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Sample records for factor a1 htra1

  1. Serine protease HtrA1 accumulates in corneal transforming growth factor beta induced protein (TGFBIp) amyloid deposits

    PubMed Central

    Karring, Henrik; Poulsen, Ebbe Toftgaard; Runager, Kasper; Thøgersen, Ida B.; Klintworth, Gordon K.; Højrup, Peter

    2013-01-01

    Purpose Specific mutations in the transforming growth factor beta induced (TGFBI) gene are associated with lattice corneal dystrophy (LCD) type 1 and its variants. In this study, we performed an in-depth proteomic analysis of human corneal amyloid deposits associated with the heterozygous A546D mutation in TGFBI. Methods Corneal amyloid deposits and the surrounding corneal stroma were procured by laser capture microdissection from a patient with an A546D mutation in TGFBI. Proteins in the captured corneal samples and healthy corneal stroma were identified with liquid chromatography-tandem mass spectrometry and quantified by calculating exponentially modified Protein Abundance Index values. Mass spectrometry data were further compared for identifying enriched regions of transforming growth factor beta induced protein (TGFBIp/keratoepithelin/βig-h3) and detecting proteolytic cleavage sites in TGFBIp. Results A C-terminal fragment of TGFBIp containing residues Y571-R588 derived from the fourth fasciclin 1 domain (FAS1–4), serum amyloid P-component, apolipoprotein A-IV, clusterin, and serine protease HtrA1 were significantly enriched in the amyloid deposits compared to the healthy cornea. The proteolytic cleavage sites in TGFBIp from the diseased cornea are in accordance with the activity of serine protease HtrA1. We also identified small amounts of the serine protease kallikrein-14 in the amyloid deposits. Conclusions Corneal amyloid caused by the A546D mutation in TGFBI involves several proteins associated with other varieties of amyloidosis. The proteomic data suggest that the sequence 571-YHIGDEILVSGGIGALVR-588 contains the amyloid core of the FAS1–4 domain of TGFBIp and point at serine protease HtrA1 as the most likely candidate responsible for the proteolytic processing of amyloidogenic and aggregated TGFBIp, which explains the accumulation of HtrA1 in the amyloid deposits. With relevance to identifying serine proteases, we also found glia-derived nexin (protease-nexin 1) in the amyloid deposits, making this serine protease inhibitor a good candidate for the physiologically relevant inhibitor of one of the amyloid-associated serine proteases in the cornea and probably in other tissues. Noteworthy, the present results are in accordance with our findings from a previous study of corneal amyloid deposits caused by the V624M mutation in TGFBI, suggesting a common mechanism for lattice corneal dystrophies (LCDs) associated with mutations in the TGFBIp FAS1–4 domain. PMID:23592924

  2. Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

    PubMed Central

    Jacobo, Sarah Melissa P.; DeAngelis, Margaret M.; Kim, Ivana K.

    2013-01-01

    Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular age-related macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD. PMID:23478260

  3. Protoporphyrins Enhance Oligomerization and Enzymatic Activity of HtrA1 Serine Protease

    PubMed Central

    Jo, Hakryul; Patterson, Victoria; Stoessel, Sean; Kuan, Chia-Yi; Hoh, Josephine

    2014-01-01

    High temperature requirement protein A1 (HtrA1), a secreted serine protease of the HtrA family, is associated with a multitude of human diseases. However, the exact functions of HtrA1 in these diseases remain poorly understood. We seek to unravel the mechanisms of HtrA1 by elucidating its interactions with chemical or biological modulators. To this end, we screened a small molecule library of 500 bioactive compounds to identify those that alter the formation of extracellular HtrA1 complexes in the cell culture medium. An initial characterization of two novel hits from this screen showed that protoporphyrin IX (PPP-IX), a precursor in the heme biosynthetic pathway, and its metalloporphyrin (MPP) derivatives fostered the oligomerization of HtrA1 by binding to the protease domain. As a result of the interaction with MPPs, the proteolytic activity of HtrA1 against Fibulin-5, a specific HtrA1 substrate in age-related macular degeneration (AMD), was increased. This physical interaction could be abolished by the missense mutations of HtrA1 found in patients with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). Furthermore, knockdown of HtrA1 attenuated apoptosis induced by PPP-IX. These results suggest that PPP-IX, or its derivatives, and HtrA1 may function as co-factors whereby porphyrins enhance oligomerization and the protease activity of HtrA1, while active HtrA1 elevates the pro-apoptotic actions of porphyrin derivatives. Further analysis of this interplay may shed insights into the pathogenesis of diseases such as AMD, CARASIL and protoporphyria, as well as effective therapeutic development. PMID:25506911

  4. HtrA1: Its future potential as a novel biomarker for cancer.

    PubMed

    Altobelli, Emma; Marzioni, Daniela; Lattanzi, Amedeo; Angeletti, Paolo Matteo

    2015-08-01

    HtrA1 appears to be involved in several physiological processes as well as in the pathogenesis of conditions such as Alzheimer's disease and osteoarthritis. It has also been hypothesized to play a role as a tumor suppressor. This manuscript reviews the current cancer-related HtrA1 research from the methodological and clinical standpoints including studies regarding its potential role as a tumor marker and/or prognostic factor. PRISMA method was used for study selection. The articles thus collected were examined and selected by two independent reviewers; any disagreement was resolved by a methodologist. A laboratory researcher reviewed the methods and laboratory techniques. Fifteen studies met the inclusion criteria and concerned the following cancer sites: the nervous system, bladder, breast, esophagus, stomach, liver, endometrium, thyroid, ovaries, pleura, lung and skin. Most articles described in vivo studies using a morphological approach and immunohistochemistry, whereas protein expression was quantified as staining intensity scored by two raters. Often the results were not comparable due to the different rating scales and study design. Current research on HtrA1 does not conclusively support its role as a tumor suppressor. PMID:26035313

  5. Down-Regulation of HtrA1 Activates the Epithelial-Mesenchymal Transition and ATM DNA Damage Response Pathways

    PubMed Central

    Wang, Ning; Eckert, Kristin A.; Zomorrodi, Ali R.; Xin, Ping; Pan, Weihua; Shearer, Debra A.; Weisz, Judith; Maranus, Costas D.; Clawson, Gary A.

    2012-01-01

    Expression of the serine protease HtrA1 is decreased or abrogated in a variety of human primary cancers, and higher levels of HtrA1 expression are directly related to better response to chemotherapeutics. However, the precise mechanisms leading to HtrA1 down regulation during malignant transformation are unclear. To investigate HtrA1 gene regulation in breast cancer, we characterized expression in primary breast tissues and seven human breast epithelial cell lines, including two non-tumorigenic cell lines. In human breast tissues, HtrA1 expression was prominent in normal ductal glands. In DCIS and in invasive cancers, HtrA1 expression was greatly reduced or lost entirely. HtrA1 staining was also reduced in all of the human breast cancer cell lines, compared with the normal tissue and non-tumorigenic cell line controls. Loss of HtrA1 gene expression was attributable primarily to epigenetic silencing mechanisms, with different mechanisms operative in the various cell lines. To mechanistically examine the functional consequences of HtrA1 loss, we stably reduced and/or overexpressed HtrA1 in the non-tumorigenic MCF10A cell line. Reduction of HtrA1 levels resulted in the epithelial-to-mesenchymal transition with acquisition of mesenchymal phenotypic characteristics, including increased growth rate, migration, and invasion, as well as expression of mesenchymal biomarkers. A concomitant decrease in expression of epithelial biomarkers and all microRNA 200 family members was also observed. Moreover, reduction of HtrA1 expression resulted in activation of the ATM and DNA damage response, whereas overexpression of HtrA1 prevented this activation. Collectively, these results suggest that HtrA1 may function as a tumor suppressor by controlling the epithelial-to-mesenchymal transition, and may function in chemotherapeutic responsiveness by mediating DNA damage response pathways. PMID:22761798

  6. The autolysis of human HtrA1 is governed by the redox state of its N-terminal domain.

    PubMed

    Risr, Michael W; Poulsen, Ebbe Toftgaard; Thomsen, Line R; Dyrlund, Thomas F; Nielsen, Tania A; Nielsen, Niels Chr; Sanggaard, Kristian W; Enghild, Jan J

    2014-06-17

    Human HtrA1 (high-temperature requirement protein A1) belongs to a conserved family of serine proteases involved in protein quality control and cell fate. The homotrimeric ubiquitously expressed protease has chymotrypsin-like specificity and primarily targets hydrophobic stretches in selected or misfolded substrate proteins. In addition, the enzyme is capable of exerting autolytic activity by removing the N-terminal insulin-like growth factor binding protein (IGFBP)/Kazal-like tandem motif without affecting the protease activity. In this study, we have addressed the mechanism governing the autolytic activity and find that it depends on the integrity of the disulfide bonds in the N-terminal IGFBP/Kazal-like domain. The specificity of the autolytic cleavage reveals a strong preference for cysteine in the P1 position of HtrA1, explaining the lack of autolysis prior to disulfide reduction. Significantly, the disulfides were reduced by thioredoxin, suggesting that autolysis of HtrA1 in vivo is linked to the endogenous redox balance and that the N-terminal domain acts as a redox-sensing switch. PMID:24846539

  7. Alpha-1-Antitrypsin: A Novel Human High Temperature Requirement Protease A1 (HTRA1) Substrate in Human Placental Tissue

    PubMed Central

    Frochaux, Violette; Hildebrand, Diana; Talke, Anja; Linscheid, Michael W.; Schlüter, Hartmut

    2014-01-01

    The human serine protease high temperature requirement A1 (HTRA1) is highly expressed in the placental tissue, especially in the last trimester of gestation. This suggests that HTRA1 is involved in placental formation and function. With the aim of a better understanding of the role of HTRA1 in the placenta, candidate substrates were screened in a placenta protein extract using a gel-based mass spectrometric approach. Protease inhibitor alpha-1-antitrypsin, actin cytoplasmic 1, tropomyosin beta chain and ten further proteins were identified as candidate substrates of HTRA1. Among the identified candidate substrates, alpha-1-antitrypsin (A1AT) was considered to be of particular interest because of its important role as protease inhibitor. For investigation of alpha-1-antitrypsin as substrate of HTRA1 synthetic peptides covering parts of the sequence of alpha-1-antitrypsin were incubated with HTRA1. By mass spectrometry a specific cleavage site was identified after met-382 (AIPM382↓383SIPP) within the reactive centre loop of alpha-1-antitrypsin, resulting in a C-terminal peptide comprising 36 amino acids. Proteolytic removal of this peptide from alpha-1-antitrypsin results in a loss of its inhibitor function. Beside placental alpha-1-antitrypsin the circulating form in human plasma was also significantly degraded by HTRA1. Taken together, our data suggest a link between the candidate substrates alpha-1-antitrypsin and the function of HTRA1 in the placenta in the syncytiotrophoblast, the cell layer attending to maternal blood in the villous tree of the human placenta. Data deposition: Mass spectrometry (MS) data have been deposited to the ProteomeXchange with identifier PXD000473. PMID:25329061

  8. The trimeric serine protease HtrA1 forms a cage-like inhibition complex with an anti-HtrA1 antibody.

    PubMed

    Ciferri, Claudio; Lipari, Michael T; Liang, Wei-Ching; Estevez, Alberto; Hang, Julie; Stawicki, Scott; Wu, Yan; Moran, Paul; Elliott, Mike; Eigenbrot, Charles; Katschke, Kenneth J; van Lookeren Campagne, Menno; Kirchhofer, Daniel

    2015-12-01

    High temperature requirement A1 (HtrA1) is a trypsin-fold serine protease implicated in the progression of age-related macular degeneration (AMD). Our interest in an antibody therapy to neutralize HtrA1 faces the complication that the target adopts a trimeric arrangement, with three active sites in close proximity. In the present study, we describe antibody 94, obtained from a human antibody phage display library, which forms a distinct macromolecular complex with HtrA1 and inhibits the enzymatic activity of recombinant and native HtrA1 forms. Using biochemical methods and negative-staining EM we were able to elucidate the molecular composition of the IgG94 and Fab94 complexes and the associated inhibition mechanism. The 246-kDa complex between the HtrA1 catalytic domain trimer (HtrA1_Cat) and Fab94 had a propeller-like organization with one Fab bound peripherally to each protomer. Low-resolution EM structures and epitope mapping indicated that the antibody binds to the surface-exposed loops B and C of the catalytic domain, suggesting an allosteric inhibition mechanism. The HtrA1_Cat-IgG94 complex (636 kDa) is a cage-like structure with three centrally located IgG94 molecules co-ordinating two HtrA1_Cat trimers and the six active sites pointing into the cavity of the cage. In both complexes, all antigen-recognition regions (paratopes) are found to bind one HtrA1 protomer and all protomers are bound by a paratope, consistent with the complete inhibition of enzyme activity. Therefore, in addition to its potential therapeutic usefulness, antibody 94 establishes a new paradigm of multimeric serine protease inhibition. PMID:26385991

  9. Structure-Based Design of a Br Halogen Bond at the Complex Interface of the Human Placental HtrA1 PDZ Domain with Its Heptapeptide Ligand.

    PubMed

    Dou, Shuo-Fen; Liu, Hong; Cao, Tong-Mei; Wen, Qing-Li; Li, Jie; Shao, Qing-Chun

    2016-04-01

    The shock-induced serine protease HtrA1 is a potential regulator of human placenta development during pregnancy. The protein contains a functional PDZ domain that has been solved in complex with a phage display-derived heptapeptide: Asp-6 Ser-5 Arg-4 Ile-3 Trp-2 Trp-1 Val0 . In this study, a rationally designed halogen bond was introduced to the domain-peptide complex based on its NMR structure in solution. We computationally compared the stabilization energies and hindrance effects due to the presence of different halogens X (X = F, Cl, Br, or I), using a hybrid quantum mechanics/molecular mechanics (QM/MM) approach, and found that the Br atom could considerably promote the peptide binding free energy (ΔΔG = -5.2 kcal/mol). Fluorescence assays confirmed that the peptide affinity to the HtrA1 PDZ domain was improved by approximately sevenfold upon bromination. Structural analysis identified a geometrically perfect halogen bond between the Br atom of the peptide Trp-1 residue and the carbonyl O atom of the HtrA1 Ile385 residue, with a bond length and an interaction energy of d = 3.20 Å and ΔE = -3.7 kcal/mol, respectively. PMID:26972470

  10. BMP-2, hypoxia, and COL1A1/HtrA1 siRNAs favor neo-cartilage hyaline matrix formation in chondrocytes.

    PubMed

    Ollitrault, David; Legendre, Florence; Drougard, Carole; Briand, Mélanie; Benateau, Hervé; Goux, Didier; Chajra, Hanane; Poulain, Laurent; Hartmann, Daniel; Vivien, Denis; Shridhar, Vijayalakshmi; Baldi, Alfonso; Mallein-Gerin, Frédéric; Boumediene, Karim; Demoor, Magali; Galera, Philippe

    2015-02-01

    Osteoarthritis (OA) is an irreversible pathology that causes a decrease in articular cartilage thickness, leading finally to the complete degradation of the affected joint. The low spontaneous repair capacity of cartilage prevents any restoration of the joint surface, making OA a major public health issue. Here, we developed an innovative combination of treatment conditions to improve the human chondrocyte phenotype before autologous chondrocyte implantation. First, we seeded human dedifferentiated chondrocytes into a collagen sponge as a scaffold, cultured them in hypoxia in the presence of a bone morphogenetic protein (BMP), BMP-2, and transfected them with small interfering RNAs targeting two markers overexpressed in OA dedifferentiated chondrocytes, that is, type I collagen and/or HtrA1 serine protease. This strategy significantly decreased mRNA and protein expression of type I collagen and HtrA1, and led to an improvement in the chondrocyte phenotype index of differentiation. The effectiveness of our in vitro culture process was also demonstrated in the nude mouse model in vivo after subcutaneous implantation. We, thus, provide here a new protocol able to favor human hyaline chondrocyte phenotype in primarily dedifferentiated cells, both in vitro and in vivo. Our study also offers an innovative strategy for chondrocyte redifferentiation and opens new opportunities for developing therapeutic targets. PMID:24957638

  11. BMP-2, Hypoxia, and COL1A1/HtrA1 siRNAs Favor Neo-Cartilage Hyaline Matrix Formation in Chondrocytes

    PubMed Central

    Ollitrault, David; Legendre, Florence; Drougard, Carole; Briand, Mlanie; Benateau, Herv; Goux, Didier; Chajra, Hanane; Poulain, Laurent; Hartmann, Daniel; Vivien, Denis; Shridhar, Vijayalakshmi; Baldi, Alfonso; Mallein-Gerin, Frdric; Boumediene, Karim; Demoor, Magali

    2015-01-01

    Osteoarthritis (OA) is an irreversible pathology that causes a decrease in articular cartilage thickness, leading finally to the complete degradation of the affected joint. The low spontaneous repair capacity of cartilage prevents any restoration of the joint surface, making OA a major public health issue. Here, we developed an innovative combination of treatment conditions to improve the human chondrocyte phenotype before autologous chondrocyte implantation. First, we seeded human dedifferentiated chondrocytes into a collagen sponge as a scaffold, cultured them in hypoxia in the presence of a bone morphogenetic protein (BMP), BMP-2, and transfected them with small interfering RNAs targeting two markers overexpressed in OA dedifferentiated chondrocytes, that is, type I collagen and/or HtrA1 serine protease. This strategy significantly decreased mRNA and protein expression of type I collagen and HtrA1, and led to an improvement in the chondrocyte phenotype index of differentiation. The effectiveness of our in vitro culture process was also demonstrated in the nude mouse model in vivo after subcutaneous implantation. We, thus, provide here a new protocol able to favor human hyaline chondrocyte phenotype in primarily dedifferentiated cells, both in vitro and in vivo. Our study also offers an innovative strategy for chondrocyte redifferentiation and opens new opportunities for developing therapeutic targets. PMID:24957638

  12. Loss-of-Function of HtrA1 Abrogates All-Trans Retinoic Acid-Induced Osteogenic Differentiation of Mouse Adipose-Derived Stromal Cells Through Deficiencies in p70S6K Activation.

    PubMed

    Glanz, Stephan; Mirsaidi, Ali; López-Fagundo, Cristina; Filliat, Gladys; Tiaden, André N; Richards, Peter J

    2016-05-01

    All-trans retinoic acid (ATRA) is a potent inducer of osteogenic differentiation in mouse adipose-derived stromal cells (mASCs), although the underlying mechanisms responsible for its mode of action have yet to be completely elucidated. High temperature requirement protease A1 (HtrA1) is a newly recognized modulator of human multipotent stromal cell (MSC) osteogenesis and as such, may play a role in regulating ATRA-dependent osteogenic differentiation of mASCs. In this study, we assessed the influence of small interfering RNA (siRNA)-induced repression of HtrA1 production on mASC osteogenesis and examined its effects on ATRA-mediated mammalian target of rapamycin (mTOR) signaling. Inhibition of HtrA1 production in osteogenic mASCs resulted in a significant reduction of alkaline phosphatase activity and mineralized matrix formation. Western blot analyses revealed the rapid activation of Akt (Ser473) and p70S6K (Thr389) in ATRA-treated mASCs, and that levels of phosphorylated p70S6K were noticeably reduced in HtrA1-deficient mASCs. Further studies using mTOR inhibitor rapamycin and siRNA specific for the p70S6K gene Rps6kb1 confirmed ATRA-mediated mASC osteogenesis as being dependent on p70S6K activation. Finally, transfection of cells with a constitutively active rapamycin-resistant p70S6K mutant could restore the mineralizing capacity of HtrA1-deficient mASCs. These findings therefore lend further support for HtrA1 as a positive mediator of MSC osteogenesis and provide new insights into the molecular mode of action of ATRA in regulating mASC lineage commitment. PMID:26950191

  13. Association of Htra1 gene polymorphisms with the risk of developing AMD in Iranian population

    PubMed Central

    Askari, Mohammad; Nikpoor, Amin Reza; Gorjipour, Fazel; Mazidi, Mohsen; Sanati, Mohammad Hosein; Aryan, Hajar; Irani, Alireza; Ghasemi Falavarjani, Khalil; Nazari, Hossein; Mousavizadeh, Kazem

    2015-01-01

    Background: Half of the cases of vision loss in people under 60 years of age have been attributed to age-related macular degeneration (AMD). This is a multifactorial disease with late onset. It has been demonstrated that many different genetic loci are implicated in the risk of developing AMD in different populations. In the current study, we investigated the association of high-temperature ‎requirement A-1 (HTRA1) gene polymorphisms with the risk of developing AMD in the Iranian population. Methods: Genomic DNA samples were extracted from 120 patients with AMD and 120 healthy age- and sex-matched controls. A 385 base-pair fragment of the HTRA1 gene promoter region was amplified using the polymerase chain reaction (PCR) technique and sequenced. The frequencies of the alleles were calculated and statistical analysis was performed using SPSS software. Results: Our study demonstrated that the rate of polymorphisms rs11200638 -625 G>A and rs2672598 -487T>C were significantly greater in AMD patients than in healthy controls from the Iranian population. Conclusions: The results of our study indicate that HTRA1 gene promoter region polymorphisms are associated with the risk of developing AMD in the Iranian population.

  14. 1,25-Dihydroxyvitamin D decreases HTRA1 promoter activity in the rhesus monkey--a plausible explanation for the influence of vitamin D on age-related macular degeneration?

    PubMed

    Pahl, Lisa; Schubert, Stephanie; Skawran, Britta; Sandbothe, Maria; Schmidtke, Jörg; Stuhrmann, Manfred

    2013-11-01

    Age-related macular degeneration is the major cause of blindness in the elderly worldwide and the risk is influenced by both environmental and genetic risk factors. One important disease-associated region in humans is located on 10q26 and includes the two candidate genes ARMS2 and HTRA1. However, determination of the causative gene has not yet been possible and examining the situation in the rhesus monkey may help understand the situation in humans. In a recent paper, we characterized the rhesus monkey 10q26-orthologue region on chromosome 9 in detail and identified the drusen-associated HTRA1 promoter SNP rs196357513 as a putative risk factor. In this study, we predicted 9 binding sites for the vitamin D-dependent transcription factor vitamin D receptor in the rhesus HTRA1 promoter, one of which is destroyed by the rs196357513-risk allele. As patients with vitamin D deficit are at increased risk for age-related macular degeneration, a luciferase assay in transiently transfected ARPE19-cells was performed to evaluate the influence of the SNP rs196357513 and of 1,25-dihydroxyvitamin D on the rhesus monkey HTRA1 promoter activity. This revealed that the luciferase activity of the promoter construct containing the rs196357513 wild type allele was significantly reduced after vitamin D stimulation. An in silico analysis and literature search imply that this regulation could also play a role in human HTRA1 expression. Moreover, HTRA1 promoter activity of the construct containing the rs196357513 risk allele appeared diminished in comparison to the construct with the wild type allele, albeit this difference was not significant. The lower promoter activity due to the rhesus monkey rs196357513 risk allele apparently contradicts the common hypothesis for the human HTRA1 promoter risk allele of SNP rs11200638, for which a higher promoter activity has been observed. Our data point to a yet unexpected effect of decreased HTRA1 expression on drusen pathogenesis. Thus not only a higher HTRA1 expression, but an imbalance of HTRA1 might be disease-relevant. Both findings require closer analysis, but if relevance for humans proves true, it would impact current age-related macular degeneration research and treatment. PMID:24076413

  15. HTRA1 (high temperature requirement A serine peptidase 1) gene is transcriptionally regulated by insertion/deletion nucleotides located at the 3' end of the ARMS2 (age-related maculopathy susceptibility 2) gene in patients with age-related macular degeneration.

    PubMed

    Iejima, Daisuke; Itabashi, Takeshi; Kawamura, Yuich; Noda, Toru; Yuasa, Shinsuke; Fukuda, Keiichi; Oka, Chio; Iwata, Takeshi

    2015-01-30

    Dry age-related macular degeneration (AMD) accounts for over 85% of AMD cases in the United States, whereas Japanese AMD patients predominantly progress to wet AMD or polypoidal choroidal vasculopathy. Recent genome-wide association studies have revealed a strong association between AMD and an insertion/deletion sequence between the ARMS2 (age-related maculopathy susceptibility 2) and HTRA1 (high temperature requirement A serine peptidase 1) genes. Transcription regulator activity was localized in mouse retinas using heterozygous HtrA1 knock-out mice in which HtrA1 exon 1 was replaced with β-galactosidase cDNA, thereby resulting in dominant expression of the photoreceptors. The insertion/deletion sequence significantly induced HTRA1 transcription regulator activity in photoreceptor cell lines but not in retinal pigmented epithelium or other cell types. A deletion construct of the HTRA1 regulatory region indicated that potential transcriptional suppressors and activators surround the insertion/deletion sequence. Ten double-stranded DNA probes for this region were designed, three of which interacted with nuclear extracts from 661W cells in EMSA. Liquid chromatography-mass spectrometry (LC-MS/MS) of these EMSA bands subsequently identified a protein that bound the insertion/deletion sequence, LYRIC (lysine-rich CEACAM1 co-isolated) protein. In addition, induced pluripotent stem cells from wet AMD patients carrying the insertion/deletion sequence showed significant up-regulation of the HTRA1 transcript compared with controls. These data suggest that the insertion/deletion sequence alters the suppressor and activator cis-elements of HTRA1 and triggers sustained up-regulation of HTRA1. These results are consistent with a transgenic mouse model that ubiquitously overexpresses HtrA1 and exhibits characteristics similar to those of wet AMD patients. PMID:25519903

  16. Joint Effect of CFH and ARMS2/HTRA1 Polymorphisms on Neovascular Age-Related Macular Degeneration in Chinese Population.

    PubMed

    Fang, Kai; Gao, Pei; Tian, Jun; Qin, Xueying; Yu, Wenzhen; Li, Juan; Chen, Qing; Huang, Lvzhen; Chen, Dafang; Hu, Yonghua; Li, Xiaoxin

    2015-01-01

    Purpose. The etiology of neovascular age-related macular degeneration (nAMD) cannot be completely explained by identified environmental risk factors or single-locus gene variants. This study was to explore the potential interactions among gene variants on nAMD in Chinese population. Methods. 43 SNPs located in different genes were genotyped in 932 Chinese individuals (464 nAMD patients and 468 controls). We explored the potential interactions among gene variants using generalized multifactor dimensionality reduction (GMDR) algorithm and the method to measure the departure from the additivity model. Results. The joint effect that involved CFH rs1061170 and HTRA1 rs3793917 was shown statistically significant (P < 0.001) with the highest cross-validation consistency (10/10) and the best testing balanced accuracy (64.50%). In addition, based on the method to measure the departure from the additivity model, the synergy index (S) was 2.63 (1.09-6.38) and the attributable proportion due to interaction (AP) was 55.7% (21.4%-89.9%), which suggested that a common pathway may exist for these genes for nAMD. Those who carried CC for rs3793917 and TC/CC for rs1061170 were at the highest risk of nAMD (OR: 9.76, 95% CI: 4.65-20.51). Conclusions. Evidence that the joint effect that involved CFH and ARMS2/HTRA1 may contribute to the risk of neovascular AMD in Chinese population was obtained. PMID:25883802

  17. A Next-Generation Sequencing of the NOTCH3 and HTRA1 Genes in CADASIL Patients.

    PubMed

    Fernndez, Angela; Gmez, Juan; Alonso, Beln; Iglesias, Sara; Coto, Eliecer

    2015-07-01

    Our purpose was to develop a next-generation sequencing procedure to search for NOTCH3 and HTRA1 mutations in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) features. A total of 70 patients were sequenced with semiconductor chips in an Ion Torrent Personal Genome Machine. The putative mutations were confirmed through Sanger sequencing of the corresponding patient. Six patients had a typical cysteine-involving NOTCH3 mutation. A new non-reported NOTCH3 variant (p.Pro2178Ser) was found in two patients. One patient was heterozygous for a non-reported HTRA1 variant, likely non-pathogenic (p.Ser139Ala). We found a typical NOTCH3 mutation in 9 % of the patients. None of the patients had HTRA1 variants with likely pathogenic effect. The next-generation sequencing (NGS) procedure here described would facilitate the rapid and cost-effective screening of large cohorts of CADASIL patients. PMID:25929831

  18. Joint Effect of CFH and ARMS2/HTRA1 Polymorphisms on Neovascular Age-Related Macular Degeneration in Chinese Population

    PubMed Central

    Gao, Pei; Tian, Jun; Yu, Wenzhen; Li, Juan; Chen, Qing; Huang, Lvzhen; Chen, Dafang; Hu, Yonghua; Li, Xiaoxin

    2015-01-01

    Purpose. The etiology of neovascular age-related macular degeneration (nAMD) cannot be completely explained by identified environmental risk factors or single-locus gene variants. This study was to explore the potential interactions among gene variants on nAMD in Chinese population. Methods. 43 SNPs located in different genes were genotyped in 932 Chinese individuals (464 nAMD patients and 468 controls). We explored the potential interactions among gene variants using generalized multifactor dimensionality reduction (GMDR) algorithm and the method to measure the departure from the additivity model. Results. The joint effect that involved CFH rs1061170 and HTRA1 rs3793917 was shown statistically significant (P < 0.001) with the highest cross-validation consistency (10/10) and the best testing balanced accuracy (64.50%). In addition, based on the method to measure the departure from the additivity model, the synergy index (S) was 2.63 (1.09–6.38) and the attributable proportion due to interaction (AP) was 55.7% (21.4%–89.9%), which suggested that a common pathway may exist for these genes for nAMD. Those who carried CC for rs3793917 and TC/CC for rs1061170 were at the highest risk of nAMD (OR: 9.76, 95% CI: 4.65–20.51). Conclusions. Evidence that the joint effect that involved CFH and ARMS2/HTRA1 may contribute to the risk of neovascular AMD in Chinese population was obtained. PMID:25883802

  19. Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease.

    PubMed

    Verdura, Edgard; Hervé, Dominique; Scharrer, Eva; Amador, Maria Del Mar; Guyant-Maréchal, Lucie; Philippi, Anne; Corlobé, Astrid; Bergametti, Françoise; Gazal, Steven; Prieto-Morin, Carol; Beaufort, Nathalie; Le Bail, Benoit; Viakhireva, Irina; Dichgans, Martin; Chabriat, Hugues; Haffner, Christof; Tournier-Lasserve, Elisabeth

    2015-08-01

    Cerebral small vessel disease represents a heterogeneous group of disorders leading to stroke and cognitive impairment. While most small vessel diseases appear sporadic and related to age and hypertension, several early-onset monogenic forms have also been reported. However, only a minority of patients with familial small vessel disease carry mutations in one of known small vessel disease genes. We used whole exome sequencing to identify candidate genes in an autosomal dominant small vessel disease family in which known small vessel disease genes had been excluded, and subsequently screened all candidate genes in 201 unrelated probands with a familial small vessel disease of unknown aetiology, using high throughput multiplex polymerase chain reaction and next generation sequencing. A heterozygous HTRA1 variant (R166L), absent from 1000 Genomes and Exome Variant Server databases and predicted to be deleterious by in silico tools, was identified in all affected members of the index family. Ten probands of 201 additional unrelated and affected probands (4.97%) harboured a heterozygous HTRA1 mutation predicted to be damaging. There was a highly significant difference in the number of likely deleterious variants in cases compared to controls (P = 4.2 × 10(-6); odds ratio = 15.4; 95% confidence interval = 4.9-45.5), strongly suggesting causality. Seven of these variants were located within or close to the HTRA1 protease domain, three were in the N-terminal domain of unknown function and one in the C-terminal PDZ domain. In vitro activity analysis of HTRA1 mutants demonstrated a loss of function effect. Clinical features of this autosomal dominant small vessel disease differ from those of CARASIL and CADASIL by a later age of onset and the absence of the typical extraneurological features of CARASIL. They are similar to those of sporadic small vessel disease, except for their familial nature. Our data demonstrate that heterozygous HTRA1 mutations are an important cause of familial small vessel disease, and that screening of HTRA1 should be considered in all patients with a hereditary small vessel disease of unknown aetiology. PMID:26063658

  20. High Temperature Requirement A1, Transforming Growth Factor Beta 1, phosphoSmad2 and Ki67 in Eutopic and Ectopic Endometrium of Women With Endometriosis

    PubMed Central

    Goteri, G.; Altobelli, E.; Tossetta, G.; Zizzi, A.; Avellini, C.; Licini, C.; Lorenzi, T.; Castellucci, M.; Ciavattini, A.

    2015-01-01

    Increasing evidence supports the hypothesis that TGFβ1 signalling may be mediated by high temperature requirement A1 (HtrA1) serine protease, acting on important regulatory mechanisms such as cell proliferation and mobility. Evidence is now accumulating to suggest that HtrA1 is involved in the development and progression of several pathologies. The aim of this study was to evaluate: i) if HtrA1 and TGFβ1 expressions differ in eutopic and ectopic endometrium in women with endometriosis; ii) if HtrA1 correlates to TGFβ1, pSmad and Ki67. This study was carried out including 10 women with ovarian endometriosis (cases) and 10 women with non endometriotic diseases (controls). Endometrial tissue underwent immunohistochemical H-score analysis for HtrA1, TGFβ1, pSmad and Ki67 molecules. Data evaluation was performed by a nonparametric Kruskal-Wallis test and Spearman correlation was applied to evaluate the relationship among the molecules investigated in the epithelial and in the stromal compartment. The HtrA1 was significantly decreased in ectopic and eutopic endometrium of women with endometriosis when compared with control endometrium in epithelial compartment. TGFβ1was significantly increased in eutopic endometrium and decreased in ectopic endometrium in epithelial and stromal compartment. In addition, Ki67 was significantly increased and an increase, but not significant, was detected for pSMAd2 in eutopic and ectopic endometrium compared to control one. In summary, the significant direct correlation between TGFβ1 and pSmad2 as well as between HtrA1 and TGFβ1 and the very significant increase of Ki67 in stromal compartment of eutopic endometrium suggest a possible involvement of HtrA1 in the pathogenesis of endometriosis. PMID:26708185

  1. Differential Expression of HrtA1 and ADAM12 in Placentas from Preeclamptic and Normotensive Pregnancies

    PubMed Central

    Enquobahrie, Daniel A.; Hevner, Karin; Qiu, Chunfang; Abetew, Dejene F.; Sorensen, Tanya K.; Williams, Michelle A.

    2014-01-01

    Background High temperature requirement factor A 1 (HtrA1) and a disintegrin and metalloproteinase 12 (ADAM12), which play roles in placental implantation and placental growth, have been implicated in the pathogenesis of preeclampsia. Methods We investigated relative mRNA expression of both genes in placental tissues from women with preeclampsia (N=18) (average gestational age 36 weeks) and an equal number of women with normotensive pregnancies (average gestational age 39 weeks). Real-time polymerase chain reaction was used to measure mRNA extracted from term placental biopsies. Differential gene expression was evaluated using Student’s T-test and fold change analyses. Results Statistically significant increases in placental HtRA1 (1.69-fold, p=0.030) and ADAM12 (1.48-fold, p=0.010) mRNA expression were observed among preeclamptic cases as compared with normotensive controls. HtrA1 expression was correlated with maternal age (p-value <0.01) among preeclampsia cases. Conclusion Increases in HtRA1 and ADAM12 placental gene expression in placentas from preeclamptic pregnancies are consistent with some earlier reports of altered serum protein concentrations in preeclamptic pregnancies. This adds to the literature suggesting that defects in placentation (e.g. involving trophoblast invasion) are of etiologic importance in preeclampsia. PMID:24860691

  2. Gene Structure of the 10q26 Locus: A Clue to Cracking the ARMS2/HTRA1 Riddle?

    PubMed

    Kortvely, Elod; Ueffing, Marius

    2016-01-01

    Age-related macular degeneration (AMD) is a sight-threatening disorder of the central retina. Being the leading cause of visual impairment in senior citizens, it represents a major public health issue in developed countries. Genetic studies of AMD identified two major susceptibility loci on chromosomes 1 and 10. The high-risk allele of the 10q26 locus encompasses three genes, PLEKHA1, ARMS2, and HTRA1 with high linkage disequilibrium and the individual contribution of the encoded proteins to disease etiology remains controversial. While PLEKHA1 and HTRA1 are highly conserved proteins, ARMS2 is only present in primates and can be detected by using RT-PCR. On the other hand, there is no unequivocal evidence for the existence of the encoded protein. However, it has been reported that risk haplotypes only affect the expression of ARMS2 (but not of HTRA1), making ARMS2 the best candidate for being the genuine AMD gene within this locus. Yet, homozygous carriers of a common haplotype carry a premature stop codon in the ARMS2 gene (R38X) and therefore lack ARMS2, but this variant is not associated with AMD. In this work we aimed at characterizing the diversity of transcripts originating from this locus, in order to find new hints on how to resolve this perplexing paradox. We found chimeric transcripts originating from the PLEKHA1 gene but ending in ARMS2. This finding may give a new explanation as to how variants in this locus contribute to AMD. PMID:26427389

  3. Gene–gene interaction of CFH, ARMS2, and ARMS2/HTRA1 on the risk of neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in Chinese population

    PubMed Central

    Huang, L; Meng, Q; Zhang, C; Sun, Y; Bai, Y; Li, S; Deng, X; Wang, B; Yu, W; Zhao, M; Li, X

    2015-01-01

    Purpose To evaluate the association and interaction of five single-nucleotide polymorphisms (SNPs) in three genes (CFH, ARMS2, and ARMS2/HTRA1) with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) in Chinese population. Methods A total of 300 nAMD and 300 PCV patients and 301 normal subjects participated in the present study. The allelic variants of rs800292, rs2274700, rs3750847, rs3793917, and rs1065489 were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). Gene–gene interactions were evaluated by the data mining approach multifactor-dimensionality reduction (MDR) method. Results The risk alleles of CFH rs800292, rs2274700, ARMS2 rs3057847, and ARMS2/HTRA1 rs3793917 showed significant difference between nAMD or PCV patients and controls (all P<0.01). The homozygosity of risk alleles for rs800292, rs2274700, rs3750847, and rs3793917 were significantly different between nAMD patients and controls (all P<0.01), and predisposed to PCV patients (all P<0.01). After cross-validation consistency (CVC) and permutation tests, the two-locus model rs2274700_rs3750847 has a balanced accuracy of 64.37% in predicting nAMD disease risk. The one-marker model, rs3750847, and two-locus model rs2274700_rs3750847 has a balanced accuracy of 66.07% and 65.89% in predicting PCV disease risk, respectively. Furthermore, CFH rs1065489 did not show significant association with nAMD (P>0.01), but was strongly associated with PCV in Chinese patients (P<0.001). Conclusions In this study, we found that the interaction of ARMS2 and ARMS2/HTRA1 is significantly associated with nAMD, and the interaction of CFH and ARMS2 is pronounced in PCV development in Chinese population. PMID:25771815

  4. Orphan nuclear receptor NR4A1 regulates transforming growth factor-β signaling and fibrosis.

    PubMed

    Palumbo-Zerr, Katrin; Zerr, Pawel; Distler, Alfiya; Fliehr, Judith; Mancuso, Rossella; Huang, Jingang; Mielenz, Dirk; Tomcik, Michal; Fürnrohr, Barbara G; Scholtysek, Carina; Dees, Clara; Beyer, Christian; Krönke, Gerhard; Metzger, Daniel; Distler, Oliver; Schett, Georg; Distler, Jörg H W

    2015-02-01

    Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-β (TGF-β) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-β target genes, thereby limiting pro-fibrotic TGF-β effects. Even though temporary upregulation of TGF-β in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-β signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-β signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases. PMID:25581517

  5. Low HbA1c and Increased Mortality Risk-is Frailty a Confounding Factor?

    PubMed Central

    Abdelhafiz, Ahmed H; Sinclair, Alan J

    2015-01-01

    Diabetes mellitus is increasingly becoming an older person disease due to the increased survival and aging of the population. Previous studies which showed benefits of tight glycemic control and a linear relationship between HbA1c and mortality have largely included younger patients newly diagnosed with diabetes and with less comorbidities. Recent studies, which included older population with diabetes, have shown a U-shaped relationship of increased mortality associated with low HbA1c. The mechanism of such relationship is unclear. There was no direct causal link between low HbA1c and mortality. It appears that malnutrition, inflammation and functional decline are characteristics shared by the populations that showed increased mortality and low HbA1c. In these studies functional status, disability or frailty was not routinely measured. Therefore, although adjustment for comorbidities was made there may be a residual confounding by unmeasured factors such as frailty. Thus, frailty or decline in functional reserve may be the main confounding factor explaining the relationship between increased mortality risk and low HbA1c. PMID:26236548

  6. Beyond HbA1c: Environmental Risk Factors for Diabetic Retinopathy

    PubMed Central

    Nwanyanwu, Kristen Harris; Newman-Casey, Paula-Anne; Gardner, Thomas W; Lim, Jennifer I

    2015-01-01

    Diabetic retinopathy affects 4.2 million people in the United States and is the leading cause of blindness in working-aged people. As the prevalence of diabetes continues to rise, cost-effective interventions to decrease blindness from diabetic retinopathy will be paramount. While HbA1c and duration of disease are known risk factors, they account for only 11% of the risk of developing microvascular complications from the disease. The assessment of environmental risk factors for diabetic eye disease allows for the determination of modifiable population-level challenges that may be addressed to facilitate the end of blindness from diabetes. PMID:26973797

  7. Differential surface activation of the A1 domain of von Willebrand factor.

    PubMed

    Tronic, Elaine H; Yakovenko, Olga; Weidner, Tobias; Baio, Joe E; Penkala, Rebecca; Castner, David G; Thomas, Wendy E

    2016-06-01

    The clotting protein von Willebrand factor (VWF) binds to platelet receptor glycoprotein Ibα (GPIbα) when VWF is activated by chemicals, high shear stress, or immobilization onto surfaces. Activation of VWF by surface immobilization is an important problem in the failure of cardiovascular implants, but is poorly understood. Here, the authors investigate whether some or all surfaces can activate VWF at least in part by affecting the orientation or conformation of the immobilized GPIbα-binding A1 domain of VWF. Platelets binding to A1 adsorbed onto polystyrene surfaces translocated rapidly at moderate and high flow, but detached at low flow, while platelets binding to A1 adsorbed onto glass or tissue-culture treated polystyrene surfaces translocated slowly, and detached only at high flow. Both x-ray photoelectron spectroscopy and conformation independent antibodies reported comparable A1 amounts on all surfaces. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and near-edge x-ray absorption fine structure spectra suggested differences in orientation on the three surfaces, but none that could explain the biological data. Instead, ToF-SIMS data and binding of conformation-dependent antibodies were consistent with the stabilization of an alternative more activated conformation of A1 by tissue culture polystyrene and especially glass. These studies demonstrate that different material surfaces differentially affect the conformation of adsorbed A1 domain and its biological activity. This is important when interpreting or designing in vitro experiments with surface-adsorbed A1 domain, and is also of likely relevance for blood-contacting biomaterials. PMID:26968213

  8. Differential surface activation of the A1 domain of von Willebrand factor

    PubMed Central

    Tronic, Elaine H.; Yakovenko, Olga; Weidner, Tobias; Baio, Joe E.; Penkala, Rebecca; Castner, David G.; Thomas, Wendy E.

    2016-01-01

    The clotting protein von Willebrand factor (VWF) binds to platelet receptor glycoprotein Ibα (GPIbα) when VWF is activated by chemicals, high shear stress, or immobilization onto surfaces. Activation of VWF by surface immobilization is an important problem in the failure of cardiovascular implants, but is poorly understood. Here, the authors investigate whether some or all surfaces can activate VWF at least in part by affecting the orientation or conformation of the immobilized GPIbα-binding A1 domain of VWF. Platelets binding to A1 adsorbed onto polystyrene surfaces translocated rapidly at moderate and high flow, but detached at low flow, while platelets binding to A1 adsorbed onto glass or tissue-culture treated polystyrene surfaces translocated slowly, and detached only at high flow. Both x-ray photoelectron spectroscopy and conformation independent antibodies reported comparable A1 amounts on all surfaces. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) and near-edge x-ray absorption fine structure spectra suggested differences in orientation on the three surfaces, but none that could explain the biological data. Instead, ToF-SIMS data and binding of conformation-dependent antibodies were consistent with the stabilization of an alternative more activated conformation of A1 by tissue culture polystyrene and especially glass. These studies demonstrate that different material surfaces differentially affect the conformation of adsorbed A1 domain and its biological activity. This is important when interpreting or designing in vitro experiments with surface-adsorbed A1 domain, and is also of likely relevance for blood-contacting biomaterials. PMID:26968213

  9. Multiple variants in UGT1A1 gene are factors to develop indirect hyper-bilirubinemia.

    PubMed

    Hu, Rei-Ting; Wang, Nai-Yuan; Huang, May-Jen; Huang, Ching-Shan; Chen, Ding-Shinn; Yang, Sien-Sing

    2014-08-01

    Most Taiwanese patients with hyper-bilirubinemia have genetic abnormalities in the uridine diphosphoglucuronate-glucuronosyltransferase 1A1 (UGT1A1) gene beyond the variants in the TATA box upstream of UGT1A1 associated with Gilbert's syndrome. To investigate the role of UGT1A1 in the pathogenesis of indirect hyper-bilirubinemia, we prospectively studied 97 consecutive patients with indirect hyper-bilirubinemia for genotypes of promoter [(TA)6TAA6, (TA)7TAA7] and coding region [nucleotide (nt)-211, nt-686, nt-1,091 and nt-1,456] of UGT1A1. Thirty-six of the patients (45.6%) were found to have Gilbert's syndrome with 7/7 genotype; among them, 14 also carried variants at nt-686. Forty-two patients (43.3%) had the 6/7 genotype; among them, 36 patients were found to have one or more variants in the coding region. Patients with higher serum total bilirubin are associated with higher likelihood of carrying Gilbert's syndrome genotype: 60.0% (P=0.007) patients with serum total bilirubin level ≥2.5 mg/dL carried the Gilbert's syndrome genotype, while only 23.9% of patients with serum total bilirubin level <2.5 mg/dL carry the same genotype (P=0.0006). Forty-one of the 61 non-Gilbert's patients had one homogenous variants or two or more heterozygous variants in UGT1A1. Further studies are necessary to confirm the role of one homo-zygous variant or two or more hetero-zygous variants in UGT1A1 gene as factors for indirect hyper-bilirubinemia. PMID:25202696

  10. Effect of the Gas6 c.834+7G>A Polymorphism and the Interaction of Known Risk Factors on AMD Pathogenesis in Hungarian Patients

    PubMed Central

    Losonczy, Gergely; Vajas, Attila; Takács, Lili; Dzsudzsák, Erika; Fekete, Ágnes; Márhoffer, Éva; Kardos, László; Ajzner, Éva; Hurtado, Begoña; de Frutos, Pablo Garcia

    2012-01-01

    Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. Numerous genetic factors contribute to the development of the multifactorial disease. We performed a case-control study to assess the risk conferred by known and candidate genetic polymorphisms on the development of AMD. We searched for genetic interactions and for differences in dry and wet AMD etiology. We enrolled 213 patients with exudative, 67 patients with dry AMD and 106 age and ethnically matched controls. Altogether 12 polymorphisms in Apolipoprotein E, complement factor H, complement factor I, complement component 3, blood coagulation factor XIII, HTRA1, LOC387715, Gas6 and MerTK genes were tested. No association was found between either the exudative or the dry form and the polymorphisms in the Apolipoprotein E, complement factor I, FXIII and MerTK genes. Gas6 c.834+7G>A polymorphism was found to be significantly protective irrespective of other genotypes, reducing the odds of wet type AMD by a half (OR = 0.50, 95%CI: 0.26–0.97, p = 0.04). Multiple regression models revealed an interesting genetic interaction in the dry AMD subgroup. In the absence of C3 risk allele, mutant genotypes of both CFH and HTRA1 behaved as strongly significant risk factors (OR = 7.96, 95%CI: 2.39 = 26.50, p = 0.0007, and OR = 36.02, 95%CI: 3.30–393.02, p = 0.0033, respectively), but reduced to neutrality otherwise. The risk allele of C3 was observed to carry a significant risk in the simultaneous absence of homozygous CFH and HTRA1 polymorphisms only, in which case it was associated with a near-five-fold relative increase in the odds of dry type AMD (OR = 4.93, 95%CI: 1.98–12.25, p = 0.0006). Our results suggest a protective role of Gas6 c.834+7G>A polymorphism in exudative AMD development. In addition, novel genetic interactions were revealed between CFH, HTRA1 and C3 polymorphisms that might contribute to the pathogenesis of dry AMD. PMID:23209669

  11. The correlation between the Glycated hemoglobin (HbA1c) in non-diabetics and cardiovascular risk factors.

    PubMed

    Wu, Xinling; Zhao, Youmin; Chai, Jianwen; Hao, Dongqin

    2016-01-01

    This study aimed to discuss the relativity between the glycated hemoglobin (HbA1c) in non-diabetics and cardiovascular risk factors and definite the significance of predicting the cardiovascular risk factors through cross-sectional research method. There were 2007 cases volunteers (including 650 cases of male, 1357 cases of female) from city community with complete information involved in the research of diabetes. The value of HbA1c 6.5% was set as the diagnose boundary of the diabetes. Differences were considered to be statistically significant at P<0.05. Hypertension, dyslipidemi, being overweight or obesity, age (male was over 45 years old and female was over 55 years old.), HbA1c 6.0% and fasting blood glucose (FBG) 6.1mmol/L were regarded as cardiovascular risk factors. Then we analyzed the number of risk factors for individuals in different HbA1c groups. Meanwhile, patients were grouped into zero, one, two, three, four or more groups with reference to the number of risk factors they had in order to compare the values of risk factors in different groups through Logistic regression. The results showed that (1) For those people who had no less than three risk factors, the frequency of risk factors was on the rise with the increase of HbA1c levels. (2) The value of HbA1c in different groups of risk factors rose with the increasing number of risk factors. There was a significant difference (P<0.001) between groups. (3) The Regression analysis showed that there was a stronger correlation between HbA1c levels and impaired glucose tolerance (IGT), fasting blood glucose (FBG) rather than age. So Non-diabetics whose HbA1c levels ranged from 6.0% to 6.5% were at high risk of cardiovascular risk factors. HbA1c levels, which can be a prediction index for cardiovascular risk factors dependent from other cardiovascular risk factors for non-diabetics, and it were highly relevant with impaired glucose tolerance (IGT) and impaired fasting blood glucose (FBG). PMID:27005508

  12. Upstream Stimulatory Factor 2, a Novel FoxA1-Interacting Protein, Is Involved in Prostate-Specific Gene Expression

    PubMed Central

    Sun, Qian; Yu, Xiuping; Degraff, David J.; Matusik, Robert J.

    2009-01-01

    The forkhead protein A1 (FoxA1) is critical for the androgenic regulation of prostate-specific promoters. Prostate tissue rescued from FoxA1 knockout mice exhibits abnormal prostate development, typified by the absence of expression of differentiation markers and inability to engage in secretion. Chromatin immunoprecipitation and coimmunoprecipitation studies revealed that FoxA1 is one of the earliest transcription factors that binds to prostate-specific promoters, and that a direct protein-protein interaction occurs between FoxA1 and androgen receptor. Interestingly, evidence of the interaction of FoxA1 with other transcription factors is lacking. The upstream stimulatory factor 2 (USF2), an E-box-binding transcription factor of the basic-helix-loop-helix-leucine-zipper family, binds to a consensus DNA sequence similar to FoxA1. Our in vitro and in vivo studies demonstrate the binding of USF2 to prostate-specific gene promoters including the probasin promoter, spermine-binding protein promoter, and prostate-specific antigen core enhancer. Furthermore, we show a direct physical interaction between FoxA1 and USF2 through the use of immunoprecipitation and glutathione-S-transferase pull-down assays. This interaction is mediated via the forkhead DNA-binding domain of FoxA1 and the DNA-binding domain of USF2. In summary, these data indicate that USF2 is one of the components of the FoxA1/androgen receptor transcriptional protein complex that contributes to the expression of androgen-regulated and prostate-specific genes. PMID:19846536

  13. Aldehyde dehydrogenase 1A1 stabilizes transcription factor Gli2 and enhances the activity of Hedgehog signaling in hepatocellular cancer.

    PubMed

    Yan, Zhengwei; Xu, Liyao; Zhang, Junyan; Lu, Quqin; Luo, Shiwen; Xu, Linlin

    2016-03-18

    The Gli transcription factors are primary transcriptional regulators that mediate the activation of Hedgehog (Hh) signaling. Recent studies have revealed that Gli proteins are also regulated transcriptionally and post-translationally through noncanonical mechanisms, independent of Hh signaling. However, the precise mechanisms involved in the regulation of Gli proteins remain unclear. Using a differential mass-spectrometry approach, we found that aldehyde dehydrogenase 1A1 (ALDH1A1) is associated with transcription factor Gli2. Overexpression of ALDH1A1 increased Gli2 protein levels; in contrast, ALDH1A1 depletion facilitated Gli2 degradation. In addition, Gli2 mRNA expression was not affected by ectopic expression of ALDH1A1, indicating the role of ALDH1A1 in the stabilization of Gli2. Further investigation showed that ALDH1A1 prolonged the stability of Gli2 protein in a catalytic-independent manner. Finally, we showed that overexpression of ALDH1A1 activated the Hh signaling pathway and promoted cell growth, migration and invasion in hepatocellular cancer cells. Together, these results illustrate regulatory roles of ALDH1A1 in the activation of the Hh signaling pathway and highlight a novel mechanism for the aberrant activation of the Hh signaling pathway in hepatocellular cancer cells. PMID:26896768

  14. Analysis of Genetic and Environmental Risk Factors and Their Interactions in Korean Patients with Age-Related Macular Degeneration

    PubMed Central

    Morrison, Margaux A.; Ahn, So Yeon; Lee, Jaebong; Kim, Ki Woong; DeAngelis, Margaret M.; Park, Kyu Hyung

    2015-01-01

    Purpose To investigate the association of genetic and environmental factors, and their interactions in Korean patients with exudative age-related macular degeneration (AMD). Methods A total of 314 robustly characterized exudative AMD patients, including 111 PCV (polypoidal choroidal vasculopathy) and 154 typical choroidal neovascularization (CNV), and 395 control subjects without any evidence of AMD were enrolled. Full ophthalmologic examinations including fluorescein angiography (FA), indocyanine green angiography (ICG) and optical coherence tomography (OCT) were done, according to which patients were divided into either PCV or typical CNV. Standardized questionnaires were used to collect information regarding underlying systemic diseases, dietary habits, smoking history and body mass index (BMI). A total of 86 SNPs from 31 candidate genes were analyzed. Genotype association and logistic regression analyses were done and stepwise regression models to best predict disease for each AMD subtype were constructed. Results Age, spherical equivalent, myopia, and ever smoking were associated with exudative AMD. Age, hypertension, hyperlipidemia, spherical equivalent, and myopia were risk factors for typical CNV, while increased education and ever smoking were significantly associated with PCV (p<.05 for all). Four SNPs, ARMS2/HTRA1 rs10490924, rs11200638, and rs2736911, and CFH rs800292, showed association with exudative AMD. Two of these SNPs, ARMS2/HTRA1 rs10490924 and rs11200638, showed significant association with typical CNV and PCV specifically. There were no significant interactions between environmental and genetic factors. The most predictive disease model for exudative AMD included age, spherical equivalent, smoking, CFH rs800292, and ARMS2 rs10490924 while that for typical CNV included age, hyperlipidemia, spherical equivalent, and ARMS2 rs10490924. Smoking, spherical equivalent, and ARMS2 rs10490924 were the most predictive variables for PCV. When comparing PCV cases to CNV cases, age, BMI, and education were the most predictive risk factors of PCV. Conclusions Only one locus, the ARMS2/HTRA1 was a significant genetic risk factor for Korean exudative AMD, including its subtypes, PCV and typical CNV. Stepwise regression revealed that CFH was important to risk of exudative AMD in general but not to any specific subtype. While increased education was a unique risk factor to PCV when compared to CNV, this association was independent of refractive error in this homogenous population from South Korea. No significant interactions between environmental and genetic risk factors were observed. PMID:26171855

  15. Transcription factor Nr4a1 couples sympathetic and inflammatory cues in CNS-recruited macrophages to limit neuroinflammation.

    PubMed

    Shaked, Iftach; Hanna, Richard N; Shaked, Helena; Chodaczek, Grzegorz; Nowyhed, Heba N; Tweet, George; Tacke, Robert; Basat, Alp Bugra; Mikulski, Zbigniew; Togher, Susan; Miller, Jacqueline; Blatchley, Amy; Salek-Ardakani, Shahram; Darvas, Martin; Kaikkonen, Minna U; Thomas, Graham D; Lai-Wing-Sun, Sonia; Rezk, Ayman; Bar-Or, Amit; Glass, Christopher K; Bandukwala, Hozefa; Hedrick, Catherine C

    2015-12-01

    The molecular mechanisms that link the sympathetic stress response and inflammation remain obscure. Here we found that the transcription factor Nr4a1 regulated the production of norepinephrine (NE) in macrophages and thereby limited experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Lack of Nr4a1 in myeloid cells led to enhanced NE production, accelerated infiltration of leukocytes into the central nervous system (CNS) and disease exacerbation in vivo. In contrast, myeloid-specific deletion of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, protected mice against EAE. Furthermore, we found that Nr4a1 repressed autocrine NE production in macrophages by recruiting the corepressor CoREST to the Th promoter. Our data reveal a new role for macrophages in neuroinflammation and identify Nr4a1 as a key regulator of catecholamine production by macrophages. PMID:26523867

  16. Mutation Analysis of Core Binding Factor A1 in Patients with Cleidocranial Dysplasia

    PubMed Central

    Quack, I.; Vonderstrass, B.; Stock, M.; Aylsworth, A. S.; Becker, A.; Brueton, L.; Lee, P. J.; Majewski, F.; Mulliken, J. B.; Suri, M.; Zenker, M.; Mundlos, S.; Otto, F.

    1999-01-01

    Summary Cleidocranial dysplasia (CCD) is a dominantly inherited disorder characterized by patent fontanelles, wide cranial sutures, hypoplasia of clavicles, short stature, supernumerary teeth, and other skeletal anomalies. We recently demonstrated that mutations in the transcription factor CBFA1, on chromosome 6p21, are associated with CCD. We have now analyzed the CBFA1 gene in 42 unrelated patients with CCD. In 18 patients, mutations were detected in the coding region of the CBFA1 gene, including 8 frameshift, 2 nonsense, and 9 missense mutations, as well as 2 novel polymorphisms. A cluster of missense mutations at arginine 225 (R225) identifies this residue as crucial for CBFA1 function. In vitro green fluorescent protein fusion studies show that R225 mutations interfere with nuclear accumulation of CBFA1 protein. There is no phenotypic difference between patients with deletions or frameshifts and those with other intragenic mutations, suggesting that CCD is generally caused by haploinsufficiency. However, we were able to extend the CCD phenotypic spectrum. A missense mutation identified in one family with supernumerary teeth and a radiologically normal skeleton indicates that mutations in CBFA1 can be associated exclusively with a dental phenotype. In addition, one patient with severe CCD and a frameshift mutation in codon 402 had osteoporosis leading to recurrent bone fractures and scoliosis, providing first evidence that CBFA1 may help maintain adult bone, in addition to its function in bone development. PMID:10521292

  17. Regulation of UGT1A1 and HNF1 transcription factor gene expression by DNA methylation in colon cancer cells

    PubMed Central

    2010-01-01

    Background UDP-glucuronosyltransferase 1A1 (UGT1A1) is a pivotal enzyme involved in metabolism of SN-38, the active metabolite of irinotecan commonly used to treat metastatic colorectal cancer. We previously demonstrated aberrant methylation of specific CpG dinucleotides in UGT1A1-negative cells, and revealed that methylation state of the UGT1A1 5'-flanking sequence is negatively correlated with gene transcription. Interestingly, one of these CpG dinucleotides (CpG -4) is found close to a HNF1 response element (HRE), known to be involved in activation of UGT1A1 gene expression, and within an upstream stimulating factor (USF) binding site. Results Gel retardation assays revealed that methylation of CpG-4 directly affect the interaction of USF1/2 with its cognate sequence without altering the binding for HNF1-alpha. Luciferase assays sustained a role for USF1/2 and HNF1-alpha in UGT1A1 regulation in colon cancer cells. Based on the differential expression profiles of HNF1A gene in colon cell lines, we also assessed whether methylation affects its expression. In agreement with the presence of CpG islands in the HNF1A promoter, treatments of UGT1A1-negative HCT116 colon cancer cells with a DNA methyltransferase inhibitor restore HNF1A gene expression, as observed for UGT1A1. Conclusions This study reveals that basal UGT1A1 expression in colon cells is positively regulated by HNF1-alpha and USF, and negatively regulated by DNA methylation. Besides, DNA methylation of HNF1A could also play an important role in regulating additional cellular drug metabolism and transporter pathways. This process may contribute to determine local inactivation of drugs such as the anticancer agent SN-38 by glucuronidation and define tumoral response. PMID:20096102

  18. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and survival of Ly6C− monocytes

    PubMed Central

    Hanna, Richard N.; Carlin, Leo M.; Hubbeling, Harper G.; Nackiewicz, Dominika; Green, Angela M.; Punt, Jennifer A.; Geissmann, Frederic; Hedrick, Catherine C.

    2012-01-01

    Transcription factors that regulate monocyte subset differentiation in bone marrow have not yet been identified. Here we show that the orphan nuclear receptor NR4A1 controls Ly6C− monocyte differentiation. Ly6C− monocytes , which function in a surveillance role in circulation, were absent in Nr4a1−/− mice. Normal numbers of myeloid progenitor cells were present in Nr4a1−/− mice, indicating that the defect occurs during later stages of monocyte development. The defect is cell-intrinsic, as wild-type mice receiving bone marrow from Nr4a1−/− mice developed reduced numbers of patrolling monocytes. Ly6C− monocytes remaining in the bone marrow of Nr4a1−/− mice were arrested in the S phase of the cell cycle and underwent apoptosis. Thus, NR4A1 functions as a master regulator of differentiation and survival of ‘patrolling’ Ly6C− monocytes. PMID:21725321

  19. Improvement of enzymatic saccharification yield in Arabidopsis thaliana by ectopic expression of the rice SUB1A-1 transcription factor

    PubMed Central

    Núñez-López, Lizeth; Aguirre-Cruz, Andrés

    2015-01-01

    Saccharification of polysaccharides releases monosaccharides that can be used by ethanol-producing microorganisms in biofuel production. To improve plant biomass as a raw material for saccharification, factors controlling the accumulation and structure of carbohydrates must be identified. Rice SUB1A-1 is a transcription factor that represses the turnover of starch and postpones energy-consuming growth processes under submergence stress. Arabidopsis was employed to test if heterologous expression of SUB1A-1 or SUB1C-1 (a related gene) can be used to improve saccharification. Cellulolytic and amylolytic enzymatic treatments confirmed that SUB1A-1 transgenics had better saccharification yield than wild-type (Col-0), mainly from accumulated starch. This improved saccharification yield was developmentally controlled; when compared to Col-0, young transgenic vegetative plants yielded 200–300% more glucose, adult vegetative plants yielded 40–90% more glucose and plants in reproductive stage had no difference in yield. We measured photosynthetic parameters, starch granule microstructure, and transcript abundance of genes involved in starch degradation (SEX4, GWD1), juvenile transition (SPL3-5) and meristematic identity (FUL, SOC1) but found no differences to Col-0, indicating that starch accumulation may be controlled by down-regulation of CONSTANS and FLOWERING LOCUS T by SUB1A-1 as previously reported. SUB1A-1 transgenics also offered less resistance to deformation than wild-type concomitant to up-regulation of AtEXP2 expansin and BGL2 glucan-1,3,-beta-glucosidase. We conclude that heterologous SUB1A-1 expression can improve saccharification yield and softness, two traits needed in bioethanol production. PMID:25780769

  20. Improvement of enzymatic saccharification yield in Arabidopsis thaliana by ectopic expression of the rice SUB1A-1 transcription factor.

    PubMed

    Núñez-López, Lizeth; Aguirre-Cruz, Andrés; Barrera-Figueroa, Blanca Estela; Peña-Castro, Julián Mario

    2015-01-01

    Saccharification of polysaccharides releases monosaccharides that can be used by ethanol-producing microorganisms in biofuel production. To improve plant biomass as a raw material for saccharification, factors controlling the accumulation and structure of carbohydrates must be identified. Rice SUB1A-1 is a transcription factor that represses the turnover of starch and postpones energy-consuming growth processes under submergence stress. Arabidopsis was employed to test if heterologous expression of SUB1A-1 or SUB1C-1 (a related gene) can be used to improve saccharification. Cellulolytic and amylolytic enzymatic treatments confirmed that SUB1A-1 transgenics had better saccharification yield than wild-type (Col-0), mainly from accumulated starch. This improved saccharification yield was developmentally controlled; when compared to Col-0, young transgenic vegetative plants yielded 200-300% more glucose, adult vegetative plants yielded 40-90% more glucose and plants in reproductive stage had no difference in yield. We measured photosynthetic parameters, starch granule microstructure, and transcript abundance of genes involved in starch degradation (SEX4, GWD1), juvenile transition (SPL3-5) and meristematic identity (FUL, SOC1) but found no differences to Col-0, indicating that starch accumulation may be controlled by down-regulation of CONSTANS and FLOWERING LOCUS T by SUB1A-1 as previously reported. SUB1A-1 transgenics also offered less resistance to deformation than wild-type concomitant to up-regulation of AtEXP2 expansin and BGL2 glucan-1,3,-beta-glucosidase. We conclude that heterologous SUB1A-1 expression can improve saccharification yield and softness, two traits needed in bioethanol production. PMID:25780769

  1. Assessing and targeting key lifestyle cardiovascular risk factors at the workplace: Effect on hemoglobin A1c levels.

    PubMed

    Lvesque, Valrie; Poirier, Paul; Desprs, Jean-Pierre; Almras, Natalie

    2015-11-01

    Purpose Despite the key role played by lifestyle habits in the epidemic of type 2 diabetes (T2D), nutritional quality and physical activity are not systematically considered in clinical practice. The project was conducted to verify whether assessing/targeting lifestyle habits could reduce hemoglobin A1c (HbA1c) levels of employees. Methods The intervention consisted of a 3-month competition among teams of five employees to favor peer-based support in the adoption of healthier lifestyle habits (Eat better, Move more, and Quit smoking) (n?=?900). A comprehensive cardiometabolic/cardiorespiratory health assessment was conducted before and after the contest (nutrition/physical activity questionnaires, blood pressure, anthropometric measurements, lipid profile, HbA1c, fitness). HbA1c levels were used to identify individuals with prediabetes (5.7%-6.4%) or T2D (?6.5%). Results At baseline, 51% of the employees had increased HbA1c levels (?5.7%). The HbA1c levels were associated with waist circumference, independently of body mass index. Subjects with prediabetes showed a higher waist circumference as well as a more deteriorated cardiometabolic profile compared to workers with normal HbA1c levels. After the intervention, employees with elevated HbA1c significantly reduced their HbA1c levels. Conclusion Results suggest that assessing/targeting key lifestyle correlates of the cardiometabolic profile represents a relevant approach to target abdominal obesity and fitness with a significant impact on HbA1c levels. Key Messages The prevalence of employees with prediabetes or undiagnosed type 2 diabetes (T2D) was rather high in our cohort, suggesting that, from a public health standpoint, identification of those individuals is not optimal. Employees with prediabetes or T2D showed a higher waist circumference and a more deteriorated cardiometabolic risk profile compared to those with normal HbA1c levels. The significant reduction in HbA1c levels observed in response to the 3-month intervention supports the notion that a program which assesses and manages cardiometabolic risk at the workplace by also focusing on key lifestyle factors (nutritional quality and physical activity levels) represents an interesting option to reduce the risk of developing diabetes among high-risk individuals or to improve glycemic control and related cardiometabolic risk in patients with T2D. PMID:26542534

  2. Translation elongation factor eEF1A1 is a novel partner of a multifunctional protein Sgt1.

    PubMed

    Novosylna, Oleksandra; Jurewicz, Ewelina; Pydiura, Nikolay; Goral, Agnieszka; Filipek, Anna; Negrutskii, Boris; El'skaya, Anna

    2015-12-01

    Mammalian translation elongation factor eEF1A is involved in ribosomal polypeptide synthesis. Also, the protein fulfills many additional duties in an eukaryotic cell. Here, we identified a novel partner of the eEF1A1 isoform, namely Sgt1, a protein that possesses co-chaperon properties and participates in antiviral defense processes. By applying different methods, we demonstrated the interaction between eEF1A1 and Sgt1 using both purified proteins and cell lysates. We also found that the D2 and D3 domains of eEF1A1 and the TPR domain of Sgt1 are involved in complex formation. Modeling of the Sgt1-eEF1A1 complex suggested both shape and charge complementarities of the eEF1A1-Sgt1 interface stabilized by a number of salt bridges. As long as such interaction mode is typical more for protein-nucleic acid interaction we suggested a possibility that Sgt1 competes with viral RNA for binding to eEF1A and obtained in vitro evidence to this effect. PMID:26545799

  3. ASP514 within the A1 domain of bovine von Willebrand factor is required for interaction with platelet glycoprotein Ib.

    PubMed

    Sinha, D; Bakhshi, M; Kunapuli, S; Vora, R; Gabriel, J L; Kirby, E P; Budzynski, A Z

    1994-09-15

    A mutant PAD-1 (D514-->Q) of the recombinant fragment PAD-1 comprising Leu469-Ser723 of the A1 domain of bovine von Willebrand factor (vWF) neither inhibited the binding of [125I]vWF to platelets nor the agglutination of human platelets induced by bovine vWF. PAD-1, on the other hand, inhibited human platelet agglutination induced by bovine vWF and [125I]vWF binding to human platelets. Collagen binding properties of the mutant, however, were indistinguishable from those of PAD-1. These results suggested that Asp514 within the A1 domain of vWF is required for interaction of bovine vWF with GPIb receptor on human platelets. PMID:8093071

  4. DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease.

    PubMed

    Suntharalingham, Jenifer P; Buonocore, Federica; Duncan, Andrew J; Achermann, John C

    2015-08-01

    DAX-1 (NR0B1) and SF-1 (NR5A1) are two nuclear receptor transcription factors that play a key role in human adrenal and reproductive development. Loss of DAX-1 function is classically associated with X-linked adrenal hypoplasia congenita. This condition typically affects boys and presents as primary adrenal insufficiency in early infancy or childhood, hypogonadotropic hypogonadism at puberty and impaired spermatogenesis. Late onset forms of this condition and variant phenotypes are increasingly recognized. In contrast, disruption of SF-1 only rarely causes adrenal insufficiency, usually in combination with testicular dysgenesis. Variants in SF-1/NR5A1 more commonly cause a spectrum of reproductive phenotypes ranging from 46,XY DSD (partial testicular dysgenesis or reduced androgen production) and hypospadias to male factor infertility or primary ovarian insufficiency. Making a specific diagnosis of DAX-1 or SF-1 associated conditions is important for long-term monitoring of endocrine and reproductive function, appropriate genetic counselling for family members, and for providing appropriate informed support for young people. PMID:26303087

  5. The translation elongation factor eEF1A1 couples transcription to translation during heat shock response

    PubMed Central

    Vera, Maria; Pani, Bibhusita; Griffiths, Lowri A; Muchardt, Christian; Abbott, Catherine M; Singer, Robert H; Nudler, Evgeny

    2014-01-01

    Translation elongation factor eEF1A has a well-defined role in protein synthesis. In this study, we demonstrate a new role for eEF1A: it participates in the entire process of the heat shock response (HSR) in mammalian cells from transcription through translation. Upon stress, isoform 1 of eEF1A rapidly activates transcription of HSP70 by recruiting the master regulator HSF1 to its promoter. eEF1A1 then associates with elongating RNA polymerase II and the 3?UTR of HSP70 mRNA, stabilizing it and facilitating its transport from the nucleus to active ribosomes. eEF1A1-depleted cells exhibit severely impaired HSR and compromised thermotolerance. In contrast, tissue-specific isoform 2 of eEF1A does not support HSR. By adjusting transcriptional yield to translational needs, eEF1A1 renders HSR rapid, robust, and highly selective; thus, representing an attractive therapeutic target for numerous conditions associated with disrupted protein homeostasis, ranging from neurodegeneration to cancer. DOI: http://dx.doi.org/10.7554/eLife.03164.001 PMID:25233275

  6. Genetic and Epigenetic Factors at COL2A1 and ABCA4 Influence Clinical Outcome in Congenital Toxoplasmosis

    PubMed Central

    Jamieson, Sarra E.; de Roubaix, Lee-Anne; Cortina-Borja, Mario; Tan, Hooi Kuan; Mui, Ernest J.; Cordell, Heather J.; Kirisits, Michael J.; Miller, E. Nancy; Peacock, Christopher S.; Hargrave, Aubrey C.; Coyne, Jessica J.; Boyer, Kenneth; Bessieres, Marie-Hélène; Buffolano, Wilma; Ferret, Nicole; Franck, Jacqueline; Kieffer, François; Meier, Paul; Nowakowska, Dorota E.; Paul, Malgorzata; Peyron, François; Stray-Pedersen, Babill; Prusa, Andrea-Romana; Thulliez, Philippe; Wallon, Martine; Petersen, Eskild; McLeod, Rima; Gilbert, Ruth E.; Blackwell, Jenefer M.

