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Sample records for factor 1a hif1a

  1. Basal HIF-1a expression levels are not predictive for radiosensitivity of human cancer cell lines

    International Nuclear Information System (INIS)

    Schilling, D.; Multhoff, G.; Helmholtz Center Munich, CCG - Innate Immunity in Tumor Biology, Munich; Bayer, C.; Emmerich, K.; Molls, M.; Vaupel, P.; Huber, R.M.

    2012-01-01

    High levels of hypoxia inducible factor (HIF)-1a in tumors are reported to be associated with tumor progression and resistance to therapy. To examine the impact of HIF-1a on radioresistance under normoxia, the sensitivity towards irradiation was measured in human tumor cell lines that differ significantly in their basal HIF-1a levels. HIF-1a levels were quantified in lysates of H1339, EPLC-272H, A549, SAS, XF354, FaDu, BHY, and CX- tumor cell lines by ELISA. Protein levels of HIF-1a, HIF-2a, carbonic anhydrase IX (CA IX), and GAPDH were assessed by Western blot analysis. Knock-down experiments were performed using HIF-1a siRNA. Clonogenic survival after irradiation was determined by the colony forming assay. According to their basal HIF-1a status, the tumor cell lines were divided into low (SAS, XF354, FaDu, A549, CX-), intermediate (EPLC-272H, BHY), and high (H1339) HIF-1a expressors. The functionality of the high basal HIF-1a expression in H1339 cells was proven by reduced CA IX expression after knocking-down HIF-1a. Linear regression analysis revealed no correlation between basal HIF-1a levels and the survival fraction at either 2 or 4 Gy in all tumor cell lines investigated. Our data suggest that basal HIF-1a levels in human tumor cell lines do not predict their radiosensitivity under normoxia. (orig.)

  2. Analysis list: Hif1a [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Hif1a Blood,Embryo + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Hif1a.1.tsv http://dbarchi...ve.biosciencedbc.jp/kyushu-u/mm9/target/Hif1a.5.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Hi...f1a.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Hif1a.Blood.tsv,http://dbarchi...ve.biosciencedbc.jp/kyushu-u/mm9/colo/Hif1a.Embryo.tsv http://dbarchive.bi...osciencedbc.jp/kyushu-u/mm9/colo/Blood.gml,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Embryo.gml ...

  3. Helicase-like transcription factor (Hltf regulates G2/M transition, Wt1/Gata4/Hif-1a cardiac transcription networks, and collagen biogenesis.

    Directory of Open Access Journals (Sweden)

    Rebecca A Helmer

    Full Text Available HLTF/Hltf regulates transcription, remodels chromatin, and coordinates DNA damage repair. Hltf is expressed in mouse brain and heart during embryonic and postnatal development. Silencing Hltf is semilethal. Seventy-four percent of congenic C57BL/6J Hltf knockout mice died, 75% within 12-24 hours of birth. Previous studies in neonatal (6-8 hour postpartum brain revealed silencing Hltf disrupted cell cycle progression, and attenuated DNA damage repair. An RNA-Seq snapshot of neonatal heart transcriptome showed 1,536 of 20,000 total transcripts were altered (p < 0.05 - 10 up- and 1,526 downregulated. Pathway enrichment analysis with MetaCore™ showed Hltf's regulation of the G2/M transition (p=9.726E(-15 of the cell cycle in heart is nearly identical to its role in brain. In addition, Brca1 and 12 members of the Brca1 associated genome surveillance complex are also downregulated. Activation of caspase 3 coincides with transcriptional repression of Bcl-2. Hltf loss caused downregulation of Wt1/Gata4/Hif-1a signaling cascades as well as Myh7b/miR499 transcription. Hltf-specific binding to promoters and/or regulatory regions of these genes was authenticated by ChIP-PCR. Hif-1a targets for prolyl (P4ha1, P4ha2 and lysyl (Plod2 collagen hydroxylation, PPIase enzymes (Ppid, Ppif, Ppil3 for collagen trimerization, and lysyl oxidase (Loxl2 for collagen-elastin crosslinking were downregulated. However, transcription of genes for collagens, fibronectin, Mmps and their inhibitors (Timps was unaffected. The collective downregulation of genes whose protein products control collagen biogenesis caused disorganization of the interstitial and perivascular myocardial collagen fibrillar network as viewed with picrosirius red-staining, and authenticated with spectral imaging. Wavy collagen bundles in control hearts contrasted with collagen fibers that were thin, short and disorganized in Hltf null hearts. Collagen bundles in Hltf null hearts were tangled and

  4. Iron overload promotes erythroid apoptosis through regulating HIF-1a/ROS signaling pathway in patients with myelodysplastic syndrome.

    Science.gov (United States)

    Zheng, Qing-Qing; Zhao, You-Shan; Guo, Juan; Zhao, Si-da; Song, Lu-Xi; Fei, Cheng-Ming; Zhang, Zheng; Li, Xiao; Chang, Chun-Kang

    2017-07-01

    Erythroid apoptosis increases significantly in myelodysplastic syndrome (MDS) patients with iron overload, but the underlying mechanism is not fully clear. In this study, we aim to explore the effect of HIF-1a/ROS on erythroid apoptosis in MDS patients with iron overload. We found that iron overload injured cellular functions through up-regulating ROS levels in MDS/AML cells, including inhibited cell viability, increased cell apoptosis and blocked cell cycle at G0/G1 phase. Interestingly, overexpression of hypoxia inducible factor-1a (HIF-1a), which was under-expressed in iron overload models, reduced ROS levels and attenuated cell damage caused by iron overload in MDS/AML cells. And gene knockdown of HIF-1a got the similar results as iron overload in MDS/AML cells. Furthermore, iron overload caused high erythroid apoptosis was closely related with ROS in MDS patients. Importantly, the HIF-1a protein levels of erythrocytes elevated obviously after incubation with desferrioxamine (DFO) from MDS patients with iron overload, accompanied by ROS levels inhibited and erythroid apoptosis reduced. Taken together, our findings determine that the HIF-1a/ROS signaling pathway plays a key role in promoting erythroid apoptosis in MDS patients with iron overload. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Expression and clinical significance of the HIF-1a/ET-2 signaling pathway during the development and treatment of polycystic ovary syndrome.

    Science.gov (United States)

    Wang, Fan; Zhang, Zhenghong; Wang, Zhaokai; Xiao, Kaizhuan; Wang, Qing; Su, Jingqian; Wang, Zhengchao

    2015-04-01

    Polycystic ovary syndrome (PCOS) is a major health problem in reproductive-aged women worldwide, but the precise pathogenesis of PCOS remains unclear. Our previous study revealed that hypoxia-inducible factor (HIF)-1a mediated endothelin (ET)-2 signaling plays an important role in ovulation in rats. Therefore, the present study used a PCOS rat model to test the hypotheses that HIF-1a signaling is expressed and inhibited in ovaries during PCOS formation and that the HIF-1a/ET-2 signaling pathway is a target of dimethyldiguanide (DMBG) in the clinical treatment of PCOS. First, the development of a PCOS model and the effect of DMBG treatment were examined through ovarian histology and serum hormone levels, which were consistent with previous reports. Second, HIF-1a and ET-2 expression were detected by immunohistochemistry and western blot. The results showed decreased HIF-1a/ET-2 expression in the ovaries of PCOS rats, whereas DMBG treatment reversed the protein decreases and improved the PCOS symptoms. Third, to understand the molecular mechanism, HIF-1a/ET-2 mRNA expression was also examined. Interestingly, HIF-1a mRNA increased in the ovaries of PCOS rats, while ET-2 mRNA decreased, indicating that HIF-1a protein degradation may be involved in POCS development and treatment. Finally, HIF prolyl hydroxylase (PHD) activity was examined to further clarify the contribution of HIF-1a signaling to the development and treatment of PCOS. The results suggested that the inhibition of HIF-1a/ET-2 signaling may be caused by increased PHD activity in PCOS. DMBG-treated PCOS may further activate HIF-1a signaling at least partly through inhibiting PHD activity. Taken together, these results indicate that HIF-1a signaling is inhibited in a PCOS rat model through increasing PHD activity. DMBG treatment improved PCOS by rescuing this pathway, suggesting that HIF-1a signaling plays an important role in the development and treatment of PCOS. This HIF-1a-mediated ET-2 signaling pathway

  6. Triiodothyronine (T3) induces HIF1A and TGFA expression in MCF7 cells by activating PI3K.

    Science.gov (United States)

    Moretto, Fernanda Cristina Fontes; De Sibio, Maria Teresa; Luvizon, Aline Carbonera; Olimpio, Regiane Marques Castro; de Oliveira, Miriane; Alves, Carlos Augusto Barnabe; Conde, Sandro José; Nogueira, Célia Regina

    2016-06-01

    High expression levels of hypoxia inducing factor 1 alpha are related to mammary carcinogenesis. In previous studies, we demonstrated that expression of transforming growth factor alpha increases upon treatment with triiodothyronine, but this expression does not occur in cellular models that do not express the estrogen receptor, or when cells are co-treated with the anti-estrogen, tamoxifen. The aim of this study was to determine the effect of the hormone triiodothyronine on the expression of the genes HIF1A and TGFA in the breast cancer cell line MCF7. The cell line was subjected to treatment with triiodothyronine at the supraphysiological dose of 10(-8)M for 10min, 30min, 1h, and 4h in the presence or absence of actinomycin D, the gene expression inhibitor, cycloheximide, the protein synthesis inhibitor, and LY294002, the phosphoinositide 3 kinase inhibitor. HIF1A and TGFA mRNA expression was analyzed by reverse transcription polymerase chain reaction. For data analysis, we used analysis of variance complemented by Tukey test and an adopted minimum of 5% significance. We found that HIF1A and TGFA expression increased in the presence of triiodothyronine at all times studied. HIF1A expression decreased in triiodothyronine-treated cells when gene transcription was also inhibited; however, TGFA expression decreased after 10 and 30min of treatment even when transcription was not inhibited. We found that activation of PI3K was necessary for triiodothyronine to modulate HIF1A and TGFA expression. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Transcription factor HIF1A: downstream targets, associated pathways, polymorphic hypoxia response element (HRE) sites, and initiative for standardization of reporting in scientific literature.

    Science.gov (United States)

    Slemc, Lucija; Kunej, Tanja

    2016-11-01

    Hypoxia-inducible factor-1α (HIF-1α) has crucial role in adapting cells to hypoxia through expression regulation of many genes. Identification of HIF-1α target genes (HIF-1α-TGs) is important for understanding the adapting mechanism. The aim of the present study was to collect known HIF-1α-TGs and identify their associated pathways. Targets and associated genomics data were retrieved using PubMed, WoS ( http://apps.webofknowledge.com/ ), HGNC ( http://www.genenames.org/ ), NCBI ( http://www.ncbi.nlm.nih.gov/ ), Ensemblv.84 ( http://www.ensembl.org/index.html ), DAVID Bioinformatics Resources ( https://david.ncifcrf.gov /), and Disease Ontology database ( http://disease-ontology.org/ ). From 51 papers, we collected 98 HIF-1α TGs found to be associated with 20 pathways, including metabolism of carbohydrates and pathways in cancer. Reanalysis of genomic coordinates of published HREs (hypoxia response elements) revealed six polymorphisms within HRE sites (HRE-SNPs): ABCG2, ACE, CA9, and CP. Due to large heterogeneity of results presentation in scientific literature, we also propose a first step towards reporting standardization of HIF-1α-target interactions consisting of ten relevant data types. Suggested minimal checklist for reporting will enable faster development of a complete catalog of HIF-1α-TGs, data sharing, bioinformatics analyses, and setting novel more targeted hypotheses. The proposed format for data standardization is not yet complete but presents a baseline for further optimization of the protocol with additional details, for example, regarding the experimental validation.

  8. Hif1a inactivation rescues photoreceptor degeneration induced by a chronic hypoxia-like stress.

    Science.gov (United States)

    Barben, Maya; Ail, Divya; Storti, Federica; Klee, Katrin; Schori, Christian; Samardzija, Marijana; Michalakis, Stylianos; Biel, Martin; Meneau, Isabelle; Blaser, Frank; Barthelmes, Daniel; Grimm, Christian

    2018-04-17

    Reduced choroidal blood flow and tissue changes in the ageing human eye impair oxygen delivery to photoreceptors and the retinal pigment epithelium. As a consequence, mild but chronic hypoxia may develop and disturb cell metabolism, function and ultimately survival, potentially contributing to retinal pathologies such as age-related macular degeneration (AMD). Here, we show that several hypoxia-inducible genes were expressed at higher levels in the aged human retina suggesting increased activity of hypoxia-inducible transcription factors (HIFs) during the physiological ageing process. To model chronically elevated HIF activity and investigate ensuing consequences for photoreceptors, we generated mice lacking von Hippel Lindau (VHL) protein in rods. This activated HIF transcription factors and led to a slowly progressing retinal degeneration in the ageing mouse retina. Importantly, this process depended mainly on HIF1 with only a minor contribution of HIF2. A gene therapy approach using AAV-mediated RNA interference through an anti-Hif1a shRNA significantly mitigated the degeneration suggesting a potential intervention strategy that may be applicable to human patients.

  9. The Long Non-coding RNA HIF1A-AS2 Facilitates the Maintenance of Mesenchymal Glioblastoma Stem-like Cells in Hypoxic Niches

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    Marco Mineo

    2016-06-01

    Full Text Available Long non-coding RNAs (lncRNAs have an undefined role in the pathobiology of glioblastoma multiforme (GBM. These tumors are genetically and phenotypically heterogeneous with transcriptome subtype-specific GBM stem-like cells (GSCs that adapt to the brain tumor microenvironment, including hypoxic niches. We identified hypoxia-inducible factor 1 alpha-antisense RNA 2 (HIF1A-AS2 as a subtype-specific hypoxia-inducible lncRNA, upregulated in mesenchymal GSCs. Its deregulation affects GSC growth, self-renewal, and hypoxia-dependent molecular reprogramming. Among the HIF1A-AS2 interactome, IGF2BP2 and DHX9 were identified as direct partners. This association was needed for maintenance of expression of their target gene, HMGA1. Downregulation of HIF1A-AS2 led to delayed growth of mesenchymal GSC tumors, survival benefits, and impaired expression of HMGA1 in vivo. Our data demonstrate that HIF1A-AS2 contributes to GSCs’ speciation and adaptation to hypoxia within the tumor microenvironment, acting directly through its interactome and targets and indirectly by modulating responses to hypoxic stress depending on the subtype-specific genetic context.

  10. Downregulation of HIF-1a sensitizes U251 glioma cells to the temozolomide (TMZ) treatment

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Jun-Hai [Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037 (China); Ma, Zhi-Xiong [National Institute of Biological Sciences, Beijing 102206 (China); Huang, Guo-Hao; Xu, Qing-Fu; Xiang, Yan [Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037 (China); Li, Ningning; Sidlauskas, Kastytis [Division of Neuropathology and Department of Neurodegenerative Disease, Institute of Neurology, University College London, London WC1N 3BG (United Kingdom); Zhang, Eric Erquan [National Institute of Biological Sciences, Beijing 102206 (China); Lv, Sheng-Qing, E-mail: lvsq0518@hotmail.com [Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University, Chongqing 400037 (China)

    2016-05-01

    Purpose: The aim of this study was to investigate the effect of downregulation of HIF-1α gene on human U251 glioma cells and examine the consequent changes of TMZ induced effects and explore the molecular mechanisms. Methods: U251 cell line stably expressing HIF-1α shRNA was acquired via lentiviral vector transfection. The mRNA and protein expression alterations of genes involved in our study were determined respectively by qRT-PCR and Western blot. Cell proliferation was measured by MTT assay and colony formation assay, cell invasion/migration capacity was determined by transwell invasion assay/wound healing assay, and cell apoptosis was detected by flow cytometry. Results: We successfully established a U251 cell line with highly efficient HIF-1α knockdown. HIF-1a downregulation sensitized U251 cells to TMZ treatment and enhanced the proliferation-inhibiting, invasion/migration-suppressing, apoptosis-inducing and differentiation-promoting effects exerted by TMZ. The related molecular mechanisms demonstrated that expression of O{sup 6}-methylguanine DNA methyltransferase gene (MGMT) and genes of Notch1 pathway were significantly upregulated by TMZ treatment. However, this upregulation was abrogated by HIF-1α knockdown. We further confirmed important regulatory roles of HIF-1α in the expression of MGMT and activation of Notch1 pathways. Conclusion: HIF-1α downregulation sensitizes U251 glioma cells to the temozolomide treatment via inhibiting MGMT expression and Notch1 pathway activation. - Highlights: • TMZ caused more significant proliferation inhibition and apoptosis in U251 cells after downregulating HIF-1α. • Under TMZ treatment, HIF-1 downregulated U251 cells exhibited weaker mobility and more differentiated state. • TMZ caused MGMT over-expression and Notch1 pathway activation, which could be abrogated by HIF-1α downregulation.

  11. Engineered myocardium model to study the roles of HIF-1α and HIF1A-AS1 in paracrine-only signaling under pathological level oxidative stress.

    Science.gov (United States)

    Acun, Aylin; Zorlutuna, Pinar

    2017-08-01

    Studying heart tissue is critical for understanding and developing treatments for cardiovascular diseases. In this work, we fabricated precisely controlled and biomimetic engineered model tissues to study how cell-cell and cell-matrix interactions influence myocardial cell survival upon exposure to pathological level oxidative stress. Specifically, the interactions of endothelial cells (ECs) and cardiomyocytes (CMs), and the role of hypoxia inducible factor-1α (HIF-1α), with its novel alternative regulator, HIF-1α antisense RNA1 (HIF1A-AS1), in these interactions were investigated. We encapsulated CMs in photo-crosslinkable, biomimetic hydrogels with or without ECs, then exposed to oxidative stress followed by normoxia. With precisely controlled microenvironment provided by the model tissues, cell-cell interactions were restricted to be solely through the secreted factors. CM survival after oxidative stress was significantly improved, in the presence of ECs, when cells were in the model tissues that were functionalized with cell attachment motifs. Importantly, the cardioprotective effect of ECs was reduced when HIF-1α expression was knocked down suggesting that HIF-1α is involved in cardioprotection from oxidative damage, provided through secreted factors conferred by the ECs. Using model tissues, we showed that cell survival increased with increased cell-cell communication and enhanced cell-matrix interactions. In addition, whole genome transcriptome analysis showed, for the first time to our knowledge, a possible role for HIF1A-AS1 in oxidative regulation of HIF-1α. We showed that although HIF1A-AS1 knockdown helps CM survival, its effect is overridden by CM-EC bidirectional interactions as we showed that the conditioned media taken from the CM-EC co-cultures improved CM survival, regardless of HIF1A-AS1 expression. Cardiovascular diseases, most of which are associated with oxidative stress, is the most common cause of death worldwide. Thus, understanding

  12. Partial HIF-1a Deficiency Increases Risk of Diabetic Embryopathy

    Czech Academy of Sciences Publication Activity Database

    Pavlínková, Gabriela; Bohuslavová, Romana; Sedmera, David; Škvorová, Lada

    2012-01-01

    Roč. 94, č. 5 (2012), s. 319-319 ISSN 1542-9768 R&D Projects: GA ČR GA301/09/0117 Grant - others:EU FP7(BE) PIRG02-GA-2007-224760 Institutional research plan: CEZ:AV0Z50520701 Keywords : diabetic embryopathy * cardiovascular defects * transcriptional regulation Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition

  13. Hypoxia-inducible factor-1α expression requires PI 3-kinase activity and correlates with Akt1 phosphorylation in invasive breast carcinomas

    NARCIS (Netherlands)

    Gort, E.H.; Groot, A.J.; Derks van de Ven, T.L.P.; Groep, P. van der; Verlaan, I.; Laar, T. van; Diest, P.J. van; Wall, E. van der; Shvarts, A.

    2006-01-01

    Hypoxia-inducible factor-1 alpha (HIF-1a) is the regulatory subunit of the heterodimeric transcription factor HIF-1 and the key factor in cellular response to low oxygen tension. Expression of HIF-1a protein is associated with poor patient survival and therapy resistance in many types of solid

  14. Factors regulated by interferon gamma and hypoxia-inducible factor 1A contribute to responses that protect mice from Coccidioides immitis infection

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    Woelk Christopher H

    2012-09-01

    Full Text Available Abstract Background Coccidioidomycosis results from airborne infections caused by either Coccidioides immitis or C. posadasii. Both are pathogenic fungi that live in desert soil in the New World and can infect normal hosts, but most infections are self-limited. Disseminated infections occur in approximately 5% of cases and may prove fatal. Mouse models of the disease have identified strains that are resistant (e.g. DBA/2 or susceptible (e.g. C57BL/6 to these pathogens. However, the genetic and immunological basis for this difference has not been fully characterized. Results Microarray technology was used to identify genes that were differentially expressed in lung tissue between resistant DBA/2 and sensitive C57BL/6 mice after infection with C. immitis. Differentially expressed genes were mapped onto biological pathways, gene ontologies, and protein interaction networks, which revealed that innate immune responses mediated by Type II interferon (i.e., IFNG and the signal transducer and activator of transcription 1 (STAT1 contribute to the resistant phenotype. In addition, upregulation of hypoxia inducible factor 1A (HIF1A, possibly as part of a larger inflammatory response mediated by tumor necrosis factor alpha (TNFA, may also contribute to resistance. Microarray gene expression was confirmed by real-time quantitative PCR for a subset of 12 genes, which revealed that IFNG HIF1A and TNFA, among others, were significantly differentially expressed between the two strains at day 14 post-infection. Conclusion These results confirm the finding that DBA/2 mice express more Type II interferon and interferon stimulated genes than genetically susceptible strains and suggest that differential expression of HIF1A may also play a role in protection.

  15. The histone demethylases JMJD1A and JMJD2B are transcriptional targets of hypoxia-inducible factor HIF

    DEFF Research Database (Denmark)

    Beyer, Sophie; Kristensen, Malene Maag; Jensen, Kim Steen

    2008-01-01

    of these modifications is exerted by histone methyltransferases and the recently discovered histone demethylases. Here we show that the hypoxia-inducible factor HIF-1a binds to specific recognition sites in the genes encoding the jumonji family histone demethylases JMJD1A and JMJD2B and induces their expression....... Accordingly, hypoxic cells express elevated levels of JMJD1A and JMJD2B mRNA and protein. Furthermore, we find increased expression of JMJD1A and JMJD2B in renal cancer cells that have lost the von Hippel Lindau tumor suppressor protein VHL and therefore display a deregulated expression of HIF. Studies...... on ectopically expressed JMJD1A and JMJD2B indicate that both proteins retain their histone lysine demethylase activity in hypoxia and thereby might impact the hypoxic gene expression program....

  16. Activation of the Hypoxia Inducible Factor 1α Subunit Pathway in Steatotic Liver Contributes to Formation of Cholesterol Gallstones.

    Science.gov (United States)

    Asai, Yoichiro; Yamada, Tetsuya; Tsukita, Sohei; Takahashi, Kei; Maekawa, Masamitsu; Honma, Midori; Ikeda, Masanori; Murakami, Keigo; Munakata, Yuichiro; Shirai, Yuta; Kodama, Shinjiro; Sugisawa, Takashi; Chiba, Yumiko; Kondo, Yasuteru; Kaneko, Keizo; Uno, Kenji; Sawada, Shojiro; Imai, Junta; Nakamura, Yasuhiro; Yamaguchi, Hiroaki; Tanaka, Kozo; Sasano, Hironobu; Mano, Nariyasu; Ueno, Yoshiyuki; Shimosegawa, Tooru; Katagiri, Hideki

    2017-05-01

    Hypoxia-inducible factor 1α subunit (HIF1A) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with nonalcoholic fatty liver disease (NAFLD). NAFLD increases the risk for cholesterol gallstone disease by unclear mechanisms. We studied the relationship between HIF1A and gallstone formation associated with liver steatosis. We performed studies with mice with inducible disruption of Hif1a in hepatocytes via a Cre adenoviral vector (inducible hepatocyte-selective HIF1A knockout [iH-HIFKO] mice), and mice without disruption of Hif1a (control mice). Mice were fed a diet rich in cholesterol and cholate for 1 or 2 weeks; gallbladders were collected and the number of gallstones was determined. Livers and biliary tissues were analyzed by histology, quantitative reverse-transcription polymerase chain reaction, immunohistochemistry, and immunoblots. We measured concentrations of bile acid, cholesterol, and phospholipid in bile and rates of bile flow. Primary hepatocytes and cholangiocytes were isolated and analyzed. HIF1A was knocked down in Hepa1-6 cells with small interfering RNAs. Liver biopsy samples from patients with NAFLD, with or without gallstones, were analyzed by quantitative reverse-transcription polymerase chain reaction. Control mice fed a diet rich in cholesterol and cholate developed liver steatosis with hypoxia; levels of HIF1A protein were increased in hepatocytes around central veins and 90% of mice developed cholesterol gallstones. Only 20% of the iH-HIFKO mice developed cholesterol gallstones. In iH-HIFKO mice, the biliary lipid concentration was reduced by 36%, compared with control mice, and bile flow was increased by 35%. We observed increased water secretion from hepatocytes into bile canaliculi to mediate these effects, resulting in suppression of cholelithogenesis. Hepatic expression of aquaporin 8 (AQP8) protein was 1.5-fold higher in iH-HIFKO mice than in control mice. Under hypoxic

  17. Polymorphisms in the hypoxia-inducible factor 1 alpha gene in Mexican patients with preeclampsia: A case-control study

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    Nava-Salazar Sonia

    2011-03-01

    Full Text Available Abstract Background Although the etiology of preeclampsia is still unclear, recent work suggests that changes in circulating angiogenic factors play a key role in its pathogenesis. In the trophoblast of women with preeclampsia, hypoxia-inducible factor 1 alpha (HIF-1α is over-expressed, and induces the expression of non-angiogenic factors and inhibitors of trophoblast differentiation. This observation prompted the study of HIF-1α and its relation to preeclampsia. It has been described that the C1772T (P582S and G1790A (A588T polymorphisms of the HIF1A gene have significantly greater transcriptional activity, correlated with an increased expression of their proteins, than the wild-type sequence. In this work, we studied whether either or both HIF1A variants contribute to preeclampsia susceptibility. Results Genomic DNA was isolated from 150 preeclamptic and 105 healthy pregnant women. Exon 12 of the HIF1A gene was amplified by PCR, and the genotypes of HIF1A were determined by DNA sequencing. In preeclamptic women and controls, the frequencies of the T allele for C1772T were 4.3 vs. 4.8%, and the frequencies of the A allele for G1790A were 0.0 vs. 0.5%, respectively. No significant differences were found between groups. Conclusion The frequency of the C1772T and G1790A polymorphisms of the HIF1A gene is very low, and neither polymorphism is associated with the development of preeclampsia in the Mexican population.

  18. Comprehensive study of angiogenic factors in women with endometriosis compared to women without endometriosis.

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    Yerlikaya, Gülen; Balendran, Sukirthini; Pröstling, Katharina; Reischer, Theresa; Birner, Peter; Wenzl, Rene; Kuessel, Lorenz; Streubel, Berthold; Husslein, Heinrich

    2016-09-01

    Endometriosis is a benign gynaecological disease, affecting women during their reproductive years. Angiogenesis represents a crucial step in the pathogenesis of endometriosis, because endometriotic lesions require neovascularization. In this study several angiogenesis-related genes have been studied in the context of endometriosis. Some of the analyzed angiogenic factors as well as their interactions were studied the first time regarding a possible association with endometriosis. This case-control study consisted of 205 biopsies of 114 patients comprising 61 endometriosis patients and 53 control patients. Among them in 29 cases paired samples were obtained. VEGFA, VEGFR2, HIF1A, HGF, NRP1, PDGFB, FGF18, TNFα, TGFB2, EPHB4, EPO and ANG mRNA expression was analyzed by qRT-PCR in ectopic tissue samples, in eutopic endometrium of women with and without endometriosis, and in unaffected peritoneum of women with and without endometriosis. VEGFR2, HIF1A, HGF, PDGFB, NRP1 and EPHB4 are overexpressed in ectopic lesions compared to eutopic tissues. VEGFR2, HGF, PDGFB, NRP1, and EPHB4 showed highest mRNA levels in peritoneal implants, in contrast HIF1A showed the highest expression in ovarian endometriomas. Correlation analyses of angiogenic factors in ectopic lesions revealed the strongest associations between VEGFR2, PDGFB, and EPHB4. We further showed a significant upregulation of VEGFR2, HIF1A and EPHB4 in eutopic endometrium of women with endometriosis compared to that of controls and a trend towards upregulation of HGF. Additionally, a significant downregulation for HIF1A, HGF and EPHB4 was observed in unaffected peritoneal tissues of women with endometriosis compared to controls. We identified new genes (EPHB4 and NRP1) that may contribute to angiogenesis in endometriosis beside known factors (VEGFA, VEGFR2, HIF1A, HGF, and PDGFB). Correlation studies revealed the putative importance of EBHB4 in association with endometriosis. Our analyses support preliminary reports

  19. Immunohistochemical overexpression of hypoxia-induced factor 1α associated with slow reduction in {sup 18}fluoro-2-deoxy-D-glucose uptake for chemoradiotherapy in patients with pharyngeal cancer

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    Chen, Shang-Wen [China Medical University Hospital, Department of Radiation Oncology, Taichung (China); China Medical University, School of Medicine, Taichung (China); Taipei Medical University, School of Medicine, Taipei (China); Lin, Ying-Chun [China Medical University Hospital, Department of Radiation Oncology, Taichung (China); China Medical University and Academia Sinica, The Ph.D. Program for Cancer Biology and Drug Discovery, Taichung (China); Chen, Rui-Yun [China Medical University Hospital, Department of Pathology, Taichung (China); Hsieh, Te-Chun; Yen, Kuo-Yang [China Medical University Hospital, Department of Nuclear Medicine and PET Center, Taichung (China); China Medical University, Department of Biomedical Imaging and Radiological Science, Taichung (China); Liang, Ji-An [China Medical University Hospital, Department of Radiation Oncology, Taichung (China); China Medical University, Graduate Institute of Clinical Medical Science, School of Medicine, College of Medicine, Taichung (China); Yang, Shih-Neng [China Medical University Hospital, Department of Radiation Oncology, Taichung (China); China Medical University, Department of Biomedical Imaging and Radiological Science, Taichung (China); Wang, Yao-Ching [China Medical University Hospital, Department of Radiation Oncology, Taichung (China); Chen, Ya-Huey [China Medical University, Graduate Institute of Cancer Biology, Taichung (China); China Medical University Hospital, Center for Molecular Medicine, Taichung (China); Chow, Nan-Haw [National Cheng Kung University, Department of Pathology, Tainan (China); Kao, Chia-Hung [China Medical University Hospital, Department of Nuclear Medicine and PET Center, Taichung (China); China Medical University, Graduate Institute of Clinical Medical Science, School of Medicine, College of Medicine, Taichung (China)

    2016-12-15

    This study examined genomic factors associated with a reduction in {sup 18}fluoro-2-deoxy-D-glucose (FDG) uptake during positron emission tomography-computed tomography (PET-CT) for definitive chemoradiotherapy (CRT) in patients with pharyngeal cancer. The pretreatment and interim PET-CT images of 25 patients with advanced pharyngeal cancers receiving definitive CRT were prospectively evaluated. The maximum standardized uptake value (SUV{sub max}) of the interim PET-CT and the reduction ratio of the SUV{sub max} (SRR) between the two images were measured. Genomic data from pretreatment incisional biopsy specimens (SLC2A1, CAIX, VEGF, HIF1A, BCL2, Claudin-4, YAP1, MET, MKI67, and EGFR) were analyzed using tissue microarrays. Differences in FDG uptake and SRRs between tumors with low and high gene expression were examined using the Mann-Whitney test. Cox regression analysis was performed to examine the effects of variables on local control. The SRR of the primary tumors (SRR-P) was 0.59 ± 0.31, whereas the SRR of metastatic lymph nodes (SRR-N) was 0.54 ± 0.32. Overexpression of HIF1A was associated with a high iSUV{sub max} of the primary tumor (P < 0.001) and neck lymph node (P = 0.04) and a low SRR-P (P = 0.02). Multivariate analysis revealed that patients who had tumors with low SRR-P or high HIF1A expression levels showed inferior local control. In patients with pharyngeal cancer requiring CRT, HIF1A overexpression was positively associated with high interim SUV{sub max} or a slow reduction in FDG uptake. Prospective trials are needed to determine whether the local control rate can be stratified using the HIF1A level as a biomarker and SRR-P. (orig.)

  20. A3 Adenosine Receptors Modulate Hypoxia-inducible Factor-1a Expression in Human A375 Melanoma Cells

    Directory of Open Access Journals (Sweden)

    Stefania Merighi

    2005-10-01

    Full Text Available Hypoxia-inducible factor-1 (HIF-1 is a key regulator of genes crucial to many aspects of cancer biology. The purine nucleoside, adenosine, accumulates within many tissues under hypoxic conditions, including that of tumors. Because the levels of both HIF-1 and adenosine are elevated within the hypoxic environment of solid tumors, we investigated whether adenosine may regulate HIF-1. Here we show that, under hypoxic conditions (< 2% 02, adenosine upregulates HIF-1α protein expression in a dose-dependent and timedependent manner, exclusively through the A3 receptor subtype. The response to adenosine was generated at the cell surface because the inhibition of A3 receptor expression, by using small interfering RNA, abolished nucleoside effects. A3 receptor stimulation in hypoxia also increases angiopoietin-2 (Ang-2 protein accumulation through the induction of HIF-1α. In particular, we found that A3 receptor stimulation activates p44/p42 and p38 mitogen-activated protein kinases, which are required for A3-induced increase of HIF-1a and Ang-2. Collectively, these results suggest a cooperation between hypoxic and adenosine signals that ultimately may lead to the increase in HIF-1-mediated effects in cancer cells.

  1. Neuroglobin-deficiency exacerbates Hif1A and c-FOS response, but does not affect neuronal survival during severe hypoxia in vivo

    DEFF Research Database (Denmark)

    Hundahl, Christian Ansgar; Luuk, Hendrik; Ilmjärv, Sten

    2011-01-01

    Neuroglobin (Ngb), a neuron-specific globin that binds oxygen in vitro, has been proposed to play a key role in neuronal survival following hypoxic and ischemic insults in the brain. Here we address whether Ngb is required for neuronal survival following acute and prolonged hypoxia in mice...

  2. Protective role of hypoxia-inducible factor-1α-dependent CD39 and CD73 in fulminant acute liver failure

    Energy Technology Data Exchange (ETDEWEB)

    Tak, Eunyoung [Asan Institute for Life Sciences and Asan-Minnesota Institute for Innovating Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Jung, Dong-Hwan; Kim, Seok-Hwan; Park, Gil-Chun [Division of Liver Transplantation and Hepatobiliary Surgery, Asan-Minnesota Institute for Innovating Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Jun, Dae Young; Lee, Jooyoung [Asan Institute for Life Sciences and Asan-Minnesota Institute for Innovating Transplantation, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Jung, Bo-hyun [Department of Surgery, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan (Korea, Republic of); Kirchner, Varvara A. [Division of Transplantation, Department of Surgery and Asan-Minnesota Institute for Innovating Transplantation, University of Minnesota, Minneapolis, MN (United States); Hwang, Shin [Division of Liver Transplantation and Hepatobiliary Surgery, Asan-Minnesota Institute for Innovating Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Song, Gi-Won, E-mail: drsong71@amc.seoul.kr [Division of Liver Transplantation and Hepatobiliary Surgery, Asan-Minnesota Institute for Innovating Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of); Lee, Sung-Gyu [Division of Liver Transplantation and Hepatobiliary Surgery, Asan-Minnesota Institute for Innovating Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul (Korea, Republic of)

    2017-01-01

    Acute liver failure (ALF) is a severe life-threatening disease which usually arises in patients with-irreversible liver illnesses. Although human ectonucleotide triphosphate diphosphohydrolase-1, E-NTPDase1 (CD39) and ecto-5′-nucleotidase, Ecto5′NTase (CD73) are known to protect tissues from ALF, the expression and function of CD39 and CD73 during ALF are currently not fully investigated. We tested whether CD39 and CD73 are upregulated by hypoxia inducible factor (HIF)-1α, and improve ischemic tolerance to ALF. To test our hypothesis, liver biopsies were obtained and we found that CD39 and CD73 mRNA and proteins from human specimens were dramatically elevated in ALF. We investigated that induction of CD39 and CD73 in ALF-related with wild type mice. In contrast, deletion of cd39 and cd73 mice has severe ALF. In this study, we concluded that CD39 and CD73 are molecular targets for the development of drugs for ALF patients care. - Highlights: • HIF-1a is stabilized during acute liver failure • Upregulation of CD39 and CD73 following acute liver failure • CD39 and CD73 are transcriptionally induced by HIF-1a • Deletion of Cd39 and CD73 aggravates murine acute liver failure • DMOG treatment induces HIF-1a stabilization, CD39 and CD73 during acute liver failure in WT mice.

  3. Hepatocyte Hypoxia Inducible Factor-1 Mediates the Development of Liver Fibrosis in a Mouse Model of Nonalcoholic Fatty Liver Disease.

    Directory of Open Access Journals (Sweden)

    Omar A Mesarwi

    Full Text Available Obstructive sleep apnea (OSA is associated with the progression of non-alcoholic fatty liver disease (NAFLD to steatohepatitis and fibrosis. This progression correlates with the severity of OSA-associated hypoxia. In mice with diet induced obesity, hepatic steatosis leads to liver tissue hypoxia, which worsens with exposure to intermittent hypoxia. Emerging data has implicated hepatocyte cell signaling as an important factor in hepatic fibrogenesis. We hypothesized that hepatocyte specific knockout of the oxygen sensing α subunit of hypoxia inducible factor-1 (HIF-1, a master regulator of the global response to hypoxia, may be protective against the development of liver fibrosis.Wild-type mice and mice with hepatocyte-specific HIF-1α knockout (Hif1a-/-hep were fed a high trans-fat diet for six months, as a model of NAFLD. Hepatic fibrosis was evaluated by Sirius red stain and hydroxyproline assay. Liver enzymes, fasting insulin, and hepatic triglyceride content were also assessed. Hepatocytes were isolated from Hif1a-/-hep mice and wild-type controls and were exposed to sustained hypoxia (1% O2 or normoxia (16% O2 for 24 hours. The culture media was used to reconstitute type I collagen and the resulting matrices were examined for collagen cross-linking.Wild-type mice on a high trans-fat diet had 80% more hepatic collagen than Hif1a-/-hep mice (2.21 μg collagen/mg liver tissue, versus 1.23 μg collagen/mg liver tissue, p = 0.03, which was confirmed by Sirius red staining. Body weight, liver weight, mean hepatic triglyceride content, and fasting insulin were similar between groups. Culture media from wild-type mouse hepatocytes exposed to hypoxia allowed for avid collagen cross-linking, but very little cross-linking was seen when hepatocytes were exposed to normoxia, or when hepatocytes from Hif1a-/-hep mice were used in hypoxia or normoxia.Hepatocyte HIF-1 mediates an increase in liver fibrosis in a mouse model of NAFLD, perhaps due to liver

  4. Oxidative balance and colon and rectal cancer: interaction of lifestyle factors and genes.

    Science.gov (United States)

    Slattery, Martha L; Lundgreen, Abbie; Welbourn, Bill; Wolff, Roger K; Corcoran, Christopher

    2012-06-01

    Pro-oxidant and anti-oxidant genetic and lifestyle factors can contribute to an individual's level of oxidative stress. We hypothesize that diet, lifestyle and genetic factors work together to influence colon and rectal cancer through an oxidative balance mechanism. We evaluated nine markers for eosinophil peroxidase (EPX), two for myeloperoxidase (MPO), four for hypoxia-inducible factor-1A (HIFIA), and 16 for inducible nitric oxide synthase (NOS2A) in conjunction with dietary antioxidants, aspirin/NSAID use, and cigarette smoking. We used data from population-based case-control studies (colon cancer n=1555 cases, 1956 controls; rectal cancer n=754 cases, 959 controls). Only NOS2A rs2297518 was associated with colon cancer (OR 0.86 95% CI 0.74, 0.99) and EPX rs2302313 and MPO rs2243828 were associated with rectal cancer (OR 0.75 95% CI 0.59, 0.96; OR 0.81 95% CI 0.67, 0.99 respectively) for main effects. However, after adjustment for multiple comparisons we observed the following significant interactions for colon cancer: NOS2A and lutein, EPX and aspirin/NSAID use, and NOS2A (4 SNPs) and cigarette smoking. For rectal cancer we observed the following interactions after adjustment for multiple comparisons: HIF1A and vitamin E, NOS2A (3SNPs) with calcium; MPO with lutein; HIF1A with lycopene; NOS2A with selenium; EPX and NOS2A with aspirin/NSAID use; HIF1A, MPO, and NOS2A (3 SNPs) with cigarette smoking. We observed significant interaction between a composite oxidative balance score and a polygenic model for both colon (p interaction 0.0008) and rectal cancer (p=0.0018). These results suggest the need to comprehensively evaluate interactions to assess the contribution of risk from both environmental and genetic factors. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Effect of Hypoxia-Inducible Factor 1α on Early Healing in Extraction Sockets

    Directory of Open Access Journals (Sweden)

    Hyun-Chang Lim

    2018-01-01

    Full Text Available The aim of the present study was to investigate the effect of hypoxia-inducible factor 1α (HIF1A on the early healing (4 weeks of extraction sockets exhibiting partial loss of the labial bone. Two extraction sockets of the maxillary incisors from each of six dogs were assigned to two treatment modalities: deproteinized bovine bone mineral (i with 10% collagen (DBBM-C soaked with HIF1A and covered by a collagen membrane (CM (HIF group or (ii treated with DBBM-C only and covered by a CM (control group. Microcomputed tomography revealed some degree of collapse of the labial contour. The totally augmented volume and new bone volume did not differ significantly between two groups (P>0.05. The histological analysis revealed that the apical area of the socket was mostly filled with newly formed bone, while there was less newly formed bone in the coronal area and incomplete cortex formation. The histomorphometric analysis revealed that the area of newly formed bone was significantly larger in the HIF group than the control group (12.16±3.04 versus 9.48±2.01 mm2, P<0.05, while there was no significant intergroup difference in the total augmented area. In conclusion, even though DBBM-C soaked with HIF1A enhanced histomorphometric bone formation, this intervention did not demonstrate superiority in preventing ridge shrinkage compared to DBBM-C alone. Clinical relevance of these findings should be further studied.

  6. Lactic Acid is Elevated in Idiopathic Pulmonary Fibrosis and Induces Myofibroblast Differentiation Via pH-Dependent Activation of Transforming Growth Factor

    Energy Technology Data Exchange (ETDEWEB)

    Kottman, R. M.; Kulkarni, Ajit A.; Smolnycki, Katie A.; Lyda, Elizabeth; Dahanayake, Thinesh; Salibi, Rami; Honnons, Sylvie; Jones, Carolyn; Isern, Nancy G.; Hu, Jian Z.; Nathan, Steven D.; Grant, Geraldine; Phipps, Richard P.; Sime, Patricia J.

    2012-10-15

    Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex disease for which the pathogenesis is poorly understood. In this study, we identified lactic acid as a metabolite that is elevated in the lung tissue of patients with IPF. Objectives: This study examines the effect of lactic acid on myofibroblast differentiation and pulmonary fibrosis. Methods:We used metabolomic analysis to examine cellular metabolism in lung tissuefrom patients with IPFanddeterminedthe effects of lactic acid and lactate dehydrogenase-5 (LDH5) overexpression on myofibroblast differentiation and transforming growth factor (TGF)-b activation in vitro. Measurements and Main Results: Lactic acid concentrations from healthy and IPF lung tissue were determined by nuclear magnetic resonance spectroscopy; a-smooth muscle actin, calponin, and LDH5 expression were assessed by Western blot of cell culture lysates. Lactic acid and LDH5 were significantly elevated in IPF lung tissue compared with controls. Physiologic concentrations of lactic acid induced myofibroblast differentiation via activation of TGF-b. TGF-b induced expression of LDH5 via hypoxia-inducible factor 1a (HIF1a). Importantly, overexpression of both HIF1a and LDH5 in human lung fibroblasts induced myofibroblast differentiation and synergized with low dose TGF-b to induce differentiation. Furthermore, inhibition of both HIF1a and LDH5 inhibited TGF-b–induced myofibroblast differentiation. Conclusions: We have identified the metabolite lactic acid as an important mediator of myofibroblast differentiation via a pHdependent activation of TGF-b. We propose that the metabolic milieu of the lung, and potentially other tissues, is an important driving force behind myofibroblast differentiation and potentially the initiation and progression of fibrotic disorders.

  7. Neurite outgrowth mediated by translation elongation factor eEF1A1: a target for antiplatelet agent cilostazol.

    Directory of Open Access Journals (Sweden)

    Kenji Hashimoto

    Full Text Available Cilostazol, a type-3 phosphodiesterase (PDE3 inhibitor, has become widely used as an antiplatelet drug worldwide. A recent second Cilostazol Stroke Prevention Study demonstrated that cilostazol is superior to aspirin for prevention of stroke after an ischemic stroke. However, its precise mechanisms of action remain to be determined. Here, we report that cilostazol, but not the PDE3 inhibitors cilostamide and milrinone, significantly potentiated nerve growth factor (NGF-induced neurite outgrowth in PC12 cells. Furthermore, specific inhibitors for the endoplasmic reticulum protein inositol 1,4,5-triphosphate (IP(3 receptors and several common signaling pathways (PLC-γ, PI3K, Akt, p38 MAPK, and c-Jun N-terminal kinase (JNK, and the Ras/Raf/ERK/MAPK significantly blocked the potentiation of NGF-induced neurite outgrowth by cilostazol. Using a proteomics analysis, we identified that levels of eukaryotic translation elongation factor eEF1A1 protein were significantly increased by treatment with cilostazol, but not cilostamide, in PC12 cells. Moreover, the potentiating effects of cilostazol on NGF-induced neurite outgrowth were significantly antagonized by treatment with eEF1A1 RNAi, but not the negative control of eEF1A1. These findings suggest that eEF1A1 and several common cellular signaling pathways might play a role in the mechanism of cilostazol-induced neurite outgrowth. Therefore, agents that can increase the eEF1A1 protein may have therapeutic relevance in diverse conditions with altered neurite outgrowth.

  8. Scaffold Attachment Factor B1: A Novel Chromatin Regulator of Prostate Cancer Metabolism

    Science.gov (United States)

    2016-10-01

    AWARD NUMBER: W81XWH-14-1-0152 TITLE: Scaffold Attachment Factor B1: A Novel Chromatin Regulator of Prostate Cancer Metabolism PRINCIPAL...TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-14-1-0152 Scaffold Attachment Factor B1: A Novel Chromatin Regulator of Prostate Cancer Metabolism... chromatin immunoprecipitation-next generation DNA sequencing (ChIP-seq) and integrative network modeling to identify the SAFB1 cistrome and the extent of

  9. The Role of Protein Elongation Factor EEF1A2 in Breast Cancer

    National Research Council Canada - National Science Library

    Lee, Jonathan M

    2004-01-01

    ... overexpression can be used as a breast cancer prognostic factor. In addition, we proposed to test the idea that EEF1A2 expression modulates sensitivity to cisplatin and taxol and that EEF1A2-inactivation could be used as a treatment for breast cancer...

  10. Regulation of eukaryotic elongation factor 1 alpha (eEF1A) by dynamic lysine methylation

    DEFF Research Database (Denmark)

    Jakobsson, Magnus E; Małecki, Jędrzej; Falnes, Pål Ø

    2018-01-01

    Lysine methylation is a frequent post-translational protein modification, which has been intensively studied in the case of histone proteins. Lysine methylations are also found on many non-histone proteins, and one prominent example is eukaryotic elongation factor 1 alpha (eEF1A). Besides its...... essential role in the protein synthesis machinery, a number of non-canonical functions have also been described for eEF1A, such as regulation of the actin cytoskeleton and the promotion of viral replication. The functional significance of the extensive lysine methylations on eEF1A, as well as the identity...

  11. Rice homeobox transcription factor HOX1a positively regulates gibberellin responses by directly suppressing EL1.

    Science.gov (United States)

    Wen, Bi-Qing; Xing, Mei-Qing; Zhang, Hua; Dai, Cheng; Xue, Hong-Wei

    2011-11-01

    Homeobox transcription factors are involved in various aspects of plant development, including maintenance of the biosynthesis and signaling pathways of different hormones. However, few direct targets of homeobox proteins have been identified. We here show that overexpression of rice homeobox gene HOX1a resulted in enhanced gibberellin (GA) response, indicating a positive effect of HOX1a in GA signaling. HOX1a is induced by GA and encodes a homeobox transcription factor with transcription repression activity. In addition, HOX1a suppresses the transcription of early flowering1 (EL1), a negative regulator of GA signaling, and further electrophoretic mobility shift assay and chromatin immunoprecipitation analysis revealed that HOX1a directly bound to the promoter region of EL1 to suppress its expression and stimulate GA signaling. These results demonstrate that HOX1a functions as a positive regulator of GA signaling by suppressing EL1, providing informative hints on the study of GA signaling. © 2011 Institute of Botany, Chinese Academy of Sciences.

  12. JUNGBRUNNEN1, a Reactive Oxygen Species–Responsive NAC Transcription Factor, Regulates Longevity in Arabidopsis

    NARCIS (Netherlands)

    Wu, A.; Devi Allu, A.; Garapati, P.; Siddiqui, H.; Dortay, H.; Zanor, M.I.; Amparo Asensi-Fabado, M.; Munne´ -Bosch, S.; Antonio, C.; Tohge, T.; Fernie, A.R.; Kaufmann, K.; Xue, G.P.; Mueller-Roeber, B.; Balazadeh, S.

    2012-01-01

    The transition from juvenility through maturation to senescence is a complex process that involves the regulation of longevity. Here, we identify JUNGBRUNNEN1 (JUB1), a hydrogen peroxide (H2O2)-induced NAC transcription factor, as a central longevity regulator in Arabidopsis thaliana. JUB1

  13. Mutational analysis of Glu272 in elongation factor 1A of E. coli

    DEFF Research Database (Denmark)

    Mansilla, Francisco; Knudsen, Charlotte Rohde; Clark, Brian F. C.

    1998-01-01

    In our previous work (Mansilla et al. (1997) Protein Eng. 10, 927-934) we showed that Arg7 of Escherichia coli elongation factor Tu (EF1A) plays an essential role in aminoacyl-tRNA (aa-tRNA) binding. Substitution of Arg7 by Ala or Glu lost this activity. We proposed that Arg7 forms a salt bridge...

  14. Mutational analysis of Glu272 in elongation factor 1A of E. coli

    DEFF Research Database (Denmark)

    Mansilla, Francisco; Knudsen, Charlotte Rohde; Clark, Brian F. C.

    1998-01-01

    In our previous work (Mansilla et al. (1997) Protein Eng. 10, 927-934) we showed that Arg7 of Escherichia coli elongation factor Tu (EF1A) plays an essential role in aminoacyl-tRNA (aa-tRNA) binding. Substitution of Arg7 by Ala or Glu lost this activity. We proposed that Arg7 forms a salt bridge ...

  15. Hypoxic preconditioning protects photoreceptors against light damage independently of hypoxia inducible transcription factors in rods.

    Science.gov (United States)

    Kast, Brigitte; Schori, Christian; Grimm, Christian

    2016-05-01

    Hypoxic preconditioning protects photoreceptors against light-induced degeneration preserving retinal morphology and function. Although hypoxia inducible transcription factors 1 and 2 (HIF1, HIF2) are the main regulators of the hypoxic response, photoreceptor protection does not depend on HIF1 in rods. Here we used rod-specific Hif2a single and Hif1a;Hif2a double knockout mice to investigate the potential involvement of HIF2 in rods for protection after hypoxic preconditioning. To identify potential HIF2 target genes in rods we determined the retinal transcriptome of hypoxic control and rod-specific Hif2a knockouts by RNA sequencing. We show that rods do not need HIF2 for hypoxia-induced increased survival after light exposure. The transcriptomic analysis revealed a number of genes that are potentially regulated by HIF2 in rods; among those were Htra1, Timp3 and Hmox1, candidates that are interesting due to their connection to human degenerative diseases of the retina. We conclude that neither HIF1 nor HIF2 are required in photoreceptors for protection by hypoxic preconditioning. We hypothesize that HIF transcription factors may be needed in other cells to produce protective factors acting in a paracrine fashion on photoreceptor cells. Alternatively, hypoxic preconditioning induces a rod-intrinsic response that is independent of HIF transcription factors. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Postoperative shoulder imbalance in Lenke Type 1A adolescent idiopathic scoliosis and related factors.

