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Sample records for gadd45a mediates arsenite-induced

  1. Gadd45a promotes DNA demethylation through TDG.

    PubMed

    Li, Zheng; Gu, Tian-Peng; Weber, Alain R; Shen, Jia-Zhen; Li, Bin-Zhong; Xie, Zhi-Guo; Yin, Ruichuan; Guo, Fan; Liu, Xiaomeng; Tang, Fuchou; Wang, Hailin; Schär, Primo; Xu, Guo-Liang

    2015-04-30

    Growth arrest and DNA-damage-inducible protein 45 (Gadd45) family members have been implicated in DNA demethylation in vertebrates. However, it remained unclear how they contribute to the demethylation process. Here, we demonstrate that Gadd45a promotes active DNA demethylation through thymine DNA glycosylase (TDG) which has recently been shown to excise 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) generated in Ten-eleven-translocation (Tet)-initiated oxidative demethylation. The connection of Gadd45a with oxidative demethylation is evidenced by the enhanced activation of a methylated reporter gene in HEK293T cells expressing Gadd45a in combination with catalytically active TDG and Tet. Gadd45a interacts with TDG physically and increases the removal of 5fC and 5caC from genomic and transfected plasmid DNA by TDG. Knockout of both Gadd45a and Gadd45b from mouse ES cells leads to hypermethylation of specific genomic loci most of which are also targets of TDG and show 5fC enrichment in TDG-deficient cells. These observations indicate that the demethylation effect of Gadd45a is mediated by TDG activity. This finding thus unites Gadd45a with the recently defined Tet-initiated demethylation pathway. PMID:25845601

  2. Gadd45a promotes DNA demethylation through TDG

    PubMed Central

    Li, Zheng; Gu, Tian-Peng; Weber, Alain R.; Shen, Jia-Zhen; Li, Bin-Zhong; Xie, Zhi-Guo; Yin, Ruichuan; Guo, Fan; Liu, Xiaomeng; Tang, Fuchou; Wang, Hailin; Schär, Primo; Xu, Guo-Liang

    2015-01-01

    Growth arrest and DNA-damage-inducible protein 45 (Gadd45) family members have been implicated in DNA demethylation in vertebrates. However, it remained unclear how they contribute to the demethylation process. Here, we demonstrate that Gadd45a promotes active DNA demethylation through thymine DNA glycosylase (TDG) which has recently been shown to excise 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) generated in Ten-eleven-translocation (Tet)—initiated oxidative demethylation. The connection of Gadd45a with oxidative demethylation is evidenced by the enhanced activation of a methylated reporter gene in HEK293T cells expressing Gadd45a in combination with catalytically active TDG and Tet. Gadd45a interacts with TDG physically and increases the removal of 5fC and 5caC from genomic and transfected plasmid DNA by TDG. Knockout of both Gadd45a and Gadd45b from mouse ES cells leads to hypermethylation of specific genomic loci most of which are also targets of TDG and show 5fC enrichment in TDG-deficient cells. These observations indicate that the demethylation effect of Gadd45a is mediated by TDG activity. This finding thus unites Gadd45a with the recently defined Tet-initiated demethylation pathway. PMID:25845601

  3. Gadd45a Protein Promotes Skeletal Muscle Atrophy by Forming a Complex with the Protein Kinase MEKK4.

    PubMed

    Bullard, Steven A; Seo, Seongjin; Schilling, Birgit; Dyle, Michael C; Dierdorff, Jason M; Ebert, Scott M; DeLau, Austin D; Gibson, Bradford W; Adams, Christopher M

    2016-08-19

    Skeletal muscle atrophy is a serious and highly prevalent condition that remains poorly understood at the molecular level. Previous work found that skeletal muscle atrophy involves an increase in skeletal muscle Gadd45a expression, which is necessary and sufficient for skeletal muscle fiber atrophy. However, the direct mechanism by which Gadd45a promotes skeletal muscle atrophy was unknown. To address this question, we biochemically isolated skeletal muscle proteins that associate with Gadd45a as it induces atrophy in mouse skeletal muscle fibers in vivo We found that Gadd45a interacts with multiple proteins in skeletal muscle fibers, including, most prominently, MEKK4, a mitogen-activated protein kinase kinase kinase that was not previously known to play a role in skeletal muscle atrophy. Furthermore, we found that, by forming a complex with MEKK4 in skeletal muscle fibers, Gadd45a increases MEKK4 protein kinase activity, which is both sufficient to induce skeletal muscle fiber atrophy and required for Gadd45a-mediated skeletal muscle fiber atrophy. Together, these results identify a direct biochemical mechanism by which Gadd45a induces skeletal muscle atrophy and provide new insight into the way that skeletal muscle atrophy occurs at the molecular level. PMID:27358404

  4. Involvement of HIF-2α-mediated inflammation in arsenite-induced transformation of human bronchial epithelial cells

    SciTech Connect

    Xu, Yuan; Zhao, Yue; Xu, Wenchao; Luo, Fei; Wang, Bairu; Li, Yuan; Pang, Ying; Liu, Qizhan

    2013-10-15

    Arsenic is a well established human carcinogen that causes diseases of the lung. Some studies have suggested a link between inflammation and lung cancer; however, it is unknown if arsenite-induced inflammation causally contributes to arsenite-caused malignant transformation of cells. In this study, we investigated the molecular mechanisms underlying inflammation during neoplastic transformation induced in human bronchial epithelial (HBE) cells by chronic exposure to arsenite. The results showed that, on acute or chronic exposure to arsenite, HBE cells over-expressed the pro-inflammatory cytokines, interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-1β (IL-1β). The data also indicated that HIF-2α was involved in arsenite-induced inflammation. Moreover, IL-6 and IL-8 were essential for the malignant progression of arsenite-transformed HBE cells. Thus, these experiments show that HIF-2α mediates arsenite-induced inflammation and that such inflammation is involved in arsenite-induced malignant transformation of HBE cells. The results provide a link between the inflammatory response and the acquisition of a malignant transformed phenotype by cells chronically exposed to arsenite and thus establish a previously unknown mechanism for arsenite-induced carcinogenesis. - Highlights: • Arsenite induces inflammation. • Arsenite-induced the increases of IL-6 and IL-8 via HIF-2α. • Inflammation is involved in arsenite-induced carcinogenesis.

  5. Terminal differentiation induction as DNA damage response in hematopoietic stem cells by GADD45A.

    PubMed

    Wingert, Susanne; Rieger, Michael A

    2016-07-01

    Hematopoietic stem cells (HSCs) sustain lifelong blood cell regeneration by balancing their ability for self-renewal with their ability to differentiate into all blood cell types. To prevent organ exhaustion and malignant transformation, long-lived HSCs, in particular, must be protected from exogenous and endogenous stress, which cause severe DNA damage. When DNA is damaged, distinct DNA repair mechanisms and cell fate controls occur in adult HSCs compared with committed cells. Growth arrest and DNA damage-inducible 45 alpha (GADD45A) is known to coordinate a variety of cellular stress responses, indicating the molecule is an important stress mediator. So far, the function of GADD45A in hematopoietic stem and progenitor cells is controversial and appears highly dependent on the cell type and stress stimulus. Recent studies have analyzed its role in cell fate decision control of prospectively isolated HSCs and have revealed unexpected functions of GADD45A, as discussed here. The upregulation of GADD45A by DNA damage-causing conditions results in enhanced HSC differentiation, probably to efficiently eliminate aberrant HSCs from the system. These findings, in concert with a few studies on other stem cell systems, have led us to propose DNA damage-induced differentiation as a novel DNA damage response mechanism in stem cells that circumvents the fatal consequences of cumulative DNA damage in the stem cell compartment. PMID:27262218

  6. Gadd45a levels in human breast cancer are hormone receptor dependent

    PubMed Central

    2013-01-01

    Background Gadd45a is a member of the Gadd45 family of genes that are known stress sensors. Gadd45a has been shown to serve as an effector in oncogenic stress in breast carcinogenesis in murine models. The present study was aimed at clarifying the expression of Gadd45a in human breast cancer and its correlation with clinicopathologic features. Methods The expression levels of Gadd45a in breast tissue samples of female breast surgery cases were examined by immunohistochemistry (IHC) using a Gadd45a antibody. Percent staining was determined and statistical analyses were applied to determine prognostic correlations. Results 56 female breast surgery cases were studied: Normal (11), Luminal A (9), Luminal B (11), HER2+ (10), Triple Negative (15). There was a highly significant difference in percent Gadd45a staining between groups [Mean]: Normal 16.3%; Luminal A 65.3%; Luminal B 80.7%; HER2+ 40.5%; TN 32%, P < 0.001, ANOVA. Gadd45a IHC levels for Normal cases found 82% negative/low. Luminal A breast cancer cases were found to be 67% high. Luminal B breast cancers were 100% high. Her2+ cases were 50% negative/low. Triple Negative cases were 67% negative/low. This difference in distribution of Gadd45a levels across breast cancer receptor subtypes was significant, P = 0.0009. Conclusions Gadd45a levels are significantly associated with hormone receptor status in human breast cancer. Normal breast tissue displays low Gadd45a levels. High Gadd45a levels are associated with Luminal A and Luminal B subtypes. Absence of hormone receptors in Triple Negative subtype is associated with Negative/Low levels of Gadd45a. Further studies are indicated to elucidate the role of Gadd45a in breast cancer as a potential prognosticator or target for treatment. PMID:23706118

  7. GADD45A expression is correlated with patient prognosis in esophageal cancer

    PubMed Central

    ISHIGURO, HIDEYUKI; KIMURA, MASAHIRO; TAKAHASHI, HIROKI; TANAKA, TATSUYA; MIZOGUCHI, KOJI; TAKEYAMA, HIROMITSU

    2016-01-01

    The prognosis of patients with esophageal cancer remains poor, and the tumor-node-metastasis classification system is not sufficient for predicting patient prognoses. Therefore, the identification of novel predictive markers for esophageal cancer is required. The present study investigated the clinicopathological significance of growth arrest and DNA damage-inducible 45α (GADD45A) and p53 in resectable esophageal squamous cell carcinoma (ESCC). The study consisted of 62 patients with esophageal cancer who underwent surgery between 2001 and 2007. The expression of the GADD45A gene product (GADD45A) and the p53 protein was analyzed by immunohistochemistry. The correlations among GADD45A expression, clinicopathological factors and prognosis were then analyzed in the patients with ESCC. GADD45A and p53 were expressed in 56.5% (35/62) and 48.4% (30/62) of patients, respectively. The expression of GADD45A did not show a marked correlation with that of p53. However, GADD45A expression correlated with pathological stage (stage 0-I vs. stages II–IV; P=0.014) and did not correlate with the tumor (T) or node (N) status. Furthermore, patients who were positive for GADD45A exhibited a significantly higher survival rate than those who were negative for GADD45A (log-rank test, P=0.009). Multivariate analysis indicated that T status, N status and GADD45A expression were significant variables predicting survival (hazard ratio, 2.486; 95% confidence interval, 1.168–5.290; P=0.018). Overall, GADD45A expression significantly affected the survival of patients with ESCC, and the reduced expression of GADD45A was correlated with a poor prognosis following curative surgery in these patients. PMID:26870203

  8. Myc and PI3K/AKT signaling cooperatively repress FOXO3a-dependent PUMA and GADD45a gene expression

    PubMed Central

    Amente, Stefano; Zhang, Jiyuan; Lubrano Lavadera, Miriam; Lania, Luigi; Avvedimento, Enrico Vittorio; Majello, Barbara

    2011-01-01

    Growth factor withdrawal inhibits cell cycle progression by stimulating expression of growth-arresting genes through the activation of Forkhead box O transcription factors such as FOXO3a, which binds to the FHRE-responsive elements of a number of target genes such as PUMA and GADD45a. Following exposure of cells to growth factors FOXO3a-mediated transcription is rapidly repressed. We determined that repression correlates with activation of PI3K/AKT pathway leading to FOXO3a phosphorylation and release of FOXO3a protein from PUMA and GADD45a chromatin. We show here that Myc significantly and selectively contributes to repression of FOXO-mediated expression of PUMA and GADD45a. We found that in Myc deprived cells inhibition of PUMA and GADD45a following serum stimulation is impaired and that Myc does not interfere with p53 induction of PUMA transcription. We observed that following activation, Myc is rapidly recruited to PUMA and GADD45a chromatin, with a concomitant switch in promoter occupancy from FOXO3a to Myc. Myc recruitment stimulates deacetylation of Histone H3 and H4 and methylation of lysine 9 in H3 (H3K9me2) on both PUMA and GADD45 chromatin. These data highlight a Myc role on cell growth by selectively inhibiting FOXO3a induced transcription of PUMA and GADD45. PMID:21835778

  9. GADD45a Promoter Regulation by a Functional Genetic Variant Associated with Acute Lung Injury

    PubMed Central

    Mitra, Sumegha; Wade, Michael S.; Sun, Xiaoguang; Moldobaeva, Nurgul; Flores, Carlos; Ma, Shwu-Fan; Zhang, Wei

    2014-01-01

    Rationale Growth arrest DNA damage inducible alpha (GADD45a) is a stress-induced gene we have shown to participate in the pathophysiology of ventilator-induced lung injury (VILI) via regulation of mechanical stress-induced Akt ubiquitination and phosphorylation. The regulation of GADD45a expression by mechanical stress and its relationship with acute lung injury (ALI) susceptibility and severity, however, remains unknown. Objectives We examined mechanical stress-dependent regulatory elements (MSRE) in the GADD45a promoter and the contribution of promoter polymorphisms in GADD45a expression and ALI susceptibility. Methods and Results Initial studies in GADD45a knockout and heterozygous mice confirmed the relationship of GADD45a gene dose to VILI severity. Human lung endothelial cells (EC) transfected with a luciferase vector containing the full length GADD45a promoter sequence (−771 to +223) demonstrated a >4 fold increase in GADD45a expression in response to 18% cyclic stretch (CS, 4 h) compared to static controls while specific promoter regions harboring CS-dependent MSRE were identified using vectors containing serial deletion constructs of the GADD45a promoter. In silico analyses of GADD45a promoter region (−371 to −133) revealed a potential binding site for specificity protein 1 (SP1), a finding supported by confirmed SP1 binding with the GADD45a promoter and by the significant attenuation of CS-dependent GADD45a promoter activity in response to SP1 silencing. Separately, case-control association studies revealed a significant association of a GADD45a promoter SNP at −589 (rs581000, G>C) with reduced ALI susceptibility. Subsequently, we found allelic variation of this SNP is associated with both differential GADD45a expression in mechanically stressed EC (18% CS, 4 h) and differential binding site of interferon regulatory factor 7 (IRF7) at this site. Conclusion These results strongly support a functional role for GADD45a in ALI/VILI and identify a

  10. New role and molecular mechanism of Gadd45a in hepatic fibrosis

    PubMed Central

    Hong, Liang; Sun, Qing-Feng; Xu, Ting-Yan; Wu, Yang-He; Zhang, Hui; Fu, Rong-Quan; Cai, Fu-Jing; Zhou, Qing-Qing; Zhou, Ke; Du, Qing-Wei; Zhang, Dong; Xu, Shuang; Ding, Ji-Guang

    2016-01-01

    AIM: To investigate the role of Gadd45a in hepatic fibrosis and the transforming growth factor (TGF)-β/Smad signaling pathway. METHODS: Wild-type male BALB/c mice were treated with CCl4 to induce a model of chronic liver injury. Hepatic stellate cells (HSCs) were isolated from the liver of BALB/c mice and were treated with small interfering RNAs (siRNAs) targeting Gadd45a or the pcDNA3.1-Gadd45a recombinant plasmid. Cellular α-smooth muscle actin (α-SMA), β-actin, type I collagen, phospho-Smad2, phospho-Smad3, Smad2, Smad3, and Smad4 were detected by Western blots. The mRNA levels of α-SMA, β-actin, and type I collagen were determined by quantitative real-time (qRT)-PCR analyses. Reactive oxygen species production was monitored by flow cytometry using 2,7-dichlorodihydrofluorescein diacetate. Gadd45a, Gadd45b, anti-Gadd45g, type I collagen, and SMA local expression in liver tissue were measured by histologic and immunohistochemical analyses. RESULTS: Significant downregulation of Gadd45a, but not Gadd45b or Gadd45g, accompanied by activation of the TGF-β/Smad signaling pathways was detected in fibrotic liver tissues of mice and isolated HSCs with chronic liver injury induced by CCl4 treatment. Overexpression of Gadd45a reduced the expression of extracellular matrix proteins and α-SMA in HSCs, whereas transient knockdown of Gadd45a with siRNA reversed this process. Gadd45a inhibited the activity of a plasminogen activator inhibitor-1 promoter construct and (CAGA)9 MLP-Luc, an artificial Smad3/4-specific reporter, as well as reduced the phosphorylation and nuclear translocation of Smad3. Gadd45a showed protective effects by scavenging reactive oxygen species and upregulating antioxidant enzymes. CONCLUSION: Gadd45a may counteract hepatic fibrosis by regulating the activation of HSCs via the inhibition of TGF-β/Smad signaling. PMID:26973416

  11. GADD45A and EPB41 as tumor suppressor genes in meningioma pathogenesis.

    PubMed

    Piaskowski, S; Rieske, P; Szybka, M; Wozniak, K; Bednarek, A; Płuciennik, E; Jaskolski, D; Sikorska, B; Liberski, Pawel Piotr

    2005-10-01

    Deletions of 1p occur in approximately 30% of meningiomas. Based on loss of heterozygosity (LOH) analysis, two regions on 1p have been suspected to be carriers of tumor suppressor genes. We chose the GADD45A and EPB41 genes as tumor suppressor candidates based on their function and chromosomal localization. We analyzed 19 cases of meningioma with LOH of 1p by means of sequencing of the GADD45A gene and Western blotting of the GADD45a protein. Twenty cases of meningioma without 1p LOH were also analyzed by Western blotting to find out if changes of the GADD45a protein expression occurred. Nineteen samples with 1p LOH (12 grade I; 7 grade II, WHO classification) and 20 samples without 1p LOH (18 grade I; 2 grade II) were also analyzed by means of real-time polymerase chain reaction to find abnormalities in EPB41 mRNA levels in meningioma. LOH analysis was performed using seven microsatellite markers: D1S508 (1p36.2), D1S199 (1p36.1) D1S2734 (1p36.1), D1S2720 (1p34), D1S197 (1p32), D1S162 (1p32), D1S429 (1p11). LOH analysis confirmed previously described localization of putative tumor suppressor genes on 1p and involvement in meningioma pathogenesis (1p36 and 1p32). The open reading frame of GADD45A and intron splicing sites showed neither mutations nor polymorphisms. GADD45a protein molecular weight and expression level were unaltered in meningiomas with and without 1p LOH. We conclude that the GADD45A gene is not involved in meningioma tumorigenesis. EPB41 gene expression was unchanged in all analyzed meningiomas. This suggests that involvement of the EPB41 gene (4.1R protein) in meningioma pathogenesis should be reconsidered. PMID:16157202

  12. DNA-damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival.

    PubMed

    Wingert, Susanne; Thalheimer, Frederic B; Haetscher, Nadine; Rehage, Maike; Schroeder, Timm; Rieger, Michael A

    2016-03-01

    Hematopoietic stem cells (HSCs) maintain blood cell production life-long by their unique abilities of self-renewal and differentiation into all blood cell lineages. Growth arrest and DNA-damage-inducible 45 alpha (GADD45A) is induced by genotoxic stress in HSCs. GADD45A has been implicated in cell cycle control, cell death and senescence, as well as in DNA-damage repair. In general, GADD45A provides cellular stability by either arresting the cell cycle progression until DNA damage is repaired or, in cases of fatal damage, by inducing apoptosis. However, the function of GADD45A in hematopoiesis remains controversial. We revealed the changes in murine HSC fate control orchestrated by the expression of GADD45A at single cell resolution. In contrast to other cellular systems, GADD45A expression did not cause a cell cycle arrest or an alteration in the decision between cell survival and apoptosis in HSCs. Strikingly, GADD45A strongly induced and accelerated the differentiation program in HSCs. Continuous tracking of individual HSCs and their progeny via time-lapse microscopy elucidated that once GADD45A was expressed, HSCs differentiate into committed progenitors within 29 hours. GADD45A-expressing HSCs failed to long-term reconstitute the blood of recipients by inducing multilineage differentiation in vivo. Importantly, γ-irradiation of HSCs induced their differentiation by upregulating endogenous GADD45A. The differentiation induction by GADD45A was transmitted by activating p38 Mitogen-activated protein kinase (MAPK) signaling and allowed the generation of megakaryocytic-erythroid, myeloid, and lymphoid lineages. These data indicate that genotoxic stress-induced GADD45A expression in HSCs prevents their fatal transformation by directing them into differentiation and thereby clearing them from the system. Stem Cells 2016;34:699-710. PMID:26731607

  13. DNA‐damage response gene GADD45A induces differentiation in hematopoietic stem cells without inhibiting cell cycle or survival

    PubMed Central

    Wingert, Susanne; Thalheimer, Frederic B.; Haetscher, Nadine; Rehage, Maike; Schroeder, Timm

    2016-01-01

    Abstract Hematopoietic stem cells (HSCs) maintain blood cell production life‐long by their unique abilities of self‐renewal and differentiation into all blood cell lineages. Growth arrest and DNA‐damage‐inducible 45 alpha (GADD45A) is induced by genotoxic stress in HSCs. GADD45A has been implicated in cell cycle control, cell death and senescence, as well as in DNA‐damage repair. In general, GADD45A provides cellular stability by either arresting the cell cycle progression until DNA damage is repaired or, in cases of fatal damage, by inducing apoptosis. However, the function of GADD45A in hematopoiesis remains controversial. We revealed the changes in murine HSC fate control orchestrated by the expression of GADD45A at single cell resolution. In contrast to other cellular systems, GADD45A expression did not cause a cell cycle arrest or an alteration in the decision between cell survival and apoptosis in HSCs. Strikingly, GADD45A strongly induced and accelerated the differentiation program in HSCs. Continuous tracking of individual HSCs and their progeny via time‐lapse microscopy elucidated that once GADD45A was expressed, HSCs differentiate into committed progenitors within 29 hours. GADD45A‐expressing HSCs failed to long‐term reconstitute the blood of recipients by inducing multilineage differentiation in vivo. Importantly, γ‐irradiation of HSCs induced their differentiation by upregulating endogenous GADD45A. The differentiation induction by GADD45A was transmitted by activating p38 Mitogen‐activated protein kinase (MAPK) signaling and allowed the generation of megakaryocytic‐erythroid, myeloid, and lymphoid lineages. These data indicate that genotoxic stress‐induced GADD45A expression in HSCs prevents their fatal transformation by directing them into differentiation and thereby clearing them from the system. Stem Cells 2016;34:699–710 PMID:26731607

  14. Characterization of two novel gadd45a genes in hybrid tilapia and their responses to the infection of Streptococcus agalactiae.

    PubMed

    Shen, Yubang; Ma, Keyi; Liu, Feng; Yue, Gen Hua

    2016-07-01

    Diseases are one of the major challenges in tilapia aquaculture. Identification of DNA markers associated with disease resistance may facilitate the acceleration of the selection for disease resistance. Gadd45a (growth arrest and DNA damage 45 A), a stress-inducible gene in humans and mice, has not been studied in fish. We characterized the two prologues of Gadd45a genes in hybrid tilapia. Gadd45a1 and Gadd45a2 shared an identical gene structure and showed an amino acid sequence identity of 73.8%. Their expressions were detected in all 10 tissues examined, with the kidney and gill having high transcriptional expressions. The expression levels of Gadd45a1 were significantly lower than those of Gadd45a2 in all examined tissues. After a challenge with a bacterial pathogen Streptococcus agalactiae, the expressions of the two genes were up-regulated significantly in the spleen, kidney, liver and intestine. These findings suggest that the two Gadd45a genes play an important role in the resistance to S. agalactiae in tilapia. We identified 10 SNPs in the two genes. The SNP markers in the two Gadd45a genes could be used to examine whether they are associated with resistance to S. agalactiae. PMID:27103004

  15. c-Jun/AP-1 pathway-mediated cyclin D1 expression participates in low dose arsenite-induced transformation in mouse epidermal JB6 Cl41 cells

    SciTech Connect

    Zhang Dongyun; Li Jingxia; Gao Jimin; Huang Chuanshu

    2009-02-15

    Arsenic is a well-documented human carcinogen associated with skin carcinogenesis. Our previous work reveals that arsenite exposure is able to induce cell transformation in mouse epidermal cell JB6 Cl41 through the activation of ERK, rather than JNK pathway. Our current studies further evaluate downstream pathway in low dose arsenite-induced cell transformation in JB6 Cl41 cells. Our results showed that treatment of cells with low dose arsenite induced activation of c-Jun/AP-1 pathway, and ectopic expression of dominant negative mutant of c-Jun (TAM67) blocked arsenite-induced transformation. Furthermore, our data indicated that cyclin D1 was an important downstream molecule involved in c-Jun/AP-1-mediated cell transformation upon low dose arsenite exposure, because inhibition of cyclin D1 expression by its specific siRNA in the JB6 Cl41 cells resulted in impairment of anchorage-independent growth of cells induced by low dose arsenite. Collectively, our results demonstrate that c-Jun/AP-1-mediated cyclin D1 expression is at least one of the key events implicated in cell transformation upon low dose arsenite exposure.

  16. Decitabine-induced demethylation of 5' CpG island in GADD45A leads to apoptosis in osteosarcoma cells.

    PubMed

    Al-Romaih, Khaldoun; Sadikovic, Bekim; Yoshimoto, Maisa; Wang, Yuzhuo; Zielenska, Maria; Squire, Jeremy A

    2008-05-01

    GADD45 genes are epigenetically inactivated in various types of cancer and tumor cell lines. To date, defects of the GADD45 gene family have not been implicated in osteosarcoma (OS) oncogenesis, and the role of this pathway in regulating apoptosis in this tumor is unknown. The therapeutic potential of Gadd45 in OS emerged when our previous studies showed that GADD45A was reexpressed by treatment with the demethylation drug decitabine. In this study, we analyze the OS cell lines MG63 and U2OS and show that on treatment with decitabine, a significant loss of DNA methylation of GADD45A was associated with elevated expression and induction of apoptosis. In vivo affects of decitabine treatment in mice showed that untreated control xenografts exhibited low nuclear staining for Gadd45a protein, whereas the nuclei from xenografts in decitabine-treated mice exhibited increased amounts of protein and elevated apoptosis. To show the specificity of this gene for decitabine-induced apoptosis in OS, GADD45A mRNAs were disrupted using short interference RNA, and the ability of the drug to induce apoptosis was reduced. Understanding the role of demethylation of GADD45A in reexpression of this pathway and restoration of apoptotic control is important for understanding OS oncogenesis and for more targeted therapeutic approaches. PMID:18472964

  17. The GADD45A (1506T>C) Polymorphism Is Associated with Ovarian Cancer Susceptibility and Prognosis

    PubMed Central

    Yuan, Cunzhong; Liu, Xiaoyan; Liu, Xiaolin; Yang, Ning; Liu, Zhenping; Yan, Shi; Shen, Keng; Kong, Beihua

    2015-01-01

    GADD45A (growth arrest and DNA damage 45 A) is the first stress-inducible gene identified to be a target of p53. However, no studies to date have assessed variants of the GADD45 gene and their potential relationship to tumor susceptibility. We investigated the association of the GADD45A (1506T>C) polymorphism with ovarian cancer development in 258 ovarian cancer patients and 332 age-matched healthy women as controls using sequence analysis. We found a statistically significant difference in the GADD45A (1506T>C) genotype distributions between the case and control groups (TT vs. TC vs. CC, P = 0.0021) and found that variant 1506T>C was significantly associated with an increased risk of ovarian cancer (P<0.001, OR = 1.71, 95% CI [1.28–2.29]). We observed a statistically significant effect between tumor histology (P = 0.032) and CA125 status (P = 0.021). Carrying the C allele (TC+CC) was associated with an increased risk of positive CA125 (OR = 3.20, 95% CI [1.15–8.71). Carrying the T allele (TT+TC) showed a significant correlation with both higher GADD45A mRNA expression and longer ovarian cancer RFS (relapse-free survival) and OS (overall survival). We are the first group to demonstrate that the GADD45A (1506T>C) polymorphism is associated with ovarian cancer susceptibility and prognosis. These data suggest that GADD45A (1506T>C) is a new tumor susceptibility gene and could be a useful molecular marker for assessing ovarian cancer risk and for predicting ovarian cancer patient prognosis. PMID:26422378

  18. Ribosomal protein S7 regulates arsenite-induced GADD45α expression by attenuating MDM2-mediated GADD45α ubiquitination and degradation

    PubMed Central

    Gao, Ming; Li, Xiaoguang; Dong, Wen; Jin, Rui; Ma, Hanghang; Yang, Pingxun; Hu, Meiru; Li, Yi; Hao, Yi; Yuan, Shengtao; Huang, Junjian; Song, Lun

    2013-01-01

    The stress-responding protein, GADD45α, plays important roles in cell cycle checkpoint, DNA repair and apoptosis. In our recent study, we demonstrate that GADD45α undergoes a dynamic ubiquitination and degradation in vivo, which process can be blocked by the cytotoxic reagent, arsenite, resulting in GADD45α accumulation to activate JNKs cell death pathway, thereby revealing a novel mechanism for the cellular GADD45α functional regulation. But the factors involved in GADD45α stability modulations are unidentified. Here, we demonstrated that MDM2 was an E3 ubiquitin ligase for GADD45α. One of MDM2-binding partner, ribosomal protein S7, interacted with and stabilized GADD45α through preventing the ubiquitination and degradation of GADD45α mediated by MDM2. This novel function of S7 is unrelated to p53 but seems to depend on S7/MDM2 interaction, for the S7 mutant lacking MDM2-binding ability lost its function to stabilize GADD45α. Further investigations indicated that arsenite treatment enhanced S7–MDM2 interaction, resulting in attenuation of MDM2-dependent GADD45α ubiquitination and degradation, thereby leading to GADD45α-dependent cell death pathway activation. Silencing S7 expression suppressed GADD45α-dependent cytotoxicity induced by arsenite. Our findings thus identify a novel function of S7 in control of GADD45α stabilization under both basal and stress conditions and its significance in mediating arsenite-induced cellular stress. PMID:23563151

  19. A novel post-translational modification of nucleolin, SUMOylation at Lys-294, mediates arsenite-induced cell death by regulating gadd45α mRNA stability.

    PubMed

    Zhang, Dongyun; Liang, Yuguang; Xie, Qipeng; Gao, Guangxun; Wei, Jinlong; Huang, Haishan; Li, Jingxia; Gao, Jimin; Huang, Chuanshu

    2015-02-20

    Nucleolin is a ubiquitously expressed protein and participates in many important biological processes, such as cell cycle regulation and ribosomal biogenesis. The activity of nucleolin is regulated by intracellular localization and post-translational modifications, including phosphorylation, methylation, and ADP-ribosylation. Small ubiquitin-like modifier (SUMO) is a category of recently verified forms of post-translational modifications and exerts various effects on the target proteins. In the studies reported here, we discovered SUMOylational modification of human nucleolin protein at Lys-294, which facilitated the mRNA binding property of nucleolin by maintaining its nuclear localization. In response to arsenic exposure, nucleolin-SUMO was induced and promoted its binding with gadd45α mRNA, which increased gadd45α mRNA stability and protein expression, subsequently causing GADD45α-mediated cell death. On the other hand, ectopic expression of Mn-SOD attenuated the arsenite-generated superoxide radical level, abrogated nucleolin-SUMO, and in turn inhibited arsenite-induced apoptosis by reducing GADD45α expression. Collectively, our results for the first time demonstrate that nucleolin-SUMO at K294R plays a critical role in its nucleus sequestration and gadd45α mRNA binding activity. This novel biological function of nucleolin is distinct from its conventional role as a proto-oncogene. Therefore, our findings here not only reveal a new modification of nucleolin protein and its novel functional paradigm in mRNA metabolism but also expand our understanding of the dichotomous roles of nucleolin in terms of cancer development, which are dependent on multiple intracellular conditions and consequently the appropriate regulations of its modifications, including SUMOylation. PMID:25561743

  20. A Novel Post-translational Modification of Nucleolin, SUMOylation at Lys-294, Mediates Arsenite-induced Cell Death by Regulating gadd45α mRNA Stability*

    PubMed Central

    Zhang, Dongyun; Liang, Yuguang; Xie, Qipeng; Gao, Guangxun; Wei, Jinlong; Huang, Haishan; Li, Jingxia; Gao, Jimin; Huang, Chuanshu

    2015-01-01

    Nucleolin is a ubiquitously expressed protein and participates in many important biological processes, such as cell cycle regulation and ribosomal biogenesis. The activity of nucleolin is regulated by intracellular localization and post-translational modifications, including phosphorylation, methylation, and ADP-ribosylation. Small ubiquitin-like modifier (SUMO) is a category of recently verified forms of post-translational modifications and exerts various effects on the target proteins. In the studies reported here, we discovered SUMOylational modification of human nucleolin protein at Lys-294, which facilitated the mRNA binding property of nucleolin by maintaining its nuclear localization. In response to arsenic exposure, nucleolin-SUMO was induced and promoted its binding with gadd45α mRNA, which increased gadd45α mRNA stability and protein expression, subsequently causing GADD45α-mediated cell death. On the other hand, ectopic expression of Mn-SOD attenuated the arsenite-generated superoxide radical level, abrogated nucleolin-SUMO, and in turn inhibited arsenite-induced apoptosis by reducing GADD45α expression. Collectively, our results for the first time demonstrate that nucleolin-SUMO at K294R plays a critical role in its nucleus sequestration and gadd45α mRNA binding activity. This novel biological function of nucleolin is distinct from its conventional role as a proto-oncogene. Therefore, our findings here not only reveal a new modification of nucleolin protein and its novel functional paradigm in mRNA metabolism but also expand our understanding of the dichotomous roles of nucleolin in terms of cancer development, which are dependent on multiple intracellular conditions and consequently the appropriate regulations of its modifications, including SUMOylation. PMID:25561743

  1. Endoplasmic reticulum stress is involved in arsenite-induced oxidative injury in rat brain

    SciTech Connect

    Lin, Anya M.Y.; Chao, P.L.; Fang, S.F.; Chi, C.W.; Yang, C.H.

    2007-10-15

    The mechanism underlying sodium arsenite (arsenite)-induced neurotoxicity was investigated in rat brain. Arsenite was locally infused in the substantia nigra (SN) of anesthetized rat. Seven days after infusion, lipid peroxidation in the infused SN was elevated and dopamine level in the ipsilateral striatum was reduced in a concentration-dependent manner (0.3-5 nmol). Furthermore, local infusion of arsenite (5 nmol) decreased GSH content and increased expression of heat shock protein 70 and heme oxygenase-1 in the infused SN. Aggregation of {alpha}-synuclein, a putative pathological protein involved in several CNS neurodegenerative diseases, was elevated in the arsenite-infused SN. From the breakdown pattern of {alpha}-spectrin, both necrosis and apoptosis were involved in the arsenite-induced neurotoxicity. Pyknotic nuclei, cellular shrinkage and cytoplasmic disintegration, indicating necrosis, and TUNEL-positive cells and DNA ladder, indicating apoptosis was observed in the arsenite-infused SN. Arsenite-induced apoptosis was mediated via two different organelle pathways, mitochondria and endoplasmic reticulum (ER). For mitochondrial activation, cytosolic cytochrome c and caspase-3 levels were elevated in the arsenite-infused SN. In ER pathway, arsenite increased activating transcription factor-4, X-box binding protein 1, C/EBP homologues protein (CHOP) and cytosolic immunoglobulin binding protein levels. Moreover, arsenite reduced procaspase 12 levels, an ER-specific enzyme in the infused SN. Taken together, our study suggests that arsenite is capable of inducing oxidative injury in CNS. In addition to mitochondria, ER stress was involved in the arsenite-induced apoptosis. Arsenite-induced neurotoxicity clinically implies a pathophysiological role of arsenite in CNS neurodegeneration.

  2. Arsenite induces endothelial cytotoxicity by down-regulation of vascular endothelial nitric oxide synthase

    SciTech Connect

    Tsou, T.-C. . E-mail: tctsou@nhri.org.tw; Tsai, F.-Y.; Hsieh, Y.-W.; Li, L.-A.; Yeh, S.C; Chang, L.W.

    2005-11-01

    Epidemiological studies have demonstrated a high association of inorganic arsenic exposure with vascular diseases. Recent research has also linked this vascular damage to impairment of endothelial nitric oxide synthase (eNOS) function by arsenic exposure. However, the role of eNOS in regulating the arsenite-induced vascular dysfunction still remains to be clarified. In our present study, we investigated the effect of arsenite on Akt1 and eNOS and its involvement in cytotoxicity of vascular endothelial cells. Our study demonstrated that arsenite decreased the protein levels of both Akt1 and eNOS accompanied with increased levels of ubiquitination of total cell lysates. We found that inhibition of the ubiquitin-proteasome pathway by MG-132 could partially protect Akt1 and eNOS from degradation by arsenite together with a proportional protection from the arsenite-induced cytoxicity. Moreover, up-regulation of eNOS protein expression significantly attenuated the arsenite-induced cytotoxicity and eNOS activity could be significantly inhibited after incubation with arsenite for 24 h in a cell-free system. Our study indicated that endothelial eNOS activity could be attenuated by arsenite via the ubiquitin-proteasome-mediated degradation of Akt1/eNOS as well as via direct inhibition of eNOS activity. Our study also demonstrated that eNOS actually played a protective role in arsenite-induced cytoxicity. These observations supported the hypothesis that the impairment of eNOS function by arsenite is one of the mechanisms leading to vascular changes and diseases.

  3. Arsenite induces cell transformation by reactive oxygen species, AKT, ERK1/2, and p70S6K1

    SciTech Connect

    Carpenter, Richard L.; Jiang, Yue; Jing, Yi; He, Jun; Rojanasakul, Yon; Liu, Ling-Zhi; Jiang, Bing-Hua

    2011-10-28

    Highlights: Black-Right-Pointing-Pointer Chronic exposure to arsenite induces cell proliferation and transformation. Black-Right-Pointing-Pointer Arsenite-induced transformation increases ROS production and downstream signalings. Black-Right-Pointing-Pointer Inhibition of ROS levels via catalase reduces arsenite-induced cell transformation. Black-Right-Pointing-Pointer Interruption of AKT, ERK, or p70S6K1 inhibits arsenite-induced cell transformation. -- Abstract: Arsenic is naturally occurring element that exists in both organic and inorganic formulations. The inorganic form arsenite has a positive association with development of multiple cancer types. There are significant populations throughout the world with high exposure to arsenite via drinking water. Thus, human exposure to arsenic has become a significant public health problem. Recent evidence suggests that reactive oxygen species (ROS) mediate multiple changes to cell behavior after acute arsenic exposure, including activation of proliferative signaling and angiogenesis. However, the role of ROS in mediating cell transformation by chronic arsenic exposure is unknown. We found that cells chronically exposed to sodium arsenite increased proliferation and gained anchorage-independent growth. This cell transformation phenotype required constitutive activation of AKT, ERK1/2, mTOR, and p70S6K1. We also observed these cells constitutively produce ROS, which was required for the constitutive activation of AKT, ERK1/2, mTOR, and p70S6K1. Suppression of ROS levels by forced expression of catalase also reduced cell proliferation and anchorage-independent growth. These results indicate cell transformation induced by chronic arsenic exposure is mediated by increased cellular levels of ROS, which mediates activation of AKT, ERK1/2, and p70S6K1.

  4. The Green Tea Component (-)-Epigallocatechin-3-Gallate Sensitizes Primary Endothelial Cells to Arsenite-Induced Apoptosis by Decreasing c-Jun N-Terminal Kinase-Mediated Catalase Activity.

    PubMed

    Kim, Jee-Youn; Choi, Ji-Young; Lee, Hyeon-Ju; Byun, Catherine Jeonghae; Park, Jung-Hyun; Park, Jae Hoon; Cho, Ho-Seong; Cho, Sung-Jin; Jo, Sangmee Ahn; Jo, Inho

    2015-01-01

    The green tea component (-)-epigallocatechin-3-gallate (EGCG) has been shown to sensitize many different types of cancer cells to anticancer drug-induced apoptosis, although it protects against non-cancerous primary cells against toxicity from certain conditions such as exposure to arsenic (As) or ultraviolet irradiation. Here, we found that EGCG promotes As-induced toxicity of primary-cultured bovine aortic endothelial cells (BAEC) at doses in which treatment with each chemical alone had no such effect. Increased cell toxicity was accompanied by an increased condensed chromatin pattern and fragmented nuclei, cleaved poly(ADP-ribose) polymerase (PARP), activity of the pro-apoptotic enzymes caspases 3, 8 and 9, and Bax translocation into mitochondria, suggesting the involvement of an apoptotic signaling pathway. Fluorescence activated cell sorting analysis revealed that compared with EGCG or As alone, combined EGCG and As (EGCG/As) treatment significantly induced production of reactive oxygen species (ROS), which was accompanied by decreased catalase activity and increased lipid peroxidation. Pretreatment with N-acetyl-L-cysteine or catalase reversed EGCG/As-induced caspase activation and EC toxicity. EGCG/As also increased the phosphorylation of c-Jun N-terminal kinase (JNK), which was not reversed by catalase. However, pretreatment with the JNK inhibitor SP600125 reversed all of the observed effects of EGCG/As, suggesting that JNK may be the most upstream protein examined in this study. Finally, we also found that all the observed effects by EGCG/As are true for other types of EC tested. In conclusion, this is firstly to show that EGCG sensitizes non-cancerous EC to As-induced toxicity through ROS-mediated apoptosis, which was attributed at least in part to a JNK-activated decrease in catalase activity. PMID:26375285

  5. The Green Tea Component (-)-Epigallocatechin-3-Gallate Sensitizes Primary Endothelial Cells to Arsenite-Induced Apoptosis by Decreasing c-Jun N-Terminal Kinase-Mediated Catalase Activity

    PubMed Central

    Lee, Hyeon-Ju; Byun, Catherine Jeonghae; Park, Jung-Hyun; Park, Jae Hoon; Cho, Ho-Seong; Cho, Sung-Jin; Jo, Sangmee Ahn; Jo, Inho

    2015-01-01

    The green tea component (-)-epigallocatechin-3-gallate (EGCG) has been shown to sensitize many different types of cancer cells to anticancer drug-induced apoptosis, although it protects against non-cancerous primary cells against toxicity from certain conditions such as exposure to arsenic (As) or ultraviolet irradiation. Here, we found that EGCG promotes As-induced toxicity of primary-cultured bovine aortic endothelial cells (BAEC) at doses in which treatment with each chemical alone had no such effect. Increased cell toxicity was accompanied by an increased condensed chromatin pattern and fragmented nuclei, cleaved poly(ADP-ribose) polymerase (PARP), activity of the pro-apoptotic enzymes caspases 3, 8 and 9, and Bax translocation into mitochondria, suggesting the involvement of an apoptotic signaling pathway. Fluorescence activated cell sorting analysis revealed that compared with EGCG or As alone, combined EGCG and As (EGCG/As) treatment significantly induced production of reactive oxygen species (ROS), which was accompanied by decreased catalase activity and increased lipid peroxidation. Pretreatment with N-acetyl-L-cysteine or catalase reversed EGCG/As-induced caspase activation and EC toxicity. EGCG/As also increased the phosphorylation of c-Jun N-terminal kinase (JNK), which was not reversed by catalase. However, pretreatment with the JNK inhibitor SP600125 reversed all of the observed effects of EGCG/As, suggesting that JNK may be the most upstream protein examined in this study. Finally, we also found that all the observed effects by EGCG/As are true for other types of EC tested. In conclusion, this is firstly to show that EGCG sensitizes non-cancerous EC to As-induced toxicity through ROS-mediated apoptosis, which was attributed at least in part to a JNK-activated decrease in catalase activity. PMID:26375285

  6. The lncRNA MALAT1, acting through HIF-1α stabilization, enhances arsenite-induced glycolysis in human hepatic L-02 cells.

    PubMed

    Luo, Fei; Liu, Xinlu; Ling, Min; Lu, Lu; Shi, Le; Lu, Xiaolin; Li, Jun; Zhang, Aihua; Liu, Qizhan

    2016-09-01

    Accelerated glycolysis, a common process in tumor cells called the Warburg effect, is associated with various biological phenomena. However, the role of glycolysis induced by arsenite, a well-established human carcinogen, is unknown. Long non-coding RNAs (lncRNAs) act as regulators in various cancers, but how lncRNAs regulate glucose metabolism remains largely unexplored. We have found that, in human hepatic epithelial (L-02) cells, arsenite increases lactate production; glucose consumption; and expression of glycolysis-related genes, including HK-2, Eno-1, and Glut-4. In L-02 cells exposed to arsenite, the lncRNA, metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and hypoxia inducible factors (HIFs)-α, the transcriptional regulators of cellular response to hypoxia, are over-expressed. In addition, HIF-1α, not HIF-2α, is involved in arsenite-induced glycolysis, and MALAT1 enhances arsenite-induced glycolysis. Although MALAT1 regulates HIF-α and promotes arsenite-induced glycolysis, MALAT1 promotes glycolysis through HIF-1α, not HIF-2α. Moreover, arsenite-increased MALAT1 enhances the disassociation of Von Hippel-Lindau (VHL) tumor suppressor from HIF-1α, alleviating VHL-mediated ubiquitination of HIF-1α, which causes accumulation of HIF-1α. In sum, these findings indicate that MALAT1, acting through HIF-1α stabilization, is a mediator that enhances glycolysis induced by arsenite. These results provide a link between the induction of lncRNAs and the glycolysis in cells exposed to arsenite, and thus establish a previously unknown mechanism for arsenite-induced hepatotoxicity. PMID:27287256

  7. Arsenite-induced autophagy is associated with proteotoxicity in human lymphoblastoid cells

    SciTech Connect

    Bolt, Alicia M.; Zhao, Fei; Pacheco, Samantha; Klimecki, Walter T.

    2012-10-15

    Epidemiological studies of arsenic-exposed populations have provided evidence that arsenic exposure in humans is associated with immunosuppression. Previously, we have reported that arsenite-induced toxicity is associated with the induction of autophagy in human lymphoblastoid cell lines (LCL). Autophagy is a cellular process that functions in the degradation of damaged cellular components, including protein aggregates formed by misfolded or damaged proteins. Accumulation of misfolded or damaged proteins in the endoplasmic reticulum (ER) lumen causes ER stress and activates the unfolded protein response (UPR). In an effort to investigate the mechanism of autophagy induction by arsenite in the LCL model, we examined the potential contribution of ER stress and activation of the UPR. LCL exposed to sodium arsenite for 8-days induced expression of UPR-activated genes, including CHOP and GRP78, at the RNA and the protein level. Evidence for activation of the three arms of the UPR was observed. The arsenite-induced activation of the UPR was associated with an accumulation of protein aggregates containing p62 and LC3, proteins with established roles in the sequestration and autophagic clearance of protein aggregates. Taken together, these data provide evidence that arsenite-induced autophagy is associated with the generation of ER stress, activation of the UPR, and formation of protein aggregates that may be targeted to the lysosome for degradation. -- Highlights: ► Arsenite induces endoplasmic reticulum stress and the unfolded protein response. ► Arsenite induces the formation of protein aggregates that contain p62 and LC3-II. ► Time-course data suggests that arsenite-induced autophagy precedes ER stress.

  8. THE EFFECTS OF HEAT SHOCK PROTEIN 70 (HSP70) AND EXPOSURE PROTOCOL ON ARSENITE INDUCED GENOTOXICITY

    EPA Science Inventory

    The Effects of Heat Shock Protein 70 (Hsp70) and Exposure Protocol on Arsenite Induced Genotoxicity

    Barnes, J.A.1,2, Collins, B.W.2, Dix, D.J.3 and Allen J.W2.
    1National Research Council, 2Environmental Carcinogenesis Division, 3Reproductive Toxicology Division, Office...

  9. MicroRNA-21 activation of ERK signaling via PTEN is involved in arsenite-induced autophagy in human hepatic L-02 cells.

    PubMed

    Liu, Xinlu; Luo, Fei; Ling, Min; Lu, Lu; Shi, Le; Lu, Xiaolin; Xu, Hui; Chen, Chao; Yang, Qianlei; Xue, Junchao; Li, Jun; Zhang, Aihua; Liu, Qizhan

    2016-06-11

    Autophagy, an evolutionarily conserved cellular process, has diverse physiological and pathological roles in biological functions. Whether autophagy is induced by arsenite, a well-established human carcinogen, and the molecular mechanisms involved, remain to be established. Further, microRNAs (miRNAs) act as regulators in various cancers, but how miRNAs regulate autophagy remains largely unexplored. We have found that, in human hepatic epithelial (L-02) cells, arsenite increases levels of autophagy-related proteins in a concentration- and time-dependent manner and elevates the number of autophagic vacuoles (AVs). Arsenite also activates the ERK pathway in a dose- and time-dependent manner. In L-02 cells exposed to arsenite, microRNA-21 (miRNA-21) is over-expressed, and its target proteins, PTEN, PDCD4, and Spry1, are decreased. Moreover, inhibition of miR-21 increases levels of PTEN, and reduces levels of Beclin 1 and LC3 II/I, indicating that miR-21 is involved in arsenite-induced autophagy. In addition, ectopic expression of PTEN blocks the effect of miR-21 on the arsenite-induced autophagy and decreases p-ERK levels. Also, ERK promotes the autophagy induced by arsenite. In sum, upon exposure of cells to arsenite, over-expression of miR-21 activates ERK through PTEN, factors that participate in arsenite-induced autophagy. This link, mediated through miRNAs, establishes a mechanism for the development of autophagy that is associated with arsenic toxicity. Such information contributes to an understanding of the liver toxicity caused by arsenite. PMID:27107786

  10. Effect of rosiglitazone in sodium arsenite-induced experimental vascular endothelial dysfunction.

    PubMed

    Kaur, Tajpreet; Goel, Rajesh Kumar; Balakumar, Pitchai

    2010-04-01

    The present study has been designed to investigate the effect of rosiglitazone, a peroxisome proliferator activated receptor gamma agonist in sodium arsenite-induced vascular endothelial dysfunction (VED) in rats. The rats were administered sodium arsenite (1.5 mg/kg/day, i.p., 2 weeks) to induce VED. The development of VED was assessed by employing isolated aortic ring preparation and estimating serum nitrite/nitrate concentration. Further, the integrity of the aortic endothelium was assessed histologically using haematoxylin-eosin staining. Moreover, the oxidative stress was assessed by estimating serum thiobarbituric acid reactive substances, aortic reactive oxygen species and reduced form of glutathione. The administration of sodium arsenite produced VED by impairing acetylcholine-induced endothelium dependent relaxation, diminishing the integrity of vascular endothelium and decreasing the serum nitrite/nitrate concentration. In addition, sodium arsenite was noted to produce oxidative stress as it increased serum thiobarbituric acid reactive substances and aortic reactive oxygen species and consequently decreased glutathione. Treatment with rosiglitazone (3 mg/kg/day, p.o., 2 weeks and 5 mg/kg/day, p.o., 2 weeks) significantly prevented sodium arsenite-induced VED by enhancing acetylcholine-induced endothelium dependent relaxation, improving the integrity of vascular endothelium, increasing the nitrite/nitrate concentration and decreasing the oxidative stress. However, the vascular protective effect of rosiglitazone was markedly abolished by co-administration of nitric oxide synthase inhibitor, N-Omega-Nitro-L-Arginine Methyl Ester (L-NAME) (25 mg/kg/day, i.p., 2 weeks). Thus, it may be concluded that rosiglitazone reduces oxidative stress, activates eNOS and enhances the generation of nitric oxide to prevent sodium arsenite-induced VED in rats. PMID:20422371

  11. Comparative effects of some local food condiments on sodium arsenite-induced clastogenicity.

    PubMed

    Odunola, O A

    2003-03-01

    The modulatory effects of the aqueous extracts of some locally consumed food condiments namely garlic (Allium sativum), ginger (Zingiber officinale), sconio (Pimpinella anisumm LINNE) and cloves (Syzygium aromaticum) on the clastogenic effects of sodium arsenite, a known inorganic clastogen were assessed in mouse bone marrow cells using the micronucleus assay method. Results of preliminary investigation of the clastogenicity of the condiments show that aqueous extracts of these condiments have very mild clastogenic activity in mice in the order garlic > ginger and sconio > cloves and that extracts of ginger and sconio seem to have the same degree of clastogenicity. Pre-treatment of mice for seven days with extracts of the condiments orally before exposure to the oral dose (2.5 mg/kg body wt.) of sodium arsenite resulted in a remarkable reduction of the magnitude of formation of micronuclei in polychromatic erythrocytes of the bone marrow. The degree of reduction of the clastogenic effect of arsenite was of the order ginger > garlic > cloves > sconio. This reduction of arsenite induced clastogenicity by aqueous extracts of the condiments may be due in part to the antioxidant properties of their chemical constituents, thus suggesting that the condiments may be useful in the prevention of arsenite-induced toxicity in areas where arsenic is an environmental contaminant. PMID:15030071

  12. EFFECT OF EXPOSURE PROTOCOL AND HEAT SHOCK PROTEIN EXPRESSION ON ARSENITE INDUCED GENOTOXICITY IN MCF-7 BREAST CANCER CELLS

    EPA Science Inventory


    Effect of exposure protocol and heat shock protein expression on arsenite induced genotoxicity in MCF-7 breast cancer cells

    The genotoxic effects of arsenic (As) are well accepted, yet its mechanism of action is not clearly defined. Heat-shock proteins (HSPs) protect...

  13. The metalloid arsenite induces nuclear export of Id3 possibly via binding to the N-terminal cysteine residues

    SciTech Connect

    Kurooka, Hisanori; Sugai, Manabu; Mori, Kentaro; Yokota, Yoshifumi

    2013-04-19

    Highlights: •Sodium arsenite induces cytoplasmic accumulation of Id3. •Arsenite binds to closely spaced N-terminal cysteine residues of Id3. •N-terminal cysteines are essential for arsenite-induced nuclear export of Id3. •Nuclear export of Id3 counteracts its transcriptional repression activity. -- Abstract: Ids are versatile transcriptional repressors that regulate cell proliferation and differentiation, and appropriate subcellular localization of the Id proteins is important for their functions. We previously identified distinct functional nuclear export signals (NESs) in Id1 and Id2, but no active NES has been reported in Id3. In this study, we found that treatment with the stress-inducing metalloid arsenite led to the accumulation of GFP-tagged Id3 in the cytoplasm. Cytoplasmic accumulation was impaired by a mutation in the Id3 NES-like sequence resembling the Id1 NES, located at the end of the HLH domain. It was also blocked by co-treatment with the CRM1-specific nuclear export inhibitor leptomycin B (LMB), but not with the inhibitors for mitogen-activated protein kinases (MAPKs). Importantly, we showed that the closely spaced N-terminal cysteine residues of Id3 interacted with the arsenic derivative phenylarsine oxide (PAO) and were essential for the arsenite-induced cytoplasmic accumulation, suggesting that arsenite induces the CRM1-dependent nuclear export of Id3 via binding to the N-terminal cysteines. Finally, we demonstrated that Id3 significantly repressed arsenite-stimulated transcription of the immediate-early gene Egr-1 and that this repression activity was inversely correlated with the arsenite-induced nuclear export. Our results imply that Id3 may be involved in the biological action of arsenite.

  14. Arsenite-induced mitotic death involves stress response and is independent of tubulin polymerization

    SciTech Connect

    Taylor, B. Frazier; McNeely, Samuel C.; Miller, Heather L.; States, J. Christopher

    2008-07-15

    Arsenite, a known mitotic disruptor, causes cell cycle arrest and cell death at anaphase. The mechanism causing mitotic arrest is highly disputed. We compared arsenite to the spindle poisons nocodazole and paclitaxel. Immunofluorescence analysis of {alpha}-tubulin in interphase cells demonstrated that, while nocodazole and paclitaxel disrupt microtubule polymerization through destabilization and hyperpolymerization, respectively, microtubules in arsenite-treated cells remain comparable to untreated cells even at supra-therapeutic concentrations. Immunofluorescence analysis of {alpha}-tubulin in mitotic cells showed spindle formation in arsenite- and paclitaxel-treated cells but not in nocodazole-treated cells. Spindle formation in arsenite-treated cells appeared irregular and multi-polar. {gamma}-tubulin staining showed that cells treated with nocodazole and therapeutic concentrations of paclitaxel contained two centrosomes. In contrast, most arsenite-treated mitotic cells contained more than two centrosomes, similar to centrosome abnormalities induced by heat shock. Of the three drugs tested, only arsenite treatment increased expression of the inducible isoform of heat shock protein 70 (HSP70i). HSP70 and HSP90 proteins are intimately involved in centrosome regulation and mitotic spindle formation. HSP90 inhibitor 17-DMAG sensitized cells to arsenite treatment and increased arsenite-induced centrosome abnormalities. Combined treatment of 17-DMAG and arsenite resulted in a supra-additive effect on viability, mitotic arrest, and centrosome abnormalities. Thus, arsenite-induced abnormal centrosome amplification and subsequent mitotic arrest is independent of effects on tubulin polymerization and may be due to specific stresses that are protected against by HSP90 and HSP70.