    2008-01-01

    Background Primary Toxoplasma gondii infection during pregnancy can be transmitted to the fetus. At birth, infected infants may have intracranial calcification, hydrocephalus, and retinochoroiditis, and new ocular lesions can occur at any age after birth. Not all children who acquire infection in utero develop these clinical signs of disease. Whilst severity of disease is influenced by trimester in which infection is acquired by the mother, other factors including genetic predisposition may contribute. Methods and Findings In 457 mother-child pairs from Europe, and 149 child/parent trios from North America, we show that ocular and brain disease in congenital toxoplasmosis associate with polymorphisms in ABCA4 encoding ATP-binding cassette transporter, subfamily A, member 4. Polymorphisms at COL2A1 encoding type II collagen associate only with ocular disease. Both loci showed unusual inheritance patterns for the disease allele when comparing outcomes in heterozygous affected children with outcomes in affected children of heterozygous mothers. Modeling suggested either an effect of mother's genotype, or parent-of-origin effects. Experimental studies showed that both ABCA4 and COL2A1 show isoform-specific epigenetic modifications consistent with imprinting. Conclusions These associations between clinical outcomes of congenital toxoplasmosis and polymorphisms at ABCA4 and COL2A1 provide novel insight into the molecular pathways that can be affected by congenital infection with this parasite. PMID:18523590

  7. Role of DAX-1 (NR0B1) and steroidogenic factor-1 (NR5A1) in human adrenal function.

    PubMed

    El-Khairi, Ranna; Martinez-Aguayo, Alejandro; Ferraz-de-Souza, Bruno; Lin, Lin; Achermann, John C

    2011-01-01

    The nuclear receptor transcription factors DAX-1 (NR0B1) and SF-1 (NR5A1) regulate many aspects of adrenal and reproductive development and function. Disruption of the genes encoding these factors can be associated with pediatric adrenal disease. DAX-1 mutations are classically associated with X-linked adrenal hypoplasia congenita, hypogonadotropic hypogonadism and impaired spermatogenesis. However, other phenotypes are also being reported, such as isolated mineralocorticoid insufficiency, premature sexual development, primary adrenal insufficiency in a 46, XX patient and late-onset X-linked adrenal hypoplasia congenita and/or hypogonadotropic hypogonadism. SF-1 mutations have also been associated with primary adrenal insufficiency, together with 46, XY disorders of sex development. However it is emerging that SF-1 changes are a relatively rare cause of primary adrenal failure in humans, and most individuals with SF-1 mutations have a spectrum of 46, XY disorders of sex development phenotypes. These conditions range from 46, XY females with streak gonads and müllerian structures, through children with ambiguous genitalia and inguinal testes, to severe penoscrotal hypospadias with undescended testes. Therefore, the human gonad appears to be more sensitive than the adrenal gland to loss of SF-1 function. This review will focus on the expanding range of phenotypes associated with DAX-1 and SF-1 mutations. PMID:21164257

  8. Steroidogenic Factor 1 (NR5A1) resides in centrosomes and maintains genomic stability by controlling centrosome homeostasis.

    PubMed

    Lai, P-Y; Wang, C-Y; Chen, W-Y; Kao, Y-H; Tsai, H-M; Tachibana, T; Chang, W-C; Chung, B-c

    2011-12-01

    SF-1 (Steroidogenic Factor 1, NR5A1) is a tissue-specific transcription factor critical for the growth, development and differentiation of steroidogenic and a few other endocrine tissues. But how SF-1 regulates cell growth is not entirely clear. Here we found that SF-1 was localized to the centrosome in addition to the nucleus, and SF-1 depletion by shRNA caused centrosome over-duplication, aberrant mitosis and genomic instability, leading to a reduction of cell number. Centrosome amplification defect was rescued by both wild-type SF-1 and transcription-defective SF-1-G35E, suggesting a non-genomic activity of SF-1 involved in centrosome homeostasis. In addition, we identified in SF-1 a centrosome localization signal, whose overexpression led to reduced localization of both SF-1 and γ-tubulin to the centrosome. Our results uncover a novel role of SF-1 in the control of centrosome homeostasis and genomic stability. PMID:21566663

  9. Steroidogenic Factor 1 (NR5A1) resides in centrosomes and maintains genomic stability by controlling centrosome homeostasis

    PubMed Central

    Lai, P-Y; Wang, C-Y; Chen, W-Y; Kao, Y-H; Tsai, H-M; Tachibana, T; Chang, W-C; Chung, B-c

    2011-01-01

    SF-1 (Steroidogenic Factor 1, NR5A1) is a tissue-specific transcription factor critical for the growth, development and differentiation of steroidogenic and a few other endocrine tissues. But how SF-1 regulates cell growth is not entirely clear. Here we found that SF-1 was localized to the centrosome in addition to the nucleus, and SF-1 depletion by shRNA caused centrosome over-duplication, aberrant mitosis and genomic instability, leading to a reduction of cell number. Centrosome amplification defect was rescued by both wild-type SF-1 and transcription-defective SF-1-G35E, suggesting a non-genomic activity of SF-1 involved in centrosome homeostasis. In addition, we identified in SF-1 a centrosome localization signal, whose overexpression led to reduced localization of both SF-1 and γ-tubulin to the centrosome. Our results uncover a novel role of SF-1 in the control of centrosome homeostasis and genomic stability. PMID:21566663

  10. Melatonin induces class A1 heat-shock factors (HSFA1s) and their possible involvement of thermotolerance in Arabidopsis.

    PubMed

    Shi, Haitao; Tan, Dun-Xian; Reiter, Russel J; Ye, Tiantian; Yang, Fan; Chan, Zhulong

    2015-04-01

    Melatonin (N-acetyl-5-methoxytryptamine) serves as an important signal molecule during plant developmental processes and multiple abiotic stress responses. However, the involvement of melatonin in thermotolerance and the underlying molecular mechanism in Arabidopsis were largely unknown. In this study, we found that the endogenous melatonin level in Arabidopsis leaves was significantly induced by heat stress treatment, and exogenous melatonin treatment conferred improved thermotolerance in Arabidopsis. The transcript levels of class A1 heat-shock factors (HSFA1s), which serve as the master regulators of heat stress responses, were significantly upregulated by heat stress and exogenous melatonin treatment in Arabidopsis. Notably, exogenous melatonin-enhanced thermotolerance was largely alleviated in HSFA1s quadruple knockout (QK) mutants, and HSFA1s-activated transcripts of heat-responsive genes (HSFA2, heat stress-associated 32 (HSA32), heat-shock protein 90 (HSP90), and 101 (HSP101)) might be contributed to melatonin-mediated thermotolerance. Taken together, this study provided direct link between melatonin and thermotolerance and indicated the involvement of HSFA1s-activated heat-responsive genes in melatonin-mediated thermotolerance in Arabidopsis. PMID:25711624

  11. Pediatric diabetes consortium type 1 diabetes new onset (NeOn) study: Factors associated with HbA1c levels one year after diagnosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To identify determinants of hemoglobin A1c (HbA1c) levels 1 yr after the diagnosis of type 1 diabetes (T1D) in participants in the Pediatric Diabetes Consortium (PDC) T1D New Onset (NeOn) Study. Diabetes-specific as well as socioeconomic factors during the first year following diagnosis were analyze...

  12. Sulfotransferase (SULT) 1A1 polymorphism as a predisposition factor for lung cancer: a case-control analysis.

    PubMed

    Wang, Yunfei; Spitz, Margaret R; Tsou, Amy Meng-Hsuan; Zhang, Kerang; Makan, Nimisha; Wu, Xifeng

    2002-02-01

    SULT1A1 enzyme is a member of the sulfotransferase family that alters biological activities of numerous carcinogenic and mutagenic compounds through sulfation. A genetic polymorphism in the coding region of SULT1A1 gene has been associated with modulated enzyme activity. There is a G-->A nucleotide polymorphism in SULT1A1 gene that codes for an Arg-->His substitution, which results in decreased activity and thermal stability of the SULT1A1 enzyme. Utilizing a case-control study design, we hypothesized that the variant allele of the SULT1A1 gene may be associated with lung cancer risk. The PCR-RFLP assay was used to successfully genotype the SULT1A1*2 allele (variant A-allele) in 463 Caucasian lung cancer cases and 485 frequency matched Caucasian controls. There was an overall significant difference between cases and controls when adjusted by sex and smoking status (adjusted OR=1.41, 95% CI: 1.04-1.91). The adjusted OR was higher for females (OR=1.64, 95% CI: 1.06-2.56) than for males (OR=1.23, 95% CI: 0.80-1.88). Furthermore, the risk was significantly higher in current smokers (OR=1.74, 95% CI: 1.08-2.29) and heavy smokers (OR=1.45, 95% CI: 1.05-2.00). Our results support the hypothesis that a genetic polymorphism in the SULT1A1 gene may be associated with increased lung cancer risk. PMID:11804685

  13. Analysis of Slovak Spotted breed for bovine beta casein A1 variant as risk factor for human health.

    PubMed

    Miluchov, Martina; Gbor, Michal; Trakovick, Anna

    2013-01-01

    The goal of work was identification A1 variant of bovine beta casein which involves ischemic heart disease and diabetes mellitus in human. The digestion of A1beta casein can result in the production of bioactive beta casomorphin-7 (BCM-7); this is not the case with A2. This bioactive peptide has been linked to physiological traits that may elicit effects on components of the vascular and immune systems. The material involved 111 Slovak Spotted breed. Bovine genomic DNA was extracted from whole blood by using commercial kit, and used in order to estimate beta-casein genotypes by means of PCR-RFLP method. The PCR products were digested with DdeI restriction enzyme. In the population included in the study were detected all three genotypes, homozygote genotype A1A1 (14 animals), heterozygote genotype A1A2 (37 animals) and homozygote genotype A2A2 (60 animals). In the total population of cattle homozygotes A2A2-0.5405 were the most frequent, while homozygotes A1A1-0.1261 were the least frequent ones. This suggests a superiority of allele A2 (0.7072) which does not produce BCM-7, and thus is safe for human consumption. The expected homozygosity for gene CSN2 is in the population stated a slight increase in homozygosity (0.5858). This caused a slight decrease in the level of possible variability realization (41.80%), which corresponds to the effective number of alleles (1.7071). PMID:24432335

  14. A molten globule intermediate of the Von Willebrand Factor A1 domain firmly tethers platelets under shear flow

    PubMed Central

    Tischer, Alexander; Madde, Pranathi; Blancas-Mejia, Luis. M.; Auton, Matthew

    2014-01-01

    Clinical mutations in patients diagnosed with Type 2A von Willebrand disease (vWD) have been identified that break the single disulfide bond linking N- and C-termini in the vWF A1 domain. We have modeled the effect of these mutations on the disulfide-bonded structure of A1 by reducing and carboxy-amidating these cysteines. Solution biophysical studies show that loss of this disulfide bond induces a molten globule conformational state lacking global tertiary structure but retaining residual secondary structure. The conformational dependence of platelet adhesion to these native and molten globule states of A1 is quantitatively compared using real-time high-speed video microscopy analysis of platelet translocation dynamics under shear flow in a parallel plate micro-fluidic flow chamber. While normal platelets translocating on surface-captured native A1 domain retain the catch-bond character of pause times that increase as a function of shear rate at low shear and decrease as a function of shear rate at high shear, platelets that interact with A1 lacking the disulfide bond remain stably attached and do not translocate. Based on these findings, we propose that the shear stress-sensitive regulation of the A1-GPIb interaction is due to folding the tertiary structure of this domain. Removal of the tertiary structure by disrupting the disulfide bond destroys this regulatory mechanism resulting in high-strength interactions between platelets and vWF A1 that are dependent only on residual secondary structure elements present in the molten globule conformation. PMID:24265179

  15. Apobec-1 Complementation Factor (A1CF) Inhibits Epithelial-Mesenchymal Transition and Migration of Normal Rat Kidney Proximal Tubular Epithelial Cells

    PubMed Central

    Huang, Liyuan; Wang, Honglian; Zhou, Yuru; Ni, Dongsheng; Hu, Yanxia; Long, Yaoshui; Liu, Jianing; Peng, Rui; Zhou, Li; Liu, Zhicheng; Lyu, Zhongshi; Mao, Zhaomin; Hao, Jin; Li, Yiman; Zhou, Qin

    2016-01-01

    Apobec-1 complementation factor (A1CF) is a member of the heterogeneous nuclear ribonucleoproteins (hnRNP) family, which participates in site-specific posttranscriptional RNA editing of apolipoprotein B (apoB) transcript. The posttranscriptional editing of apoB mRNA by A1CF in the small intestine is required for lipid absorption. Apart from the intestine, A1CF mRNA is also reported to be highly expressed in the kidneys. However, it is remained unknown about the functions of A1CF in the kidneys. The aim of this paper is to explore the potential functions of A1CF in the kidneys. Our results demonstrated that in C57BL/6 mice A1CF was weakly expressed in embryonic kidneys from E15.5dpc while strongly expressed in mature kidneys after birth, and it mainly existed in the tubules of inner cortex. More importantly, we identified A1CF negatively regulated the process of epithelial-mesenchymal transition (EMT) in kidney tubular epithelial cells. Our results found ectopic expression of A1CF up-regulated the epithelial markers E-cadherin, and down-regulated the mesenchymal markers vimentin and α-smooth muscle actin (α-SMA) in NRK52e cells. In addition, knockdown of A1CF enhanced EMT contrary to the overexpression effect. Notably, the two A1CF variants led to the similar trend in the EMT process. Taken together, these data suggest that A1CF may be an antagonistic factor to the EMT process of kidney tubular epithelial cells. PMID:26848653

  16. Individual, physical and psychological risk factors for neck pain in Australian office workers: a 1-year longitudinal study

    PubMed Central

    Michaleff, Zoe; Maher, Christopher G.; Refshauge, Kathryn

    2009-01-01

    Neck pain is more prevalent in office workers than in the general community. To date, findings from prospective studies that investigated causal relationships between putative risk factors and the onset of neck pain in this population have been limited by high loss to follow-up. The aim of this research was to prospectively evaluate a range of risk factors for neck pain in office workers, using validated and reliable objective measures as well as attain an estimate of 1-year incidence. We assembled a cohort of 53 office workers without neck pain and measured individual, physical, workplace and psychological factors at baseline. We followed participants for 1 year to measure the incidence of neck pain. We achieved 100% participant follow-up. Cox regression analysis was applied to examine the relationship between the putative risk factors and the cumulative incidence of neck pain. The 1-year incidence proportion of neck pain in Australian office workers was estimated in this study to be 0.49 (95% CI 0.36–0.62). Predictors of neck pain with moderate to large effect sizes were female gender (HR: 3.07; 95% CI: 1.18–7.99) and high psychological stress (HR: 1.64; 95% CI: 0.66–4.07). Protective factors included increased mobility of the cervical spine (HR: 0.44; 95% CI: 0.19–1.05) and frequent exercise (HR: 0.64; 95% CI: 0.27–1.51). These results reveal that neck pain is common in Australian office workers and that there are risk factors that are potentially modifiable. PMID:19399537

  17. Anharmonic Franck-Condon Factors for the X̃(2)B1 ← X̃(1)A1 Photoionization of Ketene.

    PubMed

    Rauhut, Guntram

    2015-10-15

    The X̃(2)B1 ← X̃(1)A1 photoelectron spectra of ketene and its doubly deuterated isotopologue have been computed from correlated vibrational wave functions as determined from vibrational configuration interaction theory relying on multidimensional Born-Oppenheimer potential energy surfaces being obtained from explicitly correlated coupled-cluster calculations. Duschinsky effects were accounted for in all cases. Excellent agreement with available experimental data was achieved. PMID:26418552

  18. The Histone Variant MacroH2A1.2 Is Necessary for the Activation of Muscle Enhancers and Recruitment of the Transcription Factor Pbx1.

    PubMed

    Dell'Orso, Stefania; Wang, A Hongjun; Shih, Han-Yu; Saso, Kayoko; Berghella, Libera; Gutierrez-Cruz, Gustavo; Ladurner, Andreas G; O'Shea, John J; Sartorelli, Vittorio; Zare, Hossein

    2016-02-01

    Histone variants complement and integrate histone post-translational modifications in regulating transcription. The histone variant macroH2A1 (mH2A1) is almost three times the size of its canonical H2A counterpart, due to the presence of an ?25kDa evolutionarily conserved non-histone macro domain. Strikingly, mH2A1 can mediate both gene repression and activation. However, the molecular determinants conferring these alternative functions remain elusive. Here, we report that mH2A1.2 is required for the activation of the myogenic gene regulatory network and muscle cell differentiation. H3K27 acetylation at prospective enhancers is exquisitely sensitive to mH2A1.2, indicating a role of mH2A1.2 in imparting enhancer activation. Both H3K27 acetylation and recruitment of the transcription factor Pbx1 at prospective enhancers are regulated by mH2A1.2. Overall, our findings indicate a role of mH2A1.2 in marking regulatory regions for activation. PMID:26832413

  19. The Histone Variant MacroH2A1.2 is Necessary for the Activation of Muscle Enhancers and Recruitment of the Transcription Factor Pbx1

    PubMed Central

    Dell’Orso, Stefania; Wang, A. Hongjun; Shih, Han-Yu; Saso, Kayoko; Berghella, Libera; Gutierrez-Cruz, Gustavo; Ladurner, Andreas G.; O’Shea, John J.; Sartorelli, Vittorio; Zare, Hossein

    2016-01-01

    SUMMARY Histone variants complement and integrate histone post-translational modifications in regulating transcription. The histone variant macroH2A1 (mH2A1) is almost three times the size of its canonical H2A counterpart due to the presence of a ~25kDa evolutionarily conserved non-histone macro domain. Strikingly, mH2A1 can mediate both gene repression and activation. However, the molecular determinants conferring these alternative functions remain elusive. Here, we report that mH2A1.2 is required for the activation of the myogenic gene regulatory network and muscle cell differentiation. H3K27 acetylation at prospective enhancers is exquisitely sensitive to mH2A1.2, indicating a role of mH2A1.2 in imparting enhancer activation. Both H3K27 acetylation and recruitment of the transcription factor Pbx1 at prospective enhancers are regulated by mH2A1.2. Overall, our findings indicate a role of mH2A1.2 in marking regulatory regions for activation. PMID:26832413

  20. Common Variation at 1q24.1 (ALDH9A1) Is a Potential Risk Factor for Renal Cancer

    PubMed Central

    Henrion, Marc Y. R.; Purdue, Mark P.; Scelo, Ghislaine; Broderick, Peter; Frampton, Matthew; Ritchie, Alastair; Meade, Angela; Li, Peng; McKay, James; Johansson, Mattias; Lathrop, Mark; Larkin, James; Rothman, Nathaniel; Wang, Zhaoming; Chow, Wong-Ho; Stevens, Victoria L.; Diver, W. Ryan; Albanes, Demetrius; Virtamo, Jarmo; Brennan, Paul; Eisen, Timothy; Chanock, Stephen; Houlston, Richard S.

    2015-01-01

    So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (Pcombined =2.30x10-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; Pcombined =2.73x10-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation. PMID:25826619

  1. Factor Analysis of Changes in Hemoglobin A1c After 12 Months of Sitagliptin Therapy in Patients With Type 2 Diabetes

    PubMed Central

    Yuasa, Shouhei; Sato, Kazuyoshi; Takai, Masahiko; Ishikawa, Masashi; Umezawa, Shinichi; Kubota, Akira; Maeda, Hajime; Kanamori, Akira; Miyakawa, Masaaki; Tanaka, Yasushi; Terauchi, Yasuo; Matsuba, Ikuro

    2016-01-01

    Background Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is an effective oral antidiabetic agent as both monotherapy and when combined with insulin. Data from three observational studies performed in patients with type 2 diabetes receiving sitagliptin therapy in the routine clinical setting were integrated to conduct factor analysis of the changes in hemoglobin A1c (HbA1c), body weight, and estimated glomerular filtration rate (eGFR) over 12 months. Methods Among patients with type 2 diabetes attending medical institutions affiliated with Kanagawa Physicians Association, those using sitagliptin were followed for 1 year. In the ASSET-K and ASSIST-K studies, patients were managed by diabetologists, while they were managed by non-diabetologists in the ATTEST-K study. Patients were not administered insulin in ASSET-K, whereas insulin was administered in ASSIST-K. HbA1c (National Glycohemoglobin Standardization Program), blood glucose (fasting/postprandial), body weight, and renal function (serum creatinine and eGFR) were the efficacy endpoints. Factor analysis was performed by analysis of variance using the magnitude of the change in HbA1c, body weight, and eGFR after 12 months of sitagliptin therapy as response variables, and the study, sex, and age as explanatory variables. Results Of 1,327 patients registered in ASSET-K (diabetologists/without insulin), 1,167 patients in ASSIST-K (diabetologists/with insulin), and 530 patients in ATTEST-K (non-diabetologists), statistical analysis was carried out on 1,074, 854, and 411 patients, respectively. There were significant inter-study differences in patient characteristics (complications, duration of diabetes, and baseline HbA1c), the sitagliptin dose, and the use of other antidiabetic agents. HbA1c decreased significantly in all three studies. According to factor analysis, the magnitude of the change in HbA1c over 12 months showed significant inter-study differences and was also significantly influenced by the age, duration of diabetes, and baseline HbA1c. Conclusions Comparison of three observational studies identified differences in patient characteristics, treatment of diabetes (use/non-use of insulin), and the level of specialist care (diabetologist/non-diabetologist). Despite such differences, consistent reduction of HbA1c by sitagliptin was demonstrated in all three studies. The patients showing most improvement in HbA1c with sitagliptin therapy were older patients with a short duration of diabetes and high baseline HbA1c level. PMID:27222674

  2. Risk and protective factors for peer victimization: a 1-year follow-up study of urban American students.

    PubMed

    Karlsson, Elisabeth; Stickley, Andrew; Lindblad, Frank; Schwab-Stone, Mary; Ruchkin, Vladislav

    2014-09-01

    This study examined whether internalizing problems, parental warmth and teacher support were associated with adolescents' experience of future peer victimization in school. Data were drawn from two rounds of the longitudinal Social and Health Assessment (SAHA). Study subjects comprised 593 US urban adolescents (aged 13.8 ± 0.8 years; 56 % female). Results showed that there was a substantial degree of continuity in peer victimization over a 1-year period. The presence of internalizing (anxiety, depressive and somatic) symptoms at baseline was associated with an increased risk of peer victimization over time. Both parental warmth and teacher support were uniquely associated with a lower risk for peer victimization. Implications of these findings for prevention efforts are discussed. PMID:24346176

  3. Targets of the StBEL5 Transcription Factor Include the FT Ortholog StSP6A1[OPEN

    PubMed Central

    Lin, Tian

    2016-01-01

    The BEL1-like family of transcription factors is ubiquitous in plants and plays important roles in regulating development. They function in tandem with KNOTTED1 types to bind to a double TTGAC motif in the upstream sequence of target genes. StBEL5 of potato (Solanum tuberosum) functions as a mobile RNA signal that is transcribed in leaves, moves down into stolons in response to short days, and induces tuber formation. Despite their importance, however, very little is known about the targets of BEL1-like transcription factors. To better understand this network, we made use of a phloem-mobile BEL5 induction model, an ethanol-inducible system coupled with RNA sequencing analysis, and a screen for tandem TTGAC cis-elements in the upstream sequence to catalog StBEL5 target genes. Induction of StBEL5 activated several genes that are also induced by StSP6A (S. tuberosum SELF-PRUNING 6A), a FLOWERING LOCUS T coregulator that functions as a signal for tuberization. Both enhancement and suppression of StBEL5 expression were also closely linked to StSP6A transcriptional activity. Site mutagenesis in tandem TTGAC motifs located in the upstream sequence of StSP6A suppressed the short day-induced activity of its promoter in both young tubers and leaves. The expression profile of StBEL5 induced in stolons from plants grown under long-day conditions revealed almost 10,000 differentially expressed genes, including important tuber marker genes and genes involved in cell growth, transcription, floral development, and hormone metabolism. In a random screen of 200 differentially expressed targets of StBEL5, 92% contained tandem TTGAC motifs in the upstream sequence within 3 kb of the transcription start site. PMID:26553650

  4. The N-terminal flanking region of the A1 domain regulates the force-dependent binding of von Willebrand factor to platelet glycoprotein Ibα.

    PubMed

    Ju, Lining; Dong, Jing-fei; Cruz, Miguel A; Zhu, Cheng

    2013-11-01

    Binding of platelet glycoprotein Ibα (GPIbα) to von Willebrand factor (VWF) initiates platelet adhesion to disrupted vascular surface under arterial blood flow. Flow exerts forces on the platelet that are transmitted to VWF-GPIbα bonds, which regulate their dissociation. Mutations in VWF and/or GPIbα may alter the mechanical regulation of platelet adhesion to cause hemostatic defects as found in patients with von Willebrand disease (VWD). Using a biomembrane force probe, we observed biphasic force-decelerated (catch) and force-accelerated (slip) dissociation of GPIbα from VWF. The VWF A1 domain that contains the N-terminal flanking sequence Gln(1238)-Glu(1260) (1238-A1) formed triphasic slip-catch-slip bonds with GPIbα. By comparison, using a short form of A1 that deletes this sequence (1261-A1) abolished the catch bond, destabilizing its binding to GPIbα at high forces. Importantly, shear-dependent platelet rolling velocities on these VWF ligands in a flow chamber system mirrored the force-dependent single-bond lifetimes. Adding the Gln(1238)-Glu(1260) peptide, which interacted with GPIbα and 1261-A1 but not 1238-A1, to whole blood decreased platelet attachment under shear stress. Soluble Gln(1238)-Glu(1260) reduced the lifetimes of GPIbα bonds with VWF and 1238-A1 but rescued the catch bond of GPIbα with 1261-A1. A type 2B VWD 1238-A1 mutation eliminated the catch bond by prolonging lifetimes at low forces, a type 2M VWD 1238-A1 mutation shifted the respective slip-catch and catch-slip transition points to higher forces, whereas a platelet type VWD GPIbα mutation enhanced the bond lifetime in the entire force regime. These data reveal the structural determinants of VWF activation by hemodynamic force of the circulation. PMID:24062306

  5. Apparently Normal Ovarian Differentiation in a Prepubertal Girl with Transcriptionally Inactive Steroidogenic Factor 1 (NR5A1/SF-1) and Adrenocortical Insufficiency

    PubMed Central

    Biason-Lauber, Anna; Schoenle, Eugen J.

    2000-01-01

    Steroidogenic factor 1 (NR5A1/SF-1) plays an essential role in the development of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, controlling expression of their many important genes. The recent description of a 46,XY patient bearing a mutation in the NR5A1 gene, causing male pseudohermaphroditism and adrenal failure, demonstrated the crucial role of SF-1 in male gonadal differentiation. The role of SF-1 in human ovarian development was, until now, unknown. We describe a phenotypically and genotypically normal girl, with signs and symptoms of adrenal insufficiency and no apparent defect in ovarian maturation, bearing a heterozygote G→T transversion in exon 4 of the NR5A1 gene that leads to the missense R255L in the SF-1 protein. The exchange does not interfere with protein translation and stability. Consistent with the clinical picture, R255L is transcriptionally inactive and has no dominant-negative activity. The inability of the mutant (MUT) NR5A1/SF-1 to bind canonical DNA sequences might offer a possible explanation for the failure of the mutant protein to transactivate target genes. This is the first report of a mutation in the NR5A1 gene in a genotypically female patient, and it suggests that NR5A1/SF-1 is not necessary for female gonadal development, confirming the crucial role of NR5A1/SF-1 in adrenal gland formation in both sexes. PMID:11038323

  6. Are the Same Clinical Risk Factors Relevant for Incident Diabetes Defined by Treatment, Fasting Plasma Glucose, and HbA1c?

    PubMed Central

    Balkau, Beverley; Soulimane, Soraya; Lange, Céline; Gautier, Alain; Tichet, Jean; Vol, Sylviane

    2011-01-01

    OBJECTIVE To compare incidences and risk factors for diabetes using seven definitions, with combinations of pharmacological treatment, fasting plasma glucose (FPG) ≥7.0 mmol/L, and HbA1c ≥6.5%. RESEARCH DESIGN AND METHODS Participants aged 30–65 years from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) cohort were followed for 9 years. RESULTS More men had incident diabetes as defined by FPG ≥7.0 mmol/L and/or treatment than by HbA1c ≥6.5% and/or treatment: 7.5% (140/1,867) and 5.3% (99/1,874), respectively (P < 0.009); for women incidences were similar: 3.2% (63/1,958) and 3.4% (66/1,954). Known risk factors predicted diabetes for almost all definitions. Among those with incident diabetes by FPG alone versus HbA1c alone, there were more men (78 vs. 35%), case patients were 8 years younger, and fewer were alcohol abstainers (12 vs. 35%) (all P < 0.005). A diabetes risk score discriminated well between those with and without incident diabetes for all definitions. CONCLUSIONS In men, FPG definitions yielded more incident cases of diabetes than HbA1c definitions, in contrast with women. An FPG-derived risk score remained relevant for HbA1c-defined diabetes. PMID:21346181

  7. Working Memory Deficit as a Risk Factor for Severe Apathy in Schizophrenia: A 1-Year Longitudinal Study.

    PubMed

    Raffard, Stéphane; Gutierrez, Laure-Anne; Yazbek, Hanan; Larue, Aurore; Boulenger, Jean-Philippe; Lançon, Christophe; Benoit, Michel; Faget, Catherine; Norton, Joanna; Capdevielle, Delphine

    2016-05-01

    Apathy, described as impaired motivation and goal-directed behavior, is a common yet often overlooked multidimensional psychopathological state in schizophrenia. Its underlying cognitive processes remain largely unexplored. Data was drawn from a longitudinal hospital study of patients with a DSM-IV diagnosis of schizophrenia; 137 (82.5%) participated at the 1-month follow-up and 81 (59.1%) at the 1-year follow-up. Apathy was assessed with the Lille Apathy Rating Scale, validated in French and in schizophrenia. Severe apathy, overall (total score > -13) and on 4 previously identified distinct dimensions, was considered. Episodic verbal learning was assessed with the California Verbal Learning Test, executive functioning with the Trail Making Test, the Six Element Test and the Stop Signal Paradigm and working memory with the Letter-Number Sequencing Test. After controlling for confounding variables, only episodic verbal learning was associated with severe overall apathy in the cross-sectional study. At 1 year, working memory was associated with an increased risk of severe overall apathy, adjusting for baseline apathy. Using a dimensional approach to apathy, specific types of cognition were found to be associated with specific dimensions of apathy. Our findings confirm the need for a multidimensional approach of negative symptoms in schizophrenia. Moreover, cognitive functioning could be a risk factor for developing severe apathy. Cognitive remediation may thus be a useful non-pharmacological intervention for treating apathy in schizophrenia patients. PMID:26834026

  8. Factors Influencing Changes in Hemoglobin A1c and Body Weight During Treatment of Type 2 Diabetes With Ipragliflozin: Interim Analysis of the ASSIGN-K Study

    PubMed Central

    Iemitsu, Kotaro; Iizuka, Takashi; Takihata, Masahiro; Takai, Masahiko; Nakajima, Shigeru; Minami, Nobuaki; Umezawa, Shinichi; Kanamori, Akira; Takeda, Hiroshi; Kawata, Takehiro; Ito, Shogo; Kikuchi, Taisuke; Amemiya, Hikaru; Kaneshiro, Mizuki; Mokubo, Atsuko; Takuma, Tetsuro; Machimura, Hideo; Tanaka, Keiji; Asakura, Taro; Kubota, Akira; Aoyagi, Sachio; Hoshino, Kazuhiko; Ishikawa, Masashi; Obana, Mitsuo; Sasai, Nobuo; Kaneshige, Hideaki; Miyakawa, Masaaki; Tanaka, Yasushi; Terauchi, Yasuo; Matsuba, Ikuro

    2016-01-01

    Background Ipragliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor that blocks glucose reabsorption in the proximal tubules. SGLT2 inhibitors are expected to be effective in patients with insulin resistance and obesity, but it is important to select treatment according to patient background factors that minimizes the risk of adverse events. There have been a limited number of investigations into the relationship between the clinical efficacy (reducing hemoglobin A1c (HbA1c) and body weight (BW)) or safety of SGLT2 inhibitors and patient characteristics. Methods ASSIGN-K is an investigator-initiated, multicenter, prospective observational study examining the efficacy and safety of ipragliflozin (50 - 100 mg/day for 52 weeks) in Japanese patients with type 2 diabetes mellitus (T2DM) who had inadequate glycemic control with HbA1c ≥ 6.0% (National Glycohemoglobin Standardization Program) despite diet and exercise therapy or diet and exercise plus antidiabetic drug therapy. We conducted an interim analysis of the relationship between changes in HbA1c or BW and characteristics in patients who had been on treatment for more than 12 weeks. Results In 257 patients completing 12 weeks of treatment, HbA1c decreased significantly from 8.23% to 7.55% (-0.68%, P < 0.01). The change in HbA1c after 12 weeks was -0.17%, -0.33%, and -1.16% when baseline HbA1c was < 7%, 7% to < 8%, and ≥ 8%, respectively (P < 0.05, P < 0.01, and P < 0.01, respectively), and -1.30%, -0.62%, and -0.62% when baseline body mass index (BMI) was < 25, 25 to < 30, and ≥ 30, respectively (all P < 0.01). Stratified analysis showed that age, gender, or BMI did not have a significant influence on the improvement in HbA1c. Multiple regression analysis showed that reduction in HbA1c was greater as baseline HbA1c increased and the duration of diabetes decreased. A higher baseline HbA1c was associated with less weight loss. Conclusions Ipragliflozin significantly improved HbA1c in patients with T2DM. HbA1c improved more when baseline HbA1c was higher and the duration of diabetes was shorter, suggesting that current treatment policies for diabetes could be re-examined. PMID:27081422

  9. CagA, a major virulence factor of Helicobacter pylori, promotes the production and underglycosylation of IgA1 in DAKIKI cells

    SciTech Connect

    Yang, Man; Li, Fu-gang; Xie, Xi-sheng; Wang, Shao-qing; Fan, Jun-ming

    2014-02-07

    Highlights: • CagA stimulated cell proliferation and the production of IgA1 in DAKIKI cells. • CagA promoted the underglycosylation of IgA1 in DAKIKI cells. • CagA decreased the expression of C1GALT1 and its chaperone Cosmc in DAKIKI cells. • Helicobacter pylori infection may participate in the pathogenesis of IgAN via CagA. - Abstract: While Helicobacter pylori (Hp) infection is closely associated with IgA nephropathy (IgAN), the underlying molecular mechanisms remain to be elucidated. This study was to investigate the effect of cytotoxin associated gene A protein (CagA), a major virulence factor of Hp, on the production and underglycosylation of IgA1 in the B cell line DAKIKI cells. Cells were cultured and treated with recombinant CagA protein. We found that CagA stimulated cell proliferation and the production of IgA1 in a dose-dependent and time-dependent manner. Moreover, CagA promoted the underglycosylation of IgA1, which at least partly attributed to the downregulation of β1,3-galactosyltransferase (C1GALT1) and its chaperone Cosmc. In conclusion, we demonstrated that Hp infection, at least via CagA, may participate in the pathogenesis of IgAN by influencing the production and glycosylation of IgA1 in B cells.

  10. The transcription factor NR4A1 (Nur77) controls bone marrow differentiation and the survival of Ly6C- monocytes.

    PubMed

    Hanna, Richard N; Carlin, Leo M; Hubbeling, Harper G; Nackiewicz, Dominika; Green, Angela M; Punt, Jennifer A; Geissmann, Frederic; Hedrick, Catherine C

    2011-08-01

    The transcription factors that regulate differentiation into the monocyte subset in bone marrow have not yet been identified. Here we found that the orphan nuclear receptor NR4A1 controlled the differentiation of Ly6C- monocytes. Ly6C- monocytes, which function in a surveillance role in circulation, were absent from Nr4a1-/- mice. Normal numbers of myeloid progenitor cells were present in Nr4a1-/- mice, which indicated that the defect occurred during later stages of monocyte development. The defect was cell intrinsic, as wild-type mice that received bone marrow from Nr4a1-/- mice developed fewer patrolling monocytes than did recipients of wild-type bone marrow. The Ly6C- monocytes remaining in the bone marrow of Nr4a1-/- mice were arrested in S phase of the cell cycle and underwent apoptosis. Thus, NR4A1 functions as a master regulator of the differentiation and survival of 'patrolling' Ly6C- monocytes. PMID:21725321

  11. Caffeic acid phenethyl ester inhibits 3-MC-induced CYP1A1 expression through induction of hypoxia-inducible factor-1α

    SciTech Connect

    Kim, Hyung Gyun; Han, Eun Hee; Im, Ji Hye; Lee, Eun Ji; Jin, Sun Woo; Jeong, Hye Gwang

    2015-09-25

    Caffeic acid phenethyl ester (CAPE), a natural component of propolis, is reported to have anticarcinogenic properties, although its precise chemopreventive mechanism remains unclear. In this study, we examined the effects of CAPE on 3-methylcholanthrene (3-MC)-induced CYP1A1 expression and activities. CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. Moreover, CAPE inhibited 3-MC-induced CYP1A1 activity, mRNA expression, protein level, and promoter activity. CAPE treatment also decreased 3-MC-inducible xenobiotic-response element (XRE)-linked luciferase, aryl hydrocarbons receptor (AhR) transactivation and nuclear localization. CAPE induced hypoxia inducible factor-1α (HIF-1α) protein level and HIF-1α responsible element (HRE) transcriptional activity. CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 protein expression. Taken together, CAPE decreases 3-MC-mediated CYP1A1 expression, and this inhibitory response is associated with inhibition of AhR and HIF-1α induction. - Highlights: • CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. • CAPE inhibited 3-MC-induced CYP1A1 expression. • CAPE induced HIF-1α induction. • CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 expression.

  12. Combined effects of collagen type I alpha1 (COL1A1) Sp1 polymorphism and osteoporosis risk factors on bone mineral density in Turkish postmenopausal women.

    PubMed

    Kurt-Sirin, Ozlem; Yilmaz-Aydogan, Hulya; Uyar, Mehmet; Seyhan, Mehmet-Fatih; Isbir, Turgay; Can, Ayse

    2014-05-01

    Identification of risk factors for osteoporosis has been essential for understanding the development of osteoporosis. The collagen type I alpha1 (COL1A1) gene is suggested to be implicated in reduced bone mineral density (BMD) in osteoporosis. In the present study, the investigation of the effects of Sp1 polymorphic variants of COL1A1 gene on BMD values, and the determination of the association between COL1A1 Sp1 gene variants and osteoporosis risk factors in the context of gene-environment interaction in Turkish postmenopausal women were aimed. For the detection of COL1A1 Sp1 polymorphism, PCR-RFLP techniques have been used. BMD for lumbar spine (L1-L4) and hip (femoral neck and total hip) was measured by DXA. This study was carried out using a sample of 254 postmenopausal women. We observed a trend decrease in BMD values in the subjects with "ss" genotype having lower BMD of lumbar spine, femoral neck and total hip than those with "SS" and "Ss" genotype, however the differences did not reach statistical significance (P>0.05). We also found that the frequencies of the BMD under mean values at the femoral neck (57.5%) and total hip (76.2%) increased considerably in the subjects carrying "Ss/ss" genotypes in combination of having family history of osteoporosis (61.5% for femoral neck) and smoking history (90.0% for total hip). This population-based study indicates that COL1A1 Sp1 polymorphism may contribute to the development of osteoporosis in combination of osteoporosis risk factors in Turkish postmenopausal women. PMID:24566004

  13. HEAT-INDUCED TAS1 TARGET1 Mediates Thermotolerance via HEAT STRESS TRANSCRIPTION FACTOR A1a–Directed Pathways in Arabidopsis[C][W

    PubMed Central

    Li, Shuxia; Liu, Jinxin; Liu, Zhongyuan; Li, Xiaorong; Wu, Feijie; He, Yuke

    2014-01-01

    Many heat stress transcription factors (Hsfs) and heat shock proteins (Hsps) have been identified to play important roles in the heat tolerance of plants. However, many of the key factors mediating the heat response pathways remain unknown. Here, we report that two genes, which are targets of TAS1 (trans-acting siRNA precursor 1)–derived small interfering RNAs that we named HEAT-INDUCED TAS1 TARGET1 (HTT1) and HTT2, are involved in thermotolerance. Microarray analysis revealed that the HTT1 and HTT2 genes were highly upregulated in Arabidopsis thaliana seedlings in response to heat shock. Overexpression of TAS1a, whose trans-acting small interfering RNAs target the HTT genes, elevated accumulation of TAS1-siRNAs and reduced expression levels of the HTT genes, causing weaker thermotolerance. By contrast, overexpression of HTT1 and HTT2 upregulated several Hsf genes, leading to stronger thermotolerance. In heat-tolerant plants overexpressing HsfA1a, the HTT genes were upregulated, especially at high temperatures. Meanwhile, HsfA1a directly activated HTT1 and HTT2 through binding to their promoters. HTT1 interacted with the heat shock proteins Hsp70-14 and Hsp40 and NUCLEAR FACTOR Y, SUBUNIT C2. Taken together, these results suggest that HTT1 mediates thermotolerance pathways because it is targeted by TAS1a, mainly activated by HsfA1a, and acts as cofactor of Hsp70-14 complexes. PMID:24728648

  14. Maternal protein restriction induces alterations in hepatic tumor necrosis factor-α/CYP7A1 signaling and disorders regulation of cholesterol metabolism in the adult rat offspring

    PubMed Central

    Liu, Xiaomei; Qi, Ying; Tian, Baoling; Chen, Dong; Gao, Hong; Xi, Chunyan; Xing, Yanlin; Yuan, Zhengwei

    2014-01-01

    It is well recognized that adverse events in utero impair fetal development and lead to the development of obesity and metabolic syndrome in adulthood. To investigate the mechanisms linking impaired fetal growth to increased cholesterol, an important clinical risk factor characterizing the metabolic syndrome and cardiovascular disease, we examined the impact of maternal undernutrition on tumor necrosis factor-α (TNF-α)/c-jun N-terminal kinase (JNK) signaling pathway and the cholesterol 7α-hydroxylase (CYP7A1) expression in the livers of the offspring with a protein restriction model. The male offspring with intrauterine growth restriction (IUGR) caused by the isocaloric low-protein diet showed decreased liver weight at birth and augmented circulation and hepatic cholesterol levels at 40 weeks of age. Maternal undernutrition significantly upregulated cytokine TNF-α expression and JNK phospholytion levels in the livers from fetal age to adulthood. Elevated JNK phospholytion could be linked to downregulated hepatocyte nuclear factor-4α and CYP7A1 expression, subsequently led to higher hepatic cholesterol. This work demonstrated that intrauterine malnutrition-induced IUGR might result in intrinsic disorder in hepatic TNF-α/CYP7A1 signaling, and contribute to the development of hypercholesterolemia in later life. PMID:25120278

  15. HEAT-INDUCED TAS1 TARGET1 Mediates Thermotolerance via HEAT STRESS TRANSCRIPTION FACTOR A1a-Directed Pathways in Arabidopsis.

    PubMed

    Li, Shuxia; Liu, Jinxin; Liu, Zhongyuan; Li, Xiaorong; Wu, Feijie; He, Yuke

    2014-04-11

    Many heat stress transcription factors (Hsfs) and heat shock proteins (Hsps) have been identified to play important roles in the heat tolerance of plants. However, many of the key factors mediating the heat response pathways remain unknown. Here, we report that two genes, which are targets of TAS1 (trans-acting siRNA precursor 1)-derived small interfering RNAs that we named HEAT-INDUCED TAS1 TARGET1 (HTT1) and HTT2, are involved in thermotolerance. Microarray analysis revealed that the HTT1 and HTT2 genes were highly upregulated in Arabidopsis thaliana seedlings in response to heat shock. Overexpression of TAS1a, whose trans-acting small interfering RNAs target the HTT genes, elevated accumulation of TAS1-siRNAs and reduced expression levels of the HTT genes, causing weaker thermotolerance. By contrast, overexpression of HTT1 and HTT2 upregulated several Hsf genes, leading to stronger thermotolerance. In heat-tolerant plants overexpressing HsfA1a, the HTT genes were upregulated, especially at high temperatures. Meanwhile, HsfA1a directly activated HTT1 and HTT2 through binding to their promoters. HTT1 interacted with the heat shock proteins Hsp70-14 and Hsp40 and NUCLEAR FACTOR Y, SUBUNIT C2. Taken together, these results suggest that HTT1 mediates thermotolerance pathways because it is targeted by TAS1a, mainly activated by HsfA1a, and acts as cofactor of Hsp70-14 complexes. PMID:24728648

  16. Epidermal Growth Factor Receptor Kinase Inhibitors Synergize with TCDD to Induce CYP1A1/1A2 in Human Breast Epithelial MCF10A Cells.

    PubMed

    Joiakim, Aby; Mathieu, Patricia A; Shelp, Catherine; Boerner, Julie; Reiners, John J

    2016-05-01

    CYP1A1andCYP1A2are transcriptionally activated in the human normal breast epithelial cell line MCF10A following exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Shifting MCF10A cultures to medium deficient in serum and epidermal growth factor (EGF) caused rapid reductions in the activated (i.e., phosphorylated) forms of extracellular regulated kinases (ERKs) and the epidermal growth factor receptor (EGFR). Shifting to serum/EGF-deficient medium also enhanced TCDD-mediated induction of cytochrome P450 (CYP)1A1 Treatment of cells cultured in complete medium with the EGFR inhibitors gefitinib (Iressa), AG1478, and CI-1033 resulted in concentration-dependent reductions of active EGFR and ERKs, and increased CYP1A1 mRNA content ∼3- to 18-fold above basal level. EGFR inhibitors synergized with TCDD and resulted in transient CYP1A1 and CYP1A2 mRNA accumulations ∼8-fold greater (maximum at 5 hours) than that achieved with only TCDD. AG1478, gefitinib, and TCDD individually induced small increases (∼1.2- to 2.5-fold) in CYP1A1 protein content but did not cause additive or synergistic accumulations of CYP1A1 protein when used in combination. The mitogen-activated protein kinase kinase inhibitor PD184352 inhibited ERK and EGFR activation in a concentration-dependent fashion without causing CYP1A1 mRNA accumulation. However, cotreatment with PD184352 potentiated TCDD-mediatedCYP1A1induction. TCDD-mediated induction ofCYP1A1in MCF7-TETon-EGFR cells, a MCF7 variant in which EGFR expression can be controlled, was not affected by the activity status of EGFR or ERKs. Hence, EGFR signaling mutes both basal and ligand-induced expression of two aryl hydrocarbon receptor-responsive P450s in MCF10A cultures. However, these effects are cell context-dependent. Furthermore, CYP1A1 mRNA and protein abundance are not closely coupled in MCF10A cultures. PMID:26953171

  17. Analysis of GFP-FOXO3a nuclear-cytoplasmic shuttling in ASTC-a-1 cells under growth factor stimulation

    NASA Astrophysics Data System (ADS)

    Wang, Xianwang; Xing, Da; Chen, Wei R.

    2010-02-01

    FOXO transcription factors are important regulators of cell survival in response to a variety of stimuli, among which are hypoxic stress, oxidative stress, and growth factor deprivation. Subcellular localization of FOXO proteins plays a major role in the regulation of their activity. In this study, using confocal imaging of the cells transfected with GFP-FOXO3a and fluorescence recovery after photobleaching technique, we visualized the dynamic nuclear translocation of GFP-FOXO3a in ASTC-a-1 cells under growth factor stimulus. In healthy cells, GFP-FOXO3a was well-distributed in the cytoplasm or widespread distributed in the cytoplasm and the nucleus but the cytoplasm was significantly more than the nucleus. Deprivation of growth factor, we monitored the nuclear localization of GFP-FOXO3a and the dynamic translocation of it from cytoplasm to nucleus. Interestingly, upon stimulation with growth factor in cells again, we visualized the dynamic nuclear exclusion of GFP-FOXO3a and cytoplasm distribution rapidly. In conclusion, these results demonstrated that FOXO3a can reversible shuttling between cytoplasm and nucleus upon stimulation with growth factor.

  18. Post-translational S-Nitrosylation Is an Endogenous Factor Fine Tuning the Properties of Human S100A1 Protein*

    PubMed Central

    Lenarčič Živković, Martina; Zaręba-Kozioł, Monika; Zhukova, Liliya; Poznański, Jarosław; Zhukov, Igor; Wysłouch-Cieszyńska, Aleksandra

    2012-01-01

    S100A1 is a member of the Ca2+-binding S100 protein family. It is expressed in brain and heart tissue, where it plays a crucial role as a modulator of Ca2+ homeostasis, energy metabolism, neurotransmitter release, and contractile performance. Biological effects of S100A1 have been attributed to its direct interaction with a variety of target proteins. The (patho)physiological relevance of S100A1 makes it an important molecular target for future therapeutic intervention. S-Nitrosylation is a post-translational modification of proteins, which plays a role in cellular signal transduction under physiological and pathological conditions. In this study, we confirmed that S100A1 protein is endogenously modified by Cys85 S-nitrosylation in PC12 cells, which are a well established model system for studying S100A1 function. We used isothermal calorimetry to show that S-nitrosylation facilitates the formation of Ca2+-loaded S100A1 at physiological ionic strength conditions. To establish the unique influence of the S-nitroso group, our study describes high resolution three-dimensional structures of human apo-S100A1 protein with the Cys85 thiol group in reduced and S-nitrosylated states. Solution structures of the proteins are based on NMR data obtained at physiological ionic strength. Comparative analysis shows that S-nitrosylation fine tunes the overall architecture of S100A1 protein. Although the typical S100 protein intersubunit four-helix bundle is conserved upon S-nitrosylation, the conformation of S100A1 protein is reorganized at the sites most important for target recognition (i.e. the C-terminal helix and the linker connecting two EF-hand domains). In summary, this study discloses cysteine S-nitrosylation as a new factor responsible for increasing functional diversity of S100A1 and helps explain the role of S100A1 as a Ca2+ signal transmitter sensitive to NO/redox equilibrium within cells. PMID:22989881

  19. Expression of CYP1A1 and CYP1B1 depends on cell-specific factors in human breast cancer cell lines: role of estrogen receptor status.

    PubMed

    Angus, W G; Larsen, M C; Jefcoate, C R

    1999-06-01

    The impact of estrogen receptor (ER) was examined for expression and activity of cytochrome P4501B1 (CYP1B1) and cytochrome P4501A1 (CYP1A1) in two pairs of ER+/ER- human breast epithelial cell lines derived from single lineages, and representing earlier (T47D) or later (MDA-MB-231) stages of tumorigenesis. Acute loss of ER was evaluated using the anti-estrogen ICI 182,780 (ICI). In all lines, CYP1B1 was expressed constitutively and was induced by 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), whereas CYP1A1 was expressed only following induction. Expression of each CYP (with or without TCDD) was greater in T47D cells than MDA cells. The ER impacted expression of these genes in opposite directions. The ER- phenotype was associated with less TCDD-induced CYP1A1 expression, but greater basal and induced CYP1B1 expression. A 48 h treatment of ER+ cells with ICI did not revert the P450 expression pattern to that of ER- cells. Based on activities of recombinant enzyme and expression levels, differences in 7,2-dimethylbenz [a]anthracene (DMBA) metabolism between the cell lines were consistent with differences in CYP1A1 and CYP1B1 expression. In T47D lines, basal microsomal DMBA metabolism was primarily due to CYP1B1, based on regioselective metabolite distribution and inhibition by anti-CYP1B1 antibodies (>80%). Metabolism in TCDD-induced microsomes was mostly due to CYP1A1 and was inhibited by anti-CYP1A1 antibody (>50%). TCDD-induced MDA+ cells demonstrated CYP1A1 activity, whereas TCDD-induced MDA- cells displayed CYP1B1 activity. Aryl hydrocarbon receptor (AhR) levels, but not AhR nuclear translocator protein (ARNT) levels were highly dependent on cell type; AhR was high and ER-independent in MDA, and low and ER-linked in T47D. AhR levels were insensitive to ICI. ER does not directly modulate the expression of CYP1A1, CYP1B1 or AhR. Indeed, factors that have replaced ER in growth regulation during clonal selection predominate in this regulation. Characteristics unique to each cell line, including ER status, determine CYP1A1 and CYP1B1 expression. PMID:10357772

  20. Caffeic acid phenethyl ester inhibits 3-MC-induced CYP1A1 expression through induction of hypoxia-inducible factor-1α.

    PubMed

    Kim, Hyung Gyun; Han, Eun Hee; Im, Ji Hye; Lee, Eun Ji; Jin, Sun Woo; Jeong, Hye Gwang

    2015-09-25

    Caffeic acid phenethyl ester (CAPE), a natural component of propolis, is reported to have anticarcinogenic properties, although its precise chemopreventive mechanism remains unclear. In this study, we examined the effects of CAPE on 3-methylcholanthrene (3-MC)-induced CYP1A1 expression and activities. CAPE reduced the formation of the benzo[a]pyrene-DNA adduct. Moreover, CAPE inhibited 3-MC-induced CYP1A1 activity, mRNA expression, protein level, and promoter activity. CAPE treatment also decreased 3-MC-inducible xenobiotic-response element (XRE)-linked luciferase, aryl hydrocarbons receptor (AhR) transactivation and nuclear localization. CAPE induced hypoxia inducible factor-1α (HIF-1α) protein level and HIF-1α responsible element (HRE) transcriptional activity. CAPE-mediated HIF-1α reduced 3-MC-inducible CYP1A1 protein expression. Taken together, CAPE decreases 3-MC-mediated CYP1A1 expression, and this inhibitory response is associated with inhibition of AhR and HIF-1α induction. PMID:26296470

  1. Male germ cell expression of the PAS domain kinase PASKIN and its novel target eukaryotic translation elongation factor eEF1A1.

    PubMed

    Eckhardt, Katrin; Troger, Juliane; Reissmann, Jana; Katschinski, Dörthe M; Wagner, Klaus F; Stengel, Petra; Paasch, Uwe; Hunziker, Peter; Borter, Emanuela; Barth, Sandra; Schlafli, Philipp; Spielmann, Patrick; Stiehl, Daniel P; Camenisch, Gieri; Wenger, Roland H

    2007-01-01

    PASKIN links energy flux and protein synthesis in yeast, regulates glycogen synthesis in mammals, and has been implicated in glucose-stimulated insulin production in pancreatic beta-cells. Using newly generated monoclonal antibodies, PASKIN was localized in the nuclei of human testis germ cells and in the midpiece of human sperm tails. A speckle-like nuclear pattern was observed for endogenous PASKIN in HeLa cells in addition to its cytoplasmic localization. By yeast two-hybrid screening, we identified the multifunctional eukaryotic translation elongation factor eEF1A1 as a novel interaction partner of PASKIN. This interaction was mapped to the PAS A and kinase domains of PASKIN and to the C-terminus of eEF1A1 using mammalian two-hybrid and GST pull-down assays. Kinase assays, mass spectrometry and site-directed mutagenesis revealed PASKIN auto-phosphorylation as well as eEF1A1 target phosphorylation mainly but not exclusively at Thr432. Wild-type but not kinase-inactive PASKIN increased the in vitro translation of a reporter cRNA. Whereas eEF1A1 did not localize to the nucleus, it co-localizes with PASKIN to the cytoplasm of HeLa cells. The two proteins also showed a remarkably similar localization in the midpiece of the sperm tail. These data suggest regulation of eEF1A1 by PASKIN-dependent phosphorylation in somatic as well as in sperm cells. PMID:17595531

  2. Squared form factors for the A1Π and B1Σ+ vibronic bands of carbon monoxide studied by high-resolution inelastic x-ray scattering

    NASA Astrophysics Data System (ADS)

    Ni, Dong-Dong; Kang, Xu; Yang, Ke; Liu, Ya-Wei; Mei, Xiao-Xun; Zhao, Xiao-Li; Xu, Long-Quan; Hiraoka, Nozomu; Tsuei, Ku-Ding; Zhu, Lin-Fan

    2015-04-01

    Using the inelastic x-ray scattering with a high resolution of 70 meV, squared form factors of molecular carbon monoxide have been determined from the ground state X 1Σ+ to the vibronic states of A 1Π and B 1Σ+ . Since the first Born approximation is satisfied in inelastic x-ray scattering, the inelastic squared form factors of the valence-shell excitations of carbon monoxide measured by this work not only provide the experimental benchmark data but also serve as the high-energy limit for the electron impact method. Based on the present experimental results, the validity conditions of the previous electron impact works are discussed. It is found that for the excitations of A 1Π (ν'=0 -6 ) the first Born approximation is reached in the region of q2<0.7 a.u. at an impact electron energy of 1.5 keV, while for B 1Σ+ (ν'=0 ) the first Born approximation does not fully hold at the impact electron energy of 1.5 keV except for the q2<0.15 a.u. The large discrepancies between the present inelastic x-ray scattering results and the theoretical calculations for most transitions suggest that the formerly reported calculations are not accurate enough.

  3. MicroRNA-33a-5p Modulates Japanese Encephalitis Virus Replication by Targeting Eukaryotic Translation Elongation Factor 1A1

    PubMed Central

    Chen, Zheng; Ye, Jing; Ashraf, Usama; Li, Yunchuan; Wei, Siqi; Wan, Shengfeng; Zohaib, Ali; Song, Yunfeng; Chen, Huanchun

    2016-01-01

    ABSTRACT Japanese encephalitis virus (JEV) is a typical mosquito-borne flavivirus responsible for acute encephalitis and meningitis in humans. However, the molecular mechanism for JEV pathogenesis is still unclear. MicroRNAs (miRNAs) are small noncoding RNAs that act as gene regulators. They are directly or indirectly involved in many cellular functions owing to their ability to target mRNAs for degradation or translational repression. However, how cellular miRNAs are regulated and their functions during JEV infection are largely unknown. In the present study, we found that JEV infection downregulated the expression of endogenous cellular miR-33a-5p. Notably, artificially transfecting with miR-33a-5p mimics led to a significant decrease in viral replication, suggesting that miR-33a-5p acts as a negative regulator of JEV replication. A dual-luciferase reporter assay identified eukaryotic translation elongation factor 1A1 (EEF1A1) as one of the miR-33a-5p target genes. Our study further demonstrated that EEF1A1 can interact with the JEV proteins NS3 and NS5 in replicase complex. Through this interaction, EEF1A1 can stabilize the components of viral replicase complex and thus facilitates viral replication during JEV infection. Taken together, these results suggest that miR-33a-5p is downregulated during JEV infection, which contributes to viral replication by increasing the intracellular level of EEF1A1, an interaction partner of JEV NS3 and NS5. This study provides a better understanding of the molecular mechanisms of JEV pathogenesis. IMPORTANCE MiRNAs are critical regulators of gene expression that utilize sequence complementarity to bind to and modulate the stability or translation efficiency of target mRNAs. Accumulating data suggest that miRNAs regulate a wide variety of molecular mechanisms in the host cells during viral infections. JEV, a neurotropic flavivirus, is one of the major causes of acute encephalitis in humans worldwide. The roles of cellular miRNAs during JEV infections are widely unexplored. The present study explores a novel role of miR-33a-5p as a negative regulator of JEV replication. We found EEF1A1 as a direct target of miR-33a-5p. We also demonstrated that EEF1A1 interacts with and stabilize the components of JEV replicase complex, which positively regulates JEV replication. These findings suggest a new insight into the molecular mechanism of JEV pathogenesis and provide a possible therapeutic entry point for viral encephalitis. PMID:26819305

  4. Correction factors for A1SL ionization chamber dosimetry in TomoTherapy: Machine-specific, plan-class, and clinical fields

    SciTech Connect

    Gago-Arias, Araceli; Rodriguez-Romero, Ruth; Sanchez-Rubio, Patricia; Miguel Gonzalez-Castano, Diego; Gomez, Faustino; Nunez, Luis; Palmans, Hugo; Sharpe, Peter; Pardo-Montero, Juan

    2012-04-15

    Purpose: Recently, an international working group on nonstandard fields presented a new formalism for ionization chamber reference dosimetry of small and nonstandard fields [Alfonso et al., Med. Phys. 35, 5179-5186 (2008)] which has been adopted by AAPM TG-148. This work presents an experimental determination of the correction factors for reference dosimetry with an Exradin A1SL thimble ionization chamber in a TomoTherapy unit, focusing on: (i) machine-specific reference field, (ii) plan-class-specific reference field, and (iii) two clinical treatments. Methods: Ionization chamber measurements were performed in the TomoTherapy unit for intermediate (machine-specific and plan-class-specific) calibration fields, based on the reference conditions defined by AAPM TG-148, and two clinical treatments (lung and head-and-neck). Alanine reference dosimetry was employed to determine absorbed dose to water at the point of interest for the fields under investigation. The corresponding chamber correction factors were calculated from alanine to ionization chamber measurements ratios. Results: Two different methods of determining the beam quality correction factor k{sub Q,Q{sub 0}} for the A1SL ionization chamber in this TomoTherapy unit, where reference conditions for conventional beam quality determination cannot be met, result in consistent values. The observed values of overall correction factors obtained for intermediate and clinical fields are consistently around 0.98 with a typical expanded relative uncertainty of 2% (k = 2), which when considered make such correction factors compatible with unity. However, all of them are systematically lower than unity, which is shown to be significant when a hypothesis test assuming a t-student distribution is performed (p=1.8x10{sup -2}). Correction factors k{sub Q{sub c{sub l{sub i{sub n,Q{sub p{sub c{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub p}{sub c}{sub s}{sub r}}}}}}}}}} and k{sub Q{sub c{sub l{sub i{sub n,Q{sub m{sub s{sub r}{sup f{sub c}{sub l}{sub i}{sub n},f{sub m}{sub s}{sub r}}}}}}}}}, which are needed for the computation of field factors for relative dosimetry of clinical beams, have been found to be very close to unity for two clinical treatments. Conclusions: The results indicate that the helical field deliveries in this study (including two clinical fields) do not introduce changes on the ion chamber correction factors for dosimetry. For those two specific clinical cases, ratios of chamber readings accurately represent field output factors. The values observed here for intermediate calibration fields are in agreement with previously published data based on alanine dosimetry but differ from values recently reported obtained via radiochromic dosimetry.

  5. ADP-Ribosylation Factor 6 Acts as an Allosteric Activator for the Folded but not Disordered Cholera Toxin A1 Polypeptide

    PubMed Central

    Banerjee, Tuhina; Taylor, Michael; Jobling, Michael G.; Burress, Helen; Yang, ZhiJie; Serrano, Albert; Holmes, Randall K.; Tatulian, Suren A.; Teter, Ken

    2014-01-01

    Summary The catalytic A1 subunit of cholera toxin (CTA1) has a disordered structure at 37°C. An interaction with host factors must therefore place CTA1 in a folded conformation for the modification of its Gsα target which resides in a lipid raft environment. Host ADP-ribosylation factors (ARFs) act as in vitro allosteric activators of CTA1, but the molecular events of this process are not fully characterized. Isotope-edited Fourier transform infrared spectroscopy monitored ARF6-induced structural changes to CTA1, which were correlated to changes in CTA1 activity. We found ARF6 prevents the thermal disordering of structured CTA1 and stimulates the activity of stabilized CTA1 over a range of temperatures. Yet ARF6 alone did not promote the refolding of disordered CTA1 to an active state. Instead, lipid rafts shifted disordered CTA1 to a folded conformation with a basal level of activity that could be further stimulated by ARF6. Thus, ARF alone is unable to activate disordered CTA1 at physiological temperature: additional host factors such as lipid rafts place CTA1 in the folded conformation required for its ARF-mediated activation. Interaction with ARF is required for in vivo toxin activity, as enzymatically active CTA1 mutants that cannot be further stimulated by ARF6 fail to intoxicate cultured cells. PMID:25257027

  6. Forkhead transcription factor FoxA1 regulates sweat secretion through Bestrophin 2 anion channel and Na-K-Cl cotransporter 1

    PubMed Central

    Cui, Chang-Yi; Childress, Victoria; Piao, Yulan; Michel, Marc; Johnson, Adiv A.; Kunisada, Makoto; Ko, Minoru S. H.; Kaestner, Klaus H.; Marmorstein, Alan D.; Schlessinger, David

    2012-01-01

    Body temperature is maintained in a narrow range in mammals, primarily controlled by sweating. In humans, the dynamic thermoregulatory organ, comprised of 2–4 million sweat glands distributed over the body, can secrete up to 4 L of sweat per day, thereby making it possible to withstand high temperatures and endure prolonged physical stress (e.g., long-distance running). The genetic basis for sweat gland function, however, is largely unknown. We find that the forkhead transcription factor, FoxA1, is required to generate mouse sweating capacity. Despite continued sweat gland morphogenesis, ablation of FoxA1 in mice results in absolute anihidrosis (lack of sweating). This inability to sweat is accompanied by down-regulation of the Na-K-Cl cotransporter 1 (Nkcc1) and the Ca2+-activated anion channel Bestrophin 2 (Best2), as well as glycoprotein accumulation in gland lumens and ducts. Furthermore, Best2-deficient mice display comparable anhidrosis and glycoprotein accumulation. These findings link earlier observations that both sodium/potassium/chloride exchange and Ca2+ are required for sweat production. FoxA1 is inferred to regulate two corresponding features of sweat secretion. One feature, via Best2, catalyzes a bicarbonate gradient that could help to drive calcium-associated ionic transport; the other, requiring Nkcc1, facilitates monovalent ion exchange into sweat. These mechanistic components can be pharmaceutical targets to defend against hyperthermia and alleviate defective thermoregulation in the elderly, and may provide a model relevant to more complex secretory processes. PMID:22223659

  7. Common and Distinct Functions of Arabidopsis Class A1 and A2 Heat Shock Factors in Diverse Abiotic Stress Responses and Development1[W][OPEN

    PubMed Central

    Liu, Hsiang-chin; Charng, Yee-yung

    2013-01-01

    There are 21 heat shock factor (HSF) homologs in Arabidopsis (Arabidopsis thaliana), of which members of class A1 (HSFA1a/HSFA1b/HSFA1d/HSFA1e) play the major role in activating the transcription of heat-induced genes, including HSFA2. Once induced, HSFA2 becomes the dominant HSF and is able to form heterooligomeric complexes with HSFA1. However, whether HSFA2 could function independently as a transcription regulator in the absence of the HSFA1s was undetermined. To address this question, we introduced a Cauliflower mosaic virus 35S promoter:HSFA2 construct into hsfa1a/hsfa1b/hsfa1d/hsfa1e quadruple knockout (QK) and wild-type (Wt) backgrounds to yield transgenic lines A2QK and A2Wt, respectively. Constitutive expression of HSFA2 rescued the developmental defects of the QK mutant and promoted callus formation in A2QK, but not in A2Wt, after heat treatment. Transcriptome analysis showed that heat stress response genes are differentially regulated by the HSFA1s and HSFA2; the genes involved in metabolism and redox homeostasis are preferentially regulated by HSFA2, while HSFA1-preferring genes are enriched in transcription function. Ectopic expression of HSFA2 complemented the defects of QK in tolerance to different heat stress regimes, and to hydrogen peroxide, but not to salt and osmotic stresses. Furthermore, we showed that HSFA1a/HSFA1b/HSFA1d are involved in thermotolerance to mild heat stress at temperatures as low as 27°C. We also noticed subfunctionalization of the four Arabidopsis A1-type HSFs in diverse abiotic stress responses. Overall, this study reveals the overlapping and distinct functions of class A1 and A2 HSFs and may enable more precise use of HSFs in engineering stress tolerance in the future. PMID:23832625

  8. Azathioprine desensitizes liver cancer cells to insulin-like growth factor 1 and causes apoptosis when it is combined with bafilomycin A1

    SciTech Connect

    Hernández-Breijo, Borja; Monserrat, Jorge; Román, Irene D.; González-Rodríguez, Águeda; Fernández-Moreno, M. Dolores; and others

    2013-11-01

    Hepatoblastoma is a primary liver cancer that affects children, due to the sensitivity of this tumor to insulin-like growth factor 1 (IGF-1). In this paper we show that azathioprine (AZA) is capable of inhibiting IGF1-mediated signaling cascade in HepG2 cells. The efficiency of AZA on inhibition of proliferation differs in the evaluated cell lines as follows: HepG2 (an experimental model of hepatoblastoma) > Hep3B (derived from a hepatocellular carcinoma) > HuH6 (derived from a hepatoblastoma) ≫ HuH7 (derived from a hepatocellular carcinoma) = Chang Liver cells (a non-malignant cellular model). The effect of AZA in HepG2 cells has been proven to derive from activation of Ras/ERK/TSC2, leading to activation of mTOR/p70S6K in a sustained manner. p70S6K phosphorylates IRS-1 in serine 307 which leads to the uncoupling between IRS-1 and p85 (the regulatory subunit of PI3K) and therefore causing the lack of response of HepG2 to IGF-1. As a consequence, proliferation induced by IGF-1 is inhibited by AZA and autophagy increases leading to senescence of HepG2 cells. Our results suggest that AZA induces the autophagic process in HepG2 activating senescence, and driving to deceleration of cell cycle but not to apoptosis. However, when simultaneous to AZA treatment the autophagy was inhibited by bafilomycin A1 and the degradation of regulatory proteins of cell cycle (e.g. Rb, E2F, and cyclin D1) provoked apoptosis. In conclusion, AZA induces resistance in hepatoblastoma cells to IGF-1, which leads to autophagy activation, and causes apoptosis when it is combined with bafilomycin A1. We are presenting here a novel mechanism of action of azathioprine, which could be useful in treatment of IGF-1 dependent tumors, especially in its combination with other drugs. - Highlights: • Azathioprine activated Ras/ERK/TSC-2/mTOR/p70S6K signaling pathway in HepG2 cells. • Azathioprine inhibited IGF-1-mediated signaling cascade. • Azathioprine induced autophagy leading to cell cycle arrest. • Cells died by apoptosis when azathioprine was combined with bafilomycin A1.

  9. Age-Related Nuclear Translocation of P2X6 Subunit Modifies Splicing Activity Interacting with Splicing Factor 3A1

    PubMed Central

    Díaz-Hernández, Juan Ignacio; Sebastián-Serrano, Álvaro; Gómez-Villafuertes, Rosa

    2015-01-01

    P2X receptors are ligand-gated ion channels sensitive to extracellular nucleotides formed by the assembling of three equal or different P2X subunits. In this work we report, for the first time, the accumulation of the P2X6 subunit inside the nucleus of hippocampal neurons in an age-dependent way. This location is favored by its anchorage to endoplasmic reticulum through its N-terminal domain. The extracellular domain of P2X6 subunit is the key to reach the nucleus, where it presents a speckled distribution pattern and is retained by interaction with the nuclear envelope protein spectrin α2. The in vivo results showed that, once inside the nucleus, P2X6 subunit interacts with the splicing factor 3A1, which ultimately results in a reduction of the mRNA splicing activity. Our data provide new insights into post-transcriptional regulation of mRNA splicing, describing a novel mechanism that could explain why this process is sensitive to changes that occur with age. PMID:25874565

  10. Identification of Scedosporium boydii catalase A1 gene, a reactive oxygen species detoxification factor highly expressed in response to oxidative stress and phagocytic cells.

    PubMed

    Mina, Sara; Staerck, Cindy; d'Almeida, Sènan M; Marot, Agnès; Delneste, Yves; Calenda, Alphonse; Tabiasco, Julie; Bouchara, Jean-Philippe; Fleury, Maxime J J

    2015-12-01

    Scedosporium boydii is an opportunistic filamentous fungus which may be responsible for a large variety of infections in both immunocompetent and immunocompromised individuals. This fungus belongs to the Scedosporium apiospermum species complex which usually ranks second among the filamentous fungi colonizing the airways of patients with cystic fibrosis (CF). Species of the S. apiospermum complex are able to chronically colonize the CF airways suggesting pathogenic mechanisms allowing persistence and growth of these fungi in the respiratory tract. Few putative virulence factors have been purified and characterized so far in the S. apiospermum complex including a cytosolic Cu,Zn-superoxide dismutase (SOD) and a monofunctional catalase (catalase A1). Upon microbial infection, host phagocytes release reactive oxygen species (ROS), such as hydrogen peroxide, as part of the antimicrobial response. Catalases are known to protect pathogens against ROS by degradation of the hydrogen peroxide. Here, we identified the S. boydii catalase A1 gene (CATA1) and investigated its expression in response to the environmental conditions encountered in the CF airways and to the oxidative stress. Results showed that S. boydii CATA1 gene expression is not affected by hypoxia, hypercapnia or pH changes. In contrast, CATA1 gene was overexpressed in response to a chemically induced oxidative stress with a relative gene expression 37-fold higher in the presence of 250 μM H(2)O(2), 20-fold higher with 250 μM menadione and 5-fold higher with 2 mM paraquat. Moreover, S. boydii CATA1 gene expression progressively increased upon exposure to activated THP-1-derived macrophages, reaching a maximum after 12 h (26 fold). Activated HL60-derived neutrophils and activated human peripheral blood neutrophils more rapidly induced S. boydii CATA1 gene overexpression, a maximum gene expression level being reached at 75 min (17 fold) and 60 min (15 fold), respectively. In contrast expression of the gene encoding the Cu,Zn-SOD (SODC gene) was not affected by H(2)O(2), menadione, paraquat or in co-culture with phagocytic cells. These results suggest that S. boydii CATA1 gene is highly stimulated by the oxidative burst response whereas SODC gene is constitutively expressed. PMID:26615753

  11. Insulin-like Growth Factor 1 Regulates the Expression of ATP-Binding Cassette Transporter A1 in Pancreatic Beta Cells.