    Science.gov (United States)

    Matsumoto, Morio; Watanabe, Kota; Kawakami, Noriaki; Tsuji, Taichi; Uno, Koki; Suzuki, Teppei; Ito, Manabu; Yanagida, Haruhisa; Minami, Shohei; Akazawa, Tsutomu

    2014-11-05

    The purpose of this study was to investigate the occurrence and factors associated with postoperative shoulder imbalance (PSI) in Lenke type 1A curve. This study included 106 patients with Lenke Type 1A curve who were followed up more than two years after posterior correction surgery. Pedicle screw (PS) constructs were used in 84 patients, and hybrid constructs in 22. The upper instrumented vertebra was rostral to the upper-end vertebra (UEV) in 70 patients, at UEV in 26, and below UEV in 10. The clavicle angle and T1 tilt angle were measured as PSI indicators, and correlations between radiographic parameters of shoulder balance and other radiographic parameters and associations between PSI and clinical parameters were investigated. For statistical analyses, paired and unpaired t-tests were used. The mean Cobb angles of the main and proximal thoracic curves were 54.6 ± 9.5 and 26.7 ± 7.9 degrees before surgery, 14.5 ± 7.5, and 14.9 ± 7.1 at follow-up. Clavicle angle and T1 tilt angle were -2.9 ± 2.8 and -2.6 ± 6.3 before surgery, 2.4 ± 2.8 and 4.4 ± 4.3 immediately after surgery, and 1.8 ± 2.1 and 3.4 ± 5.5 at follow-up. Twenty patients developed distal adding-on. Clavicle angle at follow-up correlated weakly but significantly with preoperative clavicle angle (r = 0.34, p = 0.001) and with the correction rates of the main thoracic curve (r = 0.34, p = 0.001); it correlated negatively with the proximal curve spontaneous correction rate (r=-0.21, p = 0.034). The clavicle angle at follow-up was significantly larger in patients with PS-only constructs (PS 2.1 degrees vs. hybrid 0.9, p = 0.02), and tended to be smaller in patients with distal adding-on (adding-on 1.1 vs. non adding-on 2.0, p = 0.09). PSI was more common with better correction of the main curve (using PS constructs), in patients with a larger preoperative clavicle angle, and with a larger and more rigid proximal curve. Distal adding-on may compensate for PSI.

  17. Heat-induced accumulation of protein synthesis elongation factor 1A indicates an important role in heat tolerance in potato

    Science.gov (United States)

    Heat stress substantially reduces crop productivity worldwide, and will become more severe due to global warming. Identification of proteins involved in heat stress response may help develop varieties for heat tolerance. Eukaryotic elongation factor 1A (eEF1A) is a cytosolic, multifunctional protei...

  18. Evaluation of toxic equivalency factors for induction of cytochromes P450 CYP1A1 and CYP1A2 enzyme activity by dioxin-like compounds

    International Nuclear Information System (INIS)

    Toyoshiba, Hiroyoshi; Walker, Nigel J.; Bailer, A. John; Portier, Christopher J.

    2004-01-01

    The toxic equivalency factor (TEF) method has been used to characterize the toxicity of human mixtures of dioxin-like compounds and is being considered for use with other classes of potentially toxic agents. TEFs are estimated by examining the relative potencies of the various congeners for a series of biological and toxicological effects. In this paper, we consider changes in activity for two enzymes, cytochrome P450 1A1 (CYP1A1)-associated 7-ethoxyresorufin-O-deethylase (EROD) and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activity, resulting from exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3,3',4,4',5-pentachlorobiphenyl (PCB), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) or a mixture of these agents. The ratio of median effective dose (ED 50 ) is one way to estimate the relative potencies, especially for gene expression and protein endpoints. ED 50 's were estimated with a nonlinear regression model in which dose-related changes in mean responses are described by a Hill function. ED 50 's along with other model parameters were estimated by fitting this model to a given data set. Significant differences in estimated model parameters were tested by likelihood ratio methods. The estimated parameters indicated that congener-specific dose-response shapes were significantly different, that additivity failed for these congeners, and that the ratios of ED 50 's did not predict the response seen for the mixture. These results indicate that for some biological responses, the use of a single relative potency factor (RPF) is not appropriate for the comparison of the dose response behavior of different dioxin-like congeners

  19. Comparative genomic and functional analyses: unearthing the diversity and specificity of nematicidal factors in Pseudomonas putida strain 1A00316

    Science.gov (United States)

    Guo, Jing; Jing, Xueping; Peng, Wen-Lei; Nie, Qiyu; Zhai, Yile; Shao, Zongze; Zheng, Longyu; Cai, Minmin; Li, Guangyu; Zuo, Huaiyu; Zhang, Zhitao; Wang, Rui-Ru; Huang, Dian; Cheng, Wanli; Yu, Ziniu; Chen, Ling-Ling; Zhang, Jibin

    2016-01-01

    We isolated Pseudomonas putida (P. putida) strain 1A00316 from Antarctica. This bacterium has a high efficiency against Meloidogyne incognita (M. incognita) in vitro and under greenhouse conditions. The complete genome of P. putida 1A00316 was sequenced using PacBio single molecule real-time (SMRT) technology. A comparative genomic analysis of 16 Pseudomonas strains revealed that although P. putida 1A00316 belonged to P. putida, it was phenotypically more similar to nematicidal Pseudomonas fluorescens (P. fluorescens) strains. We characterized the diversity and specificity of nematicidal factors in P. putida 1A00316 with comparative genomics and functional analysis, and found that P. putida 1A00316 has diverse nematicidal factors including protein alkaline metalloproteinase AprA and two secondary metabolites, hydrogen cyanide and cyclo-(l-isoleucyl-l-proline). We show for the first time that cyclo-(l-isoleucyl-l-proline) exhibit nematicidal activity in P. putida. Interestingly, our study had not detected common nematicidal factors such as 2,4-diacetylphloroglucinol (2,4-DAPG) and pyrrolnitrin in P. putida 1A00316. The results of the present study reveal the diversity and specificity of nematicidal factors in P. putida strain 1A00316. PMID:27384076

  20. PPARGC1A sequence variation and cardiovascular risk-factor levels

    DEFF Research Database (Denmark)

    Brito, E C; Vimaleswaran, K S; Brage, S

    2009-01-01

    .005; rs13117172, p = 0.008) and fasting glucose concentrations (rs7657071, p = 0.002). None remained significant after correcting for the number of statistical comparisons. We proceeded by testing for gene x physical activity interactions for the polymorphisms that showed nominal evidence of association...... in the main effect models. None of these tests was statistically significant. CONCLUSIONS/INTERPRETATION: Variants at PPARGC1A may influence several metabolic traits in this European paediatric cohort. However, variation at PPARGC1A is unlikely to have a major impact on cardiovascular or metabolic health...

  1. DRE-binding Transcription factor (DREB1A) as a master regulator ...

    African Journals Online (AJOL)

    eisa

    2011-10-31

    Oct 31, 2011 ... African Journal of Biotechnology Vol. 10(67), pp. ... In this review, we presented evidences which show ... Key words: Abiotic stress, DREB1A gene, tolerance plant. .... membranes and/or proteins (Diamant et al., 2001, Garg et al., 2002). .... suggested that the A. thaliana plasma membrane Na+/H+ antiporter ...

  2. Up-regulation of CHAF1A, a poor prognostic factor, facilitates cell proliferation of colon cancer

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Zehua; Cui, Feifei; Yu, Fudong; Peng, Xiao; Jiang, Tao; Chen, Dawei [Department of General Surgery, Shanghai Jiaotong University Affiliated First People’s Hospital, 85 Wujin Road, Shanghai 200080 (China); Lu, Su [Department of Pathology, Shanghai Jiaotong University Affiliated First People’s Hospital, 85 Wujin Road, Shanghai 200080 (China); Tang, Huamei, E-mail: tanghuamei@gmail.com [Department of Pathology, Shanghai Jiaotong University Affiliated First People’s Hospital, 85 Wujin Road, Shanghai 200080 (China); Peng, Zhihai, E-mail: zhihai.peng@hotmail.com [Department of General Surgery, Shanghai Jiaotong University Affiliated First People’s Hospital, 85 Wujin Road, Shanghai 200080 (China)

    2014-06-27

    Highlights: • We identified that CHAF1A was up-regulated in colon tumor mucosa in TMA. • The expression pattern of CHAF1A was validated with qPCR and western-blot. • CHAF1A overexpression is an independent indicator for poor colon cancer survival. • CHAF1A facilitates cell proliferation of colon cancer both in vitro and in vivo. - Abstract: Deregulation of chromatin assembly factor 1, p150 subunit A (CHAF1A) has recently been reported to be involved in the development of some cancer types. In this study, we identified that the frequency of positive CHAF1A staining in primary tumor mucosa (45.8%, 93 of 203 samples) was significantly elevated compared to that in paired normal mucosa (18.7%, 38 of 203 samples). The increased expression was strongly associated with cancer stage, tumor invasion, and histological grade. The five-year survival rate of patients with CHAF1A-positive tumors was remarkably lower than that of patients with CHAF1A-negative tumors. Colon cancer cells with CHAF1A knockdown exhibited decreased cell growth index, reduction in colony formation ability, elevated cell apoptosis rate as well as impaired colon tumorigenicity in nude mice. Hence, CHAF1A upregulation functions as a poor prognostic indicator of colon cancer, potentially contributing to its progression by mediating cancer cell proliferation.

  3. Up-regulation of CHAF1A, a poor prognostic factor, facilitates cell proliferation of colon cancer

    International Nuclear Information System (INIS)

    Wu, Zehua; Cui, Feifei; Yu, Fudong; Peng, Xiao; Jiang, Tao; Chen, Dawei; Lu, Su; Tang, Huamei; Peng, Zhihai

    2014-01-01

    Highlights: • We identified that CHAF1A was up-regulated in colon tumor mucosa in TMA. • The expression pattern of CHAF1A was validated with qPCR and western-blot. • CHAF1A overexpression is an independent indicator for poor colon cancer survival. • CHAF1A facilitates cell proliferation of colon cancer both in vitro and in vivo. - Abstract: Deregulation of chromatin assembly factor 1, p150 subunit A (CHAF1A) has recently been reported to be involved in the development of some cancer types. In this study, we identified that the frequency of positive CHAF1A staining in primary tumor mucosa (45.8%, 93 of 203 samples) was significantly elevated compared to that in paired normal mucosa (18.7%, 38 of 203 samples). The increased expression was strongly associated with cancer stage, tumor invasion, and histological grade. The five-year survival rate of patients with CHAF1A-positive tumors was remarkably lower than that of patients with CHAF1A-negative tumors. Colon cancer cells with CHAF1A knockdown exhibited decreased cell growth index, reduction in colony formation ability, elevated cell apoptosis rate as well as impaired colon tumorigenicity in nude mice. Hence, CHAF1A upregulation functions as a poor prognostic indicator of colon cancer, potentially contributing to its progression by mediating cancer cell proliferation

  4. Translation elongation factor 1A facilitates the assembly of the tombusvirus replicase and stimulates minus-strand synthesis.

    OpenAIRE

    Zhenghe Li; Judit Pogany; Steven Tupman; Anthony M Esposito; Terri Goss Kinzy; Peter D Nagy

    2010-01-01

    Replication of plus-strand RNA viruses depends on host factors that are recruited into viral replicase complexes. Previous studies showed that eukaryotic translation elongation factor (eEF1A) is one of the resident host proteins in the highly purified tombusvirus replicase complex. Using a random library of eEF1A mutants, we identified one mutant that decreased and three mutants that increased Tomato bushy stunt virus (TBSV) replication in a yeast model host. Additional in vitro assays with w...

  5. ABCE1: A special factor that orchestrates translation at the crossroad between recycling and initiation

    Czech Academy of Sciences Publication Activity Database

    Mancera-Martínez, E.; Brito Querido, J.; Valášek, Leoš Shivaya; Simonetti, A.; Hashem, Y.

    2017-01-01

    Roč. 14, č. 10 (2017), s. 1279-1285 ISSN 1547-6286 R&D Projects: GA ČR(CZ) GA14-05394S Institutional support: RVO:61388971 Keywords : ABCE1 * cryo-EM * ribosome Subject RIV: EE - Microbiology, Virology OBOR OECD: Microbiology Impact factor: 3.900, year: 2016

  6. Mipu1, a novel direct target gene, is involved in hypoxia inducible factor 1-mediated cytoprotection.

    Directory of Open Access Journals (Sweden)

    Kangkai Wang

    Full Text Available Mipu1 (myocardial ischemic preconditioning up-regulated protein 1, recently identified in our lab, is a novel zinc-finger transcription factor which is up-regulated during ischemic preconditioning. However, it is not clear what transcription factor contributes to its inducible expression. In the present study, we reported that HIF-1 regulates the inducible expression of Mipu1 which is involved in the cytoprotection of HIF-1α against oxidative stress by inhibiting Bax expression. Our results showed that the inducible expression of Mipu1 was associated with the expression and activation of transcription factor HIF-1 as indicated by cobalt chloride (CoCl2 treatment, HIF-1α overexpression and knockdown assays. EMSA and luciferase reporter gene assays showed that HIF-1α bound to the hypoxia response element (HRE within Mipu1 promoter region and promoted its transcription. Moreover, our results revealed that Mipu1 inhibited the expression of Bax, an important pro-apoptosis protein associated with the intrinsic pathway of apoptosis, elevating the cytoprotection of HIF-1 against hydrogen peroxide (H2O2-mediated injury in H9C2 cells. Our findings implied that Bax may be a potential target gene of transcription factor Mipu1, and provided a novel insight for understanding the cytoprotection of HIF-1 and new clues for further elucidating the mechanisms by which Mipu1 protects cell against pathological stress.

  7. The UGT1A6_19_GG genotype is a breast cancer risk factor

    Directory of Open Access Journals (Sweden)

    Christina eJustenhoven

    2013-06-01

    Full Text Available Validation of an association between the UGT1A6_19_T>G (rs6759892 polymorphism and overall breast cancer risk. A pilot study included two population-based case-control studies from Germany (MARIE-GENICA. An independent validation study comprised four independent breast cancer case-control studies from Finland (KBCP, OBCS, Germany (BBCC and Sweden (SASBAC. The pooled analysis included 7,418 cases and 8,720 controls from all six studies. Participants were of European descent. Genotyping was done by MALDI-TOF MS and statistical analysis was performed by logistic regression adjusted for age and study. The increased overall breast cancer risk for women with the UGT1A6_19_GG genotype which was observed in the pilot study was confirmed in the set of four independent study collections (OR 1.13, 95% CI 1.05-1.22; p = 0.001. The pooled study showed a similar effect (OR 1.09, 95% CI 1.04-1.14; p = 0.001. We confirmed the association of UGT1A6_19_GG with increased overall breast cancer risk and conclude that our result from a well powered multi-stage study adds a novel candidate to the panel of validated breast cancer susceptibility loci.

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

    Directory of Open Access Journals (Sweden)

    Harvey Mario

    2010-01-01

    Full Text Available Abstract 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.

  9. Kinetics of the interactions between yeast elongation factors 1A and 1Balpha, guanine nucleotides, and aminoacyl-tRNA

    DEFF Research Database (Denmark)

    Gromadski, Kirill B; Schümmer, Tobias; Strømgaard, Anne

    2007-01-01

    of guanine nucleotides. At the concentrations of nucleotides and factors prevailing in the cell, the overall exchange rate is expected to be in the range of 6 s(-1), which is compatible with the rate of protein synthesis in the cell. eEF1A.GTP binds Phe-tRNA(Phe) with a K(d) of 3 nm, whereas eEF1A.GDP shows...... no significant binding, indicating that eEF1A has similar tRNA binding properties as its prokaryotic homolog, EF-Tu. Udgivelsesdato: 2007-Dec-7...

  10. AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance.

    KAUST Repository

    Burla, Romina; Carcuro, Mariateresa; Raffa, Grazia D; Galati, Alessandra; Raimondo, Domenico; Rizzo, Angela; La Torre, Mattia; Micheli, Emanuela; Ciapponi, Laura; Cenci, Giovanni; Cundari, Enrico; Musio, Antonio; Biroccio, Annamaria; Cacchione, Stefano; Gatti, Maurizio; Saggio, Isabella

    2015-01-01

    Telomeres are nucleoprotein complexes that protect the ends of linear chromosomes from incomplete replication, degradation and detection as DNA breaks. Mammalian telomeres are protected by shelterin, a multiprotein complex that binds the TTAGGG telomeric repeats and recruits a series of additional factors that are essential for telomere function. Although many shelterin-associated proteins have been so far identified, the inventory of shelterin-interacting factors required for telomere maintenance is still largely incomplete. Here, we characterize AKTIP/Ft1 (human AKTIP and mouse Ft1 are orthologous), a novel mammalian shelterin-bound factor identified on the basis of its homology with the Drosophila telomere protein Pendolino. AKTIP/Ft1 shares homology with the E2 variant ubiquitin-conjugating (UEV) enzymes and has been previously implicated in the control of apoptosis and in vesicle trafficking. RNAi-mediated depletion of AKTIP results in formation of telomere dysfunction foci (TIFs). Consistent with these results, AKTIP interacts with telomeric DNA and binds the shelterin components TRF1 and TRF2 both in vivo and in vitro. Analysis of AKTIP- depleted human primary fibroblasts showed that they are defective in PCNA recruiting and arrest in the S phase due to the activation of the intra S checkpoint. Accordingly, AKTIP physically interacts with PCNA and the RPA70 DNA replication factor. Ft1-depleted p53-/- MEFs did not arrest in the S phase but displayed significant increases in multiple telomeric signals (MTS) and sister telomere associations (STAs), two hallmarks of defective telomere replication. In addition, we found an epistatic relation for MST formation between Ft1 and TRF1, which has been previously shown to be required for replication fork progression through telomeric DNA. Ch-IP experiments further suggested that in AKTIP-depleted cells undergoing the S phase, TRF1 is less tightly bound to telomeric DNA than in controls. Thus, our results collectively

  11. AKTIP/Ft1, a New Shelterin-Interacting Factor Required for Telomere Maintenance.

    KAUST Repository

    Burla, Romina

    2015-06-25

    Telomeres are nucleoprotein complexes that protect the ends of linear chromosomes from incomplete replication, degradation and detection as DNA breaks. Mammalian telomeres are protected by shelterin, a multiprotein complex that binds the TTAGGG telomeric repeats and recruits a series of additional factors that are essential for telomere function. Although many shelterin-associated proteins have been so far identified, the inventory of shelterin-interacting factors required for telomere maintenance is still largely incomplete. Here, we characterize AKTIP/Ft1 (human AKTIP and mouse Ft1 are orthologous), a novel mammalian shelterin-bound factor identified on the basis of its homology with the Drosophila telomere protein Pendolino. AKTIP/Ft1 shares homology with the E2 variant ubiquitin-conjugating (UEV) enzymes and has been previously implicated in the control of apoptosis and in vesicle trafficking. RNAi-mediated depletion of AKTIP results in formation of telomere dysfunction foci (TIFs). Consistent with these results, AKTIP interacts with telomeric DNA and binds the shelterin components TRF1 and TRF2 both in vivo and in vitro. Analysis of AKTIP- depleted human primary fibroblasts showed that they are defective in PCNA recruiting and arrest in the S phase due to the activation of the intra S checkpoint. Accordingly, AKTIP physically interacts with PCNA and the RPA70 DNA replication factor. Ft1-depleted p53-/- MEFs did not arrest in the S phase but displayed significant increases in multiple telomeric signals (MTS) and sister telomere associations (STAs), two hallmarks of defective telomere replication. In addition, we found an epistatic relation for MST formation between Ft1 and TRF1, which has been previously shown to be required for replication fork progression through telomeric DNA. Ch-IP experiments further suggested that in AKTIP-depleted cells undergoing the S phase, TRF1 is less tightly bound to telomeric DNA than in controls. Thus, our results collectively

  12. Fetal antigen 1 (FA1), a circulating member of the epidermal growth factor (EGF) superfamily

    DEFF Research Database (Denmark)

    Jensen, Charlotte Harken; Krogh, T N; Støving, René Klinkby

    1997-01-01

    We describe an ELISA technique for quantification of fetal antigen 1 (FA1), a glycoprotein belonging to the EGF-superfamily. The ELISA is based on immunospecifically purified polyclonal antibodies and has a dynamic range of 0.7-5.3 ng/ml, intra- and inter-assay C.V.s of less than 3.2% and an aver......We describe an ELISA technique for quantification of fetal antigen 1 (FA1), a glycoprotein belonging to the EGF-superfamily. The ELISA is based on immunospecifically purified polyclonal antibodies and has a dynamic range of 0.7-5.3 ng/ml, intra- and inter-assay C.V.s of less than 3.......2% and an average recovery of 105% in serum and 98% in urine. Comparison of FA1 in amniotic fluid, serum and urine revealed parallel titration curves, identical elution volumes following size chromatography, immunological identity and similar profiles when analysed by MALDI-MS. The reference interval for serum FA1...... was 12.3-46.6 ng/ml and the levels were 10 times higher in patients with renal failure. FA1 showed no diurnal variation, no variation during the menstrual cycle and was not influenced by the acute phase reaction. In humans (n = 10) the renal clearance of FA1 was 11 ml/min and an identical high renal...

  13. Copy number variations of E2F1: a new genetic risk factor for testicular cancer.

    Science.gov (United States)

    Rocca, Maria Santa; Di Nisio, Andrea; Marchiori, Arianna; Ghezzi, Marco; Opocher, Giuseppe; Foresta, Carlo; Ferlin, Alberto

    2017-03-01

    Testicular germ cell tumor (TGCT) is one of the most heritable forms of cancer. In last years, many evidence suggested that constitutional genetic factors, mainly single nucleotide polymorphisms, can increase its risk. However, the possible contribution of copy number variations (CNVs) in TGCT susceptibility has not been substantially addressed. Indeed, an increasing number of studies have focused on the effect of CNVs on gene expression and on the role of these structural genetic variations as risk factors for different forms of cancer. E2F1 is a transcription factor that plays an important role in regulating cell growth, differentiation, apoptosis and response to DNA damage. Therefore, deficiency or overexpression of this protein might significantly influence fundamental biological processes involved in cancer development and progression, including TGCT. We analyzed E2F1 CNVs in 261 cases with TGCT and 165 controls. We found no CNVs in controls, but 17/261 (6.5%) cases showed duplications in E2F1 Blot analysis demonstrated higher E2F1 expression in testicular samples of TGCT cases with three copies of the gene. Furthermore, we observed higher phosphorylation of Akt and mTOR in samples with E2F1 duplication. Interestingly, normal, non-tumoral testicular tissue in patient with E2F1 duplication showed lower expression of E2F1 and lower AKT/mTOR phosphorylation with respect to adjacent tumor tissue. Furthermore, increased expression of E2F1 obtained in vitro in NTERA-2 testicular cell line induced increased AKT/mTOR phosphorylation. This study suggests for the first time an involvement of E2F1 CNVs in TGCT susceptibility and supports previous preliminary data on the importance of AKT/mTOR signaling pathway in this cancer. © 2017 Society for Endocrinology.

  14. A novel phenotype of a hepatocyte nuclear factor homeobox A (HNF1A) gene mutation, presenting with neonatal cholestasis

    NARCIS (Netherlands)

    de Vries, Aleida G. M.; Bakker-van Waarde, Willie M.; Dassel, Anne C. M.; Losekoot, Monique; Duiker, Evelien W.; Gouw, Annette S. H.; Bodewes, Frank A. J. A.

    We report a novel phenotype of a hepatocyte nuclear factor homeobox A (HNF1A) mutation (heterozygote c.130dup, p.Leu44fs) presenting with transient neonatal cholestasis, subsequently followed by persistent elevation of transaminases, maturity-onset diabetes of the young (MODY) type 3 and

  15. Prep1, A Homeodomain Transcription Factor Involved in Glucose and Lipid Metabolism

    Directory of Open Access Journals (Sweden)

    Francesco Oriente

    2018-06-01

    Full Text Available The three-amino acid loop extension (TALE homeodomain proteins are a family of transcription factor including the mammalian Pbx, MEIS and Prep proteins. TALE proteins can bind other transcription factors such as Pdx-1 and play an important role in the regulation of glucose metabolism. Experiments performed in mutant mice have shown that while the single Pbx1 or Pdx-1 knockout mice feature pancreatic islet malformations, impaired glucose tolerance and hypoinsulinemia, the trans-heterozygous Pbx1+/−Pdx1+/− mice develop age-dependent overt diabetes mellitus. In contrast, Prep1 plays a different role with respect to these proteins. Indeed, Prep1 hypomorphic mice, expressing low levels of protein, feature pancreatic islet hypoplasia accompanied by hypoinsulinemia similar to Pbx1 or Pdx1. Nevertheless, these animals show increased insulin sensitivity in skeletal muscle, liver and adipose tissue accompanied by protection from streptozotocin-induced diabetes. In addition, Prep1 hypomorphic mice feature reduced triglyceride synthesis and do not develop steatohepatitis after a methionine and coline deficient diet. In this review we have underlined how important metabolic functions are controlled by TALE proteins, in particular by Prep1, leading to hypothesis that its suppression might represent beneficial effect in the care of metabolic diseases.

  16. Pbx and Prdm1a transcription factors differentially regulate subsets of the fast skeletal muscle program in zebrafish

    Directory of Open Access Journals (Sweden)

    Zizhen Yao

    2013-04-01

    The basic helix–loop–helix factor Myod initiates skeletal muscle differentiation by directly and sequentially activating sets of muscle differentiation genes, including those encoding muscle contractile proteins. We hypothesize that Pbx homeodomain proteins direct Myod to a subset of its transcriptional targets, in particular fast-twitch muscle differentiation genes, thereby regulating the competence of muscle precursor cells to differentiate. We have previously shown that Pbx proteins bind with Myod on the promoter of the zebrafish fast muscle gene mylpfa and that Pbx proteins are required for Myod to activate mylpfa expression and the fast-twitch muscle-specific differentiation program in zebrafish embryos. Here we have investigated the interactions of Pbx with another muscle fiber-type regulator, Prdm1a, a SET-domain DNA-binding factor that directly represses mylpfa expression and fast muscle differentiation. The prdm1a mutant phenotype, early and increased fast muscle differentiation, is the opposite of the Pbx-null phenotype, delayed and reduced fast muscle differentiation. To determine whether Pbx and Prdm1a have opposing activities on a common set of genes, we used RNA-seq analysis to globally assess gene expression in zebrafish embryos with single- and double-losses-of-function for Pbx and Prdm1a. We find that the levels of expression of certain fast muscle genes are increased or approximately wild type in pbx2/4-MO;prdm1a−/− embryos, suggesting that Pbx activity normally counters the repressive action of Prdm1a for a subset of the fast muscle program. However, other fast muscle genes require Pbx but are not regulated by Prdm1a. Thus, our findings reveal that subsets of the fast muscle program are differentially regulated by Pbx and Prdm1a. Our findings provide an example of how Pbx homeodomain proteins act in a balance with other transcription factors to regulate subsets of a cellular differentiation program.

  17. Human HMG box transcription factor HBP1: a role in hCD2 LCR function.

    Science.gov (United States)

    Zhuma, T; Tyrrell, R; Sekkali, B; Skavdis, G; Saveliev, A; Tolaini, M; Roderick, K; Norton, T; Smerdon, S; Sedgwick, S; Festenstein, R; Kioussis, D

    1999-01-01

    The locus control region (LCR) of the human CD2 gene (hCD2) confers T cell-specific, copy-dependent and position-independent gene expression in transgenic mice. This LCR consists of a strong T cell-specific enhancer and an element without enhancer activity (designated HSS3), which is required for prevention of position effect variegation (PEV) in transgenic mice. Here, we identified the HMG box containing protein-1 (HBP1) as a factor binding to HSS3 of the hCD2 LCR. Within the LCR, HBP1 binds to a novel TTCATTCATTCA sequence that is higher in affinity than other recently reported HBP1-binding sites. Mice transgenic for a hCD2 LCR construct carrying a deletion of the HBP1-binding sequences show a propensity for PEV if the transgene integrates in a heterochromatic region of the chromosome such as the centromere or telomere. We propose that HBP1 plays an important role in chromatin opening and remodelling activities by binding to and bending the DNA, thus allowing DNA-protein and/or protein-protein interactions, which increase the probability of establishing an active locus. PMID:10562551

  18. Interactions between environmental factors and melatonin receptor type 1A polymorphism in relation to oral cancer susceptibility and clinicopathologic development.

    Directory of Open Access Journals (Sweden)

    Feng-Yan Lin

    Full Text Available The purpose of this study was to explore the combined effect of melatonin receptor type 1A (MTNR1A gene polymorphisms and exposure to environmental carcinogens on the susceptibility and clinicopathological characteristics of oral cancer.Three polymorphisms of the MTNR1A gene from 618 patients with oral cancer and 560 non-cancer controls were analyzed by real-time polymerase chain reaction (PCR. The CTA haplotype of the studied MTNR1A polymorphisms (rs2119882, rs13140012, rs6553010 was related to a higher risk of oral cancer. Moreover, MTNR1A gene polymorphisms exhibited synergistic effects of environmental factors (betel quid and tobacco use on the susceptibility of oral cancer. Finally, oral-cancer patients with betel quid-chewing habit who had T/T allele of MTNR1A rs13140012 were at higher risk for developing an advanced clinical stage and lymph node metastasis.These results support gene-environment interactions of MTNR1A polymorphisms with smoking and betel quid-chewing habits possibly altering oral-cancer susceptibility and metastasis.

  19. Soybean (Glycine max) WRINKLED1 transcription factor, GmWRI1a, positively regulates seed oil accumulation.

    Science.gov (United States)

    Chen, Liang; Zheng, Yuhong; Dong, Zhimin; Meng, Fanfan; Sun, Xingmiao; Fan, Xuhong; Zhang, Yunfeng; Wang, Mingliang; Wang, Shuming

    2018-04-01

    Soybean is the world's most important leguminous crop producing high-quality protein and oil. Elevating oil accumulation in soybean seed is always many researchers' goal. WRINKLED1 (WRI1) encodes a transcription factor of the APETALA2/ethylene responsive element-binding protein (AP2/EREBP) family that plays important roles during plant seed oil accumulation. In this study, we isolated and characterized three distinct orthologues of WRI1 in soybean (Glycine max) that display different organ-specific expression patterns, among which GmWRI1a was highly expressed in maturing soybean seed. Electrophoretic mobility shift assays and yeast one-hybrid experiments demonstrated that the GmWRI1a protein was capable of binding to AW-box, a conserved sequence in the proximal upstream regions of many genes involved in various steps of oil biosynthesis. Transgenic soybean seeds overexpressing GmWRI1a under the control of the seed-specific napin promoter showed the increased total oil and fatty acid content and the changed fatty acid composition. Furthermore, basing on the activated expressions in transgenic soybean seeds and existence of AW-box element in the promoter regions, direct downstream genes of GmWRI1a were identified, and their products were responsible for fatty acid production, elongation, desaturation and export from plastid. We conclude that GmWRI1a transcription factor can positively regulate oil accumulation in soybean seed by a complex gene expression network related to fatty acid biosynthesis.

  20. Insulin-like growth factor 1 (IGF-1): a growth hormone

    Science.gov (United States)

    Laron, Z

    2001-01-01

    Aim—To contribute to the debate about whether growth hormone (GH) and insulin-like growth factor 1 (IGF-1) act independently on the growth process. Methods—To describe growth in human and animal models of isolated IGF-1 deficiency (IGHD), such as in Laron syndrome (LS; primary IGF-1 deficiency and GH resistance) and IGF-1 gene or GH receptor gene knockout (KO) mice. Results—Since the description of LS in 1966, 51 patients were followed, many since infancy. Newborns with LS are shorter (42–47 cm) than healthy babies (49–52 cm), suggesting that IGF-1 has some influence on intrauterine growth. Newborn mice with IGF-1 gene KO are 30% smaller. The postnatal growth rate of patients with LS is very slow, the distance from the lowest normal centile increasing progressively. If untreated, the final height is 100–136 cm for female and 109–138 cm for male patients. They have acromicia, organomicria including the brain, heart, gonads, genitalia, and retardation of skeletal maturation. The availability of biosynthetic IGF-1 since 1988 has enabled it to be administered to children with LS. It accelerated linear growth rates to 8–9 cm in the first year of treatment, compared with 10–12 cm/year during GH treatment of IGHD. The growth rate in following years was 5–6.5 cm/year. Conclusion—IGF-1 is an important growth hormone, mediating the protein anabolic and linear growth promoting effect of pituitary GH. It has a GH independent growth stimulating effect, which with respect to cartilage cells is possibly optimised by the synergistic action with GH. PMID:11577173

  1. Molecular characterization of Quercus suber MYB1, a transcription factor up-regulated in cork tissues.

    Science.gov (United States)

    Almeida, Tânia; Menéndez, Esther; Capote, Tiago; Ribeiro, Teresa; Santos, Conceição; Gonçalves, Sónia

    2013-01-15

    The molecular processes associated with cork development in Quercus suber L. are poorly understood. A previous molecular approach identified a list of genes potentially important for cork formation and differentiation, providing a new basis for further molecular studies. This report is the first molecular characterization of one of these candidate genes, QsMYB1, coding for an R2R3-MYB transcription factor. The R2R3-MYB gene sub-family has been described as being involved in the phenylpropanoid and lignin pathways, both involved in cork biosynthesis. The results showed that the expression of QsMYB1 is putatively mediated by an alternative splicing (AS) mechanism that originates two different transcripts (QsMYB1.1 and QsMYB1.2), differing only in the 5'-untranslated region, due to retention of the first intron in one of the variants. Moreover, within the retained intron, a simple sequence repeat (SSR) was identified. The upstream regulatory region of QsMYB1 was extended by a genome walking approach, which allowed the identification of the putative gene promoter region. The relative expression pattern of QsMYB1 transcripts determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR) revealed that both transcripts were up-regulated in cork tissues; the detected expression was several times higher in newly formed cork harvested from trees producing virgin, second or reproduction cork when compared with wood. Moreover, the expression analysis of QsMYB1 in several Q. suber organs showed very low expression in young branches and roots, whereas in leaves, immature acorns or male flowers, no expression was detected. These preliminary results suggest that QsMYB1 may be related to secondary growth and, in particular, with the cork biosynthesis process with a possible alternative splicing mechanism associated with its regulatory function. Copyright © 2012 Elsevier GmbH. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Lizeth Núñez-López

    2015-03-01

    Full Text Available 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.

  3. Comparative analysis of the ternary complex factors Elk-1, SAP-1a and SAP-2 (ERP/NET).

    Science.gov (United States)

    Price, M A; Rogers, A E; Treisman, R

    1995-06-01

    A transcription factor ternary complex composed of Serum Response Factor (SRF) and Ternary Complex Factor (TCF) mediates the response of the c-fos Serum Response Element (SRE) to growth factors and mitogens. Three Ets domain proteins, Elk-1, SAP-1 and ERP/NET, have been reported to have the properties of TCF. Here we compare Elk-1 and SAP-1a with the human ERP/NET homologue SAP-2. All three TCF RNAs are ubiquitously expressed at similar relative levels. All three proteins contain conserved regions that interact with SRF and the c-fos SRE with comparable efficiency, but in vitro complex formation by SAP-2 is strongly inhibited by its C-terminal sequences. Similarly, only Elk-1 and SAP-1a efficiently bind the c-fos SRE in vivo; ternary complex formation by SAP-2 is weak and is substantially unaffected by serum stimulation or v-ras co-expression. All three TCFs contain C-terminal transcriptional activation domains that are phosphorylated following growth factor stimulation. Activation requires conserved S/T-P motifs found in all the TCF family members. Each TCF activation domain can be phosphorylated in vitro by partially purified ERK2, and ERK activation in vivo is sufficient to potentiate transcriptional activation.

  4. Functional Investigations of HNF1A Identify Rare Variants as Risk Factors for Type 2 Diabetes in the General Population

    Science.gov (United States)

    Najmi, Laeya Abdoli; Aukrust, Ingvild; Flannick, Jason; Molnes, Janne; Burtt, Noel; Molven, Anders; Groop, Leif; Altshuler, David; Johansson, Stefan; Njølstad, Pål Rasmus

    2017-01-01

    Variants in HNF1A encoding hepatocyte nuclear factor 1α (HNF-1A) are associated with maturity-onset diabetes of the young form 3 (MODY 3) and type 2 diabetes. We investigated whether functional classification of HNF1A rare coding variants can inform models of diabetes risk prediction in the general population by analyzing the effect of 27 HNF1A variants identified in well-phenotyped populations (n = 4,115). Bioinformatics tools classified 11 variants as likely pathogenic and showed no association with diabetes risk (combined minor allele frequency [MAF] 0.22%; odds ratio [OR] 2.02; 95% CI 0.73–5.60; P = 0.18). However, a different set of 11 variants that reduced HNF-1A transcriptional activity to diabetes in the general population (combined MAF 0.22%; OR 5.04; 95% CI 1.99–12.80; P = 0.0007). Our functional investigations indicate that 0.44% of the population carry HNF1A variants that result in a substantially increased risk for developing diabetes. These results suggest that functional characterization of variants within MODY genes may overcome the limitations of bioinformatics tools for the purposes of presymptomatic diabetes risk prediction in the general population. PMID:27899486

  5. The adenovirus oncoprotein E1a stimulates binding of transcription factor ETF to transcriptionally activate the p53 gene.

    Science.gov (United States)

    Hale, T K; Braithwaite, A W

    1999-08-20

    Expression of the tumor suppressor protein p53 plays an important role in regulating the cellular response to DNA damage. During adenovirus infection, levels of p53 protein also increase. It has been shown that this increase is due not only to increased stability of the p53 protein but to the transcriptional activation of the p53 gene during infection. We demonstrate here that the E1a proteins of adenovirus are responsible for activating the mouse p53 gene and that both major E1a proteins, 243R and 289R, are required for complete activation. E1a brings about the binding of two cellular transcription factors to the mouse p53 promoter. One of these, ETF, binds to three upstream sites in the p53 promoter and one downstream site, whereas E2F binds to one upstream site in the presence of E1a. Our studies indicate that E2F binding is not essential for activation of the p53 promoter but that ETF is. Our data indicate the ETF site located downstream of the start site of transcription is the key site in conferring E1a responsiveness on the p53 promoter.

  6. Proprotein convertase subtilisin/kexin type 7 (PCSK7) is essential for the zebrafish development and bioavailability of transforming growth factor β1a (TGFβ1a).

    Science.gov (United States)

    Turpeinen, Hannu; Oksanen, Anna; Kivinen, Virpi; Kukkurainen, Sampo; Uusimäki, Annemari; Rämet, Mika; Parikka, Mataleena; Hytönen, Vesa P; Nykter, Matti; Pesu, Marko

    2013-12-20

    Proprotein convertase subtilisin/kexin (PCSK) enzymes convert proproteins into bioactive end products. Although other PCSK enzymes are known to be essential for biological processes ranging from cholesterol metabolism to host defense, the in vivo importance of the evolutionarily ancient PCSK7 has remained enigmatic. Here, we quantified the expressions of all pcsk genes during the 1st week of fish development and in several tissues. pcsk7 expression was ubiquitous and evident already during the early development. To compare mammalian and zebrafish PCSK7, we prepared homology models, which demonstrated remarkable structural conservation. When the PCSK7 function in developing larvae was inhibited, we found that PCSK7-deficient fish have defects in various organs, including the brain, eye, and otic vesicle, and these result in mortality within 7 days postfertilization. A genome-wide analysis of PCSK7-dependent gene expression showed that, in addition to developmental processes, several immune system-related pathways are also regulated by PCSK7. Specifically, the PCSK7 contributed to the mRNA expression and proteolytic cleavage of the cytokine TGFβ1a. Consequently, tgfβ1a morphant fish displayed phenotypical similarities with pcsk7 morphants, underscoring the importance of this cytokine in the zebrafish development. Targeting PCSK activity has emerged as a strategy for treating human diseases. Our results suggest that inhibiting PCSK7 might interfere with normal vertebrate development.

  7. The bZip transscription factor HY5 mediates CRY1a-induced anthocyanin biosynthesis in tomato.

    Science.gov (United States)

    Liu, Chao-Chao; Chi, Cheng; Jin, Li-Juan; Zhu, Jianhua; Yu, Jing-Quan; Zhou, Yan-Hong

    2018-03-22

    The production of anthocyanin is regulated by light and corresponding photoreceptors. In this study, we found that exposure to blue light and overexpression of CRY1a are associated with increased accumulation of anthocyanin in tomato (Solanum lycopersicum L.). These responses are the result of changes in mRNA and the protein levels of SlHY5, a transcription factor. In vitro and in vivo experiments using EMSA and ChIP-qPCR assays revealed that SlHY5 could directly recognize and bind to the G-box and ACE motifs in the promoters of anthocyanin biosynthesis genes, such as CHS1, CHS2 and DFR. Silencing of SlHY5 in OE-CRY1a lines decreased the accumulation of anthocyanin. The findings presented here not only deepened our understanding of how light controls anthocyanin biosynthesis and associated photoprotection in tomato leaves, but also allowed us to explore potential targets for improving pigment production. This article is protected by copyright. All rights reserved.

  8. Resistance to amoxicillin-clavulanate and its relation to virulence-related factors in Yersinia enterocolitica biovar 1A

    Directory of Open Access Journals (Sweden)

    N Singhal

    2016-01-01

    Full Text Available Recent studies have reported that the virulence factors (VFs were detected more frequently in amoxicillin-clavulanate (AMC susceptible clinical isolates of Escherichia coli. Here, we have evaluated the relationship between VFs and AMC-resistance phenotype in clinical isolates of Y. enterocolitica biovar 1A. The presence/absence of VFs was compared with their minimum inhibitory concentrations for AMC in strains of two serovars. We observed that the strains of the serovar O: 6, 30-6, 31 showed a similar relationship between the number of VFs and resistance to clavulanic acid as in E. coli but not of serovar O: 6, 30. Variations in the promoters/complete coding sequences (CCDSs of β-lactamase gene (bla A or the serological characteristics could not account for unusual susceptibility to AMC displayed by the strains of the serovar O: 6, 30. Therefore, we speculate that since the clinical strains of serovar O: 6, 30-6, 31 originated from the environment they were less exposed to antibiotics compared to clinical strains of serovar O: 6, 30. Thus, AMC susceptibility seems to be influenced by factors other than serotypes or promoters/CCDS of β-lactamase genes.

  9. Local Overexpression of V1a-Vasopressin Receptor Enhances Regeneration in Tumor Necrosis Factor-Induced Muscle Atrophy

    Directory of Open Access Journals (Sweden)

    Alessandra Costa

    2014-01-01

    Full Text Available Skeletal muscle atrophy occurs during disuse and aging, or as a consequence of chronic diseases such as cancer and diabetes. It is characterized by progressive loss of muscle tissue due to hypotrophic changes, degeneration, and an inability of the regeneration machinery to replace damaged myofibers. Tumor necrosis factor (TNF is a proinflammatory cytokine known to mediate muscle atrophy in many chronic diseases and to inhibit skeletal muscle regeneration. In this study, we investigated the role of Arg-vasopressin-(AVP-dependent pathways in muscles in which atrophy was induced by local overexpression of TNF. AVP is a potent myogenesis-promoting factor and is able to enhance skeletal muscle regeneration by stimulating Ca2+/calmodulin-dependent kinase and calcineurin signaling. We performed morphological and molecular analyses and demonstrated that local over-expression of the AVP receptor V1a enhances regeneration of atrophic muscle. By upregulating the regeneration/differentiation markers, modulating the inflammatory response, and attenuating fibrogenesis, the stimulation of AVP-dependent pathways creates a favourable environment for efficient and sustained muscle regeneration and repair even in the presence of elevated levels of TNF. This study highlights a novel in vivo role for AVP-dependent pathways, which may represent an interesting strategy to counteract muscle decline in aging or in muscular pathologies.

  10. Protein Kinase A (PKA) Type I Interacts with P-Rex1, a Rac Guanine Nucleotide Exchange Factor

    Science.gov (United States)

    Chávez-Vargas, Lydia; Adame-García, Sendi Rafael; Cervantes-Villagrana, Rodolfo Daniel; Castillo-Kauil, Alejandro; Bruystens, Jessica G. H.; Fukuhara, Shigetomo; Taylor, Susan S.; Mochizuki, Naoki; Reyes-Cruz, Guadalupe; Vázquez-Prado, José

    2016-01-01

    Morphology of migrating cells is regulated by Rho GTPases and fine-tuned by protein interactions and phosphorylation. PKA affects cell migration potentially through spatiotemporal interactions with regulators of Rho GTPases. Here we show that the endogenous regulatory (R) subunit of type I PKA interacts with P-Rex1, a Rac guanine nucleotide exchange factor that integrates chemotactic signals. Type I PKA holoenzyme interacts with P-Rex1 PDZ domains via the CNB B domain of RIα, which when expressed by itself facilitates endothelial cell migration. P-Rex1 activation localizes PKA to the cell periphery, whereas stimulation of PKA phosphorylates P-Rex1 and prevents its activation in cells responding to SDF-1 (stromal cell-derived factor 1). The P-Rex1 DEP1 domain is phosphorylated at Ser-436, which inhibits the DH-PH catalytic cassette by direct interaction. In addition, the P-Rex1 C terminus is indirectly targeted by PKA, promoting inhibitory interactions independently of the DEP1-PDZ2 region. A P-Rex1 S436A mutant construct shows increased RacGEF activity and prevents the inhibitory effect of forskolin on sphingosine 1-phosphate-dependent endothelial cell migration. Altogether, these results support the idea that P-Rex1 contributes to the spatiotemporal localization of type I PKA, which tightly regulates this guanine exchange factor by a multistep mechanism, initiated by interaction with the PDZ domains of P-Rex1 followed by direct phosphorylation at the first DEP domain and putatively indirect regulation of the C terminus, thus promoting inhibitory intramolecular interactions. This reciprocal regulation between PKA and P-Rex1 might represent a key node of integration by which chemotactic signaling is fine-tuned by PKA. PMID:26797121

  11. Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch.

    Science.gov (United States)

    Nunes, Diana N; Dias-Neto, Emmanuel; Cardó-Vila, Marina; Edwards, Julianna K; Dobroff, Andrey S; Giordano, Ricardo J; Mandelin, Jami; Brentani, Helena P; Hasselgren, Catrin; Yao, Virginia J; Marchiò, Serena; Pereira, Carlos A B; Passetti, Fabio; Calin, George A; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

    2015-03-24

    Six members of the microRNA-17 (miR-17) family were mapped to three different chromosomes, although they share the same seed sequence and are predicted to target common genes, among which are those encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. Here, we evaluated the in vivo expression profile of the miR-17 family in the murine retinopathy of prematurity (ROP) model, whereby Vegfa expression is highly enhanced at the early stage of retinal neovascularization, and we found simultaneous reduction of all miR-17 family members at this stage. Using gene reporter assays, we observed binding of these miRs to specific sites in the 3' UTRs of Hif1a and Vegfa. Furthermore, overexpression of these miRs decreased HIF1A and VEGFA expression in vitro. Our data indicate that this miR-17 family elicits a regulatory synergistic down-regulation of Hif1a and Vegfa expression in this biological model. We propose the existence of a coordinated regulatory network, in which diverse miRs are synchronously regulated to target the Hif1a transcription factor, which in turn, potentiates and reinforces the regulatory effects of the miRs on Vegfa to trigger and sustain a significant physiological response.

  12. Enhanced salt stress tolerance in transgenic potato plants expressing IbMYB1, a sweet potato transcription factor.

    Science.gov (United States)

    Cheng, Yu-Jie; Kim, Myoung-Duck; Deng, Xi-Ping; Kwak, Sang-Soo; Chen, Wei

    2013-12-01

    IbMYB1, a transcription factor (TF) for R2R3-type MYB TFs, is a key regulator of anthocyanin biosynthesis during storage of sweet potatoes. Anthocyanins provide important antioxidants of nutritional value to humans, and also protect plants from oxidative stress. This study aimed to increase transgenic potatoes' (Solanum tuberosum cv. LongShu No.3) tolerance to environmental stress and enhance their nutritional value. Transgenic potato plants expressing IbMYB1 genes under the control of an oxidative stress-inducible peroxidase (SWPA2) promoter (referred to as SM plants) were successfully generated through Agrobacterium-mediated transformation. Two representative transgenic SM5 and SM12 lines were evaluated for enhanced tolerance to salinity, UV-B rays, and drought conditions. Following treatment of 100 mM NaCl, seedlings of SM5 and SM12 lines showed less root damage and more shoot growth than control lines expressing only an empty vector. Transgenic potato plants in pots treated with 400 mM NaCl showed high amounts of secondary metabolites, including phenols, anthocyanins, and flavonoids, compared with control plants. After treatment of 400 mM NaCl, transgenic potato plants also showed high DDPH radical scavenging activity and high PS II photochemical efficiency compared with the control line. Furthermore, following treatment of NaCl, UV-B, and drought stress, the expression levels of IbMYB1 and several structural genes in the flavonoid biosynthesis such as CHS, DFR, and ANS in transgenic plants were found to be correlated with plant phenotype. The results suggest that enhanced IbMYB1 expression affects secondary metabolism, which leads to improved tolerance ability in transgenic potatoes.

  13. Isoforms of elongation factor eEF1A may be differently regulated at post-transcriptional level in breast cancer progression

    Directory of Open Access Journals (Sweden)

    Vislovukh A. A.

    2013-01-01

    Full Text Available Eukaryotic translation elongation factor 1A exists as two 98 % homologous isoforms: eEF1A1 (A1 and eEF1A2 (A2 which are tissue and development specific. Despite high homology in an open reading frame (ORF region, mRNAs coding for eEF1A1 and eEF1A2 are different in their untranslated regions (UTR, suggesting a possibility of their dissimilar post-transcriptional regulation. Aim. To analyze the existence of cis-acting motifs in the UTRs of EEF1A1/A2 mRNAs, to confirm the possibility of post-transcriptional control of eEF1A1 and eEF1A2 expression. Methods. An ensemble of bioinformatic methods was applied to predict regulatory motifs in the UTRs of EEF1A1/A2 mRNAs. Dual-luciferase reporter assay was employed to detect post-transcriptional regulation of eEF1A1/A2 expression. Results. Numerous regulatory motifs in the UTR of EEF1A1/A2 mRNAs were found bioinformatically. The experimental evidence was obtained for the existence of negative regulation of EEF1A1 and positive regulation of EEF1A2 mRNA in the model of breast cancer development. Conclusions. EEF1A1 and EEF1A2 mRNAs contain distinct motifs in the UTRs and are differently regulated in cancer suggesting the possibility of their control by different cellular signals.

  14. Aromatic hydrocarbon receptor inhibits lysophosphatidic acid-induced vascular endothelial growth factor-A expression in PC-3 prostate cancer cells

    International Nuclear Information System (INIS)

    Wu, Pei-Yi; Lin, Yueh-Chien; Lan, Shun-Yan; Huang, Yuan-Li; Lee, Hsinyu

    2013-01-01

    Highlights: •LPA-induced VEGF-A expression was regulated by HIF-1α and ARNT. •PI3K mediated LPA-induced VEGF-A expression. •AHR signaling inhibited LPA-induced VEGF-A expression in PC-3 cells. -- Abstract: Lysophosphatidic acid (LPA) is a lipid growth factor with multiple biological functions and has been shown to stimulate cancer cell secretion of vascular endothelial growth factor-A (VEGF-A) and trigger angiogenesis. Hypoxia-inducible factor-1 (HIF-1), a heterodimer consisting of HIF-1α and HIF-1β (also known as aromatic hydrocarbon receptor nuclear translocator (ARNT)) subunits, is an important regulator of angiogenesis in prostate cancer (PC) through the enhancement of VEGF-A expression. In this study, we first confirmed the ability of LPA to induce VEGF-A expression in PC-3 cells and then validated that LPA-induced VEGF-A expression was regulated by HIF-1α and ARNT through phosphatidylinositol 3-kinase activation. Aromatic hydrocarbon receptor (AHR), a receptor for dioxin-like compounds, functions as a transcription factor through dimerization with ARNT and was found to inhibit prostate carcinogenesis and vanadate-induced VEGF-A production. Since ARNT is a common dimerization partner of AHR and HIF-1α, we hypothesized that AHR might suppress LPA-induced VEGF-A expression in PC-3 cells by competing with HIF-1α for ARNT. Here we demonstrated that overexpression and ligand activation of AHR inhibited HIF-1-mediated VEGF-A induction by LPA treatment of PC-3 cells. In conclusion, our results suggested that AHR activation may inhibit LPA-induced VEGF-A expression in PC-3 cells by attenuating HIF-1α signaling, and subsequently, suppressing angiogenesis and metastasis of PC. These results suggested that AHR presents a potential therapeutic target for the prevention of PC metastasis

  15. A Novel WRKY transcription factor is required for induction of PR-1a gene expression by salicylic acid and bacterial elicitors

    NARCIS (Netherlands)

    van Verk, Marcel C|info:eu-repo/dai/nl/327618671; Pappaioannou, Dimitri; Neeleman, Lyda; Bol, John F; Linthorst, Huub J M

    PR-1a is a salicylic acid-inducible defense gene of tobacco (Nicotiana tabacum). One-hybrid screens identified a novel tobacco WRKY transcription factor (NtWRKY12) with specific binding sites in the PR-1a promoter at positions -564 (box WK(1)) and -859 (box WK(2)). NtWRKY12 belongs to the class of

  16. The redox protein thioredoxin-1 (Trx-1) increases hypoxia-inducible factor 1alpha protein expression: Trx-1 overexpression results in increased vascular endothelial growth factor production and enhanced tumor angiogenesis.

