, the factors which could influence the nuclear contents of S100A4 in cancer cells are not clear. It has also been reported that Interleukin-1β (IL-1β) promotes the nuclear translocation of S100A4 in chondrocytes. Previous studies have shown that IL-1β promotes the stemness of colon cancer cells, and S100A4 is also involved in maintaining cancer-initiating cells in head and neck cancers. We speculate that IL-1β might promote the nuclear translocation of S100A4 protein in MGC803 gastric cancer cells and therefore enhance their stem-like properties. The results from Western-blot and qRT-PCR analysis showed that IL-1β increased the nuclear and total cellular content of S100A4 protein and S100A4 mRNA level in MGC803 cells. LY294002, a pharmacological inhibitor of Phosphoinositide 3-kinase (PI3K) reversed the above effects. Functional studies indicated that IL-1β promoted the colony-forming and spheroid-forming capabilities of the cells and the expression of SOX2 and NANOG gene. PI3K or S100A4 inhibition reversed the IL-1β-mediated increase in colony and spheroid-forming capabilities of the cells. LY294002 also reversed the elevated SOX2 and NANOG expression induced by IL-1β. Our study demonstrated that IL-1β promote the nuclear translocation of S100A4 protein in gastric cancer cells MGC803, which are PI3K dependent, suggesting the existence of IL-1β-PI3K-S100A4 pathway for the first time. The study also showed that IL-1β promoted stem-like properties of the cells through the new pathway. © 2018 Wiley Periodicals, Inc.

Farnesoid X receptor is essential for the survival of renal medullary collecting duct cells under hypertonic stress.

PubMed

Xu, Sujuan; Huang, Shizheng; Luan, Zhilin; Chen, Tingyue; Wei, Yuanyi; Xing, Miaomiao; Li, Yaqing; Du, Chunxiu; Wang, Bing; Zheng, Feng; Wang, Nanping; Guan, Youfei; Gustafsson, Jan-Åke; Zhang, Xiaoyan

2018-05-22

Hypertonicity in renal medulla is critical for the kidney to produce concentrated urine. Renal medullary cells have to survive high medullary osmolarity during antidiuresis. Previous study reported that farnesoid X receptor (FXR), a nuclear receptor transcription factor activated by endogenous bile acids, increases urine concentrating ability by up-regulating aquaporin 2 expression in medullary collecting duct cells (MCDs). However, whether FXR is also involved in the maintenance of cell survival of MCDs under dehydration condition and hypertonic stress remains largely unknown. In the present study, we demonstrate that 24-hours water restriction selectively up-regulated renal medullary expression of FXR with little MCD apoptosis in wild-type mice. In contrast, water deprivation caused a massive apoptosis of MCDs in both global FXR gene-deficient mice and collecting duct-specific FXR knockout mice. In vitro studies showed that hypertonicity significantly increased FXR and tonicity response enhancer binding protein (TonEBP) expression in mIMCD3 cell line and primary cultured MCDs. Activation and overexpression of FXR markedly increased cell viability and decreased cell apoptosis under hyperosmotic conditions. In addition, FXR can increase gene expression and nuclear translocation of TonEBP. We conclude that FXR protects MCDs from hypertonicity-induced cell injury very likely via increasing TonEBP expression and nuclear translocation. This study provides insights into the molecular mechanism by which FXR enhances urine concentration via maintaining cell viability of MCDs under hyperosmotic condition.

Effects of Inadequate Sleep on Blood Pressure and Endothelial Inflammation in Women: Findings From the American Heart Association Go Red for Women Strategically Focused Research Network.