    PubMed

    Lyu, J; Imachi, H; Iwama, H; Zhang, H; Murao, K

    2016-05-01

    ATP-binding cassette transporter A1 (ABCA1) in pancreatic beta cells influences insulin secretion and cholesterol homeostasis. The present study investigates whether insulin-like growth factor 1 (IGF-1), which mediates stimulation of ABCA1 gene expression, could also interfere with the phosphatidylinositol 3-kinase (PI3-K) cascade.ABCA1 expression was examined by real-time polymerase chain reaction (PCR), Western blot analysis, and a reporter gene assay in rat insulin-secreting INS-1 cells incubated with IGF-1. The binding of forkhead box O1 (FoxO1) protein to the ABCA1 promoter was assessed by a chromatin immunoprecipitation (ChIP) assay. ABCA1 protein levels increased in response to rising concentrations of IGF-1. Real-time PCR analysis showed a significant increase in ABCA1 mRNA expression. However, both effects were suppressed after silencing the IGF-1 receptor. In parallel with its effect on endogenous ABCA1 mRNA levels, IGF-1 induced the activity of a reporter construct containing the ABCA1 promoter, while it was abrogated by LY294002, a specific inhibitor of PI3-K. Constitutively active Akt stimulated activity of the ABCA1 promoter, and a dominant-negative mutant of Akt or mutagenesis of the FoxO1 response element in the ABCA1 promoter abolished the ability of IGF-1 to stimulate promoter activity. A ChIP assay showed that FoxO1 mediated its transcriptional activity by directly binding to the ABCA1 promoter region. The knockdown of FoxO1 disrupted the effect of IGF-1 on ABCA1 expression. Furthermore, IGF-1 promoted cholesterol efflux and reduced the pancreatic lipotoxicity. These results demonstrate that the PI3-K/Akt/FoxO1 pathway contributes to the regulation of ABCA1 expression in response to IGF-1 stimulation. PMID:26743528

  12. HbA1c Variability as an Independent Risk Factor for Diabetic Retinopathy in Type 1 Diabetes: A German/Austrian Multicenter Analysis on 35,891 Patients

    PubMed Central

    Hermann, Julia M.; Hammes, Hans-Peter; Rami-Merhar, Birgit; Rosenbauer, Joachim; Schütt, Morten; Siegel, Erhard; Holl, Reinhard W.

    2014-01-01

    Objective This study aimed to analyze the effect of HbA1c variability on the occurrence of diabetic retinopathy in type 1 diabetes patients. Patients and Methods 35,891 patients with childhood, adolescent or adult onset of type 1 diabetes from a large multicentre survey, the German/Austrian prospective documentation system (DPV), were analysed. Cox proportional hazard models were used to examine whether intra-individual HbA1c variability expressed as variation coefficient is an independent risk factor for the occurrence of diabetic retinopathy. Results Kaplan-Meier curves stratified by median HbA1c and variation coefficient revealed that retinopathy-free survival probability is lower when both median HbA1c and HbA1c variability are above the 50th percentile. Cox regression models confirmed this finding: After adjustment for age at diabetes onset, gender and median HbA1c, HbA1c variability was independently associated with the occurrence of diabetic retinopathy. Time-covariate interactions used to model non-proportionality indicated an effect decreasing with duration of diabetes for both median HbA1c and HbA1c variability. Predictive accuracy increased significantly when adding HbA1c variability to the Cox regression model. Conclusions In patients with type 1 diabetes, HbA1c variability adds to the risk of diabetic retinopathy independently of average metabolic control. PMID:24609115

  13. Insulin-like growth factor I gene promoter polymorphism, collagen type II α1 (COL2A1) gene, and the prevalence of radiographic osteoarthritis: the Rotterdam Study

    PubMed Central

    Zhai, G; Rivadeneira, F; Houwing-Duisterma..., J; Meulenbelt, I; Bijkerk, C; Hofman, A; van Meurs, J B J; Uitterlinden, A; Pols, H; Slagboom, P; van Duijn, C M

    2004-01-01

    Objective: To examine the role of an IGF-I gene promoter polymorphism in the prevalence of radiographic osteoarthritis (ROA), and study its interaction with the COL2A1 gene. Methods: Individuals genotyped for IGF-I (n = 1546) and COL2A1 gene polymorphisms (n = 808) were selected from a random sample (n = 1583) derived from the Rotterdam study. The presence of ROA was defined as a Kellgren score of 2 or more in at least one of four joints (knee, hip, hand, and spine). Genotype specific odds ratios (OR) were adjusted for age, sex, body mass index, and bone mineral density using logistic regression. Interaction with the COL2A1 genotype was tested. Results: Overall, no association was found between the IGF-I polymorphism and ROA. In subjects aged 65 years or younger (n = 971), the prevalence of ROA increased with the absence of the 192 base pair (bp) allele (p for trend = 0.03). Compared with homozygotes for the 192 bp allele, the prevalence of ROA was 1.4 times higher in heterozygotes (95% confidence interval, 1.0 to 1.8) and 1.9 times higher in non-carriers (1.1 to 3.3). There was evidence of interaction between the IGF-I and COL2A1 genes. Individuals with the risk genotype of both genes had an increased prevalence of ROA (OR 3.4 (1.1 to 10.7)). No effect was observed in subjects older than 65 years. Conclusions: Subjects with genetically determined low IGF-I expression (non-carriers of the 192 bp allele) may be at increased risk of ROA before the age of 65 years. Furthermore, an interaction between the IGF-I and COL2A1 genes is suggested. PMID:15082485

  14. Evaluation of proton-coupled folate transporter (SLC46A1) polymorphisms as risk factors for neural tube defects and oral clefts.

    PubMed

    VanderMeer, Julia E; Carter, Tonia C; Pangilinan, Faith; Mitchell, Adam; Kurnat-Thoma, Emma; Kirke, Peadar N; Troendle, James F; Molloy, Anne M; Munger, Ronald G; Feldkamp, Marcia L; Mansilla, Maria A; Mills, James L; Murray, Jeff C; Brody, Lawrence C

    2016-04-01

    Many folate-related genes have been investigated for possible causal roles in neural tube defects (NTDs) and oral clefts. However, no previous reports have examined the major gene responsible for folate uptake, the proton-coupled folate transporter (SLC46A1). We tested for association between these birth defects and single nucleotide polymorphisms in the SLC46A1 gene. The NTD study population included 549 complete and incomplete case-family triads, and 999 controls from Ireland. The oral clefts study population comprised a sample from Utah (495 complete and incomplete case-family triads and 551 controls) and 221 Filipino multiplex cleft families. There was suggestive evidence of increased NTD case risk with the rs17719944 minor allele (odds ratio (OR): 1.29; 95% confidence intervals (CI): [1.00-1.67]), and decreased maternal risk of an NTD pregnancy with the rs4795436 minor allele (OR: 0.62; [0.39-0.99]). In the Utah sample, the rs739439 minor allele was associated with decreased case risk for cleft lip with cleft palate (genotype relative risk (GRR): 0.56 [0.32-0.98]). Additionally, the rs2239907 minor allele was associated with decreased case risk for cleft lip with cleft palate in several models, and with cleft palate only in a recessive model (OR: 0.41; [0.20-0.85]). These associations did not remain statistically significant after correcting for multiple hypothesis testing. Nominal associations between SLC46A1 polymorphisms and both Irish NTDs and oral clefts in the Utah population suggest some role in the etiology of these birth defects, but further investigation in other populations is needed. © 2016 Wiley Periodicals, Inc. PMID:26789141

  15. Sorption and extraction of lactic and succinic acids at pH > pK[sub a1]. 1: Factors governing equilibria

    SciTech Connect

    Tung, L.A.; King, C.J. )

    1994-12-01

    Many fermentation to produce carboxylic acid operate most effectively at pH above pK[sub a1] of the acid product, under which conditions the acid is largely in the carboxylate form. One approach to acid recovery from such solutions is to use solid sorbents or liquid extractants that are strongly enough basic to provide substantial capacity even at moderately high values of pH. Data are presented for sorption of lactic and succinic acids by several commercially available basic polymeric sorbents. Performance at pH > pK[sub a1] is a function of sorbent basicity, and apparent pK[sub a] or monomer pK[sub a] can be used to predict sorbent performance. Data are also presented for the extraction of the acids by two commercial amine extractants, Alamine 336 and Amberlite LA-2, in various diluents. The extractants sustain capacity to higher pH in diluents that stabilize the acid-amine complex. Secondary amines provide higher capacities than do tertiary amines in diluents that solvate the additional proton. Competitive uptakes of sulfate, phosphate, and carboxylate were also measured.

  16. The ratio of FoxA1 to FoxA2 in lung adenocarcinoma is regulated by LncRNA HOTAIR and chromatin remodeling factor LSH

    PubMed Central

    Wang, Ranran; Shi, Ying; Chen, Ling; Jiang, Yiqun; Mao, Chao; Yan, Bin; Liu, Shuang; Shan, Bin; Tao, Yongguang; Wang, Xiang

    2015-01-01

    The lncRNA HOTAIR is a critical regulator of cancer progression. Chromatin remodeling factor LSH is critical for normal development of plants and mammals. However, the underlying mechanisms causing this in cancer are not entirely clear. The functional diversification of the FOXA1 and FOXA2 contributes to the target genes during evolution and carcinogenesis. Little is known about the ratio of FOXA1 to FOXA2 in cancer. We here found that both HOTAIR and LSH overexpression was significantly correlated with poor survival in patients with lung adenocarcinoma cancer (ADC). Also, the ratio of FOXA1 and FOXA2 is linked with poor survival in patients with lung ADC. HOTAIR regulates the ratio of FOXA1 to FOXA2 and migration and invasion. HOTAIR and the ratio of FOXA1 to FOXA2 are negatively correlated. HOTAIR knockdown inhibits migration and invasion. HOTAIR is associated with LSH, and this association linked with the binding of LSH in the promoter of FOXA1, not FOXA2. Targeted inhibition of HOTAIR suppresses the migratory and invasive properties. These data suggest that HOTAIR is an important mediator of the ratio of FOXA1 and FOXA2 and LSH involves in, and suggest that HOTAIR inhibition may represent a promising therapeutic option for suppressing lung ADC progression. PMID:26658322

  17. Factors related to changes in the quality of life among Polish adolescents and adults with cystic fibrosis over a 1-year period

    PubMed Central

    Dębska, Grażyna; Mazurek, Henryk

    2015-01-01

    Background The aim of this study was to determine the effects of clinical factors, physical activity, and sociodemographic variables on 1-year changes in health-related quality of life (HRQoL) in Polish adolescents and adults with cystic fibrosis (CF). Method The study included 67 subjects with CF (mean age 21.1±5.1 years; range 14–37 years; 34 males and 33 females). The Cystic Fibrosis Quality of Life Questionnaire was used at baseline and after 1 year. Lung function data, body weight, and body height were extracted from medical records. Clinical assessment was performed with the Shwachman–Kulczycki scale. Results The highest scores in both HRQoL examinations came from the domains of physical and social functioning, and the lowest from future concerns, body image, and career concerns. No significant changes of Cystic Fibrosis Quality of Life Questionnaire scores were documented over a period of 1 year. Patients with better baseline spirometry results more frequently reported an improvement in the treatment issues (subjects with FEV1 >50% of predicted, P=0.020) and in the career concerns (patients with FVC >50% of predicted, P=0.039). The improvement in the career concerns also depended upon daily physical activity (P=0.024), which was shown to modulate future concerns (P=0.032), along with place of residence and living conditions (P=0.003). Moreover, the time elapsed from the last pulmonary exacerbation was related to the change in social functioning (P=0.026). Conclusion When planning treatment, attention should be paid to interventions which may improve HRQoL. Systematic chronic therapy improves lung function, related to treatment issues and career concerns. Maintaining good physical condition and activity may positively influence future and career concerns. Special attention must be devoted to patients living in rural areas and enduring difficult living conditions, as they are especially vulnerable to deterioration in future concerns. PMID:26719679

  18. Loss of Interdependent Binding by the FoxO1 and FoxA1/A2 Forkhead Transcription Factors Culminates in Perturbation of Active Chromatin Marks and Binding of Transcriptional Regulators at Insulin-sensitive Genes.

    PubMed

    Yalley, Akua; Schill, Daniel; Hatta, Mitsutoki; Johnson, Nicole; Cirillo, Lisa Ann

    2016-04-15

    FoxO1 binds to insulin response elements located in the promoters of insulin-like growth factor-binding protein 1 (IGFBP1) and glucose-6-phosphatase (G6Pase), activating their expression. Insulin-mediated phosphorylation of FoxO1 promotes cytoplasmic translocation, inhibiting FoxO1-mediated transactivation. We have previously demonstrated that FoxO1 opens and remodels chromatin assembled from the IGFBP1 promoter via a highly conserved winged helix motif. This finding, which established FoxO1 as a "pioneer" factor, suggested a model whereby FoxO1 chromatin remodeling at regulatory targets facilitates binding and recruitment of additional regulatory factors. However, the impact of FoxO1 phosphorylation on its ability to bind chromatin and the effect of FoxO1 loss on recruitment of neighboring transcription factors at its regulatory targets in liver chromatin is unknown. In this study, we demonstrate that an amino acid substitution that mimics insulin-mediated phosphorylation of a serine in the winged helix DNA binding motif curtails FoxO1 nucleosome binding. We also demonstrate that shRNA-mediated loss of FoxO1 binding to the IGFBP1 and G6Pase promoters in HepG2 cells significantly reduces binding of RNA polymerase II and the pioneer factors FoxA1/A2. Knockdown of FoxA1 similarly reduced binding of RNA polymerase II and FoxO1. Reduction in acetylation of histone H3 Lys-27 accompanies loss of FoxO1 and FoxA1/A2 binding. Interdependent binding of FoxO1 and FoxA1/A2 possibly entails cooperative binding because FoxO1 and FoxA1/A2 facilitate one another's binding to IGFPB1 promoter DNA. These results illustrate how transcription factors can nucleate transcriptional events in chromatin in response to signaling events and suggest a model for regulation of hepatic glucose metabolism through interdependent FoxO/FoxA binding. PMID:26929406

  19. The expression of the nuclear receptors NR5A1 and NR5A2 and transcription factor GATA6 correlates with steroidogenic gene expression in the bovine corpus luteum.

    PubMed

    Taniguchi, Hiroaki; Komiyama, Junichi; Viger, Robert S; Okuda, Kiyoshi

    2009-09-01

    The corpus luteum (CL) is the major site of progesterone (P4) production during the luteal phase of the estrous cycle in cattle. To better understand the molecular mechanisms underlying P4 production, we compared the mRNA and protein expression profiles of key components of the steroidogenic pathway (StAR, CYP11A, and 3beta-HSD) during the bovine CL luteal phase with that of several transcription factors (NR5A1, NR5A2, GATA4, GATA6) known for their roles in the control of steroidogenic gene expression. In the bovine CL, StAR, CYP11A, and 3beta-HSD mRNA and protein levels remained constant at the mid and late luteal phases but markedly declined at the regressed luteal stage. NR5A1 and NR5A2 exhibited a similar pattern with a significant decrease in expression at the regressed luteal stage. Both GATA4 and GATA6 mRNA and proteins could be detected in bovine CL; GATA6 levels, however, were generally higher. Although GATA4 expression did not change during the luteal phase, GATA6 showed a marked decrease at the regressed luteal stage, like NR5A1, NR5A2, and the other steroidogenic markers. Thus, we suggest that NR5A1, NR5A2, and GATA6, but not GATA4, contribute to the transcriptional regulation of steroidogenic gene expression, and hence P4 production, in the bovine CL. Furthermore, we have demonstrated the association of NR5A1 and NR5A2 with the bovine StAR promoter in the mid-luteal CL using chromatin immunoprecipitation, suggesting that these factors have definitive roles in the regulation of StAR gene transcription in vivo. PMID:19455657

  20. Human NR5A1/SF-1 Mutations Show Decreased Activity on BDNF (Brain-Derived Neurotrophic Factor), an Important Regulator of Energy Balance: Testing Impact of Novel SF-1 Mutations Beyond Steroidogenesis

    PubMed Central

    Malikova, Jana; Camats, Núria; Fernández-Cancio, Mónica; Heath, Karen; González, Isabel; Caimarí, María; del Campo, Miguel; Albisu, Marian; Kolouskova, Stanislava; Audí, Laura; Flück, Christa E.

    2014-01-01

    Context Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. Objective To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. Patients 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. Methods SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). Results Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. Conclusions Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations. PMID:25122490

  1. Role of von Willebrand Factor-A1 Domain Variants P1266L, H1268D, C1272R, and C1272F in VWD: A Molecular Modeling and Simulation Analysis Approach.

    PubMed

    George Priya Doss, C; Ali, Shabana Kouser

    2016-01-01

    von Willebrand disease (VWD) is an autosomal inherited disorder related to trauma-related bleeding in affected people. VWD results from deficiency of von Willebrand factor (VWF)-a glycoprotein involved in hemostasis and carrier for factor VIII (FVIII). Mutations in A1 domain of von Willebrand factor (VWD) gene are exceptionally polymorphic and associated with adhesion movement, clearance, and binding properties that could be interfaced with thrombosis. To address this issue, we implemented in silico prediction algorithms, namely, SIFT, PolyPhen 2.0, I-Mutant 3.0, SNAP, Align GVGD, PhD-SNP, SNPs&GO, and MutPred to classify the variants as pathogenic and affecting protein stability. Based on prediction scores, four variants, namely, P1266L, H1268D, C1272R, and C1272F, were predicted as highly deleterious from a pool of 72 nsSNPs/variants in A1 domain of VWD belonging to type 2A and 2B. Upon literature survey, amino acid substitution (P→L) at position 1266 is involved in improving the connection with platelets, substitution (C→F) at position 1272 results in extreme bleeding in patients, and substitution (H→D) at position 1268 disturbs the salt bridge scaffold were considered for further analysis. Through molecular dynamic simulation analysis over a period of 100ns showed that four mutations near N-terminal region bring about a change in structure and function of the native VWD protein. PMID:26827609

  2. ChIP-on-chip analysis reveals angiopoietin 2 (Ang2, ANGPT2) as a novel target of steroidogenic factor-1 (SF-1, NR5A1) in the human adrenal gland

    PubMed Central

    Ferraz-de-Souza, Bruno; Lin, Lin; Shah, Sonia; Jina, Nipurna; Hubank, Mike; Dattani, Mehul T.; Achermann, John C.

    2011-01-01

    The nuclear receptor steroidogenic factor-1 (SF-1, NR5A1) is a key regulator of adrenal and gonadal biology. Disruption of SF-1 can lead to disorders of adrenal development, while increased SF-1 dosage has been associated with adrenocortical tumorigenesis. We aimed to identify a novel subset of SF-1 target genes in the adrenal by using chromatin immunoprecipitation (ChIP) microarrays (ChIP-on-chip) combined with systems analysis. SF-1 ChIP-on-chip was performed in NCI-H295R human adrenocortical cells using promoter tiling arrays, leading to the identification of 445 gene loci where SF-1-binding regions were located from 10 kb upstream to 3 kb downstream of a transcriptional start. Network analysis of genes identified as putative SF-1 targets revealed enrichment for angiogenic process networks. A 1.1-kb SF-1-binding region was identified in the angiopoietin 2 (Ang2, ANGPT2) promoter in a highly repetitive region, and SF-1-dependent activation was confirmed in luciferase assays. Angiogenesis is paramount in adrenal development and tumorigenesis, but until now a direct link between SF-1 and vascular remodeling has not been established. We have identified Ang2 as a potentially important novel target of SF-1 in the adrenal gland, indicating that regulation of angiogenesis might be an important additional mechanism by which SF-1 exerts its actions in the adrenal gland.Ferraz-de-Souza, B., Lin, L., Shah, S., Jina, N., Hubank, M., Dattani, M. T., Achermann, J. C. ChIP-on-chip analysis reveals angiopoietin 2 (Ang2, ANGPT2) as a novel target of steroidogenic factor-1 (SF-1, NR5A1) in the human adrenal gland. PMID:21163858

  3. Exenatide once weekly improved glycaemic control, cardiometabolic risk factors and a composite index of an HbA1c < 7%, without weight gain or hypoglycaemia, over 52 weeks

    PubMed Central

    Bergenstal, R M; Li, Y; Porter, T K Booker; Weaver, C; Han, J

    2013-01-01

    Aims Type 2 diabetes mellitus (T2DM) is often associated with cardiovascular (CV) risk factors such as obesity, hypertension and dyslipidemia. The objective of this analysis was to evaluate potential effects of exenatide once weekly (ExQW), a GLP-1 receptor agonist, on glycaemic control and CV risk factors. Methods This analysis included 675 Intent-to-Treat patients with T2DM [baseline (mean ± SD) HbA1c, 8.1 ± 1.2%; fasting blood glucose (FBG), 166 ± 48 mg/dl; weight, 94.3 ± 19.4 kg; systolic/diastolic blood pressure (SBP/DBP), 129 ± 15/78 ± 9 mm Hg; total cholesterol, 178.5 ± 41.9 mg/dl; low-density lipoprotein (LDL), 100.1 ± 35.0 mg/dl; high-density lipoprotein (HDL), 44.5 ± 11.6 mg/dl; triglycerides, 155.6 ± 3.3 mg/dl; alanine aminotransferase (ALT), 32.1 ± 19.5 U/l] treated with diet and exercise alone or in combination with metformin, sulfonylurea, and/or thiazolidinedione who received 52 weeks of ExQW in four clinical trials. Results At 52 weeks, ExQW significantly improved HbA1c [mean (SE) change from baseline, −1.3 (0.05)%], FBG [−36.3 (2.02) mg/dl], body weight [−2.6 (0.19) kg], SBP/DBP [−3.6 (0.56) mm Hg/−1.2 (0.34) mm Hg], total cholesterol, −4.4 (1.33) mg/dl; LDL, −2.6 (1.08) mg/dl; HDL, 1.1 (0.31) mg/dl; triglycerides, −7 (1.6)%], and ALT [−4.3 (0.71) IU/l] concentrations, with greater improvements in patients with elevated analyte levels at baseline. Improvements were observed across a range of background antihyperglycaemia therapies. Of patients completing 52 weeks, 19% achieved the composite American Diabetes Association goal (HbA1c < 7.0%, BP < 130/80 mm Hg, LDL < 100 mg/dl), compared to 1% at baseline. Nearly half (48%) achieved HbA1c < 7.0% without weight gain or major/minor hypoglycaemia. Nausea was the most frequent adverse event and was predominantly mild. Hypoglycaemia was infrequent, and more common with a sulfonylurea. Conclusions With 52 weeks of ExQW, patients experienced sustained improvements in glycaemic control and CV risk factors, with an increased likelihood of achieving both a clinically relevant composite outcome (HbA1c < 7% without weight gain or increased risk of hypoglycaemia) and a composite of key therapeutic goals (HbA1c < 7%, BP < 130/80 mm Hg, LDL < 100 mg/dl). PMID:23078638

  4. Platelet GpIbα Binding to von Willebrand Factor Under Fluid Shear: Contributions of the D'D3‐Domain, A1‐Domain Flanking Peptide and O‐Linked Glycans

    PubMed Central

    Madabhushi, Sri R.; Zhang, Changjie; Kelkar, Anju; Dayananda, Kannayakanahalli M.; Neelamegham, Sriram

    2014-01-01

    Background Von Willebrand Factor (VWF) A1‐domain binding to platelet receptor GpIbα is an important fluid‐shear dependent interaction that regulates both soluble VWF binding to platelets, and platelet tethering onto immobilized VWF. We evaluated the roles of different structural elements at the N‐terminus of the A1‐domain in regulating shear dependent platelet binding. Specifically, the focus was on the VWF D′D3‐domain, A1‐domain N‐terminal flanking peptide (NFP), and O‐glycans on this peptide. Methods and Results Full‐length dimeric VWF (ΔPro‐VWF), dimeric VWF lacking the D′D3 domain (ΔD′D3‐VWF), and ΔD′D3‐VWF variants lacking either the NFP (ΔD′D3NFP─‐VWF) or just O‐glycans on this peptide (ΔD′D3OG─‐VWF) were expressed. Monomeric VWF‐A1 and D′D3‐A1 were also produced. In ELISA, the apparent dissociation constant (KD) of soluble ΔPro‐VWF binding to immobilized GpIbα (KD≈100 nmol/L) was 50‐ to 100‐fold higher than other proteins lacking the D′D3 domain (KD~0.7 to 2.5 nmol/L). Additionally, in surface plasmon resonance studies, the on‐rate of D′D3‐A1 binding to immobilized GpIbα (kon=1.8±0.4×104 (mol/L)−1·s−1; KD=1.7 μmol/L) was reduced compared with the single VWF‐A1 domain (kon=5.1±0.4×104 (mol/L)−1·s−1; KD=1.2 μmol/L). Thus, VWF‐D′D3 primarily controls soluble VWF binding to GpIbα. In contrast, upon VWF immobilization, all molecular features regulated A1‐GpIbα binding. Here, in ELISA, the number of apparent A1‐domain sites available for binding GpIbα on ΔPro‐VWF was ≈50% that of the ΔD′D3‐VWF variants. In microfluidics based platelet adhesion measurements on immobilized VWF and thrombus formation assays on collagen, human platelet recruitment varied as ΔPro‐VWF<ΔD′D3‐VWF<ΔD′D3NFP─‐VWF<ΔD′D3OG─‐VWF. Conclusions Whereas VWF‐D′D3 is the major regulator of soluble VWF binding to platelet GpIbα, both the D′D3‐domain and N‐terminal peptide regulate platelet translocation and thrombus formation. PMID:25341886

  5. Complete sequence of the genes encoding the VH and VL regions of low- and high-affinity monoclonal IgM and lgA1 rheumatoid factors produced by CD5+ B cells from a rheumatoid arthritis patient

    PubMed Central

    Harindranath, Nagaradona; Goldfarb, Inna S.; Ikematsu, Hideyuki; Burastero, Samuele E.; Wilder, Ronald L.; Notkins, Abner L.; Casali, Paolo

    2015-01-01

    We have characterized the VH and VL genes of three low-affinity polyreactive and two high-affinlty monoreactive IgM and lgA1 rheumatoid factor (RF) mAb generated using circulating CD5+ B cells from a single rheumatoid arthritis patient. We found that four and one RF mAb utilized genes of the VHIV and VHIII families, respectively. The VHIV gene usage by these RF mAb differs from the preferential VHIII, VHI, and, to a lesser extent, VHII gene usage by the IgM with RF activity found In patients with mixed cryoglobulinemia, Waldenstrom's macroglobulinemia, and other monoclonal gammopathies. In addition, in contrast to the preponderant χL chain usage by the RF In these patients, a λL chain was utilized by all RF mAb from our rheumatoid arthritis patient. Two RF mAbs utilized VλI, two VλIV, and one VλIII L chains. The VH genes of the two low-affinity polyreactive IgM RF mAb were in germline configuration. When compared with the deduced amino acid sequence of the putatively corresponding genomic segment, the VH gene of the high-affinity monoreactive IgM RF mAb displayed five amino acid differences, all of which are in the complementarity determining regions (CDR), possibly the result of a process of somatic point mutation and clonal selection driven by Ag. The unavailability of the corresponding genomic VH segment sequences made it impossible to infer whether the VH genes utilized by the two lgA1 RF were in a germline or somatically mutated configuration. Sequencing of the genes encoding the H chain CDR3 (D segments) revealed that all three low-affinity polyreactive RF mAb displayed a much longer D segment (36–45 bases) than their high-affinity monoreactive counterparts (15–24 bases), raising the possibility that a long D segment may be one of the factors involved in antibody polyreactivity. PMID:1718404

  6. Serum- and Growth-Factor-Free Three-Dimensional Culture System Supports Cartilage Tissue Formation by Promoting Collagen Synthesis via Sox9–Col2a1 Interaction

    PubMed Central

    Ahmed, Nazish; Iu, Jonathan; Brown, Chelsea E.; Taylor, Drew Wesley

    2014-01-01

    Objective: One of the factors preventing clinical application of regenerative medicine to degenerative cartilage diseases is a suitable source of cells. Chondrocytes, the only cell type of cartilage, grown in vitro under culture conditions to expand cell numbers lose their phenotype along with the ability to generate hyaline cartilaginous tissue. In this study we determine that a serum- and growth-factor-free three-dimensional (3D) culture system restores the ability of the passaged chondrocytes to form cartilage tissue in vitro, a process that involves sox9. Methods: Bovine articular chondrocytes were passaged twice to allow for cell number expansion (P2) and cultured at high density on 3D collagen-type-II-coated membranes in high glucose content media supplemented with insulin and dexamethasone (SF3D). The cells were characterized after monolayer expansion and following 3D culture by flow cytometry, gene expression, and histology. The early changes in signaling transduction pathways during redifferentiation were characterized. Results: The P2 cells showed a progenitor-like antigen profile of 99% CD44+ and 40% CD105+ and a gene expression profile suggestive of interzone cells. P2 in SF3D expressed chondrogenic genes and accumulated extracellular matrix. Downregulating insulin receptor (IR) with HNMPA-(AM3) or the PI-3/AKT kinase pathway (activated by insulin treatment) with Wortmannin inhibited collagen synthesis. HNMPA-(AM3) reduced expression of Col2, Col11, and IR genes as well as Sox6 and -9. Co-immunoprecipitation and chromatin immunoprecipitation analyses of HNMPA-(AM3)-treated cells showed binding of the coactivators Sox6 and Med12 with Sox9 but reduced Sox9–Col2a1 binding. Conclusions: We describe a novel culture method that allows for increase in the number of chondrocytes and promotes hyaline-like cartilage tissue formation in part by insulin-mediated Sox9–Col2a1 binding. The suitability of the tissue generated via this approach for use in joint repair needs to be examined in vivo. PMID:24606204

  7. Novel mechanism of transcriptional repression of the human ATP binding cassette transporter A1 gene in hepatic cells by the winged helix/forkhead box transcription factor A2.

    PubMed

    Thymiakou, Efstathia; Kardassis, Dimitris

    2014-06-01

    ATP binding cassette transporter A1 (ABCA1) plays a key role in the biogenesis of HDL by promoting the efflux of cellular cholesterol and phospholipids to lipid free apoA-I. Mutations in the ABCA1 gene cause Tangier disease which is characterized by near or complete absence of circulating plasma HDL. In the present study we show that the winged helix/forkhead box containing transcription factor A2 (FOXA2) shown previously to play a role in glucose and bile acid homeostasis in the liver and in energy utilization in adipose tissue is a negative modulator of ABCA1 gene expression in hepatic cells. We show that the ABCA1 promoter contains three FOXA2 binding elements in the proximal region. Two of the sites are localized in a region of the ABCA1 promoter enriched in binding elements for transcriptional repressor proteins whereas the third site is the core of the TATA element of the ABCA1 promoter. Inhibition of FOXA2 binding to the ABCA1 promoter by site-directed mutagenesis or FOXA2 gene expression by siRNA was associated with increased ABCA1 promoter activity and protein levels. Overexpression of FOXA2 inhibited both the constitutive ABCA1 gene expression as well as ABCA1 gene induction by oxysterols and retinoids via nuclear receptors LXRα/RXRα. In summary, the present study identifies transcription factor FOXA2 as a negative modulator of ABCA1 gene expression in hepatic cells and reveals a novel mechanism of transcriptional repression by FOXA2 which involves the TATA element of the ABCA1 gene. PMID:24807696

  8. A1C test

    MedlinePlus

    HbA1C test; Glycated hemoglobin test; Glycosylated hemoglobin test; Hemoglobin glycosylated test; Glycohemoglobin test ... have recently eaten does not affect the A1C test, so you do not need to fast to ...

  9. A1C

    MedlinePlus

    A1C is a blood test for type 2 diabetes and prediabetes. It measures your average blood glucose, or blood sugar, level over the past 3 ... A1C alone or in combination with other diabetes tests to make a diagnosis. They also use the ...

  10. A1C Test

    MedlinePlus

    ... eAG on their DiabetesPro web site . The NGSP web site also provides a calculator to convert hemoglobin A1c in SI units mmol/mol into percentage. ^ Back to top Is there anything else I should know? The A1c test will not reflect temporary, acute blood glucose increases ...

  11. Raman spectroscopy and principal factor multivariate curve resolution analysis of concentrated A1[sub 2]O[sub 3]-Na[sub 2]O-H[sub 2]O solutions

    SciTech Connect

    Schoonover, J. R.

    2002-01-01

    Principal factor multivariate curve resolution has been applied to a series of Raman spectra for samples representing, highly concentrated alkaline aluminate slurries. Factors are extracted that represent the behavior of the dominant chemical species present, including aluminate monomer, aluminate oligomers, water, and hydroxide. The analysis is particularly useful in unraveling the numerous contributions in the v(0H) region of the spectrum. These extracted factors were further examined by comparing their scores to measured physiochemical properties such as density, relative humidity, and molar concentrations of components, weight fractions, and water activity.

  12. Inflammatory markers associated with osteoarthritis after destabilization surgery in young mice with and without Receptor for Advanced Glycation End-products (RAGE)

    PubMed Central

    Larkin, D. Justin; Kartchner, Jeffrey Z.; Doxey, Alexander S.; Hollis, Weston R.; Rees, Jeffrey L.; Wilhelm, Spencer K.; Draper, Christian S.; Peterson, Danielle M.; Jackson, Gregory G.; Ingersoll, Chelsey; Haynie, S. Scott; Chavez, Elizabeth; Reynolds, Paul R.; Kooyman, David L.

    2013-01-01

    HtrA1, Ddr-2, and Mmp-13 are reliable biomarkers for osteoarthritis (OA), yet the exact mechanism for the upregulation of HtrA-1 is unknown. Some have shown that chondrocyte hypertrophy is associated with early indicators of inflammation including TGF-β and the Receptor for Advanced Glycation End-products (RAGE). To examine the correlation of inflammation with the expression of biomarkers in OA, we performed right knee destabilization surgery on 4-week-old-wild type and RAGE knock-out (KO) mice. We assayed for HtrA-1, TGF-β1, Mmp-13, and Ddr-2 in articular cartilage at 3, 7, 14, and 28 days post-surgery by immunohistochemistry on left and right knee joints. RAGE KO and wild type mice both showed staining for key OA biomarkers. However, RAGE KO mice were significantly protected against OA compared to controls. We observed a difference in the total number of chondrocytes and percentage of chondrocytes staining positive for OA biomarkers between RAGE KO and control mice. The percentage of cells staining for OA biomarkers correlated with severity of cartilage degradation. Our results indicate that the absence of RAGE did protect against the development of advanced OA. We conclude that HtrA-1 plays a role in lowering TGF-β1 expression in the process of making articular cartilage vulnerable to damage associated with OA progression. PMID:23755017

  13. Led Astray by Hemoglobin A1c

    PubMed Central

    Chen, Jean; Diesburg-Stanwood, Amy; Bodor, Geza; Rasouli, Neda

    2016-01-01

    Hemoglobin A1c (A1c) is used frequently to diagnose and treat diabetes mellitus. Therefore, it is important be aware of factors that may interfere with the accuracy of A1c measurements. This is a case of a rare hemoglobin variant that falsely elevated a nondiabetic patient’s A1c level and led to a misdiagnosis of diabetes. A 67-year-old male presented to endocrine clinic for further management after he was diagnosed with diabetes based on an elevated A1c of 10.7%, which is approximately equivalent to an average blood glucose of 260 mg/dL. Multiple repeat A1c levels remained >10%, but his home fasting and random glucose monitoring ranged from 92 to 130 mg/dL. Hemoglobin electrophoresis and subsequent genetic analysis diagnosed the patient with hemoglobin Wayne, a rare hemoglobin variant. This variant falsely elevates A1c levels when A1c is measured using cation-exchange high-performance liquid chromatography. When the boronate affinity method was applied instead, the patient’s A1c level was actually 4.7%. Though hemoglobin Wayne is clinically silent, this patient was erroneously diagnosed with diabetes and started on an antiglycemic medication. Due to this misdiagnosis, the patient was at risk of escalation in his “diabetes management” and hypoglycemia. Therefore, it is important that providers are aware of factors that may result in hemoglobin A1c inaccuracy including hemoglobin variants. PMID:26848480

  14. Effects of Thyroxine Exposure on Osteogenesis in Mouse Calvarial Pre-Osteoblasts

    PubMed Central

    Cray, James J.; Khaksarfard, Kameron; Weinberg, Seth M.; Elsalanty, Mohammed; Yu, Jack C.

    2013-01-01

    The incidence of craniosynostosis is one in every 1,800–2500 births. The gene-environment model proposes that if a genetic predisposition is coupled with environmental exposures, the effects can be multiplicative resulting in severely abnormal phenotypes. At present, very little is known about the role of gene-environment interactions in modulating craniosynostosis phenotypes, but prior evidence suggests a role for endocrine factors. Here we provide a report of the effects of thyroid hormone exposure on murine calvaria cells. Murine derived calvaria cells were exposed to critical doses of pharmaceutical thyroxine and analyzed after 3 and 7 days of treatment. Endpoint assays were designed to determine the effects of the hormone exposure on markers of osteogenesis and included, proliferation assay, quantitative ALP activity assay, targeted qPCR for mRNA expression of Runx2, Alp, Ocn, and Twist1, genechip array for 28,853 targets, and targeted osteogenic microarray with qPCR confirmations. Exposure to thyroxine stimulated the cells to express ALP in a dose dependent manner. There were no patterns of difference observed for proliferation. Targeted RNA expression data confirmed expression increases for Alp and Ocn at 7 days in culture. The genechip array suggests substantive expression differences for 46 gene targets and the targeted osteogenesis microarray indicated 23 targets with substantive differences. 11 gene targets were chosen for qPCR confirmation because of their known association with bone or craniosynostosis (Col2a1, Dmp1, Fgf1, 2, Igf1, Mmp9, Phex, Tnf, Htra1, Por, and Dcn). We confirmed substantive increases in mRNA for Phex, FGF1, 2, Tnf, Dmp1, Htra1, Por, Igf1 and Mmp9, and substantive decreases for Dcn. It appears thyroid hormone may exert its effects through increasing osteogenesis. Targets isolated suggest a possible interaction for those gene products associated with calvarial suture growth and homeostasis as well as craniosynostosis. PMID:23935926

  15. [UGT1A1 Genotyping for Proper Use of Irinotecan].

    PubMed

    Matsuoka, Ayumu; Ando, Yuichi

    2015-07-01

    Irinotecan is a camptothecin analog used worldwide for a broad range of solid tumors, including colorectal and lung cancers. It can cause severe adverse drug reactions, such as neutropenia or diarrhea. Irinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by the UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Recent pharmacogenetic studies on irinotecan have revealed the impact of UGT1A1 polymorphisms on severe adverse effects. A variant in the promoter of the UGT1A1 gene, the UGT1A1 *28 allele, has been extensively studied, and pharmacogenetic relationships between the variant and severe toxicities of irinotecan have been reported. The US FDA and pharmaceutical companies revised the irinotecan label in 2005, and it now includes homozygosity for the UGT1A1*28 genotype as one of the risk factors for severe neutropenia. A variant in exon 1 of the UGT1A1 gene, the UGT1A1*6 allele, mainly found in East Asians, is also an important risk factor associated with severe neutropenia. The concurrence of UGT1A1*28 and UGT1A1*6, even when heterozygous, markedly alters the disposition of irinotecan, potentially increasing toxicity, which is now written on the label of irinotecan in Japan. For patients showing homozygosity for UGT1A1*28, *6, or compound heterozygosity for UGT1A1*6 and *28, dose reduction of irinotecan is strongly recommended. Genotyping tests for UGT1A1 *6 and *28 have been approved in Japan and are currently used in oncology practice. Moreover, a recent Phase 2 trial for FOLFIRINOX in Japan excluded patients who showed homozygosity for UGT1A1*28, *6, or compound heterozygosity for UGT1A1*6 and *28. At present, irinotecan chemotherapy based on a patient's UGT1A1 genetic status is scientifically reasonable. PMID:26591441

  16. A-1 Test Stand work

    NASA Technical Reports Server (NTRS)

    2010-01-01

    A structural steel beam to support the new thrust measurement system on the A-1 Test Stand at NASA's John C. Stennis Space Center is lifted to waiting employees for installation. The beam is part of the thrust takeout structure needed to support the new measurement system. Four such beams have been installed at the stand in preparation for installation of the system in upcoming weeks. Operators are preparing the stand for testing the next generation of rocket engines for the U.S. space program.

  17. Led Astray by Hemoglobin A1c: A Case of Misdiagnosis of Diabetes by Falsely Elevated Hemoglobin A1c.

    PubMed

    Chen, Jean; Diesburg-Stanwood, Amy; Bodor, Geza; Rasouli, Neda

    2016-01-01

    Hemoglobin A1c (A1c) is used frequently to diagnose and treat diabetes mellitus. Therefore, it is important be aware of factors that may interfere with the accuracy of A1c measurements. This is a case of a rare hemoglobin variant that falsely elevated a nondiabetic patient's A1c level and led to a misdiagnosis of diabetes. A 67-year-old male presented to endocrine clinic for further management after he was diagnosed with diabetes based on an elevated A1c of 10.7%, which is approximately equivalent to an average blood glucose of 260 mg/dL. Multiple repeat A1c levels remained >10%, but his home fasting and random glucose monitoring ranged from 92 to 130 mg/dL. Hemoglobin electrophoresis and subsequent genetic analysis diagnosed the patient with hemoglobin Wayne, a rare hemoglobin variant. This variant falsely elevates A1c levels when A1c is measured using cation-exchange high-performance liquid chromatography. When the boronate affinity method was applied instead, the patient's A1c level was actually 4.7%. Though hemoglobin Wayne is clinically silent, this patient was erroneously diagnosed with diabetes and started on an antiglycemic medication. Due to this misdiagnosis, the patient was at risk of escalation in his "diabetes management" and hypoglycemia. Therefore, it is important that providers are aware of factors that may result in hemoglobin A1c inaccuracy including hemoglobin variants. PMID:26848480

  18. A-1 Test Stand work

    NASA Technical Reports Server (NTRS)

    2010-01-01

    Employees at NASA's John C. Stennis Space Center work to maneuver a structural steam beam into place on the A-1 Test Stand on Jan. 13. The beam was one of several needed to form the thrust takeout structure that will support a new thrust measurement system being installed on the stand for future rocket engine testing. Once lifted onto the stand, the beams had to be hoisted into place through the center of the test stand, with only two inches of clearance on each side. The new thrust measurement system represents a state-of-the-art upgrade from the equipment installed more than 40 years ago when the test stand was first constructed.

  19. Mutations in NR5A1 Associated with Ovarian Insufficiency

    PubMed Central

    Loureno, Diana; Brauner, Raja; Lin, Lin; De Perdigo, Arantzazu; Weryha, Georges; Muresan, Mihaela; Boudjenah, Radia; Guerra-Junior, Gil; Maciel-Guerra, Andra T.; Achermann, John C.; McElreavey, Ken; Bashamboo, Anu

    2009-01-01

    BACKGROUND The genetic causes of nonsyndromic ovarian insufficiency are largely unknown. A nuclear receptor, NR5A1 (also called steroidogenic factor 1), is a key transcriptional regulator of genes involved in the hypothalamicpituitarysteroidogenic axis. Mutation of NR5A1 causes 46,XY disorders of sex development, with or without adrenal failure, but growing experimental evidence from studies in mice suggests a key role for this factor in ovarian development and function as well. METHODS To test the hypothesis that mutations in NR5A1 cause disorders of ovarian development and function, we sequenced NR5A1 in four families with histories of both 46,XY disorders of sex development and 46,XX primary ovarian insufficiency and in 25 subjects with sporadic ovarian insufficiency. None of the affected subjects had clinical signs of adrenal insufficiency. RESULTS Members of each of the four families and 2 of the 25 subjects with isolated ovarian insufficiency carried mutations in the NR5A1 gene. In-frame deletions and frameshift and missense mutations were detected. Functional studies indicated that these mutations substantially impaired NR5A1 transactivational activity. Mutations were associated with a range of ovarian anomalies, including 46,XX gonadal dysgenesis and 46,XX primary ovarian insufficiency. We did not observe these mutations in more than 700 control alleles. CONCLUSIONS NR5A1 mutations are associated with 46,XX primary ovarian insufficiency and 46,XY disorders of sex development. PMID:19246354

  20. Production of a_1 in heavy meson decays

    NASA Astrophysics Data System (ADS)

    Wang, Wei; Zhao, Zhen-Xing

    2016-02-01

    In this work, we study various decays of heavy B / D mesons into the a_1(1260), based on the form factors derived in different nonperturbative or factorization approaches. These decay modes are helpful to explore the dynamics in the heavy to light transitions. Meanwhile they can also provide insights to a newly discovered state, the a_1(1420) with I^G(J^{PC})= 1^-(1^{++}) observed in the π ^+ f_0(980) final state in the π ^-p→ π ^+π ^-π ^- p process. Available theoretical explanations include tetraquark or rescattering effects due to a_1(1260) decays. If the a_1(1420) were induced by the rescattering, its production rates are completely determined by those of the a_1(1260). Our numerical results for decays into the a_1(1260) indicate that there is a promising prospect to study these decays on experiments including BES-III, LHCb, Babar, Belle, and CLEO-c, the forthcoming Super-KEKB factory and the under-design Circular Electron-Positron Collider.

  1. 14 CFR 374a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 4 2010-01-01 2010-01-01 false Purpose. 374a.1 Section 374a.1 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.1 Purpose. Section 401...

  2. 14 CFR 374a.1 - Purpose.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 14 Aeronautics and Space 4 2011-01-01 2011-01-01 false Purpose. 374a.1 Section 374a.1 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.1 Purpose. Section 401...

  3. 14 CFR 374a.1 - Purpose.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 14 Aeronautics and Space 4 2013-01-01 2013-01-01 false Purpose. 374a.1 Section 374a.1 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.1 Purpose. Section 401...

  4. 14 CFR 374a.1 - Purpose.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 14 Aeronautics and Space 4 2014-01-01 2014-01-01 false Purpose. 374a.1 Section 374a.1 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.1 Purpose. Section 401...

  5. 14 CFR 374a.1 - Purpose.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 14 Aeronautics and Space 4 2012-01-01 2012-01-01 false Purpose. 374a.1 Section 374a.1 Aeronautics and Space OFFICE OF THE SECRETARY, DEPARTMENT OF TRANSPORTATION (AVIATION PROCEEDINGS) SPECIAL REGULATIONS EXTENSION OF CREDIT BY AIRLINES TO FEDERAL POLITICAL CANDIDATES § 374a.1 Purpose. Section 401...

  6. 22 CFR 3a.1 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Definitions. 3a.1 Section 3a.1 Foreign Relations DEPARTMENT OF STATE GENERAL ACCEPTANCE OF EMPLOYMENT FROM FOREIGN GOVERNMENTS BY MEMBERS OF THE UNIFORMED SERVICES § 3a.1 Definitions. For purposes of this part— (a) Applicant means any person...

  7. 12 CFR 708a.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 12 Banks and Banking 6 2011-01-01 2011-01-01 false Definitions. 708a.1 Section 708a.1 Banks and Banking NATIONAL CREDIT UNION ADMINISTRATION REGULATIONS AFFECTING CREDIT UNIONS BANK CONVERSIONS AND MERGERS Conversion of Insured Credit Unions to Mutual Savings Banks § 708a.1 Definitions. As used in this part: Clear and conspicuous means text...

  8. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 1 2013-04-01 2013-04-01 false Purpose. 3a.1 Section 3a.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.1 Purpose. This part 3a describes...

  9. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 1 2012-04-01 2012-04-01 false Purpose. 3a.1 Section 3a.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.1 Purpose. This part 3a describes...

  10. 18 CFR 3a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Purpose. 3a.1 Section 3a.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES NATIONAL SECURITY INFORMATION General § 3a.1 Purpose. This part 3a describes...

  11. 45 CFR 12a.1 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 45 Public Welfare 1 2012-10-01 2012-10-01 false Definitions. 12a.1 Section 12a.1 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION USE OF FEDERAL REAL PROPERTY TO ASSIST THE HOMELESS § 12a.1 Definitions. Applicant means any representative of the homeless which has submitted an application to the Department of...

  12. A1C Test and Diabetes

    MedlinePlus

    ... Can the A1C test be used to diagnose type 2 diabetes and prediabetes? Yes. In 2009, an international expert ... How is the A1C test used to diagnose type 2 diabetes and prediabetes? The A1C test can be used ...

  13. 8 CFR 274a.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 8 Aliens and Nationality 1 2011-01-01 2011-01-01 false Definitions. 274a.1 Section 274a.1 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS CONTROL OF EMPLOYMENT OF ALIENS Employer Requirements § 274a.1 Definitions. For the purpose of this part— (a) The term unauthorized alien means, with respect to employment of...

  14. 46 CFR 147A.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 5 2010-10-01 2010-10-01 false Purpose. 147A.1 Section 147A.1 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) DANGEROUS CARGOES INTERIM REGULATIONS FOR SHIPBOARD FUMIGATION General § 147A.1 Purpose. The purpose of this part is to prescribe the requirements for shipboard fumigation that are critical for the health...

  15. S100A1: Structure, Function, and Therapeutic Potential

    PubMed Central

    Wright, Nathan T.; Cannon, Brian R.; Zimmer, Danna B.; Weber, David J.

    2009-01-01

    S100A1 is a member of the S100 family of calcium-binding proteins. As with most S100 proteins, S100A1 undergoes a large conformational change upon binding calcium as necessary to interact with numerous protein targets. Targets of S100A1 include proteins involved in calcium signaling (ryanidine receptors 1 & 2, Serca2a, phopholamban), neurotransmitter release (synapsins I & II), cytoskeletal and filament associated proteins (CapZ, microtubules, intermediate filaments, tau, mocrofilaments, desmin, tubulin, F-actin, titin, and the glial fibrillary acidic protein GFAP), transcription factors and their regulators (e.g. myoD, p53), enzymes (e.g. aldolase, phosphoglucomutase, malate dehydrogenase, glycogen phosphorylase, photoreceptor guanyl cyclases, adenylate cyclases, glyceraldehydes-3-phosphate dehydrogenase, twitchin kinase, Ndr kinase, and F1 ATP synthase), and other Ca2+-activated proteins (annexins V & VI, S100B, S100A4, S100P, and other S100 proteins). There is also a growing interest in developing inhibitors of S100A1 since they may be beneficial for treating a variety of human diseases including neurological diseases, diabetes mellitus, heart failure, and several types of cancer. The absence of significant phenotypes in S100A1 knockout mice provides some early indication that an S100A1 antagonist could have minimal side effects in normal tissues. However, development of S100A1-mediated therapies is complicated by S100A1’s unusual ability to function as both an intracellular signaling molecule and as a secreted protein. Additionally, many S100A1 protein targets have only recently been identified, and so fully characterizing both these S100A1-target complexes and their resulting functions is a necessary prerequisite. PMID:19890475

  16. Reversibility of Intersystem Crossing in the {a}1A1(000) and {a}1A1(010) States of Methylene, CH_2

    NASA Astrophysics Data System (ADS)

    Le, Anh T.; Sears, Trevor; Hall, Gregory

    2015-06-01

    The lowest energy singlet ( {a}1A1) and triplet ( {X}3B1) electronic states of methylene, CH_2, are only separated by 3150 wn, but differ greatly in chemical reactivity. Overall methylene reaction rates and chemical behavior are therefore strongly dependent on collisionally-mediated singlet-triplet interconversion. Collisions with inert partners tend to depopulate the excited singlet state and populate vibrationally excited triplet levels in CH_2. This process is generally considered as irreversible for large molecules, however, this is not the case for small molecules such as CH_2. An investigation of the decay kinetics of CH_2 in the presence of argon and various amounts of oxygen has been carried out using transient frequency modulation (FM) absorption spectroscopy, to monitor ortho and para rotational levels in both the {a}1A1(000) and {a}1A1(010) states. In the {a}1A1(000) state, all observed rotational levels follow double exponential decay kinetics, a direct consequence of reversible intersystem crossing. The relative amplitude of the slower decay component is an indicator of how quickly the reverse crossing from excited triplet levels becomes significant during the reaction and relaxation of singlet methylene. The para rotational levels show more obvious signs of reversibility than ortho rotational levels. Adding oxygen enhances the visibility of reversibility for both ortho and para levels. However, in the {a}1A1(010) state where the FM signal is 5-10 times smaller than the {a}1A1(000) state, there is no evidence of double exponential decay kinetics. Acknowledgments: Work at Brookhaven National Laboratory was carried out under Contract No. DE-AC02-98CH10886 and DE-SC0012704 with the U.S. Department of Energy and supported by its Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences and Biosciences.

  17. 42 CFR 54a.1 - Scope.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    .... 290aa, et seq., which are administered by the Substance Abuse and Mental Health Services Administration. This part does not apply to direct funding under any such authorities for only mental health services... 42 Public Health 1 2012-10-01 2012-10-01 false Scope. 54a.1 Section 54a.1 Public Health...

  18. 42 CFR 54a.1 - Scope.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    .... 290aa, et seq., which are administered by the Substance Abuse and Mental Health Services Administration. This part does not apply to direct funding under any such authorities for only mental health services... 42 Public Health 1 2010-10-01 2010-10-01 false Scope. 54a.1 Section 54a.1 Public Health...

  19. 42 CFR 54a.1 - Scope.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    .... 290aa, et seq., which are administered by the Substance Abuse and Mental Health Services Administration. This part does not apply to direct funding under any such authorities for only mental health services... 42 Public Health 1 2013-10-01 2013-10-01 false Scope. 54a.1 Section 54a.1 Public Health...

  20. 42 CFR 54a.1 - Scope.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    .... 290aa, et seq., which are administered by the Substance Abuse and Mental Health Services Administration. This part does not apply to direct funding under any such authorities for only mental health services... 42 Public Health 1 2011-10-01 2011-10-01 false Scope. 54a.1 Section 54a.1 Public Health...

  1. Blood Test: Hemoglobin A1C

    MedlinePlus

    ... Cerebral Palsy: Caring for Your Child All About Food Allergies Blood Test: Hemoglobin A1c KidsHealth > For Parents > Blood Test: Hemoglobin A1c Print A A A Text Size What's in this article? What It Is Why It's Done Preparation The Procedure What to Expect Getting the Results ...

  2. Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma

    PubMed Central

    Hedrick, Erik; Lee, Syng-Ook; Kim, Gyungeun; Abdelrahim, Maen; Jin, Un-Ho; Safe, Stephen; Abudayyeh, Ala

    2015-01-01

    The orphan nuclear receptor NR4A1 exhibits pro-oncogenic activity in cancer cell lines. NR4A1 activates mTOR signaling, regulates genes such as thioredoxin domain containing 5 and isocitrate dehydrogenase 1 that maintain low oxidative stress, and coactivates specificity protein 1 (Sp1)-regulated pro-survival and growth promoting genes. Transfection of renal cell carcinoma (RCC) ACHN and 786-O cells with oligonucleotides that target NR4A1 results in a 40–60% decrease in cell proliferation and induction of apoptosis. Moreover, knockdown of NR4A1 in RCC cells decreased bcl-2, survivin and epidermal growth factor receptor expression, inhibited of mTOR signaling, induced oxidative and endoplasmic reticulum stress, and decreased TXNDC5 and IDH1. We have recently demonstrated that selected 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compounds including the p-hydroxyphenyl (DIM-C-pPhOH) and p-carboxymethyl (DIM-C-pPhCO2Me) analogs bind NR4A1 and act as antagonists. Both DIM-C-pPhOH and DIM-C-pPhCO2Me inhibited growth and induced apoptosis in ACHN and 786-O cells, and the functional and genomic effects of the NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. These results indicate that NR4A1 antagonists target multiple growth promoting and pro-survival pathways in RCC cells and in tumors (xenograft) and represent a novel chemotherapy for treating RCC. PMID:26035713

  3. Rethinking Factors

    ERIC Educational Resources Information Center

    Feldman, Ziv

    2014-01-01

    This article describes an exciting exploration-based activity in which students develop an alternative definition of factor that can help them solve problems like the one presented above. Students work in groups to collect data, analyze the data to make conjectures, and then spend a significant amount of time debating and justifying their…

  4. Decisive Factors.

    ERIC Educational Resources Information Center

    Goldman, Robin, Comp.

    1989-01-01

    Two books on private donor decision-making are reviewed: "Decision Making in Foundations: A Case Study" by A. Hope Williams and "Factors Accounting for Variations in Levels of Private Giving to Higher Education in the United States" by Sally Spaid Drachman. (MSE)

  5. Rheumatoid Factor

    MedlinePlus

    ... profit organization and does not endorse non-AACC products and services. Advertising & Sponsorship: Policy | Opportunities PLEASE NOTE: Your web browser does not have JavaScript enabled. Unless ... this page helpful? Also known as: RF Formal name: Rheumatoid Factor Related tests: Cyclic Citrullinated Peptide Antibody , ANA , ESR , C- ...

  6. Human SLC26A1 Gene Variants: A Pilot Study

    PubMed Central

    Dawson, Paul A.; Sim, Pearl; Mudge, David W.

    2013-01-01

    Kidney stones are a global health problem, incurring massive health costs annually. Why stones recur in many patients remains unknown but likely involves environmental, physiological, and genetic factors. The solute linked carrier (SLC) 26A1 gene has previously been linked to kidney stones in mice. SLC26A1 encodes the sulfate anion transporter 1 (SAT1) protein, and its loss in mice leads to hyperoxaluria and calcium oxalate renal stones. To investigate the possible involvement of SAT1 in human urolithiasis, we screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis, which is the commonest type. DNA sequence analyses showed missense mutations in seven patients: one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The M132 amino acid in human SAT1 is conserved with 15 other species and is located within the third transmembrane domain of the predicted SAT1 protein structure, suggesting that this amino acid may be important for SAT1 function. These initial findings demonstrate genetic variants in SLC26A1 of recurrent stone formers and warrant wider independent studies of SLC26A1 in humans with recurrent calcium oxalate stones. PMID:24250268

  7. The Association Between A1C and Subclinical Cardiovascular Disease

    PubMed Central

    McNeely, Marguerite J.; McClelland, Robyn L.; Bild, Diane E.; Jacobs, David R.; Tracy, Russell P.; Cushman, Mary; Goff, David C.; Astor, Brad C.; Shea, Steven; Siscovick, David S.

    2009-01-01

    OBJECTIVE To test the hypothesis that A1C is associated with subclinical cardiovascular disease (CVD) in a population without evident diabetes, after adjusting for traditional CVD risk factors and BMI. RESEARCH DESIGN AND METHODS This was a cross-sectional study of 5,121 participants without clinically evident CVD or diabetes (fasting glucose ≥7.0 mmol/l or use of diabetes medication), aged 47–86 years, enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Measurements included carotid intimal-medial wall thickness (CIMT) and coronary artery calcification (CAC). Results were adjusted for age, sex, ethnicity, smoking, systolic blood pressure, LDL cholesterol, HDL cholesterol, antihypertensive medication use, lipid-lowering medication use, and BMI. RESULTS Compared with those in the lowest quartile for A1C ([mean ± SD] 5.0 ± 0.2%), participants in the highest quartile (6.0 ± 0.3%) had higher adjusted mean values for common CIMT (0.85 vs. 0.87 mm, P = 0.003) and internal CIMT (1.01 vs. 1.08 mm, P = 0.003). A1C quartile was not associated with prevalence of CAC in the entire cohort (P = 0.27); however, the association was statistically significant in women (adjusted prevalence of CAC in lowest and highest A1C quartiles 37.5 vs. 43.0%, P = 0.01). Among those with some CAC, higher A1C quartile tended to be associated with higher CAC score, but the results were not statistically significant (adjusted P = 0.11). CONCLUSIONS In this multiethnic cohort, there were small, positive associations between A1C, common CIMT, and internal CIMT in the absence of clinically evident diabetes. An association between higher A1C and CAC prevalence was evident only in women. PMID:19549732

  8. 32 CFR 383a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... DEFENSE COMMISSARY AGENCY (DeCA) § 383a.1 Purpose. Pursuant to the authority vested in the Secretary of Defense under title 10, United States Code, this part establishes the Defense Commissary Agency (DeCA)...

  9. 32 CFR 169a.1 - Purpose.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... National Technical Information Service, 5285 Port Royal Road, Springfield, VA 22161 2 See footnote 1 to... and Industrial Activities Cost Comparison Handbook.” 4 See footnote 1 to § 169a.1(a)....

  10. A-1 modification work under way

    NASA Technical Reports Server (NTRS)

    2008-01-01

    Phil Schemanski of Pratt & Whitney Rocketdyne removes equipment inside the thrust drum on the A-1 Test Stand as part of a comprehensive modification project to prepare for testing the new J-2X engine.

  11. TMS installation at A-1 Test Stand

    NASA Technical Reports Server (NTRS)

    2010-01-01

    Stennis Space Center employees maneuver a new thrust measurement system in preparation for its installation on the A-1 Test Stand on March 3. The system was fabricated by Thrust Measurement Systems in Illinois and represents a state-of-the-art upgrade from the equipment used on the stand for more than 40 years. The A-1 Test Stand is being upgraded to provide testing for the next generation of rocket engines for America's space program.

  12. Behavioral factors.

    PubMed

    Zero, D T; Lussi, A

    2006-01-01

    During and after an erosive challenge, behavioral factors play a role in modifying the extent of erosive tooth wear. The manner that dietary acids are introduced into the mouth (gulping, sipping, use of a straw) will affect how long the teeth are in contact with the erosive challenge. The frequency and duration of exposure to an erosive agent is of paramount importance. Night-time exposure (e.g. baby bottle-feeding) to erosive agents may be particularly destructive because of the absence of salivary flow. Health-conscious individuals tend to ingest acidic drinks and juices more frequently and tend to have higher than average oral hygiene. While good oral hygiene is of proven value in the prevention of periodontal disease and dental caries, frequent toothbrushing with abrasive oral hygiene products may enhance erosive tooth wear. Unhealthy lifestyles such as consumption of designer drugs, alcopops and alcohol abuse are other important behavioral factors. PMID:16687888

  13. Methamphetamine Regulation of Sulfotransferase 1A1 and 2A1 Expression in Rat Brain Sections

    PubMed Central

    Zhou, Tianyan; Huang, Chaoqun; Chen, Yue; Xu, Jiaojiao; Shanbhag, Preeti Devaraya; Chen, Guangping

    2012-01-01

    Sulfotransferase catalyzed sulfation regulates the biological activities of various neurotransmitters/hormones and detoxifies xenobiotics. Rat sulfotransferase rSULT1A1 catalyzes the sulfation of neurotransmitters and xenobiotic phenolic compounds. rSULT2A1 catalyzes the sulfation of hydroxysteroids and xenobiotic alcoholic compounds. In this work, Western blot and real-time RT-PCR were used to investigate the effect of methamphetamine on rSULT1A1 and rSULT2A1 protein and mRNA expression in rat cerebellum, frontal cortex, hippocampus, and striatum. After 1-day treatment, significant induction of rSULT1A1 was observed only in the cerebellum; rSULT2A1 was induced significantly in the cerebellum, frontal cortex, and hippocampus. After 7-days of exposure, rSULT1A1 was induced in the cerebellum, frontal cortex, and hippocampus, while rSULT2A1 was induced significantly in all four regions. Western blot results agreed with the real-time RT-PCR results, suggesting that the induction occurred at the gene transcriptional level. Results indicate that rSULT1A1 and rSULT2A1 are expressed in rat frontal cortex, cerebellum, striatum, and hippocampus. rSULT1A1 and rSULT2A1are inducible by methamphetamine in rat brain sections in a time dependable manner. rSULT2A1 is more inducible than rSULT1A1 by methamphetamine in rat brain sections. Induction activity of methamphetamine is in the order of cerebellum > frontal cortex, hippocampus > striatum. These results suggest that the physiological functions of rSULT1A1 and rSULT2A1 in different brain regions can be affected by methamphetamine. PMID:23026138

  14. MybA1 gene diversity across the Vitis genus.

    PubMed

    Péros, Jean-Pierre; Launay, Amandine; Berger, Gilles; Lacombe, Thierry; This, Patrice

    2015-06-01

    The MybA1 gene in the genus Vitis encodes a transcription factor, belonging to the R2R3 Myb family, that controls the last steps in the anthocyanins biosynthesis pathway. Polymorphism within MybA1 has been associated with color variation in berries of V. vinifera and other Vitis species. In this work, we analyzed the sequence variation in MybA1 both in the subg. Muscadinia and in an extended set of Asian, American and European genotypes of subg. Vitis. Our aims were to infer the evolution of this gene during the speciation process and to identify polymorphisms that could potentially generate changes in gene regulation. The results show that MybA1 experienced many insertions and deletions in non-coding regions but also in the third exon sequence. Owing to the larger set of Vitis species compared here, new indels were identified and the origin of previously described indels was reconsidered. A large number of single nucleotide polymorphisms were found in non-coding regions but also in the sequence coding for the R2R3 domain and the C terminal part of the protein. Some of these changes led to amino acid substitutions and therefore could have modified MybA1 protein activity. Bayesian phylogenetic analysis of all polymorphisms did not provide a consensus tree depicting the geographical partitioning of the species but allowed highlighting several species relationships within subgenus Vitis. Finally, the evolutionary events described could be useful to gain more insight into the role of MybA1 for anthocyanin biosynthesis in grapevine. PMID:25896368

  15. The linker between the D3 and A1 domains of vWF suppresses A1-GPIbα catch bonds by site-specific binding to the A1 domain

    PubMed Central

    Tischer, Alexander; Cruz, Miguel A; Auton, Matthew

    2013-01-01

    Platelet attachment to von Willebrand factor (vWF) requires the interaction between the platelet GP1bα and exposed vWF-A1 domains. Structural insights into the mechanism of the A1-GP1bα interaction have been limited to an N-terminally truncated A1 domain that lacks residues Q1238 − E1260 that make up the linker between the D3 and A1 domains of vWF. We have demonstrated that removal of these residues destabilizes quaternary interactions in the A1A2A3 tridomain and contributes to platelet activation under high shear (Auton et al., J Biol Chem 2012;287:14579–14585). In this study, we demonstrate that removal of these residues from the single A1 domain enhances platelet pause times on immobilized A1 under rheological shear. A rigorous comparison between the truncated A1-1261 and full length A1-1238 domains demonstrates a kinetic stabilization of the A1 domain induced by these N-terminal residues as evident in the enthalpy of the unfolding transition. This stabilization occurs through site and sequence-specific binding of the N-terminal peptide to A1. Binding of free N-terminal peptide to A1-1261 has an affinity and this binding although free to dissociate is sufficient to suppress the platelet pause times to levels comparable to A1-1238 under shear stress. Our results support a dual-structure/function role for this linker region involving a conformational equilibria that maintains quaternary A domain associations in the inactive state of vWF at low shear and an intra-A1-domain conformation that regulates the strength of platelet GP1bα-vWF A1 domain associations in the active state of vWF at high shear. PMID:23775931

  16. Pneumococcal IgA1 protease subverts specific protection by human IgA1.

    PubMed

    Janoff, E N; Rubins, J B; Fasching, C; Charboneau, D; Rahkola, J T; Plaut, A G; Weiser, J N

    2014-03-01

    Bacterial immunoglobulin A1 (IgA1) proteases may sabotage the protective effects of IgA. In vitro, both exogenous and endogenously produced IgA1 protease inhibited phagocytic killing of Streptococcus pneumoniae by capsule-specific IgA1 human monoclonal antibodies (hMAbs) but not IgA2. These IgA1 proteases cleaved and reduced binding of the the effector Fcα1 heavy chain but not the antigen-binding F(ab)/light chain to pneumococcal surfaces. In vivo, IgA1 protease-resistant IgA2, but not IgA1 protease-sensitive IgA1, supported 60% survival in mice infected with wild-type S. pneumoniae. IgA1 hMAbs protected mice against IgA1 protease-deficient but not -producing pneumococci. Parallel mouse sera with human IgA2 showed more efficient complement-mediated reductions in pneumococci with neutrophils than did IgA1, particularly with protease-producing organisms. After natural human pneumococcal bacteremia, purified serum IgG inhibited IgA1 protease activity in 7 of 11 patients (64%). These observations provide the first evidence in vivo that IgA1 protease can circumvent killing of S. pneumoniae by human IgA. Acquisition of IgA1 protease-neutralizing IgG after infection directs attention to IgA1 protease both as a determinant of successful colonization and infection and as a potential vaccine candidate. PMID:23820749

  17. NERVA Reactor Based on NRX A1

    NASA Technical Reports Server (NTRS)

    1963-01-01

    This artist's concept from 1963 shows a proposed NERVA (Nuclear Engine for Rocket Vehicle Application) incorporating the NRX-A1, the first NERVA-type cold flow reactor. The NERVA engine, based on Kiwi nuclear reactor technology, was intended to power a RIFT (Reactor-In-Flight-Test) nuclear stage, for which Marshall Space Flight Center had development responsibility.

  18. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... title to the housing unit for which his or her grant was made. (b) The term Veterans Mortgage Life Insurance (VMLI) means the mortgage protection life insurance authorized for veterans under 38 U.S.C....

  19. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... title to the housing unit for which his or her grant was made. (b) The term Veterans Mortgage Life Insurance (VMLI) means the mortgage protection life insurance authorized for veterans under 38 U.S.C....

  20. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... title to the housing unit for which his or her grant was made. (b) The term Veterans Mortgage Life Insurance (VMLI) means the mortgage protection life insurance authorized for veterans under 38 U.S.C....

  1. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... title to the housing unit for which his or her grant was made. (b) The term Veterans Mortgage Life Insurance (VMLI) means the mortgage protection life insurance authorized for veterans under 38 U.S.C....

  2. 38 CFR 8a.1 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 8a.1 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS VETERANS MORTGAGE LIFE... title to the housing unit for which his or her grant was made. (b) The term Veterans Mortgage Life Insurance (VMLI) means the mortgage protection life insurance authorized for veterans under 38 U.S.C....

  3. 8 CFR 245a.1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ..., if any, or (2) a crime treated as a misdemeanor under 8 CFR 245a.1(p). For purposes of this... CFR part 245a, the crime shall be treated as a misdemeanor. (q) Subject of an Order to Show Cause... performance standards of the English/citizenship course prescribed by the recognized program in which he...

  4. AME survey-003 A1-part 2: the motivation factors of medical doctors in China

    PubMed Central

    Káplár, Zoltán; Lǐ, Yáo T.

    2015-01-01

    Background The professional moral and job satisfaction of medical profession remain highly disputed in media in China. On the other hand, there is wide disaffection of patients toward doctors in China. This survey aims to obtain a better understanding of the motivation of Chinese medical professionals. Methods An anonymous online cross-sectional survey, AME survey III, was conducted using the platform provided by DXY (www.dxy.cn) during the period of September 10-23, 2015. In total 2,356 DXY users completed the survey, including 1,740 males and 617 females, with a mean age of 31.96±7.03 yrs. Results The reasons (multiple choices) for career disaffection included poor patient/doctor relationship (88.6%), imbalance between workload and pay (79.5%), could not enter the preferred specialty (14.14%), and working in small clinics with no career progress (11.17%). If given the choice to enter the specialty as well as the hospital grade of their choice, 73.8% dissatisfied respondents replied they would like to be a doctor. For the dis-satisfied respondents, university teacher appeared to be the most popular career choice. The cited high workload was considered to be due to (I) imbalance in geographical allocation of doctors and insufficient training of doctors; (II) many red-tapism formalities; (III) Chinese patients often have unreasonable requests; (IV) over-examination and over-treatment; (V) high pressure to publish papers. One hundred and twelve respondents have their child/children attending university or graduated from university, 25.0% of them are pursuing a career in medicine. Nine hundred and ninety respondents have child/children while did not reach university age yet, among them 23.62% would like their child/children to study medicine. 64.87% of the 2,356 participants favor China to open up medical market to qualified foreign medical organizations to take part in fair competition, and 57.91% favor the government supporting regulated private hospitals. Conclusions The moral and motivation of medical doctors in China are likely to be similar to other continuously evolving societies. Cost-effective use of existing resources should be explored as the first priority. PMID:26807373

  5. TMS installation at A-1 Test Stand

    NASA Technical Reports Server (NTRS)

    2010-01-01

    Employees at NASA's John C. Stennis Space Center complete installation of the new thrust measurement system on the A-1 Test Stand. The new TMS is a state-of-the-art upgrade from the previous system, which was installed when the testing structure was built in the 1960s. It is an advanced calibration system capable of measuring vertical and horizontal thrust loads with accuracy within 0.15 percent at 225,000 pounds. It also will allow engineers to measure thrust as they gimbal (or tilt) engines during tests. The new TMS is part of upgrades for the A-1 Test Stand in preparation for testing the next generation of American space program rocket engines.

  6. TMS installation at A-1 Test Stand

    NASA Technical Reports Server (NTRS)

    2010-01-01

    A new thrust measurement system is lifted onto the A-1 Test Stand deck at NASA's John C. Stennis Space Center in preparation for its installation. The new system is a state-of-the-art upgrade for the testing structure, which is being prepared for testing of next-generation rocket engines. The system was fabricated by Thrust Measurement Systems in Illinois at a cost of about $3.5 million.

  7. Decommissioning Project of Bohunice A1 NPP

    SciTech Connect

    Stubna, M.; Pekar, A.; Moravek, J.; Spirko, M.