  15. Prophylactic neuroprotective efficiency of co-administration of Ginkgo biloba and Trifolium pretense against sodium arsenite-induced neurotoxicity and dementia in different regions of brain and spinal cord of rats.

    PubMed

    Abdou, Heba M; Yousef, Mokhtar I; El Mekkawy, Desouki A; Al-Shami, Ahmed S

    2016-08-01

    The present study was carried out to evaluate the potential protective role of co-administration of Ginkgo biloba, Trifolium pretenseagainst sodium arsenite-induced neurotoxicity in different parts of brain (Cerebral cortex, Hippocampus, striatum and Hind brain) and in the spinal cord of rats. Sodium arsenite caused impairment in the acquisition and learning in all the behavioral tasks and caused significant increase in tumor necrosis factor-α,thiobarbituric acid-reactive substances andlipid profile, while caused significant decrease in glutathione, total thiol content, total antioxidant capacity, acetylcholinesterase, monoamine oxidase and ATPases activities. These results were confirmed by histopathological, fluorescence and scanning electron microscopy examination of different regions of brain. From these results sodium arsenite-induced neurodegenerative disorder in different regions of brain and spinal cord and this could be mediated through modifying the intracellular brain ions homeostasis, cholinergic dysfunction and oxidative damage. The presence of Ginkgo biloba and/orTrifolium pretense with sodium arsenite minimized its neurological damages. It was pronounced that using Ginkgo biloba and Trifolium pretense in combination was more effective as protective agents compared to use eachone of them alone. PMID:27234133

  16. Protective effects of Vernonia amygdalina against sodium arsenite-induced genotoxicity in rat

    PubMed Central

    Adetutu, Adewale; Oyewo, Emmanuel Bukoye; Adesokan, Ayoade A.

    2013-01-01

    Objectives: Contamination of the environment with arsenic (As) from both human and natural sources is known as a global problem. This study investigated the chemoprotective potential of Vernonia amygdalina leave extract against sodium arsenite-induced genotoxicity and hepatotoxicity. Materials and Methods: Genotoxic effects were evaluated in the rat bone marrow using micronuclei. The gamma glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP) activities were assayed in rat serum. Results: Pre-treatment with extract of V. amygdalina at doses 5 mg/kg and 10 mg/kg significantly decreased the frequency of micronucleated polychromatic erythrocytes (PCEs). The GGT and ALP activities were elevated more than fourfold, in the liver of rats treated with sodium arsenite, while it was reduced almost to half when the sodium arsenit-treated rats were fed fresh V. amgdalina leave extracts The phytochemical constituents of V. amygdalina assayed in this study may be responsible for high radical scavenging of the DPPH free radical observed. Conclusion: The present results indicate that V. amygdalina extract is capable of suppressing the chromosomal aberration induced by sodium arsenite in rat. Thus, V. amygdalina may be a potent chemoprotective agent against the toxicity of sodium arsenite in rats. PMID:23900237

  17. The novel role of fenofibrate in preventing nicotine- and sodium arsenite-induced vascular endothelial dysfunction in the rat.

    PubMed

    Kaur, Jagdeep; Reddy, Krishna; Balakumar, Pitchai

    2010-09-01

    The present study investigated the effect of fenofibrate, an agonist of PPAR-alpha, in nicotine- and sodium arsenite-induced vascular endothelial dysfunction (VED) in rats. Nicotine (2 mg/kg/day, i.p., 4 weeks) and sodium arsenite (1.5 mg/kg/day, i.p., 2 weeks) were administered to produce VED in rats. The scanning electron microscopy study in thoracic aorta revealed that administration of nicotine or sodium arsenite impaired the integrity of vascular endothelium. Further, administration of nicotine or sodium arsenite significantly decreased serum and aortic concentrations of nitrite/nitrate and subsequently reduced acetylcholine-induced endothelium-dependent relaxation. Moreover, nicotine or sodium arsenite produced oxidative stress by increasing serum thiobarbituric acid reactive substances (TBARS) and aortic superoxide generation. However, treatment with fenofibrate (30 mg/kg/day, p.o.) or atorvastatin (30 mg/kg/day p.o., a standard agent) significantly prevented nicotine- and sodium arsenite-induced VED and oxidative stress by improving the integrity of vascular endothelium, increasing the concentrations of serum and aortic nitrite/nitrate, enhancing the acetylcholine-induced endothelium-dependent relaxation and decreasing serum TBARS and aortic superoxide anion generation. Conversely, co-administration of L-NAME (25 mg/kg/day, i.p.), an inhibitor of nitric oxide synthase, markedly attenuated these vascular protective effects of fenofibrate. The administration of nicotine or sodium arsenite altered the lipid profile by increasing serum cholesterol and triglycerides and consequently decreasing high-density lipoprotein levels, which were significantly prevented by treatment with fenofibrate or atorvastatin. It may be concluded that fenofibrate improves the integrity and function of vascular endothelium, and the vascular protecting potential of fenofibrate in preventing the development of nicotine- and sodium arsenite-induced VED may be attributed to its

  18. Arsenite induces endothelial cell permeability increase through a reactive oxygen species-vascular endothelial growth factor pathway.

    PubMed

    Bao, Lingzhi; Shi, Honglian

    2010-11-15

    As a potent environmental oxidative stressor, arsenic exposure has been reported to exacerbate cardiovascular diseases and increase vascular endothelial cell monolayer permeability. However, the underlying mechanism of this effect is not well understood. In this paper, we test our hypothesis that reactive oxygen species (ROS)-induced vascular endothelial growth factor (VEGF) expression may play an important role in an arsenic-caused increase of endothelial cell monolayer permeability. The mouse brain vascular endothelial cell bEnd3 monolayer was exposed to arsenite for 1, 3, and 6 days. The monolayer permeability, VEGF protein release, and ROS generation were determined. In addition, VE-cadherin and zonula occludens-1 (ZO-1), two membrane structure proteins, were immunostained to elucidate the effects of arsenite on the cell-cell junction. The roles of ROS and VEGF in arsenite-induced permeability was determined by inhibiting ROS with antioxidants and immuno-depleting VEGF with a VEGF antibody. We observed that arsenite increased bEnd3 monolayer permeability, elevated the production of cellular ROS, and increased VEGF release. VE-cadherin and ZO-1 disruptions were also found in cells treated with arsenite. Furthermore, both antioxidant (N-acetyl cysteine and tempol) and the VEGF antibody treatments significantly lowered the arsenite-induced permeability of the bEnd3 monolayer as well as VEGF expression. VE-cadherin and ZO-1 disruptions were also diminished by N-acetyl cysteine and the VEGF antibody. Our data suggest that the increase in VEGF expression caused by ROS may play an important role in the arsenite-induced increase in endothelial cell permeability. PMID:20954712

  19. Sensitivity to sodium arsenite in human melanoma cells depends upon susceptibility to arsenite-induced mitotic arrest

    SciTech Connect

    McNeely, Samuel C.; Belshoff, Alex C.; Taylor, B. Frazier; Fan, Teresa W-M.; McCabe, Michael J.; Pinhas, Allan R.

    2008-06-01

    Arsenic induces clinical remission in patients with acute promyelocytic leukemia and has potential for treatment of other cancers. The current study examines factors influencing sensitivity to arsenic using human malignant melanoma cell lines. A375 and SK-Mel-2 cells were sensitive to clinically achievable concentrations of arsenite, whereas SK-Mel-3 and SK-Mel-28 cells required supratherapeutic levels for toxicity. Inhibition of glutathione synthesis, glutathione S-transferase (GST) activity, and multidrug resistance protein (MRP) transporter function attenuated arsenite resistance, consistent with studies suggesting that arsenite is extruded from the cell as a glutathione conjugate by MRP-1. However, MRP-1 was not overexpressed in resistant lines and GST-{pi} was only slightly elevated. ICP-MS analysis indicated that arsenite-resistant SK-Mel-28 cells did not accumulate less arsenic than arsenite-sensitive A375 cells, suggesting that resistance was not attributable to reduced arsenic accumulation but rather to intrinsic properties of resistant cell lines. The mode of arsenite-induced cell death was apoptosis. Arsenite-induced apoptosis is associated with cell cycle alterations. Cell cycle analysis revealed arsenite-sensitive cells arrested in mitosis whereas arsenite-resistant cells did not, suggesting that induction of mitotic arrest occurs at lower intracellular arsenic concentrations. Higher intracellular arsenic levels induced cell cycle arrest in the S-phase and G{sub 2}-phase in SK-Mel-3 and SK-Mel-28 cells, respectively. The lack of arsenite-induced mitotic arrest in resistant cell lines was associated with a weakened spindle checkpoint resulting from reduced expression of spindle checkpoint protein BUBR1. These data suggest that arsenite has potential for treatment of solid tumors but a functional spindle checkpoint is a prerequisite for a positive response to its clinical application.

  20. Ameliorative Effects of Acacia Honey against Sodium Arsenite-Induced Oxidative Stress in Some Viscera of Male Wistar Albino Rats

    PubMed Central

    Aliyu, Muhammad; Ibrahim, Sani; Inuwa, Hajiya M.; Sallau, Abdullahi B.; Abbas, Olagunju; Aimola, Idowu A.; Habila, Nathan; Uche, Ndidi S.

    2013-01-01

    Cancer is a leading cause of death worldwide and its development is frequently associated with oxidative stress-induced by carcinogens such as arsenicals. Most foods are basically health-promoting or disease-preventing and a typical example of such type is honey. This study was undertaken to investigate the ameliorative effects of Acacia honey on sodium arsenite-induced oxidative stress in the heart, lung and kidney tissues of male Wistar rats. Male Wistar albino rats divided into four groups of five rats each were administered distilled water, Acacia honey (20%), sodium arsenite (5 mg/kg body weight), Acacia honey, and sodium arsenite daily for one week. They were sacrificed anesthetically using 60 mg/kg sodium pentothal. The tissues were used for the assessment of glutathione peroxidase, catalase, and superoxide dismutase activities, protein content and lipid peroxidation. Sodium arsenite significantly (P < 0.05) suppressed the glutathione peroxidase, catalase, superoxide dismutase activities with simultaneous induction of lipid peroxidation. Administration of Acacia honey significantly increased (P < 0.05) glutathione peroxidase, catalase, and superoxide dismutase activities with concomitant suppression of lipid peroxidation as evident by the decrease in malondialdehyde level. From the results obtained, Acacia honey mitigates sodium arsenite induced-oxidative stress in male Wistar albino rats, which suggest that it may attenuate oxidative stress implicated in chemical carcinogenesis. PMID:24368942

  1. Stress-induced Start Codon Fidelity Regulates Arsenite-inducible Regulatory Particle-associated Protein (AIRAP) Translation*

    PubMed Central

    Zach, Lolita; Braunstein, Ilana; Stanhill, Ariel

    2014-01-01

    Initial steps in protein synthesis are highly regulated processes as they define the reading frame of the translation machinery. Eukaryotic translation initiation is a process facilitated by numerous factors (eIFs), aimed to form a “scanning” mechanism toward the initiation codon. Translation initiation of the main open reading frame (ORF) in an mRNA transcript has been reported to be regulated by upstream open reading frames (uORFs) in a manner of re-initiation. This mode of regulation is governed by the phosphorylation status of eIF2α and controlled by cellular stresses. Another mode of translational initiation regulation is leaky scanning, and this regulatory process has not been extensively studied. We have identified arsenite-inducible regulatory particle-associated protein (AIRAP) transcript to be translationally induced during arsenite stress conditions. AIRAP transcript contains a single uORF in a poor-kozak context. AIRAP translation induction is governed by means of leaky scanning and not re-initiation. This induction of AIRAP is solely dependent on eIF1 and the uORF kozak context. We show that eIF1 is phosphorylated under specific conditions that induce protein misfolding and have biochemically characterized this site of phosphorylation. Our data indicate that leaky scanning like re-initiation is responsive to stress conditions and that leaky scanning can induce ORF translation by bypassing poor kozak context of a single uORF transcript. PMID:24898249

  2. Acute Sodium Arsenite-Induced Hematological and Biochemical Changes in Wistar Rats: Protective Effects of Ethanol Extract of Ageratum conyzoides

    PubMed Central

    Ola-Davies, Olufunke Eunice; Akinrinde, Akinleye Stephen

    2016-01-01

    Background: Ageratum conyzoides L. (Asteraceae) is an annual herbaceous plant used in folklore medicine for the treatment of a wide range of diseases. Objective: To investigate the protective effect of the ethanol leaf extract of A. conyzoides (EEAC) against hematological, serum biochemical and histological alterations induced by Sodium arsenite administration to Wistar rats. Materials and Methods: Twenty male Wistar rats were randomly assigned into four groups of five rats each. Group I received propylene glycol and Group II rats were given the (EEAC, 100 mg/kg b.w.) orally for 7 days. Group III were given a single oral dose of sodium arsenite (NaAsO2, 2.5 mg/kg b.w.). Animals in Group IV were pretreated with 100 mg/kg EEAC for 7 days followed by a single oral dose of sodium arsenite. Results: Arsenic exposure resulted in significant reductions (P < 0.05) in values of packed cell volume (PCV), hemoglobin concentration (Hb) and red blood cell (RBC) count, and elevation in total white blood cell (WBC) count with insignificant reductions in serum total protein, albumin, and globulin levels. Alterations in aspartate aminotransferase, alanine transferase, alkaline phosphatase, and gamma glutamyl transferase activities, as well as in serum levels of urea, creatinine, glucose, cholesterol, and triglyceride levels, were not statistically significant. EEAC significantly restored (P < 0.05) the PCV, Hb, RBC, and WBC as well as serum albumin, globulin, and total protein to normal values. Conclusion: The results of this study indicate that EEAC possess strong potentials to protect against toxicities induced by sodium arsenite. SUMMARY Ageratum conyzoides produced significant reversal of the reduction in the erythrocytic indices (packed cell volume, red blood cell, and Hb) caused by sodium arseniteSodium arsenite-induced slight elevations in serum aspartate aminotransferase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP), correlating with the

  3. 14-Deoxy-11,12-didehydroandrographolide induces DDIT3-dependent endoplasmic reticulum stress-mediated autophagy in T-47D breast carcinoma cells.

    PubMed

    Tan, Heng Kean; Muhammad, Tengku Sifzizul Tengku; Tan, Mei Lan

    2016-06-01

    14-Deoxy-11,12-didehydroandrographolide (14-DDA), a major diterpenoid isolated from Andrographis paniculata (Burm.f.) Nees, is known to be cytotoxic and elicits a non-apoptotic cell death in T-47D breast carcinoma cells. In this study, the mechanistic toxicology properties of 14-DDA in T-47D cells were further investigated. 14-DDA is found to induce the formation of endoplasmic reticulum (ER) vacuoles and autophagosomes, with concurrent upregulation of LC3-II in the breast carcinoma cells. It stimulated an increase in cytosolic calcium concentration and caused a collapse in mitochondrial membrane potential in these cells. In addition, both DDIT3 and GADD45A, molecules implicated in ER stress pathway, were significantly upregulated. DDIT3 knockdown suppressed the formation of both ER vacuoles and autophagosomes, indicating that 14-DDA-induced ER stress and autophagy is dependent on this transcription factor. Collectively, it is possible that GADD45A/p38 MAPK/DDIT3 pathway is involved in the 14-DDA-induced ER-stress-mediated autophagy in T-47D cells. PMID:27049118

  4. Association of genetic polymorphisms in GADD45A, MDM2, and p14{sup ARF} with the risk of chronic benzene poisoning in a Chinese occupational population

    SciTech Connect

    Sun Pin; Zhang Zhongbin; Wan Junxiang; Zhao Naiqing; Jin Xipeng; Xia Zhaolin

    2009-10-01

    Benzene reactive metabolites can lead to DNA damage and trigger the p53-dependent defense responses to maintain genomic stability. We hypothesized that the p53-dependent genes may play a role in the development of chronic benzene poisoning (CBP). In a case-control study of 303 patients with benzene poisoning and 295 workers occupationally exposed to benzene in south China, we investigated associations between the risk of CBP and polymorphisms in three p53-dependent genes. Potential interactions of these polymorphisms with lifestyle factors were also explored. We found p14{sup ARF} rs3731245 polymorphism was associated with risk of CBP (P = 0.014). Compared with those carrying the GG genotype, individuals carrying p14{sup ARF} rs3731245 GA+AA genotypes had a reduced risk of CBP ([adjusted odds ratio (OR{sub adj}) = 0.57, 95%CI = 0.36-0.89]. Further analysis showed p14{sup ARF} TGA/TAG diplotype was associated with an increased risk of CBP (P = 0.0006), whereas p14{sup ARF} TGG/TAA diplotype was associated with a decreased risk of CBP (P = 0.0000001). In addition, we found individuals carrying both MDM2 Del1518 WW genotype and p14{sup ARF} rs3731245 GA+AA genotypes had a lower risk of CBP (OR{sub adj} = 0.25; 95%CI = 0.10-0.62; P = 0.003). Although these results require confirmation and extension, our findings suggest that genetic polymorphisms in p14{sup ARF} may have an impact on the risk of CBP in the study population.

  5. p53 activation by Ni(II) is a HIF-1α independent response causing caspases 9/3-mediated apoptosis in human lung cells

    SciTech Connect

    Wong, Victor C.; Morse, Jessica L.; Zhitkovich, Anatoly

    2013-06-15

    Hypoxia mimic nickel(II) is a human respiratory carcinogen with a suspected epigenetic mode of action. We examined whether Ni(II) elicits a toxicologically significant activation of the tumor suppressor p53, which is typically associated with genotoxic responses. We found that treatments of H460 human lung epithelial cells with NiCl{sub 2} caused activating phosphorylation at p53-Ser15, accumulation of p53 protein and depletion of its inhibitor MDM4 (HDMX). Confirming the activation of p53, its knockdown suppressed the ability of Ni(II) to upregulate MDM2 and p21 (CDKN1A). Unlike DNA damage, induction of GADD45A by Ni(II) was p53-independent. Ni(II) also increased p53-Ser15 phosphorylation and p21 expression in normal human lung fibroblasts. Although Ni(II)-induced stabilization of HIF-1α occurred earlier, it had no effect on p53 accumulation and Ser15 phosphorylation. Ni(II)-treated H460 cells showed no evidence of necrosis and their apoptosis and clonogenic death were suppressed by p53 knockdown. The apoptotic role of p53 involved a transcription-dependent program triggering the initiator caspase 9 and its downstream executioner caspase 3. Two most prominently upregulated proapoptotic genes by Ni(II) were PUMA and NOXA but only PUMA induction required p53. Knockdown of p53 also led to derepression of antiapoptotic MCL1 in Ni(II)-treated cells. Overall, our results indicate that p53 plays a major role in apoptotic death of human lung cells by Ni(II). Chronic exposure to Ni(II) may promote selection of resistant cells with inactivated p53, providing an explanation for the origin of p53 mutations by this epigenetic carcinogen. - Highlights: • Ni(II) is a strong activator of the transcription factor p53. • Apoptosis is a principal form of death by Ni(II) in human lung epithelial cells. • Ni(II)-activated p53 triggers caspases 9/3-mediated apoptotic program. • NOXA and PUMA are two main proapoptotic genes induced by Ni(II). • HIF-1α and p53 are independent

  6. Histone H2AX Is Involved in FoxO3a-Mediated Transcriptional Responses to Ionizing Radiation to Maintain Genome Stability

    PubMed Central

    Tarrade, Stephane; Bhardwaj, Tanya; Flegal, Matthew; Bertrand, Lindsey; Velegzhaninov, Ilya; Moskalev, Alexey; Klokov, Dmitry

    2015-01-01

    Histone H2AX plays a crucial role in molecular and cellular responses to DNA damage and in the maintenance of genome stability. It is downstream of ataxia telangiectasia mutated (ATM) damage signaling pathway and there is an emerging role of the transcription factor FoxO3a, a regulator of a variety of other pathways, in activating this signaling. We asked whether H2AX may feedback to FoxO3a to affect respective FoxO3a-dependent pathways. We used a genetically matched pair of mouse embryonic fibroblast H2AX+/+ and H2AX−/− cell lines to carry out comprehensive time-course and dose-response experiments and to show that the expression of several FoxO3a-regulated genes was altered in H2AX−/− compared to H2AX+/+ cells at both basal and irradiated conditions. Hspa1b and Gadd45a were down-regulated four- to five-fold and Ddit3, Cdkn1a and Sod2 were up-regulated 2–3-fold in H2AX−/− cells. Using the luciferase reporter assay, we directly demonstrated that transcriptional activity of FoxoO3a was reduced in H2AX−/− cells. FoxO3a localization within the nuclear phospho-ATM (Ser1981) foci in irradiated cells was affected by the H2AX status, as well as its posttranslational modification (phospho-Thr32). These differences were associated with genomic instability and radiosensitivity in H2AX−/− cells. Finally, knockdown of H2AX in H2AX+/+ cells resulted in FoxO3a-dependent gene expression patterns and increased radiosensitivity that partially mimicked those found in H2AX−/− cells. Taken together, our data suggest a role for FoxO3a in the maintenance of genome integrity in response to DNA damage that is mediated by H2AX via yet unknown mechanisms. PMID:26694365

  7. In Vitro Protective Potentials of Annona muricata Leaf Extracts Against Sodium Arsenite-induced Toxicity.

    PubMed

    George, Vazhappilly Cijo; Kumar, Devanga Ragupathi Naveen; Suresh, Palamadai Krishnan; Kumar, Rangasamy Ashok

    2015-01-01

    Sodium arsenite (NaAsO2) is a metalloid which is present widely in the environment and its chronic exposure can contribute to the induction of oxidative stress, resulting in disturbances in various metabolic functions including liver cell death. Hence, there is a need to develop drugs from natural sources, which can reduce arsenic toxicity. While there have been reports regarding the antioxidant and protective potentials of Annona muricataleaf extracts, our study is the first ofits kind to extend these findings by specifically evaluating its ability to render protection against sodium arsenite (NaAsO2) induced toxicity (10 μM) in WRL-68 (human hepatic cells) and human erythrocytes by employing XTT and haemolysis inhibition assays respectively. The methanolic extract exhibited higher activity than the aqueous extract in both assays. The results showed a dose-dependent decrease in arsenic toxicity in both WRL-68 cells and erythrocytes, suggesting the protective nature of Annona muricatato mitigate arsenic toxicity. Hence the bioactive extracts can further be scrutinized for the identification and characterization of their principal contributors. PMID:26033234

  8. EFFECTS OF HEAT SHOCK PROTEIN 70 (HSP70) ON ARSENITE INDUCED GENOTOXICITY

    EPA Science Inventory

    Arsenic (As), a human carcinogen, is known to be genotoxic although its mechanism(s) of action for tumorigenesis is not well understood. Among the toxicity-related properties of this chemical are its clastogenic and aneugenic activities, as well as its capacity for inducing stres...

  9. Protective effect of Juglans nigra on sodium arsenite-induced toxicity in rats

    PubMed Central

    Owumi, Solomon E.; Odunola, Oyeronke A.; Gbadegesin, Michael A.; Nulah, Kathleen L.

    2013-01-01

    Background: Consumption of arsenic contaminated water has been implicated in metalloid-induced carcinogenesis. Dietary intake of certain plant products with chemoprotective properties may protect against the onset of diseases and promote maintenance of health. Objectives: We investigated the outcome of black walnut Juglans nigra (JN) consumption on sodium arsenite (SA)-induced toxicity in rats. Materials and Methods: Wister albino rats were treated as follows: Control, SA only (positive control) (2.5 mg/kg body weight), JN only (100 mg/kg weight), and JN+SA coadministered. After 5 weeks animals were sacrificed whole blood, femur, liver and testis harvested were assessed for hepatic transaminases and clastogenicity. Histology of the liver, sperm morphology and quality were also assessed. Data were analyzed (ANOVA) and expressed as means ±SD. Results: SA treatment elevated hepatic transaminases level in serum (P < 0.05), induced histological changes in liver: fibroplasia and periportal hepatocytes infiltration by mononuclear cells. These changes were ameliorated by JN (P < 0.05) coadministration. SA induced micronuclei formation (P < 0.05). Again JN decreased (P < 0.05) micronuclei formation by 50%. Sperm count and motility decreased (P < 0.05) in all groups compared to control. Conclusion: JN showed no protection against arsenite effect on sperm quality. Hepatoprotective and anticlastogenic effects were apparent suggesting a chemopreventive potential active against arsenite genotoxicity and chromosomal instability which have implication for metalloid-induced carcinogenesis. PMID:23901214

  10. Sodium arsenite induces chromosome endoreduplication and inhibits protein phosphatase activity in human fibroblasts

    SciTech Connect

    Rong-Nan Huang; I-Ching Ho; Ling-Hui Yih

    1995-08-01

    Arsenic, strongly associated with increased risks of human cancers, is a potent clastogen in a variety of mammalian cell systems. The effect of sodium arsenite (a trivalent arsenic compound) on chromatid separation was studied in human skin fibroblasts (HFW). Human fibroblasts were arrested in S phase by the aid of serum starvation and aphidicolin blocking and then these cells were allowed to synchronously progress into G2 phase. Treatment of the G2-enriched HFW cells with sodium arsenite (0-200 {mu}M) resulted in arrest of cells in the G2 phase, interference with mitotic division, inhibition of spindle assembly, and induction of chromosome endoreduplication in their second mitosis. Sodium arsenite treatment also inhibited the activities of serine/threonine protein phosphatases and enhanced phosphorylation levels of a small heat shock protein (HSP27). These results suggest that sodium arsenite may mimic okadaic acid to induce chromosome endoreduplication through its inhibitory effect on protein phosphatase activity. 61 refs., 6 figs., 2 tabs.

  11. Sodium arsenite induces apoptosis and Epstein-Barr virus reactivation in lymphoblastoid cells.

    PubMed

    Zebboudj, Abderezak; Maroui, Mohamed Ali; Dutrieux, Jacques; Touil-Boukoffa, Chafia; Bourouba, Mehdi; Chelbi-Alix, Mounira K; Nisole, Sébastien

    2014-12-01

    Epstein-Barr virus (EBV) is associated with several malignancies, including carcinomas, such as nasopharyngeal carcinoma, and lymphomas, such as Burkitt's lymphoma and Hodgkin's lymphoma. The Latent Membrane Protein 1 (LMP1) is the major oncogene protein of EBV as its expression is responsible for the induction of cell transformation, immortalization and proliferation. Arsenic trioxide was shown to induce a cytotoxic effect on nasopharyngeal cancer cells associated with LMP1 down-regulation. However, the effect of arsenic on EBV-associated lymphoproliferative malignancies has been less studied. We investigated the effect of two different arsenical compounds, arsenic trioxide (As2O3) and sodium arsenite (NaAsO2) on the induction of cell death in P3HR1 cells, an Epstein-Barr virus-positive Burkitt lymphoma derived cell line. Both compounds inhibited cell growth and induced cell death. By flow-cytometry and Western blot analysis, we provide evidence that NaAsO2 induced caspase-dependent apoptosis whereas As2O3 triggered autophagic cell death. Furthermore, we show that NaAsO2 treatment led to a dramatic decrease of the expression level of LMP1 and the cellular protein PML. Importantly, this down-regulation was associated with a reactivation of EBV lytic cycle through the induction of immediate-early proteins Zta and Rta. These results are in agreement with a model in which LMP1 maintains EBV in a latent state by stabilizing PML expression. Altogether, our results suggest that NaAsO2 would represent a better therapeutic candidate than As2O3 in EBV-induced B lymphoma for its capacity to promote viral reactivation. PMID:25241256

  12. Mediation Analysis

    PubMed Central

    MacKinnon, David P.; Fairchild, Amanda J.; Fritz, Matthew S.

    2010-01-01

    Mediating variables are prominent in psychological theory and research. A mediating variable transmits the effect of an independent variable on a dependent variable. Differences between mediating variables and confounders, moderators, and covariates are outlined. Statistical methods to assess mediation and modern comprehensive approaches are described. Future directions for mediation analysis are discussed. PMID:16968208

  13. Sodium arsenite accelerates TRAIL-mediated apoptosis in melanoma cells through upregulation of TRAIL-R1/R2 surface levels and downregulation of cFLIP expression

    SciTech Connect

    Ivanov, Vladimir N. . E-mail: vni3@columbia.edu; Hei, Tom K.

    2006-12-10

    AP-1/cJun, NF-{kappa}B and STAT3 transcription factors control expression of numerous genes, which regulate critical cell functions including proliferation, survival and apoptosis. Sodium arsenite is known to suppress both the IKK-NF-{kappa}B and JAK2-STAT3 signaling pathways and to activate the MAPK/JNK-cJun pathways, thereby committing some cancers to undergo apoptosis. Indeed, sodium arsenite is an effective drug for the treatment of acute promyelocytic leukemia with little nonspecific toxicity. Malignant melanoma is highly refractory to conventional radio- and chemotherapy. In the present study, we observed strong effects of sodium arsenite treatment on upregulation of TRAIL-mediated apoptosis in human and mouse melanomas. Arsenite treatment upregulated surface levels of death receptors, TRAIL-R1 and TRAIL-R2, through increased translocation of these proteins from cytoplasm to the cell surface. Furthermore, activation of cJun and suppression of NF-{kappa}B by sodium arsenite resulted in upregulation of the endogenous TRAIL and downregulation of the cFLIP gene expression (which encodes one of the main anti-apoptotic proteins in melanomas) followed by cFLIP protein degradation and, finally, by acceleration of TRAIL-induced apoptosis. Direct suppression of cFLIP expression by cFLIP RNAi also accelerated TRAIL-induced apoptosis in these melanomas, while COX-2 suppression substantially increased levels of both TRAIL-induced and arsenite-induced apoptosis. In contrast, overexpression of permanently active AKTmyr inhibited TRAIL-mediated apoptosis via downregulation of TRAIL-R1 levels. Finally, AKT overactivation increased melanoma survival in cell culture and dramatically accelerated growth of melanoma transplant in vivo, highlighting a role of AKT suppression for effective anticancer treatment.

  14. Mediation Analysis with Multiple Mediators

    PubMed Central

    VanderWeele, T.J.; Vansteelandt, S.

    2014-01-01

    Recent advances in the causal inference literature on mediation have extended traditional approaches to direct and indirect effects to settings that allow for interactions and non-linearities. In this paper, these approaches from causal inference are further extended to settings in which multiple mediators may be of interest. Two analytic approaches, one based on regression and one based on weighting are proposed to estimate the effect mediated through multiple mediators and the effects through other pathways. The approaches proposed here accommodate exposure-mediator interactions and, to a certain extent, mediator-mediator interactions as well. The methods handle binary or continuous mediators and binary, continuous or count outcomes. When the mediators affect one another, the strategy of trying to assess direct and indirect effects one mediator at a time will in general fail; the approach given in this paper can still be used. A characterization is moreover given as to when the sum of the mediated effects for multiple mediators considered separately will be equal to the mediated effect of all of the mediators considered jointly. The approach proposed in this paper is robust to unmeasured common causes of two or more mediators. PMID:25580377

  15. Specialized Mediation.

    ERIC Educational Resources Information Center

    Hammond, Carol; And Others

    1992-01-01

    Six articles discuss librarians as mediators in special circumstances. Highlights include the reference librarian and the information paraprofessional; effective reference mediation for nontraditional public library users, including mentally impaired patrons and illiterate adults; the academic librarian's role in the education process; and…

  16. Arsenite induces apoptosis in human mesenchymal stem cells by altering Bcl-2 family proteins and by activating intrinsic pathway

    SciTech Connect

    Yadav, Santosh; Shi Yongli; Wang Feng; Wang He

    2010-05-01

    Purpose: Environmental exposure to arsenic is an important public health issue. The effects of arsenic on different tissues and organs have been intensively studied. However, the effects of arsenic on bone marrow mesenchymal stem cells (MSCs) have not been reported. This study is designed to investigate the cell death process caused by arsenite and its related underlying mechanisms on MSCs. The rationale is that absorbed arsenic in the blood circulation can reach to the bone marrow and may affect the cell survival of MSCs. Methods: MSCs of passage 1 were purchased from Tulane University, grown till 70% confluency level and plated according to the experimental requirements followed by treatment with arsenite at various concentrations and time points. Arsenite (iAs{sup III}) induced cytotoxic effects were confirmed by cell viability and cell cycle analysis. For the presence of canonic apoptosis markers; DNA damage, exposure of intramembrane phosphotidylserine, protein and m-RNA expression levels were analyzed. Results: iAs{sup III} induced growth inhibition, G2-M arrest and apoptotic cell death in MSCs, the apoptosis induced by iAs{sup III} in the cultured MSCs was, via altering Bcl-2 family proteins and by involving intrinsic pathway. Conclusion: iAs{sup III} can induce apoptosis in bone marrow-derived MSCs via Bcl-2 family proteins, regulating intrinsic apoptotic pathway. Due to the multipotency of MSC, acting as progenitor cells for a variety of connective tissues including bone, adipose, cartilage and muscle, these effects of arsenic may be important in assessing the health risk of the arsenic compounds and understanding the mechanisms of arsenic-induced harmful effects.

  17. Arsenite induces DNA-protein crosslinks and cytokeratin expression in the WRL-68 human hepatic cell line.

    PubMed

    Ramírez, P; Del Razo, L M; Gutierrez-Ruíz, M C; Gonsebatt, M E

    2000-04-01

    The induction of DNA-protein crosslinks (DPC) has been proposed as an indicator of early biological effects due to the fact that known or suspected carcinogens induce an increased proportion of proteins tightly bound to DNA. Arsenic, a human carcinogen, is reduced and methylated mainly in liver cells generating a number of intermediate reactive forms which could lead to the formation of DNA-protein crosslinks. The induction of DPC by arsenite [As(III)] was investigated in the WRL-68 human hepatic cell line, testing the possibility that cytokeratins or cytokeratin-like proteins, due to their high content of SH groups, could participate in DPC. The formation and decay of DPC was dose-related. Arsenite was the only intracellular species present since no methylated As forms could be detected. Thus, DPC can be attributed to the presence of arsenite, an important species present in liver during As exposure, whose permanence in the tissue would depend on the methylation rate of the organism. Several cytokeratins were identified by immunoblotting among the proteins crosslinked with DNA, including cytokeratin 18 (CK18), a specific liver intermediate filament. An augmented presence of CK18 was detected in treated cultures by immunoblotting of total protein PAGE. In liver cells cytokeratin synthesis is tightly correlated with differentiation programs, thus arsenite could not only be damaging DNA but also modifying differentiation patterns in this tissue. PMID:10753206

  18. Association of Chromosomal Alterations with Arsenite-Induced Tumorigenicity of Human HaCaT Keratinocytes in Nude Mice

    PubMed Central

    Chien, Chia-Wen; Chiang, Ming-Chang; Ho, I-Ching; Lee, Te-Chang

    2004-01-01

    Inorganic arsenic is a well-documented human carcinogen. Chronic low-dose exposure to inorganic arsenic is associated with an increased incidence of a variety of cancers, including skin, lung, bladder, and liver cancer. Because genetic alterations often occur during cancer development, the objective of this study was to explore what types of genetic alterations were induced by chronic exposure of human HaCaT cells to arsenic. After 20 passages in the presence of inorganic trivalent arsenite at concentrations of 0.5 or 1 μM, HaCaT cells had higher intracellular levels of glutathione, became more resistance to arsenite, and showed an increased frequency of micronuclei. Furthermore, the previously nontumorigenic HaCaT cells became tumorigenic, as shown by subcutaneous injection into Balb/c nude mice. Cell lines derived from the tumors formed by injection of arsenite-exposed HaCaT cells into nude mice expressed higher levels of keratin 6, a proliferation marker of keratinocytes, than did parental HaCaT cells, whereas the expression of keratins 5, 8, and 10 was significantly decreased. Comparative genomic hybridization demonstrated chromosomal alterations in the 11 cell lines derived from these tumors; all 11 showed significant loss of chromosome 9q, and seven showed significant gain of chromosome 4q. The present results show that long-term exposure to low doses of arsenite transformed nontumorigenic human keratinocytes to cells that were tumorigenic in nude mice and that chromosomal alterations were observed in all cell lines established from the tumors. PMID:15579417

  19. Mediator Deathwork

    ERIC Educational Resources Information Center

    Walter, Tony

    2005-01-01

    The most discussed and analyzed form of deathwork is the dyadic "therapist" [double arrow] "client" relationship, but this far from exhausts the various types of professional work involving the dead. Mediator deathwork is where the professional gleans or constructs information about the dead, edits and polishes it, and publicly presents the edited…

  20. Arsenite evokes IL-6 secretion, autocrine regulation of STAT3 signaling, and miR-21 expression, processes involved in the EMT and malignant transformation of human bronchial epithelial cells

    SciTech Connect

    Luo, Fei; Xu, Yuan; Ling, Min; Zhao, Yue; Xu, Wenchao; Liang, Xiao; Jiang, Rongrong; Wang, Bairu; Bian, Qian; Liu, Qizhan

    2013-11-15

    Arsenite is an established human carcinogen, and arsenite-induced inflammation contributes to malignant transformation of cells, but the molecular mechanisms by which cancers are produced remain to be established. The present results showed that, evoked by arsenite, secretion of interleukin-6 (IL-6), a pro-inflammatory cytokine, led to the activation of STAT3, a transcription activator, and to increased levels of a microRNA, miR-21. Blocking IL-6 with anti-IL-6 antibody and inhibiting STAT3 activation reduced miR-21 expression. For human bronchial epithelial cells, cultured in the presence of anti-IL-6 antibody for 3 days, the arsenite-induced EMT and malignant transformation were reversed. Thus, IL-6, acting on STAT3 signaling, which up-regulates miR-21in an autocrine manner, contributes to the EMT induced by arsenite. These data define a link from inflammation to EMT in the arsenite-induced malignant transformation of HBE cells. This link, mediated through miRNAs, establishes a mechanism for arsenite-induced lung carcinogenesis. - Highlights: • Arsenite evokes IL-6 secretion. • IL-6 autocrine mediates STAT3 signaling and up-regulates miR-21expression. • Inflammation is involved in arsenite-induced EMT.

  1. Resolving Problems through Mediation.

    ERIC Educational Resources Information Center

    Notar, Susan

    1997-01-01

    Examines state variations in use of mediation to resolve domestic relations disputes. Mediation may be optional or mandatory, requested by the parties or the judge. Mediator qualifications vary considerably. Child support is less likely than custody and visitation to be the sole topic for mediation. More states are likely to use mediation in…

  2. Student Mediator's Training Manual.

    ERIC Educational Resources Information Center

    Good Shepherd Neighborhood House, Philadelphia, PA.

    Mediation is a process that enables two or more persons in a dispute to find mutually agreeable solutions to their differences with the aid of a mediator. The mediator does not take sides, but helps the disputants consider their options. Mediation is voluntary, and disputing parties must agree to participate. Furthermore, the mediator does not…

  3. School Mediation Trainer's Guide.

    ERIC Educational Resources Information Center

    Good Shepherd Neighborhood House, Philadelphia, PA.

    Mediation is a process that enables two or more persons in a dispute to find mutually agreeable solutions to their differences with the aid of a mediator. The mediator does not take sides, but helps the disputants consider their options. Mediation is voluntary, and disputing parties must agree to participate. The mediator does not have the power…

  4. Ligand-dependent corepressor contributes to transcriptional repression by C2H2 zinc-finger transcription factor ZBRK1 through association with KRAB-associated protein-1

    PubMed Central

    Calderon, Mario R.; Verway, Mark; Benslama, Radia Ouelaa; Birlea, Mirela; Bouttier, Manuella; Dimitrov, Vassil; Mader, Sylvie; White, John H.

    2014-01-01

    We identified a novel interaction between ligand-dependent corepressor (LCoR) and the corepressor KRAB-associated protein-1 (KAP-1). The two form a complex with C2H2 zinc-finger transcription factor ZBRK1 on an intronic binding site in the growth arrest and DNA-damage-inducible α (GADD45A) gene and a novel site in the fibroblast growth factor 2 (FGF2) gene. Chromatin at both sites is enriched for histone methyltransferase SETDB1 and histone 3 lysine 9 trimethylation, a repressive epigenetic mark. Depletion of ZBRK1, KAP-1 or LCoR led to elevated GADD45A and FGF2 expression in malignant and non-malignant breast epithelial cells, and caused apoptotic death. Loss of viability could be rescued by simultaneous knockdowns of FGF2 and transcriptional coregulators or by blocking FGF2 function. FGF2 was not concurrently expressed with any of the transcriptional coregulators in breast malignancies, suggesting an inverse correlation between their expression patterns. We propose that ZBRK1, KAP-1 and LCoR form a transcriptional complex that silences gene expression, in particular FGF2, which maintains breast cell viability. Given the broad expression patterns of both LCoR and KAP-1 during development and in the adult, this complex may have several regulatory functions that extend beyond cell survival, mediated by interactions with ZBRK1 or other C2H2 zinc-finger proteins. PMID:24829459

  5. The accumulations of HIF-1α and HIF-2α by JNK and ERK are involved in biphasic effects induced by different levels of arsenite in human bronchial epithelial cells

    SciTech Connect

    Xu, Yuan; Li, Yuan; Li, Huiqiao; Pang, Ying; Zhao, Yue; Jiang, Rongrong; Shen, Lu; Zhou, Jianwei; Wang, Xinru; Liu, Qizhan

    2013-01-15

    The biphasic effects of arsenite, in which low levels of arsenite induce cell proliferation and high levels of arsenite induce DNA damage and apoptosis, apparently contribute to arsenite-induced carcinogenesis. However, the mechanisms underlying this phenomenon are not well understood. In this study, we investigated the effects of different levels of arsenite on cell proliferation, DNA damage and apoptosis as well as on signal transduction pathways in human bronchial epithelial (HBE) cells. Our results show that a low level of arsenite activates extracellular signal-regulated kinases (ERK), which probably mediate arsenite-inhibited degradation of ubiquitinated hypoxia-inducible factor-2α (HIF-2α) in HBE cells. ERK inhibition blocks cell proliferation induced by a low level of arsenite, in part via HIF-2α. In contrast, a high level of arsenite activates c-Jun N-terminal kinases (JNK), which provoke a response to suppress ubiquitinated HIF-1α degradation. Down-regulation of HIF-1α by inhibiting JNK, however, increases the DNA damage but decreases the apoptosis induced by a high level of arsenite. Thus, data in the present study suggest that the accumulations of HIF-1α and HIF-2α by JNK and ERK are involved in different levels of arsenite-induced biphasic effects, with low levels of arsenite inducing cell proliferation and high levels of arsenite inducing DNA damage and apoptosis in HBE cells. -- Highlights: ► Biphasic effects induced by different concentrations of arsenite. ► Different regulation of ERK or JNK signal pathway by arsenite. ► Different regulation of HIF1α or HIF 2α by arsenite.

  6. Arsenic promotes centrosome abnormalities and cell colony formation in p53 compromised human lung cells

    SciTech Connect

    Liao Weiting; Lin Pinpin; Cheng, T.-S.; Yu, H.-S.; Chang, Louis W.

    2007-12-01

    Epidemiological evidence indicated that residents, especially cigarette smokers, in arseniasis areas had significantly higher lung cancer risk than those living in non-arseniasis areas. Thus, an interaction between arsenic and cigarette smoking in lung carcinogenesis was suspected. p53 dysfunction or mutation in lung epithelial cells was frequently observed in cigarette smokers. Our present study was to explore the differential effects by arsenic on H1355 cells (human lung adenocarcinoma cell line with mutation in p53), BEAS-2B (immortalized lung epithelial cell with functional p53) and pifithrin-{alpha}-treated BEAS-2B cells (p53-inhibited cells). These cells were treated with different doses of sodium arsenite (0, 0.1, 1, 5 and 10 {mu}M) for 48 h. A greater reduction in cell viability was observed in the BEAS-2B cells vs. p53 compromised cells (H1355 or p53-inhibited BEAS-2B). Similar observation was also made on 7-day cell survival (growth) study. TUNEL analysis confirmed that there was indeed a significantly reduced arsenite-induced apoptosis found in p53-compromised cells. Centrosomal abnormality has been attributed to eventual chromosomal missegregation, aneuploidy and tumorigenesis. In our present study, reduced p21 and Gadd45a expressions and increased centrosomal abnormality (atopic and multiple centrosomes) were observed in both arsenite-treated H1355 and p53-inhibited BEAS-2B cells as compared with similarly treated BEAS-2B cells. Increased anchorage-independent growth (colony formation) of BEAS-2B cells co-treated with pifithrin-{alpha} and 5 {mu}M sodium arsenite was also observed in soft agar. Our present investigation demonstrated that arsenic would act specifically on p53 compromised cells (either with p53 dysfunction or inhibited) to induce centrosomal abnormality and colony formation. These findings provided strong evidence on the carcinogenic promotional role of arsenic, especially under the condition of p53 dysfunction.

  7. Causal mediation analysis with a latent mediator.

    PubMed

    Albert, Jeffrey M; Geng, Cuiyu; Nelson, Suchitra

    2016-05-01

    Health researchers are often interested in assessing the direct effect of a treatment or exposure on an outcome variable, as well as its indirect (or mediation) effect through an intermediate variable (or mediator). For an outcome following a nonlinear model, the mediation formula may be used to estimate causally interpretable mediation effects. This method, like others, assumes that the mediator is observed. However, as is common in structural equations modeling, we may wish to consider a latent (unobserved) mediator. We follow a potential outcomes framework and assume a generalized structural equations model (GSEM). We provide maximum-likelihood estimation of GSEM parameters using an approximate Monte Carlo EM algorithm, coupled with a mediation formula approach to estimate natural direct and indirect effects. The method relies on an untestable sequential ignorability assumption; we assess robustness to this assumption by adapting a recently proposed method for sensitivity analysis. Simulation studies show good properties of the proposed estimators in plausible scenarios. Our method is applied to a study of the effect of mother education on occurrence of adolescent dental caries, in which we examine possible mediation through latent oral health behavior. PMID:26363769

  8. The importance of mediation

    SciTech Connect

    Nastri, W.H.

    1996-12-31

    Environmental mediation involving hazardous materials often includes a neutral, third party to assist other groups with resolving disputes or with negotiations. Most often, mediators facilitate discussion and suggest possible resolutions among parties, rather than advise as to what action must be taken to reach an agreement. There is opportunity for all sides to express grievances and frustrations as well as hearing possible solutions to resolve discrepancies. Most often, those involved with mediation attain a sense of confidence, competency, and satisfaction with the mediation process. An honest broker is an example of a third party mediator believed capable of assisting mediation in an unbiased manner. The opposing groups must be confident that an honest broker is credible and will provide his/her services to reach a satisfactory conclusion; therefore, the reputation of the mediator is crucial to the success of the mediation process.

  9. Bayesian Mediation Analysis

    ERIC Educational Resources Information Center

    Yuan, Ying; MacKinnon, David P.

    2009-01-01

    In this article, we propose Bayesian analysis of mediation effects. Compared with conventional frequentist mediation analysis, the Bayesian approach has several advantages. First, it allows researchers to incorporate prior information into the mediation analysis, thus potentially improving the efficiency of estimates. Second, under the Bayesian…

  10. Causal Mediation Analysis with Multiple Mediators

    PubMed Central

    Daniel, R M; De Stavola, B L; Cousens, S N; Vansteelandt, S

    2015-01-01

    In diverse fields of empirical research—including many in the biological sciences—attempts are made to decompose the effect of an exposure on an outcome into its effects via a number of different pathways. For example, we may wish to separate the effect of heavy alcohol consumption on systolic blood pressure (SBP) into effects via body mass index (BMI), via gamma-glutamyl transpeptidase (GGT), and via other pathways. Much progress has been made, mainly due to contributions from the field of causal inference, in understanding the precise nature of statistical estimands that capture such intuitive effects, the assumptions under which they can be identified, and statistical methods for doing so. These contributions have focused almost entirely on settings with a single mediator, or a set of mediators considered en bloc; in many applications, however, researchers attempt a much more ambitious decomposition into numerous path-specific effects through many mediators. In this article, we give counterfactual definitions of such path-specific estimands in settings with multiple mediators, when earlier mediators may affect later ones, showing that there are many ways in which decomposition can be done. We discuss the strong assumptions under which the effects are identified, suggesting a sensitivity analysis approach when a particular subset of the assumptions cannot be justified. These ideas are illustrated using data on alcohol consumption, SBP, BMI, and GGT from the Izhevsk Family Study. We aim to bridge the gap from “single mediator theory” to “multiple mediator practice,” highlighting the ambitious nature of this endeavor and giving practical suggestions on how to proceed. PMID:25351114

  11. Arsenic exposure induces the Warburg effect in cultured human cells

    SciTech Connect

    Zhao, Fei; Severson, Paul; Pacheco, Samantha; Futscher, Bernard W.; Klimecki, Walter T.

    2013-08-15

    Understanding how arsenic exacts its diverse, global disease burden is hampered by a limited understanding of the particular biological pathways that are disrupted by arsenic and underlie pathogenesis. A reductionist view would predict that a small number of basic pathways are generally perturbed by arsenic, and manifest as diverse diseases. Following an initial observation that arsenite-exposed cells in culture acidify their media more rapidly than control cells, the report here shows that low level exposure to arsenite (75 ppb) is sufficient to induce aerobic glycolysis (the Warburg effect) as a generalized phenomenon in cultured human primary cells and cell lines. Expanded studies in one such cell line, the non-malignant pulmonary epithelial line, BEAS-2B, established that the arsenite-induced Warburg effect was associated with increased accumulation of intracellular and extracellular lactate, an increased rate of extracellular acidification, and inhibition by the non-metabolized glucose analog, 2-deoxy-D-glucose. Associated with the induction of aerobic glycolysis was a pathway-wide induction of glycolysis gene expression, as well as protein accumulation of an established glycolysis master-regulator, hypoxia-inducible factor 1A. Arsenite-induced alteration of energy production in human cells represents the type of fundamental perturbation that could extend to many tissue targets and diseases. - Highlights: • Chronic arsenite exposure induces aerobic glycolysis, dubbed the “Warburg effect”. • Arsenite-induced Warburg effect is a general phenomenon in cultured human cells. • HIF-1A may mediate arsenite induced Warburg effect.

  12. Teaching Mediated Public Relations.

    ERIC Educational Resources Information Center

    Kent, Michael L.

    2001-01-01

    Discusses approaches to teaching a mediated public relations course, emphasizing the World Wide Web. Outlines five course objectives, assignments and activities, evaluation, texts, and lecture topics. Argues that students mastering these course objectives will understand ethical issues relating to media use, using mediated technology in public…

  13. Peer-Mediated Instruction.

    ERIC Educational Resources Information Center

    Rosenbaum, Peter S.

    The concept of peer-mediated instruction (PMI) grew out of the author's earlier research on applying techniques of drill and practice computer-assisted instruction (CAI) to language skills learning. Peer-mediated instruction directs pupils to work in pairs, interacting with one another according to structured pattern of dialogue. This book…

  14. Arsenite induced poly(ADP-ribosyl)ation of tumor suppressor P53 in human skin keratinocytes as a possible mechanism for carcinogenesis associated with arsenic exposure

    SciTech Connect

    Komissarova, Elena V.; Rossman, Toby G.

    2010-03-15

    Arsenite is an environmental pollutant. Exposure to inorganic arsenic in drinking water is associated with elevated cancer risk, especially in skin. Arsenite alone does not cause skin cancer in animals, but arsenite can enhance the carcinogenicity of solar UV. Arsenite is not a significant mutagen at non-toxic concentrations, but it enhances the mutagenicity of other carcinogens. The tumor suppressor protein P53 and nuclear enzyme PARP-1 are both key players in DNA damage response. This laboratory demonstrated earlier that in cells treated with arsenite, the P53-dependent increase in p21{sup WAF1/CIP1} expression, normally a block to cell cycle progression after DNA damage, is deficient. Here we show that although long-term exposure of human keratinocytes (HaCaT) to a nontoxic concentration (0.1 muM) of arsenite decreases the level of global protein poly(ADP-ribosyl)ation, it increases poly(ADP-ribosyl)ation of P53 protein and PARP-1 protein abundance. We also demonstrate that exposure to 0.1 muM arsenite depresses the constitutive expression of p21 mRNA and P21 protein in HaCaT cells. Poly(ADP-ribosyl)ation of P53 is reported to block its activation, DNA binding and its functioning as a transcription factor. Our results suggest that arsenite's interference with activation of P53 via poly(ADP-ribosyl)ation may play a role in the comutagenic and cocarcinogenic effects of arsenite.

  15. Generalized Causal Mediation Analysis

    PubMed Central

    Albert, Jeffrey M.; Nelson, Suchitra

    2010-01-01

    Summary The goal of mediation analysis is to assess direct and indirect effects of a treatment or exposure on an outcome. More generally, we may be interested in the context of a causal model as characterized by a directed acyclic graph (DAG), where mediation via a specific path from exposure to outcome may involve an arbitrary number of links (or ‘stages’). Methods for estimating mediation (or pathway) effects are available for a continuous outcome and a continuous mediator related via a linear model, while for a categorical outcome or categorical mediator, methods are usually limited to two-stage mediation. We present a method applicable to multiple stages of mediation and mixed variable types using generalized linear models. We define pathway effects using a potential outcomes framework and present a general formula that provides the effect of exposure through any specified pathway. Some pathway effects are nonidentifiable and their estimation requires an assumption regarding the correlation between counterfactuals. We provide a sensitivity analysis to assess of the impact of this assumption. Confidence intervals for pathway effect estimates are obtained via a bootstrap method. The method is applied to a cohort study of dental caries in very low birth weight adolescents. A simulation study demonstrates low bias of pathway effect estimators and close-to-nominal coverage rates of confidence intervals. We also find low sensitivity to the counterfactual correlation in most scenarios. PMID:21306353

  16. [Mediation in health].