PubMed

Aggarwal, Brooke; Makarem, Nour; Shah, Riddhi; Emin, Memet; Wei, Ying; St-Onge, Marie-Pierre; Jelic, Sanja

2018-06-09

Insufficient sleep increases blood pressure. However, the effects of milder, highly prevalent but frequently neglected sleep disturbances, including poor sleep quality and insomnia, on vascular health in women are unclear. We investigated whether poor sleep patterns are associated with blood pressure and endothelial inflammation in a diverse sample of women. Women who participated in the ongoing American Heart Association Go Red for Women Strategically Focused Research Network were studied (n=323, 57% minority, mean age=39±17 years, range=20-79 years). Sleep duration, sleep quality, and time to sleep onset were assessed using the Pittsburgh Sleep Quality Index (score ≥5=poor sleep quality). Risk for obstructive sleep apnea was evaluated using the Berlin questionnaire, and insomnia was assessed using the Insomnia Severity Index. In a subset of women who participated in the basic study (n=26), sleep duration was assessed objectively using actigraphy, and endothelial inflammation was assessed directly in harvested endothelial cells by measuring nuclear translocation of nuclear factor kappa B. Vascular reactivity was measured by brachial artery flow-mediated dilation (n=26). Systolic and diastolic blood pressure were measured by trained personnel (n=323). Multivariable linear regressions were used to evaluate associations between sleep patterns and blood pressure, nuclear factor kappa B, and flow-mediated dilation. Mean sleep duration was 6.8±1.3 hours/night in the population study and 7.5±1.1 hour/night in the basic study. In the population study sample, 50% had poor sleep quality versus 23% in the basic study, and 37% had some level of insomnia versus 15% in the basic study. Systolic blood pressure was associated directly with poor sleep quality, and diastolic blood pressure was of borderline significance with obstructive sleep apnea risk after adjusting for confounders ( P =0.04 and P =0.08, respectively). Poor sleep quality was associated with endothelial nuclear factor kappa B activation (β=30.6; P =0.03). Insomnia and longer sleep onset latency were also associated with endothelial nuclear factor kappa B activation (β=27.6; P =0.002 and β=8.26; P =0.02, respectively). No evidence was found for an association between sleep and flow-mediated dilation. These findings provide direct evidence that common but frequently neglected sleep disturbances such as poor sleep quality and insomnia are associated with increased blood pressure and vascular inflammation even in the absence of inadequate sleep duration in women. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02835261. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

State of the environment in the arrangement area of the enterprises for repairing and utilization of nuclear-powered submarines.

PubMed

Dovgusha, V V; Bychenkov, V S; Blekher AYa; Belyaev, A V; Krupkin, A B; Kovygin GPh; Puzikov, A G; Ryabchikov, S G; Stepanov, S V; Toropov, S A

2001-01-01

The influence of nuclear-powered utilization (disjunction) upon the state of health of the soil, vegetation and atmospheric air was studied. It was stated that the concentration of hazardous metals in the air of an industrial site did not exceed the permissible levels. In the residential area the cases of increased concentrations of manganese and chromium were noted. The major pollutants of vegetation are manganese, titanium, copper and nickel. The authors propose a complex of anthropogenic factors to be the cause of the environmental contamination by hard metals. The volume activity of radioactive aerosols in the studied site is confined to the local hum.

NUCLEAR REACTOR

DOEpatents

Miller, H.I.; Smith, R.C.

1958-01-21

This patent relates to nuclear reactors of the type which use a liquid fuel, such as a solution of uranyl sulfate in ordinary water which acts as the moderator. The reactor is comprised of a spherical vessel having a diameter of about 12 inches substantially surrounded by a reflector of beryllium oxide. Conventionnl control rods and safety rods are operated in slots in the reflector outside the vessel to control the operation of the reactor. An additional means for increasing the safety factor of the reactor by raising the ratio of delayed neutrons to prompt neutrons, is provided and consists of a soluble sulfate salt of beryllium dissolved in the liquid fuel in the proper proportion to obtain the result desired.

Carbocysteine counteracts the effects of cigarette smoke on cell growth and on the SIRT1/FoxO3 axis in bronchial epithelial cells.