    2002-02-26

    The first (pilot) nuclear power plant A1 in the Slovak Republic, situated on Jaslovske Bohunice site (60 km from Bratislava) with the capacity of 143 MWel, was commissioned in 1972 and was running with interruptions till 1977. A KS 150 reactor (HWGCR) with natural uranium as fuel, D2O as moderator and gaseous CO2 as coolant was installed in the A1 plant. Outlet steam from primary reactor coolant system with the temperature of 410 C was led to 6 modules of steam generators and from there to turbine generators. Refueling was carried out on-line at plant full power. The first serious incident associated with refueling occurred in 1976 when a locking mechanism at a fuel assembly failed. The core was not damaged during that incident and following a reconstruction of the damaged technology channel, the plant continued in operation. However, serious problems were occurring with the integrity of steam generators (CO2 gas on primary side, water and steam on secondary side) when the plant had to be shut down frequently due to failures and subsequent repairs. The second serious accident occurred in 1977 when a fuel assembly was overheated with a subsequent release of D2O into gas cooling circuit due to a human failure in the course of replacement of a fuel assembly. Subsequent rapid increase in humidity of the primary system resulted in damages of fuel elements in the core and the primary system was contaminated by fission products. In-reactor structures had been damaged, too. Activity had penetrated also into certain parts of the secondary system via leaking steam generators. Radiation situation in the course of both events on the plant site and around it had been below the level of limits specified. Based on a technical and economical justification of the demanding character of equipment repairs for the restoration of plant operation, and also due to a decision made not to continue with further construction of gas cooled reactors in Czechoslovakia, a decision was made in 1977 to terminate plant operation. The decision on the A1 plant decommissioning was issued in 1979.

  8. ADAM12-cleaved ephrin-A1 contributes to lung metastasis.

    PubMed

    Ieguchi, K; Tomita, T; Omori, T; Komatsu, A; Deguchi, A; Masuda, J; Duffy, S L; Coulthard, M G; Boyd, A; Maru, Y

    2014-04-24

    Eph receptor tyrosine kinases and their ephrin ligands have been implicated in neuronal development and neovascularization. Overexpression of ephrin-A1 has been implicated in tumor progression and poor prognosis. However, the mechanisms are not clear. Here, we report a role of the Eph/ephrin system in a cell adhesion mechanism. Clustered erythropoietin-producing hepatocellular receptor A1 (EphA1)/ephrin-A1 complexes on the plasma membrane did not undergo endocytosis, and the cell remained adherent to one another. The cell-cell contacts were maintained in an Eph tyrosine kinase activity-independent manner even in the absence of E-cadherin. EphA1 and ephrin-A1 co-localized in pulmonary endothelial cells, and regulated vascular permeability and metastasis in the lungs. We identified ADAM12 (A disintegrin and metalloproteinase 12) as an EphA1-binding partner by yeast two-hybrid screening and found that ADAM12 enhanced ephrin-A1 cleavage in response to transforming growth factor-β1 in primary tumors. Released soluble ephrin-A1 in the serum deteriorated the EphA1/ephrin-A1-mediated cell adhesion in the lungs in an endocrine manner, causing lung hyperpermeability that facilitated tumor cell entry into the lungs. Depletion of soluble ephrin-A1 by its neutralizing antibody significantly inhibited lung metastasis. PMID:23686306

  9. PLC Software Program for Leak Detector Station A1 SALW-LD-ST-A1

    SciTech Connect

    KOCH, M.R.

    2001-01-25

    This document describes the software program for the programmable logic controller for the leak detector station ''SALW-LD-ST-A1''. The appendices contains a copy of the printout of the software program.

  10. NR4A1 Antagonists Inhibit β1-Integrin-Dependent Breast Cancer Cell Migration.

    PubMed

    Hedrick, Erik; Lee, Syng-Ook; Doddapaneni, Ravi; Singh, Mandip; Safe, Stephen

    2016-05-01

    Overexpression of the nuclear receptor 4A1 (NR4A1) in breast cancer patients is a prognostic factor for decreased survival and increased metastasis, and this has been linked to NR4A1-dependent regulation of transforming growth factor β (TGF-β) signaling. Results of RNA interference studies demonstrate that basal migration of aggressive SKBR3 and MDA-MB-231 breast cancer cells is TGF-β independent and dependent on regulation of β1-integrin gene expression by NR4A1 which can be inhibited by the NR4A1 antagonists 1,1-bis(3'-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) and a relatedp-carboxymethylphenyl [1,1-bis(3'-indolyl)-1-(p-carboxymethylphenyl)methane (DIM-C-pPhCO2Me)] analog. The NR4A1 antagonists also inhibited TGF-β-induced migration of MDA-MB-231 cells by blocking nuclear export of NR4A1, which is an essential step in TGF-β-induced cell migration. We also observed that NR4A1 regulates expression of both β1- and β3-integrins, and unlike other β1-integrin inhibitors which induce prometastatic β3-integrin, NR4A1 antagonists inhibit expression of both β1- and β3-integrin, demonstrating a novel mechanism-based approach for targeting integrins and integrin-dependent breast cancer metastasis. PMID:26929200

  11. Three Major Loci Involved in Age-Related Macular Degeneration are also Associated with Polypoidal Choroidal Vasculopathy

    PubMed Central

    Lima, Luiz H.; Schubert, Carl; Ferrara, Daniela C.; Merriam, Joanna E.; Imamura, Yutaka; Freund, K. Bailey; Spaide, Richard F.; Yannuzzi, Lawrence A.; Allikmets, Rando

    2009-01-01

    Purpose To investigate the frequency of variants in three major age-related macular degeneration (AMD)-associated loci in patients with polypoidal choroidal vasculopathy (PCV) of European-American descent. Design Cross-sectional case-control association study. Participants Fifty-five patients with PCV, 368 patients with advanced AMD and 368 age- and ethnically-matched unaffected controls of European-American descent. Methods Association analysis of allele and genotype frequencies, determined by TaqMan assays, was performed for the following haplotype-tagging single nucleotide polymorphisms (htSNPs): risk alleles in the complement factor H (CFH) gene (Y402H and IVS14) in the ARMS2/HTRA1 locus on 10q26 (A69S) and protective alleles in CFH (IVS1 and IVS6) and in the complement factor B/complement component C2 (CFB/C2) locus (IVS10 and H9L). Main Outcome Measures Allele and genotype frequencies of the htSNPs in the CFH, CFB/C2, and ARMS2/HTRA1 loci. Results Four AMD-associated haplotype-tagging alleles (rs547154, rs1061170, rs1410996, rs10490924) in the three major loci, CFH, CFB/C2 and ARMS2/HTRA1, were statistically significantly associated also with the PCV phenotype (P<0.05). Three other alleles from the same loci (rs4151667, rs529825, rs3766404) showed a trend towards association (P<0.2), but did not reach statistical significance possibly because of the combined effects of a relatively small sample size and low minor allele frequency in the screened populations. Conclusion The PCV phenotype in Caucasian patients is associated with the major alleles/genotypes in the AMD-associated loci, suggesting that PCV and AMD are genetically similar in the tested loci. PMID:20378180

  12. A 1-D dusty plasma photonic crystal

    SciTech Connect

    Mitu, M. L.; Ticoş, C. M.; Toader, D.; Banu, N.; Scurtu, A.; Department of Physics, University of Bucharest, 077125 Bucharest

    2013-09-21

    It is demonstrated numerically that a 1-D plasma crystal made of micron size cylindrical dust particles can, in principle, work as a photonic crystal for terahertz waves. The dust rods are parallel to each other and arranged in a linear string forming a periodic structure of dielectric-plasma regions. The dispersion equation is found by solving the waves equation with the boundary conditions at the dust-plasma interface and taking into account the dielectric permittivity of the dust material and plasma. The wavelength of the electromagnetic waves is in the range of a few hundred microns, close to the interparticle separation distance. The band gaps of the 1-D plasma crystal are numerically found for different types of dust materials, separation distances between the dust rods and rod diameters. The distance between levitated dust rods forming a string in rf plasma is shown experimentally to vary over a relatively wide range, from 650 μm to about 1350 μm, depending on the rf power fed into the discharge.

  13. Isolation and characterization of cyp19a1a and cyp19a1b promoters in the protogynous hermaphrodite orange-spotted grouper (Epinephelus coioides).

    PubMed

    Zhang, Weimin; Lu, Huijie; Jiang, Haiyan; Li, Mu; Zhang, Shen; Liu, Qiongyou; Zhang, Lihong

    2012-02-01

    Aromatase (CYP19A1) catalyzes the conversion of androgens to estrogens. In teleosts, duplicated copies of cyp19a1 genes, namely cyp19a1a and cyp19a1b, were identified, however, the transcriptional regulation of these two genes remains poorly understood. In the present study, the 5'-flanking regions of the orange-spotted grouper cyp19a1a (gcyp19a1a) and cyp19a1b (gcyp19a1b) genes were isolated and characterized. The proximal promoter regions of both genes were relatively conserved when compared to those of the other teleosts. Notably, a conserved FOXO transcriptional factor binding site was firstly reported in the proximal promoter of gcyp19a1a, and deletion of the region (-112 to -60) containing this site significantly decreased the promoter activities. The deletion of the region (-246 to -112) containing the two conserved FTZ-F1 sites also dramatically decreased the transcriptional activities of gcyp19a1a promoter, and both two FTZ-F1 sites were shown to be stimulatory cis-acting elements. A FTZ-F1 homologue isolated from ricefield eel (eFTZ-F1) up-regulated gcyp19a1a promoter activities possibly via the FTZ-F1 sites, however, a previously identified orange-spotted grouper FTZ-F1 homologue (gFTZ-F1) did not activate the transcription of gcyp19a1a promoter unexpectedly. As to gcyp19a1b promoter, all the deletion constructs did not show good promoter activities in either TM4 or U251-MG cells. Estradiol (100nM) up-regulated gcyp19a1b promoter activities by about 13- and 36-fold in TM4 and U251-MG cells, respectively, via the conserved ERE motif, but did not stimulate gcyp19a1a promoter activities. These results are helpful to further elucidate the regulatory mechanisms of cyp19a1a and cyp19a1b expression in the orange-spotted grouper as well as other teleosts. PMID:22197207

  14. Development of a Neutron Detector for A1 at MAMI

    NASA Astrophysics Data System (ADS)

    Pierce, Zoe

    2015-04-01

    The Mainz A1 spectrometers perform high precision measurements to investigate the structure of the nucleus and its constituents. Previous knowledge of the neutron form factor (FF) is limited due to poor detection efficiencies. Our goal is to create a neutron detector with an efficiency better than 80%, leading to the improvement of the measurements of the neutron electric FF and reducing systematic uncertainties. This new detector would also open up the possibility to study non-mesonic two-body weak decays. The neutron detector should have a large active detector volume, a high detection efficiency (>80%), a good resolution (<.5 ns), and must be low in cost. The proposed design of the detector follows a modular concept with an active detector volume of approximately one cubic meter. In order to allow high beam currents and their resulting high rates, this detector will be highly segmented using 32 crossed layers consisting of 64 bars, utilizing solid and liquid organic scintillators, with dimensions (15 x 30 x 960) mm3. In total 4096 channels have to be read out via WLS fibers using silicon multi pixel photon counters (MPPC). Funded by NSF IRES Award IIA-1358175 Collaboration: MAMI A1 Collaboration.

  15. Architecture for a 1-GHz Digital RADAR

    NASA Technical Reports Server (NTRS)

    Mallik, Udayan

    2011-01-01

    An architecture for a Direct RF-digitization Type Digital Mode RADAR was developed at GSFC in 2008. Two variations of a basic architecture were developed for use on RADAR imaging missions using aircraft and spacecraft. Both systems can operate with a pulse repetition rate up to 10 MHz with 8 received RF samples per pulse repetition interval, or at up to 19 kHz with 4K received RF samples per pulse repetition interval. The first design describes a computer architecture for a Continuous Mode RADAR transceiver with a real-time signal processing and display architecture. The architecture can operate at a high pulse repetition rate without interruption for an infinite amount of time. The second design describes a smaller and less costly burst mode RADAR that can transceive high pulse repetition rate RF signals without interruption for up to 37 seconds. The burst-mode RADAR was designed to operate on an off-line signal processing paradigm. The temporal distribution of RF samples acquired and reported to the RADAR processor remains uniform and free of distortion in both proposed architectures. The majority of the RADAR's electronics is implemented in digital CMOS (complementary metal oxide semiconductor), and analog circuits are restricted to signal amplification operations and analog to digital conversion. An implementation of the proposed systems will create a 1-GHz, Direct RF-digitization Type, L-Band Digital RADAR--the highest band achievable for Nyquist Rate, Direct RF-digitization Systems that do not implement an electronic IF downsample stage (after the receiver signal amplification stage), using commercially available off-the-shelf integrated circuits.

  16. HDL/ApoA-1 infusion and ApoA-1 gene therapy in atherosclerosis

    PubMed Central

    Chyu, Kuang-Yuh; Shah, Prediman K.

    2015-01-01

    The HDL hypothesis stating that simply raising HDL cholesterol (HDL-C) may produce cardiovascular benefits has been questioned recently based on several randomized clinical trials using CETP inhibitors or niacin to raise HDL-C levels. However, extensive pre-clinical data support the vascular protective effects of administration of exogenous ApoA-1 containing preβ-HDL like particles. Several small proof-of-concept clinical trials using such HDL/ApoA-1 infusion therapy have shown encouraging results but definitive proof of efficacy must await large scale clinical trials. In addition to HDL infusion therapy an alternative way to exploit beneficial cardiovascular effects of HDL/ApoA-1 is to use gene transfer. Preclinical studies have shown evidence of benefit using this approach; however clinical validation is yet lacking. This review summarizes our current knowledge of the aforementioned strategies. PMID:26388776

  17. Development of a Neutron Detector for A1 at MAMI

    NASA Astrophysics Data System (ADS)

    Pierce, Zoe; A1 MAMI Collaboration

    2014-09-01

    The Mainz A1 spectrometers perform high precision measurements to investigate the structure of the nucleus and its constituents. Previous knowledge of the neutron form factor (FF) is limited due to poor detection efficiencies. Our goal is to create a neutron detector with an efficiency better than 80%, leading to the improvement of the measurements of the neutron electric FF and reducing systematic uncertainties. This new detector would also open up the possibility to study non-mesonic two-body weak decays. The neutron detector should have a large active detector volume, a high detection efficiency (>80%), a good resolution (<.5 ns), and must be low in cost. The proposed design of the detector follows a modular concept with an active detector volume of approximately one cubic meter. In order to allow high beam currents and their resulting high rates, this detector will be highly segmented using 32 crossed layers consisting of 64 bars, utilizing solid and liquid organic scintillators, with dimensions (15 x 30 x 960) mm3. In total 4096 channels have to be read out via WLS fibers using silicon multi pixel photon counters (MPPC). The Mainz A1 spectrometers perform high precision measurements to investigate the structure of the nucleus and its constituents. Previous knowledge of the neutron form factor (FF) is limited due to poor detection efficiencies. Our goal is to create a neutron detector with an efficiency better than 80%, leading to the improvement of the measurements of the neutron electric FF and reducing systematic uncertainties. This new detector would also open up the possibility to study non-mesonic two-body weak decays. The neutron detector should have a large active detector volume, a high detection efficiency (>80%), a good resolution (<.5 ns), and must be low in cost. The proposed design of the detector follows a modular concept with an active detector volume of approximately one cubic meter. In order to allow high beam currents and their resulting high rates, this detector will be highly segmented using 32 crossed layers consisting of 64 bars, utilizing solid and liquid organic scintillators, with dimensions (15 x 30 x 960) mm3. In total 4096 channels have to be read out via WLS fibers using silicon multi pixel photon counters (MPPC). Funded by NSF IRES Award IIA-1358175 MAMI A1 Collaboration.

  18. Polymorphic variants of UGT1A1 in neonatal jaundice in southern Brazil.

    PubMed

    Carvalho, Clarissa Gutiérrez; Castro, Simone Martins; Santin, Ana Paula; de Azevedo, Laura Alencastro; Pereira, Maria Luiza Saraiva; Giugliani, Roberto

    2010-10-01

    Alterations in the hepatic conjugation of bilirubin due to uridyl-diphosphate-glucuronosyltransferase 1A1 (UGT1A1) polymorphisms have been proposed as risk factors to neonatal jaundice. Herein, we estimated the frequency of genotypes of the promoter region of UGT1A1 gene in newborns and evaluated its association with severe hyperbilirubinemia. Prospective study of cases and controls including all newborns admitted for phototherapy at HCPA, Brazil, during 9 months; 490 babies were enrolled and PCR was performed. Polymorphic genotypes were detected in 16% of the patients and 7 of the 10 possible genotypes were identified with higher prevalence of polymorphisms in Afro-descendants. In this sample, the variants of UGT1A1 were not associated to severe hyperbilirubinemia; other genic factors should be sought in this high miscegenation area of Brazil. PMID:20061399

  19. Factor V deficiency

    MedlinePlus

    Factor V deficiency is a condition that is passed down through families, which affects the ability of the blood ... These proteins are called blood coagulation factors. Factor V deficiency is caused by a lack of Factor ...

  20. Modulation of the Bacillus anthracis Secretome by the Immune Inhibitor A1 Protease

    PubMed Central

    Pflughoeft, Kathryn J.; Swick, Michelle C.; Engler, David A.; Yeo, Hye-Jeong

    2014-01-01

    The Bacillus anthracis secretome includes protective antigen, lethal factor, and edema factor, which are the components of anthrax toxin, and other proteins with known or potential roles in anthrax disease. Immune inhibitor A1 (InhA1) is a secreted metalloprotease that is unique to pathogenic members of the Bacillus genus and has been associated with cleavage of host proteins during infection. Here, we report the effect of InhA1 on the B. anthracis secretome. Differential in-gel electrophoresis of proteins present in culture supernatants from a parent strain and an isogenic inhA1-null mutant revealed multiple differences. Of the 1,340 protein spots observed, approximately one-third were less abundant and one-third were more abundant in the inhA1 secretome than in the parent strain secretome. Proteases were strongly represented among those proteins exhibiting a 9-fold or greater change. InhA1 purified from a B. anthracis culture supernatant directly cleaved each of the anthrax toxin proteins as well as an additional secreted protease, Npr599. The conserved zinc binding motif HEXXH of InhA1 (HEYGH) was critical for its proteolytic activity. Our data reveal that InhA1 directly and indirectly modulates the form and/or abundance of over half of all the secreted proteins of B. anthracis. The proteolytic activity of InhA1 on established secreted virulence factors, additional proteases, and other secreted proteins suggests that this major protease plays an important role in virulence not only by cleaving mammalian substrates but also by modulating the B. anthracis secretome itself. PMID:24214942

  1. Knowledge of A1c Predicts Diabetes Self-Management and A1c Level among Chinese Patients with Type 2 Diabetes

    PubMed Central

    Hsue, Cunyi; Fish, Anne F.; Chen, Yufeng; Guo, Xiaohui; Lou, Qingqing; Anderson, Robert

    2016-01-01

    This study was to identify current A1c understanding status among Chinese patients with type 2 diabetes, assess if knowledge of A1c affects their diabetes self-management and their glycemic control and recognize the factors influencing knowledge of A1c among patients with type 2 diabetes. A multi-center, cross-sectional survey was conducted between April and July 2010 in 50 medical centers in the Mainland China. Participants were recruited from inpatients and outpatients who were admitted to or visited those medical centers. The survey included core questions about their demographic characteristics, diabetes self-management behavior, and A1c knowledge. Overall, of 5957 patients, the percentage of patients with good understanding was 25.3%. In the multivariable logistic regression model, the variables related to the knowledge of A1c status are presented. We discovered that patients with longer diabetes duration (OR = 1.05; 95%CI = 1.04–1.06) and having received diabetes education (OR = 1.80; 95%CI = 1.49–2.17) were overrepresented in the good understanding of A1c group. In addition, compared to no education level, higher education level was statistically associated with good understanding of A1c (P<0.001). The percentage of patients with good understanding varied from region to region (P<0.001), with Eastern being highest (OR = 1.54; 95%CI = 1.32–1.80), followed by Central (OR = 1.25; 95%CI = 1.02–1.53), when referring to Western. Only a minority of patients with type 2 diabetes in China understood their A1c value. The patients who had a good understanding of their A1c demonstrated significantly better diabetes self-management behavior and had lower A1c levels than those who did not. PMID:26959422

  2. Knowledge of A1c Predicts Diabetes Self-Management and A1c Level among Chinese Patients with Type 2 Diabetes.

    PubMed

    Yang, Shengnan; Kong, Weimin; Hsue, Cunyi; Fish, Anne F; Chen, Yufeng; Guo, Xiaohui; Lou, Qingqing; Anderson, Robert

    2016-01-01

    This study was to identify current A1c understanding status among Chinese patients with type 2 diabetes, assess if knowledge of A1c affects their diabetes self-management and their glycemic control and recognize the factors influencing knowledge of A1c among patients with type 2 diabetes. A multi-center, cross-sectional survey was conducted between April and July 2010 in 50 medical centers in the Mainland China. Participants were recruited from inpatients and outpatients who were admitted to or visited those medical centers. The survey included core questions about their demographic characteristics, diabetes self-management behavior, and A1c knowledge. Overall, of 5957 patients, the percentage of patients with good understanding was 25.3%. In the multivariable logistic regression model, the variables related to the knowledge of A1c status are presented. We discovered that patients with longer diabetes duration (OR = 1.05; 95%CI = 1.04-1.06) and having received diabetes education (OR = 1.80; 95%CI = 1.49-2.17) were overrepresented in the good understanding of A1c group. In addition, compared to no education level, higher education level was statistically associated with good understanding of A1c (P<0.001). The percentage of patients with good understanding varied from region to region (P<0.001), with Eastern being highest (OR = 1.54; 95%CI = 1.32-1.80), followed by Central (OR = 1.25; 95%CI = 1.02-1.53), when referring to Western. Only a minority of patients with type 2 diabetes in China understood their A1c value. The patients who had a good understanding of their A1c demonstrated significantly better diabetes self-management behavior and had lower A1c levels than those who did not. PMID:26959422

  3. Diagnosis and Management of Patients with a1-Antitrypsin (A1AT) Deficiency

    PubMed Central

    Nelson, David; Teckman, Jeffrey; Di Bisceglie, Adrian; Brenner, David A.

    2012-01-01

    α1-antitrypsin (A1AT) deficiency is an autosomal co-dominant disease that can cause chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) in children and adults and increases risk for emphysema in adults. The development of symptomatic disease varies—some patients have life-threatening symptoms in childhood whereas others remain asymptomatic and healthy into old age. As a result of this variability, patients present across multiple disciplines, including pediatrics, adult medicine, hepatology, genetics, and pulmonology. This can give physicians the mistaken impression that the condition is less common than it actually is, and can lead to fragmented care that omits critical interventions commonly performed other specialists. We sought to present a rational approach for hepatologists to manage adult patients with A1AT deficiency. PMID:22200689

  4. Should Studies of Diabetes Treatment Stratification Correct for Baseline HbA1c?

    PubMed Central

    Jones, Angus G.; Lonergan, Mike; Henley, William E.; Pearson, Ewan R.; Hattersley, Andrew T.; Shields, Beverley M.

    2016-01-01

    Aims Baseline HbA1c is a major predictor of response to glucose lowering therapy and therefore a potential confounder in studies aiming to identify other predictors. However, baseline adjustment may introduce error if the association between baseline HbA1c and response is substantially due to measurement error and regression to the mean. We aimed to determine whether studies of predictors of response should adjust for baseline HbA1c. Methods We assessed the relationship between baseline HbA1c and glycaemic response in 257 participants treated with GLP-1R agonists and assessed whether it reflected measurement error and regression to the mean using duplicate ‘pre-baseline’ HbA1c measurements not included in the response variable. In this cohort and an additional 2659 participants treated with sulfonylureas we assessed the relationship between covariates associated with baseline HbA1c and treatment response with and without baseline adjustment, and with a bias correction using pre-baseline HbA1c to adjust for the effects of error in baseline HbA1c. Results Baseline HbA1c was a major predictor of response (R2 = 0.19,β = -0.44,p<0.001).The association between pre-baseline and response was similar suggesting the greater response at higher baseline HbA1cs is not mainly due to measurement error and subsequent regression to the mean. In unadjusted analysis in both cohorts, factors associated with baseline HbA1c were associated with response, however these associations were weak or absent after adjustment for baseline HbA1c. Bias correction did not substantially alter associations. Conclusions Adjustment for the baseline HbA1c measurement is a simple and effective way to reduce bias in studies of predictors of response to glucose lowering therapy. PMID:27050911

  5. FoxA1 as a lineage-specific oncogene in luminal type breast cancer

    SciTech Connect

    Yamaguchi, Noritaka; Ito, Emi; Azuma, Sakura; Honma, Reiko; Yanagisawa, Yuka; Nishikawa, Akira; Kawamura, Mika; Imai, Jun-ichi

    2008-01-25

    The forkhead transcription factor FoxA1 is thought to be involved in mammary tumorigenesis. However, the precise role of FoxA1 in breast cancer development is controversial. We examined expression of FoxA1 in 35 human breast cancer cell lines and compared it with that of ErbB2, a marker of poor prognosis in breast cancer. We found that FoxA1 is expressed at high levels in all ErbB2-positive cell lines and a subset of ErbB2-negative cell lines. Down-regulation of FoxA1 by RNA interference significantly suppressed proliferation of ErbB2-negative and FoxA1-positive breast cancer cell lines. Down-regulation of FoxA1 also enhanced the toxic effect of Herceptin on ErbB2-positive cell lines through induction of apoptosis. Taken together with previous data that FoxA1 is a marker of luminal cells in mammary gland, our present results suggest that FoxA1 plays an important role as a lineage-specific oncogene in proliferation of cancer cells derived from mammary luminal cells.

  6. Oral squamous cancer cell exploits hnRNP A1 to regulate cell cycle and proliferation.

    PubMed

    Yu, Cheng; Guo, Jihua; Liu, Yu; Jia, Jun; Jia, Rong; Fan, Mingwen

    2015-09-01

    Oral squamous cell carcinoma (OSCC) is a common human malignant tumor with high mortality. So far, the molecular pathogenesis of OSCC remains largely unclear. Heterogeneous nuclear ribonucleoprotein (hnRNP) A1 is an important multi-function splicing factor and closely related to tumorigenesis. hnRNP A1 is overexpressed in various tumors, and promotes aerobic glycolysis and elongation of telomere, but the function of hnRNP A1 in cell cycle and proliferation remains unclear. We found that hnRNP A1 was overexpressed in OSCC tissues, and was required for the growth of OSCC cells. Moreover, hnRNP A1 was highly expressed in the G2/M cell cycle phase. Knockdown of hnRNP A1 induced G2/M arrest. DNA microarray assay result showed that hnRNP A1 regulated the expression of a number of target genes associated with G2/M phase. Moreover, hnRNP A1 controlled the alternative splicing of CDK2 exon 5. These findings suggested that hnRNP A1 plays key roles in the regulation of cell cycle progression and pathogenesis of OSCC. PMID:25752295

  7. Is There a Role for HbA1c in Pregnancy?

    PubMed

    Hughes, Ruth C E; Rowan, Janet; Florkowski, Chris M

    2016-01-01

    Outside pregnancy, HbA1c analysis is used for monitoring, screening for and diagnosing diabetes and prediabetes. During pregnancy, the role for HbA1c analysis is not yet established. Physiological changes lower HbA1c levels, and pregnancy-specific reference ranges may need to be recognised. Other factors that influence HbA1c are also important to consider, particularly since emerging data suggest that, in early pregnancy, HbA1c elevations close to the reference range may both identify women with underlying hyperglycaemia and be associated with adverse pregnancy outcomes. In later pregnancy, HbA1c analysis is less useful than an oral glucose tolerance test (OGTT) at detecting gestational diabetes. Postpartum, HbA1c analysis detects fewer women with abnormal glucose tolerance than an OGTT, but the ease of testing may improve follow-up rates and combining HbA1c analysis with fasting plasma glucose or waist circumference may improve detection rates. This article discusses the relevance of HbA1c testing at different stages of pregnancy. PMID:26739347

  8. Correlation between UGT1A1 polymorphisms and raltegravir plasma trough concentrations in Japanese HIV-1-infected patients.

    PubMed

    Yagura, Hiroki; Watanabe, Dai; Ashida, Misa; Kushida, Hiroyuki; Hirota, Kazuyuki; Ikuma, Motoko; Ogawa, Yoshihiko; Yajima, Keishiro; Kasai, Daisuke; Nishida, Yasuharu; Uehira, Tomoko; Yoshino, Munehiro; Shirasaka, Takuma

    2015-10-01

    Raltegravir (RAL), an HIV integrase inhibitor, is metabolized mainly by UDP-glucuronosyltransferase 1A1 (UGT1A1). Polymorphisms in UGT1A1 may cause alterations in the pharmacodynamics of RAL, which is taken twice daily with no dietary restrictions. We compared the effect of two polymorphic alleles in this gene, UGT1A1*6 and UGT1A1*28 on plasma RAL concentrations in Japanese HIV-1-infected patients. Of 114 Japanese HIV-1-infected patients who received RAL, the frequencies of UGT1A1*6 and UGT1A1*28 were 18% and 13%, respectively. The percentage of homozygotes for UGT1A1*6 and UGT1A1*28 was 6% and 4%, respectively, the percentage of compound heterozygotes for UGT1A1*6 and UGT1A1*28 was 2%, and that of heterozygotes for UGT1A1*6 and UGT1A1*28 was 22% and 17%, respectively. RAL plasma trough concentrations were compared for each polymorphism. Significantly higher levels of RAL were observed with patients who were homozygous for UGT1A1*6 (median: 1.0 μg/mL) than for the normal allele (median: 0.11 μg/mL; p = 0.021). Multivariate logistic regression analysis showed that the presence of one or two alleles of UGT1A1*6 or two alleles of UGT1A1*28 were independent factors associated with high RAL plasma trough concentrations (≥ 0.17 μg/mL). These results indicated that UGT1A1*6 and UGT1A1*28 are both factors influencing the RAL plasma trough concentrations in Japanese HIV-1-infected patients. PMID:26233886

  9. Methylation of the Cyclin A1 Promoter Correlates with Gene Silencing in Somatic Cell Lines, while Tissue-Specific Expression of Cyclin A1 Is Methylation Independent

    PubMed Central

    Müller, Carsten; Readhead, Carol; Diederichs, Sven; Idos, Gregory; Yang, Rong; Tidow, Nicola; Serve, Hubert; Berdel, Wolfgang E.; Koeffler, H. Phillip

    2000-01-01

    Gene expression in mammalian organisms is regulated at multiple levels, including DNA accessibility for transcription factors and chromatin structure. Methylation of CpG dinucleotides is thought to be involved in imprinting and in the pathogenesis of cancer. However, the relevance of methylation for directing tissue-specific gene expression is highly controversial. The cyclin A1 gene is expressed in very few tissues, with high levels restricted to spermatogenesis and leukemic blasts. Here, we show that methylation of the CpG island of the human cyclin A1 promoter was correlated with nonexpression in cell lines, and the methyl-CpG binding protein MeCP2 suppressed transcription from the methylated cyclin A1 promoter. Repression could be relieved by trichostatin A. Silencing of a cyclin A1 promoter-enhanced green fluorescent protein (EGFP) transgene in stable transfected MG63 osteosarcoma cells was also closely associated with de novo promoter methylation. Cyclin A1 could be strongly induced in nonexpressing cell lines by trichostatin A but not by 5-aza-cytidine. The cyclin A1 promoter-EGFP construct directed tissue-specific expression in male germ cells of transgenic mice. Expression in the testes of these mice was independent of promoter methylation, and even strong promoter methylation did not suppress promoter activity. MeCP2 expression was notably absent in EGFP-expressing cells. Transcription from the transgenic cyclin A1 promoter was repressed in most organs outside the testis, even when the promoter was not methylated. These data show the association of methylation with silencing of the cyclin A1 gene in cancer cell lines. However, appropriate tissue-specific repression of the cyclin A1 promoter occurs independently of CpG methylation. PMID:10757815

  10. Methylation of the cyclin A1 promoter correlates with gene silencing in somatic cell lines, while tissue-specific expression of cyclin A1 is methylation independent.

    PubMed

    Müller, C; Readhead, C; Diederichs, S; Idos, G; Yang, R; Tidow, N; Serve, H; Berdel, W E; Koeffler, H P

    2000-05-01

    Gene expression in mammalian organisms is regulated at multiple levels, including DNA accessibility for transcription factors and chromatin structure. Methylation of CpG dinucleotides is thought to be involved in imprinting and in the pathogenesis of cancer. However, the relevance of methylation for directing tissue-specific gene expression is highly controversial. The cyclin A1 gene is expressed in very few tissues, with high levels restricted to spermatogenesis and leukemic blasts. Here, we show that methylation of the CpG island of the human cyclin A1 promoter was correlated with nonexpression in cell lines, and the methyl-CpG binding protein MeCP2 suppressed transcription from the methylated cyclin A1 promoter. Repression could be relieved by trichostatin A. Silencing of a cyclin A1 promoter-enhanced green fluorescent protein (EGFP) transgene in stable transfected MG63 osteosarcoma cells was also closely associated with de novo promoter methylation. Cyclin A1 could be strongly induced in nonexpressing cell lines by trichostatin A but not by 5-aza-cytidine. The cyclin A1 promoter-EGFP construct directed tissue-specific expression in male germ cells of transgenic mice. Expression in the testes of these mice was independent of promoter methylation, and even strong promoter methylation did not suppress promoter activity. MeCP2 expression was notably absent in EGFP-expressing cells. Transcription from the transgenic cyclin A1 promoter was repressed in most organs outside the testis, even when the promoter was not methylated. These data show the association of methylation with silencing of the cyclin A1 gene in cancer cell lines. However, appropriate tissue-specific repression of the cyclin A1 promoter occurs independently of CpG methylation. PMID:10757815

  11. 29 CFR 2550.404a-1 - Investment duties.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 29 Labor 9 2011-07-01 2011-07-01 false Investment duties. 2550.404a-1 Section 2550.404a-1 Labor... FIDUCIARY RESPONSIBILITY § 2550.404a-1 Investment duties. (a) In general. Section 404(a)(1)(B) of the... use in the conduct of an enterprise of a like character and with like aims. (b) Investment duties....

  12. Acidic Residue Glu199 Increases SUMOylation Level of Nuclear Hormone Receptor NR5A1

    PubMed Central

    Wang, Chiung-Min; Liu, Runhua; Wang, Lizhong; Yang, Wei-Hsiung

    2013-01-01

    Steroidogenic factor 1 (NR5A1/SF1) is a well-known master regulator in controlling adrenal and sexual development, as well as regulating numerous genes involved in adrenal and gonadal steroidogenesis. Several studies including ours have demonstrated that NR5A1 can be SUMOylated on lysine 194 (K194, the major site) and lysine 119 (K119, the minor site), and the cycle of SUMOylation regulates NR5A1s transcriptional activity. An extended consensus negatively charged amino acid-dependent SUMOylation motif (NDSM) enhances the specificity of substrate modification by SUMO has been reported; however, the mechanism of NDSM for NR5A1 remains to be clarified. In this study, we investigated the functional significance of the acidic residue located downstream from the core consensus SUMO site of NR5A1. Here we report that E199A (glutamic acid was replaced with alanine) of NR5A1 reduced, but not completely abolished, its SUMOylation level. We next characterized the functional role of NR5A1 E199A on target gene expression and protein levels. We found that E199A alone, as well as combination with K194R, increased Mc2r and Cyp19a1 reporter activities. Moreover, E199A alone as well as combination with K194R enhanced NR5A1-mediated STAR protein levels in mouse adrenocortical cancer Y1 cells. We also observed that E199A increased interaction of NR5A1 with CDK7 and SRC1. Overall, we provide the evidence that the acidic residue (E199) located downstream from the core consensus SUMO site of NR5A1 is, at least in part, required for SUMOylation of NR5A1 and for its mediated target gene and protein expression. PMID:24232453

  13. Characterization of Prohibitin 1 as a Host Partner of Vibrio vulnificus RtxA1 Toxin.

    PubMed

    Kim, Bo A; Lim, Ju Young; Rhee, Joon Haeng; Kim, Young Ran

    2016-01-01

    RtxA1 toxin, which results in cytoskeletal rearrangement, contact cytotoxicity, hemolysis, tissue invasion, and lethality in mice, is the most potent cytotoxic virulence factor of Vibrio vulnificus. Bioinformatics analysis of rtxA1 predicted 4 functional domains that presumably performed discrete functions during host cell killing. V. vulnificus RtxA1 has a unique domain designated as RtxA1-D2, corresponding to amino acids 1951-2574, which is absent in Vibrio cholerae multifunctional-autoprocessing repeats-in-toxin, suggesting that this domain confers specific biological functions to V. vulnificus RtxA1. HeLa cells expressing green fluorescent protein-RtxA1-D2 became round and lost their viability. A yeast 2-hybrid system identified prohibitin (PHB) 1 as the host partner of RtxA1-D2. The specific interaction of RtxA1-D2 with PHB1 was confirmed by performing immunoprecipitation. Interestingly, V. vulnificus RtxA1 up-regulated PHB1 expression on the cytoplasmic membrane of host cells. Extracellular signal-regulated kinase and p38 mitogen-activated protein kinase pathways were confirmed as being important in the up-regulation of PHB1 by using inhibitors. Down-regulation of PHB1 by small interfering RNAs decreased the cytotoxicity of RtxA1-D2 against HeLa cells. The pretreatment of an anti-PHB1 antibody impaired the cytotoxicity of V. vulnificus RtxA1. These results suggest that the involvement PHB1 in the RtxA1 cytotoxicity has significant implications for the pathogenesis of V. vulnificus infections. PMID:26136468

  14. Risk Factors for Scleroderma

    MedlinePlus

    ... You are here: Home For Patients Risk Factors Risk Factors for Scleroderma The cause of scleroderma is still ... 4-to-1. There is likely no single risk factor for scleroderma. A number of scientific studies suggest ...

  15. Risk Factors and Prevention

    MedlinePlus

    ... Resources Risk Factors & Prevention Back to Patient Resources Risk Factors & Prevention Even people who look healthy and free ... Blood Pressure , high cholesterol, diabetes, and thyroid disease. Risk Factors For Arrhythmias and Heart Disease The following conditions ...

  16. Fracture mechanics in fiber reinforced composite materials, taking as examples B/A1 and CRFP

    NASA Technical Reports Server (NTRS)

    Peters, P. W. M.

    1982-01-01

    The validity of linear elastic fracture mechanics and other fracture criteria was investigated with laminates of boron fiber reinforced aluminum (R/A1) and of carbon fiber reinforced epoxide (CFRP). Cracks are assessed by fracture strength Kc or Kmax (critical or maximum value of the stress intensity factor). The Whitney and Nuismer point stress criterion and average stress criterion often show that Kmax of fiber composite materials increases with increasing crack length; however, for R/A1 and CFRP the curve showing fracture strength as a function of crack length is only applicable in a small domain. For R/A1, the reason is clearly the extension of the plastic zone (or the damage zone n the case of CFRP) which cannot be described with a stress intensity factor.

  17. Annexin A1 in primary tumors promotes melanoma dissemination.

    PubMed

    Boudhraa, Zied; Rondepierre, Fabien; Ouchchane, Lemlih; Kintossou, Roselyne; Trzeciakiewicz, Anna; Franck, Frederic; Kanitakis, Jean; Labeille, Bruno; Joubert-Zakeyh, Juliette; Bouchon, Bernadette; Perrot, Jean Luc; Mansard, Sandrine; Papon, Janine; Dechelotte, Pierre; Chezal, Jean-Michel; Miot-Noirault, Elisabeth; Bonnet, Mathilde; D'Incan, Michel; Degoul, Françoise

    2014-10-01

    Metastatic melanoma is one of the most aggressive forms of skin cancer and has a poor prognosis. We have previously identified Annexin A1 (ANXA1) as a potential murine melanoma-spreading factor that may modulate cell invasion by binding to formyl peptide receptors (FPRs). Here, we report that (1) in a B16Bl6 spontaneous metastasis model, a siRNA-induced decrease in tumoral ANXA1 expression significantly reduced tumoral MMP2 activity and number of lung metastases; (2) in a retrospective study of 61 patients, metastasis-free survival was inversely related to ANXA1 expression levels in primary tumors (HR 3.15 [1.03-9.69], p = 0.045); (3) in human melanoma cell lines, ANXA1 level was positively correlated with in vitro invasion capacity whereas normal melanocytes contained low ANXA1 levels, and (4) the ANXA1 N-terminal peptide ANXA12-26 stimulated MMP2 activity after interaction with FPRs and significantly stimulated the in vitro invasion of melanomas by acting on FPRs. These findings identify ANXA1 as a proinvasive protein in melanoma that holds promise as a potential prognostic marker and therapeutic target. PMID:24997993

  18. Diagnostics for a 1.2 kA, 1 MeV, electron induction injector

    NASA Astrophysics Data System (ADS)

    Houck, T. L.; Anderson, D. E.; Eylon, S.; Henestroza, E.; Lidia, S. M.; Vanecek, D. L.; Westenskow, G. A.; Yu, S. S.

    1998-12-01

    We are constructing a 1.2 kA, 1 MeV, electron induction injector as part of the RTA program, a collaborative effort between LLNL and LBNL to develop relativistic klystrons for Two-Beam Accelerator applications. The RTA injector will also be used in the development of a high-gradient, low-emittance, electron source and beam diagnostics for the second axis of the Dual Axis Radiographic Hydrodynamic Test (DARHT) Facility. The electron source will be a 3.5″-diameter, thermionic, flat-surface, m-type cathode with a maximum shroud field stress of approximately 165 kV/cm. Additional design parameters for the injector include a pulse length of over 150 ns flat top (1% energy variation), and a normalized edge emittance of less than 200 π-mm-mr. Precise measurement of the beam parameters is required so that performance of the RTA injector can be confidently scaled to the 4 kA, 3 MeV, and 2-microsecond pulse parameters of the DARHT injector. Planned diagnostics include an isolated cathode with resistive divider for direct measurement of current emission, resistive wall and magnetic probe current monitors for measuring beam current and centroid position, capacitive probes for measuring A-K gap voltage, an energy spectrometer, and a pepperpot emittance diagnostic. Details of the injector, beam line, and diagnostics are presented.

  19. Nkx3.2 Promotes Primary Chondrogenic Differentiation by Upregulating Col2a1 Transcription

    PubMed Central

    Kawato, Yoshitaka; Hirao, Makoto; Ebina, Kosuke; Shi, Kenrin; Hashimoto, Jun; Honjo, Yui; Yoshikawa, Hideki; Myoui, Akira

    2012-01-01

    Background The Nkx3.2 transcription factor promotes chondrogenesis by forming a positive regulatory loop with a crucial chondrogenic transcription factor, Sox9. Previous studies have indicated that factors other than Sox9 may promote chondrogenesis directly, but these factors have not been identified. Here, we test the hypothesis that Nkx3.2 promotes chondrogenesis directly by Sox9-independent mechanisms and indirectly by previously characterized Sox9-dependent mechanisms. Methodology/Principal Findings C3H10T1/2 pluripotent mesenchymal cells were cultured with bone morphogenetic protein 2 (BMP2) to induce endochondral ossification. Overexpression of wild-type Nkx3.2 (WT-Nkx3.2) upregulated glycosaminoglycan (GAG) production and expression of type II collagen α1 (Col2a1) mRNA, and these effects were evident before WT-Nkx3.2-mediated upregulation of Sox9. RNAi-mediated inhibition of Nkx3.2 abolished GAG production and expression of Col2a1 mRNA. Dual luciferase reporter assays revealed that WT-Nkx3.2 upregulated Col2a1 enhancer activity in a dose-dependent manner in C3H10T1/2 cells and also in N1511 chondrocytes. In addition, WT-Nkx3.2 partially restored downregulation of GAG production, Col2 protein expression, and Col2a1 mRNA expression induced by Sox9 RNAi. ChIP assays revealed that Nkx3.2 bound to the Col2a1 enhancer element. Conclusions/Significance Nkx3.2 promoted primary chondrogenesis by two mechanisms: Direct and Sox9-independent upregulation of Col2a1 transcription and upregulation of Sox9 mRNA expression under positive feedback system. PMID:22511961

  20. The Atypical Histone MacroH2A1.2 Interacts with HER-2 Protein in Cancer Cells*

    PubMed Central

    Li, Xiufen; Kuang, Jinqiu; Shen, Yi; Majer, Martin M.; Nelson, Chad C.; Parsawar, Krishna; Heichman, Karen A.; Kuwada, Scott K.

    2012-01-01

    Because HER-2 has been demonstrated in the nuclei of cancer cells, we hypothesized that it might interact with transcription factors that activate ERBB2 transcription. Macrohistone 2A1 (H2AFY; mH2A1) was found to interact with HER-2 in cancer cells that overexpress HER-2. Of the two human mH2A1 isoforms, mH2A1.2, but not mH2A1.1, interacted with HER-2 in human cancer cell lines. Overexpression of mH2A1.2, but not mH2A1.1, in cancer cells significantly increased HER-2 expression and tumorigenicity. Inhibition of HER-2 kinase activity diminished mH2A1 expression and mH2A1.2-induced ERBB2 transcription in cancer cells. Chromatin immunoprecipitation of mH2A1.2 in cancer cells stably transfected with mH2A1.2 showed enrichment of mH2A1.2 at the HER-2 promoter, suggesting a role for mH2A1.2 in driving HER-2 overexpression. The evolutionarily conserved macro domain of mH2A1.2 was sufficient for the interaction between HER-2 and mH2A1.2 and for mH2A1.2-induced ERBB2 transcription. Within the macro domain of mH2A1.2, a trinucleotide insertion (-EIS-) sequence not found in mH2A1.1 was essential for the interaction between HER-2 and mH2A1.2 as well as mH2A1.2-induced HER-2 expression and cell proliferation. PMID:22589551

  1. Multiple and additive functions of ALDH3A1 and ALDH1A1: cataract phenotype and ocular oxidative damage in Aldh3a1(-/-)/Aldh1a1(-/-) knock-out mice.

    PubMed

    Lassen, Natalie; Bateman, J Bronwyn; Estey, Tia; Kuszak, Jer R; Nees, David W; Piatigorsky, Joram; Duester, Gregg; Day, Brian J; Huang, Jie; Hines, Lisa M; Vasiliou, Vasilis

    2007-08-31

    ALDH3A1 (aldehyde dehydrogenase 3A1) is abundant in the mouse cornea but undetectable in the lens, and ALDH1A1 is present at lower (catalytic) levels in the cornea and lens. To test the hypothesis that ALDH3A1 and ALDH1A1 protect the anterior segment of the eye against environmentally induced oxidative damage, Aldh1a1(-/-)/Aldh3a1(-/-) double knock-out and Aldh1a1(-/-) and Aldh3a1(-/-) single knock-out mice were evaluated for biochemical changes and cataract formation (lens opacification). The Aldh1a1/Aldh3a1- and Aldh3a1-null mice develop cataracts in the anterior and posterior subcapsular regions as well as punctate opacities in the cortex by 1 month of age. The Aldh1a1-null mice also develop cataracts later in life (6-9 months of age). One- to three-month-old Aldh-null mice exposed to UVB exhibited accelerated anterior lens subcapsular opacification, which was more pronounced in Aldh3a1(-/-) and Aldh3a1(-/-)/Aldh1a1(-/-) mice compared with Aldh1a1(-/-) and wild type animals. Cataract formation was associated with decreased proteasomal activity, increased protein oxidation, increased GSH levels, and increased levels of 4-hydroxy-2-nonenal- and malondialdehyde-protein adducts. In conclusion, these findings support the hypothesis that corneal ALDH3A1 and lens ALDH1A1 protect the eye against cataract formation via nonenzymatic (light filtering) and enzymatic (detoxification) functions. PMID:17567582

  2. FoxA1 binding to the MMTV LTR modulates chromatin structure and transcription

    SciTech Connect

    Holmqvist, Per-Henrik; Belikov, Sergey; Zaret, Kenneth S.; Wrange, Oerjan . E-mail: orjan.wrange@cmb.ki.se

    2005-04-01

    Novel binding sites for the forkhead transcription factor family member Forkhead box A (FoxA), previously referred to as Hepatocyte Nuclear Factor 3 (HNF3), were found within the mouse mammary tumor virus long terminal repeat (MMTV LTR). The effect of FoxA1 on MMTV LTR chromatin structure, and expression was evaluated in Xenopus laevis oocytes. Mutagenesis of either of the two main FoxA binding sites showed that the distal site, -232/-221, conferred FoxA1-dependent partial inhibition of glucocorticoid receptor (GR) driven MMTV transcription. The proximal FoxA binding segment consisted of two individual FoxA sites at -57/-46 and -45/-34, respectively, that mediated an increased basal MMTV transcription. FoxA1 binding altered the chromatin structure of both the inactive- and the hormone-activated MMTV LTR. Hydroxyl radical foot printing revealed FoxA1-mediated changes in the nucleosome arrangement. Micrococcal nuclease digestion showed the hormone-dependent sub-nucleosome complex, containing {approx}120 bp of DNA, to be expanded by FoxA1 binding to the proximal segment into a larger complex containing {approx}200 bp. The potential function of the FoxA1-mediated expression of the MMTV provirus for maintenance of expression in different tissues is discussed.

  3. S100A1 and S100B are dispensable for endochondral ossification during skeletal development.

    PubMed

    Mori, Yoshifumi; Mori, Daisuke; Chung, Ung-Il; Tanaka, Sakae; Heierhorst, Jörg; Buchou, Thierry; Baudier, Jacques; Kawaguchi, Hiroshi; Saito, Taku

    2014-01-01

    S100A1 and S100B are induced by the SOX trio transcription factors (SOX9, SOX5, and SOX6) in chondrocytes, and inhibit their hypertrophic differentiation in culture. However, functional roles of S100A1 and S100B during in vivo skeletal development are yet to be determined. Here we show that mice deficient of both the S100a1 and S100b genes displayed normal skeletal growth from embryonic stage to adulthood. Although no compensatory upregulation of other S100 family members was observed in S100a1/S100b double mutants, the related S100a2, S100a4, S100a10, and S100a11 were expressed at similarly high levels to S100a1 and S100b in mouse primary chondrocytes. Furthermore, overexpression of these other S100 members suppressed the hypertrophic differentiation of chondrocytes in vitro as efficiently as S100A1 and S100B. Taken together, the present study demonstrates that S100A1 and S100B are dispensable for endochondral ossification during skeletal development, most likely because their deficiency may be masked by other S100 proteins which have similar functions to those of S100A1 and S100B. PMID:25152033

  4. Col4a1 mutations cause progressive retinal neovascular defects and retinopathy

    PubMed Central

    Alavi, Marcel V.; Mao, Mao; Pawlikowski, Bradley T.; Kvezereli, Manana; Duncan, Jacque L.; Libby, Richard T.; John, Simon W. M.; Gould, Douglas B.

    2016-01-01

    Mutations in collagen, type IV, alpha 1 (COL4A1), a major component of basement membranes, cause multisystem disorders in humans and mice. In the eye, these include anterior segment dysgenesis, optic nerve hypoplasia and retinal vascular tortuosity. Here we investigate the retinal pathology in mice carrying dominant-negative Col4a1 mutations. To this end, we examined retinas longitudinally in vivo using fluorescein angiography, funduscopy and optical coherence tomography. We assessed retinal function by electroretinography and studied the retinal ultrastructural pathology. Retinal examinations revealed serous chorioretinopathy, retinal hemorrhages, fibrosis or signs of pathogenic angiogenesis with chorioretinal anastomosis in up to approximately 90% of Col4a1 mutant eyes depending on age and the specific mutation. To identify the cell-type responsible for pathogenesis we generated a conditional Col4a1 mutation and determined that primary vascular defects underlie Col4a1-associated retinopathy. We also found focal activation of Müller cells and increased expression of pro-angiogenic factors in retinas from Col4a1+/Δex41mice. Together, our findings suggest that patients with COL4A1 and COL4A2 mutations may be at elevated risk of retinal hemorrhages and that retinal examinations may be useful for identifying patients with COL4A1 and COL4A2 mutations who are also at elevated risk of hemorrhagic strokes. PMID:26813606

  5. NR4A1 Promotes PDGF-BB-Induced Cell Colony Formation in Soft Agar

    PubMed Central

    Eger, Glenda; Papadopoulos, Natalia; Lennartsson, Johan; Heldin, Carl-Henrik

    2014-01-01

    The fibroblast mitogen platelet-derived growth factor -BB (PDGF-BB) induces a transient expression of the orphan nuclear receptor NR4A1 (also named Nur77, TR3 or NGFIB). The aim of the present study was to investigate the pathways through which NR4A1 is induced by PDGF-BB and its functional role. We demonstrate that in PDGF-BB stimulated NIH3T3 cells, the MEK1/2 inhibitor CI-1040 strongly represses NR4A1 expression, whereas Erk5 downregulation delays the expression, but does not block it. Moreover, we report that treatment with the NF-κB inhibitor BAY11-7082 suppresses NR4A1 mRNA and protein expression. The majority of NR4A1 in NIH3T3 was found to be localized in the cytoplasm and only a fraction was translocated to the nucleus after continued PDGF-BB treatment. Silencing NR4A1 slightly increased the proliferation rate of NIH3T3 cells; however, it did not affect the chemotactic or survival abilities conferred by PDGF-BB. Moreover, overexpression of NR4A1 promoted anchorage-independent growth of NIH3T3 cells and the glioblastoma cell lines U-105MG and U-251MG. Thus, whereas NR4A1, induced by PDGF-BB, suppresses cell growth on a solid surface, it increases anchorage-independent growth. PMID:25269081

  6. Epigenetic Modulation of Collagen 1A1: Therapeutic Implications in Fibrosis and Endometriosis.

    PubMed

    Zheng, Ye; Khan, Zaraq; Zanfagnin, Valentina; Correa, Luiz F; Delaney, Abigail A; Daftary, Gaurang S

    2016-04-01

    Progressive fibrosis is recalcitrant to conventional therapy and commonly complicates chronic diseases and surgical healing. We evaluate here a novel mechanism that regulates scar-tissue collagen (COL1A1/Col1a1) expression and characterizes its translational relevance as a targeted therapy for fibrosis in an endometriosis disease model. Endometriosis is caused by displacement and implantation of uterine endometrium onto abdominal organs and spreads with progressive scarring. Transcription factor KLF11 is specifically diminished in endometriosis lesions. Loss of KLF11-mediated repression of COL1A1/Col1a1 expression resulted in increased fibrosis. To determine the biological significance of COL1A1/Col1a1 expression on fibrosis, we modulated its expression. In human endometrial-stromal fibroblasts, KLF11 recruited SIN3A/HDAC (histone deacetylase), resulting in COL1A1-promoter deacetylation and repression. This role of KLF11 was pharmacologically replicated by a histone acetyl transferase inhibitor (garcinol). In contrast, opposite effects were obtained with a HDAC inhibitor (suberoyl anilide hydroxamic acid), confirming regulatory specificity for these reciprocally active epigenetic mechanisms. Fibrosis was concordantly reversed in Klf11(-/-)animals by histone acetyl transferase inhibitor and in wild-type animals by HDAC inhibitor treatments. Aberrant lesional COL1A1 regulation is significant because fibrosis depended on lesion rather than host genotype. This is the first report demonstrating feasibility for targeted pharmacological reversal of fibrosis, an intractable phenotype of diverse chronic diseases. PMID:26935598

  7. Lattice equations arising from discrete Painlevé systems. I. (A2 + A1)(1) and ( A 1 + A1 ' ) ( 1 ) cases

    NASA Astrophysics Data System (ADS)

    Joshi, Nalini; Nakazono, Nobutaka; Shi, Yang

    2015-09-01

    We introduce the concept of ω-lattice, constructed from τ functions of Painlevé systems, on which quad-equations of ABS (Adler-Bobenko-Suris) type appear. In particular, we consider the A5 ( 1 ) - and A6 ( 1 ) -surface q-Painlevé systems corresponding affine Weyl group symmetries are of (A2 + A1)(1)- and (A1 + A1)(1)-types, respectively.

  8. Factor XIII Deficiency.

    PubMed

    Karimi, Mehran; Bereczky, Zsuzsanna; Cohan, Nader; Muszbek, László

    2009-06-01

    Factor XIII (FXIII) is a tetrameric zymogen (FXIII-A (2)B (2)) that is converted into an active transglutaminase (FXIIIa) by thrombin and Ca (2+) in the terminal phase of the clotting cascade. By cross-linking fibrin chains and alpha (2) plasmin inhibitor to fibrin, FXIIIa mechanically stabilizes fibrin and protects it from fibrinolysis. Severe deficiency of the potentially active A subunit (FXIII-A) is a rare but severe hemorrhagic diathesis. Delayed umbilical stump bleeding is characteristic, and subcutaneous, intramuscular, and intracranial bleeding occurs with a relatively high frequency in nonsupplemented patients. In addition, impaired wound healing and spontaneous abortion in women are also features of FXIII deficiency. The extremely rare B subunit deficiency results in milder bleeding symptoms. FXIII concentrate is now available for on-demand treatment and primary prophylaxis. A quantitative FXIII activity assay is recommended as a screening test for the diagnosis of FXIII deficiency. For classification purposes, FXIII-A (2)B (2) antigen in the plasma is first determined, and if decreased, further measurement of the individual subunits is recommended in the plasma and FXIII-A in platelet lysate. Analytical aspects of FXIII activity and antigen assays are discussed in this article. There are no hot-spot mutations in the F13A1 and F13B genes, and the majority of causative mutations are missense/nonsense point mutations. PMID:19598071

  9. Targeting NR4A1 (TR3) in Cancer Cells and Tumors

    PubMed Central

    Lee, Syng-Ook; Li, Xi; Khan, Shaheen; Safe, Stephen

    2015-01-01

    Introduction NR4A1 (TR3, Nur77) is a member of the nuclear receptor superfamily of transcription factors and there is evidence that this receptor is highly expressed in multiple tumor types. Moreover, RNA interference studies indicate that NR4A1 exhibits growth promoting, angiogenic and prosurvival activity in most cancers. Areas Covered This review summarizes studies on several apoptosis-inducing agents that activate nuclear export of NR4A1 which subsequently forms a mitochondrial NR4A1-bcl-2 complex that induces the intrinsic pathway for apoptosis. Cytosporone B and related compounds that induce NR4A1-dependent apoptosis in cancer cells through both modulation of nuclear NR4A1 and nuclear export are also discussed. A relatively new class of diindolylmethane analogs (C-DIMs) including 1,1-bis(3′-indolyl)-1-(p-methoxyphenyl)methane (DIM-C-pPhOCH3) (NR4A1 activator) and 1,1-bis(3′-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH) (NR4A1 deactivator) are discussed in more detail. These anticancer drugs (C-DIMs) act strictly through nuclear NR4A1 and induce apoptosis in cancer cells and tumors. Expert Opinion It is clear that NR4A1 plays an important pro-oncogenic role in cancer cells and tumors, and there is increasing evidence that this receptor can be targeted by anticancer drugs that induce cell death via NR4A1-dependent and -independent pathways. Moreover, since many of these compounds exhibit relatively low toxicity, they represent an important class of mechanism-based anticancer drugs with excellent potential for clinical applications. PMID:21204731

  10. Crystallization and preliminary X-ray analysis of alginate lyases A1-II and A1-II′ from Sphingomonas sp. A1

    SciTech Connect

    Yamasaki, Masayuki; Ogura, Kohei; Moriwaki, Satoko; Hashimoto, Wataru; Murata, Kousaku; Mikami, Bunzo

    2005-03-01

    The crystallization and preliminary characterization of the family PL-7 alginate lyases A1-II and A1-II′ from Sphingomonas sp. A1 are presented. Alginate lyases depolymerize alginate, a heteropolysaccharide consisting of α-l-guluronate and β-d-mannuronate, through a β-elimination reaction. The alginate lyases A1-II (25 kDa) and A1-II′ (25 kDa) from Sphingomonas sp. A1, which belong to polysaccharide lyase family PL-7, exhibit 68% homology in primary structure but have different substrate specificities. To determine clearly the structural basis for substrate recognition in the depolymerization mechanism by alginate lyases, both proteins were crystallized at 293 K using the vapour-diffusion method. A crystal of A1-II belonged to space group P2{sub 1} and diffracted to 2.2 Å resolution, with unit-cell parameters a = 51.3, b = 30.1, c = 101.6 Å, β = 100.2°, while a crystal of A1-II′ belonged to space group P2{sub 1}2{sub 1}2{sub 1} and diffracted to 1.0 Å resolution, with unit-cell parameters a = 34.6, b = 68.5, c = 80.3 Å.

  11. The salt-sensitive structure and zinc inhibition of Borrelia burgdorferi protease BbHtrA.

    PubMed

    Russell, Theresa M; Tang, Xiaoling; Goldstein, Jason M; Bagarozzi, Dennis; Johnson, Barbara J B

    2016-02-01

    HtrA serine proteases are highly conserved and essential ATP-independent proteases with chaperone activity. Bacteria express a variable number of HtrA homologues that contribute to the virulence and pathogenicity of bacterial pathogens. Lyme disease spirochetes possess a single HtrA protease homologue, Borrelia burgdorferi HtrA (BbHtrA). Previous studies established that, like the human orthologue HtrA1, BbHtrA is proteolytically active against numerous extracellular proteins in vitro. In this study, we utilized size exclusion chromatography and blue native polyacrylamide gel electrophoresis (BN-PAGE) to demonstrate BbHtrA oligomeric structures that were substrate independent and salt sensitive. Examination of the influence of transition metals on the activity of BbHtrA revealed that this protease is inhibited by Zn(2+)  > Cu(2+)  > Mn(2+) . Extending this analysis to two other HtrA proteases, E. coli DegP and HtrA1, revealed that all three HtrA proteases were reversibly inhibited by ZnCl2 at all micro molar concentrations examined. Commercial inhibitors for HtrA proteases are not available and physiologic HtrA inhibitors are unknown. Our observation of conserved zinc inhibition of HtrA proteases will facilitate structural and functional studies of additional members of this important class of proteases. PMID:26480895

  12. 26 CFR 1.1311(a)-1 - Introduction.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 11 2010-04-01 2010-04-01 true Introduction. 1.1311(a)-1 Section 1.1311(a)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Readjustment of Tax Between Years and Special Limitations § 1.1311(a)-1 Introduction....

  13. 5 CFR Appendix A-1 to Subpart I... - Windchill Chart

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... ADMINISTRATION (GENERAL) Pay for Duty Involving Physical Hardship or Hazard Pt. 550, Subpt. I, App. A-1 Appendix A-1 to Subpart I of Part 550—Windchill Chart EC01SE91.002 windchill chart in non-metric units... 5 Administrative Personnel 1 2011-01-01 2011-01-01 false Windchill Chart A Appendix A-1 to...

  14. 5 CFR Appendix A-1 to Subpart I... - Windchill Chart

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... ADMINISTRATION (GENERAL) Pay for Duty Involving Physical Hardship or Hazard Pt. 550, Subpt. I, App. A-1 Appendix A-1 to Subpart I of Part 550—Windchill Chart EC01SE91.002 windchill chart in non-metric units... 5 Administrative Personnel 1 2010-01-01 2010-01-01 false Windchill Chart A Appendix A-1 to...

  15. 5 CFR Appendix A-1 to Subpart I... - Windchill Chart

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 5 Administrative Personnel 1 2012-01-01 2012-01-01 false Windchill Chart A Appendix A-1 to Subpart I of Part 550 Administrative Personnel OFFICE OF PERSONNEL MANAGEMENT CIVIL SERVICE REGULATIONS PAY ADMINISTRATION (GENERAL) Pay for Duty Involving Physical Hardship or Hazard Pt. 550, Subpt. I, App. A-1 Appendix A-1 to Subpart I of Part...

  16. 5 CFR Appendix A-1 to Subpart I... - Windchill Chart

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... ADMINISTRATION (GENERAL) Pay for Duty Involving Physical Hardship or Hazard Pt. 550, Subpt. I, App. A-1 Appendix A-1 to Subpart I of Part 550—Windchill Chart EC01SE91.002 windchill chart in non-metric units... 5 Administrative Personnel 1 2014-01-01 2014-01-01 false Windchill Chart A Appendix A-1 to...

  17. 26 CFR 48.4222(a)-1 - Registration.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Registration. 48.4222(a)-1 Section 48.4222(a)-1... TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Exemptions, Registration, Etc. § 48.4222(a)-1 Registration. (a) General rule. Except as provided in § 48.4222(b)-1, tax-free sales under section 4221 may...

  18. 26 CFR 48.4222(a)-1 - Registration.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Registration. 48.4222(a)-1 Section 48.4222(a)-1... TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Exemptions, Registration, Etc. § 48.4222(a)-1 Registration. (a) General rule. Except as provided in § 48.4222(b)-1, tax-free sales under section 4221 may...

  19. Aldehyde dehydrogenase 3A1 associates with prostate tumorigenesis

    PubMed Central

    Yan, J; De Melo, J; Cutz, J-C; Aziz, T; Tang, D

    2014-01-01

    Background: Accumulating evidence demonstrates high levels of aldehyde dehydrogense (ALDH) activity in human cancer types, in part, because of its association with cancer stem cells. Whereas ALDH1A1 and ALDH7A1 isoforms were reported to associate with prostate tumorigenesis, whether other ALDH isoforms are associated with prostate cancer (PC) remains unclear. Methods: ALDH3A1 expression was analysed in various PC cell lines. Xenograft tumours and 54 primary and metastatic PC tumours were stained using immunohistochemistry for ALDH3A1 expression. Results: In comparison with the non-stem counterparts, a robust upregulation of ALDH3A1 was observed in DU145-derived PC stem cells (PCSCs). As DU145 PCSCs produced xenograft tumours with more advanced features compared with those derived from DU145 cells, higher levels of ALDH3A1 were detected in the former; a dramatic elevation of ALDH3A1 occurred in DU145 cell-derived lung metastasis compared with local xenograft tumours. Furthermore, while ALDH3A1 was not observed in prostate glands, ALDH3A1 was clearly present in PIN, and further increased in carcinomas. In comparison with the paired local carcinomas, ALDH3A1 was upregulated in lymph node metastatic tumours; the presence of ALDH3A1 in bone metastatic PC was also demonstrated. Conclusions: We report here the association of ALDH3A1 with PC progression. PMID:24762960

  20. 42 CFR 136a.1 - Purpose of the regulations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 42 Public Health 1 2014-10-01 2014-10-01 false Purpose of the regulations. 136a.1 Section 136a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES INDIAN HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES INDIAN HEALTH Purpose § 136a.1 Purpose of the regulations....

  1. 42 CFR 136a.1 - Purpose of the regulations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 42 Public Health 1 2011-10-01 2011-10-01 false Purpose of the regulations. 136a.1 Section 136a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES INDIAN HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES INDIAN HEALTH Purpose § 136a.1 Purpose of the regulations....

  2. Organic anion transporting polypeptide 1a1 null mice are sensitive to cholestatic liver injury.

    PubMed

    Zhang, Youcai; Csanaky, Iván L; Cheng, Xingguo; Lehman-McKeeman, Lois D; Klaassen, Curtis D

    2012-06-01

    Organic anion transporting polypeptide 1a1 (Oatp1a1) is predominantly expressed in livers of mice and is thought to transport bile acids (BAs) from blood into liver. Because Oatp1a1 expression is markedly decreased in mice after bile duct ligation (BDL). We hypothesized that Oatp1a1-null mice would be protected against liver injury during BDL-induced cholestasis due largely to reduced hepatic uptake of BAs. To evaluate this hypothesis, BDL surgeries were performed in both male wild-type (WT) and Oatp1a1-null mice. At 24 h after BDL, Oatp1a1-null mice showed higher serum alanine aminotransferase levels and more severe liver injury than WT mice, and all Oatp1a1-null mice died within 4 days after BDL, whereas all WT mice survived. At 24 h after BDL, surprisingly Oatp1a1-null mice had higher total BA concentrations in livers than WT mice, suggesting that loss of Oatp1a1 did not prevent BA accumulation in the liver. In addition, secondary BAs dramatically increased in serum of Oatp1a1-null BDL mice but not in WT BDL mice. Oatp1a1-null BDL mice had similar basolateral BA uptake (Na(+)-taurocholate cotransporting polypeptide and Oatp1b2) and BA-efflux (multidrug resistance-associated protein [Mrp]-3, Mrp4, and organic solute transporter α/β) transporters, as well as BA-synthetic enzyme (Cyp7a1) in livers as WT BDL mice. Hepatic expression of small heterodimer partner Cyp3a11, Cyp4a14, and Nqo1, which are target genes of farnesoid X receptor, pregnane X receptor, peroxisome proliferator-activated receptor alpha, and NF-E2-related factor 2, respectively, were increased in WT BDL mice but not in Oatp1a1-null BDL mice. These results demonstrate that loss of Oatp1a1 function exacerbates cholestatic liver injury in mice and suggest that Oatp1a1 plays a unique role in liver adaptive responses to obstructive cholestasis. PMID:22461449

  3. Relationship Between A1C and Fasting Plasma Glucose in Dysglycemia or Type 2 Diabetes

    PubMed Central

    Ramachandran, Ambady; Riddle, Matthew C.; Kabali, Conrad; Gerstein, Hertzel C.

    2012-01-01

    OBJECTIVE A1C measurement has advantages over measures of plasma glucose. Few studies have evaluated the A1C–fasting plasma glucose (FPG) relationship and whether oral antidiabetes drugs (OADs) and ethnic or geographic variations affect the relationship. Baseline A1C and FPG data from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial participants were analyzed to 1) elucidate the relationship between A1C and FPG in people with moderate dysglycemia (A1C 5.6–9.0% [38–75 mmol/mol]) and additional risk factors for cardiovascular disease, 2) determine whether this relationship is altered by use of an OAD, and 3) study whether geographic and ethnic differences exist. RESEARCH DESIGN AND METHODS Analysis was performed of 12,527 participants with dysglycemia or early type 2 diabetes recruited in North America, South America, Europe, Australia, and Asia who comprised white, Latin American, Asian, black, and other ethnicities. The A1C-FPG relationships were analyzed using cubic B spline curves in all participants and in subgroups not using an OAD or using an OAD and comprising persons of different ethnic or geographic origin. RESULTS A strong relationship between FPG in the range of 5.6–9.0 mmol/L and the corresponding A1C was seen across different geographic regions and ethnic groups. A smaller increase in A1C per unit increase in FPG occurred for persons taking an OAD versus those not taking an OAD. CONCLUSIONS The strong relationship between A1C and FPG in moderate dysglycemia is not significantly affected by ethnic or geographic differences. Use of an OAD alters the relationship and should be considered when interpreting A1C level. PMID:22323416

  4. Harman induces CYP1A1 enzyme through an aryl hydrocarbon receptor mechanism

    SciTech Connect

    El Gendy, Mohamed A.M.; El-Kadi, Ayman O.S.

    2010-11-15

    Harman is a common compound in several foods, plants and beverages. Numerous studies have demonstrated its mutagenic, co-mutagenic and carcinogenic effects; however, the exact mechanism has not been fully identified. Aryl hydrocarbon receptor (AhR) is a transcription factor regulating the expression of the carcinogen-activating enzyme; cytochrome P450 1A1 (CYP1A1). In the present study, we examined the ability of harman to induce AhR-mediated signal transduction in human and rat hepatoma cells; HepG2 and H4IIE cells. Our results showed that harman significantly induced CYP1A1 mRNA in a time- and concentration-dependent manner. Similarly, harman significantly induced CYP1A1 at protein and activity levels in a concentration-dependent manner. Moreover, the AhR antagonist, resveratrol, inhibited the increase in CYP1A1 activity by harman. The RNA polymerase inhibitor, actinomycin D, completely abolished the CYP1A1 mRNA induction by harman, indicating a transcriptional activation. The role of AhR in CYP1A1 induction by harman was confirmed by using siRNA specific for human AhR. The ability of harman to induce CYP1A1 was strongly correlated with its ability to stimulate AhR-dependent luciferase activity and electrophoretic mobility shift assay. At post-transcriptional and post-translational levels, harman did not affect the stability of CYP1A1 at the mRNA and the protein levels, excluding other mechanisms participating in the obtained effects. We concluded that harman can directly induce CYP1A1 gene expression in an AhR-dependent manner and may represent a novel mechanism by which harman promotes mutagenicity, co-mutagenicity and carcinogenicity.

  5. Chiral dynamics of a1(1260) ? 3?

    NASA Astrophysics Data System (ADS)

    Tegen, R.; Greiner, W.

    2003-06-01

    We calculate the sequential decays a1 rightarrow pisigma rightarrow 3pi and a1 rightarrow pirho rightarrow 3pi using chiral SU(2) otimes SU(2) current commutation relations. Proper vertices a1pisigma, sigmapipi, a1pirho, rhopipi are derived from Ward identities and yield energy-dependent decay widths Gammarhorightarrowpipi and Gammasigmarightarrowpipi necessary for the total Gammaa1rightarrow3pi decay width. Both sequential decays (via pisigma and pirho) are necessary to reproduce Gammatota1. We find evidence for a substantial quenching of the sigma rightarrow pipi decay width in a1 rightarrow pisigma rightarrow 3pi.

  6. Accurate identification of UDP-glucuronosyltransferase 1A1 (UGT1A1) inhibitors using UGT1A1-overexpressing HeLa cells.