    PubMed

    Decastello, Alice

    2008-02-10

    The author presents mediation as an alternative dispute resolution method. Mediation is a process where the parties are ready to settle their dispute out of court, by way of negotiation and with the involvement of an independent third person as mediator. In the mediation process the mediator shall not decide the dispute, nor examine the default or give legal advice or express his/her opinion - the mediator's duty is to help the parties bring their positions closer and come to a settlement agreement within a short time (120 days). The author gives a summary of the applications of the Hungarian Act on Mediation in Public Health and draws conclusions from the practical experience since entry into force of the legislation and illustrates the advantages of mediation over the court procedure (which may drag on for years). The primary advantages of mediation are that both the mediators and the parties are bound by the obligation of secrecy, the procedure is cheaper than the court proceedings, and the parties can "save their faces" because in mediation the winner-winner formula asserts itself - against lawsuits where the winner-loser positions are confronted. The author also analyses the specific data and information available so far. As for the future, the legislation needs to be amended at several points. It is particularly expedient to regulate the legal relationship between the insurance companies and the health service providers because the liability insurance may not cover the damages the courts adjudicate. And so some of the service providers may go bankrupt as the difference in excess of the upper limit of coverage - it might as well be up to HUF 5 million per case - shall be paid from own budget, to the charge of the upkeep costs. It is also required to review and amend the regulations on expert activities, just as it is inevitable to make data supply compulsory - otherwise it will be impossible to monitor the number of mediation procedures in health. At present

  17. A MALAT1/HIF-2α feedback loop contributes to arsenite carcinogenesis

    PubMed Central

    Xu, Yuan; Liu, Yi; Liu, Xinlu; Lu, Lu; Li, Jun; Wang, Qingling; Wei, Shaofeng; Shi, Le; Lu, Xiaolin; Liu, Qizhan; Zhang, Aihua

    2016-01-01

    Arsenic is well established as a human carcinogen, but the molecular mechanisms leading to arsenic-induced carcinogenesis are complex and elusive. It is also not known if lncRNAs are involved in arsenic-induced liver carcinogenesis. We have found that MALAT1, a non-coding RNA, is over-expressed in the sera of people exposed to arsenite and in hepatocellular carcinomas (HCCs), and MALAT1 has a close relation with the clinicopathological characteristics of HCC. In addition, hypoxia-inducible factor (HIF)-2α is up-regulated in HCCs, and MALAT1 and HIF-2α have a positive correlation in HCC tissues. During the malignant transformation of human hepatic epithelial (L-02) cells induced by a low concentration (2.0 μM) of arsenite, MALAT1 and HIF-2α are increased. In addition, arsenite-induced MALAT1 causes disassociation of the von Hippel-Lindau (VHL) protein from HIF-2α, therefore, alleviating VHL-mediated HIF-2α ubiquitination, which causes HIF-2α accumulation. In turn, HIF-2α transcriptionally regulates MALAT1, thus forming a positive feedback loop to ensure expression of arsenite-induced MALAT1 and HIF-2α, which are involved in malignant transformation. Moreover, MALAT1 and HIF-2α promote the invasive and metastatic capacities of arsenite-induced transformed L-02 cells and in HCC-LM3 cells. The capacities of MALAT1 and HIF-2α to promote tumor growth are validated in mouse xenograft models. In mice, arsenite induces an inflammatory response, and MALAT1 and HIF-2α are over-expressed. Together, these findings suggest that the MALAT1/HIF-2α feedback loop is involved in regulation of arsenite-induced malignant transformation. Our results not only confirm a novel mechanism involving reciprocal regulation between MALAT1 and HIF-2α, but also expand the understanding of the carcinogenic potential of arsenite. PMID:26735578

  18. A MALAT1/HIF-2α feedback loop contributes to arsenite carcinogenesis.

    PubMed

    Luo, Fei; Sun, Baofei; Li, Huiqiao; Xu, Yuan; Liu, Yi; Liu, Xinlu; Lu, Lu; Li, Jun; Wang, Qingling; Wei, Shaofeng; Shi, Le; Lu, Xiaolin; Liu, Qizhan; Zhang, Aihua

    2016-02-01

    Arsenic is well established as a human carcinogen, but the molecular mechanisms leading to arsenic-induced carcinogenesis are complex and elusive. It is also not known if lncRNAs are involved in arsenic-induced liver carcinogenesis. We have found that MALAT1, a non-coding RNA, is over-expressed in the sera of people exposed to arsenite and in hepatocellular carcinomas (HCCs), and MALAT1 has a close relation with the clinicopathological characteristics of HCC. In addition, hypoxia-inducible factor (HIF)-2α is up-regulated in HCCs, and MALAT1 and HIF-2α have a positive correlation in HCC tissues. During the malignant transformation of human hepatic epithelial (L-02) cells induced by a low concentration (2.0 μM) of arsenite, MALAT1 and HIF-2α are increased. In addition, arsenite-induced MALAT1 causes disassociation of the von Hippel-Lindau (VHL) protein from HIF-2α, therefore, alleviating VHL-mediated HIF-2α ubiquitination, which causes HIF-2α accumulation. In turn, HIF-2α transcriptionally regulates MALAT1, thus forming a positive feedback loop to ensure expression of arsenite-induced MALAT1 and HIF-2α, which are involved in malignant transformation. Moreover, MALAT1 and HIF-2α promote the invasive and metastatic capacities of arsenite-induced transformed L-02 cells and in HCC-LM3 cells. The capacities of MALAT1 and HIF-2α to promote tumor growth are validated in mouse xenograft models. In mice, arsenite induces an inflammatory response, and MALAT1 and HIF-2α are over-expressed. Together, these findings suggest that the MALAT1/HIF-2α feedback loop is involved in regulation of arsenite-induced malignant transformation. Our results not only confirm a novel mechanism involving reciprocal regulation between MALAT1 and HIF-2α, but also expand the understanding of the carcinogenic potential of arsenite. PMID:26735578

  19. [Interleukin-1-mediated diseases].

    PubMed

    Holzinger, D; Becker, H; Jacobi, A M

    2013-04-01

    Interleukin-1 (IL-1)-mediated diseases are caused by an inappropriately high production and release of IL-1 beta which results in a multitude of symptoms, e.g. arthritis, exanthema, conjunctivitis, serositis, fever and loss of hearing. If IL-1-mediated diseases remain unrecognized or are recognized and treated too late, long-term complications, such as amyloidosis may occur. In recent years the diagnostic and therapeutic options with respect to IL-1-mediated diseases have drastically improved. These diseases often manifesting in childhood can now be treated with monoclonal antibodies against IL-1 or with IL-1 receptor antagonists. Increased IL-1 secretion does not only play a role in relatively rare hereditary diseases, such as cryopyrin-associated periodic fever syndromes or familial Mediterranean fever but also in widespread diseases, such as gout or type 2 diabetes. This article will focus on pathogenic, diagnostic and therapeutic aspects of IL-1-mediated inflammatory diseases. PMID:23460390

  20. Metadata based mediator generation

    SciTech Connect

    Critchlow, T

    1998-03-01

    Mediators are a critical component of any data warehouse, particularly one utilizing partially materialized views; they transform data from its source format to the warehouse representation while resolving semantic and syntactic conflicts. The close relationship between mediators and databases, requires a mediator to be updated whenever an associated schema is modified. This maintenance may be a significant undertaking if a warehouse integrates several dynamic data sources. However, failure to quickly perform these updates significantly reduces the reliability of the warehouse because queries do not have access to the m current data. This may result in incorrect or misleading responses, and reduce user confidence in the warehouse. This paper describes a metadata framework, and associated software designed to automate a significant portion of the mediator generation task and thereby reduce the effort involved in adapting the schema changes. By allowing the DBA to concentrate on identifying the modifications at a high level, instead of reprogramming the mediator, turnaround time is reduced and warehouse reliability is improved.

  1. [Immune-mediated neuropathies].

    PubMed

    Stoll, G; Reiners, K

    2016-08-01

    The Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are the most common immune-mediated polyneuropathies, which can show variable clinical and electrophysiological manifestations. Rarer immune-mediated neuropathies encompass paraproteinemic neuropathies (PPN), multifocal motor neuropathy (MMN) and vasculitic neuropathies. The diagnosis usually relies on the history of symptom evolution, distribution of nerve dysfunction and particularly on characteristic features in nerve conduction studies, aided by cerebrospinal fluid (CSF) examination and nerve biopsy findings. The therapeutic toolbox encompasses corticosteroids, immunoglobulins and plasmapheresis often accompanied by long-term immunosuppression. It is important to note that immune-mediated neuropathies selectively respond to treatment and contraindications need to be considered. Despite treatment a considerable number of patients suffer from permanent neurological deficits. PMID:27474733

  2. Immunologically mediated oral diseases.

    PubMed

    Jimson, Sudha; Balachader, N; Anita, N; Babu, R

    2015-04-01

    Immune mediated diseases of oral cavity are uncommon. The lesions may be self-limiting and undergo remission spontaneously. Among the immune mediated oral lesions the most important are lichen planus, pemphigus, erythema multiformi, epidermolysis bullosa, systemic lupus erythematosis. Cellular and humoral mediated immunity play a major role directed against epithelial and connective tissue in chronic and recurrent patterns. Confirmatory diagnosis can be made by biopsy, direct and indirect immunoflouresence, immune precipitation and immunoblotting. Therapeutic agents should be selected after thorough evaluation of immune status through a variety of tests and after determining any aggravating or provoking factors. Early and appropriate diagnosis is important for proper treatment planning contributing to better prognosis and better quality of life of patient. PMID:26015713

  3. Immunologically Mediated Dementias

    PubMed Central

    Rosenbloom, Michael H.; Smith, Sallie; Akdal, Gulden; Geschwind, Michael D.

    2009-01-01

    Although most dementias are due to neurodegenerative or vascular disease, it is important to diagnose immunologically mediated dementias quickly because they can be both rapidly progressive and readily treatable. They usually affect function of limbic and cortical structures, but subcortical involvement can also occur. Because of the variety of symptoms and the rapid course, these dementias present a particular challenge to the clinician and may require evaluation and intervention in the inpatient setting. Diagnostic workup typically reveals evidence of an autoimmune process and, in some cases, cancer. In contrast to the neurodegenerative processes, many of the immunologically mediated dementias respond to immunomodulatory therapy. PMID:19664365

  4. Mediator-nucleosome interaction.

    PubMed

    Lorch, Y; Beve, J; Gustafsson, C M; Myers, L C; Kornberg, R D

    2000-07-01

    Mediator, a multiprotein complex involved in the regulation of RNA polymerase II transcription, binds to nucleosomes and acetylates histones. Three lines of evidence identify the Nut1 subunit of Mediator as responsible for the histone acetyltransferase (HAT) activity. An "in-gel" HAT assay reveals a single band of the appropriate size. Sequence alignment shows significant similarity of Nut1 to the GCN5-related N-acetyltransferase superfamily. Finally, recombinant Nut1 exhibits HAT activity in an in-gel assay. PMID:10949041

  5. Hypercharged anomaly mediation.

    PubMed

    Dermísek, Radovan; Verlinde, Herman; Wang, Lian-Tao

    2008-04-01

    We show that, in string models with the minimal supersymmetric standard model residing on D-branes, the bino mass can be generated in a geometrically separated hidden sector. Hypercharge mediation thus naturally teams up with anomaly mediation. The mixed scenario predicts a distinctive yet viable superpartner spectrum, provided that the ratio alpha between the bino and gravitino mass lies in the range 0.05 < or = |alpha| < or = 0.25 and m(3/2) > or = 35 TeV. We summarize some of the experimental signatures of this scenario. PMID:18517937

  6. Carrier-mediated electrodialysis.

    PubMed

    Hansen, Steven P; Fyles, Thomas M

    2011-06-14

    Supported liquid membranes containing valinomycin or a calix[4]arene carrier can support electrodialysis under an imposed transmembrane potential. Under optimal conditions both transmembrane flux and carrier-based cation selectivity are enhanced relative to simple dialysis mediated by the same carriers. PMID:21308126

  7. Bradykinin-mediated angioedema.

    PubMed

    Obtułowicz, Krystyna

    2016-02-01

    Angioedema and urticaria often constitute a challenge in daily clinical practice. They may either co- -occur or present as independent conditions. They are characterized by a complex pathomechanism, and their symptoms may be triggered by diverse factors. These differences are crucial for developing a successful treatment regimen. Both conditions may have an allergic origin (immunoglobulin [Ig] E and non-IgE-related), usually induced by histamine, or a nonallergic one, such as bradykinin-mediated angioedema in patients with C1 inhibitor (C1-INH) deficiency or angioedema induced by certain drugs (eg, angiotensin-converting enzyme inhibitors). Currently, we distinguish 5 types of nonallergic angioedema: hereditary angioedema (HAE) due to C1-INH deficiency, acquired angioedema (AAE), and angioedema induced by the renin-angiotensin-aldosterone system, all of which are mediated by bradykinin, as well as pseudoallergic angioedema and idiopathic angioedema. Bradykinin-mediated angioedema (eg, laryngeal angioedema) may be life-threatening because of resistance to corticosteroids and antihistamine drugs. C1-INH concentrates are the drugs of choice in the treatment of HAE and AAE. In recent years, some new drugs have been introduced in the treatment of bradykinin-mediated angioedema, such as bradykinin B2-receptor antagonist, icatibant, and kallikrein inhibitor, ecallantide, which allow to improve treatment outcomes. PMID:26842379

  8. Phenomenologically Investigating Mediated "Nature"

    ERIC Educational Resources Information Center

    Adams, Tony E.

    2005-01-01

    During the summer of 2001 I worked as a bartender in Wyoming, two miles east of Yellowstone National Park. This opportunity provided me with unique experiences of "the wilderness" and as a result, allowed me to become aware of intricacies of living within a primarily simulated and mass mediated culture, i.e., the United States. Following tenets of…

  9. Axionic mirage mediation

    SciTech Connect

    Nakamura, Shuntaro; Okumura, Ken-ichi; Yamaguchi, Masahiro

    2008-06-01

    Although mirage mediation is one of the most plausible mediation mechanisms of supersymmetry breaking, it suffers from two crucial problems. One is the {mu}/B{mu} problem, and the second is the cosmological one. The former stems from the fact that the B parameter tends to be comparable with the gravitino mass, which is 2 orders of magnitude larger than the other soft masses. The latter problem is caused by the decay of the modulus whose branching ratio into the gravitino pair is sizable. In this paper, we propose a model of mirage mediation, in which Peccei-Quinn symmetry is incorporated. In this axionic mirage mediation, it is shown that the Peccei-Quinn symmetry breaking scale is dynamically determined around 10{sup 10} GeV to 10{sup 12} GeV due to the supersymmetry breaking effects, and the {mu} problem can be solved naturally. Furthermore, in our model, the lightest supersymmetric particle (LSP) is the axino, that is, the superpartner of the axion. The overabundance of the LSPs due to decays of the modulus/gravitino, which is the most serious cosmological difficulty in the mirage mediation, can be avoided if the axino is sufficiently light. The next-LSPs (NLSPs) produced by the gravitino decay eventually decay into the axino LSPs, yielding the dominant component of the axinos remaining today. It is shown that the axino with a mass of O(100) MeV is naturally realized, which can constitute the dark matter of the Universe, with a free-streaming length of the order of 0.1 Mpc. The saxion, the real scalar component of the axion supermultiplet, can also be cosmologically harmless due to the dilution of the modulus decay. The lifetime of the NLSP is relatively long, but much shorter than 1 sec, when the big-bang nucleosynthesis commences. The decay of the NLSP would provide intriguing collider signatures.

  10. Mediation analysis with multiple versions of the mediator

    PubMed Central

    VanderWeele, Tyler J.

    2013-01-01

    The causal inference literature has provided definitions of direct and indirect effects based on counterfactuals that generalize the approach found in the social science literature. However, these definitions presuppose well defined hypothetical interventions on the mediator. In many settings there may be multiple ways to fix the mediator to a particular value and these different hypothetical interventions may have very different implications for the outcome of interest. In this paper we consider mediation analysis when multiple versions of the mediator are present. Specifically, we consider the problem of attempting to decompose a total effect of an exposure on an outcome into the portion through the intermediate and the portion through other pathways. We consider the setting in which there are multiple versions of the mediator but the investigator only has access to data on the particular measurement, not which version of the mediator may have brought that value about. We show that the quantity that is estimated as a natural indirect effect using only the available data does indeed have an interpretation as a particular type of mediated effect; however, the quantity estimated as a natural direct effect in fact captures both a true direct effect and an effect of the exposure on the outcome mediated through the effect of the version of the mediator that is not captured by the mediator measurement. The results are illustrated using two examples from the literature, one in which the versions of the mediator are unknown and another in which the mediator itself has been dichotomized. PMID:22475830

  11. Current Directions in Mediation Analysis

    PubMed Central

    MacKinnon, David P.; Fairchild, Amanda J.

    2010-01-01

    Mediating variables continue to play an important role in psychological theory and research. A mediating variable transmits the effect of an antecedent variable on to a dependent variable, thereby providing more detailed understanding of relations among variables. Methods to assess mediation have been an active area of research for the last two decades. This paper describes the current state of methods to investigate mediating variables. PMID:20157637

  12. [Anorexia and corporal mediations].

    PubMed

    Bureau, Hélène; Moro, Marie Rose

    2013-01-01

    The body, the central point of expression of the anorexic symptom, is an important therapeutic lever.The young anorexic girl protects herself through corporal hypertonicity. This tension is consistent with her fears of seeing her body becoming that of an adult and to feel emotions and sensations with too much force. Corporal mediation consists in helping the young girls get to grips with this body. PMID:23923454

  13. An Alternative Framework for Defining Mediation.

    ERIC Educational Resources Information Center

    Collins, Linda M.; Graham, John W.; Flaherty, Brian P.

    1998-01-01

    Presents an alternative framework for evaluating mediated relationships. The distinguishing feature of mediation is that mediation involves a chain reaction. The definition presented emphasizes the intra-individual, time-ordered nature of mediation. (SLD)

  14. Merlin Mediation System

    Energy Science and Technology Software Center (ESTSC)

    2001-10-16

    Merlin Mediation System (a.k.a., Merlin) is a set of reusable software components that provide seamless integration of information contained in multiple, heterogeneous data sources located across many computers. These software components utilize a combination of mediator and expert system technologies to provide intelligence for understanding and integrating data. Merlin provides a virtual database independent of operating systems, platforms, and user applications. Merlin in an implementation of "intelligent middleware" that solves data access and integration issues.more » Merlin resides between user applications and their independent data sources. a user application may be invoked via a Web browser or reside on an individual's workstation. The data sources can reside on multiple separate heterogeneous computer polatforms and may be recorded in a variety of formats (e.g., relational databases, flat files, object-oriented databases). Merlin creates a "virtual object database" so that the user application sees the data retrieved from the various sources as though it wre returned from a single, integrated database. In addition, Merlin provides advanced data instance integration capabilities such as object unification and fusion, abstraction, aggregation, and data and schema translations. It is important to note that Merlin is not bound to any single user application nor to any specific data source. Merlin's software components utilize a combination of mediator and expert system technologies to assure their adaptability for use by various disciplines. These software components accept domain-specific details (e.g., schema, mappings, expert system rules) as data from a "knowledge base". This enables the same software to be used for a variety of domains and user applications with no source code modifications or recompilations required.« less

  15. Immunologically mediated abortion (IMA).

    PubMed

    Giacomucci, E; Bulletti, C; Polli, V; Prefetto, R A; Flamigni, C

    1994-06-01

    Roughly 20% of all clinical pregnancies evolve into "spontaneous abortions". The causes of spontaneous abortion have been determined in under 60% of the total and comprise genetic, infectious, hormonal and immunological factors. In some cases the immune tolerance mechanism may be impaired and the foetus immunologically rejected (IMA, immunologically mediated abortion). The immunological mechanism implicated depends on the time in which pregnancy loss takes place. During preimplantation and up to the end of implantation (13th day) the cell-mediated immune mechanism (potential alloimmune etiologies) is responsible for early abortion. This mechanism involves immunocompetent decidual cells (eGL, endometrial granulated lymphocytes) already present during pre-decidualization (late luteal phase) and their production of soluble factors or cytokines. Once the implantation process is over, after blastocyst penetration of the stroma and the decidual reaction of uterine tissue, IMA could be caused by cell-mediated and humoral mechanism (anti-paternal cytotoxic antibodies or autoantibody etiology), by the production of paternal anti major histocompatibility complex antibodies, or even by an autoimmune disorder leading to the production of autoantibodies (antiphospholipid antibodies, antinuclear antibodies or polyclonal B cell activation). The diagnostic work-up adopted to select IMA patients is crucial and includes primary (karyotype of both partners, toxo-test, hysterosalpingography, endometrial biopsy, thyroid function tests, serum hprolactin, luteal phase dating) and secondary (full hemochromocytometric test, search for LE cells, lupus anticoagulant, anticardiolipin, antinuclear antibodies, Rheumatoid factor, blood complement VDRL) investigations. Therapeutical approaches vary. If autoimmune disorders are demonstrated therapies with different combinations of corticosteroids, aspirin and heparin or intravenous immunoglobulin are administered. Otherwise, therapy with paternal

  16. Copper mediated carbometalation reactions.

    PubMed

    Müller, D S; Marek, I

    2016-08-01

    Since the first discovery of carbocupration of alkynes in the 1970s a tremendous amount of research has been carried out in this field. The exceptionally high selectivities obtained attribute to the great synthetic value of carbocupration reactions. This tutorial review will present the most important features of carbocupration of alkynes and highlight the most relevant reviews. Then a comprehensive review of copper mediated carbometalation of cyclopropenes will follow. The latter method has received much attention over the last decade as it allows the highly selective construction of poly-substituted cyclopropanes which can be transformed into acyclic derivatives bearing one or multiple tertiary or quaternary carbon stereocenters. PMID:26808300

  17. Molecular Mediators of Angiogenesis

    PubMed Central

    Ucuzian, Areck A.; Gassman, Andrew A.; East, Andrea T.; Greisler, Howard P.

    2010-01-01

    Angiogenesis, or the formation of new blood vessels from the preexisting vasculature, is a key component in numerous physiologic and pathologic responses and has broad impact in many medical and surgical specialties. In this review, we discuss the key cellular steps which lead to the neovascularization of tissues, and highlight the main molecular mechanisms and mediators in this process. We include discussions on proteolytic enzymes, cell/matrix interactions, pertinent cell signaling pathways, and end with a survey of the mechanisms which lead to the stabilization and maturation of neovasculatures. PMID:20061852

  18. Holographic Gauge Mediation

    SciTech Connect

    Benini, Francesco; Dymarsky, Anatoly; Franco, Sebastian; Kachru, Shamit; Simic, Dusan; Verlinde, Herman; /Princeton, Inst. Advanced Study

    2009-06-19

    We discuss gravitational backgrounds where supersymmetry is broken at the end of a warped throat, and the SUSY-breaking is transmitted to the Standard Model via gauginos which live in (part of) the bulk of the throat geometry. We find that the leading effect arises from splittings of certain 'messenger mesons,' which are adjoint KK-modes of the D-branes supporting the Standard Model gauge group. This picture is a gravity dual of a strongly coupled field theory where SUSY is broken in a hidden sector and transmitted to the Standard Model via a relative of semi-direct gauge mediation.

  19. Ferrofluid mediated nanocytometry.

    PubMed

    Kose, Ayse Rezzan; Koser, Hur

    2012-01-01

    We present a low-cost, flow-through nanocytometer that utilizes a colloidal suspension of non-functionalized magnetic nanoparticles for label-free manipulation and separation of microparticles. Our size-based separation is mediated by angular momentum transfer from magnetically excited ferrofluid particles to microparticles. The nanocytometer is capable of rapidly sorting and focusing two or more species, with up to 99% separation efficiency and a throughput of 3 × 10(4) particles/s per mm(2) of channel cross-section. The device is readily scalable and applicable to live cell sorting with biocompatible ferrofluids, offering competitive cytometer performance in a simple and inexpensive package. PMID:22076536

  20. Magnetically mediated thermoacoustic imaging

    NASA Astrophysics Data System (ADS)

    Feng, Xiaohua; Gao, Fei; Zheng, Yuanjin

    2014-03-01

    In this paper, alternating magnetic field is explored for inducing thermoacoustic effect on dielectric objects. Termed as magnetically mediated thermo-acoustic (MMTA) effect that provides a contrast in conductivity, this approach employs magnetic resonance for delivering energy to a desired location by applying a large transient current at radio frequency below 50MHz to a compact magnetically resonant coil. The alternating magnetic field induces large electric field inside conductive objects, which then undergoes joule heating and emanates acoustic signal thermo-elastically. The magnetic mediation approach with low radio frequency can potentially provide deeper penetration than microwave radiation due to the non-magnetic nature of human body and therefore extend thermoacoustic imaging to deep laid organs. Both incoherent time domain method that applies a pulsed radio frequency current and coherent frequency domain approach that employs a linear chirp signal to modulate the envelop of the current are discussed. Owing to the coherent processing nature, the latter approach is capable of achieving much better signal to noise ratio and therefore potential for portable imaging system. Phantom experiments are carried out to demonstrate the signal generation together with some preliminary imaging results. Ex-vivo tissue studies are also investigated.

  1. Interpreter-mediated dentistry.

    PubMed

    Bridges, Susan; Drew, Paul; Zayts, Olga; McGrath, Colman; Yiu, Cynthia K Y; Wong, H M; Au, T K F

    2015-05-01

    The global movements of healthcare professionals and patient populations have increased the complexities of medical interactions at the point of service. This study examines interpreter mediated talk in cross-cultural general dentistry in Hong Kong where assisting para-professionals, in this case bilingual or multilingual Dental Surgery Assistants (DSAs), perform the dual capabilities of clinical assistant and interpreter. An initial language use survey was conducted with Polyclinic DSAs (n = 41) using a logbook approach to provide self-report data on language use in clinics. Frequencies of mean scores using a 10-point visual analogue scale (VAS) indicated that the majority of DSAs spoke mainly Cantonese in clinics and interpreted for postgraduates and professors. Conversation Analysis (CA) examined recipient design across a corpus (n = 23) of video-recorded review consultations between non-Cantonese speaking expatriate dentists and their Cantonese L1 patients. Three patterns of mediated interpreting indicated were: dentist designated expansions; dentist initiated interpretations; and assistant initiated interpretations to both the dentist and patient. The third, rather than being perceived as negative, was found to be framed either in response to patient difficulties or within the specific task routines of general dentistry. The findings illustrate trends in dentistry towards personalized care and patient empowerment as a reaction to product delivery approaches to patient management. Implications are indicated for both treatment adherence and the education of dental professionals. PMID:25828074

  2. Enable, mediate, advocate.

    PubMed

    Saan, Hans; Wise, Marilyn

    2011-12-01

    The authors of the Ottawa Charter selected the words enable, mediate and advocate to describe the core activities in what was, in 1986, the new Public Health. This article considers these concepts and the values and ideas upon which they were based. We discuss their relevance in the current context within which health promotion is being conducted, and discuss the implications of changes in the health agenda, media and globalization for practice. We consider developments within health promotion since 1986: its central role in policy rhetoric, the increasing understanding of complexities and the interlinkage with many other societal processes. So the three core activities are reviewed: they still fit well with the main health promotion challenges, but should be refreshed by new ideas and values. As the role of health promotion in the political arena has grown we have become part of the policy establishment and that is a mixed blessing. Making way for community advocates is now our challenge. Enabling requires greater sensitivity to power relations involved and an understanding of the role of health literacy. Mediating keeps its central role as it bridges vital interests of parties. We conclude that these core concepts in the Ottawa Charter need no serious revision. There are, however, lessons from the last 25 years that point to ways to address present and future challenges with greater sensitivity and effectiveness. We invite the next generation to avoid canonizing this text: as is true of every heritage, the heirs must decide on its use. PMID:22080073

  3. Hexokinase mediates stomatal closure.

    PubMed

    Kelly, Gilor; Moshelion, Menachem; David-Schwartz, Rakefet; Halperin, Ofer; Wallach, Rony; Attia, Ziv; Belausov, Eduard; Granot, David

    2013-09-01

    Stomata, composed of two guard cells, are the gates whose controlled movement allows the plant to balance the demand for CO2 for photosynthesis with the loss of water through transpiration. Increased guard-cell osmolarity leads to the opening of the stomata and decreased osmolarity causes the stomata to close. The role of sugars in the regulation of stomata is not yet clear. In this study, we examined the role of hexokinase (HXK), a sugar-phosphorylating enzyme involved in sugar-sensing, in guard cells and its effect on stomatal aperture. We show here that increased expression of HXK in guard cells accelerates stomatal closure. We further show that this closure is induced by sugar and is mediated by abscisic acid. These findings support the existence of a feedback-inhibition mechanism that is mediated by a product of photosynthesis, namely sucrose. When the rate of sucrose production exceeds the rate at which sucrose is loaded into the phloem, the surplus sucrose is carried toward the stomata by the transpiration stream and stimulates stomatal closure via HXK, thereby preventing the loss of precious water. PMID:23738737

  4. Protein mediated membrane adhesion

    NASA Astrophysics Data System (ADS)

    Carlson, Andreas; Mahadevan, L.

    2015-05-01

    Adhesion in the context of mechanical attachment, signaling, and movement in cellular dynamics is mediated by the kinetic interactions between membrane-embedded proteins in an aqueous environment. Here, we present a minimal theoretical framework for the dynamics of membrane adhesion that accounts for the kinetics of protein binding, the elastic deformation of the membrane, and the hydrodynamics of squeeze flow in the membrane gap. We analyze the resulting equations using scaling estimates to characterize the spatiotemporal features of the adhesive patterning and corroborate them using numerical simulations. In addition to characterizing aspects of cellular dynamics, our results might also be applicable to a range of phenomena in physical chemistry and materials science where flow, deformation, and kinetics are coupled to each other in slender geometries.

  5. Colistin-mediated neurotoxicity

    PubMed Central

    Wadia, Subeer; Tran, Betty

    2014-01-01

    We describe a 51-year-old man who developed renal and neural toxicity after the administration of colistin. He developed respiratory apnoea, neuromuscular blockade and severe comatose encephalopathy with the lack of brainstem reflexes. After discontinuation of the antibiotic, he made a prompt recovery to his baseline neurological function. The case illustrates the importance of recognising the toxicities associated with colistin. Although recent literature details its nephrotoxicity, current data have been discordant with the rare cases of respiratory apnoea or neuromuscular blockade once cited over 30 years ago. Additionally, no cases have ever described the profound encephalopathy with lack of brainstem function described here. The awareness of colistin's potentially fatal effects must be kept in mind when administering this antibiotic. Vigilance of the encephalopathic picture can also facilitate the diagnosis of colistin-mediated neurotoxicity in a patient with altered mental status of otherwise unknown aetiology. PMID:25199193

  6. Symbiont-mediated protection

    PubMed Central

    Haine, Eleanor R

    2007-01-01

    Despite the fact that all vertically transmitted symbionts sequester resources from their hosts and are therefore costly to maintain, there is an extraordinary diversity of them in invertebrates. Some spread through host populations by providing their hosts with fitness benefits or by manipulating host sex ratio, but some do not: their maintenance in host lineages remains an enigma. In this review, I explore the evolutionary ecology of vertically transmitted symbionts and their impact on host resistance, and provide an overview of the evidence for the three-way interactions between these symbionts, natural enemies and invertebrate hosts. A number of recent empirical and theoretical studies suggest that vertically transmitted symbionts may protect their hosts from pathogens. If this ‘symbiont-mediated protection’ is widespread, it is likely that vertically transmitted symbionts contribute significantly to variation in measures of invertebrate resistance to natural enemies. PMID:18055391

  7. Microbially mediated phosphine emission.

    PubMed

    Roels, Joris; Huyghe, Gwen; Verstraete, Willy

    2005-02-15

    There is still a lot of controversy in literature concerning the question whether a biochemical system exists enabling micro-organisms to reduce phosphate to phosphine gas. The search for so-called 'de novo synthesised' phosphine is complicated by the fact that soils, slurries, sludges, etc., which are often used as inocula, usually contain matrix bound phosphine (MBP). Matrix bound phosphine is a general term used to indicate non-gaseous reduced phosphorus compounds that are transformed into phosphine gas upon reaction with bases or acids. A study was carried out to compare the different digestion methods, used to transform matrix bound phosphine into phosphine gas. It was demonstrated that caustic and acidic digestion methods should be used to measure the matrix bound phosphine of the inoculum prior to inoculation to avoid false positive results concerning de novo synthesis. This is especially true if anthropogenically influenced inocula possibly containing minute steel or aluminium particles are used. The comparative study on different digestion methods also revealed that the fraction of phosphorus in mild steel, converted to phosphine during acid corrosion depended on the temperature. Following these preliminary studies, anaerobic growth experiments were set up using different inocula and media to study the emission of phosphine gas. Phosphine was detected in the headspace gases and its quantity and timeframe of emission depended on the medium composition, suggesting microbially mediated formation of the gas. The amount of phosphine emitted during the growth experiments never exceeded the bound phosphine present in inocula, prior to inoculation. Hence, de novo synthesis of phosphine from phosphate could not be demonstrated. Yet, microbially mediated conversion to phosphine of hitherto unknown reduced phosphorus compounds in the inoculum was evidenced. PMID:15713333

  8. Mediation and managed care.

    PubMed

    Dubler, N N

    1998-03-01

    Managed care has not only intensified existing conflicts between patient and provider, it has, by its very nature, changed the shape and scope of the healthcare enterprise and introduced an entirely new set of disputes. The decision-making dynamics have been altered, and the cast of players has expanded. Traditionally, the therapeutic interaction took place between the physician and the patient although it occasionally included the patient's family. Whatever obligations existed, such as fidelity, confidentiality, and standard of care, they bound only those parties. Now, as the managed care organization has interposed itself between the patient and the physician, the dyad has become a triad. The power balance has shifted, and a new set of rights and responsibilities now flows between and among the players, each of whom has interests that may or may not coincide. This article argues that, because of its cost containment origins and orientation, managed care increases the likelihood that misunderstandings, disagreements and disputes will develop into full-blown conflicts. If managed care is to succeed financially and operate with integrity, it must develop techniques for managing the increasing conflicts that arise inevitably between and among the organizations, physicians, and patients. It is clear that the voice of the patient needs to be strengthened within the new complex decision-making, review, and appeal procedures. Mediation is the most appropriate method of dispute resolution for the managed care setting because it balances the disparities in power endemic to the bureaucratization of medicine and refocuses the interests of the various parties. Using bioethics consultation as a model for dispute mediation provides a set of principles and guideline tasks that can be applied effectively to managed care. PMID:9514387

  9. Moral Functioning as Mediated Action

    ERIC Educational Resources Information Center

    Tappan, Mark B.

    2006-01-01

    In this paper, I argue that it is quite useful, both theoretically and empirically, to adopt a socio-cultural approach to the study of moral development. This entails viewing "moral functioning" as a form of mediated action, and moral development as the process by which persons gradually appropriate a variety of "moral mediational means". Mediated…

  10. 29 CFR 1203.1 - Mediation services.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 29 Labor 4 2013-07-01 2013-07-01 false Mediation services. 1203.1 Section 1203.1 Labor Regulations Relating to Labor (Continued) NATIONAL MEDIATION BOARD APPLICATIONS FOR SERVICE § 1203.1 Mediation services. Applications for the mediation services of the National Mediation Board under section 5, First, of the...

  11. 29 CFR 1203.1 - Mediation services.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 4 2011-07-01 2011-07-01 false Mediation services. 1203.1 Section 1203.1 Labor Regulations Relating to Labor (Continued) NATIONAL MEDIATION BOARD APPLICATIONS FOR SERVICE § 1203.1 Mediation services. Applications for the mediation services of the National Mediation Board under section 5, First, of the...

  12. 22 CFR 143.33 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Mediation. 143.33 Section 143.33 Foreign... Mediation. (a) Referral of complaints for mediation. The agency will refer to the Federal Mediation and... participate in the mediation process to the extent necessary to reach an agreement or make an...

  13. 29 CFR 1202.1 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false Mediation. 1202.1 Section 1202.1 Labor Regulations Relating to Labor (Continued) NATIONAL MEDIATION BOARD RULES OF PROCEDURE § 1202.1 Mediation. The mediation..., or where conferences are refused. The National Mediation Board may proffer its services in case...

  14. 29 CFR 1203.1 - Mediation services.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false Mediation services. 1203.1 Section 1203.1 Labor Regulations Relating to Labor (Continued) NATIONAL MEDIATION BOARD APPLICATIONS FOR SERVICE § 1203.1 Mediation services. Applications for the mediation services of the National Mediation Board under section 5, First, of the...

  15. 32 CFR 776.38 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 5 2010-07-01 2010-07-01 false Mediation. 776.38 Section 776.38 National... Professional Conduct § 776.38 Mediation. (a) Mediation: (1) A covered attorney may act as a mediator between... mediation, including the advantages and risks involved, and the effect on the...

  16. 29 CFR 35.32 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Mediation. (a) Referral to mediation. CRC will promptly refer to the Federal Mediation and Conciliation Service or the mediation agency designated by the Secretary of Health and Human Services under 45 CFR part... 29 Labor 1 2010-07-01 2010-07-01 true Mediation. 35.32 Section 35.32 Labor Office of the...

  17. 34 CFR 81.13 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false Mediation. 81.13 Section 81.13 Education Office of the... Mediation. (a) Voluntary mediation is available for proceedings that are pending before the OALJ. (b) A... mediation by filing a motion with the ALJ assigned to the case. The OALJ arranges for a mediator if...

  18. 24 CFR 3288.35 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 5 2010-04-01 2010-04-01 false Mediation. 3288.35 Section 3288.35...-Administered States § 3288.35 Mediation. (a) Mediator. The dispute resolution provider will provide for the... identifies any other party that should be included in the mediation, the mediator will contact the...

  19. Microbially mediated mineral carbonation

    NASA Astrophysics Data System (ADS)

    Power, I. M.; Wilson, S. A.; Dipple, G. M.; Southam, G.

    2010-12-01

    Mineral carbonation involves silicate dissolution and carbonate precipitation, which are both natural processes that microorganisms are able to mediate in near surface environments (Ferris et al., 1994; Eq. 1). (Ca,Mg)SiO3 + 2H2CO3 + H2O → (Ca,Mg)CO3 + H2O + H4SiO4 + O2 (1) Cyanobacteria are photoautotrophs with cell surface characteristics and metabolic processes involving inorganic carbon that can induce carbonate precipitation. This occurs partly by concentrating cations within their net-negative cell envelope and through the alkalinization of their microenvironment (Thompson & Ferris, 1990). Regions with mafic and ultramafic bedrock, such as near Atlin, British Columbia, Canada, represent the best potential sources of feedstocks for mineral carbonation. The hydromagnesite playas near Atlin are a natural biogeochemical model for the carbonation of magnesium silicate minerals (Power et al., 2009). Field-based studies at Atlin and corroborating laboratory experiments demonstrate the ability of a microbial consortium dominated by filamentous cyanobacteria to induce the precipitation of carbonate minerals. Phototrophic microbes, such as cyanobacteria, have been proposed as a means for producing biodiesel and other value added products because of their efficiency as solar collectors and low requirement for valuable, cultivable land in comparison to crops (Dismukes et al., 2008). Carbonate precipitation and biomass production could be facilitated using specifically designed ponds to collect waters rich in dissolved cations (e.g., Mg2+ and Ca2+), which would allow for evapoconcentration and provide an appropriate environment for growth of cyanobacteria. Microbially mediated carbonate precipitation does not require large quantities of energy or chemicals needed for industrial systems that have been proposed for rapid carbon capture and storage via mineral carbonation (e.g., Lackner et al., 1995). Therefore, this biogeochemical approach may represent a readily

  20. Ultrasound mediated gene transfection

    NASA Astrophysics Data System (ADS)

    Williamson, Rene G.; Apfel, Robert E.; Brandsma, Janet L.

    2002-05-01

    Gene therapy is a promising modality for the treatment of a variety of human diseases both inherited and acquired, such as cystic fibrosis and cancer. The lack of an effective, safe method for the delivery of foreign genes into the cells, a process known as transfection, limits this effort. Ultrasound mediated gene transfection is an attractive method for gene delivery since it is a noninvasive technique, does not introduce any viral particles into the host and can offer very good temporal and spatial control. Previous investigators have shown that sonication increases transfection efficiency with and without ultrasound contrast agents. The mechanism is believed to be via a cavitation process where collapsing bubble nuclei permeabilize the cell membrane leading to increased DNA transfer. The research is focused on the use of pulsed wave high frequency focused ultrasound to transfect DNA into mammalian cells in vitro and in vivo. A better understanding of the mechanism behind the transfection process is also sought. A summary of some in vitro results to date will be presented, which includes the design of a sonication chamber that allows us to model the in vivo case more accurately.

  1. An Alternative Framework for Defining Mediation.

    PubMed

    Collins, L M; Graham, J J; Flaherty, B P

    1998-04-01

    The present article provides an alternative framework for evaluating mediated relationships. From this perspective. a mediated process is a chain reaction, beginning with an independent variable that affects a mediator that in turn affects an outcome. The definition of mediation offered here, presented for stage sequences, states three conditions for establishing mediation: (a) the independent variable affects the probability of the sequence no mediator to mediator to outcome; (b) the independent variable affects the probability of a transition into the mediator stage; (c) the mediator affects the probability of a transition into the outcome stage at every level of the independent variable. This definition of mediation is compared and contrasted with the well-known definition of mediation for continuous variables discussed in Baron and Kenny (1986), Judd and Kenny (1981), and Kenny, Kashy, and Bolger (1997). The definition presented in this article emphasizes the intraindividual, time-ordered nature of mediation. PMID:26771887

  2. 44 CFR 7.942 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... participate in the mediation process to the extent necessary to reach an agreement or for the mediator to make... reach an agreement, the mediator shall prepare a written statement of the agreement and have...

  3. Arsenite promotes apoptosis and dysfunction in microvascular endothelial cells via an alteration of intracellular calcium homeostasis.

    PubMed

    Suriyo, Tawit; Watcharasit, Piyajit; Thiantanawat, Apinya; Satayavivad, Jutamaad

    2012-04-01

    Vascular endothelium has been considered as a target for arsenic-induced cardiovascular toxicity. The present study demonstrated that arsenite caused slow and sustained elevation of intracellular free calcium levels ([Ca2+]i) in HMEC-1, a human microvessel-derived endothelial cell line, in a concentration-dependent manner. Pretreatment with U-73122 (a specific PLC inhibitor) or 2-APB (a specific IP3 receptor antagonist) attenuated this effect, suggesting that PLC/IP3 signaling cascade is involved in arsenite-induced elevation of [Ca2+]i. Cytotoxic concentrations of arsenite (5 and 10 μM) significantly enhanced endothelial nitric oxide synthase (eNOS) phosphorylation, nitric oxide (NO) production and apoptosis after 24-h exposure. Additionally, 2-APB attenuated eNOS phosphorylation and apoptosis induced by arsenite, indicating that Ca2+ -mediated eNOS activation participates in arsenite-induced endothelial cell apoptosis. Moreover, we also found that non-apoptotic concentrations of arsenite (0.5 and 1 μM) dramatically mitigated thrombin-induced rapid transient rise of [Ca2+]i, eNOS phosphorylation and NO production, suggesting functional disruption of endothelial by arsenite, and these effects occurred without an alteration of PLC-β1 and thrombin receptor levels. Altogether, the results reveal that arsenite induces apoptotic cell death and endothelial dysfunction as indicated by the reduction of thrombin responses, particularly related to an alteration of intracellular Ca2+ homeostasis. PMID:22244921

  4. Estimation of Causal Mediation Effects for a Dichotomous Outcome in Multiple-Mediator Models using the Mediation Formula

    PubMed Central

    Nelson, Suchitra; Albert, Jeffrey M.

    2013-01-01

    Mediators are intermediate variables in the causal pathway between an exposure and an outcome. Mediation analysis investigates the extent to which exposure effects occur through these variables, thus revealing causal mechanisms. In this paper, we consider the estimation of the mediation effect when the outcome is binary and multiple mediators of different types exist. We give a precise definition of the total mediation effect as well as decomposed mediation effects through individual or sets of mediators using the potential outcomes framework. We formulate a model of joint distribution (probit-normal) using continuous latent variables for any binary mediators to account for correlations among multiple mediators. A mediation formula approach is proposed to estimate the total mediation effect and decomposed mediation effects based on this parametric model. Estimation of mediation effects through individual or subsets of mediators requires an assumption involving the joint distribution of multiple counterfactuals. We conduct a simulation study that demonstrates low bias of mediation effect estimators for two-mediator models with various combinations of mediator types. The results also show that the power to detect a non-zero total mediation effect increases as the correlation coefficient between two mediators increases, while power for individual mediation effects reaches a maximum when the mediators are uncorrelated. We illustrate our approach by applying it to a retrospective cohort study of dental caries in adolescents with low and high socioeconomic status. Sensitivity analysis is performed to assess the robustness of conclusions regarding mediation effects when the assumption of no unmeasured mediator-outcome confounders is violated. PMID:23650048

  5. Mediator-Generated Pressure Tactics

    ERIC Educational Resources Information Center

    Byrnes, Joseph F.

    1978-01-01

    Two examples of bluff pressures (as opposed to real pressures) used by mediators to effect contract settlements are presented, along with advice to negotiators on avoiding or minimizing such tactics. (Author/IRT)

  6. Mediated Character of Economic Interactions

    NASA Astrophysics Data System (ADS)

    Stepanic, Josip; Bertovic, Igor; Kasac, Josip

    2003-06-01

    Economic interactions are conducted between economic agents - individuals and collectives, through exchange of natural or artificial entities - goods, services and money, in a myriad of combinations. In this article we adopt a microscopic point of view, concentrate on the exchanged entities, and extract their relevant attributes as seen from structurally simple economic processes. Following that, we approach the interpretation of the economic interactions with their mediated character emphasized. Mediators of the interaction are locally available environment units. They are locally recognized and appropriately interpreted in a given value set as goods and money. The overall intensity of economic interactions considered is related to mediators' spatial and temporal characteristics. Extracted characteristics of mediators and economic processes are compacted in the set of formal rules. The approach is connected with similar approaches in economy and physics.

  7. Bradykinin-mediated diseases.

    PubMed

    Kaplan, Allen P

    2014-01-01

    Diseases which have been demonstrated to be caused by increased plasma levels of bradykinin all have angioedema as the common major clinical manifestation. Angioedema due to therapy with angiotensin-converting enzyme (ACE) inhibitors is caused by suppressed bradykinin degradation so that it accumulates. This occurs because ACE metabolizes bradykinin by removal of Phe-Arg from the C-terminus, which inactivates it. By contrast, angioedema due to C1 inhibitor deficiency (either hereditary types I and II, or acquired) is caused by bradykinin overproduction. C1 inhibitor inhibits factor XIIa, kallikrein and activity associated with the prekallikrein-HK (high-molecular-weight kininogen) complex. In its absence, uncontrolled activation of the plasma bradykinin cascade is seen once there has been an initiating stimulus. C4 levels are low in all types of C1 inhibitor deficiency due to the instability of C1 (C1r, in particular) such that some activated C1 always circulates and depletes C4. In the hereditary disorder, formation of factor XIIf (factor XII fragment) during attacks of swelling causes C4 levels to drop toward zero, and C2 levels decline. A kinin-like molecule, once thought to be a cleavage product derived from C2 that contributes to the increased vascular permeability seen in hereditary angioedema (HAE), is now thought to be an artifact, i.e. no such molecule is demonstrable. The acquired C1 inhibitor deficiency is associated with clonal disorders of B cell hyperreactivity, including lymphoma and monoclonal gammopathy. Most cases have an IgG autoantibody to C1 inhibitor which inactivates it so that the presentation is strikingly similar to type I HAE. New therapies for types I and II HAE include C1 inhibitor replacement therapy, ecallantide, a kallikrein antagonist, and icatibant, a B2 receptor antagonist. A newly described type III HAE has normal C1 inhibitor, although it is thought to be mediated by bradykinin, as is an antihistamine-resistant subpopulation of

  8. 7 CFR 900.108 - Mediator's report.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Mediator's report. 900.108 Section 900.108 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements... Mediator's report. The mediator, upon the completion of mediation proceedings, shall submit to...

  9. 15 CFR 20.12 - Mediation.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Procedures § 20.12 Mediation. (a) DOC will refer to a mediation service designated by the Secretary all... mediator shall send a copy of the agreement to DOC. DOC will take no further action on the complaint unless... DOC. Mediation ends if: (1) 60 days elapse from the time DOC receives the complaint; or (2) Prior...

  10. 15 CFR 20.12 - Mediation.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Procedures § 20.12 Mediation. (a) DOC will refer to a mediation service designated by the Secretary all... mediator shall send a copy of the agreement to DOC. DOC will take no further action on the complaint unless... DOC. Mediation ends if: (1) 60 days elapse from the time DOC receives the complaint; or (2) Prior...

  11. 15 CFR 20.12 - Mediation.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Procedures § 20.12 Mediation. (a) DOC will refer to a mediation service designated by the Secretary all... mediator shall send a copy of the agreement to DOC. DOC will take no further action on the complaint unless... DOC. Mediation ends if: (1) 60 days elapse from the time DOC receives the complaint; or (2) Prior...

  12. 15 CFR 20.12 - Mediation.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Procedures § 20.12 Mediation. (a) DOC will refer to a mediation service designated by the Secretary all... mediator shall send a copy of the agreement to DOC. DOC will take no further action on the complaint unless... DOC. Mediation ends if: (1) 60 days elapse from the time DOC receives the complaint; or (2) Prior...

  13. 43 CFR 17.332 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ..., and Enforcement Procedures § 17.332 Mediation. (a) Referral of complaints for mediation. DOI will... it. The FMCS shall send the agreement to DOI. DOI, however, retains the right to monitor the... process without prior approval of the head of the mediation agency. (e) DOI will use the mediation...

  14. Mediation in Schools: Tapping the Potential

    ERIC Educational Resources Information Center

    Hendry, Richard

    2010-01-01

    This article explores the developing role of mediation as a conflict resolution process in schools. It gives an accepted definition and clarifies the purposes of mediation, outlining the range of contexts in and beyond schools in which mediation is already offered as a formal intervention. The typical process of mediation itself is described. The…

  15. 14 CFR 1252.402 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 5 2010-01-01 2010-01-01 false Mediation. 1252.402 Section 1252.402... Procedures § 1252.402 Mediation. (a) Referral of complaints for mediation. NASA will refer to the Federal Mediation and Conciliation Service all complaints that: (1) Fall within the jurisdiction of the Act...

  16. 15 CFR 20.12 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Mediation. 20.12 Section 20.12... Procedures § 20.12 Mediation. (a) DOC will refer to a mediation service designated by the Secretary all... further processing. (b) Both the complainant and the recipient shall participate in the mediation...

  17. 7 CFR 614.11 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 6 2010-01-01 2010-01-01 false Mediation. 614.11 Section 614.11 Agriculture... AGRICULTURE CONSERVATION OPERATIONS NRCS APPEAL PROCEDURES § 614.11 Mediation. (a) A participant who wishes to pursue mediation must file request for mediation under this part with the NRCS official designated in...

  18. 15 CFR 923.54 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 3 2010-01-01 2010-01-01 false Mediation. 923.54 Section 923.54... Mediation. (a) Section 307(h) of the Act provides for mediation of serious disagreement between any Federal... cases, mediation by the Secretary, with the assistance of the Executive Office of the President, may...

  19. 15 CFR 930.111 - OCRM mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 3 2010-01-01 2010-01-01 false OCRM mediation. 930.111 Section 930... FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.111 OCRM mediation. The availability of mediation does not preclude use by the parties of alternative means...

  20. Mediation and Counseling Services: A Viable Partnership

    ERIC Educational Resources Information Center

    Hodges, Shannon

    2009-01-01

    Mediation has become common in many areas of society, including marital dissolution, community disputes, governmental agencies, and business and industry. Though higher education has been slower than society to adopt mediation services, campus mediation is becoming increasingly more common. This article explains why mediation is a viable…

  1. 45 CFR 91.43 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Mediation. 91.43 Section 91.43 Public Welfare... Enforcement Procedures § 91.43 Mediation. (a) HHS will promptly refer to a mediation agency designated by the... mediation process to the extent necessary to reach an agreement or make an informed judgment that...

  2. 24 CFR 146.35 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 1 2010-04-01 2010-04-01 false Mediation. 146.35 Section 146.35... ASSISTANCE Investigation, Settlement, and Enforcement Procedures § 146.35 Mediation. (a) HUD shall refer to the Federal Mediation and Conciliation Service, a mediation agency designated by the Secretary...

  3. 34 CFR 110.32 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 1 2010-07-01 2010-07-01 false Mediation. 110.32 Section 110.32 Education Regulations..., Conciliation, and Enforcement Procedures § 110.32 Mediation. (a) ED promptly refers to the Federal Mediation and Conciliation Service or to the mediation agency designated by the Secretary of Health and...

  4. 38 CFR 18.543 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 38 Pensions, Bonuses, and Veterans' Relief 2 2010-07-01 2010-07-01 false Mediation. 18.543 Section... Enforcement Procedures § 18.543 Mediation. (a) Referral of complaints for mediation. VA will refer to the Federal Mediation and Conciliation Service all complaints that: (1) Fall within the jurisdiction of...

  5. 10 CFR 4.333 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 10 Energy 1 2010-01-01 2010-01-01 false Mediation. 4.333 Section 4.333 Energy NUCLEAR REGULATORY... Investigation, Conciliation, and Enforcement Procedures § 4.333 Mediation. (a) Referral of complaints for mediation. NRC will refer to a mediation agency designated by the Secretary of the Department of Health...

  6. 45 CFR 1156.16 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 3 2010-10-01 2010-10-01 false Mediation. 1156.16 Section 1156.16 Public Welfare... Procedures § 1156.16 Mediation. (a) Referral of complaints for mediation. The Endowment will promptly refer all complaints to the agency designated by the Secretary of HHS to manage the mediation process...

  7. 7 CFR 780.9 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 7 2010-01-01 2010-01-01 false Mediation. 780.9 Section 780.9 Agriculture Regulations... PROGRAMS APPEAL REGULATIONS § 780.9 Mediation. (a) Any request for mediation must be submitted after... once: (1) If resolution of an adverse decision is not achieved in mediation, a participant may...

  8. 22 CFR 218.33 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Mediation. 218.33 Section 218.33 Foreign... § 218.33 Mediation. (a) Referral of complaints for mediation. The agency will refer to the Federal Mediation and Conciliation Service all complaints that: (1) fall within the jurisdiction of...

  9. Web Feature Service Semantic Mediation

    NASA Astrophysics Data System (ADS)

    Hobona, G.; Bermudez, L. E.; Brackin, R.; Percivall, G. S.

    2012-12-01

    Scientists from different organizations and disciplines need to work together to find the solutions to complex problems. Multi-disciplinary science typically involves users with specialized tools and their own preferred view of the data including unique characteristics of the user's information model and symbology. Even though organizations use web services to expose data, there are still semantic inconsistencies that need to be solved. Recent activities within the OGC Interoperability Program (IP) have helped advance semantic mediation solutions when using OGC services to help solve complex problems. The OGC standards development process is influenced by the feedback of activities within the Interoperability Program, which conducts international interoperability initiatives such as Testbeds, Pilot Projects, Interoperability Experiments, and Interoperability Support Services. These activities are designed to encourage rapid development, testing, validation, demonstration and adoption of open, consensus based standards and best practices. Two recent Testbeds, the OGC Web Services Phase 8 and Phase 9, have advanced the use of semantic mediation approaches to increase semantic interoperability among geospatial communities. The Cross-Community Interoperability (CCI) thread within these two testbeds, advanced semantic mediation approaches for data discovery, access and use of heterogeneous data models and heterogeneous metadata models. This presentation will provide an overview of the interoperability program, the CCI Thread and will explain the methodology to mediate heterogeneous GML Application Profiles served via WFS, including discovery of services via a catalog standard interface and mediating symbology applicable to each application profile.

  10. Mediation Analysis in Psychosomatic Medicine Research

    PubMed Central

    Lockhart, Ginger; MacKinnon, David P.; Ohlrich, Vanessa

    2012-01-01

    This article presents an overview of statistical mediation analysis and its application to psychosomatic medicine research. The article begins with a description of the major approaches to mediation analysis and an evaluation of the strengths and limits of each. Emphasis is placed on longitudinal mediation models, and an application using latent growth modeling is presented. The article concludes with a description of recent developments in mediation analysis and suggestions for the use of mediation for future work in psychosomatic medicine research. PMID:21148809

  11. Radical-Mediated Enzymatic Polymerizations

    PubMed Central

    Zavada, Scott R.; Battsengel, Tsatsral; Scott, Timothy F.

    2016-01-01

    Polymerization reactions are commonly effected by exposing monomer formulations to some initiation stimulus such as elevated temperature, light, or a chemical reactant. Increasingly, these polymerization reactions are mediated by enzymes―catalytic proteins―owing to their reaction efficiency under mild conditions as well as their environmental friendliness. The utilization of enzymes, particularly oxidases and peroxidases, for generating radicals via reduction-oxidation mechanisms is especially common for initiating radical-mediated polymerization reactions, including vinyl chain-growth polymerization, atom transfer radical polymerization, thiol–ene step-growth polymerization, and polymerization via oxidative coupling. While enzyme-mediated polymerization is useful for the production of materials intended for subsequent use, it is especially well-suited for in situ polymerizations, where the polymer is formed in the place where it will be utilized. Such polymerizations are especially useful for biomedical adhesives and for sensing applications. PMID:26848652

  12. Radical-Mediated Enzymatic Polymerizations.

    PubMed

    Zavada, Scott R; Battsengel, Tsatsral; Scott, Timothy F

    2016-01-01

    Polymerization reactions are commonly effected by exposing monomer formulations to some initiation stimulus such as elevated temperature, light, or a chemical reactant. Increasingly, these polymerization reactions are mediated by enzymes--catalytic proteins--owing to their reaction efficiency under mild conditions as well as their environmental friendliness. The utilization of enzymes, particularly oxidases and peroxidases, for generating radicals via reduction-oxidation mechanisms is especially common for initiating radical-mediated polymerization reactions, including vinyl chain-growth polymerization, atom transfer radical polymerization, thiol-ene step-growth polymerization, and polymerization via oxidative coupling. While enzyme-mediated polymerization is useful for the production of materials intended for subsequent use, it is especially well-suited for in situ polymerizations, where the polymer is formed in the place where it will be utilized. Such polymerizations are especially useful for biomedical adhesives and for sensing applications. PMID:26848652

  13. Gauge mediated mini-split

    NASA Astrophysics Data System (ADS)

    Cohen, Timothy; Craig, Nathaniel; Knapen, Simon

    2016-03-01

    We propose a simple model of split supersymmetry from gauge mediation. This model features gauginos that are parametrically a loop factor lighter than scalars, accommodates a Higgs boson mass of 125 GeV, and incorporates a simple solution to the μ- b μ problem. The gaugino mass suppression can be understood as resulting from collective symmetry breaking. Imposing collider bounds on μ and requiring viable electroweak symmetry breaking implies small a-terms and small tan β — the stop mass ranges from 105 to 108 GeV. In contrast with models with anomaly + gravity mediation (which also predict a one-loop loop suppression for gaugino masses), our gauge mediated scenario predicts aligned squark masses and a gravitino LSP. Gluinos, electroweakinos and Higgsinos can be accessible at the LHC and/or future colliders for a wide region of the allowed parameter space.