    Science.gov (United States)

    Welsh, Sarah J; Bellamy, William T; Briehl, Margaret M; Powis, Garth

    2002-09-01

    Hypoxia-inducible factor 1 (HIF-1), a heterodimer of HIF-1alpha and HIF-1beta subunits, is a transcriptional activator central to the cellular response to low oxygen that includes metabolic adaptation, angiogenesis, metastasis, and inhibited apoptosis. Thioredoxin-1 (Trx-1) is a small redox protein overexpressed in a number of human primary tumors. We have examined the effects of Trx-1 on HIF activity and the activation of downstream genes. Stable transfection of human breast carcinoma MCF-7 cells with human Trx-1 caused a significant increase in HIF-1alpha protein levels under both normoxic (20% oxygen) and hypoxic (1% oxygen) conditions. Trx-1 increased hypoxia-induced HIF-1 transactivation activity measured using a luciferase reporter under the control of the hypoxia response element. Changes in HIF-1alpha mRNA levels did not account for the changes observed at the protein level, and HIF-1beta protein levels did not change. Trx-1 transfection also caused a significant increase in the protein products of hypoxia-responsive genes, including vascular endothelial growth factor (VEGF) and nitric oxide synthase 2 in a number of different cell lines (MCF-7 human breast and HT29 human colon carcinomas and WEHI7.2 mouse lymphoma cells) under both normoxic and hypoxic conditions. The pattern of expression of the different isoforms of VEGF was not changed by Trx-1. Transfection of a redox-inactive Trx-1 (C32S/C35S) markedly decreased levels of HIF-1alpha protein, HIF-1 transactivating activity, and VEGF protein in MCF-7 cells compared with empty vector controls. In vivo studies using WEHI7.2 cells transfected with Trx-1 showed significantly increased tumor VEGF and angiogenesis. The results suggest that Trx-1 increases HIF-1alpha protein levels in cancer cells and increases VEGF production and tumor angiogenesis.

  17. The eukaryotic translation elongation factor eEF1A2 induces neoplastic properties and mediates tumorigenic effects of ZNF217 in precursor cells of human ovarian carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Yu; Wong, Nicholas; Guan, Yinghui; Salamanca, Clara M.; Cheng, Jung Chien; Lee, Jonathan M.; Gray, Joe W.; Auersperg, Nelly

    2008-04-25

    Ovarian epithelial carcinomas (OEC) frequently exhibit amplifications at the 20q13 locus which is the site of several oncogenes, including the eukaryotic elongation factor EEF1A2 and the transcription factor ZNF217. We reported previously that overexpressed ZNF217 induces neoplastic characteristics in precursor cells of OEC. Unexpectedly, ZNF217, which is a transcriptional repressor, enhanced expression of eEF1A2. In this study, array comparative genomic hybridization, single nucleotide polymorphism and Affymetrix analysis of ZNF217-overexpressing cell lines confirmed consistently increased expression of eEF1A2 but not of other oncogenes, and revealed early changes in EEF1A2 gene copy numbers and increased expression at crisis during immortalization. We defined the influence of eEF1A2 overexpression on immortalized ovarian surface epithelial cells, and investigated interrelationships between effects of ZNF217 and eEF1A2 on cellular phenotypes. Lentivirally induced eEF1A2 overexpression caused delayed crisis, apoptosis resistance and increases in serum-independence, saturation densities, and anchorage independence. siRNA to eEF1A2 reversed apoptosis resistance and reduced anchorage independence in eEF1A2-overexpressing lines. Remarkably, siRNA to eEF1A2 was equally efficient in inhibiting both anchorage independence and resistance to apoptosis conferred by ZNF217 overexpression. Our data define neoplastic properties that are caused by eEF1A2 in nontumorigenic ovarian cancer precursor cells, and suggest that eEF1A2 plays a role in mediating ZNF217-induced neoplastic progression.

  18. [Insulin-like growth factor-binding protein-1: a new biochemical marker of nonalcoholic fatty liver disease?].

    Science.gov (United States)

    Graffigna, Mabel Nora; Belli, Susana H; de Larrañaga, Gabriela; Fainboim, Hugo; Estepo, Claudio; Peres, Silvia; García, Natalia; Levalle, Oscar

    2009-03-01

    to assess the presence of nonalcoholic fatty liver disease in patients with risk factors for this pathology (obesity, dyslipidemia, metabolic syndrome and diabetes type 2) and to determine the role of insulin, HOMA index, insulin-like growth factor-binding protein-1, sex hormone-binding globulin and plasminogen activator inhibitor type 1, as biochemical markers. Ninety-one patients with risk factors for nonalcoholic fatty liver disease were evaluated. Serum transaminases, insulin, sex hormone-binding globulin, insulin-like growth factor-binding protein-1 and plasminogen activator inhibitor type 1 were measured. The diagnosis of fatty liver was performed by ultrasonography and liver biopsies were performed to 31 subjects who had steatosis by ultrasonography and high alanine aminotransferase. Nonalcoholic fatty liver disease was present in 65 out of 91 patients (71,4%). Liver biopsy performed to 31 subjects confirmed nonalcoholic steatohepatitis. Twenty-five patients had different degrees of fibrosis. Those individuals with fatty liver had higher waist circumference, serum levels of triglycerides, insulin and HOMA index, and lower serum insulin-like growth factor-binding protein-1 concentration. The degree ofhepatic steatosis by ultrasonography was positively correlated to waist circumference, triglycerides, insulin and HOMA index (p<0,003; p<0,003; p<0,002 and p<0,001, respectively), and was negatively correlated to HDL-cholesterol and insulin-like growth factor-binding protein-1 (p<0,025 and p<0,018, respectively). We found a high prevalence of NAFLD in patients with risk factors, most of them overweight or obese. Although SHBG and PAI-1 have a closely relationship to insulin resistance, they did not show to be markers of NAFLD. Regardless of low IGFBP-1 levels associated with NAFLD, serum IGFBP-1 measure is less accessible than insulin and triglycerides levels, HOMA index and waist circumference. Moreover, it is not a better marker for NAFLD than the above

  19. Translation elongation factor eEF1A2 is a potential oncoprotein that is overexpressed in two-thirds of breast tumours

    Directory of Open Access Journals (Sweden)

    Miller William R

    2005-09-01

    Full Text Available Abstract Background The tissue-specific translation elongation factor eEF1A2 was recently shown to be a potential oncogene that is overexpressed in ovarian cancer. Although there is no direct evidence for an involvement of eEF1A2 in breast cancer, the genomic region to which EEF1A2 maps, 20q13, is frequently amplified in breast tumours. We therefore sought to establish whether eEF1A2 expression might be upregulated in breast cancer. Methods eEF1A2 is highly similar (98% to the near-ubiquitously expressed eEF1A1 (formerly known as EF1-α making analysis with commercial antibodies difficult. We have developed specific anti-eEF1A2 antibodies and used them in immunohistochemical analyses of tumour samples. We report the novel finding that although eEF1A2 is barely detectable in normal breast it is moderately to strongly expressed in two-thirds of breast tumours. This overexpression is strongly associated with estrogen receptor positivity. Conclusion eEF1A2 should be considered as a putative oncogene in breast cancer that may be a useful diagnostic marker and therapeutic target for a high proportion of breast tumours. The oncogenicity of eEF1A2 may be related to its role in protein synthesis or to its potential non-canonical functions in cytoskeletal remodelling or apoptosis.

  20. Translation elongation factor eEF1A2 is a potential oncoprotein that is overexpressed in two-thirds of breast tumours

    International Nuclear Information System (INIS)

    Tomlinson, Victoria AL; Newbery, Helen J; Wray, Naomi R; Jackson, Juliette; Larionov, Alexey; Miller, William R; Dixon, J Michael; Abbott, Catherine M

    2005-01-01

    The tissue-specific translation elongation factor eEF1A2 was recently shown to be a potential oncogene that is overexpressed in ovarian cancer. Although there is no direct evidence for an involvement of eEF1A2 in breast cancer, the genomic region to which EEF1A2 maps, 20q13, is frequently amplified in breast tumours. We therefore sought to establish whether eEF1A2 expression might be upregulated in breast cancer. eEF1A2 is highly similar (98%) to the near-ubiquitously expressed eEF1A1 (formerly known as EF1-α) making analysis with commercial antibodies difficult. We have developed specific anti-eEF1A2 antibodies and used them in immunohistochemical analyses of tumour samples. We report the novel finding that although eEF1A2 is barely detectable in normal breast it is moderately to strongly expressed in two-thirds of breast tumours. This overexpression is strongly associated with estrogen receptor positivity. eEF1A2 should be considered as a putative oncogene in breast cancer that may be a useful diagnostic marker and therapeutic target for a high proportion of breast tumours. The oncogenicity of eEF1A2 may be related to its role in protein synthesis or to its potential non-canonical functions in cytoskeletal remodelling or apoptosis

  1. Potential Risk Factors for the Onset of Complex Regional Pain Syndrome Type 1: A Systematic Literature Review

    Directory of Open Access Journals (Sweden)

    Tracey Pons

    2015-01-01

    Full Text Available Anaesthetists in the acute and chronic pain teams are often involved in treating Complex Regional Pain Syndromes. Current literature about the risk factors for the onset of Complex Regional Pain Syndrome Type 1 (CRPS 1 remains sparse. This syndrome has a low prevalence, a highly variable presentation, and no gold standard for diagnosis. In the research setting, the pathogenesis of the syndrome continues to be elusive. There is a growing body of literature that addresses efficacy of a wide range of interventions as well as the likely mechanisms that contribute to the onset of CRPS 1. The objective for this systematic search of the literature focuses on determining the potential risk factors for the onset of CRPS 1. Eligible articles were analysed, dated 1996 to April 2014, and potential risk factors for the onset of CRPS 1 were identified from 10 prospective and 6 retrospective studies. Potential risk factors for the onset of CRPS 1 were found to include being female, particularly postmenopausal female, ankle dislocation or intra-articular fracture, immobilisation, and a report of higher than usual levels of pain in the early phases of trauma. It is not possible to draw definite conclusions as this evidence is heterogeneous and of mixed quality, relevance, and weighting strength against bias and has not been confirmed across multiple trials or in homogenous studies.

  2. PcFKH1, a novel regulatory factor from the forkhead family, controls the biosynthesis of penicillin in Penicillium chrysogenum.

    Science.gov (United States)

    Domínguez-Santos, Rebeca; García-Estrada, Carlos; Kosalková, Katarina; Prieto, Carlos; Santamarta, Irene; Martín, Juan-Francisco

    2015-08-01

    Penicillin biosynthesis in Penicillium chrysogenum (re-identified as Penicillium rubens) is a good example of a biological process subjected to complex global regulatory networks and serves as a model to study fungal secondary metabolism. The winged-helix family of transcription factors recently described, which includes the forkhead type of proteins, is a key type of regulatory proteins involved in this process. In yeasts and humans, forkhead transcription factors are involved in different processes (cell cycle regulation, cell death control, pre-mRNA processing and morphogenesis); one member of this family of proteins has been identified in the P. chrysogenum genome (Pc18g00430). In this work, we have characterized this novel transcription factor (named PcFKH1) by generating knock-down mutants and overexpression strains. Results clearly indicate that PcFKH1 positively controls antibiotic biosynthesis through the specific interaction with the promoter region of the penDE gene, thus regulating penDE mRNA levels. PcFKH1 also binds to the pcbC promoter, but with low affinity. In addition, it also controls other ancillary genes of the penicillin biosynthetic process, such as phlA (encoding phenylacetyl CoA ligase) and ppt (encoding phosphopantetheinyl transferase). PcFKH1 also plays a role in conidiation and spore pigmentation, but it does not seem to be involved in hyphal morphology or cell division in the improved laboratory reference strain Wisconsin 54-1255. A genome-wide analysis of processes putatively coregulated by PcFKH1 and PcRFX1 (another winged-helix transcription factor) in P. chrysogenum provided evidence of the global effect of these transcription factors in P. chrysogenum metabolism. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  3. Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats.

    Science.gov (United States)

    Shi, Xudan; Doycheva, Desislava Met; Xu, Liang; Tang, Jiping; Yan, Min; Zhang, John H

    2016-11-01

    Hypoxic ischemic (HI) encephalopathy remains the leading cause of perinatal brain injury resulting in long term disabilities. Stabilization of blood brain barrier (BBB) after HI is an important target, therefore, in this study we aim to determine the role of sestrin2, a stress inducible protein which is elevated after various insults, on BBB stabilization after moderate and severe HI injuries. Rat pups underwent common carotid artery ligation followed by either 150min (severe model) or 100min (moderate model) of hypoxia. 1h post HI, rats were intranasally administered with recombinant human sestrin2 (rh-sestrin2) and sacrificed for infarct area, brain water content, righting reflex and geotaxis reflex. Sestrin2 was silenced using siRNA and an activator/inhibitor of hypoxia inducible factor1α (HIF1α) was used to examine their roles on BBB permeability. Rats subjected to severe HI exhibited larger infarct area and higher sestrin2 expression compared to rats in the moderate HI group. rh-sestrin2 attenuated brain infarct and edema, while silencing sestrin2 reversed these protective effects after severe HI. HIF1α induced sestrin2 activation in severe HI but not in moderate HI groups. A HIF1a agonist was shown to increase permeability of the BBB via vascular endothelial growth factor (VEGF) after moderate HI. However, after severe HI, HIF1α activated both VEGF and sestrin2. But HIF1α dependent sestrin2 activation was the predominant pathway after severe HI which inhibited VEGF and attenuated BBB permeability. rh-sestrin2 attenuated BBB permeability via upregulation of endogenous sestrin2 which was induced by HIF1α after severe HI. However, HIF1α's effects as a prodeath or prosurvival signal were influenced by the severity of HI injury. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Characterization of novel peptide-specific antibodies against the translation elongation factor eEF1A2 and their application for cancer research

    Directory of Open Access Journals (Sweden)

    Shalak V. F.

    2014-11-01

    Full Text Available Aim. We intend to characterize the new peptide-specific antibodies against the isoform 2 of translation elongation factor 1A (eEF1A2 and determine its presence in the postoperative samples of human breast, lung and stomach tumor tissues. Methods. The analysis of antibody specificity was performed by enzyme-linked immunosorbent assay, immunoblotting and immunohistochemistry. Immunoblotting and immunohistochemistry were used for the determination of the eEF1A2 in the human tumor samples, as well as in the samples of normal tissues surrounding tumors. Results. The antibodies obtained against the eEF1A2 specifically recognized this protein in the cell extracts and histological sections and did not cross-react with the elongation factor 1A isoform 1. eEF1A2 was revealed in the postoperative samples of breast, lung and stomach tumors as well as in the putative normal tissues surrounding tumors. Conclusions. The antibodies obtained against eEF1A2 are highly specific for the antigen and can be used for the immunological studies of tumors.

  5. Polymorphism in cytochrome P450 1A2 and their interaction with risk factors in determining risk of squamous cell lung carcinoma in men.

    Science.gov (United States)

    Singh, Arvind P; Pant, Mohan C; Ruwali, Munindra; Shah, Parag P; Prasad, Rajendra; Mathur, Neeraj; Parmar, Devendra

    The present case-control study was carried out to investigate the association of functionally important polymorphisms of cytochrome P450 1A2 (CYP1A2) involved in the metabolic activation of tobacco derived procarcinogens with squamous cell carcinoma (SCC) of lung in North Indian men. The study consisted of 200 male cases with SCC of lung and an equal number of age and sex matched healthy controls. Our data showed that variant genotype of CYP1A2*1D and CYP1A2*1F were significantly associated with increased susceptibility to SCC of lung. Likewise, GSTM1 null genotype was found to be over represented in patients when compared to controls. Haplotype analysis revealed that haplotype, G-Tdel-T-C was significantly associated with risk to SCC of lung. Moreover, a significant increase in the risk to SCC of lung in the cases carrying combination of variant genotype of CYP1A2 with either CYP1A1 or GSTM1 have shown that gene-gene interactions may play an important role in squamous cell lung cancer risk. Our data also revealed that smokers or tobacco chewers carrying variant alleles of either CYP1A2*1D or CYP1A2*1F were at increased risk to SCC of lung, further demonstrating that CYP1A2 genotypes interact with environmental risk factors in enhancing the risk to squamous cell lung carcinoma.

  6. Mammalian translation elongation factor eEF1A2: X-ray structure and new features of GDP/GTP exchange mechanism in higher eukaryotes.

    Science.gov (United States)

    Crepin, Thibaut; Shalak, Vyacheslav F; Yaremchuk, Anna D; Vlasenko, Dmytro O; McCarthy, Andrew; Negrutskii, Boris S; Tukalo, Michail A; El'skaya, Anna V

    2014-11-10

    Eukaryotic elongation factor eEF1A transits between the GTP- and GDP-bound conformations during the ribosomal polypeptide chain elongation. eEF1A*GTP establishes a complex with the aminoacyl-tRNA in the A site of the 80S ribosome. Correct codon-anticodon recognition triggers GTP hydrolysis, with subsequent dissociation of eEF1A*GDP from the ribosome. The structures of both the 'GTP'- and 'GDP'-bound conformations of eEF1A are unknown. Thus, the eEF1A-related ribosomal mechanisms were anticipated only by analogy with the bacterial homolog EF-Tu. Here, we report the first crystal structure of the mammalian eEF1A2*GDP complex which indicates major differences in the organization of the nucleotide-binding domain and intramolecular movements of eEF1A compared to EF-Tu. Our results explain the nucleotide exchange mechanism in the mammalian eEF1A and suggest that the first step of eEF1A*GDP dissociation from the 80S ribosome is the rotation of the nucleotide-binding domain observed after GTP hydrolysis. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  7. Magic-factor 1, a partial agonist of Met, induces muscle hypertrophy by protecting myogenic progenitors from apoptosis.

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    Marco Cassano

    2008-09-01

    Full Text Available Hepatocyte Growth Factor (HGF is a pleiotropic cytokine of mesenchymal origin that mediates a characteristic array of biological activities including cell proliferation, survival, motility and morphogenesis. Its high affinity receptor, the tyrosine kinase Met, is expressed by a wide range of tissues and can be activated by either paracrine or autocrine stimulation. Adult myogenic precursor cells, the so called satellite cells, express both HGF and Met. Following muscle injury, autocrine HGF-Met stimulation plays a key role in promoting activation and early division of satellite cells, but is shut off in a second phase to allow myogenic differentiation. In culture, HGF stimulation promotes proliferation of muscle precursors thereby inhibiting their differentiation.Magic-Factor 1 (Met-Activating Genetically Improved Chimeric Factor-1 or Magic-F1 is an HGF-derived, engineered protein that contains two Met-binding domains repeated in tandem. It has a reduced affinity for Met and, in contrast to HGF it elicits activation of the AKT but not the ERK signaling pathway. As a result, Magic-F1 is not mitogenic but conserves the ability to promote cell survival. Here we show that Magic-F1 protects myogenic precursors against apoptosis, thus increasing their fusion ability and enhancing muscular differentiation. Electrotransfer of Magic-F1 gene into adult mice promoted muscular hypertrophy and decreased myocyte apoptosis. Magic-F1 transgenic mice displayed constitutive muscular hypertrophy, improved running performance and accelerated muscle regeneration following injury. Crossing of Magic-F1 transgenic mice with alpha-sarcoglycan knock-out mice -a mouse model of muscular dystrophy- or adenovirus-mediated Magic-F1 gene delivery resulted in amelioration of the dystrophic phenotype as measured by both anatomical/histological analysis and functional tests.Because of these features Magic-F1 represents a novel molecular tool to counteract muscle wasting in major

  8. PhOBF1, a petunia ocs element binding factor, plays an important role in antiviral RNA silencing.

    Science.gov (United States)

    Sun, Daoyang; Li, Shaohua; Niu, Lixin; Reid, Michael S; Zhang, Yanlong; Jiang, Cai-Zhong

    2017-02-01

    Virus-induced gene silencing (VIGS) is a common reverse genetics strategy for characterizing the function of genes in plants. The detailed mechanism governing RNA silencing efficiency triggered by viruses is largely unclear. Here, we reveal that a petunia (Petunia hybrida) ocs element binding factor, PhOBF1, one of the basic leucine zipper (bZIP) transcription factors, was up-regulated by Tobacco rattle virus (TRV) infection. Simultaneous silencing of PhOBF1 and a reporter gene, phytoene desaturase (PDS) or chalcone synthase (CHS), by TRV-based VIGS led to a failure of the development of leaf photobleaching or the white-corollas phenotype. PhOBF1 silencing caused down-regulation of RNA silencing-related genes, including RNA-dependent RNA polymerases (RDRs), Dicer-like RNase III enzymes (DCLs), and Argonautes (AGOs). After inoculation with the TRV-PhPDS, PhOBF1-RNAi lines exhibited a substantially impaired PDS silencing efficiency, whereas overexpression of PhOBF1 resulted in a recovery of the silencing phenotype (photobleaching) in systemic leaves. A compromised resistance to TRV and Tobacco mosaic virus was found in PhOBF1-RNAi lines, while PhOBF1-overexpressing lines displayed an enhanced resistance to their infections. Compared with wild-type plants, PhOBF1-silenced plants accumulated lower levels of free salicylic acid (SA), salicylic acid glucoside, and phenylalanine, contrarily to higher levels of those in plants overexpressing PhOBF1. Furthermore, transcripts of a number of genes associated with the shikimate and phenylpropanoid pathways were decreased or increased in PhOBF1-RNAi or PhOBF1-overexpressing lines, respectively. Taken together, the data suggest that PhOBF1 regulates TRV-induced RNA silencing efficiency through modulation of RDRs, DCLs, and AGOs mediated by the SA biosynthesis pathway. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  9. Cytokine-like factor-1, a novel soluble protein, shares homology with members of the cytokine type I receptor family.

    Science.gov (United States)

    Elson, G C; Graber, P; Losberger, C; Herren, S; Gretener, D; Menoud, L N; Wells, T N; Kosco-Vilbois, M H; Gauchat, J F

    1998-08-01

    In this report we describe the identification, cloning, and expression pattern of human cytokine-like factor 1 (hCLF-1) and the identification and cloning of its murine homologue. They were identified from expressed sequence tags using amino acid sequences from conserved regions of the cytokine type I receptor family. Human CLF-1 and murine CLF-1 shared 96% amino acid identity and significant homology with many cytokine type I receptors. CLF-1 is a secreted protein, suggesting that it is either a soluble subunit within a cytokine receptor complex, like the soluble form of the IL-6R alpha-chain, or a subunit of a multimeric cytokine, e.g., IL-12 p40. The highest levels of hCLF-1 mRNA were observed in lymph node, spleen, thymus, appendix, placenta, stomach, bone marrow, and fetal lung, with constitutive expression of CLF-1 mRNA detected in a human kidney fibroblastic cell line. In fibroblast primary cell cultures, CLF-1 mRNA was up-regulated by TNF-alpha, IL-6, and IFN-gamma. Western blot analysis of recombinant forms of hCLF-1 showed that the protein has the tendency to form covalently linked di- and tetramers. These results suggest that CLF-1 is a novel soluble cytokine receptor subunit or part of a novel cytokine complex, possibly playing a regulatory role in the immune system and during fetal development.

  10. Dwarf Tiller1, a Wuschel-related homeobox transcription factor, is required for tiller growth in rice.

    Directory of Open Access Journals (Sweden)

    Wenfei Wang

    2014-03-01

    Full Text Available Unlike many wild grasses, domesticated rice cultivars have uniform culm height and panicle size among tillers and the main shoot, which is an important trait for grain yield. However, the genetic basis of this trait remains unknown. Here, we report that Dwarf Tiller1 (DWT1 controls the developmental uniformity of the main shoot and tillers in rice (Oryza sativa. Most dwt1 mutant plants develop main shoots with normal height and larger panicles, but dwarf tillers bearing smaller panicles compared with those of the wild type. In addition, dwt1 tillers have shorter internodes with fewer and un-elongated cells compared with the wild type, indicating that DWT1 affects cell division and cell elongation. Map-based cloning revealed that DWT1 encodes a Wuschel-related homeobox (WOX transcription factor homologous to the Arabidopsis WOX8 and WOX9. The DWT1 gene is highly expressed in young panicles, but undetectable in the internodes, suggesting that DWT1 expression is spatially or temporally separated from its effect on the internode growth. Transcriptomic analysis revealed altered expression of genes involved in cell division and cell elongation, cytokinin/gibberellin homeostasis and signaling in dwt1 shorter internodes. Moreover, the non-elongating internodes of dwt1 are insensitive to exogenous gibberellin (GA treatment, and some of the slender rice1 (slr1 dwt1 double mutant exhibits defective internodes similar to the dwt1 single mutant, suggesting that the DWT1 activity in the internode elongation is directly or indirectly associated with GA signaling. This study reveals a genetic pathway synchronizing the development of tillers and the main shoot, and a new function of WOX genes in balancing branch growth in rice.

  11. DWARF TILLER1, a WUSCHEL-Related Homeobox Transcription Factor, Is Required for Tiller Growth in Rice

    Science.gov (United States)

    Wang, Wenfei; Li, Gang; Zhao, Jun; Chu, Huangwei; Lin, Wenhui; Zhang, Dabing; Wang, Zhiyong; Liang, Wanqi

    2014-01-01

    Unlike many wild grasses, domesticated rice cultivars have uniform culm height and panicle size among tillers and the main shoot, which is an important trait for grain yield. However, the genetic basis of this trait remains unknown. Here, we report that DWARF TILLER1 (DWT1) controls the developmental uniformity of the main shoot and tillers in rice (Oryza sativa). Most dwt1 mutant plants develop main shoots with normal height and larger panicles, but dwarf tillers bearing smaller panicles compared with those of the wild type. In addition, dwt1 tillers have shorter internodes with fewer and un-elongated cells compared with the wild type, indicating that DWT1 affects cell division and cell elongation. Map-based cloning revealed that DWT1 encodes a WUSCHEL-related homeobox (WOX) transcription factor homologous to the Arabidopsis WOX8 and WOX9. The DWT1 gene is highly expressed in young panicles, but undetectable in the internodes, suggesting that DWT1 expression is spatially or temporally separated from its effect on the internode growth. Transcriptomic analysis revealed altered expression of genes involved in cell division and cell elongation, cytokinin/gibberellin homeostasis and signaling in dwt1 shorter internodes. Moreover, the non-elongating internodes of dwt1 are insensitive to exogenous gibberellin (GA) treatment, and some of the slender rice1 (slr1) dwt1 double mutant exhibits defective internodes similar to the dwt1 single mutant, suggesting that the DWT1 activity in the internode elongation is directly or indirectly associated with GA signaling. This study reveals a genetic pathway synchronizing the development of tillers and the main shoot, and a new function of WOX genes in balancing branch growth in rice. PMID:24625559

  12. Dlf1, a WRKY transcription factor, is involved in the control of flowering time and plant height in rice.

    Directory of Open Access Journals (Sweden)

    Yuhui Cai

    Full Text Available Flowering time and plant height are important agronomic traits for crop production. In this study, we characterized a semi-dwarf and late flowering (dlf1 mutation of rice that has pleiotropic effects on these traits. The dlf1 mutation was caused by a T-DNA insertion and the cloned Dlf1 gene was found to encode a WRKY transcription factor (OsWRKY11. The dlf1 mutant contains a T-DNA insertion at the promoter region, leading to enhanced accumulation of Dlf1 transcripts, resulting in a semidominant mutation. The dlf1 mutation suppressed the transcription of Ehd2/RID1/OsId1 and its downstream flowering-time genes including Hd1, Ehd1 and Hd3a under both long-day (LD and short-day (SD conditions. Knock-down of Dlf1 expression exhibited early flowering at LD condition related to the wild-type plants. Accumulation of Dlf1 mRNA was observed in most tissues, and two splicing forms of Dlf1 cDNAs were obtained (OsWRKY11.1 and OsWRKY11.2. These two proteins showed transactivation activity in yeast cells. Dlf1 protein was found to be localized in the nucleus. Enhanced expression of OsWRKY11.2 or its 5' truncated gene showed similar phenotypes to the dlf1 mutant, suggesting that it might function as a negative regulator. We conclude that Dlf1 acts as a transactivator to downregulate Ehd2/RID1/OsId1 in the signal transduction pathway of flowering and plays an important role in the regulation of plant height in rice.

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

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyung Gyun [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Han, Eun Hee [Division of Life Science, Korea Basic Science Institute, Daejeon (Korea, Republic of); Im, Ji Hye; Lee, Eun Ji; Jin, Sun Woo [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of); Jeong, Hye Gwang, E-mail: hgjeong@cnu.ac.kr [Department of Toxicology, College of Pharmacy, Chungnam National University, Daejeon (Korea, Republic of)

    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.

  14. Stress-inducible expression of AtDREB1A transcription factor greatly improves drought stress tolerance in transgenic indica rice.

    Science.gov (United States)

    Ravikumar, G; Manimaran, P; Voleti, S R; Subrahmanyam, D; Sundaram, R M; Bansal, K C; Viraktamath, B C; Balachandran, S M

    2014-06-01

    The cultivation of rice (Oryza sativa L.), a major food crop, requires ample water (30 % of the fresh water available worldwide), and its productivity is greatly affected by drought, the most significant environmental factor. Much research has focussed on identifying quantitative trait loci, stress-regulated genes and transcription factors that will contribute towards the development of climate-resilient/tolerant crop plants in general and rice in particular. The transcription factor DREB1A, identified from the model plant Arabidopsis thaliana, has been reported to enhance stress tolerance against drought stress. We developed transgenic rice plants with AtDREB1A in the background of indica rice cultivar Samba Mahsuri through Agrobacterium-mediated transformation. The AtDREB1A gene was stably inherited and expressed in T1 and T2 plants and in subsequent generations, as indicated by the results of PCR, Southern blot and RT-PCR analyses. Expression of AtDREB1A was induced by drought stress in transgenic rice lines, which were highly tolerant to severe water deficit stress in both the vegetative and reproductive stages without affecting their morphological or agronomic traits. The physiological studies revealed that the expression of AtDREB1A was associated with an increased accumulation of the osmotic substance proline, maintenance of chlorophyll, increased relative water content and decreased ion leakage under drought stress. Most of the homozygous lines were highly tolerant to drought stress and showed significantly a higher grain yield and spikelet fertility relative to the nontransgenic control plants under both stressed and unstressed conditions. The improvement in drought stress tolerance in combination with agronomic traits is very essential in high premium indica rice cultivars, such as Samba Mahsuri, so that farmers can benefit in times of seasonal droughts and water scarcity.

  15. E1A-dependent trans-activation of the human MYC promoter is mediated by the E2F factor

    International Nuclear Information System (INIS)

    Hiebert, S.W.; Lipp, M.; Nevins, J.R.

    1989-01-01

    E2F is a cellular transcription factor that binds to two sites in the adenovirus E2 promoter. Previous experiments have implicated E2F in the E1A-dependent transactivation of the E2 gene since levels of active E2F increase markedly during adenovirus infection in parallel with the increase in E2 transcription, and an E2F binding site can confer E1A inducibility to a heterologous promoter. Here the authors show that E2F binds to two sequence elements within the P2 promoter of the human MYC gene which are within a region that is critical for promoter activity. The MYC promoter can be trans-activated in an E1A-dependent manner and site-directed mutagenesis demonstrates that these E2F elements are essential for trans-activation. Finally, they also find that adenovirus infection of quiescent cells results in a stimulation of the endogenous MYC gene. They conclude that the activation of the E2F factor, which is likely responsible for the activation of viral E2 transcription, is also responsible for the E1A-dependent induction of MYC transcription

  16. 17β-estradiol-induced regulation of the novel 5-HT1A-related transcription factors NUDR and Freud-1 in SH SY5Y cells.

    Science.gov (United States)

    Adeosun, Samuel O; Albert, Paul R; Austin, Mark C; Iyo, Abiye H

    2012-05-01

    Nuclear deformed epidermal autoregulatory factor-1 (NUDR/Deaf-1) and five prime repressor element under dual repression (Freud-1) are novel transcriptional regulators of the 5-HT(1A) receptor, a receptor that has been implicated in the pathophysiology of various psychiatric illnesses. The antidepressant effect of 17β-Estradiol (17βE(2)) is purported to involve the downregulation of this receptor. We investigated the possible role of NUDR and Freud-1 in 17βE(2)-induced downregulation of the 5-HT(1A) receptor in the neuroblastoma cell line SH SY5Y. Cells were treated with 10 nM of 17βE(2) for 3 or 48 h, followed by a 24-h withdrawal period. Proteins were isolated and analyzed by western blotting. 17βE(2) treatment increased NUDR immunoreactivity while Freud-1 and the 5-HT(1A) receptor showed significant decreases. Upon withdrawal of 17βE(2), protein expression returned to control levels, except for NUDR, which remained significantly elevated in the 3-h treatment. Taken together, these data support a non-genomic downregulation of 5-HT(1A) receptor protein by 17βE(2), which does not involve NUDR and Freud-1. Rather, changes in both transcription factors seem to be compensatory/homeostatic responses to changes in 5-HT(1A) receptor induced by 17βE(2). These observations further highlight the importance of NUDR and Freud-1 in regulating 5-HT(1A) receptor expression.

  17. Synthesis of insulin-like growth factor 1 analogue (188Re/99Tcm-IGF-1A) and the binding with pancreatic carcinoma cell

    International Nuclear Information System (INIS)

    Zhang Bin; Wu Yiwei; Fan Guanglei; Fan Wo

    2007-01-01

    Objective: An useful and stable method was developed for labeling insulin-like growth factor 1 analogue (IGF-1A) with 188 Re/ 99 Tc m , and its binding characteristic was studied with human pancreatic cancer cell Patu8988 in this study. Methods: The direct labeling method was adopted to label IGF- 1A under different conditions: 2 to 10 μl Tween80; 0.75 to 25 g/L SnCl 2 ·2H 2 O; 20 to 100 μg IGF-1A; 10 to 500 μl 188 ReO 4 - . The labeling rate was dynamically measured from 5 min to 6 h after labeling. The in vitro stabilities of 188 Re/ 99 Tc m -IGF-1A were accessed by dynamic labeling rates measured at 2 to 24 h. SPECT imaging after intravenous injection of 99 Tc m -IGF-1A and intratumoral injection of 188 Re-IGF-1A in nude mice was performed. Results: The best condition for labeling 188 Re was: 100 μl SnCl 2 ·2H 2 O (10 g/L), 50 μl IGF-1A (2 g/L), 300 μl Na 3 PO 4 , l0 μl 0.1% Tween80, 50 μl 188 ReO 4 - with 30 min reaction time at room temperature and pH 7.0. The maximum labeling rate of 188 Re-IGF-1A was (94.07 ± 0.32)%. The radiochemical purity was (76.57 ± 9.96)% at 24 h after mixing with human serum. The maximum binding efficiency of 188 Re-IGF-1A with Patu8988 cell was (24.13 ± 2.03)% , and the specific binding was 12.68%. The best labeling condition of 99 Tc m was: 100 μl SnCl 2 ·2H 2 O (3 g/L), 40 μl IGF-1A (2 g/L), 2 μl 0.1% Tween80, 50 μl 99 Tc m O - 4. The maximum labeling rate of 99 Tc m -IGF-1A was (94.43 ± 0.75)% and the radiochemical purity was (54.07 ± 3.86)% at 24 h after mixing with human serum. The maximum binding with Patu8988 cell was (22.95 ± 3.94)%, and the specific binding rate was 19.31%. The tumors in nude mice could be best imaged at 6 h after intravenous injection of 99 Tc m -IGF-1A and 48 h after intratumoral injection of 188 Re-IGF-1A. Conclusions: The presented method of labeling IGF-1A with 188 Re/ 99 Tc m was stable and efficient. 188 Re/ 99 Tc m -IGF-1A could bind with the pancreatic cancer cell Patu8988

  18. Yip1A, a Novel Host Factor for the Activation of the IRE1 Pathway of the Unfolded Protein Response during Brucella Infection

    Science.gov (United States)

    Taguchi, Yuki; Imaoka, Koichi; Kataoka, Michiyo; Uda, Akihiko; Nakatsu, Daiki; Horii-Okazaki, Sakuya; Kunishige, Rina; Kano, Fumi; Murata, Masayuki

    2015-01-01

    Brucella species replicate within host cells in the form of endoplasmic reticulum (ER)-derived vacuoles. The mechanisms by which the bacteria are sequestered into such vacuoles and obtain a continuous membrane supply for their replication remain to be elucidated. In the present study, we provided several lines of evidence that demonstrate the mechanism by which B. abortus acquires the ER-derived membrane. First, during Brucella infection, the IRE1 pathway, but not the PERK and ATF6 pathways, of the unfolded protein response (UPR) was activated in a time-dependent manner, and the COPII vesicle components Sar1, Sec23, and Sec24D were upregulated. Second, a marked accretion of ER-derived vacuoles was observed around replicating bacteria using fluorescent microscopy and electron microscopy. Third, we identified a novel host factor, Yip1A, for the activation of the IRE1 pathway in response to both tunicamycin treatment and infection with B. abortus. We found that Yip1A is responsible for the phosphorylation of IRE1 through high-order assembly of Ire1 molecules at ER exit sites (ERES) under the UPR conditions. In Yip1A-knockdown cells, B. abortus failed to generate the ER-derived vacuoles, and remained in endosomal/lysosomal compartments. These results indicate that the activation of the IRE1 pathway and the subsequent formation of ER-derived vacuoles are critical for B. abortus to establish a safe replication niche, and that Yip1A is indispensable for these processes. Furthermore, we showed that the autophagy-related proteins Atg9 and WIPI1, but not DFCP1, were required for the biogenesis of the ER-derived membrane compartments.  On the basis of our findings, we propose a model for intracellular Brucella replication that exploits the host UPR and ER-derived vacuole formation machineries, both of which depend on Yip1A-mediated IRE1 activation. PMID:25742138

  19. Loss of translation elongation factor (eEF1A2) expression in vivo differentiates between Wallerian degeneration and dying-back neuronal pathology.

    Science.gov (United States)

    Murray, Lyndsay M; Thomson, Derek; Conklin, Annalijn; Wishart, Thomas M; Gillingwater, Thomas H

    2008-12-01

    Wallerian degeneration and dying-back pathology are two well-known cellular pathways capable of regulating the breakdown and loss of axonal and synaptic compartments of neurons in vivo. However, the underlying mechanisms and molecular triggers of these pathways remain elusive. Here, we show that loss of translation elongation factor eEF1A2 expression in lower motor neurons and skeletal muscle fibres in homozygous Wasted mice triggered a dying-back neuropathy. Synaptic loss at the neuromuscular junction occurred in advance of axonal pathology and by a mechanism morphologically distinct from Wallerian degeneration. Dying-back pathology in Wasted mice was accompanied by reduced expression levels of the zinc finger protein ZPR1, as found in other dying-back neuropathies such as spinal muscular atrophy. Surprisingly, experimental nerve lesion revealed that Wallerian degeneration was significantly delayed in homozygous Wasted mice; morphological assessment revealed that approximately 80% of neuromuscular junctions in deep lumbrical muscles at 24 h and approximately 50% at 48 h had retained motor nerve terminals following tibial nerve lesion. This was in contrast to wild-type and heterozygous Wasted mice where < 5% of neuromuscular junctions had retained motor nerve terminals at 24 h post-lesion. These data show that eEF1A2 expression is required to prevent the initiation of dying-back pathology at the neuromuscular junction in vivo. In contrast, loss of eEF1A2 expression significantly inhibited the initiation and progression of Wallerian degeneration in vivo. We conclude that loss of eEF1A2 expression distinguishes mechanisms underlying dying-back pathology from those responsible for Wallerian degeneration in vivo and suggest that eEF1A2-dependent cascades may provide novel molecular targets to manipulate neurodegenerative pathways in lower motor neurons.

  20. The Drosophila melanogaster CHD1 chromatin remodeling factor modulates global chromosome structure and counteracts HP1a and H3K9me2.

    Science.gov (United States)

    Bugga, Lakshmi; McDaniel, Ivy E; Engie, Liana; Armstrong, Jennifer A

    2013-01-01

    CHD1 is a conserved chromatin remodeling factor that localizes to active genes and functions in nucleosome assembly and positioning as well as histone turnover. Mouse CHD1 is required for the maintenance of stem cell pluripotency while human CHD1 may function as a tumor suppressor. To investigate the action of CHD1 on higher order chromatin structure in differentiated cells, we examined the consequences of loss of CHD1 and over-expression of CHD1 on polytene chromosomes from salivary glands of third instar Drosophila melanogaster larvae. We observed that chromosome structure is sensitive to the amount of this remodeler. Loss of CHD1 resulted in alterations of chromosome structure and an increase in the heterochromatin protein HP1a, while over-expression of CHD1 disrupted higher order chromatin structure and caused a decrease in levels of HP1a. Over-expression of an ATPase inactive form of CHD1 did not result in severe chromosomal defects, suggesting that the ATPase activity is required for this in vivo phenotype. Interestingly, changes in CHD1 protein levels did not correlate with changes in the levels of the euchromatin mark H3K4me3 or elongating RNA Polymerase II. Thus, while CHD1 is localized to transcriptionally active regions of the genome, it can function to alter the levels of HP1a, perhaps through changes in methylation of H3K9.

  1. The Drosophila melanogaster CHD1 chromatin remodeling factor modulates global chromosome structure and counteracts HP1a and H3K9me2.

    Directory of Open Access Journals (Sweden)

    Lakshmi Bugga

    Full Text Available CHD1 is a conserved chromatin remodeling factor that localizes to active genes and functions in nucleosome assembly and positioning as well as histone turnover. Mouse CHD1 is required for the maintenance of stem cell pluripotency while human CHD1 may function as a tumor suppressor. To investigate the action of CHD1 on higher order chromatin structure in differentiated cells, we examined the consequences of loss of CHD1 and over-expression of CHD1 on polytene chromosomes from salivary glands of third instar Drosophila melanogaster larvae. We observed that chromosome structure is sensitive to the amount of this remodeler. Loss of CHD1 resulted in alterations of chromosome structure and an increase in the heterochromatin protein HP1a, while over-expression of CHD1 disrupted higher order chromatin structure and caused a decrease in levels of HP1a. Over-expression of an ATPase inactive form of CHD1 did not result in severe chromosomal defects, suggesting that the ATPase activity is required for this in vivo phenotype. Interestingly, changes in CHD1 protein levels did not correlate with changes in the levels of the euchromatin mark H3K4me3 or elongating RNA Polymerase II. Thus, while CHD1 is localized to transcriptionally active regions of the genome, it can function to alter the levels of HP1a, perhaps through changes in methylation of H3K9.

  2. Phylogenetic Diversity in Core Region of Hepatitis C Virus Genotype 1a as a Factor Associated with Fibrosis Severity in HIV-1-Coinfected Patients

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    Micaela Parra

    2017-01-01

    Full Text Available High hepatitis C virus (HCV genetic diversity impacts infectivity/pathogenicity, influencing chronic liver disease progression associated with fibrosis degrees and hepatocellular carcinoma. HCV core protein is crucial in cell-growth regulation and host-gene expression. Liver fibrosis is accelerated by unknown mechanisms in human immunodeficiency virus-1- (HIV-1- coinfected individuals. We aimed to study whether well-defined HCV-1a core polymorphisms and genetic heterogeneity are related to fibrosis in a highly homogeneous group of interferon-treated HIV-HCV-coinfected patients. Genetic heterogeneity was weighed by Faith’s phylogenetic diversity (PD, which has been little studied in HCV. Eighteen HCV/HIV-coinfected patients presenting different liver fibrosis stages before anti-HCV treatment-initiation were recruited. Sampling at baseline and during and after treatment was performed up to 72 weeks. At inter/intrahost level, HCV-1a populations were studied using molecular cloning and Sanger sequencing. Over 400 complete HCV-1a core sequences encompassing 573 positions of C were obtained. Amino acid substitutions found previously at positions 70 and 91 of HCV-1b core region were not observed. However, HCV genetic heterogeneity was higher in mild than in severe fibrosis cases. These results suggest a potential utility of PD as a virus-related factor associated with chronic hepatitis C progression. These observations should be reassessed in larger cohorts to corroborate our findings and assess other potential covariates.

  3. Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone–related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor

    Science.gov (United States)

    Kong, Li; Zhao, Yun-Peng; Tian, Qing-Yun; Feng, Jian-Quan; Kobayashi, Tatsuya; Merregaert, Joseph; Liu, Chuan-Ju

    2016-01-01

    Chondrogenesis and endochondral ossification are precisely controlled by cellular interactions with surrounding matrix proteins and growth factors that mediate cellular signaling pathways. Here, we report that extracellular matrix protein 1 (ECM1) is a previously unrecognized regulator of chondrogenesis. ECM1 is induced in the course of chondrogenesis and its expression in chondrocytes strictly depends on parathyroid hormone–related peptide (PTHrP) signaling pathway. Overexpression of ECM1 suppresses, whereas suppression of ECM1 enhances, chondrocyte differentiation and hypertrophy in vitro and ex vivo. In addition, target transgene of ECM1 in chondrocytes or osteoblasts in mice leads to striking defects in cartilage development and endochondral bone formation. Of importance, ECM1 seems to be critical for PTHrP action in chondrogenesis, as blockage of ECM1 nearly abolishes PTHrP regulation of chondrocyte hypertrophy, and overexpression of ECM1 rescues disorganized growth plates of PTHrP-null mice. Furthermore, ECM1 and progranulin chondrogenic growth factor constitute an interaction network and act in concert in the regulation of chondrogenesis.—Kong, L., Zhao, Y.-P., Tian, Q.-Y., Feng, J.-Q., Kobayashi, T., Merregaert, J., Liu, C.-J. Extracellular matrix protein 1, a direct targeting molecule of parathyroid hormone–related peptide, negatively regulates chondrogenesis and endochondral ossification via associating with progranulin growth factor. PMID:27075243

  4. Allelic variants of OsSUB1A cause differential expression of transcription factor genes in response to submergence in rice.

    Science.gov (United States)

    Sharma, Niharika; Dang, Trang Minh; Singh, Namrata; Ruzicic, Slobodan; Mueller-Roeber, Bernd; Baumann, Ute; Heuer, Sigrid

    2018-01-08

    Flooding during seasonal monsoons affects millions of hectares of rice-cultivated areas across Asia. Submerged rice plants die within a week due to lack of oxygen, light and excessive elongation growth to escape the water. Submergence tolerance was first reported in an aus-type rice landrace, FR13A, and the ethylene-responsive transcription factor (TF) gene SUB1A-1 was identified as the major tolerance gene. Intolerant rice varieties generally lack the SUB1A gene but some intermediate tolerant varieties, such as IR64, carry the allelic variant SUB1A-2. Differential effects of the two alleles have so far not been addressed. As a first step, we have therefore quantified and compared the expression of nearly 2500 rice TF genes between IR64 and its derived tolerant near isogenic line IR64-Sub1, which carries the SUB1A-1 allele. Gene expression was studied in internodes, where the main difference in expression between the two alleles was previously shown. Nineteen and twenty-six TF genes were identified that responded to submergence in IR64 and IR64-Sub1, respectively. Only one gene was found to be submergence-responsive in both, suggesting different regulatory pathways under submergence in the two genotypes. These differentially expressed genes (DEGs) mainly included MYB, NAC, TIFY and Zn-finger TFs, and most genes were downregulated upon submergence. In IR64, but not in IR64-Sub1, SUB1B and SUB1C, which are also present in the Sub1 locus, were identified as submergence responsive. Four TFs were not submergence responsive but exhibited constitutive, genotype-specific differential expression. Most of the identified submergence responsive DEGs are associated with regulatory hormonal pathways, i.e. gibberellins (GA), abscisic acid (ABA), and jasmonic acid (JA), apart from ethylene. An in-silico promoter analysis of the two genotypes revealed the presence of allele-specific single nucleotide polymorphisms, giving rise to ABRE, DRE/CRT, CARE and Site II cis-elements, which

  5. Analyzing the soybean transcriptome during autoregulation of mycorrhization identifies the transcription factors GmNF-YA1a/b as positive regulators of arbuscular mycorrhization.

    Science.gov (United States)

    Schaarschmidt, Sara; Gresshoff, Peter M; Hause, Bettina

    2013-06-18

    Similarly to the legume-rhizobia symbiosis, the arbuscular mycorrhiza interaction is controlled by autoregulation representing a feedback inhibition involving the CLAVATA1-like receptor kinase NARK in shoots. However, little is known about signals and targets down-stream of NARK. To find NARK-related transcriptional changes in mycorrhizal soybean (Glycine max) plants, we analyzed wild-type and two nark mutant lines interacting with the arbuscular mycorrhiza fungus Rhizophagus irregularis. Affymetrix GeneChip analysis of non-inoculated and partially inoculated plants in a split-root system identified genes with potential regulation by arbuscular mycorrhiza or NARK. Most transcriptional changes occur locally during arbuscular mycorrhiza symbiosis and independently of NARK. RT-qPCR analysis verified nine genes as NARK-dependently regulated. Most of them have lower expression in roots or shoots of wild type compared to nark mutants, including genes encoding the receptor kinase GmSIK1, proteins with putative function as ornithine acetyl transferase, and a DEAD box RNA helicase. A predicted annexin named GmAnnx1a is differentially regulated by NARK and arbuscular mycorrhiza in distinct plant organs. Two putative CCAAT-binding transcription factor genes named GmNF-YA1a and GmNF-YA1b are down-regulated NARK-dependently in non-infected roots of mycorrhizal wild-type plants and functional gene analysis confirmed a positive role for these genes in the development of an arbuscular mycorrhiza symbiosis. Our results indicate GmNF-YA1a/b as positive regulators in arbuscular mycorrhiza establishment, whose expression is down-regulated by NARK in the autoregulated root tissue thereby diminishing subsequent infections. Genes regulated independently of arbuscular mycorrhization by NARK support an additional function of NARK in symbioses-independent mechanisms.

  6. Sda1, a Cys2-His2 zinc finger transcription factor, is involved in polyol metabolism and fumonisin B1 production in Fusarium verticillioides.

    Directory of Open Access Journals (Sweden)

    Martha Malapi-Wight

    Full Text Available The ubiquitous ascomycete Fusarium verticillioides causes ear rot and stalk rot of maize, both of which reduce grain quality and yield. Additionally, F. verticillioides produces the mycotoxin fumonisin B1 (FB1 during infection of maize kernels, and thus potentially compromises human and animal health. The current knowledge is fragmentary regarding the regulation of FB1 biosynthesis, particularly when considering interplay with environmental factors such as nutrient availability. In this study, SDA1 of F. verticillioides, predicted to encode a Cys-2 His-2 zinc finger transcription factor, was shown to play a key role in catabolizing select carbon sources. Growth of the SDA1 knock-out mutant (Δsda1 was completely inhibited when sorbitol was the sole carbon source and was severely impaired when exclusively provided mannitol or glycerol. Deletion of SDA1 unexpectedly increased FB1 biosynthesis, but reduced arabitol and mannitol biosynthesis, as compared to the wild-type progenitor. Trichoderma reesei ACE1, a regulator of cellulase and xylanase expression, complemented the F. verticillioides Δsda1 mutant, which indicates that Ace1 and Sda1 are functional orthologs. Taken together, the data indicate that Sda1 is a transcriptional regulator of carbon metabolism and toxin production in F. verticillioides.

  7. Protein Kinase A (PKA) Type I Interacts with P-Rex1, a Rac Guanine Nucleotide Exchange Factor: EFFECT ON PKA LOCALIZATION AND P-Rex1 SIGNALING.