    PubMed

    Sun, Hua; Zhou, Xiaotong; Wu, Baojian

    2015-01-01

    1. UDP-glucuronosyltransferase 1A1 (UGT1A1) plays an irreplaceable role in detoxification of bilirubin and many drugs (e.g., SN-38). Here we aimed to explore the potential of UGT1A1-overexpressing HeLa cells (or HeLa1A1 cells) as a tool to accurately identify UGT1A1 inhibitors. 2. Determination of glucuronidation rates (β-estradiol and SN-38 as the substrates) was performed using HeLa1A1 cells and uridine diphosphoglucuronic acid (UDPGA)-supplemented cDNA expressed UGT1A1 enzyme (or microsomes). The inhibitory effects (IC50 values) of 20 structurally diverse compounds on the UGT1A1 activity were determined using HeLa1A1 cells and microsomal incubations. 3. In HeLa1A1 cells, the IC50 values for inhibition of β-estradiol glucuronidation by the tested compounds ranged from 0.33 to 94.6 µM. In the microsomal incubations, the IC50 values ranged from 0.47 to 155 µM. It was found that the IC50 values of all test compounds derived from the cells were well consistent with those from the microsomes (deviated by less than two-fold). Further, the IC50 values from the cells were strongly correlated with those from microsomes (r = 0.944, p < 0.001). Likewise, the IC50 values (0.37-77.3 µM) for inhibition of SN-38 glucuronidation in the cells were close to those (0.42-122 µM) for glucuronidation inhibition in microsomes. A strong correlation was also observed between the two sets of IC50 values (r = 0.978, p < 0.001). 4. In conclusion, UGT1A1-overexpressing HeLa cells were an appropriate tool to accurately depict the inhibition profiles of chemicals against UGT1A1. PMID:26068529

  7. Methods for Tumor Targeting with Salmonella typhimurium A1-R.

    PubMed

    Hoffman, Robert M; Zhao, Ming

    2016-01-01

    Salmonella typhimurium A1-R (S. typhimurium A1-R) has shown great preclinical promise as a broad-based anti-cancer therapeutic (please see Chapter 1 ). The present chapter describes materials and methods for the preclinical study of S. typhimurium A1-R in clinically-relevant mouse models. Establishment of orthotopic metastatic mouse models of the major cancer types is described, as well as other useful models, for efficacy studies of S. typhimurium A1-R or other tumor-targeting bacteria, as well. Imaging methods are described to visualize GFP-labeled S. typhimurium A1-R, as well as GFP- and/or RFP-labeled cancer cells in vitro and in vivo, which S. typhimurium A1-R targets. The mouse models include metastasis to major organs that are life-threatening to cancer patients including the liver, lung, bone, and brain and how to target these metastases with S. typhimurium A1-R. Various routes of administration of S. typhimurium A1-R are described with the advantages and disadvantages of each. Basic experiments to determine toxic effects of S. typhimurium A1-R are also described. Also described are methodologies for combining S. typhimurium A1-R and chemotherapy. The testing of S. typhimurium A1-R on patient tumors in patient-derived orthotopic xenograft (PDOX) mouse models is also described. The major methodologies described in this chapter should be translatable for clinical studies. PMID:26846809

  8. Human factors in mining

    SciTech Connect

    Sanders, M.S.; Peay, J.M.

    1988-01-01

    There is a growing awareness among mining professionals that the human factor plays a significant role in safety and productivity. Since the 1960's, the science of human factors, or ergonomics, has been making inroads into the mining industry, and a considerable amount of research has documented human-factor-related mining problems and solutions. This report is directed toward summarizing the application of human factors to improving safety, productivity, and the general physical and psychological working conditions of miners and toward familiarizing the readers with the role of human factors in the mining industry and the benefits that can accrue by systematically applying available human factors principles and data.

  9. Crystal Structure of Human Factor VIII: Implications for the Formation of the Factor IXa-Factor VIIIa Complex

    SciTech Connect

    Chi Ki Ngo,J.; Huang, M.; Roth, D.; Furie, B.; Furie, B.

    2008-01-01

    Factor VIII is a procofactor that plays a critical role in blood coagulation, and is missing or defective in hemophilia A. We determined the X-ray crystal structure of B domain-deleted human factor VIII. This protein is composed of five globular domains and contains one Ca(2+) and two Cu(2+) ions. The three homologous A domains form a triangular heterotrimer where the A1 and A3 domains serve as the base and interact with the C2 and C1 domains, respectively. The structurally homologous C1 and C2 domains reveal membrane binding features. Based on biochemical studies, a model of the factor IXa-factor VIIIa complex was constructed by in silico docking. Factor IXa wraps across the side of factor VIII, and an extended interface spans the factor VIII heavy and light chains. This model provides insight into the activation of factor VIII and the interaction of factor VIIIa with factor IXa on the membrane surface.

  10. Crystal Structure of Human Factor VIII: Implications for the Formation of the Factor IXa-Factor VIIIa Complex

    SciTech Connect

    Ngo, J.C.; Huang, M.; Roth, D.A.; Furie, B.C.; Furie, B.

    2008-06-03

    Factor VIII is a procofactor that plays a critical role in blood coagulation, and is missing or defective in hemophilia A. We determined the X-ray crystal structure of B domain-deleted human factor VIII. This protein is composed of five globular domains and contains one Ca{sup 2+} and two Cu{sup 2+} ions. The three homologous A domains form a triangular heterotrimer where the A1 and A3 domains serve as the base and interact with the C2 and C1 domains, respectively. The structurally homologous C1 and C2 domains reveal membrane binding features. Based on biochemical studies, a model of the factor IXa-factor VIIIa complex was constructed by in silico docking. Factor IXa wraps across the side of factor VIII, and an extended interface spans the factor VIII heavy and light chains. This model provides insight into the activation of factor VIII and the interaction of factor VIIIa with factor IXa on the membrane surface.

  11. An abundant dysfunctional apolipoprotein A1 in human atheroma.

    PubMed

    Huang, Ying; DiDonato, Joseph A; Levison, Bruce S; Schmitt, Dave; Li, Lin; Wu, Yuping; Buffa, Jennifer; Kim, Timothy; Gerstenecker, Gary S; Gu, Xiaodong; Kadiyala, Chandra S; Wang, Zeneng; Culley, Miranda K; Hazen, Jennie E; Didonato, Anthony J; Fu, Xiaoming; Berisha, Stela Z; Peng, Daoquan; Nguyen, Truc T; Liang, Shaohong; Chuang, Chia-Chi; Cho, Leslie; Plow, Edward F; Fox, Paul L; Gogonea, Valentin; Tang, W H Wilson; Parks, John S; Fisher, Edward A; Smith, Jonathan D; Hazen, Stanley L

    2014-02-01

    Recent studies have indicated that high-density lipoproteins (HDLs) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma are dysfunctional and are extensively oxidized by myeloperoxidase (MPO). In vitro oxidation of either apoA1 or HDL particles by MPO impairs their cholesterol acceptor function. Here, using phage display affinity maturation, we developed a high-affinity monoclonal antibody that specifically recognizes both apoA1 and HDL that have been modified by the MPO-H2O2-Cl(-) system. An oxindolyl alanine (2-OH-Trp) moiety at Trp72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirmed a critical role for apoA1 Trp72 in MPO-mediated inhibition of the ATP-binding cassette transporter A1 (ABCA1)-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation but accounts for 20% of the apoA1 in atherosclerosis-laden arteries. OxTrp72-apoA1 recovered from human atheroma or plasma is lipid poor, virtually devoid of cholesterol acceptor activity and demonstrated both a potent proinflammatory activity on endothelial cells and an impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n = 627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a proatherogenic process in the artery wall. PMID:24464187

  12. Annexin A1 Is Increased in the Plasma of Preeclamptic Women

    PubMed Central

    Perucci, Luiza O.; Carneiro, Fernanda S.; Ferreira, Cláudia N.; Sugimoto, Michelle A.; Soriani, Frederico M.; Martins, Gustavo G.; Lima, Kátia M.; Guimarães, Flávia L.; Teixeira, Antônio L.; Dusse, Luci M.; Gomes, Karina B.; Sousa, Lirlândia P.

    2015-01-01

    Background Preeclampsia (PE) is a pregnancy disease associated with exacerbated inflammatory response. Annexin A1 (AnxA1) is a glucocorticoid-regulated protein endowed with anti-inflammatory and proresolving properties that has been much studied in various animal models of inflammation but poorly studied in the context of human inflammatory diseases. The main objective of this study was to measure AnxA1 levels in PE women and to compare those levels in normotensive pregnant and non-pregnant women. We evaluated the association among AnxA1, ultrasensitive C reactive protein (us-CRP) and soluble tumor necrosis factor alpha receptor type 1 (sTNF-R1) plasma levels of the study participants. Methods This study included 40 non-pregnant, 38 normotensive pregnant and 51 PE women. PE women were stratified in early (N = 23) and late (N = 28) subgroups, according to gestational age (GA) at onset of clinical symptoms. Protein AnxA1 and us-CRP plasma levels were determined by ELISA and immunoturbidimetric assays, respectively. Transcript levels of AnxA1 in peripheral blood mononuclear cells (PBMC) were measured by real time RT-PCR. Results Increased levels of AnxA1 coincided with higher us-CRP levels in the plasma of PE women. Pregnant women with early PE had higher levels of AnxA1 and us-CRP than normotensive pregnant women with GA <34 weeks. No significant difference was found for AnxA1 and us-CRP, comparing late PE and normotensive pregnant women with GA ≥34 weeks. AnxA1 mRNA levels in PBMC were similar among the studied groups. AnxA1 was positively correlated with sTNF-R1, but not with us-CRP. Conclusions Our data show that increased AnxA1 levels were associated with a systemic inflammatory phenotype in PE, suggesting AnxA1 deregulation in PE pathogenesis. However, more studies are needed to clarify the role of AnxA1 and other proresolving molecules in the context of the systemic inflammatory response in this intriguing disease. PMID:26398190

  13. Adenosine A1 Receptors (A1R) Regulate Bone Resorption II Adenosine A1R Blockade or Deletion Increases Bone Density and Prevents Ovariectomy-Induced Bone Loss

    PubMed Central

    Kara, Firas M.; Doty, Stephen B.; Boskey, Adele; Goldring, Steven; Zaidi, Mone; Fredholm, Bertil B.; Cronstein, Bruce N.

    2010-01-01

    Objective Accelerated osteoclastic bone resorption plays a central role in the pathogenesis of osteoporosis and other bone diseases. Because identifying the molecular pathways that regulate osteoclast activity provides a key to understanding the causes of these diseases and to the development of new treatments we studied the effect of adenosine A1 receptor blockade or deletion on bone density. Methods Bone mineral density (BMD) in adenosine A1 receptor knockout mice was analyzed by DEXA scan and the trabecular and cortical bone volume was determined by Micro CT. Mice were ovariectomized or sham-operated, and 5 weeks after surgery, when osteopenia had developed, several parameters were analysed by DEXA scan and MicroCT. Histological examination of bones from A1 knockout and wild type mice was carried out. Visualization of osteoblast function (bone formation) after Tetracycline double labeling was performed by fluorescence microscopy. Results MicroCT analysis of bones from A1KO mice showed significantly increased bone volume. Electron microscopy of bones from A1KO mice shows an absence of ruffled borders of osteoclasts and osteoclast bone resorption. Immunohistology demonstrates that although osteoclasts are present in the A1KO mice they are smaller and often not associated with bone. No morphologic changes in osteoblasts were observed and bone labeling studies reveal no change in bone formation rates in the A1KO mice. Conclusion These results suggest that the adenosine A1 receptor may be a useful target in treating diseases characterized by excessive bone turnover such as osteoporosis and prosthetic joint loosening. PMID:20112380

  14. Immunoglobulins in nasal secretions of healthy humans: structural integrity of secretory immunoglobulin A1 (IgA1) and occurrence of neutralizing antibodies to IgA1 proteases of nasal bacteria.

    PubMed

    Kirkeby, L; Rasmussen, T T; Reinholdt, J; Kilian, M

    2000-01-01

    Certain bacteria, including overt pathogens as well as commensals, produce immunoglobulin A1 (IgA1) proteases. By cleaving IgA1, including secretory IgA1, in the hinge region, these enzymes may interfere with the barrier functions of mucosal IgA antibodies, as indicated by experiments in vitro. Previous studies have suggested that cleavage of IgA1 in nasal secretions may be associated with the development and perpetuation of atopic disease. To clarify the potential effect of IgA1 protease-producing bacteria in the nasal cavity, we have analyzed immunoglobulin isotypes in nasal secretions of 11 healthy humans, with a focus on IgA, and at the same time have characterized and quantified IgA1 protease-producing bacteria in the nasal flora of the subjects. Samples in the form of nasal wash were collected by using a washing liquid that contained lithium as an internal reference. Dilution factors and, subsequently, concentrations in undiluted secretions could thereby be calculated. IgA, mainly in the secretory form, was found by enzyme-linked immunosorbent assay to be the dominant isotype in all subjects, and the vast majority of IgA (median, 91%) was of the A1 subclass, corroborating results of previous analyses at the level of immunoglobulin-producing cells. Levels of serum-type immunoglobulins were low, except for four subjects in whom levels of IgG corresponded to 20 to 66% of total IgA. Cumulative levels of IgA, IgG, and IgM in undiluted secretions ranged from 260 to 2,494 (median, 777) microg ml(-1). IgA1 protease-producing bacteria (Haemophilus influenzae, Streptococcus pneumoniae, or Streptococcus mitis biovar 1) were isolated from the nasal cavities of seven subjects at 2.1 x 10(3) to 7.2 x 10(6) CFU per ml of undiluted secretion, corresponding to 0.2 to 99.6% of the flora. Nevertheless, alpha-chain fragments characteristic of IgA1 protease activity were not detected in secretions from any subject by immunoblotting. Neutralizing antibodies to IgA1 proteases of autologous isolates were detected in secretions from five of the seven subjects but not in those from two subjects harboring IgA1 protease-producing S. mitis biovar 1. alpha-chain fragments different from Fc(alpha) and Fd(alpha) were detected in some samples, possibly reflecting nonspecific proteolytic activity of microbial or host origin. These results add to previous evidence for a role of secretory immunity in the defense of the nasal mucosa but do not help identify conditions under which bacterial IgA1 proteases may interfere with this defense. PMID:10618273

  15. Immunoglobulins in Nasal Secretions of Healthy Humans: Structural Integrity of Secretory Immunoglobulin A1 (IgA1) and Occurrence of Neutralizing Antibodies to IgA1 Proteases of Nasal Bacteria

    PubMed Central

    Kirkeby, Line; Rasmussen, Trine Tang; Reinholdt, Jesper; Kilian, Mogens

    2000-01-01

    Certain bacteria, including overt pathogens as well as commensals, produce immunoglobulin A1 (IgA1) proteases. By cleaving IgA1, including secretory IgA1, in the hinge region, these enzymes may interfere with the barrier functions of mucosal IgA antibodies, as indicated by experiments in vitro. Previous studies have suggested that cleavage of IgA1 in nasal secretions may be associated with the development and perpetuation of atopic disease. To clarify the potential effect of IgA1 protease-producing bacteria in the nasal cavity, we have analyzed immunoglobulin isotypes in nasal secretions of 11 healthy humans, with a focus on IgA, and at the same time have characterized and quantified IgA1 protease-producing bacteria in the nasal flora of the subjects. Samples in the form of nasal wash were collected by using a washing liquid that contained lithium as an internal reference. Dilution factors and, subsequently, concentrations in undiluted secretions could thereby be calculated. IgA, mainly in the secretory form, was found by enzyme-linked immunosorbent assay to be the dominant isotype in all subjects, and the vast majority of IgA (median, 91%) was of the A1 subclass, corroborating results of previous analyses at the level of immunoglobulin-producing cells. Levels of serum-type immunoglobulins were low, except for four subjects in whom levels of IgG corresponded to 20 to 66% of total IgA. Cumulative levels of IgA, IgG, and IgM in undiluted secretions ranged from 260 to 2,494 (median, 777) ?g ml?1. IgA1 protease-producing bacteria (Haemophilus influenzae, Streptococcus pneumoniae, or Streptococcus mitis biovar 1) were isolated from the nasal cavities of seven subjects at 2.1 103 to 7.2 106 CFU per ml of undiluted secretion, corresponding to 0.2 to 99.6% of the flora. Nevertheless, ?-chain fragments characteristic of IgA1 protease activity were not detected in secretions from any subject by immunoblotting. Neutralizing antibodies to IgA1 proteases of autologous isolates were detected in secretions from five of the seven subjects but not in those from two subjects harboring IgA1 protease-producing S. mitis biovar 1. ?-chain fragments different from Fc? and Fd? were detected in some samples, possibly reflecting nonspecific proteolytic activity of microbial or host origin. These results add to previous evidence for a role of secretory immunity in the defense of the nasal mucosa but do not help identify conditions under which bacterial IgA1 proteases may interfere with this defense. PMID:10618273

  16. Col11a1 Regulates Bone Microarchitecture during Embryonic Development

    PubMed Central

    Hafez, Anthony; Squires, Ryan; Pedracini, Amber; Joshi, Alark; Seegmiller, Robert E.; Oxford, Julia Thom

    2016-01-01

    Collagen XI alpha 1 (Col11a1) is an extracellular matrix molecule required for embryonic development with a role in both nucleating the formation of fibrils and regulating the diameter of heterotypic fibrils during collagen fibrillar assembly. Although found in many different tissues throughout the vertebrate body, Col11a1 plays an essential role in endochondral ossification. To further understand the function of Col11a1 in the process of bone formation, we compared skeletal mineralization in wild-type (WT) mice and Col11a1-deficient mice using X-ray microtomography (micro-CT) and histology. Changes in trabecular bone microstructure were observed and are presented here. Additionally, changes to the periosteal bone collar of developing long bones were observed and resulted in an increase in thickness in the case of Col11a1-deficient mice compared to WT littermates. Vertebral bodies were incompletely formed in the absence of Col11a1. The data demonstrate that Col11a1 depletion results in alteration to newly-formed bone and is consistent with a role for Col11a1 in mineralization. These findings indicate that expression of Col11a1 in the growth plate and perichondrium is essential for trabecular bone and bone collar formation during endochondral ossification. The observed changes to mineralized tissues further define the function of Col11a1. PMID:26779434

  17. An abundant dysfunctional apolipoprotein A1 in human atheroma

    PubMed Central

    Huang, Ying; DiDonato, Joseph A.; Levison, Bruce S.; Schmitt, Dave; Li, Lin; Wu, Yuping; Buffa, Jennifer; Kim, Timothy; Gerstenecker, Gary; Gu, Xiaodong; Kadiyala, Chandra; Wang, Zeneng; Culley, Miranda K.; Hazen, Jennie E.; DiDonato, Anthony J.; Fu, Xiaoming; Berisha, Stela; Peng, Daoquan; Nguyen, Truc; Liang, Shaohong; Chuang, Chia-Chi; Cho, Leslie; Plow, Edward F.; Fox, Paul L.; Gogonea, Valentin; Tang, W.H. Wilson; Parks, John S.; Fisher, Edward A.; Smith, Jonathan D.; Hazen, Stanley L.

    2014-01-01

    Recent studies indicate high density lipoproteins (HDL) and their major structural protein, apolipoprotein A1 (apoA1), recovered from human atheroma, are dysfunctional and extensively oxidized by myeloperoxidase (MPO), while in vitro oxidation of apoA1/HDL by MPO impairs its cholesterol acceptor function. We developed a high affinity monoclonal antibody (mAb) that specifically recognizes apoA1/HDL modified by the MPO/H2O2/Cl-system using phage display affinity maturation. An oxindolyl alanine (2-OH-Trp) moiety at tryptophan 72 of apoA1 is the immunogenic epitope. Mutagenesis studies confirm a critical role for apoA1 Trp72 in MPO-mediated inhibition of ABCA1-dependent cholesterol acceptor activity of apoA1 in vitro and in vivo. ApoA1 containing a 2-OH-Trp72 group (oxTrp72-apoA1) is in low abundance within the circulation, but accounts for 20% of the apoA1 in atherosclerotic plaque. OxTrp72-apoA1 recovered from human atheroma or plasma was lipid-poor, virtually devoid of cholesterol acceptor activity, and demonstrated both potent pro-inflammatory activities on endothelial cells and impaired HDL biogenesis activity in vivo. Elevated oxTrp72-apoA1 levels in subjects presenting to a cardiology clinic (n=627) were associated with increased cardiovascular disease risk. Circulating oxTrp72-apoA1 levels may serve as a way to monitor a pro-atherogenic process in the artery wall. PMID:24464187

  18. Mesonic Form Factors

    SciTech Connect

    Frederic D. R. Bonnet; Robert G. Edwards; George T. Fleming; Randal Lewis; David Richards

    2003-07-22

    We have started a program to compute the electromagnetic form factors of mesons. We discuss the techniques used to compute the pion form factor and present preliminary results computed with domain wall valence fermions on MILC asqtad lattices, as well as Wilson fermions on quenched lattices. These methods can easily be extended to rho-to-gamma-pi transition form factors.

  19. Multilevel Mixture Factor Models

    ERIC Educational Resources Information Center

    Varriale, Roberta; Vermunt, Jeroen K.

    2012-01-01

    Factor analysis is a statistical method for describing the associations among sets of observed variables in terms of a small number of underlying continuous latent variables. Various authors have proposed multilevel extensions of the factor model for the analysis of data sets with a hierarchical structure. These Multilevel Factor Models (MFMs)…

  20. Human factors in mining

    SciTech Connect

    Sanders, M.S.; Peay, J.M.

    1988-01-01

    This Bureau of Mines report is directed toward summarizing the application of human factors to improving safety, productivity, and the general physical and psychological working conditions of miners and toward familiarizing readers with the role of human factors in the mining industry and the benefits that car accrue by systematically applying human factors principles and data.

  1. Acyl-Carbon Bond Cleaving Cytochrome P450 Enzymes: CYP17A1, CYP19A1 and CYP51A1.

    PubMed

    Akhtar, Muhammad; Wright, J Neville

    2015-01-01

    Cytochrome P450 (P450 or CYP) enzymes in their resting state contain the heme-iron in a high-spin FeIII state. Binding of a substrate to a P450 enzyme allows transfer of the first electron, producing a Fe(II) species that reacts with oxygen to generate a low-spin iron superoxide intermediate (FeIII-O-O•) ready to accept the second electron to produce an iron peroxy anion intermediate (a, FeIII-O-O-). In classical monooxygenation reactions, the peroxy anion upon protonation fragments to form the reactive Compound I intermediate (Por•+FeIV=O), or its ferryl radical resonance form (FeIV-O•). However, when the substrate projects a carbonyl functionality, of the type b, at the active site as is the case for reactions catalyzed by CYP17A1, CYP19A1 and CYP51A1, the peroxy anion (FeIII-O-O-) is trapped, yielding a tetrahedral intermediate (c) that fragments to an acyl-carbon cleavage product (d plus an acid). Analogous acyl-carbon cleavage reactions are also catalyzed by certain hepatic P450s and CYP125A1 from Mycobacterium tuberculosis. A further improvisation on the theme is provided by aldehyde deformylases that convert long-chain aliphatic aldehydes to hydrocarbons. CYP17A1 is involved in the biosynthesis of corticoids as well as androgens. The flux toward these two classes of hormones seems to be regulated by cytochrome b 5, at the level of the acyl-carbon cleavage reaction. It is this regulation of CYP17A1 that provides a safety mechanism, ensuring that during corticoid biosynthesis, which requires 17α-hydroxylation by CYP17A1, androgen formation is avoided (Fig. 4.1). PMID:26002733

  2. Sex differences in apolipoprotein A1 and nevirapine-induced toxicity

    PubMed Central

    Marinho, Aline; Dias, Clara; Antunes, Alexandra; Caixas, Umbelina; Branco, Teresa; Marques, Matilde; Monteiro, Emília; Pereira, Sofia

    2014-01-01

    Nevirapine (NVP) is associated with severe liver and skin toxicity through sulfotransferase (SULT) bioactivation of the phase I metabolite 12-hydroxy-NVP [1–3]. The female sex, a well-known risk factor for NVP-induced toxicity, is associated with higher SULT expression [4] and lower plasma levels of 12-hydroxy-NVP [3]. Interestingly, apolipoprotein A1 (ApoA1) increases SULT2B1 activity and ApoA1 synthesis is increased by NVP [5, 6]. Herein, we explore the effect of ApoA1 levels on NVP metabolism and liver function. The study protocol was firstly approved by the hospitals’ Ethics Committees. All included individuals were HIV-infected patients treated with NVP for at least one month. The plasma concentrations of NVP and its phase I metabolites were quantified by HPLC [7]. ApoA1 levels were assessed by an immunoturbidimetric assay. Forty-nine HIV-infected patients on NVP were included (53% men, 59% Caucasian). NVP plasma levels were correlated with HDL-cholesterol (Spearman r=0.2631; p=0.0441) and ApoA1 (Spearman r=0.3907; p=0.0115). Women had higher ApoA1 levels than men (Student's t Test; p=0.0051). In both sexes, 12-hydroxy-NVP levels were negatively correlated with ApoA1 (male: Spearman r=−0.3810; p=0.0499 female: Spearman r=−0.5944; p=0.0415). In men, ApoA1 was positively correlated with aspartate aminotransferase (AST, Spearman r=0.5507; p=0.0413), while in women ApoA1 was associated (Spearman r=0.6408; p=0.0056) with alanine aminotransferase (ALT). These results show sex differences in NVP-induced ApoA1 synthesis. The higher ApoA1 levels in women might stabilize SULT2B1 [6]. This would explain the lower levels of 12-hydroxy-NVP [3] and the higher hepatotoxicity found in women, due to increased sulfonation of this metabolite. These data support a role for ApoA1 in the sex dimorphic mechanism leading to NVP-induced toxicity. PMID:25394082

  3. 26 CFR 1.56A-1 - Imposition of tax.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 1 2010-04-01 2010-04-01 true Imposition of tax. 1.56A-1 Section 1.56A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES Regulations Applicable to Taxable Years Beginning in 1969 and Ending in 1970 § 1.56A-1 Imposition of tax. (a) In general. Section 56(a) imposes an income tax...

  4. 17 CFR 260.7a-1 - Form for application.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Form for application. 260.7a-1 Section 260.7a-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 307 260.7a-1 Form for application. Form T-3 shall be used...

  5. HbA1c, Fructosamine, and Glycated Albumin in the Detection of Dysglycaemic Conditions.

    PubMed

    Ribeiro, Rogério Tavares; Macedo, Maria Paula; Raposo, João Filipe

    2016-01-01

    Glycated haemoglobin (HbA1c) is currently the gold standard for glucose monitoring in patients with diabetes, and has been increasingly adopted as a criteria for diabetes diagnosis. However, conditions that determine alterations in haemoglobin metabolism can interfere with the reliability of HbA1c measurements. Glycated albumin and fructosamine (total glycated serum proteins) are alternative markers of glycaemia, which have been recognised to provide additional information to HbA1c or to provide a reliable measure when HbA1c is observed not to be dependable. Additionally, while HbA1c monitors the exposure to circulating glycaemia in the previous 3 months, glycated albumin and fructosamine represent exposure for a shorter period, which may be beneficial to monitor rapid metabolic alterations or changes in diabetes treatment. The present review further discusses the relative value of HbA1c, glycated albumin, and fructosamine, in prediabetes and diabetes diagnosis, evaluation of glucose variability, and complications risk prediction. Also, a novel molecular role for albumin is presented by which glycated albumin contributes to glucose intolerance development and thus to progression to diabetes, besides the role of glycated albumin as a pro-atherogenic factor. PMID:26126638

  6. macroH2A1 histone variant represses rDNA transcription.

    PubMed

    Cong, Rong; Das, Sadhan; Douet, Julien; Wong, Jiemin; Buschbeck, Marcus; Mongelard, Fabien; Bouvet, Philippe

    2014-01-01

    The regulation of ribosomal DNA transcription is an important step for the control of cell growth. Epigenetic marks such as DNA methylation and posttranslational modifications of canonical histones have been involved in this regulation, but much less is known about the role of histone variants. In this work, we show that the histone variant macroH2A1 is present on the promoter of methylated rDNA genes. The inhibition of the expression of macroH2A1 in human HeLa and HepG2 cells and in a mouse ES cell line resulted in an up to 5-fold increase of pre-rRNA levels. This increased accumulation of pre-rRNA is accompanied by an increase of the loading of RNA polymerase I and UBF on the rDNA without any changes in the number of active rDNA genes. The inhibition of RNA polymerase I transcription by actinomycin D or by knocking down nucleolin, induces the recruitment of macroH2A1 on the rDNA and the relocalization of macroH2A1 in the nucleolus. Interestingly, the inhibition of rDNA transcription induced by nucleolin depletion is alleviated by the inactivation of macroH2A1. These results demonstrate that macroH2A1 is a new factor involved in the regulation of rDNA transcription. PMID:24071584

  7. Bayesian Exploratory Factor Analysis

    PubMed Central

    Conti, Gabriella; Frühwirth-Schnatter, Sylvia; Heckman, James J.; Piatek, Rémi

    2014-01-01

    This paper develops and applies a Bayesian approach to Exploratory Factor Analysis that improves on ad hoc classical approaches. Our framework relies on dedicated factor models and simultaneously determines the number of factors, the allocation of each measurement to a unique factor, and the corresponding factor loadings. Classical identification criteria are applied and integrated into our Bayesian procedure to generate models that are stable and clearly interpretable. A Monte Carlo study confirms the validity of the approach. The method is used to produce interpretable low dimensional aggregates from a high dimensional set of psychological measurements. PMID:25431517

  8. Bayesian Exploratory Factor Analysis.

    PubMed

    Conti, Gabriella; Frühwirth-Schnatter, Sylvia; Heckman, James J; Piatek, Rémi

    2014-11-01

    This paper develops and applies a Bayesian approach to Exploratory Factor Analysis that improves on ad hoc classical approaches. Our framework relies on dedicated factor models and simultaneously determines the number of factors, the allocation of each measurement to a unique factor, and the corresponding factor loadings. Classical identification criteria are applied and integrated into our Bayesian procedure to generate models that are stable and clearly interpretable. A Monte Carlo study confirms the validity of the approach. The method is used to produce interpretable low dimensional aggregates from a high dimensional set of psychological measurements. PMID:25431517

  9. Power factor corrector on insulated metal substrate

    SciTech Connect

    Aime, G.; Barbaroux, J.; Ferrieux, J.P.

    1995-12-31

    This paper describes a high density Power Factor Correction converter for AC-DC applications with sinusoidal input current. After analysis of the thermal behavior of several types of Insulated-Metal Substrates, study and design have been implemented on IMS with Surface Mount components. Experimental results are discussed for a 1 kW prototype operating at 100 kHz.

  10. TaMFT-A1 Is Associated with Seed Germination Sensitive to Temperature in Winter Wheat

    PubMed Central

    Wang, Shuwen; Zhu, Meirong; Carver, Brett F.; Yan, Liuling

    2013-01-01

    The ability of seed to germinate under favorable environmental conditions is critical for seedling emergence, plant establishment, subsequent development and growth of adult plants, and it is controlled by internal genetic factors and external environmental factors. Winter wheat in the southern Great Plains is often planted six weeks before the optimal planting date to produce more biomass for cattle grazing during the winter season. A high seed germination rate in this higher soil temperature environment is required for this specific management system. In this study, a major QTL for temperature-sensitive germination was mapped on the short arm of chromosome 3A (QTsg.osu-3A) in a RIL population generated from two winter wheat cultivars. Furthermore, TaMFT-A1, previously reported to regulate seed dormancy and pre-harvest sprouting in spring wheat cultivars, was mapped tightly associated with the peak of QTsg.osu-3A. However, allelic variation in TaMFT-A1 between the two winter wheat cultivars differed from that was observed in spring wheat cultivars. There were 87 SNPs (single nucleotide polymorphisms) and 12 indels (insertions/deletions) in TaMFT-A1 between the Jagger allele for high germination and the 2174 allele for low germination in the after-ripened seeds, in comparison with 2 SNPs between the two alleles for differential pre-harvest sprouting in spring wheat cultivars. The Jagger TaMFT-A1 allele is a novel haplotype and appears extensively in winter wheat cultivars. TaMFT-A1 transcript levels were up-regulated by high temperature but down-regulated by low temperature or seed storage time. These findings suggest that TaMFT-A1 may invoke different mechanisms for controlling seed dormancy/germination among winter wheat cultivars. PMID:24069187

  11. Role of CYP1A1 haplotypes in modulating susceptibility to coronary artery disease.

    PubMed

    Lakshmi, Sana Venkata Vijaya; Naushad, Shaik Mohammad; Saumya, Kankanala; Rao, Damera Seshagiri; Kutala, Vijay Kumar

    2012-10-01

    To investigate the role of cytochrome P450 1A1 (CYP1A1) haplotypes in modulating susceptibility to coronary artery disease (CAD), a case-control study was conducted by enrolling 352 CAD cases and 282 healthy controls. PCR-RFLP, multiplex PCR, competitive ELISA techniques were employed for the analysis of CYP1A1 [ml (T-->C), m2 (A-->G) and m4 (C-->A)] haplotypes, glutathione-S-transferase (GST)T1/GSTM1 null variants and plasma 8-oxo-2'deoxyguanosine (8-oxodG) respectively. Two CYP1A1 haplotypes, i.e. CAC and TGC showed independent association with CAD risk, while all-wild CYP1A1 haplotype i.e. TAC showed reduced risk for CAD. All the three variants showed mild linkage disequilibrium (D': 0.05 to 0.17). GSTT1 null variant also exerted independent association with CAD risk (OR: 2.53, 95% CI 1.55-4.12). Among the conventional risk factors, smoking showed synergetic interaction with CAC haplotype of CYP1A1 and GSTT1 null genotype in inflating CAD risk. High risk alleles of this pathway showed dose-dependent association with percentage of stenosis and number of vessels affected. Elevated 8-oxodG levels were observed in subjects with CYP1A1 CAC haplotype and GSTT1 null variant. Multiple linear regression model of these xenobiotic variants explained 36% variability in 8-oxodG levels. This study demonstrated the association of CYP1A1 haplotypes and GSTT1 null variant with CAD risk and this association was attributed to increased oxidative DNA damage. PMID:23259321

  12. Regulation of translation by upstream translation initiation codons of surfactant protein A1 splice variants

    PubMed Central

    Tsotakos, Nikolaos; Silveyra, Patricia; Lin, Zhenwu; Thomas, Neal; Vaid, Mudit

    2014-01-01

    Surfactant protein A (SP-A), a molecule with roles in lung innate immunity and surfactant-related functions, is encoded by two genes in humans: SFTPA1 (SP-A1) and SFTPA2 (SP-A2). The mRNAs from these genes differ in their 5′-untranslated regions (5′-UTR) due to differential splicing. The 5′-UTR variant ACD′ is exclusively found in transcripts of SP-A1, but not in those of SP-A2. Its unique exon C contains two upstream AUG codons (uAUGs) that may affect SP-A1 translation efficiency. The first uAUG (u1) is in frame with the primary start codon (p), but the second one (u2) is not. The purpose of this study was to assess the impact of uAUGs on SP-A1 expression. We employed RT-qPCR to determine the presence of exon C-containing SP-A1 transcripts in human RNA samples. We also used in vitro techniques including mutagenesis, reporter assays, and toeprinting analysis, as well as in silico analyses to determine the role of uAUGs. Exon C-containing mRNA is present in most human lung tissue samples and its expression can, under certain conditions, be regulated by factors such as dexamethasone or endotoxin. Mutating uAUGs resulted in increased luciferase activity. The mature protein size was not affected by the uAUGs, as shown by a combination of toeprint and in silico analysis for Kozak sequence, secondary structure, and signal peptide and in vitro translation in the presence of microsomes. In conclusion, alternative splicing may introduce uAUGs in SP-A1 transcripts, which in turn negatively affect SP-A1 translation, possibly affecting SP-A1/SP-A2 ratio, with potential for clinical implication. PMID:25326576

  13. 32 CFR 809a.1 - Random installation entry point checks.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Random installation entry point checks. 809a.1... Entry Policy § 809a.1 Random installation entry point checks. The installation commander determines when, where, and how to implement random checks of vehicles or pedestrians. The commander conducts...

  14. 26 CFR 1.665(a)-1 - Undistributed net income.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Undistributed net income. 1.665(a)-1 Section 1... Before January 1, 1969 1.665(a)-1 Undistributed net income. (a) The term undistributed net income means for any taxable year the distributable net income of the trust for that year as determined...

  15. 26 CFR 1.665(a)-1 - Undistributed net income.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 8 2013-04-01 2013-04-01 false Undistributed net income. 1.665(a)-1 Section 1... Beginning Before January 1, 1969 1.665(a)-1 Undistributed net income. (a) The term undistributed net income means for any taxable year the distributable net income of the trust for that year as...

  16. 26 CFR 1.665(a)-1 - Undistributed net income.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 8 2012-04-01 2012-04-01 false Undistributed net income. 1.665(a)-1 Section 1... Beginning Before January 1, 1969 1.665(a)-1 Undistributed net income. (a) The term undistributed net income means for any taxable year the distributable net income of the trust for that year as...

  17. 26 CFR 1.665(a)-1 - Undistributed net income.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 8 2011-04-01 2011-04-01 false Undistributed net income. 1.665(a)-1 Section 1... Beginning Before January 1, 1969 1.665(a)-1 Undistributed net income. (a) The term undistributed net income means for any taxable year the distributable net income of the trust for that year as...

  18. 29 CFR 2550.403a-1 - Establishment of trust.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 29 Labor 9 2010-07-01 2010-07-01 false Establishment of trust. 2550.403a-1 Section 2550.403a-1 Labor Regulations Relating to Labor (Continued) EMPLOYEE BENEFITS SECURITY ADMINISTRATION, DEPARTMENT OF LABOR FIDUCIARY RESPONSIBILITY UNDER THE EMPLOYEE RETIREMENT INCOME SECURITY ACT OF 1974 RULES AND REGULATIONS FOR FIDUCIARY RESPONSIBILITY...

  19. 32 CFR 809a.1 - Random installation entry point checks.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 6 2012-07-01 2012-07-01 false Random installation entry point checks. 809a.1... Entry Policy § 809a.1 Random installation entry point checks. The installation commander determines when, where, and how to implement random checks of vehicles or pedestrians. The commander conducts...

  20. 32 CFR 809a.1 - Random installation entry point checks.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 6 2011-07-01 2011-07-01 false Random installation entry point checks. 809a.1... Entry Policy § 809a.1 Random installation entry point checks. The installation commander determines when, where, and how to implement random checks of vehicles or pedestrians. The commander conducts...

  1. 32 CFR 809a.1 - Random installation entry point checks.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 6 2013-07-01 2013-07-01 false Random installation entry point checks. 809a.1... Entry Policy § 809a.1 Random installation entry point checks. The installation commander determines when, where, and how to implement random checks of vehicles or pedestrians. The commander conducts...

  2. 26 CFR 1.56A-1 - Imposition of tax.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ...) or by reason of a special rate of tax (such as the rate of tax on corporate capital gains). The tax... 26 Internal Revenue 1 2011-04-01 2009-04-01 true Imposition of tax. 1.56A-1 Section 1.56A-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY INCOME TAX INCOME TAXES...

  3. Attenuation of plasma annexin A1 in human obesity.

    PubMed

    Kosicka, Anna; Cunliffe, Adam D; Mackenzie, Richard; Zariwala, M Gulrez; Perretti, Mauro; Flower, Roderick J; Renshaw, Derek

    2013-01-01

    Obesity-related metabolic disorders are characterized by mild chronic inflammation, leukocyte infiltration, and tissue fibrosis as a result of adipocytokine production from the expanding white adipose tissue. Annexin A1 (AnxA1) is an endogenous glucocorticoid regulated protein, which modulates systemic anti-inflammatory processes and, therefore, may be altered with increasing adiposity in humans. Paradoxically, we found that plasma AnxA1 concentrations inversely correlated with BMI, total percentage body fat, and waist-to-hip ratio in human subjects. Plasma AnxA1 was also inversely correlated with plasma concentrations of the acute-phase protein, C-reactive protein (CRP), and the adipocytokine leptin, suggesting that as systemic inflammation increases, anti-inflammatory AnxA1 is reduced. In addition, AnxA1 gene expression and protein were significantly up-regulated during adipogenesis in a human adipocyte cell line compared to vehicle alone, demonstrating for the first time that AnxA1 is expressed and excreted from human adipocytes. These data demonstrate a failure in the endogenous anti-inflammatory system to respond to increasing systemic inflammation resulting from expanding adipose tissue, a condition strongly linked to the development of type 2 diabetes and cardiovascular disease. These data raise the possibility that a reduction in plasma AnxA1 may contribute to the chronic inflammatory phenotype observed in human obesity. PMID:23038751

  4. 26 CFR 31.3306(a)-1 - Who are employers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Who are employers. 31.3306(a)-1 Section 31.3306... Federal Unemployment Tax Act (Chapter 23, Internal Revenue Code of 1954) § 31.3306(a)-1 Who are employers... calendar week, is with respect to such year an employer subject to the tax. (1a) For 1970 and...

  5. 26 CFR 31.3231(a)-1 - Who are employers.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Who are employers. 31.3231(a)-1 Section 31.3231... Who are employers. (a) Each of the following persons is an employer within the meaning of the act: (1... indirectly owned or controlled by one or more employers as defined in paragraph (a)(1) of this section,...

  6. 42 CFR 5a.1 - Statutory basis and purpose.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 1 2010-10-01 2010-10-01 false Statutory basis and purpose. 5a.1 Section 5a.1 Public Health PUBLIC HEALTH SERVICE, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL PROVISIONS RURAL... the Public Health Service Act. These provisions define “underserved rural community” for purposes...

  7. 17 CFR 240.14a-1 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Definitions. 240.14a-1 Section 240.14a-1 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, SECURITIES EXCHANGE ACT OF 1934 Rules and Regulations Under the Securities Exchange Act of 1934 Regulation 14a:...

  8. Note on the photoproduction of the charged A1

    NASA Astrophysics Data System (ADS)

    Condo, G. T.; Handler, T.

    1987-05-01

    Arguments made nearly 15 years ago by Fox and Hey are updated in the light of recent experimental findings. These indicate that the charge-exchange photoproduction of the A1 should dominate that of the A2. Consistency with the experimental data demands an A1 mass of 1335+/-20 MeV and width of 180+/-55 MeV.

  9. 17 CFR 260.7a-1 - Form for application.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Form for application. 260.7a-1... RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 307 260.7a-1 Form for application. Form T-3 shall be used for applications for qualification of indentures pursuant to section 307(a)....

  10. 26 CFR 49.4262(a)-1 - Taxable transportation.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 26 Internal Revenue 16 2013-04-01 2013-04-01 false Taxable transportation. 49.4262(a)-1 Section 49...) MISCELLANEOUS EXCISE TAXES FACILITIES AND SERVICES EXCISE TAXES Transportation of Persons § 49.4262(a)-1 Taxable transportation. (a) In general. Unless excluded under section 4262(b) (see § 49.4262(b)-1),...

  11. 26 CFR 49.4262(a)-1 - Taxable transportation.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Taxable transportation. 49.4262(a)-1 Section 49...) MISCELLANEOUS EXCISE TAXES FACILITIES AND SERVICES EXCISE TAXES Transportation of Persons § 49.4262(a)-1 Taxable transportation. (a) In general. Unless excluded under section 4262(b) (see § 49.4262(b)-1),...

  12. 26 CFR 49.4262(a)-1 - Taxable transportation.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 26 Internal Revenue 16 2012-04-01 2012-04-01 false Taxable transportation. 49.4262(a)-1 Section 49...) MISCELLANEOUS EXCISE TAXES FACILITIES AND SERVICES EXCISE TAXES Transportation of Persons § 49.4262(a)-1 Taxable transportation. (a) In general. Unless excluded under section 4262(b) (see § 49.4262(b)-1),...

  13. 26 CFR 49.4262(a)-1 - Taxable transportation.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 26 Internal Revenue 16 2011-04-01 2011-04-01 false Taxable transportation. 49.4262(a)-1 Section 49...) MISCELLANEOUS EXCISE TAXES FACILITIES AND SERVICES EXCISE TAXES Transportation of Persons § 49.4262(a)-1 Taxable transportation. (a) In general. Unless excluded under section 4262(b) (see § 49.4262(b)-1),...

  14. Catalytic and Immunochemical Detection of Hepatic and Extrahepatic Microsomal Cytochrome P450 1A1 (CYP1A1) in White-sided Dolphin (Lagenorhynchus acutus)

    PubMed Central

    Wilson, Joanna Y.; Moore, Michael J.; Stegeman, John J.

    2009-01-01

    We have characterized microsomal systems and measured the levels of microsomal cytochrome P450 1A1 (CYP1A1) and ethoxyresorufin-O-deethylase activity in multiple internal organs of male and female white-sided dolphin (Lagenorhynchus acutus) from the northwest Atlantic Ocean. Internal organs were sampled within 24 hours of death, sometimes in a period of hours, collection times which are significantly less than usually seen for marine mammals. Tissue autolysis, as assessed by histological analysis of liver, was minimal to none in all individuals. Total P420 did not correlate with time from death to sampling, suggesting that it is a poor indicator of P450 degradation in cetacean tissues where perfusion isn’t practical. The total hepatic microsomal P450 content, cytochrome b5 content, and NADPH-cytochrome c (P450) reductase (CPR) activity averaged 0.29 nmol mg−1, 0.12 nmol mg−1, and 238 nmol mg−1 min−1, respectively. Microsomal CPR activity in liver was higher than that in lung and kidney, and was higher than that reported in liver of most other cetacean species. Immunodetected CYP1A1 content was low in all organs, less than 3 pmoles CYP1A equivalents mg−1. EROD activity ranged from 9 – 376 pmoles mg−1 min−1 and was greater in liver than in other tissues. Hepatic microsomal EROD activity and CYP1A1 content did not correlate. However, hepatic EROD activity, but not CYP1A1 protein content, was well correlated with both total PCB and Σmono-ortho PCB concentrations in blubber. Length, as a proxy for age, did not correlate with hepatic EROD activity or CYP1A1 protein levels, and sex did not influence the relationship between EROD and contaminant concentrations. We cannot easily control for the extent of tissue degradation in cetacean studies nor do we have a complete history of these animals. Therefore, other factors such as degradation or hormonal state may have a role in the observed relationships. Yet, as in other mammals, hepatic tissues appear to be a major site of CYP1A1 expression and probably of biotransformation of CYP1A substrates in white-sided dolphin. The expression of an EROD catalyst in liver likely reflects induction by PCBs, but the P450 enzyme catalyzing hepatic EROD activity in these whales may not be CYP1A1. PMID:20005581

  15. A1/Bfl-1 in leukocyte development and cell death

    PubMed Central

    Ottina, Eleonora; Tischner, Denise; Herold, Marco J.; Villunger, Andreas

    2012-01-01

    The function of the anti-apoptotic Bcl-2 family member Bcl2a1/Bfl-1/A1 is poorly understood due to the lack of appropriate loss-of-function mouse models and redundant effects with other Bcl-2 pro-survival proteins upon overexpression. Expression analysis of A1 suggests predominant roles in leukocyte development, their survival upon viral or bacterial infection, as well as during allergic reactions. In addition, A1 has been implicated in autoimmunity and the pathology and therapy resistance of hematological as well as solid tumors that may aberrantly express this protein. In this review, we aim to summarize current knowledge on A1 biology, focusing on its role in the immune system and compare it to that of other pro-survival Bcl-2 proteins. PMID:22342458

  16. Identification of an evolutionarily conserved regulatory element of the zebrafish col2a1a gene.

    PubMed

    Dale, Rodney M; Topczewski, Jacek

    2011-09-15

    Zebrafish (Danio rerio) is an excellent model organism for the study of vertebrate development including skeletogenesis. Studies of mammalian cartilage formation were greatly advanced through the use of a cartilage specific regulatory element of the Collagen type II alpha 1 (Col2a1) gene. In an effort to isolate such an element in zebrafish, we compared the expression of two col2a1 homologues and found that expression of col2a1b, a previously uncharacterized zebrafish homologue, only partially overlaps with col2a1a. We focused our analysis on col2a1a, as it is expressed in both the stacked chondrocytes and the perichondrium. By comparing the genomic sequence surrounding the predicted transcriptional start site of col2a1a among several species of teleosts we identified a small highly conserved sequence (R2) located 1.7 kb upstream of the presumptive transcriptional initiation site. Interestingly, neither the sequence nor location of this element is conserved between teleost and mammalian Col2a1. We generated transient and stable transgenic lines with just the R2 element or the entire 1.7 kb fragment 5' of the transcriptional initiation site. The identified regulatory elements enable the tracking of cellular development in various tissues by driving robust reporter expression in craniofacial cartilage, ear, notochord, floor plate, hypochord and fins in a pattern similar to the expression of endogenous col2a1a. Using a reporter gene driven by the R2 regulatory element, we analyzed the morphogenesis of the notochord sheath cells as they withdraw from the stack of initially uniform cells and encase the inflating vacuolated notochord cells. Finally, we show that like endogenous col2a1a, craniofacial expression of these reporter constructs depends on Sox9a transcription factor activity. At the same time, notochord expression is maintained after Sox9a knockdown, suggesting that other factors can activate expression through the identified regulatory element in this tissue. PMID:21723274

  17. Role of COL4A1 in basement-membrane integrity and cerebral small-vessel disease. The COL4A1 stroke syndrome.

    PubMed

    Volonghi, I; Pezzini, A; Del Zotto, E; Giossi, A; Costa, P; Ferrari, D; Padovani, A

    2010-01-01

    Type IV collagens are basement membrane (BM) proteins expressed in all tissues including the vasculature. COL4A1 and COL4A2, the most abundant type IV collagens, form heterotrimers with a 2:1 stoichiometry and each heterotrimer forms a triple helix along the length of the collagenous domains. Recently, mutations in COL4A1 on chromosome 13q34, encoding the alpha1 chain of type IV collagen, have been linked to a spectrum of cerebral small-vessel disease in humans, including perinatal intracerebral hemorrhage (ICH) with consequent porencephaly, adult-onset ICH, microbleeds, lacunar strokes, and leukoaraiosis, which follows an autosomal dominant pattern of inheritance. This variable phenotype has been named the "COL4A1 stroke syndrome". In COL4A1 stroke syndrome most mutations are missense mutations involving a glycine residue, including G562E, G749S, G805R, G1130D, G1236R, G1423R, G720D, G1580R, and G755R. Mutations replacing a highly conserved hydrophobic glycine residue likely lead to synthesis of an abnormal protein with abnormal structure and inhibit heterotrimer secretion into the vascular BM, modify its structural properties (when imaged with electron microscopy BM is uneven, with inconsistent density and focal disruptions), and, thus, increase the fragility of the vessel wall when exposed to environmental factors. Although pathological changes in BM also occur in other tissues (mostly retina and kidney), the major site of vessel damage is the brain. In the present review article we will focus on the molecular basis of the COL4A1 stroke syndrome, summarize data on its variable phenotype, and explore additional questions concerning the possible genotype-phenotype correlations and the mechanisms leading to cerebral small-vessel disease in this clinically heterogeneous condition. PMID:20166936

  18. A1-A1 mutant with improved binding and inhibition of beta2GPI/antibody complexes in antiphospholipid syndrome

    PubMed Central

    Kolyada, Alexey; Karageorgos, Ioannis; Mahlawat, Pardeep; Beglova, Natalia

    2014-01-01

    Beta2-glycoprotein I (β2GPI) is the most common antigen for autoimmune antibodies in antiphospholipid syndrome (APS). Thrombosis is a clinical feature of APS. We made a molecule (A1-A1) that consists of two identical β2GPI-binding modules from ApoE receptor 2. A1-A1 binds to β2GPI/anti-β2GPI antibody complexes preventing their association with ApoER2 and anionic phospholipids, and reducing thrombus size in the mouse model of APS. Here, we describe a mutant of A1-A1 (mA1-A1ND) with improved affinity for β2GPI. mA1-A1ND inhibits the binding of β2GPI to cardiolipin in the presence of anti-β2GPI antibodies and inhibits β2GPI/antibody complexes in plasma samples of APS patients affecting the clotting time. Inhibition of the clotting time demonstrates the presence of soluble β2GPI/anti-β2GPI antibody complexes in patients’ plasma. These complexes either already exist in patients’ plasma or form rapidly in the vicinity of phospholipids. All members of the LDL receptor family can bind β2GPI. Modelling studies of A1 in a complex with domain V of β2GPI (β2GPI-DV) revealed two possible orientations of a ligand-binding module from lipoprotein receptors on β2GPI-DV. In both orientations, the ligand-binding module interferes with the binding of β2GPI to anionic phospholipids, however it interacts with two different though overlapping sets of lysine residues in β2GPI-DV, depending on the orientation. PMID:25546421

  19. Analytic Couple Modeling Introducing Device Design Factor, Fin Factor, Thermal Diffusivity Factor, and Inductance Factor

    NASA Technical Reports Server (NTRS)

    Mackey, Jon; Sehirlioglu, Alp; Dynys, Fred

    2014-01-01

    A set of convenient thermoelectric device solutions have been derived in order to capture a number of factors which are previously only resolved with numerical techniques. The concise conversion efficiency equations derived from governing equations provide intuitive and straight-forward design guidelines. These guidelines allow for better device design without requiring detailed numerical modeling. The analytical modeling accounts for factors such as i) variable temperature boundary conditions, ii) lateral heat transfer, iii) temperature variable material properties, and iv) transient operation. New dimensionless parameters, similar to the figure of merit, are introduced including the device design factor, fin factor, thermal diffusivity factor, and inductance factor. These new device factors allow for the straight-forward description of phenomenon generally only captured with numerical work otherwise. As an example a device design factor of 0.38, which accounts for thermal resistance of the hot and cold shoes, can be used to calculate a conversion efficiency of 2.28 while the ideal conversion efficiency based on figure of merit alone would be 6.15. Likewise an ideal couple with efficiency of 6.15 will be reduced to 5.33 when lateral heat is accounted for with a fin factor of 1.0.

  20. Effect of DNA methylation profile on OATP3A1 and OATP4A1 transcript levels in colorectal cancer.

    PubMed

    Rawłuszko-Wieczorek, Agnieszka Anna; Horst, Nikodem; Horbacka, Karolina; Bandura, Artur Szymon; Świderska, Monika; Krokowicz, Piotr; Jagodziński, Paweł Piotr

    2015-08-01

    Epidemiological studies indicate that 17β-estradiol (E2) prevents colorectal cancer (CRC). Organic anion transporting polypeptides (OATPs) are involved in the cellular uptake of various endogenous and exogenous substrates, including hormone conjugates. Because transfer of estrone sulfate (E1-S) can contribute to intra-tissue conversion of estrone to the biologically active form -E2, it is evident that the expression patterns of OATPs may be relevant to the analysis of CRC incidence and therapy. We therefore evaluated DNA methylation and transcript levels of two members of the OATP family, OATP3A1 and OATP4A1, that may be involved in E1-S transport in colorectal cancer patients. We detected a significant reduction in OATP3A1 and a significant increase in OATP4A1 mRNA levels in cancerous tissue, compared with histopathologically unchanged tissue (n=103). Moreover, we observed DNA hypermethylation in the OATP3A1 promoter region in a small subset of CRC patients and in HCT116 and Caco-2 colorectal cancer cell lines. We also observed increased OATP3A1 transcript following treatment with 5-aza-2-deoxycytidine and sodium butyrate. The OATP4A1 promoter region was hypomethylated in analyzed tissues and CRC cell lines and was not affected by these treatments. Our results suggest a potential mechanism for OATP3A1 downregulation that involves DNA methylation during colorectal carcinogenesis. PMID:26349991

  1. The Correlation of Hemoglobin A1c to Blood Glucose

    PubMed Central

    Sikaris, Ken

    2009-01-01

    The understanding that hemoglobin A1c (HbA1c) represents the average blood glucose level of patients over the previous 120 days underlies the current management of diabetes. Even in making such a statement, we speak of “average blood glucose” as though “blood glucose” were itself a simple idea. When we consider all the blood glucose forms—arterial versus venous versus capillary, whole blood versus serum versus fluoride-preserved plasma, fasting versus nonfasting—we can start to see that this is not a simple issue. Nevertheless, it seems as though HbA1c correlates to any single glucose measurement. Having more than one measurement and taking those measurements in the preceding month improves the correlation further. In particular, by having glucose measurements that reflect both the relatively lower overnight glucose levels and measurements that reflect the postprandial peaks improves not only our ability to manage diabetes patients, but also our understanding of how HbA1c levels are determined. Modern continuous glucose monitoring (CGM) devices may take thousands of glucose results over a week. Several studies have shown that CGM glucose averages account for the vast proportion of the variation of HbA1c. The ability to relate HbA1c to average glucose may become a popular method for reporting HbA1c, eliminating current concerns regarding differences in HbA1c standardization. Hemoglobin A1c expressed as an average glucose may be more understandable to patients and improve not only their understanding, but also their ability to improve their diabetes management. PMID:20144279

  2. Interaction of the CYP1A1 gene polymorphism and smoking in non-small cell lung cancer susceptibility.

    PubMed

    Xie, Y Q; Chen, J M; Liu, Y

    2015-01-01

    Many studies have shown that genetic factors, environmental factors, and bad living habits, especially smoking, are risk factors for lung cancer. However, not all smokers develop lung cancer, which may be related to different genetic backgrounds. Currently, most research has investigated the GSTM1, XRCC1, XRCC3, CYP2D6, and C188T genes. Little research has been done on the cytochrome P450 (CYP) 1A1 gene, and results have varied. In addition, no results have been reported on the interactive effects of smoking and the CYP1A1 gene on lung cancer development. We used polymerase chain reaction restriction fragment length polymorphism to detect the CYP1A1 genotype, and investigate the effects of the CYP1A1 gene deletion and smoking alone, and in combination, on non-small cell lung cancer susceptibility. We enrolled 150 non-small cell lung cancer patients and 150 healthy control subjects. Subjects' smoking habits and CYP1A1 gene polymorphism were analyzed to investigate their role in the occurrence of lung cancer. The CYP1A1 gene deletion was found in 73.3% of non-small cell lung cancer patients and 20.0% of healthy subjects. The OR value was 2.28 (P < 0.05). Among smoking subjects, 77.8% exhibited non-small cell lung cancer, significantly higher than the 27.3% in non-smokers (P < 0.05). The OR value for the interaction of smoking and CYP1A1 gene deletion was 5.60, larger than the product of their individual OR values. The CYP1A1 gene deletion is a lung cancer risk factor, and interacts with smoking in non-small cell lung cancer development. PMID:26782595

  3. Case of Small Vessel Disease Associated with COL4A1 Mutations following Trauma

    PubMed Central

    Plancher, Joao McONeil; Hufnagel, Robert B.; Vagal, Achala; Peariso, Katrina; Saal, Howard M.; Broderick, Joseph P.

    2015-01-01

    With this case report, we would like to heighten the awareness of clinicians about COL4A1 as a single-gene disorder causing cerebral small vessel disease and describe a previously unreported pathogenic missense substitution in COL4A1 (p.Gly990Val) and a new clinical presentation. We identified a heterozygous putatively pathogenic mutation of COL4A1 in a 50-year-old female with a history of congenital cataracts and glaucoma who presented with multiple diffusion-positive infarcts and areas of contrast enhancement following mild head trauma. We believe that this presentation of multiple areas of acute brain and vascular injury in the setting of mild head trauma is a new manifestation of this genetic disorder. Imaging findings of multiple acute infarcts and regions of contrast enhancement with associated asymptomatic old deep microhemorrhages and leukomalacia in adults after head trauma should raise a high suspicion for a COL4A1 genetic disorder. Radiographic patterns of significant leukoaraiosis and deep microhemorrhages can also be seen in patients with long-standing vasculopathy associated with hypertension, which our patient lacked. Our findings demonstrate the utility of genetic screening for COL4A1 mutations in young patients who have small vessel vasculopathy on brain imaging but who do not have significant cardiovascular risk factors. PMID:26120313

  4. Case of Small Vessel Disease Associated with COL4A1 Mutations following Trauma.

    PubMed

    Plancher, Joao McONeil; Hufnagel, Robert B; Vagal, Achala; Peariso, Katrina; Saal, Howard M; Broderick, Joseph P

    2015-01-01

    With this case report, we would like to heighten the awareness of clinicians about COL4A1 as a single-gene disorder causing cerebral small vessel disease and describe a previously unreported pathogenic missense substitution in COL4A1 (p.Gly990Val) and a new clinical presentation. We identified a heterozygous putatively pathogenic mutation of COL4A1 in a 50-year-old female with a history of congenital cataracts and glaucoma who presented with multiple diffusion-positive infarcts and areas of contrast enhancement following mild head trauma. We believe that this presentation of multiple areas of acute brain and vascular injury in the setting of mild head trauma is a new manifestation of this genetic disorder. Imaging findings of multiple acute infarcts and regions of contrast enhancement with associated asymptomatic old deep microhemorrhages and leukomalacia in adults after head trauma should raise a high suspicion for a COL4A1 genetic disorder. Radiographic patterns of significant leukoaraiosis and deep microhemorrhages can also be seen in patients with long-standing vasculopathy associated with hypertension, which our patient lacked. Our findings demonstrate the utility of genetic screening for COL4A1 mutations in young patients who have small vessel vasculopathy on brain imaging but who do not have significant cardiovascular risk factors. PMID:26120313

  5. UV-A1 cytotoxicity and antioxidant defence in keratinocytes and fibroblasts.

    PubMed

    Leccia, M T; Richard, M J; Joanny-Crisci, F; Beani, J C

    1998-01-01

    The levels of antioxidant molecules and lipid peroxidation, under basal conditions, were measured in normal, human cutaneous keratinocytes and fibroblasts. Total glutathione, glutathione peroxidase and superoxide dismutases are significantly higher in normal keratinocytes compared to normal fibroblasts (respectively +248%, +193% and +155%). Under the same conditions, lipid peroxidation is significantly lower in basal keratinocytes compared to fibroblasts. UV-A1 cytotoxicity was investigated in both cutaneous cell types showing that diploid keratinocytes are more resistant to UV-A1 oxidative stress than fibroblasts (by a factor of around 8). We studied the same parameters in two keratinocyte cell lines, NCTC2544 and HaCaT cells, and in MRC5 fibroblasts. Antioxidant content and lipid peroxidation under basal conditions are quite different in these cell lines compared to those of the normal corresponding cells. Furthermore, NCTC2544 keratinocytes are more sensitive to UV-A1 radiation than normal keratinocytes whereas HaCaT keratinocytes are more resistant, and MRC5 fibroblasts are more resistant than normal cutaneous fibroblasts. These findings suggest that (i) cultured epidermal and dermal cells have different sensitivities to UV-A1 radiation that may be linked to different antioxidant capacities and (ii) cell line response to UV-A1 radiation may differ from that of normal cells. PMID:9854158

  6. S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction.

    PubMed

    Ritterhoff, Julia; Vlkers, Mirko; Seitz, Andreas; Spaich, Kristin; Gao, Erhe; Peppel, Karsten; Pleger, Sven T; Zimmermann, Wolfram H; Friedrich, Oliver; Fink, Rainer H A; Koch, Walter J; Katus, Hugo A; Most, Patrick

    2015-08-01

    Restoring expression levels of the EF-hand calcium (Ca(2+)) sensor protein S100A1 has emerged as a key factor in reconstituting normal Ca(2+) handling in failing myocardium. Improved sarcoplasmic reticulum (SR) function with enhanced Ca(2+) resequestration appears critical for S100A1's cyclic adenosine monophosphate-independent inotropic effects but raises concerns about potential diastolic SR Ca(2+) leakage that might trigger fatal arrhythmias. This study shows for the first time a diminished interaction between S100A1 and ryanodine receptors (RyR2s) in experimental HF. Restoring this link in failing cardiomyocytes, engineered heart tissue and mouse hearts, respectively, by means of adenoviral and adeno-associated viral S100A1 cDNA delivery normalizes diastolic RyR2 function and protects against Ca(2+)- and ?-adrenergic receptor-triggered proarrhythmogenic SR Ca(2+) leakage in vitro and in vivo. S100A1 inhibits diastolic SR Ca(2+) leakage despite aberrant RyR2 phosphorylation via protein kinase A and calmodulin-dependent kinase II and stoichiometry with accessory modulators such as calmodulin, FKBP12.6 or sorcin. Our findings demonstrate that S100A1 is a regulator of diastolic RyR2 activity and beneficially modulates diastolic RyR2 dysfunction. S100A1 interaction with the RyR2 is sufficient to protect against basal and catecholamine-triggered arrhythmic SR Ca(2+) leak in HF, combining antiarrhythmic potency with chronic inotropic actions. PMID:26005840

  7. Hormonal regulation of the human sterol 27-hydroxylase gene CYP27A1.

    PubMed Central

    Araya, Zufan; Tang, Wanjin; Wikvall, Kjell

    2003-01-01

    The nucleotide sequence data reported in this paper will appear in EMBL Nucleotide Sequence Database under the accession number AJ 544720. The mitochondrial sterol 27-hydroxylase (CYP27A1) is a multifunctional cytochrome P450 enzyme that catalyses important hydroxylations in the biosynthesis of bile acids and bioactivation of vitamin D(3). Previous results [Babiker, Andersson, Lund, Xiu, Deeb, Reshef, Leitersdorf, Diczfalusy and Bj örkhem (1997) J. Biol. Chem. 272, 26253-26261] suggest that CYP27A1 plays an important role in cholesterol homoeostasis and affects atherogenesis. In the present study, the regulation of the human CYP27A1 gene by growth hormone (GH), insulin-like growth factor-1 (IGF-1), dexamethasone, thyroid hormones and PMA was studied. HepG2 cells were transfected transiently with luciferase reporter gene constructs containing DNA fragments flanking the 5'-region of the human CYP27A1 gene. GH, IGF-1 and dexamethasone increased the promoter activity by 2-3-fold, whereas thyroxine (T(4)) and PMA repressed the activity significantly when measured with luciferase activity expressed in the cells. The endogenous CYP27A1 enzyme activity in the cells was stimulated by GH, IGF-1 and dexamethasone, whereas T(4) and PMA inhibited the activity. Experiments with progressive deletion/luciferase reporter gene constructs indicated that the response elements for GH may be localized in a region upstream to position -1094 bp. The putative response elements for dexamethasone were mapped to positions between -792 and -1095 bp. The -451 bp fragment of the human CYP27A1 gene was found to confer the activation by IGF-1, and the inhibition by T(4) and PMA. Results of the present study suggest that CYP27A1 is regulated in human cells by hormones and signal-transduction pathways. PMID:12597773

  8. Increased APRIL Expression Induces IgA1 Aberrant Glycosylation in IgA Nephropathy.

    PubMed

    Zhai, Ya-Ling; Zhu, Li; Shi, Su-Fang; Liu, Li-Jun; Lv, Ji-Cheng; Zhang, Hong

    2016-03-01

    Aberrant glycosylated IgA1 molecules, mainly galactose-deficient IgA1 (Gd-IgA1), are important causal factors in IgA nephropathy; however, the underlying mechanism for the production of aberrantly glycosylated IgA1 is unknown. A recent genome-wide association study identified a novel IgAN susceptibility gene, TNFSF13, which encoded a proliferation-inducing ligand (APRIL) that promotes lymphocyte proliferation and IgA class switching. We aimed to explore the mechanism of APRIL's involvement in IgAN.We enrolled 166 patients with IgAN and 77 healthy controls and detected the plasma APRIL levels by the ELISA method, identified the mRNA expression of APRIL and its receptors by relative quantitative PCR, and confirmed by in vitro experiment.We identified increased plasma APRIL levels in IgAN, which was further proved by upregulated mRNA expression in B-lymphocytes from 27 IgAN patients. Analysis of the clinical characteristics of patients with IgAN showed that higher plasma APRIL level was associated with more severe clinical presentations (high proteinuria and low eGFR). The plasma APRIL level was positively correlated with Gd-IgA1 levels. Furthermore, exogenous APRIL could induce more production of Gd-IgA1 in cultured lymphocytes from patients with IgAN, compared with that from healthy controls. And, the relative higher expression of receptors of APRIL, that is, BCMA and TACI, in B-lymphocytes from IgAN patients were observed.Our findings implied that in patients with IgAN, increased APRIL is accompanied elevated expression of its receptors in B-lymphocytes, which induces overproduction of Gd-IgA1, ultimately contributing to the pathogenesis of IgAN. PMID:26986150

  9. Association of Neonatal Hyperbilirubinemia with UGT1A1 Gene Polymorphisms: A Meta-Analysis

    PubMed Central

    Yu, Zibi; Zhu, Kaichang; Wang, Li; Liu, Ying; Sun, Jianmei

    2015-01-01

    Background The results of studies on association between the polymorphisms in the coding region and the promoter of uridine diphosphateglucuronosyl transferase 1A1 (UGT1A1) and neonatal hyperbilirubinemia are controversial. This study aimed to determine whether the UGT1A1 gene polymorphisms of Gly71Arg and TATA promoter were significant risk factors associated with neonatal hyperbilirubinemia. Material/Methods The PubMed, Cochrane Library, and Embase databases were searched for papers that describe the association between UGT1A1 polymorphisms and neonatal hyperbilirubinemia. Summary odds ratios and 95% confidence intervals (CI) were estimated based on a fixed-effects model or random-effects model, depending on the absence or presence of significant heterogeneity. Results A total of 32 eligible studies and 6520 participants were identified. Among them, 24 studies focused on the association of neonatal hyperbilirubinemia with UGT1A1 Gly71Arg polymorphisms, and a significant difference was found for the comparison of AA vs. AG+GG (OR=3.47, 95% CI=2.29–5.28, P<0.0001). We included 19 studies on the association of neonatal hyperbilirubinemia with UGT1A1 TATA promoter polymorphism, which also found a statistically significant difference between 7/7 and 6/7 + 6/6 (OR=2.24, 95% CI=1.29–3.92, P=0.004). Conclusions This meta-analysis demonstrated that UGT1A1 polymorphisms (Gly71Arg and TATA promoter) significantly increase the risk of neonatal hyperbilirubinemia. PMID:26467199

  10. Exploratory Bi-Factor Analysis

    ERIC Educational Resources Information Center

    Jennrich, Robert I.; Bentler, Peter M.

    2011-01-01

    Bi-factor analysis is a form of confirmatory factor analysis originally introduced by Holzinger. The bi-factor model has a general factor and a number of group factors. The purpose of this article is to introduce an exploratory form of bi-factor analysis. An advantage of using exploratory bi-factor analysis is that one need not provide a specific…

  11. FACTORS AFFECTING PITCH DISCRIMINATION.

    ERIC Educational Resources Information Center

    BERGAN, JOHN R.

    EFFECTS OF TONAL MEMORY OF TWO KINDS OF FACTORS WERE STUDIED. THE FACTORS WERE (1) THE CHARACTERISTICS OF STIMULI PRESENTED TO THE SUBJECT IN A PITCH IDENTIFICATION TASK, AND (2) THOSE EFFECTING THE RESPONSE THAT THE SUBJECT MAKES IN SUCH A TASK. FIVE HYPOTHESES WERE ADVANCED FOR STUDY. THE UNDERLYING ASSUMPTION WAS THAT THERE ARE IMPORTANT

  12. Change in prognostic factors

    PubMed Central

    Hoelzer, D; Gökbuget, N

    2012-01-01

    The purpose of evaluating prognostic factors in acute lymphoblastic leukemia is, first, to stratify patients into adverse- or good-risk groups, second, to determine different treatment options accordingly and, third, to evaluate their potential outcome. Prognostic factors are particularly relevant for disease-free survival and overall survival.

  13. [Vulnerability factors to depression].

    PubMed

    Bugán, Antal; Margitics, Ferenc; Pauwlik, Zsuzsa

    2006-01-01

    The objective of this study is to reveal in their complexity the biological and cognitive vulnerability factors, as well as the environmental and socialisation predisposing factors playing a role in the development of depression in non-clinical sample of subjects (college students). Biological vulnerability was examined through temperament and character features, cognitive vulnerability was examined through dysfunctional attitudes, attributional style and coping strategies, and environmental, socialization predisposing factors were observed through certain family socialisation effects (type of family atmosphere, educational objectives, educational and rearing attitudes and style) and parental rearing behaviour. 681 college students were involved in this study (465 females, 216 males). Students were assigned to the study group if they fell in the fourth quartile of the sample based on the results obtained by the Beck's Depression Inventory: 170 persons (128 females, 42 males). Students who fell in the first quartile of the sample on the basis of their results obtained by the mentioned Inventory formed the control group: 204 persons (118 females, 86 males). The results of our study have demonstrated that in a sub-clinical sample the lack of parental care was observed to be a socialization predisposing factor in the development of depression, while certain dysfunctional attitudes and pessimistic interpretation styles were detected to be cognitive vulnerability factors, and harm avoidance proved to be a biological vulnerability factor. We also managed to reveal the effects of certain background factors, which produce their influence indirectly through mediating factors. PMID:17090835

  14. Overview of environmental factors

    NASA Technical Reports Server (NTRS)

    Purvis, C. K.

    1989-01-01

    The orbital environment is complex, dynamic, and comprised of both natural and system-induced components. Several environment factors are important for materials. Materials selection/suitability determination requires consideration of each and all factors, including synergisms among them. Understanding and evaluating these effects will require ground testing, modeling, and focused flight experimentation.

  15. Factorizing RSA Keys

    NASA Astrophysics Data System (ADS)

    Blakey, Ed

    Factorization is notoriously difficult. Though the problem is not known to be NP-hard, neither efficient, algorithmic solution nor technologically practicable, quantum-computer solution has been found. This apparent complexity, which renders infeasible the factorization of sufficiently large values, makes secure the RSA cryptographic system.