  14. Fracture healing and lipid mediators.

    PubMed

    O'Connor, J Patrick; Manigrasso, Michaele B; Kim, Brian D; Subramanian, Sangeeta

    2014-01-01

    Lipid mediators regulate bone regeneration during fracture healing. Prostaglandins and leukotrienes are well-known lipid mediators that regulate inflammation and are synthesized from the Ω-6 fatty acid, arachidonic acid. Cyclooxygenase (COX-1 or COX-2) and 5-lipoxygenase (5-LO) catalyze the initial enzymatic steps in the synthesis of prostaglandins and leukotrienes, respectively. Inhibition or genetic ablation of COX-2 activity impairs fracture healing in animal models. Genetic ablation of COX-1 does not affect the fracture callus strength in mice, suggesting that COX-2 activity is primarily responsible for regulating fracture healing. Inhibition of cyclooxygenase activity with nonsteroidal anti-inflammatory drugs (NSAIDs) is performed clinically to reduce heterotopic ossification, although clinical evidence that NSAID treatment impairs fracture healing remains controversial. In contrast, inhibition or genetic ablation of 5-LO activity accelerates fracture healing in animal models. Even though prostaglandins and leukotrienes regulate inflammation, loss of COX-2 or 5-LO activity appears to primarily affect chondrogenesis during fracture healing. Prostaglandin or prostaglandin analog treatment, prostaglandin-specific synthase inhibition and prostaglandin or leukotriene receptor antagonism also affect callus chondrogenesis. Unlike the Ω-6-derived lipid mediators, lipid mediators derived from Ω-3 fatty acids, such as resolvin E1 (RvE1), have anti-inflammatory activity. In vivo, RvE1 can inhibit osteoclastogenesis and limit bone resorption. Although Ω-6 and Ω-3 lipid mediators have clear-cut effects on inflammation, the role of these lipid mediators in bone regeneration is more complex, with apparent effects on callus chondrogenesis and bone remodeling. PMID:24795811

  15. Water-Mediated Hydrophobic Interactions.

    PubMed

    Ben-Amotz, Dor

    2016-05-27

    Hydrophobic interactions are driven by the combined influence of the direct attraction between oily solutes and an additional water-mediated interaction whose magnitude (and sign) depends sensitively on both solute size and attraction. The resulting delicate balance can lead to a slightly repulsive water-mediated interaction that drives oily molecules apart rather than pushing them together and thus opposes their direct (van der Waals) attraction for each other. As a consequence, competing solute size-dependent crossovers weaken hydrophobic interactions sufficiently that they are only expected to significantly exceed random thermal energy fluctuations for processes that bury more than ∼1 nm(2) of water-exposed area. PMID:27215821

  16. [Aesthetic surgeons and mediatic field].

    PubMed

    Volte, Ray

    2003-10-01

    Media alter our image; aesthetic surgery has become a good thing for journalists wanting a better TV audience. The standard plastic reconstructive and aesthetic surgeon does not recognize himself in most of the TV shows: operate prepuberic children, enhance buttocks and pectoralis muscles, struggle with transsexuals em leader What is become whim mammoplasties, abdominoplasties, face lifts? We are partially responsible for this mediatic lynchage because we do not occupy the mediatic field. The journalists, without any professional ethical code, make an object out of us. So now is the time of our uprising. PMID:14599902

  17. Notch-Mediated Cell Adhesion.

    PubMed

    Murata, Akihiko; Hayashi, Shin-Ichi

    2016-01-01

    Notch family members are generally recognized as signaling molecules that control various cellular responses in metazoan organisms. Early fly studies and our mammalian studies demonstrated that Notch family members are also cell adhesion molecules; however, information on the physiological roles of this function and its origin is limited. In this review, we discuss the potential present and ancestral roles of Notch-mediated cell adhesion in order to explore its origin and the initial roles of Notch family members dating back to metazoan evolution. We hypothesize that Notch family members may have initially emerged as cell adhesion molecules in order to mediate multicellularity in the last common ancestor of metazoan organisms. PMID:26784245

  18. Notch-Mediated Cell Adhesion

    PubMed Central

    Murata, Akihiko; Hayashi, Shin-Ichi

    2016-01-01

    Notch family members are generally recognized as signaling molecules that control various cellular responses in metazoan organisms. Early fly studies and our mammalian studies demonstrated that Notch family members are also cell adhesion molecules; however, information on the physiological roles of this function and its origin is limited. In this review, we discuss the potential present and ancestral roles of Notch-mediated cell adhesion in order to explore its origin and the initial roles of Notch family members dating back to metazoan evolution. We hypothesize that Notch family members may have initially emerged as cell adhesion molecules in order to mediate multicellularity in the last common ancestor of metazoan organisms. PMID:26784245

  19. Water-Mediated Hydrophobic Interactions

    NASA Astrophysics Data System (ADS)

    Ben-Amotz, Dor

    2016-05-01

    Hydrophobic interactions are driven by the combined influence of the direct attraction between oily solutes and an additional water-mediated interaction whose magnitude (and sign) depends sensitively on both solute size and attraction. The resulting delicate balance can lead to a slightly repulsive water-mediated interaction that drives oily molecules apart rather than pushing them together and thus opposes their direct (van der Waals) attraction for each other. As a consequence, competing solute size-dependent crossovers weaken hydrophobic interactions sufficiently that they are only expected to significantly exceed random thermal energy fluctuations for processes that bury more than ˜1 nm2 of water-exposed area.

  20. Dynamical Messengers for Gauge Mediation

    SciTech Connect

    Hook, Anson; Torroba, Gonzalo; /SLAC /Stanford U., Phys. Dept.

    2011-08-17

    We construct models of indirect gauge mediation where the dynamics responsible for breaking supersymmetry simultaneously generates a weakly coupled subsector of messengers. This provides a microscopic realization of messenger gauge mediation where the messenger and hidden sector fields are unified into a single sector. The UV theory is SQCD with massless and massive quarks plus singlets, and at low energies it flows to a weakly coupled quiver gauge theory. One node provides the primary source of supersymmetry breaking, which is then transmitted to the node giving rise to the messenger fields. These models break R-symmetry spontaneously, produce realistic gaugino and sfermion masses, and give a heavy gravitino.

  1. Re/Mediating Adolescent Literacies.

    ERIC Educational Resources Information Center

    Elkins, John, Ed.; Luke, Allan, Ed.

    Suggesting that teaching in New Times requires that educators read and re/mediate the social relations, the cultural knowledges, and the relationships of power between adolescents and their social, biological, and semiotic universes, this collection of essays offers new ways of seeing and talking about adolescents and their literacies. Most of the…

  2. Mediation analysis with principal stratification.

    PubMed

    Gallop, Robert; Small, Dylan S; Lin, Julia Y; Elliott, Michael R; Joffe, Marshall; Ten Have, Thomas R

    2009-03-30

    In assessing the mechanism of treatment efficacy in randomized clinical trials, investigators often perform mediation analyses by analyzing if the significant intent-to-treat treatment effect on outcome occurs through or around a third intermediate or mediating variable: indirect and direct effects, respectively. Standard mediation analyses assume sequential ignorability, i.e. conditional on covariates the intermediate or mediating factor is randomly assigned, as is the treatment in a randomized clinical trial. This research focuses on the application of the principal stratification (PS) approach for estimating the direct effect of a randomized treatment but without the standard sequential ignorability assumption. This approach is used to estimate the direct effect of treatment as a difference between expectations of potential outcomes within latent subgroups of participants for whom the intermediate variable behavior would be constant, regardless of the randomized treatment assignment. Using a Bayesian estimation procedure, we also assess the sensitivity of results based on the PS approach to heterogeneity of the variances among these principal strata. We assess this approach with simulations and apply it to two psychiatric examples. Both examples and the simulations indicated robustness of our findings to the homogeneous variance assumption. However, simulations showed that the magnitude of treatment effects derived under the PS approach were sensitive to model mis-specification. PMID:19184975

  3. Mediation and the Electronic World.

    ERIC Educational Resources Information Center

    Swan, John; And Others

    1992-01-01

    Three articles discuss the issue of the mediator's role in the library of the electronic age. Topics addressed include computer-assisted instruction; online catalogs; computer networks; professional identity; reference service and bibliographic instruction; CD-ROMs; online systems; personal home microcomputers; Internet and list servers;…

  4. Counterpoint: Response to Mediator Caraway.

    ERIC Educational Resources Information Center

    Gregory, Gordon A.; Heinen, Mark

    1991-01-01

    In the Fall 1989 issue, Caraway discussed the advantages of grievance mediation, compared with arbitration. This article reexamines the issue from the viewpoint of the individual grievant and points to recent conflicting developments in the National Labor Relations Board's deferral doctrine. An introduction by Perry A. Zirkel summarizes the…

  5. Mediation: A Violence Prevention Approach.

    ERIC Educational Resources Information Center

    Conflict Resolution Unlimited, Inc., Bellevue, WA.

    Young people need help in learning alternative dispute resolution skills. A program that aims to do this, set in a context of preventing violent behavior, is presented here. It is structured into sixteen 45-minute sessions which can be presented by one teacher. The training is organized around the following seven themes: The Mediation Process,…

  6. Eicosanoids mediate insect hemocyte migration

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hemocyte chemotaxis toward infection and wound sites is an essential component of insect defense reactions, although the biochemical signal mechanisms responsible for mediating chemotaxis in insect cells are not well understood. Here we report on the outcomes of experiments designed to test the hyp...

  7. Bioanalytical insights into mediator lipidomics.

    PubMed

    Kasuga, Kie; Suga, Takahiro; Mano, Nariyasu

    2015-09-10

    The importance of lipids in health and disease has been widely acknowledged. Lipids are well known to undergo enzymatic and/or non-enzymatic conversions to lipid mediators (LMs), which demonstrate potent actions in various biological events, such as the regulation of cellular signaling pathways and the promotion and resolution of inflammation. LMs activate G-protein-coupled receptors (GPCRs) to exert various functions. Monitoring these mediators in disease is essential to uncover the mechanisms of pathogenesis for many diseases, such as asthma, rheumatoid arthritis, Alzheimer's disease, and cancer. Along with technical developments in mass spectrometry, highly sensitive and multiplexed analyses of LMs in the human periphery and other tissues have become available. These advancements enable the temporal and spatial profiling of LMs; therefore, the findings obtained from LM profiling are expected to decode pathology. As trace amounts of LMs can exert functions, the development of a highly sensitive, accurate, and robust analytical method is necessary. Although not mandatory, mediator lipidomics validation is becoming popular and remains challenging. Because LMs already exist in biological matrices, evaluations of the matrix effect and extraction efficiencies are important issues. Thus, more careful analyses are required. In this review, we focus on mediator lipidomics, including polyunsaturated fatty acids (PUFAs), such as omega-3 and omega-6 fatty acids, and LMs derived from PUFAs, such as eicosanoids, lipoxins and resolvins. In addition to the recent progress in human mediator lipidomics, bioanalytical insights derived from this field (i.e., effective sample preparation from biological matrices and evaluation of the matrix effect) are described herein. PMID:25769667

  8. [Familiy mediation within the counselling system].

    PubMed

    Bastine, Reiner; Römer-Wolf, Birgit; Decker, Frauke; Haid-Loh, Achim; Mayer, Stefan; Normann, Katrin

    2006-01-01

    Family mediation has been established as a method of resolving family conflicts within the counselling system. Unfortunately there existed only rare information about the real presence and efficacy of family mediation services within this system. 726 counselling centres from all over the country participated at the present study, which was outlined to evaluate their supply of family mediation and the use of it. The results show that nearly one third of the centres are offering family mediation as a regular service to their clients, and that mediative skills are quite frequently used by the counselling professionals. Centres, which offer a regular service of mediation, have an obviously higher percentage of honorary staff, indicating that this service might have a more fragile status. Each centre, which conducted mediation, had an average mediation caseload of 32 in 2003, which means a percentage of 7 percent of all counselling cases treated in this year. These mediations needed an average treatment of 7 hours. Most frequent cases in mediation are separated married or separated non-married parents with 2 children. In most cases, family mediation was used to regulate conflicts in separation, divorce or post divorce, mainly concerned with issues of child custody. In contrast to the researchers' expectations, children were introduced at the mediation process only rarely. The need for mediation in the local population was rated much higher than the factual demand for and the factual supply of mediation. Based on the outcomes of the study, some recommendations are made: for the improvement of the supply of family mediation, for the expansion of the issues to which mediation is offered, and for strengthening the approaches to include children into the mediation process. PMID:17152893

  9. Ratio-of-Mediator-Probability Weighting for Causal Mediation Analysis in the Presence of Treatment-by-Mediator Interaction

    ERIC Educational Resources Information Center

    Hong, Guanglei; Deutsch, Jonah; Hill, Heather D.

    2015-01-01

    Conventional methods for mediation analysis generate biased results when the mediator--outcome relationship depends on the treatment condition. This article shows how the ratio-of-mediator-probability weighting (RMPW) method can be used to decompose total effects into natural direct and indirect effects in the presence of treatment-by-mediator…

  10. Mediation from Multilevel to Structural Equation Modeling

    PubMed Central

    MacKinnon, David P.; Valente, Matthew J.

    2016-01-01

    Background/Aims The purpose of this article is to outline multilevel structural equation modeling (MSEM) for mediation analysis of longitudinal data. The introduction of mediating variables can improve experimental and nonexperimental studies of child growth in several ways as discussed throughout this article. Single-mediator individual-level and multilevel mediation models illustrate several current issues in the estimation of mediation with longitudinal data. The strengths of incorporating structural equation modeling (SEM) with multilevel mediation modeling are described. Summary and Key Messages Longitudinal mediation models are pervasive in many areas of research including child growth. Longitudinal mediation models are ideally modeled as repeated measurements clustered within individuals. Further, the combination of MSEM and SEM provides an ideal approach for several reasons, including the ability to assess effects at different levels of analysis, incorporation of measurement error and possible random effects that vary across individuals. PMID:25413658

  11. 13 CFR 117.12 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... complainant in the mediation process in an effort to reach a mutually satisfactory settlement of the complaint... mediator at the same time. (c) If the complainant and the recipient reach a mutually...

  12. 22 CFR 218.33 - Mediation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... the recipient shall participate in the mediation process to the extend necessary to reach an agreement... complainant and the recipient reach an agreement, the mediator shall prepare a written statement of...

  13. 22 CFR 143.33 - Mediation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... participate in the mediation process to the extent necessary to reach an agreement or make an informed... complainant need not meet with the mediator at the same time. (c) If the complainant and the recipient...

  14. Mediator Architecture and RNA Polymerase II Interaction.

    PubMed

    Plaschka, Clemens; Nozawa, Kayo; Cramer, Patrick

    2016-06-19

    Integrated structural biology recently elucidated the architecture of Mediator and its position on RNA polymerase II. Here we summarize these achievements and list open questions on Mediator structure and mechanism. PMID:26851380

  15. An Adviser Agent for Mediator Training

    NASA Astrophysics Data System (ADS)

    Tanaka, Takahiro; Katagami, Daisuke; Nitta, Katsumi

    This paper describes an agent that shows advices for supporting mediator on our online mediation support system. The purpose of the advice is an education of mediator, and the agent presents it instead of the teacher. In this research, at first, we defined a mediation model that is an argumentation model between 3 people. Then, we defined some advice models based on the mediation model. The advice models create advice elements. The adviser agent monitors the mediation, gathers advice elements referring to advice models, and creates advice from elements according to the mediation scene. As a result, it becomes possible that is advising instead of the teacher according to the situation, education purpose and learner's level. We inspected the effectiveness of the advice by the experiment of moot mediation.

  16. Nodal-mediated epigenesis requires dynamin-mediated endocytosis

    PubMed Central

    Ertl, Robin P.; Robertson, Anthony J.; Saunders, Diane; Coffman, James A.

    2011-01-01

    Nodal proteins are diffusible morphogens that drive pattern formation via short-range feedback activation coupled to long-range Lefty-mediated inhibition. In the sea urchin embryo, specification of the secondary (oral-aboral) axis occurs via zygotic expression of nodal, which is localized to the prospective oral ectoderm at early blastula stage. In mid-blastula stage embryos treated with low micromolar nickel or zinc, nodal expression expands progressively beyond the confines of this localized domain to encompass the entire equatorial circumference of the embryo, producing radialized embryos lacking an oral-aboral axis. RNAseq analysis of embryos treated with nickel, zinc or cadmium (which does not radialize embryos) showed that several genes involved in endocytosis were similarly perturbed by nickel and zinc but not cadmium. Inhibiting dynamin, a GTPase required for receptor-mediated endocytosis, phenocopies the effects of nickel and zinc, suggesting that dynamin-mediated endocytosis is required as a sink to limit the range of Nodal signaling. PMID:21337468

  17. Mediation in the Schools. ERIC Digest.

    ERIC Educational Resources Information Center

    Trevaskis, David Keller

    This digest discusses mediation as a form of conflict management that is receiving widespread attention in schools. Mediation involves a neutral third person, called a mediator, who assists the disputants in resolving their problem with the consent of all parties. It offers a risk-free way to settle disputes for the parties involved. Unresolved…

  18. Single-Level and Multilevel Mediation Analysis

    ERIC Educational Resources Information Center

    Tofighi, Davood; Thoemmes, Felix

    2014-01-01

    Mediation analysis is a statistical approach used to examine how the effect of an independent variable on an outcome is transmitted through an intervening variable (mediator). In this article, we provide a gentle introduction to single-level and multilevel mediation analyses. Using single-level data, we demonstrate an application of structural…

  19. Causal Mediation Analysis: Warning! Assumptions Ahead

    ERIC Educational Resources Information Center

    Keele, Luke

    2015-01-01

    In policy evaluations, interest may focus on why a particular treatment works. One tool for understanding why treatments work is causal mediation analysis. In this essay, I focus on the assumptions needed to estimate mediation effects. I show that there is no "gold standard" method for the identification of causal mediation effects. In…

  20. Axino dark matter in mirage mediation

    SciTech Connect

    Nakamura, Shuntaro; Okumura, Ken-ichi; Yamaguchi, Masahiro

    2009-04-17

    The mirage mediation of supersymmetry breaking is a phenomenologically quite interesting possibility, however, it suffers from two major problems: the moduli-induced gravitino problem and the {mu}-B{mu} problem. In this paper, we propose that the axionic extension of mirage mediation, axionic mirage mediation can solve both problems simultaneously. We address the cosmological consequences of the scenario extensively.

  1. Methods for Mediation Analysis with Missing Data

    ERIC Educational Resources Information Center

    Zhang, Zhiyong; Wang, Lijuan

    2013-01-01

    Despite wide applications of both mediation models and missing data techniques, formal discussion of mediation analysis with missing data is still rare. We introduce and compare four approaches to dealing with missing data in mediation analysis including list wise deletion, pairwise deletion, multiple imputation (MI), and a two-stage maximum…

  2. 7 CFR 900.109 - Mediation agreement.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Mediation agreement. 900.109 Section 900.109 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing... Mediation agreement. An agreement arrived at by mediation shall not become effective until approved by...

  3. 45 CFR 617.10 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 3 2010-10-01 2010-10-01 false Mediation. 617.10 Section 617.10 Public Welfare... OF AGE IN PROGRAMS OR ACTIVITIES RECEIVING FEDERAL FINANCIAL ASSISTANCE FROM NSF § 617.10 Mediation. (a) NSF will refer to the Federal Mediation and Conciliation Service all complaints that fall...

  4. 34 CFR 300.506 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 34 Education 2 2010-07-01 2010-07-01 false Mediation. 300.506 Section 300.506 Education... DISABILITIES Procedural Safeguards Due Process Procedures for Parents and Children § 300.506 Mediation. (a... due process complaint, to resolve disputes through a mediation process. (b) Requirements....

  5. 41 CFR 101-8.717 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 41 Public Contracts and Property Management 2 2010-07-01 2010-07-01 true Mediation. 101-8.717... FINANCIAL ASSISTANCE 8.7-Discrimination Prohibited on the Basis of Age § 101-8.717 Mediation. (a) GSA promptly refers to the mediation agency designated by the Secretary, HHS, all sufficient complaints...

  6. 7 CFR 205.663 - Mediation.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) ORGANIC FOODS PRODUCTION ACT PROVISIONS NATIONAL ORGANIC PROGRAM Administrative Compliance § 205.663 Mediation. Any dispute with respect... a qualified mediator mutually agreed upon by the parties to the mediation. If a State...

  7. 7 CFR 205.663 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ..., Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) ORGANIC FOODS PRODUCTION ACT PROVISIONS NATIONAL ORGANIC PROGRAM Administrative Compliance § 205.663 Mediation. Any dispute with respect... a qualified mediator mutually agreed upon by the parties to the mediation. If a State...

  8. 7 CFR 205.663 - Mediation.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) ORGANIC FOODS PRODUCTION ACT PROVISIONS NATIONAL ORGANIC PROGRAM Administrative Compliance § 205.663 Mediation. Any dispute with respect... a qualified mediator mutually agreed upon by the parties to the mediation. If a State...

  9. Sequestered gravity in gauge mediation

    NASA Astrophysics Data System (ADS)

    Antoniadis, Ignatios; Benakli, Karim; Quiros, Mariano

    2016-07-01

    We present a novel mechanism of supersymmetry breaking embeddable in string theory and simultaneously sharing the main advantages of (sequestered) gravity and gauge mediation. It is driven by a Scherk-Schwarz deformation along a compact extra dimension, transverse to a brane stack supporting the supersymmetric extension of the Standard Model. This fixes the magnitude of the gravitino mass, together with that of the gauginos of a bulk gauge group, at a scale as high as 10^{10} GeV. Supersymmetry breaking is mediated to the observable sector dominantly by gauge interactions using massive messengers transforming non-trivially under the bulk and Standard Model gauge groups and leading to a neutralino LSP as dark matter candidate. The Higgsino mass μ and soft Higgs-bilinear B_μ term could be generated at the same order of magnitude as the other soft terms by effective supergravity couplings as in the Giudice-Masiero mechanism.

  10. General gauge mediation and deconstruction

    NASA Astrophysics Data System (ADS)

    McGarrie, Moritz

    2010-11-01

    We locate a supersymmetry breaking hidden sector and supersymmetric standard model on different lattice points of an orbifold moose. The hidden sector is encoded in a set of current correlators and the effects of the current correlators are mediated by the lattice site gauge groups with "lattice hopping" functions and through the bifundamental matter that links the lattice sites together. We show how the gaugino mass, scalar mass and Casimir energy of the lattice can be computed for a general set of current correlators and then give specific formulas when the hidden sector is specified to be a generalised messenger sector. The results reproduce the effect of five dimensional gauge mediation from a purely four dimensional construction.

  11. Elastocapillary-mediated interfacial assembly

    NASA Astrophysics Data System (ADS)

    Evans, Arthur

    2015-11-01

    Particles confined to an interface are present in a large number of industrial applications and ubiquitous in cellular biophysics. Interactions mediated by the interface, such as capillary effects in the presence of surface tension, give rise to rafts and aggregates whose structure is ultimately determined by geometric characteristics of these adsorbed particles. A common strategy for assembling interfacial structures relies on exploiting these interactions by tuning particle anisotropy, either by constructing rigid particles with heterogeneous wetting properties or fabricating particles that have a naturally anisotropic shape. Less explored, however, is the scenario where the interface causes the particles to deform. In this talk I will discuss the implications for interfacial assembly using elastocapillary-mediated interactions. The competition between surface energy and elasticity can wrinkle and buckle adsorbed soft particles, leading to complicated (but programmable) aggregates.

  12. Direct mediation, duality and unification

    NASA Astrophysics Data System (ADS)

    Abel, Steven; Khoze, Valentin V.

    2008-11-01

    It is well-known that in scenarios with direct gauge mediation of supersymmetry breaking the messenger fields significantly affect the running of Standard Model couplings and introduce Landau poles which are difficult to avoid. Among other things, this appears to remove any possibility of a meaningful unification prediction and is often viewed as a strong argument against direct mediation. We propose two ways that Seiberg duality can circumvent this problem. In the first, which we call ``deflected-unification'', the SUSY-breaking hidden sector is a magnetic theory which undergoes a Seiberg duality to an electric phase. Importantly, the electric version has fewer fundamental degrees of freedom coupled to the MSSM compared to the magnetic formulation. This changes the β-functions of the MSSM gauge couplings so as to push their Landau poles above the unification scale. We show that this scenario is realised for recently suggested models of gauge mediation based on a metastable SCQD-type hidden sector directly coupled to MSSM. The second possibility for avoiding Landau poles, which we call ``dual-unification'', begins with the observation that, if the mediating fields fall into complete SU(5) multiplets, then the MSSM+messengers exhibits a fake unification at unphysical values of the gauge couplings. We show that, in known examples of electric/magnetic duals, such a fake unification in the magnetic theory reflects a real unification in the electric theory. We therefore propose that the Standard Model could itself be a magnetic dual of some unknown electric theory in which the true unification takes place. This scenario maintains the unification prediction (and unification scale) even in the presence of Landau poles in the magnetic theory below the GUT scale. We further note that this dual realization of grand unification can explain why Nature appears to unify, but the proton does not decay.

  13. Mediators and Metaphorical Analysis: A Phenomenological Study of Florida Family Court Mediators

    ERIC Educational Resources Information Center

    Storrow, Rebecca A.

    2012-01-01

    Florida family court mediation programs have typically been assessed with quantitative analysis. To understand the complexity of the experience of being a family mediator, it was necessary to explore how mediators practiced through qualitative research. Metaphors have been considered to be representations of mediators' mental models regarding…

  14. Plasmid-mediated quinolone resistance

    PubMed Central

    Jacoby, George A.; Strahilevitz, Jacob; Hooper, David C.

    2014-01-01

    Summary Three mechanisms for plasmid-mediated quinolone resistance (PMQR) have been discovered since 1998. Plasmid genes qnrA, qnrB, qnrC, qnrD, qnrS, and qnrVC code for proteins of the pentapeptide repeat family that protects DNA gyrase and topoisomerase IV from quinolone inhibition. The qnr genes appear to have been acquired from chromosomal genes in aquatic bacteria, are usually associated with mobilizing or transposable elements on plasmids, and are often incorporated into sul1-type integrons. The second plasmid-mediated mechanism involves acetylation of quinolones with an appropriate amino nitrogen target by a variant of the common aminoglycoside acetyltransferase AAC(6′)-Ib. The third mechanism is enhanced efflux produced by plasmid genes for pumps QepAB and OqxAB. PMQR has been found in clinical and environmental isolates around the world and appears to be spreading. The plasmid-mediated mechanisms provide only low-level resistance that by itself does not exceed the clinical breakpoint for susceptibility but nonetheless facilitates selection of higher-level resistance and makes infection by pathogens containing PMQR harder to treat. PMID:25584197

  15. Flavor mediation delivers natural SUSY

    NASA Astrophysics Data System (ADS)

    Craig, Nathaniel; McCullough, Matthew; Thaler, Jesse

    2012-06-01

    If supersymmetry (SUSY) solves the hierarchy problem, then naturalness considerations coupled with recent LHC bounds require non-trivial superpartner flavor structures. Such "Natural SUSY" models exhibit a large mass hierarchy between scalars of the third and first two generations as well as degeneracy (or alignment) among the first two generations. In this work, we show how this specific beyond the standard model (SM) flavor structure can be tied directly to SM flavor via "Flavor Mediation". The SM contains an anomaly-free SU(3) flavor symmetry, broken only by Yukawa couplings. By gauging this flavor symmetry in addition to SM gauge symmetries, we can mediate SUSY breaking via (Higgsed) gauge mediation. This automatically delivers a natural SUSY spectrum. Third-generation scalar masses are suppressed due to the dominant breaking of the flavor gauge symmetry in the top direction. More subtly, the first-two-generation scalars remain highly degenerate due to a custodial U(2) symmetry, where the SU(2) factor arises because SU(3) is rank two. This custodial symmetry is broken only at order ( m c /m t )2. SUSY gauge coupling unification predictions are preserved, since no new charged matter is introduced, the SM gauge structure is unaltered, and the flavor symmetry treats all matter multiplets equally. Moreover, the uniqueness of the anomaly-free SU(3) flavor group makes possible a number of concrete predictions for the superpartner spectrum.

  16. Substrate Mediated Enzyme Prodrug Therapy

    PubMed Central

    Fejerskov, Betina; Zelikin, Alexander N.

    2012-01-01

    In this report, we detail Substrate Mediated Enzyme Prodrug Therapy (SMEPT) as a novel approach in drug delivery which relies on enzyme-functionalized cell culture substrates to achieve a localized conversion of benign prodrug(s) into active therapeutics with subsequent delivery to adhering cells or adjacent tissues. For proof-of-concept SMEPT, we use surface adhered micro-structured physical hydrogels based on poly(vinyl alcohol), β-glucuronidase enzyme and glucuronide prodrugs. We demonstrate enzymatic activity mediated by the assembled hydrogel samples and illustrate arms of control over rate of release of model fluorescent cargo. SMEPT was not impaired by adhering cells and afforded facile time - and dose – dependent uptake of the in situ generated fluorescent cargo by hepatic cells, HepG2. With the use of a glucuronide derivative of an anticancer drug, SN-38, SMEPT afforded a decrease in cell viability to a level similar to that achieved using parent drug. Finally, dose response was achieved using SMEPT and administration of judiciously chosen concentration of SN-38 glucuronide prodrug thus revealing external control over drug delivery using drug eluting surface. We believe that this highly adaptable concept will find use in diverse biomedical applications, specifically surface mediated drug delivery and tissue engineering. PMID:23152927

  17. Male-mediated developmental toxicity.

    PubMed

    Anderson, Diana; Schmid, Thomas E; Baumgartner, Adolf

    2014-01-01

    Male-mediated developmental toxicity has been of concern for many years. The public became aware of male-mediated developmental toxicity in the early 1990s when it was reported that men working at Sellafield might be causing leukemia in their children. Human and animal studies have contributed to our current understanding of male-mediated effects. Animal studies in the 1980s and 1990s suggested that genetic damage after radiation and chemical exposure might be transmitted to offspring. With the increasing understanding that there is histone retention and modification, protamine incorporation into the chromatin and DNA methylation in mature sperm and that spermatozoal RNA transcripts can play important roles in the epigenetic state of sperm, heritable studies began to be viewed differently. Recent reports using molecular approaches have demonstrated that DNA damage can be transmitted to babies from smoking fathers, and expanded simple tandem repeats minisatellite mutations were found in the germline of fathers who were exposed to radiation from the Chernobyl nuclear power plant disaster. In epidemiological studies, it is possible to clarify whether damage is transmitted to the sons after exposure of the fathers. Paternally transmitted damage to the offspring is now recognized as a complex issue with genetic as well as epigenetic components. PMID:24369136

  18. Selectron NLSP in gauge mediation

    NASA Astrophysics Data System (ADS)

    Calibbi, Lorenzo; Mariotti, Alberto; Petersson, Christoffer; Redigolo, Diego

    2014-09-01

    We discuss gauge mediation models in which the smuon and the selectron are mass-degenerate co-NLSP, which we, for brevity, refer to as selectron NLSP. In these models, the stau, as well as the other superpartners, are parametrically heavier than the NLSP. We start by taking a bottom-up perspective and investigate the conditions under which selectron NLSP spectra can be realized in the MSSM. We then give a complete characterization of gauge mediation models realizing such spectra at low energies. The splitting between the slepton families is induced radiatively by the usual hierarchies in the Standard Model Yukawa couplings and hence, no new sources of flavour misalignment are introduced. We construct explicit weakly coupled messenger models which give rise to selectron NLSP, while accommodating a 126 GeV MSSM Higgs mass, both within the framework of General Gauge Mediation and in extensions where direct couplings between the messengers and the Higgs fields are present. In the latter class of models, large A-terms and relatively light stops can be achieved. The collider signatures of these models typically involve multilepton final states. We discuss the relevant LHC bounds and provide examples of models where the decay of the NLSP selectron is prompt, displaced or long-lived. The prompt case can be viewed as an ultraviolet completion of a simplified model recently considered by the CMS collaboration.

  19. Male-mediated developmental toxicity

    PubMed Central

    Anderson, Diana; Schmid, Thomas E; Baumgartner, Adolf

    2014-01-01

    Male-mediated developmental toxicity has been of concern for many years. The public became aware of male-mediated developmental toxicity in the early 1990s when it was reported that men working at Sellafield might be causing leukemia in their children. Human and animal studies have contributed to our current understanding of male-mediated effects. Animal studies in the 1980s and 1990s suggested that genetic damage after radiation and chemical exposure might be transmitted to offspring. With the increasing understanding that there is histone retention and modification, protamine incorporation into the chromatin and DNA methylation in mature sperm and that spermatozoal RNA transcripts can play important roles in the epigenetic state of sperm, heritable studies began to be viewed differently. Recent reports using molecular approaches have demonstrated that DNA damage can be transmitted to babies from smoking fathers, and expanded simple tandem repeats minisatellite mutations were found in the germline of fathers who were exposed to radiation from the Chernobyl nuclear power plant disaster. In epidemiological studies, it is possible to clarify whether damage is transmitted to the sons after exposure of the fathers. Paternally transmitted damage to the offspring is now recognized as a complex issue with genetic as well as epigenetic components. PMID:24369136

  20. Activation of the p38 MAPK/Akt/ERK1/2 signal pathways is required for the protein stabilization of CDC6 and cyclin D1 in low-dose arsenite-induced cell proliferation.

    PubMed

    Liu, Youhong; Hock, Janet M; Sullivan, Con; Fang, Geying; Cox, Allison J; Davis, Kathleen T; Davis, Bruce H; Li, Xiong

    2010-12-15

    Arsenic trioxide (ATO) is a first-line anti-cancer agent for acute promyelocytic leukemia, and induces apoptosis in other solid cancer cell lines including breast cancer cells. However, as with arsenites found in drinking water and used as raw materials for wood preservatives, insecticides, and herbicides, low doses of ATO can induce carcinogenesis after long-term exposure. At 24 h after exposure, ATO (0.01-1 µM) significantly increased cell proliferation and promoted cell cycle progression from the G1 to S/G2 phases in the non-tumorigenic MCF10A breast epithelial cell line. The expression of 14 out of 96 cell-cycle-associated genes significantly increased, and seven of these genes including cell division cycle 6 (CDC6) and cyclin D1 (CCND1) were closely related to cell cycle progression from G1 to S phase. Low-dose ATO steadily increased gene transcript and protein levels of both CDC6 and cyclin D1 in a dose- and time-dependent manner. Low-dose ATO produced reactive oxygen species (ROS), and activated the p38 MAPK, Akt, and ERK1/2 pathways at different time points within 60 min. Small molecular inhibitors and siRNAs inhibiting the activation of p38 MAPK, Akt, and ERK1/2 decreased the ATO-increased expression of CDC6 protein. Inhibiting the activation of Akt and ERK1/2, but not p38 MAPK, decreased the ATO-induced expression of cyclin D1 protein. This study reports for the first time that p38 MAPK/Akt/ERK1/2 activation is required for the protein stabilization of CDC6 in addition to cyclin D1 in ATO-induced cell proliferation and cell cycle modulation from G1 to S phase. PMID:20862710

  1. The Dual Nature of Nek9 in Adenovirus Replication

    PubMed Central

    Jung, Richard; Radko, Sandi

    2015-01-01

    to replication. We show that the virus uses a cellular protein, Nek9, in order to block activation of p53-regulated gene GADD45A, which is an important player in stress response and p53-mediated cell cycle arrest. Importantly, our study also identifies Nek9 as a transcriptional repressor. PMID:26676776

  2. Hydrological models are mediating models

    NASA Astrophysics Data System (ADS)

    Babel, L. V.; Karssenberg, D.

    2013-08-01

    Despite the increasing role of models in hydrological research and decision-making processes, only few accounts of the nature and function of models exist in hydrology. Earlier considerations have traditionally been conducted while making a clear distinction between physically-based and conceptual models. A new philosophical account, primarily based on the fields of physics and economics, transcends classes of models and scientific disciplines by considering models as "mediators" between theory and observations. The core of this approach lies in identifying models as (1) being only partially dependent on theory and observations, (2) integrating non-deductive elements in their construction, and (3) carrying the role of instruments of scientific enquiry about both theory and the world. The applicability of this approach to hydrology is evaluated in the present article. Three widely used hydrological models, each showing a different degree of apparent physicality, are confronted to the main characteristics of the "mediating models" concept. We argue that irrespective of their kind, hydrological models depend on both theory and observations, rather than merely on one of these two domains. Their construction is additionally involving a large number of miscellaneous, external ingredients, such as past experiences, model objectives, knowledge and preferences of the modeller, as well as hardware and software resources. We show that hydrological models convey the role of instruments in scientific practice by mediating between theory and the world. It results from these considerations that the traditional distinction between physically-based and conceptual models is necessarily too simplistic and refers at best to the stage at which theory and observations are steering model construction. The large variety of ingredients involved in model construction would deserve closer attention, for being rarely explicitly presented in peer-reviewed literature. We believe that devoting

  3. Computer-mediated focus groups.

    PubMed

    Walston, J T; Lissitz, R W

    2000-10-01

    This article discusses the feasibility and effectiveness of computer-mediated (CM) focus groups. The study describes technological and practical considerations the authors learned from conducting such groups and reports on a comparison of the reactions of CM and face-to-face (FTF) participants in focus groups discussing academic dishonesty. The results suggest that the CM environment, in comparison to FTF, may lessen members' concern about what the moderator thinks of them and discourage participants from withholding embarrassing information. The article concludes with a list of suggestions for this technique and a discussion of the potential advantages and limitations associated with CM focus groups. PMID:11183483

  4. The evolution of inflammatory mediators

    PubMed Central

    Rowley, Andrew F.

    1996-01-01

    Invertebrates do not display the level of sophistication in immune reactivity characteristic of mammals and other ‘higher’ vertebrates. Their great number and diversity of forms, however, reflect their evolutionary success and hence they must have effective mechanisms of defence to deal with parasites and pathogens and altered self tissues. Inflammation appears to be an important first line defence in all invertebrates and vertebrates. This brief review deals with the inflammatory responses of invertebrates and fish concentrating on the cell types involved and the mediators of inflammation, in particular, eicosanoids, cytokines and adhesion molecules. PMID:18475690

  5. Lipid mediators in diabetic nephropathy

    PubMed Central

    2014-01-01

    The implications of lipid lowering drugs in the treatment of diabetic nephropathy have been considered. At the same time, the clinical efficacy of lipid lowering drugs has resulted in improvement in the cardiovascular functions of chronic kidney disease (CKD) patients with or without diabetes, but no remarkable improvement has been observed in the kidney outcome. Earlier lipid mediators have been shown to cause accumulative effects in diabetic nephropathy (DN). Here, we attempt to analyze the involvement of lipid mediators in DN. The hyperglycemia-induced overproduction of diacyglycerol (DAG) is one of the causes for the activation of protein kinase C (PKCs), which is responsible for the activation of pathways, including the production of VEGF, TGFβ1, PAI-1, NADPH oxidases, and NFҟB signaling, accelerating the development of DN. Additionally, current studies on the role of ceramide are one of the major fields of study in DN. Researchers have reported excessive ceramide formation in the pathobiological conditions of DN. There is less report on the effect of lipid lowering drugs on the reduction of PKC activation and ceramide synthesis. Regulating PKC activation and ceramide biosynthesis could be a protective measure in the therapeutic potential of DN. Lipid lowering drugs also upregulate anti-fibrotic microRNAs, which could hint at the effects of lipid lowering drugs in DN. PMID:25206927

  6. Transporter-mediated biofuel secretion.

    PubMed

    Doshi, Rupak; Nguyen, Tuan; Chang, Geoffrey

    2013-05-01

    Engineering microorganisms to produce biofuels is currently among the most promising strategies in renewable energy. However, harvesting these organisms for extracting biofuels is energy- and cost-intensive, limiting the commercial feasibility of large-scale production. Here, we demonstrate the use of a class of transport proteins of pharmacological interest to circumvent the need to harvest biomass during biofuel production. We show that membrane-embedded transporters, better known to efflux lipids and drugs, can be used to mediate the secretion of intracellularly synthesized model isoprenoid biofuel compounds to the extracellular milieu. Transporter-mediated biofuel secretion sustainably maintained an approximate three- to fivefold boost in biofuel production in our Escherichia coli test system. Because the transporters used in this study belong to the ubiquitous ATP-binding cassette protein family, we propose their use as "plug-and-play" biofuel-secreting systems in a variety of bacteria, cyanobacteria, diatoms, yeast, and algae used for biofuel production. This investigation showcases the potential of expressing desired membrane transport proteins in cell factories to achieve the export or import of substances of economic, environmental, or therapeutic importance. PMID:23613592

  7. Transporter-mediated biofuel secretion

    PubMed Central

    Doshi, Rupak; Nguyen, Tuan; Chang, Geoffrey

    2013-01-01

    Engineering microorganisms to produce biofuels is currently among the most promising strategies in renewable energy. However, harvesting these organisms for extracting biofuels is energy- and cost-intensive, limiting the commercial feasibility of large-scale production. Here, we demonstrate the use of a class of transport proteins of pharmacological interest to circumvent the need to harvest biomass during biofuel production. We show that membrane-embedded transporters, better known to efflux lipids and drugs, can be used to mediate the secretion of intracellularly synthesized model isoprenoid biofuel compounds to the extracellular milieu. Transporter-mediated biofuel secretion sustainably maintained an approximate three- to fivefold boost in biofuel production in our Escherichia coli test system. Because the transporters used in this study belong to the ubiquitous ATP-binding cassette protein family, we propose their use as “plug-and-play” biofuel-secreting systems in a variety of bacteria, cyanobacteria, diatoms, yeast, and algae used for biofuel production. This investigation showcases the potential of expressing desired membrane transport proteins in cell factories to achieve the export or import of substances of economic, environmental, or therapeutic importance. PMID:23613592

  8. Head module control of mediator interactions.

    PubMed

    Takagi, Yuichiro; Calero, Guillermo; Komori, Hirofumi; Brown, Jesse A; Ehrensberger, Andreas H; Hudmon, Andy; Asturias, Francisco; Kornberg, Roger D

    2006-08-01

    Yeast Mediator proteins interacting with Med17(Srb4) have been expressed at a high level with the use of recombinant baculoviruses and recovered in homogeneous form as a seven subunit, 223 kDa complex. Electron microscopy and single-particle analysis identify this complex as the Mediator head module. The recombinant head module complements "headless" Mediator for the initiation of transcription in vitro. The module interacts with an RNA polymerase II-TFIIF complex, but not with the polymerase or TFIIF alone. This interaction is lost in the presence of a DNA template and associated RNA transcript, recapitulating the release of Mediator that occurs upon the initiation of transcription. Disruption of the head module in a temperature-sensitive mutant in vivo leads to the release of middle and tail modules from a transcriptionally active promoter. The head module evidently controls Mediator-RNA polymerase II and Mediator-promoter interactions. PMID:16885025

  9. [Progress in natural laccase mediators from lignocelluloses].

    PubMed

    Qiu, Weihua; Chen, Hongzhang

    2014-05-01

    Laccase is one of the most important oxidoreductase with industrialization potential. However, due to the high cost and catalytic toxicity of laccase synthetic mediator, the laccase-mediator-system still cannot achieve industrialization. Therefore, searching for high efficient, environment-friendly, and cheap natural mediator from small molecule precursors or intermediates and degradation products of lignin has been considered as a hot research topic. Therefore, we introduce the type and catalytic mechanism of laccase mediator, the composition and separation of natural laccase mediator from water washed solution of steam exploded straw, black liquor and lignocelluloses degradation products during the fermentation of white-rot fungi. We also provide the theoretical and technical direction for exploring of high reactive of laccase natural mediators and achieving the oriented high-value utilization of lignocellulose degradation products. PMID:25118396

  10. Robust Mediation Analysis Based on Median Regression

    PubMed Central

    Yuan, Ying; MacKinnon, David P.

    2014-01-01

    Mediation analysis has many applications in psychology and the social sciences. The most prevalent methods typically assume that the error distribution is normal and homoscedastic. However, this assumption may rarely be met in practice, which can affect the validity of the mediation analysis. To address this problem, we propose robust mediation analysis based on median regression. Our approach is robust to various departures from the assumption of homoscedasticity and normality, including heavy-tailed, skewed, contaminated, and heteroscedastic distributions. Simulation studies show that under these circumstances, the proposed method is more efficient and powerful than standard mediation analysis. We further extend the proposed robust method to multilevel mediation analysis, and demonstrate through simulation studies that the new approach outperforms the standard multilevel mediation analysis. We illustrate the proposed method using data from a program designed to increase reemployment and enhance mental health of job seekers. PMID:24079925

  11. Hyaluronan-mediated cellular adhesion

    NASA Astrophysics Data System (ADS)

    Curtis, Jennifer

    2005-03-01

    Many cells surround themselves with a cushioning halo of polysaccharides that is further strengthened and organized by proteins. In fibroblasts and chrondrocytes, the primary component of this pericellular matrix is hyaluronan, a large linear polyanion. Hyaluronan production is linked to a variety of disease, developmental, and physiological processes. Cells manipulate the concentration of hyaluronan and hyaluronan receptors for numerous activities including modulation of cell adhesion, cell motility, and differentiation. Recent investigations by identify hyaluronan's role in mediating early-stage cell adhesion. An open question is how the cell removes the 0.5-10 micron thick pericellular matrix to allow for further mature adhesion events requiring nanometer scale separations. In this investigation, holographic optical tweezers are used to study the adhesion and viscoelastic properties of chondrocytes' pericellular matrix. Ultimately, we aim to shed further light on the spatial and temporal details of the dramatic transition from micron to nanometer gaps between the cell and its adhesive substrate.

  12. Mediating consolation with suicidal patients.

    PubMed

    Gilje, Fredricka; Talseth, Anne-Grethe

    2007-07-01

    Psychiatric nurses frequently encounter suicidal patients. Caring for such patients often raises ethical questions and dilemmas. The research question for this study was: 'What understandings are revealed in texts about consolation and psychiatric nurses' responses to suicidal patients?' A Gadamerian approach guided re-interpretation of published texts. Through synthesizing four interpretive phases, a comprehensive interpretation emerged. This revealed being 'at home' with self, or an ethical way of being, as a hermeneutic understanding of a way to become ready to mediate consolation with suicidal patients. Trustworthiness was addressed by means of the qualities of auditability, credibility and confirmability. This re-interpretation adds to nursing knowledge, enhances understanding of previous research findings, provides pre-understanding for further research and reveals the value of hermeneutic inquiry in nursing. It also deepens understanding of a published model of consolation. These understandings may help to guide nurses who are struggling with suicidal patients. PMID:17562733

  13. Detergent-mediated protein aggregation

    PubMed Central

    Neale, Chris; Ghanei, Hamed; Holyoake, John; Bishop, Russell E.; Privé, Gilbert G.; Pomès, Régis

    2016-01-01

    Because detergents are commonly used to solvate membrane proteins for structural evaluation, much attention has been devoted to assessing the conformational bias imparted by detergent micelles in comparison to the native environment of the lipid bilayer. Here, we conduct six 500-ns simulations of a system with >600,000 atoms to investigate the spontaneous self assembly of dodecylphosphocholine detergent around multiple molecules of the integral membrane protein PagP. This detergent formed equatorial micelles in which acyl chains surround the protein’s hydrophobic belt, confirming existing models of the detergent solvation of membrane proteins. In addition, unexpectedly, the extracellular and periplasmic apical surfaces of PagP interacted with the headgroups of detergents in other micelles 85 and 60% of the time, respectively, forming complexes that were stable for hundreds of nanoseconds. In some cases, an apical surface of one molecule of PagP interacted with an equatorial micelle surrounding another molecule of PagP. In other cases, the apical surfaces of two molecules of PagP simultaneously bound a neat detergent micelle. In these ways, detergents mediated the non-specific aggregation of folded PagP. These simulation results are consistent with dynamic light scattering experiments, which show that, at detergent concentrations ≥600 mM, PagP induces the formation of large scattering species that are likely to contain many copies of the PagP protein. Together, these simulation and experimental results point to a potentially generic mechanism of detergent-mediated protein aggregation. PMID:23466535

  14. RNA mediated assembly of nanostructures

    NASA Astrophysics Data System (ADS)

    Rouge, Jessica Lynn

    The first chapter of this work presents a comprehensive look at RNA mediated nanoparticle formation. The overall goal of this research is to gain a deeper understanding of the RNA-particle formation mechanism and the basic properties of the materials selected by modified RNA molecules. Understanding such RNA-substrate interactions and how they translate into the physical and chemical characteristics of the nanoparticles they create are important fundamental concepts when considering these biotemplated materials as potential chemical catalysts. The RNA sequences discussed in the first chapter (referred to as Pdases) were discovered using RNA in vitro selection techniques. These Pdases were found to be capable of forming inorganic palladium (Pd) containing nanoparticles with impressive control over an individual particle's size and shape, despite incubation with the same organometallic precursor. This discovery held exciting implications for inorganic nanoparticle design while also generating numerous questions regarding the mechanism of RNA mediated particle growth. The central question that arose after this initial discovery was how could a biomolecule be used to tailor the physical size and shape of inorganic materials? Starting with a chemical proof designed to uncover the composition of the nanoparticles formed by RNA mediation, this chapter investigates the basic material properties of the nanoparticles while also introducing surprising results regarding the effect of multiple sequences on nanoparticle growth outcomes. In the second chapter, the experiments shift to developing methods to investigate nanoparticle growth mechanisms by fluorescence spectroscopy. A fluorescence polarization anisotropy (FPA) assay is presented in which the strengths of the technique are adapted for studying the formation of RNA mediated Pd nanoparticles in real time. This is a unique application of FPA, as it has been adapted to encompass both the biochemical and materials analysis

  15. Tests of Mediation: Paradoxical Decline in Statistical Power as a Function of Mediator Collinearity

    ERIC Educational Resources Information Center

    Beasley, T. Mark

    2014-01-01

    Increasing the correlation between the independent variable and the mediator ("a" coefficient) increases the effect size ("ab") for mediation analysis; however, increasing a by definition increases collinearity in mediation models. As a result, the standard error of product tests increase. The variance inflation caused by…

  16. Coordinated regulation of Nrf2 and histone H3 serine 10 phosphorylation in arsenite-activated transcription of the human heme oxygenase-1 gene.

    PubMed

    Ray, Paul D; Huang, Bo-Wen; Tsuji, Yoshiaki

    2015-10-01

    Expression of the antioxidant gene heme oxygenase-1 (HO-1) is primarily induced through NF-E2-related factor 2 (Nrf2)-mediated activation of the antioxidant response element (ARE). Gene transcription is coordinately regulated by transcription factor activity at enhancer elements and epigenetic alterations such as the posttranslational modification of histone proteins. However, the role of histone modifications in the Nrf2-ARE axis remains largely uncharacterized. The environmental contaminant arsenite is a potent inducer of both HO-1 expression and phosphorylation of histone H3 serine 10 (H3S10); therefore, we investigated the relationships between Nrf2 and H3S10 phosphorylation in arsenite-induced, ARE-dependent, transcriptional activation of the human HO-1 gene. Arsenite increased phosphorylation of H3S10 both globally and at the HO-1 promoter concomitantly with HO-1 transcription in human HaCaT keratinocytes. Conversely, arsenite-induced H3S10 phosphorylation and HO-1 expression were blocked by N-acetylcysteine (NAC), the c-Jun N-terminal kinase (JNK) inhibitor SP600125, and JNK knockdown (siJNK). Interestingly, ablation of arsenite-induced H3S10 phosphorylation by SP600125 or siJNK did not inhibit Nrf2 nuclear accumulation nor ARE binding, despite inhibiting HO-1 expression. In response to arsenite, binding of Nrf2 to the HO-1 ARE preceded phosphorylation of H3S10 at the HO-1 ARE. Furthermore, arsenite-mediated occupancy of phosphorylated H3S10 at the HO-1 ARE was decreased in Nrf2-deficient mouse embryonic fibroblasts. These results suggest the involvement of H3S10 phosphorylation in the Nrf2-ARE axis by proposing that Nrf2 may influence H3S10 phosphorylation at the HO-1 ARE and additional promoter regions. Our data highlights the complex interplay between Nrf2 and H3S10 phosphorylation in arsenite-activated HO-1 transcription. PMID:26291278

  17. Forms of Mediation: The Case of Interpreter-Mediated Interactions in Medical Systems

    ERIC Educational Resources Information Center

    Baraldi, Claudio

    2009-01-01

    This paper analyses the forms of mediation in interlinguistic interactions performed in Italian healthcare services and in contexts of migration. The literature encourages dialogic transformative mediation, empowering participants' voices and changing cultural presuppositions in social systems. It may be doubtful, however, whether mediation can…

  18. 7 CFR 400.94 - Mediation.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... be made after issuance of the adverse decision by the Agency and before the appellant has a NAD... have any balance of the days remaining in the 30-day period to appeal to NAD if mediation is concluded... issued as a result of mediation, the participant will have a new 30-day period for appeals to NAD. (e)...

  19. 7 CFR 400.94 - Mediation.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... be made after issuance of the adverse decision by the Agency and before the appellant has a NAD... have any balance of the days remaining in the 30-day period to appeal to NAD if mediation is concluded... issued as a result of mediation, the participant will have a new 30-day period for appeals to NAD. (e)...

  20. 7 CFR 400.94 - Mediation.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... be made after issuance of the adverse decision by the Agency and before the appellant has a NAD... have any balance of the days remaining in the 30-day period to appeal to NAD if mediation is concluded... issued as a result of mediation, the participant will have a new 30-day period for appeals to NAD. (e)...

  1. 7 CFR 400.94 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... be made after issuance of the adverse decision by the Agency and before the appellant has a NAD... have any balance of the days remaining in the 30-day period to appeal to NAD if mediation is concluded... issued as a result of mediation, the participant will have a new 30-day period for appeals to NAD. (e)...

  2. 45 CFR 617.10 - Mediation.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Regulations Relating to Public Welfare (Continued) NATIONAL SCIENCE FOUNDATION NONDISCRIMINATION ON THE BASIS... the complainant and the recipient shall participate in the mediation process to the extent necessary... participate in the mediation process. (c) If the complainant and the recipient reach an agreement,...

  3. A Conceptual Framework for Mediated Environments

    ERIC Educational Resources Information Center

    Childs, Mark

    2010-01-01

    Background: Immersive virtual worlds are one of a range of different platforms that can be grouped under the concept of mediated environments, i.e. environments that create a metaphorical space in which participants can position themselves and be embodied. Synthesising the literatures concerning the various mediated environment technologies…

  4. Computer-Mediated Communication and Shared Learning.

    ERIC Educational Resources Information Center

    Dicks, Dennis J.

    1992-01-01

    Discussion of computer-mediated communication focuses on techniques developed to help groups of people communicate effectively, including cooperative learning, team building, groupware for cooperative work, decision support systems, organizational design, and shared learning. Implications for the design of computer-mediated communication systems…

  5. Que Es la Mediacion? (What Is Mediation?).

    ERIC Educational Resources Information Center

    Consortium for Appropriate Dispute Resolution in Special Education (CADRE), Eugene, OR.

    This brief paper, in Spanish, discusses the use of mediation as a method for resolving disagreements between schools or early intervention programs and parents of children with disabilities. It identifies benefits of mediation such as maintenance of an ongoing and positive relationship between the school and family, simple resolution of conflicts…

  6. State Mediation Systems. Quick Turn Around (QTA).

    ERIC Educational Resources Information Center

    National Association of State Directors of Special Education, Alexandria, VA.