PubMed

Pace, E; Di Vincenzo, S; Ferraro, M; Bruno, A; Dino, P; Bonsignore, M R; Battaglia, S; Saibene, F; Lanata, L; Gjomarkaj, M

2016-08-01

Cigarette smoke may accelerate cellular senescence by increasing oxidative stress. Altered proliferation and altered expression of anti-aging factors, including SIRT1 and FoxO3, characterise cellular senescence. The effects of carbocysteine on the SIRT1/FoxO3 axis and on downstream molecular mechanisms in human bronchial epithelial cells exposed to cigarette smoke are largely unknown. Aim of this study was to explore whether carbocysteine modulated SIRT1/FoxO3 axis, and downstream molecular mechanisms associated to cellular senescence, in a bronchial epithelial cell line (16-HBE) exposed to cigarette smoke. 16HBE cells were stimulated with/without cigarette smoke extracts (CSE) and carbocysteine. Flow cytometry and clonogenic assay were used to assess cell proliferation; western blot analysis was used for assessing nuclear expression of SIRT1 and FoxO3. The nuclear co-localization of SIRT1 and FoxO3 was assessed by fluorescence microscopy. Beta galactosidase (a senescence marker) and SIRT1 activity were assessed by specific staining and colorimetric assays, respectively. ChiP Assay and flow cytometry were used for assessing survivin gene regulation and protein expression, respectively. CSE decreased cell proliferation, the nuclear expression of SIRT1 and FoxO3 and increased beta galactosidase staining. CSE, reduced SIRT1 activity and FoxO3 localization on survivin promoter thus increasing survivin expression. In CSE stimulated bronchial epithelial cells carbocysteine reverted these phenomena by increasing cell proliferation, and SIRT1 and FoxO3 nuclear expression, and by reducing beta galactosidase staining and survivin expression. The study shows for the first time that carbocysteine may revert some senescence processes induced by oxidative stress due to cigarette smoke exposure. Copyright © 2016 Elsevier Inc. All rights reserved.

A HUMAN FACTORS META MODEL FOR U.S. NUCLEAR POWER PLANT CONTROL ROOM MODERNIZATION

DOE Office of Scientific and Technical Information (OSTI.GOV)

Joe, Jeffrey C.

Over the last several years, the United States (U.S.) Department of Energy (DOE) has sponsored human factors research and development (R&D) and human factors engineering (HFE) activities through its Light Water Reactor Sustainability (LWRS) program to modernize the main control rooms (MCR) of commercial nuclear power plants (NPP). Idaho National Laboratory (INL), in partnership with numerous commercial nuclear utilities, has conducted some of this R&D to enable the life extension of NPPs (i.e., provide the technical basis for the long-term reliability, productivity, safety, and security of U.S. NPPs). From these activities performed to date, a human factors meta model formore » U.S. NPP control room modernization can now be formulated. This paper discusses this emergent HFE meta model for NPP control room modernization, with the goal of providing an integrated high level roadmap and guidance on how to perform human factors R&D and HFE for those in the U.S. nuclear industry that are engaging in the process of upgrading their MCRs.« less

Transcription factor FoxA (HNF3) on a nucleosome at an enhancer complex in liver chromatin.

PubMed

Chaya, D; Hayamizu, T; Bustin, M; Zaret, K S

2001-11-30

Nucleosome-like particles and acetylated histones occur near active promoters and enhancers, and certain transcription factors can recognize their target sites on the surface of a nucleosome in vitro; yet it has been unclear whether transcription factors can occupy target sites on nucleosomes in native chromatin. We developed a method for sequential chromatin immunoprecipitation of distinct nuclear proteins that are simultaneously cross-linked to nucleosome-sized genomic DNA segments. We find that core histone H2A co-occupies, along with the FoxA (hepatocyte nuclear factor-3) transcription factor, DNA for the albumin transcriptional enhancer in native liver chromatin, where the enhancer is active. Because histone H2A on nuclear DNA is only known to exist in nucleosomes, we conclude that transcription factors can form a stable complex on nucleosomes at an active enhancer element in vivo.

Mechanism regulating nuclear calcium signaling.