  16. Plant transcription factors.

    PubMed

    Meshi, T; Iwabuchi, M

    1995-12-01

    Transcriptional regulation of gene expression relies on the recognition of promoter elements by transcription factors. In the past several years, a considerable number of (putative) transcription factors have been identified in plants. Some genes coding for these factors were isolated by south-western screening with oligonucleotides as a probe or by homology-based screening, and others were initially isolated by genetic means and subsequently identified as the genes for transcription factors. These transcription factors often form families of structurally related proteins with similar DNA-binding specificities and in addition, they are sometimes involved in related phenomena. Some groups of factors homo- and/or heterodimerize to increase the length and variability of the target sequences. Transcriptional activators, in general, comprise a modular activation domain. The activities of the transcription factors are controlled by post-translational modification, like phosphorylation and glycosylation, as well as at the levels of nuclear transport, oligomerization, etc. In this review, we will summarize the current knowledge of plant transcription factors to help understand the mechanistic aspects of the transcriptional regulation of genes. PMID:8589926

  17. Commentary: improving persistently elevated HbA1c in diabetes mellitus patients in Nigeria.

    PubMed

    Oghagbon, Efosa K

    2014-01-01

    Glycated hemoglobin (HbA1c) level in patients with diabetes reflects quality of disease control and propensity to develop hyperglycemic complications. During more than 12 years of using HbA1c for monitoring of glycemic control among patients at Nigerian hospitals, the mean glycated hemoglobin ranged from 7.9% 2.4 to 8.3% 2.2. Most of these patients (63% to 68%) had poor glycemic controls with mean HbA1c greater than 7%. Factors that are implicated in this scenario are: 1) high cost of HbA1c testing, 2) ineffective management of risk factors, 3) poor patient compliance, 4) improperly managed diabetes education program, and 5) health care system defect. Central to improving diabetes glycemia is education of doctors, other health workers and patients, within the confines of an overhauled national health system. Physicians need to increase adherence to diabetes mellitus management guidelines and patients must be enrolled into a well-structured education program at health centers. Doctors, as leader of the health team, should drive such education schemes, which must be based on standard training curriculum, sufficient number of trained diabetes educators, and effective monitoring of patients. The most appropriate diabetes education model features small-to-moderate sized participant groups and makes use of motivational interviewing rather than a traditional advice-giving format. Improved health care funding is mandatory given the issue of cost and this can be helped by increased participation of patients in Nigeria's National Health Insurance Scheme. Failure to address the persistently elevated HbA1c will affect long-term quality of life, longevity and health care services in Nigeria. PMID:25417436

  18. Commentary: improving persistently elevated HbA1c in diabetes mellitus patients in Nigeria.

    PubMed

    Oghagbon, Efosa K

    2014-01-01

    Glycated hemoglobin (HbA1c) level in patients with diabetes reflects quality of disease control and propensity to develop hyperglycemic complications. During more than 12 years of using HbA1c for monitoring of glycemic control among patients at Nigerian hospitals, the mean glycated hemoglobin ranged from 7.9% 2.4 to 8.3% 2.2. Most of these patients (63% to 68%) had poor glycemic controls with mean HbA1c greater than 7%. Factors that are implicated in this scenario are: 1) high cost of HbA1c testing, 2) ineffective management of risk factors, 3) poor patient compliance, 4) improperly managed diabetes education program, and 5) health care system defect. Central to improving diabetes glycemia is education of doctors, other health workers and patients, within the confines of an overhauled national health system. Physicians need to increase adherence to diabetes mellitus management guidelines and patients must be enrolled into a well-structured education program at health centers. Doctors, as leader of the health team, should drive such education schemes, which must be based on standard training curriculum, sufficient number of trained diabetes educators, and effective monitoring of patients. The most appropriate diabetes education model features small-to-moderate sized participant groups and makes use of motivational interviewing rather than a traditional advice-giving format. Improved health care funding is mandatory given the issue of cost and this can be helped by increased participation of patients in Nigeria's National Health Insurance Scheme. Failure to address the persistently elevated HbA1c will affect long-term quality of life, longevity and health care services in Nigeria. PMID:25507164

  19. A 1K Shadow RAM for circumvention applications

    SciTech Connect

    Murray, J.R.

    1991-01-01

    A 1K bit Shadow RAM has been developed for storage of critical data in a high transient radiation environment. The circuit includes a 1K bit (128 {times} 8) static RAM with two non-volatile (NV) shadows. The NV shadows are used to back-up the data in the static RAM allowing the circuit to be powered down during transient radiation without losing critical data. This paper will describe the circuit's operation and characterization results.

  20. Block LU factorization

    NASA Technical Reports Server (NTRS)

    Demmel, James W.; Higham, Nicholas J.; Schreiber, Robert S.

    1992-01-01

    Many of the currently popular 'block algorithms' are scalar algorithms in which the operations have been grouped and reordered into matrix operations. One genuine block algorithm in practical use is block LU factorization, and this has recently been shown by Demmel and Higham to be unstable in general. It is shown here that block LU factorization is stable if A is block diagonally dominant by columns. Moreover, for a general matrix the level of instability in block LU factorization can be founded in terms of the condition number kappa(A) and the growth factor for Gaussian elimination without pivoting. A consequence is that block LU factorization is stable for a matrix A that is symmetric positive definite or point diagonally dominant by rows or columns as long as A is well-conditioned.

  1. Identification and characterization of the novel Col10a1 regulatory mechanism during chondrocyte hypertrophic differentiation

    PubMed Central

    Gu, J; Lu, Y; Li, F; Qiao, L; Wang, Q; Li, N; Borgia, J A; Deng, Y; Lei, G; Zheng, Q

    2014-01-01

    The majority of human skeleton develops through the endochondral pathway, in which cartilage-forming chondrocytes proliferate and enlarge into hypertrophic chondrocytes that eventually undergo apoptosis and are replaced by bone. Although at a terminal differentiation stage, hypertrophic chondrocytes have been implicated as the principal engine of bone growth. Abnormal chondrocyte hypertrophy has been seen in many skeletal dysplasia and osteoarthritis. Meanwhile, as a specific marker of hypertrophic chondrocytes, the type X collagen gene (COL10A1) is also critical for endochondral bone formation, as mutation and altered COL10A1 expression are often accompanied by abnormal chondrocyte hypertrophy in many skeletal diseases. However, how the type X collagen gene is regulated during chondrocyte hypertrophy has not been fully elucidated. We have recently demonstrated that Runx2 interaction with a 150-bp mouse Col10a1 cis-enhancer is required but not sufficient for its hypertrophic chondrocyte-specific reporter expression in transgenic mice, suggesting requirement of additional Col10a1 regulators. In this study, we report in silico sequence analysis of this 150-bp enhancer and identification of its multiple binding factors, including AP1, MEF2, NFAT, Runx1 and TBX5. Using this enhancer as bait, we performed yeast one-hybrid assay and identified multiple candidate Col10a1-interacting genes, including cyclooxygenase 1 (Cox-1) and Cox-2. We have also performed mass spectrometry analysis and detected EF1-alpha, Fus, GdF7 and Runx3 as components of the specific complex formed by the cis-enhancer and nuclear extracts from hypertrophic MCT (mouse chondrocytes immortalized with large T antigen) cells that express Col10a1 abundantly. Notably, some of the candidate genes are differentially expressed in hypertrophic MCT cells and have been associated with chondrocyte hypertrophy and Runx2, an indispensible Col10a1 regulator. Intriguingly, we detected high-level Cox-2 expression in hypertrophic MCT cells. Electrophoretic mobility shift assay and chromatin immunoprecipitation assays confirmed the interaction between Cox-2 and Col10a1 cis-enhancer, supporting its role as a candidate Col10a1 regulator. Together, our data support a Cox-2-containing, Runx2-centered Col10a1 regulatory mechanism, during chondrocyte hypertrophic differentiation. PMID:25321476

  2. Glycated haemoglobin A1c is associated with low-grade albuminuria in Chinese adults

    PubMed Central

    Huang, Xiaolin; Zhou, Yulin; Xu, Baihui; Sun, Wanwan; Lin, Lin; Sun, Jichao; Xu, Min; Lu, Jieli; Bi, Yufang; Wang, Weiqing; Xu, Yu; Ning, Guang

    2015-01-01

    Background and objective Diabetes is a strong risk factor for cardiovascular diseases, whereas few studies have investigated simultaneously the associations of glycated haemoglobin A1c (HbA1c), fasting blood glucose (fasting plasma glucose (FPG)) and 2 h postload blood glucose (2 h PG) with low-grade albuminuria, which is an earlier marker of cardiovascular diseases in the general population. Our study aimed to investigate and compare associations of HbA1c, FPG, and 2 h PG levels with risks of low-grade albuminuria in the middle-aged and elderly Chinese. Design and methods This was a cross-sectional study involving 9188 participants aged 40 years or older. All participants underwent a standard 75 g oral glucose tolerance test. Low-grade albuminuria was defined as the highest quartile of urinary albumin-to-creatinine ratio (ACR) (>6.10 mg/g in males and >8.76 mg/g in females) in respondents without microalbuminuria or macroalbuminuria. Results HbA1c, FPG and 2 h PG were all significantly correlated with urinary ACR after adjustment for confounders (all p values <0.0001). After adjustment for HbA1c, the relationships of FPG and 2 h PG with ACR reduced to null. HbA1c levels were still significantly associated with ACR after further adjustment for FPG and 2 h PG. Multiple logistic regression showed that risks of low-grade albuminuria were positively associated with HbA1c levels in a dose–response manner. Compared with participants with HbA1c ≤37 mmol/mol (5.5%), ORs (95% CIs) for low-grade albuminuria were 1.05 (0.94 to 1.18), 1.25 (1.04 to 1.50), 1.40 (1.04 to 1.90) and 2.21 (1.61 to 3.03) for HbA1c categories of 38–42 mmol/mol (5.6–6.0%), 43–48 mmol/mol (6.1–6.5%), 49–53 mmol/mol (6.6–7.0%), and >53 mmol/mol (7.0%), respectively (pfor trend <0.0001). Conclusions HbA1c, but not FPG or 2 h PG, was independently associated with an increased risk of low-grade albuminuria in the middle-aged and elderly Chinese. PMID:26243552

  3. Identification and characterization of the novel Col10a1 regulatory mechanism during chondrocyte hypertrophic differentiation.

    PubMed

    Gu, J; Lu, Y; Li, F; Qiao, L; Wang, Q; Li, N; Borgia, J A; Deng, Y; Lei, G; Zheng, Q

    2014-01-01

    The majority of human skeleton develops through the endochondral pathway, in which cartilage-forming chondrocytes proliferate and enlarge into hypertrophic chondrocytes that eventually undergo apoptosis and are replaced by bone. Although at a terminal differentiation stage, hypertrophic chondrocytes have been implicated as the principal engine of bone growth. Abnormal chondrocyte hypertrophy has been seen in many skeletal dysplasia and osteoarthritis. Meanwhile, as a specific marker of hypertrophic chondrocytes, the type X collagen gene (COL10A1) is also critical for endochondral bone formation, as mutation and altered COL10A1 expression are often accompanied by abnormal chondrocyte hypertrophy in many skeletal diseases. However, how the type X collagen gene is regulated during chondrocyte hypertrophy has not been fully elucidated. We have recently demonstrated that Runx2 interaction with a 150-bp mouse Col10a1 cis-enhancer is required but not sufficient for its hypertrophic chondrocyte-specific reporter expression in transgenic mice, suggesting requirement of additional Col10a1 regulators. In this study, we report in silico sequence analysis of this 150-bp enhancer and identification of its multiple binding factors, including AP1, MEF2, NFAT, Runx1 and TBX5. Using this enhancer as bait, we performed yeast one-hybrid assay and identified multiple candidate Col10a1-interacting genes, including cyclooxygenase 1 (Cox-1) and Cox-2. We have also performed mass spectrometry analysis and detected EF1-alpha, Fus, GdF7 and Runx3 as components of the specific complex formed by the cis-enhancer and nuclear extracts from hypertrophic MCT (mouse chondrocytes immortalized with large T antigen) cells that express Col10a1 abundantly. Notably, some of the candidate genes are differentially expressed in hypertrophic MCT cells and have been associated with chondrocyte hypertrophy and Runx2, an indispensible Col10a1 regulator. Intriguingly, we detected high-level Cox-2 expression in hypertrophic MCT cells. Electrophoretic mobility shift assay and chromatin immunoprecipitation assays confirmed the interaction between Cox-2 and Col10a1 cis-enhancer, supporting its role as a candidate Col10a1 regulator. Together, our data support a Cox-2-containing, Runx2-centered Col10a1 regulatory mechanism, during chondrocyte hypertrophic differentiation. PMID:25321476

  4. Precipitating factors of insomnia.

    PubMed

    Bastien, Célyne H; Vallières, Annie; Morin, Charles M

    2004-01-01

    Insomnia is a prevalent health complaint whose onset is precipitated by a variety of factors. There is an important need to identify and describe these factors to improve our understanding of risk factors and the natural history of insomnia. This article is aimed at identifying and describing the types of precipitating factors related to the onset of insomnia. A total of 345 patients evaluated for insomnia at a sleep-disorders clinic completed a sleep survey and underwent a semistructured clinical interview. As part of the evaluation, the specific precipitating events related to the onset of insomnia were identified. Subsequently, these factors were categorized (work-school, family, physical or psychological health, or indeterminate), and their affective valence (negative, positive, or indeterminate) was coded. The most common precipitating factors of insomnia were related to family, health, and work-school events. Sixty-five percent of precipitating events had a negative valence. These events differed with the age of onset of insomnia but not with the gender of participants. These findings are useful to identify potential risk factors for insomnia and improve our understanding of the natural history of insomnia. PMID:15600224

  5. Environmental Factors in Autism

    PubMed Central

    Grabrucker, Andreas M.

    2013-01-01

    Autism is a neurodevelopmental disorders characterized by impairments in communication and social behavior, and by repetitive behaviors. Although genetic factors might be largely responsible for the occurrence of autism they cannot fully account for all cases and it is likely that in addition to a certain combination of autism-related genes, specific environmental factors might act as risk factors triggering the development of autism. Thus, the role of environmental factors in autism is an important area of research and recent data will be discussed in this review. Interestingly, the results show that many environmental risk factors are interrelated and their identification and comparison might unveil a common scheme of alterations on a contextual as well as molecular level. For example, both, disruption in the immune system and in zinc homeostasis may affect synaptic transmission in autism. Thus, here, a model is proposed that interconnects the most important and scientifically recognized environmental factors. Moreover, similarities in how these risk factors impact synapse function are discussed and a possible influence on an already well described genetic pathway leading to the development of autism via zinc homeostasis is proposed. PMID:23346059

  6. Risk Factors for Tuberculosis

    PubMed Central

    Narasimhan, Padmanesan; Wood, James; MacIntyre, Chandini Raina; Mathai, Dilip

    2013-01-01

    The risk of progression from exposure to the tuberculosis bacilli to the development of active disease is a two-stage process governed by both exogenous and endogenous risk factors. Exogenous factors play a key role in accentuating the progression from exposure to infection among which the bacillary load in the sputum and the proximity of an individual to an infectious TB case are key factors. Similarly endogenous factors lead in progression from infection to active TB disease. Along with well-established risk factors (such as human immunodeficiency virus (HIV), malnutrition, and young age), emerging variables such as diabetes, indoor air pollution, alcohol, use of immunosuppressive drugs, and tobacco smoke play a significant role at both the individual and population level. Socioeconomic and behavioral factors are also shown to increase the susceptibility to infection. Specific groups such as health care workers and indigenous population are also at an increased risk of TB infection and disease. This paper summarizes these factors along with health system issues such as the effects of delay in diagnosis of TB in the transmission of the bacilli. PMID:23476764

  7. Characterization of recombinant shrimp allergen Pen a 1 (tropomyosin).

    PubMed

    Reese, G; Jeoung, B J; Daul, C B; Lehrer, S B

    1997-01-01

    Tropomyosin (Pen a 1) from brown shrimp, Penaeus aztecus, has been identified as the only major shrimp allergen. Since beef, pork and chicken are other tropomyosin-containing foods that are not very allergenic, tropomyosins can serve to investigate the contribution of the structural properties of a protein to its allergenicity. The aim of this study was to determine the primary structure of Pen a 1 and to identify IgE-binding epitopes. The screening of a unidirectional expression cDNA library from shrimp tail muscle with the Pen-a-1-specific monoclonal antibody 4.9.5 resulted in 4 positive Escherichia coli clones. Immunoblot analysis with human sera from shrimp-allergic subjects demonstrated IgE binding of all 4 recombinant shrimp proteins. Three of 4 expressed recombinant proteins have a molecular weight of approximately 36 kD, consistent with the molecular weight of natural Pen a 1. The DNA sequence analysis identified these recombinant shrimp proteins as tropomyosin and could be aligned with the sequence of greasyback shrimp (Metapenaeus ensis) tropomyosin (Met e 1). In order to characterize contiguous IgE-binding epitopes of Pen a 1, a peptide library (Novagen epitope mapping system) expressing 10-30 amino-acid-residue-long recombinant Pen a 1 peptides was constructed and screened with human IgE. Four recombinant, IgE-reactive Pen a 1 peptides were selected and sequenced. They show various degrees of sequence identity with tropomyosins of other arthropods, such as fruitfly and house dust mite, helminths and vertebrates. PMID:9130534

  8. The diverse chemistry of cytochrome P450 17A1 (P450c17, CYP17A1).

    PubMed

    Yoshimoto, Francis K; Auchus, Richard J

    2015-07-01

    The steroid hydroxylation and carbon-carbon bond cleavage activities of cytochrome P450 17A1 (CYP17A1) are responsible for the production of glucocorticoids and androgens, respectively. The inhibition of androgen synthesis is an important strategy to treat androgen-dependent prostate cancer. We discuss the different enzymatic activities towards the various substrates of CYP17A1, demonstrating its promiscuity. Additionally, a novel interhelical interaction is proposed between the F-G loop and the B'-helix to explain the 16α-hydroxylase activity of human CYP17A1 with progesterone as the substrate. The techniques used by biochemists to study this important enzyme are also summarized. This article is part of a Special Issue entitled 'Steroid/Sterol signaling'. PMID:25482340

  9. Clothing factors and vaginitis.

    PubMed

    Heidrich, F E; Berg, A O; Bergman, J J

    1984-10-01

    Associations of clothing factors and vulvovaginal symptoms, signs, and microbiology were sought in 203 women seeking care at a university family medicine clinic. Clothing factors studied were use of panty hose, underwear for sleep, cotton lining panels, and pants vs skirts. Women wearing and not wearing panty hose had similar rates of vaginitis symptoms and signs, but yeast vaginitis was about three times more common among wearers. Relationships of other clothing factors to vaginitis were not found. Nonspecific vaginitis was not found to be related to clothing. PMID:6481318

  10. Introduction to Human Factors

    PubMed Central

    Bergman, Eric

    2012-01-01

    This paper provides an introduction to “human factors engineering,” an applied science that seeks to optimize usability and safety of systems. Human factors engineering pursues this goal by aligning system design with the perceptual, cognitive, and physical capabilities of users. Human factors issues loom large in the diabetes management domain because patients and health care professionals interact with a complex variety of systems, including medical device hardware and software, which are themselves embedded within larger systems of institutions, people, and processes. Usability considerations must be addressed in these systems and devices to ensure safe and effective diabetes management. PMID:22538128

  11. Factorizations in finite groups

    SciTech Connect

    Kulikov, Viktor S

    2013-02-28

    A necessary condition for uniqueness of factorizations of elements of a finite group G with factors belonging to a union of some conjugacy classes of G is given. This condition is sufficient if the number of factors belonging to each conjugacy class is big enough. The result is applied to the problem on the number of irreducible components of the Hurwitz space of degree d marked coverings of P{sup 1} with given Galois group G and fixed collection of local monodromies. Bibliography: 9 titles.

  12. The Impact of HbA1c Testing on Total Annual Healthcare Expenditures Among Newly Diagnosed Patients with Diabetes

    PubMed Central

    Bhounsule, Prajakta; Peterson, Andrew M.

    2015-01-01

    Background In 2010, diabetes was the seventh leading cause of death in the United States. Diabetes also imposes a huge financial burden on the US economy. In 2009, the American Diabetes Association International Expert Committee recommended the use of the glycated hemoglobin (HbA1c) test as a uniform diagnostic measure to identify patients with diabetes. Although HbA1c is a convenient diagnostic test, it is also more expensive than older tests and could, therefore, have an impact on patients’ healthcare expenditures. Objectives To determine if HbA1c testing has an impact on total annual healthcare expenditures among newly diagnosed patients with diabetes and to analyze the factors that are associated with the total healthcare expenditures among diabetic patients before and after HbA1c was implemented as a standard diagnostic factor. Methods This was an observational, retrospective, cross-sectional study. The Medical Expenditure Panel Survey-Household Component 2009 and 2011 databases were used to form the study cohort of patients with diabetes. The total mean healthcare expenditures among patients with diabetes formed the dependent variable. A proxy variable representing a diagnosis of diabetes with and without the use of HbA1c testing in 2009 and in 2011, respectively, formed the main independent variable along with demographic factors, comorbidities, and healthcare services utilization in both years. A generalized linear regression was conducted to determine the association of HbA1c testing with total diabetes-related healthcare expenditures. Results The mean total healthcare expenditure decreased in 2011 compared with 2009. The HbA1c test did not show an association with the total healthcare expenditures versus earlier diabetes-related diagnostic factors. The total expenditures were associated with private insurance, the incidence of a previous heart attack, prescription drug refills, inpatient hospital stays, home care, hospital discharges, and visits to outpatient providers and physicians in both years. Conclusions The HbA1c diagnostic factor did not yield any association with diabetes healthcare expenditures. Although the total healthcare expenditures were reduced in 2011 compared with 2009, it cannot be established that the reduction in costs is solely attributed to the implementation of the HbA1c diagnostic criteria. Further research on healthcare expenditures for diabetic patients diagnosed with and without the use of HbA1c testing is warranted to establish any possible association. PMID:26557226

  13. Prostaglandin transporter, SLCO2A1, mediates the invasion and apoptosis of lung cancer cells via PI3K/AKT/mTOR pathway

    PubMed Central

    Zhu, Qiaoliang; Liang, Xiang; Dai, Jing; Guan, Xin

    2015-01-01

    Treatment of lung cancer involves regulation of various key factors in many signaling pathways. The prostaglandin transporter, solute carrier organic anion transporter family member 2A1 (SLCO2A1), is a promising regulatory factor of cancer cells. By analyzing the invasion and apoptosis status of lung cancer cells, and detecting the expression changes of key factors in PI3K/AKT/mTOR pathway after overexpression and knockdown of SLCO2A1 in vitro, this study intended to investigate the function of SLCO2A1 in mediating lung cancer cells. Results showed overexpression of SLCO2A1 could induce the invasion of lung cancer cells, and its knockdown inhibited the invasion and induced the apoptosis of cells. mTOR, AKT and S6 in PI3K/AKT/mTOR pathway were not affected by SLCO2A1. But the expression levels of p-mTOR, p-AKT and p-S6 were up-regulated or down-regulated with the overexpression or knockdown of SLCO2A1. Thus SLCO2A1 was inferred to mediate the invasion and apoptosis of lung cancer cells via PI3K/AKT/mTOR pathway. These results implied SLCO2A1 could be a regulatory factor of the invasion and apoptosis of lung cancer cells and serve as a promising target for lung cancer therapy. PMID:26464663

  14. The complex understanding of Annexin A1 phosphorylation.

    PubMed

    D'Acunto, Cosimo Walter; Gbelcova, Helena; Festa, Michela; Ruml, Tomas

    2014-01-01

    Annexin A1 (ANXA1) is the first characterized member of the annexins superfamily. It binds the cellular membrane phospholipids in Ca(2+) regulated manner. Annexin A1 has been found in several tissues and many physiological roles as hormones secretion, vesiculation, inflammatory response, apoptosis and differentiation have been shown. Its subcellular localization and binding with many partner proteins are altered accordingly with its physiological role. The Annexin A1 membrane localization is crucial for binding to receptors, suggesting a paracrine and juxtacrine extracellular action. Annexin A1 is subjected to several post-translational modifications. In particular the protein is phosphorylated on several residues both on the N-terminal functional domain and on the C-terminus core. Different kinases have been identified as responsible for the phosphorylation status of selective residues. The specific change in the phosphorylation status on the different sites alters ANXA1 localization, binding properties and functions. This review shows the physiological relevance of the ANXA1 phosphorylation leading to the conclusion that numerous and different roles of Annexin A1 could be associated with different phosphorylations to alter not only intracellular localization and bindings to its partners but also the extracellular receptor interactions. PMID:24103589

  15. CYP24A1 is a potential biomarker for the progression and prognosis of human colorectal cancer.

    PubMed

    Sun, Hongyan; Wang, Chuanwen; Hao, Miao; Sun, Ran; Wang, Yuqian; Liu, Tie; Cong, Xianling; Liu, Ya

    2016-04-01

    Our study aims to fully evaluate clinicopathological and prognostic values of CYP24A1 in colorectal cancer (CRC) patients. Tissue microarrays of formalin-fixed and paraffin-embedded tumor samples and matched adjacent nontumor colorectal tissues from 99 CRC patients were studied for CYP24A1 protein expression by immunohistochemistry. Messenger RNA expression of CYP24A1 was further evaluated by quantitative real-time polymerase chain reaction in 12 pairs of fresh frozen CRC samples. CYP24A1 expression was significantly higher in CRC tissues compared to corresponding noncancerous tissues. The expression of CYP24A1 protein in CRC was correlated with the depth of tumor invasion (P = .000), lymph node metastasis (P = .030), venous permeation (P = .016), and overall survival (P = .008). A Kaplan-Meier analysis of the CRC patients with high CYP24A1 expression showed significantly reduced overall survival and disease-free survival compared to the patients with low expression (P = 0.026 and .009). A prognostic significance of CYP24A1 was also found in the subgroup of venous permeation condition classification. A multivariate Cox regression analysis showed that CYP24A1 expression was an independent prognostic factor for CRC recurrence (P = .032). In conclusion, CYP24A1 expression is closely associated with CRC progression, and it might be a novel prognostic biomarker for CRC. PMID:26997443

  16. New microbial growth factor

    NASA Technical Reports Server (NTRS)

    Bok, S. H.; Casida, L. E., Jr.

    1977-01-01

    A screening procedure was used to isolate from soil a Penicillium sp., two bacterial isolates, and a Streptomyces sp. that produced a previously unknown microbial growth factor. This factor was an absolute growth requirement for three soil bacteria. The Penicillium sp. and one of the bacteria requiring the factor, an Arthrobacter sp., were selected for more extensive study concerning the production and characteristics of the growth factor. It did not seem to be related to the siderochromes. It was not present in soil extract, rumen fluid, or any other medium component tested. It appears to be a glycoprotein of high molecular weight and has high specific activity. When added to the diets for a meadow-vole mammalian test system, it caused an increased consumption of diet without a concurrent increase in rate of weight gain.

  17. Aerospace Human Factors

    NASA Technical Reports Server (NTRS)

    Jordan, Kevin

    1999-01-01

    The following contains the final report on the activities related to the Cooperative Agreement between the human factors research group at NASA Ames Research Center and the Psychology Department at San Jose State University. The participating NASA Ames division has been, as the organization has changed, the Aerospace Human Factors Research Division (ASHFRD and Code FL), the Flight Management and Human Factors Research Division (Code AF), and the Human Factors Research and Technology Division (Code IH). The inclusive dates for the report are November 1, 1984 to January 31, 1999. Throughout the years, approximately 170 persons worked on the cooperative agreements in one capacity or another. The Cooperative Agreement provided for research personnel to collaborate with senior scientists in ongoing NASA ARC research. Finally, many post-MA/MS and post-doctoral personnel contributed to the projects. It is worth noting that 10 former cooperative agreement personnel were hired into civil service positions directly from the agreements.

  18. Beware the impact factor

    NASA Astrophysics Data System (ADS)

    2013-02-01

    The journal impact factor is a good predictor of the quality of journals as measured by citations to primary research articles. It is, however, a poor indicator of citations to specific papers or of the future performance of individual researchers.

  19. Coagulation Factors Test

    MedlinePlus

    ... Related tests: Prothrombin Time (PT) ; Partial Thromboplastin Time (PTT) ; Fibrinogen ; von Willebrand Factor At a Glance Test ... prolonged Prothrombin Time (PT) or Partial Thromboplastin Time (PTT) . These tests are used as screening tools to ...

  20. von Willebrand Factor Test

    MedlinePlus

    ... Tests , Complete Blood Count , Coagulation Factor VIII , PT , PTT At a Glance Test Sample The Test Common ... platelet aggregation, etc.), PT (prothrombin time) , and/or PTT (partial thromboplastin time) . Other tests may be ordered ...

  1. Teleoperator human factors study

    NASA Technical Reports Server (NTRS)

    1984-01-01

    The progress made on the Teleoperator Human Factors Study program is summarized. Technical and programmatic problems that were encountered were discussed along with planned activities. The report contains four sections: Work Performed, Future Work, Problems Encountered, and Cost Information

  2. Teleoperator human factors study

    NASA Technical Reports Server (NTRS)

    1984-01-01

    The progress made on the Teleoperator Human Factors Study program is summarized. Technical and programmatic problems that were encountered are discussed along with planned activity. Work performed, future work, problems encountered, and cost information comprise the topics addressed herein.

  3. Automated Factor Slice Sampling.

    PubMed

    Tibbits, Matthew M; Groendyke, Chris; Haran, Murali; Liechty, John C

    2014-01-01

    Markov chain Monte Carlo (MCMC) algorithms offer a very general approach for sampling from arbitrary distributions. However, designing and tuning MCMC algorithms for each new distribution, can be challenging and time consuming. It is particularly difficult to create an efficient sampler when there is strong dependence among the variables in a multivariate distribution. We describe a two-pronged approach for constructing efficient, automated MCMC algorithms: (1) we propose the "factor slice sampler", a generalization of the univariate slice sampler where we treat the selection of a coordinate basis (factors) as an additional tuning parameter, and (2) we develop an approach for automatically selecting tuning parameters in order to construct an efficient factor slice sampler. In addition to automating the factor slice sampler, our tuning approach also applies to the standard univariate slice samplers. We demonstrate the efficiency and general applicability of our automated MCMC algorithm with a number of illustrative examples. PMID:24955002

  4. Automated Factor Slice Sampling

    PubMed Central

    Tibbits, Matthew M.; Groendyke, Chris; Haran, Murali; Liechty, John C.

    2013-01-01

    Markov chain Monte Carlo (MCMC) algorithms offer a very general approach for sampling from arbitrary distributions. However, designing and tuning MCMC algorithms for each new distribution, can be challenging and time consuming. It is particularly difficult to create an efficient sampler when there is strong dependence among the variables in a multivariate distribution. We describe a two-pronged approach for constructing efficient, automated MCMC algorithms: (1) we propose the “factor slice sampler”, a generalization of the univariate slice sampler where we treat the selection of a coordinate basis (factors) as an additional tuning parameter, and (2) we develop an approach for automatically selecting tuning parameters in order to construct an efficient factor slice sampler. In addition to automating the factor slice sampler, our tuning approach also applies to the standard univariate slice samplers. We demonstrate the efficiency and general applicability of our automated MCMC algorithm with a number of illustrative examples. PMID:24955002

  5. Factor II deficiency

    MedlinePlus

    ... blood. It leads to problems with blood clotting (coagulation). Factor II is also known as prothrombin. ... blood clots form. This process is called the coagulation cascade. It involves special proteins called coagulation, or ...

  6. Nucleon Form Factors

    SciTech Connect

    Cornelis de Jager

    2004-09-01

    The experimental and theoretical status of elastic electron scattering from the nucleon is reviewed. As a consequence of new experimental facilities, data of unprecedented precision have recently become available for the electromagnetic and the strange form factors of the nucleon.

  7. Factors Affecting Wound Healing

    PubMed Central

    Guo, S.; DiPietro, L.A.

    2010-01-01

    Wound healing, as a normal biological process in the human body, is achieved through four precisely and highly programmed phases: hemostasis, inflammation, proliferation, and remodeling. For a wound to heal successfully, all four phases must occur in the proper sequence and time frame. Many factors can interfere with one or more phases of this process, thus causing improper or impaired wound healing. This article reviews the recent literature on the most significant factors that affect cutaneous wound healing and the potential cellular and/or molecular mechanisms involved. The factors discussed include oxygenation, infection, age and sex hormones, stress, diabetes, obesity, medications, alcoholism, smoking, and nutrition. A better understanding of the influence of these factors on repair may lead to therapeutics that improve wound healing and resolve impaired wounds. PMID:20139336

  8. A Function for the hnRNP A1/A2 Proteins in Transcription Elongation

    PubMed Central

    Lemieux, Bruno; Blanchette, Marco; Monette, Anne; Mouland, Andrew J.; Wellinger, Raymund J.; Chabot, Benoit

    2015-01-01

    The hnRNP A1 and A2 proteins regulate processes such as alternative pre-mRNA splicing and mRNA stability. Here, we report that a reduction in the levels of hnRNP A1 and A2 by RNA interference or their cytoplasmic retention by osmotic stress drastically increases the transcription of a reporter gene. Based on previous work, we propose that this effect may be linked to a decrease in the activity of the transcription elongation factor P-TEFb. Consistent with this hypothesis, the transcription of the reporter gene was stimulated when the catalytic component of P-TEFb, CDK9, was inhibited with DRB. While low levels of A1/A2 stimulated the association of RNA polymerase II with the reporter gene, they also increased the association of CDK9 with the repressor 7SK RNA, and compromised the recovery of promoter-distal transcription on the Kitlg gene after the release of pausing. Transcriptome analysis revealed that more than 50% of the genes whose expression was affected by the siRNA-mediated depletion of A1/A2 were also affected by DRB. RNA polymerase II-chromatin immunoprecipitation assays on DRB-treated and A1/A2-depleted cells identified a common set of repressed genes displaying increased occupancy of polymerases at promoter-proximal locations, consistent with pausing. Overall, our results suggest that lowering the levels of hnRNP A1/A2 elicits defective transcription elongation on a fraction of P-TEFb-dependent genes, hence favoring the transcription of P-TEFb-independent genes. PMID:26011126

  9. FGF growth factor analogs

    DOEpatents

    Zamora, Paul O.; Pena, Louis A.; Lin, Xinhua; Takahashi, Kazuyuki

    2012-07-24

    The present invention provides a fibroblast growth factor heparin-binding analog of the formula: ##STR00001## where R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, X, Y and Z are as defined, pharmaceutical compositions, coating compositions and medical devices including the fibroblast growth factor heparin-binding analog of the foregoing formula, and methods and uses thereof.

  10. Tracking Diabetes: New York City's A1C Registry

    PubMed Central

    Chamany, Shadi; Silver, Lynn D; Bassett, Mary T; Driver, Cynthia R; Berger, Diana K; Neuhaus, Charlotte E; Kumar, Namrata; Frieden, Thomas R

    2009-01-01

    Context: In December 2005, in characterizing diabetes as an epidemic, the New York City Board of Health mandated the laboratory reporting of hemoglobin A1C laboratory test results. This mandate established the United States’ first population-based registry to track the level of blood sugar control in people with diabetes. But mandatory A1C reporting has provoked debate regarding the role of public health agencies in the control of noncommunicable diseases and, more specifically, both privacy and the doctor-patient relationship. Methods: This article reviews the rationale for adopting the rule requiring the reporting of A1C test results, experience with its implementation, and criticisms raised in the context of the history of public health practice. Findings: For many decades, public health agencies have used identifiable information collected through mandatory laboratory reporting to monitor the population's health and develop programs for the control of communicable and noncommunicable diseases. The registry program sends quarterly patient rosters stratified by A1C level to more than one thousand medical providers, and it also sends letters, on the provider's letterhead whenever possible, to patients at risk of diabetes complications (A1C level >9 percent), advising medical follow-up. The activities of the registry program are similar to those of programs for other reportable conditions and constitute a joint effort between a governmental public health agency and medical providers to improve patients’ health outcomes. Conclusions: Mandatory reporting has proven successful in helping combat other major epidemics. New York City's A1C Registry activities combine both traditional and novel public health approaches to reduce the burden of an epidemic chronic disease, diabetes. Despite criticism that mandatory reporting compromises individuals’ right to privacy without clear benefit, the early feedback has been positive and suggests that the benefits will outweigh the potential harms. Further evaluation will provide additional information that other local health jurisdictions may use in designing their strategies to address chronic disease. PMID:19751279

  11. [Environmental factors of longevity].

    PubMed

    Christen, Yves

    2003-03-01

    A PROBABLE ROLE: The great increase in life expectancy over the past decades and too short a time lapse for any major genetic mutations to intervene, are arguments in favour of the intervention of environmental factors in longevity. A FAIRLY LONG LIST: Various environmental factors can be envisaged: prenatal environment, pollution, radiation and oncogenic agents, notably tobacco, food (quantitatively and qualitatively), medicinal products, stress, education and socio-professional life style, isolation, number of children and sexual activity, sports and exercising, etc. It is highly likely that all these factors, or at least some of them, have a real effect on longevity, although this is difficult to demonstrate directly. A COMBINED EFFECT: The basic idea of this paper is that these environmental factors should be seen as agents, the effects of which would be combined with those of genetic factors, considered as agents of radically different nature. We suggest that, in order to have any real effect, these environmental factors have to work on the same cell mechanisms as those that affect the genetic process, notably the mechanisms related to oxidative stress and genetic expression. PMID:12712686

  12. [Laryngeal cancer risk factors].

    PubMed

    Jurkiewicz, Dariusz; Dzaman, Karolina; Rapiejko, Piotr

    2006-07-01

    Laryngeal cancer is the most common of head and neck cancers. Neoplasm used to develop basing on DNA mutation which leads to uncontrolled growth and cells' division. It is due to spontaneous mutations or influence of chemical, biological and physical factors. Laryngeal cancer generation is conditioned by many synergic factors. Some of them certainly participate in cancer genesis and this thesis is accepted by medical environment and other of them have been discussed giving different information. Definition of the risk factors role in laryngeal cancer etiology is very difficult especially regarding their contemporary occurrence in one person. Most common risk factors are environmental factors, gastroesophageal reflux, viral infections, diet, radiation, individual predisposition. Some of them, such as cigarette smoking and abuse alcohol are significantly oftener confirmed in patients with neoplasm diagnosis and others' role in developing of illness has been still researched. Thus the purpose of the study was to present so far achievements in laryngeal cancer etiology and to emphasize controversies relating to some factors' role in cancer genesis. PMID:17007303

  13. Characterization of SLCO5A1/OATP5A1, a Solute Carrier Transport Protein with Non-Classical Function

    PubMed Central

    Sebastian, Katrin; Detro-Dassen, Silvia; Rinis, Natalie; Fahrenkamp, Dirk; Müller-Newen, Gerhard; Merk, Hans F.; Schmalzing, Günther

    2013-01-01

    Organic anion transporting polypeptides (OATP/SLCO) have been identified to mediate the uptake of a broad range of mainly amphipathic molecules. Human OATP5A1 was found to be expressed in the epithelium of many cancerous and non-cancerous tissues throughout the body but protein characterization and functional analysis have not yet been performed. This study focused on the biochemical characterization of OATP5A1 using Xenopus laevis oocytes and Flp-In T-REx-HeLa cells providing evidence regarding a possible OATP5A1 function. SLCO5A1 is highly expressed in mature dendritic cells compared to immature dendritic cells (∼6.5-fold) and SLCO5A1 expression correlates with the differentiation status of primary blood cells. A core- and complex- N-glycosylated polypeptide monomer of ∼105 kDa and ∼130 kDa could be localized in intracellular membranes and on the plasma membrane, respectively. Inducible expression of SLCO5A1 in HeLa cells led to an inhibitory effect of ∼20% after 96 h on cell proliferation. Gene expression profiling with these cells identified immunologically relevant genes (e.g. CCL20) and genes implicated in developmental processes (e.g. TGM2). A single nucleotide polymorphism leading to the exchange of amino acid 33 (L→F) revealed no differences regarding protein expression and function. In conclusion, we provide evidence that OATP5A1 might be a non-classical OATP family member which is involved in biological processes that require the reorganization of the cell shape, such as differentiation and migration. PMID:24376674

  14. Cytochrome P450 CYP1A1: wider roles in cancer progression and prevention

    PubMed Central

    2009-01-01

    CYP1A1 is one of the main cytochrome P450 enzymes, examined extensively for its capacity to activate compounds with carcinogenic properties. Continuous exposure to inhalation chemicals and environmental carcinogens is thought to increase the level of CYP1A1 expression in extrahepatic tissues, through the aryl hydrocarbon receptor (AhR). Although the latter has long been recognized as a ligand-induced transcription factor, which is responsible for the xenobiotic activating pathway of several phase I and phase II metabolizing enzymes, recent evidence suggests that the AhR is involved in various cell signaling pathways critical to cell cycle regulation and normal homeostasis. Disregulation of these pathways is implicated in tumor progression. In addition, it is becoming increasingly evident that CYP1A1 plays an important role in the detoxication of environmental carcinogens, as well as in the metabolic activation of dietary compounds with cancer preventative activity. Ultimately the contribution of CYP1A1 to cancer progression or prevention may depend on the balance of procarcinogen activation/detoxication and dietary natural product extrahepatic metabolism. PMID:19531241

  15. HnRNP A1 controls a splicing regulatory circuit promoting mesenchymal-to-epithelial transition

    PubMed Central

    Bonomi, Serena; di Matteo, Anna; Buratti, Emanuele; Cabianca, Daphne S.; Baralle, Francisco E.; Ghigna, Claudia; Biamonti, Giuseppe

    2013-01-01

    Epithelial-to-mesenchymal transition (EMT) is an embryonic program used by cancer cells to acquire invasive capabilities becoming metastatic. ΔRon, a constitutively active isoform of the Ron tyrosine kinase receptor, arises from skipping of Ron exon 11 and provided the first example of an alternative splicing variant causatively linked to the activation of tumor EMT. Splicing of exon 11 is controlled by two adjacent regulatory elements, a silencer and an enhancer of splicing located in exon 12. The alternative splicing factor and oncoprotein SRSF1 directly binds to the enhancer, induces the production of ΔRon and activates EMT leading to cell locomotion. Interestingly, we now find an important role for hnRNP A1 in controlling the activity of the Ron silencer. HnRNP A1 is able to antagonize the binding of SRSF1 and prevent exon skipping. Notably, hnRNP A1, by inhibiting the production of ΔRon, activates the reversal program, namely the mesenchymal-to-epithelial transition, which instead occurs at the final metastasis sites. Also, hnRNP A1 affects Ron splicing by regulating the expression level of hnRNP A2/B1, which similarly to SRSF1 can promote ΔRon production. These results shed light on how splicing regulation contributes to the tumor progression and provide potential targets to develop anticancer therapies. PMID:23863836

  16. Crucial role for the VWF A1 domain in binding to type IV collagen.

    PubMed

    Flood, Veronica H; Schlauderaff, Abraham C; Haberichter, Sandra L; Slobodianuk, Tricia L; Jacobi, Paula M; Bellissimo, Daniel B; Christopherson, Pamela A; Friedman, Kenneth D; Gill, Joan Cox; Hoffmann, Raymond G; Montgomery, Robert R

    2015-04-01

    Von Willebrand factor (VWF) contains binding sites for platelets and for vascular collagens to facilitate clot formation at sites of injury. Although previous work has shown that VWF can bind type IV collagen (collagen 4), little characterization of this interaction has been performed. We examined the binding of VWF to collagen 4 in vitro and extended this characterization to a murine model of defective VWF-collagen 4 interactions. The interactions of VWF and collagen 4 were further studied using plasma samples from a large study of both healthy controls and subjects with different types of von Willebrand disease (VWD). Our results show that collagen 4 appears to bind VWF exclusively via the VWF A1 domain, and that specific sequence variations identified through VWF patient samples and through site-directed mutagenesis in the VWF A1 domain can decrease or abrogate this interaction. In addition, VWF-dependent platelet binding to collagen 4 under flow conditions requires an intact VWF A1 domain. We observed that decreased binding to collagen 4 was associated with select VWF A1 domain sequence variations in type 1 and type 2M VWD. This suggests an additional mechanism through which VWF variants may alter hemostasis. PMID:25662333

  17. Analysis of energy production at a 1 MW CPV site in southern California

    NASA Astrophysics Data System (ADS)

    Bowman, John; Jensen, Steffen; Melia, Jane

    2012-10-01

    SolFocus has been operating a 1 MW CPV site at Victor Valley College in the southern Mojave Desert of California for over 21 months. Data gathered from site monitoring equipment as well as from nearby weather stations has enabled a detailed analysis of energy production and an in-depth evaluation of our energy prediction model. This paper reviews the results of this analysis, and presents our detailed findings on the relationships between energy production and several environmental factors such as wind speed and humidity.

  18. Association of a butyrophilin, subfamily 2, member A1 gene polymorphism with hypertension

    PubMed Central

    MURAKATA, YOSHIKO; FUJIMAKI, TETSUO; YAMADA, YOSHIJI

    2014-01-01

    The C→T polymorphism (rs6929846) of the butyrophilin, subfamily 2, member A1 (BTN2A1) gene has been previously identified as a susceptibility locus for myocardial infarction by a genome-wide association study. As hypertension is a major risk factor for myocardial infarction, the association between the BTN2A1 polymorphism, rs6929846, and myocardial infarction may be partly due to its effect on hypertension susceptibility. The aim of the present study was to examine the possible association of rs6929846 with hypertension. The study subjects comprised 5,959 community-dwelling individuals (2,183 subjects with hypertension and 3,776 controls) who were recruited to a population-based cohort study. The rs6929846 genotype was determined by a method that combined polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons between the genotype distributions (P=0.0090) and allele frequencies (P=0.0051) by the χ2 test revealed that rs6929846 was significantly associated with hypertension. Multivariable logistic regression analysis with adjustment for age, gender, body mass index and smoking status revealed that rs6929846 was significantly associated with hypertension (P=0.0008; odds ratio, 1.29; dominant model), with the minor T allele representing a risk factor for this condition. Among all the individuals, systolic, diastolic and mean blood pressure was significantly higher in the combined group of individuals with the CT or TT genotypes compared to the CC genotype group. BTN2A1 may thus be a susceptibility gene for hypertension. Therefore, determining the genotype for this polymorphism may provide genetic risk assessment information for hypertension. PMID:25279152

  19. Endoxifen and Other Metabolites of Tamoxifen Inhibit Human Hydroxysteroid Sulfotransferase 2A1 (hSULT2A1)

    PubMed Central

    Squirewell, Edwin J.; Qin, Xiaoyan

    2014-01-01

    Although tamoxifen is a successful agent for treatment and prevention of estrogen-dependent breast cancer, its use has been limited by the low incidence of endometrial cancer. Human hydroxysteroid sulfotransferase 2A1 (hSULT2A1) catalyzes the formation of an α-sulfooxy metabolite of tamoxifen that is reactive toward DNA, and this has been implicated in its carcinogenicity. Also, hSULT2A1 functions in the metabolism of steroid hormones such as dehydroepiandrosterone (DHEA) and pregnenolone (PREG). These roles of hSULT2A1 in steroid hormone metabolism and in generating a reactive metabolite of tamoxifen led us to examine its interactions with tamoxifen and several of its major metabolites. We hypothesized that metabolites of tamoxifen may regulate the catalytic activity of hSULT2A1, either through direct inhibition or through serving as alternate substrates for the enzyme. We found that 4-hydroxy-N-desmethyltamoxifen (endoxifen) is a potent inhibitor of hSULT2A1-catalyzed sulfation of PREG and DHEA, with Ki values of 3.5 and 2.8 μM, respectively. In the hSULT2A1-catalyzed sulfation of PREG, 4-hydroxytamoxifen (4-OHTAM) and N-desmethyltamoxifen (N-desTAM) exhibited Ki values of 12.7 and 9.8 μM, respectively, whereas corresponding Ki values of 19.4 and 17.2 μM were observed with DHEA as substrate. A Ki value of 9.1 μM was observed for tamoxifen-N-oxide with DHEA as substrate, and this increased to 16.9 μM for the hSULT2A1-catalyzed sulfation of PREG. Three metabolites were substrates for hSULT2A1, with relative sulfation rates of 4-OHTAM > N-desTAM > > endoxifen. These results may be useful in interpreting ongoing clinical trials of endoxifen and in improving the design of related molecules. PMID:25157097

  20. Purification and structural characterisation of phospholipase A1 (Vespapase, Ves a 1) from Thai banded tiger wasp (Vespa affinis) venom.

    PubMed

    Sukprasert, Sophida; Rungsa, Prapenpuksiri; Uawonggul, Nunthawun; Incamnoi, Paroonkorn; Thammasirirak, Sompong; Daduang, Jureerut; Daduang, Sakda

    2013-01-01

    The Thai banded tiger wasp (Vespa affinis) is one of the most dangerous vespid species in Southeast Asia, and stinging accidents involving this species still cause fatalities. In the present study, four forms of V. affinis phospholipase A(1) were identified through a proteomics approach. Two of these enzymes were purified by reverse-phase chromatography, and their biochemical properties were characterised. These enzymes, designated Ves a 1s, are not glycoproteins and exist as 33441.5 and 33474.4 Da proteins, which corresponded with the 34-kDa band observed via SDS-PAGE. The thermal stabilities of these enzymes were stronger than snake venom. Using an in vivo assay, no difference was found in the toxicities of the different isoforms. Furthermore, the toxicity of these enzymes does not appear to be correlated with their PLA(1) activity. The cDNAs of the full-length version of Ves a 1s revealed that the Ves a 1 gene consists of a 1005-bp ORF, which encodes 334 amino acid residues, and 67- and 227-bp 5' and 3' UTRs, respectively. The two isoforms are different by three nucleotide substitutions, resulting in the replacement of two amino acids. Through sequence alignment, these enzymes were classified as members of the pancreatic lipase family. The structural modelling of Ves a 1 used the rat pancreatic lipase-related protein 2 (1bu8A) as a template because it has PLA(1) activity, which demonstrated that this enzyme belongs to the α/β hydrolase fold family. The Ves a 1 structure, which is composed of seven α-helixes and eleven β-strands, contains the β-strand/ɛSer/α-helix structural motif, which contains the Gly-X-Ser-X-Gly consensus sequence. The typical surface structures that play important roles in substrate selectivity (the lid domain and the β9 loop) were shortened in the Ves a 1 structure, which suggests that this enzyme may only exhibit phospholipase activity. Moreover, the observed insertion of proline into the lid domain of the Ves a 1 structure is rare. We therefore propose that this proline residue might be involved in the stability and activity of Ves a 1s. PMID:23159790

  1. Benzodi(pyridothiophene): a novel acceptor unit for application in A1-A-A1 type photovoltaic small molecules.

    PubMed

    Chen, Jianhua; Xiao, Manjun; Duan, Linrui; Wang, Qiong; Tan, Hua; Su, Ning; Liu, Yu; Yang, Renqiang; Zhu, Weiguo

    2016-01-21

    A series of novel A1-A-A1 type small molecules (SMs) of BDPT-2BT, BDPT-2FBT and BDPT-2DPP were designed and synthesized, in which benzodi(pyridothiophene) (BDPT) was used as a novel weak central acceptor (A) unit, and benzothiadiazole (BT), fluorinated benzothiadiazole (FBT) and diketopyrrolopyrrole (DPP) were used as terminal acceptor (A1) units, respectively. The pentacyclic BDPT aromatic unit can form big conjugated and planar SMs with the A1 unit, resulting in enhanced π-π stacking and crystallinity. The effect of the A1 unit on the optical, electrochemical and photovoltaic properties of three SMs was observed. The broader absorption spectrum, lower HOMO energy level, higher photo-response efficiency and better photovoltaic properties were exhibited for BDPT-2DPP. A maximum PCE of 3.97% with a Voc of 0.84 V, a Jsc of 9.0 mA cm(-2) and a FF of 52.37% was obtained in the BDPT-2DPP/PC71BM-based solar cells, which is 1.8 and 1.5 times the values of the BDPT-2BT and BDPT-2FBT-based cells, respectively. PMID:26667581

  2. Role of extrahepatic UDP-glucuronosyltransferase 1A1: Advances in understanding breast milk-induced neonatal hyperbilirubinemia.

    PubMed

    Fujiwara, Ryoichi; Maruo, Yoshihiro; Chen, Shujuan; Tukey, Robert H

    2015-11-15

    Newborns commonly develop physiological hyperbilirubinemia (also known as jaundice). With increased bilirubin levels being observed in breast-fed infants, breast-feeding has been recognized as a contributing factor for the development of neonatal hyperbilirubinemia. Bilirubin undergoes selective metabolism by UDP-glucuronosyltransferase (UGT) 1A1 and becomes a water soluble glucuronide. Although several factors such as gestational age, dehydration and weight loss, and increased enterohepatic circulation have been associated with breast milk-induced jaundice (BMJ), deficiency in UGT1A1 expression is a known cause of BMJ. It is currently believed that unconjugated bilirubin is metabolized mainly in the liver. However, recent findings support the concept that extrahepatic tissues, such as small intestine and skin, contribute to bilirubin glucuronidation during the neonatal period. We will review the recent advances made towards understanding biological and molecular events impacting BMJ, especially regarding the role of extrahepatic UGT1A1 expression. PMID:26342858

  3. 26 CFR 1.926(a)-1 - Distributions to shareholders.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... methods of section 925(a)(1) and (2). Distributions out of this classification will be made on a pro rata basis so that 15/23 (16/23 with regard to distribution to a non-corporate shareholder) of each..., military property, 7.5/23 (8/23 with regard to distributions to a non-corporate shareholder) of...

  4. 26 CFR 1.402A-1 - Designated Roth Accounts.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... (QDRO), and thus, a portion of the account is not payable to the employee and is payable to the employee.... Q-1. What is a designated Roth account? A-1. A designated Roth account is a separate account under a... case of a section 403(b) plan). Q-2. How is a distribution from a designated Roth account taxed?...

  5. Solution structure of the strawberry allergen Fra a 1.

    PubMed

    Seutter von Loetzen, Christian; Schweimer, Kristian; Schwab, Wilfried; Rösch, Paul; Hartl-Spiegelhauer, Olivia

    2012-12-01

    The PR10 family protein Fra a 1E from strawberry (Fragaria x ananassa) is down-regulated in white strawberry mutants, and transient RNAi (RNA interference)-mediated silencing experiments confirmed that Fra a 1 is involved in fruit pigment synthesis. In the present study, we determined the solution structure of Fra a 1E. The protein fold is identical with that of other members of the PR10 protein family and consists of a seven-stranded antiparallel β-sheet, two short V-shaped α-helices and a long C-terminal α-helix that encompass a hydrophobic pocket. Whereas Fra a 1E contains the glycine-rich loop that is highly conserved throughout the protein family, the volume of the hydrophobic pocket and the size of its entrance are much larger than expected. The three-dimensional structure may shed some light on its physiological function and may help to further understand the role of PR10 proteins in plants. PMID:22913709

  6. 26 CFR 1.167(a)-1 - Depreciation in general.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 26 Internal Revenue 2 2010-04-01 2010-04-01 false Depreciation in general. 1.167(a)-1 Section 1... Depreciation in general. (a) Reasonable allowance. Section 167(a) provides that a reasonable allowance for the... the taxpayer for the production of income shall be allowed as a depreciation deduction. The...

  7. 26 CFR 1.402A-1 - Designated Roth Accounts.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... (CONTINUED) INCOME TAXES (CONTINUED) Pension, Profit-Sharing, Stock Bonus Plans, Etc. § 1.402A-1 Designated... Roth account. Q-8. What is the relationship between the accounting for designated Roth contributions as... accounting for designated Roth contributions as investment in the contract for purposes of section 72...

  8. The Heart of a 1:1 Classroom

    ERIC Educational Resources Information Center

    Tulbert, Carrie Ann

    2012-01-01

    Many educators believe that the act of building relationships is the core of learning. When technology is integrated into every classroom, do relationships improve or disintegrate among the key stakeholders in an educational environment? The purpose of this study is to determine the extent to which technology in a 1:1 school district can alter…

  9. Synthesis of Arecatannin A1 from Dimeric Epicatechin Electrophile.

    PubMed

    Suda, Manato; Takanashi, Kohki; Katoh, Miyuki; Matsumoto, Kiriko; Kawaguchi, Koichiro; Kawahara, Sei-ichi; Fujii, Hiroshi; Makabe, Hidefumi

    2015-06-01

    Synthesis of arrecatannin A1 (1) was accomplished from dimeric epicatechin electrophile, which was prepared by Zn(OTf)2 mediated self-condensation, and monomeric catechin nucleophile. The condensation was successfully worked using Yb(OTf)3 as a Lewis acid in good yield. PMID:26197527

  10. 26 CFR 1.926(a)-1 - Distributions to shareholders.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... either of the administrative pricing methods of section 925(a)(1) or (2), (D) Out of earnings and profits... income and other exempt foreign trade income determined under either of the administrative pricing... earnings and profits attributable to other exempt foreign trade income determined under the...

  11. 26 CFR 1.926(a)-1 - Distributions to shareholders.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... either of the administrative pricing methods of section 925(a)(1) or (2), (D) Out of earnings and profits... income and other exempt foreign trade income determined under either of the administrative pricing... earnings and profits attributable to other exempt foreign trade income determined under the...

  12. 26 CFR 1.926(a)-1 - Distributions to shareholders.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... either of the administrative pricing methods of section 925(a)(1) or (2), (D) Out of earnings and profits... income and other exempt foreign trade income determined under either of the administrative pricing... earnings and profits attributable to other exempt foreign trade income determined under the...

  13. 26 CFR 1.926(a)-1 - Distributions to shareholders.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... either of the administrative pricing methods of section 925(a)(1) or (2), (D) Out of earnings and profits... income and other exempt foreign trade income determined under either of the administrative pricing... earnings and profits attributable to other exempt foreign trade income determined under the...

  14. 26 CFR 1.50A-1 - Determination of amount.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... Computing Credit for Expenses of Work Incentive Programs § 1.50A-1 Determination of amount. (a) In general. Except as otherwise provided in this section and in § 1.50A-2, the amount of the work incentive program... preferences), section 72(m)(5)(B) (relating to 10 percent tax on premature distributions to...

  15. Milk A1 and A2 peptides and diabetes.

    PubMed

    Clemens, Roger A

    2011-01-01

    Food-derived peptides, specifically those derived from milk, may adversely affect health by increasing the risk of insulin-dependent diabetes. This position is based on the relationship of type 1 diabetes (T1D) and the consumption of variants A1 and B ?-casein from cow's milk. It appears that ?-casomorphin-7 (BCM-7) from ?-casein may function as an immunosuppressant and impair tolerance to dietary antigens in the gut immune system, which, in turn, may contribute to the onset of T1D. There are thirteen genetic variants of ?-casein in dairy cattle. Among those variants are A1, A2, and B, which are also found in human milk. The amino acid sequences of ?-casomorphins among these bovine variants and those found in human milk are similar, often differing only by a single amino acid. In vitro studies indicate BCM-7 can be produced from A1 and B during typical digestive processes; however, BCM-7 is not a product of A2 digestion. Evidence from several epidemiological studies and animal models does not support the association of milk proteins, even proteins in breast milk, and the development of T1D. Ecological data, primarily based on A1/ A2 variations among livestock breeds, do not demonstrate causation, even among countries where there is considerable dairy consumption. PMID:21335999

  16. The Heart of a 1:1 Classroom

    ERIC Educational Resources Information Center

    Tulbert, Carrie Ann

    2012-01-01

    Many educators believe that the act of building relationships is the core of learning. When technology is integrated into every classroom, do relationships improve or disintegrate among the key stakeholders in an educational environment? The purpose of this study is to determine the extent to which technology in a 1:1 school district can alter

  17. 29 CFR 1912a.1 - Purpose and scope.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Regulations Relating to Labor (Continued) OCCUPATIONAL SAFETY AND HEALTH ADMINISTRATION, DEPARTMENT OF LABOR (CONTINUED) NATIONAL ADVISORY COMMITTEE ON OCCUPATIONAL SAFETY AND HEALTH § 1912a.1 Purpose and scope. (a) Section 7(a) of the Williams-Steiger Occupational Safety and Health Act of 1970 establishes a...

  18. Design and Interpretation of Human Sulfotransferase A1 Assays.

    PubMed

    Wang, Ting; Cook, Ian; Leyh, Thomas S

    2016-04-01

    The human sulfotransferases (SULTs) regulate the activities of hundreds, if not thousands, of small molecule metabolites via transfer of the sulfuryl-moiety (-SO3) from the nucleotide donor, 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the hydroxyls and amines of the recipients. Our understanding of the molecular basis of SULT catalysis has expanded considerably in recent years. The basic kinetic mechanism of these enzymes, previously thought to be ordered, has been redefined as random for SULT2A1, a representative member of the superfamily. An active-site cap whose structure and dynamics are highly responsive to nucleotides was discovered and shown to be critical in determining SULT selectivity, a topic of longstanding interest to the field. We now realize that a given SULT can operate in two specificity modes-broad and narrow-depending on the disposition of the cap. More recent work has revealed that the caps of the SULT1A1 are controlled by homotropic allosteric interactions between PAPS molecules bound at the dimer's active sites. These interactions cause the catalytic efficiency of SULT1A1 to vary in a substrate-dependent fashion by as much as two orders of magnitude over a range of PAPS concentrations that spans those found in human tissues. SULT catalysis is further complicated by the fact that these enzymes are frequently inhibited by their substrates. This review provides an overview of the mechanistic features of SULT1A1 that are important for the design and interpretation of SULT1A1 assays. PMID:26658224

  19. Vibration-rotational intensities for the X 1Sigma(+) state of A1H and A1D

    NASA Technical Reports Server (NTRS)

    Tipping, R. H.; Pineiro, A. Lopez; Chackerian, C., Jr.

    1987-01-01

    In the present calculation of vibrational-rotational line strengths for the ground electronic state of A1H and A1D, the vibrational and rotational quantum numbers used are respectively in the Delta-v zero-5 range for v-prime between zero and 15, and J-prime-J of + or - 1 for J-prime in the zero-50 range. The transition matrix elements were obtained on the basis of the Meyer and Rosmus (1975) ab initio dipole-moment function, together with the numerical vibrational-rotational energy function.

  20. Power Factor Controller Study.

    SciTech Connect

    Knudson Engineers, Inc.

    1989-08-01

    The complete report is divided into three parts as follows: (1) This report combines a historical perspective with a current assessment of the use of power factor controllers for three-phase ac motor energy savings. The power factor controller (PFC) is a power electronics device that reduces voltage to a motor during periods of reduced motor torque requirements. (2) A power factor controller (PFC) is a power electronics device that reduces voltage to a motor during periods of reduced motor torque requirements. This report is the DEMONSTRATION phase of the PFC study. The phase report consists of three task reports -- Site Selection, Demonstration Preparation, and Demonstration. The reports explain how three sites were selected for demonstration, describe what was measured at each site and the method of measurement, and compare measured energy savings with calculated predictions of energy savings. The report concludes that PFCs can save energy on carefully selected motor applications. (3) The results of the demonstration task are described in this report. A power factor controller (PFC) is a power electronics device that reduces voltage to a motor during periods of reduced motor torque requirements. The demonstration phase of this study calculates projected energy savings with the use of a PFC and compares measured performance with the calculations. The effect of the PFC on motor power requirements, power factor and energy consumption shall be measured.

  1. Breast cancer risk factors.

    PubMed

    Kamińska, Marzena; Ciszewski, Tomasz; Łopacka-Szatan, Karolina; Miotła, Paweł; Starosławska, Elżbieta

    2015-09-01

    Breast cancer is the most frequently diagnosed neoplastic disease in women around menopause often leading to a significant reduction of these women's ability to function normally in everyday life. The increased breast cancer incidence observed in epidemiological studies in a group of women actively participating in social and professional life implicates the necessity of conducting multidirectional studies in order to identify risk factors associated with the occurrence of this type of neoplasm. Taking the possibility of influencing the neoplastic transformation process in individuals as a criterion, all the risk factors initiating the process can be divided into two groups. The first group would include inherent factors such as age, sex, race, genetic makeup promoting familial occurrence of the neoplastic disease or the occurrence of benign proliferative lesions of the mammary gland. They all constitute independent parameters and do not undergo simple modification in the course of an individual's life. The second group would include extrinsic factors conditioned by lifestyle, diet or long-term medical intervention such as using oral hormonal contraceptives or hormonal replacement therapy and their influence on the neoplastic process may be modified to a certain degree. Identification of modifiable factors may contribute to development of prevention strategies decreasing breast cancer incidence. PMID:26528110

  2. Breast cancer risk factors

    PubMed Central

    Ciszewski, Tomasz; Łopacka-Szatan, Karolina; Miotła, Paweł; Starosławska, Elżbieta

    2015-01-01

    Breast cancer is the most frequently diagnosed neoplastic disease in women around menopause often leading to a significant reduction of these women's ability to function normally in everyday life. The increased breast cancer incidence observed in epidemiological studies in a group of women actively participating in social and professional life implicates the necessity of conducting multidirectional studies in order to identify risk factors associated with the occurrence of this type of neoplasm. Taking the possibility of influencing the neoplastic transformation process in individuals as a criterion, all the risk factors initiating the process can be divided into two groups. The first group would include inherent factors such as age, sex, race, genetic makeup promoting familial occurrence of the neoplastic disease or the occurrence of benign proliferative lesions of the mammary gland. They all constitute independent parameters and do not undergo simple modification in the course of an individual's life. The second group would include extrinsic factors conditioned by lifestyle, diet or long-term medical intervention such as using oral hormonal contraceptives or hormonal replacement therapy and their influence on the neoplastic process may be modified to a certain degree. Identification of modifiable factors may contribute to development of prevention strategies decreasing breast cancer incidence. PMID:26528110

  3. Carbon Monoxide Releasing Molecule-A1 (CORM-A1) Improves Neurogenesis: Increase of Neuronal Differentiation Yield by Preventing Cell Death

    PubMed Central

    Almeida, Ana S.; Soares, Nuno L.; Vieira, Melissa; Gramsbergen, Jan Bert

    2016-01-01

    Cerebral ischemia and neurodegenerative diseases lead to impairment or death of neurons in the central nervous system. Stem cell based therapies are promising strategies currently under investigation. Carbon monoxide (CO) is an endogenous product of heme degradation by heme oxygenase (HO) activity. Administration of CO at low concentrations produces several beneficial effects in distinct tissues, namely anti-apoptotic and anti-inflammatory. Herein the CO role on modulation of neuronal differentiation was assessed. Three different models with increasing complexity were used: human neuroblastoma SH-S5Y5 cell line, human teratocarcinoma NT2 cell line and organotypic hippocampal slice cultures (OHSC). Cell lines were differentiated into post-mitotic neurons by treatment with retinoic acid (RA) supplemented with CO-releasing molecule A1 (CORM-A1). CORM-A1 positively modulated neuronal differentiation, since it increased final neuronal production and enhanced the expression of specific neuronal genes: Nestin, Tuj1 and MAP2. Furthermore, during neuronal differentiation process, there was an increase in proliferative cell number (ki67 mRNA expressing cells) and a decrease in cell death (lower propidium iodide (PI) uptake, limitation of caspase-3 activation and higher Bcl-2 expressing cells). CO supplementation did not increase the expression of RA receptors. In the case of SH-S5Y5 model, small amounts of reactive oxygen species (ROS) generation emerges as important signaling molecules during CO-promoted neuronal differentiation. CO’s improvement of neuronal differentiation yield was validated using OHSC as ex vivo model. CORM-A1 treatment of OHSC promoted higher levels of cells expressing the neuronal marker Tuj1. Still, CORM-A1 increased cell proliferation assessed by ki67 expression and also prevented cell death, which was followed by increased Bcl-2 expression, decreased levels of active caspase-3 and PI uptake. Likewise, ROS signaling emerged as key factors in CO’s increasing number of differentiated neurons in OHSC. In conclusion, CO’s increasing number of differentiated neurons is a novel biological role disclosed herein. CO improves neuronal yield due to its capacity to reduce cell death, promoting an increase in proliferative population. However, one cannot disregard a direct CO’s effect on specific cellular processes of neuronal differentiation. Further studies are needed to evaluate how CO can potentially modulate cell mechanisms involved in neuronal differentiation. In summary, CO appears as a promising therapeutic molecule to stimulate endogenous neurogenesis or to improve in vitro neuronal production for cell therapy strategies. PMID:27144388

  4. Association of CYP1A1 Gene Polymorphism with Ischemic Stroke in South Indian Population.

    PubMed

    Sultana, Shehnaz; Kolla, Venkata Karunakar; Peddireddy, Vidyullatha; Jeedigunta, Yasovanthi; Penagaluru, Pranay K; Joshi, Sindhu; Penagaluru, Usha Rani; Penagaluru, Pardhananda Reddy

    2011-03-01

    Stroke is a major cause of morbidity and mortality worldwide. Genetic and environmental factors are involved in the pathogenesis of stroke. Hypertension, diabetes mellitus, and cigarette smoking are the major risk factors, and smoking doubles the risk of ischemic stroke. Smoking cessation decreased the risk for ischemic stroke. CYP1A1 is the phase I metabolizing enzyme which plays a key role in metabolic activation of polycyclic aromatic hydrocarbons which are present in cigarette smoke and considered carcinogenic. So far, the association of CYP1A1 gene polymorphism with stroke has not been investigated in Indian population. So, the study is taken up to evaluate the association of this polymorphism with ischemic stroke in a South Indian population. We genotyped 215 ischemic stroke patients and 162 age-matched controls using polymerase chain reaction-restriction fragment length polymorphism. Statistical analysis showed that CYP1A1 "CC" genotype is associated with five times increased risk of ischemic stroke (odds ratio (OR) = 5.14; 95% confidence interval (95% CI) = 1.14-23.14, p = 0.01), while "TT" (OR = 0.78, 95% CI = 0.51-1.19, p = 0.25) and "TC" (OR = 1.04, 95% CI = 0.67-1.60, p = 0.85) genotypes were nonsignificant with the increased risk of stroke. T and C allele frequencies in stroke were 76.5% and 23.5% as against 81.8% and 18.2% in control group, respectively, thus, suggesting no statistically significant differences in the T (OR = 0.72, 95% CI = 0.50-1.03, p = 0.07) and C (OR = 1.37, 95% CI = 0.96-1.97, p = 0.07) allele frequencies between the two groups. The distribution of CYP1A1 genotypes and allelic frequency within the stroke subtypes showed a significant association of CC genotype only in intracranial large artery atherosclerosis (OR = 5.21, 95% CI = 1.03-26.38, p = 0.02) while other subtypes did not show any association. Further analysis of CYP1A1 genotypes in patients and control subjects with smoking habit also showed a similar trend. Hence, we conclude that the CYP1A1 CC genotype is associated with the increased risk of ischemic stroke. PMID:24323584

  5. Anxiety Sensitivity and Panic Attacks: A 1-Year Longitudinal Study

    ERIC Educational Resources Information Center

    Li, Wen; Zinbarg, Richard E.