    Science.gov (United States)

    Chávez-Vargas, Lydia; Adame-García, Sendi Rafael; Cervantes-Villagrana, Rodolfo Daniel; Castillo-Kauil, Alejandro; Bruystens, Jessica G H; Fukuhara, Shigetomo; Taylor, Susan S; Mochizuki, Naoki; Reyes-Cruz, Guadalupe; Vázquez-Prado, José

    2016-03-18

    Morphology of migrating cells is regulated by Rho GTPases and fine-tuned by protein interactions and phosphorylation. PKA affects cell migration potentially through spatiotemporal interactions with regulators of Rho GTPases. Here we show that the endogenous regulatory (R) subunit of type I PKA interacts with P-Rex1, a Rac guanine nucleotide exchange factor that integrates chemotactic signals. Type I PKA holoenzyme interacts with P-Rex1 PDZ domains via the CNB B domain of RIα, which when expressed by itself facilitates endothelial cell migration. P-Rex1 activation localizes PKA to the cell periphery, whereas stimulation of PKA phosphorylates P-Rex1 and prevents its activation in cells responding to SDF-1 (stromal cell-derived factor 1). The P-Rex1 DEP1 domain is phosphorylated at Ser-436, which inhibits the DH-PH catalytic cassette by direct interaction. In addition, the P-Rex1 C terminus is indirectly targeted by PKA, promoting inhibitory interactions independently of the DEP1-PDZ2 region. A P-Rex1 S436A mutant construct shows increased RacGEF activity and prevents the inhibitory effect of forskolin on sphingosine 1-phosphate-dependent endothelial cell migration. Altogether, these results support the idea that P-Rex1 contributes to the spatiotemporal localization of type I PKA, which tightly regulates this guanine exchange factor by a multistep mechanism, initiated by interaction with the PDZ domains of P-Rex1 followed by direct phosphorylation at the first DEP domain and putatively indirect regulation of the C terminus, thus promoting inhibitory intramolecular interactions. This reciprocal regulation between PKA and P-Rex1 might represent a key node of integration by which chemotactic signaling is fine-tuned by PKA. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. Relation of Transcriptional Factors to the Expression and Activity of Cytochrome P450 and UDP-Glucuronosyltransferases 1A in Human Liver: Co-Expression Network Analysis.

    Science.gov (United States)

    Zhong, Shilong; Han, Weichao; Hou, Chuqi; Liu, Junjin; Wu, Lili; Liu, Menghua; Liang, Zhi; Lin, Haoming; Zhou, Lili; Liu, Shuwen; Tang, Lan

    2017-01-01

    Cytochrome P450 (CYPs) and UDP-glucuronosyltransferases (UGTs) play important roles in the metabolism of exogenous and endogenous compounds. The gene transcription of CYPs and UGTs can be enhanced or reduced by transcription factors (TFs). This study aims to explore novel TFs involved in the regulatory network of human hepatic UGTs/CYPs. Correlations between the transcription levels of 683 key TFs and CYPs/UGTs in three different human liver expression profiles (n = 640) were calculated first. Supervised weighted correlation network analysis (sWGCNA) was employed to define hub genes among the selected TFs. The relationship among 17 defined TFs, CYPs/UGTs expression, and activity were evaluated in 30 liver samples from Chinese patients. The positive controls (e.g., PPARA, NR1I2, NR1I3) and hub TFs (NFIA, NR3C2, and AR) in the Grey sWGCNA Module were significantly and positively associated with CYPs/UGTs expression. And the cancer- or inflammation-related TFs (TEAD4, NFKB2, and NFKB1) were negatively associated with mRNA expression of CYP2C9/CYP2E1/UGT1A9. Furthermore, the effect of NR1I2, NR1I3, AR, TEAD4, and NFKB2 on CYP450/UGT1A gene transcription translated into moderate influences on enzyme activities. To our knowledge, this is the first study to integrate Gene Expression Omnibus (GEO) datasets and supervised weighted correlation network analysis (sWGCNA) for defining TFs potentially related to CYPs/UGTs. We detected several novel TFs involved in the regulatory network of hepatic CYPs and UGTs in humans. Further validation and investigation may reveal their exact mechanism of CYPs/UGTs regulation.

  9. E3B1, a human homologue of the mouse gene product Abi-1, sensitizes activation of Rap1 in response to epidermal growth factor

    International Nuclear Information System (INIS)

    Jenei, Veronika; Andersson, Tommy; Jakus, Judit; Dib, Karim

    2005-01-01

    E3B1, a human homologue of the mouse gene product Abi-1, has been implicated in growth-factor-mediated regulation of the small GTPases p21 Ras and Rac. E3b1 is a regulator of Rac because it can form a complex with Sos-1 and eps8, and such a Sos-1-e3B1-eps8 complex serves as a guanine nucleotide exchange factor for Rac. In the present study, we found that overexpression of e3B1 in NIH3T3/EGFR cells sensitized EGF-induced activation of Rac1, whereas it had no impact on EGF-induced activation of p21 Ras . Remarkably, we found that EGF-induced activation of the p21 Ras -related GTPase Rap1 was also sensitized in NIH3T3/EGFR-e3B1 cells. Thus, in NIH3T3/EGFR-e3B1 cells, maximal EGF-induced activation of Rap1 occurs with a dose of EGF much lower than in NIH3T3/EGFR cells. We also report that overexpression of e3B1 in NIH3T3/EGFR cells renders EGF-induced activation of Rap1 completely dependent on Src tyrosine kinases but not on c-Abl. However, EGF-induced tyrosine phosphorylation of the Rap GEF C3G occurred regardless of whether e3B1 was overexpressed or not, and this did not involve Src tyrosine kinases. Accordingly, we propose that overexpression of e3B1 in NIH3T3/EGFR cells leads to mobilization of Src tyrosine kinases that participate in EGF-induced activation of Rap1 and inhibition of cell proliferation

  10. McWRI1, a transcription factor of the AP2/SHEN family, regulates the biosynthesis of the cuticular waxes on the apple fruit surface under low temperature

    Science.gov (United States)

    Ji, Qianlong; Zhang, Kezhong; Yang, Mingfeng

    2017-01-01

    Cuticular waxes of plant and organ surfaces play an important role in protecting plants from biotic and abiotic stress and extending the freshness, storage time and shelf life in the post-harvest agricultural products. WRI1, a transcription factor of AP2/SHEN families, had been found to trigger the related genes taking part in the biosynthesis of seed oil in many plants. But whether WRI1 is involved in the biosynthesis of the cuticular waxes on the Malus fruits surface has been unclear. We investigated the changes of wax composition and structure, the related genes and WRI1 expression on Malus asiatica Nakai and sieversii fruits with the low temperature treatments, found that low temperature induced the up-regulated expression of McWRI1, which promoted gene expression of McKCS, McLACs and McWAX in very-long-chain fatty acid biosynthesis pathway, resulting in the accumulation of alkanes component and alteration of wax structure on the fruit surface. Corresponding results were verified in McWRI1 silenced by VIGS, and WRI1 silenced down-regulated the related genes on two kinds of fruits, it caused the diversity alteration in content of some alkanes, fatty acid and ester component in two kinds of fruits. We further conducted Y1H assay to find that McWRI1 transcription factor activated the promoter of McKCS, McLAC and McWAX to regulate their expression. These results demonstrated that McWRI1 is involved in regulating the genes related synthesis of very long chain fatty acid on surface of apple fruits in storage process, providing a highlight for improvement of the modified atmosphere storage of apple fruits. PMID:29073205

  11. Transforming growth factor-β induced Warburg-like metabolic reprogramming may underpin the development of peritoneal endometriosis.

    Science.gov (United States)

    Young, Vicky J; Brown, Jeremy K; Maybin, Jacqueline; Saunders, Philippa T K; Duncan, W Colin; Horne, Andrew W

    2014-09-01

    TGF-β is believed to play a major role in the etiology of peritoneal endometriosis. In tumors, TGF-β induces the metabolic conversion of glucose to lactate via glycolysis, a process referred to as the "Warburg effect." Lactate increases cell invasion, angiogenesis, and immune suppression, all crucial steps in the development of endometriosis. The aim of this study was to determine whether TGF-β induces a "Warburg-like" effect in peritoneal endometriosis. The study was informed by human tissue analysis and cel culture. The study was conducted at the university research institute. We studied women undergoing surgical investigation for endometriosis. Concentrations of lactate and TGF-β1 in peritoneal fluid (n = 16) were measured by commercial assay. Expression of genes implicated in glycolysis was measured in endometrial and peritoneal biopsies (n = 31) by quantitative RT-PCR and immunohistochemistry. The effect of TGF-β1 on primary human peritoneal mesothelial cells (n = 6) and immortalized mesothelial (MeT-5A) cells (n = 3) was assessed by quantitative RT-PCR, Western blot, and commercial assays. Lactate, TGF-β1, and markers of glycolysis were measured. Concentrations of lactate in peritoneal fluid paralleled those of TGF-β1, being significantly higher in women with endometriosis compared to women without (P Endometriosis lesions expressed higher levels of glycolysis-associated genes HIF1A, PDK1, and LDHA than eutopic endometrium, and adjacent peritoneum had higher levels of HIF1A and SLC2A1 than peritoneum from women without disease (P endometriosis lesions and peritoneal mesothelium in women with endometriosis may favor development of endometriosis.

  12. The growth hormone-insulin-like growth factor axis in glycogen storage disease type 1: evidence of different growth patterns and insulin-like growth factor levels in patients with glycogen storage disease type 1a and 1b.

    Science.gov (United States)

    Melis, Daniela; Pivonello, Rosario; Parenti, Giancarlo; Della Casa, Roberto; Salerno, Mariacarolina; Balivo, Francesca; Piccolo, Pasquale; Di Somma, Carolina; Colao, Annamaria; Andria, Generoso

    2010-04-01

    To investigate the growth hormone (GH)-insulin-like growth factor (IGF) system in patients with glycogen storage disease type 1 (GSD1). This was a prospective, case-control study. Ten patients with GSD1a and 7 patients with GSD1b who were given dietary treatment and 34 sex-, age-, body mass index-, and pubertal stage-matched control subjects entered the study. Auxological parameters were correlated with circulating GH, either at basal or after growth hormone releasing hormone plus arginine test, insulin-like growth factors (IGF-I and IGF-II), and anti-pituitary antibodies (APA). Short stature was detected in 10.0% of patients with GSD1a, 42.9% of patients with GSD1b (P = .02), and none of the control subjects. Serum IGF-I levels were lower in patients with GSD1b (P = .0001). An impaired GH secretion was found in 40% of patients with GSD1a (P = .008), 57.1% of patients with GSD1b (P = .006), and none of the control subjects. Short stature was demonstrated in 3 of 4 patients with GSD1b and GH deficiency. The prevalence of APA was significantly higher in patients with GSD1b than in patients with GSD1a (P = .02) and control subjects (P = .03). The GH response to the provocative test inversely correlated with the presence of APA (P = .003). Compared with levels in control subjects, serum IGF-II and insulin levels were higher in both groups of patients, in whom IGF-II levels directly correlated with height SD scores (P = .003). Patients with GSD1a have an impaired GH secretion associated with reference range serum IGF-I levels and normal stature, whereas in patients with GSD1b, the impaired GH secretion, probably because of the presence of APA, was associated with reduced IGF-I levels and increased prevalence of short stature. The increased IGF-II levels, probably caused by increased insulin levels, in patients with GSD1 are presumably responsible for the improved growth pattern observed in patients receiving strict dietary treatment. Copyright 2010 Mosby, Inc. All

  13. Expression of Tissue factor in Adenocarcinoma and Squamous Cell Carcinoma of the Uterine Cervix: Implications for immunotherapy with hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor

    International Nuclear Information System (INIS)

    Cocco, Emiliano; Azodi, Masoud; Schwartz, Peter E; Rutherford, Thomas J; Pecorelli, Sergio; Lockwood, Charles J; Santin, Alessandro D; Varughese, Joyce; Buza, Natalia; Bellone, Stefania; Glasgow, Michelle; Bellone, Marta; Todeschini, Paola; Carrara, Luisa; Silasi, Dan-Arin

    2011-01-01

    Cervical cancer continues to be an important worldwide health problem for women. Up to 35% of patients who are diagnosed with and appropriately treated for cervical cancer will recur and treatment results are poor for recurrent disease. Given these sobering statistics, development of novel therapies for cervical cancer remains a high priority. We evaluated the expression of Tissue Factor (TF) in cervical cancer and the potential of hI-con1, an antibody-like-molecule targeted against TF, as a novel form of immunotherapy against multiple primary cervical carcinoma cell lines with squamous- and adenocarcinoma histology. Because TF is a transmembrane receptor for coagulation factor VII/VIIa (fVII), in this study we evaluated the in vitro expression of TF in cervical carcinoma cell lines by immunohistochemistry (IHC), real time-PCR (qRT-PCR) and flow cytometry. Sensitivity to hI-con1-dependent cell-mediated-cytotoxicity (IDCC) was evaluated in 5-hrs- 51 chromium-release-assays against cervical cancer cell lines in vitro. Cytoplasmic and/or membrane TF expression was observed in 8 out of 8 (100%) of the tumor tissues tested by IHC and in 100% (11 out of 11) of the cervical carcinoma cell lines tested by real-time-PCR and flow cytometry but not in normal cervical keratinocytes (p = 0.0023 qRT-PCR; p = 0.0042 flow cytometry). All primary cervical cancer cell lines tested overexpressing TF, regardless of their histology, were highly sensitive to IDCC (mean killing ± SD, 56.2% ± 15.9%, range, 32.4%-76.9%, p < 0.001), while negligible cytotoxicity was seen in the absence of hI-con1 or in the presence of rituximab-control-antibody. Low doses of interleukin-2 further increased the cytotoxic effect induced by hI-con1 (p = 0.025) while human serum did not significantly decrease IDCC against cervical cancer cell lines (p = 0.597). TF is highly expressed in squamous and adenocarcinoma of the uterine cervix. hI-con1 induces strong cytotoxicity against primary cervical cancer cell

  14. MiR-203 involves in neuropathic pain development and represses Rap1a expression in nerve growth factor differentiated neuronal PC12 cells.

    Science.gov (United States)

    Li, Haixia; Huang, Yuguang; Ma, Chao; Yu, Xuerong; Zhang, Zhiyong; Shen, Le

    2015-01-01

    Although microRNAs (miRNAs) have been shown to play a role in numerous biological processes, their function in neuropathic pain is not clear. The rat bilateral sciatic nerve chronic constriction injury (bCCI) is an established model of neuropathic pain, so we examined miRNA expression and function in the spinal dorsal horn in bCCI rats. Microarray and real-time polymerase chain reaction were used to examine the expression of miRNA in nerve system of bCCI rats, and the targets of miRNA were predicted by bioinformatic approaches. The function of specific miRNA was estimated through the methods of gene engineering. This study revealed substantially (∼10-fold) decreased miR-203 expression in the spinal dorsal horns but not the dorsal root ganglions, hippocampus, or anterior cingulate cortexes of bCCI rats. Rap1a protein expression was upregulated in bCCI rat spinal dorsal horns. We further verified that miR-203 directly targeted the 3'-untranslated region of the rap1a gene, thereby decreasing rap1a protein expression in neuron-like cells. Rap1a has diverse neuronal functions and their perturbation is responsible for several mental disorders. For example, Rap1a/MEK/ERK is involved in peripheral sensitization. These data suggest a potential role for miR-203 in regulating neuropathic pain development, and Rap1a is a validated target gene in vitro. Results from our study and others indicate the possibility that Rap1a may be involved in pain. We hope that these results can provide support for future research into miR-203 in gene therapy for neuropathic pain.

  15. Serum levels of pancreatic stone protein (PSP/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY carriers from the third decade of life onward

    Directory of Open Access Journals (Sweden)

    Bacon Siobhan

    2012-07-01

    Full Text Available Abstract Background Mutations in the transcription factor hepatocyte nuclear factor-1-alpha (HNF1A result in the commonest type of maturity onset diabetes of the young (MODY. HNF1A-MODY carriers have reduced pancreatic beta cell mass, partially due to an increased rate of apoptosis. To date, it has not been possible to determine when apoptosis is occurring in HNF1A-MODY.We have recently demonstrated that beta cell apoptosis stimulates the expression of the pancreatic stone protein/regenerating (PSP/reg gene in surviving neighbour cells, and that PSP/reg1A protein is subsequently secreted from these cells. The objective of this study was to determine whether serum levels of PSP/reg1A are elevated during disease progression in HNF1A-MODY carriers, and whether it may provide information regarding the onset of beta-cell apoptosis. Methods We analysed serum PSP/reg1A levels and correlated with clinical and biochemical parameters in subjects with HNF1A-MODY, glucokinase (GCK-MODY, and type 1 diabetes mellitus. A control group of normoglycaemic subjects was also analysed. Results PSP/reg1A serum levels were significantly elevated in HNF1A-MODY (n = 37 subjects compared to controls (n = 60 (median = 12.50 ng/ml, IQR = 10.61-17.87 ng/ml versus median = 10.72 ng/ml, IQR = 8.94-12.54 ng/ml, p = 0.0008. PSP/reg1A correlated negatively with insulin levels during OGTT, (rho = −0.40, p = 0.02. Interestingly we noted a significant positive correlation of PSP/reg1A with age of the HNF1A-MODY carriers (rho = 0.40 p = 0.02 with an age of 25 years separating carriers with low and high PSP/reg1A levels. Patients with type 1 diabetes mellitus also had elevated serum levels of PSP/reg1A compared to controls, however this was independent of the duration of diabetes. Conclusion Our data suggest that beta cell apoptosis contributes increasingly to the pathophysiology of HNF1A-MODY in patients 25 years and over

  16. Serum levels of pancreatic stone protein (PSP)/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward

    LENUS (Irish Health Repository)

    Bacon, Siobhan

    2012-07-18

    AbstractBackgroundMutations in the transcription factor hepatocyte nuclear factor-1-alpha (HNF1A) result in the commonest type of maturity onset diabetes of the young (MODY). HNF1A-MODY carriers have reduced pancreatic beta cell mass, partially due to an increased rate of apoptosis. To date, it has not been possible to determine when apoptosis is occurring in HNF1A-MODY.We have recently demonstrated that beta cell apoptosis stimulates the expression of the pancreatic stone protein\\/regenerating (PSP\\/reg) gene in surviving neighbour cells, and that PSP\\/reg1A protein is subsequently secreted from these cells. The objective of this study was to determine whether serum levels of PSP\\/reg1A are elevated during disease progression in HNF1A-MODY carriers, and whether it may provide information regarding the onset of beta-cell apoptosis.MethodsWe analysed serum PSP\\/reg1A levels and correlated with clinical and biochemical parameters in subjects with HNF1A-MODY, glucokinase (GCK-MODY), and type 1 diabetes mellitus. A control group of normoglycaemic subjects was also analysed.ResultsPSP\\/reg1A serum levels were significantly elevated in HNF1A-MODY (n = 37) subjects compared to controls (n = 60) (median = 12.50 ng\\/ml, IQR = 10.61-17.87 ng\\/ml versus median = 10.72 ng\\/ml, IQR = 8.94-12.54 ng\\/ml, p = 0.0008). PSP\\/reg1A correlated negatively with insulin levels during OGTT, (rho = −0.40, p = 0.02). Interestingly we noted a significant positive correlation of PSP\\/reg1A with age of the HNF1A-MODY carriers (rho = 0.40 p = 0.02) with an age of 25 years separating carriers with low and high PSP\\/reg1A levels. Patients with type 1 diabetes mellitus also had elevated serum levels of PSP\\/reg1A compared to controls, however this was independent of the duration of diabetes.ConclusionOur data suggest that beta cell apoptosis contributes increasingly to the pathophysiology of HNF1A-MODY in patients 25 years and

  17. Mechanism of Androgen Receptor Corepression by CKβBP2/CRIF1, a Multifunctional Transcription Factor Coregulator Expressed in Prostate Cancer

    OpenAIRE

    Tan, Jiann-an; Bai, Suxia; Grossman, Gail; Titus, Mark A.; Ford, O. Harris; Pop, Elena A.; Smith, Gary J.; Mohler, James L.; Wilson, Elizabeth M.; French, Frank S.

    2013-01-01

    The transcription factor coregulator Casein kinase IIβbinding protein 2 or CR6-interacting factor 1 (CKβBP2/CRIF1) binds the androgen receptor (AR) in prostate cancer cells and in response to dihydrotestosterone localizes with AR on the prostate-specific antigen gene enhancer, but does not bind DNA suggesting CKβBP2/CRIF1 localization in chromatin is determined by AR. In this study we show also that CKβBP2/CRIF1 inhibits wild-type AR and AR N-terminal transcriptional activity, binds to the AR...

  18. Identification and functional characterization of Rca1, a transcription factor involved in both antifungal susceptibility and host response in Candida albicans.

    Science.gov (United States)

    Vandeputte, Patrick; Pradervand, Sylvain; Ischer, Françoise; Coste, Alix T; Ferrari, Sélène; Harshman, Keith; Sanglard, Dominique

    2012-07-01

    The identification of novel transcription factors associated with antifungal response may allow the discovery of fungus-specific targets for new therapeutic strategies. A collection of 241 Candida albicans transcriptional regulator mutants was screened for altered susceptibility to fluconazole, caspofungin, amphotericin B, and 5-fluorocytosine. Thirteen of these mutants not yet identified in terms of their role in antifungal response were further investigated, and the function of one of them, a mutant of orf19.6102 (RCA1), was characterized by transcriptome analysis. Strand-specific RNA sequencing and phenotypic tests assigned Rca1 as the regulator of hyphal formation through the cyclic AMP/protein kinase A (cAMP/PKA) signaling pathway and the transcription factor Efg1, but also probably through its interaction with a transcriptional repressor, most likely Tup1. The mechanisms responsible for the high level of resistance to caspofungin and fluconazole observed resulting from RCA1 deletion were investigated. From our observations, we propose that caspofungin resistance was the consequence of the deregulation of cell wall gene expression and that fluconazole resistance was linked to the modulation of the cAMP/PKA signaling pathway activity. In conclusion, our large-scale screening of a C. albicans transcription factor mutant collection allowed the identification of new effectors of the response to antifungals. The functional characterization of Rca1 assigned this transcription factor and its downstream targets as promising candidates for the development of new therapeutic strategies, as Rca1 influences host sensing, hyphal development, and antifungal response.

  19. p44 and p34 subunits of the BTF2/TFIIH transcription factor have homologies with SSL1, a yeast protein involved in DNA repair.

    NARCIS (Netherlands)

    S. Humbert; H. van Vuuren; Y. Lutz; J.H.J. Hoeijmakers (Jan); J-M. Egly (Jean-Marc); V. Moncollin

    1994-01-01

    textabstractThe human BTF2 (TFIIH) transcription factor is a multisubunit protein involved in transcription initiation by RNA polymerase II (B) as well as in DNA repair. In addition to the previously characterized p62 and p89/ERCC3 subunits, we have cloned two other subunits of BTF2, p44 and p34.

  20. Adenovirus type 5 E1A and E6 proteins of low-risk cutaneous beta-human papillomaviruses suppress cell transformation through interaction with FOXK1/K2 transcription factors.

    Science.gov (United States)

    Komorek, Jessica; Kuppuswamy, Mohan; Subramanian, T; Vijayalingam, S; Lomonosova, Elena; Zhao, Ling-Jun; Mymryk, Joe S; Schmitt, Kimberly; Chinnadurai, G

    2010-03-01

    The adenovirus (Adv) oncoprotein E1A stimulates cell proliferation and inhibits differentiation. These activities are primarily linked to the N-terminal region (exon 1) of E1A, which interacts with multiple cellular protein complexes. The C terminus (exon 2) of E1A antagonizes these processes, mediated in part through interaction with C-terminal binding proteins 1 and 2 (CtBP1/2). To identify additional cellular E1A targets that are involved in the modulation of E1A C-terminus-mediated activities, we undertook tandem affinity purification of E1A-associated proteins. Through mass spectrometric analysis, we identified several known E1A-interacting proteins as well as novel E1A targets, such as the forkhead transcription factors, FOXK1/K2. We identified a Ser/Thr-containing sequence motif in E1A that mediated interaction with FOXK1/K2. We demonstrated that the E6 proteins of two beta-human papillomaviruses (HPV14 and HPV21) associated with epidermodysplasia verruciformis also interacted with FOXK1/K2 through a motif similar to that of E1A. The E1A mutants deficient in interaction with FOXK1/K2 induced enhanced cell proliferation and oncogenic transformation. The hypertransforming activity of the mutant E1A was suppressed by HPV21 E6. An E1A-E6 chimeric protein containing the Ser/Thr domain of the E6 protein in E1A interacted efficiently with FOXK1/K2 and inhibited cell transformation. Our results suggest that targeting FOXK1/K2 may be a common mechanism for certain beta-HPVs and Adv5. E1A exon 2 mutants deficient in interaction with the dual-specificity kinases DYRK1A/1B and their cofactor HAN11 also induced increased cell proliferation and transformation. Our results suggest that the E1A C-terminal region may suppress cell proliferation and oncogenic transformation through interaction with three different cellular protein complexes: FOXK1/K2, DYRK(1A/1B)/HAN11, and CtBP1/2.

  1. The role of IL-1 gene polymorphisms (IL1A, IL1B, and IL1RN) as a risk factor in unsuccessful implants retaining overdentures.

    Science.gov (United States)

    Sampaio Fernandes, Margarida; Vaz, Paula; Braga, Ana Cristina; Sampaio Fernandes, João Carlos; Figueiral, Maria Helena

    2017-10-01

    Implant-supported overdentures are an alternative predictable rehabilitation method that has a high impact on improving the patient's quality of life. However, some biological complications may interfere with the maintenance and survival of these overdenture implants. The goal of this article was to assess the factors that affect peri-implant success, through a hypothetical prediction model for biological complications of implant overdentures. A retrospective observational, prevalence study was conducted in 58 edentulous Caucasian patients rehabilitated with implant overdentures. A total of 229 implants were included in the study. Anamnestic, clinical, and implant-related parameters were collected and recorded in a single database. "Patient" was chosen as the unit of analysis, and a complete screening protocol was established. The data analytical study included assessing the odds ratio, concerning the presence or absence of a particular risk factor, by using binary logistic regression modeling. Probability values (p values) inferior to 0.05 were considered as representing statistically significant evidence. The performed prediction model included the following variables: mean probing depth, metal exposure, IL1B_allele2, maxillary edentulousness, and Fusobacterium nucleatum. The F. nucleatum showed significant association with the outcome. Introducing a negative coefficient appeared to prevent complications or even boost the biological defense when associated with other factors. The prediction model developed in this study could serve as a basis for further improved models that would assist clinicians in the daily diagnosis and treatment planning practice of oral rehabilitation with implant overdentures. Copyright © 2017 Japan Prosthodontic Society. Published by Elsevier Ltd. All rights reserved.

  2. Fetal antigen 1, a member of the epidermal growth factor superfamily, in neurofibromas and serum from patients with neurofibromatosis type 1

    DEFF Research Database (Denmark)

    Jensen, Charlotte Harken; Schroder, H D; Teisner, B

    1999-01-01

    Fetal antigen 1 (FA1) is a 26-32 kDa glycoprotein containing six epidermal growth factor-like repeats closely related to the delta/notch/serrate proteins in Drosophila. FA1 has been shown to be involved in cell differentiation in a juxtacrine/paracrine manner. As neurofibromatosis type 1 (NF-1......), also called von Recklinghausen disease, involves aberrant growth of tissues derived from the neural crest, the expression of FA1 was examined in neurofibroma skin biopsies and serum from patients with NF-1. FA1 was found in the spindle cells of all (n = 10) skin tumour specimens from adult NF-1...

  3. The interindividual differences in the 3-demthylation of caffeine alias CYP1A2 is determined by both genetic and environmental factors

    DEFF Research Database (Denmark)

    Rasmussen, Birgitte B; Brix, Thomas H; Kyvik, Kirsten O

    2002-01-01

    . The mean (+/- SD) caffeine ratio was 5.9 +/- 3.4. The caffeine ratio was statistically significantly higher in men compared to women, in smoking men and women compared to non-smoking persons of the same gender and in women not taking oral contraceptives compared with women on oral contraceptives. Thus, we...... confirmed that CYP1A2 is more active in men than in women, that it is induced by smoking and inhibited by oral contraceptives. In the subsequent analysis of heritability, we included 49 monozygotic twin pairs and 34 same gender dizygotic twin pairs concordant for non-smoking and non-use of oral...... contraceptives. The intraclass correlation coefficient was 0.798 (95% confidence interval, 0.696-0.900) and 0.394 (95% confidence interval, 0.109-0.680) in the monozygotic and dizygotic twins, respectively. The correlation was statistically significantly higher (P = 0.0015) in the former compared with the latter...

  4. The human RNA polymerase II-associated factor 1 (hPaf1: a new regulator of cell-cycle progression.

    Directory of Open Access Journals (Sweden)

    Nicolas Moniaux

    2009-09-01

    Full Text Available The human PAF (hPAF complex is part of the RNA polymerase II transcription apparatus and regulates multiple steps in gene expression. Further, the yeast homolog of hPaf1 has a role in regulating the expression of a subset of genes involved in the cell-cycle. We therefore investigated the role of hPaf1 during progression of the cell-cycle.Herein, we report that the expression of hPaf1, a subunit of the hPAF complex, increases with cell-cycle progression and is regulated in a cell-cycle dependant manner. hPaf1 specifically regulates a subclass of genes directly implicated in cell-cycle progression during G1/S, S/G2, and G2/M. In prophase, hPaf1 aligns in filament-like structures, whereas in metaphase it is present within the pole forming a crown-like structure, surrounding the centrosomes. Moreover, hPaf1 is degraded during the metaphase to anaphase transition. In the nucleus, hPaf1 regulates the expression of cyclins A1, A2, D1, E1, B1, and Cdk1. In addition, expression of hPaf1 delays DNA replication but favors the G2/M transition, in part through microtubule assembly and mitotic spindle formation.Our results identify hPaf1 and the hPAF complex as key regulators of cell-cycle progression. Mutation or loss of stoichiometry of at least one of the members may potentially lead to cancer development.

  5. TaMYB13-1, a R2R3 MYB transcription factor, regulates the fructan synthetic pathway and contributes to enhanced fructan accumulation in bread wheat

    Science.gov (United States)

    Kooiker, Maarten; Drenth, Janneke; Glassop, Donna; McIntyre, C. Lynne; Xue, Gang-Ping

    2013-01-01

    Fructans are the major component of temporary carbon reserve in the stem of temperate cereals, which is used for grain filling. Three families of fructosyltransferases are directly involved in fructan synthesis in the vacuole of Triticum aestivum. The regulatory network of the fructan synthetic pathway is largely unknown. Recently, a sucrose-upregulated wheat MYB transcription factor (TaMYB13-1) was shown to be capable of activating the promoter activities of sucrose:sucrose 1-fructosyltransferase (1-SST) and sucrose:fructan 6-fructosyltransferase (6-SFT) in transient transactivation assays. This work investigated TaMYB13-1 target genes and their influence on fructan synthesis in transgenic wheat. TaMYB13-1 overexpression resulted in upregulation of all three families of fructosyltransferases including fructan:fructan 1-fructosyltransferase (1-FFT). A γ-vacuolar processing enzyme (γ-VPE1), potentially involved in processing the maturation of fructosyltransferases in the vacuole, was also upregulated by TaMYB13-1 overexpression. Multiple TaMYB13 DNA-binding motifs were identified in the Ta1-FFT1 and Taγ-VPE1 promoters and were bound strongly by TaMYB13-1. The expression profiles of these target genes and TaMYB13-1 were highly correlated in recombinant inbred lines and during stem development as well as the transgenic and non-transgenic wheat dataset, further supporting a direct regulation of these genes by TaMYB13-1. TaMYB13-1 overexpression in wheat led to enhanced fructan accumulation in the leaves and stems and also increased spike weight and grain weight per spike in transgenic plants under water-limited conditions. These data suggest that TaMYB13-1 plays an important role in coordinated upregulation of genes necessary for fructan synthesis and can be used as a molecular tool to improve the high fructan trait. PMID:23873993

  6. SHH1, a homeodomain protein required for DNA methylation, as well as RDR2, RDM4, and chromatin remodeling factors, associate with RNA polymerase IV.

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    Julie A Law

    2011-07-01

    Full Text Available DNA methylation is an evolutionarily conserved epigenetic modification that is critical for gene silencing and the maintenance of genome integrity. In Arabidopsis thaliana, the de novo DNA methyltransferase, domains rearranged methyltransferase 2 (DRM2, is targeted to specific genomic loci by 24 nt small interfering RNAs (siRNAs through a pathway termed RNA-directed DNA methylation (RdDM. Biogenesis of the targeting siRNAs is thought to be initiated by the activity of the plant-specific RNA polymerase IV (Pol-IV. However, the mechanism through which Pol-IV is targeted to specific genomic loci and whether factors other than the core Pol-IV machinery are required for Pol-IV activity remain unknown. Through the affinity purification of nuclear RNA polymerase D1 (NRPD1, the largest subunit of the Pol-IV polymerase, we found that several previously identified RdDM components co-purify with Pol-IV, namely RNA-dependent RNA polymerase 2 (RDR2, CLASSY1 (CLSY1, and RNA-directed DNA methylation 4 (RDM4, suggesting that the upstream siRNA generating portion of the RdDM pathway may be more physically coupled than previously envisioned. A homeodomain protein, SAWADEE homeodomain homolog 1 (SHH1, was also found to co-purify with NRPD1; and we demonstrate that SHH1 is required for de novo and maintenance DNA methylation, as well as for the accumulation of siRNAs at specific loci, confirming it is a bonafide component of the RdDM pathway.

  7. PfeIK1, a eukaryotic initiation factor 2α kinase of the human malaria parasite Plasmodium falciparum, regulates stress-response to amino-acid starvation

    Directory of Open Access Journals (Sweden)

    Ranford-Cartwright Lisa

    2009-05-01

    Full Text Available Abstract Background Post-transcriptional control of gene expression is suspected to play an important role in malaria parasites. In yeast and metazoans, part of the stress response is mediated through phosphorylation of eukaryotic translation initiation factor 2α (eIF2α, which results in the selective translation of mRNAs encoding stress-response proteins. Methods The impact of starvation on the phosphorylation state of PfeIF2α was examined. Bioinformatic methods were used to identify plasmodial eIF2α kinases. The activity of one of these, PfeIK1, was investigated using recombinant protein with non-physiological substrates and recombinant PfeIF2α. Reverse genetic techniques were used to disrupt the pfeik1 gene. Results The data demonstrate that the Plasmodium falciparum eIF2α orthologue is phosphorylated in response to starvation, and provide bioinformatic evidence for the presence of three eIF2α kinases in P. falciparum, only one of which (PfPK4 had been described previously. Evidence is provided that one of the novel eIF2α kinases, PfeIK1, is able to phosphorylate the P. falciparum eIF2α orthologue in vitro. PfeIK1 is not required for asexual or sexual development of the parasite, as shown by the ability of pfeik1- parasites to develop into sporozoites. However, eIF2α phosphorylation in response to starvation is abolished in pfeik1- asexual parasites Conclusion This study strongly suggests that a mechanism for versatile regulation of translation by several kinases with a similar catalytic domain but distinct regulatory domains, is conserved in P. falciparum.

  8. Pin1, a new player in the fate of HIF-1α degradation: an hypothetical mechanism inside vascular damage as Alzheimer’s disease risk factor.

    Directory of Open Access Journals (Sweden)

    Elena eLonati

    2014-01-01

    Full Text Available Aetiology of neurodegenerative mechanisms underlying Alzheimer's disease (AD are still under elucidation. The contribution of cerebrovascular deficiencies (such as cerebral ischemia/stroke has been strongly endorsed in recent years. Reduction of blood supply leading to hypoxic condition is known to activate cellular responses mainly controlled by hypoxia-inducible transcription factor-1 (HIF-1. Thus alterations of oxygen responsive HIF-1α subunit in the central nervous system may contribute to the cognitive decline, especially influencing mechanisms associated to APP (amyloid precursor protein amyloidogenic metabolism. Although HIF-1α protein level is known to be regulated by von Hippel-Lindau (VHL ubiquitin-proteasome system, it has been recently suggested that Gsk-3β (glycogen synthase kinase-3β promotes a VHL-independent HIF-1α degradation. Here we provide evidences that in rat primary hippocampal cell cultures, HIF-1α degradation might be mediated by a synergic action of Gsk-3β and Pin1 (peptidyl-prolyl cis/trans isomerase. In post-ischemic conditions, such as those mimicked with oxygen glucose deprivation (OGD, HIF-1α protein level increases remaining unexpectedly high for long time after normal condition restoration jointly with the increase of LDH (lactate dehydrogenase and BACE1 (β-secretase 1 protein expression (70% and 140% respectively. Interestingly the Pin1 activity decreases about 40%-60% and Pin1S16 inhibitory phosphorylation significantly increases, indicating that Pin1 binding to its substrate and enzymatic activity are reduced by treatment. Co-immunoprecipitation experiments demonstrate that HIF-1α/Pin1 in normoxia are associated, and that in presence of specific Pin1 and Gsk-3β inhibitors their interaction is reduced in parallel to an increase of HIF-1α protein level. Thus we suggest that in post-OGD neurons the high level of HIF-1α might be due to Pin1 binding ability and activity reduction which affects HIF-1

  9. Dimerization Is Not a Determining Factor for Functional High Affinity Human Plasminogen Binding by the Group A Streptococcal Virulence Factor PAM and Is Mediated by Specific Residues within the PAM a1a2 Domain*

    Science.gov (United States)

    Bhattacharya, Sarbani; Liang, Zhong; Quek, Adam J.; Ploplis, Victoria A.; Law, Ruby; Castellino, Francis J.

    2014-01-01

    A emm53 subclass of Group A Streptococcus pyogenes (GAS) interacts tightly with human plasma plasminogen (hPg) and plasmin (hPm) via the kringle 2 (K2hPg) domain of hPg/hPm and the N-terminal a1a2 regions of a GAS coiled-coil M-like protein (PAM). Previous studies have shown that a monomeric PAM fragment, VEK30 (residues 97–125 + Tyr), interacted specifically with isolated K2hPg. However, the binding strength of VEK30 (KD = 56 nm) was ∼60-fold weaker than that of full-length dimeric PAM (KD = 1 nm). To assess whether this attenuated binding was due to the inability of VEK30 to dimerize, we defined the minimal length of PAM required to dimerize using a series of peptides with additional PAM residues placed at the NH2 and COOH termini of VEK30. VEK64 (PAM residues 83–145 + Tyr) was found to be the smallest peptide that adopted an α-helical dimer, and was bound to K2hPg with nearly the same affinity as PAM (KD = 1–2 nm). However, addition of two PAM residues (Arg126-His127) to the COOH terminus of VEK30 (VEK32) maintained a monomeric peptidic structure, but exhibited similar K2hPg binding affinity as full-length dimeric PAM. We identified five residues in a1a2 (Arg113, His114, Glu116, Arg126, His127), mutation of which reduced PAM binding affinity for K2hPg by ∼1000-fold. Replacement of these critical residues by Ala in the GAS genome resulted in reduced virulence, similar to the effects of inactivating the PAM gene entirely. We conclude that rather than dimerization of PAM, the five key residues in the binding domain of PAM are essential to mediate the high affinity interaction with hPg, leading to increased GAS virulence. PMID:24962580

  10. Dimerization is not a determining factor for functional high affinity human plasminogen binding by the group A streptococcal virulence factor PAM and is mediated by specific residues within the PAM a1a2 domain.

    Science.gov (United States)

    Bhattacharya, Sarbani; Liang, Zhong; Quek, Adam J; Ploplis, Victoria A; Law, Ruby; Castellino, Francis J

    2014-08-01

    A emm53 subclass of Group A Streptococcus pyogenes (GAS) interacts tightly with human plasma plasminogen (hPg) and plasmin (hPm) via the kringle 2 (K2hPg) domain of hPg/hPm and the N-terminal a1a2 regions of a GAS coiled-coil M-like protein (PAM). Previous studies have shown that a monomeric PAM fragment, VEK30 (residues 97-125 + Tyr), interacted specifically with isolated K2hPg. However, the binding strength of VEK30 (KD = 56 nm) was ∼60-fold weaker than that of full-length dimeric PAM (KD = 1 nm). To assess whether this attenuated binding was due to the inability of VEK30 to dimerize, we defined the minimal length of PAM required to dimerize using a series of peptides with additional PAM residues placed at the NH2 and COOH termini of VEK30. VEK64 (PAM residues 83-145 + Tyr) was found to be the smallest peptide that adopted an α-helical dimer, and was bound to K2hPg with nearly the same affinity as PAM (KD = 1-2 nm). However, addition of two PAM residues (Arg(126)-His(127)) to the COOH terminus of VEK30 (VEK32) maintained a monomeric peptidic structure, but exhibited similar K2hPg binding affinity as full-length dimeric PAM. We identified five residues in a1a2 (Arg(113), His(114), Glu(116), Arg(126), His(127)), mutation of which reduced PAM binding affinity for K2hPg by ∼ 1000-fold. Replacement of these critical residues by Ala in the GAS genome resulted in reduced virulence, similar to the effects of inactivating the PAM gene entirely. We conclude that rather than dimerization of PAM, the five key residues in the binding domain of PAM are essential to mediate the high affinity interaction with hPg, leading to increased GAS virulence. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  11. Suppression of mitochondrial respiration with auraptene inhibits the progression of renal cell carcinoma: involvement of HIF-1α degradation.

    Science.gov (United States)

    Jang, Yunseon; Han, Jeongsu; Kim, Soo Jeong; Kim, Jungim; Lee, Min Joung; Jeong, Soyeon; Ryu, Min Jeong; Seo, Kang-Sik; Choi, Song-Yi; Shong, Minho; Lim, Kyu; Heo, Jun Young; Kweon, Gi Ryang

    2015-11-10

    Renal cell carcinoma (RCC) progression resulting from the uncontrolled migration and enhanced angiogenesis is an obstacle to effective therapeutic intervention. Tumor metabolism has distinctive feature called Warburg effect, which enhances the aerobic glycolysis rapidly supplying the energy for migration of tumor. To manipulate this metabolic change characteristic of aggressive tumors, we utilized the citrus extract, auraptene, known as a mitochondrial inhibitor, testing its anticancer effects against the RCC4 cell line. We found that auraptene impaired RCC4 cell motility through reduction of mitochondrial respiration and glycolytic pathway-related genes. It also strongly disrupted VEGF-induced angiogenesis in vitro and in vivo. Hypoxia-inducible factor 1a (HIF-1a), a key regulator of cancer metabolism, migration and angiogenesis that is stably expressed in RCCs by virtue of a genetic mutation in the von Hippel-Lindau (VHL) tumor-suppressor protein, was impeded by auraptene, which blocked HIF-1a translation initiation without causing cytotoxicity. We suggest that blockade HIF-1a and reforming energy metabolism with auraptene is an effective approach for suspension RCC progression.

  12. Aged garlic extract and S-allylcysteine prevent apoptotic cell death in a chemical hypoxia model

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    Marisol Orozco-Ibarra

    Full Text Available BACKGROUND: Aged garlic extract (AGE and its main constituent S-allylcysteine (SAC are natural antioxidants with protective effects against cerebral ischemia or cancer, events that involve hypoxia stress. Cobalt chloride (CoCl2 has been used to mimic hypoxic conditions through the stabilization of the α subunit of hypoxia inducible factor (HIF-Ια and up-regulation of HIF-1a-dependent genes as well as activation of hypoxic conditions such as reactive oxygen species (ROS generation, loss of mitochondrial membrane potential and apoptosis. The present study was designed to assess the effect of AGE and SAC on the CoCl2-chemical hypoxia model in PC12 cells RESULTS: We found that CoCl2 induced the stabilization of HIF-1a and its nuclear localization. CoCl2 produced ROS and apoptotic cell death that depended on hypoxia extent. The treatment with AGE and SAC decreased ROS and protected against CoCl2-induced apoptotic cell death which depended on the CoCl2 concentration and incubation time. SAC or AGE decreased the number of cells in the early and late stages of apoptosis. Interestingly, this protective effect was associated with attenuation in HIF-1a stabilization, activity not previously reported for AGE and SAC CONCLUSIONS: Obtained results show that AGE and SAC decreased apoptotic CoCl2-induced cell death. This protection occurs by affecting the activity of HIF-1a and supports the use of these natural compounds as a therapeutic alternative for hypoxic conditions

  13. Structural rationale for the cross-resistance of tumor cells bearing the A399V variant of elongation factor eEF1A1 to the structurally unrelated didemnin B, ternatin, nannocystin A and ansatrienin B

    Science.gov (United States)

    Sánchez-Murcia, Pedro A.; Cortés-Cabrera, Álvaro; Gago, Federico

    2017-10-01

    At least four classes of structurally distinct natural products with potent antiproliferative activities target the translation elongation factor eEF1A1, which is best known as the G-protein that delivers amino acyl transfer RNAs (aa-tRNAs) to ribosomes during mRNA translation. We present molecular models in atomic detail that provide a common structural basis for the high-affinity binding of didemnin B, ternatin, ansatrienin B and nannocystin A to eEF1A1, as well as a rationale based on molecular dynamics results that accounts for the deleterious effect of replacing alanine 399 with valine. The proposed binding site, at the interface between domains I and III, is eminently hydrophobic and exists only in the GTP-bound conformation. Drug binding at this site is expected to disrupt neither loading of aa-tRNAs nor GTP hydrolysis but would give rise to stabilization of this particular conformational state, in consonance with reported experimental findings. The experimental solution of the three-dimensional structure of mammalian eEF1A1 has proved elusive so far and the highly homologous eEF1A2 from rabbit muscle has been crystallized and solved only as a homodimer in a GDP-bound conformation. Interestingly, in this dimeric structure the large interdomain cavity where the drugs studied are proposed to bind is occupied by a mostly hydrophobic α-helix from domain I of the same monomer. Since binding of this α-helix and any of these drugs to domain III of eEF1A(1/2) is, therefore, mutually exclusive and involves two distinct protein conformations, one intriguing possibility that emerges from our study is that the potent antiproliferative effect of these natural products may arise not only from inhibition of protein synthesis, which is the current dogma, but also from interference with some other non-canonical functions. From this standpoint, this type of drugs could be considered antagonists of eEF1A1/2 oligomerization, a hypothesis that opens up novel areas of research.

  14. Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice

    DEFF Research Database (Denmark)

    Klein, A B; Santini, M A; Aznar, S

    2010-01-01

    Changes in brain-derived neurotrophic factor (BDNF) expression have been implicated in the etiology of psychiatric disorders. To investigate pathological mechanisms elicited by perturbed BDNF signaling, we examined mutant mice with central depletion of BDNF (BDNF(2L/2LCk-cre)). A severe impairment...... specific for the serotonin 2A receptor (5-HT(2A)R) in prefrontal cortex was described previously in these mice. This is of much interest, as 5-HT(2A)Rs have been linked to neuropsychiatric disorders and anxiety-related behavior. Here we further characterized the serotonin receptor alterations triggered...... was decreased in hippocampus of BDNF mutants, but unchanged in frontal cortex. Molecular analysis indicated corresponding changes in 5-HT(2A) and 5-HT(1A) mRNA expression but normal 5-HT(2C) content in these brain regions in BDNF(2L/2LCk-cre) mice. We investigated whether the reduction in frontal 5-HT(2A...

  15. The yeast rapid tRNA decay pathway competes with elongation factor 1A for substrate tRNAs and acts on tRNAs lacking one or more of several modifications.

    Science.gov (United States)

    Dewe, Joshua M; Whipple, Joseph M; Chernyakov, Irina; Jaramillo, Laura N; Phizicky, Eric M

    2012-10-01

    The structural and functional integrity of tRNA is crucial for translation. In the yeast Saccharomyces cerevisiae, certain aberrant pre-tRNA species are subject to nuclear surveillance, leading to 3' exonucleolytic degradation, and certain mature tRNA species are subject to rapid tRNA decay (RTD) if they are appropriately hypomodified or bear specific destabilizing mutations, leading to 5'-3' exonucleolytic degradation by Rat1 and Xrn1. Thus, trm8-Δ trm4-Δ strains are temperature sensitive due to lack of m(7)G(46) and m(5)C and the consequent RTD of tRNA(Val(AAC)), and tan1-Δ trm44-Δ strains are temperature sensitive due to lack of ac(4)C(12) and Um(44) and the consequent RTD of tRNA(Ser(CGA)) and tRNA(Ser(UGA)). It is unknown how the RTD pathway interacts with translation and other cellular processes, and how generally this pathway acts on hypomodified tRNAs. We provide evidence here that elongation factor 1A (EF-1A) competes with the RTD pathway for substrate tRNAs, since its overexpression suppresses the tRNA degradation and the growth defect of strains subject to RTD, whereas reduced levels of EF-1A have the opposite effect. We also provide evidence that RTD acts on a variety of tRNAs lacking one or more different modifications, since trm1-Δ trm4-Δ mutants are subject to RTD of tRNA(Ser(CGA)) and tRNA(Ser(UGA)) due to lack of m(2,2)G(26) and m(5)C, and since trm8-Δ, tan1-Δ, and trm1-Δ single mutants are each subject to RTD. These results demonstrate that RTD interacts with the translation machinery and acts widely on hypomodified tRNAs.

  16. Respuesta a la hipoxia: Un mecanismo sistémico basado en el control de la expresión génica Response to hypoxia: A systemic mechanism based on the control of gene expression

    Directory of Open Access Journals (Sweden)

    Carlos Caramelo

    2006-04-01

    Full Text Available La respuesta hipóxica, sobre la que se dispone de nuevos datos críticamente importantes, puede esquematizarse en tres sistemas, vg. de detección o sensor de oxígeno, de regulación, que controla la expresión génica y efector. El elemento principal de organización del sistema regulador es un factor de transcripción específico, el factor inducible por hipoxia 1 (HIF-1. En presencia de oxígeno, la subunidad a del HIF-1 (HIF-1a se modifica por las hidroxilasas, que constituyen el punto central del mecanismo sensor, induciendo su catabolismo por el proteosoma. Por el contrario, en hipoxia, o en presencia de algunos factores de crecimiento que incrementan su síntesis, el HIF-1a se transloca al núcleo, donde, unido al HIF-1b, actúa como factor transcripcional de genes con elementos de respuesta hipóxica (HRE en su promotor. Estos regulan la síntesis de una amplia serie de proteínas, que abarcan desde enzimas respiratorias y transportadores hasta hormonas involucradas en la regulación a escala del organismo de la circulación y la eritropoyesis. El papel del HIF-1 no se restringe a la mera inducción de una respuesta adaptativa a la falta de oxígeno, sino que participa significativamente en los mecanismos de reparación celular. Una simple lista de algunas alteraciones de importancia fisiopatológica, tanto estimulatorias como inhibitorias, que involucran al sistema de HIF-1, incluiría: enfermedad pulmonar crónica, adaptación al tabaco/humo, anemia/hemorragia, isquemia/reperfusión, crecimiento, vascularización y resistencia celular de los tumores, preeclampsia y crecimiento intrauterino retardado, hiper o hipovascularización retiniana, sobredosis de fármacos, enfermedad inflamatoria intestinal y curación de heridas. Esta sola enumeración ilustra la importancia de este mecanismo.New, critically important data have been recently generated about the response to hypoxia. This response can be schematized in three main systems or

  17. Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: subanalysis of the Phase III OPTiM trial

    Directory of Open Access Journals (Sweden)

    Harrington KJ

    2016-11-01

    Full Text Available Kevin J Harrington,1 Robert HI Andtbacka,2 Frances Collichio,3 Gerald Downey,4 Lisa Chen,5 Zsolt Szabo,6 Howard L Kaufman7 1The Institute of Cancer Research/The Royal Marsden Hospital NIHR Biomedical Research Centre, London, UK; 2Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; 3Division of Hematology and Oncology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 4Amgen Ltd, Cambridge, UK; 5Amgen Inc, Thousand Oaks, CA, USA; 6Amgen GmbH, Zug, Switzerland; 7Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA Objectives: Talimogene laherparepvec is the first oncolytic immunotherapy to receive approval in Europe, the USA and Australia. In the randomized, open-label Phase III OPTiM trial (NCT00769704, talimogene laherparepvec significantly improved durable response rate (DRR versus granulocyte-macrophage colony-stimulating factor (GM-CSF in 436 patients with unresectable stage IIIB–IVM1c melanoma. The median overall survival (OS was longer versus GM-CSF in patients with earlier-stage melanoma (IIIB–IVM1a. Here, we report a detailed subgroup analysis of the OPTiM study in patients with IIIB–IVM1a disease. Patients and methods: The patients were randomized (2:1 ratio to intralesional talimogene laherparepvec or subcutaneous GM-CSF and were evaluated for DRR, overall response rate (ORR, OS, safety, benefit–risk and numbers needed to treat. Descriptive statistics were used for subgroup comparisons. Results: Among 249 evaluated patients with stage IIIB–IVM1a melanoma, DRR was higher with talimogene laherparepvec compared with GM-CSF (25.2% versus 1.2%; P<0.0001. ORR was also higher in the talimogene laherparepvec arm (40.5% versus 2.3%; P<0.0001, and 27 patients in the talimogene laherparepvec arm had a complete response, compared with none in GM-CSF-treated patients. The incidence rates of exposure-adjusted adverse events (AE and serious AEs were similar with both treatments. Conclusion

  18. Hypoxia in Tumor Angiogenesis and Metastasis: Evaluation of VEGF and MMP Over-expression and Down-Regulation of HIF-1alpha with RNAi in Hypoxic Tumor Cells

    Science.gov (United States)

    Shah, Shruti

    Background: As tumor mass grows beyond a few millimeters in diameter, the angiogenic "switch" is turned on leading to recruitment of blood vessels from surrounding artery and veins. However, the tumor mass is poorly perfused and there are pockets of hypoxia or lower oxygen concentrations relative to normal tissue. Hypoxia-inducing factor-1a (HIF-1a), a transcription factor, is activated when the oxygen concentration is low. Upon activation of HIF-1a, a number of other genes also turn on that allows the tumor to become more aggressive and resistant to therapy. Purpose: The main objectives of this study were to evaluate the effect of hypoxia-induced HIF-1a followed by over-expression of angiogenic and metastatic markers in tumor cells and down-regulation of HIF-1a using nanoparticle-delivered RNA interference therapy. Methods: Human ovarian (SKOV3) and breast (MDA-MB-231) adenocarcinoma cells were incubated under normoxic and hypoxic conditions. Following hypoxia treatment of the cells, HIF-1α, vascular endothelial growth factor (VEGF), matrix metalloproteinase 2 (MMP-2), and MMP-9 expression was analyzed qualitatively and quantitatively. For intracellular delivery of HIF-1a gene silencing small interfering RNA (siRNA), type B gelatin nanoparticles were fabricated using the solvent displacement method and the surface was modified with poly(ethylene glycol) (PEG, Mol. wt. 2kDa). Cellular uptake and distribution of the nanoparticles was observed with Cy3-siRNA loaded, FITC-conjugated gelatin nanoparticles. Cytotoxicity of the nanoparticle formulations was evaluated in both the cell lines. siRNA was transfected in the gelatin nanoparticles under hypoxic conditions. Total cellular protein and RNA were extracted for analysis of HIF1a, VEGF, MMP-2 and MMP-9 expression. Results: MDA-MB-231 and SKOV3 cells show increased expression of HIF1a under hypoxic conditions compared to baseline levels at normoxic conditions. ELISA and western blots of VEGF, MMP-2 and MMP-9 appear to

  19. Similarities between the Epstein-Barr Virus (EBV) Nuclear Protein EBNA1 and the Pioneer Transcription Factor FoxA: Is EBNA1 a “Bookmarking” Oncoprotein that Alters the Host Cell Epigenotype?