PubMed

Malviya, Anant N; Klein, Christian

2006-01-01

Although the outer nuclear membrane is continuous with the endoplasmic reticulum, it is possible to isolate nuclei both intact and free from endoplasmic reticulum contaminants. The outer and the inner nuclear membranes can be purified free from cross-contamination. Evidence in support of autonomous regulation of nuclear calcium signaling relies upon the investigations with isolated nuclei. Mechanisms for generating calcium signaling in the nucleus have been identified. Two calcium transporting systems, an ATP-dependant nuclear Ca(2+)-ATPase and an IP4-mediated inositol 1,3,4,5-tetrakisphosphate receptor, are located on the outer nuclear membrane. Thus, ATP and IP4, depending on external free calcium concentrations, are responsible for filling the nuclear envelope calcium pool. The inositol 1,4,5-trisphosphate receptor is located on the inner nuclear membrane with its ligand binding domain facing toward the nucleoplasm. Likewise, the ryanodine receptor is located on the inner nuclear membrane and its ligand cADP-ribose is generated within the nucleus. A 120 kDa protein fragment of nuclear PLC-gamma1 is stimulated in vivo by epidermal growth factor nuclear signaling coincident with the time course of nuclear membrane epidermal growth factor receptor activation. Stimulated 120 kDa protein fragment interacts with PIKE, a nuclear GTPase, and together they form a complex with PI[3]kinase serving as a module for nuclear PI[3]K stimulation. Thus, the nucleus has its own IP(3) generating system.

Lipoxin A4-Induced Heme Oxygenase-1 Protects Cardiomyocytes against Hypoxia/Reoxygenation Injury via p38 MAPK Activation and Nrf2/ARE Complex

PubMed Central

Chen, Xiao-Qing; Wu, Sheng-Hua; Zhou, Yu; Tang, Yan-Rong

2013-01-01

Objective To investigate whether lipoxin A4 (LXA4) increases expression of heme oxygenase-1(HO-1) in cardiomyocytes, whether LXA4-induced HO-1 protects cardiomyocytes against hypoxia/reoxygenation (H/R) injury, and what are the mechanisms involved in the LXA4-induced HO-1 induction. Methods Rat cardiomyocytes were exposed to H/R injury with or without preincubation with LXA4 or HO-1 inhibitor ZnPP-IX or various signal molecule inhibitors. Expressions of HO-1 protein and mRNA were analyzed by using Western blot and RT-PCR respectively. Activity of nuclear factor E2-related factor 2 (Nrf2) binding to the HO-1 E1 enhancer was assessed by chromatin immunoprecipitation. Nrf2 binding to the HO-1 antioxidant responsive element (ARE) were measured by using electrophoretic mobility shift assay. Results Pretreatment of the cells undergoing H/R lesion with LXA4 significantly reduced the lactate dehydrogenase and creatine kinase productions, increased the cell viability, and increased the expressions of HO-1 protein and mRNA and HO-1 promoter activity. HO-1 inhibition abolished the protective role of LXA4 on the cells undergoing H/R lesion. LXA4 increased p38 mitogen-activated protein kinase (p38 MAPK) activation, nuclear translocation of Nrf2, Nrf2 binding to the HO-1 ARE and E1 enhancer in cardiomyocytes with or without H/R exposure. Conclusion The protection role of LXA4 against H/R injury of cardiomyocytes is related to upregulation of HO-1, via activation of p38 MAPK pathway and nuclear translocation of Nrf2 and Nrf2 binding to the HO-1 ARE and E1 enhancer, but not via activation of phosphatidyinositol-3-kinase or extracellular signal-regulated kinase pathway. PMID:23826208

Roles of oxidative stress, adiponectin, and nuclear hormone receptors in obesity-associated insulin resistance and cardiovascular risk.