    This report presents an analysis of the results of a survey of State Directors of Special Education on their state mediation systems. It notes requirements under the 1997 amendments to the Individuals with Disabilities Education Act (IDEA) that a mediation process must be available to parents desiring its use in conflict resolution. This report…

  7. A General Approach to Causal Mediation Analysis

    ERIC Educational Resources Information Center

    Imai, Kosuke; Keele, Luke; Tingley, Dustin

    2010-01-01

    Traditionally in the social sciences, causal mediation analysis has been formulated, understood, and implemented within the framework of linear structural equation models. We argue and demonstrate that this is problematic for 3 reasons: the lack of a general definition of causal mediation effects independent of a particular statistical model, the…

  8. On Mediation in Virtual Learning Environments.

    ERIC Educational Resources Information Center

    Davies, Larry; Hassan, W. Shukry

    2001-01-01

    Discusses concepts of mediation and focuses on the importance of implementing comprehensive virtual learning environments. Topics include education and technology as they relate to cultural change, social institutions, the Internet and computer-mediated communication, software design and human-computer interaction, the use of MOOs, and language.…

  9. 45 CFR 16.18 - Mediation.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 1 2012-10-01 2012-10-01 false Mediation. 16.18 Section 16.18 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION PROCEDURES OF THE DEPARTMENTAL GRANT APPEALS BOARD § 16.18 Mediation. (a) In cases pending before the Board. If the Board decides that...

  10. 45 CFR 16.18 - Mediation.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 45 Public Welfare 1 2011-10-01 2011-10-01 false Mediation. 16.18 Section 16.18 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION PROCEDURES OF THE DEPARTMENTAL GRANT APPEALS BOARD § 16.18 Mediation. (a) In cases pending before the Board. If the Board decides that...

  11. 45 CFR 16.18 - Mediation.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 45 Public Welfare 1 2013-10-01 2013-10-01 false Mediation. 16.18 Section 16.18 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION PROCEDURES OF THE DEPARTMENTAL GRANT APPEALS BOARD § 16.18 Mediation. (a) In cases pending before the Board. If the Board decides that...

  12. Is Retrieval Mediated after Repeated Testing?

    ERIC Educational Resources Information Center

    Kole, James A.; Healy, Alice F.

    2013-01-01

    In 2 main experiments, the mediated priming effect was used to determine whether retrieval continues to be mediated after repeated testing. In each experiment, participants used the keyword method to learn French vocabulary, then completed a modified lexical decision task in which they first translated a French word, and then made a lexical…

  13. A Mediation Strategy for Special Education Disputes.

    ERIC Educational Resources Information Center

    Mills, Guy E.; Duff-Mallams, Karla

    1999-01-01

    This article discusses the development of mediation as an alternative to litigation in resolving special education disputes. It describes the successes and challenges associated with special education mediation cases in Missouri prior to the 1997 IDEA amendments, which require such intervention, with an examination of four specific cases.…

  14. Verbal Mediation and Satiation in Young Children.

    ERIC Educational Resources Information Center

    Cook, Harold; Smothergill, Daniel

    The study demonstrates: (1) the occurrence of verbal mediation with its facilitory effect, and (2) the interfering effect of verbal satiation on mediational processes in a three-state chaining paradigm. 40 preschool children were randomly assigned to either a control (no satiation) or an experimental (satiation) group. The subjects in the control…

  15. 45 CFR 617.10 - Mediation.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... OF AGE IN PROGRAMS OR ACTIVITIES RECEIVING FEDERAL FINANCIAL ASSISTANCE FROM NSF § 617.10 Mediation. (a) NSF will refer to the Federal Mediation and Conciliation Service all complaints that fall within... possible. NSF will take no further administrative action on any complaint if the complainant refuses...

  16. 45 CFR 617.10 - Mediation.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... OF AGE IN PROGRAMS OR ACTIVITIES RECEIVING FEDERAL FINANCIAL ASSISTANCE FROM NSF § 617.10 Mediation. (a) NSF will refer to the Federal Mediation and Conciliation Service all complaints that fall within... possible. NSF will take no further administrative action on any complaint if the complainant refuses...

  17. 45 CFR 617.10 - Mediation.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... OF AGE IN PROGRAMS OR ACTIVITIES RECEIVING FEDERAL FINANCIAL ASSISTANCE FROM NSF § 617.10 Mediation. (a) NSF will refer to the Federal Mediation and Conciliation Service all complaints that fall within... possible. NSF will take no further administrative action on any complaint if the complainant refuses...

  18. Parent Mediation Empowers Sibling Conflict Resolution

    ERIC Educational Resources Information Center

    Ross, Hildy S.; Lazinski, Marysia J.

    2014-01-01

    Research Findings: For the current study, formal mediation procedures were adapted for families and parents were trained and asked to mediate their children's disputes; control group parents intervened as they normally would. Conflict negotiations with parents and their children (ages 3½-11 years) occurring 3 and 7 weeks following training,…

  19. Mediation Training for Middle School Students.

    ERIC Educational Resources Information Center

    Conflict Resolution Unlimited, Inc., Bellevue, WA.

    Young people need help in learning how to use alternative dispute resolution skills at school. Methods for teaching these skills are presented in this manual. The training centers on the following major themes: The Mediation Process, Cultural Diversity, Communication Skills, Feelings, Mediation Techniques, Dealing with Difficult Situations, and…

  20. 7 CFR 400.94 - Mediation.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ...: (a) Appellants have the right to seek mediation or other forms of alternative dispute resolution in... without resolution. If a new adverse decision that raises new matters or relies on different grounds is... in certified States that are not currently offering mediation on the subject in dispute. An...

  1. Semiotic Mediation within an AT Frame

    ERIC Educational Resources Information Center

    Maracci, Mirko; Mariotti, Maria Alessandra

    2013-01-01

    This article is meant to present a specific elaboration of the notion of mediation in relation to the use of artefacts to enhance mathematics teaching and learning: the elaboration offered by the Theory of Semiotic Mediation. In particular, it provides an explicit model--consistent with the activity-actions-operations framework--of the actions…

  2. Intercultural Conflict and Mediation: An Intergroup Perspective

    ERIC Educational Resources Information Center

    Rubenfeld, Sara; Clement, Richard

    2012-01-01

    This study investigates the role of components of intercultural competence in the use of intercultural mediation behaviors. Through the use of the Revised Intercultural Mediation Measure, an instrument revised by the authors, 291 Anglophone and 161 Francophone participants in Canada were asked to indicate their likelihood of employing various…

  3. Integrating Mediators and Moderators in Research Design

    ERIC Educational Resources Information Center

    MacKinnon, David P.

    2011-01-01

    The purpose of this article is to describe mediating variables and moderating variables and provide reasons for integrating them in outcome studies. Separate sections describe examples of moderating and mediating variables and the simplest statistical model for investigating each variable. The strengths and limitations of incorporating mediating…

  4. Sociocultural Theory and the Mediated Learning Experience.

    ERIC Educational Resources Information Center

    Kozulin, Alex

    2002-01-01

    Discusses the two theories that have contributed most to the development of the mediational approach to learning, Vygotskian sociocultural theory and Feuerstein's theory of Mediated Learning Experience. Both theories emphasize the importance of sociocultural forces in shaping a child's development and learning, and have generated a number of…

  5. Age-related deficits in skeletal muscle recovery following disuse are associated with neuromuscular junction instability and ER stress, not impaired protein synthesis

    PubMed Central

    Baehr, Leslie M.; West, Daniel W.D.; Marcotte, George; Marshall, Andrea G.; De Sousa, Luis Gustavo; Baar, Keith; Bodine, Sue C.

    2016-01-01

    Age-related loss of muscle mass and strength can be accelerated by impaired recovery of muscle mass following a transient atrophic stimulus. The aim of this study was to identify the mechanisms underlying the attenuated recovery of muscle mass and strength in old rats following disuse-induced atrophy. Adult (9 month) and old (29 month) male F344BN rats underwent hindlimb unloading (HU) followed by reloading. HU induced significant atrophy of the hindlimb muscles in both adult (17-38%) and old (8-29%) rats, but only the adult rats exhibited full recovery of muscle mass and strength upon reloading. Upon reloading, total RNA and protein synthesis increased to a similar extent in adult and old muscles. At baseline and upon reloading, however, proteasome-mediated degradation was suppressed leading to an accumulation of ubiquitin-tagged proteins and p62. Further, ER stress, as measured by CHOP expression, was elevated at baseline and upon reloading in old rats. Analysis of mRNA expression revealed increases in HDAC4, Runx1, myogenin, Gadd45a, and the AChRs in old rats, suggesting neuromuscular junction instability/denervation. Collectively, our data suggests that with aging, impaired neuromuscular transmission and deficits in the proteostasis network contribute to defects in muscle fiber remodeling and functional recovery of muscle mass and strength. PMID:26826670

  6. Human T-cell leukemia virus type-1-encoded protein HBZ represses p53 function by inhibiting the acetyltransferase activity of p300/CBP and HBO1

    PubMed Central

    Hoang, Kimson; Ankney, John A.; Nguyen, Stephanie T.; Rushing, Amanda W.; Polakowski, Nicholas; Miotto, Benoit; Lemasson, Isabelle

    2016-01-01

    Adult T-cell leukemia (ATL) is an often fatal malignancy caused by infection with the complex retrovirus, human T-cell Leukemia Virus, type 1 (HTLV-1). In ATL patient samples, the tumor suppressor, p53, is infrequently mutated; however, it has been shown to be inactivated by the viral protein, Tax. Here, we show that another HTLV-1 protein, HBZ, represses p53 activity. In HCT116 p53+/+ cells treated with the DNA-damaging agent, etoposide, HBZ reduced p53-mediated activation of p21/CDKN1A and GADD45A expression, which was associated with a delay in G2 phase-arrest. These effects were attributed to direct inhibition of the histone acetyltransferase (HAT) activity of p300/CBP by HBZ, causing a reduction in p53 acetylation, which has be linked to decreased p53 activity. In addition, HBZ bound to, and inhibited the HAT activity of HBO1. Although HBO1 did not acetylate p53, it acted as a coactivator for p53 at the p21/CDKN1A promoter. Therefore, through interactions with two separate HAT proteins, HBZ impairs the ability of p53 to activate transcription. This mechanism may explain how p53 activity is restricted in ATL cells that do not express Tax due to modifications of the HTLV-1 provirus, which accounts for a majority of patient samples. PMID:26625199

  7. Meta-data based mediator generation

    SciTech Connect

    Critchlaw, T

    1998-06-28

    Mediators are a critical component of any data warehouse; they transform data from source formats to the warehouse representation while resolving semantic and syntactic conflicts. The close relationship between mediators and databases requires a mediator to be updated whenever an associated schema is modified. Failure to quickly perform these updates significantly reduces the reliability of the warehouse because queries do not have access to the most current data. This may result in incorrect or misleading responses, and reduce user confidence in the warehouse. Unfortunately, this maintenance may be a significant undertaking if a warehouse integrates several dynamic data sources. This paper describes a meta-data framework, and associated software, designed to automate a significant portion of the mediator generation task and thereby reduce the effort involved in adapting to schema changes. By allowing the DBA to concentrate on identifying the modifications at a high level, instead of reprogramming the mediator, turnaround time is reduced and warehouse reliability is improved.

  8. Causal Mediation Analyses for Randomized Trials.

    PubMed

    Lynch, Kevin G; Cary, Mark; Gallop, Robert; Ten Have, Thomas R

    2008-01-01

    In the context of randomized intervention trials, we describe causal methods for analyzing how post-randomization factors constitute the process through which randomized baseline interventions act on outcomes. Traditionally, such mediation analyses have been undertaken with great caution, because they assume that the mediating factor is also randomly assigned to individuals in addition to the randomized baseline intervention (i.e., sequential ignorability). Because the mediating factors are typically not randomized, such analyses are unprotected from unmeasured confounders that may lead to biased inference. We review several causal approaches that attempt to reduce such bias without assuming that the mediating factor is randomized. However, these causal approaches require certain interaction assumptions that may be assessed if there is enough treatment heterogeneity with respect to the mediator. We describe available estimation procedures in the context of several examples from the literature and provide resources for software code. PMID:19484136

  9. Confounding in the Estimation of Mediation Effects.

    PubMed

    Li, Yan; Bienias, Julia L; Bennett, David A

    2007-03-01

    A mediation effect explains the relationship of a risk factor and an outcome through a mediator variable which is a step in their pathway. Under the assumption of no cycling in the causal relationship, we consider various situations in which a fourth variable may interfere the estimation of a mediation effect as a confounding factor. Our asymptotic results, which are supported by a Monte Carlo study, show that adjusting for confounding factors under certain conditions might lead to biased estimates. A general guideline is provided for when it is appropriate to adjust for confounding factors in estimating a mediation effect. We apply the guideline to the estimation of the mediation effect of Alzheimer's disease pathology in the relationship between the Apolipoprotein E ε4 allele and cognitive function among 125 deceased participants from the Religious Orders Study, a longitudinal, clinical-pathologic study of aging and Alzheimer's disease. PMID:17940582

  10. Confounding in the Estimation of Mediation Effects

    PubMed Central

    Li, Yan; Bienias, Julia L.; Bennett, David A.

    2007-01-01

    Summary A mediation effect explains the relationship of a risk factor and an outcome through a mediator variable which is a step in their pathway. Under the assumption of no cycling in the causal relationship, we consider various situations in which a fourth variable may interfere the estimation of a mediation effect as a confounding factor. Our asymptotic results, which are supported by a Monte Carlo study, show that adjusting for confounding factors under certain conditions might lead to biased estimates. A general guideline is provided for when it is appropriate to adjust for confounding factors in estimating a mediation effect. We apply the guideline to the estimation of the mediation effect of Alzheimer’s disease pathology in the relationship between the Apolipoprotein E ε4 allele and cognitive function among 125 deceased participants from the Religious Orders Study, a longitudinal, clinical-pathologic study of aging and Alzheimer’s disease. PMID:17940582

  11. 7 CFR 785.5 - Fees for mediation services.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 7 2010-01-01 2010-01-01 false Fees for mediation services. 785.5 Section 785.5... AGRICULTURE SPECIAL PROGRAMS CERTIFIED STATE MEDIATION PROGRAM § 785.5 Fees for mediation services. A requirement that non-USDA parties who elect to participate in mediation pay a fee for mediation services...

  12. Pure Mediated Priming: A Retrospective Semantic Matching Model

    ERIC Educational Resources Information Center

    Jones, Lara L.

    2010-01-01

    Mediated priming refers to the activation of a target (e.g., "stripes") by a prime (e.g., "lion") that is related indirectly via a connecting mediator (e.g., tiger). In previous mediated priming studies (e.g., McNamara & Altarriba, 1988), the mediator was associatively related to the prime. In contrast, pure mediated priming (e.g., "spoon" [right…

  13. Atomic Force Microscope Mediated Chromatography

    NASA Technical Reports Server (NTRS)

    Anderson, Mark S.

    2013-01-01

    The atomic force microscope (AFM) is used to inject a sample, provide shear-driven liquid flow over a functionalized substrate, and detect separated components. This is demonstrated using lipophilic dyes and normal phase chromatography. A significant reduction in both size and separation time scales is achieved with a 25-micron-length column scale, and one-second separation times. The approach has general applications to trace chemical and microfluidic analysis. The AFM is now a common tool for ultra-microscopy and nanotechnology. It has also been demonstrated to provide a number of microfluidic functions necessary for miniaturized chromatography. These include injection of sub-femtoliter samples, fluidic switching, and sheardriven pumping. The AFM probe tip can be used to selectively remove surface layers for subsequent microchemical analysis using infrared and tip-enhanced Raman spectroscopy. With its ability to image individual atoms, the AFM is a remarkably sensitive detector that can be used to detect separated components. These diverse functional components of microfluidic manipulation have been combined in this work to demonstrate AFM mediated chromatography. AFM mediated chromatography uses channel-less, shear-driven pumping. This is demonstrated with a thin, aluminum oxide substrate and a non-polar solvent system to separate a mixture of lipophilic dyes. In conventional chromatographic terms, this is analogous to thin-layer chromatography using normal phase alumina substrate with sheardriven pumping provided by the AFM tip-cantilever mechanism. The AFM detection of separated components is accomplished by exploiting the variation in the localized friction of the separated components. The AFM tip-cantilever provides the mechanism for producing shear-induced flows and rapid pumping. Shear-driven chromatography (SDC) is a relatively new concept that overcomes the speed and miniaturization limitations of conventional liquid chromatography. SDC is based on a

  14. Mediation: A Process That Works (Some Practical Thoughts for School Systems on Mediation of Special Education Disputes).

    ERIC Educational Resources Information Center

    Ekstrand, Richard E.

    The paper examines the issues and process involved in mediation of special education disputes. Mediation is an informal, optional procedure that may save time, money, and emotional strain for both staff and parents. Issues should not be mediated if there is no willingness to accept the mediation decision. Mediation should begin after all efforts…

  15. Gold Nanoparticle Mediated Cancer Immunotherapy

    PubMed Central

    Almeida, Joao Paulo Mattos; Figueroa, Elizabeth Raquel; Drezek, Rebekah Anna

    2013-01-01

    Significant progress has been made in the field of cancer immunotherapy, where the goal is to activate or modulate the body’s immune response against cancer. However, current immunotherapy approaches exhibit limitations of safety and efficacy due to systemic delivery. In this context, the use of nanotechnology for the delivery of cancer vaccines and immune adjuvants presents a number of advantages such as targeted delivery to immune cells, enhanced therapeutic effect, and reduced adverse outcomes. Recently, gold nanoparticles (AuNP) have been explored as immunotherapy carriers, creating new AuNP applications that merit a critical overview. This review highlights recent advances in the development of AuNP mediated immunotherapies that harness AuNP biodistribution, optical properties and their ability to deliver macromolecules such as peptides and oligonucleotides. It has been demonstrated that the use of AuNP carriers can improve the delivery and safety of immunotherapy agents, and that AuNP immunotherapies are well suited for synergistic combination therapy with existing cancer therapies like photothermal ablation. PMID:24103304

  16. Bacterially mediated mineralization of vaterite

    NASA Astrophysics Data System (ADS)

    Rodriguez-Navarro, Carlos; Jimenez-Lopez, Concepcion; Rodriguez-Navarro, Alejandro; Gonzalez-Muñoz, Maria Teresa; Rodriguez-Gallego, Manuel

    2007-03-01

    Myxococcus xanthus, a common soil bacterium, plays an active role in the formation of spheroidal vaterite. Bacterial production of CO 2 and NH 3 and the transformation of the NH 3 to NH4+ and OH -, thus increasing solution pH and carbonate alkalinity, set the physicochemical conditions (high supersaturation) leading to vaterite precipitation in the microenvironment around cells, and directly onto the surface of bacterial cells. In the latter case, fossilization of bacteria occurs. Vaterite crystals formed by aggregation of oriented nanocrystals with c-axis normal to the bacterial cell-wall, or to the core of the spherulite when bacteria were not encapsulated. While preferred orientation of vaterite c-axis appears to be determined by electrostatic affinity (ionotropic effect) between vaterite crystal (0001) planes and the negatively charged functional groups of organic molecules on the bacterium cell-wall or on extracellular polymeric substances (EPS), analysis of the changes in the culture medium chemistry as well as high resolution transmission electron microscopy (HRTEM) observations point to polymorph selection by physicochemical (kinetic) factors (high supersaturation) and stabilization by organics, both connected with bacterial activity. The latter is in agreement with inorganic precipitation of vaterite induced by NH 3 and CO 2 addition in the protein-rich sterile culture medium. Our results as well as recent studies on vaterite precipitation in the presence of different types of bacteria suggest that bacterially mediated vaterite precipitation is not strain-specific, and could be more common than previously thought.

  17. Nucleotide-mediated airway clearance.

    PubMed

    Schmid, Andreas; Clunes, Lucy A; Salathe, Mathias; Verdugo, Pedro; Dietl, Paul; Davis, C William; Tarran, Robert

    2011-01-01

    A thin layer of airway surface liquid (ASL) lines the entire surface of the lung and is the first point of contact between the lung and the environment. Surfactants contained within this layer are secreted in the alveolar region and are required to maintain a low surface tension and to prevent alveolar collapse. Mucins are secreted into the ASL throughout the respiratory tract and serve to intercept inhaled pathogens, allergens and toxins. Their removal by mucociliary clearance (MCC) is facilitated by cilia beating and hydration of the ASL by active ion transport. Throughout the lung, secretion, ion transport and cilia beating are under purinergic control. Pulmonary epithelia release ATP into the ASL which acts in an autocrine fashion on P2Y(2) (ATP) receptors. The enzymatic network describes in Chap. 2 then mounts a secondary wave of signaling by surface conversion of ATP into adenosine (ADO), which induces A(2B) (ADO) receptor-mediated responses. This chapter offers a comprehensive description of MCC and the extensive ramifications of the purinergic signaling network on pulmonary surfaces. PMID:21560046

  18. Protease-mediated drug delivery

    NASA Astrophysics Data System (ADS)

    Dickson, Eva F.; Goyan, Rebecca L.; Kennedy, James C.; Mackay, M.; Mendes, M. A. K.; Pottier, Roy H.

    2003-12-01

    Drugs used in disease treatment can cause damage to both malignant and normal tissue. This toxicity limits the maximum therapeutic dose. Drug targeting is of high interest to increase the therapeutic efficacy of the drug without increasing systemic toxicity. Certain tissue abnormalities, disease processes, cancers, and infections are characterized by high levels of activity of specific extracellular and/or intracellular proteases. Abnormally high activity levels of specific proteases are present at sites of physical or chemical trauma, blood clots, malignant tumors, rheumatoid arthritis, inflammatory bowel disease, gingival disease, glomerulonerphritis, and acute pancreatitis. Abnormal protease activity is suspected in development of liver thrombosis, pulmonary emphysema, atherosclerosis, and muscular dystrophy. Inactiviating disease-associated proteases by the administration of appropriate protease inhibitors has had limited success. Instead, one could use such proteases to target drugs to treat the condition. Protease mediated drug delivery offers such a possibility. Solubilizing groups are attached to insoluble drugs via a polypeptide chain which is specifically cleavable by certian proteases. When the solubilized drug enounters the protease, the solubilizing moieties are cleaved, and the drug precipitates at the disease location. Thus, a smaller systemic dosage could result in a therapeutic drug concentration at the treatment site with less systemic toxicity.

  19. Immune-mediated disorders of cats.

    PubMed

    Werner, L L; Gorman, N T

    1984-09-01

    Immune-mediated disorders in cats share many clinical and pathologic similarities with their counterparts in other species. Cats, however, are unique among domestic animals owing to the involvement of feline leukemia virus. In addition, a number of other infectious organisms can produce immune-mediated sequelae--that is, FIP virus, FeSFV, and H. felis. Therefore, the diagnostic and therapeutic aims in the management of feline immune-mediated disorders must take into account the probability of a primary or underlying disease process. PMID:6149649

  20. Resistance Factor-Mediated Spectinomycin Resistance

    PubMed Central

    Smith, David H.; Janjigian, J. A.; Prescott, Naomi; Anderson, Porter W.

    1970-01-01

    Of 100 natural isolates of drug-resistant enteric bacteria, 51 were resistant to spectinomycin (Spc) and 46 contained transferable R factors mediating Spc resistance. All SpcR R factors mediated streptomycin and bluensomycin resistance and were fi+ type. Extracts of R-SpcR strains adenylated Spc, dihydrospectinomycin, actinamine, streptomycin, and bluensomycin in vitro in the presence of adenosine triphosphate and Mg++. Results of genetic and biochemical studies support the hypothesis that these reactions are mediated by a single enzyme. PMID:16557684

  1. Gauge - Mediated Supersymmetry Breaking in String Compactifications

    SciTech Connect

    Diaconescu, Duiliu-Emanuel; Florea, Bogdan; Kachru, Shamit; Svrcek, Peter; /Stanford U., Phys. Dept. /SLAC

    2006-01-04

    We provide string theory examples where a toy model of a SUSY GUT or the MSSM is embedded in a compactification along with a gauge sector which dynamically breaks supersymmetry. We argue that by changing microscopic details of the model (such as precise choices of flux), one can arrange for the dominant mediation mechanism transmitting SUSY breaking to the Standard Model to be either gravity mediation or gauge mediation. Systematic improvement of such examples may lead to top-down models incorporating a solution to the SUSY flavor problem.

  2. kuzbanian-mediated cleavage of Drosophila Notch

    PubMed Central

    Lieber, Toby; Kidd, Simon; Young, Michael W.

    2002-01-01

    Loss of Kuzbanian, a member of the ADAM family of metalloproteases, produces neurogenic phenotypes in Drosophila. It has been suggested that this results from a requirement for kuzbanian-mediated cleavage of the Notch ligand Delta. Using transgenic Drosophila expressing transmembrane Notch proteins, we show that kuzbanian, independent of any role in Delta processing, is required for the cleavage of Notch. We show that Kuzbanian can physically associate with Notch and that removal of kuzbanian activity by RNA-mediated interference in Drosophila tissue culture cells eliminates processing of ligand-independent transmembrane Notch molecules. Our data suggest that in Drosophila, kuzbanian can mediate S2 cleavage of Notch. PMID:11799064

  3. Towards the natural gauge mediation

    NASA Astrophysics Data System (ADS)

    Ding, Ran; Li, Tianjun; Wang, Liucheng; Zhu, Bin

    2015-10-01

    The sweet spot supersymmetry (SUSY) solves the μ/ B μ problem in the Minimal Supersymmetric Standard Model (MSSM) with gauge mediated SUSY breaking (GMSB) via the generalized Giudice-Masiero (GM) mechanism where only the μ-term and soft Higgs masses are generated at the unification scale of the Grand Unified Theory (GUT) due to the approximate PQ symmetry. Because all the other SUSY breaking soft terms are generated via the GMSB below the GUT scale, there exists SUSY electroweak (EW) fine-tuning problem to explain the 125 GeV Higgs boson mass due to small trilinear soft term. Thus, to explain the Higgs boson mass, we propose the GMSB with both the generalized GM mechanism and Higgs-messenger interactions. The renormalization group equations are runnings from the GUT scale down to EW scale. So the EW symmetry breaking can be realized easier. We can keep the gauge coupling unification and solution to the flavor problem in the GMSB, as well as solve the μ/ B μ -problem. Moreover, there are only five free parameters in our model. So we can determine the characteristic low energy spectra and explore its distinct phenomenology. The fine-tuning measure can be as low as 100. For some benchmark points, the stop mass can be as low as 1.7 TeV while the glunio mass is around 2.5 TeV. The gravitino dark matter can come from a thermal production with the correct relic density and be consistent with the thermal leptogenesis. Because gluino and stop can be relatively light in our model, how to search for such GMSB at the upcoming run II of the LHC experiment could be very interesting.

  4. Selecting a model of supersymmetry breaking mediation

    SciTech Connect

    AbdusSalam, S. S.; Allanach, B. C.; Dolan, M. J.; Feroz, F.; Hobson, M. P.

    2009-08-01

    We study the problem of selecting between different mechanisms of supersymmetry breaking in the minimal supersymmetric standard model using current data. We evaluate the Bayesian evidence of four supersymmetry breaking scenarios: mSUGRA, mGMSB, mAMSB, and moduli mediation. The results show a strong dependence on the dark matter assumption. Using the inferred cosmological relic density as an upper bound, minimal anomaly mediation is at least moderately favored over the CMSSM. Our fits also indicate that evidence for a positive sign of the {mu} parameter is moderate at best. We present constraints on the anomaly and gauge mediated parameter spaces and some previously unexplored aspects of the dark matter phenomenology of the moduli mediation scenario. We use sparticle searches, indirect observables and dark matter observables in the global fit and quantify robustness with respect to prior choice. We quantify how much information is contained within each constraint.

  5. Upscaling of Bio-mediated Soil Improvement

    SciTech Connect

    J. T. DeJong; B. C. Martinez; B. M. Mortensen; D. C. Nelson; J. T. Waller; M. H. Weil; T. R. Ginn; T. Weathers; T. Barkouki; Y. Fujita; G. Redden; C. Hunt; D. Major; B. Tunyu

    2009-10-01

    As demand for soil improvement continues to increase, new, sustainable, and innocuous methods are needed to alter the mechanical properties of soils. Recent research has demonstrated the potential of bio-mediated soil improvement for geotechnical applications (DeJong et al. 2006, Whiffin et al. 2007). Upscaling the bio-mediated treatment process for in situ implementation presents a number of challenges to be addressed, including soil and pore fluid interactions, bioaugmentation versus biostimulation of microbial communities, controlled distribution of mediated calcite precipitation, and permanence of the cementation. Current studies are utilizing large-scale laboratory experiments, non-destructive geophysical measurements, and modeling, to develop an optimized and predictable bio-mediated treatment method.

  6. Molecular biology Mediating transcription and RNA export

    PubMed Central

    Rubin, Jonathan D.; Taatjes, Dylan J.

    2016-01-01

    The finding that the Mediator protein complex contributes to messenger RNA export from the nucleus in yeast adds to a growing list of roles for the complex in regulating transcriptional processes. PMID:26450052

  7. Characterization of the Biomedical Query Mediation Process

    PubMed Central

    Hruby, Gregory W.; Boland, Mary Regina; Cimino, James J.; Gao, Junfeng; Wilcox, Adam B.; Hirschberg, Julia; Weng, Chunhua

    To most medical researchers, databases are obscure black boxes. Query analysts are often indispensable guides aiding researchers to perform mediated data queries. However, this approach does not scale up and is time-consuming and expensive. We analyzed query mediation dialogues to inform future designs of intelligent query mediation systems. Thirty-one mediated query sessions for 22 research projects were recorded and transcribed. We analyzed 10 of these to develop an annotation schema for dialogue acts through iterative refinement. Three coders independently annotated all 3160 dialogue acts. We assessed the inter-rater agreement and resolved disagreement by group consensus. This study contributes early knowledge of the query negotiation space for medical research. We conclude that research data query formulation is not a straightforward translation from researcher data needs to database queries, but rather iterative, process-oriented needs assessment and refinement. PMID:24303242

  8. Genesis and intersubjectivity: levels of mediation.

    PubMed

    Yamamoto, Toshiya

    2012-09-01

    I will make a brief comment on the thesis of José C. Loredo-Narciandi and José C. Sánchez-González (2012) "Neither Dichotomies Nor Dualism; Simply Genesis". Denying any reductionism and reification, they insists the importance of inseparable relation between subject and object, then discuss about genesis. I pointed out that their argument lacks an important element, i.e., mediator that differ from mere physical object. After discussing mediators nature, I discriminate the three level of interaction which mediated by mediator. The first is the pre-interaction level, the second is physical interaction level and the third is sign or language interaction level. The last argument of mine is about how we can solve the problem of reification and reductionism. In the argument it is pointed out that intersubjectivity is key concept for understanding and solving the problem appropriately. PMID:22628155

  9. Confronting Conflict Peacefully: Peer Mediation in Schools.

    ERIC Educational Resources Information Center

    Cutrona, Cheryl; Guerin, Diane

    1994-01-01

    Suggests peer mediation as an alternative dispute resolution approach. Indicates the need to shift the focus from crisis intervention to prevention and to integrate dispute resolution skills into the school environment. (JOW)

  10. Dark matter prospects in deflected mirage mediation

    NASA Astrophysics Data System (ADS)

    Holmes, Michael; Nelson, Brent D.

    2009-07-01

    The recently introduced deflected mirage mediation (DMM) model is a string-motivated paradigm in which all three of the major supersymmetry-breaking transmission mechanisms are operative. We begin a systematic exploration of the parameter space of this rich model context, paying special attention to the pattern of gaugino masses which arise. In this work we focus on the dark matter phenomenology of the DMM model as such signals are the least influenced by the model-dependent scalar masses. We find that a large portion of the parameter space in which the three mediation mechanisms have a similar effective mass scale of 1 TeV or less will be probed by future direct and indirect detection experiments. Distinguishing deflected mirage mediation from the mirage model without gauge mediation will prove difficult without collider input, though we indicate how gamma ray signals may provide an opportunity for distinguishing between the two paradigms.

  11. 34 CFR 303.419 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... REHABILITATIVE SERVICES, DEPARTMENT OF EDUCATION EARLY INTERVENTION PROGRAM FOR INFANTS AND TODDLERS WITH... explain the benefits of the mediation process and encourage the parents to use the process. (Authority:...

  12. Extensible Ontological Modeling Framefork for Subject Mediation

    NASA Astrophysics Data System (ADS)

    Kalinichenko, L. A.; Skvortsov, N. A.

    An approach for extensible ontological model construction in a mediation environment intended for heterogeneous information sources integration in various subject domains is presented. A mediator ontological language (MOL) may depend on a subject domain and is to be defined at the mediator consolidation phase. On the other hand, for different information sources different ontological models (languages) can be used to define their own ontologies. Reversible mapping of the source ontological models into MOL is needed for information sources registration at the mediator. An approach for such reversible mapping is demonstrated for a class of the Web information sources. It is assumed that such sources apply the DAML+OIL ontological model. A subset of the hybrid object-oriented and semi-structured canonical mediator data model is used for the core of MOL. Construction of a reversible mapping of DAML+OIL into an extension of the core of MOL is presented in the paper. Such mapping is a necessary pre-requisite for contextualizing and registration of information sources at the mediator. The mapping shows how extensible MOL can be constructed. The approach proposed is oriented on digital libraries where retrieval is focused on information content, rather than on information entities.

  13. Mediators of transdiagnostic group cognitive behavior therapy.

    PubMed

    Talkovsky, Alexander M; Norton, Peter J

    2014-12-01

    The efficacy of cognitive-behavioral therapy (CBT) for anxiety is well established. Investigations into the mechanisms of change in CBT report changes in cognitive vulnerabilities mediating improvements over the course of treatment. As anxiety disorders share certain risk factors, there is a trend toward CBT emphasizing these vulnerabilities, including negative affectivity (NA) and also more specific constructs such as anxiety sensitivity (AS) and intolerance of uncertainty (IU). The purpose of this investigation was to analyze potential mediators of anxiety reduction over the course of transdiagnostic group CBT. NA, AS, and IU all decreased over the course of treatment. Among the potential mediators, change in NA had a significant relationship with change in anxiety but change in AS and change in IU did not. Neither the main effect of primary diagnosis nor the interactions between potential mediators and primary diagnoses were significant, indicating that there were no differential changes in anxiety or the potential mediators across primary diagnoses. Results strongly point toward NA as an overarching mediator of anxiety reduction during transdiagnostic group CBT. PMID:25445082

  14. Gazetteer Brokering through Semantic Mediation

    NASA Astrophysics Data System (ADS)

    Hobona, G.; Bermudez, L. E.; Brackin, R.

    2013-12-01

    web technologies, including ontologies and a semantic mediator. The semantically-enhanced SPEGG allowed a client to submit a single query (e.g. ';hills') and to retrieve data from two separate gazetteers with different vocabularies (e.g. where one refers to ';summits' another refers to ';hills'). Supporting the SPEGG was a SPARQL server that held the ontologies and processed queries on them. Earth Science surveys and forecast always have a place on Earth. Being able to share the information about a place and solve inconsistencies about that place from different sources will enable geoscientists to better do their research. In the advent of mobile geo computing and location based services (LBS), brokering gazetteers will provide geoscientists with access to gazetteer services rich with information and functionality beyond that offered by current generic gazetteers.

  15. Sharp sensitivity bounds for mediation under unmeasured mediator-outcome confounding

    PubMed Central

    Ding, Peng; Vanderweele, Tyler J.

    2016-01-01

    It is often of interest to decompose the total effect of an exposure into a component that acts on the outcome through some mediator and a component that acts independently through other pathways. Said another way, we are interested in the direct and indirect effects of the exposure on the outcome. Even if the exposure is randomly assigned, it is often infeasible to randomize the mediator, leaving the mediator-outcome confounding not fully controlled. We develop a sensitivity analysis technique that can bound the direct and indirect effects without parametric assumptions about the unmeasured mediator-outcome confounding.

  16. Estimating and Testing Mediation Effects with Censored Data

    ERIC Educational Resources Information Center

    Wang, Lijuan; Zhang, Zhiyong

    2011-01-01

    This study investigated influences of censored data on mediation analysis. Mediation effect estimates can be biased and inefficient with censoring on any one of the input, mediation, and output variables. A Bayesian Tobit approach was introduced to estimate and test mediation effects with censored data. Simulation results showed that the Bayesian…

  17. 29 CFR 1403.4 - Assignment of mediators.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false Assignment of mediators. 1403.4 Section 1403.4 Labor Regulations Relating to Labor (Continued) FEDERAL MEDIATION AND CONCILIATION SERVICE FUNCTIONS AND DUTIES § 1403.4 Assignment of mediators. The Federal Service will assign one or more mediators to each labor-management dispute in which it has...

  18. Mediation...An Alternative That Works. Second Edition.

    ERIC Educational Resources Information Center

    Davis, Albie

    A 5-part handbook provides elementary and secondary educators and community organizations with background information and resources for teaching mediation strategies. An introduction (part I) provides a rationale for mediation as a form of dispute resolution and for mediation programs in the schools. Part II seeks to define mediation by describing…

  19. A State Space Modeling Approach to Mediation Analysis

    ERIC Educational Resources Information Center

    Gu, Fei; Preacher, Kristopher J.; Ferrer, Emilio

    2014-01-01

    Mediation is a causal process that evolves over time. Thus, a study of mediation requires data collected throughout the process. However, most applications of mediation analysis use cross-sectional rather than longitudinal data. Another implicit assumption commonly made in longitudinal designs for mediation analysis is that the same mediation…

  20. 15 CFR 930.115 - Termination of mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 3 2010-01-01 2010-01-01 false Termination of mediation. 930.115... MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.115 Termination of mediation. Mediation shall terminate: (a) At any time the Federal and State agencies agree to...

  1. Surveying Parental Mediation: Connections, Challenges and Questions for Media Literacy

    ERIC Educational Resources Information Center

    Mendoza, Kelly

    2009-01-01

    This paper examines three strategies of parental mediation--coviewing, restrictive mediation, and active mediation--in order to make connections, challenge, and raise questions for media literacy. Coviewing, whether it is intentional practice, or whether it functions to promote media literacy, is explored. Restrictive mediation, how it connects to…

  2. 15 CFR 923.83 - Mediation of amendments.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 3 2010-01-01 2010-01-01 false Mediation of amendments. 923.83... Programs § 923.83 Mediation of amendments. (a) Section 307(h)(2) of the Act provides for mediation of... management program. Accordingly mediation is available to states or federal agencies when a...

  3. Reducing Levels of Elementary School Violence with Peer Mediation

    ERIC Educational Resources Information Center

    Schellenberg, Rita Cantrell; Parks-Savage, Agatha; Rehfuss, Mark

    2007-01-01

    The effectiveness of an existing peer mediation program in a diverse, suburban elementary school was examined. Peer mediation was available to all students (N = 825). Three-year longitudinal data showed significant reductions in the school's out-of-school suspensions after implementation of the peer mediation program. Mediation training also…

  4. Guidelines for the Investigation of Mediating Variables in Business Research

    PubMed Central

    Coxe, Stefany; Baraldi, Amanda N.

    2013-01-01

    Business theories often specify the mediating mechanisms by which a predictor variable affects an outcome variable. In the last 30 years, investigations of mediating processes have become more widespread with corresponding developments in statistical methods to conduct these tests. The purpose of this article is to provide guidelines for mediation studies by focusing on decisions made prior to the research study that affect the clarity of conclusions from a mediation study, the statistical models for mediation analysis, and methods to improve interpretation of mediation results after the research study. Throughout this article, the importance of a program of experimental and observational research for investigating mediating mechanisms is emphasized. PMID:25237213

  5. Arsenic promotes angiogenesis in vitro via a heme oxygenase-1-dependent mechanism

    SciTech Connect

    Meng Dan; Wang Xin; Chang Qingshan; Hitron, Andrew; Zhang Zhuo; Xu Mei; Chen Gang; Luo Jia; Jiang Binghua; Fang Jing; Shi Xianglin

    2010-05-01

    Angiogenesis and vessel remodeling are fundamental to the pathogenesis of a number of diseases caused by environmental arsenic exposure, including tumorigenesis and cardiovascular diseases. Arsenic (AsIII) has been shown to stimulate angiogenesis and vascular remodeling in vivo. However, the exact molecular mechanisms accounting for arsenic-induced angiogenesis are not clear. The present study investigates the role of heme oxygenase-1 (HO-1) in sodium arsenite-mediated angiogenesis in vitro. Transwell assay, three-dimensional Matrigel assay, RT-PCR, ELISA and immunoblotting were used to determine cell migration, vascular tube formation, mRNA and protein expression. Chromatin immunoprecipitation and luciferase assay were applied to examine the DNA binding with protein and HO-1 transcriptional activity. Here, we report that low concentrations of arsenite (0.1-1 muM) stimulated cell migration and vascular tube formation in human microvascular endothelial cells (HMVEC). Arsenite induced HO-1 mRNA and protein expression. Knock down of HO-1 expression decreased arsenite-induced VEGF expression, cell migration, and tube formation. We showed that arsenite promoted dissociation of Bach1 (a transcriptional repressor) from the HO-1 enhancers and increased Nrf2 binding to these elements. Site directed mutagenesis assay identified that Bach1 cysteine residues 557 and 574 were essential for the induction of HO-1 gene in response to arsenite. These findings demonstrate a role for HO-1 in arsenite-mediated angiogenesis in vitro.

  6. DNA damage-induced regulatory interplay between DAXX, p53, ATM kinase and Wip1 phosphatase

    PubMed Central

    Brazina, Jan; Svadlenka, Jan; Macurek, Libor; Andera, Ladislav; Hodny, Zdenek; Bartek, Jiri; Hanzlikova, Hana

    2015-01-01

    Death domain-associated protein 6 (DAXX) is a histone chaperone, putative regulator of apoptosis and transcription, and candidate modulator of p53-mediated gene expression following DNA damage. DAXX becomes phosphorylated upon DNA damage, however regulation of this modification, and its relationship to p53 remain unclear. Here we show that in human cells exposed to ionizing radiation or genotoxic drugs etoposide and neocarzinostatin, DAXX became rapidly phosphorylated in an ATM kinase-dependent manner. Our deletion and site-directed mutagenesis experiments identified Serine 564 (S564) as the dominant ATM-targeted site of DAXX, and immunofluorescence experiments revealed localization of S564-phosphorylated DAXX to PML nuclear bodies. Furthermore, using a panel of human cell types, we identified the p53-regulated Wip1 protein phosphatase as a key negative regulator of DAXX phosphorylation at S564, both in vitro and in cells. Consistent with the emerging oncogenic role of Wip1, its DAXX-dephosphorylating impact was most apparent in cancer cell lines harboring gain-of-function mutant and/or overexpressed Wip1. Unexpectedly, while Wip1 depletion increased DAXX phosphorylation both before and after DNA damage and increased p53 stability and transcriptional activity, knock-down of DAXX impacted neither p53 stabilization nor p53-mediated expression of Gadd45a, Noxa, Mdm2, p21, Puma, Sesn2, Tigar or Wip1. Consistently, analyses of cells with genetic, TALEN-mediated DAXX deletion corroborated the notion that neither phosphorylated nor non-phosphorylated DAXX is required for p53-mediated gene expression upon DNA damage. Overall, we identify ATM kinase and Wip1 phosphatase as opposing regulators of DAXX-S564 phosphorylation, and propose that the role of DAXX phosphorylation and DAXX itself are independent of p53-mediated gene expression. PMID:25659035

  7. POWER ANALYSIS FOR COMPLEX MEDIATIONAL DESIGNS USING MONTE CARLO METHODS

    PubMed Central

    Thoemmes, Felix; MacKinnon, David P.; Reiser, Mark R.

    2013-01-01

    Applied researchers often include mediation effects in applications of advanced methods such as latent variable models and linear growth curve models. Guidance on how to estimate statistical power to detect mediation for these models has not yet been addressed in the literature. We describe a general framework for power analyses for complex mediational models. The approach is based on the well known technique of generating a large number of samples in a Monte Carlo study, and estimating power as the percentage of cases in which an estimate of interest is significantly different from zero. Examples of power calculation for commonly used mediational models are provided. Power analyses for the single mediator, multiple mediators, three-path mediation, mediation with latent variables, moderated mediation, and mediation in longitudinal designs are described. Annotated sample syntax for Mplus is appended and tabled values of required sample sizes are shown for some models. PMID:23935262

  8. What Do Grievants Think of Grievance Mediation: A Riposte to "Counterpoint: Response to Mediator Caraway."

    ERIC Educational Resources Information Center

    Jascourt, Hugh D.

    1992-01-01

    In a previous article, Gordon A. Gregory and Mark Heinen criticized John M. Caraway's article describing recent successful experiences with the use of mediation in place of arbitration for failing to note the perception of the grievants. A reexamination of the data show that 80 percent of the grievants were satisfied with the mediation procedure.…

  9. A neural mediator of human anxiety sensitivity.

    PubMed

    Harrison, Ben J; Fullana, Miquel A; Soriano-Mas, Carles; Via, Esther; Pujol, Jesus; Martínez-Zalacaín, Ignacio; Tinoco-Gonzalez, Daniella; Davey, Christopher G; López-Solà, Marina; Pérez Sola, Victor; Menchón, José M; Cardoner, Narcís

    2015-10-01

    Advances in the neuroscientific understanding of bodily autonomic awareness, or interoception, have led to the hypothesis that human trait anxiety sensitivity (AS)-the fear of bodily autonomic arousal-is primarily mediated by the anterior insular cortex. Despite broad appeal, few experimental studies have comprehensively addressed this hypothesis. We recruited 55 individuals exhibiting a range of AS and assessed them with functional magnetic resonance imaging (fMRI) during aversive fear conditioning. For each participant, three primary measures of interest were derived: a trait Anxiety Sensitivity Index score; an in-scanner rating of elevated bodily anxiety sensations during fear conditioning; and a corresponding estimate of whole-brain functional activation to the conditioned versus nonconditioned stimuli. Using a voxel-wise mediation analysis framework, we formally tested for 'neural mediators' of the predicted association between trait AS score and in-scanner anxiety sensations during fear conditioning. Contrary to the anterior insular hypothesis, no evidence of significant mediation was observed for this brain region, which was instead linked to perceived anxiety sensations independently from AS. Evidence for significant mediation was obtained for the dorsal anterior cingulate cortex-a finding that we argue is more consistent with the hypothesized role of human cingulofrontal cortex in conscious threat appraisal processes, including threat-overestimation. This study offers an important neurobiological validation of the AS construct and identifies a specific neural substrate that may underlie high AS clinical phenotypes, including but not limited to panic disorder. PMID:26147233

  10. Architecture of the Mediator head module.

    PubMed

    Imasaki, Tsuyoshi; Calero, Guillermo; Cai, Gang; Tsai, Kuang-Lei; Yamada, Kentaro; Cardelli, Francesco; Erdjument-Bromage, Hediye; Tempst, Paul; Berger, Imre; Kornberg, Guy Lorch; Asturias, Francisco J; Kornberg, Roger D; Takagi, Yuichiro

    2011-07-14

    Mediator is a key regulator of eukaryotic transcription, connecting activators and repressors bound to regulatory DNA elements with RNA polymerase II (Pol II). In the yeast Saccharomyces cerevisiae, Mediator comprises 25 subunits with a total mass of more than one megadalton (refs 5, 6) and is organized into three modules, called head, middle/arm and tail. Our understanding of Mediator assembly and its role in regulating transcription has been impeded so far by limited structural information. Here we report the crystal structure of the essential Mediator head module (seven subunits, with a mass of 223 kilodaltons) at a resolution of 4.3 ångströms. Our structure reveals three distinct domains, with the integrity of the complex centred on a bundle of ten helices from five different head subunits. An intricate pattern of interactions within this helical bundle ensures the stable assembly of the head subunits and provides the binding sites for general transcription factors and Pol II. Our structural and functional data suggest that the head module juxtaposes transcription factor IIH and the carboxy-terminal domain of the largest subunit of Pol II, thereby facilitating phosphorylation of the carboxy-terminal domain of Pol II. Our results reveal architectural principles underlying the role of Mediator in the regulation of gene expression. PMID:21725323

  11. Light mediators in dark matter direct detections

    SciTech Connect

    Li, Tai; Miao, Sen; Zhou, Yu-Feng

    2015-03-17

    In an extended effective operator framework, we investigate in detail the effects of light mediators on the event spectra of dark matter (DM)-nucleus scatterings. The presence of light mediators changes the interpretation of the current experimental data, especially the determination of DM particle mass. We show by analytic and numerical illustrations that in general for all the operators relevant to spin-independent scatterings, the DM particle mass allowed by a given set of experimental data increases significantly when the mediator particle becomes lighter. For instance, in the case of CDMS-II-Si experiment, the allowed DM particle mass can reach ∼50 (100) GeV at 68% (90%) confidence level, which is much larger than ∼10 GeV in the case with contact interactions. The increase of DM particle mass saturates when the mediator mass is below O(10) MeV. The upper limits from other experiments such as SuperCDMS, CDMSlite, CDEX, XENON10/100, LUX, PandaX etc. all tend to be weaker toward high DM mass regions. In a combined analysis, we show that the presence of light mediators can partially relax the tension in the current results of CDMS-II-Si, SuperCDMS and LUX.

  12. Surmounting elusive barriers: the case for bioethics mediation.

    PubMed

    Bergman, Edward J

    2013-01-01

    This article describes, analyzes, and advocates for management of clinical healthcare conflict by a process commonly referred to as bioethics mediation. Section I provides a brief introduction to classical mediation outside the realm of clinical healthcare. Section II highlights certain distinguishing characteristics of bioethics mediation. Section III chronicles the history of bioethics mediation and references a number of seminal writings on the subject. Finally, Section IV analyzes barriers that have, thus far, limited the widespread implementation of bioethics mediation. PMID:23631331

  13. Intercellular Lipid Mediators and GPCR Drug Discovery

    PubMed Central

    Im, Dong-Soon

    2013-01-01

    G-protein-coupled receptors (GPCR) are the largest superfamily of receptors responsible for signaling between cells and tissues, and because they play important physiological roles in homeostasis, they are major drug targets. New technologies have been developed for the identification of new ligands, new GPCR functions, and for drug discovery purposes. In particular, intercellular lipid mediators, such as, lysophosphatidic acid and sphingosine 1-phosphate have attracted much attention for drug discovery and this has resulted in the development of fingolimod (FTY-720) and AM095. The discovery of new intercellular lipid mediators and their GPCRs are discussed from the perspective of drug development. Lipid GPCRs for lysophospholipids, including lysophosphatidylserine, lysophosphatidylinositol, lysophosphatidylcholine, free fatty acids, fatty acid derivatives, and other lipid mediators are reviewed. PMID:24404331

  14. Tau pathology-mediated presynaptic dysfunction.

    PubMed

    Moreno, H; Morfini, G; Buitrago, L; Ujlaki, G; Choi, S; Yu, E; Moreira, J E; Avila, J; Brady, S T; Pant, H; Sugimori, M; Llinás, R R

    2016-06-14

    Brain tauopathies are characterized by abnormal processing of tau protein. While somatodendritic tau mislocalization has attracted considerable attention in tauopathies, the role of tau pathology in axonal transport, connectivity and related dysfunctions remains obscure. We have previously shown using the squid giant synapse that presynaptic microinjection of recombinant human tau protein (htau42) results in failure of synaptic transmission. Here, we evaluated molecular mechanisms mediating this effect. Thus, the initial event, observed after htau42 presynaptic injection, was an increase in transmitter release. This event was mediated by calcium release from intracellular stores and was followed by a reduction in evoked transmitter release. The effect of htau42 on synaptic transmission was recapitulated by a peptide comprising the phosphatase-activating domain of tau, suggesting activation of phosphotransferases. Accordingly, findings indicated that htau42-mediated toxicity involves the activities of both GSK3 and Cdk5 kinases. PMID:27012611

  15. mitochondrial pathway for biosynthesis of lipid mediators

    PubMed Central

    Tyurina, Yulia Y.; Poloyac, Samuel M.; Tyurin, Vladimir A.; Kapralov, Alexander A.; Jiang, Jianfei; Anthonymuthu, Tamil Selvan; Kapralova, Valentina I.; Vikulina, Anna S.; Jung, Mi-Yeon; Epperly, Michael W.; Mohammadyani, Dariush; Klein-Seetharaman, Judith; Jackson, Travis C.; Kochanek, Patrick M.; Pitt, Bruce R.; Greenberger, Joel S.; Vladimirov, Yury A.; Bayır, Hülya; Kagan, Valerian E.

    2014-01-01

    The central role of mitochondria in metabolic pathways and in cell death mechanisms requires sophisticated signaling systems. Essential in this signaling process is an array of lipid mediators derived from polyunsaturated fatty acids. However, the molecular machinery for the production of oxygenated polyunsaturated fatty acids is localized in the cytosol and their biosynthesis has not been identified in mitochondria. Here we report that a range of diversified polyunsaturated molecular species derived from a mitochondria-specific phospholipid, cardiolipin, are oxidized by the intermembrane space hemoprotein, cytochrome c. We show that an assortment of oxygenated cardiolipin species undergoes phospholipase A2-catalyzed hydrolysis thus generating multiple oxygenated fatty acids, including well known lipid mediators. This represents a new biosynthetic pathway for lipid mediators. We demonstrate that this pathway including oxidation of polyunsaturated cardiolipins and accumulation of their hydrolysis products – oxygenated linoleic, arachidonic acids and monolyso-cardiolipins – is activated in vivo after acute tissue injury. PMID:24848241

  16. Antibody-Mediated Lung Transplant Rejection

    PubMed Central

    Hachem, Ramsey

    2012-01-01

    Antibody-mediated rejection after lung transplantation remains enigmatic. However, emerging evidence over the past several years suggests that humoral immunity plays an important role in allograft rejection. Indeed, the development of donor-specific antibodies after transplantation has been identified as an independent risk factor for acute cellular rejection and bronchiolitis obliterans syndrome. Furthermore, cases of acute antibody-mediated rejection resulting in severe allograft dysfunction have been reported, and these demonstrate that antibodies can directly injure the allograft. However, the incidence and toll of antibody-mediated rejection are unknown because there is no widely accepted definition and some cases may be unrecognized. Clearly, humoral immunity has become an important area for research and clinical investigation. PMID:23002428

  17. Mediator kinase module and human tumorigenesis

    PubMed Central

    Clark, Alison D.; Oldenbroek, Marieke; Boyer, Thomas G.

    2016-01-01

    Mediator is a conserved multi-subunit signal processor through which regulatory informatiosn conveyed by gene-specific transcription factors is transduced to RNA Polymerase II (Pol II). In humans, MED13, MED12, CDK8 and Cyclin C (CycC) comprise a four-subunit “kinase” module that exists in variable association with a 26-subunit Mediator core. Genetic and biochemical studies have established the Mediator kinase module as a major ingress of developmental and oncogenic signaling through Mediator, and much of its function in signal-dependent gene regulation derives from its resident CDK8 kinase activity. For example, CDK8-targeted substrate phosphorylation impacts transcription factor half-life, Pol II activity and chromatin chemistry and functional status. Recent structural and biochemical studies have revealed a precise network of physical and functional subunit interactions required for proper kinase module activity. Accordingly, pathologic change in this activity through altered expression or mutation of constituent kinase module subunits can have profound consequences for altered signaling and tumor formation. Herein, we review the structural organization, biological function and oncogenic potential of the Mediator kinase module. We focus principally on tumor-associated alterations in kinase module subunits for which mechanistic relationships as opposed to strictly correlative associations are established. These considerations point to an emerging picture of the Mediator kinase module as an oncogenic unit, one in which pathogenic activation/deactivation through component change drives tumor formation through perturbation of signal-dependent gene regulation. It follows that therapeutic strategies to combat CDK8-driven tumors will involve targeted modulation of CDK8 activity or pharmacologic manipulation of dysregulated CDK8-dependent signaling pathways. PMID:26182352

  18. Criminal mediation for minors in Israel.

    PubMed

    Kandel, Isack; Arie, Yael; Glasner, Sharon

    2007-01-01

    Mediation was introduced in Canada in 1974 in order to handle a crime of robbery and vandalization committed by adolescents. After mediation, these adolescents agreed to apologize to each of their victims and pay restitution. Several countries (Canada, England, Finland, and the U.S.) have now made this opportunity available in the cases of young offenders. This review describes the process in the south of Israel. We find this method very powerful, but further studies are needed. Due to resource problems, it will not become mainstream in the near future. PMID:17334626

  19. Interface-mediated growth of monodispersed nanostructures.

    PubMed

    Wang, Xun; Peng, Qing; Li, Yadong

    2007-08-01

    This Account focuses on the recent development of interface-mediated growth of monodispersed nanostructures in our laboratory. By rationally tuning the chemical reactions at various gas-liquid, solid-solid, liquid-liquid, and liquid-solid-solution interfaces, we could readily synthesize nanostructures such as hollow microspheres, core-shell nanoparticles, and monodispersed nanocrystals. These advances in interface-mediated synthesis could lead to progress in the development of nanocrystal crystallography and encourage some more unique and exciting research and applications to nanoscience and nanotechnology. PMID:17500508

  20. Bridge mediated ultrafast heterogeneous electron transfer

    NASA Astrophysics Data System (ADS)

    Ramakrishna, S.; Willig, F.; May, V.