    Science.gov (United States)

    Niller, Hans Helmut; Minarovits, Janos

    2012-01-01

    EBNA1, a nuclear protein expressed in all EBV-associated neoplasms is indispensable for the maintenance of the viral episomes in latently infected cells. EBNA1 may induce genetic alterations by upregulating cellular recombinases, production of reactive oxygen species (ROS) and affecting p53 levels and function. All these changes may contribute to tumorigenesis. In this overview we focus, however, on the epigenetic alterations elicited by EBNA1 by drawing a parallel between EBNA1 and the FoxA family of pioneer transcription factors. Both EBNA1 and FoxA induce local DNA demethylation, nucleosome destabilization and bind to mitotic chromosomes. Local DNA demethylation and nucleosome rearrangement mark active promoters and enhancers. In addition, EBNA1 and FoxA, when associated with mitotic chromatin may “bookmark” active genes and ensure their reactivation in postmitotic cells (epigenetic memory). We speculate that DNA looping induced by EBNA1-EBNA1 interactions may reorganize the cellular genome. Such chromatin loops, sustained in mitotic chromatin similarly to the long-distance interactions mediated by the insulator protein CTCF, may also mediate the epigenetic inheritance of gene expression patterns. We suggest that EBNA1 has the potential to induce patho-epigenetic alterations contributing to tumorigenesis. PMID:25436603

  20. Generation of an induced pluripotent stem cell (iPSC line from a patient with maturity-onset diabetes of the young type 3 (MODY3 carrying a hepatocyte nuclear factor 1-alpha (HNF1A mutation

    Directory of Open Access Journals (Sweden)

    Frank Griscelli

    2018-05-01

    Full Text Available Heterozygous non-synonymous (p.S142F mutation in HNF1A leads to maturity-onset diabetes of the young (MODY type 3, which is a subtype of dominant inherited young-onset non-autoimmune diabetes due to the defect of insulin secretion from pancreatic beta cells. We generated induced pluripotent stem cells (iPSCs from a patient with HNF1A p.S142F mutation. Cells from this patient, which were reprogrammed by non-integrative viral transduction had normal karyotype, harboured the HNF1A p.S142F mutation, expressed pluripotency hallmarks.

  1. RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome

    DEFF Research Database (Denmark)

    Steg, Ph Gabriel; Mehta, Shamir R; Jukema, J Wouter

    2011-01-01

    To establish the safety, tolerability and most promising regimen of darexaban (YM150), a novel, oral, direct factor Xa inhibitor, for prevention of ischaemic events in acute coronary syndrome (ACS)....

  2. Targeting GPR30 in Abiraterone and MDV3100 Resistant Prostate Cancer

    Science.gov (United States)

    2017-12-01

    chemotactic cytokines GROa, GROb, and GROg activate human neutrophil and basophil leukocytes. Journal of Biological Chemistry 268 15419–15424. Gregory AD...adenocarcinoma engineered to release IL-2, IL-4, IL-7, IL-10, IFN-a, IFN-g, and TNF-a. Laboratory Investigation 74 146–157. Nelson AW, Tilley WD, Neal...factor-1a (HIF-1a) in breast cancer cells and cardiomyocytes. Journal of Biological Chemistry 286 10773–10782. (doi:10.1074/jbc.M110.172247) Ryckman C

  3. Changes in 5-HT2A-mediated behavior and 5-HT2A- and 5-HT1A receptor binding and expression in conditional brain-derived neurotrophic factor knock-out mice

    DEFF Research Database (Denmark)

    Klein, A B; Santini, M A; Aznar, S

    2010-01-01

    Changes in brain-derived neurotrophic factor (BDNF) expression have been implicated in the etiology of psychiatric disorders. To investigate pathological mechanisms elicited by perturbed BDNF signaling, we examined mutant mice with central depletion of BDNF (BDNF(2L/2LCk-cre)). A severe impairmen...

  4. Causes of death and prognostic factors in multiple endocrine neoplasia type 1: a prospective study: comparison of 106 MEN1/Zollinger-Ellison syndrome patients with 1613 literature MEN1 patients with or without pancreatic endocrine tumors.

    Science.gov (United States)

    Ito, Tetsuhide; Igarashi, Hisato; Uehara, Hirotsugu; Berna, Marc J; Jensen, Robert T

    2013-05-01

    Multiple endocrine neoplasia type 1 (MEN1) is classically characterized by the development of functional or nonfunctional hyperplasia or tumors in endocrine tissues (parathyroid, pancreas, pituitary, adrenal). Because effective treatments have been developed for the hormone excess state, which was a major cause of death in these patients in the past, coupled with the recognition that nonendocrine tumors increasingly develop late in the disease course, the natural history of the disease has changed. An understanding of the current causes of death is important to tailor treatment for these patients and to help identify prognostic factors; however, it is generally lacking.To add to our understanding, we conducted a detailed analysis of the causes of death and prognostic factors from a prospective long-term National Institutes of Health (NIH) study of 106 MEN1 patients with pancreatic endocrine tumors with Zollinger-Ellison syndrome (MEN1/ZES patients) and compared our results to those from the pooled literature data of 227 patients with MEN1 with pancreatic endocrine tumors (MEN1/PET patients) reported in case reports or small series, and to 1386 patients reported in large MEN1 literature series. In the NIH series over a mean follow-up of 24.5 years, 24 (23%) patients died (14 MEN1-related and 10 non-MEN1-related deaths). Comparing the causes of death with the results from the 227 patients in the pooled literature series, we found that no patients died of acute complications due to acid hypersecretion, and 8%-14% died of other hormone excess causes, which is similar to the results in 10 large MEN1 literature series published since 1995. In the 2 series (the NIH and pooled literature series), two-thirds of patients died from an MEN1-related cause and one-third from a non-MEN1-related cause, which agrees with the mean values reported in 10 large MEN1 series in the literature, although in the literature the causes of death varied widely. In the NIH and pooled literature

  5. Characterization of StABF1, a stress-responsive bZIP transcription factor from Solanum tuberosum L. that is phosphorylated by StCDPK2 in vitro.

    Science.gov (United States)

    Muñiz García, María Noelia; Giammaria, Verónica; Grandellis, Carolina; Téllez-Iñón, María Teresa; Ulloa, Rita María; Capiati, Daniela Andrea

    2012-04-01

    ABF/AREB bZIP transcription factors mediate plant abiotic stress responses by regulating the expression of stress-related genes. These proteins bind to the abscisic acid (ABA)-responsive element (ABRE), which is the major cis-acting regulatory sequence in ABA-dependent gene expression. In an effort to understand the molecular mechanisms of abiotic stress resistance in cultivated potato (Solanum tuberosum L.), we have cloned and characterized an ABF/AREB-like transcription factor from potato, named StABF1. The predicted protein shares 45-57% identity with A. thaliana ABFs proteins and 96% identity with the S. lycopersicum SlAREB1 and presents all of the distinctive features of ABF/AREB transcription factors. Furthermore, StABF1 is able to bind to the ABRE in vitro. StABF1 gene is induced in response to ABA, drought, salt stress and cold, suggesting that it might be a key regulator of ABA-dependent stress signaling pathways in cultivated potato. StABF1 is phosphorylated in response to ABA and salt stress in a calcium-dependent manner, and we have identified a potato CDPK isoform (StCDPK2) that phosphorylates StABF1 in vitro. Interestingly, StABF1 expression is increased during tuber development and by tuber-inducing conditions (high sucrose/nitrogen ratio) in leaves. We also found that StABF1 calcium-dependent phosphorylation is stimulated by tuber-inducing conditions and inhibited by gibberellic acid, which inhibits tuberization.

  6. 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*

    OpenAIRE

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

    2016-01-01

    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 ...

  7. Stimulation of Transforming Growth Factor-β1-Induced Endothelial-To-Mesenchymal Transition and Tissue Fibrosis by Endothelin-1 (ET-1): A Novel Profibrotic Effect of ET-1.

    Science.gov (United States)

    Wermuth, Peter J; Li, Zhaodong; Mendoza, Fabian A; Jimenez, Sergio A

    2016-01-01

    TGF-β-induced endothelial-to-mesenchymal transition (EndoMT) is a newly recognized source of profibrotic activated myofibroblasts and has been suggested to play a role in the pathogenesis of various fibrotic processes. Endothelin-1 (ET-1) has been implicated in the development of tissue fibrosis but its participation in TGF-β-induced EndoMT has not been studied. Here we evaluated the role of ET-1 on TGF-β1-induced EndoMT in immunopurified CD31+/CD102+ murine lung microvascular endothelial cells. The expression levels of α-smooth muscle actin (α-SMA), of relevant profibrotic genes, and of various transcription factors involved in the EndoMT process were assessed employing quantitative RT-PCR, immunofluorescence histology and Western blot analysis. TGF-β1 caused potent induction of EndoMT whereas ET-1 alone had a minimal effect. However, ET-1 potentiated TGF-β1-induced EndoMT and TGF-β1-stimulated expression of mesenchymal cell specific and profibrotic genes and proteins. ET-1 also induced expression of the TGF-β receptor 1 and 2 genes, suggesting a plausible autocrine mechanism to potentiate TGF-β-mediated EndoMT and fibrosis. Stimulation of TGF-β1-induced skin and lung fibrosis by ET-1 was confirmed in vivo in an animal model of TGF-β1-induced tissue fibrosis. These results suggest a novel role for ET-1 in the establishment and progression of tissue fibrosis.

  8. Renal Cell Carcinoma Programmed Death-ligand 1, a New Direct Target of Hypoxia-inducible Factor-2 Alpha, is Regulated by von Hippel-Lindau Gene Mutation Status.

    Science.gov (United States)

    Messai, Yosra; Gad, Sophie; Noman, Muhammad Zaeem; Le Teuff, Gwenael; Couve, Sophie; Janji, Bassam; Kammerer, Solenne Florence; Rioux-Leclerc, Nathalie; Hasmim, Meriem; Ferlicot, Sophie; Baud, Véronique; Mejean, Arnaud; Mole, David Robert; Richard, Stéphane; Eggermont, Alexander M M; Albiges, Laurence; Mami-Chouaib, Fathia; Escudier, Bernard; Chouaib, Salem

    2016-10-01

    Clear cell renal cell carcinomas (ccRCC) frequently display a loss of function of the von Hippel-Lindau (VHL) gene. To elucidate the putative relationship between VHL mutation status and immune checkpoint ligand programmed death-ligand 1 (PD-L1) expression. A series of 32 renal tumors composed of 11 VHL tumor-associated and 21 sporadic RCCs were used to evaluate PD-L1 expression levels after sequencing of the three exons and exon-intron junctions of the VHL gene. The 786-O, A498, and RCC4 cell lines were used to investigate the mechanisms of PD-L1 regulation. Fisher's exact test was used for VHL mutation and Kruskal-Wallis test for PD-L1 expression. If no covariate accounted for the association of VHL and PD-L1, then a Kruskal-Wallis test was used; otherwise Cochran-Mantel-Haenzsel test was used. We also used the Fligner-Policello test to compare two medians when the distributions had different dispersions. We demonstrated that tumors from ccRCC patients with VHL biallelic inactivation (ie, loss of function) display a significant increase in PD-L1 expression compared with ccRCC tumors carrying one VHL wild-type allele. Using the inducible VHL 786-O-derived cell lines with varying hypoxia-inducible factor-2 alpha (HIF-2α) stabilization levels, we showed that PD-L1 expression levels positively correlate with VHL mutation and HIF-2α expression. Targeting HIF-2α decreased PD-L1, while HIF-2α overexpression increased PD-L1 mRNA and protein levels in ccRCC cells. Interestingly, chromatin immunoprecipitation and luciferase assays revealed a direct binding of HIF-2α to a transcriptionally active hypoxia-response element in the human PD-L1 proximal promoter in 786-O cells. Our work provides the first evidence that VHL mutations positively correlate with PD-L1 expression in ccRCC and may influence the response to ccRCC anti-PD-L1/PD-1 immunotherapy. We investigated the relationship between von Hippel-Lindau mutations and programmed death-ligand 1 expression. We

  9. THE ASSOCIATION OF GENE POLYMORPHISMS WITH ATHLETE STATUS IN UKRAINIANS

    Directory of Open Access Journals (Sweden)

    Svitlana B. Drozdovska

    2013-06-01

    Full Text Available Athletic performance is a polygenic trait influenced by both environmental and genetic factors. Objective: to investigate individually and in combination the association of common gene polymorphisms with athlete status in Ukrainians. Methods: A total of 210 elite Ukrainian athletes (100 endurance-oriented and 110 power-orientated athletes and 326 controls were genotyped for ACE I/D, HIF1A Pro582Ser, NOS3 –786 T/C, PPARA intron 7 G/C, PPARG Pro12Ala and PPARGC1B Ala203Pro gene polymorphisms, most of which were previously reported to be associated with athlete status or related intermediate phenotypes in different populations. Results: Power-oriented athletes exhibited an increased frequency of the HIF1A Ser (16.1 vs. 9.420P = 0.034 and NOS3 T alleles (78.3 vs. 66.220P = 0.0019 in comparison with controls. Additionally, we found that the frequency of the PPARG Ala allele was significantly higher in power-oriented athletes compared with the endurance-oriented athletes (24.7 vs. 13.520P = 0.0076. Next, we determined the total genotype score (TGS, from the accumulated combination of the three polymorphisms, with a maximum value of 100 for the theoretically optimal polygenic score in athletes and controls. The mean TGS was significantly higher in power-oriented athletes (39.1 ± 2.3 vs. 32.6 ± 1.5; P = 0.0142 than in controls. Conclusions: We found that the HIF1A Ser, NOS3 T and PPARG Ala alleles were associated with power athlete status in Ukrainians.

  10. Comparative and Experimental Studies on the Genes Altered by Chronic Hypoxia in Human Brain Microendothelial Cells

    Directory of Open Access Journals (Sweden)

    Eugenia Mata-Greenwood

    2017-05-01

    Full Text Available Background : Hypoxia inducible factor 1 alpha (HIF1A is a master regulator of acute hypoxia; however, with chronic hypoxia, HIF1A levels return to the normoxic levels. Importantly, the genes that are involved in the cell survival and viability under chronic hypoxia are not known. Therefore, we tested the hypothesis that chronic hypoxia leads to the upregulation of a core group of genes with associated changes in the promoter DNA methylation that mediates the cell survival under hypoxia.Results : We examined the effect of chronic hypoxia (3 days; 0.5% oxygen on human brain micro endothelial cells (HBMEC viability and apoptosis. Hypoxia caused a significant reduction in cell viability and an increase in apoptosis. Next, we examined chronic hypoxia associated changes in transcriptome and genome-wide promoter methylation. The data obtained was compared with 16 other microarray studies on chronic hypoxia. Nine genes were altered in response to chronic hypoxia in all 17 studies. Interestingly, HIF1A was not altered with chronic hypoxia in any of the studies. Furthermore, we compared our data to three other studies that identified HIF-responsive genes by various approaches. Only two genes were found to be HIF dependent. We silenced each of these 9 genes using CRISPR/Cas9 system. Downregulation of EGLN3 significantly increased the cell death under chronic hypoxia, whereas downregulation of ERO1L, ENO2, adrenomedullin, and spag4 reduced the cell death under hypoxia.Conclusions : We provide a core group of genes that regulates cellular acclimatization under chronic hypoxic stress, and most of them are HIF independent.

  11. Evaluation of Genes Involved in Limb Development, Angiogenesis, and Coagulation as Risk Factors for Congenital Limb Deficiencies

    Science.gov (United States)

    Browne, Marilyn L.; Carter, Tonia C.; Kay, Denise M.; Kuehn, Devon; Brody, Lawrence C.; Romitti, Paul A.; Liu, Aiyi; Caggana, Michele; Druschel, Charlotte M.; Mills, James L.

    2012-01-01

    We conducted a population-based case-control study of single nucleotide polymorphisms (SNPs) in selected genes to find common variants that play a role in the etiology of limb deficiencies (LD)s. Included in the study were 389 infants with LDs of unknown cause and 980 unaffected controls selected from all births in New York State (NYS) for the years 1998 to 2005. We used cases identified from the NYS Department of Health (DOH) Congenital Malformations Registry. Genotypes were obtained for 132 SNPs in genes involved in limb development (SHH, WNT7A, FGF4, FGF8, FGF10, TBX3, TBX5, SALL4, GREM1, GDF5, CTNNB1, EN1, CYP26A1, CYP26B1), angiogenesis (VEGFA, HIF1A, NOS3), and coagulation (F2, F5, MTHFR). Genotype call rates were >97% and SNPs were tested for departure from Hardy-Weinberg expectations by race/ethnic subgroups. For each SNP, odds ratios (OR)s and confidence intervals (CI)s were estimated and corrected for multiple comparisons for all LDs combined and for LD subtypes. Among non-Hispanic white infants, associations between FGF10 SNPs rs10805683 and rs13170645 and all LDs combined were statistically significant following correction for multiple testing (OR=1.99; 95% CI=1.43-2.77; uncorrected p=0.000043 for rs10805683 heterozygous genotype, and OR=2.37; 95% CI=1.48-3.78; uncorrected p=0.00032 for rs13170645 homozygous minor genotype). We also observed suggestive evidence for associations with SNPs in other genes including CYP26B1 and WNT7A. Animal studies have shown that FGF10 induces formation of the apical ectodermal ridge and is necessary for limb development. Our data suggest that common variants in FGF10 increase the risk for a wide range of non-syndromic limb deficiencies. PMID:22965740

  12. Association of genetic polymorphisms with chronic obstructive pulmonary disease in the Hainan population: a case-control study

    Directory of Open Access Journals (Sweden)

    Ding YP

    2014-12-01

    Full Text Available Yipeng Ding,1,* Danlei Yang,2,* Xiaojie Xun,3 Zhifeng Wang,4 Pei Sun,1 Dongchuan Xu,1 Ping He,1 Huan Niu,1 Tianbo Jin3,5 1Department of Emergency, People’s Hospital of Hainan Province, Haikou, Hainan, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 3School of Life Sciences, Northwest University, Xi'an, People’s Republic of China; 4Department of Respiration, People’s Hospital of Qionghai, Qionghai, Hainan, People’s Republic of China; 5National Engineering Research Center for Miniaturized Detection Systems, Xi'an, People’s Republic of China *The authors are joint first authors Purpose: Chronic obstructive pulmonary disease (COPD is predicted to become the third most common cause of death and the fifth most common cause of disability in the world by 2020. Recently, variants in the hypoxia-inducible factor 1α (HIF1A, cholinergic receptor, neuronal nicotinic, alpha polypeptide-5, and iron-responsive element-binding protein 2 gene (IREB2 genes were found to be associated with COPD. This study aims to identify whether the variations in these genes are related to COPD in the Hainan population of the People’s Republic of China. Patients and methods: We genotyped 12 single nucleotide polymorphisms in a case-control study with 200 COPD cases and 401 controls from Hainan, People’s Republic of China. Odds ratios and 95% confidence intervals were estimated using the chi-squared (Χ2 test, genetic model analysis, haplotype analysis, and stratification analysis. Results: In the genetic model analysis, we found that the genotype T/T of rs13180 of IREB2 decreased the COPD risk by 0.52-fold (P=0.025. But in the further stratification analysis, we failed to find the association between the selected single nucleotide polymorphisms with COPD risk in Han population. In addition, the haplotype

  13. Adrenomedullin is a key Protein Mediating Rotary Cell Culture System that Induces the Effects of Simulated Microgravity on Human Breast Cancer Cells

    Science.gov (United States)

    Chen, Li; Yang, Xi; Cui, Xiang; Jiang, Minmin; Gui, Yu; Zhang, Yanni; Luo, Xiangdong

    2015-11-01

    Microgravity or simulated microgravity promotes stem cell proliferation and inhibits differentiation. But, researchers have not yet been able to understand the underlying mechanism through which microgravity or simulated microgravity brings about stem cell proliferation and inhibition of differentiation. In this study, we investigated the effect of simulated microgravity (SMG) on MDA-MB-231 and MCF-7 human breast cancer cells using rotary cell culture system (RCCS). SMG induced a significant accumulation of these cancer cells in S phase of the cell cycle. But, compared with the static group, there was no effect on the overall growth rate of cells in the RCCS group. Furthermore, the expression of cyclin D1 was inhibited in the RCCS group, indicating that RCCS induced cell cycle arrest. In addition, RCCS also induced glycolytic metabolism by increasing the expression of adrenomedullin (ADM), but not HIF1 a. The addition of ADM further enhanced the effects of SMG, which was induced by RCCS. But, the addition of adrenomedullin antagonist (AMA) reversed these effects of SMG. Finally, our results proved that RCCS, which induced cells cycle arrest of breast cancer cells, enhanced glycolysis and upregulated the expression of ADM. But, this did not lead to an increase in hypoxia-inducible factor-1 a (HIF1 a) expression. Thus, we have uncovered a new mechanism for understanding the Warburg effect in breast cancer cells, this mechanism is not the same as hypoxia induced glycolysis.

  14. Variations of CITED2 are associated with congenital heart disease (CHD in Chinese population.

    Directory of Open Access Journals (Sweden)

    Yan Liu

    Full Text Available CITED2 was identified as a cardiac transcription factor which is essential to the heart development. Cited2-deficient mice showed cardiac malformations, adrenal agenesis and neural crest defects. To explore the potential impact of mutations in CITED2 on congenital heart disease (CHD in humans, we screened the coding region of CITED2 in a total of 700 Chinese people with congenital heart disease and 250 healthy individuals as controls. We found five potential disease-causing mutations, p.P140S, p.S183L, p.S196G, p.Ser161delAGC and p. Ser192_Gly193delAGCGGC. Two mammalian two-hybrid assays showed that the last four mutations significantly affected the interaction between p300CH1 and CITED2 or HIF1A. Further studies showed that four CITED2 mutations recovered the promoter activity of VEGF by decreasing its competitiveness with HIF1A for binding to p300CH1 and three mutations decreased the consociation of TFAP2C and CITED2 in the transactivation of PITX2C. Both VEGF and PITX2C play very important roles in cardiac development. In conclusion, we demonstrated that CITED2 has a potential causative impact on congenital heart disease.

  15. Leptin and cancer: Pathogenesis and modulation

    Directory of Open Access Journals (Sweden)

    Deep Dutta

    2012-01-01

    Full Text Available Leptin, a product of Ob gene from adipocytes regulates appetite, energy expenditure and body mass composition by decreasing orexigenic and increasing anorexigenic neuropeptide release from hypothalamus. Research over the past few years have suggested leptin/leptin receptor dysregulation to have a role in the development of a large variety of malignancies like breast ca, thyroid ca, endometrial ca and gastrointestinal malignancies, predominantly through JAK/STAT pathway which modulates PI3K/AKT3 signaling, ERK1/2 signaling, expression of antiapoptotic proteins (like XIAP, systemic inflammation (TNF-α, IL6, angiogenic factors (VEGF and hypoxia inducible factor-1a (HIF-1a expression. In this review, the current understanding of leptin′s role in carcinogenesis has been elaborated. Also a few agents modulating leptin signaling to inhibit cancer cell growth has been described.

  16. GENETIC ASPECTS OF SPORTS PERFORMANCE

    Directory of Open Access Journals (Sweden)

    Fatma Ebru KOKU

    2015-03-01

    Full Text Available As participation in both amateur and professional sports increases, so does the importance of sports performance and the factors influencing it. Determinants of success in sports can be classified as training, genetic, epigenetic, dietary, motivational, equipment and other environmental factors. The effect of genetics on sports performance and skill has been examined for many years. Autosomal genes, mitochondrial DNA and various genes located in the Y chromosome have all been associated with sports performance. It is not possible to link physical performance to a single genetic polymorphism. Genes that have been most extensively studied in their relation to performance include ACE, ACTN3, ADRA2A, ADRB2, PPARA, PPARGC1A, AMPD1, HIF1A, NOS3, BDKRB2, VEGFR2 and VEGFA. For the time being, genetic screening tests may be useful in determining the weaknesses and strengths of a sportsperson, but not in predicting athletic success.

  17. The Algorithm Theoretical Basis Document for Level 1A Processing

    Science.gov (United States)

    Jester, Peggy L.; Hancock, David W., III

    2012-01-01

    The first process of the Geoscience Laser Altimeter System (GLAS) Science Algorithm Software converts the Level 0 data into the Level 1A Data Products. The Level 1A Data Products are the time ordered instrument data converted from counts to engineering units. This document defines the equations that convert the raw instrument data into engineering units. Required scale factors, bias values, and coefficients are defined in this document. Additionally, required quality assurance and browse products are defined in this document.

  18. Porcine EEF1A1 and EEF1A2 genes: genomic structure, polymorphism, mapping and expression

    Czech Academy of Sciences Publication Activity Database

    Svobodová, K.; Horák, Pavel; Stratil, Antonín; Bartenschlager, H.; Van Poucke, M.; Chalupová, P.; Dvořáková, Věra; Knorr, Ch.; Stupka, R.; Čítek, J.; Šprysl, M.; Palánová, Anna; Peelman, L. J.; Geldermann, H.; Knoll, A.

    2015-01-01

    Roč. 42, č. 8 (2015), s. 1257-1264 ISSN 0301-4851 R&D Projects: GA ČR(CZ) GA523/06/1302; GA ČR GA523/09/0844 Institutional support: RVO:67985904 Keywords : EEF1A1 * EEF1A2 * gene expression Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.698, year: 2015

  19. Minimum Data Set Q1a Report

    Data.gov (United States)

    U.S. Department of Health & Human Services — The MDS Q1a report summarizes, by state and county, percentages of residents that answered Yes to Q1a - Residents expresses or indicates preference to return to the...

  20. Psychopharmacology of 5-HT1A receptors

    International Nuclear Information System (INIS)

    Cowen, Philip J.

    2000-01-01

    Serotonin 1A (5-HT 1A ) receptors are located on both 5-HT cell bodies where they act as inhibitory autoreceptors and at postsynaptic sites where they mediate the effects of 5-HT released from nerve terminals. The sensitivity of 5-HT 1A receptors in humans can be measured using the technique of pharmacological challenge. For example, acute administration of a selective 5-HT 1A receptor agonist, such as ipsapirone, decreases body temperature and increases plasma cortisol through activation of pre- and postsynaptic 5-HT 1A receptors, respectively. Use of this technique has demonstrated that unmedicated patients with major depression have decreased sensitivity of both pre- and postsynaptic 5-HT 1A receptors. Treatment with selective serotonin reuptake inhibitors further down-regulates 5-HT 1A receptor activity. Due to the hypotheses linking decreased sensitivity of 5-HT 1A autoreceptors with the onset of antidepressant activity, there is current interest in the therapeutic efficacy of combined treatment with selective serotonin reuptake inhibitors and 5-HT 1A receptor antagonists

  1. PPARGC1A is upregulated and facilitates lung cancer metastasis.

    Science.gov (United States)

    Li, Jin-Dong; Feng, Qing-Chuan; Qi, Yu; Cui, Guanghui; Zhao, Song

    2017-10-15

    Lung cancer remains a leading cause of cancer-related mortality, with metastatic progression remaining the single largest cause of lung cancer mortality. Hence it is imperative to determine reliable biomarkers for lung cancer prognosis. We performed quantitative real-time PCR (qRT-PCR) analysis to explore epithelial-mesenchymal transition (EMT) inducers that regulate EMT process in three patients with advanced lung cancer disease. Peroxisome proliferator-activated receptor gamma (PPARGC1A) was uniformly the topmost overexpressed gene in all three human non-small cell lung cancer (NSCLC) patient samples. Further evaluation in human normal lung and metastatic lung cancer cell lines revealed that the expression of PPARGC1A was upregulated in metastatic lung cancer cell lines. Metagenomic analysis revealed direct correlation among PPARGC1A, zinc-finger transcription factor snail homolog 1 (SNAI1), and metastatic lung disease. Upregulation of PPARGC1A transcript expression was independent of a differential upregulation of the upstream AMP-dependent protein kinase (AMPK) activation or steady state expression of the silent mating type information regulation 2 homolog 1 (SIRT1). Xenograft tail vein colonization assays proved that the high expression of PPARGC1A was a prerequisite for metastatic progression of lung cancer to brain. Our results indicate that PPARGC1A might be a potential biomarker for lung cancer prognosis. Copyright © 2017. Published by Elsevier Inc.

  2. A Single Meal Containing Raw, Crushed Garlic Influences Expression of Immunity- and Cancer-Related Genes in Whole Blood of Humans.

    Science.gov (United States)

    Charron, Craig S; Dawson, Harry D; Albaugh, George P; Solverson, Patrick M; Vinyard, Bryan T; Solano-Aguilar, Gloria I; Molokin, Aleksey; Novotny, Janet A

    2015-11-01

    Preclinical and epidemiologic studies suggest that garlic intake is inversely associated with the progression of cancer and cardiovascular disease. We designed a study to probe the mechanisms of garlic action in humans. We conducted a randomized crossover feeding trial in which 17 volunteers consumed a garlic-containing meal (100 g white bread, 15 g butter, and 5 g raw, crushed garlic) or a garlic-free control meal (100 g white bread and 15 g butter) after 10 d of consuming a controlled, garlic-free diet. Blood was collected before and 3 h after test meal consumption for gene expression analysis in whole blood. Illumina BeadArray was used to screen for genes of interest, followed by real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on selected genes. To augment human study findings, Mono Mac 6 cells were treated with a purified garlic extract (0.5 μL/mL), and mRNA was measured by qRT-PCR at 0, 3, 6, and 24 h. The following 7 genes were found to be upregulated by garlic intake: aryl hydrocarbon receptor (AHR), aryl hydrocarbon receptor nuclear translocator (ARNT), hypoxia-inducible factor 1α (HIF1A), proto-oncogene c-Jun (JUN), nuclear factor of activated T cells (NFAT) activating protein with immunoreceptor tyrosine-based activation motif 1 (NFAM1), oncostatin M (OSM), and V-rel avian reticuloendotheliosis viral oncogene homolog (REL). Fold-increases in mRNA transcripts ranged from 1.6 (HIF1A) to 3.0 (NFAM1) (P garlic, respectively). OSM is a pleiotropic cytokine that inhibits several tumor cell lines in culture. These data indicate that the bioactivity of garlic is multifaceted and includes activation of genes related to immunity, apoptosis, and xenobiotic metabolism in humans and Mono Mac 6 cells. This trial is registered at clinicaltrials.gov as NCT01293591. © 2015 American Society for Nutrition.

  3. A Single Meal Containing Raw, Crushed Garlic Influences Expression of Immunity- and Cancer-Related Genes in Whole Blood of Humans1234

    Science.gov (United States)

    Charron, Craig S; Dawson, Harry D; Albaugh, George P; Solverson, Patrick M; Vinyard, Bryan T; Solano-Aguilar, Gloria I; Molokin, Aleksey; Novotny, Janet A

    2015-01-01

    Background: Preclinical and epidemiologic studies suggest that garlic intake is inversely associated with the progression of cancer and cardiovascular disease. Objective: We designed a study to probe the mechanisms of garlic action in humans. Methods: We conducted a randomized crossover feeding trial in which 17 volunteers consumed a garlic-containing meal (100 g white bread, 15 g butter, and 5 g raw, crushed garlic) or a garlic-free control meal (100 g white bread and 15 g butter) after 10 d of consuming a controlled, garlic-free diet. Blood was collected before and 3 h after test meal consumption for gene expression analysis in whole blood. Illumina BeadArray was used to screen for genes of interest, followed by real-time quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR) on selected genes. To augment human study findings, Mono Mac 6 cells were treated with a purified garlic extract (0.5 μL/mL), and mRNA was measured by qRT-PCR at 0, 3, 6, and 24 h. Results: The following 7 genes were found to be upregulated by garlic intake: aryl hydrocarbon receptor (AHR), aryl hydrocarbon receptor nuclear translocator (ARNT), hypoxia-inducible factor 1α (HIF1A), proto-oncogene c-Jun (JUN), nuclear factor of activated T cells (NFAT) activating protein with immunoreceptor tyrosine-based activation motif 1 (NFAM1), oncostatin M (OSM), and V-rel avian reticuloendotheliosis viral oncogene homolog (REL). Fold-increases in mRNA transcripts ranged from 1.6 (HIF1A) to 3.0 (NFAM1) (P garlic, respectively). OSM is a pleiotropic cytokine that inhibits several tumor cell lines in culture. Conclusion: These data indicate that the bioactivity of garlic is multifaceted and includes activation of genes related to immunity, apoptosis, and xenobiotic metabolism in humans and Mono Mac 6 cells. This trial is registered at clinicaltrials.gov as NCT01293591. PMID:26423732

  4. Response of skeletal muscle mitochondria to hypoxia.

    Science.gov (United States)

    Hoppeler, Hans; Vogt, Michael; Weibel, Ewald R; Flück, Martin

    2003-01-01

    This review explores the current concepts relating the structural and functional modifications of skeletal muscle mitochondria to the molecular mechanisms activated when organisms are exposed to a hypoxic environment. In contrast to earlier assumptions it is now established that permanent or long-term exposure to severe environmental hypoxia decreases the mitochondrial content of muscle fibres. Oxidative muscle metabolism is shifted towards a higher reliance on carbohydrates as a fuel, and intramyocellular lipid substrate stores are reduced. Moreover, in muscle cells of mountaineers returning from the Himalayas, we find accumulations of lipofuscin, believed to be a mitochondrial degradation product. Low mitochondrial contents are also observed in high-altitude natives such as Sherpas. In these subjects high-altitude performance seems to be improved by better coupling between ATP demand and supply pathways as well as better metabolite homeostasis. The hypoxia-inducible factor 1 (HIF-1) has been identified as a master regulator for the expression of genes involved in the hypoxia response, such as genes coding for glucose transporters, glycolytic enzymes and vascular endothelial growth factor (VEGF). HIF-1 achieves this by binding to hypoxia response elements in the promoter regions of these genes, whereby the increase of HIF-1 in hypoxia is the consequence of a reduced degradation of its dominant subunit HIF-1a. A further mechanism that seems implicated in the hypoxia response of muscle mitochondria is related to the formation of reactive oxygen species (ROS) in mitochondria during oxidative phosphorylation. How exactly ROS interfere with HIF-1a as well as MAP kinase and other signalling pathways is debated. The current evidence suggests that mitochondria themselves could be important players in oxygen sensing.

  5. Gene-gene interactions and gene polymorphisms of VEGFA and EG-VEGF gene systems in recurrent pregnancy loss.

    Science.gov (United States)

    Su, Mei-Tsz; Lin, Sheng-Hsiang; Chen, Yi-Chi; Kuo, Pao-Lin

    2014-06-01

    Both vascular endothelial growth factor A (VEGFA) and endocrine gland-derived vascular endothelial growth factor (EG-VEGF) systems play major roles in angiogenesis. A body of evidence suggests VEGFs regulate critical processes during pregnancy and have been associated with recurrent pregnancy loss (RPL). However, little information is available regarding the interaction of these two major major angiogenesis-related systems in early human pregnancy. This study was conducted to investigate the association of gene polymorphisms and gene-gene interaction among genes in VEGFA and EG-VEGF systems and idiopathic RPL. A total of 98 women with history of idiopathic RPL and 142 controls were included, and 5 functional SNPs selected from VEGFA, KDR, EG-VEGF (PROK1), PROKR1 and PROKR2 were genotyped. We used multifactor dimensionality reduction (MDR) analysis to choose a best model and evaluate gene-gene interactions. Ingenuity pathways analysis (IPA) was introduced to explore possible complex interactions. Two receptor gene polymorphisms [KDR (Q472H) and PROKR2 (V331M)] were significantly associated with idiopathic RPL (P<0.01). The MDR test revealed that the KDR (Q472H) polymorphism was the best loci to be associated with RPL (P=0.02). IPA revealed EG-VEGF and VEGFA systems shared several canonical signaling pathways that may contribute to gene-gene interactions, including the Akt, IL-8, EGFR, MAPK, SRC, VHL, HIF-1A and STAT3 signaling pathways. Two receptor gene polymorphisms [KDR (Q472H) and PROKR2 (V331M)] were significantly associated with idiopathic RPL. EG-VEGF and VEGFA systems shared several canonical signaling pathways that may contribute to gene-gene interactions, including the Akt, IL-8, EGFR, MAPK, SRC, VHL, HIF-1A and STAT3.

  6. Risk Factors

    Science.gov (United States)

    ... cells do not invade nearby tissues or spread. Risk Factors Key Points Factors That are Known to ... chemicals . Factors That are Known to Increase the Risk of Cancer Cigarette Smoking and Tobacco Use Tobacco ...

  7. Increased size of solid organs in patients with Chuvash polycythemia and in mice with altered expression of HIF-1α and HIF-2α

    Science.gov (United States)

    Yoon, Donghoon; Okhotin, David V.; Kim, Bumjun; Okhotina, Yulia; Okhotin, Daniel J.; Miasnikova, Galina Y.; Sergueeva, Adelina I.; Polyakova, Lydia A.; Maslow, Alexei; Lee, Yonggu; Semenza, Gregg L.; Prchal, Josef T.

    2010-01-01

    Chuvash polycythemia, the first hereditary disease associated with dysregulated oxygen-sensing to be recognized, is characterized by a homozygous germ-line loss-of-function mutation of the VHL gene (VHLR200W) resulting in elevated hypoxia inducible factor (HIF)-1α and HIF-2α levels, increased red cell mass and propensity to thrombosis. Organ volume is determined by the size and number of cells, and the underlying molecular control mechanisms are not fully elucidated. Work from several groups has demonstrated that the proliferation of cells is regulated in opposite directions by HIF-1α and HIF-2α. HIF-1α inhibits cell proliferation by displacing MYC from the promoter of the gene encoding the cyclin-dependent kinase inhibitor, p21Cip1, thereby inducing its expression. In contrast, HIF-2α promotes MYC activity and cell proliferation. Here we report that the volumes of liver, spleen, and kidneys relative to body mass were larger in 30 individuals with Chuvash polycythemia than in 30 matched Chuvash controls. In Hif1a+/− mice, which are heterozygous for a null (knockout) allele at the locus encoding HIF-1α, hepatic HIF-2α mRNA was increased (2-fold) and the mass of the liver was increased, compared with wild-type littermates, without significant difference in cell volume. Hepatic p21Cip1 mRNA levels were 9.5-fold lower in Hif1a+/− mice compared with wild-type littermates. These data suggest that, in addition to increased red cell mass, the sizes of liver, spleen, and kidneys are increased in Chuvash polycythemia. At least in the liver, this phenotype may result from increased HIF-2α and decreased p21Cip1 levels leading to increased hepatocyte proliferation. PMID:20140661

  8. Gene expression levels of gamma-glutamyl hydrolase in tumor tissues may be a useful biomarker for the proper use of S-1 and tegafur-uracil/leucovorin in preoperative chemoradiotherapy for patients with rectal cancer.

    Science.gov (United States)

    Sadahiro, Sotaro; Suzuki, T; Tanaka, A; Okada, K; Saito, G; Miyakita, H; Ogimi, T; Nagase, H

    2017-06-01

    Preoperative chemoradiotherapy (CRT) using 5-fluorouracil (5-FU)-based chemotherapy is the standard of care for rectal cancer. The effect of additional chemotherapy during the period between the completion of radiotherapy and surgery remains unclear. Predictive factors for CRT may differ between combination chemotherapy with S-1 and with tegafur-uracil/leucovorin (UFT/LV). The subjects were 54 patients with locally advanced rectal cancer who received preoperative CRT with S-1 or UFT/LV. The pathological tumor response was assessed according to the tumor regression grade (TRG). The expression levels of 18 CRT-related genes were determined using RT-PCR assay. A pathological response (TRG 1-2) was observed in 23 patients (42.6%). In a multivariate logistic regression analysis for pathological response, the overall expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, were significant, and the accuracy rate of the predictive model was 83.3%. The effects of the gene expression levels of GGH on the response differed significantly according to the treatment regimen. The total pathological response rate of both high-GGH patients in the S-1 group and low-GGH patients in the UFT/LV group was 58.3%. Additional treatment with 5-FU-based chemotherapy during the interval between radiotherapy and surgery is not beneficial in patients who have received 5-FU-based CRT. The expression levels of four genes, HIF1A, MTHFD1, GGH and TYMS, in tumor tissues can predict the response to preoperative CRT including either S-1 or UFT/LV. In particular, the gene expression level of GGH in tumor tissues may be a useful biomarker for the appropriate use of S-1 and UFT/LV in CRT.

  9. UDP-glucuronosyltransferases 1A6 and 1A10 catalyze reduced menadione glucuronidation

    International Nuclear Information System (INIS)

    Nishiyama, Takahito; Ohnuma, Tomokazu; Inoue, Yuu; Kishi, Takehiko; Ogura, Kenichiro; Hiratsuka, Akira

    2008-01-01

    Menadione (2-methyl-1,4-naphthoquine), also known as vitamin K3, has been widely used as a model compound in the field of oxidative stress-related research. The metabolism of menadione has been studied, and it is known that menadione undergoes a two-electron reduction by NAD(P)H:Quinone oxidoreductase 1 (NQO1) after which the reduced form of menadione (2-methyl-1,4-naphthalenediol, menadiol) is glucuronidated and excreted in urine. To investigate which human UDP-glucuronosyltransferase (UGT) isoforms participate in the glucuronidation of menadiol reduced by NQO1 from menadione, we first constructed heterologously expressed NQO1 in Sf9 cells and tested the menadiol glucuronidating activity of 16 human recombinant UGT isoforms. Of the 16 UGT isoforms, UGTs 1A6, 1A7, 1A8, 1A9, and 1A10 catalyzed menadiol glucuronidation, and, of these, UGTs 1A6 and 1A10 catalyzed menadiol glucuronidation at much higher rates than the other UGTs. Menadiol was regioselectively glucuronidated in the manner of 4-position > 1-position by UGTs 1A7, 1A8, 1A9, and 1A10. In contrast to these UGTs, only UGT1A6 exhibited 1-menadiol-preferential glucuronidating activity. The results suggest possible detoxification pathways for quinones via NQO1 reduction followed by UGT glucuronidation

  10. n kommunikasiestrategie vir kleinboeront- wikkeling1/a ...

    African Journals Online (AJOL)

    Ian

    WIKKELING1/A COMMUNICATION STRATEGY FOR. SMALL FARMER DEVELOPMENT1. H.C. Viljoen2, J. Laubscher3 and G.J.O. Marincowitz4. UITTREKSEL. Enige doeltreffende voorligting- en inligtingstelsel moet op die behoeftes en idioom van die boer berus. Aangesien die inligtingsbehoeftes van die kommersiële ...

  11. Genetic polymorphisms of cytochrome P450-1A2 (CYP1A2 among Emiratis.

    Directory of Open Access Journals (Sweden)

    Mohammad M Al-Ahmad

    Full Text Available Cytochrome P450 1A2 (CYP1A2 is one of the CYP450 mixed-function oxidase system that is of clinical importance due to the large number of drug interactions associated with its induction and inhibition. In addition, significant inter-individual differences in the elimination of drugs metabolized by CYP1A2 enzyme have been observed which are largely due to the highly polymorphic nature of CYP1A2 gene. However, there are limited studies on CYP1A2 phenotypes and CYP1A2 genotypes among Emiratis and thus this study was carried out to fill this gap. Five hundred and seventy six non-smoker Emirati subjects were asked to consume a soft drink containing caffeine (a non-toxic and reliable probe for predicting CYP1A2 phenotype and then provide a buccal swab along with a spot urine sample. Taq-Man Real Time PCR was used to determine the CYP1A2 genotype of each individual. Phenotyping was carried out by analyzing the caffeine metabolites using High Performance Liquid Chromatography (HPLC analysis. We found that 1.4%, 16.3% and 82.3% of the Emirati subjects were slow, intermediate and rapid CYP1A2 metabolizers, respectively. In addition, we found that 1.4% of the subjects were homozygote for derived alleles while 16.1% were heterozygote and 82.5% were homozygote for the ancestral allele. The genotype frequency of the ancestral allele, CYP1A2*1A/*1A, is the highest in this population, followed by CYP1A2 *1A/*1C and CYP1A2 *1A/*1K genotypes, with frequencies of 0.825, 0.102 and 0.058, respectively. The degree of phenotype/genotype concordance was equal to 81.6%. The CYP1A2*1C/*1C and CYP1A2*3/*3 genotypes showed significantly the lowest enzyme phenotypic activity. The frequency of slow activity CYP1A2 enzyme alleles is very low among Emiratis which correlates with the presence of low frequencies of derived alleles in CYP1A2 gene.

  12. Earth and Sky, Unit 1A

    DEFF Research Database (Denmark)

    Gammelgaard Nielsen, Anders

    2011-01-01

    The assignment known as ‘Earth and sky’ is the final first year course at Unit 1a. The aim of the assignment is to strengthen the student’s abilities to manage a project process individu- ally. The process involves develop- ing the ability to make independent decisions.The point of departure...... for the ‘Earth and sky’ assignment is ex- perience students acquired during their group study tour to Austra- lia. Building in particular on the re- search conducted on the Sydney Opera House and the architectur- al principles of spatial creation that this building represents....

  13. Allele mining across DREB1A and DREB1B in diverse rice ...

    Indian Academy of Sciences (India)

    Low temperature stress is one of the major limiting factors affecting rice productivity in higher altitudes. DREB1A and ..... to isolate useful alleles from related genotypes. A total of ... work also suggests that DREB induction and cold response.

  14. Factor XII (Hageman factor) deficiency

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000545.htm Factor XII (Hageman factor) deficiency To use the sharing features on this ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  15. UPWIND 1A2 Metrology. Final Report

    DEFF Research Database (Denmark)

    Eecen, P.J.; Wagenaar, J.W.; Stefanatos, N.

    . Since this problem covers many areas of wind energy, the work package is defined as a crosscutting activity. The objectives of the metrology work package are to develop metrology tools in wind energy to significantly enhance the quality of measurement and testing techniques. The first deliverable...... is a valuable tool for the further assessment and interest has been shown from other work packages, such as Training. This report describes the activities that have been carried out in the Work Package 1A2 Metrology of the UpWind project. Activities from Risø are described in a separate report: T.F. Pedersen...... was to perform a state of the art assessment to identify all relevant measurands. The required accuracies and required sampling frequencies have been identified from the perspective of the users of the data (the other work packages in UpWind). This work led to the definition of the Metrology Database, which...

  16. Over-expression of Sub1 A, a submergence tolerance gene from ...

    African Journals Online (AJOL)

    Sub1A, an ethylene-response-factor-like (ERE-like) gene, mediates the extinguished submergence tolerance of rice. To gain further insight into the function of Sub1A in other species, we transformed tobacco plants with the gene under the control of the ubiquitin promoter. Compared to the wild-type plants, transgenic plants ...

  17. Comparative and evolutionary studies of vertebrate ALDH1A-like genes and proteins.

    Science.gov (United States)

    Holmes, Roger S

    2015-06-05

    Vertebrate ALDH1A-like genes encode cytosolic enzymes capable of metabolizing all-trans-retinaldehyde to retinoic acid which is a molecular 'signal' guiding vertebrate development and adipogenesis. Bioinformatic analyses of vertebrate and invertebrate genomes were undertaken using known ALDH1A1, ALDH1A2 and ALDH1A3 amino acid sequences. Comparative analyses of the corresponding human genes provided evidence for distinct modes of gene regulation and expression with putative transcription factor binding sites (TFBS), CpG islands and micro-RNA binding sites identified for the human genes. ALDH1A-like sequences were identified for all mammalian, bird, lizard and frog genomes examined, whereas fish genomes displayed a more restricted distribution pattern for ALDH1A1 and ALDH1A3 genes. The ALDH1A1 gene was absent in many bony fish genomes examined, with the ALDH1A3 gene also absent in the medaka and tilapia genomes. Multiple ALDH1A1-like genes were identified in mouse, rat and marsupial genomes. Vertebrate ALDH1A1, ALDH1A2 and ALDH1A3 subunit sequences were highly conserved throughout vertebrate evolution. Comparative amino acid substitution rates showed that mammalian ALDH1A2 sequences were more highly conserved than for the ALDH1A1 and ALDH1A3 sequences. Phylogenetic studies supported an hypothesis for ALDH1A2 as a likely primordial gene originating in invertebrate genomes and undergoing sequential gene duplication to generate two additional genes, ALDH1A1 and ALDH1A3, in most vertebrate genomes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  18. Functionality of promoter microsatellites of arginine vasopressin receptor 1A (AVPR1A): implications for autism

    LENUS (Irish Health Repository)

    Tansey, Katherine E

    2011-03-31

    Abstract Background Arginine vasopressin (AVP) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. The arginine vasopressin receptor 1A gene (AVPR1A) is widely expressed in the brain and is considered to be a key receptor for regulation of social behaviour. Moreover, genetic variation at AVPR1A has been reported to be associated with autism. Evidence from non-human mammals implicates variation in the 5\\'-flanking region of AVPR1A in variable gene expression and social behaviour. Methods We examined four tagging single nucleotide polymorphisms (SNPs) (rs3803107, rs1042615, rs3741865, rs11174815) and three microsatellites (RS3, RS1 and AVR) at the AVPR1A gene for association in an autism cohort from Ireland. Two 5\\'-flanking region polymorphisms in the human AVPR1A, RS3 and RS1, were also tested for their effect on relative promoter activity. Results The short alleles of RS1 and the SNP rs11174815 show weak association with autism in the Irish population (P = 0.036 and P = 0.008, respectively). Both RS1 and RS3 showed differences in relative promoter activity by length. Shorter repeat alleles of RS1 and RS3 decreased relative promoter activity in the human neuroblastoma cell line SH-SY5Y. Conclusions These aligning results can be interpreted as a functional route for this association, namely that shorter alleles of RS1 lead to decreased AVPR1A transcription, which may proffer increased susceptibility to the autism phenotype.

  19. Adrm1, a putative cell adhesion regulating protein, is a novel proteasome-associated factor

    DEFF Research Database (Denmark)

    Jørgensen, Jakob Ploug; Lauridsen, Anne-Marie; Kristensen, Poul

    2006-01-01

    . Adrm1 has been described as an interferon-gamma-inducible, heavily glycosylated membrane protein of 110 kDa. However, we found Adrm1 in mouse tissues only as a 42 kDa peptide, corresponding to the mass of the non-glycosylated peptide chain, and it could not be induced in HeLa cells with interferon...

  20. NARMER-1: a photon point-kernel code with build-up factors

    Science.gov (United States)

    Visonneau, Thierry; Pangault, Laurence; Malouch, Fadhel; Malvagi, Fausto; Dolci, Florence

    2017-09-01

    This paper presents an overview of NARMER-1, the new generation of photon point-kernel code developed by the Reactor Studies and Applied Mathematics Unit (SERMA) at CEA Saclay Center. After a short introduction giving some history points and the current context of development of the code, the paper exposes the principles implemented in the calculation, the physical quantities computed and surveys the generic features: programming language, computer platforms, geometry package, sources description, etc. Moreover, specific and recent features are also detailed: exclusion sphere, tetrahedral meshes, parallel operations. Then some points about verification and validation are presented. Finally we present some tools that can help the user for operations like visualization and pre-treatment.