PubMed

Matsuda, Morihiro; Shimomura, Iichiro

2014-08-01

Obesity leads to the development of type 2 diabetes mellitus, which is a strong risk factor for cardiovascular disease. A better understanding of the molecular basis of obesity will lead to the establishment of effective prevention strategies for cardiovascular diseases. Adipocytes have been shown to generate a variety of endocrine factors termed adipokines/adipocytokines. Obesity-associated changes to these adipocytokines contribute to the development of cardiovascular diseases. Adiponectin, which is one of the most well-characterized adipocytokines, is produced exclusively by adipocytes and exerts insulin-sensitizing and anti-atherogenic effects. Obese subjects have lower levels of circulating adiponectin, and this is recognized as one of the factors involved in obesity-induced insulin resistance and atherosclerosis. Another pathophysiological feature of obesity may involve the low-grade chronic inflammation in adipose tissue. This inflammatory process increases oxidative stress in adipose tissue, which may affect remote organs, leading to the development of diabetes, hypertension, and atherosclerosis. Nuclear hormone receptors (NRs) regulate the transcription of the target genes in response to binding with their ligands, which include metabolic and nutritional substrates. Among the various NRs, peroxisome proliferator-activated receptor γ promotes the transcription of adiponectin and antioxidative enzymes, whereas mineralocorticoid receptor mediates the effects of aldosterone and glucocorticoid to induce oxidative stress in adipocytes. It is hypothesized that both play crucial roles in the pathophysiology of obesity-associated insulin resistance and cardiovascular diseases. Thus, reduced adiponectin and increased oxidative stress play pathological roles in obesity-associated insulin resistance to increase the cardiovascular disease risk, and various NRs may be involved in this pathogenesis.

Reciprocal repression between microRNA-133 and calcineurin regulates cardiac hypertrophy: a novel mechanism for progressive cardiac hypertrophy.

PubMed

Dong, De-Li; Chen, Chang; Huo, Rong; Wang, Ning; Li, Zhe; Tu, Yu-Jie; Hu, Jun-Tao; Chu, Xia; Huang, Wei; Yang, Bao-Feng

2010-04-01

Cardiac hypertrophy involves a remodeling process of the heart in response to diverse pathological stimuli. Both calcineurin/nuclear factor of activated T cells pathway and microRNA-133 (miR-133) have been shown to play a critical role in cardiac hypertrophy. It has been recognized that the expression and activity of calcineurin increases and miR-133 expression decreases in the hypertrophic heart, and inhibition of calcineurin or increase of miR-133 expression protects against cardiac hypertrophy. Here we tested the interaction between miR-133 and calcineurin in cardiac hypertrophy. Cardiac hypertrophy in vivo and in vitro was induced by transverse aortic constriction and phenylephrine treatment. mRNA levels were measured by using real-time PCR methods. Luciferase assays showed that transfection of miR-133 in HEK293 cells downregulated calcineurin expression, which was reversed by cotransfection with the miR-133-specific 2'-O-methyl antisense inhibitory oligoribonucleotides. These results were confirmed in cultured primary cardiomyocytes. miR-133 expression was downregulated, and calcineurin activity was enhanced in both in vivo and in vitro cardiac hypertrophy models. Treatment of cells and animals with cyclosporin A, an inhibitor of calcineurin, prevented miR-133 downregulation. Moreover, the antisense oligodeoxynucleotides against the catalytic subunits of calcineurin Abeta and the decoy oligodeoxynucleotides targeting nuclear factor of activated T cells transcription factor, a calcineurin downstream effector, increased miR-133 expression in cultured primary cardiomyocytes. Our data show that reciprocal repression between miR-133 and calcineurin regulates cardiac hypertrophy.

Yes-Associated Protein (YAP) Promotes the Nuclear Import of p73

NASA Astrophysics Data System (ADS)

Zhang, Heng; Wu, Shengnan

2011-01-01

p73 has been identified as a structural and functional homolog of the tumor suppressor p53. However, mechanisms that regulate the localization of p73 have not been fully clarified. The Yes-associated protein (YAP) is a transcriptional coactivator. As a transcriptional coactivator, YAP needs to bind transcription factors to stimulate gene expression. p73 is a reported YAP target transcription factors and YAP has been shown to positively regulate p73 in promoting apoptosis. Previous studies show that p73 interacts with YAP through its PPPY motif, and increases p73 transactivation of apoptotic genes. In this study, we focused on YAP's regulation of the localization of p73. After transient transfection into Rat pheochromocytoma (PC12) cells and Human embryonic kidney 293T cells with GFP-YAP and/or YFP-p73, and incubated for 24 hours expression. p73 was fused to YFP to allow the examination of its subcellular localization. When expressed alone, YFP-p73 was distributed throughout the cell. When coexpressed with YAP, nuclear accumulation of YFP-p73 became evident. We quantitated the effect of YAP on the redistribution of YFP-p73 by counting cells with nuclear-only YFP signal. We found that YAP can influence the subcellular distribution of p73. Altogether, coexpression with YAP affected the subcellular distribution of the p73 protein. Our studies attribute a central role to YAP in regulating p73 accumulation and YAP, at least in part, might promote the nuclear import of p73.