    2007-01-01

    The hypothesis that anxiety sensitivity (AS) is a risk factor for panic genesis has obtained compelling support, but the clinical/practical importance of AS in panic genesis has been questioned. In addition, the association between panic experience and AS increase has not been clearly demonstrated. Through this 1-year longitudinal study among…

  6. Rapid communication: effect of inhaled chromium on pulmonary A1AT.

    PubMed

    Cohen, Mitchell D; Sisco, Maureen; Baker, Kathy; Chen, Lung-Chi; Schlesinger, Richard B

    2002-07-01

    A major health hazard to coal miners is development of emphysema following long-term exposure to coal dust. One mechanism underlying development of emphysema is the oxidation of critical methionine (Met) residues in antiproteolytic factor, alpha1-antitrypsin (A1AT) resulting in a protease-antiprotease imbalance in the lung. Several studies have documented an association between the incidence and severity of emphysema among miners and their exposure to crystalline silica (i.e., SiO(2)). However, what remains unclear is the role of other co-inhaled nonemphysematogenic nonoxidant inorganic constituent in disease pathogenesis. We hypothesize that in miners, inhaled trivalent chromium (Cr(3+), the only form of Cr in coal) may potentially affect lung A1AT activity in situ via Cr complexing with Met residues, and thereby exacerbate any SiO(2)-induced imbalance. To ascertain if Cr(3+) could, in fact, affect A1AT activity, in vitro studies were done to assess elastase inhibitory activity following A1AT incubation with soluble Cr(3+). In addition, to determine if Cr(3+) found in the lungs as detoxification products of inhaled hexavalent Cr (Cr(6+)) could affect A1AT in situ, lavages from the lungs of chromate-exposed rats were also analyzed for elastase inhibitory activity The in vitro results indicate that Cr(3+) ions clearly inhibited A1AT function, with an IC50 of 1.1 mM being estimated under the experimental conditions used. The in vivo results indicate that long-term inhalation (12 wk or longer) of chromate-bearing atmospheres also gave rise to significant (i.e., 50-70%) inhibition of the antielastase activity of A1AT. Together, these results clearly suggest that the Cr(3+) present in coal dusts could potentially act to inhibit A1AT activity in the lungs of miners and thereby promote the emphysematogenicity of SiO(2) or of other emphysematogens present as coconstituents in these dusts. PMID:12122574

  7. The Orphan Nuclear Receptor NR4A1 (Nur77) Regulates Oxidative and Endoplasmic Reticulum Stress in Pancreatic Cancer Cells

    PubMed Central

    Kang, Jeong Han; Kim, Sang Bae; Guthrie, Aaron S.; Sreevalsan, Sandeep; Lee, Ju-Seog; Safe, Stephen

    2015-01-01

    NR4A1 (Nur77, TR3) is an orphan nuclear receptor that is overexpressed in pancreatic cancer and exhibits pro-oncogenic activity. RNAi interference of NR4A1 expression in Panc-1 cells induced apoptosis and subsequent proteomic analysis revealed the induction of several markers of endoplasmic reticulum (ER) stress including glucose-related protein 78 (GRP78), CCAAT/enhancer-binding protein-homologous protein (CHOP), and activating transcription factor-4 (ATF-4). Treatment of pancreatic cancer cells with the NR4A1 antagonist 1,1-bis(3?-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH), gave similar results. Moreover, both NR4A1 knockdown and DIM-C-pPhOH induced reactive oxygen species (ROS), and induction of ROS and ER stress by these agents was attenuated after co-treatment with antioxidants. Manipulation of NR4A1 expression coupled with gene expression profiling identified a number of ROS metabolism transcripts regulated by NR4A1. Knockdown of one of these transcripts, thioredoxin domain containing 5 (TXNDC5), recapitulated the elevated ROS and ER stress; thus, demonstrating that NR4A1 regulates levels of ER stress and ROS in pancreatic cancer cells to facilitate cell proliferation and survival. Finally, inactivation of NR4A1 by knockdown or DIM-C-pPhOH decreased TXNDC5, resulting in activation of ROS/ER stress and pro-apoptotic pathways. PMID:24515801

  8. Apolipoprotein A1 as a novel anti-implantation biomarker in polycystic ovary syndrome: A case-control study

    PubMed Central

    Amjadi, Fatemehsadat; Aflatoonian, Reza; Javanmard, Shaghayegh Haghjoo; Saifi, Bita; Ashrafi, Mahnaz; Mehdizadeh, Mehdi

    2015-01-01

    Background: Women with polycystic ovary syndrome have lower pregnancy rates, possibly due to the decreased uterine receptivity. Successful implantation depends on protein networks that are essential for cross-talk between the embryo and endometrium. Apolipoprotein A1 has been proposed as a putative anti-implantation factor. In this study, we evaluated apolipoprotein A1 expression in human endometrial tissues. Materials and Methods: Endometrial apolipoprotein A1 messenger RNA (mRNA) and protein expression were investigated using quantitative real-time polymerase chain reaction (PCR) and Western blot. The distribution of apolipoprotein A1 was also detected by immunostaining. Samples were obtained from 10 patients with polycystic ovary syndrome and 15 healthy fertile women in the proliferative (on day 2 or day 3 before ovulation, n = 7) and secretory (on days 3-5 after ovulation, n = 8) phases. Results: Endometrial apolipoprotein A1 expression was upregulated in patients with polycystic ovary syndrome compared to normal subjects. However, apolipoprotein A1 expression in the proliferative phase was significantly higher than in the luteal phase (P value < 0.05). Conclusion: It seems that differentially expressed apolipoprotein A1 negatively affects endometrial receptivity in patients with polycystic ovary syndrome. The results showed that apolipoprotein A1 level significantly changes in the human endometrium during the menstrual cycle with minimum expression in the secretory phase, coincident with the receptive phase (window of implantation). Further studies are required to clarify the clinical application of this protein. PMID:26941806

  9. Factor Loading Estimation Error and Stability Using Exploratory Factor Analysis

    ERIC Educational Resources Information Center

    Sass, Daniel A.

    2010-01-01

    Exploratory factor analysis (EFA) is commonly employed to evaluate the factor structure of measures with dichotomously scored items. Generally, only the estimated factor loadings are provided with no reference to significance tests, confidence intervals, and/or estimated factor loading standard errors. This simulation study assessed factor loading…

  10. Geothermal Plant Capacity Factors

    SciTech Connect

    Greg Mines; Jay Nathwani; Christopher Richard; Hillary Hanson; Rachel Wood

    2015-01-01

    The capacity factors recently provided by the Energy Information Administration (EIA) indicated this plant performance metric had declined for geothermal power plants since 2008. Though capacity factor is a term commonly used by geothermal stakeholders to express the ability of a plant to produce power, it is a term frequently misunderstood and in some instances incorrectly used. In this paper we discuss how this capacity factor is defined and utilized by the EIA, including discussion on the information that the EIA requests from operations in their 923 and 860 forms that are submitted both monthly and annually by geothermal operators. A discussion is also provided regarding the entities utilizing the information in the EIA reports, and how those entities can misinterpret the data being supplied by the operators. The intent of the paper is to inform the facility operators as the importance of the accuracy of the data that they provide, and the implications of not providing the correct information.

  11. Growth factors and plasticity.

    PubMed

    Sizonenko, Stéphane V; Bednarek, Nathalie; Gressens, Pierre

    2007-08-01

    Neuroprotective strategies can prevent lesions from getting worse but agents that have neurotrophic properties can also affect repair in a developing brain. Although prevention and treatment in the early stages of brain lesions are desirable, delayed cell death or improved post-lesion plasticity are the only realistic targets in many cases. Several trophic factors can limit delayed cell death in animal models of perinatal brain damage. In addition, melatonin and brain-derived neurotrophic factor have been shown to promote post-lesion plasticity following neonatal excitotoxic white-matter damage in newborn mice. Despite these promising results, additional preclinical data are required for most of the trophic factors that have been tested, although some candidate drugs, e.g. melatonin or erythropoietin, might reach clinical trials in the near future. PMID:17336172

  12. Multi-factor authentication

    DOEpatents

    Hamlet, Jason R; Pierson, Lyndon G

    2014-10-21

    Detection and deterrence of spoofing of user authentication may be achieved by including a cryptographic fingerprint unit within a hardware device for authenticating a user of the hardware device. The cryptographic fingerprint unit includes an internal physically unclonable function ("PUF") circuit disposed in or on the hardware device, which generates a PUF value. Combining logic is coupled to receive the PUF value, combines the PUF value with one or more other authentication factors to generate a multi-factor authentication value. A key generator is coupled to generate a private key and a public key based on the multi-factor authentication value while a decryptor is coupled to receive an authentication challenge posed to the hardware device and encrypted with the public key and coupled to output a response to the authentication challenge decrypted with the private key.

  13. Psychological Factors in Asthma

    PubMed Central

    2008-01-01

    Asthma has long been considered a condition in which psychological factors have a role. As in many illnesses, psychological variables may affect outcome in asthma via their effects on treatment adherence and symptom reporting. Emerging evidence suggests that the relation between asthma and psychological factors may be more complex than that, however. Central cognitive processes may influence not only the interpretation of asthma symptoms but also the manifestation of measurable changes in immune and physiologic markers of asthma. Furthermore, asthma and major depressive disorder share several risk factors and have similar patterns of dysregulation in key biologic systems, including the neuroendocrine stress response, cytokines, and neuropeptides. Despite the evidence that depression is common in people with asthma and exerts a negative impact on outcome, few treatment studies have examined whether improving symptoms of depression do, in fact, result in better control of asthma symptoms or improved quality of life in patients with asthma. PMID:20525122

  14. DSN human factors project

    NASA Technical Reports Server (NTRS)

    Chafin, R. L.; Martin, T. H.

    1980-01-01

    The project plan was to hold focus groups to identify the factors influencing the ease of use characteristics of software and to bond the problem. A questionnaire survey was conducted to evaluate those factors which were more appropriately measured with that method. The performance oriented factors were analyzed and relationships hypothesized. The hypotheses were put to test in the experimental phase of the project. In summary, the initial analysis indicates that there is an initial performance effect favoring computer controlled dialogue but the advantage fades fast as operators become experienced. The user documentation style is seen to have a significant effect on performance. The menu and prompt command formats are preferred by inexperienced operators. The short form mnemonic is least favored. There is no clear best command format but the short form mnemonic is clearly the worst.

  15. The Transcription Factor Encyclopedia

    PubMed Central

    2012-01-01

    Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe. PMID:22458515

  16. The transcription factor encyclopedia.

    PubMed

    Yusuf, Dimas; Butland, Stefanie L; Swanson, Magdalena I; Bolotin, Eugene; Ticoll, Amy; Cheung, Warren A; Zhang, Xiao Yu Cindy; Dickman, Christopher T D; Fulton, Debra L; Lim, Jonathan S; Schnabl, Jake M; Ramos, Oscar H P; Vasseur-Cognet, Mireille; de Leeuw, Charles N; Simpson, Elizabeth M; Ryffel, Gerhart U; Lam, Eric W-F; Kist, Ralf; Wilson, Miranda S C; Marco-Ferreres, Raquel; Brosens, Jan J; Beccari, Leonardo L; Bovolenta, Paola; Benayoun, Bérénice A; Monteiro, Lara J; Schwenen, Helma D C; Grontved, Lars; Wederell, Elizabeth; Mandrup, Susanne; Veitia, Reiner A; Chakravarthy, Harini; Hoodless, Pamela A; Mancarelli, M Michela; Torbett, Bruce E; Banham, Alison H; Reddy, Sekhar P; Cullum, Rebecca L; Liedtke, Michaela; Tschan, Mario P; Vaz, Michelle; Rizzino, Angie; Zannini, Mariastella; Frietze, Seth; Farnham, Peggy J; Eijkelenboom, Astrid; Brown, Philip J; Laperrière, David; Leprince, Dominique; de Cristofaro, Tiziana; Prince, Kelly L; Putker, Marrit; del Peso, Luis; Camenisch, Gieri; Wenger, Roland H; Mikula, Michal; Rozendaal, Marieke; Mader, Sylvie; Ostrowski, Jerzy; Rhodes, Simon J; Van Rechem, Capucine; Boulay, Gaylor; Olechnowicz, Sam W Z; Breslin, Mary B; Lan, Michael S; Nanan, Kyster K; Wegner, Michael; Hou, Juan; Mullen, Rachel D; Colvin, Stephanie C; Noy, Peter John; Webb, Carol F; Witek, Matthew E; Ferrell, Scott; Daniel, Juliet M; Park, Jason; Waldman, Scott A; Peet, Daniel J; Taggart, Michael; Jayaraman, Padma-Sheela; Karrich, Julien J; Blom, Bianca; Vesuna, Farhad; O'Geen, Henriette; Sun, Yunfu; Gronostajski, Richard M; Woodcroft, Mark W; Hough, Margaret R; Chen, Edwin; Europe-Finner, G Nicholas; Karolczak-Bayatti, Magdalena; Bailey, Jarrod; Hankinson, Oliver; Raman, Venu; LeBrun, David P; Biswal, Shyam; Harvey, Christopher J; DeBruyne, Jason P; Hogenesch, John B; Hevner, Robert F; Héligon, Christophe; Luo, Xin M; Blank, Marissa Cathleen; Millen, Kathleen Joyce; Sharlin, David S; Forrest, Douglas; Dahlman-Wright, Karin; Zhao, Chunyan; Mishima, Yuriko; Sinha, Satrajit; Chakrabarti, Rumela; Portales-Casamar, Elodie; Sladek, Frances M; Bradley, Philip H; Wasserman, Wyeth W

    2012-01-01

    Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe. PMID:22458515

  17. WRKY transcription factors

    PubMed Central

    Bakshi, Madhunita; Oelmüller, Ralf

    2014-01-01

    WRKY transcription factors are one of the largest families of transcriptional regulators found exclusively in plants. They have diverse biological functions in plant disease resistance, abiotic stress responses, nutrient deprivation, senescence, seed and trichome development, embryogenesis, as well as additional developmental and hormone-controlled processes. WRKYs can act as transcriptional activators or repressors, in various homo- and heterodimer combinations. Here we review recent progress on the function of WRKY transcription factors in Arabidopsis and other plant species such as rice, potato, and parsley, with a special focus on abiotic, developmental, and hormone-regulated processes. PMID:24492469

  18. Factor D Enzyme

    NASA Technical Reports Server (NTRS)

    2004-01-01

    The trauma caused by the open heart surgery often triggers massive inflammation because the immune system overreacts. Factor D, the protein which plays a key role in the biological steps that activate this immune response prevents the imune system from inappropriately rurning out of control, allowing the patient to recover more rapidly. Factor D blockers, with their great potential to alleviate the complication of inflammation associated with heart surgery, are now being developed for clinical trials. These new drugs, developed from space research, should be commercially available as soon as year 2001.

  19. Anti-nutritional Factors.

    PubMed

    2016-01-01

    Anti-nutritional factors such as trypsin inhibitor, phytic acid and cyanogen are as important as nutritional content of any edible plant part. The anti-nutritional factors can be defined as those substances generated in natural food substances by the normal metabolism of species and by different mechanisms (e.g. inactivation of some nutrients, diminution of the digestive process or metabolic utilization of feed) which exert effects contrary to optimum nutrition. Hence, trypsin inhibitor, phytic acid and cyanogens present in edibles with the methods in the chapter would be helpful. PMID:26939264

  20. DRD2 A1 allele and P300 abnormalities in obesity

    SciTech Connect

    Blum, K. |; Wood, R.; Sheridan, L.P.J.

    1994-09-01

    Obesity is a heterogeneous and prevalent disorder having both inheritable and environmental components. The role of the dopamine system in P300 has been implicated. We genotyped 193 neuropsychiatrically ill patients with and without comorbid drug and alcohol/abuse/dependence and obesity for the prevalence of the A1 allele of the DRD2 gene. We found a significant linear trend ({chi}{sup 2} = 40.4, df=1, p<0.00001) where the percent prevalence of the A1 increased with increasing polysubstance abuse. Where the A1 allele was found in 44% of 40 obese subjects, the A1 allele prevalence was found in as much as 91% of 11 obese subjects with comorbid polysubstance abuse. 53 obese subjects having a mean body weight (BMI) of 34.6{+-}8.2 were mapped for brain electrical activity and compared with 15 controls with a BMI of 22.3{+-}3.0 (P<.001). The P3 amplitude was significantly different (two tailed; t=3.24, df=16.2, P = 0.005), whereas P3 latency was not significant. Preliminarily, we found a significant decreased P3 amplitude correlated with parental polysubstance abuse (p=0.4) with prolongation of P3 latency correlated with the three risk factors of parental substance abuse, chemical dependency and carbohydrate bingeing (P<0.02). Finally, in a small sample, the A1 allele was present in 25% of probands having 0 risk compared to 66% in those obese subjects with any risk. This work represents the first electrophysiological data to implicate P3 abnormalities in a subset of obesity and further confirms an association of the DRD2 gene and a electrophysiological marker previously indicated to have predictive value in vulnerability to addictive behaviors.

  1. TERRA, hnRNP A1, and DNA-PKcs Interactions at Human Telomeres

    PubMed Central

    Le, Phuong N.; Maranon, David G.; Altina, Noelia H.; Battaglia, Christine L. R.; Bailey, Susan M.

    2013-01-01

    Maintenance of telomeres, repetitive elements at eukaryotic chromosomal termini, and the end-capping structure and function they provide, are imperative for preserving genome integrity and stability. The discovery that telomeres are transcribed into telomere repeat containing RNA (TERRA) has revolutionized our view of this repetitive, rather unappreciated region of the genome. We have previously shown that the non-homologous end-joining, shelterin associated DNA dependent protein kinase catalytic subunit (DNA-PKcs) participates in mammalian telomeric end-capping, exclusively at telomeres created by leading-strand synthesis. Here, we explore potential roles of DNA-PKcs and its phosphorylation target heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) in the localization of TERRA at human telomeres. Evaluation of co-localized foci utilizing RNA-FISH and three-dimensional (3D) reconstruction strategies provided evidence that both inhibition of DNA-PKcs kinase activity and siRNA depletion of hnRNP A1 result in accumulation of TERRA at individual telomeres; depletion of hnRNP A1 also resulted in increased frequencies of fragile telomeres. These observations are consistent with previous demonstrations that decreased levels of the nonsense RNA-mediated decay factors SMG1 and UPF1 increase TERRA at telomeres and interfere with replication of leading-strand telomeres. We propose that hTR mediated stimulation of DNA-PKcs and subsequent phosphorylation of hnRNP A1 influences the cell cycle dependent distribution of TERRA at telomeres by contributing to the removal of TERRA from telomeres, an action important for progression of S-phase, and thereby facilitating efficient telomere replication and end-capping. PMID:23616949

  2. Effects of Sleep Disorders on Hemoglobin A1c Levels in Type 2 Diabetic Patients

    PubMed Central

    Keskin, Ahmet; Ünalacak, Murat; Bilge, Uğur; Yildiz, Pinar; Güler, Seda; Selçuk, Engin Burak; Bilgin, Muzaffer

    2015-01-01

    Background: Studies have reported the presence of sleep disorders in approximately 50–70% of diabetic patients, and these may contribute to poor glycemic control, diabetic neuropathy, and overnight hypoglycemia. The aim of this study was to determine the frequency of sleep disorders in diabetic patients, and to investigate possible relationships between scores of these sleep disorders and obstructive sleep apnea syndrome (OSAS) and diabetic parameters (fasting blood glucose, glycated hemoglobin A1c [HbA1c], and lipid levels). Methods: We used the Berlin questionnaire (BQ) for OSAS, the Epworth Sleepiness Scale (ESS), and the Pittsburgh Sleep Quality Index (PSQI) to determine the frequency of sleep disorders and their possible relationships with fasting blood glucose, HbA1c, and lipid levels. Results: The study included 585 type 2 diabetic patients admitted to family medicine clinics between October and December 2014. Sleep, sleep quality, and sleep scores were used as the dependent variables in the analysis. The ESS scores showed that 54.40% of patients experienced excessive daytime sleepiness, and according to the PSQI, 64.30% experienced poor-quality sleep. The BQ results indicated that 50.20% of patients were at high-risk of OSAS. HbA1c levels correlated significantly with the ESS and PSQI results (r = 0.23, P < 0.001 and r = 0.14, P = 0.001, respectively), and were significantly higher in those with high-risk of OSAS as defined by the BQ (P < 0.001). These results showed that HbA1c levels were related to sleep disorders. Conclusions: Sleep disorders are common in diabetic patients and negatively affect the control of diabetes. Conversely, poor diabetes control is an important factor disturbing sleep quality. Addressing sleep disturbances in patients who have difficulty controlling their blood glucose has dual benefits: Preventing diabetic complications caused by sleep disturbance and improving diabetes control. PMID:26668142

  3. SPICE macromodel for a 1-megawatt power MOSFET switch

    SciTech Connect

    Helms, C.; Ackermann, M.; Fischer, T.; Deveney, M.

    1993-08-01

    This paper presents a SPICE macromodel for a 1-megawatt high power electrical switch which uses power MOSFETs as the active switching elements. The model accurately predicts the time dependent switching current and provides a reasonable representation of the time dependent switch resistance and voltage drop across the switch. Techniques for extracting model parameters for commercial power MOSFETs are discussed along with suggestions for extending the model to spark gaps and other high power switches.

  4. The Allosteric Binding Sites of Sulfotransferase 1A1

    PubMed Central

    Cook, Ian; Wang, Ting; Falany, Charles N.

    2015-01-01

    Human sulfotransferases (SULTs) comprise a small, 13-member enzyme family that regulates the activities of thousands of compounds—endogenous metabolites, drugs, and other xenobiotics. SULTs transfer the sulfuryl-moiety (–SO3) from a nucleotide donor, PAPS (3′-phosphoadenosine 5′-phosphosulfate), to the hydroxyls and primary amines of acceptors. SULT1A1, a progenitor of the family, has evolved to sulfonate compounds that are remarkably structurally diverse. SULT1A1, which is found in many tissues, is the predominant SULT in liver, where it is a major component of phase II metabolism. Early work demonstrated that catechins and nonsteroidal anti-inflammatory drugs inhibit SULT1A1 and suggested that the inhibition was not competitive versus substrates. Here, the mechanism of inhibition of a single, high affinity representative from each class [epigallocatechin gallate (EGCG) and mefenamic acid] is determined using initial-rate and equilibrium-binding studies. The findings reveal that the inhibitors bind at sites separate from those of substrates, and at saturation turnover of the enzyme is reduced to a nonzero value. Further, the EGCG inhibition patterns suggest a molecular explanation for its isozyme specificity. Remarkably, the inhibitors bind at sites that are separate from one another, and binding at one site does not affect affinity at the other. For the first time, it is clear that SULT1A1 is allosterically regulated, and that it contains at least two, functionally distinct allosteric sites, each of which responds to a different class of compounds. PMID:25534770

  5. 26 CFR 31.6402(a)-1 - Credits or refunds.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 6402 of special application to credits or refunds of employment taxes, see §§ 31.6402(a)-2, 31.6402(a..., see §§ 301.6402-1 and 301.6402-2. For provisions relating to adjustments without interest of... income tax withholding, see §§ 31.6413(a)-1 and 31.6413(a)-2. (b) Period of limitation. For the period...

  6. Metabolism of prostaglandins A1 and E1 in man.

    PubMed Central

    Golub, M; Zia, P; Matsuno, M; Horton, R

    1975-01-01

    To investigate the in vivo whole blood metabolic clearance rates and sites of metabolism of prostaglandins A1 and E1 in man, constant infusions of the tritiated compounds were administered to normal subjects and to patients undergoing cardiac catheterization. The whole blood metabolic clearance rate of [3H]prostaglandin A1 in eight men was 5,003 +/- 864 liters/day (SD) or 2,546 +/- 513 liters/day per m2 (SD). Nonradioactive prostaglandin A1 was similarly infused in two subjects, and the metabolic clearance rates were determined, utilizing a specific radioimmunoassay. The clearance rates with this method correlated closely with those determined by the isotope infusions. Extraction studies of prostaglandin A1 showed that pulmonary, splanchnic, renal, and extremity perfusions resulted in 8.1 +/- 4.1, 56.1 +/- 10.1, 50.3 +/- 3.4, and 34.4 +/- 5.9% (SEM) removal, respectively. With [3H]=prostaglandin E1, the whole blood metabolic clearance rate was determined from the pulmonary artery concentration in three patients and averaged 4,832 +/- 1,518 liters/day (SD) or 2,686 +/- 654 liters/day per m2 (SD). Pulmonary extraction was 67.8 +/- 6.8% (SEM) and extremity removal averaged 6.6 +/- 4.9% (SEM). These results indicate that A prostaglandins are metabolized by several organs, such as the liver and kidney, and possibly by intravascular pathways as well. In man, the E prostaglandins are primarily metabolized by the lung, but extraction is not complete and approximately one-third may escape lung metabolism. Thus, these findings suggest that both E and A prostaglandins in the venous circulation may reach the systemic circulation in man. PMID:1202078

  7. C/2013 A1 (Siding Spring vs. Mars)

    NASA Technical Reports Server (NTRS)

    Moorhead, Althea; Cooke, William

    2013-01-01

    Comet C/2013 A1 (Siding Spring): recently discovered long period comet. Will have close encounter with Mars on October 19, 2014. Collision is extremely unlikely. Passing through the coma and/or tail is likely. Increases risk to Martian spacecraft. Meteoroids (100 microns or larger): approx. or <20% chance of impact per square meter due to coma and tail. Gas may also a ect Martian atmosphere.

  8. Structural and functional analysis of human HtrA3 protease and its subdomains

    SciTech Connect

    Glaza, Przemyslaw; Osipiuk, Jerzy; Wenta, Tomasz; Zurawa-Janicka, Dorota; Jarzab, Miroslaw; Lesner, Adam; Banecki, Bogdan; Skorko-Glonek, Joanna; Joachimiak, Andrzej; Lipinska, Barbara; van Raaij, Mark J.

    2015-06-25

    Human HtrA3 protease, which induces mitochondria-mediated apoptosis, can be a tumor suppressor and a potential therapeutic target in the treatment of cancer. However, there is little information about its structure and biochemical properties. HtrA3 is composed of an N-terminal domain not required for proteolytic activity, a central serine protease domain and a C-terminal PDZ domain. HtrA3S, its short natural isoform, lacks the PDZ domain which is substituted by a stretch of 7 C-terminal amino acid residues, unique for this isoform. This paper presents the crystal structure of the HtrA3 protease domain together with the PDZ domain (ΔN-HtrA3), showing that the protein forms a trimer whose protease domains are similar to those of human HtrA1 and HtrA2. The ΔN-HtrA3 PDZ domains are placed in a position intermediate between that in the flat saucer-like HtrA1 SAXS structure and the compact pyramidal HtrA2 X-ray structure. The PDZ domain interacts closely with the LB loop of the protease domain in a way not found in other human HtrAs. ΔN-HtrA3 with the PDZ removed (ΔN-HtrA3-ΔPDZ) and an N-terminally truncated HtrA3S (ΔN-HtrA3S) were fully active at a wide range of temperatures and their substrate affinity was not impaired. This indicates that the PDZ domain is dispensable for HtrA3 activity. As determined by size exclusion chromatography, ΔN-HtrA3 formed stable trimers while both ΔN-HtrA3-ΔPDZ and ΔN-HtrA3S were monomeric. This suggests that the presence of the PDZ domain, unlike in HtrA1 and HtrA2, influences HtrA3 trimer formation. The unique C-terminal sequence of ΔN-HtrA3S appeared to have little effect on activity and oligomerization. Additionally, we examined the cleavage specificity of ΔN-HtrA3. Results reported in this paper provide new insights into the structure and function of ΔN-HtrA3, which seems to have a unique combination of features among human HtrA proteases.

  9. Structural and functional analysis of human HtrA3 protease and its subdomains

    DOE PAGESBeta

    Glaza, Przemyslaw; Osipiuk, Jerzy; Wenta, Tomasz; Zurawa-Janicka, Dorota; Jarzab, Miroslaw; Lesner, Adam; Banecki, Bogdan; Skorko-Glonek, Joanna; Joachimiak, Andrzej; Lipinska, Barbara; et al

    2015-06-25

    Human HtrA3 protease, which induces mitochondria-mediated apoptosis, can be a tumor suppressor and a potential therapeutic target in the treatment of cancer. However, there is little information about its structure and biochemical properties. HtrA3 is composed of an N-terminal domain not required for proteolytic activity, a central serine protease domain and a C-terminal PDZ domain. HtrA3S, its short natural isoform, lacks the PDZ domain which is substituted by a stretch of 7 C-terminal amino acid residues, unique for this isoform. This paper presents the crystal structure of the HtrA3 protease domain together with the PDZ domain (ΔN-HtrA3), showing that themore » protein forms a trimer whose protease domains are similar to those of human HtrA1 and HtrA2. The ΔN-HtrA3 PDZ domains are placed in a position intermediate between that in the flat saucer-like HtrA1 SAXS structure and the compact pyramidal HtrA2 X-ray structure. The PDZ domain interacts closely with the LB loop of the protease domain in a way not found in other human HtrAs. ΔN-HtrA3 with the PDZ removed (ΔN-HtrA3-ΔPDZ) and an N-terminally truncated HtrA3S (ΔN-HtrA3S) were fully active at a wide range of temperatures and their substrate affinity was not impaired. This indicates that the PDZ domain is dispensable for HtrA3 activity. As determined by size exclusion chromatography, ΔN-HtrA3 formed stable trimers while both ΔN-HtrA3-ΔPDZ and ΔN-HtrA3S were monomeric. This suggests that the presence of the PDZ domain, unlike in HtrA1 and HtrA2, influences HtrA3 trimer formation. The unique C-terminal sequence of ΔN-HtrA3S appeared to have little effect on activity and oligomerization. Additionally, we examined the cleavage specificity of ΔN-HtrA3. Results reported in this paper provide new insights into the structure and function of ΔN-HtrA3, which seems to have a unique combination of features among human HtrA proteases.« less

  10. Structural and Functional Analysis of Human HtrA3 Protease and Its Subdomains

    PubMed Central

    Glaza, Przemyslaw; Osipiuk, Jerzy; Wenta, Tomasz; Zurawa-Janicka, Dorota; Jarzab, Miroslaw; Lesner, Adam; Banecki, Bogdan; Skorko-Glonek, Joanna; Joachimiak, Andrzej; Lipinska, Barbara

    2015-01-01

    Human HtrA3 protease, which induces mitochondria-mediated apoptosis, can be a tumor suppressor and a potential therapeutic target in the treatment of cancer. However, there is little information about its structure and biochemical properties. HtrA3 is composed of an N-terminal domain not required for proteolytic activity, a central serine protease domain and a C-terminal PDZ domain. HtrA3S, its short natural isoform, lacks the PDZ domain which is substituted by a stretch of 7 C-terminal amino acid residues, unique for this isoform. This paper presents the crystal structure of the HtrA3 protease domain together with the PDZ domain (ΔN-HtrA3), showing that the protein forms a trimer whose protease domains are similar to those of human HtrA1 and HtrA2. The ΔN-HtrA3 PDZ domains are placed in a position intermediate between that in the flat saucer-like HtrA1 SAXS structure and the compact pyramidal HtrA2 X-ray structure. The PDZ domain interacts closely with the LB loop of the protease domain in a way not found in other human HtrAs. ΔN-HtrA3 with the PDZ removed (ΔN-HtrA3-ΔPDZ) and an N-terminally truncated HtrA3S (ΔN-HtrA3S) were fully active at a wide range of temperatures and their substrate affinity was not impaired. This indicates that the PDZ domain is dispensable for HtrA3 activity. As determined by size exclusion chromatography, ΔN-HtrA3 formed stable trimers while both ΔN-HtrA3-ΔPDZ and ΔN-HtrA3S were monomeric. This suggests that the presence of the PDZ domain, unlike in HtrA1 and HtrA2, influences HtrA3 trimer formation. The unique C-terminal sequence of ΔN-HtrA3S appeared to have little effect on activity and oligomerization. Additionally, we examined the cleavage specificity of ΔN-HtrA3. Results reported in this paper provide new insights into the structure and function of ΔN-HtrA3, which seems to have a unique combination of features among human HtrA proteases. PMID:26110759

  11. The A1Σu+ system of Mg2

    NASA Astrophysics Data System (ADS)

    Knöckel, Horst; Rühmann, Steffen; Tiemann, Eberhard

    2014-10-01

    The A1Σu+-X1Σg+ UV spectrum of Mg2 has been investigated with high resolution employing Fourier-transform spectroscopy and laser excitation. Computer simulation and fit of line positions to the overlapping structures in the spectra yield precise transition frequencies. Starting with the well characterized ground state X1Σg+ from former work, we derived excited energy levels and report on the evaluation of the A1Σu+ excited state, which is found to interact with another electronic state, which we identify as the lower part of the (1)1Πu state. A coupled channels fit to the level energies of the upper state yields a reliable potential energy curve for the A1Σu+ state for the range of vibrational levels 1 ≤ v' ≤ 46. A potential energy curve for the (1)1Πu state is proposed, but the (1)1Πu state is only characterized by its coupling to the A state, and no direct transition to a level of the (1)1Πu state could be uniquely identified due to the overlapping spectral structures. Supplementary material in the form of one dat file available from the Journal web page at http://dx.doi.org/10.1140/epjd/e2014-50289-9

  12. Mutations in COL1A1 Gene Change Dentin Nanostructure.

    PubMed

    Duan, Xiaohong; Liu, Zhenxia; Gan, Yunna; Xia, Dan; Li, Qiang; Li, Yanling; Yang, Jiaji; Gao, Shan; Dong, Mingdong

    2016-04-01

    Although many studies have attempted to associate specific gene mutations with dentin phenotypic severity, it remains unknown how the mutations in COL1A1 gene influence the mechanical behavior of dentin collagen and matrix. Here, we reported one osteogenesis imperfecta (OI) pedigree caused by two new inserting mutations in exon 5 of COL1A1 (NM_000088.3:c.440_441insT;c.441_442insA), which resulted in the unstable expression of COL1A1 mRNA and half quantity of procollagen production. We investigated the morphological and mechanical features of proband's dentin using atomic force microscope (AFM), scanning electron microscope, and transmission electron microscope. Increased D-periodic spacing, variably enlarged collagen fibrils coating with fewer minerals were found in the mutated collagen. AFM analysis demonstrated rougher dentin surface and sparsely decreased Young's modulus in proband's dentin. We believe that our findings provide new insights into the genetic-/nano- mechanisms of dentin diseases, and may well explain OI dentin features with reduced mechanical strength and a lower crosslinked density. Anat Rec, 299:511-519, 2016. © 2015 Wiley Periodicals, Inc. PMID:26694865

  13. Factor Analysis and Counseling Research

    ERIC Educational Resources Information Center

    Weiss, David J.

    1970-01-01

    Topics discussed include factor analysis versus cluster analysis, analysis of Q correlation matrices, ipsativity and factor analysis, and tests for the significance of a correlation matrix prior to application of factor analytic techniques. Techniques for factor extraction discussed include principal components, canonical factor analysis, alpha…

  14. Peptide growth factors, part A

    SciTech Connect

    Barnes, D.; Sirbasku, D.A.

    1987-01-01

    This book contains information on the following topics: Epidermal Growth Factor;Transforming Growth Factors;Bone and Cartilage Growth Factors;Somatomedin/Insulin-Like Growth Factors;Techniques for the Study of Growth Factor Activity;Assays, Phosphorylation, and Surface Membrane Effects.

  15. Radiation View Factor With Shadowing

    Energy Science and Technology Software Center (ESTSC)

    1992-02-24

    FACET calculates the radiation geometric view factor (alternatively called shape factor, angle factor, or configuration factor) between surfaces for axisymmetric, two-dimensional planar and three-dimensional geometries with interposed third surface obstructions. FACET was developed to calculate view factors as input data to finite element heat transfer analysis codes.

  16. Introduction to human factors

    SciTech Connect

    Winters, J.M.

    1988-03-01

    Some background is given on the field of human factors. The nature of problems with current human/computer interfaces is discussed, some costs are identified, ideal attributes of graceful system interfaces are outlined, and some reasons are indicated why it's not easy to fix the problems. (LEW)

  17. Robust Bayesian Factor Analysis

    ERIC Educational Resources Information Center

    Hayashi, Kentaro; Yuan, Ke-Hai

    2003-01-01

    Bayesian factor analysis (BFA) assumes the normal distribution of the current sample conditional on the parameters. Practical data in social and behavioral sciences typically have significant skewness and kurtosis. If the normality assumption is not attainable, the posterior analysis will be inaccurate, although the BFA depends less on the current…

  18. Factors Predicting Educational Productivity.

    ERIC Educational Resources Information Center

    Hanes, Carol E.; Jordan, K. Forbis

    Since 1968 educational productivity studies at the University of Florida have been analyzing data from six States and one city. Linear regression was used to identify high and low productive units by measuring the relationship between statistically selected input factors and a measure of student achievement. Discriminant analysis was employed to…

  19. Teleoperator human factors study

    NASA Technical Reports Server (NTRS)

    Bradford, K. Z.; Schappell, R. T.

    1985-01-01

    The progress made on the Teleoperator Human Factors Study program during the period of September 7, 1985 to October 6, 1985 is discussed. Technical and programmatic problems that were encountered are discussed along with activity planned for the following month. The main portion of the report has been separated into four sections: Work Performed, Future Work, Problems Encountered, and Cost Information.

  20. ERYTHROPOIETIC FACTOR PURIFICATION

    DOEpatents

    White, W.F.; Schlueter, R.J.

    1962-05-01

    A method is given for purifying and concentrating the blood plasma erythropoietic factor. Anemic sheep plasma is contacted three times successively with ion exchange resins: an anion exchange resin, a cation exchange resin at a pH of about 5, and a cation exchange resin at a pH of about 6. (AEC)

  1. The Three Faith Factors.

    ERIC Educational Resources Information Center

    DiIulio, John J., Jr.

    2002-01-01

    Discusses whether religion can affect health and social welfare and what types of religious influences are most beneficial to the individual and society, identifying three separate but related faith factors: organic religion, programmatic religion, and ecological religion. Examines research on faith-based approaches to social and urban problems.

  2. Factorization and Quarkonium Production

    SciTech Connect

    Kang, Z.B.; Qiu, J.W.; Sterman, G.

    2011-05-01

    It is possible to extend the formalism for high-pT heavy quarkonium factorization beyond leading power. This extension may be helpful in interpreting the relative roles of octet and singlet channels in the formalism of nonrelativistic QCD (NRQCD). It may enable us to understand the origin of the surprisingly large results for cross sections calculated in the color singlet sector of NRQCD.

  3. Assessment of Human Factors

    NASA Technical Reports Server (NTRS)

    Mount, Frances; Foley, Tico

    1999-01-01

    Human Factors Engineering, often referred to as Ergonomics, is a science that applies a detailed understanding of human characteristics, capabilities, and limitations to the design, evaluation, and operation of environments, tools, and systems for work and daily living. Human Factors is the investigation, design, and evaluation of equipment, techniques, procedures, facilities, and human interfaces, and encompasses all aspects of human activity from manual labor to mental processing and leisure time enjoyments. In spaceflight applications, human factors engineering seeks to: (1) ensure that a task can be accomplished, (2) maintain productivity during spaceflight, and (3) ensure the habitability of the pressurized living areas. DSO 904 served as a vehicle for the verification and elucidation of human factors principles and tools in the microgravity environment. Over six flights, twelve topics were investigated. This study documented the strengths and limitations of human operators in a complex, multifaceted, and unique environment. By focusing on the man-machine interface in space flight activities, it was determined which designs allow astronauts to be optimally productive during valuable and costly space flights. Among the most promising areas of inquiry were procedures, tools, habitat, environmental conditions, tasking, work load, flexibility, and individual control over work.

  4. Nucleon Form Factors

    SciTech Connect

    Kees de Jager

    2002-10-01

    A review of data on the nucleon electro-weak form factors in the space-like region is presented. Recent results from experiments using polarized beams and either polarized targets or nucleon recoil polarimeters have yielded a significant improvement on the precision of the electromagnetic data obtained with the traditional Rosenbluth separation. An outlook is presented of planned experiments.

  5. Inelastic Scattering Form Factors

    Energy Science and Technology Software Center (ESTSC)

    1992-01-01

    ATHENA-IV computes form factors for inelastic scattering calculations, using single-particle wave functions that are eigenstates of motion in either a Woods-Saxon potential well or a harmonic oscillator well. Two-body forces of Gauss, Coulomb, Yukawa, and a sum of cut-off Yukawa radial dependences are available.

  6. CYP24A1 Inhibition Enhances the Antitumor Activity of Calcitriol

    PubMed Central

    Muindi, Josephia R.; Yu, Wei-Dong; Ma, Yingyu; Engler, Kristie L.; Kong, Rui-Xian; Trump, Donald L.; Johnson, Candace S.

    2010-01-01

    High systemic exposures to calcitriol are necessary for optimal antitumor effects. Human prostate cancer PC3 cells are insensitive to calcitriol treatment. Therefore, we investigated whether the inhibition of 24-hydroxylase (CYP24A1), the major calcitriol inactivating enzyme, by ketoconazole (KTZ) or RC2204 modulates calcitriol serum pharmacokinetics and biologic effects. Dexamethasone (Dex) was added to minimize calcitriol-induced hypercalcemia and as a steroid replacement for the KTZ inhibition of steroid biosynthesis cytochrome P450 enzymes. KTZ effectively inhibited time-dependent calcitriol-inducible CYP24A1 protein expression and enzyme activity in PC3 cells and C3H/HeJ mouse kidney tissues. Systemic calcitriol exposure area under the curve was higher in mice treated with a combination of calcitriol and KTZ than with calcitriol alone. KTZ and Dex synergistically potentiated calcitriol-mediated antiproliferative effects in PC3 cells in vitro; this effect was associated with enhanced apoptosis. After treatment with calcitriol and KTZ/Dex, although caspase-9 and caspase-3 were not activated and cytochrome c was not released by mitochondria, caspase-8 was activated and the truncated Bid protein level was increased. Translocation of apoptosis-inducing factor to the nucleus was observed, indicating a role of the apoptosis-inducing factor-mediated and caspase-independent apoptotic pathways. Calcitriol and KTZ/Dex combination suppressed the clonogenic survival and enhanced the growth inhibition observed with calcitriol alone in PC3 human prostate cancer xenograft mouse model. Our results show that the administration of calcitriol in combination with CYP24A1 inhibitor enhances antiproliferative effects, increases systemic calcitriol exposure, and promotes the activation of caspase-independent apoptosis pathway. PMID:20591973

  7. Wound healing genes and susceptibility to cutaneous leishmaniasis in Brazil: Role of COL1A1

    PubMed Central

    Almeida, Lucas; Oliveira, Joyce; Guimarães, Luiz Henrique; Carvalho, Edgar M; Blackwell, Jenefer M

    2015-01-01

    Previous studies have demonstrated a role for wound healing genes in resolution of cutaneous lesions caused by Leishmania spp. in both mice and humans, including the gene FLI1 encoding Friend leukaemia virus integration 1. Reduction of Fli1 expression in mice has been shown to result in up-regulation of collagen type I alpha 1 (Col1a1) and alpha 2 (Col1a2) genes and, conversely, in down-regulation of the matrix metalloproteinase 1 (Mmp1) gene, suggesting that Fli1 suppression is involved in activation of the profibrotic gene program. Here we examined single nucleotide polymorphisms (SNPs) in these genes as risk factors for cutaneous (CL) and mucosal leishmaniasis (ML), and leishmaniasis per se, caused by L. braziliensis in humans. SNPs were genotyped in 168 nuclear families (250 CL; 87 ML cases) and replicated in 157 families (402 CL; 39 ML cases). Family-based association tests (FBAT) showed the strongest association between SNPs rs1061237 (combined P=0.002) and rs2586488 (combined P=0.027) at COL1A1 and CL disease. This contributes to our further understanding of the role of wound healing in the resolution of CL disease, providing potential for therapies modulating COL1A1 via drugs acting on FLI1. PMID:25562121

  8. Association between UGT1A1 Polymorphism and Risk of Laryngeal Squamous Cell Carcinoma

    PubMed Central

    Huangfu, Hui; Pan, Hong; Wang, Binquan; Wen, Shuxin; Han, Rui; Li, Li

    2016-01-01

    Laryngeal cancer is one of the largest subgroups of head and neck cancers. In addition to smoking and alcohol consumption, genetic polymorphisms are also risk factors for the development of laryngeal cancer. However, the exact relation between genetic variants and pathogenesis of laryngeal cancer has remained elusive. The aim of this study was to examine UGT1A1*6 (rs4148323 A/G) polymorphisms in 103 patients with laryngeal cancer and 220 controls using the high resolution melting curve (HRM) technique and to explore the association between UGT1A1*6 (rs4148323 A/G) polymorphisms and laryngeal cancer. The results showed an association between the rs4148323 G allele and increased risk of laryngeal cancer. While there was no statistically significant difference between rs4148323 genotype frequencies and different histological grades or different clinical stages of laryngeal cancer, stratification analysis indicated smoking or alcohol consumption and rs4148323 G allele combined to increase the risk of laryngeal cancer. In conclusion, the rs4148323 G allele is associated with the high UGT1A1 enzyme activity, and might increase the risk of laryngeal cancer. Furthermore, smoking or alcohol consumption and the rs4148323 G allele act synergistically to increase the risk of laryngeal cancer. PMID:26751466

  9. Signal integration by the CYP1A1 promoter--a quantitative study.

    PubMed

    Schulthess, Pascal; Löffler, Alexandra; Vetter, Silvia; Kreft, Luisa; Schwarz, Michael; Braeuning, Albert; Blüthgen, Nils

    2015-06-23

    Genes involved in detoxification of foreign compounds exhibit complex spatiotemporal expression patterns in liver. Cytochrome P450 1A1 (CYP1A1), for example, is restricted to the pericentral region of liver lobules in response to the interplay between aryl hydrocarbon receptor (AhR) and Wnt/β-catenin signaling pathways. However, the mechanisms by which the two pathways orchestrate gene expression are still poorly understood. With the help of 29 mutant constructs of the human CYP1A1 promoter and a mathematical model that combines Wnt/β-catenin and AhR signaling with the statistical mechanics of the promoter, we systematically quantified the regulatory influence of different transcription factor binding sites on gene induction within the promoter. The model unveils how different binding sites cooperate and how they establish the promoter logic; it quantitatively predicts two-dimensional stimulus-response curves. Furthermore, it shows that crosstalk between Wnt/β-catenin and AhR signaling is crucial to understand the complex zonated expression patterns found in liver lobules. This study exemplifies how statistical mechanical modeling together with combinatorial reporter assays has the capacity to disentangle the promoter logic that establishes physiological gene expression patterns. PMID:25934798

  10. Trajectory analysis for the nucleus and dust of comet C/2013 A1 (Siding Spring)

    SciTech Connect

    Farnocchia, Davide; Chesley, Steven R.; Chodas, Paul W.; Tricarico, Pasquale; Kelley, Michael S. P.; Farnham, Tony L.

    2014-08-01

    Comet C/2013 A1 (Siding Spring) will experience a high velocity encounter with Mars on 2014 October 19 at a distance of 135,000 km ± 5000 km from the planet center. We present a comprehensive analysis of the trajectory of both the comet nucleus and the dust tail. The nucleus of C/2013 A1 cannot impact on Mars even in the case of unexpectedly large nongravitational perturbations. Furthermore, we compute the required ejection velocities for the dust grains of the tail to reach Mars as a function of particle radius and density and heliocentric distance of the ejection. A comparison between our results and the most current modeling of the ejection velocities suggests that impacts are possible only for millimeter to centimeter size particles released more than 13 AU from the Sun. However, this level of cometary activity that far from the Sun is considered extremely unlikely. The arrival time of these particles spans a 20-minute time interval centered at 2014 October 19 at 20:09 TDB, i.e., around the time that Mars crosses the orbital plane of C/2013 A1. Ejection velocities larger than currently estimated by a factor >2 would allow impacts for smaller particles ejected as close as 3 AU from the Sun. These particles would reach Mars from 19:13 TDB to 20:40 TDB.

  11. The stressor Criterion-A1 and PTSD: a matter of opinion?

    PubMed

    Van Hooff, Miranda; McFarlane, Alexander C; Baur, Jenelle; Abraham, Maria; Barnes, Daniel J

    2009-01-01

    Considerable controversy exists with regard to the interpretation and definition of the stressor "A1" criterion for Post Traumatic Stress Disorder (PTSD). At present, classifying an event as either traumatic (satisfying DSM-IV Criterion-A1 for PTSD), or non-traumatic (life event) is determined by the rater's subjective interpretation of the diagnostic criteria. This has implications in research and clinical practice. Utilizing a sample of 860 Australian adults, this study is the first to provide a detailed examination of the impact of event categorization on the prevalence of trauma and PTSD. Overall, events classified as non-traumatic were associated with higher rates of PTSD. Unanimous agreement between raters occurred for 683 (79.4%) events. As predicted, the categorization method employed (single rater, multiple rater-majority, multiple rater-unanimous) substantially altered the prevalence of Criterion-A1 events and PTSD, raising doubts about the functionality of PTSD diagnostic criteria. Factors impacting on the categorization process and suggestions for minimizing discrepancies in future research are discussed. PMID:18511232

  12. Peptide growth factors, part B

    SciTech Connect

    Barnes, D.; Sirbasku, D.A.

    1987-01-01

    This book discusses the following topics: Platelet-Derived Growth Factor;Nerve and Glial Growth Factors;PC12 Pheochromocytoma Cells;Techniques for the Study of Growth Factor Activity;Genetic Approaches and Biological Effects.

  13. Association of CYP8A1 (Prostacyclin I2 synthase) polymorphism rs5602 with breast cancer in Mexican woman

    PubMed Central

    Beltran-Sarmiento, Eduardo; Floriano-Sánchez, Esaú; Bandala, Cindy; Lara-Padilla, Eleazar; Cárdenas-Rodríguez, Noemí

    2016-01-01

    Breast cancer (BCa) is the most common cancer in Mexican women. Certain risk factors, such as environmental and lifestyle factors have been implicated in BCa initiation and progression. Moreover, genetic factors, such as single nucleotide polymorphisms (SNPs) of the P450 system, have been reported in BCa. In this report, and for the first time in the literature, we analyzed the rs5602 (67730 T > C) polymorphism in the CYP8A1 in patients with BCa and in healthy Mexican women to identify a potential risk between this polymorphism and BCa. Leukocyte cells from 38 control patients and tissue from radical mastectomy surgeries in 64 BCa patients were used for polymorphism analysis using an allelic discrimination assay with TaqMan probes. Links with clinic-pathological characteristics were also analyzed. Statistical analysis was performed using the standard χ2 or Fisher exact test statistic. All CYP8A1 genotypes were detected in patients with BCa and the controls. Significant differences were observed in the distribution of CYP8A1 genotypes between the patients and controls (P=0.0008) and allele C was significantly associated with BCa risk (OR 2.08, 95% CI 1.166-3.72, P=0.0178). All polymorphism frequencies were in Hardy-Weinberg Equilibrium (HWE) in the controls (P > 0.05). We found that variant 67730 T > C was significantly associated with an increased risk of BCa (P < 0.05). We not observed an association of the TT and TC + CC genotypes with the clinical stage, BIRADS, estrogen receptor (ER) status, progesterone receptor (PR) status, HER2 status, p53 status, CD34 status, metastasis or therapy use. These results indicate that the CYP8A1 rs5602 SNP is a possible risk factor for BCa in Mexican women. This study showed an association between the CYP8A1 polymorphism and BCa risk in a Mexican population. PMID:27186408

  14. Galactose-Deficient IgA1 in African Americans with IgA Nephropathy: Serum Levels and Heritability

    PubMed Central

    Hastings, M. Colleen; Moldoveanu, Zina; Julian, Bruce A.; Novak, Jan; Sanders, John T.; McGlothan, Kim R.; Gharavi, Ali G.

    2010-01-01

    Background and objectives: Serum levels of galactose-deficient IgA1 (Gd-IgA1) are elevated and heritable in Caucasian and Asian patients with IgA nephropathy (IgAN), but have not been characterized in African Americans (AA). Our objective was to determine whether serum Gd-IgA1 levels are increased in AA patients with IgAN and whether this is a heritable trait in this group. Design, setting, participants, & measurements: Blood and urine samples were obtained from 18 adult and 11 pediatric AA patients with biopsy-proven IgAN and from 34 of their first-degree relatives. Healthy controls included 150 Caucasian adults, 65 AA adults, 45 Caucasian children, and 49 AA children. Serum total IgA and Gd-IgA1 levels were measured in patients and controls. Significant differences between patient and control groups for serum total IgA, Gd-IgA1, and ratio of Gd-IgA1/total IgA were determined by the Mann-Whitney U test. Heritability was calculated using SOLAR. Results: After stratifying by age, 7 of 11 pediatric and 9 of 18 adult AA patients with IgAN had serum Gd-IgA1 levels above the 95th percentile for age-appropriate AA controls. For first-degree relatives, the serum Gd-IgA1 level was >95th percentile for 1 of 8 when the patient's level was <95th percentile and 12 of 26 when the patient's level was >95th percentile (P = 0.116, Fisher exact test). Heritability was 0.74 (P = 0.007). Conclusions: Serum levels of Gd-IgA1 are often elevated in AA patients with IgAN and their first-degree relatives. Thus, aberrant IgA1 glycosylation is a heritable risk factor for IgAN in African Americans. PMID:20634323

  15. Characteristics Associated With Maintenance of Mean A1C <6.5% in People With Dysglycemia in the ORIGIN Trial

    PubMed Central

    2013-01-01

    OBJECTIVE To assess the success and baseline predictors of maintaining glycemic control for up to 5 years of therapy using basal insulin glargine or standard glycemic care in people with dysglycemia treated with zero or one oral glucose-lowering agents. RESEARCH DESIGN AND METHODS Data from 12,537 participants in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were examined by baseline glycemic status (with or without type 2 diabetes) and by therapeutic approach (titrated insulin glargine or standard therapy) using an intention-to-treat analysis. Median values for fasting plasma glucose (FPG) and A1C and percentages with A1C <6.5% (48 mmol/mol) during randomized treatment were calculated. Factors independently associated with maintaining updated mean A1C <6.5% were analyzed with linear regression models. RESULTS Median A1C in the whole population was 6.4% at baseline; at 5 years, it was 6.2% with glargine treatment and 6.5% with standard care. Of those with diabetes at baseline, 60% using glargine and 45% using standard care had A1C <6.5% at 5 years. Lack of diabetes and lower baseline A1C were independently associated with 5-year mean A1C <6.5%. Maintaining mean A1C <6.5% was more likely with glargine (odds ratio [OR] 2.98 [95% CI 2.67–3.32], P < 0.001) than standard care after adjustment for other independent predictors. CONCLUSIONS Systematic intervention with basal insulin glargine or standard care early in the natural history of dysglycemia can maintain glycemic control near baseline levels for at least 5 years, whether diabetes is present at baseline or not. Keeping mean A1C <6.5% is more likely in people with lower baseline A1C and with the glargine-based regimen. PMID:23656980

  16. A rapid and efficient newly established method to detect COL1A1-PDGFB gene fusion in dermatofibrosarcoma protuberans

    SciTech Connect

    Yokoyama, Yoko; Shimizu, Akira; Okada, Etsuko; Ishikawa, Osamu; Motegi, Sei-ichiro

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer We developed new method to rapidly identify COL1A1-PDGFB fusion in DFSP. Black-Right-Pointing-Pointer New PCR method using a single primer pair detected COL1A1-PDGFB fusion in DFSP. Black-Right-Pointing-Pointer This is the first report of DFSP with a novel COL1A1 breakpoint in exon 5. -- Abstract: The detection of fusion transcripts of the collagen type 1{alpha}1 (COL1A1) and platelet-derived growth factor-BB (PDGFB) genes by genetic analysis has recognized as a reliable and valuable molecular tool for the diagnosis of dermatofibrosarcoma protuberans (DFSP). To detect the COL1A1-PDGFB fusion, almost previous reports performed reverse transcription polymerase chain reaction (RT-PCR) using multiplex forward primers from COL1A1. However, it has possible technical difficulties with respect to the handling of multiple primers and reagents in the procedure. The objective of this study is to establish a rapid, easy, and efficient one-step method of PCR using only a single primer pair to detect the fusion transcripts of the COL1A1 and PDGFB in DFSP. To validate new method, we compared the results of RT-PCR in five patients of DFSP between the previous method using multiplex primers and our established one-step RT-PCR using a single primer pair. In all cases of DFSP, the COL1A1-PDGFB fusion was detected by both previous method and newly established one-step PCR. Importantly, we detected a novel COL1A1 breakpoint in exon 5. The newly developed method is valuable to rapidly identify COL1A1-PDGFB fusion transcripts in DFSP.

  17. Bafilomycin A1 targets both autophagy and apoptosis pathways in pediatric B-cell acute lymphoblastic leukemia.

    PubMed

    Yuan, Na; Song, Lin; Zhang, Suping; Lin, Weiwei; Cao, Yan; Xu, Fei; Fang, Yixuan; Wang, Zhen; Zhang, Han; Li, Xin; Wang, Zhijian; Cai, Jinyang; Wang, Jian; Zhang, Yi; Mao, Xinliang; Zhao, Wenli; Hu, Shaoyan; Chen, Suning; Wang, Jianrong

    2015-03-01

    B-cell acute lymphoblastic leukemia is the most common type of pediatric leukemia. Despite improved remission rates, current treatment regimens for pediatric B-cell acute lymphoblastic leukemia are often associated with adverse effects and central nervous system relapse, necessitating more effective and safer agents. Bafilomycin A1 is an inhibitor of vacuolar H(+)-ATPase that is frequently used at high concentration to block late-phase autophagy. Here, we show that bafilomycin A1 at a low concentration (1 nM) effectively and specifically inhibited and killed pediatric B-cell acute lymphoblastic leukemia cells. It targeted both early and late stages of the autophagy pathway by activating mammalian target of rapamycin signaling and by disassociating the Beclin 1-Vps34 complex, as well as by inhibiting the formation of autolysosomes, all of which attenuated functional autophagy. Bafilomycin A1 also targeted mitochondria and induced caspase-independent apoptosis by inducing the translocation of apoptosis-inducing factor from mitochondria to the nucleus. Moreover, bafilomycin A1 induced the binding of Beclin 1 to Bcl-2, which further inhibited autophagy and promoted apoptotic cell death. In primary cells from pediatric patients with B-cell acute lymphoblastic leukemia and a xenograft model, bafilomycin A1 specifically targeted leukemia cells while sparing normal cells. An in vivo mouse toxicity assay confirmed that bafilomycin A1 is safe. Our data thus suggest that bafilomycin A1 is a promising candidate drug for the treatment of pediatric B-cell acute lymphoblastic leukemia. PMID:25512644

  18. Correlation of dysfunction of nonmuscle myosin IIA with increased induction of Cyp1a1 in Hepa-1 cells.

    PubMed

    Ebina, Masayuki; Shibazaki, Masahiko; Kudo, Kyoko; Kasai, Shuya; Kikuchi, Hideaki

    2011-03-01

    The aryl hydrocarbon receptor (AhR) is one of the best known ligand-activated transcription factors and it induces Cyp1a1 transcription by binding with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Recent focus has been on the relationship of AhR with signaling pathways that modulate cell shape and migration. In nonmuscle cells, nonmuscle myosin II is one of the key determinants of cell morphology, but it has not been investigated whether its function is related to Cyp1a1 induction. In this study, we observed that (-)-blebbistatin, which is a specific inhibitor of nonmuscle myosin II, increased the level of CYP1A1-mRNA in Hepa-1 cells. Comparison of (-)-blebbistatin with (+)-blebbistatin, which is an inactive enantiomer, indicated that the increase of CYP1A1-mRNA was due to nonmuscle myosin II inhibition. Subsequent knockdown experiments observed that reduction of nonmuscle myosin IIA, which is only an isoform of nonmuscle myosin II expressed in Hepa-1 cells, was related to the enhancement of TCDD-dependent Cyp1a1 induction. Moreover, chromatin immunoprecipitation assay indicated that the increase of Cyp1a1 induction was the result of transcriptional activation due to increased binding of AhR and RNA polymerase II to the enhancer and proximal promoter regions of Cyp1a1, respectively. These findings provide a new insight into the correlation between the function of nonmuscle myosin II and gene induction. PMID:21216307

  19. Sulfotransferase 1A1 Substrate Selectivity: A Molecular Clamp Mechanism.

    PubMed

    Cook, Ian; Wang, Ting; Leyh, Thomas S

    2015-10-01

    The human cytosolic sulfotransferases (SULTs) regulate hundreds, perhaps thousands, of small molecule metabolites and xenobiotics via transfer of a sulfuryl moiety (-SO3) from PAPS (3'-phosphoadenosine 5'-phosphosulfate) to the hydroxyls and primary amines of the recipients. In liver, where it is abundant, SULT1A1 engages in modifying metabolites and neutralizing toxins. The specificity of 1A1 is the broadest of any SULT, and understanding its selectivity is fundamental to understanding its biology. Here, for the first time, we show that SULT1A1 substrates separate naturally into two classes: those whose affinities are either enhanced ?20-fold (positive synergy) or unaffected (neutral synergy) by the presence of a saturating nucleotide. kcat for the positive-synergy substrates is shown to be ?100-fold greater than that of neutral-synergy compounds; consequently, the catalytic efficiency (kcat/Km) is approximately 3 orders of magnitude greater for the positive-synergy species. All-atom dynamics modeling suggests a molecular mechanism for these observations in which the binding of only positive-synergy compounds causes two phenylalanine residues (F81 and 84) to reposition and "sandwich" the phenolic moiety of the substrates, thus enhancing substrate affinity and positioning the nucleophilic oxygen for attack. Molecular dynamics movies reveal that the neutral-synergy compounds "wander" about the active site, infrequently achieving a reactive position. In-depth analysis of select point mutants strongly supports the model and provides an intimate view of the interdependent catalytic functions of subsections of the active site. PMID:26340710

  20. Elbow joint luxation in a 1-month-old foal.

    PubMed

    Rubio-Martínez, L M; Vázquez, F J; Romero, A; Ormazábal, J R

    2008-01-01

    This paper reports on luxation of the elbow joint without concomitant fracture in a 1-month-old foal. Conservative treatment, with closed reduction and full-limb bandaging, including caudal and lateral splints, seemed successful initially, however, failed to provide enough stability and luxation recurred, and open reduction and surgical placement of prosthetic collateral ligaments was required. Luxation of the elbow joint should be considered when acute non-weight bearing forelimb lameness occurs associated with pain and swelling in the area of the elbow in young foals. Closed reduction failed to provide sufficient joint stability. PMID:18271829

  1. Structure of the BoNT/A1--receptor complex.

    PubMed

    Benoit, Roger M; Frey, Daniel; Wieser, Mara M; Thieltges, Katherine M; Jaussi, Rolf; Capitani, Guido; Kammerer, Richard A

    2015-12-01

    Botulinum neurotoxin A causes botulism but is also used for medical and cosmetic applications. A detailed molecular understanding of BoNT/A--host receptor interactions is therefore fundamental for improving current clinical applications and for developing new medical strategies targeting human disorders. Towards this end, we recently solved an X-ray crystal structure of BoNT/A1 in complex with its neuronal protein receptor SV2C. Based on our findings, we discuss the potential implications for BoNT/A function. PMID:26260692

  2. Superfluid Fermi Gas in a 1D Optical Lattice

    SciTech Connect

    Orso, G.; Shlyapnikov, G.V.

    2005-12-31

    We calculate the superfluid transition temperature for a two-component 3D Fermi gas in a 1D tight optical lattice and discuss a dimensional crossover from the 3D to quasi-2D regime. For the geometry of finite size discs in the 1D lattice, we find that even for a large number of atoms per disc the critical effective tunneling rate for a quantum transition to the Mott insulator state can be large compared to the loss rate caused by three-body recombination. This allows the observation of the Mott transition, in contrast to the case of Bose-condensed gases in the same geometry.

  3. Helicopter human factors

    NASA Technical Reports Server (NTRS)

    Hart, Sandra G.

    1988-01-01

    The state-of-the-art helicopter and its pilot are examined using the tools of human-factors analysis. The significant role of human error in helicopter accidents is discussed; the history of human-factors research on helicopters is briefly traced; the typical flight tasks are described; and the noise, vibration, and temperature conditions typical of modern military helicopters are characterized. Also considered are helicopter controls, cockpit instruments and displays, and the impact of cockpit design on pilot workload. Particular attention is given to possible advanced-technology improvements, such as control stabilization and augmentation, FBW and fly-by-light systems, multifunction displays, night-vision goggles, pilot night-vision systems, night-vision displays with superimposed symbols, target acquisition and designation systems, and aural displays. Diagrams, drawings, and photographs are provided.

  4. Factors regulating microglia activation

    PubMed Central

    Kierdorf, Katrin; Prinz, Marco

    2013-01-01

    Microglia are resident macrophages of the central nervous system (CNS) that display high functional similarities to other tissue macrophages. However, it is especially important to create and maintain an intact tissue homeostasis to support the neuronal cells, which are very sensitive even to minor changes in their environment. The transition from the “resting” but surveying microglial phenotype to an activated stage is tightly regulated by several intrinsic (e.g., Runx-1, Irf8, and Pu.1) and extrinsic factors (e.g., CD200, CX3CR1, and TREM2). Under physiological conditions, minor changes of those factors are sufficient to cause fatal dysregulation of microglial cell homeostasis and result in severe CNS pathologies. In this review, we discuss recent achievements that gave new insights into mechanisms that ensure microglia quiescence. PMID:23630462

  5. Human factors workplace considerations

    NASA Technical Reports Server (NTRS)

    Haines, Richard F.

    1988-01-01

    Computer workstations assume many different forms and play different functions today. In order for them to assume the effective interface role which they should play they must be properly designed to take into account the ubiguitous human factor. In addition, the entire workplace in which they are used should be properly configured so as to enhance the operational features of the individual workstation where possible. A number of general human factors workplace considerations are presented. This ongoing series of notes covers such topics as achieving comfort and good screen visibility, hardware issues (e.g., mouse maintenance), screen symbology features (e.g., labels, cursors, prompts), and various miscellaneous subjects. These notes are presented here in order to: (1) illustrate how one's workstation can be used to support telescience activities of many other people working within an organization, and (2) provide a single complete set of considerations for future reference.

  6. Risk Factors in Stroke

    PubMed Central

    Mustacchi, Piero

    1985-01-01

    In the United States, stroke accounts for 160,000 annual deaths; only 16% of the 1.8 million stroke survivors are fully independent. The incidence of stroke increases with age. Hemorrhagic strokes outnumber ischemic strokes before age 15. Japanese men in this country have a lower stroke mortality than their age peers in Japan. Excessive stroke mortality for US nonwhites may not be entirely due to the greater prevalence of hypertension among blacks. Hypertension emerges as the single most powerful and reversible risk factor in stroke and for survival after stroke. Impaired cardiac function is the second most important precursor of stroke. The recurrence of stroke in survivors is high. The frequency of completed stroke is high in persons with transient ischemic attacks, but not in those with asymptomatic carotid bruits. Other reversible risk factors are smoking, the use of oral contraceptives, alcoholic excess, a low level of physical activity, blood hyperviscosity and drug abuse. PMID:3898597

  7. Growth factors for nanobacteria

    NASA Astrophysics Data System (ADS)

    Ciftcioglu, Neva; Kajander, E. Olavi

    1999-12-01

    Nanobacteria are novel microorganisms recently isolated from fetal bovine serum and blood of cows and humans. These coccoid, gram negative bacteria in alpha-2 subgroup of Proteobacteria grow slowly under mammalian cell culture conditions but not in common media for microbes. Now we have found two different kinds of culture supplement preparations that improve their growth and make them culturable in the classical sense. These are supernatant fractions of conditioned media obtained from 1 - 3 months old nanobacteria cultures and from about a 2 weeks old Bacillus species culture. Both improved multiplication and particle yields and the latter increased their resistance to gentamicin. Nanobacteria cultured with any of the methods shared similar immunological property, structure and protein pattern. The growth supporting factors were heat-stabile and nondialyzable, and dialysis improved the growth promoting action. Nanobacteria formed stony colonies in a bacteriological medium supplemented with the growth factors. This is an implication that nanobacterial growth is influenced by pre-existing bacterial flora.

  8. Power Factor Controller

    NASA Technical Reports Server (NTRS)

    1997-01-01

    Frank Nola invented the Power Factor Controller (PFC) at Marshall Space Flight Center more than a decade ago. Nola came up with a way to curb power wastage in AC induction motors. The PFC matches voltage with the motor's actual need by continuously sensing shifts between voltage and current. When it senses a light load it cuts the voltage to the minimum needed. Potential energy savings range from 8 to 65 percent.

  9. Human Factors Review Plan

    SciTech Connect

    Paramore, B.; Peterson, L.R.

    1985-12-01

    ''Human Factors'' is concerned with the incorporation of human user considerations into a system in order to maximize human reliability and reduce errors. This Review Plan is intended to assist in the assessment of human factors conditions in existing DOE facilities. In addition to specifying assessment methodologies, the plan describes techniques for improving conditions which are found to not adequately support reliable human performance. The following topics are addressed: (1) selection of areas for review describes techniques for needs assessment to assist in selecting and prioritizing areas for review; (2) human factors engineering review is concerned with optimizing the interfaces between people and equipment and people and their work environment; (3) procedures review evaluates completeness and accuracy of procedures, as well as their usability and management; (4) organizational interface review is concerned with communication and coordination between all levels of an organization; and (5) training review evaluates training program criteria such as those involving: trainee selection, qualification of training staff, content and conduct of training, requalification training, and program management.

  10. CYP287A1 is a carotenoid 2-β-hydroxylase required for deinoxanthin biosynthesis in Deinococcus radiodurans R1.

    PubMed

    Zhou, Zhengfu; Zhang, Wei; Su, Shiyou; Chen, Ming; Lu, Wei; Lin, Min; Molnár, István; Xu, Yuquan

    2015-12-01

    The carotenoid deinoxanthin is a crucial resistance factor against various stresses in the radiation-resistant bacterium Deinococcus radiodurans. Disruption of the gene dr2473 encoding the cytochrome P450 CYP287A1 led to the accumulation of 2-deoxydeinoxanthin in D. radiodurans, demonstrating that CYP287A1 is a novel β-carotene 2-hydroxylase. The dr2473 knockout mutant was shown to be more sensitive to UV radiation and oxidative stress than the wild-type strain D. radiodurans R1, indicating that the C2 alcohol of deinoxanthin is important for antioxidant activity. PMID:26311221

  11. FACTORS INFLUENCING THE DESIGN OF BIOACCUMULATION FACTOR AND BIOTA-SEDIMENT ACCUMULATION FACTOR FIELD STUDIES

    EPA Science Inventory

    A series of modeling simulations were performed to develop an understanding of the underlying factors and principles involved in developing field sampling designs for measuring bioaccumulation factors (BAFs) and biota-sediment accumulation factors (BSAFs. These simulations reveal...

  12. Lessons Learned in Decommissioning of NPP A-1 After Accident

    SciTech Connect

    Prazska, M.; Rezbarik, J.; Majersky, D.; Sekely, S.; Solcanyi, S.

    2002-02-25

    Decommissioning of the NPP A-1 in Jaslovske Bohunice is encountered with great variation of the problems connected primarily with the high radiation fields and the high activity of the contaminated materials. Decontamination of the contaminated objects and the thorough radiological protection of decontamination workers are therefore the tasks of top priority. The successful realization of these jobs is based on the experience, good working practice and the utilization of all proven methods together with the newly developed ones. Since 1996, AllDeco Ltd. has applied the decontamination methods and processes in a wide scale in the decommissioning and dismantling of the NPP A-1 in the cooperation with SE-VYZ Inc. The monitoring of the radiation situation and the investigation of the type and character of the radioactive waste were first steps in the decontamination of all objects. For this works, remote controlled mechanical manipulators and remote controlled electrical carriage equipped with instruments recording the levels of dose rates and with telemetric data transmission system were used. The recorded data were used for the modeling and 3D visualization of the radiation fields and for following planning and preparation of the decontamination projects or ''working programs'' based on the ALARA principle. The minimization of the radioactive waste was also taken into consideration. A lot of time and energy was spent on the preparation and training of the staff including non-active trials of planned procedures. The gained experience was evaluated and lessons learned were given in the final reports.

  13. Concept of a (1-. cap alpha. ) performance confidence interval

    SciTech Connect

    Leong, H.H.; Johnson, G.R.; Bechtel, T.N.

    1980-01-01

    A multi-input, single-output system is assumed to be represented by some model. The distribution functions of the input and the output variables are considered to be at least obtainable through experimental data. Associated with the computer response of the model corresponding to given inputs, a conditional pseudoresponse set is generated. This response can be constructed by means of the model by using the simulated pseudorandom input variates from a neighborhood defined by a preassigned probability allowance. A pair of such pseudoresponse values can then be computed by a procedure corresponding to a (1-..cap alpha..) probability for the conditional pseudoresponse set. The range defined by such a pair is called a (1-..cap alpha..) performance confidence interval with respect to the model. The application of this concept can allow comparison of the merit of two models describing the same system, or it can detect a system change when the current response is out of the performance interval with respect to the previously identified model. 6 figures.

  14. Risk factors for cancer.

    PubMed

    Lyman, G H

    1992-09-01

    It is no longer reasonable to divide cancers into those that are genetic in origin and those that are environmental in origin. With rare exception, carcinogenesis involves environmental factors that directly or indirectly exert a change in the cell's genome. Virtually all causes of cancer are multifactorial, sometimes involving an inherited predisposition to the carcinogenic effects of environmental factors, which include chemicals, ionizing radiation, and oncogenic virus. Carcinogenesis is a multistep process including induction, promotion, and progression. Initiation requires an irreversible change in the cellular genome, whereas promotion is commonly associated with prolonged and reversible exposure. Tumor progression results in genotypic and phenotypic changes associated with tumor growth, invasion, and metastasis. Most information on human cancer risk is based on epidemiologic studies involving both exposed and unexposed individuals. The quality of such studies depends on their ability to assess the strength of any association of exposure and disease and careful attention to any potential bias. Few cancers are inherited in a Mendelian fashion. Several preneoplastic conditions, however, are clearly inherited and several malignancies demonstrate weak familial patterns. Environmental factors may exert their effect on DNA in a random fashion, but certain consistent changes, including specific translocations of genetic information, are often found. Currently, there is great interest in the close proximity of certain oncogenes governing growth control to the consistent chromosomal changes observed. Such changes may represent a final common pathway of action for environmental carcinogens. Sufficient laboratory and epidemiologic evidence exists to establish a causal association of several chemical agents with cancer. The most important carcinogenic chemicals are associated with life-style factors, whereas agents related to other environmental, occupational, or medical exposure are numerically less important. Most chemical agents exert their carcinogenic effects as electrophilic reactants covalently binding to DNA. Certain agents such as asbestos are carcinogenic by virtue of their physical properties. Several short-term tests have been used to screen for chemical carcinogens. Whole-animal studies remain the standard for predicting carcinogen risk in humans, although major limitations in such studies exist. Ionizing radiation also exerts its carcinogenic effect through damage to cellular macromolecules including DNA. Excess cancer risk appears after a latent period of several years following exposure. Risk increases in approximately a linear fashion in proportion to the radiation energy, cumulative dose, and a variety of host biologic factors. The greatest source of average radiation exposure to the US population is from the uranium decay product radon.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:1410059

  15. Delineating the mode of action of adenosine A1 receptor allosteric modulators.

    PubMed

    Valant, Celine; Aurelio, Luigi; Urmaliya, Vijay B; White, Paul; Scammells, Peter J; Sexton, Patrick M; Christopoulos, Arthur

    2010-09-01

    Despite the identification of 2-amino-3-benzoylthiophenes (2A3BTs) as the first example of small-molecule allosteric potentiators of agonist function at a G protein-coupled receptor (GPCR)-the adenosine A(1) receptor-their mechanism of action is still not fully understood. We now report the mechanistic basis for the complex behaviors noted for 2A3BTs at A(1) receptors. Using a combination of membrane-based and intact-cell radioligand binding, multiple signaling assays, and a native tissue bioassay, we found that the allosteric interaction between 2A3BTs and the agonists 2-chloro-N(6)-[(3)H]cyclopentyladenosine or (-)-N(6)-(2-phenylisopropyl)adenosine (R-PIA) or the antagonist [(3)H]8-cyclopentyl-1,3-dipropylxanthine is consistent with a ternary complex model involving recognition of a single extracellular allosteric site. However, when allowed access to the intracellular milieu, 2A3BTs have a secondary action as direct G protein inhibitors; this latter property is receptor-independent as it is observed in nontransfected cells and also after stimulation of another GPCR. In addition, we found that 2A3BTs can signal as allosteric agonists in their own right but show bias toward certain pathways relative to the orthosteric agonist, R-PIA. These results indicate that 2A3BTs have a dual mode of action when interacting with the A(1) receptor and that they can engender novel functional selectivity in A(1) signaling. These mechanisms need to be factored into allosteric ligand structure-activity studies. PMID:20547736

  16. Nur transcription factors in stress and addiction

    PubMed Central

    Campos-Melo, Danae; Galleguillos, Danny; Sánchez, Natalia; Gysling, Katia; Andrés, María E.