  1. Fractalkine (CX3CL1, a new factor protecting β-cells against TNFα

    Directory of Open Access Journals (Sweden)

    Sabine Rutti

    2014-10-01

    Conclusions: We demonstrate for the first time that human islets express and secrete CX3CL1 and CX3CL1 impacts them by decreasing glucagon secretion without affecting insulin secretion. Moreover, CX3CL1 decreases basal apoptosis of human β-cells. We further demonstrate that CX3CL1 protects β-cells from the adverse effects of TNFα on their function by restoring the expression and phosphorylation of key proteins of the insulin secretion pathway.

  2. The Role of Protein Elongation Factor eEF1A2 in Breast Cancer

    Science.gov (United States)

    2006-09-01

    apoptosis . A summary of common EMT markers is listed in Table I. Importantly, these developmental regulators can induce EMT in a nondevelopmental...1978; Chen et al., 1997), apoptosis (Chen et al., 1997), and metabolic regulation (Bissell et al., 1977) has been known for decades, the molecular...marks the Spemann organizer in vertebrate gastrulation and is one of the fi rst identifi ed regulators of embryological patterning (De Robertis et al

  3. Arabidopsis dynamin-related protein 1A polymers bind, but do not tubulate, liposomes

    International Nuclear Information System (INIS)

    Backues, Steven K.; Bednarek, Sebastian Y.

    2010-01-01

    The Arabidopsis dynamin-related protein 1A (AtDRP1A) is involved in endocytosis and cell plate maturation in Arabidopsis. Unlike dynamin, AtDRP1A does not have any recognized membrane binding or protein-protein interaction domains. We report that GTPase active AtDRP1A purified from Escherichia coli as a fusion to maltose binding protein forms homopolymers visible by negative staining electron microscopy. These polymers interact with protein-free liposomes whose lipid composition mimics that of the inner leaflet of the Arabidopsis plasma membrane, suggesting that lipid-binding may play a role in AtDRP1A function. However, AtDRP1A polymers do not appear to assemble and disassemble in a dynamic fashion and do not have the ability to tubulate liposomes in vitro, suggesting that additional factors or modifications are necessary for AtDRP1A's in vivo function.

  4. The eEF1A proteins: at the crossroads of oncogenesis, apoptosis and viral infections.

    Directory of Open Access Journals (Sweden)

    Georges eHerbein

    2015-04-01

    Full Text Available Eukaryotic translation elongation factors 1 alpha, eEF1A1 and eEF1A2, are not only translation factors, but also pleiotropic proteins that are highly expressed in human tumors, including breast cancer, ovarian cancer and lung cancer. eEF1A1 modulates cytoskeleton, exhibits chaperone-like activity and also controls cell proliferation and cell death. By contrast eEF1A2 protein favors oncogenesis as shown by the fact that overexpression of eEF1A2 leads to cellular transformation and gives rise to tumors in nude mice. The eEF1A2 protein stimulates the phospholipid signaling and activates the Akt-dependent cell migration and actin remodeling that ultimately favors tumorigenesis. By contrast, inactivation of eEF1A proteins leads to immunodeficiency, neural and muscular defects, and favors apoptosis. Finally, eEF1A proteins interact with several viral proteins resulting in enhanced viral replication, decreased apoptosis and increased cellular transformation. This review summarizes the recent findings on eEF1A proteins indicating that eEF1A proteins play a critical role in numerous human diseases through enhancement of oncogenesis, blockade of apoptosis and increased viral pathogenesis.

  5. Robust factorization

    DEFF Research Database (Denmark)

    Aanæs, Henrik; Fisker, Rune; Åström, Kalle

    2002-01-01

    Factorization algorithms for recovering structure and motion from an image stream have many advantages, but they usually require a set of well-tracked features. Such a set is in generally not available in practical applications. There is thus a need for making factorization algorithms deal effect...

  6. Organizational factors

    International Nuclear Information System (INIS)

    Holy, J.

    1999-12-01

    The following organizational factors are considered with respect to the human factor and operating safety of nuclear power plants: external influences; objectives and strategy; positions and ways of management; allocation of resources; working with human resources; operators' training; coordination of work; knowledge of organization and management; proceduralization of the topic; labour organizing culture; self-improvement system; and communication. (P.A.)

  7. El factoring

    Directory of Open Access Journals (Sweden)

    Alberto Rosenthal

    1988-04-01

    Full Text Available RESUMEN El artículo  presenta, una conceptualización general de lo que es el factoring, el origen del mismo, su evolución y hace una clasificación de los distintos tipos de factoring.

  8. Differences in UGT1A1, UGT1A7, and UGT1A9 polymorphisms between Uzbek and Japanese populations.

    Science.gov (United States)

    Maeda, Hiromichi; Hazama, Shoichi; Shavkat, Abdiev; Okamoto, Ken; Oba, Koji; Sakamoto, Junichi; Takahashi, Kenichi; Oka, Masaki; Nakamura, Daisuke; Tsunedomi, Ryouichi; Okayama, Naoko; Mishima, Hideyuki; Kobayashi, Michiya

    2014-06-01

    Uridine-diphosphate glucuronosyltransferase 1A (UGT1A) is a key enzyme involved in irinotecan metabolism, and polymorphisms in the UGT1A gene are associated with irinotecan-induced toxicity. The aim of this study was to elucidate the allele frequencies of UGT1A polymorphisms in healthy Uzbek volunteers, and to compare them with those of the Japanese population. A total of 97 healthy volunteers from Uzbekistan were enrolled and blood samples were collected from each participant. Genotyping analysis was performed by fragment size analysis for UGT1A1*28, direct sequencing for UGT1A7*3 and UGT1A9*22, and TaqMan assays for UGT1A1*93, UGT1A1*6, UGT1A1*27, UGT1A1*60, and UGT1A7*12. The frequencies of polymorphisms were compared with the Japanese population by using the data previously reported from our study group. When the Uzbek and Japanese populations were compared, heterozygotes or homozygotes for UGT1A1*28, UGT1A1*60, and UGT1A1*93 were significantly more frequent in the Uzbek population (P Japanese population (P Japanese population. A comprehensive study of the influence of UGT1A1 polymorphisms on the risk of irinotecan-induced toxicity is necessary for optimal use of irinotecan treatment.

  9. Scutellarin inhibits cytochrome P450 isoenzyme 1A2 (CYP1A2) in rats.

    Science.gov (United States)

    Jian, Tun-Yu; He, Jian-Chang; He, Gong-Hao; Feng, En-Fu; Li, Hong-Liang; Bai, Min; Xu, Gui-Li

    2012-08-01

    Scutellarin is the most important flavone glycoside in the herbal drug Erigeron breviscapus (Vant.) Hand.-Mazz. It is used frequently in the clinic to treat ischemic vascular diseases in China. However, the direct relationship between scutellarin and cytochrome P450 (CYP450) is unclear. The present study investigated the in vitro and in vivo effects of scutellarin on cytochrome P450 1A2 (CYP 1A2) metabolism. According to in vitro experiments, scutellarin (10-250 µM) decreased the formation of 4-acetamidophenol in a concentration-dependent manner, with an IC₅₀ value of 108.20 ± 0.657 µM. Furthermore, scutellarin exhibited a weak mixed-type inhibition against the activity of CYP1A2 in rat liver microsomes, with a K(i) value of 95.2 µM. Whereas in whole animal studies, scutellarin treatment for 7 days (at 5, 15, 30 mg/kg, i.p.) decreased the clearance (CL), and increased the T(1/2) (at 15, 30 mg/kg, i.p.), it did not affect the V(d) of phenacetin. Scutellarin treatment (at 5, 15, 30 mg/kg, i.p.) increased the AUC(0-∞) by 14.3%, 67.3% and 159.2%, respectively. Scutellarin at 30 mg/kg also weakly inhibited CYP1A2 activity, in accordance with our in vitro study. Thus, the results indicate that CYP1A2 is inhibited directly, but weakly, by scutellarin in vivo, and provide useful information on the safe and effective use of scutellarin in clinical practice. Copyright © 2012 John Wiley & Sons, Ltd.

  10. El factoring

    Directory of Open Access Journals (Sweden)

    Alberto Rosenthal

    2015-04-01

    Full Text Available RESUMEN Se presenta la segunda parte del artículo aparecido en  el número 6 de la revista EAN. Su contenido es complementario a lo expuesto en dicho número, en está aparecen las ventajas del factoring, conveniencias, limitaciones así como la forma  de efectuar un factor en Colombia,  su necesidad, incidencia económica, etc.

  11. Peginterferon beta-1a – nowa postać interferonu beta-1a

    Directory of Open Access Journals (Sweden)

    Zdzisław Maciejek

    2015-11-01

    Full Text Available W 2014 roku, po zakończeniu próby klinicznej III fazy ADVANCE, do leczenia postaci rzutowo-remisyjnej stwardnienia rozsianego wprowadzono nową pegylowaną postać interferonu beta-1a o wydłużonym czasie działania. Do badania zakwalifikowano 1512 chorych ze 183 ośrodków z 26 krajów (500 uczestników przyjmowało placebo, 512 – peginterferon beta-1a w dawce 125 µg podawany podskórnie co 2 tygodnie, 500 – peginterferon beta-1a w dawce 125 µg podawany podskórnie co 4 tygodnie. Grupy były zbliżone pod względem wieku, płci, czasu trwania choroby i niepełnosprawności ocenianej w Expanded Disability Status Scale. Cel badania stanowiła ocena skuteczności i bezpieczeństwa pegylowanego interferonu beta-1a po 2 latach terapii w porównaniu z grupą placebo, która w drugim roku również otrzymywała ten lek. Skuteczność peginterferonu beta-1a podawanego co 2 tygodnie w porównaniu z placebo przejawiała się redukcją rocznego wskaźnika rzutów (o 37%, liczby nowych lub powiększonych ognisk T2-zależnych (o 67%, ryzyka wystąpienia rzutu (o 39% i ryzyka utrwalonej 12-tygodniowej progresji niepełnosprawności (o 33%. Najczęstsze działania niepożądane towarzyszące kuracji (94% chorych to odczyn w miejscu wkłucia, objawy grypopodobne, gorączka i bóle głowy. U 16% osób przyjmujących lek co 2 tygodnie i 22% otrzymujących go co 4 tygodnie odnotowano poważne objawy niepożądane (rzuty, zapalenie płuc, infekcje dróg moczowych. Reasumując: leczenie peginterferonem beta-1a cechowały skuteczność, dobra tolerancja i bezpieczeństwo.

  12. Quality factors

    International Nuclear Information System (INIS)

    Kerr, G.D.

    1986-01-01

    The quality factor, Q, is a dimensionless modifier used in converting absorbed dose, expressed in rads (or grays), to dose equivalent, expressed in rems (or seiverts). The dose equivalent is used in radiation protection to account for the biological effectiveness of different kinds of radiation. The quality factor is related to both the linear energy transfer (LET) and relative biological effectiveness (RBE). The RBE's obtained from biological experiments depend in a complex way on the observed biological effect, the specific test organism, and the experimental conditions. Judgement is involved, therefore, in the choice of the quality factor. Questions regarding the adequacy of current Q values for neutrons were raised first in a 1980 statement by the National Council on Radiation Protection (NCRP) and later in a 1985 statement by the International Commission on Radiological Protection (ICRP). In 1980, the NCRP alerted the technical community to possible future increases between a factor of three and ten in the Q for neutrons, and in 1985, the ICRP suggested an increase by a factor of two in Q for neutrons. Both the ICRP and NRCP are now recommending essentially the same guidance with regard to Q for neutrons: an increase by a factor of two. The Q for neutrons is based on a large, albeit unfocused, body of experimental data. In spite of the lack of focus, the data supporting a change in the neutron quality factor are substantial. However, the proposed doubling of Q for neutrons is clouded by other issues regarding its application. 33 refs., 4 figs., 6 tabs

  13. Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior.

    Science.gov (United States)

    Vahid-Ansari, Faranak; Daigle, Mireille; Manzini, M Chiara; Tanaka, Kenji F; Hen, René; Geddes, Sean D; Béïque, Jean-Claude; James, Jonathan; Merali, Zul; Albert, Paul R

    2017-12-06

    Freud-1/Cc2d1a represses the gene transcription of serotonin-1A (5-HT1A) autoreceptors, which negatively regulate 5-HT tone. To test the role of Freud-1 in vivo , we generated mice with adulthood conditional knock-out of Freud-1 in 5-HT neurons ( cF1ko ). In cF1ko mice, 5-HT1A autoreceptor protein, binding and hypothermia response were increased, with reduced 5-HT content and neuronal activity in the dorsal raphe. The cF1ko mice displayed increased anxiety- and depression-like behavior that was resistant to chronic antidepressant (fluoxetine) treatment. Using conditional Freud-1/5-HT1A double knock-out ( cF1/1A dko ) to disrupt both Freud-1 and 5-HT1A genes in 5-HT neurons, no increase in anxiety- or depression-like behavior was seen upon knock-out of Freud-1 on the 5-HT1A autoreceptor-negative background; rather, a reduction in depression-like behavior emerged. These studies implicate transcriptional dysregulation of 5-HT1A autoreceptors by the repressor Freud-1 in anxiety and depression and provide a clinically relevant genetic model of antidepressant resistance. Targeting specific transcription factors, such as Freud-1, to restore transcriptional balance may augment response to antidepressant treatment. SIGNIFICANCE STATEMENT Altered regulation of the 5-HT1A autoreceptor has been implicated in human anxiety, major depression, suicide, and resistance to antidepressants. This study uniquely identifies a single transcription factor, Freud-1, as crucial for 5-HT1A autoreceptor expression in vivo Disruption of Freud-1 in serotonin neurons in mice links upregulation of 5-HT1A autoreceptors to anxiety/depression-like behavior and provides a new model of antidepressant resistance. Treatment strategies to reestablish transcriptional regulation of 5-HT1A autoreceptors could provide a more robust and sustained antidepressant response. Copyright © 2017 the authors 0270-6474/17/3711967-12$15.00/0.

  14. Polymorphisms of UGT1A1*6, UGT1A1*27 & UGT1A1*28 in three major ethnic groups from Malaysia.

    Science.gov (United States)

    Teh, L K; Hashim, H; Zakaria, Z A; Salleh, M Z

    2012-08-01

    Genetic polymorphisms of uridine diphosphate glucuronyltransferase 1A1 (UGT1A1) have been associated with a wide variation of responses among patients prescribed with irinotecan. Lack of this enzyme is known to be associated with a high incidence of severe toxicity. The objective of this study was to investigate the prevalence of three different variants of UGT1A1 (UGT1A1*6, UGT1A1*27 and UGT1A1*28), which are associated with reduced enzyme activity and increased irinotecan toxicity, in the three main ethnic groups in Malaysia (Malays, Chinese and Indians). A total of 306 healthy unrelated volunteers were screened for UGT1A1*28, UGT1A1*6 and UGT1A1*27. Blood samples (5 ml) were obtained from each subject and DNA was extracted. PCR based methods were designed and validated for detection of UGT1A1*, UUGT1A1*27 and UUGT1A1*28. Direct DNA sequencing was performed to validate the results of randomly selected samples. Malays and Indian have two-fold higher frequency of homozygous of UGT1A1*28 (7TA/7TA) which was 8 and 8.8 per cent, respectively compared to the Chinese (4.9%). However, the distribution of UGT1A1*6 and UGT1A1*27 showed no significant differences among them. UGT1A1*27 which has not been detected in Caucasian and African American population, was found in the Malaysian Malays (3.33%) and Malaysian Chinese (2.0%). There was interethnic variability in the frequency of UGT1A1*28 in the Malaysian population. Our results suggest that genotyping of UUGT1A1*6, UGT1A1*28 and UGT1A1*27 need to be performed before patients are prescribed with irinotecan due to their high prevalence of allelic variant which could lead to adverse drug reaction.

  15. Visualisation of serotonin-1A (5-HT1A) receptors in the central nervous system

    International Nuclear Information System (INIS)

    Passchier, J.; Waarde, A. van

    2001-01-01

    The 5-HT 1A subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT 1A receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy. Here, we review the radioligands which are available for visualisation and quantification of this important neuroreceptor in the human brain, using positron emission tomography (PET) or single-photon emission tomography (SPET). More than 20 compounds have been labelled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogues of the agonist, 8-OH-DPAT, structural analogues of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl- 11 C] WAY-100635 (WAY), [carbonyl- 11 C]desmethyl-WAY-100635 (DWAY), p-[ 18 F]MPPF and [ 11 C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT 1A receptor distribution in the brain (even the raphe nuclei are visualised), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centres within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) production of a radioiodinated or technetium-labelled ligand for SPET. (orig.)

  16. Inhibitory Effects of Commonly Used Herbal Extracts on UDP-Glucuronosyltransferase 1A4, 1A6, and 1A9 Enzyme Activities

    Science.gov (United States)

    Mohamed, Mohamed-Eslam F.

    2011-01-01

    The aim of this study was to investigate the effect of commonly used botanicals on UDP-glucuronosyltransferase (UGT) 1A4, UGT1A6, and UGT1A9 activities in human liver microsomes. The extracts screened were black cohosh, cranberry, echinacea, garlic, ginkgo, ginseng, milk thistle, saw palmetto, and valerian in addition to the green tea catechin epigallocatechin gallate (EGCG). Formation of trifluoperazine glucuronide, serotonin glucuronide, and mycophenolic acid phenolic glucuronide was used as an index reaction for UGT1A4, UGT1A6, and UGT1A9 activities, respectively, in human liver microsomes. Inhibition potency was expressed as the concentration of the inhibitor at 50% activity (IC50) and the volume in which the dose could be diluted to generate an IC50-equivalent concentration [volume/dose index (VDI)]. Potential inhibitors were EGCG for UGT1A4, milk thistle for both UGT1A6 and UGT1A9, saw palmetto for UGT1A6, and cranberry for UGT1A9. EGCG inhibited UGT1A4 with an IC50 value of (mean ± S.E.) 33.8 ± 3.1 μg/ml. Milk thistle inhibited both UGT1A6 and UGT1A9 with IC50 values of 59.5 ± 3.6 and 33.6 ± 3.1 μg/ml, respectively. Saw palmetto and cranberry weakly inhibited UGT1A6 and UGT1A9, respectively, with IC50 values >100 μg/ml. For each inhibition, VDI was calculated to determine the potential of achieving IC50-equivalent concentrations in vivo. VDI values for inhibitors indicate a potential for inhibition of first-pass glucuronidation of UGT1A4, UGT1A6, and UGT1A9 substrates. These results highlight the possibility of herb-drug interactions through modulation of UGT enzyme activities. Further clinical studies are warranted to investigate the in vivo extent of the observed interactions. PMID:21632963

  17. Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness

    Directory of Open Access Journals (Sweden)

    Albert Paul R

    2011-05-01

    Full Text Available Abstract The serotonin-1A (5-HT1A receptor is among the most abundant and widely distributed 5-HT receptors in the brain, but is also expressed on serotonin neurons as an autoreceptor where it plays a critical role in regulating the activity of the entire serotonin system. Over-expression of the 5-HT1A autoreceptor has been implicated in reducing serotonergic neurotransmission, and is associated with major depression and suicide. Extensive characterization of the transcriptional regulation of the 5-HT1A gene (HTR1A using cell culture systems has revealed a GC-rich "housekeeping" promoter that non-selectively drives its expression; this is flanked by a series of upstream repressor elements for REST, Freud-1/CC2D1A and Freud-2/CC2D1B factors that not only restrict its expression to neurons, but may also regulate the level of expression of 5-HT1A receptors in various subsets of neurons, including serotonergic neurons. A separate set of allele-specific factors, including Deaf1, Hes1 and Hes5 repress at the HTR1A C(-1019G (rs6295 polymorphism in serotonergic neurons in culture, as well as in vivo. Pet1, an obligatory enhancer for serotonergic differentiation, has been identified as a potent activator of 5-HT1A autoreceptor expression. Taken together, these results highlight an integrated regulation of 5-HT1A autoreceptors that differs in several aspects from regulation of post-synaptic 5-HT1A receptors, and could be selectively targeted to enhance serotonergic neurotransmission.

  18. Stress-induced alterations in 5-HT1A receptor transcriptional modulators NUDR and Freud-1.

    Science.gov (United States)

    Szewczyk, Bernadeta; Kotarska, Katarzyna; Daigle, Mireille; Misztak, Paulina; Sowa-Kucma, Magdalena; Rafalo, Anna; Curzytek, Katarzyna; Kubera, Marta; Basta-Kaim, Agnieszka; Nowak, Gabriel; Albert, Paul R

    2014-11-01

    The effect of stress on the mRNA and protein level of the 5-HT1A receptor and two of its key transcriptional modulators, NUDR and Freud-1, was examined in the prefrontal cortex (PFC) and hippocampus (Hp) using rodent models: olfactory bulbectomy (OB) and prenatal stress (PS) in male and female rats; chronic mild stress in male rats (CMS) and pregnancy stress. In PFC, CMS induced the most widespread changes, with significant reduction in both mRNA and protein levels of NUDR, 5-HT1A receptor and in Freud-1 mRNA; while in Hp 5-HT1A receptor and Freud-1 protein levels were also decreased. In male, but not female OB rats PFC Freud-1 and 5-HT1A receptor protein levels were reduced, while in Hp 5-HT1A receptor, Freud-1 and NUDR mRNA's but not protein were reduced. In PS rats PFC 5-HT1A receptor protein was reduced more in females than males; while in Hp Freud-1 protein was increased in females. In pregnancy stress, PFC NUDR, Freud-1 and 5-HT1A protein receptor levels were reduced, and in HP 5-HT1A receptor protein levels were also reduced; in HP only NUDR and Freud-1 mRNA levels were reduced. Overall, CMS and stress during pregnancy produced the most salient changes in 5-HT1A receptor and transcription factor expression, suggesting a primary role for altered transcription factor expression in chronic regulation of 5-HT1A receptor expression. By contrast, OB (in males) and PS (in females) produced gender-specific reductions in PFC 5-HT1A receptor protein levels, suggesting a role for post-transcriptional regulation. These and previous data suggest that chronic stress might be a key regulator of NUDR/Freud-1 gene expression.

  19. Program Specificity for Ptf1a in Pancreas versus Neural Tube Development Correlates with Distinct Collaborating Cofactors and Chromatin Accessibility

    Science.gov (United States)

    Meredith, David M.; Borromeo, Mark D.; Deering, Tye G.; Casey, Bradford H.; Savage, Trisha K.; Mayer, Paul R.; Hoang, Chinh; Tung, Kuang-Chi; Kumar, Manonmani; Shen, Chengcheng; Swift, Galvin H.

    2013-01-01

    The lineage-specific basic helix-loop-helix transcription factor Ptf1a is a critical driver for development of both the pancreas and nervous system. How one transcription factor controls diverse programs of gene expression is a fundamental question in developmental biology. To uncover molecular strategies for the program-specific functions of Ptf1a, we identified bound genomic regions in vivo during development of both tissues. Most regions bound by Ptf1a are specific to each tissue, lie near genes needed for proper formation of each tissue, and coincide with regions of open chromatin. The specificity of Ptf1a binding is encoded in the DNA surrounding the Ptf1a-bound sites, because these regions are sufficient to direct tissue-restricted reporter expression in transgenic mice. Fox and Sox factors were identified as potential lineage-specific modifiers of Ptf1a binding, since binding motifs for these factors are enriched in Ptf1a-bound regions in pancreas and neural tube, respectively. Of the Fox factors expressed during pancreatic development, Foxa2 plays a major role. Indeed, Ptf1a and Foxa2 colocalize in embryonic pancreatic chromatin and can act synergistically in cell transfection assays. Together, these findings indicate that lineage-specific chromatin landscapes likely constrain the DNA binding of Ptf1a, and they identify Fox and Sox gene families as part of this process. PMID:23754747

  20. Risk factors

    International Nuclear Information System (INIS)

    Dennery, M.; Dupont, M.A.

    2007-01-01

    This article deals with the development of risk management in the gas sector business: why a risk factor legal mention must precede any published financial information? Do gas companies have to face new risks? Is there specific risks bound to gas activities? Why companies want to master their risks? Is it mandatory or just a new habit? Do they expect a real benefit in return? These are the risk management questions that are analyzed in this article which is based on the public communication of 15 gas companies randomly selected over the world. The information comes from their annual reports or from documents available on their web sites. The intention of this document is not to be exhaustive or to make statistics but only to shade light on the risk factors of the gas sector. (J.S.)

  1. Organizational factors

    International Nuclear Information System (INIS)

    Wahlstroem, B.; Kettunen, J.

    2005-01-01

    The goal of this lecture is to give an overview of important concepts connected to organisational factors and to provide an understanding of mechanisms by which they can contribute to safe or unsafe behaviour of people. The lecture gives examples of ways to organise work, organisational deficiencies and good practices applied in safety oriented organisations. The lecture also gives an introduction to international work and Finnish national regulation connected to organisation and management. (orig.)

  2. Factor analysis

    CERN Document Server

    Gorsuch, Richard L

    2013-01-01

    Comprehensive and comprehensible, this classic covers the basic and advanced topics essential for using factor analysis as a scientific tool in psychology, education, sociology, and related areas. Emphasizing the usefulness of the techniques, it presents sufficient mathematical background for understanding and sufficient discussion of applications for effective use. This includes not only theory but also the empirical evaluations of the importance of mathematical distinctions for applied scientific analysis.

  3. RAB1A promotes Vaccinia virus replication by facilitating the production of intracellular enveloped virions

    Energy Technology Data Exchange (ETDEWEB)

    Pechenick Jowers, Tali; Featherstone, Rebecca J.; Reynolds, Danielle K.; Brown, Helen K. [The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, Midlothian EH25 9RG, Scotland (United Kingdom); James, John; Prescott, Alan [Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland (United Kingdom); Haga, Ismar R. [The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, Midlothian EH25 9RG, Scotland (United Kingdom); Beard, Philippa M., E-mail: pip.beard@roslin.ed.ac.uk [The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, Midlothian EH25 9RG, Scotland (United Kingdom)

    2015-01-15

    Vaccinia virus (VACV) is a large double-stranded DNA virus with a complex cytoplasmic replication cycle that exploits numerous cellular proteins. This work characterises the role of a proviral cellular protein, the small GTPase RAB1A, in VACV replication. Using siRNA, we identified RAB1A as required for the production of extracellular enveloped virions (EEVs), but not intracellular mature virions (IMVs). Immunofluorescence and electron microscopy further refined the role of RAB1A as facilitating the wrapping of IMVs to become intracellular enveloped virions (IEVs). This is consistent with the known function of RAB1A in maintenance of ER to Golgi transport. VACV can therefore be added to the growing list of viruses which require RAB1A for optimal replication, highlighting this protein as a broadly proviral host factor. - Highlights: • Characterisation of the role of the small GTPase RAB1A in VACV replication. • RAB1A is not required for production of the primary virion form (IMV). • RAB1A is required for production of processed virion forms (IEVs, CEVs and EEVs). • Consistent with known role of RAB1A in ER to Golgi transport.

  4. Odin (ANKS1A modulates EGF receptor recycling and stability.

    Directory of Open Access Journals (Sweden)

    Jiefei Tong

    Full Text Available The ANKS1A gene product, also known as Odin, was first identified as a tyrosine-phosphorylated component of the epidermal growth factor receptor network. Here we show that Odin functions as an effector of EGFR recycling. In EGF-stimulated HEK293 cells tyrosine phosphorylation of Odin was induced prior to EGFR internalization and independent of EGFR-to-ERK signaling. Over-expression of Odin increased EGF-induced EGFR trafficking to recycling endosomes and recycling back to the cell surface, and decreased trafficking to lysosomes and degradation. Conversely, Odin knockdown in both HEK293 and the non-small cell lung carcinoma line RVH6849, which expresses roughly 10-fold more EGF receptors than HEK293, caused decreased EGFR recycling and accelerated trafficking to the lysosome and degradation. By governing the endocytic fate of internalized receptors, Odin may provide a layer of regulation that enables cells to contend with receptor cell densities and ligand concentration gradients that are physiologically and pathologically highly variable.

  5. Mutations in HNF1A Result in Marked Alterations of Plasma Glycan Profile

    Science.gov (United States)

    Thanabalasingham, Gaya; Huffman, Jennifer E.; Kattla, Jayesh J.; Novokmet, Mislav; Rudan, Igor; Gloyn, Anna L.; Hayward, Caroline; Adamczyk, Barbara; Reynolds, Rebecca M.; Muzinic, Ana; Hassanali, Neelam; Pucic, Maja; Bennett, Amanda J.; Essafi, Abdelkader; Polasek, Ozren; Mughal, Saima A.; Redzic, Irma; Primorac, Dragan; Zgaga, Lina; Kolcic, Ivana; Hansen, Torben; Gasperikova, Daniela; Tjora, Erling; Strachan, Mark W.J.; Nielsen, Trine; Stanik, Juraj; Klimes, Iwar; Pedersen, Oluf B.; Njølstad, Pål R.; Wild, Sarah H.; Gyllensten, Ulf; Gornik, Olga; Wilson, James F.; Hastie, Nicholas D.; Campbell, Harry; McCarthy, Mark I.; Rudd, Pauline M.; Owen, Katharine R.; Lauc, Gordan; Wright, Alan F.

    2013-01-01

    A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepatocyte nuclear factor 4-α (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167), and nondiabetic controls (n = 98). The DG9-glycan index was markedly lower in HNF1A-MODY than in controls or other diabetes subtypes, offered good discrimination between HNF1A-MODY and both type 1 and type 2 diabetes (C statistic ≥0.90), and enabled us to detect three previously undetected HNF1A mutations in patients with diabetes. In conclusion, glycan profiles are altered substantially in HNF1A-MODY, and the DG9-glycan index has potential clinical value as a diagnostic biomarker of HNF1A dysfunction. PMID:23274891

  6. Amelioration of Ischemia/Reperfusion Injury During Resuscitation from Hemorrhage by Induction of Heme Oxygenase-1 (HO-1) in a Conscious Mouse Model of Uncontrolled Hemorrhage

    Science.gov (United States)

    2013-10-01

    against menadione -induced-oxidative stress, also induces HIF1a and this may explain their cytoprotective effect. KEY RESEARCH ACCOMPLISHMENTS: Due to...August 2010 - October 2011 : Compared CDDO-lm, CAPE, CAPA induced H0-1 mediated cytoprotection against menadione -induced-oxidative stress in HUVEC cells...Pharmaceutical Scientists (AAPS) 2013: Comparison of atmospheric oxygen versus physiological levels on cytotoxicity of menadione and cytoprotection by

  7. Epigenetic Control of Prolyl and Asparaginyl Hydroxylases in Prostate Cancer

    Science.gov (United States)

    2011-07-01

    melanoma, renal carcinoma and breast cancer cell lines. Furthermore, we show that neither HIF-1a protein levels nor hypoxic response through an HRE ...constitutively expressed gene to control for equivalent DNase digestion between the cell lines examined. HRE -Luciferase assay Cell lines ,85% confluent in 60...mm dishes were transfected with an HRE -luciferase reporter vector [19] (2.5 mg) and Renilla luciferase (1.5 mg) according to Lipofectamine 2000

  8. Novel Preclinical Testing Strategies for Treatment of Metastatic Pheochromocytoma

    Science.gov (United States)

    2015-11-01

    Schleswig-Holstein Lübeck, Lübeck, Germany Abstract There is currently no effective treatment for metastatic pheochromocytomas and paragangliomas. A...Supplementary Fig. S2) and deregulated fatty acid metabolism (Fig. 2b), leading to higher levels of palmitate and linoleate, increased long chain fatty...mitochondria18. This pathway required HIF-1a, which is deregulated in SDHB-mutant tumours, and may potentially contribute to disease maintenance39. The

  9. 12 CFR 528.1a - Supplementary guidelines.

    Science.gov (United States)

    2010-01-01

    ... 12 Banks and Banking 5 2010-01-01 2010-01-01 false Supplementary guidelines. 528.1a Section 528.1a Banks and Banking OFFICE OF THRIFT SUPERVISION, DEPARTMENT OF THE TREASURY NONDISCRIMINATION REQUIREMENTS § 528.1a Supplementary guidelines. The Office's policy statement found at 12 CFR 528.9 supplements...

  10. Varicose and cheerio collaborate with pebble to mediate semaphorin-1a reverse signaling in Drosophila.

    Science.gov (United States)

    Jeong, Sangyun; Yang, Da-Som; Hong, Young Gi; Mitchell, Sarah P; Brown, Matthew P; Kolodkin, Alex L

    2017-09-26

    The transmembrane semaphorin Sema-1a acts as both a ligand and a receptor to regulate axon-axon repulsion during neural development. Pebble (Pbl), a Rho guanine nucleotide exchange factor, mediates Sema-1a reverse signaling through association with the N-terminal region of the Sema-1a intracellular domain (ICD), resulting in cytoskeletal reorganization. Here, we uncover two additional Sema-1a interacting proteins, varicose (Vari) and cheerio (Cher), each with neuronal functions required for motor axon pathfinding. Vari is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins, members of which can serve as scaffolds to organize signaling complexes. Cher is related to actin filament cross-linking proteins that regulate actin cytoskeleton dynamics. The PDZ domain binding motif found in the most C-terminal region of the Sema-1a ICD is necessary for interaction with Vari, but not Cher, indicative of distinct binding modalities. Pbl/Sema-1a-mediated repulsive guidance is potentiated by both vari and cher Genetic analyses further suggest that scaffolding functions of Vari and Cher play an important role in Pbl-mediated Sema-1a reverse signaling. These results define intracellular components critical for signal transduction from the Sema-1a receptor to the cytoskeleton and provide insight into mechanisms underlying semaphorin-induced localized changes in cytoskeletal organization.

  11. KDM1A/LSD1 regulates the differentiation and maintenance of spermatogonia in mice.

    Directory of Open Access Journals (Sweden)

    Dexter A Myrick

    Full Text Available The proper regulation of spermatogenesis is crucial to ensure the continued production of sperm and fertility. Here, we investigated the function of the H3K4me2 demethylase KDM1A/LSD1 during spermatogenesis in developing and adult mice. Conditional deletion of Kdm1a in the testis just prior to birth leads to fewer spermatogonia and germ cell loss before 3 weeks of age. These results demonstrate that KDM1A is required for spermatogonial differentiation, as well as germ cell survival, in the developing testis. In addition, inducible deletion of Kdm1a in the adult testis results in the abnormal accumulation of meiotic spermatocytes, as well as apoptosis and progressive germ cell loss. These results demonstrate that KDM1A is also required during adult spermatogenesis. Furthermore, without KDM1A, the stem cell factor OCT4 is ectopically maintained in differentiating germ cells. This requirement for KDM1A is similar to what has been observed in other stem cell populations, suggesting a common function. Taken together, we propose that KDM1A is a key regulator of spermatogenesis and germ cell maintenance in the mouse.

  12. Human factors

    International Nuclear Information System (INIS)

    Brown, G.J.

    1991-01-01

    Recent reactor accidents have spurred the major review, described here, of the contribution of operator personnel to safety in Scottish Nuclear Power Stations. The review aims to identify factors leading to the Chernobyl accident and take preventative measures to avoid possible recurrence. Scottish Nuclear power stations aim to remove the operator from a position where failure to take correct action could lead to a safety hazard. Instead operators concentrate on routine and breakdown maintenance and measures are taken to minimize the probability of operator error. The review concluded that most safety procedures were satisfactory but safety analysis supported by good design practices may offer a significant reduction in the risk of operator error. (UK)

  13. Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer's disease.

    Science.gov (United States)

    Janel, N; Alexopoulos, P; Badel, A; Lamari, F; Camproux, A C; Lagarde, J; Simon, S; Feraudet-Tarisse, C; Lamourette, P; Arbones, M; Paul, J L; Dubois, B; Potier, M C; Sarazin, M; Delabar, J M

    2017-06-20

    Early identification of Alzheimer's disease (AD) risk factors would aid development of interventions to delay the onset of dementia, but current biomarkers are invasive and/or costly to assess. Validated plasma biomarkers would circumvent these challenges. We previously identified the kinase DYRK1A in plasma. To validate DYRK1A as a biomarker for AD diagnosis, we assessed the levels of DYRK1A and the related markers brain-derived neurotrophic factor (BDNF) and homocysteine in two unrelated AD patient cohorts with age-matched controls. Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers. These results associate a decreased level of DYRK1A with AD and challenge the use of DYRK1A inhibitors in peripheral tissues as treatment. These measures will be useful for diagnosis purposes.

  14. CYP1A1, CYP1A2, SULT1A1 AND SULT1E1 ALLELIC POLYMORPHISM IN CASE OF GENITAL ENDOMETRIOSIS

    Directory of Open Access Journals (Sweden)

    Konstantin Sergeevich Kublinskiy

    2016-02-01

    Up-to-date molecular and genetic analyses reveal that women predisposed to genital endometriosis possess Allele G and Genotypes AG and GG of the polymorphic option A-4889G of the CYP1A1 gene and Allele A and Genotypes CA and AA of the polymorphic option C-734A of the CYP1A2 gene. The polymorphism of the promoter regions of the SULT1A1 (G-638A and SULT1E1 (C-174T genes is not associated with genital endometriosis in women.

  15. CD25+ B-1a Cells Express Aicda

    Directory of Open Access Journals (Sweden)

    Hiroaki Kaku

    2017-06-01

    Full Text Available B-1a cells are innate-like B-lymphocytes producing natural antibodies. Activation-induced cytidine deaminase (AID, a product of the Aicda gene, plays a central role in class-switch recombination and somatic hypermutation in B cells. Although a role for Aicda in B-1a cells has been suggested on the basis of experiments with knock out (KO mice, whether B-1a cells express Aicda, and if so, which B-1a cell subpopulation expresses Aicda, remains unknown. Here, we demonstrate that B-1 cells express Aicda, but at a level below that expressed by germinal center (GC B cells. We previously reported that B-1a cells can be subdivided based on CD25 expression. We show here that B-1a cell Aicda expression is concentrated in the CD25+ B-1a cell subpopulation. These results suggest the possibility that previous studies of memory B cells identified on the basis of Aicda expression may have inadvertently included an unknown number of CD25+ B-1a cells. Although B-1a cells develop normally in the absence of Aicda, a competitive reconstitution assay reveals enhanced vigor for AID KO B-1a cell bone marrow (BM progenitors, as compared with wild-type BM B-1 cell progenitors. These results suggest that AID inhibits the development of B-1a cells from BM B-1 cell progenitors in a competitive environment.

  16. Effects of radiation sensitivity of 17-DMAG on hypoxic carcinima cells

    International Nuclear Information System (INIS)

    Wu Xiaofen; Hong Chengjiao; Zhang Baoguo

    2011-01-01

    Objective: To investigate the radiosensitivity effect of 17-DMAG on human HeLa cells of cervical cancer, which was induced by Hypoxia mimetic cobalt chloride(CoCl 2 ). Methods: First, HeLa cells was treated by different concentrations of CoCl 2 for 24 hours. And HIF-1α protein level was detected by Western blot analysis. Then the HeLa cells was dealed with CoCl 2 in concentration of 200 μmol/L. Cells were pre-treated with different concentrations of 17-DMAG 16h after receiving different doses of 2, 4, 6, 8 Gy irradiation. The method of colony-forming was used to detect the radiation sensitivity. HIF-la protein level was detected by Western blot analysis. Results: When CoCl 2 was in concentration in 200 μmol/L, the HIF-1a protein expression was highest; HeLa cells were cultured in different concenreations of 17-DMAG and exposed to different doses of Irradiation, the cell servival rate was significant(P<0.01); After 17-DMAG pretreatment hypoxia of HeLa cells, HIF-1a protein expression with the drug concentration were inhibited significantly. Conclusions: 17-DMAG pretreatment hypoxia of HeLa cells can enhance radiosensitization and the mechanism may be through inhibition of HIF-1a protein expression. (authors)

  17. Strong synergistic induction of CYP1A1 expression by andrographolide plus typical CYP1A inducers in mouse hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Jaruchotikamol, Atika [Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194 (Japan); Jarukamjorn, Kanokwan [Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002 (Thailand); Sirisangtrakul, Wanna [Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194 (Japan); Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002 (Thailand); Sakuma, Tsutomu; Kawasaki, Yuki [Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194 (Japan); Nemoto, Nobuo [Department of Toxicology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194 (Japan)

    2007-10-15

    The effects of andrographolide, the major diterpenoid constituent of Andrographis paniculata, on the expression of cytochrome P450 superfamily 1 members, including CYP1A1, CYP1A2, and CYP1B1, as well as on aryl hydrocarbon receptor (AhR) expression in primary cultures of mouse hepatocytes were investigated in comparison with the effects of typical CYP1A inducers, including benz[a]anthracene, {beta}-naphthoflavone, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Andrographolide significantly induced the expression of CYP1A1 and CYP1A2 mRNAs in a concentration-dependent manner, as did the typical CYP1A inducers, but did not induce that of CYP1B1 or AhR. Interestingly, andrographolide plus the typical CYP1A inducers synergistically induced CYP1A1 expression, and the synergism was blocked by an AhR antagonist, resveratrol. The CYP1A1 enzyme activity showed a similar pattern of induction. This is the first report that shows that andrographolide has a potency to induce CYP1A1 enzyme and indicates that andrographolide could be a very useful compound for investigating the regulatory mechanism of the CYP1A1 induction pathway. In addition, our findings suggest preparing advice for rational administration of A. paniculata, according to its ability to induce CYP1A1 expression.

  18. Strong synergistic induction of CYP1A1 expression by andrographolide plus typical CYP1A inducers in mouse hepatocytes

    International Nuclear Information System (INIS)

    Jaruchotikamol, Atika; Jarukamjorn, Kanokwan; Sirisangtrakul, Wanna; Sakuma, Tsutomu; Kawasaki, Yuki; Nemoto, Nobuo

    2007-01-01

    The effects of andrographolide, the major diterpenoid constituent of Andrographis paniculata, on the expression of cytochrome P450 superfamily 1 members, including CYP1A1, CYP1A2, and CYP1B1, as well as on aryl hydrocarbon receptor (AhR) expression in primary cultures of mouse hepatocytes were investigated in comparison with the effects of typical CYP1A inducers, including benz[a]anthracene, β-naphthoflavone, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Andrographolide significantly induced the expression of CYP1A1 and CYP1A2 mRNAs in a concentration-dependent manner, as did the typical CYP1A inducers, but did not induce that of CYP1B1 or AhR. Interestingly, andrographolide plus the typical CYP1A inducers synergistically induced CYP1A1 expression, and the synergism was blocked by an AhR antagonist, resveratrol. The CYP1A1 enzyme activity showed a similar pattern of induction. This is the first report that shows that andrographolide has a potency to induce CYP1A1 enzyme and indicates that andrographolide could be a very useful compound for investigating the regulatory mechanism of the CYP1A1 induction pathway. In addition, our findings suggest preparing advice for rational administration of A. paniculata, according to its ability to induce CYP1A1 expression

  19. X-1A in flight with flight data superimposed

    Science.gov (United States)

    1953-01-01

    This photo of the X-1A includes graphs of the flight data from Maj. Charles E. Yeager's Mach 2.44 flight on December 12, 1953. (This was only a few days short of the 50th anniversary of the Wright brothers' first powered flight.) After reaching Mach 2.44, then the highest speed ever reached by a piloted aircraft, the X-1A tumbled completely out of control. The motions were so violent that Yeager cracked the plastic canopy with his helmet. He finally recovered from a inverted spin and landed on Rogers Dry Lakebed. Among the data shown are Mach number and altitude (the two top graphs). The speed and altitude changes due to the tumble are visible as jagged lines. The third graph from the bottom shows the G-forces on the airplane. During the tumble, these twice reached 8 Gs or 8 times the normal pull of gravity at sea level. (At these G forces, a 200-pound human would, in effect, weigh 1,600 pounds if a scale were placed under him in the direction of the force vector.) Producing these graphs was a slow, difficult process. The raw data from on-board instrumentation recorded on oscillograph film. Human computers then reduced the data and recorded it on data sheets, correcting for such factors as temperature and instrument errors. They used adding machines or slide rules for their calculations, pocket calculators being 20 years in the future. Three second generation Bell Aircraft Corporations X-1s were built, though four were requested. They were the X-1A (48-1384); X-1B (48-1385); X-1C (canceled and never built); X-1D (48-1386). These aircraft were similar to the X-1s, except they were five feet longer, had conventional canopies, and were powered by Reaction Motors, Inc. XLR11-RM-5 rocket engines. The RM-5, like the previous engines, had no throttle and was controlled by igniting one or more of the four thrust chambers at will. The original program outline called for the X-1A and X-1B to be used for dynamic stability and air loads investigations. The X-1D was to be used

  20. Rice SUB1A constrains remodeling of the transcriptome and metabolome during submergence and post-submergence recovery”.

    Science.gov (United States)

    The rice (Oryza sativa L.) ethylene-responsive transcription factor SUB1A confers tolerance to prolonged, complete submergence by limiting underwater elongation growth. Rice encoding SUB1A-1 also recovers photosynthetic function and re-commences development towards flowering more rapidly after desu...

  1. Dissecting the expression of EEF1A1/2 genes in human prostate cancer cells: the potential of EEF1A2 as a hallmark for prostate transformation and progression.

    Science.gov (United States)

    Scaggiante, B; Dapas, B; Bonin, S; Grassi, M; Zennaro, C; Farra, R; Cristiano, L; Siracusano, S; Zanconati, F; Giansante, C; Grassi, G

    2012-01-03

    In prostate adenocarcinoma, the dissection of the expression behaviour of the eukaryotic elongation factors (eEF1A1/2) has not yet fully elucidated. The EEF1A1/A2 expressions were investigated by real-time PCR, western blotting (cytoplasmic and cytoskeletal/nuclear-enriched fractions) and immunofluorescence in the androgen-responsive LNCaP and the non-responsive DU-145 and PC-3 cells, displaying a low, moderate and high aggressive phenotype, respectively. Targeted experiments were also conducted in the androgen-responsive 22Rv1, a cell line marking the progression towards androgen-refractory tumour. The non-tumourigenic prostate PZHPV-7 cell line was the control. Compared with PZHPV-7, cancer cells showed no major variations in EEF1A1 mRNA; eEF1A1 protein increased only in cytoskeletal/nuclear fraction. On the contrary, a significant rise of EEF1A2 mRNA and protein were found, with the highest levels detected in LNCaP. Eukaryotic elongation factor 1A2 immunostaining confirmed the western blotting results. Pilot evaluation in archive prostate tissues showed the presence of EEF1A2 mRNA in near all neoplastic and perineoplastic but not in normal samples or in benign adenoma; in contrast, EEF1A1 mRNA was everywhere detectable. Eukaryotic elongation factor 1A2 switch-on, observed in cultured tumour prostate cells and in human prostate tumour samples, may represent a feature of prostate cancer; in contrast, a minor involvement is assigned to EEF1A1. These observations suggest to consider EEF1A2 as a marker for prostate cell transformation and/or possibly as a hallmark of cancer progression.

  2. Incorporation of a prolyl hydroxylase inhibitor into scaffolds: a strategy for stimulating vascularization.

    Science.gov (United States)

    Sham, Adeline; Martinez, Eliana C; Beyer, Sebastian; Trau, Dieter W; Raghunath, Michael

    2015-03-01

    Clinical applications of tissue engineering are constrained by the ability of the implanted construct to invoke vascularization in adequate extent and velocity. To overcome the current limitations presented by local delivery of single angiogenic factors, we explored the incorporation of prolyl hydroxylase inhibitors (PHIs) into scaffolds as an alternative vascularization strategy. PHIs are small molecule drugs that can stabilize the alpha subunit of hypoxia-inducible factor-1 (HIF-1), a key transcription factor that regulates a variety of angiogenic mechanisms. In this study, we conjugated the PHI pyridine-2,4-dicarboxylic acid (PDCA) through amide bonds to a gelatin sponge (Gelfoam(®)). Fibroblasts cultured on PDCA-Gelfoam were able to infiltrate and proliferate in these scaffolds while secreting significantly more vascular endothelial growth factor than cells grown on Gelfoam without PDCA. Reporter cells expressing green fluorescent protein-tagged HIF-1α exhibited dose-dependent stabilization of this angiogenic transcription factor when growing within PDCA-Gelfoam constructs. Subsequently, we implanted PDCA-Gelfoam scaffolds into the perirenal fat tissue of Sprague Dawley rats for 8 days. Immunostaining of explants revealed that the PDCA-Gelfoam scaffolds were amply infiltrated by cells and promoted vascular ingrowth in a dose-dependent manner. Thus, the incorporation of PHIs into scaffolds appears to be a feasible strategy for improving vascularization in regenerative medicine applications.

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

    International Nuclear Information System (INIS)

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

    2010-01-01

    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.

  4. HIF-1α effects on angiogenic potential in human small cell lung carcinoma

    Directory of Open Access Journals (Sweden)

    Xia Wanli

    2011-08-01

    Full Text Available Abstract Background Hypoxia-inducible factor-1 alpha (HIF-1α maybe an important regulatory factor for angiogenesis of small cell lung cancer (SCLC. Our study aimed to investigate the effect of HIF-1α on angiogenic potential of SCLC including two points: One is the effect of HIF-1α on the angiogenesis of SCLC in vivo. The other is the regulation of angiogenic genes by HIF-1α in vitro and in vivo. Methods In vivo we used an alternative method to study the effect of HIF-1a on angiogenic potential of SCLC by buliding NCI-H446 cell transplantation tumor on the chick embryo chorioallantoic membrane (CAM surface. In vitro we used microarray to screen out the angiogenic genes regulated by HIF-1a and tested their expression level in CAM transplantation tumor by RT-PCR and Western-blot analysis. Results In vivo angiogenic response surrounding the SCLC transplantation tumors in chick embryo chorioallantoic membrane (CAM was promoted after exogenous HIF-1α transduction (p In vitro the changes of angiogenic genes expression induced by HIF-1α in NCI-H446 cells were analyzed by cDNA microarray experiments. HIF-1α upregulated the expression of angiogenic genes VEGF-A, TNFAIP6, PDGFC, FN1, MMP28, MMP14 to 6.76-, 6.69-, 2.26-, 2.31-, 4.39-, 2.97- fold respectively and glycolytic genes GLUT1, GLUT2 to2.98-, 3.74- fold respectively. In addition, the expression of these angiogenic factors were also upregulated by HIF-1α in the transplantion tumors in CAM as RT-PCR and Western-blot analysis indicated. Conclusions These results indicated that HIF-1α may enhance the angiogenic potential of SCLC by regulating some angiogenic genes such as VEGF-A, MMP28 etc. Therefore, HIF-1α may be a potential target for the gene targeted therapy of SCLC.

  5. Chondroprotective effect of zinc oxide nanoparticles in conjunction with hypoxia on bovine cartilage-matrix synthesis.

    Science.gov (United States)

    Mirza, Eraj Humayun; Pan-Pan, Chong; Wan Ibrahim, Wan Mohd Azhar Bin; Djordjevic, Ivan; Pingguan-Murphy, Belinda

    2015-11-01

    Articular cartilage is a tissue specifically adapted to a specific niche with a low oxygen tension (hypoxia), and the presence of such conditions is a key factor in regulating growth and survival of chondrocytes. Zinc deficiency has been linked to cartilage-related disease, and presence of Zinc is known to provide antibacterial benefits, which makes its inclusion attractive in an in vitro system to reduce infection. Inclusion of 1% zinc oxide nanoparticles (ZnONP) in poly octanediol citrate (POC) polymer cultured in hypoxia has not been well determined. In this study we investigated the effects of ZnONP on chondrocyte proliferation and matrix synthesis cultured under normoxia (21% O2 ) and hypoxia (5% O2 ). We report an upregulation of chondrocyte proliferation and sulfated glycosaminoglycan (S-GAG) in hypoxic culture. Results demonstrate a synergistic effect of oxygen concentration and 1% ZnONP in up-regulation of anabolic gene expression (Type II collagen and aggrecan), and a down regulation of catabolic (MMP-13) gene expression. Furthermore, production of transcription factor hypoxia-inducible factor 1A (HIF-1A) in response to hypoxic condition to regulate chondrocyte survival under hypoxia is not affected by the presence of 1% ZnONP. Presence of 1% ZnONP appears to act to preserve homeostasis of cartilage in its hypoxic environment. © 2015 Wiley Periodicals, Inc.