Inhibition of inflammation by astaxanthin alleviates cognition deficits in diabetic mice.

PubMed

Zhou, Xiaoyan; Zhang, Fang; Hu, Xiaotong; Chen, Jing; Wen, Xiangru; Sun, Ying; Liu, Yonghai; Tang, Renxian; Zheng, Kuiyang; Song, Yuanjian

2015-11-01

Neurons in the hippocampal and cortical functional regions are more susceptible to damage induced by hyperglycemia, which can result in severe spatial learning and memory impairment. Neuroprotection ameliorates cognitive impairment induced by hyperglycemia in diabetic encephalopathy (DE). Astaxanthin has been widely studied in diabetes mellitus and diabetic complications due to its hypoglycemic, antioxidant and anti-apoptotic effects. However, whether astaxanthin can alleviate cognition deficits induced by DE and its precise mechanisms remain undetermined. In this study, DE was induced by streptozotocin (STZ, 150 mg/kg) in ICR mice. We observed the effect of astaxanthin on cognition and investigated its potential mechanisms in DE mice. Results showed that astaxanthin treatment significantly decreased the latency and enhanced the distance and time spent in the target quadrant in the Morris water maze test. Furthermore, neuronal survival was significantly increased in the hippocampal CA3 region and the frontal cortex following treatment with astaxanthin. Meanwhile, immunoblotting was used to observe the nuclear translocation of nuclear factor-kappaB (NF-κB) p65 and the expression of tumor necrosis factor-α (TNF-α) in the hippocampus and frontal cortex. The results indicated that astaxanthin could inhibit NF-κB nuclear translocation and downregulate TNF-α expression in the hippocampus and frontal cortex. Overall, the present study implied that astaxanthin could improve cognition by protecting neurons against inflammation injury potentially through inhibiting the nuclear translocation of NF-κB and down-regulating TNF-α. Copyright © 2015. Published by Elsevier Inc.

Rapidity and transverse-momentum dependence of the inclusive J/ψ nuclear modification factor in p-Pb collisions at $$\\sqrt{s_{N\\ N}}$$ = 5.02 TeV

DOE PAGES

Adam, J.; Adamová, D.; Aggarwal, M. M.; ...

2015-06-09

Here we have studied the transverse-momentum (p T) dependence of the inclusive J/more » $$\\psi$$ production in p-Pb collisions at root $$\\sqrt{s_{N\\ N}}$$ = 5.02 TeV, in three center-of-mass rapidity (y cms) regions, down to zero p T. Results in the forward and backward rapidity ranges (2.03 < y cms < 3.53 and -4.46 < y cms < -2.96) are obtained by studying the J/$$\\psi$$ decay to μ +μ -, while the mid-rapidity region (-1.37 < y cms < 0.43) is investigated by measuring the e +e - decay channel. The p T dependence of the J/$$\\psi$$ production cross section and nuclear modification factor are presented for each of the rapidity intervals, as well as the J/psi mean p T values. Forward and mid-rapidity results show a suppression of the J/$$\\psi$$ yield, with respect to pp collisions, which decreases with increasing p T. At backward rapidity no significant J/$$\\psi$$ suppression is observed. Theoretical models including a combination of cold nuclear matter effects such as shadowing and partonic energy loss, are in fair agreement with the data, except at forward rapidity and low transverse momentum. Finally, the implications of the p-Pb results for the evaluation of cold nuclear matter effects on J/$$\\psi$$ production in Pb-Pb collisions are also discussed.« less