    2013-01-01

    The Nur transcription factors Nur77 (NGFI-B, NR4A1), Nurr1 (NR4A2), and Nor-1 (NR4A3) are a sub-family of orphan members of the nuclear receptor superfamily. These transcription factors are products of immediate early genes, whose expression is rapidly and transiently induced in the central nervous system by several types of stimuli. Nur factors are present throughout the hypothalamus-pituitary-adrenal (HPA) axis where are prominently induced in response to stress. Drugs of abuse and stress also induce the expression of Nur factors in nuclei of the motivation/reward circuit of the brain, indicating their participation in the process of drug addiction and in non-hypothalamic responses to stress. Repeated use of addictive drugs and chronic stress induce long-lasting dysregulation of the brain motivation/reward circuit due to reprogramming of gene expression and enduring alterations in neuronal function. Here, we review the data supporting that Nur transcription factors are key players in the molecular basis of the dysregulation of neuronal circuits involved in chronic stress and addiction. PMID:24348325

  17. Diabetic retinopathy and systemic factors.

    PubMed

    Frank, Robert N

    2015-01-01

    Diabetic retinopathy, an oculardisease, is governed by systemic as well as local ocular factors. These include primarily chronic levels of blood glucose. Individuals with chronically elevated blood glucose levels have substantially more, and more severe, retinopathy than those with lower blood glucose levels. The relationship of blood glucose to retinopathy is continuous, with no threshold although individuals with hemoglobin A1c levels (a measure of chronic glycemia) <6.5%, generally develop little or no retinopathy. Blood pressure levels have been claimed to influence retinopathy development and progression, but multiple controlled clinical trials of antihypertensive agents in diabetic subjects have produced only weak evidence of benefit from blood pressure lowering on the incidence and progression of diabetic retinopathy. Elevated blood lipids seem to play a role in the progression of retinopathy, and two trials of fenofibrate, a lipid-lowering agent that has not proved effective in preventing cardiovascular disease, have shown benefit in preventing retinopathy progression. The mechanism of this effect may not, however, be directly related to the reduction in blood lipids. Finally, there is strong, but only circumstantial, evidence for a genetic or epigenetic influence on the pathogenesis of diabetic retinopathy. Despite the power of large-scale epidemiologic studies and modern molecular biological and computational techniques, the gene or genes, which predispose or protect against the development and progression of diabetic retinopathy remain elusive. PMID:25949071

  18. Diabetic Retinopathy and Systemic Factors

    PubMed Central

    Frank, Robert N.

    2015-01-01

    Diabetic retinopathy, an oculardisease, is governed by systemic as well as local ocular factors. These include primarily chronic levels of blood glucose. Individuals with chronically elevated blood glucose levels have substantially more, and more severe, retinopathy than those with lower blood glucose levels. The relationship of blood glucose to retinopathy is continuous, with no threshold although individuals with hemoglobin A1c levels (a measure of chronic glycemia) <6.5%, generally develop little or no retinopathy. Blood pressure levels have been claimed to influence retinopathy development and progression, but multiple controlled clinical trials of antihypertensive agents in diabetic subjects have produced only weak evidence of benefit from blood pressure lowering on the incidence and progression of diabetic retinopathy. Elevated blood lipids seem to play a role in the progression of retinopathy, and two trials of fenofibrate, a lipid-lowering agent that has not proved effective in preventing cardiovascular disease, have shown benefit in preventing retinopathy progression. The mechanism of this effect may not, however, be directly related to the reduction in blood lipids. Finally, there is strong, but only circumstantial, evidence for a genetic or epigenetic influence on the pathogenesis of diabetic retinopathy. Despite the power of large-scale epidemiologic studies and modern molecular biological and computational techniques, the gene or genes, which predispose or protect against the development and progression of diabetic retinopathy remain elusive. PMID:25949071

  19. Local Population Characteristics and Hemoglobin A1c Testing Rates among Diabetic Medicare Beneficiaries

    PubMed Central

    Yasaitis, Laura C.; Bubolz, Thomas; Skinner, Jonathan S.; Chandra, Amitabh

    2014-01-01

    Background Proposed payment reforms in the US healthcare system would hold providers accountable for the care delivered to an assigned patient population. Annual hemoglobin A1c (HbA1c) tests are recommended for all diabetics, but some patient populations may face barriers to high quality healthcare that are beyond providers' control. The magnitude of fine-grained variations in care for diabetic Medicare beneficiaries, and their associations with local population characteristics, are unknown. Methods HbA1c tests were recorded for 480,745 diabetic Medicare beneficiaries. Spatial analysis was used to create ZIP code-level estimated testing rates. Associations of testing rates with local population characteristics that are outside the control of providers – population density, the percent African American, with less than a high school education, or living in poverty – were assessed. Results In 2009, 83.3% of diabetic Medicare beneficiaries received HbA1c tests. Estimated ZIP code-level rates ranged from 71.0% in the lowest decile to 93.1% in the highest. With each 10% increase in the percent of the population that was African American, associated HbA1c testing rates were 0.24% lower (95% CI −0.32–−0.17); for identical increases in the percent with less than a high school education or the percent living in poverty, testing rates were 0.70% lower (−0.95–−0.46) and 1.6% lower (−1.8–−1.4), respectively. Testing rates were lowest in the least and most densely populated ZIP codes. Population characteristics explained 5% of testing rate variations. Conclusions HbA1c testing rates are associated with population characteristics, but these characteristics fail to explain the vast majority of variations. Consequently, even complete risk-adjustment may have little impact on some process of care quality measures; much of the ZIP code-related variations in testing rates likely result from provider-based differences and idiosyncratic local factors not related to poverty, education, or race. PMID:25360615

  20. Collisionally-Mediated Singlet-Triplet Crossing in ˜{a}1A1 CH_2 Revisited: (010) Coupling

    NASA Astrophysics Data System (ADS)

    Le, Anh T.; Hall, Gregory; Sears, Trevor

    2014-06-01

    Methylene, CH2, possesses a ground ˜{X}3B1 ground electronic state and an excited ˜{a}1A1 state only 3150cm-1 higher in energy. The collision-induced singlet-triplet crossing in the gaseous mixtures is important in determining overall reaction rates and chemical behavior. Accidental near-degeneracies between rotational levels of the singlet state and the vibrationally excited triplet state result in a few gateway rotational levels that mediate collision-induced intersystem crossing. The mixed states can be recognized and quantified by deperturbation, knowing the zero-order singlet and triplet energy levels. Hyperfine structure can be used as alternative indicator of singlet-triplet mixing. Non-zero mixing will induce hyperfine splittings intermediate between the unresolved hyperfine structure of pure singlet and the resolvable (≈50MHz) splittings of pure triplet, arising from the (I\\cdotS) interaction in the ortho states, where nuclear spin I=1. Collision-induced intersystem crossing rates from the (010) state are comparable to those for (000), yet the identities and characters of the presumed gateway states are unknown. A new spectrometer is under construction to investigate triplet mixing rotational levels of ˜{a}1A1(010) by sub-Doppler measurements of perturbation-induced hyperfine splittings. Their observation will permit the identification of gateway states and quantification of the degree of triplet contamination of the singlet wavefunction. Progress in the measurements and the analysis of rotational energy transfer in (010) will be reported. Acknowledgments: Work at Brookhaven National Laboratory was carried out under Contract No. DE-AC02-98CH10886 with the U.S. Department of Energy and supported by its Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences and Biosciences. C.-H. Chang, G. E. Hall, T. J. Sears, J. Chem. Phys 133, 144310(2010) G. E. Hall, A. V. Komissarov, and T. J. Sears, J. Phys. Chem. A 108 7922-7927 (2004)

  1. Risk Factors for Eating Disorders

    ERIC Educational Resources Information Center

    Striegel-Moore, Ruth H.; Bulik, Cynthia M.

    2007-01-01

    The authors review research on risk factors for eating disorders, restricting their focus to studies in which clear precedence of the hypothesized risk factor over onset of the disorder is established. They illustrate how studies of sociocultural risk factors and biological factors have progressed on parallel tracks and propose that major advances

  2. Risk Factors for Eating Disorders

    ERIC Educational Resources Information Center

    Striegel-Moore, Ruth H.; Bulik, Cynthia M.

    2007-01-01

    The authors review research on risk factors for eating disorders, restricting their focus to studies in which clear precedence of the hypothesized risk factor over onset of the disorder is established. They illustrate how studies of sociocultural risk factors and biological factors have progressed on parallel tracks and propose that major advances…

  3. Pulmonary toxicity of cyclophosphamide: a 1-year study

    SciTech Connect

    Morse, C.C.; Sigler, C.; Lock, S.; Hakkinen, P.J.; Haschek, W.M.; Witschi, H.P.

    1985-01-01

    The development of cyclophosphamide-induced pulmonary lesions over a 1-year period was studied in mice. Male BALB/c mice received a single intraperitoneal injection of 100 mg/kg of cyclophosphamide. Within 3 weeks there were scattered foci of intraalveolar foamy macrophages. With time, these foci increased in size and, 1 year later, occupied large areas in all lung lobes. There was also diffuse interstitial fibrosis. Chemical determination done 3, 12, 24, and 52 weeks after cyclophosphamide showed that lungs of animals treated with cyclophosphamide had significantly more hydroxyproline per lung than controls. One year after cyclophosphamide pressure - volume curves measured in vivo were shifted down and to the right and total lung volumes were decreased. A single injection of cyclophosphamide produced an irreversible and progressive pulmonary lesion. 16 references, 5 figures, 3 tables.

  4. Underwater Imaging Using a 1 × 16 CMUT Linear Array

    PubMed Central

    Zhang, Rui; Zhang, Wendong; He, Changde; Zhang, Yongmei; Song, Jinlong; Xue, Chenyang

    2016-01-01

    A 1 × 16 capacitive micro-machined ultrasonic transducer linear array was designed, fabricated, and tested for underwater imaging in the low frequency range. The linear array was fabricated using Si-SOI bonding techniques. Underwater transmission performance was tested in a water tank, and the array has a resonant frequency of 700 kHz, with pressure amplitude 182 dB (μPa·m/V) at 1 m. The −3 dB main beam width of the designed dense linear array is approximately 5 degrees. Synthetic aperture focusing technique was applied to improve the resolution of reconstructed images, with promising results. Thus, the proposed array was shown to be suitable for underwater imaging applications. PMID:26938536

  5. Operating nanoliter scale NMR microcoils in a 1 tesla field

    NASA Astrophysics Data System (ADS)

    McDowell, Andrew F.; Adolphi, Natalie L.

    2007-09-01

    Microcoil probes enclosing sample volumes of 1.2, 3.3, 7.0, and 81 nanoliters are constructed as nuclear magnetic resonance (NMR) detectors for operation in a 1 tesla permanent magnet. The probes for the three smallest volumes utilize a novel auxiliary tuning inductor for which the design criteria are given. The signal-to-noise ratio (SNR) and line width of water samples are measured. Based on the measured DC resistance of the microcoils, together with the calculated radio frequency (RF) resistance of the tuning inductor, the SNR is calculated and shown to agree with the measured values. The details of the calculations indicate that the auxiliary inductor does not degrade the NMR probe performance. The diameter of the wire used to construct the microcoils is shown to affect the signal line widths.

  6. Underwater Imaging Using a 1 × 16 CMUT Linear Array.

    PubMed

    Zhang, Rui; Zhang, Wendong; He, Changde; Zhang, Yongmei; Song, Jinlong; Xue, Chenyang

    2016-01-01

    A 1 × 16 capacitive micro-machined ultrasonic transducer linear array was designed, fabricated, and tested for underwater imaging in the low frequency range. The linear array was fabricated using Si-SOI bonding techniques. Underwater transmission performance was tested in a water tank, and the array has a resonant frequency of 700 kHz, with pressure amplitude 182 dB (μPa·m/V) at 1 m. The -3 dB main beam width of the designed dense linear array is approximately 5 degrees. Synthetic aperture focusing technique was applied to improve the resolution of reconstructed images, with promising results. Thus, the proposed array was shown to be suitable for underwater imaging applications. PMID:26938536

  7. Upregulation of COL6A1 is predictive of poor prognosis in clear cell renal cell carcinoma patients

    PubMed Central

    Shen, Yijun; Zhang, Hailiang; Shi, Guohai; Zhu, Yao; Dai, Bo; Ye, Dingwei

    2015-01-01

    Background: The extracellular matrix (ECM) is reported to play an important role in tumorigenesis and progression. Collagen VI is an important ECM protein. In this study, we investigated the potential role of the COL6A1 gene, which encodes the ?1 polypeptide of collagen VI, in the biological functions involved in the progression and outcome of clear cell renal cell carcinoma (ccRCC). Materials and methods: A total of 288 ccRCC patients who underwent radical nephrectomy (RN) or nephron sparing nephrectomy (NSS) at Fudan University Shanghai Cancer Center (FUSCC) were enrolled. Total RNA was extracted from frozen samples obtained from the tissue bank of FUSCC and expression of COL6A1 was determined by qRT-PCR. The clinical relationship between COL6A1 expression and ccRCC prognosis was analyzed. These data were then validated in the Cancer Genome Atlas (TCGA) cohort. We also investigated the effect of COL6A1 overexpression in a xenografted tumor model in nude mice in vivo. Results: In multivariate analysis of TCGA cohorts, COL6A1 high expression was predictive of poor prognosis in ccRCC patients overall survival (OS) (HR: 2.588 95%CI 1.6164.146) and disease free survival(DFS) (HR: 3.106 95%CI 1.5346.288). In FUSCC cohorts, after adjusted for relevant factors, the COL6A1 expression indicates poor prognosis in ccRCC patientss OS (HR 2.211; 95% CI, 1.3608.060) and DFS (HR 3.052; 95%CI, 1.5006.210). COL6A1 overexpression promoted tumor growth in xenografted nude mice. Conclusion: Increased COL6A1 expression correlates with poor prognosis in ccRCC patients. Moreover, COL6A1 stimulates tumor growth in vivo. PMID:26317545

  8. Neutron quality factor

    SciTech Connect

    1995-06-01

    Both the International Commission on Radiological Protection (ICRP) and the National Council on Radiation Protection and Measurements (NCRP) have recommended that the radiation quality weighting factor for neutrons (Q{sub n}, or the corresponding new modifying factor, w{sub R}) be increased by a value of two for most radiation protection practices. This means an increase in the recommended value for Q{sub n} from a nominal value of 10 to a nominal value of 20. This increase may be interpreted to mean that the biological effectiveness of neutrons is two times greater than previously thought. A decision to increase the value of Q{sub n} will have a major impact on the regulations and radiation protection programs of Federal agencies responsible for the protection of radiation workers. Therefore, the purposes of this report are: (1) to examine the general concept of {open_quotes}quality factor{close_quotes} (Q) in radiation protection and the rationale for the selection of specific values of Q{sub n}; and (2) to make such recommendations to the Federal agencies, as appropriate. This report is not intended to be an exhaustive review of the scientific literature on the biological effects of neutrons, with the aim of defending a particular value for Q{sub n}. Rather, the working group examined the technical issues surrounding the current recommendations of scientific advisory bodies on this matter, with the aim of determining if these recommendations should be adopted by the Federal agencies. Ultimately, the group concluded that there was no compelling basis for a change in Q{sub n}. The report was prepared by Federal scientists working under the auspices of the Science Panel of the Committee on Interagency Radiation Research and Policy Coordination (CIRRPC).

  9. Milestones and impact factors.

    PubMed

    Ozonoff, David M; Grandjean, Philippe

    2010-01-01

    Environmental Health has just received its first Impact Factor by Thomson ISI. At a level of 2.48, this achievement is quite satisfactory and places Environmental Health in the top 25% of environmental science journals. When the journal was launched in 2002, it was still unclear whether the Open Access publishing model could be made into a viable commercial enterprise within the biomedical field. During the past eight years, Open Access journals have become widely available, although still covering only about 15% of journal titles. Major funding agencies and institutions, including prominent US universities, now require that researchers publish in Open Access journals. Because of the profound role of scientific journals for the sharing of results and communication between researchers, the advent of Open Access may be of as much significance as the transition from handwriting to printing via moveable type. As Environmental Health is an electronic Open Access journal, the numbers of downloads at the journal website can be retrieved. The top-20 list of articles most frequently accessed shows that all of them have been downloaded over 10,000 times. Back in 2002, the first article published was accessed only 49 times during the following month. A year later, the server had over 1,000 downloads per month, and now the total number of monthly downloads approaches 50,000. These statistics complement the Impact Factor and confirm the viability of Open Access in our field of research. The advent of digital media and its decentralized mode of distribution - the internet - have dramatically changed the control and financing of scientific information dissemination, while facilitating peer review, accelerating editorial handling, and supporting much needed transparency. Both the meaning and means of "having an impact" are therefore changing, as will the degree and way in which scientific journals remain "factors" in that impact. PMID:20615249

  10. Study of the Comet C/2013 A1 (Siding Spring)

    NASA Astrophysics Data System (ADS)

    Vodniza, Alberto Q.; Pereira, Mario R.

    2014-11-01

    The comet called C/2013 A1 (SIDING SPRING) was discovered on January 3, 2013 in Australia. In January 28/2014, NASA announced that is preparing for the close encounter that will happen between the comet C/2013 A1 and Mars on October 19-2014. The Mission called “MAVEN” will insert in Mars orbit on september 21—2014. The comet will pass just 138,000 kilometers far from the surface of Mars. The probability that the comet collides with Mars is small but the dust particles emitted by the comet can cause damage to spacecrafts and probes that are in orbit around that planet. NASA is making preparations to take all precautions. If the comet is quite active, there will be almost no time to take security measures with Mars orbiters. For that reason NASA is already ahead of the facts. According to scientists of the "JET PROPULSION LABORATORY-JPL", dust particles spewing from the comet may be traveling at 56 km / sec in relation to the orbiters, fifty times faster than the speed of a bullet. From our Observatory, located in Pasto-Colombia, we captured several pictures, videos and astrometry data during several days. The pictures of the asteroid were captured with the following equipment: CGE PRO 1400 CELESTRON (f/11 Schmidt-Cassegrain Telescope) and STL-1001 SBIG camera. Astrometry was carried out, and we calculated the orbital elements.Summary And Conclusions: We obtained the following orbital parameters: eccentricity = 1.0003983, orbital inclination = 129.03078 deg, longitude of the ascending node = 300.99538 deg, argument of perihelion = 2.42310 deg, perihelion distance = 1.40023196 A.U. The parameters were calculated based on 20 observations (Jan 21 to April 02) with mean residual = 0.334 arcseconds. We also obtained the light curve of the body with our data (January to November/2014)Acknowledgements: The authors would like to thank to University of Narino-Pasto-Colombia.

  11. Nucleon elastic form factors

    SciTech Connect

    D. Day

    2007-03-01

    The nucleon form factors are still the subject of active investigation even after an experimental effort spanning 50 years. This is because they are of critical importance to our understanding of the electromagnetic properties of nuclei and provide a unique testing ground for QCD motivated models of nucleon structure. Progress in polarized beams, polarized targets and recoil polarimetry have allowed an important and precise set of data to be collected over the last decade. I will review the experimental status of elastic electron scattering from the nucleon along with an outlook for future progress.

  12. Psychosocial factors in obesity.

    PubMed

    Mustajoki, P

    1987-01-01

    Obese people as a group have similar mental health as normal weight people, and there are no psychiatric features characteristic of obesity in general. However, small subgroups of obese individuals may have psychiatric abnormalities which are specific for obesity, such as body image disturbance or periodic compulsive overeating (bulimia). Obesity is strongly related to sociocultural factors. In western countries obesity is commoner in lower than in higher social classes. Thus, the development of obesity is influenced by social status. However, also the converse is true: recent observations suggest that obese people lose social status. This is probably due to prejudice and discrimination against obese persons in the modern western society. PMID:3477994

  13. The "impact factor" revisited

    PubMed Central

    Dong, Peng; Loh, Marie; Mondry, Adrian

    2005-01-01

    The number of scientific journals has become so large that individuals, institutions and institutional libraries cannot completely store their physical content. In order to prioritize the choice of quality information sources, librarians and scientists are in need of reliable decision aids. The "impact factor" (IF) is the most commonly used assessment aid for deciding which journals should receive a scholarly submission or attention from research readership. It is also an often misunderstood tool. This narrative review explains how the IF is calculated, how bias is introduced into the calculation, which questions the IF can or cannot answer, and how different professional groups can benefit from IF use. PMID:16324222

  14. Human Factors Model

    NASA Technical Reports Server (NTRS)

    1993-01-01

    Jack is an advanced human factors software package that provides a three dimensional model for predicting how a human will interact with a given system or environment. It can be used for a broad range of computer-aided design applications. Jack was developed by the computer Graphics Research Laboratory of the University of Pennsylvania with assistance from NASA's Johnson Space Center, Ames Research Center and the Army. It is the University's first commercial product. Jack is still used for academic purposes at the University of Pennsylvania. Commercial rights were given to Transom Technologies, Inc.

  15. The Nucleosome Remodeling Factor

    PubMed Central

    Alkhatib, Suehyb G.; Landry, Joseph W.

    2016-01-01

    An essential component of the chromatin remodeling machinery is NURF (Nucleosome Remodeling Factor), the founding member of the ISWI family of chromatin remodeling complexes. In vertebrates and invertebrates alike, NURF has many important functions in chromatin biology including regulating transcription, establishing boundary elements, and promoting higher order chromatin structure. Since NURF is essential to many aspects of chromatin biology, knowledge of its function is required to fully understand how the genome is regulated. This review will summarize what is currently known of its biological functions, conservation in the most prominent model organisms, biochemical functions as a nucleosome remodeling enzyme, and its possible relevance to human cancer. PMID:21920360

  16. Human factors: Aeronautics

    NASA Technical Reports Server (NTRS)

    Jenkins, James P.

    1988-01-01

    The objectives of the Aeronautics Human Factors Research and Technology program are to provide the technology base and capability to design effective crew-cockpit systems and to advance solutions to human problems affecting air transport and rotorcraft effectiveness and safety. Advanced automation technologies, information display capabilities under computer control, and concern for the effects of human error in flight operations are elements which drive the directions of the program. Thus, the program has four thrusts: flight management, human engineering methods, rotorcraft, and subsonic transports.

  17. From compatible factorization to near-compatible factorization

    NASA Astrophysics Data System (ADS)

    Aldiabat, Raja'i.; Ibrahim, Haslinda

    2014-12-01

    A compatible factorization of order ν, is an ν× ν-1/2 array in which the entries in row i form a near-one-factor with focus i, and the triples associated with the rows contain no repetitions. In this paper, we aim to amend this compatible factorization so that we can display ν(ν-1)/2 - 2ν/3 triples with the minimum repeated triples. Throughout this paper we propose a new type of factorization called near-compatible factorization. First, we present the compatible factorization towards developing a near-compatible factorization. Second, we discuss briefly the necessary and sufficient conditions for the existence of near-compatible factorization. Then, we exemplify the construction for case ν = 9 as a groundwork in developing near-compatible factorization.

  18. Fabrication of Nb/A1 Superconducting Tunnel Junction

    NASA Astrophysics Data System (ADS)

    Cho, Sung-Ik; Park, Young-Sik; Park, Jang-Hyun; Lee, Yong-Ho; Lee, Sang-Kil; Kim, Sug-Whan; Han, Won-Yong

    2004-12-01

    We report the successful fabrication and I--V curve superconductivity test results of the Nb/Al-based superconducting tunnel junctions. STJs with side-lengths of 20, 40, 60 and 80 μm were fabricated by deposition of polycrystalline Nb/Al/AlOx/Al/Nb 5-layer thin films incorporated on a 3-inch Si wafer. STJ was designed by TannerTM L-Edit 8.3 program, and fabricated in SQUID fabrication facility, KRISS. 5-layer STJ thin-films were fabricated using UV photolithography, DC magnetron sputtering, Reactive ion etching, and CVD(Chemical Vapor Deposition) techniques. Superconducting state test for STJ was succeeded in 4K with liquid helium cooling system. Their performance indicators such as energy gap, normal resistance, normal resistivity, dynamic resistance, dynamic resistivity, and quality factor were measured from I--V curve. Fabricated Nb/Al STJ shows 11% higher FWHM energy resolution than genuine Nb STJ.

  19. Apolipoprotein A1/C3/A5 haplotypes and serum lipid levels

    PubMed Central

    2011-01-01

    Background The association of single nucleotide polymorphisms (SNPs) in the apolipoprotein (Apo) A1/C3/A4/A5 gene cluster and serum lipid profiles is inconsistent. The present study was undertaken to detect the association between the ApoA1/C3/A5 gene polymorphisms and their haplotypes with serum lipid levels in the general Chinese population. Methods A total of 1030 unrelated subjects (492 males and 538 females) aged 15-89 were randomly selected from our previous stratified randomized cluster samples. Genotyping of the ApoA1 -75 bp G>A, ApoC3 3238C>G, ApoA5 -1131T>C, ApoA5 c.553G>T and ApoA5 c.457G>A was performed by polymerse chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Pair-wise linkage disequilibria and haplotype analysis among the five SNPs were estimated. Results The levels of high-density lipoprotein cholesterol (HDL-C) and ApoA1 were lower in males than in femailes (P < 0.05 for each). The allelic and genotypic frequencies of the SNPs were no significant difference between males and females except ApoC3 3238C>G. There were 11 haplotypes with a frequency >1% identified in the cluster in our population. At the global level, the haplotypes comprised of all five SNPs were significantly associated with all seven lipid traits. In particular, haplotype G-G-C-C-A (6%; in the order of ApoA5 c.553G>T, ApoA5 c.457G>A, ApoA5 -1131T>C, ApoC3 3238C>G, and ApoA1 -75bp G>A) and G-A-T-C-G (4%) showed consistent association with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), ApoA1, ApoB, and the ApoA1/ApoB ratio. In addition, carriers of haplotype G-G-T-C-G (26%) had increased serum concentration of HDL-C and ApoA1, whereas carriers of G-G-C-G-G (15%) had high concentrations of TC, triglyceride (TG) and ApoB. We also found that haplotypes with five SNPs explain much more serum lipid variation than any single SNP alone, especially for TG (4.4% for haplotype vs. 2.4% for -1131T>C max based on R-square) and HDL-C (5.1% for haplotype vs. 0.9% for c.553G>T based on R-square). Serum lipid parameters were also correlated with genotypes and several environment factors. Conclusions Several common SNPs and their haplotypes in the ApoA1/C3/A5 gene cluster are closely associated with modifications of serum lipid parameters in the general Chinese population. PMID:21854571

  20. Factors regulating cheese shreddability.

    PubMed

    Childs, J L; Daubert, C R; Stefanski, L; Foegeding, E A

    2007-05-01

    Two sets of cheeses were evaluated to determine factors that affect shred quality. The first set of cheeses was made up of 3 commercial cheeses, Monterey Jack, Mozzarella, and process. The second set of cheeses was made up of 3 Mozzarella cheeses with varying levels of protein and fat at a constant moisture content. A shred distribution of long shreds, short shreds, and fines was obtained by shredding blocks of cheese in a food processor. A probe tack test was used to directly measure adhesion of the cheese to a stainless-steel surface. Surface energy was determined based on the contact angles of standard liquids, and rheological characterization was done by a creep and recovery test. Creep and recovery data were used to calculate the maximum and initial compliance and retardation time. Shredding defects of fines and adhesion to the blade were observed in commercial cheeses. Mozzarella did not adhere to the blade but did produce the most fines. Both Monterey Jack and process cheeses adhered to the blade and produced fines. Furthermore, adherence to the blade was correlated positively with tack energy and negatively with retardation time. Mozzarella cheese, with the highest fat and lowest protein contents, produced the most fines but showed little adherence to the blade, even though tack energy increased with fat content. Surface energy was not correlated with shredding defects in either group of cheese. Rheological properties and tack energy appeared to be the key factors involved in shredding defects. PMID:17430914

  1. The atrial natriuretic factor.

    PubMed

    Genest, J

    1986-10-01

    In less than three years since the rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats was reported the factor responsible for the diuretic, natriuretic, and vasodilating activity of the atrial homogenates was isolated, its chemical structure elucidated, and its total synthesis achieved. Also the cDNA and the gene encoding for the atrial natriuretic factor in mice, rats, and man have been cloned and the chromosomal site identified. The major effects of this hormone are vasodilatation, prevention and inhibition of the contraction induced by noradrenaline and angiotensin II, diuresis, and natriuresis associated in most instances with a pronounced increase in glomerular filtration rate and filtration fraction, inhibition of aldosterone secretion, and considerable stimulation of particulate guanylate cyclase activity. High density specific binding sites have been demonstrated in the zona glomerulosa of the adrenal cortex, in the renal glomeruli, and in the collecting ducts, and in the brain areas involved in the regulation of blood pressure and of sodium and water (AV3V region, subfornical organ, nucleus tractus solitarius, area postrema). PMID:2945572

  2. Risk factors in surgery.

    PubMed

    Dionigi, R; Rovera, F; Dionigi, G; Imperatori, A; Ferrari, A; Dionigi, P; Dominioni, L

    2001-11-01

    Improved surgical and anesthetic techniques and postoperative care have not significantly changed wound infection rates over the last 30 years. Many risk factors, related both to the host and to the surgical practice, have been identified in different studies. Control of nosocomial infections has become more challenging recently, due to a widespread bacterial resistance to antibiotics and to more frequent surgical indications in elderly patients at increased risk. A change in the microbiology of postoperative infections has also been noticed, characterized by a greater incidence of infections caused by methicillin-resistant Staphylococcus aureus, by polymicrobic flora and by fungi. This paper reviews the most important risk factors encountered in general surgery, that we observed during a 6-year prospective study of wound infection carried out in our Department of Surgery at the University of Insubria in Varese. Furthermore, the epidemiologic data on wound infections recorded in 4,002 patients undergoing general surgical procedures (mostly gastrointestinal operations), are presented and discussed. PMID:11936382

  3. Decryption of tissue factor

    PubMed Central

    Butenas, Saulius; Krudysz-Amblo, Jolanta

    2012-01-01

    Tissue factor (TF) is a transmembrane protein which, in complex with factor (F)VIIa, initiates blood coagulation. Numerous studies have determined TF epitopes and individual amino acids which play an important role in the TF/FVIIa complex formation and its activity towards natural substrates. However the subject of cell-surface TF activity remains controversial. It has been almost commonly accepted that TF on the cell surface has low (if any) activity, i.e. is encrypted and requires specific conditions/reagents to become active, i.e. decrypted. One of the leading theories suggests that cell membrane lipid composition plays a crucial role in TF decryption, whereas another assigns the key role to the formation of the Cys186-Cys209 disulfide bond. Despite a number of studies published from several laboratories, the role of this bond in the activity of the TF/FVIIa complex remains elusive and controversial. One of the causes of this controversy could be related to the lack of specificity of the reagents used for the cell treatment leading to possible alterations in other cell surface proteins and cell membrane environment. In conclusion, the influence of the Cys186-Cys209 this bond on cell surface TF function remains unclear. PMID:22401800

  4. Genetic factors in malaria*

    PubMed Central

    Luzzatto, L.

    1974-01-01

    Some of the available information on the genetics of Plasmodium is reviewed, and some of its peculiarities are emphasized. Genetic factors in the human host that may affect susceptibility to malaria are critically evaluated. Most of the studies thus far have been concerned with the genetics of host erythrocytes but there is recent evidence that genes affecting immune processes may also be involved. At least two genes affecting red cells confer relative resistance to P. falciparum: the autosomal gene for haemoglobin S (Hb S) and the sex-linked gene for the glucose-6-phosphate dehydrogenase (G6PD) variant known as A-. Whereas malaria selection can be regarded as established for these genes, it still remains a hypothesis for some other polymorphic traits of red cells. Differential susceptibility to P. falciparum of red cells with different genotypes has been tested by in vitro cultures, in which the invasion of new cells and intracellular development of the parasite can be followed by parasite counts and by 14C-isoleucine uptake. A model that relates genetic factors in Plasmodium and in man and that may account for certain features of host—parasite interactions is presented. PMID:4613502

  5. Rheumatoid factor and glomerulonephritis

    PubMed Central

    Miyazaki, M.; Endoh, M.; Suga, T.; Yano, N.; Kuramoto, T.; Matsumoto, Y.; Eguchi, K.; Yagame, M.; Miura, M.; Nomoto, Y.; Sakai, H.

    1990-01-01

    It is presently unknown whether rheumatoid factors have a pathogenic role in the development of various types of glomerulonephritis with immune deposits. Three isotypes of rheumatoid factors (RFs), which are autoantibodies to IgG, were measured using the solid-phase fluorescence immunoassay in sera from patients with diffuse proliferative lupus nephritis (DPLN), membranous lupus nephritis (MLN), IgA nephropathy (IgAN) and idiopathic membranous nephropathy (MN). RF activity of immunoglobulins deposited in the glomeruli from these patients was also studied by examining the binding of the FITC-conjugated human IgG and Fc portion of IgG to the glomeruli of renal biopsy specimens. IgG, IgA and IgM RFs were significantly increased in sera from patients with DPLN, and the increase was significantly lower in patients with MLN, IgAN and MN. Human IgG bound to immunoglobulin on the glomeruli only in DPLN, but not in MLN, IgAN or MN. The Fc portion of IgG was demonstrated to be involved in this reaction. It was suggested that RFs and IgG may play a major role in immune deposits on the glomeruli in DPLN and may be involved in the development of DPLN; however, this is not likely in MLN, IgAN or MN. PMID:2201469

  6. Factors influencing glabridin stability.

    PubMed

    Ao, Mingzhang; Shi, Yue; Cui, Yongming; Guo, Wentao; Wang, Jing; Yu, Longjiang

    2010-12-01

    Glabridin, a polyphenolic isoflavan of Glycyrrhiza glabra, has shown a variety of pharmaceutical properties. We have previously studied the isolation of glabridin using macroporous resin and found that it is partially degraded, giving a dark color. To illustrate the degradation of glabridin, the present work studied the stability of glabridin under various conditions. Licorice extract containing about 20% glabridin, obtained from G. glabra by silica gel column chromatography, was used in the stability study. Seven different factors (temperature, illumination, humidity, pH, solvent, oxygen, and oxidant) were studied and content changes were determined through HPLC analysis. Except for oxygen, all the above factors had an effect on the stability of glabridin, with illumination being the main one. Moreover, the interactions between temperature and pH, temperature and humidity, and illumination and pH can promote the degradation of glabridin. In conclusion, we suggest that a dark, dry and airtight environment provides the optimized condition for the long-term storage of glabridin. PMID:21299118

  7. SARSCEST (human factors)

    NASA Technical Reports Server (NTRS)

    Parsons, H. Mcilvaine

    1988-01-01

    People interact with the processes and products of contemporary technology. Individuals are affected by these in various ways and individuals shape them. Such interactions come under the label 'human factors'. To expand the understanding of those to whom the term is relatively unfamiliar, its domain includes both an applied science and applications of knowledge. It means both research and development, with implications of research both for basic science and for development. It encompasses not only design and testing but also training and personnel requirements, even though some unwisely try to split these apart both by name and institutionally. The territory includes more than performance at work, though concentration on that aspect, epitomized in the derivation of the term ergonomics, has overshadowed human factors interest in interactions between technology and the home, health, safety, consumers, children and later life, the handicapped, sports and recreation education, and travel. Two aspects of technology considered most significant for work performance, systems and automation, and several approaches to these, are discussed.

  8. Factors in risk perception

    PubMed

    Sjoberg

    2000-02-01

    Risk perception is a phenomenon in search of an explanation. Several approaches are discussed in this paper. Technical risk estimates are sometimes a potent factor in accounting for perceived risk, but in many important applications it is not. Heuristics and biases, mainly availability, account for only a minor portion of risk perception, and media contents have not been clearly implicated in risk perception. The psychometric model is probably the leading contender in the field, but its explanatory value is only around 20% of the variance of raw data. Adding a factor of "unnatural risk" considerably improves the psychometric model. Cultural Theory, on the other hand, has not been able to explain more than 5-10% of the variance of perceived risk, and other value scales have similarly failed. A model is proposed in which attitude, risk sensitivity, and specific fear are used as explanatory variables; this model seems to explain well over 30-40% of the variance and is thus more promising than previous approaches. The model offers a different type of psychological explanation of risk perception, and it has many implications, e.g., a different approach to the relationship between attitude and perceived risk, as compared with the usual cognitive analysis of attitude. PMID:10795334

  9. Enhanced target factor analysis.

    PubMed

    Rostami, Akram; Abdollahi, Hamid; Maeder, Marcel

    2016-03-10

    Target testing or target factor analysis, TFA, is a well-established soft analysis method. TFA answers the question whether an independent target test vector measured at the same wavelengths as the collection of spectra in a data matrix can be excluded as the spectrum of one of the components in the system under investigation. Essentially, TFA cannot positively prove that a particular test spectrum is the true spectrum of one of the components, it can, only reject a spectrum. However, TFA will not reject, or in other words TFA will accept, many spectra which cannot be component spectra. Enhanced Target Factor Analysis, ETFA addresses the above problem. Compared with traditional TFA, ETFA results in a significantly narrower range of positive results, i.e. the chance of a false positive test result is dramatically reduced. ETFA is based on feasibility testing as described in Refs. [16-19]. The method has been tested and validated with computer generated and real data sets. PMID:26893084

  10. Auxin response factors.

    PubMed

    Chandler, John William

    2016-05-01

    Auxin signalling involves the activation or repression of gene expression by a class of auxin response factor (ARF) proteins that bind to auxin response elements in auxin-responsive gene promoters. The release of ARF repression in the presence of auxin by the degradation of their cognate auxin/indole-3-acetic acid repressors forms a paradigm of transcriptional response to auxin. However, this mechanism only applies to activating ARFs, and further layers of complexity of ARF function and regulation are being revealed, which partly reflect their highly modular domain structure. This review summarizes our knowledge concerning ARF binding site specificity, homodimer and heterodimer multimeric ARF association and cooperative function and how activator ARFs activate target genes via chromatin remodelling and evolutionary information derived from phylogenetic comparisons from ARFs from diverse species. ARFs are regulated in diverse ways, and their importance in non-auxin-regulated pathways is becoming evident. They are also embedded within higher-order transcription factor complexes that integrate signalling pathways from other hormones and in response to the environment. The ways in which new information concerning ARFs on many levels is causing a revision of existing paradigms of auxin response are discussed. PMID:26487015

  11. macroH2A1 Histone Variants Are Depleted on Active Genes but Concentrated on the Inactive X Chromosome†

    PubMed Central

    Changolkar, Lakshmi N.; Pehrson, John R.

    2006-01-01

    Using a novel thiol affinity chromatography approach to purify macroH2A1-containing chromatin fragments, we examined the distribution of macroH2A1 histone variants in mouse liver chromatin. We found that macroH2A1 was depleted on the transcribed regions of active genes. This depletion was observed on all of the 20 active genes that we probed, with only one site showing a small amount of enrichment. In contrast, macroH2A1 was concentrated on the inactive X chromosome, consistent with our previous immunofluorescence studies. This preferential localization was seen on genes that are active in liver, genes that are inactive in liver, and intergenic regions but was absent from four regions that escape X inactivation. These results support the hypothesis that macroH2As function as transcriptional repressors. Also consistent with this hypothesis is our finding that the heterochromatin protein HP1β copurifies with the macroH2A1-containing chromatin fragments. This study presents the first detailed examination of the distribution of macroH2A1 variants on specific sequences. Our results indicate that macroH2As have complex distribution patterns that are influenced by both local factors and long-range mechanisms. PMID:16738309

  12. Virtual and In Vitro Screens Reveal a Potential Pharmacophore that Avoids the Fibrillization of A?1-42.

    PubMed

    Hernndez-Rodrguez, Maricarmen; Correa-Basurto, Jos; Nicols-Vzquez, Mara Ins; Miranda-Ruvalcaba, Ren; Bentez-Cardoza, Claudia Guadalupe; Resndiz-Albor, Aldo Arturo; Mndez-Mndez, Juan Vicente; Rosales-Hernndez, Martha C

    2015-01-01

    Among the multiple factors that induce Alzheimer's disease, aggregation of the amyloid ? peptide (A?) is considered the most important due to the ability of the 42-amino acid A? peptides (A?1-42) to form oligomers and fibrils, which constitute A? pathological aggregates. For this reason, the development of inhibitors of A?1-42 pathological aggregation represents a field of research interest. Several A?1-42 fibrillization inhibitors possess tertiary amine and aromatic moieties. In the present study, we selected 26 compounds containing tertiary amine and aromatic moieties with or without substituents and performed theoretical studies that allowed us to select four compounds according to their free energy values for A?1-42 in ?-helix (A?-?), random coil (A?-RC) and ?-sheet (A?-?) conformations. Docking studies revealed that compound 5 had a higher affinity for A?-? and A?-RC than the other compounds. In vitro, this compound was able to abolish Thioflavin T fluorescence and favored an RC conformation of A?1-42 in circular dichroism studies, resulting in the formation of amorphous aggregates as shown by atomic force microscopy. The results obtained from quantum studies allowed us to identify a possible pharmacophore that can be used to design A?1-42 aggregation inhibitors. In conclusion, compounds with higher affinity for A?-? and A?-RC prevented the formation of oligomeric species. PMID:26172152

  13. Vascular anastomosis using a 1.9-μm laser

    NASA Astrophysics Data System (ADS)

    Stewart, Robert B.; Zelt, D. T.; LaMuraglia, Glenn M.; Kung, Robert T.

    1993-07-01

    A 1.9 micrometers laser is used to weld small diameter vessels. The absorption characteristic of tissues at this wavelength renders this laser suitable for welding of vessels with diameters in the 1 to 3 mm range. The appropriate laser power range for welding is 120 to 200 mW with a fluence on target of approximately 100 J/cm2. For vessel wall thicknesses matching the optical absorption depth, measured burst pressure was approximately 400 mmHg. In this case the acute weld strength is greater than 3 X 106 dynes/cm2. Anastomotic compliance of the welded zone was a factor of two lower than native vessel tissue both immediately following welding and after 10 weeks of healing. The advantages offered by this laser wavelength are convenient energy delivery via fiber optics, no irrigation needed for tissue cooling, and applicability to small vessel anastomoses.

  14. CYP1A1 Ile462Val polymorphism and colorectal cancer risk in Polish patients.

    PubMed

    Gil, Justyna; Gaj, Paweł; Misiak, Błażej; Ostrowski, Jerzy; Karpinski, Pawel; Jarczyńska, Alicja; Kielan, Wojciech; Sasiadek, Maria Malgorzata

    2014-07-01

    Colorectal cancer (CRC) is an epidemiological problem of a great importance in Poland; each year approximately 14,600 new cases of the disease are diagnosed. Mortality associated with CRC reaches approximately 10,400 cases per year (according to the National Cancer Registry). The 5-year survival rate is approximately 25 %, which is one of the lowest rates in Europe. The etiology of sporadic colorectal cancer (CRC) is multifactorial and has been attributed to an interplay between both environmental and genetic risk factors. In addition, there is a general consensus that genetic factors may modulate the influence of environmental insults. Following these assumptions, we performed a study on widely described polymorphisms in xenobiotic-metabolizing enzymes and DNA repair genes which may influence individual susceptibility to cancer. We selected five candidate polymorphisms in following genes: ERCC1 Asp118Asn (rs11615), XPC i11C/A (rs2279017), XRCC3 Met241Thr (rs861539) CYP1A1 Ile462Val (rs1048943) and NAT2 A803G (rs1208) and assessed the importance of chosen SNPs on groups consisting of 478 CRC patients and 404 controls. Only CYP1A1 Ile462Val was statistically significant in CRC patients over 50 years old: OR 2.05 (1.29-3.28); p = 1.25E-02 and this association was more pronounced in the female group of CRC patients after the age of 50: OR 2.72 (1.43-5.14); p = 1.14E-02. PMID:24939416

  15. Capacity, Strategies, and Metamemory: Tests of a Three-Factor Model of Memory Development.

    ERIC Educational Resources Information Center

    DeMarie, Darlene; Ferron, John

    2003-01-01

    This study obtained multiple measures of three factors (capacity, strategies, and metamemory) hypothesized to cause memory improvement with age among younger (ages 5 to 8) to older (ages 8 to 11) children. Results suggested that fit of the 3-factor model was statistically significantly better than a 1-factor, general memory model for both age…

  16. Genetic determination of high-density lipoprotein-cholesterol and apolipoprotein A-1 plasma levels in a family study of cardiac catheterization patients

    SciTech Connect

    Prenger, V.L.; Beaty, T.H.; Kwiterovich, P.O. )

    1992-11-01

    Plasma levels of two lipoprotein risk factors, high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-1 (apo A-1), have been shown to be negatively associated with the risk of developing coronary artery disease, and several reports have examined familial factors in HDL-C and apo A-1 levels. A number of studies suggest that shared genes influence familial resemblance of these lipoprotein levels far more than do shared environments. Possible mechanisms for the inheritance of these risk factors (HDL-C and apo A-1 plasma levels) are explored using data from 390 individuals in 69 families ascertained through probands undergoing diagnostic cardiac catheterization. Segregation analysis was used to test a series of specific models of inheritance. Evidence for single-locus control of apo A-1 levels, with Mendelian transmission of a dominant allele leading to elevated apo A-1 levels, was seen in these families, although there was additional correlation among sibs present. This locus accounted for 48.6% and 37.2% of the total variation in apo A-1 levels in males and females, respectively. Similar evidence of segregation at a single locus controlling HDL-C levels was not seen in these families. 27 refs., 3 figs., 5 tabs.

  17. Aryl hydrocarbon-induced interactions at multiple DNA elements of diverse sequence--a multicomponent mechanism for activation of cytochrome P4501A1 (CYP1A1) gene transcription.

    PubMed Central

    Robertson, R W; Zhang, L; Pasco, D S; Fagan, J B

    1994-01-01

    In vivo footprinting experiments, augmented with gel shift and transfection analyses suggest that activation of the CYP1A1 gene by aryl hydrocarbons may be a multicomponent process. During the first 30 minutes of exposure to aryl hydrocarbon carcinogens and environmental contaminants, in vivo footprints appear at nine distinct sites within a 281 bp region centered 950 bp upstream of the CYP1A1 transcription start site. Six of these sites are unrelated in sequence to the three xenobiotic response elements (XREs) within this region, at which the aryl hydrocarbon (AH) receptor is known to bind. These six display a variety of footprint patterns, are diverse in sequence and range in G-C content from 60 to 75%. This diversity suggests that multiple nuclear factors may be responsible for these six in vivo footprints. These observations are consistent with competition gel shift experiments showing that the nuclear factors binding at two of these sites are different from each other, as well as from the AH receptor. Gel shifts also indicate that the sequence-specific factors binding at these sites are expressed constitutively. This is consistent with a model in which in vivo footprints are induced at these six sites, not through direct activation or de novo synthesis of DNA-binding factors, but through a two phase mechanism in which binding of the nuclear AH receptor complex to XREs facilitates the binding of constitutive factors at these sites. This facilitation could be mediated either through specific protein-protein interactions or through alterations in chromatin structure that make these sites accessible to constitutive nuclear factors. A function for the sequences at which aryl hydrocarbons induce in vivo footprints is suggested by transfection experiments showing that one of these sequences cooperates with a weak XRE to confer on a reporter gene responsiveness to aryl hydrocarbons. Images PMID:8202380

  18. Development of a 1-m Robotic Telescope System

    NASA Astrophysics Data System (ADS)

    Han, Wonyong; Mack, Peter; Lee, Chung-Uk; Park, Jang-Hyun; Jin, Ho; Kim, Seung-Lee; Kim, Ho-Il; Yuk, In-Soo; Lee, Woo-Baik; Bradstreet, Matthew

    2005-10-01

    Korea Astronomy & Space Science Institute (KASI) has installed a 1-m robotic telescope at Mt. Lemmon, AZ, in collaboration with a company, Astronomical Consultants & Equipment, Inc (ACE). The telescope system is totally designed to make fully robotic observations, and can be operated in both interactive and unattended robotic modes. The telescope is newly designed and manufactured regarding both mechanical and optical parts. The optical system is designed to collect 80% of the incident light within 0.''5 with an f/7.5 Ritchey-Chretien design. The telescope mount is an equatorial fork with a friction drive system, and it allows fully programmable tracking speeds with a typical range of 15'' s-1 and an accuracy of ±5''hr-1. The mount system includes an integral pointing model to correct for mechanical errors and misalignments, and an auto-guide unit is also available. To gather environmental information a weather station and an all sky camera are installed at the site. In this paper we introduce the system design and the performance of the mechanical and optical quality of the telescope system based on the results of test observations using some variable stars.

  19. C/2013 A1 (Siding Spring): Breathtaker or nightmare?

    NASA Astrophysics Data System (ADS)

    Ye, Q.; Hui, M.

    2014-07-01

    The dynamically new comet, C/2013 A1 (Siding Spring), is to make a close approach to Mars on 2014 October 19 at 18:30 UT at a distance of ~40 Martian radii. Such an event is extremely rare (occurs once every 100,000 years) and offers a precious opportunity for the spacecraft on Mars to closely study the comet itself. However, at the same time, the high-speed meteoroids released from the comet also pose a threat to physically damage the spacecraft. Here we report our observations and modeling results of C/Siding Spring for characterizing the comet and assessing the risk posed to the spacecraft on Mars. We find that the optical tail of C/Siding Spring is dominated by larger particles at the time of the observation. By parameterizing the dust activity with a semi-analytic model, we find that the ejection speed of C/Siding Spring is comparable to comets such as the Rosetta target, 67P/Churyumov-Gerasimenko. Under nominal situation, the simulated dust cone will miss the planet by about 20 Martian radii. At the extreme ends of the uncertainties, the simulated dust cone will engulf Mars, but the meteoric influx at Mars is still comparable to the nominal sporadic influx, seemingly indicating that an intense and enduring meteoroid bombardment due to C/Siding Spring is unlikely.

  20. Active flow control on a 1:4 car model

    NASA Astrophysics Data System (ADS)

    Heinemann, Till; Springer, Matthias; Lienhart, Hermann; Kniesburges, Stefan; Othmer, Carsten; Becker, Stefan

    2014-05-01

    Lift and drag of a passenger car are strongly influenced by the flow field around its rear end. The bluff body geometry produces a detached, transient flow which induces fluctuating forces on the body, affecting the rear axle, which may distress dynamic stability and comfort significantly. The investigations presented here deal with a 1:4 scale model of a simplified test car geometry that produces fluctuating lift and drag due to its strongly rounded rear geometry. To examine the influence of active flow control on this behavior, steady air jets were realized to exhaust from thin slots across the rear in three different configurations. Investigations were performed at and included the capturing of effective integral lift and drag, velocity measurements in the surrounding flow field with Laser Doppler Anemometry, surface pressure measurements and surface oil flow visualization on the rear. The flow field was found to be dominated by two longitudinal vortices, developing from the detachment of the flow at the upper C-pillar positions, and a recirculating, transverse vortex above the rear window. With an air jet emerging from a slot across the surface right below the rear window section, tangentially directed upstream toward the roof section, total lift could be reduced by more than 7 %, with rear axle lift reduction of about 5 % and negligible drag affection (1 %).

  1. Crystal structure and absolute configuration of preaustinoid A1.

    PubMed

    Stierle, Andrea; Stierle, Donald; Decato, Daniel

    2015-08-01

    The absolute structure of the title compound preaustinoid A1 [systematic name: (5aR,7aS,8R,10S,12R,13aR,13bS)-methyl 10-hy-droxy-5,5,7a,10,12,13b-hexa-methyl-14-methyl-ene-3,9,11-trioxohexa-deca-hydro-8,12-methano-cyclo-octa-[3,4]benzo[1,2-c]oxepine-8-carboxyl-ate], C26H36O7, has been determined by resonant scattering using Cu Kα radiation [Flack parameter = 0.07 (15)]. The structure is consistent with that reported previously [Stierle et al. (2011). J. Nat. Prod. 74, 2272-2277], determined by detailed analysis of MS and NMR data. The mol-ecule consists of a fused four-ring arrangement. The seven-membered oxepan-2-one ring has a chair conformation, as do the central cyclo-hexane rings, while the outer cyclo-hexa-1,3-dione ring has a boat conformation. In the crystal, mol-ecules are linked via O-H⋯O hydrogen bonds, forming helical chains propagating along [100]. PMID:26396816

  2. Annexin A1 localization and its relevance to cancer.

    PubMed

    Boudhraa, Zied; Bouchon, Bernadette; Viallard, Claire; D'Incan, Michel; Degoul, Françoise

    2016-02-01

    Annexin A1 (ANXA1) is a Ca(2+)-regulated phospholipid-binding protein involved in various cell processes. ANXA1 was initially widely studied in inflammation resolution, but its overexpression was later reported in a large number of cancers. Further in-depth investigations have revealed that this protein could have many roles in cancer progression and act at different levels (from cancer initiation to metastasis). This is partly due to the location of ANXA1 in different cell compartments. ANXA1 can be nuclear, cytoplasmic and/or membrane associated. This last location allows ANXA1 to be proteolytically cleaved and/or to become accessible to its cognate partners, the formyl-peptide receptors. Indeed, in some cancers, ANXA1 is found at the cell surface, where it stimulates formyl-peptide receptors to trigger oncogenic pathways. In the present review, we look at the different locations of ANXA1 and their association with the deregulated pathways often observed in cancers. We have specifically detailed the non-classic pathways of ANXA1 externalization, the significance of its cleavage and the role of the ANXA1-formyl-peptide receptor complex in cancer progression. PMID:26769657

  3. Conceptual Design for a 1-GeV IFEL Accelerator

    NASA Astrophysics Data System (ADS)

    Kimura, W. D.; Musumeci, P.; Quimby, D. C.; Gottschalk, S. C.; Pellegrini, C.

    2004-12-01

    A conceptual design for a multistaged 1-GeV IFEL laser-driven accelerator (laser linac) was developed using the Staged Electron Laser Acceleration (STELLA) inverse free electron laser (IFEL) model created at STI Optronics. A comparison with the UCLA TREDI model yields good agreement with the STELLA model. The 1-GeV IFEL laser linac consists of an IFEL buncher for forming microbunches and four IFEL acceleration stages. Electrons enter the laser linac from a conventional microwave-driven linac (51 MeV). The acceleration stages are driven by 10-TW laser beams at 1.06-μm. It is found good trapping occurs as the electrons are accelerated; however, refocusing of the e-beam between acceleration stages is needed to control detrapping effects. The energy spread of the trapped electrons is also small. This design exercise was in support of the task placed upon the EM Structure-Based Accelerators Working Group at the 2004 Advanced Accelerator Concepts Workshop. It demonstrates that a 1-GeV IFEL laser linac is feasible with present technology.

  4. Nucleon Electromagnetic Form Factors

    SciTech Connect

    Marc Vanderhaeghen; Charles Perdrisat; Vina Punjabi

    2007-10-01

    There has been much activity in the measurement of the elastic electromagnetic proton and neutron form factors in the last decade, and the quality of the data has greatly improved by performing double polarization experiments, in comparison with previous unpolarized data. Here we review the experimental data base in view of the new results for the proton, and neutron, obtained at JLab, MAMI, and MIT-Bates. The rapid evolution of phenomenological models triggered by these high-precision experiments will be discussed, including the recent progress in the determination of the valence quark generalized parton distributions of the nucleon, as well as the steady rate of improvements made in the lattice QCD calculations.

  5. Psychosomatic factors in pruritus

    PubMed Central

    Tey, Hong Liang; Wallengren, Joanna; Yosipovitch, Gil

    2013-01-01

    Pruritus and psyche are intricately and reciprocally related, with psychophysiological evidence and psychopathological explanations helping us to understand their complex association. Their interaction may be conceptualized and classified into 3 groups: pruritic diseases with psychiatric sequelae, pruritic diseases aggravated by psychosocial factors, and psychiatric disorders causing pruritus. Management of chronic pruritus is directed at treating the underlying causes and adopting a multidisciplinary approach to address the dermatologic, somatosensory, cognitive, and emotional aspects. Pharmcotherapeutic agents that are useful for chronic pruritus with comorbid depression and/or anxiety comprise selective serotonin reuptake inhibitors, mirtazapine, tricyclic antidepressants (amitriptyline and doxepin), and anticonvulsants (gabapentin, pregabalin); the role of neurokinin receptor-1 antagonists awaits verification. Antipsychotics are required for treating itch and formication associated with schizophrenia and delusion of parasitosis (including Morgellons disease). PMID:23245971

  6. Psychosomatic factors in pruritus.

    PubMed

    Tey, Hong Liang; Wallengren, Joanna; Yosipovitch, Gil

    2013-01-01

    Pruritus and psyche are intricately and reciprocally related, with psychophysiological evidence and psychopathological explanations helping us to understand their complex association. Their interaction may be conceptualized and classified into 3 groups: pruritic diseases with psychiatric sequelae, pruritic diseases aggravated by psychosocial factors, and psychiatric disorders causing pruritus. Management of chronic pruritus is directed at treating the underlying causes and adopting a multidisciplinary approach to address the dermatologic, somatosensory, cognitive, and emotional aspects. Pharmcotherapeutic agents that are useful for chronic pruritus with comorbid depression and/or anxiety comprise selective serotonin reuptake inhibitors, mirtazapine, tricyclic antidepressants (amitriptyline and doxepin), and anticonvulsants (gabapentin, pregabalin); the role of neurokinin receptor-1 antagonists awaits verification. Antipsychotics are required for treating itch and formication associated with schizophrenia and delusion of parasitosis (including Morgellons disease). PMID:23245971

  7. Exposure factors handbook

    SciTech Connect

    Konz, J.J.; Lisi, K.; Friebele, E.; Dixon, D.A.

    1989-07-01

    The document provides a summary of the available data on various factors used in assessing human exposure including drinking-water consumption, consumption rates of broad classes of food including fruits, vegetables, beef, dairy products, and fish; soil ingestion; inhalation rate; skin area; lifetime; activity patterns; and body weight. Additionally, a number of specific exposure scenarios are identified with recommendations for default values to use when site-specific data are not available. The basic equations using these parameters to calculate exposure levels are also presented for each scenario. Default values are presented as ranges from typical to reasonable worst case and as frequency distributions where appropriate data were available. Finally, procedures for assessing the uncertainties in exposure assessments are also presented with illustrative examples. These procedures include qualitative and quantitative methods such as Monte Carlo and sensitivity analysis.

  8. Applications of SRG Factorization

    NASA Astrophysics Data System (ADS)

    Anderson, E. R.; Bogner, S. K.; Furnstahl, R. J.; Hebeler, K.; Hergert, H.; Perry, R. J.

    2012-10-01

    Recent calculations of nuclear structure make use of the similarity renormalization group to soften the nuclear potential through a series of unitary transformations, which suppress short range correlations.footnotetextE.D. Jurgenson, P. Navr'atil, and R.J. Furnstahl, Phys. Rev. Lett. 103, 082501 (2009).(,)footnotetextE. R. Anderson, S. K. Bogner, R. J. Furnstahl, and R. J. Perry, Phys. Rev. C 82, 054001 (2010) Not only does this lead to a decoupling of scales in the potential, but also simplifications for other operators. One consequence, in particular, is that operator expectation values of high-energy probes in low-energy nuclear states exhibit factorization. As a result, phenomena previously attributed to strong short-range correlations induced by the nucleon-nucleon interaction, such as nuclear scaling and the EMC effect, can now be understood more clearly as a result of low-momentum nuclear structure. Recent results are reported.

  9. Unity power factor converter

    NASA Technical Reports Server (NTRS)

    Wester, Gene W. (Inventor)

    1980-01-01

    A unity power factor converter capable of effecting either inversion (dc-to-dc) or rectification (ac-to-dc), and capable of providing bilateral power control from a DC source (or load) through an AC transmission line to a DC load (or source) for power flow in either direction, is comprised of comparators for comparing the AC current i with an AC signal i.sub.ref (or its phase inversion) derived from the AC ports to generate control signals to operate a switch control circuit for high speed switching to shape the AC current waveform to a sine waveform, and synchronize it in phase and frequency with the AC voltage at the AC ports, by selectively switching the connections to a series inductor as required to increase or decrease the current i.

  10. Human factors: Space

    NASA Technical Reports Server (NTRS)

    Jenkins, James P.

    1988-01-01

    The objectives are to provide a technology base for intelligent operator interfaces, especially with autonomous subsystems, and to develop a new generation of high performance space suits, gloves, and tools/end effectors to meet the requirements of advanced space missions. The technology base is intended to meet the requirements of productivity, efficiency, and safety in complex manned operations within automated onboard systems and extravehicular activities (EVA) environments. Crew station research is the first of two major areas. Development of methods for the astronaut to supervise, monitor, and evaluate the performance of robotic systems, other space subsystems, and orbital vehicles are key areas of research. The second major area is development of an EVA space suit and gloves. Emphasis in the space human factors research program is placed on technology baseline studies and development of methods, techniques, and data to support productive and safe operations by the astronaut and crew as they interface with complex systems, advance automation, and robotic assistants.

  11. Helicopter Human Factors

    NASA Technical Reports Server (NTRS)

    Hart, Sandra G.; Sridhar, Banavar (Technical Monitor)

    1995-01-01

    Even under optimal conditions, helicopter flight is a most demanding form of human-machine interaction, imposing continuous manual, visual, communications, and mental demands on pilots. It is made even more challenging by small margins for error created by the close proximity of terrain in NOE flight and missions flown at night and in low visibility. Although technology advances have satisfied some current and proposed requirements, hardware solutions alone are not sufficient to ensure acceptable system performance and pilot workload. However, human factors data needed to improve the design and use of helicopters lag behind advances in sensor, display, and control technology. Thus, it is difficult for designers to consider human capabilities and limitations when making design decisions. This results in costly accidents, design mistakes, unrealistic mission requirements, excessive training costs, and challenge human adaptability. NASA, in collaboration with DOD, industry, and academia, has initiated a program of research to develop scientific data bases and design principles to improve the pilot/vehicle interface, optimize training time and cost, and maintain pilot workload and system performance at an acceptable level. Work performed at Ames, and by other research laboratories, will be reviewed to summarize the most critical helicopter human factors problems and the results of research that has been performed to: (1) Quantify/model pilots use of visual cues for vehicle control; (2) Improve pilots' performance with helmet displays of thermal imagery and night vision goggles for situation awareness and vehicle control; (3) Model the processes by which pilots encode maps and compare them to the visual scene to develop perceptually and cognitively compatible electronic map formats; (4) Evaluate the use of spatially localized auditory displays for geographical orientation, target localization, radio frequency separation; (5) Develop and flight test control/display concepts; (6) Quantify, model, predict, and improve pilots, workload-management strategies; and (7) Design computer-game trainers to reduce training time and cost.

  12. Implications of iron deficiency/anemia on the classification of diabetes using HbA1c

    PubMed Central

    Attard, S M; Herring, A H; Wang, H; Howard, A-G; Thompson, A L; Adair, L S; Mayer-Davis, E J; Gordon-Larsen, P

    2015-01-01

    Background/Objectives: Nonglycemic factors like iron deficiency (ID) or anemia may interfere with classification of diabetes and prediabetes using hemoglobin A1c (HbA1c). However, few population-based studies of diabetes in areas with endemic ID/anemia have been conducted. We aimed to determine how mutually exclusive categories of ID alone, anemia alone and iron-deficiency anemia (IDA) were each associated with prediabetes and diabetes prevalence using fasting blood glucose (FBG) versus HbA1c in a population-based study of adults with endemic ID/anemia. Subjects/Methods: We used data from the China Health and Nutrition Survey, a longitudinal, population-based study across 228 communities within nine provinces of China. This analysis included 7308 adults seen in the 2009 survey aged 18–75 years. We used descriptive and covariate-adjusted models to examine relative risk of prediabetes and diabetes using FBG alone, HbA1c alone, HbA1c and FBG, or neither (normoglycemia) by anemia alone, ID alone, IDA or normal iron/hemoglobin. Results: Approximately 65% of individuals with diabetes in our sample were concordantly classified with diabetes using both FBG and HbA1c, while 35% had a discordant diabetes classification: they were classified using either FBG or HbA1c, but not both. Fewer participants with ID alone versus normal iron/hemoglobin were classified with diabetes using HbA1c only. From covariate-adjusted, multinomial regression analyses, the adjusted prevalence of prediabetes using HbA1c only was 22% for men with anemia alone, but 13% for men with normal iron/hemoglobin. In contrast, the predicted prevalence of prediabetes using HbA1c only was 8% for women with ID alone, compared with 13% for women with normal iron/hemoglobin. Conclusions: These findings suggest potential misclassification of diabetes using HbA1c in areas of endemic ID/anemia. Estimating diabetes prevalence using HbA1c may result in under-diagnosis in women with ID and over-diagnosis in men with anemia. PMID:26098445

  13. Geometric frustration on a 1/9th site depleted triangular lattice

    NASA Astrophysics Data System (ADS)

    Hopkinson, John; Beck, Jarrett

    2013-03-01

    In the searches both for new spin liquid and spin ice (artificial and macroscopic) candidates, geometrically frustrated two-dimensional spin systems have played a prominent role. Here we present a study of the classical antiferromagnetic Ising (AFI) model on the sorrel net, a 1/9th site depleted and 1/7th bond depleted triangular lattice. The AFI model on this corner-shared triangle net is found to have a large residual entropy per spin S/N = 0 . 48185 +/- 0 . 00008 , indicating the sorrel net is highly geometrically frustrated. Anticipating that it may be difficult to achieve perfect bond depletion, we investigate the physics resulting from turning back on the depleted bonds (J2). We present the phase diagram, analytic expressions for the long range partially ordered ground state spin structure for antiferromagnetic J2 and the short range ordered ground state spin structure for ferromagnetic J2, the magnetic susceptibility and the static structure factor. We briefly comment on the possibility that artificial spin ice on the sorrel lattice could by made, and on a recent report [T. D. Keene et al., Dalton Trans. 40 2983 (2011)] of the creation of a 1/9th depleted cobalt hydroxide oxalate. This work was supported by NSERC (JMH) and NSERC USRA (JJB)

  14. Regulation of AMPA receptor subunit GluA1 surface expression by PAK3 phosphorylation

    PubMed Central

    Hussain, Natasha K.; Thomas, Gareth M.; Luo, Junjie; Huganir, Richard L.

    2015-01-01

    AMPA receptors (AMPARs) are the major excitatory receptors of the brain and are fundamental to synaptic plasticity, memory, and cognition. Dynamic recycling of AMPARs in neurons is regulated through several types of posttranslational modification, including phosphorylation. Here, we identify a previously unidentified signal transduction cascade that modulates phosphorylation of serine residue 863 (S863) in the GluA1 AMPAR subunit and controls surface trafficking of GluA1 in neurons. Activation of the EphR–Ephrin signal transduction pathway enhances S863 phosphorylation. Further, EphB2 can interact with Zizimin1, a guanine–nucleotide exchange factor that activates Cdc42 and stimulates S863 phosphorylation in neurons. Among the numerous targets downstream of Cdc42, we determined that the p21-activated kinase-3 (PAK3) phosphorylates S863 in vitro. Moreover, specific loss of PAK3 expression and pharmacological inhibition of PAK both disrupt activity-dependent phosphorylation of S863 in cortical neurons. EphB2, Cdc42, and PAKs are broadly capable of controlling dendritic spine formation and synaptic plasticity and are implicated in multiple cognitive disorders. Collectively, these data delineate a novel signal cascade regulating AMPAR trafficking that may contribute to the molecular mechanisms that govern learning and cognition. PMID:26460013

  15. Strain-Dependent Anterior Segment Dysgenesis and Progression to Glaucoma in Col4a1 Mutant Mice

    PubMed Central

    Mao, Mao; Smith, Richard S.; Alavi, Marcel V.; Marchant, Jeffrey K.; Cosma, Mihai; Libby, Richard T.; John, Simon W. M.; Gould, Douglas B.

    2015-01-01

    Purpose Mutations in the gene encoding collagen type IV alpha 1 (COL4A1) cause multisystem disorders including anterior segment dysgenesis (ASD) and optic nerve hypoplasia. The penetrance and severity of individual phenotypes depends on genetic context. Here, we tested the effects of a Col4a1 mutation in two different genetic backgrounds to compare how genetic context influences ocular dysgenesis, IOP, and progression to glaucoma. Methods Col4a1 mutant mice maintained on a C57BL/6J background were crossed to either 129S6/SvEvTac or CAST/EiJ and the F1 progeny were analyzed by slit-lamp biomicroscopy and optical coherence tomography. We also measured IOPs and compared tissue sections of eyes and optic nerves. Results. We found that the CAST/EiJ inbred strain has a relatively uniform and profound suppression on the effects of Col4a1 mutation and that mutant CASTB6F1 mice were generally only very mildly affected. In contrast, mutant 129B6F1 mice had more variable and severe ASD and IOP dysregulation that were associated with glaucomatous signs including lost or damaged retinal ganglion cell axons and excavation of the optic nerve head. Conclusions. Ocular defects in Col4a1 mutant mice model ASD and glaucoma that are observed in a subset of patients with COL4A1 mutations. We demonstrate that different inbred strains of mice give graded severities of ASD and we detected elevated IOP and glaucomatous damage in 129B6F1, but not CASTB6F1 mice that carried a Col4a1 mutation. These data demonstrate that genetic context differences are one factor that may contribute to the variable penetrance and severity of ASD and glaucoma in patients with COL4A1 mutations. PMID:26567795

  16. Factors affecting growth factor activity in goat milk.

    PubMed

    Wu, F Y; Tsao, P H; Wang, D C; Lin, S; Wu, J S; Cheng, Y K

    2006-06-01

    Growth factors that are present in goat milk may be responsible for its beneficial effects on the digestive system as described in ancient Chinese medical texts. To develop a nutraceutical product rich in growth factors for promoting gastrointestinal health, it is essential to collect milk with consistently high growth factor activity. Therefore, we investigated the factors affecting growth factor activity in goat milk. Among the 5 breeds of dairy goats tested, milk from Nubian goats had the highest growth factor activity. Tight-junction leakage induced by a 24-h milking interval did not increase growth factor activity in the milk. Milk collected from pregnant does had a significantly higher growth factor activity than milk collected postpartum. Growth factor activity decreased during the first 8 wk of lactation, fluctuated thereafter, and then increased dramatically after natural mating. During wk 1 to 8, growth factor activity was inversely correlated with milk yield and week of lactation. No correlation was observed during wk 9 to 29. After natural mating of the goats, the growth factor activity in the milk correlated significantly with somatic cell count and conductivity (a measure of membrane permeability), and correlated inversely with milk yield. Based on the above data, goat milk with higher growth factor activity could be selectively collected from Nubian pregnant does. PMID:16702258

  17. Factor Rotation and Standard Errors in Exploratory Factor Analysis

    ERIC Educational Resources Information Center

    Zhang, Guangjian; Preacher, Kristopher J.

    2015-01-01

    In this article, we report a surprising phenomenon: Oblique CF-varimax and oblique CF-quartimax rotation produced similar point estimates for rotated factor loadings and factor correlations but different standard error estimates in an empirical example. Influences of factor rotation on asymptotic standard errors are investigated using a numerical…

  18. Factor Rotation and Standard Errors in Exploratory Factor Analysis

    ERIC Educational Resources Information Center

    Zhang, Guangjian; Preacher, Kristopher J.

    2015-01-01

    In this article, we report a surprising phenomenon: Oblique CF-varimax and oblique CF-quartimax rotation produced similar point estimates for rotated factor loadings and factor correlations but different standard error estimates in an empirical example. Influences of factor rotation on asymptotic standard errors are investigated using a numerical

  19. BDNF mediates improvements in executive function following a 1-year exercise intervention

    PubMed Central

    Leckie, Regina L.; Oberlin, Lauren E.; Voss, Michelle W.; Prakash, Ruchika S.; Szabo-Reed, Amanda; Chaddock-Heyman, Laura; Phillips, Siobhan M.; Gothe, Neha P.;