  6. Serotonin type-1A receptor imaging in depression

    International Nuclear Information System (INIS)

    Drevets, Wayne C.; Frank, Ellen; Price, Julie C.; Kupfer, David J.; Greer, Phil J.; Mathis, Chester

    2000-01-01

    Regional 5-hydroxytryptamine 1A (5-HT 1A ) receptor binding potential (BP) of depressed subjects with primary, recurrent, familial mood disorders was compared to that of healthy controls by using positron emission tomography and [carbonyl- 11 C]WAY-100635 {[ 11 C]N-(2-(4-(2-methoxyphenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide}. The mean 5-HT 1A receptor BP was reduced 42% in the midbrain raphe and 25-33% in limbic and neocortical areas in the mesiotemporal, occipital, and parietal cortex. The magnitude of these abnormalities was most prominent in bipolar depressives and unipolar depressives who had bipolar relatives. These abnormal reductions in 5-HT 1A receptor BP are consistent with in vivo evidence that 5-HT 1A receptor sensitivity is reduced in major depressive disorder and postmortem data showing a widespread deficit of 5-HT 1A receptor expression in primary mood disorders

  7. Analysis list: Ptf1a [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Ptf1a Embryo,Pancreas + mm9 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/P...tf1a.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/target/Ptf1a.5.tsv http://dbarchive.biosciencedbc....jp/kyushu-u/mm9/target/Ptf1a.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Ptf1a.Embryo.tsv,http://dbarchive.bioscience...dbc.jp/kyushu-u/mm9/colo/Ptf1a.Pancreas.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/mm9/colo/Embryo.gml,http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/colo/Pancreas.gml ...

  8. Analysis list: DYRK1A [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available DYRK1A Neural,Uterus + hg19 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/...DYRK1A.1.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/target/DYRK1A.5.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/hg19/target/DYRK1A.10.tsv http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/DYRK1A.Neural....tsv,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/DYRK1A.Uterus.tsv http://dbarchive.bioscience...dbc.jp/kyushu-u/hg19/colo/Neural.gml,http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/colo/Uterus.gml ...

  9. Identification of CYP1A inducing compounds in crude oil

    Energy Technology Data Exchange (ETDEWEB)

    Khan, C.W.; Hodson, P.V. [Queen' s Univ., Kingston, ON (Canada). Dept. of Biology; Hollebone, B.P.; Wang, Z. [Environment Canada, Ottawa, ON (Canada). Environmental Technology Advancement Directorate; Brown, R.S. [Queen' s Univ., Kingston, ON (Canada). Dept. of Chemistry

    2004-07-01

    One of the major sources of polycyclic aromatic hydrocarbons (PAHs) in aquatic ecosystems is crude oil. PAHs are responsible for developmental malformations in the early life stages of fish. The induction of CYP1A enzyme is characteristic of developmental toxicity caused by crude oil. As such, it is an effective biomarker of PAH uptake. It is not known which PAHs cause toxicity because of the complex chemical composition of crude oil. In this study, an approach called Toxicity Identification and Evaluation (TIE) was used with different crude oils to separate bioavailable PAHs into petroleum sub-fractions. The extent of CYP1A induction in rainbow trout was measured after 48 hour exposures to each fraction. Low temperature vacuum distillation was used to create white gas, kerosene, coal tar/bitumen and wax fractions. Hepatic CYP1A activity was induced by whole oil and some fractions. The highest PAH concentration was found in the coal tar/bitumen fraction which accounted for most CYP1A induction in whole oil. The wax fraction also caused moderate CYP1A induction, but the white gas fraction did not cause any CYP1A induction. The hypothesis that alkyl PAH may be the most significant source of CYP1A inducers in the coal tar/bitumen fraction was supported by chemical analysis of CYP1A induction potency. Results showed that benzo[a]pyrene accounts for nearly all of the CYP1A induction caused by the wax fraction.

  10. Psychopharmacology of 5-HT{sub 1A} receptors

    Energy Technology Data Exchange (ETDEWEB)

    Cowen, Philip J

    2000-07-01

    Serotonin{sub 1A} (5-HT{sub 1A}) receptors are located on both 5-HT cell bodies where they act as inhibitory autoreceptors and at postsynaptic sites where they mediate the effects of 5-HT released from nerve terminals. The sensitivity of 5-HT{sub 1A} receptors in humans can be measured using the technique of pharmacological challenge. For example, acute administration of a selective 5-HT{sub 1A} receptor agonist, such as ipsapirone, decreases body temperature and increases plasma cortisol through activation of pre- and postsynaptic 5-HT{sub 1A} receptors, respectively. Use of this technique has demonstrated that unmedicated patients with major depression have decreased sensitivity of both pre- and postsynaptic 5-HT{sub 1A} receptors. Treatment with selective serotonin reuptake inhibitors further down-regulates 5-HT{sub 1A} receptor activity. Due to the hypotheses linking decreased sensitivity of 5-HT{sub 1A} autoreceptors with the onset of antidepressant activity, there is current interest in the therapeutic efficacy of combined treatment with selective serotonin reuptake inhibitors and 5-HT{sub 1A} receptor antagonists.

  11. Mutations in HNF1A result in marked alterations of plasma glycan profile

    DEFF Research Database (Denmark)

    Thanabalasingham, Gaya; Huffman, Jennifer E; Kattla, Jayesh J

    2013-01-01

    A recent genome-wide association study identified hepatocyte nuclear factor 1-α (HNF1A) as a key regulator of fucosylation. We hypothesized that loss-of-function HNF1A mutations causal for maturity-onset diabetes of the young (MODY) would display altered fucosylation of N-linked glycans on plasma...... proteins and that glycan biomarkers could improve the efficiency of a diagnosis of HNF1A-MODY. In a pilot comparison of 33 subjects with HNF1A-MODY and 41 subjects with type 2 diabetes, 15 of 29 glycan measurements differed between the two groups. The DG9-glycan index, which is the ratio of fucosylated...... to nonfucosylated triantennary glycans, provided optimum discrimination in the pilot study and was examined further among additional subjects with HNF1A-MODY (n = 188), glucokinase (GCK)-MODY (n = 118), hepatocyte nuclear factor 4-α (HNF4A)-MODY (n = 40), type 1 diabetes (n = 98), type 2 diabetes (n = 167...

  12. Functional polymorphisms of UDP-glucuronosyltransferases 1A1, 1A6 and 1A8 are not involved in chronic pancreatitis.

    NARCIS (Netherlands)

    Verlaan, M.; Morsche, R.H.M. te; Pap, A.; Laheij, R.J.F.; Jansen, J.B.M.J.; Peters, W.H.M.; Drenth, J.P.H.

    2004-01-01

    OBJECTIVES: Chronic pancreatitis (CP) is associated with alcohol abuse, smoking and other dietary or environmental factors. UDP-glucuronosyltransferases (UGTs) are phase II detoxifying enzymes responsible for glucuronidation of various exogenous and endogenous compounds. Genetic variations,

  13. Molecular factors in migraine

    Science.gov (United States)

    Kowalska, Marta; Prendecki, Michał; Kozubski, Wojciech; Lianeri, Margarita; Dorszewska, Jolanta

    2016-01-01

    Migraine is a common neurological disorder that affects 11% of adults worldwide. This disease most likely has a neurovascular origin. Migraine with aura (MA) and more common form - migraine without aura (MO) – are the two main clinical subtypes of disease. The exact pathomechanism of migraine is still unknown, but it is thought that both genetic and environmental factors are involved in this pathological process. The first genetic studies of migraine were focused on the rare subtype of MA: familial hemiplegic migraine (FHM). The genes analysed in familial and sporadic migraine are: MTHFR, KCNK18, HCRTR1, SLC6A4, STX1A, GRIA1 and GRIA3. It is possible that migraine is a multifactorial disease with polygenic influence. Recent studies have shown that the pathomechanisms of migraine involves both factors responsible for immune response and oxidative stress such as: cytokines, tyrosine metabolism, homocysteine; and factors associated with pain transmission and emotions e.g.: serotonin, hypocretin-1, calcitonin gene-related peptide, glutamate. The correlations between genetic variants of the HCRTR1 gene, the polymorphism 5-HTTLPR and hypocretin-1, and serotonin were observed. It is known that serotonin inhibits the activity of hypocretin neurons and may affect the appearance of the aura during migraine attack. The understanding of the molecular mechanisms of migraine, including genotype-phenotype correlations, may contribute to finding markers important for the diagnosis and treatment of this disease. PMID:27191890

  14. Circulating CD36 is reduced in HNF1A-MODY carriers.

    Science.gov (United States)

    Bacon, Siobhan; Kyithar, Ma P; Schmid, Jasmin; Costa Pozza, Andre; Handberg, Aase; Byrne, Maria M

    2013-01-01

    Premature atherosclerosis is a significant cause of morbidity and mortality in type 2 diabetes mellitus. Maturity onset diabetes of the young (MODY) accounts for approximately 2% of all diabetes, with mutations in the transcription factor; hepatocyte nuclear factor 1 alpha (HNF1A) accounting for the majority of MODY cases. There is somewhat limited data available on the prevalence of macrovascular disease in HNF1A-MODY carriers with diabetes. Marked insulin resistance and the associated dyslipidaemia are not clinical features of HNF1A-MODY carriers. The scavenger protein CD36 has been shown to play a substantial role in the pathogenesis of atherosclerosis, largely through its interaction with oxidised LDL. Higher levels of monocyte CD36 and plasma CD36(sCD36) are seen to cluster with insulin resistance and diabetes. The aim of this study was to determine levels of sCD36 in participants with HNF1A-MODY diabetes and to compare them with unaffected normoglycaemic family members and participants with type 2 diabetes mellitus. We recruited 37 participants with HNF1A-MODY diabetes and compared levels of sCD36 with BMI-matched participants with type 2 diabetes mellitus and normoglycaemic HNF1A-MODY negative family controls. Levels of sCD36 were correlated with phenotypic and biochemical parameters. HNF1A-MODY participants were lean, normotensive, with higher HDL and lower triglyceride levels when compared to controls and participants with type 2 diabetes mellitus. sCD36 was also significantly lower in HNF1A-MODY participants when compared to both the normoglycaemic family controls and to lean participants with type 2 diabetes mellitus. In conclusion, sCD36 is significantly lower in lean participants with HNF1A-MODY diabetes when compared to weight-matched normoglycaemic familial HNF1A-MODY negative controls and to lean participants with type 2 diabetes mellitus. Lower levels of this pro-atherogenic marker may result from the higher HDL component in the lipid profile of

  15. Circulating CD36 is reduced in HNF1A-MODY carriers.

    Directory of Open Access Journals (Sweden)

    Siobhan Bacon

    Full Text Available INTRODUCTION: Premature atherosclerosis is a significant cause of morbidity and mortality in type 2 diabetes mellitus. Maturity onset diabetes of the young (MODY accounts for approximately 2% of all diabetes, with mutations in the transcription factor; hepatocyte nuclear factor 1 alpha (HNF1A accounting for the majority of MODY cases. There is somewhat limited data available on the prevalence of macrovascular disease in HNF1A-MODY carriers with diabetes. Marked insulin resistance and the associated dyslipidaemia are not clinical features of HNF1A-MODY carriers. The scavenger protein CD36 has been shown to play a substantial role in the pathogenesis of atherosclerosis, largely through its interaction with oxidised LDL. Higher levels of monocyte CD36 and plasma CD36(sCD36 are seen to cluster with insulin resistance and diabetes. The aim of this study was to determine levels of sCD36 in participants with HNF1A-MODY diabetes and to compare them with unaffected normoglycaemic family members and participants with type 2 diabetes mellitus. METHODS: We recruited 37 participants with HNF1A-MODY diabetes and compared levels of sCD36 with BMI-matched participants with type 2 diabetes mellitus and normoglycaemic HNF1A-MODY negative family controls. Levels of sCD36 were correlated with phenotypic and biochemical parameters. RESULTS: HNF1A-MODY participants were lean, normotensive, with higher HDL and lower triglyceride levels when compared to controls and participants with type 2 diabetes mellitus. sCD36 was also significantly lower in HNF1A-MODY participants when compared to both the normoglycaemic family controls and to lean participants with type 2 diabetes mellitus. CONCLUSION: In conclusion, sCD36 is significantly lower in lean participants with HNF1A-MODY diabetes when compared to weight-matched normoglycaemic familial HNF1A-MODY negative controls and to lean participants with type 2 diabetes mellitus. Lower levels of this pro-atherogenic marker may

  16. Phenotypes and genotypes in individuals with SMC1A variants

    DEFF Research Database (Denmark)

    Huisman, Sylvia; Mulder, Paul A; Redeker, Egbert

    2017-01-01

    , stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group...

  17. Role of pelvic lymphadenectomy in stage 1A endometrial carcinoma ...

    African Journals Online (AJOL)

    Hossam Hassan Aly Hassan El Sokkary

    2013-10-31

    Oct 31, 2013 ... phadenectomy in managing stage 1A diagnosed preoperatively, we try to evaluate this need. Objective: To ... Methods: 60 Cases of endometrial carcinoma diagnosed by fractional curettage and proved to be stage 1A .... The strongest argument for routine staging is the avoidance of pelvic radiation therapy ...

  18. Charcot-Marie-Tooth disease type 1A

    DEFF Research Database (Denmark)

    Hertz, Jens Michael; Børglum, A D; Brandt, C A

    1994-01-01

    Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant peripheral neuropathy associated with a DNA duplication on chromosome 17p11.2-p12 in the majority of cases. Most of the sporadic cases are due to a de novo duplication. We have screened for this duplication in 11 Danish patients...

  19. Induction of mesenchymal cell phenotypes in lung epithelial cells by adenovirus E1A.

    Science.gov (United States)

    Behzad, A R; Morimoto, K; Gosselink, J; Green, J; Hogg, J C; Hayashi, S

    2006-12-01

    Epithelial-mesenchymal transformation is now recognised as an important feature of tissue remodelling. The present report concerns the role of adenovirus infection in inducing this transformation in an animal model of chronic obstructive pulmonary disease. Guinea pig primary peripheral lung epithelial cells (PLECs) transfected with adenovirus E1A (E1A-PLECs) were compared to guinea pig normal lung fibroblasts (NLFs) transfected with E1A (E1A-NLFs). These cells were characterised by PCR, immunocytochemistry, electron microscopy, and Western and Northern blot analyses. Electrophoretic mobility shift assays were performed in order to examine nuclear factor (NF)-kappaB and activator protein (AP)-1 binding activities. E1A-PLECs and E1A-NLFs positive for E1A DNA, mRNA and protein expressed cytokeratin and vimentin but not smooth muscle alpha-actin. Both exhibited cuboidal morphology and junctional complexes, but did not contain lamellar bodies or express surfactant protein A, B or C mRNAs. These two cell types differed, however, in their NF-kappaB and AP-1 binding after lipopolysaccharide stimulation, possibly due to differences in the expression of the subunits that comprise these transcriptional complexes. E1A transfection results in the transformation of peripheral lung epithelial cells and normal lung fibroblasts to a phenotype intermediate between that of the two primary cells. It is postulated that this intermediate phenotype may play a major role in the remodelling of the airways in chronic obstructive pulmonary disease associated with persistence of adenovirus E1A DNA.

  20. Carnitine palmitoyltransferase 1A (CPT1A): a transcriptional target of PAX3-FKHR and mediates PAX3-FKHR–dependent motility in alveolar rhabdomyosarcoma cells

    International Nuclear Information System (INIS)

    Liu, Lingling; Wang, Yong-Dong; Wu, Jing; Cui, Jimmy; Chen, Taosheng

    2012-01-01

    Alveolar rhabdomyosarcoma (ARMS) has a high propensity to metastasize, leading to its aggressiveness and a poor survival rate among those with the disease. More than 80% of aggressive ARMSs harbor a PAX3-FKHR fusion transcription factor, which regulates cell migration and promotes metastasis, most likely by regulating the fusion protein’s transcriptional targets. Therefore, identifying druggable transcription targets of PAX3-FKHR that are also downstream effectors of PAX3-FKHR–mediated cell migration and metastasis may lead to novel therapeutic approaches for treating ARMS. To identify genes whose expression is directly affected by the level of PAX3-FKHR in an ARMS cellular-context, we first developed an ARMS cell line in which PAX3-FKHR is stably down-regulated, and showed that stably downregulating PAX3-FKHR in ARMS cells significantly decreased the cells’ motility. We used microarray analysis to identify genes whose expression level decreased when PAX3-FKHR was downregulated. We used mutational analysis, promoter reporter assays, and electrophoretic mobility shift assays to determine whether PAX3-FKHR binds to the promoter region of the target gene. We used siRNA and pharmacologic inhibitor to downregulate the target gene of PAX3-FKHR and investigated the effect of such downregulation on cell motility. We found that when PAX3-FKHR was downregulated, the expression of carnitine palmitoyltransferase 1A (CPT1A) decreased. We showed that PAX3-FKHR binds to a paired-domain binding-site in the CPT1A promoter region, indicating that CPT1A is a novel transcriptional target of PAX3-FKHR. Furthermore, downregulating CPT1A decreased cell motility in ARMS cells, indicating that CPT1A is a downstream effector of PAX3-FKHR–mediated cell migration and metastasis. Taken together, we have identified CPT1A as a novel transcriptional target of PAX3-FKHR and revealed the novel function of CPT1A in promoting cell motility. CPT1A may represent a novel therapeutic target for

  1. Modulation of thyroid hormone receptor transactivation by the early region 1A (E1A-like inhibitor of differentiation 1 (EID1

    Directory of Open Access Journals (Sweden)

    Diana Vargas

    2008-01-01

    Full Text Available Transcriptional activation (TA mediated by the effect of thyroid hormones on target genes requires co-activator proteins such as the early region 1A (E1A associated 300 kDa binding protein (p300 and the cAMP response element binding protein (CREB binding protein (CBP, known as the p300/CBP complex, which acetylate histones 3 and 4 to allow transcriptional machinery access to the target gene promoter. Little is known on the role of p300 in thyroid hormone receptor (TR mediated TA but the E1A-like inhibitor of differentiation 1 (EID1, an inhibitor of p300 histone acetyltransferase (HAT, is a functional homolog of E1A and may inhibit myogenic differentiation factor D (MyoD transcriptional activity and reduces muscle cell differentiation. We evaluated the influence of EID1 on TR-mediated transcriptional activity using transfection and mammalian two-hybrid studies to show that EID1 may partially reduces TA activity of the TR receptor, probably due to p300 blockage since EID1 mutants cannot reduce TR-mediated TA. The EID1 does not affect the function of p160 co-activator proteins (160 kDa proteins of steroid receptor co-activators and is functionally independent of co-repressor proteins or TR binding. Summarizing, EID1 reduces TR-mediated transcriptional activity by blocking p300 and may play an important role in thyroid receptor activity in muscle and other tissues.

  2. Retinoids repress Ah receptor CYP1A1 induction pathway through the SMRT corepressor

    International Nuclear Information System (INIS)

    Fallone, Frederique; Villard, Pierre-Henri; Seree, Eric; Rimet, Odile; Nguyen, Quock Binh; Bourgarel-Rey, Veronique; Fouchier, Francis; Barra, Yves; Durand, Alain; Lacarelle, Bruno

    2004-01-01

    CYP1A1 isoform is mainly regulated by the transcription factor AhR and to a lesser extent by the nuclear receptor RAR. The effect of a coexposure with 3MC, a AhR ligand, and RA, a RAR ligand, which are, respectively, strong and weak CYP1A1 inducers, is poorly known. We showed in Caco-2 cells that addition of RA significantly decreased 3MC-induced CYP1A1 expression by -55% for mRNA level and -30% for promoter and enzymatic activities. We further showed that RA decreased AhR protein level. Moreover, a physical interaction between AhR and the RAR-corepressor SMRT has been described in vitro. Using the corepressor inhibitor TSA, transfected-cells with SMRT cDNA, and coimmunoprecipitation experiments, we demonstrated that RA addition repressed AhR function through a marked AhR/SMRT physical interaction. This interaction explains the decrease of 3MC-induced CYP1A1 expression. This new mechanism involving the repression of AhR-induced CYP1A1 expression by retinoids allows better knowledge of the CYP1A1 regulation

  3. High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes.

    Science.gov (United States)

    McDonald, Tim J; Shields, Beverley M; Lawry, Jane; Owen, Katharine R; Gloyn, Anna L; Ellard, Sian; Hattersley, Andrew T

    2011-08-01

    Maturity-onset diabetes of the young (MODY) as a result of mutations in hepatocyte nuclear factor 1-α (HNF1A) is often misdiagnosed as type 1 diabetes or type 2 diabetes. Recent work has shown that high-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY than type 1 diabetes, type 2 diabetes, or glucokinase (GCK)-MODY. We aim to replicate these findings in larger numbers and other MODY subtypes. hs-CRP levels were assessed in 750 patients (220 HNF1A, 245 GCK, 54 HNF4-α [HNF4A], 21 HNF1-β (HNF1B), 53 type 1 diabetes, and 157 type 2 diabetes). hs-CRP was lower in HNF1A-MODY (median [IQR] 0.3 [0.1-0.6] mg/L) than type 2 diabetes (1.40 [0.60-3.45] mg/L; P MODY (1.45 [0.46-2.88] mg/L; P MODY (0.60 [0.30-1.80] mg/L; P MODY (0.60 [0.10-2.8] mg/L; P = 0.07). hs-CRP discriminated HNF1A-MODY from type 2 diabetes with hs-CRP MODY than other forms of diabetes and may be used as a biomarker to select patients for diagnostic HNF1A genetic testing.

  4. EVA1A/TMEM166 Regulates Embryonic Neurogenesis by Autophagy

    Directory of Open Access Journals (Sweden)

    Mengtao Li

    2016-03-01

    Full Text Available Self-renewal and differentiation of neural stem cells is essential for embryonic neurogenesis, which is associated with cell autophagy. However, the mechanism by which autophagy regulates neurogenesis remains undefined. Here, we show that Eva1a/Tmem166, an autophagy-related gene, regulates neural stem cell self-renewal and differentiation. Eva1a depletion impaired the generation of newborn neurons, both in vivo and in vitro. Conversely, overexpression of EVA1A enhanced newborn neuron generation and maturation. Moreover, Eva1a depletion activated the PIK3CA-AKT axis, leading to the activation of the mammalian target of rapamycin and the subsequent inhibition of autophagy. Furthermore, addition of methylpyruvate to the culture during neural stem cell differentiation rescued the defective embryonic neurogenesis induced by Eva1a depletion, suggesting that energy availability is a significant factor in embryonic neurogenesis. Collectively, these data demonstrated that EVA1A regulates embryonic neurogenesis by modulating autophagy. Our results have potential implications for understanding the pathogenesis of neurodevelopmental disorders caused by autophagy dysregulation.

  5. EХPERIENCE IN INTERFERON β-1A USE FOR TREATMENT OF MULTIPLE SCLEROSIS IN CHILDREN

    Directory of Open Access Journals (Sweden)

    L. M. Kuzenkova

    2013-01-01

    Full Text Available Aim: to evaluate the impact of subcutaneous interferon β-1a on matrix metalloproteinases 3, 8, 9 (MMP, cytokines (tumor necrosis factor α — TNF α, and transforming growth factor β1 — TGF β1 levels in serum of children with relapsing-remitting multiple sclerosis. Patients and methods: the results of treatment of 32 patients with relapsing-remitting multiple sclerosis aged 12–18 years (22 girls and 10 boys were analyzed. Treatment efficacy was assessed by the number of relapsing-remitting multiple sclerosis exacerbations during 12 months, MRI data, MMP and cytokines dynamics in serum. Results: statistical evidence acquired for MMPs, their tissue inhibitor and cytokines levels decrease (p < 0,005 in patients receiving therapy with subcutaneous INF β-1a. Conclusions: subcutaneous interferon β-1а is highly efficient in treatment of relapsing-remitting multiple sclerosis in children and adolescents.

  6. Albumin stimulates the activity of the human UDP-glucuronosyltransferases 1A7, 1A8, 1A10, 2A1 and 2B15, but the effects are enzyme and substrate dependent.

    Science.gov (United States)

    Manevski, Nenad; Troberg, Johanna; Svaluto-Moreolo, Paolo; Dziedzic, Klaudyna; Yli-Kauhaluoma, Jari; Finel, Moshe

    2013-01-01

    Human UDP-glucuronosyltransferases (UGTs) are important enzymes in metabolic elimination of endo- and xenobiotics. It was recently shown that addition of fatty acid free bovine serum albumin (BSA) significantly enhances in vitro activities of UGTs, a limiting factor in in vitro-in vivo extrapolation. Nevertheless, since only few human UGT enzymes were tested for this phenomenon, we have now performed detailed enzyme kinetic analysis on the BSA effects in six previously untested UGTs, using 2-4 suitable substrates for each enzyme. We also examined some of the previously tested UGTs, but using additional substrates and a lower BSA concentration, only 0.1%. The latter concentration allows the use of important but more lipophilic substrates, such as estradiol and 17-epiestradiol. In five newly tested UGTs, 1A7, 1A8, 1A10, 2A1, and 2B15, the addition of BSA enhanced, to a different degree, the in vitro activity by either decreasing reaction's K(m), increasing its V(max), or both. In contrast, the activities of UGT2B17, another previously untested enzyme, were almost unaffected. The results of the assays with the previously tested UGTs, 1A1, 1A6, 2B4, and 2B7, were similar to the published BSA only as far as the BSA effects on the reactions' K(m) are concerned. In the cases of V(max) values, however, our results differ significantly from the previously published ones, at least with some of the substrates. Hence, the magnitude of the BSA effects appears to be substrate dependent, especially with respect to V(max) increases. Additionally, the BSA effects may be UGT subfamily dependent since K(m) decreases were observed in members of subfamilies 1A, 2A and 2B, whereas large V(max) increases were only found in several UGT1A members. The results shed new light on the complexity of the BSA effects on the activity and enzyme kinetics of the human UGTs.

  7. Albumin stimulates the activity of the human UDP-glucuronosyltransferases 1A7, 1A8, 1A10, 2A1 and 2B15, but the effects are enzyme and substrate dependent.

    Directory of Open Access Journals (Sweden)

    Nenad Manevski

    Full Text Available Human UDP-glucuronosyltransferases (UGTs are important enzymes in metabolic elimination of endo- and xenobiotics. It was recently shown that addition of fatty acid free bovine serum albumin (BSA significantly enhances in vitro activities of UGTs, a limiting factor in in vitro-in vivo extrapolation. Nevertheless, since only few human UGT enzymes were tested for this phenomenon, we have now performed detailed enzyme kinetic analysis on the BSA effects in six previously untested UGTs, using 2-4 suitable substrates for each enzyme. We also examined some of the previously tested UGTs, but using additional substrates and a lower BSA concentration, only 0.1%. The latter concentration allows the use of important but more lipophilic substrates, such as estradiol and 17-epiestradiol. In five newly tested UGTs, 1A7, 1A8, 1A10, 2A1, and 2B15, the addition of BSA enhanced, to a different degree, the in vitro activity by either decreasing reaction's K(m, increasing its V(max, or both. In contrast, the activities of UGT2B17, another previously untested enzyme, were almost unaffected. The results of the assays with the previously tested UGTs, 1A1, 1A6, 2B4, and 2B7, were similar to the published BSA only as far as the BSA effects on the reactions' K(m are concerned. In the cases of V(max values, however, our results differ significantly from the previously published ones, at least with some of the substrates. Hence, the magnitude of the BSA effects appears to be substrate dependent, especially with respect to V(max increases. Additionally, the BSA effects may be UGT subfamily dependent since K(m decreases were observed in members of subfamilies 1A, 2A and 2B, whereas large V(max increases were only found in several UGT1A members. The results shed new light on the complexity of the BSA effects on the activity and enzyme kinetics of the human UGTs.

  8. Mutational analysis of COL1A1 and COL1A2 genes among Estonian osteogenesis imperfecta patients.

    Science.gov (United States)

    Zhytnik, Lidiia; Maasalu, Katre; Reimann, Ene; Prans, Ele; Kõks, Sulev; Märtson, Aare

    2017-08-15

    Osteogenesis imperfecta (OI) is a rare bone disorder. In 90% of cases, OI is caused by mutations in the COL1A1/2 genes, which code procollagen α1 and α2 chains. The main aim of the current research was to identify the mutational spectrum of COL1A1/2 genes in Estonian patients. The small population size of Estonia provides a unique chance to explore the collagen I mutational profile of 100% of OI families in the country. We performed mutational analysis of peripheral blood gDNA of 30 unrelated Estonian OI patients using Sanger sequencing of COL1A1 and COL1A2 genes, including all intron-exon junctions and 5'UTR and 3'UTR regions, to identify causative OI mutations. We identified COL1A1/2 mutations in 86.67% of patients (26/30). 76.92% of discovered mutations were located in the COL1A1 (n = 20) and 23.08% in the COL1A2 (n = 6) gene. Half of the COL1A1/2 mutations appeared to be novel. The percentage of quantitative COL1A1/2 mutations was 69.23%. Glycine substitution with serine was the most prevalent among missense mutations. All qualitative mutations were situated in the chain domain of pro-α1/2 chains. Our study shows that among the Estonian OI population, the range of collagen I mutations is quite high, which agrees with other described OI cohorts of Northern Europe. The Estonian OI cohort differs due to the high number of quantitative variants and simple missense variants, which are mostly Gly to Ser substitutions and do not extend the chain domain of COL1A1/2 products.

  9. Exercise induces transient transcriptional activation of the PGC-1a gene in human skeletal muscle

    DEFF Research Database (Denmark)

    Pilegaard, Henriette; Saltin, Bengt; Neufer, P. Darrell

    2003-01-01

    Endurance exercise training induces mitochondrial biogenesis in skeletal muscle. The peroxisome proliferator activated receptor co-activator 1a (PGC-1a) has recently been identified as a nuclear factor critical for coordinating the activation of genes required for mitochondrial biogenesis in cell...... culture and rodent skeletal muscle. To determine whether PGC-1a transcription is regulated by acute exercise and exercise training in human skeletal muscle, seven male subjects performed 4 weeks of one-legged knee extensor exercise training. At the end of training, subjects completed 3 h of two......-legged knee extensor exercise. Biopsies were obtained from the vastus lateralis muscle of both the untrained and trained legs before exercise and after 0, 2, 6 and 24 h of recovery. Time to exhaustion (2 min maximum resistance), as well as hexokinase II (HKII), citrate synthase and 3-hydroxyacyl...

  10. Oxidative stress reduces levels of dysbindin-1A via its PEST domain.

    Science.gov (United States)

    Yap, Mei-Yi Alicia; Lo, Yew-Long; Talbot, Konrad; Ong, Wei-Yi

    2014-12-01

    Oxidative stress resulting from the generation of reactive oxygen species has been proposed as an etiological factor in schizophrenia. The present study tests the hypothesis that oxidative stress can affect levels of dysbindin-1A, encoded by Dtnbp1, a genetic risk factor for schizophrenia, via its PEST domain. In vitro studies on SH-SY5Y cells indicate that oxidative stress triggers proteasomal degradation of dysbindin-1A, and that this requires interactions with its PEST domain, which may be a TRIM32 target. We specifically found (a) that oxidative stress induced in SH-SY5Y cells by 500 µM hydrogen peroxide reduced levels of full-length dysbindin-1, but did not reduce levels of that protein lacking its PEST domain and (b) that levels of full-length dysbindin-1, but not dysbindin-1 lacking its PEST domain, were higher in cells treated with the proteasome inhibitor MG132. Oxidative stress thus emerges as the first known cellular factor regulating dysbindin-1 isoforms with PEST domains. These findings are consistent with the previously noted fact that phosphorylation of PEST domains often marks proteins for proteasomal degradation, and raises the possibility that treatments reducing oxidative stress in the brain, especially during development, may lower schizophrenia risk. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Circulating CD36 Is Reduced in HNF1A-MODY Carriers.

    LENUS (Irish Health Repository)

    Bacon, Siobhan

    2013-01-01

    Premature atherosclerosis is a significant cause of morbidity and mortality in type 2 diabetes mellitus. Maturity onset diabetes of the young (MODY) accounts for approximately 2% of all diabetes, with mutations in the transcription factor; hepatocyte nuclear factor 1 alpha (HNF1A) accounting for the majority of MODY cases. There is somewhat limited data available on the prevalence of macrovascular disease in HNF1A-MODY carriers with diabetes. Marked insulin resistance and the associated dyslipidaemia are not clinical features of HNF1A-MODY carriers. The scavenger protein CD36 has been shown to play a substantial role in the pathogenesis of atherosclerosis, largely through its interaction with oxidised LDL. Higher levels of monocyte CD36 and plasma CD36(sCD36) are seen to cluster with insulin resistance and diabetes. The aim of this study was to determine levels of sCD36 in participants with HNF1A-MODY diabetes and to compare them with unaffected normoglycaemic family members and participants with type 2 diabetes mellitus.

  12. An HRE-Binding Py-Im Polyamide Impairs Hypoxic Signaling in Tumors.

    Science.gov (United States)

    Szablowski, Jerzy O; Raskatov, Jevgenij A; Dervan, Peter B

    2016-04-01

    Hypoxic gene expression contributes to the pathogenesis of many diseases, including organ fibrosis, age-related macular degeneration, and cancer. Hypoxia-inducible factor-1 (HIF1), a transcription factor central to the hypoxic gene expression, mediates multiple processes including neovascularization, cancer metastasis, and cell survival. Pyrrole-imidazole polyamide 1: has been shown to inhibit HIF1-mediated gene expression in cell culture but its activity in vivo was unknown. This study reports activity of polyamide 1: in subcutaneous tumors capable of mounting a hypoxic response and showing neovascularization. We show that 1: distributes into subcutaneous tumor xenografts and normal tissues, reduces the expression of proangiogenic and prometastatic factors, inhibits the formation of new tumor blood vessels, and suppresses tumor growth. Tumors treated with 1: show no increase in HIF1α and have reduced ability to adapt to the hypoxic conditions, as evidenced by increased apoptosis in HIF1α-positive regions and the increased proximity of necrotic regions to vasculature. Overall, these results show that a molecule designed to block the transcriptional activity of HIF1 has potent antitumor activity in vivo, consistent with partial inhibition of the tumor hypoxic response. Mol Cancer Ther; 15(4); 608-17. ©2015 AACR. ©2015 American Association for Cancer Research.

  13. Simultaneous Expression of Cancer Stem Cell-Like Properties and Cancer-Associated Fibroblast-Like Properties in a Primary Culture of Breast Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Ishikawa, Mami; Inoue, Takahiro; Shirai, Takuma; Takamatsu, Kazuhiko; Kunihiro, Shiori; Ishii, Hirokazu [Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe 650-0047 (Japan); Nishikata, Takahito, E-mail: nisikata@konan-u.ac.jp [Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe 650-0047 (Japan); Frontier Institute for Biomolecular Engineering Research (FIBER), Konan University, Kobe 650-0047 (Japan)

    2014-07-31

    The importance of cancer-associated fibroblasts (CAFs) in cancer biology has been recently highlighted owing to their critical roles in cancer growth, progression, metastasis, and therapeutic resistance. We have previously established a primary culture of breast cancer cells, which showed epithelial-mesenchymal transition and cancer stem cell-like properties. In this study, we found that the primary culture also showed CAF-like properties. For example, hypoxia inducible factor 1α (HIF1A) and its downstream genes, nuclear factor-kappa B2 (NF-κB2) and BCL2/adenovirus E1B 19 kd-interacting protein 3 (BNIP3), and many enzymes involved in glycolysis, such as GAPDH, LDH, PGAM1, and PKM2, were highly overexpressed in the primary culture. Moreover, media conditioned with the primary culture cells enhanced the growth of breast cancer cells. Similar to previous CAF studies, this enhancement suggested to be occurred through fibroblast growth factor signaling. This MCKH primary culture cell, which showed simultaneous expression of tumorigenic and CAF properties, offers a unique experimental system for studying the biology of CAFs.

  14. Functional Analyses of a Novel CITED2 Nonsynonymous Mutation in Chinese Tibetan Patients with Congenital Heart Disease.

    Science.gov (United States)

    Liu, Shiming; Su, Zhaobing; Tan, Sainan; Ni, Bin; Pan, Hong; Liu, Beihong; Wang, Jing; Xiao, Jianmin; Chen, Qiuhong

    2017-08-01

    CITED2 gene is an important cardiac transcription factor that plays a fundamental role in the formation and development of embryonic cardiovascular. Previous studies have showed that knock-out of CITED2 in mice might result in various cardiac malformations. However, the mechanisms of CITED2 mutation on congenital heart disease (CHD) in Chinese Tibetan population are still poorly understood. In the present study, 187 unrelated Tibetan patients with CHD and 200 unrelated Tibetan healthy controls were screened for variants in the CITED2 gene; we subsequently identified one potential disease-causing mutation p.G143A in a 6-year-old girl with PDA and functional analyses of the mutation were carried out. Our study showed that the novel mutation of CITED2 significantly enhanced the expression activity of vascular endothelial growth factor (VEGF) under the role of co-receptor hypoxia inducible factor 1-aipha (HIF-1A), which is closely related with embryonic cardiac development. As a result, CITED2 gene mutation may play a significant role in the development of pediatric congenital heart disease.

  15. Serotonin type-1A receptor imaging in depression

    Energy Technology Data Exchange (ETDEWEB)

    Drevets, Wayne C. E-mail: drevets@pet.upmc.edu; Frank, Ellen; Price, Julie C.; Kupfer, David J.; Greer, Phil J.; Mathis, Chester

    2000-07-01

    Regional 5-hydroxytryptamine{sub 1A} (5-HT{sub 1A}) receptor binding potential (BP) of depressed subjects with primary, recurrent, familial mood disorders was compared to that of healthy controls by using positron emission tomography and [carbonyl-{sup 11}C]WAY-100635 {l_brace}[{sup 11}C]N-(2-(4-(2-methoxyphenyl)-1-piperazin-1-yl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide{r_brace}. The mean 5-HT{sub 1A} receptor BP was reduced 42% in the midbrain raphe and 25-33% in limbic and neocortical areas in the mesiotemporal, occipital, and parietal cortex. The magnitude of these abnormalities was most prominent in bipolar depressives and unipolar depressives who had bipolar relatives. These abnormal reductions in 5-HT{sub 1A} receptor BP are consistent with in vivo evidence that 5-HT{sub 1A} receptor sensitivity is reduced in major depressive disorder and postmortem data showing a widespread deficit of 5-HT{sub 1A} receptor expression in primary mood disorders.

  16. Mutation analysis of the COL1A1 and COL1A2 genes in Vietnamese patients with osteogenesis imperfecta.

    Science.gov (United States)

    Ho Duy, Binh; Zhytnik, Lidiia; Maasalu, Katre; Kändla, Ivo; Prans, Ele; Reimann, Ene; Märtson, Aare; Kõks, Sulev

    2016-08-12

    The genetics of osteogenesis imperfecta (OI) have not been studied in a Vietnamese population before. We performed mutational analysis of the COL1A1 and COL1A2 genes in 91 unrelated OI patients of Vietnamese origin. We then systematically characterized the mutation profiles of these two genes which are most commonly related to OI. Genomic DNA was extracted from EDTA-preserved blood according to standard high-salt extraction methods. Sequence analysis and pathogenic variant identification was performed with Mutation Surveyor DNA variant analysis software. Prediction of the pathogenicity of mutations was conducted using Alamut Visual software. The presence of variants was checked against Dalgleish's osteogenesis imperfecta mutation database. The sample consisted of 91 unrelated osteogenesis imperfecta patients. We identified 54 patients with COL1A1/2 pathogenic variants; 33 with COL1A1 and 21 with COL1A2. Two patients had multiple pathogenic variants. Seventeen novel COL1A1 and 10 novel COL1A2 variants were identified. The majority of identified COL1A1/2 pathogenic variants occurred in a glycine substitution (36/56, 64.3 %), usually serine (23/36, 63.9 %). We found two pathogenic variants of the COL1A1 gene c.2461G > A (p.Gly821Ser) in four unrelated patients and one, c.2005G > A (p.Ala669Thr), in two unrelated patients. Our data showed a lower number of collagen OI pathogenic variants in Vietnamese patients compared to reported rates for Asian populations. The OI mutational profile of the Vietnamese population is unique and related to the presence of a high number of recessive mutations in non-collagenous OI genes. Further analysis of OI patients negative for collagen mutations, is required.

  17. Association of BDNF and BMPR1A with clinicopathologic parameters in benign and malignant gallbladder lesions

    Science.gov (United States)

    2013-01-01

    Background Neurotrophic factors such as brain derived neurotrophic factor (BDNF) are synthesized in a variety of neural and non-neuronal cell types and regulate survival, proliferation and apoptosis. In addition, bone morphogenetic proteins (BMPs) inhibit the proliferation of pulmonary large carcinoma cells bone morphogenetic protein receptor, type IA (BMPR1A). Little is known about the expression of BDNF or BMPR1A in malignant gall bladder lesions. This study was to evaluate BDNF and BMPR1A expression and evaluate the clinicopathological significance in benign and malignant lesions of the gallbladder. Methods The BDNF and BMPR1A expression of gallbladder adenocarcinoma, peritumoral tissues, adenoma, polyp and chronic cholecystitis were Immunohistochemically determined. Results BDNF expression was significantly higher in gallbladder adenocarcinoma than in peritumoral tissues, adenoma, polyps and chronic cholecystitis samples. However, BMPR1A expression was significantly lower in gallbladder adenocarcinoma than in peritumoral tissues, adenomas, polyps and chronic cholecystitis tissues. The specimens with increased expression of BDNF in the benign lesions exhibited moderate- or severe-dysplasia of gallbladder epithelium. BDNF expression was significantly lower in well-differentiated adenocarcinomas with maximum tumor diameter 2 cm, metastasis of lymph node, and invasiveness of regional tissues in gallbladder adenocarcinoma. BMPR1A expression were significantly higher in the well-differentiated adenocarcinoma with maximal tumor diameter 2 cm, metastasis of lymph node, and invasiveness of regional tissues in gallbladder. Univariate Kaplan-Meier analysis indicated increased expression of BDNF or decreased expression of BMPR1A was associated with decreased disease specific survival (DSS) rates. Similarly, multivariate Cox regression analysis showed increased expression of BDNF or decreased expression of BMPR1A are independent predictors of poor DSS rates in gallbladder

  18. Trimming of mammalian transcriptional networks using network component analysis

    Directory of Open Access Journals (Sweden)

    Liao James C

    2010-10-01

    Full Text Available Abstract Background Network Component Analysis (NCA has been used to deduce the activities of transcription factors (TFs from gene expression data and the TF-gene binding relationship. However, the TF-gene interaction varies in different environmental conditions and tissues, but such information is rarely available and cannot be predicted simply by motif analysis. Thus, it is beneficial to identify key TF-gene interactions under the experimental condition based on transcriptome data. Such information would be useful in identifying key regulatory pathways and gene markers of TFs in further studies. Results We developed an algorithm to trim network connectivity such that the important regulatory interactions between the TFs and the genes were retained and the regulatory signals were deduced. Theoretical studies demonstrated that the regulatory signals were accurately reconstructed even in the case where only three independent transcriptome datasets were available. At least 80% of the main target genes were correctly predicted in the extreme condition of high noise level and small number of datasets. Our algorithm was tested with transcriptome data taken from mice under rapamycin treatment. The initial network topology from the literature contains 70 TFs, 778 genes, and 1423 edges between the TFs and genes. Our method retained 1074 edges (i.e. 75% of the original edge number and identified 17 TFs as being significantly perturbed under the experimental condition. Twelve of these TFs are involved in MAPK signaling or myeloid leukemia pathways defined in the KEGG database, or are known to physically interact with each other. Additionally, four of these TFs, which are Hif1a, Cebpb, Nfkb1, and Atf1, are known targets of rapamycin. Furthermore, the trimmed network was able to predict Eno1 as an important target of Hif1a; this key interaction could not be detected without trimming the regulatory network. Conclusions The advantage of our new algorithm

  19. DICER-ARGONAUTE2 complex in continuous fluorogenic assays of RNA interference enzymes.

    Directory of Open Access Journals (Sweden)

    Mark A Bernard

    Full Text Available Mechanistic studies of RNA processing in the RNA-Induced Silencing Complex (RISC have been hindered by lack of methods for continuous monitoring of enzymatic activity. "Quencherless" fluorogenic substrates of RNAi enzymes enable continuous monitoring of enzymatic reactions for detailed kinetics studies. Recombinant RISC enzymes cleave the fluorogenic substrates targeting human thymidylate synthase (TYMS and hypoxia-inducible factor 1-α subunit (HIF1A. Using fluorogenic dsRNA DICER substrates and fluorogenic siRNA, DICER+ARGONAUTE2 mixtures exhibit synergistic enzymatic activity relative to either enzyme alone, and addition of TRBP does not enhance the apparent activity. Titration of AGO2 and DICER in enzyme assays suggests that AGO2 and DICER form a functional high-affinity complex in equimolar ratio. DICER and DICER+AGO2 exhibit Michaelis-Menten kinetics with DICER substrates. However, AGO2 cannot process the fluorogenic siRNA without DICER enzyme, suggesting that AGO2 cannot self-load siRNA into its active site. The DICER+AGO2 combination processes the fluorogenic siRNA substrate (Km=74 nM with substrate inhibition kinetics (Ki=105 nM, demonstrating experimentally that siRNA binds two different sites that affect Dicing and AGO2-loading reactions in RISC. This result suggests that siRNA (product of DICER bound in the active site of DICER may undergo direct transfer (as AGO2 substrate to the active site of AGO2 in the DICER+AGO2 complex. Competitive substrate assays indicate that DICER+AGO2 cleavage of fluorogenic siRNA is specific, since unlabeled siRNA and DICER substrates serve as competing substrates that cause a concentration-dependent decrease in fluorescent rates. Competitive substrate assays of a series of DICER substrates in vitro were correlated with cell-based assays of HIF1A mRNA knockdown (log-log slope=0.29, suggesting that improved DICER substrate designs with 10-fold greater processing by the DICER+AGO2 complex can provide a

  20. Apolipoprotein M can discriminate HNF1A-MODY from Type 1 diabetes.

    Science.gov (United States)

    Mughal, S A; Park, R; Nowak, N; Gloyn, A L; Karpe, F; Matile, H; Malecki, M T; McCarthy, M I; Stoffel, M; Owen, K R

    2013-02-01

    Missed diagnosis of maturity-onset diabetes of the young (MODY) has led to an interest in biomarkers that enable efficient prioritization of patients for definitive molecular testing. Apolipoprotein M (apoM) was suggested as a biomarker for hepatocyte nuclear factor 1 alpha (HNF1A)-MODY because of its reduced expression in Hnf1a(-/-) mice. However, subsequent human studies examining apoM as a biomarker have yielded conflicting results. We aimed to evaluate apoM as a biomarker for HNF1A-MODY using a highly specific and sensitive ELISA. ApoM concentration was measured in subjects with HNF1A-MODY (n = 69), Type 1 diabetes (n = 50), Type 2 diabetes (n = 120) and healthy control subjects (n = 100). The discriminative accuracy of apoM and of the apoM/HDL ratio for diabetes aetiology was evaluated. Mean (standard deviation) serum apoM concentration (μmol/l) was significantly lower for subjects with HNF1A-MODY [0.86 (0.29)], than for those with Type 1 diabetes [1.37 (0.26), P = 3.1 × 10(-18) ) and control subjects [1.34 (0.22), P = 7.2 × 10(-19) ). There was no significant difference in apoM concentration between subjects with HNF1A-MODY and Type 2 diabetes [0.89 (0.28), P = 0.13]. The C-statistic measure of discriminative accuracy for apoM was 0.91 for HNF1A-MODY vs. Type 1 diabetes, indicating high discriminative accuracy. The apoM/HDL ratio was significantly lower in HNF1A-MODY than other study groups. However, this ratio did not perform well in discriminating HNF1A-MODY from either Type 1 diabetes (C-statistic = 0.79) or Type 2 diabetes (C-statistic = 0.68). We confirm an earlier report that serum apoM levels are lower in HNF1A-MODY than in controls. Serum apoM provides good discrimination between HNF1A-MODY and Type 1 diabetes and warrants further investigation for clinical utility in diabetes diagnostics. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  1. Radium-226 in certified uranium reference ores DL-1a, BL-4a, DH-1a and BL-5

    International Nuclear Information System (INIS)

    Smith, C.W.; Steger, H.F.

    1983-05-01

    Radium-226 radioactivity in uranium reference ores BL-4a and BL-5 and uranium-thorium reference ores DL-1a and DH-1a was determined in an interlaboratory program. Twelve of thirteen participants used certified radium solutions from the United States National Bureau of Standards (NBS) for calibration purposes. Recommended values of sup(226)Ra activity and associated parameters were calculated by statistical treatment of the results. In all cases, the recommended values are within 2 percent of activities predicted assuming secular equilibrium in the sup(238)U decay series. The recommended values for radium activity are 1.40, 15.5, 31.5 and 857 Bq/ for DL-1a, BL-4a, DH-1a and BL-5, respectively

  2. Heart disease - risk factors

    Science.gov (United States)

    Heart disease - prevention; CVD - risk factors; Cardiovascular disease - risk factors; Coronary artery disease - risk factors; CAD - risk ... a certain health condition. Some risk factors for heart disease you cannot change, but some you can. ...

  3. Lipoprotein composition in HNF1A-MODY: differentiating between HNF1A-MODY and type 2 diabetes.

    Science.gov (United States)

    McDonald, Tim J; McEneny, Jane; Pearson, Ewan R; Thanabalasingham, Gaya; Szopa, Magdalena; Shields, Beverley M; Ellard, Sian; Owen, Katharine R; Malecki, Maciej T; Hattersley, Andrew T; Young, Ian S

    2012-05-18

    The young-onset diabetes seen in HNF1A-MODY is often misdiagnosed as Type 2 diabetes. Type 2 diabetes, unlike HNF1A-MODY, is associated with insulin resistance and a characteristic dyslipidaemia. We aimed to compare the lipid profiles in HNF1A-MODY, Type 2 diabetes and control subjects and to determine if lipids can be used to aid the differential diagnosis of diabetes sub-type. 1) 14 subjects in each group (HNF1A-MODY, Type 2 diabetes and controls) were matched for gender and BMI. Fasting lipid profiles and HDL lipid constituents were compared in the 3 groups. 2) HDL-cholesterol was assessed in a further 267 patients with HNF1A-MODY and 297 patients with a diagnosis of Type 2 diabetes to determine its discriminative value. 1) In HNF1A-MODY subjects, plasma-triglycerides were lower (1.36 vs. 1.93 mmol/l, p = 0.07) and plasma-HDL-cholesterol was higher than in subjects with Type 2 diabetes (1.47 vs. 1.15 mmol/l, p = 0.0008), but was similar to controls. Furthermore, in the isolated HDL; HDL-phospholipid and HDL-cholesterol ester content were higher in HNF1A-MODY, than in Type 2 diabetes (1.59 vs. 1.33 mmol/L, p = 0.04 and 1.10 vs. 0.83 mmol/L, p = 0.019, respectively), but were similar to controls (1.59 vs. 1.45 mmol/L, p = 0.35 and 1.10 vs. 1.21 mmol/L, p = 0.19, respectively). 2) A plasma-HDL-cholesterol > 1.12 mmol/L was 75% sensitive and 64% specific (ROC AUC = 0.76) at discriminating HNF1A-MODY from Type 2 diabetes. The plasma-lipid profiles of HNF1A-MODY and the lipid constituents of HDL are similar to non-diabetic controls. However, HDL-cholesterol was higher in HNF1A-MODY than in Type 2 diabetes and could be used as a biomarker to aid in the identification of patients with HNF1A-MODY. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. Franck-Condon Simulations including Anharmonicity of the Ã(1)A''-X̃(1)A' Absorption and Single Vibronic Level Emission Spectra of HSiCl and DSiCl.

    Science.gov (United States)

    Mok, Daniel W K; Lee, Edmond P F; Chau, Foo-Tim; Dyke, John M

    2009-03-10

    RCCSD(T) and/or CASSCF/MRCI calculations have been carried out on the X̃(1)A' and Ã(1)A'' states of HSiCl employing basis sets of up to the aug-cc-pV5Z quality. Contributions from core correlation and extrapolation to the complete basis set limit were included in determining the computed equilibrium geometrical parameters and relative electronic energy of these two states of HSiCl. Franck-Condon factors which include allowance for anharmonicity and Duschinsky rotation between these two states of HSiCl and DSiCl were calculated employing RCCSD(T) and CASSCF/MRCI potential energy functions, and were used to simulate the Ã(1)A'' ← X̃(1)A' absorption and Ã(1)A'' → X̃(1)A' single vibronic level (SVL) emission spectra of HSiCl and DSiCl. Simulated absorption and experimental LIF spectra, and simulated and observed Ã(1)A''(0,0,0) → X̃(1)A' SVL emission spectra, of HSiCl and DSiCl are in very good agreement. However, agreement between simulated and observed Ã(1)A''(0,1,0) → X̃(1)A' and Ã(1)A''(0,2,1) → X̃(1)A' SVL emission spectra of DSiCl is not as good. Preliminary calculations on low-lying excited states of HSiCl suggest that vibronic interaction between low-lying vibrational levels of the Ã(1)A'' state and highly excited vibrational levels of the ã(3)A'' is possible. Such vibronic interaction may change the character of the low-lying vibrational levels of the Ã(1)A'' state, which would lead to perturbation in the SVL emission spectra from these vibrational levels.