    2002-01-01

    Bridge mediated photoinduced ultrafast heterogeneous electron transfer (ET) from a molecularly anchored chromophore to a semiconductor surface is modelled theoretically. The continuum levels of the semiconductor substrate are taken into account in the numerical calculations via a polynomial expansion. Electron transfer for the direct injection case in the strong coupling limit is studied and compared with cases where intermediate bridging states are successively introduced to weaken the effective electronic coupling. The role of vibronic coherences in the strong electronic coupling limit as well as in off-resonant bridge mediated electron transfer is also discussed.

  1. Neutrophil-Mediated Phagocytosis of Staphylococcus aureus

    PubMed Central

    van Kessel, Kok P. M.; Bestebroer, Jovanka; van Strijp, Jos A. G.

    2014-01-01

    Initial elimination of invading Staphylococcus aureus from the body is mediated by professional phagocytes. The neutrophil is the major phagocyte of the innate immunity and plays a key role in the host defense against staphylococcal infections. Opsonization of the bacteria with immunoglobulins and complement factors enables efficient recognition by the neutrophil that subsequently leads to intracellular compartmentalization and killing. Here, we provide a review of the key processes evolved in neutrophil-mediated phagocytosis of S. aureus and briefly describe killing. As S. aureus is not helpless against the professional phagocytes, we will also highlight its immune evasion arsenal related to phagocytosis. PMID:25309547

  2. Nucleotide chloramines and neutrophil-mediated cytotoxicity.

    PubMed

    Bernofsky, C

    1991-03-01

    Hypochlorite is a reactive oxidant formed as an end product of the respiratory burst in activated neutrophils. It is responsible for killing bacteria and has been implicated in neutrophil-mediated tissue injury associated with the inflammatory process. Although hypochlorite is a potent cytotoxic agent, the primary mechanism by which it exerts its effect is unclear. This review examines evidence that the primary event in hypochlorite cytotoxicity is the loss of adenine nucleotides from the target cell. This loss appears to be mediated by the formation of adenine nucleotide chloramines which are reactive intermediates with a free radical character and are capable of forming stable ligands with proteins and nucleic acids. PMID:1848195

  3. A security mediator for health care information.

    PubMed Central

    Wiederhold, G.; Bilello, M.; Sarathy, V.; Qian, X.

    1996-01-01

    The TIHI (Trusted Interoperation of Healthcare Information) project addresses a security issue that arises when some information is being shared among collaborating enterprises, although not all enterprise information is sharable. It assumes that protection exists to prevent intrusion by adversaries through secure transmission and firewalls. The TIHI system design provides a gateway, owned by the enterprise security officer, to mediate queries and responses. The latter are typically transmitted via the Internet. The enterprise policy is determined by rules provided to the mediator. We show examples of typical rules. The problem and our solution, although developed in a healthcare context, is equally valid among collaborating enterprises. PMID:8947640

  4. Redox polymer mediation for enzymatic biofuel cells

    NASA Astrophysics Data System (ADS)

    Gallaway, Joshua

    Mediated biocatalytic cathodes prepared from the oxygen-reducing enzyme laccase and redox-conducting osmium hydrogels were characterized for use as cathodes in enzymatic biofuel cells. A series of osmium-based redox polymers was synthesized with redox potentials spanning the range from 0.11 V to 0.85 V (SHE), and the resulting biocatalytic electrodes were modeled to determine reaction kinetic constants using the current response, measured osmium concentration, and measured apparent electron diffusion. As in solution-phase systems, the bimolecular rate constant for mediation was found to vary greatly with mediator potential---from 250 s-1M-1 when mediator and enzyme were close in potential to 9.4 x 10 4 s-1M-1 when this overpotential was large. Optimum mediator potential for a cell operating with a non-limiting platinum anode and having no mass transport limitation from bulk solution was found to be 0.66 V (SHE). Redox polymers were synthesized under different concentrations, producing osmium variation. An increase from 6.6% to 7.2% osmium increased current response from 1.2 to 2.1 mA/cm2 for a planar film in 40°C oxygen-saturated pH 4 buffer, rotating at 900 rpm. These results translated to high surface area electrodes, nearly doubling current density to 13 mA/cm2, the highest to date for such an electrode. The typical fungal laccase from Trametes versicolor was replaced by a bacterially-expressed small laccase from Streptomyces coelicolor, resulting in biocatalytic films that reduced oxygen at increased pH, with full functionality at pH 7, producing 1.5 mA/cm 2 in planar configuration. Current response was biphasic with pH, matching the activity profile of the free enzyme in solution. The mediated enzyme electrode system was modeled with respect to apparent electron diffusion, mediator concentration, and transport of oxygen from bulk solution, all of which are to some extent controlled by design. Each factor was found to limit performance in certain circumstances

  5. Auxin-dependent compositional change in Mediator in ARF7- and ARF19-mediated transcription

    PubMed Central

    Ito, Jun; Fukaki, Hidehiro; Onoda, Makoto; Li, Lin; Li, Chuanyou; Tasaka, Masao; Furutani, Masahiko

    2016-01-01

    Mediator is a multiprotein complex that integrates the signals from transcription factors binding to the promoter and transmits them to achieve gene transcription. The subunits of Mediator complex reside in four modules: the head, middle, tail, and dissociable CDK8 kinase module (CKM). The head, middle, and tail modules form the core Mediator complex, and the association of CKM can modify the function of Mediator in transcription. Here, we show genetic and biochemical evidence that CKM-associated Mediator transmits auxin-dependent transcriptional repression in lateral root (LR) formation. The AUXIN/INDOLE 3-ACETIC ACID 14 (Aux/IAA14) transcriptional repressor inhibits the transcriptional activity of its binding partners AUXIN RESPONSE FACTOR 7 (ARF7) and ARF19 by making a complex with the CKM-associated Mediator. In addition, TOPLESS (TPL), a transcriptional corepressor, forms a bridge between IAA14 and the CKM component MED13 through the physical interaction. ChIP assays show that auxin induces the dissociation of MED13 but not the tail module component MED25 from the ARF7 binding region upstream of its target gene. These findings indicate that auxin-induced degradation of IAA14 changes the module composition of Mediator interacting with ARF7 and ARF19 in the upstream region of their target genes involved in LR formation. We suggest that this regulation leads to a quick switch of signal transmission from ARFs to target gene expression in response to auxin. PMID:27217573

  6. Auxin-dependent compositional change in Mediator in ARF7- and ARF19-mediated transcription.

    PubMed

    Ito, Jun; Fukaki, Hidehiro; Onoda, Makoto; Li, Lin; Li, Chuanyou; Tasaka, Masao; Furutani, Masahiko

    2016-06-01

    Mediator is a multiprotein complex that integrates the signals from transcription factors binding to the promoter and transmits them to achieve gene transcription. The subunits of Mediator complex reside in four modules: the head, middle, tail, and dissociable CDK8 kinase module (CKM). The head, middle, and tail modules form the core Mediator complex, and the association of CKM can modify the function of Mediator in transcription. Here, we show genetic and biochemical evidence that CKM-associated Mediator transmits auxin-dependent transcriptional repression in lateral root (LR) formation. The AUXIN/INDOLE 3-ACETIC ACID 14 (Aux/IAA14) transcriptional repressor inhibits the transcriptional activity of its binding partners AUXIN RESPONSE FACTOR 7 (ARF7) and ARF19 by making a complex with the CKM-associated Mediator. In addition, TOPLESS (TPL), a transcriptional corepressor, forms a bridge between IAA14 and the CKM component MED13 through the physical interaction. ChIP assays show that auxin induces the dissociation of MED13 but not the tail module component MED25 from the ARF7 binding region upstream of its target gene. These findings indicate that auxin-induced degradation of IAA14 changes the module composition of Mediator interacting with ARF7 and ARF19 in the upstream region of their target genes involved in LR formation. We suggest that this regulation leads to a quick switch of signal transmission from ARFs to target gene expression in response to auxin. PMID:27217573

  7. Flexible Mediation Analysis in the Presence of Nonlinear Relations: Beyond the Mediation Formula.

    PubMed

    Loeys, Tom; Moerkerke, Beatrijs; De Smet, Olivia; Buysse, Ann; Steen, Johan; Vansteelandt, Stijn

    2013-11-01

    In the social sciences, mediation analysis has typically been formulated in the context of linear models using the Baron & Kenny (1986) approach. Extensions to nonlinear models have been considered but lack formal justification. By placing mediation analysis within the counterfactual framework of causal inference one can define causal mediation effects in a way that is not tied to a specific statistical model and identify them under certain no unmeasured confounding assumptions. Corresponding estimation procedures using parametric or nonparametric models, based on the so-called mediation formula, have recently been proposed in the psychological literature and made accessible through the R-package mediation. A number of limitations of the latter approach are discussed and a more flexible approach using natural effects models is proposed as an alternative. The latter builds on the same counterfactual framework but enables interpretable and parsimonious modeling of direct and mediated effects and facilitates tests of hypotheses that would otherwise be difficult or impossible to test. We illustrate the approach in a study of individuals who ended a romantic relationship and explore whether the effect of attachment anxiety during the relationship on unwanted pursuit behavior after the breakup is mediated by negative affect during the breakup. PMID:26745597

  8. Safe Space or Separation? Mediating the Tension.

    ERIC Educational Resources Information Center

    Montero, Janina

    1995-01-01

    Discussion of diversity on college campuses examines ways in which institutions can address the separation of groups on campus and resulting dissention. Nine recommendations are made for mediating the dissention, including study of campus climate, administrative flexibility, better understanding of the groups and dynamics involved, reestablishment…

  9. 7 CFR 780.9 - Mediation.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... issuance of an adverse decision but before any hearing in an appeal of the adverse decision to NAD. (b) An... any remaining appeal rights under this part or appeal to NAD in accordance with part 11 of this title and NAD procedures. (2) If an adverse decision is modified as a result of mediation, a participant...

  10. Instructional Components of Mediational Dynamic Assessment.

    ERIC Educational Resources Information Center

    Symons, Sonya E.; Vye, Nancy J.

    The instructional components of mediation, a teaching technique used in dynamic assessment, were evaluated with 100 four-year-old children attending daycare or preschools in London, Ontario. The effects of familiarization with task materials, task-specific rule teaching, and elaborated feedback were assessed using a pretest-posttest design.…

  11. Mediators of Preschoolers' Early Mathematics Concepts

    ERIC Educational Resources Information Center

    Berghout Austin, Ann M.; Blevins-Knabe, Belinda; Ota, Carrie; Rowe, Trevor; Knudsen Lindauer, Shelley L.

    2011-01-01

    The purpose of this study was to extend existing research relative to the predictors of early mathematics skills. Using Vygotskian theory as a framework, our primary goal was to determine whether social skills or letter awareness skills served as better mediators between receptive language and early mathematics concepts. The secondary goal was to…

  12. RNAi-mediated plant protection against aphids.

    PubMed

    Yu, Xiu-Dao; Liu, Zong-Cai; Huang, Si-Liang; Chen, Zhi-Qin; Sun, Yong-Wei; Duan, Peng-Fei; Ma, You-Zhi; Xia, Lan-Qin

    2016-06-01

    Aphids (Aphididae) are major agricultural pests that cause significant yield losses of crop plants each year by inflicting damage both through the direct effects of feeding and by vectoring harmful plant viruses. Expression of double-stranded RNA (dsRNA) directed against suitable insect target genes in transgenic plants has been shown to give protection against pests through plant-mediated RNA interference (RNAi). Thus, as a potential alternative and effective strategy for insect pest management in agricultural practice, plant-mediated RNAi for aphid control has received close attention in recent years. In this review, the mechanism of RNAi in insects and the so far explored effective RNAi target genes in aphids, their potential applications in the development of transgenic plants for aphid control and the major challenges in this regard are reviewed, and the future prospects of using plant-mediated RNAi for aphid control are discussed. This review is intended to be a helpful insight into the generation of aphid-resistant plants through plant-mediated RNAi strategy. © 2016 Society of Chemical Industry. PMID:26888776

  13. A Comparison of Three Tests of Mediation

    ERIC Educational Resources Information Center

    Warbasse, Rosalia E.

    2009-01-01

    A simulation study was conducted to evaluate the performance of three tests of mediation: the bias-corrected and accelerated bootstrap (Efron & Tibshirani, 1993), the asymmetric confidence limits test (MacKinnon, 2008), and a multiple regression approach described by Kenny, Kashy, and Bolger (1998). The evolution of these methods is reviewed and…

  14. Teaching Responsibly with Technology-Mediated Communication

    ERIC Educational Resources Information Center

    Veltsos, Jennifer R.; Veltsos, Christophe

    2010-01-01

    Technology-mediated communication, or "new media," such as blogs, Twitter, wikis, and social network sites, can be an endless source of ideas for activities or inspiration for classroom discussion. Many instructors ask students to monitor current events by following keywords and industry leaders on Twitter and reading both corporate and trade…

  15. Factors Mediating the Adjustment to Involuntary Childlessness.

    ERIC Educational Resources Information Center

    Sabatelli, Ronald M.; And Others

    1988-01-01

    Explored stressors that accompany experience of involuntary childlessness and examined mediators of adjustment to infertility in married individuals. Data showed deleterious effect that coping with infertility can have on couple's sexual relationship. Findings suggest important relationship between self-esteem, marital commitment, and positive…

  16. Teaching Task Sequencing via Verbal Mediation.

    ERIC Educational Resources Information Center

    Rusch, Frank R.; And Others

    1987-01-01

    Verbal sequence training was used to teach a moderately mentally retarded woman to sequence job-related tasks. Learning to say the tasks in the proper sequence resulted in the employee performing her tasks in that sequence, and the employee was capable of mediating her own work behavior when scheduled changes occurred. (Author/JDD)

  17. Causal mediation analyses with rank preserving models.

    PubMed

    Have, Thomas R Ten; Joffe, Marshall M; Lynch, Kevin G; Brown, Gregory K; Maisto, Stephen A; Beck, Aaron T

    2007-09-01

    We present a linear rank preserving model (RPM) approach for analyzing mediation of a randomized baseline intervention's effect on a univariate follow-up outcome. Unlike standard mediation analyses, our approach does not assume that the mediating factor is also randomly assigned to individuals in addition to the randomized baseline intervention (i.e., sequential ignorability), but does make several structural interaction assumptions that currently are untestable. The G-estimation procedure for the proposed RPM represents an extension of the work on direct effects of randomized intervention effects for survival outcomes by Robins and Greenland (1994, Journal of the American Statistical Association 89, 737-749) and on intervention non-adherence by Ten Have et al. (2004, Journal of the American Statistical Association 99, 8-16). Simulations show good estimation and confidence interval performance by the proposed RPM approach under unmeasured confounding relative to the standard mediation approach, but poor performance under departures from the structural interaction assumptions. The trade-off between these assumptions is evaluated in the context of two suicide/depression intervention studies. PMID:17825022

  18. Instructional Design in Computer Mediated Learning.

    ERIC Educational Resources Information Center

    Bull, Kay Sather; Kimball, Sarah Leigh; Stansberry, Susan

    This paper outlines assumptions and principles related to computer mediated learning (CML) and suggests instructional design and classroom strategies for CML planning and practice. The pedagogy of control is contrasted with the pedagogy of choice and the latter constructivist viewpoint is recommended as the basis of CML. Assumptions about learning…

  19. A Mediated Lifespace: Working Relationally with Girls

    ERIC Educational Resources Information Center

    Hoskins, Marie L.; Mathieson, Lindsay C.

    2004-01-01

    A lifespace has to do with how selves are mediated by combining multiple cultural symbols to construct an identity in the world. The authors cite examples from media texts, as well as from a narrative study conducted with 10 adolescent girls in a treatment program for eating disorders, that illustrate the importance of practitioners considering…

  20. 7 CFR 900.108 - Mediator's report.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 8 2011-01-01 2011-01-01 false Mediator's report. 900.108 Section 900.108 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing Agreements and Orders; Fruits, Vegetables, Nuts), DEPARTMENT OF AGRICULTURE GENERAL REGULATIONS...

  1. 15 CFR 923.54 - Mediation.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... an appropriate forum for conflict resolution. (b) State-Federal differences should be addressed... parties agree to a resolution of the serious disagreement, (2) If one of the parties withdraws from mediation, (3) In the event the parties fail to reach a resolution of the serious disagreement within...

  2. One Teacher's Journey through the Mediated Intersections

    ERIC Educational Resources Information Center

    Beach, Crystal L.

    2015-01-01

    Today's classrooms often have a plethora of new ways of reading and writing entering the room, but too often these new ways of "doing" are disregarded and checked at the door. For this reason, one educator shares her journey through the mediated intersections of media, culture, and education. In this piece, she explores how literacy…

  3. Nonthermal dark matter in mirage mediation

    SciTech Connect

    Nagai, Minoru; Nakayama, Kazunori

    2007-12-15

    In mirage-mediation models there exists a modulus field whose mass is O(1000) TeV and its late decay may significantly change the standard thermal relic scenario of the dark matter. We study nonthermal production of the dark matter directly from the modulus decay, and find that for some parameter regions nonthermally produced neutralinos can become the dark matter.

  4. 29 CFR 35.32 - Mediation.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... CFR part 90, all complaints that: (1) Fall within the jurisdiction of the Act or this part, unless the... to reach an agreement or to make an informed judgment that an agreement is not possible. The... mediator is impractical. (c) When agreement is reached. If the complainant and the recipient reach...

  5. Web-Mediated Knowledge Synthesis for Educators

    ERIC Educational Resources Information Center

    DeSchryver, Michael

    2015-01-01

    Ubiquitous and instant access to information on the Web is challenging what constitutes 21st century literacies. This article explores the notion of Web-mediated knowledge synthesis, an approach to integrating Web-based learning that may result in generative synthesis of ideas. This article describes the skills and strategies that may support…

  6. Strategic Game Moves Mediate Implicit Science Learning

    ERIC Educational Resources Information Center

    Rowe, Elizabeth; Baker, Ryan S.; Asbell-Clarke, Jodi

    2015-01-01

    Educational games have the potential to be innovative forms of learning assessment, by allowing us to not just study their knowledge but the process that takes students to that knowledge. This paper examines the mediating role of players' moves in digital games on changes in their pre-post classroom measures of implicit science learning. We…

  7. Mediating Artifact in Teacher Professional Development

    ERIC Educational Resources Information Center

    Svendsen, Bodil

    2015-01-01

    This article focuses on teacher professional development (TPD) in natural science through the 5E model as mediating artifact. The study was conducted in an upper secondary school, grounded in a school-based intervention research project. My contribution to the field of research on TPD is founded on the hypothesis that teachers would be best…

  8. Guidelines for Good Practice: Technology Mediated Instruction.

    ERIC Educational Resources Information Center

    Academic Senate for California Community Colleges, Sacramento.

    Technology Mediated Instruction (TMI) is an alternate mode of instructional delivery that provides several benefits. In addition to assisting information transfer through integration of course material, TMI fosters instructor-student interaction through methods such as interactive question-answer areas, video-based office hours, e-mail, and…

  9. Deubiquitinating enzymes regulate PARK2-mediated mitophagy

    PubMed Central

    Wang, Yuqing; Serricchio, Mauro; Jauregui, Miluska; Shanbhag, Riya; Stoltz, Tasha; Di Paolo, Caitlin T; Kim, Peter K; McQuibban, G Angus

    2015-01-01

    The selective degradation of mitochondria by the process of autophagy, termed mitophagy, is one of the major mechanisms of mitochondrial quality control. The best-studied mitophagy pathway is the one mediated by PINK1 and PARK2/Parkin. From recent studies it has become clear that ubiquitin-ligation plays a pivotal role and most of the focus has been on the role of ubiquitination of mitochondrial proteins in mitophagy. Even though ubiquitination is a reversible process, very little is known about the role of deubiquitinating enzymes (DUBs) in mitophagy. Here, we report that 2 mitochondrial DUBs, USP30 and USP35, regulate PARK2-mediated mitophagy. We show that USP30 and USP35 can delay PARK2-mediated mitophagy using a quantitative mitophagy assay. Furthermore, we show that USP30 delays mitophagy by delaying PARK2 recruitment to the mitochondria during mitophagy. USP35 does not delay PARK2 recruitment, suggesting that it regulates mitophagy through an alternative mechanism. Interestingly, USP35 only associates with polarized mitochondria, and rapidly translocates to the cytosol during CCCP-induced mitophagy. It is clear that PARK2-mediated mitophagy is regulated at many steps in this important quality control pathway. Taken together, these findings demonstrate an important role of mitochondrial-associated DUBs in mitophagy. Because defects in mitochondria quality control are implicated in many neurodegenerative disorders, our study provides clear rationales for the design and development of drugs for the therapeutic treatment of neurodegenerative diseases such as Parkinson and Alzheimer diseases. PMID:25915564

  10. Mediated Learning Experience and Deaf Learners.

    ERIC Educational Resources Information Center

    Martin, David S.

    A classroom cognitive intervention model for adolescents and adults who are deaf is described. The model provides mediated learning experiences whereby a person assists the learner in interpreting experience and learning problem-solving strategies. The program, entitled instrumental enrichment (IE), is based on the following principles: IE uses a…

  11. Mediation: One Alternative to Traditional Judicial Proceedings.

    ERIC Educational Resources Information Center

    Dunn, Merrily S.

    1996-01-01

    Presents a model of conflict resolution as an alternative, or in addition, to traditional disciplinary systems. Method relies on mediation and employs a "win/win" philosophy which allows and encourages students to peacefully resolve their own disputes. Believes that the program bolsters self-esteem and helps students resolve differences. (RJM)

  12. Multiscale Simulation of Protein Mediated Membrane Remodeling

    PubMed Central

    Ayton, Gary S.; Voth, Gregory A.

    2009-01-01

    Proteins interacting with membranes can result in substantial membrane deformations and curvatures. This effect is known in its broadest terms as membrane remodeling. This review article will survey current multiscale simulation methodologies that have been employed to examine protein-mediated membrane remodeling. PMID:19922811

  13. 45 CFR 16.18 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Mediation. 16.18 Section 16.18 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION PROCEDURES OF THE DEPARTMENTAL GRANT APPEALS... grants dispute, the Board may, within the limitations of its resources, offer persons trained...

  14. Integrating Computer-Mediated Communication Strategy Instruction

    ERIC Educational Resources Information Center

    McNeil, Levi

    2016-01-01

    Communication strategies (CSs) play important roles in resolving problematic second language interaction and facilitating language learning. While studies in face-to-face contexts demonstrate the benefits of communication strategy instruction (CSI), there have been few attempts to integrate computer-mediated communication and CSI. The study…

  15. Community Building and Computer-Mediated Conferencing

    ERIC Educational Resources Information Center

    Moisey, Susan Darlene; Neu, Candace; Cleveland-Innes, Martha

    2008-01-01

    This study examined the relationship between community cohesion and computer-mediated conferencing (CMC), as well as other variables potentially associated with the development of a learning community. Within the context of a graduate-level course in instructional design (a core course in the Masters of Distance Education program at Athabasca…

  16. IgE-mediated food hypersensitivity disorders.

    PubMed

    Gotua, M; Lomidze, N; Dolidze, N; Gotua, T

    2008-04-01

    Food allergy has become a serious health concern especially in developed countries in the past two decades. In general population approximately 4-6% of children and 1-3% of adults experience food allergy. The article reviews IgE-mediated food hypersensitivity disorders. Epidemiology, Mechanism, Clinical manifestations, Genetically modified crops (GMOs), Diagnosis, Prevention and Treatment of IgE-mediated food allergies are discussed. The investigations show that over 90% of IgE-mediated food allergies in childhood are caused by: cow's milk, hen's egg, soy, peanuts, tree nuts, wheat, fish and shellfish. Also the causes of food allergy are food additives, genetically modified crops. Risk factors for food-dependent exercise-induced anaphylaxis include asthma and previous allergic reactions to the causative food. Food allergy is one of the most common causes of systematic anaphylaxis and anaphylactoid reactions, with an annual incidence of four cases per million populations and estimated 500 deaths annually. In addition to gastrointestinal symptoms, individuals may experience urticaria, angioedema, atopic dermatitis, oral syndrome, asthma, rhinitis, conjunctivitis, hypotension, shock and cardiac arrhythmias, caused by the massive release of mediators from mast cells and basophiles. Diagnosis of food allergy is based on history, detailed dietary analysis, skin testing, measuring specific IgE in blood serum and challenge tests. Treatment and prevention includes: avoidance diet, application of auto-injectable epinephrine, H1 and H2 antihistamines, corticosteroids, antileukotrienes, prostaglandin synthetase inhibitors, cromolyn sodium, etc. PMID:18487689

  17. Proteinaceous Molecules Mediating Bifidobacterium-Host Interactions.

    PubMed

    Ruiz, Lorena; Delgado, Susana; Ruas-Madiedo, Patricia; Margolles, Abelardo; Sánchez, Borja

    2016-01-01

    Bifidobacteria are commensal microoganisms found in the gastrointestinal tract. Several strains have been attributed beneficial traits at local and systemic levels, through pathogen exclusion or immune modulation, among other benefits. This has promoted a growing industrial and scientific interest in bifidobacteria as probiotic supplements. However, the molecular mechanisms mediating this cross-talk with the human host remain unknown. High-throughput technologies, from functional genomics to transcriptomics, proteomics, and interactomics coupled to the development of both in vitro and in vivo models to study the dynamics of the intestinal microbiota and their effects on host cells, have eased the identification of key molecules in these interactions. Numerous secreted or surface-associated proteins or peptides have been identified as potential mediators of bifidobacteria-host interactions and molecular cross-talk, directly participating in sensing environmental factors, promoting intestinal colonization, or mediating a dialogue with mucosa-associated immune cells. On the other hand, bifidobacteria induce the production of proteins in the intestine, by epithelial or immune cells, and other gut bacteria, which are key elements in orchestrating interactions among bifidobacteria, gut microbiota, and host cells. This review aims to give a comprehensive overview on proteinaceous molecules described and characterized to date, as mediators of the dynamic interplay between bifidobacteria and the human host, providing a framework to identify knowledge gaps and future research needs. PMID:27536282

  18. Children and TV II: Mediating the Medium.

    ERIC Educational Resources Information Center

    Winick, Mariann Pezzella; Wehrenberg, Judith S.

    This guidebook focuses on the reality of children's television viewing and the possibilities open to teachers for mediating the experience to enhance children's development and enrich the school curriculum. A Piagetian framework is used to examine and structure material suitable for the classroom. Part I of the guide reviews the historic…

  19. Learning Style Theory and Computer Mediated Communication.

    ERIC Educational Resources Information Center

    Atkins, Hilary; Moore, David; Sharpe, Simon; Hobbs, Dave

    This paper looks at the low participation rates in computer mediated conferences (CMC) and argues that one of the causes of this may be an incompatibility between students' learning styles and the style adopted by CMC. Curry's Onion Model provides a well-established framework within which to view the main learning style theories (Riding and…

  20. Maternally-Mediated Effects on Development*

    EPA Science Inventory

    In standard Segment II mammalian bioassays for developmental toxicity, it is the pregnant animal that is exposed to the test article, so in this sense, all in utero developmental toxicity is mediated by the mother. This will include absorption, distribution, metabolism and excret...

  1. Excursion-Set-Mediated Genetic Algorithm

    NASA Technical Reports Server (NTRS)

    Noever, David; Baskaran, Subbiah

    1995-01-01

    Excursion-set-mediated genetic algorithm (ESMGA) is embodiment of method of searching for and optimizing computerized mathematical models. Incorporates powerful search and optimization techniques based on concepts analogous to natural selection and laws of genetics. In comparison with other genetic algorithms, this one achieves stronger condition for implicit parallelism. Includes three stages of operations in each cycle, analogous to biological generation.

  2. Mediation Training for High School Students.

    ERIC Educational Resources Information Center

    Conflict Resolution Unlimited, Inc., Bellevue, WA.

    Young people need help in learning alternative dispute resolution skills at school. Teaching high school students how to understand conflict and then develop effective ways to deal with it is the purpose of this program. Designed for five 3-hour sessions using two trainers, it is organized around seven major themes: The Mediation Process, Cultural…

  3. Peer Mediation and Middle School Students

    ERIC Educational Resources Information Center

    Calbreath, Wes; Crews, Moody E.

    2011-01-01

    With the constant concern over violence in schools, school officials are looking for ways to head off this potential problem and to better assure a safe environment for all students. One way that has become popular is the implementation of peer mediation programs where students assist other students in learning how to deal with conflict through…

  4. Comments: Causal Interpretations of Mediation Effects

    ERIC Educational Resources Information Center

    Jo, Booil; Stuart, Elizabeth A.

    2012-01-01

    The authors thank Dr. Lindsay Page for providing a nice illustration of the use of the principal stratification framework to define causal effects, and a Bayesian model for effect estimation. They hope that her well-written article will help expose education researchers to these concepts and methods, and move the field of mediation analysis in…

  5. 7 CFR 205.663 - Mediation.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 7 Agriculture 3 2011-01-01 2011-01-01 false Mediation. 205.663 Section 205.663 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) ORGANIC FOODS PRODUCTION ACT PROVISIONS NATIONAL ORGANIC PROGRAM...

  6. 7 CFR 205.663 - Mediation.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 7 Agriculture 3 2012-01-01 2012-01-01 false Mediation. 205.663 Section 205.663 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Standards, Inspections, Marketing Practices), DEPARTMENT OF AGRICULTURE (CONTINUED) ORGANIC FOODS PRODUCTION ACT PROVISIONS NATIONAL ORGANIC PROGRAM...

  7. 10 CFR 1040.89-6 - Mediation.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... Federal Mediation and Conciliation Service, in accordance with 45 CFR 90.43(c)(3), all complaints that: (1... of Civil Rights and Diversity, will accept a judgment that an agreement is not possible. However, the... Director, Office of Civil Rights and Diversity, DOE. DOE will take no further action on the...

  8. 10 CFR 1040.89-6 - Mediation.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... Federal Mediation and Conciliation Service, in accordance with 45 CFR 90.43(c)(3), all complaints that: (1... of Civil Rights and Diversity, will accept a judgment that an agreement is not possible. However, the... Director, Office of Civil Rights and Diversity, DOE. DOE will take no further action on the...

  9. 10 CFR 1040.89-6 - Mediation.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... Federal Mediation and Conciliation Service, in accordance with 45 CFR 90.43(c)(3), all complaints that: (1... of Civil Rights and Diversity, will accept a judgment that an agreement is not possible. However, the... Director, Office of Civil Rights and Diversity, DOE. DOE will take no further action on the...

  10. 10 CFR 1040.89-6 - Mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... Federal Mediation and Conciliation Service, in accordance with 45 CFR 90.43(c)(3), all complaints that: (1... of Civil Rights and Diversity, will accept a judgment that an agreement is not possible. However, the... Director, Office of Civil Rights and Diversity, DOE. DOE will take no further action on the...

  11. 10 CFR 1040.89-6 - Mediation.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... Federal Mediation and Conciliation Service, in accordance with 45 CFR 90.43(c)(3), all complaints that: (1... of Civil Rights and Diversity, will accept a judgment that an agreement is not possible. However, the... Director, Office of Civil Rights and Diversity, DOE. DOE will take no further action on the...

  12. Mediation-Arbitration: The Wisconsin Experience.

    ERIC Educational Resources Information Center

    Riley, Stevens L.

    This paper, addressed to public school employers, discusses lessons to be learned from the Wisconsin Legislature's passage of a 1978 law known as mediation-arbitration, which allows employers and unions to agree to an alternative voluntary impasse procedure to the one set forth in the statutes. First, the paper discusses the history of the agency…

  13. 34 CFR 300.506 - Mediation.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 34 Education 2 2011-07-01 2010-07-01 true Mediation. 300.506 Section 300.506 Education Regulations of the Offices of the Department of Education (Continued) OFFICE OF SPECIAL EDUCATION AND REHABILITATIVE SERVICES, DEPARTMENT OF EDUCATION ASSISTANCE TO STATES FOR THE EDUCATION OF CHILDREN...

  14. Computer-Mediated Communication and Interpersonal Perceptions.

    ERIC Educational Resources Information Center

    Adkins, Mark E.

    A study investigated the conditions under which computer-mediated communication (CMC) (electronic mail) senders were perceived as self-absorbed by CMC receivers. Experience with electronic mail was the independent variable and perceived self-absorption, attraction, and homophily were the dependent variables. Two-hundred fifty volunteers from a…

  15. Host defence mediates interspecific competition in ectoparasites.

    PubMed

    Bush, Sarah E; Malenke, Jael R

    2008-05-01

    1. Interspecific competition influences which, how many and where species coexist in biological communities. Interactions between species in different trophic levels can mediate interspecific competition; e.g. predators are known to reduce competition between prey species by suppressing their population sizes. A parallel phenomenon may take place in host-parasite systems, with host defence mediating competition between parasite species. 2. We experimentally investigated the impact of host defence (preening) on competitive interactions between two species of feather-feeding lice: 'wing' lice Columbicola columbae and 'body' lice Campanulotes compar. Both species are host-specific parasites that co-occur on rock pigeons Columba livia. 3. We show that wing lice and body lice compete and that host defence mediates the magnitude of this competitive interaction. 4. Competition is asymmetrical; wing louse populations are negatively impacted by body lice, but not vice versa. This competitive asymmetry is consistent with the fact that body lice predominate in microhabitats on the host's body that offer the most food and the most space. 5. Our results indicate that host-defence-mediated competition can influence the structure of parasite communities and may play a part in the evolution of parasite diversity. PMID:18194262

  16. Proteinaceous Molecules Mediating Bifidobacterium-Host Interactions

    PubMed Central

    Ruiz, Lorena; Delgado, Susana; Ruas-Madiedo, Patricia; Margolles, Abelardo; Sánchez, Borja

    2016-01-01

    Bifidobacteria are commensal microoganisms found in the gastrointestinal tract. Several strains have been attributed beneficial traits at local and systemic levels, through pathogen exclusion or immune modulation, among other benefits. This has promoted a growing industrial and scientific interest in bifidobacteria as probiotic supplements. However, the molecular mechanisms mediating this cross-talk with the human host remain unknown. High-throughput technologies, from functional genomics to transcriptomics, proteomics, and interactomics coupled to the development of both in vitro and in vivo models to study the dynamics of the intestinal microbiota and their effects on host cells, have eased the identification of key molecules in these interactions. Numerous secreted or surface-associated proteins or peptides have been identified as potential mediators of bifidobacteria-host interactions and molecular cross-talk, directly participating in sensing environmental factors, promoting intestinal colonization, or mediating a dialogue with mucosa-associated immune cells. On the other hand, bifidobacteria induce the production of proteins in the intestine, by epithelial or immune cells, and other gut bacteria, which are key elements in orchestrating interactions among bifidobacteria, gut microbiota, and host cells. This review aims to give a comprehensive overview on proteinaceous molecules described and characterized to date, as mediators of the dynamic interplay between bifidobacteria and the human host, providing a framework to identify knowledge gaps and future research needs. PMID:27536282

  17. Mediating Artifact in Teacher Professional Development

    NASA Astrophysics Data System (ADS)

    Svendsen, Bodil

    2015-07-01

    This article focuses on teacher professional development (TPD) in natural science through the 5E model as mediating artifact. The study was conducted in an upper secondary school, grounded in a school-based intervention research project. My contribution to the field of research on TPD is founded on the hypothesis that teachers would be best facilitated to make their practice more inquiry based if they are provided with a mediating artifact. In this study the artifact is a model 5E, which is a conceptual way of thinking, to help teachers reflect on their practice. The aim is to encourage teachers to make changes themselves, by applying extended use of inquiry into their practice. This mediated artifact could thus be used across different national contexts. The main research question is; how can the 5E model as a mediating artifact enhance TPD? The article addresses the processes of the use of the 5E model and its influence on teachers' perception of the model. This is in order for teachers to conceptualize their goals related to inquiry and scientific thinking, and to solve the problems involved in achieving those goals in their own contexts. The study concludes that, after the intervention, the teachers' approaches and strategies demonstrate greater emphasis on learning.

  18. Mediated electrochemical oxidation of organic wastes using a Co(III) mediator in a neutral electrolyte

    DOEpatents

    Balazs, G. Bryan; Lewis, Patricia R.

    1999-01-01

    An electrochemical cell with a Co(III) mediator and neutral pH anolyte provides efficient destruction of organic and mixed wastes. The organic waste is concentrated in the anolyte reservoir, where the cobalt mediator oxidizes the organics and insoluble radioactive species and is regenerated at the anode until all organics are converted to carbon dioxide and destroyed. The neutral electrolyte is non-corrosive, and thus extends the lifetime of the cell and its components.

  19. Mediated electrochemical oxidation of organic wastes using a Co(III) mediator in a neutral electrolyte

    DOEpatents

    Balazs, G.B.; Lewis, P.R.

    1999-07-06

    An electrochemical cell with a Co(III) mediator and neutral pH anolyte provides efficient destruction of organic and mixed wastes. The organic waste is concentrated in the anolyte reservoir, where the cobalt mediator oxidizes the organics and insoluble radioactive species and is regenerated at the anode until all organics are converted to carbon dioxide and destroyed. The neutral electrolyte is non-corrosive, and thus extends the lifetime of the cell and its components. 2 figs.

  20. Can Computer-Mediated Interventions Change Theoretical Mediators of Safer Sex? A Meta-Analysis

    ERIC Educational Resources Information Center

    Noar, Seth M.; Pierce, Larson B.; Black, Hulda G.

    2010-01-01

    The purpose of this study was to conduct a meta-analysis of computer-mediated interventions (CMIs) aimed at changing theoretical mediators of safer sex. Meta-analytic aggregation of effect sizes from k = 20 studies indicated that CMIs significantly improved HIV/AIDS knowledge, d = 0.276, p less than 0.001, k = 15, N = 6,625; sexual/condom…

  1. A review of causal estimation of effects in mediation analyses.

    PubMed

    Ten Have, Thomas R; Joffe, Marshall M

    2012-02-01

    We describe causal mediation methods for analysing the mechanistic factors through which interventions act on outcomes. A number of different mediation approaches have been presented in the biomedical, social science and statistical literature with an emphasis on different aspects of mediation. We review the different sets of assumptions that allow identification and estimation of effects in the simple case of a single intervention, a temporally subsequent mediator and outcome. These assumptions include various no confounding assumptions including sequential ignorability assumptions and also interaction assumptions involving the treatment and mediator. The understanding of such assumptions is crucial since some can be assessed under certain conditions (e.g. treatment-mediator interactions), whereas others cannot (sequential ignorability). These issues become more complex with multiple mediators and longitudinal outcomes. In addressing these assumptions, we review several causal approaches to mediation analyses. PMID:21163849

  2. Expression of Ferritin Light Chain (FTL) Is Elevated in Glioblastoma, and FTL Silencing Inhibits Glioblastoma Cell Proliferation via the GADD45/JNK Pathway

    PubMed Central

    Wu, Tingfeng; Li, Yuntao; Liu, Baohui; Zhang, Shenqi; Wu, Liquan; Zhu, Xiaonan; Chen, Qianxue

    2016-01-01

    Accumulating evidence suggests that iron-associated proteins contribute to tumor initiation and development. Ferritin light chain (FTL), a key protein in iron metabolism, is associated with the survival of glioblastoma multiforme (GBM) patients; however, the molecular mechanisms underlying this association remain largely unclear. Therefore, in the present study, we investigated the role of FTL in the pathogenesis of GBM. By using quantitative real-time RT-PCR, we found that expression of FTL was higher in patients with GBM than in those with low-grade glioma. Immunofluorescence showed that FTL was mainly localized in the nucleus of GBM cells and was closely associated with mitotic spindles. Knockdown of FTL resulted in inhibition of cell growth and activation of the GADD45A/JNK pathway in GBM cells. Immunoblotting revealed that levels of GADD45A protein decreased in GBM cells when FTL expression increased. Furthermore, transfection of GADD45A in GBM cells significantly decreased cell viability, and this effect was impeded by co-transfection of FTL. Moreover, FTL was found to localize with GADD45A in GBM cells, and a coimmunoprecipitation experiment showed that the two proteins physically interacted. Taken together, these results demonstrate a novel mechanism by which FTL regulates the growth of GBM cells via the GADD45/JNK pathway. PMID:26871431

  3. Evaluation of High-throughput Genotoxicity Assays Used in Profiling the US EPA ToxCast Chemicals

    EPA Science Inventory

    Three high-throughput screening (HTS) genotoxicity assays-GreenScreen HC GADD45a-GFP (Gentronix Ltd.), CellCiphr p53 (Cellumen Inc.) and CellSensor p53RE-bla (Invitrogen Corp.)-were used to analyze the collection of 320 predominantly pesticide active compounds being tested in Pha...

  4. Mediated electrochemical oxidation of organic wastes without electrode separators

    DOEpatents

    Farmer, Joseph C.; Wang, Francis T.; Hickman, Robert G.; Lewis, Patricia R.

    1996-01-01

    An electrochemical cell/electrolyte/mediator combination for the efficient destruction of organic contaminants using metal salt mediators in a sulfuric acid electrolyte, wherein the electrodes and mediator are chosen such that hydrogen gas is produced at the cathode and no cell membrane is required.

  5. Mediated electrochemical oxidation of organic wastes without electrode separators

    DOEpatents

    Farmer, J.C.; Wang, F.T.; Hickman, R.G.; Lewis, P.R.

    1996-05-14

    An electrochemical cell/electrolyte/mediator combination is described for the efficient destruction of organic contaminants using metal salt mediators in a sulfuric acid electrolyte, wherein the electrodes and mediator are chosen such that hydrogen gas is produced at the cathode and no cell membrane is required. 3 figs.

  6. Estimation of mediation effects for zero-inflated regression models.

    PubMed

    Wang, Wei; Albert, Jeffrey M

    2012-11-20

    The goal of mediation analysis is to identify and explicate the mechanism that underlies a relationship between a risk factor and an outcome via an intermediate variable (mediator). In this paper, we consider the estimation of mediation effects in zero-inflated (ZI) models intended to accommodate 'extra' zeros in count data. Focusing on the ZI negative binomial models, we provide a mediation formula approach to estimate the (overall) mediation effect in the standard two-stage mediation framework under a key sequential ignorability assumption. We also consider a novel decomposition of the overall mediation effect for the ZI context using a three-stage mediation model. Estimation of the components of the overall mediation effect requires an assumption involving the joint distribution of two counterfactuals. Simulation study results demonstrate low bias of mediation effect estimators and close-to-nominal coverage probability of confidence intervals. We also modify the mediation formula method by replacing 'exact' integration with a Monte Carlo integration method. The method is applied to a cohort study of dental caries in very low birth weight adolescents. For overall mediation effect estimation, sensitivity analysis was conducted to quantify the degree to which key assumption must be violated to reverse the original conclusion. PMID:22714572

  7. 15 CFR 930.114 - Secretarial mediation efforts.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 3 2013-01-01 2013-01-01 false Secretarial mediation efforts. 930.114... MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.114 Secretarial mediation efforts. (a) Following the close of the hearing, the hearing officer shall transmit...

  8. 15 CFR 930.114 - Secretarial mediation efforts.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 15 Commerce and Foreign Trade 3 2011-01-01 2011-01-01 false Secretarial mediation efforts. 930.114... MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.114 Secretarial mediation efforts. (a) Following the close of the hearing, the hearing officer shall transmit...

  9. 15 CFR 930.112 - Request for Secretarial mediation.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 15 Commerce and Foreign Trade 3 2013-01-01 2013-01-01 false Request for Secretarial mediation. 930... RESOURCE MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.112 Request for Secretarial mediation. (a) The Secretary or other head of a Federal agency, or...

  10. 15 CFR 930.114 - Secretarial mediation efforts.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 15 Commerce and Foreign Trade 3 2012-01-01 2012-01-01 false Secretarial mediation efforts. 930.114... MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.114 Secretarial mediation efforts. (a) Following the close of the hearing, the hearing officer shall transmit...

  11. 15 CFR 930.112 - Request for Secretarial mediation.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 15 Commerce and Foreign Trade 3 2011-01-01 2011-01-01 false Request for Secretarial mediation. 930... RESOURCE MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.112 Request for Secretarial mediation. (a) The Secretary or other head of a Federal agency, or...

  12. 15 CFR 930.112 - Request for Secretarial mediation.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 15 Commerce and Foreign Trade 3 2014-01-01 2014-01-01 false Request for Secretarial mediation. 930... RESOURCE MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.112 Request for Secretarial mediation. (a) The Secretary or other head of a Federal agency, or...

  13. 15 CFR 930.114 - Secretarial mediation efforts.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 15 Commerce and Foreign Trade 3 2014-01-01 2014-01-01 false Secretarial mediation efforts. 930.114... MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.114 Secretarial mediation efforts. (a) Following the close of the hearing, the hearing officer shall transmit...

  14. 15 CFR 930.112 - Request for Secretarial mediation.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 15 Commerce and Foreign Trade 3 2012-01-01 2012-01-01 false Request for Secretarial mediation. 930... RESOURCE MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.112 Request for Secretarial mediation. (a) The Secretary or other head of a Federal agency, or...

  15. Prospective and Retrospective Processing in Associative Mediated Priming

    ERIC Educational Resources Information Center

    Jones, Lara L.

    2012-01-01

    Mediated priming refers to the faster word recognition of a target (e.g., milk) following presentation of a prime (e.g., pasture) that is related indirectly via a connecting "mediator" (e.g., cow). Association strength may be an important factor in whether mediated priming occurs prospectively (with target activation prior to its presentation) or…

  16. Estimation of Mediation Effects for Zero-inflated Regression Models

    PubMed Central

    Wang, Wei; Albert, Jeffrey M.

    2012-01-01

    The goal of mediation analysis is to identify and explicate the mechanism that underlies a relationship between a risk factor and an outcome via an intermediate variable (mediator). In this paper, we consider the estimation of mediation effects in zero-inflated (ZI) models intended to accommodate `extra' zeros in count data. Focusing on the ZI negative binomial (ZINB) models, we provide a mediation formula approach to estimate the (overall) mediation effect in the standard two-stage mediation framework under a key sequential ignorability assumption. We also consider a novel decomposition of the overall mediation effect for the ZI context using a three-stage mediation model. Estimation of the components of the overall mediation effect requires an assumption involving the joint distribution of two counterfactuals. Simulation study results demonstrate low bias of mediation effect estimators and close-to-nominal coverage probability (CP) of confidence intervals. We also modify the mediation formula method by replacing `exact' integration with a Monte Carlo integration method. The method is applied to a cohort study of dental caries in very low birth weight adolescents. For overall mediation effect estimation, sensitivity analysis was conducted to quantify the degree to which key assumption must be violated to reverse the original conclusion. PMID:22714572

  17. Mediation: Toward a Civilized System of Dispute Resolution.

    ERIC Educational Resources Information Center

    Keltner, John W. Sam

    Because the intervention of a neutral third party is currently gaining favor as an alternative form of dispute resolution, this book explores the process of mediation in the context of managing struggle and examines some of the characteristics of mediators, their training and ethics, and the techniques and skills of good mediation. The theory…

  18. RESPECT: Gang Mediation at Albuquerque, New Mexico's Washington Middle School.

    ERIC Educational Resources Information Center

    Tabish, Kenneth R.; Orell, Linda Henry

    1996-01-01

    Presents conflict resolution and mediation techniques used to resolve conflicts among rival gangs at Washington Middle School, an inner-city school in Albuquerque, New Mexico. Discusses formal mediation techniques and mediation for both male and female gang members. Focuses on preserving self-respect and dignity for gang members in all conflict…

  19. 15 CFR 930.112 - Request for Secretarial mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 3 2010-01-01 2010-01-01 false Request for Secretarial mediation. 930... RESOURCE MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.112 Request for Secretarial mediation. (a) The Secretary or other head of a Federal agency, or...

  20. The Use of Propensity Scores in Mediation Analysis

    ERIC Educational Resources Information Center

    Jo, Booil; Stuart, Elizabeth A.; MacKinnon, David P.; Vinokur, Amiram D.

    2011-01-01

    Mediation analysis uses measures of hypothesized mediating variables to test theory for how a treatment achieves effects on outcomes and to improve subsequent treatments by identifying the most efficient treatment components. Most current mediation analysis methods rely on untested distributional and functional form assumptions for valid…

  1. 7 CFR 900.103 - Application for mediation.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 8 2010-01-01 2010-01-01 false Application for mediation. 900.103 Section 900.103 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (Marketing... Application for mediation. An application for mediation by a cooperative, shall be in writing and...

  2. 29 CFR 1203.3 - Interpretation of mediation agreements.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false Interpretation of mediation agreements. 1203.3 Section 1203.3 Labor Regulations Relating to Labor (Continued) NATIONAL MEDIATION BOARD APPLICATIONS FOR SERVICE § 1203.3 Interpretation of mediation agreements. (a) Applications may be filed with the Board's Chief...

  3. 15 CFR 930.114 - Secretarial mediation efforts.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 15 Commerce and Foreign Trade 3 2010-01-01 2010-01-01 false Secretarial mediation efforts. 930.114... MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.114 Secretarial mediation efforts. (a) Following the close of the hearing, the hearing officer shall transmit...

  4. 29 CFR 1202.2 - Interpretation of mediation agreements.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 4 2010-07-01 2010-07-01 false Interpretation of mediation agreements. 1202.2 Section 1202.2 Labor Regulations Relating to Labor (Continued) NATIONAL MEDIATION BOARD RULES OF PROCEDURE § 1202.2 Interpretation of mediation agreements. Under section 5, Second, of title I of the Railway...

  5. Mediation: An Emerging Form of Dispute Resolution on College Campuses.

    ERIC Educational Resources Information Center

    Hayes, James A.; Balogh, Cynthia P.

    1990-01-01

    Surveyed National Association of Student Personnel Administrators member institutions (N=704) to determine existence and characteristics of student affairs mediation programs. Found 29 campuses had established formal mediation programs. Argues that establishing formal mediation programs provides many institutional benefits. (Author/CM)

  6. Parental Mediation of Children's Viewing in a Changing Television Environment.

    ERIC Educational Resources Information Center

    Tidhar, Chava E.; Levinsohn, Hanna

    1997-01-01

    This study surveyed the effects of cable television on Israeli parents' mediation of their childrens' viewing. Results indicate the introduction of cable television changed strategies of parental control and mediation and parents' assessment of television's influence on children. Active parental mediation was closely related to the attribution of…

  7. 40 CFR 7.180 - Mediation of age discrimination complaints.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Mediation of age discrimination... Discrimination Prohibited on the Basis of Age § 7.180 Mediation of age discrimination complaints. (a) The OCR will refer all accepted complaints alleging age discrimination to the Mediation Agency designated...

  8. Assessing Mediational Models: Testing and Interval Estimation for Indirect Effects

    ERIC Educational Resources Information Center

    Biesanz, Jeremy C.; Falk, Carl F.; Savalei, Victoria

    2010-01-01

    Theoretical models specifying indirect or mediated effects are common in the social sciences. An indirect effect exists when an independent variable's influence on the dependent variable is mediated through an intervening variable. Classic approaches to assessing such mediational hypotheses (Baron & Kenny, 1986; Sobel, 1982) have in recent years…

  9. Charge transfer-mediated singlet fission.

    PubMed

    Monahan, N; Zhu, X-Y

    2015-04-01

    Singlet fission, the splitting of a singlet exciton into two triplet excitons in molecular materials, is interesting not only as a model many-electron problem, but also as a process with potential applications in solar energy conversion. Here we discuss limitations of the conventional four-electron and molecular dimer model in describing singlet fission in crystalline organic semiconductors, such as pentacene and tetracene. We emphasize the need to consider electronic delocalization, which is responsible for the decisive role played by the Mott-Wannier exciton, also called the charge transfer (CT) exciton, in mediating singlet fission. At the strong electronic coupling limit, the initial excitation creates a quantum superposition of singlet, CT, and triplet-pair states, and we present experimental evidence for this interpretation. We also discuss the most recent attempts at translating this mechanistic understanding into design principles for CT state-mediated intramolecular singlet fission in oligomers and polymers. PMID:25648486

  10. Charge Transfer-Mediated Singlet Fission

    NASA Astrophysics Data System (ADS)

    Monahan, N.; Zhu, X.-Y.

    2015-04-01

    Singlet fission, the splitting of a singlet exciton into two triplet excitons in molecular materials, is interesting not only as a model many-electron problem, but also as a process with potential applications in solar energy conversion. Here we discuss limitations of the conventional four-electron and molecular dimer model in describing singlet fission in crystalline organic semiconductors, such as pentacene and tetracene. We emphasize the need to consider electronic delocalization, which is responsible for the decisive role played by the Mott-Wannier exciton, also called the charge transfer (CT) exciton, in mediating singlet fission. At the strong electronic coupling limit, the initial excitation creates a quantum superposition of singlet, CT, and triplet-pair states, and we present experimental evidence for this interpretation. We also discuss the most recent attempts at translating this mechanistic understanding into design principles for CT state-mediated intramolecular singlet fission in oligomers and polymers.

  11. An improved model of direct gauge mediation

    NASA Astrophysics Data System (ADS)

    Agashe, Kaustubh

    1998-09-01

    We present a new, improved model of gauge mediation of dynamical SUSY Breaking: the model does not have gauge messengers or ~10 TeV scalars charged under the Standard Model (SM), thus avoiding the problem of negative (mass)2 for supersymmetric SM (SSM) scalars faced by some earlier models. The gauge mediation is direct, i.e., the messengers which communicate SUSY breaking to the SSM fields carry quantum numbers of the gauge group which breaks SUSY. These messenger fields couple to a modulus field. The model has a very simple particle content: the modulus and the messengers are the only chiral superfields (other than the SSM fields) in the model. The inverted hierarchy mechanism is used to generate a local SUSY breaking minimum for the modulus field in a perturbative regime thus making the model calculable.

  12. Symbiont-mediated functions in insect hosts

    PubMed Central

    Su, Qi; Zhou, Xiaomao; Zhang, Youjun

    2013-01-01

    The bacterial endosymbionts occur in a diverse array of insect species and are usually rely within the vertical transmission from mothers to offspring. In addition to primary symbionts, plant sap-sucking insects may also harbor several diverse secondary symbionts. Bacterial symbionts play a prominent role in insect nutritional ecology by aiding in digestion of food or supplementing nutrients that insect hosts can’t obtain sufficient amounts from a restricted diet of plant phloem. Currently, several other ecologically relevant traits mediated by endosymbionts are being investigated, including defense toward pathogens and parasites, adaption to environment, influences on insect-plant interactions, and impact of population dynamics. Here, we review recent theoretical predictions and experimental observations of these traits mediated by endosymbionts and suggest that clarifying the roles of symbiotic microbes may be important to offer insights for ameliorating pest invasiveness or impact. PMID:23710278

  13. Endopeptidase-Mediated Beta Lactam Tolerance

    PubMed Central

    Dörr, Tobias; Davis, Brigid M.; Waldor, Matthew K.