Nuclear localization of Klotho in brain: an anti-aging protein

PubMed Central

German, Dwight C.; Khobahy, Ida; Pastor, Johanne; Kuro-o, Makoto; Liu, Xinran

2011-01-01

Klotho is a putative age-suppressing gene whose over-expression in mice results in extension of life span. The klotho gene encodes a single-pass transmembrane protein whose extracellular domain is shed and released into blood, urine, and cerebrospinal fluid, potentially functioning as a humoral factor. The extracellular domain of Klotho has an activity that increases the expression of anti-oxidant enzymes and confers resistance to oxidative stress in cultured cells and in whole animals. The transmembrane form of the Klotho protein directly binds to multiple fibroblast growth factor receptors and modifies their ligand affinity and specificity. The purpose of the present study was to determine the precise cellular localization of Klotho in the mouse brain. Using light microscopic immunohistochemical methods, we found the highest levels of Klotho immunoreactivity in two brain regions: the choroid plexus, and cerebellar Purkinje cells. In the choroid plexus cells, Klotho was found not only on the plasma membrane but also in large amounts near the nuclear membrane. Likewise, in the Purkinje cell Klotho was found throughout the cell including dendrites, axon and soma with large amounts near the nuclear membrane. Using immunoelectron microscopy, we found Klotho in the cell membrane, but the highest concentration was localized in the peripheral portion of the nucleus and the nucleolus in both cell types. This new finding suggests that in addition to Klotho being secreted from cells in brain, it also has a nuclear function. PMID:22245317

Myeloid leukemia factor 1 associates with a novel heterogeneous nuclear ribonucleoprotein U-like molecule.

PubMed

Winteringham, Louise N; Endersby, Raelene; Kobelke, Simon; McCulloch, Ross K; Williams, James H; Stillitano, Justin; Cornwall, Scott M; Ingley, Evan; Klinken, S Peter

2006-12-15

Myeloid leukemia factor 1 (MLF1) is an oncoprotein associated with hemopoietic lineage commitment and acute myeloid leukemia. Here we show that Mlf1 associated with a novel binding partner, Mlf1-associated nuclear protein (Manp), a new heterogeneous nuclear ribonucleoprotein (hnRNP) family member, related to hnRNP-U. Manp localized exclusively in the nucleus and could redirect Mlf1 from the cytoplasm into the nucleus. The nuclear content of Mlf1 was also regulated by 14-3-3 binding to a canonical 14-3-3 binding motif within the N terminus of Mlf1. Significantly Mlf1 contains a functional nuclear export signal and localized primarily to the nuclei of hemopoietic cells. Mlf1 was capable of binding DNA, and microarray analysis revealed that it affected the expression of several genes, including transcription factors. In summary, this study reveals that Mlf1 translocates between nucleus and cytoplasm, associates with a novel hnRNP, and influences gene expression.

Compatibility studies on Mo-coating systems for nuclear fuel cladding applications

NASA Astrophysics Data System (ADS)

Koh, Huan Chin; Hosemann, Peter; Glaeser, Andreas M.; Cionea, Cristian

2017-12-01

To improve the safety factor of nuclear power plants in accident scenarios, molybdenum (Mo), with its high-temperature strength, is proposed as a potential fuel-cladding candidate. However, Mo undergoes rapid oxidation and sublimation at elevated temperatures in oxygen-rich environments. Thus, it is necessary to coat Mo with a protective layer. The diffusional interactions in two systems, namely, Zircaloy-2 (Zr2) on a Mo tube, and iron-chromium-aluminum (FeCrAl) on a Mo rod, were studied by aging coated Mo substrates in high vacuum at temperatures ranging from 650 °C to 1000° for 1000 h. The specimens were characterized using scanning electron microscopy (SEM), energy-dispersive spectrometry (EDS) and nanoindentation. In both systems, pores in the coating increased in size and number with increasing temperature over time, and cracks were also observed; intermetallic phases formed between the Mo and its coatings.