    2015-01-01

    In many bacteria, inhibition of cell wall synthesis leads to cell death and lysis. The pathways and enzymes that mediate cell lysis after exposure to cell wall-acting antibiotics (e.g. beta lactams) are incompletely understood, but the activities of enzymes that degrade the cell wall (‘autolysins’) are thought to be critical. Here, we report that Vibrio cholerae, the cholera pathogen, is tolerant to antibiotics targeting cell wall synthesis. In response to a wide variety of cell wall- acting antibiotics, this pathogen loses its rod shape, indicative of cell wall degradation, and becomes spherical. Genetic analyses revealed that paradoxically, V. cholerae survival via sphere formation required the activity of D,D endopeptidases, enzymes that cleave the cell wall. Other autolysins proved dispensable for this process. Our findings suggest the enzymes that mediate cell wall degradation are critical for determining bacterial cell fate - sphere formation vs. lysis – after treatment with antibiotics that target cell wall synthesis. PMID:25884840

  14. Exosomes: Mediators of Neurodegeneration, Neuroprotection and Therapeutics

    PubMed Central

    Kalani, Anuradha; Tyagi, Alka

    2014-01-01

    Exosomes have emerged as prominent mediators of neurodegenerative diseases where they have been shown to carry disease particles such as beta amyloid and prions from their cells of origin to other cells. Their simple structure and ability to cross the blood-brain barrier allow great opportunity to design a “makeup” with drugs and genetic elements, such as siRNA or miRNA, and use them as delivery vehicles for neurotherapeutics. Their role in neuroprotection is evident by the fact that they are involved in the regeneration of peripheral nerves and repair of neuronal injuries. This review is focused on the role of exosomes in mediating neurodegeneration and neuroprotection. PMID:23999871

  15. Yeast Oligo-mediated Genome Engineering (YOGE)

    PubMed Central

    DiCarlo, JE; Conley, AJ; Penttilä, M; Jäntti, J; Wang, HH; Church, GM

    2014-01-01

    High-frequency oligonucleotide-directed recombination engineering (recombineering) has enabled rapid modification of several prokaryotic genomes to date. Here, we present a method for oligonucleotide-mediated recombineering in the model eukaryote and industrial production host S. cerevisiae, which we call Yeast Oligo-mediated Genome Engineering (YOGE). Through a combination of overexpression and knockouts of relevant genes and optimization of transformation and oligonucleotide designs, we achieve high gene modification frequencies at levels that only require screening of dozens of cells. We demonstrate the robustness of our approach in three divergent yeast strains, including those involved in industrial production of bio-based chemicals. Furthermore, YOGE can be iteratively executed via cycling to generate genomic libraries up to 105 individuals at each round for diversity generation. YOGE cycling alone, or in combination with phenotypic selections or endonuclease-based negative genotypic selections, can be used to easily generate modified alleles in yeast populations with high frequencies. PMID:24160921

  16. Naturalness from Runaways in Direct Mediation

    SciTech Connect

    Schafer-Nameki, Sakura; Tamarit, Carlos; Torroba, Gonzalo; /SLAC

    2011-02-07

    Postulating that the NMSSM singlet is a meson of a microscopic confining theory opens up new model-building possibilities. Based on this, we construct calculable models of direct mediation that solve the {mu}/B{mu} problem and simultaneously lead to realistic phenomenology. The singlet that couples to the Higgs fields develops a runaway produced by soft interactions, then stabilized by a small superpotential perturbation. The mechanism is first realized in an O'Raifeartaigh model of direct gauge mediation with metastable supersymmetry breaking. Focusing then on the microscopic theory, we argue that super QCD with massless and massive flavors in the free magnetic phase gives rise to this dynamics in the infrared. A deformation of the SQCD superpotential leads to large spontaneous R-symmetry breaking, gaugino masses naturally at the scale of the Higgs mass parameters, and absence of CP violating phases.

  17. Yeast oligo-mediated genome engineering (YOGE).

    PubMed

    DiCarlo, James E; Conley, Andrew J; Penttilä, Merja; Jäntti, Jussi; Wang, Harris H; Church, George M

    2013-12-20

    High-frequency oligonucleotide-directed recombination engineering (recombineering) has enabled rapid modification of several prokaryotic genomes to date. Here, we present a method for oligonucleotide-mediated recombineering in the model eukaryote and industrial production host Saccharomyces cerevisiae , which we call yeast oligo-mediated genome engineering (YOGE). Through a combination of overexpression and knockouts of relevant genes and optimization of transformation and oligonucleotide designs, we achieve high gene-modification frequencies at levels that only require screening of dozens of cells. We demonstrate the robustness of our approach in three divergent yeast strains, including those involved in industrial production of biobased chemicals. Furthermore, YOGE can be iteratively executed via cycling to generate genomic libraries up to 10 (5) individuals at each round for diversity generation. YOGE cycling alone or in combination with phenotypic selections or endonuclease-based negative genotypic selections can be used to generate modified alleles easily in yeast populations with high frequencies. PMID:24160921

  18. Gravity-mediated (or composite) dark matter

    NASA Astrophysics Data System (ADS)

    Lee, Hyun Min; Park, Myeonghun; Sanz, Verónica

    2014-02-01

    Dark matter could have an electroweak origin, yet it could communicate with the visible sector exclusively through gravitational interactions. In a setup addressing the hierarchy problem, we propose a new dark-matter scenario where gravitational mediators, arising from the compactification of extra dimensions, are responsible for dark-matter interactions and its relic abundance in the Universe. We write an explicit example of this mechanism in warped extra dimensions and work out its constraints. We also develop a dual picture of the model, based on a four-dimensional scenario with partial compositeness. We show that gravity-mediated dark matter is equivalent to a mechanism of generating viable dark matter scenarios in a strongly coupled, near-conformal theory, such as in composite Higgs models.

  19. Supersymmetry Breaking, Gauge Mediation, and the LHC

    SciTech Connect

    Shih, David

    2015-04-14

    Gauge mediated SUSY breaking (GMSB) is a promising class of supersymmetric models that automatically satisfies the precision constraints. Prior work of Meade, Seiberg and Shih in 2008 established the full, model-independent parameter space of GMSB, which they called "General Gauge Mediation" (GGM). During the first half of 2010-2015, Shih and his collaborators thoroughly explored the parameter space of GGM and established many well-motivated benchmark models for use by the experimentalists at the LHC. Through their work, the current constraints on GGM from LEP, the Tevatron and the LHC were fully elucidated, together with the possible collider signatures of GMSB at the LHC. This ensured that the full discovery potential for GGM could be completely realized at the LHC.

  20. Naturalness from runaways in direct mediation

    SciTech Connect

    Schaefer-Nameki, Sakura; Tamarit, Carlos; Torroba, Gonzalo

    2011-02-01

    Postulating that the nonminimal supersymmetric standard model singlet is a meson of a microscopic confining theory opens up new model-building possibilities. Based on this, we construct calculable models of direct mediation that solve the {mu}/B{sub {mu}} problem and simultaneously lead to realistic phenomenology. The singlet that couples to the Higgs fields develops a runaway produced by soft interactions and then stabilized by a small superpotential perturbation. The mechanism is first realized in an O'Raifeartaigh model of direct gauge mediation with metastable supersymmetry breaking. Focusing then on the microscopic theory, we argue that super QCD with massless and massive flavors in the free magnetic phase gives rise to this dynamics in the infrared. A deformation of the super QCD superpotential leads to large spontaneous R-symmetry breaking, gaugino masses naturally at the scale of the Higgs mass parameters, and the absence of CP violating phases.

  1. CEACAM1-Mediated Inhibition of Virus Production.

    PubMed

    Vitenshtein, Alon; Weisblum, Yiska; Hauka, Sebastian; Halenius, Anne; Oiknine-Djian, Esther; Tsukerman, Pinchas; Bauman, Yoav; Bar-On, Yotam; Stern-Ginossar, Noam; Enk, Jonatan; Ortenberg, Rona; Tai, Julie; Markel, Gal; Blumberg, Richard S; Hengel, Hartmut; Jonjic, Stipan; Wolf, Dana G; Adler, Heiko; Kammerer, Robert; Mandelboim, Ofer

    2016-06-14

    Cells in our body can induce hundreds of antiviral genes following virus sensing, many of which remain largely uncharacterized. CEACAM1 has been previously shown to be induced by various innate systems; however, the reason for such tight integration to innate sensing systems was not apparent. Here, we show that CEACAM1 is induced following detection of HCMV and influenza viruses by their respective DNA and RNA innate sensors, IFI16 and RIG-I. This induction is mediated by IRF3, which bound to an ISRE element present in the human, but not mouse, CEACAM1 promoter. Furthermore, we demonstrate that, upon induction, CEACAM1 suppresses both HCMV and influenza viruses in an SHP2-dependent process and achieves this broad antiviral efficacy by suppressing mTOR-mediated protein biosynthesis. Finally, we show that CEACAM1 also inhibits viral spread in ex vivo human decidua organ culture. PMID:27264178

  2. Fibronectin mediates mesendodermal cell fate decisions

    PubMed Central

    Cheng, Paul; Andersen, Peter; Hassel, David; Kaynak, Bogac L.; Limphong, Pattraranee; Juergensen, Lonny; Kwon, Chulan; Srivastava, Deepak

    2013-01-01

    Non-cell-autonomous signals often play crucial roles in cell fate decisions during animal development. Reciprocal signaling between endoderm and mesoderm is vital for embryonic development, yet the key signals and mechanisms remain unclear. Here, we show that endodermal cells efficiently promote the emergence of mesodermal cells in the neighboring population through signals containing an essential short-range component. The endoderm-mesoderm interaction promoted precardiac mesoderm formation in mouse embryonic stem cells and involved endodermal production of fibronectin. In vivo, fibronectin deficiency resulted in a dramatic reduction of mesoderm accompanied by endodermal expansion in zebrafish embryos. This event was mediated by regulation of Wnt signaling in mesodermal cells through activation of integrin-β1. Our findings highlight the importance of the extracellular matrix in mediating short-range signals and reveal a novel function of endoderm, involving fibronectin and its downstream signaling cascades, in promoting the emergence of mesoderm. PMID:23715551

  3. Lithium-mediated protection against ethanol neurotoxicity.

    PubMed

    Luo, Jia

    2010-01-01

    Lithium has long been used as a mood stabilizer in the treatment of manic-depressive (bipolar) disorder. Recent studies suggest that lithium has neuroprotective properties and may be useful in the treatment of acute brain injuries such as ischemia and chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. One of the most important neuroprotective properties of lithium is its anti-apoptotic action. Ethanol is a neuroteratogen and fetal alcohol spectrum disorders (FASD) are caused by maternal ethanol exposure during pregnancy. FASD is the leading cause of mental retardation. Ethanol exposure causes neuroapoptosis in the developing brain. Ethanol-induced loss of neurons in the central nervous system underlies many of the behavioral deficits observed in FASD. Excessive alcohol consumption is also associated with Wernicke-Korsakoff syndrome and neurodegeneration in the adult brain. Recent in vivo and in vitro studies indicate that lithium is able to ameliorate ethanol-induced neuroapoptosis. Lithium is an inhibitor of glycogen synthase kinase 3 (GSK3) which has recently been identified as a mediator of ethanol neurotoxicity. Lithium's neuroprotection may be mediated by its inhibition of GSK3. In addition, lithium also affects many other signaling proteins and pathways that regulate neuronal survival and differentiation. This review discusses the recent evidence of lithium-mediated protection against ethanol neurotoxicity and potential underlying mechanisms. PMID:20661453

  4. Model Analysis of Fomite Mediated Influenza Transmission

    PubMed Central

    Zhao, Jijun; Eisenberg, Joseph E.; Spicknall, Ian H.; Li, Sheng; Koopman, James S.

    2012-01-01

    Fomites involved in influenza transmission are either hand- or droplet-contaminated. We evaluated the interactions of fomite characteristics and human behaviors affecting these routes using an Environmental Infection Transmission System (EITS) model by comparing the basic reproduction numbers (R0) for different fomite mediated transmission pathways. Fomites classified as large versus small surface sizes (reflecting high versus low droplet contamination levels) and high versus low touching frequency have important differences. For example, 1) the highly touched large surface fomite (public tables) has the highest transmission potential and generally strongest control measure effects; 2) transmission from droplet-contaminated routes exceed those from hand-contaminated routes except for highly touched small surface fomites such as door knob handles; and 3) covering a cough using the upper arm or using tissues effectively removes virus from the system and thus decreases total fomite transmission. Because covering a cough by hands diverts pathogens from the droplet-fomite route to the hand-fomite route, this has the potential to increase total fomite transmission for highly touched small surface fomites. An improved understanding and more refined data related to fomite mediated transmission routes will help inform intervention strategies for influenza and other pathogens that are mediated through the environment. PMID:23300585

  5. Galectin-4-mediated transcytosis of transferrin receptor

    PubMed Central

    Perez Bay, Andres E.; Schreiner, Ryan; Benedicto, Ignacio; Rodriguez-Boulan, Enrique J.

    2014-01-01

    ABSTRACT Some native epithelia, for example, retinal pigment epithelium (RPE) and kidney proximal tubule (KPT), constitutively lack the basolateral sorting adaptor AP-1B; this results in many basolateral plasma membrane proteins being repositioned to the apical domain, where they perform essential functions for their host organs. We recently reported the underlying apical polarity reversal mechanism: in the absence of AP-1B-mediated basolateral sorting, basolateral proteins are shuttled to the apical plasma membrane through a transcytotic pathway mediated by the plus-end kinesin KIF16B. Here, we demonstrate that this apical transcytotic pathway requires apical sorting of basolateral proteins, which is mediated by apical signals and galectin-4. Using RPE and KPT cell lines, and AP-1B-knockdown MDCK cells, we show that mutation of the N-glycan linked to N727 in the basolateral marker transferrin receptor (TfR) or knockdown of galectin-4 inhibits TfR transcytosis to apical recycling endosomes and the apical plasma membrane, and promotes TfR lysosomal targeting and subsequent degradation. Our results report a new role of galectins in basolateral to apical epithelial transcytosis. PMID:25179596

  6. Membrane-mediated interaction between retroviral capsids

    NASA Astrophysics Data System (ADS)

    Zhang, Rui; Nguyen, Toan

    2012-02-01

    A retrovirus is an RNA virus that is replicated through a unique strategy of reverse transcription. Unlike regular enveloped viruses which are assembled inside the host cells, the assembly of retroviral capsids happens right on the cell membrane. During the assembly process, the partially formed capsids deform the membrane, giving rise to an elastic energy. When two such partial capsids approach each other, this elastic energy changes. Or in other words, the two partial capsids interact with each other via the membrane. This membrane mediated interaction between partial capsids plays an important role in the kinetics of the assembly process. In this work, this membrane mediated interaction is calculated both analytically and numerically. It is worth noting that the diferential equation determining the membrane shape in general nonlinear and cannot be solved analytically,except in the linear region of small deformations. And it is exactly the nonlinear regime that is important for the assembly kinetics of retroviruses as it provides a large energy barrier. The theory developed here is applicable to more generic cases of membrane mediated interactions between two membrane-embedded proteins.

  7. Molecular architecture of the yeast Mediator complex

    PubMed Central

    Robinson, Philip J; Trnka, Michael J; Pellarin, Riccardo; Greenberg, Charles H; Bushnell, David A; Davis, Ralph; Burlingame, Alma L; Sali, Andrej; Kornberg, Roger D

    2015-01-01

    The 21-subunit Mediator complex transduces regulatory information from enhancers to promoters, and performs an essential role in the initiation of transcription in all eukaryotes. Structural information on two-thirds of the complex has been limited to coarse subunit mapping onto 2-D images from electron micrographs. We have performed chemical cross-linking and mass spectrometry, and combined the results with information from X-ray crystallography, homology modeling, and cryo-electron microscopy by an integrative modeling approach to determine a 3-D model of the entire Mediator complex. The approach is validated by the use of X-ray crystal structures as internal controls and by consistency with previous results from electron microscopy and yeast two-hybrid screens. The model shows the locations and orientations of all Mediator subunits, as well as subunit interfaces and some secondary structural elements. Segments of 20–40 amino acid residues are placed with an average precision of 20 Å. The model reveals roles of individual subunits in the organization of the complex. DOI: http://dx.doi.org/10.7554/eLife.08719.001 PMID:26402457

  8. [Sphingolipid-mediated apoptotic signaling pathways].

    PubMed

    Cuvillier, Olivier; Andrieu-Abadie, Nathalie; Ségui, Bruno; Malagarie-Cazenave, Sophie; Tardy, Claudine; Bonhoure, Elisabeth; Levade, Thierry

    2003-01-01

    Various sphingolipids are being viewed as bioactive molecules and/or second messengers. Among them, ceramide (or N-acylsphingosine) and sphingosine generally behave as pro-apoptotic mediators. Indeed, ceramide mediates the death signal initiated by numerous stress agents which either stimulate its de novo synthesis or activate sphingomyelinases that release ceramide from sphingomyelin. For instance, the early generation of ceramide promoted by TNF is mediated by a neutral sphingomyelinase the activity of which is regulated by the FAN adaptor protein, thereby controlling caspase activation and the cell death programme. In addition, the activity of this neutral sphingomyelinase is negatively modulated by caveolin, a major constituent of some membrane microdomains. The enzyme sphingosine kinase also plays a crucial role in apoptosis signalling by regulating the intracellular levels of two sphingolipids having opposite effects, namely the pro-apoptotic sphingosine and the anti-apoptotic sphingosine 1-phosphate molecule. Ceramide and sphingosine metabolism therefore appears as a pivotal regulatory pathway in the determination of cell fate. PMID:14708343

  9. Neuroprotective strategies against calpain-mediated neurodegeneration.

    PubMed

    Yildiz-Unal, Aysegul; Korulu, Sirin; Karabay, Arzu

    2015-01-01

    Calpains are calcium-dependent proteolytic enzymes that have deleterious effects on neurons upon their pathological over-activation. According to the results of numerous studies to date, there is no doubt that abnormal calpain activation triggers activation and progression of apoptotic processes in neurodegeneration, leading to neuronal death. Thus, it is very crucial to unravel all the aspects of calpain-mediated neurodegeneration in order to protect neurons through eliminating or at least minimizing its lethal effects. Protecting neurons against calpain-activated apoptosis basically requires developing effective, reliable, and most importantly, therapeutically applicable approaches to succeed. From this aspect, the most significant studies focusing on preventing calpain-mediated neurodegeneration include blocking the N-methyl-d-aspartate (NMDA)-type glutamate receptor activities, which are closely related to calpain activation; directly inhibiting calpain itself via intrinsic or synthetic calpain inhibitors, or inhibiting its downstream processes; and utilizing the neuroprotectant steroid hormone estrogen and its receptors. In this review, the most remarkable neuroprotective strategies for calpain-mediated neurodegeneration are categorized and summarized with respect to their advantages and disadvantages over one another, in terms of their efficiency and applicability as a therapeutic regimen in the treatment of neurodegenerative diseases. PMID:25709452

  10. Gravitational rescue of minimal gauge mediation

    NASA Astrophysics Data System (ADS)

    Iyer, Abhishek M.; Mummidi, V. Suryanarayana; Vempati, Sudhir K.

    2016-03-01

    Gravity mediated supersymmetry breaking becomes comparable to gauge mediated supersymmetry breaking contributions when messenger masses are close to the GUT scale. By suitably arranging the gravity contributions, one can modify the soft supersymmetry breaking sector to generate a large stop mixing parameter and a light Higgs mass of 125 GeV. In this kind of hybrid models, however, the nice features of gauge mediation like flavor conservation, etc. are lost. To preserve the nice features, gravitational contributions should become important for lighter messenger masses and should be important only for certain fields. This is possible when the hidden sector contains multiple (at least two) spurions with hierarchical vacuum expectation values. In this case, the gravitational contributions can be organized to be “just right.” We present a complete model with two spurion hidden sector where the gravitational contribution is from a warped flavor model in a Randall-Sundrum setting. Along the way, we present simple expressions to handle renormalization group equations when supersymmetry is broken by two different sectors at two different scales.

  11. Bias in Cross-Sectional Analyses of Longitudinal Mediation: Partial and Complete Mediation under an Autoregressive Model

    ERIC Educational Resources Information Center

    Maxwell, Scott E.; Cole, David A.; Mitchell, Melissa A.

    2011-01-01

    Maxwell and Cole (2007) showed that cross-sectional approaches to mediation typically generate substantially biased estimates of longitudinal parameters in the special case of complete mediation. However, their results did not apply to the more typical case of partial mediation. We extend their previous work by showing that substantial bias can…

  12. Deflected Mirage Mediation: A Phenomenological Framework for Generalized Supersymmetry Breaking

    SciTech Connect

    Everett, Lisa L.; Kim, Ian-Woo; Ouyang, Peter; Zurek, Kathryn M.

    2008-09-05

    We present a general phenomenological framework for dialing between gravity mediation, gauge mediation, and anomaly mediation. The approach is motivated from recent developments in moduli stabilization, which suggest that gravity mediated terms can be effectively loop suppressed and thus comparable to gauge and anomaly mediated terms. The gauginos exhibit a mirage unification behavior at a ''deflected'' scale, and gluinos are often the lightest colored sparticles. The approach provides a rich setting in which to explore generalized supersymmetry breaking at the CERN Large Hadron Collider.

  13. Conserved structures of mediator and RNA polymerase II holoenzyme.

    PubMed

    Asturias, F J; Jiang, Y W; Myers, L C; Gustafsson, C M; Kornberg, R D

    1999-02-12

    Single particles of the mediator of transcriptional regulation (Mediator) and of RNA polymerase II holoenzyme were revealed by electron microscopy and image processing. Mediator alone appeared compact, but at high pH or in the presence of RNA polymerase II it displayed an extended conformation. Holoenzyme contained Mediator in a fully extended state, partially enveloping the globular polymerase, with points of apparent contact in the vicinity of the polymerase carboxyl-terminal domain and the DNA-binding channel. A similarity in appearance and conformational behavior of yeast and murine complexes indicates a conservation of Mediator structure among eukaryotes. PMID:9974391

  14. Predictors of Parental Mediation Regarding Children's Smartphone Use.

    PubMed

    Hwang, Yoori; Jeong, Se-Hoon

    2015-12-01

    Children's addiction to smartphones has become a serious issue, and parental mediation could help prevent children's problematic use of smartphones. This research examined the factors that predict and explain parents' intention to mediate children's behavior over smartphone use. Based on a survey of 460 parents of elementary school students, we found that parental mediation was predicted by (a) parent's own addiction to smartphones, (b) perceived severity of smartphone addiction, and (c) personality traits such as neuroticism, openness, and agreeableness. To the best of our knowledge, this study is the first to examine the predictors of parental mediation regarding children's smartphone addiction, and the findings suggest some strategies to increase parental mediation. PMID:26544162

  15. Docosapentaenoic acid derived metabolites and mediators - The new world of lipid mediator medicine in a nutshell.

    PubMed

    Weylandt, Karsten-H

    2016-08-15

    Recent years have seen the description and elucidation of a new class of anti-inflammatory and pro-resolving lipid mediators. The arachidonic acid (AA)-derived compounds in this class are called lipoxins and have been described in great detail since their discovery thirty years ago. The new players are mediators derived from fish oil omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), called resolvins, protectins and maresins. Taken together, these mediators are also called specialized pro-resolution mediators (SPMs). As compared to the AA/EPA/DHA-derived compounds, research regarding mediators formed from the n-3 and n-6 docosapentaenoic acids (DPAn-3 and DPAn-6) is sparse. However, mono- di- and trihydroxy derivates of the DPAs have anti-inflammatory properties as well, even though mechanisms of their anti-inflammatory action have not been fully elucidated. This review aims to summarize current knowledge regarding the DPA-derived SPMs and their actions. PMID:26546723

  16. Bias in cross-sectional analyses of longitudinal mediation.

    PubMed

    Maxwell, Scott E; Cole, David A

    2007-03-01

    Most empirical tests of mediation utilize cross-sectional data despite the fact that mediation consists of causal processes that unfold over time. The authors considered the possibility that longitudinal mediation might occur under either of two different models of change: (a) an autoregressive model or (b) a random effects model. For both models, the authors demonstrated that cross-sectional approaches to mediation typically generate substantially biased estimates of longitudinal parameters even under the ideal conditions when mediation is complete. In longitudinal models where variable M completely mediates the effect of X on Y, cross-sectional estimates of the direct effect of X on Y, the indirect effect of X on Y through M, and the proportion of the total effect mediated by M are often highly misleading. PMID:17402810

  17. Nonimmunoglobulin E-Mediated Immune Reactions to Foods

    PubMed Central

    2006-01-01

    Adverse food reactions are abnormal responses to ingested foods. Reactions vary from immunologic to nonimmunologic immune reactions and can be either immunoglobulin E (IgE) mediated or non-IgE mediated. Food-induced IgE-mediated reactions range from localized urticaria to anaphylaxis and have been well studied. However, in comparison, there has been significantly less research into non-IgE-mediated food reactions. Non-IgE-mediated reactions can cause respiratory, gastrointestinal, and cutaneous symptoms. The most recent evidence suggests that these reactions are probably T-cell mediated as evidenced in lymphocyte proliferation assays. This review will explore the symptoms and testing methods of the most common non-IgE-mediated reactions. PMID:20525161

  18. Tests of Mediation: Paradoxical Decline in Statistical Power as a Function of Mediator Collinearity.

    PubMed

    Beasley, T Mark

    2014-01-01

    Increasing the correlation between the independent variable and the mediator (a coefficient) increases the effect size (ab) for mediation analysis; however, increasing a by definition increases collinearity in mediation models. As a result, the standard error of product tests increase. The variance inflation due to increases in a at some point outweighs the increase of the effect size (ab) and results in a loss of statistical power. This phenomenon also occurs with nonparametric bootstrapping approaches because the variance of the bootstrap distribution of ab approximates the variance expected from normal theory. Both variances increase dramatically when a exceeds the b coefficient, thus explaining the power decline with increases in a. Implications for statistical analysis and applied researchers are discussed. PMID:24954952

  19. Tests of Mediation: Paradoxical Decline in Statistical Power as a Function of Mediator Collinearity

    PubMed Central

    Beasley, T. Mark

    2013-01-01

    Increasing the correlation between the independent variable and the mediator (a coefficient) increases the effect size (ab) for mediation analysis; however, increasing a by definition increases collinearity in mediation models. As a result, the standard error of product tests increase. The variance inflation due to increases in a at some point outweighs the increase of the effect size (ab) and results in a loss of statistical power. This phenomenon also occurs with nonparametric bootstrapping approaches because the variance of the bootstrap distribution of ab approximates the variance expected from normal theory. Both variances increase dramatically when a exceeds the b coefficient, thus explaining the power decline with increases in a. Implications for statistical analysis and applied researchers are discussed. PMID:24954952

  20. Radioprotection and Cell Cycle Arrest of Intestinal Epithelial Cells by Darinaparsin, a Tumor Radiosensitizer

    SciTech Connect

    Tian, Junqiang; Doi, Hiroshi; Saar, Matthias; Santos, Jennifer; Li, Xuejun; Peehl, Donna M.; Knox, Susan J.

    2013-12-01

    Purpose: It was recently reported that the organic arsenic compound darinaparsin (DPS) is a cytotoxin and radiosensitizer of tumor cells in vitro and in subcutaneous xenograft tumors. Surprisingly, it was also found that DPS protects normal intestinal crypt epithelial cells (CECs) from clonogenic death after ionizing radiation (IR). Here we tested the DPS radiosensitizing effect in a clinically relevant model of prostate cancer and explored the radioprotective effect and mechanism of DPS on CECs. Methods and Materials: The radiation modification effect of DPS was tested in a mouse model of orthotopic xenograft prostate cancer and of IR-induced acute gastrointestinal syndrome. The effect of DPS on CEC DNA damage and DNA damage responses was determined by immunohistochemistry. Results: In the mouse model of IR-induced gastrointestinal syndrome, DPS treatment before IR accelerated recovery from body weight loss and increased animal survival. DPS decreased post-IR DNA damage and cell death, suggesting that the radioprotective effect was mediated by enhanced DNA damage repair. Shortly after DPS injection, significant cell cycle arrest was observed in CECs at both G1/S and G2/M checkpoints, which was accompanied by the activation of cell cycle inhibitors p21 and growth arrest and DNA-damage-inducible protein 45 alpha (GADD45A). Further investigation revealed that DPS activated ataxia telangiectasia mutated (ATM), an important inducer of DNA damage repair and cell cycle arrest. Conclusions: DPS selectively radioprotected normal intestinal CECs and sensitized prostate cancer cells in a clinically relevant model. This effect may be, at least in part, mediated by DNA damage response activation and has the potential to significantly increase the therapeutic index of radiation therapy.

  1. Tear Mediators in Corneal Ectatic Disorders

    PubMed Central

    Pásztor, Dorottya; Kolozsvári, Bence Lajos; Csutak, Adrienne; Berta, András; Hassan, Ziad; Ujhelyi, Bernadett; Gogolák, Péter; Fodor, Mariann

    2016-01-01

    Purpose To compare the concentrations of 11 tear mediators in order to reveal the biochemical difference between pellucid marginal degeneration (PMD) and keratoconus (KC). Methods We have designed a cross-sectional study in which patients with corneal ectasia based on slit-lamp biomicroscopy and Pentacam HR (keratometry values (K1, K2, Kmax), astigmatism, minimal radius of curvature (Rmin), corneal thickness (Apex and Min), indices (surface variation, vertical asymmetry, keratoconus, central keratoconus, height asymmetry and decentration)) were enrolled. Eyes of keratoconic patients were similar to the PMD patients in age and severity (K2, Kmax and Rmin). Non-stimulated tear samples were collected from nine eyes of seven PMD patients, 55 eyes of 55 KC patients and 24 eyes of 24 healthy controls. The mediators’ (interleukin -6, -10, chemokine ligand 5, -8, -10, matrix metalloproteinase (MMP) -9, -13, tissue inhibitor of metalloproteinases (TIMP)-1, tissue plasminogen activator, plasminogen activator inhibitor, nerve growth factor) concentrations were measured using Cytometric Bead Array. Results MMP-9 was the only mediator which presented relevant variances between the two patient groups (p = 0.005). The ratios of MMP-9 and TIMP-1 were 2.45, 0.40 and 0.23 in PMD, KC and the controls, respectively. Conclusion As far as we are aware, this is the first study that aims to reveal the biochemical differences between PMD and KC. Further studies of biomarkers to investigate the precise role of these mediators need to be defined, and it is important to confirm the observed changes in a larger study to gain further insights into the molecular alterations in PMD. PMID:27074131

  2. Inflammatory mediators in mastitis and lactation insufficiency.

    PubMed

    Ingman, Wendy V; Glynn, Danielle J; Hutchinson, Mark R

    2014-07-01

    Mastitis is a common inflammatory disease during lactation that causes reduced milk supply. A growing body of evidence challenges the central role of pathogenic bacteria in mastitis, with disease severity associated with markers of inflammation rather than infection. Inflammation in the mammary gland may be triggered by microbe-associated molecular patterns (MAMPs) as well as danger-associated molecular patterns (DAMPs) binding to pattern recognition receptors such as the toll-like receptors (TLRs) on the surface of mammary epithelial cells and local immune cell populations. Activation of the TLR4 signalling pathway and downstream nuclear factor kappa B (NFkB) is critical to mediating local mammary gland inflammation and systemic immune responses in mouse models of mastitis. However, activation of NFkB also induces epithelial cell apoptosis and reduced milk protein synthesis, suggesting that inflammatory mediators activated during mastitis promote partial involution. Perturbed milk flow, maternal stress and genetic predisposition are significant risk factors for mastitis, and could lead to a heightened TLR4-mediated inflammatory response, resulting in increased susceptibility and severity of mastitis disease in the context of low MAMP abundance. Therefore, heightened host inflammatory signalling may act in concert with pathogenic or commensal bacterial species to cause both the inflammation associated with mastitis and lactation insufficiency. Here, we present an alternate paradigm to the widely held notion that breast inflammation is driven principally by infectious bacterial pathogens, and suggest there may be other therapeutic strategies, apart from the currently utilised antimicrobial agents, that could be employed to prevent and treat mastitis in women. PMID:24961655

  3. Vector-Mediated In Vivo Antibody Expression.

    PubMed

    Schnepp, Bruce C; Johnson, Philip R

    2014-08-01

    This article focuses on a novel vaccine strategy known as vector-mediated antibody gene transfer, with a particular focus on human immunodeficiency virus (HIV). This strategy provides a solution to the problem of current vaccines that fail to generate neutralizing antibodies to prevent HIV-1 infection and AIDS. Antibody gene transfer allows for predetermination of antibody affinity and specificity prior to "immunization" and avoids the need for an active humoral immune response against the HIV envelope protein. This approach uses recombinant adeno-associated viral (rAAV) vectors, which have been shown to transduce muscle with high efficiency and direct the long-term expression of a variety of transgenes, to deliver the gene encoding a broadly neutralizing antibody into the muscle. Following rAAV vector gene delivery, the broadly neutralizing antibodies are endogenously synthesized in myofibers and passively distributed to the circulatory system. This is an improvement over classical passive immunization strategies that administer antibody proteins to the host to provide protection from infection. Vector-mediated gene transfer studies in mice and monkeys with anti-HIV and simian immunodeficiency virus (SIV)-neutralizing antibodies demonstrated long-lasting neutralizing activity in serum with complete protection against intravenous challenge with virulent HIV and SIV. These results indicate that existing potent anti-HIV antibodies can be rapidly moved into the clinic. However, this methodology need not be confined to HIV. The general strategy of vector-mediated antibody gene transfer can be applied to other difficult vaccine targets such as hepatitis C virus, malaria, respiratory syncytial virus, and tuberculosis. PMID:26104192

  4. Cold agglutinin-mediated autoimmune hemolytic anemia.

    PubMed

    Berentsen, Sigbjørn; Randen, Ulla; Tjønnfjord, Geir E

    2015-06-01

    Cold antibody types account for about 25% of autoimmune hemolytic anemias. Primary chronic cold agglutinin disease (CAD) is characterized by a clonal lymphoproliferative disorder. Secondary cold agglutinin syndrome (CAS) complicates specific infections and malignancies. Hemolysis in CAD and CAS is mediated by the classical complement pathway and is predominantly extravascular. Not all patients require treatment. Successful CAD therapy targets the pathogenic B-cell clone. Complement modulation seems promising in both CAD and CAS. Further development and documentation are necessary before clinical use. We review options for possible complement-directed therapy. PMID:26043385

  5. Cell mediated immune regulation in autoimmunity.

    PubMed

    Gillissen, G; Pusztai-Markos, Z

    1979-01-01

    Autoimmunity is the term for the immune conditions characterized by a specific humoral or cell mediated response to the body's own tissues. The termination of the natural state of self tolerance may lead to immunopathological manifestations with clinical consequences, i.e. autoimmune diseases. In a very general sense, one may classify autoimmune diseases into two groups with respect to the underlying mechanism: 1. There are autoimmune diseases which develop in the presence of a normal intact regulation mechanism. 2. Another group whose development must be understood on the basis of a cellular dysfunction. In the first case, dequestered or semi-sequestered autoantigens are liberated as a consequence of exogenic influences inducing the sensitization of immunocompetent cells. The immune system then reacts with these autoantigens in the same way as with foreign substances. This kind of autoimmune disease will, however, not be dealt with here. In the second case, autoantigens are normally, i.e. in healthy individuals, accessible to the immunocompetent cells. To understand the reason for the development of an autoimmune reaction one must first clarify the mechanism of self tolerance. Then one must examine the way in which a break of this physiological state takes place. One of the major unanswered questions is the relative importance of antibody-mediated and cell-mediated immune mechanisms in the onset and further development of autoimmune diseases. Recently it has been suggested that a dysfunction at the cellular level might represent the basic cause which induces the termination of selftolerance. Most of the conceptions about the mechanism by which autoimmune diseases are triggered were gained through experiments with animals. It is, however, difficult to use these experimental results to explain human diseases; in humans many questions are still open. Undoubtedly, the mechanisms of induction and maintenance of self tolerance and also the ways in which autoimmune

  6. Deterministic mediated superdense coding with linear optics

    NASA Astrophysics Data System (ADS)

    Pavičić, Mladen

    2016-02-01

    We present a scheme of deterministic mediated superdense coding of entangled photon states employing only linear-optics elements. Ideally, we are able to deterministically transfer four messages by manipulating just one of the photons. Two degrees of freedom, polarization and spatial, are used. A new kind of source of heralded down-converted photon pairs conditioned on detection of another pair with an efficiency of 92% is proposed. Realistic probabilistic experimental verification of the scheme with such a source of preselected pairs is feasible with today's technology. We obtain the channel capacity of 1.78 bits for a full-fledged implementation.

  7. Reagents for diverse iodosilane-mediated transformations.

    PubMed

    Shibuya, Masatoshi; Abe, Masanori; Fujita, Shoji; Yamamoto, Yoshihiko

    2016-06-21

    It was observed that a PhSiH2I-mediated protocol using PhSiH3 and cat. I2 caused the deiodination of 2-(iodomethyl)-2-phenyltetrahydrofuran. Stemming from the investigation of the mechanism, we found that the PhSiH3-I2 system selectively promotes diverse cascade transformations from cyclic ethers to acyclic alkyl iodides, and the PhSiH3-N-iodosuccinimide (NIS) system also promotes cascade transformations from cyclic ethers to acyclic alcohols. PMID:27220485

  8. Microwave-mediated enzymatic modifications of DNA.

    PubMed

    Das, Rakha Hari; Ahirwar, Rajesh; Kumar, Saroj; Nahar, Pradip

    2015-02-15

    Here we report microwave-induced specific cleavage, ligation, dephosphorylation, and phosphorylation of nucleic acids catalyzed by restriction endonucleases, T4 DNA ligase, T4 polynucleotide kinase, and calf intestinal alkaline phosphatase. The microwave-mediated method has dramatically reduced the reaction time to 20 to 50s. In control experiments, the same reactions failed to give the desired reaction products when carried out in the same time periods but without microwave irradiation. Because the microwave method is rapid, it could be a useful alternative to the time-consuming conventional procedure for enzymatic modification of DNA. PMID:25447491

  9. Dark matter signals in deflected mirage mediation

    SciTech Connect

    Holmes, Michael

    2010-02-10

    We investigate the parameter space of a specific class of model within the deflected mirage mediation (DMM) scenario. We look at neutralino properties and compute the thermal relic density as well as interaction rates with xenon direct detection experiments. We find that there are portions of the parameter space which are in line with the current WMAP constraints. Further we find that none of the investigated parameter space is in conflict with current bounds from the Xenon10 experiment and that future large-scale liquid xenon experiments will probe a large portion of the model space.

  10. Natural supersymmetric spectrum in mirage mediation

    NASA Astrophysics Data System (ADS)

    Asano, Masaki; Higaki, Tetsutaro

    2012-08-01

    The current results of LHC experiments exclude a large area of the light new particle region, namely, natural parameter space, in supersymmetric extension models. One of the possibilities for achieving the correct electroweak symmetry breaking naturally is the low-scale messenger scenario. Actually, the next-to-minimal supersymmetric standard model with TeV scale mirage mediation realizes the natural electroweak symmetry breaking with various mass spectra. In this paper, we show the possible mass spectrum in the scenario, e.g., the degenerate and/or hierarchical mass spectrum, and discuss these features.

  11. Ubiquitin-Mediated Degradation of Aurora Kinases

    PubMed Central

    Lindon, Catherine; Grant, Rhys; Min, Mingwei

    2016-01-01

    The Aurora kinases are essential regulators of mitosis in eukaryotes. In somatic cell divisions of higher eukaryotes, the paralogs Aurora kinase A (AurA) and Aurora kinase B (AurB) play non-overlapping roles that depend on their distinct spatiotemporal activities. These mitotic roles of Aurora kinases depend on their interactions with different partners that direct them to different mitotic destinations and different substrates: AurB is a component of the chromosome passenger complex that orchestrates the tasks of chromosome segregation and cytokinesis, while AurA has many known binding partners and mitotic roles, including a well-characterized interaction with TPX2 that mediates its role in mitotic spindle assembly. Beyond the spatial control conferred by different binding partners, Aurora kinases are subject to temporal control of their activation and inactivation. Ubiquitin-mediated proteolysis is a critical route to irreversible inactivation of these kinases, which must occur for ordered transition from mitosis back to interphase. Both AurA and AurB undergo targeted proteolysis after anaphase onset as substrates of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase, even while they continue to regulate steps during mitotic exit. Temporal control of Aurora kinase destruction ensures that AurB remains active at the midbody during cytokinesis long after AurA activity has been largely eliminated from the cell. Differential destruction of Aurora kinases is achieved despite the fact that they are targeted at the same time and by the same ubiquitin ligase, making these substrates an interesting case study for investigating molecular determinants of ubiquitin-mediated proteolysis in higher eukaryotes. The prevalence of Aurora overexpression in cancers and their potential as therapeutic targets add importance to the task of understanding the molecular determinants of Aurora kinase stability. Here, we review what is known about ubiquitin-mediated targeting

  12. Mechanisms of platelet-mediated liver regeneration.

    PubMed

    Lisman, Ton; Porte, Robert J

    2016-08-01

    Platelets have multiple functions beyond their roles in thrombosis and hemostasis. Platelets support liver regeneration, which is required after partial hepatectomy and acute or chronic liver injury. Although it is widely assumed that platelets stimulate liver regeneration by local excretion of mitogens stored within platelet granules, definitive evidence for this is lacking, and alternative mechanisms deserve consideration. In-depth knowledge of mechanisms of platelet-mediated liver regeneration may lead to new therapeutic strategies to treat patients with failing regenerative responses. PMID:27297793

  13. Sensory neurons and circuits mediating itch

    PubMed Central

    LaMotte, Robert H.; Dong, Xinzhong; Ringkamp, Matthias

    2014-01-01

    Chemicals used experimentally to evoke itch elicit activity in diverse subpopulations of cutaneous pruriceptive neurons, all of which also respond to painful stimuli. However, itch is distinct from pain: it evokes different behaviors, such as scratching, and originates from the skin or certain mucosae but not from muscle, joints or viscera. New insights regarding the neurons that mediate the sensation of itch have been gained from experiments in which gene expression has been manipulated in different types of pruriceptive neurons as well as from comparisons between psychophysical measurements of itch and the neuronal discharges and other properties of peripheral and central pruriceptive neurons. PMID:24356071

  14. Electroweak naturalness and deflected mirage mediation

    NASA Astrophysics Data System (ADS)

    Barger, Vernon; Everett, Lisa L.; Garon, Todd S.

    2016-04-01

    We investigate the question of electroweak naturalness within the deflected mirage mediation (DMM) framework for supersymmetry breaking in the minimal supersymmetric standard model. The class of DMM models considered are nine-parameter theories that fall within the general classification of the 19-parameter phenomenological minimal supersymmetric standard model. Our results show that these DMM models have regions of parameter space with very low electroweak fine-tuning, at levels comparable to the phenomenological minimal supersymmetric standard model. These parameter regions should be probed extensively in the current LHC run.

  15. Gene transfer mediated by alpha2-macroglobulin.

    PubMed Central

    Schneider, H; Huse, K; Birkenmeier, G; Otto, A; Scholz, G H

    1996-01-01

    alpha2-Macroglobulin covalently linked to poly(L)-lysine can be used as a vehicle for receptor-mediated gene transfer. This modified alpha2-macroglobulin maintains its ability to bind to the alpha2-macroglobulin receptor, and was shown to introduce a luciferase reporter gene plasmid into HepG2 human hepatoma cells in vitro. The alpha2-macroglobulin receptor is a very large and multifunctional cell surface receptor, whose rapid and efficient internalization rate makes it attractive for gene therapy, e.g. for hepatic gene targeting via injection into the portal vein. PMID:8871570

  16. Literacy Mediations and Mediators in the "Escuela Dominical" of a Gitano Evangelist Church

    ERIC Educational Resources Information Center

    Poveda, David; Palomares-Valera, Manuel; Cano, Ana

    2006-01-01

    In this paper we examine discourse and interaction during Saturday morning religious instruction classes in a Gitano (Spanish Romani) evangelist church. The focus is on adults as literacy mediators for the children in the process of learning ways to use and interpret the Bible. The analysis centres on two aspects: (1) the forms of textuality that…

  17. Mediation in Special Education: A Resource Manual for Mediators. Revised and Updated.

    ERIC Educational Resources Information Center

    Schrag, Judy A.

    This resource manual presents information on mediation practices in special education disagreements between the school and parents. The manual provides an overview of requirements in the Individuals with Disabilities Education Act (IDEA) and gives definitions for alternative dispute resolution processes, such as arbitration and litigation. A chart…

  18. Ultrasound-mediated nail drug delivery system.

    PubMed

    Abadi, Danielle; Zderic, Vesna

    2011-12-01

    A novel ultrasound-mediated drug delivery system has been developed for treatment of a nail fungal disorder (onychomycosis) by improving delivery to the nail bed using ultrasound to increase the permeability of the nail. The slip-in device consists of ultrasound transducers and drug delivery compartments above each toenail. The device is connected to a computer, where a software interface allows users to select their preferred course of treatment. In in vitro testing, canine nails were exposed to 3 energy levels (acoustic power of 1.2 W and exposure durations of 30, 60, and 120 seconds). A stereo -microscope was used to determine how much of a drug-mimicking compound was delivered through the nail layers by measuring brightness on the cross section of each nail tested at each condition, where brightness level decreases coincide with increases in permeability. Each of the 3 energy levels tested showed statistical significance when compared to the control (P < .05) with a permeability factor of 1.3 after 30 seconds of exposure, 1.3 after 60 seconds, and 1.5 after 120 seconds, where a permeability factor of 1 shows no increase in permeability. Current treatments for onychomycosis include systemic, topical, and surgical. Even when used all together, these treatments typically take a long time to result in nail healing, thus making this ultrasound-mediated device a promising alternative. PMID:22124008

  19. Mediators and mucociliary clearance in asthma.

    PubMed

    Pavia, D; Lopez-Vidriero, M T; Clarke, S W

    1987-01-01

    Lung mucociliary clearance is significantly reduced in asthmatic patients compared to healthy controls even during clinical remission. Further retardation in mucous clearance occurs during sleep per se and this may be a contributing factor to nocturnal asthma. Chemical mediators of anaphylaxis appear to have various and, sometimes opposing effects on the two essential components for mucociliary clearance, namely cilia and mucus. Some mediators such as leukotrienes C4 and D4 are potent secretagogues and histamine increases the water flux into the lumen of the airways from the mucosa. Slow-reacting substance of anaphylaxis (SRS-A) reduces mucus transport whereas histamine enhances it. Ciliostimulation has been reported following allergen challenge and this contrasts with the cilioinhibitory effect of asthmatics' sputa. It appears however, that the net effect of the various chemicals of anaphylaxis is one of impairment of mucus clearance. Some pharmacological agents, used for the relief of bronchospasm and control of asthma, also stimulate mucociliary transport, a desirable additional effect. PMID:3311245

  20. AXL mediates resistance to cetuximab therapy

    PubMed Central

    Brand, Toni M.; Iida, Mari; Stein, Andrew P.; Corrigan, Kelsey L.; Braverman, Cara; Luthar, Neha; Toulany, Mahmoud; Gill, Parkash S.; Salgia, Ravi; Kimple, Randall J.; Wheeler, Deric L.

    2014-01-01

    The EGFR antibody cetuximab is used to treat numerous cancers, but intrinsic and acquired resistance to this agent is a common clinical problem. In this study we show that overexpression of the oncogenic receptor kinase AXL is sufficient to mediate acquired resistance to cetuximab in models of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), where AXL was overexpressed, activated and tightly associated with EGFR expression in cells resistant to cetuximab (CtxR cells). Using RNAi methods and novel AXL targeting agents, we found that AXL activation stimulated cell proliferation, EGFR activation and MAPK signaling in CtxR cells. Notably, EGFR directly regulated the expression of AXL mRNA through MAPK signaling and the transcription factor c-Jun in CtxR cells, creating a positive feedback loop that maintained EGFR activation by AXL. Cetuximab-sensitive parental cells were rendered resistant to cetuximab by stable overexpression of AXL or stimulation with EGFR ligands, the latter of which increased AXL activity and association with the EGFR. In tumor xenograft assays, the development of resistance following prolonged treatment with cetuximab was associated with AXL hyperactivation and EGFR association. Furthermore, in an examination of patient-derived xenografts established from surgically resected HNSCCs, AXL was overexpressed and activated in tumors that displayed intrinsic resistance to cetuximab. Collectively, our results identify AXL as a key mediator of cetuximab resistance, providing a rationale for clinical evaluation of AXL targeting drugs to treat cetuximab-resistant cancers. PMID:25136066

  1. Triplex-mediated genome targeting and editing.

    PubMed

    Reza, Faisal; Glazer, Peter M

    2014-01-01

    Genome targeting and editing in vitro and in vivo can be achieved through an interplay of exogenously introduced molecules and the induction of endogenous recombination machinery. The former includes a repertoire of sequence-specific binding molecules for targeted induction and appropriation of this machinery, such as by triplex-forming oligonucleotides (TFOs) or triplex-forming peptide nucleic acids (PNAs) and recombinagenic donor DNA, respectively. This versatile targeting and editing via recombination approach facilitates high-fidelity and low-off-target genome mutagenesis, repair, expression, and regulation. Herein, we describe the current state-of-the-art in triplex-mediated genome targeting and editing with a perspective towards potential translational and therapeutic applications. We detail several materials and methods for the design, delivery, and use of triplex-forming and recombinagenic molecules for mediating and introducing specific, heritable, and safe genomic modifications. Furthermore we denote some guidelines for endogenous genome targeting and editing site identification and techniques to test targeting and editing efficiency. PMID:24557900

  2. Automated Database Mediation Using Ontological Metadata Mappings

    PubMed Central

    Marenco, Luis; Wang, Rixin; Nadkarni, Prakash

    2009-01-01

    Objective To devise an automated approach for integrating federated database information using database ontologies constructed from their extended metadata. Background One challenge of database federation is that the granularity of representation of equivalent data varies across systems. Dealing effectively with this problem is analogous to dealing with precoordinated vs. postcoordinated concepts in biomedical ontologies. Model Description The authors describe an approach based on ontological metadata mapping rules defined with elements of a global vocabulary, which allows a query specified at one granularity level to fetch data, where possible, from databases within the federation that use different granularities. This is implemented in OntoMediator, a newly developed production component of our previously described Query Integrator System. OntoMediator's operation is illustrated with a query that accesses three geographically separate, interoperating databases. An example based on SNOMED also illustrates the applicability of high-level rules to support the enforcement of constraints that can prevent inappropriate curator or power-user actions. Summary A rule-based framework simplifies the design and maintenance of systems where categories of data must be mapped to each other, for the purpose of either cross-database query or for curation of the contents of compositional controlled vocabularies. PMID:19567801

  3. General gauge mediation in five dimensions

    SciTech Connect

    McGarrie, Moritz; Russo, Rodolfo

    2010-08-01

    We use the ''general gauge mediation'' (GGM) formalism to describe a five-dimensional setup with an S{sup 1}/Z{sub 2} orbifold. We first consider a model independent supersymmetry breaking hidden sector on one boundary and generic chiral matter on another. Using the definition of GGM, the effects of the hidden sector are contained in a set of global symmetry current correlator functions and is mediated through the bulk. We find the gaugino, sfermion and hyperscalar mass formulas for minimal and generalized messengers in different regimes of a large, small and intermediate extra dimension. Then we use the five-dimensional GGM formalism to construct a model in which an SU(5) Intriligator, Seiberg and Shih (ISS) model is located on the hidden boundary. We weakly gauge a global symmetry of the ISS model and associate it with the bulk vector superfield. Compared to four-dimensional GGM, there is a natural way to adjust the gaugino versus sfermion mass ratio by a factor (Ml){sup 2}, where M is a characteristic mass scale of the supersymmetry breaking sector and l is the length of the extra dimension.

  4. Peptide-mediated interference with baculovirus transduction.

    PubMed

    Mäkelä, Anna R; Närvänen, Ale; Oker-Blom, Christian

    2008-03-20

    Baculovirus represents a multifunctional platform with potential for biomedical applications including disease therapies. The importance of F3, a tumor-homing peptide, in baculovirus transduction was previously recognized by the ability of F3 to augment viral binding and gene delivery to human cancer cells following display on the viral envelope. Here, F3 was utilized as a molecular tool to expand understanding of the poorly characterized baculovirus-mammalian cell interactions. Baculovirus-mediated transduction of HepG2 hepatocarcinoma cells was strongly inhibited by coincubating the virus with synthetic F3 or following incorporation of F3 into viral nucleocapsid by genetic engineering, the former suggesting direct interaction of the soluble peptide with the virus particles. Since internalization and nuclear accumulation of the virus were significantly inhibited or delayed, but the kinetics of viral binding, initial uptake, and endosomal release were unaffected, F3 likely interferes with cytoplasmic trafficking and subsequent nuclear transport of the virus. A polyclonal antibody raised against nucleolin, the internalizing receptor of F3, failed to inhibit cellular binding, but considerably reduced viral transduction efficiency, proposing the involvement of nucleolin in baculovirus entry. Together, these results render the F3 peptide a tool for elucidating the mechanism and molecular details conferring to baculovirus-mediated gene transduction in mammalian cells. PMID:18294718

  5. Mechanisms of Immune-Mediated Liver Injury

    PubMed Central

    Adams, David H.; Ju, Cynthia; Ramaiah, Shashi K.; Uetrecht, Jack; Jaeschke, Hartmut

    2010-01-01

    Hepatic inflammation is a common finding during a variety of liver diseases including drug-induced liver toxicity. The inflammatory phenotype can be attributed to the innate immune response generated by Kupffer cells, monocytes, neutrophils, and lymphocytes. The adaptive immune system is also influenced by the innate immune response leading to liver damage. This review summarizes recent advances in specific mechanisms of immune-mediated hepatotoxicity and its application to drug-induced liver injury. Basic mechanisms of activation of lymphocytes, macrophages, and neutrophils and their unique mechanisms of recruitment into the liver vasculature are discussed. In particular, the role of adhesion molecules and various inflammatory mediators in this process are explored. In addition, the authors describe mechanisms of liver cell damage by these inflammatory cells and critically evaluate the functional significance of each cell type for predictive and idiosyncratic drug-induced liver injury. It is expected that continued advances in our understanding of immune mechanisms of liver injury will lead to an earlier detection of the hepatotoxic potential of drugs under development and to an earlier identification of susceptible individuals at risk for predictive and idiosyncratic drug toxicities. PMID:20071422

  6. Immune mediators of chronic pelvic pain syndrome

    PubMed Central

    Murphy, Stephen F.; Schaeffer, Anthony J.; Thumbikat, Praveen

    2016-01-01

    The cause of chronic pelvic pain syndrome (CPPS) has yet to be established. Since the late 1980s, cytokine, chemokine, and immunological classification studies using human samples have focused on identifying biomarkers for CPPS, but no diagnostically beneficial biomarkers have been identified, and these studies have done little to deepen our understanding of the mechanisms underlying chronic prostatic pain. Given the large number of men thought to be affected by this condition and the ineffective nature of current treatments, there is a pressing need to elucidate these mechanisms. Prostatitis types IIIa and IIIb are classified according to the presence of pain without concurrent presence of bacteria; however, it is becoming more evident that, although levels of bacteria are not directly associated with levels of pain, the presence of bacteria might act as the initiating factor that drives primary activation of mast-cell-mediated inflammation in the prostate. Mast cell activation is also known to suppress regulatory T cell (Treg) control of self-tolerance and also activate neural sensitization. This combination of established autoimmunity coupled with peripheral and central neural sensitization can result in the development of multiple symptoms, including pelvic pain and bladder irritation. Identifying these mechanisms as central mediators in CPPS offers new insight into the prospective treatment of the disease. PMID:24686526

  7. Harm mediates the disgust-immorality link.

    PubMed

    Schein, Chelsea; Ritter, Ryan S; Gray, Kurt

    2016-09-01

    Many acts are disgusting, but only some of these acts are immoral. Dyadic morality predicts that disgusting acts should be judged as immoral to the extent that they seem harmful. Consistent with this prediction, 3 studies reveal that perceived harm mediates the link between feelings of disgust and moral condemnation-even for ostensibly harmless "purity" violations. In many cases, accounting for perceived harm completely eliminates the link between disgust and moral condemnation. Analyses also reveal the predictive power of anger and typicality/weirdness in moral judgments of disgusting acts. The mediation of disgust by harm holds across diverse acts including gay marriage, sex acts, and religious blasphemy. Revealing the endogenous presence and moral relevance of harm within disgusting-but-ostensibly harmless acts argues against modular accounts of moral cognition such as moral foundations theory. Instead, these data support pluralistic conceptions of harm and constructionist accounts of morality and emotion. Implications for moral cognition and the concept of "purity" are discussed. (PsycINFO Database Record PMID:27100369

  8. Singlet-stabilized minimal gauge mediation

    SciTech Connect

    Curtin, David; Tsai, Yuhsin

    2011-04-01

    We propose singlet-stabilized minimal gauge mediation as a simple Intriligator, Seiberg and Shih-based model of direct gauge mediation which avoids both light gauginos and Landau poles. The hidden sector is a massive s-confining supersymmetric QCD that is distinguished by a minimal SU(5) flavor group. The uplifted vacuum is stabilized by coupling the meson to an additional singlet sector with its own U(1) gauge symmetry via nonrenormalizable interactions suppressed by a higher scale {Lambda}{sub UV} in the electric theory. This generates a nonzero vacuum expectation value for the singlet meson via the inverted hierarchy mechanism, but requires tuning to a precision {approx}({Lambda}/{Lambda}{sub UV}){sup 2}, which is {approx}10{sup -4}. In the course of this analysis we also outline some simple model-building rules for stabilizing uplifted-ISS models, which lead us to conclude that meson deformations are required (or at least heavily favored) to stabilize the adjoint component of the magnetic meson.

  9. Probing of Strain Mediated Hybrid Multiferroic Devices

    NASA Astrophysics Data System (ADS)

    Fohtung, Edwin; Kim, J.; Marsh, M.; Lei, Na; Chen, S.; Sinha, S.; Ravelosona, D.; Fullerton, Eric; Shpyrko, Oleg

    2012-02-01

    Smart materials for sensor technology, (non) volatile device memories for information technology, and ultrasound generators in medical imaging have one thing in common, their active elements consist of ferroelectrics (FE) driven by voltages or ferromagnetics (FM) driven by magnetization. In the quest to design high functionality devices to meet today's consumer technological demands, high focus has been given to multiferroic [1]. However, the coexistence of magnetic order and ferroelectric polarization combined in a single-phase material has proven to be rear as most of these materials tend to have low magnetic ordering temperatures and are often antiferromagnets, in which the magnetoelectric (ME) coupling effect is intrinsically small. We utilize an alternative approach to design multiferroic-hybrid devices based on FE-FM composites where the ME coupling emerges from strain-mediated interaction between individual phases [2]. We develop a nonlinear thermodynamic theory for strain-mediated direct ME effect and Bragg Ptychographic Coherent Diffraction Imaging (BCDI) serves as the unique tool of choice for sub-nanometer resolution nondestructive probing of the order parameters in the devices [1] N. Spaldin and M. Fiebig, Science 309, 391 (2005). [2] E. Fohtung et al., submitted (2012)

  10. Agrobacterium-mediated transformation of Fusarium proliferatum.

    PubMed

    Bernardi-Wenzel, J; Quecine, M C; Azevedo, J L; Pamphile, J A

    2016-01-01

    Fusarium proliferatum is an important pathogen that is associated with plant diseases and primarily affects aerial plant parts by producing different mycotoxins, which are toxic to humans and animals. Within the last decade, this fungus has also been described as one of the causes of red root rot or sudden death syndrome in soybean, which causes extensive damage to this crop. This study describes the Agrobacterium tumefaciens-mediated transformation of F. proliferatum as a tool for the disruption of pathogenicity genes. The genetic transformation was performed using two binary vectors (pCAMDsRed and pFAT-GFP) containing the hph (hygromycin B resistance) gene as a selection marker and red and green fluorescence, respectively. The presence of acetosyringone and the use of filter paper or nitrocellulose membrane were evaluated for their effect on the transformation efficiency. A mean processing rate of 94% was obtained with 96 h of co-cultivation only in the presence of acetosyringone and the use of filter paper or nitrocellulose membrane did not affect the transformation process. Hygromycin B resistance and the presence of the hph gene were confirmed by PCR, and fluorescence due to the expression of GFP and DsRed protein was monitored in the transformants. A high rate of mitotic stability (95%) was observed. The efficiency of Agrobacterium-mediated transformation of F. proliferatum allows the technique to be used for random insertional mutagenesis studies and to analyze fungal genes involved in the infection process. PMID:27323127

  11. Scattering of dark particles with light mediators

    NASA Astrophysics Data System (ADS)

    Soper, Davison E.; Spannowsky, Michael; Wallace, Chris J.; Tait, Tim M. P.

    2014-12-01

    We present a treatment of the high energy scattering of dark Dirac fermions from nuclei, mediated by the exchange of a light vector boson. The dark fermions are produced by proton-nucleus interactions in a fixed target and, after traversing shielding that screens out strongly interacting products, appear similarly to neutrino neutral current scattering in a detector. Using the Fermilab experiment E613 as an example, we place limits on a secluded dark matter scenario. Visible scattering in the detector includes both the familiar regime of large momentum transfer to the nucleus (Q2) described by deeply inelastic scattering, as well as small Q2 kinematics described by the exchanged vector mediator fluctuating into a quark-antiquark pair whose interaction with the nucleus is described by a saturation model. We find that the improved description of the low Q2 scattering leads to important corrections, resulting in more robust constraints in a regime where a description entirely in terms of deeply inelastic scattering cannot be trusted.

  12. [Biological investigation of kinin-mediated angioedema].

    PubMed

    Defendi, F; Charignon, D; Ghannam, A; Ponard, D; Drouet, C

    2015-03-01

    Kinin-mediated angioedema results from accumulation of kinins, vasoactive and vasopermeant peptides, on the vascular endothelium. The disease is characterized by sudden episodes of swelling in the subcutaneous and submucosal tissues; the edema may occur spontaneously or it may be precipitated by triggering factors such as physical or emotional stress, or certain medicines. The characterization of kinin formation and catabolism systems helps improve knowledge of the aetiopathogenic mechanisms involved and provides the basis for classification of kinin-mediated angioedema conditions; thus, we may distinguish between angioedema with C1 inhibitor deficiency, whether inherited or acquired, and angioedema with normal C1 inhibitor activity, associated with increased kinin-forming activity or deficiency in kinin catabolism enzymes. In support of the clinical diagnosis, the physician may request laboratory investigation for a functional and molecular definition of the disease. Laboratory diagnosis is based on the characterization of: (1) kinin production control by C1 inhibitor investigation (function, antigen levels and circulating species); (2) kinin production (kininogenase activity, kininogen cleavage species); and (3) kinin catabolism enzymes (aminopeptidase P, carboxypeptidase N, angiotensin-I converting enzyme and dipeptidyl peptidase IV). An abnormal biological phenotype is supported by examination of susceptibility genes (SERPING1, F12 and XPNPEP2) and mutation segregation in the families. PMID:25683013

  13. Ultrasound-Mediated Polymeric Micelle Drug Delivery.

    PubMed

    Xia, Hesheng; Zhao, Yue; Tong, Rui

    2016-01-01

    The synthesis of multi-functional nanocarriers and the design of new stimuli-responsive means are equally important for drug delivery. Ultrasound can be used as a remote, non-invasive and controllable trigger for the stimuli-responsive release of nanocarriers. Polymeric micelles are one kind of potential drug nanocarrier. By combining ultrasound and polymeric micelles, a new modality (i.e., ultrasound-mediated polymeric micelle drug delivery) has been developed and has recently received increasing attention. A major challenge remaining in developing ultrasound-responsive polymeric micelles is the improvement of the sensitivity or responsiveness of polymeric micelles to ultrasound. This chapter reviews the recent advance in this field. In order to understand the interaction mechanism between ultrasound stimulus and polymeric micelles, ultrasound effects, such as thermal effect, cavitation effect, ultrasound sonochemistry (including ultrasonic degradation, ultrasound-initiated polymerization, ultrasonic in-situ polymerization and ultrasound site-specific degradation), as well as basic micellar knowledge are introduced. Ultrasound-mediated polymeric micelle drug delivery has been classified into two main streams based on the different interaction mechanism between ultrasound and polymeric micelles; one is based on the ultrasound-induced physical disruption of the micelle and reversible release of payload. The other is based on micellar ultrasound mechanochemical disruption and irreversible release of payload. PMID:26486348

  14. Autophagy mediates degradation of nuclear lamina

    PubMed Central

    Dou, Zhixun; Xu, Caiyue; Donahue, Greg; Shimi, Takeshi; Pan, Ji-An; Zhu, Jiajun; Ivanov, Andrejs; Capell, Brian C.; Drake, Adam M.; Shah, Parisha P.; Catanzaro, Joseph M.; Ricketts, M. Daniel; Lamark, Trond; Adam, Stephen A.; Marmorstein, Ronen; Zong, Wei-Xing; Johansen, Terje; Goldman, Robert D.; Adams, Peter D.; Berger, Shelley L.

    2015-01-01

    Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents, and is associated with human diseases1–3. While extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known regarding the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery4–6, is present in the nucleus and directly interacts with the nuclear lamina protein Lamin B1, and binds to lamin-associated domains (LADs) on chromatin. This LC3-Lamin B1 interaction does not downregulate Lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated Ras. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers Lamin B1 to the lysosome. Inhibiting autophagy or the LC3-Lamin B1 interaction prevents activated Ras-induced Lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests this new function of autophagy as a guarding mechanism protecting cells from tumorigenesis. PMID:26524528

  15. Photoreceptor phagocytosis is mediated by phosphoinositide signaling

    PubMed Central

    Mustafi, Debarshi; Kevany, Brian M.; Genoud, Christel; Bai, Xiaodong; Palczewski, Krzysztof

    2013-01-01

    Circadian oscillations in peripheral tissues, such as the retinal compartment of the eye, are critical to anticipating changing metabolic demands. Circadian shedding of retinal photoreceptor cell discs with subsequent phagocytosis by the neighboring retinal pigmented epithelium (RPE) is essential for removal of toxic metabolites and lifelong survival of these postmitotic neurons. Defects in photoreceptor phagocytosis can lead to severe retinal pathology, but the biochemical mechanisms remain poorly defined. By first documenting a 2.8-fold burst of photoreceptor phagocytosis events in the mouse eye in the morning compared with the afternoon by serial block face imaging, we established time points to assess transcriptional readouts by RNA sequencing (RNA-Seq). We identified 365 oscillating protein-coding transcripts that implicated the phosphoinositide lipid signaling network mediating the discrete steps of photoreceptor phagocytosis. Moreover, examination of overlapping cistromic sites by core clock transcription factors and promoter elements of these effector genes provided a functional basis for the circadian cycling of these transcripts. RNA-Seq also revealed oscillating expression of 16 long intergenic noncoding RNAs and key histone modifying enzymes critical for circadian gene expression. Our phenotypic and genotypic characterization reveals a complex global landscape of overlapping and temporally controlled networks driving the essential circadian process in the eye.—Mustafi, D., Kevany, B. M., Genoud, C., Bai, X., Palczewski, K. Photoreceptor phagocytosis is mediated by phosphoinositide signaling. PMID:23913857

  16. Vibrationally mediated photodissociation of hydrogen peroxide

    SciTech Connect

    Ticich, T.M.; Likar, M.D.; Duebal, H.; Butler, L.J.; Crim, F.F.

    1987-11-15

    Vibrationally mediated photodissociation is a means of studying the spectroscopy of bound vibrational overtone states and of probing the electronic photodissociation dynamics of highly vibrationally excited molecules. In these experiments, a highly vibrationally excited hydrogen peroxide molecule prepared by initial excitation in the region of the third (4..nu../sub OH/) or fourth (5..nu../sub OH/) overtone of the OH stretching vibration absorbs an additional photon to dissociate to OH fragments whose individual quantum state populations are measured by laser induced fluorescence. This technique is a means of obtaining excitation spectra for bound highly vibrationally excited states and confirms the accuracy of a model that incorporates the role of the torsional vibration in the vibrational overtone spectroscopy. The photodissociation dynamics of highly vibrationally excited molecules are substantially different from those observed for dissociation by single photons of comparable or greater energy. Approximately 11% of the OH fragments formed in the vibrationally mediated photodissociation through 4..nu../sub OH/ are vibrationally excited as compared to an unobservable amount (less than or equal to2%) in the single photon ultraviolet dissociation.

  17. Sodium orthovanadate inhibits p53-mediated apoptosis.

    PubMed

    Morita, Akinori; Yamamoto, Shinichi; Wang, Bing; Tanaka, Kaoru; Suzuki, Norio; Aoki, Shin; Ito, Azusa; Nanao, Tomohisa; Ohya, Soichiro; Yoshino, Minako; Zhu, Jin; Enomoto, Atsushi; Matsumoto, Yoshihisa; Funatsu, Osamu; Hosoi, Yoshio; Ikekita, Masahiko

    2010-01-01

    Sodium orthovanadate (vanadate) inhibits the DNA-binding activity of p53, but its precise effects on p53 function have not been examined. Here, we show that vanadate exerts a potent antiapoptotic activity through both transcription-dependent and transcription-independent mechanisms relative to other p53 inhibitors, including pifithrin (PFT) alpha. We compared the effects of vanadate to PFTalpha and PFTmicro, an inhibitor of transcription-independent apoptosis by p53. Vanadate suppressed p53-associated apoptotic events at the mitochondria, including the loss of mitochondrial membrane potential, the conformational change of Bax and Bak, the mitochondrial translocation of p53, and the interaction of p53 with Bcl-2. Similarly, vanadate suppressed the apoptosis-inducing activity of a mitochondrially targeted temperature-sensitive p53 in stable transfectants of SaOS-2 cells. In radioprotection assays, which rely on p53, vanadate completely protected mice from a sublethal dose of 8 Gy and partially from a lethal dose of 12 Gy. Together, our findings indicated that vanadate effectively suppresses p53-mediated apoptosis by both transcription-dependent and transcription-independent pathways, and suggested that both pathways must be inhibited to completely block p53-mediated apoptosis. PMID:20048077

  18. Immune mediators of chronic pelvic pain syndrome.

    PubMed

    Murphy, Stephen F; Schaeffer, Anthony J; Thumbikat, Praveen

    2014-05-01

    The cause of chronic pelvic pain syndrome (CPPS) has yet to be established. Since the late 1980s, cytokine, chemokine, and immunological classification studies using human samples have focused on identifying biomarkers for CPPS, but no diagnostically beneficial biomarkers have been identified, and these studies have done little to deepen our understanding of the mechanisms underlying chronic prostatic pain. Given the large number of men thought to be affected by this condition and the ineffective nature of current treatments, there is a pressing need to elucidate these mechanisms. Prostatitis types IIIa and IIIb are classified according to the presence of pain without concurrent presence of bacteria; however, it is becoming more evident that, although levels of bacteria are not directly associated with levels of pain, the presence of bacteria might act as the initiating factor that drives primary activation of mast-cell-mediated inflammation in the prostate. Mast cell activation is also known to suppress regulatory T cell (Treg) control of self-tolerance and also activate neural sensitization. This combination of established autoimmunity coupled with peripheral and central neural sensitization can result in the development of multiple symptoms, including pelvic pain and bladder irritation. Identifying these mechanisms as central mediators in CPPS offers new insight into the prospective treatment of the disease. PMID:24686526

  19. A Drosophila metallophosphoesterase mediates deglycosylation of rhodopsin

    PubMed Central

    Cao, Jinguo; Li, Yi; Xia, Wenjing; Reddig, Keith; Hu, Wen; Xie, Wei; Li, Hong-Sheng; Han, Junhai

    2011-01-01

    Oligosaccharide chains of newly synthesized membrane receptors are trimmed and modified to optimize their trafficking and/or signalling before delivery to the cell surface. For most membrane receptors, the functional significance of oligosaccharide chain modification is unknown. During the maturation of Rh1 rhodopsin, a Drosophila light receptor, the oligosaccharide chain is trimmed extensively. Neither the functional significance of this modification nor the enzymes mediating this process are known. Here, we identify a dmppe (Drosophila metallophosphoesterase) mutant with incomplete deglycosylation of Rh1, and show that the retained oligosaccharide chain does not affect Rh1 localization or signalling. The incomplete deglycosylation, however, renders Rh1 more sensitive to endocytic degradation, and causes morphological and functional defects in photoreceptors of aged dmppe flies. We further demonstrate that the dMPPE protein functions as an Mn2+/Zn2+-dependent phosphoesterase and mediates in vivo dephosphorylation of α-Man-II. Most importantly, the dephosphorylated α-Man-II is required for the removal of the Rh1 oligosaccharide chain. These observations suggest that the glycosylation status of membrane proteins is controlled through phosphorylation/dephosphorylation, and that MPPE acts as the phosphoesterase in this regulation. PMID:21804530

  20. Pro-resolving lipid mediators are leads for resolution physiology.

    PubMed

    Serhan, Charles N

    2014-06-01

    Advances in our understanding of the mechanisms that bring about the resolution of acute inflammation have uncovered a new genus of pro-resolving lipid mediators that include the lipoxin, resolvin, protectin and maresin families, collectively called specialized pro-resolving mediators. Synthetic versions of these mediators have potent bioactions when administered in vivo. In animal experiments, the mediators evoke anti-inflammatory and novel pro-resolving mechanisms, and enhance microbial clearance. Although they have been identified in inflammation resolution, specialized pro-resolving mediators are conserved structures that also function in host defence, pain, organ protection and tissue remodelling. This Review covers the mechanisms of specialized pro-resolving mediators and omega-3 essential fatty acid pathways that could help us to understand their physiological functions. PMID:24899309

  1. Depression and pain: testing of serial multiple mediators

    PubMed Central

    Wongpakaran, Tinakon; Wongpakaran, Nahathai; Tanchakvaranont, Sitthinant; Bookkamana, Putipong; Pinyopornpanish, Manee; Wannarit, Kamonporn; Satthapisit, Sirina; Nakawiro, Daochompu; Hiranyatheb, Thanita; Thongpibul, Kulvadee

    2016-01-01

    Purpose Despite the fact that pain is related to depression, few studies have been conducted to investigate the variables that mediate between the two conditions. In this study, the authors explored the following mediators: cognitive function, self-sacrificing interpersonal problems, and perception of stress, and the effects they had on pain symptoms among patients with depressive disorders. Participants and methods An analysis was performed on the data of 346 participants with unipolar depressive disorders. The 17-item Hamilton Depression Rating Scale, Mini-Mental State Examination, the pain subscale of the health-related quality of life (SF-36), the self-sacrificing subscale of the Inventory of Interpersonal Problems, and the Perceived Stress Scale were used. Parallel multiple mediator and serial multiple mediator models were used. An alternative model regarding the effect of self-sacrificing on pain was also proposed. Results Perceived stress, self-sacrificing interpersonal style, and cognitive function were found to significantly mediate the relationship between depression and pain, while controlling for demographic variables. The total effect of depression on pain was significant. This model, with an additional three mediators, accounted for 15% of the explained variance in pain compared to 9% without mediators. For the alternative model, after controlling for the mediators, a nonsignificant total direct effect level of self-sacrificing was found, suggesting that the effect of self-sacrificing on pain was based only on an indirect effect and that perceived stress was found to be the strongest mediator. Conclusion Serial mediation may help us to see how depression and pain are linked and what the fundamental mediators are in the chain. No significant, indirect effect of self-sacrificing on pain was observed, if perceived stress was not part of the depression and/or cognitive function mediational chain. The results shown here have implications for future

  2. 15 CFR 930.115 - Termination of mediation.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.115... the agencies fail to reach a resolution of the disagreement within 15 days following...

  3. 15 CFR 930.115 - Termination of mediation.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.115... the agencies fail to reach a resolution of the disagreement within 15 days following...

  4. 15 CFR 930.115 - Termination of mediation.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.115... the agencies fail to reach a resolution of the disagreement within 15 days following...

  5. 15 CFR 930.115 - Termination of mediation.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... MANAGEMENT FEDERAL CONSISTENCY WITH APPROVED COASTAL MANAGEMENT PROGRAMS Secretarial Mediation § 930.115... the agencies fail to reach a resolution of the disagreement within 15 days following...

  6. Mediators of change following a senior school physical activity intervention.

    PubMed

    Lubans, David R; Sylva, Kathy

    2009-01-01

    It has been suggested that the low level of effectiveness of youth interventions is due to a lack of knowledge regarding the mechanisms responsible for behaviour change. The identification of behaviour mediators is necessary for the progression of physical activity research, as it allows researchers to determine which components of an intervention are responsible for mediating behaviour change. The purpose of this study was to identify mediators of behaviour change in a physical activity intervention for senior school students. Participants (n=78) were randomly allocated to control or intervention conditions for a period of 10 weeks. Moderate-to-vigorous physical activity (MVPA) and potential mediators were assessed at baseline and post-intervention (10 weeks). Hypothesized mediators were derived from Bandura's Social Cognitive Theory and included: peer support, exercise self-efficacy and outcome expectancy. Mediation was assessed using the product-of-coefficients test described by MacKinnon and colleagues, based on the criteria for mediation identified by Baron and Kenny. While none of the variables satisfied all four criteria for mediation among males or females, self-efficacy was able to satisfy the first three criteria among females in the study. Exercise self-efficacy may be a mediator of physical activity behaviour in adolescent girls. PMID:18069061

  7. The Mediator complex: a central integrator of transcription

    PubMed Central

    Allen, Benjamin L.; Taatjes, Dylan J.

    2016-01-01

    The RNA polymerase II (pol II) enzyme transcribes all protein-coding and most non-coding RNA genes and is globally regulated by Mediator, a large, conformationally flexible protein complex with variable subunit composition (for example, a four-subunit CDK8 module can reversibly associate). These biochemical characteristics are fundamentally important for Mediator's ability to control various processes important for transcription, including organization of chromatin architecture and regulation of pol II pre-initiation, initiation, re-initiation, pausing, and elongation. Although Mediator exists in all eukaryotes, a variety of Mediator functions appear to be specific to metazoans, indicative of more diverse regulatory requirements. PMID:25693131

  8. The role of mediation in resolving workplace relationship conflict.

    PubMed

    McKenzie, Donna Margaret

    2015-01-01

    Stress triggered by workplace-based interpersonal conflict can result in damaged relationships, loss of productivity, diminished job satisfaction and increasingly, workers' compensation claims for psychological injury. This paper examined the literature on the role and effectiveness of mediation, as the most common method of Alternative Dispute Resolution, in resolving workplace relationship conflict. Available evidence suggests that mediation is most effective when supported by organisational commitment to ADR strategies, policies and processes, and conducted by independent, experienced and qualified mediators. The United States Postal Service program REDRESS™ is described as an illustration of the successful use of mediation to resolve conflict in the workplace. PMID:25660062

  9. Using mediation to resolve disputes among hospitals and physicians.

    PubMed

    Duncheon, M A

    1999-06-01

    The wide variety of economic cooperative arrangements in which hospitals and physicians engage can lead to disputes. As methods of dispute resolution, litigation and arbitration are costly and time-consuming and can have long-lasting adverse effects on relationships between the disputing parties. An alternative method of dispute resolution is mediation, the process of voluntarily negotiating a settlement with the help of a mediator. Mediation generally is quicker, less costly, and less likely to be adversarial than litigation or arbitration. In addition, mediation offers privacy regarding the nature of the dispute, thus preserving valuable reputations. PMID:10558174

  10. Cell-mediated immune deficiency in Hodgkin's disease.

    PubMed

    Kumar, R K; Penny, R

    1982-10-01

    Disturbances of the immune system frequently accompany the development of lymphomas in man. In the early stages of non-Hodgkin's lymphomas, abnormalities of immunological function are usually minimal, but impairment of both antibody- and cell-mediated immunity is often noted in advanced disease. In contrast, while antibody-mediated immune responses in patients with Hodgkin's disease usually remain intact until late in the course of the illness, cell-mediated immune dysfunction is an early and consistent feature. Here Rakesh Kumar and Ronald Penny discuss the abnormalities of cell-mediated immunity in Hodgkin's disease. PMID:25290229

  11. Megakaryocyte-mediated inhibition of osteoclast development.

    PubMed

    Kacena, Melissa A; Nelson, Tracy; Clough, Mary E; Lee, Sun-Kyeong; Lorenzo, Joseph A; Gundberg, Caren M; Horowitz, Mark C

    2006-11-01

    A growing body of evidence indicates that megakaryocytes (MK) or their growth factors play a role in skeletal homeostasis. We previously identified a novel regulatory pathway that controls bone formation, which is mediated by MK. In vivo megakaryocytosis resulted in massive bone formation. The co-culture of MK with osteoblasts (OB) resulted in increased OB proliferation in vitro, by a mechanism that required direct cell-to-cell contact. Here, we examined a second MK-mediated pathway that regulates osteoclast (OC) development. We have begun examining the unique inhibitory effect of MK on OC development. Spleen or bone marrow (BM) cells from C57BL/6 mice, as a source of OC precursors, were cultured with M-CSF and RANKL to induce OC development. MK were prepared by culturing fetal liver cells with thrombopoietin and separating cells into MK and non-MK populations. MK were titrated into spleen cell cultures and OC were identified as tartrate-resistant acid phosphatase-positive giant cells with >3 nuclei. There was a significant, P < 0.001, up to 10-fold reduction in OC formed when MK were added to the spleen cell cultures. We determined that 30% (vol:vol) MK conditioned media (CM) were able to completely block OC development from precursors, whereas 3% MK CM resulted in up to a 10-fold reduction in OC development, P < 0.001. These data indicate that a soluble factor(s) was responsible, at least in part, for the inhibition. We examined MK CM for known inhibitors of OC formation, using ELISAs. IL-4 was undetectable in MK CM, whereas IL-10 and IFN-gamma levels were similar in MK and non-MK CM. TGFbeta-1 levels were increased 2-fold in MK CM compared to control CM but were not responsible for the inhibition in OC development. Although, we found a significant increase in the levels of osteoprotegerin (OPG) in MK CM, antibody neutralization studies, MK derived from OPG-deficient mice, and tandem mass spectrophotometry, all confirm that OPG was not responsible for the MK-mediated

  12. Solvent mediated self-assembly of solids

    SciTech Connect

    De Yoreo, J.; Wilson, W.D.; Palmore, T.

    1997-12-12

    Solvent-mediated crystallization represents a robust approach to self-assembly of nanostructures and microstructures. In organic systems, the relative ease with which the structure of hydrogen- bonded molecules can be manipulated allows for generation of a wide variety of nanoscale crystal structures. In living organisms, control over the micron-to-millimeter form of inorganic crystals is achieved through introduction of bio-organic molecules. The purpose of this proposal is to understand the interplay between solution chemistry, molecular structure, surface chemistry, and the processes of nucleation and crystal growth in solvent-mediated systems, with the goal of developing the atomic and molecular basis of a solvent-mediated self-assembly technology. We will achieve this purpose by: (1) utilizing an atomic force microscopy (AFM) approach that provides in situ, real time imaging during growth from solutions, (2) by modifying kinetic Monte Carlo (KMC) models to include solution-surface kinetics, (3) by introducing quantum chemistry (QC) calculations of the potentials of the relevant chemical species and the near-surface structure of the solution, and (4) by utilizing molecular dynamics (MD) simulations to identify the minimum energy pathways to the solid state. Our work will focus on two systems chosen to address both the manometer and micron-to-millimeter length scales of assembly, the family of 2,5- diketopiperazines (X-DKPs) and the system of CaCO{sub 3} with amino acids. Using AFM, we will record the evolution of surface morphology, critical lengths, step speeds, and step-step interactions as a function of supersaturation and temperature. In the case of the X-DKPs, these measurements will be repeated as the molecular structure of the growth unit is varied. In the case of CaCO{sub 3}, they will be performed as a function of solution chemistry including pH, ionic strength, and amino acid content. In addition, we will measure nucleation rates and orientations of

  13. Chiral flavor violation from extended gauge mediation

    NASA Astrophysics Data System (ADS)

    Evans, Jared A.; Shih, David; Thalapillil, Arun

    2015-07-01

    Models of extended gauge mediation, in which large A-terms arise through direct messenger-MSSM superpotential couplings, are well-motivated by the discovery of the 125 GeV Higgs. However, since these models are not necessarily MFV, the flavor constraints could be stringent. In this paper, we perform the first detailed and quantitative study of the flavor violation in these models. To facilitate our study, we introduce a new tool called FormFlavor for computing precision flavor observables in the general MSSM. We validate FormFlavor and our qualitative understanding of the flavor violation in these models by comparing against analytical expressions. Despite being non-MFV, we show that these models are protected against the strongest constraints by a special flavor texture, which we dub chiral flavor violation (χFV). This results in only mild bounds from current experiments, and exciting prospects for experiments in the near future.

  14. Turgor-mediated transport of sugars

    SciTech Connect

    Daie, J.

    1986-04-01

    Membrane associated processes have been suggested to be modulated by cellular turgor. The nature of this regulation is not, however, clearly understood. Evidence is presented that active but not passive transport of sugars is turgor regulated. Isolated phloem tissue, vascular bundles or storage parenchyma of celery were incubated in buffered solutions adjusted to 100, 200 or 400 m osmolal that contained various concentrations of /sup 14/C-sugars. Cellular turgor was manipulated by using the non-permeating PEG (3350). Saturating carrier-mediated sucrose transport which is present only in phloem-containing tissue was enhanced under low turgor conditions. Sucrose diffusion, the predominant mode of uptake in non-phloem parenchyma tissue was not affected by cellular turgor. Furthermore, GA and IAA seem to interact with cellular turgor to bring about modified rates of sucrose uptake. The data are consistent with observations that sucrose loading is enhanced under mild water deficit conditions.

  15. Nitric oxide rescues thalidomide mediated teratogenicity

    PubMed Central

    Siamwala, Jamila H.; Veeriah, Vimal; Priya, M. Krishna; Rajendran, Saranya; Saran, Uttara; Sinha, Swaraj; Nagarajan, Shunmugam; T, Pradeep; Chatterjee, Suvro

    2012-01-01

    Thalidomide, a sedative drug given to pregnant women, unfortunately caused limb deformities in thousands of babies. Recently the drug was revived because of its therapeutic potential; however the search is still ongoing for an antidote against thalidomide induced limb deformities. In the current study we found that nitric oxide (NO) rescues thalidomide affected chick (Gallus gallus) and zebrafish (Danio rerio) embryos. This study confirms that NO reduced the number of thalidomide mediated limb deformities by 94% and 80% in chick and zebrafish embryos respectively. NO prevents limb deformities by promoting angiogenesis, reducing oxidative stress and inactivating caspase-3 dependent apoptosis. We conclude that NO secures angiogenesis in the thalidomide treated embryos to protect them from deformities. PMID:22997553

  16. Nanoparticle mediated non-covalent drug delivery☆

    PubMed Central

    Doane, Tennyson; Burda, Clemens

    2013-01-01

    The use of nanoparticles (NPs) for enhanced drug delivery has been heavily explored during the last decade. Within the field, it is has become increasingly apparent that the physical properties of the particles themselves dictate their efficacy, and the relevant non-covalent chemistry at the NP interface also influences how drugs are immobilized and delivered. In this review, we reflect on the physical chemistry of NP mediated drug delivery (and more specifically, non-covalent drug delivery) at the three main experimental stages of drug loading, NP–drug conjugate transport, and the resulting cellular drug delivery. Through a critical evaluation of advances in drug delivery within the last decade, an outlook for biomedical applications of nanoscale transport vectors will be presented. PMID:22664231

  17. ROS and ROS-Mediated Cellular Signaling

    PubMed Central

    Zhang, Jixiang; Wang, Xiaoli; Vikash, Vikash; Ye, Qing; Wu, Dandan; Liu, Yulan; Dong, Weiguo

    2016-01-01

    It has long been recognized that an increase of reactive oxygen species (ROS) can modify the cell-signaling proteins and have functional consequences, which successively mediate pathological processes such as atherosclerosis, diabetes, unchecked growth, neurodegeneration, inflammation, and aging. While numerous articles have demonstrated the impacts of ROS on various signaling pathways and clarify the mechanism of action of cell-signaling proteins, their influence on the level of intracellular ROS, and their complex interactions among multiple ROS associated signaling pathways, the systemic summary is necessary. In this review paper, we particularly focus on the pattern of the generation and homeostasis of intracellular ROS, the mechanisms and targets of ROS impacting on cell-signaling proteins (NF-κB, MAPKs, Keap1-Nrf2-ARE, and PI3K-Akt), ion channels and transporters (Ca2+ and mPTP), and modifying protein kinase and Ubiquitination/Proteasome System. PMID:26998193

  18. Mast Cell-Mediated Mechanisms of Nociception

    PubMed Central

    Aich, Anupam; Afrin, Lawrence B.; Gupta, Kalpna

    2015-01-01

    Mast cells are tissue-resident immune cells that release immuno-modulators, chemo-attractants, vasoactive compounds, neuropeptides and growth factors in response to allergens and pathogens constituting a first line of host defense. The neuroimmune interface of immune cells modulating synaptic responses has been of increasing interest, and mast cells have been proposed as key players in orchestrating inflammation-associated pain pathobiology due to their proximity to both vasculature and nerve fibers. Molecular underpinnings of mast cell-mediated pain can be disease-specific. Understanding such mechanisms is critical for developing disease-specific targeted therapeutics to improve analgesic outcomes. We review molecular mechanisms that may contribute to nociception in a disease-specific manner. PMID:26690128

  19. General gauge mediation at the weak scale

    NASA Astrophysics Data System (ADS)

    Knapen, Simon; Redigolo, Diego; Shih, David

    2016-03-01

    We completely characterize General Gauge Mediation (GGM) at the weak scale by solving all IR constraints over the full parameter space. This is made possible through a combination of numerical and analytical methods, based on a set of algebraic relations among the IR soft masses derived from the GGM boundary conditions in the UV. We show how tensions between just a few constraints determine the boundaries of the parameter space: electroweak symmetry breaking (EWSB), the Higgs mass, slepton tachyons, and left-handed stop/sbottom tachyons. While these constraints allow the left-handed squarks to be arbitrarily light, they place strong lower bounds on all of the right-handed squarks. Meanwhile, light EW superpartners are generic throughout much of the parameter space. This is especially the case at lower messenger scales, where a positive threshold correction to m h coming from light Higgsinos and winos is essential in order to satisfy the Higgs mass constraint.

  20. Autophagy mediates the mitotic senescence transition

    PubMed Central

    Young, Andrew R.J.; Narita, Masako; Ferreira, Manuela; Kirschner, Kristina; Sadaie, Mahito; Darot, Jeremy F.J.; Tavaré, Simon; Arakawa, Satoko; Shimizu, Shigeomi; Watt, Fiona M.; Narita, Masashi

    2009-01-01

    As a stress response, senescence is a dynamic process involving multiple effector mechanisms whose combination determines the phenotypic quality. Here we identify autophagy as a new effector mechanism of senescence. Autophagy is activated during senescence and its activation is correlated with negative feedback in the PI3K–mammalian target of rapamycin (mTOR) pathway. A subset of autophagy-related genes are up-regulated during senescence: Overexpression of one of those genes, ULK3, induces autophagy and senescence. Furthermore, inhibition of autophagy delays the senescence phenotype, including senescence-associated secretion. Our data suggest that autophagy, and its consequent protein turnover, mediate the acquisition of the senescence phenotype. PMID:19279323

  1. Symbiont-mediated RNA interference in insects

    PubMed Central

    Whitten, Miranda M. A.; Facey, Paul D.; Del Sol, Ricardo; Fernández-Martínez, Lorena T.; Evans, Meirwyn C.; Mitchell, Jacob J.; Bodger, Owen G.

    2016-01-01

    RNA interference (RNAi) methods for insects are often limited by problems with double-stranded (ds) RNA delivery, which restricts reverse genetics studies and the development of RNAi-based biocides. We therefore delegated to insect symbiotic bacteria the task of: (i) constitutive dsRNA synthesis and (ii) trauma-free delivery. RNaseIII-deficient, dsRNA-expressing bacterial strains were created from the symbionts of two very diverse pest species: a long-lived blood-sucking bug, Rhodnius prolixus, and a short-lived globally invasive polyphagous agricultural pest, western flower thrips (Frankliniella occidentalis). When ingested, the manipulated bacteria colonized the insects, successfully competed with the wild-type microflora, and sustainably mediated systemic knockdown phenotypes that were horizontally transmissible. This represents a significant advance in the ability to deliver RNAi, potentially to a large range of non-model insects. PMID:26911963

  2. TAL effector-mediated genome visualization (TGV).

    PubMed

    Miyanari, Yusuke

    2014-09-01

    The three-dimensional remodeling of chromatin within nucleus is being recognized as determinant for genome regulation. Recent technological advances in live imaging of chromosome loci begun to explore the biological roles of the movement of the chromatin within the nucleus. To facilitate better understanding of the functional relevance and mechanisms regulating genome architecture, we applied transcription activator-like effector (TALE) technology to visualize endogenous repetitive genomic sequences in mouse cells. The application, called TAL effector-mediated genome visualization (TGV), allows us to label specific repetitive sequences and trace nuclear remodeling in living cells. Using this system, parental origin of chromosomes was specifically traced by distinction of single-nucleotide polymorphisms (SNPs). This review will present our approaches to monitor nuclear dynamics of target sequences and highlights key properties and potential uses of TGV. PMID:24704356

  3. Viable Supersymmetry and Leptogenesis with Anomaly Mediation

    SciTech Connect

    Ibe, Masahiro; Kitano, Ryuichiro; Murayama, Hitoshi; Yanagida, Tsutomu

    2005-01-13

    The seesaw mechanism that explains the small neutrino masses comes naturally with supersymmetric (SUSY) grand unification and leptogenesis. However, the framework suffers from the SUSY flavor and CP problems, and has a severe cosmological gravitino problem. We propose anomaly mediation as a simple solution to all these problems, which is viable once supplemented by the D-terms for U(1)_Y and U(1)_B-L. Even though the right-handed neutrino mass explicitly breaks U(1)_B-L and hence reintroduces the flavor problem, we show that it lacks the logarithmic enhancement and poses no threat to the framework. The thermal leptogenesis is then made easily consistent with the gravitino constraint.

  4. Yukawa unification predictions with effective "mirage" mediation.

    PubMed

    Anandakrishnan, Archana; Raby, Stuart

    2013-11-22

    In this Letter we analyze the consequences, for the LHC, of gauge and third family Yukawa coupling unification with a particular set of boundary conditions defined at the grand unified theory (GUT) scale, which we characterize as effective "mirage" mediation. We perform a global χ2 analysis including the observables M(W), M(Z), G(F), α(em)(-1), α(s)(M(Z)), M(t), m(b)(m(b)), M(τ), BR(B→X(s)γ), BR(B(s)→μ(+)μ(-)), and M(h). The fit is performed in the minimal supersymmetric standard model in terms of 10 GUT scale parameters, while tanβ and μ are fixed at the weak scale. We find good fits to the low energy data and a supersymmetry spectrum which is dramatically different than previously studied in the context of Yukawa unification. PMID:24313477

  5. Yukawa Unification Predictions with Effective ``Mirage'' Mediation

    NASA Astrophysics Data System (ADS)

    Anandakrishnan, Archana; Raby, Stuart

    2013-11-01

    In this Letter we analyze the consequences, for the LHC, of gauge and third family Yukawa coupling unification with a particular set of boundary conditions defined at the grand unified theory (GUT) scale, which we characterize as effective “mirage” mediation. We perform a global χ2 analysis including the observables MW, MZ, GF, αem-1, αs(MZ), Mt, mb(mb), Mτ, BR(B→Xsγ), BR(Bs→μ+μ-), and Mh. The fit is performed in the minimal supersymmetric standard model in terms of 10 GUT scale parameters, while tan⁡β and μ are fixed at the weak scale. We find good fits to the low energy data and a supersymmetry spectrum which is dramatically different than previously studied in the context of Yukawa unification.

  6. The mediating role of facebook fan pages.

    PubMed

    Chih, Wen-Hai; Hsu, Li-Chun; Wang, Kai-Yu; Lin, Kuan-Yu

    2014-01-01

    Using the dual mediation hypothesis, this study investigates the role of interestingness (the power of attracting or holding one's attention) attitude towards the news, in the formation of Facebook Fan Page users' electronic word-of-mouth intentions. A total of 599 Facebook fan page users in Taiwan were recruited and structural equation modeling (SEM) was used to test the research hypotheses. The results show that both perceived news entertainment and informativeness positively influence interestingness attitude towards the news. Interestingness attitude towards the news subsequently influences hedonism and utilitarianism attitudes towards the Fan Page, which then influence eWOM intentions. Interestingness attitude towards the news plays a more important role than hedonism and utilitarianism attitudes in generating electronic word-of-mouth intentions. Based on the findings, the implications and future research suggestions are provided. PMID:24875695

  7. Topoisomerase I-mediated DNA damage.

    PubMed

    Pourquier, P; Pommier, Y

    2001-01-01

    Topoisomerase I is a ubiquitous and essential enzyme in multicellular organisms. It is involved in multiple DNA transactions including DNA replication, transcription, chromosome condensation and decondensation, and probably DNA recombination. Besides its activity of DNA relaxation necessary to eliminate torsional stresses associated with these processes, topoisomerase I may have other functions related to its interaction with other cellular proteins. Topoisomerase I is the target of the novel anticancer drugs, the camptothecins. Recently a broad range of physiological and environmentally-induced DNA modifications have also been shown to poison topoisomerases. This review summarizes the various factors that enhance or suppress top1 cleavage complexes and discusses the significance of such effects. We also review the different mechanisms that have been proposed for the repair of topoisomerase I-mediated DNA lesions. PMID:11034544

  8. The Chronus II temporal database mediator.

    PubMed Central

    O'Connor, Martin J.; Tu, Samson W.; Musen, Mark A.

    2002-01-01

    Clinical databases typically contain a significant amount of temporal information. This information is often crucial in medical decision-support systems. Although temporal queries are common in clinical systems, the medical informatics field has no standard means for representing or querying temporal data. Over the past decade, the temporal database community has made a significant amount of progress in temporal systems. Much of this research can be applied to clinical database systems. This paper outlines a temporal database mediator called Chronus II. Chronus II extends the standard relational model and the SQL query language to support temporal queries. It provides an expressive general-purpose temporal query language that is tuned to the querying requirements of clinical decision support systems. This paper describes how we have used Chronus II to tackle a variety of clinical problems in decision support systems developed by our group. PMID:12474882

  9. Symbiont-mediated RNA interference in insects.

    PubMed

    Whitten, Miranda M A; Facey, Paul D; Del Sol, Ricardo; Fernández-Martínez, Lorena T; Evans, Meirwyn C; Mitchell, Jacob J; Bodger, Owen G; Dyson, Paul J

    2016-02-24

    RNA interference (RNAi) methods for insects are often limited by problems with double-stranded (ds) RNA delivery, which restricts reverse genetics studies and the development of RNAi-based biocides. We therefore delegated to insect symbiotic bacteria the task of: (i) constitutive dsRNA synthesis and (ii) trauma-free delivery. RNaseIII-deficient, dsRNA-expressing bacterial strains were created from the symbionts of two very diverse pest species: a long-lived blood-sucking bug, Rhodnius prolixus, and a short-lived globally invasive polyphagous agricultural pest, western flower thrips (Frankliniella occidentalis). When ingested, the manipulated bacteria colonized the insects, successfully competed with the wild-type microflora, and sustainably mediated systemic knockdown phenotypes that were horizontally transmissible. This represents a significant advance in the ability to deliver RNAi, potentially to a large range of non-model insects. PMID:26911963

  10. Cell-mediated immunity in anorexia nervosa.

    PubMed Central

    Cason, J; Ainley, C C; Wolstencroft, R A; Norton, K R; Thompson, R P

    1986-01-01

    Twelve patients with anorexia nervosa were studied for cell-mediated immunity in terms of delayed hypersensitivity reactions to recall antigens, lymphocyte transformation responses to T-cell mitogens, and numbers of circulating leucocytes and T-cell subpopulations. Compared to controls, all patients had reduced cutaneous reactions and four were anergic. There was a mild leucopenia in patients and both T4+ and T3+ numbers were slightly reduced. Mean peak transformation responses for patients were slightly lower than controls for phytohaemagglutinin, but not for concanavalin A; however, patients required greater doses of mitogens to elicit peak transformation responses. Plasmas from patients did not contain inhibitors of transformation responses. We conclude that there are functional cellular abnormalities associated with the under-nutrition of anorexia nervosa. PMID:3742879

  11. LHC benchmarks from flavored gauge mediation

    NASA Astrophysics Data System (ADS)

    Ierushalmi, N.; Iwamoto, S.; Lee, G.; Nepomnyashy, V.; Shadmi, Y.

    2016-07-01

    We present benchmark points for LHC searches from flavored gauge mediation models, in which messenger-matter couplings give flavor-dependent squark masses. Our examples include spectra in which a single squark — stop, scharm, or sup — is much lighter than all other colored superpartners, motivating improved quark flavor tagging at the LHC. Many examples feature flavor mixing; in particular, large stop-scharm mixing is possible. The correct Higgs mass is obtained in some examples by virtue of the large stop A-term. We also revisit the general flavor and CP structure of the models. Even though the A-terms can be substantial, their contributions to EDM's are very suppressed, because of the particular dependence of the A-terms on the messenger coupling. This holds regardless of the messenger-coupling texture. More generally, the special structure of the soft terms often leads to stronger suppression of flavor- and CP-violating processes, compared to naive estimates.

  12. Oxygen radicals and asbestos-mediated disease.

    PubMed Central

    Quinlan, T R; Marsh, J P; Janssen, Y M; Borm, P A; Mossman, B T

    1994-01-01

    Asbestos fibers are potent elaborators of active oxygen species whether by reactions involving iron on the surface of the fiber, or by attempted phagocytosis of fibers by cell types resident in the lung. The link between production of active oxygen species and the pathogenesis of asbestos-mediated disease has been highlighted by studies outlined here exploring the use of antioxidant scavengers which inhibit the cytotoxic effects of asbestos both in vitro and in vivo. The use of antioxidant enzymes ameliorates the induction of certain genes necessary for cell proliferation, such as ornithine decarboxylase, implicating oxidants as causative factors in some abnormal cell replicative events. Based on these observations, antioxidant enzymes likely represent an important lung defense mechanism in response to oxidative stress. In addition, their gene expression in lung or in cells from bronchoalveolar lavage might be a valuable biomarker of chronic inflammation and pulmonary disease after inhalation of oxidants. PMID:7705283

  13. BioShuttle-mediated Plasmid Transfer

    PubMed Central

    Braun, Klaus; von Brasch, Leonie; Pipkorn, Ruediger; Ehemann, Volker; Jenne, Juergen; Spring, Herbert; Debus, Juergen; Didinger, Bernd; Rittgen, Werner; Waldeck, Waldemar

    2007-01-01

    An efficient gene transfer into target tissues and cells is needed for safe and effective treatment of genetic diseases like cancer. In this paper, we describe the development of a transport system and show its ability for transporting plasmids. This non-viral peptide-based BioShuttle-mediated transfer system consists of a nuclear localization address sequence realizing the delivery of the plasmid phNIS-IRES-EGFP coding for two independent reporter genes into nuclei of HeLa cells. The quantification of the transfer efficiency was achieved by measurements of the sodium iodide symporter activity. EGFP gene expression was measured with Confocal Laser Scanning Microscopy and quantified with biostatistical methods by analysis of the frequency of the amplitude distribution in the CLSM images. The results demonstrate that the “BioShuttle”-Technology is an appropriate tool for an effective transfer of genetic material carried by a plasmid. PMID:18026568

  14. Epigenetics and therapeutic targets mediating neuroprotection.

    PubMed

    Qureshi, Irfan A; Mehler, Mark F

    2015-12-01

    The rapidly evolving science of epigenetics is transforming our understanding of the nervous system in health and disease and holds great promise for the development of novel diagnostic and therapeutic approaches targeting neurological diseases. Increasing evidence suggests that epigenetic factors and mechanisms serve as important mediators of the pathogenic processes that lead to irrevocable neural injury and of countervailing homeostatic and regenerative responses. Epigenetics is, therefore, of considerable translational significance to the field of neuroprotection. In this brief review, we provide an overview of epigenetic mechanisms and highlight the emerging roles played by epigenetic processes in neural cell dysfunction and death and in resultant neuroprotective responses. This article is part of a Special Issue entitled SI: Neuroprotection. PMID:26236020

  15. Modelling Toehold-Mediated RNA Strand Displacement

    PubMed Central

    Šulc, Petr; Ouldridge, Thomas E.; Romano, Flavio; Doye, Jonathan P.K.; Louis, Ard A.

    2015-01-01

    We study the thermodynamics and kinetics of an RNA toehold-mediated strand displacement reaction with a recently developed coarse-grained model of RNA. Strand displacement, during which a single strand displaces a different strand previously bound to a complementary substrate strand, is an essential mechanism in active nucleic acid nanotechnology and has also been hypothesized to occur in vivo. We study the rate of displacement reactions as a function of the length of the toehold and temperature and make two experimentally testable predictions: that the displacement is faster if the toehold is placed at the 5′ end of the substrate; and that the displacement slows down with increasing temperature for longer toeholds. PMID:25762335

  16. Cell-mediated immunity in epidermodysplasia verruciformis.

    PubMed

    Gliński, W; Jablonska, S; Langner, A; Obalek, S; Haftek, M; Proniewska, M

    1976-01-01

    Investigations were performed in 6 cases of epidermodysplasia verruciformis and 2 healthy family members. Nonspecific cell-mediated immunity (CMI) was studied by measuring response to phytohemagglutinin (PHA) and concanavalin A (Con A), percentrages of E- and EAC-rosette-forming lymphocytes, bacterial skin tests, and allergic reactions to dinitrochloro-benzene (DNCB). Impairment of CMI was manifested by reduction in the percentage of E rosettes, and lowered response to PHA, and- to a lesser degree- to Con A. The immune response to DNCB sensitization was invariably negative. Impairment of CMI was greater in cases of long duration and with extensive lesions. The cases of similar duration and extent of lesions, which never showed tendency to tumor formation, were not different in CMI in comparison with cases with numerous tumors. Only in cases with very advanced tumors CMI was impaired parallel to the gravity of the patient's general condition. PMID:1017532

  17. CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction.

    PubMed

    Tabeling, Christoph; Yu, Hanpo; Wang, Liming; Ranke, Hannes; Goldenberg, Neil M; Zabini, Diana; Noe, Elena; Krauszman, Adrienn; Gutbier, Birgitt; Yin, Jun; Schaefer, Michael; Arenz, Christoph; Hocke, Andreas C; Suttorp, Norbert; Proia, Richard L; Witzenrath, Martin; Kuebler, Wolfgang M

    2015-03-31

    Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo. Ca(2+) mobilization and transient receptor potential canonical 6 (TRPC6) translocation were studied in human pulmonary (PASMCs) or coronary (CASMCs) artery smooth muscle cells. CFTR inhibition or deficiency diminished HPV and aggravated ventilation-perfusion mismatch. In PASMCs, hypoxia caused CFTR to interact with TRPC6, whereas CFTR inhibition attenuated hypoxia-induced TRPC6 translocation to caveolae and Ca(2+) mobilization. Ca(2+) mobilization by sphingosine-1-phosphate (S1P) was also attenuated by CFTR inhibition in PASMCs, but amplified in CASMCs. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, whereas exogenous nSMase caused TRPC6 translocation and vasoconstriction that were blocked by CFTR inhibition. nSMase- and hypoxia-induced vasoconstriction, yet not TRPC6 translocation, were blocked by inhibition or deficiency of sphingosine kinase 1 (SphK1) or antagonism of S1P receptors 2 and 4 (S1P2/4). S1P and nSMase had synergistic effects on pulmonary vasoconstriction that involved TRPC6, phospholipase C, and rho kinase. Our findings demonstrate a central role of CFTR and sphingolipids in HPV. Upon hypoxia, nSMase triggers TRPC6 translocation, which requires its interaction with CFTR. Concomitant SphK1-dependent formation of S1P and activation of S1P2/4 result in phospholipase C-mediated TRPC6 and rho kinase activation, which conjointly trigger vasoconstriction. PMID:25829545

  18. Gab2-Mediated Signaling Promotes Melanoma Metastasis

    PubMed Central

    Horst, Basil; Gruvberger-Saal, Sofia K.; Hopkins, Benjamin D.; Bordone, Lindsey; Yang, Ying; Chernoff, Karen A.; Uzoma, Ijeoma; Schwipper, Volker; Liebau, Jutta; Nowak, Norma J.; Brunner, Georg; Owens, David; Rimm, David L.; Parsons, Ramon; Celebi, Julide Tok

    2009-01-01

    Metastatic melanoma is a disease with a poor prognosis that currently lacks effective treatments. Critical biological features of metastasis include acquisition of migratory competence, growth factor independence, and invasive potential. In an attempt to identify genes that contribute to melanoma pathogenesis, a genome-wide search using bacterial artificial chromosome array comparative genomic hybridization and single nucleotide polymorphism arrays in a series of 64 metastatic melanoma samples and 20 melanoma cell lines identified increased copy numbers of Gab2 located on 11q14.1. Gab2 is an adaptor protein that potentiates the activation of the Ras-Erk and PI3K-Akt pathways and has recently been implicated in human cancer; however, its role in melanoma has not been explored. In this study, we found that Gab2 was either amplified (∼11%) and/or overexpressed (∼50%) in melanoma. Gab2 protein expression correlated with clinical melanoma progression, and higher levels of expression were seen in metastatic melanomas compared with primary melanoma and melanocytic nevi. We found that overexpression of Gab2 potentiates, whereas silencing of Gab2 reduces, migration and invasion of melanoma cells. Gab2 mediated the hyperactivation of Akt signaling in the absence of growth factors, whereas inhibition of the PI3K-Akt pathway decreased Gab2-mediated tumor cell migration and invasive potential. Gab2 overexpression resulted in enhanced tumor growth and metastatic potential in vivo. These studies demonstrate a previously undefined role for Gab2 in melanoma tumor progression and metastasis. PMID:19342374

  19. AXL mediates resistance to cetuximab therapy.

    PubMed

    Brand, Toni M; Iida, Mari; Stein, Andrew P; Corrigan, Kelsey L; Braverman, Cara M; Luthar, Neha; Toulany, Mahmoud; Gill, Parkash S; Salgia, Ravi; Kimple, Randall J; Wheeler, Deric L

    2014-09-15

    The EGFR antibody cetuximab is used to treat numerous cancers, but intrinsic and acquired resistance to this agent is a common clinical outcome. In this study, we show that overexpression of the oncogenic receptor tyrosine kinase AXL is sufficient to mediate acquired resistance to cetuximab in models of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), where AXL was overexpressed, activated, and tightly associated with EGFR expression in cells resistant to cetuximab (Ctx(R) cells). Using RNAi methods and novel AXL-targeting agents, we found that AXL activation stimulated cell proliferation, EGFR activation, and MAPK signaling in Ctx(R) cells. Notably, EGFR directly regulated the expression of AXL mRNA through MAPK signaling and the transcription factor c-Jun in Ctx(R) cells, creating a positive feedback loop that maintained EGFR activation by AXL. Cetuximab-sensitive parental cells were rendered resistant to cetuximab by stable overexpression of AXL or stimulation with EGFR ligands, the latter of which increased AXL activity and association with the EGFR. In tumor xenograft models, the development of resistance following prolonged treatment with cetuximab was associated with AXL hyperactivation and EGFR association. Furthermore, in an examination of patient-derived xenografts established from surgically resected HNSCCs, AXL was overexpressed and activated in tumors that displayed intrinsic resistance to cetuximab. Collectively, our results identify AXL as a key mediator of cetuximab resistance, providing a rationale for clinical evaluation of AXL-targeting drugs to treat cetuximab-resistant cancers. Cancer Res; 74(18); 5152-64. ©2014 AACR. PMID:25136066

  20. CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction

    PubMed Central

    Tabeling, Christoph; Yu, Hanpo; Wang, Liming; Ranke, Hannes; Goldenberg, Neil M.; Zabini, Diana; Noe, Elena; Krauszman, Adrienn; Gutbier, Birgitt; Yin, Jun; Schaefer, Michael; Arenz, Christoph; Hocke, Andreas C.; Suttorp, Norbert; Proia, Richard L.; Witzenrath, Martin; Kuebler, Wolfgang M.

    2015-01-01

    Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo. Ca2+ mobilization and transient receptor potential canonical 6 (TRPC6) translocation were studied in human pulmonary (PASMCs) or coronary (CASMCs) artery smooth muscle cells. CFTR inhibition or deficiency diminished HPV and aggravated ventilation-perfusion mismatch. In PASMCs, hypoxia caused CFTR to interact with TRPC6, whereas CFTR inhibition attenuated hypoxia-induced TRPC6 translocation to caveolae and Ca2+ mobilization. Ca2+ mobilization by sphingosine-1-phosphate (S1P) was also attenuated by CFTR inhibition in PASMCs, but amplified in CASMCs. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, whereas exogenous nSMase caused TRPC6 translocation and vasoconstriction that were blocked by CFTR inhibition. nSMase- and hypoxia-induced vasoconstriction, yet not TRPC6 translocation, were blocked by inhibition or deficiency of sphingosine kinase 1 (SphK1) or antagonism of S1P receptors 2 and 4 (S1P2/4). S1P and nSMase had synergistic effects on pulmonary vasoconstriction that involved TRPC6, phospholipase C, and rho kinase. Our findings demonstrate a central role of CFTR and sphingolipids in HPV. Upon hypoxia, nSMase triggers TRPC6 translocation, which requires its interaction with CFTR. Concomitant SphK1-dependent formation of S1P and activation of S1P2/4 result in phospholipase C-mediated TRPC6 and rho kinase activation, which conjointly trigger vasoconstriction. PMID:25829545