  5. The presence of both serotonin 1A receptor (HTR1A and dopamine transporter (DAT1 gene variants increase the risk of borderline personality disorder

    Directory of Open Access Journals (Sweden)

    Peter R Joyce

    2014-01-01

    Full Text Available Dysfunction in the dopaminergic and serotonergic neurotransmitter systems has been demonstrated to be important in the aetiology of Borderline personality disorder (BPD. We investigated the relationship of two BPD risk factors, the HTR1A promoter polymorphism -1019C>G (rs6295 and the DAT1 repeat allele, with BPD in a major depressive disorder cohort of 367 patients. Out-patients with major depressive disorder were recruited for two treatment trials and assessed for personality disorders, including BPD. DNA samples were collected and the rs6295 polymorphism was detected with a TaqMan® assay. The DAT1 repeat allele was genotyped using a modified PCR method. The impact of polymorphisms on BPD was statistically analysed using uncontrolled logistic and multiple logistic regression models. BPD patients had higher frequencies of the DAT1 9,9 (OR=2.67 and 9,10 (OR=3.67 genotypes and also those homozygous HTR1A G allele (OR=2.03. No significant interactions between HTR1A and DAT1 genotypes, were observed; however, an increased risk of BPD was observed for those patients who were either 9,10; G,G (OR=6.64 and 9,9; C,G (OR=5.42. Furthermore, the odds of BPD in patients exhibiting high-risk variants of these two genes differed from those of patients in low-risk groups by up to a factor of 9. Our study provides evidence implicating the importance of the serotonergic and dopaminergic systems in BPD and that the interaction between genes from different neurotransmitters may play a role in the susceptibility to BPD.

  6. Sentinel-1A Product Geolocation Accuracy: Commissioning Phase Results

    Directory of Open Access Journals (Sweden)

    Adrian Schubert

    2015-07-01

    Full Text Available Sentinel-1A (S1A is an Earth observation satellite carrying a state-of-the-art Synthetic Aperture Radar (SAR imaging instrument. It was launched by the European Space Agency (ESA on 3 April 2014. With the end of the in-orbit commissioning phase having been completed at the end of September 2014, S1A data products are already consistently providing highly accurate geolocation. StripMap (SM mode products were acquired regularly and tested for geolocation accuracy and consistency during dedicated corner reflector (CR campaigns. At the completion of this phase, small geometric inconsistencies had been understood and mitigated, with the high quality of the final product geolocation estimates reflecting the mission’s success thus far. This paper describes the measurement campaign, the methods used during geolocation estimation, and presents best estimates of the product Absolute Location Error (ALE available at the beginning of S1A’s operational phase.

  7. DH-1a: a certified uranium-thorium reference ore

    International Nuclear Information System (INIS)

    Steger, H.F.; Bowman, W.S.; Zechanowitsch, G.

    1981-09-01

    A 122-kg sample of uranium-thorium ore, DH-1a, from Elliot Lake, Ontario, was prepared as a compositional reference material to replace the similar certified ore, DH-1. DH-1a was ground to minus 74μm, blended in one lot, and bottled in 200 g units. The homogeneity of DH-1a with respect to uranium was confirmed using the volumetric umpire method. The recommended value for uranium is based on the data from the confirmation of homogeneity. For thorium, twelve laboratories provided results in a free choice analytical program. A statistical analysis of the data gave a recommended value of 0.263 percent for uranium and 0.091 percent for thorium

  8. Cyp1a reporter zebrafish reveals target tissues for dioxin

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Kun-Hee [Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju (Korea, Republic of); Department of Microbiology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Park, Hye-Jeong [Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju (Korea, Republic of); Kim, Jin Hee [Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju (Korea, Republic of); Department of Microbiology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Kim, Suhyun [Graduate School of Medicine, Korea University, Ansan (Korea, Republic of); Williams, Darren R. [New Drug Targets Laboratory, School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju (Korea, Republic of); Kim, Myeong-Kyu [Department of Neurology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Jung, Young Do [Department of Biochemistry, Chonnam National University Medical School, Gwangju (Korea, Republic of); Teraoka, Hiroki [School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu (Japan); Park, Hae-Chul [Graduate School of Medicine, Korea University, Ansan (Korea, Republic of); Choy, Hyon E., E-mail: hyonchoy@chonnam.ac.kr [Department of Microbiology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Shin, Boo Ahn, E-mail: bashin@chonnam.ac.kr [Department of Microbiology, Chonnam National University Medical School, Gwangju (Korea, Republic of); Choi, Seok-Yong, E-mail: zebrafish@chonnam.ac.kr [Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju (Korea, Republic of); School of Biological Sciences and Technology, Chonnam National University, Gwangju (Korea, Republic of)

    2013-06-15

    Highlights: •2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic anthropogenic substance ever identified. •Transgenic cyp1a reporter zebrafish reveals target tissues for TCDD. •The retinal bipolar cells, otic vesicle, lateral line, pancreas, cloaca and pectoral fin bud are novel targets in zebrafish for TCDD. •Our findings will further understanding of human health risks by TCDD. -- Abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is the unintentional byproduct of various industrial processes, is classified as human carcinogen and could disrupt reproductive, developmental and endocrine systems. Induction of cyp1a1 is used as an indicator of TCDD exposure. We sought to determine tissues that are vulnerable to TCDD toxicity using a transgenic zebrafish (Danio rerio) model. We inserted a nuclear enhanced green fluorescent protein gene (EGFP) into the start codon of a zebrafish cyp1a gene in a fosmid clone using DNA recombineering. The resulting recombineered fosmid was then used to generate cyp1a reporter zebrafish, embryos of which were exposed to TCDD. Expression pattern of EGFP in the reporter zebrafish mirrored that of endogenous cyp1a mRNA. In addition, exposure of the embryos to TCDD at as low as 10 pM for 72 h, which does not elicit morphological abnormalities of embryos, markedly increased GFP expression. Furthermore, the reporter embryos responded to other AhR ligands as well. Exposure of the embryos to TCDD revealed previously reported (the cardiovascular system, liver, pancreas, kidney, swim bladder and skin) and unreported target tissues (retinal bipolar cells, otic vesicle, lateral line, cloaca and pectoral fin bud) for TCDD. Transgenic cyp1a reporter zebrafish we have developed can further understanding of ecotoxicological relevance and human health risks by TCDD. In addition, they could be used to identify agonists of AhR and antidotes to TCDD toxicity.

  9. Postural instability in Charcot-Marie-Tooth 1A disease.

    Science.gov (United States)

    Tozza, Stefano; Aceto, Maria Gabriella; Pisciotta, Chiara; Bruzzese, Dario; Iodice, Rosa; Santoro, Lucio; Manganelli, Fiore

    2016-09-01

    The aim of this study was to evaluate the influence of somatosensory impairment, distal muscle weakness and foot deformities on the balance in 21 CMT1A patients using a baropodometric platform. Stabilometric analysis by measuring sway area and velocity of a centre of pressure (CoP) both at open and closed eyes were used to assess postural imbalance. Static analysis, by measuring the load and the plantar surface of forefoot, midfoot and hindfoot was used to define the footprint shape and to assess as a whole foot deformities. Stabilometric and static results were compared with those of a control group. In CMT1A patients, stabilometric findings were correlated with static parameters, Achilles' tendon retraction, distal muscle strength and CMT examination score (CMTES). CMT1A patients compared to controls had lower plantar surface and load on midfoot, and higher load on a forefoot. CMT1A patients had a greater postural instability, since they had a higher CoP velocity, both at open and closed eyes. Moreover, the CoP velocity correlated inversely with the strength of ankle dorsi-flexion muscles and directly with CMTES as whole and with the item "motor symptoms legs". Postural imbalance was not correlated with sensory impairment and foot deformities as expressed by static analysis and Achilles' tendon retraction. In this study we demonstrated an altered balance in CMT1A patients during upright standing. The imbalance in our CMT patients seems to be related to the weakness of ankle dorsi-flexor muscles rather than sensory impairment or foot deformities. These results could be due to a mildly affected CMT1A population, evaluated in an early stage of the disease. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Homozygous EEF1A2 mutation causes dilated cardiomyopathy, failure to thrive, global developmental delay, epilepsy and early death.

    Science.gov (United States)

    Cao, Siqi; Smith, Laura L; Padilla-Lopez, Sergio R; Guida, Brandon S; Blume, Elizabeth; Shi, Jiahai; Morton, Sarah U; Brownstein, Catherine A; Beggs, Alan H; Kruer, Michael C; Agrawal, Pankaj B

    2017-09-15

    Eukaryotic elongation factor 1A (EEF1A), is encoded by two distinct isoforms, EEF1A1 and EEF1A2; whereas EEF1A1 is expressed almost ubiquitously, EEF1A2 expression is limited such that it is only detectable in skeletal muscle, heart, brain and spinal cord. Currently, the role of EEF1A2 in normal cardiac development and function is unclear. There have been several reports linking de novo dominant EEF1A2 mutations to neurological issues in humans. We report a pair of siblings carrying a homozygous missense mutation p.P333L in EEF1A2 who exhibited global developmental delay, failure to thrive, dilated cardiomyopathy and epilepsy, ultimately leading to death in early childhood. A third sibling also died of a similar presentation, but DNA was unavailable to confirm the mutation. Functional genomic analysis was performed in S. cerevisiae and zebrafish. In S. cerevisiae, there was no evidence for a dominant-negative effect. Previously identified putative de novo mutations failed to complement yeast strains lacking the EEF1A ortholog showing a major growth defect. In contrast, the introduction of the mutation seen in our family led to a milder growth defect. To evaluate its function in zebrafish, we knocked down eef1a2 expression using translation blocking and splice-site interfering morpholinos. EEF1A2-deficient zebrafish had skeletal muscle weakness, cardiac failure and small heads. Human EEF1A2 wild-type mRNA successfully rescued the morphant phenotype, but mutant RNA did not. Overall, EEF1A2 appears to be critical for normal heart function in humans, and its deficiency results in clinical abnormalities in neurologic function as well as in skeletal and cardiac muscle defects. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Serotonin-1A receptors in major depression quantified using PET: controversies, confounds, and recommendations.

    Science.gov (United States)

    Shrestha, Saurav; Hirvonen, Jussi; Hines, Christina S; Henter, Ioline D; Svenningsson, Per; Pike, Victor W; Innis, Robert B

    2012-02-15

    The serotonin-1A (5-HT(1A)) receptor is of particular interest in human positron emission tomography (PET) studies of major depressive disorder (MDD). Of the eight studies investigating this issue in the brains of patients with MDD, four reported decreased 5-HT(1A) receptor density, two reported no change, and two reported increased 5-HT(1A) receptor density. While clinical heterogeneity may have contributed to these differing results, methodological factors by themselves could also explain the discrepancies. This review highlights several of these factors, including the use of the cerebellum as a reference region and the imprecision of measuring the concentration of parent radioligand in arterial plasma, the method otherwise considered to be the 'gold standard'. Other potential confounds also exist that could restrict or unexpectedly affect the interpretation of results. For example, the radioligand may be a substrate for an efflux transporter - like P-gp - at the blood-brain barrier; furthermore, the binding of the radioligand to the receptor in various stages of cellular trafficking is unknown. Efflux transport and cellular trafficking may also be differentially expressed in patients compared to healthy subjects. We believe that, taken together, the existing disparate findings do not reliably answer the question of whether 5-HT(1A) receptors are altered in MDD or in subgroups of patients with MDD. In addition, useful meta-analysis is precluded because only one of the imaging centers acquired all the data necessary to address these methodological concerns. We recommend that in the future, individual centers acquire more thorough data capable of addressing methodological concerns, and that multiple centers collaborate to meaningfully pool their data for meta-analysis. Published by Elsevier Inc.

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

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Fei; Severson, Paul; Pacheco, Samantha; Futscher, Bernard W.; Klimecki, Walter T., E-mail: klimecki@pharmacy.arizona.edu

    2013-08-15

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

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

    International Nuclear Information System (INIS)

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

    2013-01-01

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

  14. Vanillin Suppresses Cell Motility by Inhibiting STAT3-Mediated HIF-1α mRNA Expression in Malignant Melanoma Cells.

    Science.gov (United States)

    Park, Eun-Ji; Lee, Yoon-Mi; Oh, Taek-In; Kim, Byeong Mo; Lim, Beong-Ou; Lim, Ji-Hong

    2017-03-01

    Recent studies have shown that vanillin has anti-cancer, anti-mutagenic, and anti-metastatic activity; however, the precise molecular mechanism whereby vanillin inhibits metastasis and cancer progression is not fully elucidated. In this study, we examined whether vanillin has anti-cancer and anti-metastatic activities via inhibition of hypoxia-inducible factor-1α (HIF-1α) in A2058 and A375 human malignant melanoma cells. Immunoblotting and quantitative real time (RT)-PCR analysis revealed that vanillin down-regulates HIF-1α protein accumulation and the transcripts of HIF-1α target genes related to cancer metastasis including fibronectin 1 ( FN1 ), lysyl oxidase-like 2 ( LOXL2 ), and urokinase plasminogen activator receptor ( uPAR ). It was also found that vanillin significantly suppresses HIF-1α mRNA expression and de novo HIF-1α protein synthesis. To understand the suppressive mechanism of vanillin on HIF-1α expression, chromatin immunoprecipitation was performed. Consequently, it was found that vanillin causes inhibition of promoter occupancy by signal transducer and activator of transcription 3 (STAT3), but not nuclear factor-κB (NF-κB), on HIF1A . Furthermore, an in vitro migration assay revealed that the motility of melanoma cells stimulated by hypoxia was attenuated by vanillin treatment. In conclusion, we demonstrate that vanillin might be a potential anti-metastatic agent that suppresses metastatic gene expression and migration activity under hypoxia via the STAT3-HIF-1α signaling pathway.

  15. Quercetin enhances hypoxia-mediated apoptosis via direct inhibition of AMPK activity in HCT116 colon cancer.

    Science.gov (United States)

    Kim, Hak-Su; Wannatung, Tirawat; Lee, Sooho; Yang, Woo Kyeom; Chung, Sung Hyun; Lim, Jong-Seok; Choe, Wonchae; Kang, Insug; Kim, Sung-Soo; Ha, Joohun

    2012-09-01

    Tumor hypoxia is considered the best validated target in clinical oncology because of its significant contribution to chemotherapy failure and drug resistance. As an approach to target hypoxia, we assessed the potential of quercetin, a flavonoid widely distributed in plants, as a anticancer agent under hypoxic conditions and examined its pharmacological mechanisms by primarily focusing on the role of AMP-activated protein kinase (AMPK). Quercetin significantly attenuated tumor growth in an HCT116 cancer xenograft in vivo model with a substantial reduction of AMPK activity. In a cell culture system, quercetin more dramatically induced apoptosis of HCT116 cancer cells under hypoxic conditions than normoxic conditions, and this was tightly associated with inhibition of hypoxia-induced AMPK activity. An in vitro kinase assay demonstrated that quercetin directly inhibits AMPK activity. Inhibition of AMPK by expressing a dominant-negative form resulted in an increase of apoptosis under hypoxia, and a constitutively active form of AMPK effectively blocked quercetin-induced apoptosis under hypoxia. Collectively, our data suggest that quercetin directly inhibits hypoxia-induced AMPK, which plays a protective role against hypoxia. Quercetin also reduced the activity of hypoxia-inducible factor-1 (HIF-1), a major transcription factor for adaptive cellular response to hypoxia. Moreover, quercetin sensitized HCT116 cancer cells to the anticancer drugs cisplatin and etoposide under hypoxic conditions. Our findings suggest that AMPK may serve as a novel target for overcoming tumor hypoxia-associated negative aspects.

  16. Passive smoking, Cyp1A1 gene polymorphism and dysmenorrhea

    Science.gov (United States)

    Liu, Hong; Yang, Fan; Li, Zhiping; Chen, Changzhong; Fang, Zhian; Wang, Lihua; Hu, Yonghua; Chen, Dafang

    2007-01-01

    Objective This study investigated whether the association between passive smoking exposure and dysmenorrhea is modified by two susceptibility genes, CYP1A1MspI and CYP1A1HincII. Methods This report includes 1645 (1124 no dysmenorrhea, 521 dysmenorrhea) nonsmoking and nondrinking newly wed female workers at Anqing, China between June 1997 and June 2000. Multiple logistic regression models were used to estimate the associations of passive smoking exposure and genetic susceptibility with dysmenorrhea, adjusting for perceived stress. Results When stratified by women genotype, the adjusted OR of dysmenorrhea was 1.6 (95%CI=1.3-2.1) for passive smoking group with Ile/Ile462 genotype, and 1.5 (95%CI=1.1-2.1) with C/C6235 genotype, compared to non passive smoking group, respectively. The data further showed that there was a significant combined effect between passive smoking and the CYP1A1 Msp1 C/C6235 and HincII Ile/Ile462 genotype (OR=2.6, 95%CI=1.3-5.2). Conclusion CYP1A1 MspI and HincII genotypes modified the association between passive smoking and dysmenorrhea. PMID:17566695

  17. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.

    NARCIS (Netherlands)

    Rudick, R.A.; Stuart, W.H.; Calabresi, P.A.; Confavreux, C.; Galetta, S.L.; Radue, E.W.; Lublin, F.D.; Weinstock-Guttman, B.; Wynn, D.R.; Lynn, F.; Panzara, M.A.; Sandrock, A.W.

    2006-01-01

    BACKGROUND: Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an alpha4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies.

  18. Novel pyridylmethylamines as highly selective 5-HT(1A) superagonists.

    Science.gov (United States)

    Bollinger, Stefan; Hübner, Harald; Heinemann, Frank W; Meyer, Karsten; Gmeiner, Peter

    2010-10-14

    To further improve the maximal serotonergic efficacy and better understand the configurational requirements for 5-HT(1A) binding and activation, we generated and biologically investigated structural variants of the lead structure befiradol. For a bioisosteric replacement of the 3-chloro-4-fluoro moiety, a focused library of 63 compounds by solution phase parallel synthesis was developed. Target binding of our compound collection was investigated, and their affinities for 5-HT(2), α(1), and α(2)-adrenergic as well as D(1)-D(4) dopamine receptors were compared. For particularly interesting test compounds, intrinsic activities at 5-HT(1A) were examined in vitro employing a GTPγS assay. The investigation guided us to highly selective 5HT(1A) superagonists. The benzothiophene-3-carboxamide 8bt revealed almost exclusive 5HT(1A) recognition with a K(i) value of 2.7 nM and a maximal efficacy of 124%. To get insights into the bioactive conformation of our compound collection, we synthesized conformationally constrained bicyclic scaffolds when SAR data indicated a chair-type geometry and an equatorially dispositioned aminomethyl substituent for the 4,4-disubstituted piperidine moiety.

  19. Italian results for stages 1A and 2

    International Nuclear Information System (INIS)

    Di Francesca, R.

    1990-01-01

    This report presents the results on Stages 1A and 2 CRP examples. The examples have been solved by SISCO and HARMONIE codes, which are used for mechanical equilibrium calculations of fast reactor cores at ENEA Fast Reactor Department. (author). 9 figs, 12 tabs

  20. 40 CFR 60.482-1a - Standards: General.

    Science.gov (United States)

    2010-07-01

    ... startup. (b) Compliance with §§ 60.482-1a to 60.482-10a will be determined by review of records and... in VOC service only during startup and shutdown, excluding startup and shutdown between batches of... 100...

  1. Role of pelvic lymphadenectomy in stage 1A endometrial carcinoma ...

    African Journals Online (AJOL)

    Introduction: Endometrial cancer is the commonest gynecological cancer mostly affecting women in the postmenopausal age group. There is a debate regarding the need of pelvic lymphadenectomy in managing stage 1A diagnosed preoperatively, we try to evaluate this need. Objective: To evaluate the role of pelvic ...

  2. Two new splice variants in porcine PPARGC1A

    Directory of Open Access Journals (Sweden)

    Peelman Luc J

    2008-12-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptor γ coactivator 1α (PPARGC1A is a coactivator with a vital and central role in fat and energy metabolism. It is considered to be a candidate gene for meat quality in pigs and is involved in the development of obesity and diabetes in humans. How its many functions are regulated, is however still largely unclear. Therefore a transcription profile of PPARGC1A in 32 tissues and 4 embryonic developmental stages in the pig was constructed by screening its cDNA for possible splice variants with exon-spanning primers. Findings This led to the discovery of 2 new splice variants in the pig, which were subsequently also detected in human tissues. In these variants, exon 8 was either completely or partly (the last 66 bp were conserved spliced out, potentially coding for a much shorter protein of respectively 337 and 359 amino acids (aa, of which the first 291 aa would be the same compared to the complete protein (796 aa. Conclusion Considering the functional domains of the PPARGC1A protein, it is very likely these splice variants considerably affect the function of the protein and alternative splicing could be one of the mechanisms by which the diverse functions of PPARGC1A are regulated.

  3. The Histone Demethylase Jhdm1a Regulates Hepatic Gluconeogenesis

    Science.gov (United States)

    Zou, Tie; Yao, Annie Y.; Cooper, Marcus P.; Boyartchuk, Victor; Wang, Yong-Xu

    2012-01-01

    Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36) demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPα. This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes. PMID:22719268

  4. The histone demethylase Jhdm1a regulates hepatic gluconeogenesis.

    Directory of Open Access Journals (Sweden)

    Dongning Pan

    Full Text Available Hepatic gluconeogenesis is required for maintaining blood glucose homeostasis; yet, in diabetes mellitus, this process is unrestrained and is a major contributor to fasting hyperglycemia. To date, the impacts of chromatin modifying enzymes and chromatin landscape on gluconeogenesis are poorly understood. Through catalyzing the removal of methyl groups from specific lysine residues in the histone tail, histone demethylases modulate chromatin structure and, hence, gene expression. Here we perform an RNA interference screen against the known histone demethylases and identify a histone H3 lysine 36 (H3K36 demethylase, Jhdm1a, as a key negative regulator of gluconeogenic gene expression. In vivo, silencing of Jhdm1a promotes liver glucose synthesis, while its exogenous expression reduces blood glucose level. Importantly, the regulation of gluconeogenesis by Jhdm1a requires its demethylation activity. Mechanistically, we find that Jhdm1a regulates the expression of a major gluconeogenic regulator, C/EBPα. This is achieved, at least in part, by its USF1-dependent association with the C/EBPα promoter and its subsequent demethylation of dimethylated H3K36 on the C/EBPα locus. Our work provides compelling evidence that links histone demethylation to transcriptional regulation of gluconeogenesis and has important implications for the treatment of diabetes.

  5. Complete COL1A1 allele deletions in osteogenesis imperfecta

    NARCIS (Netherlands)

    van Dijk, Fleur S.; Huizer, Margriet; Kariminejad, Ariana; Marcelis, Carlo L.; Plomp, Astrid S.; Terhal, Paulien A.; Meijers-Heijboer, Hanne; Weiss, Marjan M.; van Rijn, Rick R.; Cobben, Jan M.; Pals, Gerard

    Purpose: To identify a molecular genetic cause in patients with a clinical diagnosis of osteogenesis imperfecta (OI) type I/IV. Methods: The authors performed multiplex ligation-dependent probe amplification analysis of the COL1A1 gene in a group of 106 index patients. Results: In four families with

  6. Complete COL1A1 allele deletions in osteogenesis imperfecta

    NARCIS (Netherlands)

    van Dijk, Fleur S.; Huizer, Margriet; Kariminejad, Ariana; Marcelis, Carlo L.; Plomp, Astrid S.; Terhal, Paulien A.; Meijers-Heijboer, Hanne; Weiss, Marjan M.; van Rijn, Rick R.; Cobben, Jan M.; Pals, Gerard

    2010-01-01

    To identify a molecular genetic cause in patients with a clinical diagnosis of osteogenesis imperfecta (OI) type I/IV. The authors performed multiplex ligation-dependent probe amplification analysis of the COL1A1 gene in a group of 106 index patients. In four families with mild osteogenesis

  7. Anomalous U(1)A and electroweak symmetry breaking

    International Nuclear Information System (INIS)

    Gogoladze, I.; Tsulaya, M.

    2000-01-01

    A new mechanism for electroweak symmetry breaking in the supersymmetric Standard Model is suggested. Our suggestion is based on the presence of an anomalous U(1) A gauge symmetry, which naturally arises in the four-dimensional superstring theory, and heavily relies on the corresponding Fayet-Illiopoulos ξ-term

  8. Anomalous U(1)A and electroweak symmetry breaking

    International Nuclear Information System (INIS)

    Gogoladze, Ilia

    2000-10-01

    We suggest a mechanism for electroweak symmetry breaking in the Supersymmetric Standard Model. Our suggestion is based on the presence of an anomalous U(1) A gauge symmetry, which naturally arises in the four dimensional superstring theory, and heavily relies on the value of the corresponding Fayet-Illiopoulos ξ-term. (author)

  9. Mutations in pseudohypoparathyroidism 1a and pseudopseudohypoparathyroidism in ethnic Chinese.

    Directory of Open Access Journals (Sweden)

    Yi-Lei Wu

    Full Text Available An inactivating mutation in the GNAS gene causes either pseudohypoparathyroidism 1a (PHP1A when it is maternally inherited or pseudopseudohypoparathyroidism (PPHP when it is paternally inherited. We investigated clinical manifestations and mutations of the GNAS gene in ethnic Chinese patients with PHP1A or PPHP. Seven patients from 5 families including 4 girls and 2 boys with PHP1A and 1 girl with PPHP were studied. All PHP1A patients had mental retardation. They were treated with calcitriol and CaCO3 with regular monitoring of serum Ca levels, urinary Ca/Cr ratios, and renal sonography. Among them, 5 patients also had primary hypothyroidism suggesting TSH resistance. One female patient had a renal stone which was treated with extracorporeal shockwave lithotripsy. She had an increased urinary Ca/Cr ratio of 0.481 mg/mg when the stone was detected. We detected mutations using PCR and sequencing as well as analysed a splice acceptor site mutation using RT-PCR, sequencing, and minigene construct. We detected 5 mutations: c.85C>T (Q29*, c.103C>T (Q35*, c.840-2A>G (R280Sfs*21, c.1027_1028delGA (D343*, and c.1174G>A (E392K. Mutations c.840-2A>G and c.1027_1028delGA were novel. The c.840-2A>G mutation at the splice acceptor site of intron 10 caused retention of intron 10 in the minigene construct but skipping of exon 11 in the peripheral blood cells. The latter was the most probable mechanism which caused a frameshift, changing Arg to Ser at residue 280 and invoking a premature termination of translation at codon 300 (R280Sfs*21. Five GNAS mutations in ethnic Chinese with PHP1A and PPHP were reported. Two of them were novel. Mutation c.840-2A>G destroyed a spice acceptor site and caused exon skipping. Regular monitoring and adjustment in therapy are mandatory to achieve optimal therapeutic effects and avoid nephrolithiasis in patients with PHP1A.

  10. Skn-1a/Oct-11 and {Delta}Np63{alpha} exert antagonizing effects on human keratin expression

    Energy Technology Data Exchange (ETDEWEB)

    Lena, Anna Maria; Cipollone, Rita; Amelio, Ivano; Catani, Maria Valeria; Ramadan, Safaa [Biochemistry IDI-IRCCS Laboratory and Department of Experimental Medicine and Biochemical Sciences, University of Rome ' Tor Vergata' , 00133, Rome (Italy); Browne, Gareth [MRC Toxicology Unit, Leicester University, Leicester LE1 9HN (United Kingdom); Melino, Gerry [Biochemistry IDI-IRCCS Laboratory and Department of Experimental Medicine and Biochemical Sciences, University of Rome ' Tor Vergata' , 00133, Rome (Italy); MRC Toxicology Unit, Leicester University, Leicester LE1 9HN (United Kingdom); Candi, Eleonora, E-mail: candi@uniroma2.it [Biochemistry IDI-IRCCS Laboratory and Department of Experimental Medicine and Biochemical Sciences, University of Rome ' Tor Vergata' , 00133, Rome (Italy)

    2010-10-29

    Research highlights: {yields} Skn-1a markedly downregulates {Delta}Np63-driven K14 expression. {yields} {Delta}Np63 inhibits Skn-1a-mediated K10 expression. {yields} {Delta}Np63, mutated in SAM domain, is less effecting in K10 downregulation. {yields} Immunolocalization in human skin of the two transcription factors is partially overlapping. {yields} The antagonistic effects of Skn-1a and p63 is through competition for overlapping responsive elements or through an indirect interaction. -- Abstract: The formation of a stratified epidermis requires a carefully controlled balance between keratinocyte proliferation and differentiation. Here, we report the reciprocal effect on keratin expression of {Delta}Np63, pivotal in normal epidermal morphogenesis and maintenance, and Skn-1a/Oct-11, a POU transcription factor that triggers and regulates the differentiation of keratinocytes. The expression of Skn-1a markedly downregulated {Delta}Np63-driven K14 expression in luciferase reporter assays. The extent of downregulation was comparable to the inhibition of Skn-1a-mediated K10 expression upon expression of {Delta}Np63. {Delta}Np63, mutated in the protein-protein interaction domain (SAM domain; mutated in human ectodermal dysplasia syndrome), was significantly less effecting in downregulating K10, raising the possibility of a direct interaction among Skn-1a and {Delta}Np63. Immunolocalization in human skin biopsies revealed that the expression of the two transcription factors is partially overlapping. Co-immunoprecipitation experiments did not, however, demonstrate a direct interaction between {Delta}Np63 and Skn-1a, suggesting that the antagonistic effects of Skn-1a and p63 on keratin promoter transactivation is probably through competition for overlapping binding sites on target gene promoter or through an indirect interaction.

  11. Skn-1a/Oct-11 and ΔNp63α exert antagonizing effects on human keratin expression

    International Nuclear Information System (INIS)

    Lena, Anna Maria; Cipollone, Rita; Amelio, Ivano; Catani, Maria Valeria; Ramadan, Safaa; Browne, Gareth; Melino, Gerry; Candi, Eleonora

    2010-01-01

    Research highlights: → Skn-1a markedly downregulates ΔNp63-driven K14 expression. → ΔNp63 inhibits Skn-1a-mediated K10 expression. → ΔNp63, mutated in SAM domain, is less effecting in K10 downregulation. → Immunolocalization in human skin of the two transcription factors is partially overlapping. → The antagonistic effects of Skn-1a and p63 is through competition for overlapping responsive elements or through an indirect interaction. -- Abstract: The formation of a stratified epidermis requires a carefully controlled balance between keratinocyte proliferation and differentiation. Here, we report the reciprocal effect on keratin expression of ΔNp63, pivotal in normal epidermal morphogenesis and maintenance, and Skn-1a/Oct-11, a POU transcription factor that triggers and regulates the differentiation of keratinocytes. The expression of Skn-1a markedly downregulated ΔNp63-driven K14 expression in luciferase reporter assays. The extent of downregulation was comparable to the inhibition of Skn-1a-mediated K10 expression upon expression of ΔNp63. ΔNp63, mutated in the protein-protein interaction domain (SAM domain; mutated in human ectodermal dysplasia syndrome), was significantly less effecting in downregulating K10, raising the possibility of a direct interaction among Skn-1a and ΔNp63. Immunolocalization in human skin biopsies revealed that the expression of the two transcription factors is partially overlapping. Co-immunoprecipitation experiments did not, however, demonstrate a direct interaction between ΔNp63 and Skn-1a, suggesting that the antagonistic effects of Skn-1a and p63 on keratin promoter transactivation is probably through competition for overlapping binding sites on target gene promoter or through an indirect interaction.

  12. Gene conversion homogenizes the CMT1A paralogous repeats

    Directory of Open Access Journals (Sweden)

    Hurles Matthew E

    2001-12-01

    Full Text Available Abstract Background Non-allelic homologous recombination between paralogous repeats is increasingly being recognized as a major mechanism causing both pathogenic microdeletions and duplications, and structural polymorphism in the human genome. It has recently been shown empirically that gene conversion can homogenize such repeats, resulting in longer stretches of absolute identity that may increase the rate of non-allelic homologous recombination. Results Here, a statistical test to detect gene conversion between pairs of non-coding sequences is presented. It is shown that the 24 kb Charcot-Marie-Tooth type 1A paralogous repeats (CMT1A-REPs exhibit the imprint of gene conversion processes whilst control orthologous sequences do not. In addition, Monte Carlo simulations of the evolutionary divergence of the CMT1A-REPs, incorporating two alternative models for gene conversion, generate repeats that are statistically indistinguishable from the observed repeats. Bounds are placed on the rate of these conversion processes, with central values of 1.3 × 10-4 and 5.1 × 10-5 per generation for the alternative models. Conclusions This evidence presented here suggests that gene conversion may have played an important role in the evolution of the CMT1A-REP paralogous repeats. The rates of these processes are such that it is probable that homogenized CMT1A-REPs are polymorphic within modern populations. Gene conversion processes are similarly likely to play an important role in the evolution of other segmental duplications and may influence the rate of non-allelic homologous recombination between them.

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

    OpenAIRE

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

    2015-01-01

    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 ...

  14. The Indian origin of paternal haplogroup R1a1* substantiates the autochthonous origin of Brahmins and the caste system.

    Science.gov (United States)

    Sharma, Swarkar; Rai, Ekta; Sharma, Prithviraj; Jena, Mamata; Singh, Shweta; Darvishi, Katayoon; Bhat, Audesh K; Bhanwer, A J S; Tiwari, Pramod Kumar; Bamezai, Rameshwar N K

    2009-01-01

    Many major rival models of the origin of the Hindu caste system co-exist despite extensive studies, each with associated genetic evidences. One of the major factors that has still kept the origin of the Indian caste system obscure is the unresolved question of the origin of Y-haplogroup R1a1*, at times associated with a male-mediated major genetic influx from Central Asia or Eurasia, which has contributed to the higher castes in India. Y-haplogroup R1a1* has a widespread distribution and high frequency across Eurasia, Central Asia and the Indian subcontinent, with scanty reports of its ancestral (R*, R1* and R1a*) and derived lineages (R1a1a, R1a1b and R1a1c). To resolve these issues, we screened 621 Y-chromosomes (of Brahmins occupying the upper-most caste position and schedule castes/tribals occupying the lower-most positions) with 55 Y-chromosomal binary markers and seven Y-microsatellite markers and compiled an extensive dataset of 2809 Y-chromosomes (681 Brahmins, and 2128 tribals and schedule castes) for conclusions. A peculiar observation of the highest frequency (up to 72.22%) of Y-haplogroup R1a1* in Brahmins hinted at its presence as a founder lineage for this caste group. Further, observation of R1a1* in different tribal population groups, existence of Y-haplogroup R1a* in ancestors and extended phylogenetic analyses of the pooled dataset of 530 Indians, 224 Pakistanis and 276 Central Asians and Eurasians bearing the R1a1* haplogroup supported the autochthonous origin of R1a1 lineage in India and a tribal link to Indian Brahmins. However, it is important to discover novel Y-chromosomal binary marker(s) for a higher resolution of R1a1* and confirm the present conclusions.

  15. Two distinct promoters drive transcription of the human D1A dopamine receptor gene.

    Science.gov (United States)

    Lee, S H; Minowa, M T; Mouradian, M M

    1996-10-11

    The human D1A dopamine receptor gene has a GC-rich, TATA-less promoter located upstream of a small, noncoding exon 1, which is separated from the coding exon 2 by a 116-base pair (bp)-long intron. Serial 3'-deletions of the 5'-noncoding region of this gene, including the intron and 5'-end of exon 2, resulted in 80 and 40% decrease in transcriptional activity of the upstream promoter in two D1A-expressing neuroblastoma cell lines, SK-N-MC and NS20Y, respectively. To investigate the function of this region, the intron and 245 bp at the 5'-end of exon 2 were investigated. Transient expression analyses using various chloramphenicol acetyltransferase constructs showed that the transcriptional activity of the intron is higher than that of the upstream promoter by 12-fold in SK-N-MC cells and by 5.5-fold in NS20Y cells in an orientation-dependent manner, indicating that the D1A intron is a strong promoter. Primer extension and ribonuclease protection assays revealed that transcription driven by the intron promoter is initiated at the junction of intron and exon 2 and at a cluster of nucleotides located 50 bp downstream from this junction. The same transcription start sites are utilized by the chloramphenicol acetyltransferase constructs employed in transfections as well as by the D1A gene expressed within the human caudate. The relative abundance of D1A transcripts originating from the upstream promoter compared with those transcribed from the intron promoter is 1.5-2.9 times in SK-N-MC cells and 2 times in the human caudate. Transcript stability studies in SK-N-MC cells revealed that longer D1A mRNA molecules containing exon 1 are degraded 1.8 times faster than shorter transcripts lacking exon 1. Although gel mobility shift assay could not detect DNA-protein interaction at the D1A intron, competitive co-transfection using the intron as competitor confirmed the presence of trans-acting factors at the intron. These data taken together indicate that the human D1A gene has

  16. Intima-media thickness and endothelial dysfunction in GCK and HNF1A-MODY patients.

    Science.gov (United States)

    Szopa, Magdalena; Osmenda, Grzegorz; Wilk, Grzegorz; Matejko, Bartłomiej; Skupien, Jan; Zapala, Barbara; Młynarski, Wojciech; Guzik, Tomasz; Malecki, Maciej T

    2015-03-01

    Mutations in the glucokinase (GCK) gene, along with hepatocyte nuclear factor 1A (HNF1A) gene mutations, are the most frequent cause of maturity-onset diabetes of the young (MODY). GCK-MODY patients are typically characterized by a moderate fasting hyperglycemia; however, little is known about atherosclerosis and intermediate-related phenotypes in these subjects. To examine carotid artery intima-media thickness (IMT) and endothelial function assessed by brachial artery flow-mediated dilatation (FMD) in GCK gene mutations carriers and HNF1A-MODY. A total of 64 subjects with GCK gene mutations, and 52 HNF1A gene mutation carriers as well as 53 nondiabetic controls were examined. IMT and FMD were assessed by ultrasonography. Appropriate statistical tests were performed to assess differences between the groups, and multivariate linear regression was done for the association with IMT and FMD. The clinical characteristics of all groups were similar with the mean age at examination of 35.1, 41.1, and 39.5 years for GCK, HNF1A and the control group respectively. The highest mean IMT value was in the HNF1A-MODY group: 7.0±1.4 mm, whereas it reached 6.3±1.4 mm in GCK mutation carriers and 6.3±1.3 mm in controls (P=0.008). After adjustment for possible clinical and biochemical cofounders, IMT remained higher in HNF1A-MODY patients as compared with GCK-MODY patients (P=0.02) and controls (P=0.0003). FMD was significantly lower in HNF1A (9.9±4.6%) and GCK-MODY (11.1±4.6%) patients in comparison with controls (13.9±4.7%; P=0.0001). After adjustment, FMD remained lower in HNF1A-MODY (P=0.0005) and GCK-MODY patients (P=0.01) as compared with controls. Both examined MODY groups demonstrated evidence of endothelial dysfunction. In addition, HNF1-MODY patients seem to be more prone to an early atherosclerotic phenotype. © 2015 European Society of Endocrinology.

  17. Aminoacyl-tRNA-charged eukaryotic elongation factor 1A is a bona fide substrate for Legionelle pneumophila effector glucosyltransferases

    DEFF Research Database (Denmark)

    Tzivelekidis, Tina; Jank, Thomas; Pohl, Corinna

    2011-01-01

    Legionella pneumophila, which is the causative organism of Legionnaires disease, translocates numerous effector proteins into the host cell cytosol by a type IV secretion system during infection. Among the most potent effector proteins of Legionella are glucosyltransferases (Lgt’s), which...

  18. Overexpression of CaTLP1, a putative transcription factor in chickpea (Cicer arietinum L.), promotes stress tolerance.

    Science.gov (United States)

    Wardhan, Vijay; Jahan, Kishwer; Gupta, Sonika; Chennareddy, Srinivasarao; Datta, Asis; Chakraborty, Subhra; Chakraborty, Niranjan

    2012-07-01

    Dehydration is the most crucial environmental constraint on plant growth and development, and agricultural productivity. To understand the underlying mechanism of stress tolerance, and to identify proteins for improving such important trait, we screened the dehydration-responsive proteome of chickpea and identified a tubby-like protein, referred to as CaTLP1. The CaTLP1 was found to predominantly bind to double-stranded DNA but incapable of transcriptional activation. We investigated the gene structure and organization and demonstrated, for the first time, that CaTLP1 may be involved in osmotic stress response in plants. The transcripts are strongly expressed in vegetative tissues but weakly in reproductive tissues. CaTLP1 is upregulated by dehydration and high salinity, and by treatment with abscisic acid (ABA), suggesting that its stress-responsive function might be associated with ABA-dependent network. Overexpression of CaTLP1 in transgenic tobacco plants conferred dehydration, salinity and oxidative stress tolerance along with improved shoot and root architecture. Molecular genetic analysis showed differential expression of CaTLP1 under normal and stress condition, and its preferential expression in the nucleus might be associated with enhanced stress tolerance. Our work suggests important roles of CaTLP1 in stress response as well as in the regulation of plant development.

  19. Myb-binding protein 1a (Mybbp1a) regulates levels and processing of pre-ribosomal RNA.

    Science.gov (United States)

    Hochstatter, Julia; Hölzel, Michael; Rohrmoser, Michaela; Schermelleh, Lothar; Leonhardt, Heinrich; Keough, Rebecca; Gonda, Thomas J; Imhof, Axel; Eick, Dirk; Längst, Gernot; Németh, Attila

    2012-07-13

    Ribosomal RNA gene transcription, co-transcriptional processing, and ribosome biogenesis are highly coordinated processes that are tightly regulated during cell growth. In this study we discovered that Mybbp1a is associated with both the RNA polymerase I complex and the ribosome biogenesis machinery. Using a reporter assay that uncouples transcription and RNA processing, we show that Mybbp1a represses rRNA gene transcription. In addition, overexpression of the protein reduces RNA polymerase I loading on endogenous rRNA genes as revealed by chromatin immunoprecipitation experiments. Accordingly, depletion of Mybbp1a results in an accumulation of the rRNA precursor in vivo but surprisingly also causes growth arrest of the cells. This effect can be explained by the observation that the modulation of Mybbp1a protein levels results in defects in pre-rRNA processing within the cell. Therefore, the protein may play a dual role in the rRNA metabolism, potentially linking and coordinating ribosomal DNA transcription and pre-rRNA processing to allow for the efficient synthesis of ribosomes.

  20. Evidence for the effect of serotonin receptor 1A gene (HTR1A) polymorphism on tractability in Thoroughbred horses.

    Science.gov (United States)

    Hori, Y; Tozaki, T; Nambo, Y; Sato, F; Ishimaru, M; Inoue-Murayama, M; Fujita, K

    2016-02-01

    Tractability, or how easily animals can be trained and controlled, is an important behavioural trait for the management and training of domestic animals, but its genetic basis remains unclear. Polymorphisms in the serotonin receptor 1A gene (HTR1A) have been associated with individual variability in anxiety-related traits in several species. In this study, we examined the association between HTR1A polymorphisms and tractability in Thoroughbred horses. We assessed the tractability of 167 one-year-old horses reared at a training centre for racehorses using a questionnaire consisting of 17 items. A principal components analysis of answers contracted the data to five principal component (PC) scores. We genotyped two non-synonymous single nucleotide polymorphisms (SNPs) in the horse HTR1A coding region. We found that one of the two SNPs, c.709G>A, which causes an amino acid change at the intracellular region of the receptor, was significantly associated with scores of four of five PCs in fillies (all Ps Horses carrying an A allele at c.709G>A showed lower tractability. This result provides the first evidence that a polymorphism in a serotonin-related gene may affect tractability in horses with the effect partially different depending on sex. © 2015 Stichting International Foundation for Animal Genetics.

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

    International Nuclear Information System (INIS)

    Androutsopoulos, Vasilis P; Tsatsakis, Aristidis M; Spandidos, Demetrios A

    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

  2. Wound healing genes and susceptibility to cutaneous leishmaniasis in Brazil: Role of COL1A1

    Science.gov (United States)

    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

  3. Corrective effects of hepatotoxicity by hepatic Dyrk1a gene delivery in mice with intermediate hyperhomocysteinemia

    Directory of Open Access Journals (Sweden)

    Alizée Latour

    2015-03-01

    Full Text Available Hyperhomocysteinemia results from hepatic metabolism dysfunction and is characterized by a high plasma homocysteine level, which is also an independent risk factor for cardiovascular disease. Elevated levels of homocysteine in plasma lead to hepatic lesions and abnormal lipid metabolism. Therefore, lowering homocysteine levels might offer therapeutic benefits. Recently, we were able to lower plasma homocysteine levels in mice with moderate hyperhomocysteinemia using an adenoviral construct designed to restrict the expression of DYRK1A, a serine/threonine kinase involved in methionine metabolism (and therefore homocysteine production, to hepatocytes. Here, we aimed to extend our previous findings by analyzing the effect of hepatocyte-specific Dyrk1a gene transfer on intermediate hyperhomocysteinemia and its associated hepatic toxicity and liver dysfunction. Commensurate with decreased plasma homocysteine and alanine aminotransferase levels, targeted hepatic expression of DYRK1A in mice with intermediate hyperhomocysteinemia resulted in elevated plasma paraoxonase-1 and lecithin:cholesterol acyltransferase activities and apolipoprotein A–I levels. It also rescued hepatic apolipoprotein E, J, and D levels. Further, Akt/GSK3/cyclin D1 signaling pathways in the liver of treated mice were altered, which may help prevent homocysteine-induced cell cycle dysfunction. DYRK1A gene therapy could be useful in the treatment of hyperhomocysteinemia in populations, such as end-stage renal disease patients, who are unresponsive to B-complex vitamin therapy.

  4. ALDH1A3 mutations cause recessive anophthalmia and microphthalmia.

    Science.gov (United States)

    Fares-Taie, Lucas; Gerber, Sylvie; Chassaing, Nicolas; Clayton-Smith, Jill; Hanein, Sylvain; Silva, Eduardo; Serey, Margaux; Serre, Valérie; Gérard, Xavier; Baumann, Clarisse; Plessis, Ghislaine; Demeer, Bénédicte; Brétillon, Lionel; Bole, Christine; Nitschke, Patrick; Munnich, Arnold; Lyonnet, Stanislas; Calvas, Patrick; Kaplan, Josseline; Ragge, Nicola; Rozet, Jean-Michel

    2013-02-07

    Anophthalmia and microphthalmia (A/M) are early-eye-development anomalies resulting in absent or small ocular globes, respectively. A/M anomalies occur in syndromic or nonsyndromic forms. They are genetically heterogeneous, some mutations in some genes being responsible for both anophthalmia and microphthalmia. Using a combination of homozygosity mapping, exome sequencing, and Sanger sequencing, we identified homozygosity for one splice-site and two missense mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in three consanguineous families segregating A/M with occasional orbital cystic, neurological, and cardiac anomalies. ALDH1A3 is a key enzyme in the formation of a retinoic acid gradient along the dorso-ventral axis during early eye development. Transitory expression of mutant ALDH1A3 open reading frames showed that both missense mutations reduce the accumulation of the enzyme, potentially leading to altered retinoic acid synthesis. Although the role of retinoic acid signaling in eye development is well established, our findings provide genetic evidence of a direct link between retinoic-acid-synthesis dysfunction and early-eye-development anomalies in humans. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  5. AVPR1A variant associated with preschoolers' lower altruistic behavior.

    Directory of Open Access Journals (Sweden)

    Reut Avinun

    Full Text Available The genetic origins of altruism, defined here as a costly act aimed to benefit non-kin individuals, have not been examined in young children. However, previous findings concerning adults pointed at the arginine vasopressin receptor 1A (AVPR1A gene as a possible candidate. AVPR1A has been associated with a range of behaviors including aggressive, affiliative and altruistic phenotypes, and recently a specific allele (327 bp of one of its promoter region polymorphisms (RS3 has been singled out in particular. We modeled altruistic behavior in preschoolers using a laboratory-based economic paradigm, a modified dictator game (DG, and tested for association between DG allocations and the RS3 "target allele." Using both population and family-based analyses we show a significant link between lower allocations and the RS3 "target allele," associating it, for the first time, with a lower proclivity toward altruistic behavior in children. This finding helps further the understanding of the intricate mechanisms underlying early altruistic behavior.

  6. Electroweak form factors

    International Nuclear Information System (INIS)

    Singh, S.K.

    2002-01-01

    The present status of electroweak nucleon form factors and the N - Δ transition form factors is reviewed. Particularly the determination of dipole mass M A in the axial vector form factor is discussed

  7. Risk Factors for Scleroderma

    Science.gov (United States)

    ... You are here: Home For Patients Risk Factors Risk Factors for Scleroderma The cause of scleroderma is ... what biological factors contribute to scleroderma pathogenesis. Genetic Risk Scleroderma does not tend to run in families ...

  8. Risk Factors and Prevention

    Science.gov (United States)

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

  9. Molecular detection of interleukin-1A +4845 G→T gene in aggresive periodontitis patients

    Directory of Open Access Journals (Sweden)

    Chiquita Prahasanti

    2012-12-01

    Full Text Available Background: Abundant researches had been conducted based on the clinical and histopathological pathogenesis of aggresive periodontitis. Nevertheless, there were still few researches which based on molecular biology, and especially related to gene polymorphism. This study was done based on IL-1A +4845G→T gene polymorphism in aggressive periodontitis patients. Purpose: The purpose of this tudy was to characterized the generic variation of IL-1A +4845G→T as a risk factor aggressive periodontitis and chronic periodontitis. Methods: DNA from patients with aggressive periodontitis and chronic periodontitis was taken determination of IL-1A +4845 G→T polimorphism was conducted with PCR-RFLP technique. Results: Homozygous allele TT polymorphism was not found in all samples, only allele GG (wild type and allele GT (heterozygous mutant were not affect aggressive periodontitis and chronic periodontitis. Conclusion: The study showed there was no significant association between IL-1A +4845G→T gene polymorphism and aggressive periodontitis and chronic periodontitis. Latar belakang: Penelitian tentang patogenesa periodontitis agresif berdasar klinis dan histopatologi telah banyak dilakukan, akan tetapi penelitian berdasar biologimolekuler terutama polimorfisme gen masih sangat jarang dilakukan. Penelitian ini dilakukan berdasarkan pada polimorfisme gen IL-1A +4845G→T pada penderita periodontitis agresif. Tujuan: Tujuan dari penelitian ini adalah untuk mengetahui variasi genetik dari IL-1A +4845G→T yang merupakan faktor risiko periodontitis agresif dan periodontitis kronis. Metode: DNA dari penderita periodontitis agresif dan periodontitis kronis diisolasi, selanjutnya dilakukan determinasi dari polimorfisme gen IL-1A +4845G→T dengan menggunakan teknik PCR-RFLP. Hasil: Pada seluruh sampel penelitian ini tidak dijumpai polimorfisme allel TT (homosigot mutan, yang didapat adalah jenis allel GG (wild type dan allel GT (heterosigot mutan yang tidak

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

    International Nuclear Information System (INIS)

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

    2015-01-01

    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. - Highlights: • Breast-feeding can be a factor for the development of neonatal hyperbilirubinemia. • UDP-glucuronosyltransferase (UGT) 1A1 is the sole bilirubin-metabolizing enzyme. • Extrahepatic UGT1A1 plays an important role in bilirubin metabolism. • We discuss the potential mechanism of breast milk-induced neonatal jaundice.

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

    Energy Technology Data Exchange (ETDEWEB)

    Fujiwara, Ryoichi, E-mail: fujiwarar@pharm.kitasato-u.ac.jp [Department of Pharmaceutics, School of Pharmacy, Kitasato University, Tokyo (Japan); Maruo, Yoshihiro [Department of Pediatrics, Shiga University of Medical Science, Shiga (Japan); Chen, Shujuan [Department of Pharmacology, Laboratory of Environmental Toxicology, University of California at San Diego, La Jolla, CA 92093 (United States); Tukey, Robert H., E-mail: rtukey@ucsd.edu [Department of Pharmacology, Laboratory of Environmental Toxicology, University of California at San Diego, La Jolla, CA 92093 (United States); Department of Chemistry & Biochemistry, Laboratory of Environmental Toxicology, University of California at San Diego, La Jolla, CA 92093 (United States)

    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. - Highlights: • Breast-feeding can be a factor for the development of neonatal hyperbilirubinemia. • UDP-glucuronosyltransferase (UGT) 1A1 is the sole bilirubin-metabolizing enzyme. • Extrahepatic UGT1A1 plays an important role in bilirubin metabolism. • We discuss the potential mechanism of breast milk-induced neonatal jaundice.

  12. Factors and factorizations of graphs proof techniques in factor theory

    CERN Document Server

    Akiyama, Jin

    2011-01-01

    This book chronicles the development of graph factors and factorizations. It pursues a comprehensive approach, addressing most of the important results from hundreds of findings over the last century. One of the main themes is the observation that many theorems can be proved using only a few standard proof techniques. This stands in marked contrast to the seemingly countless, complex proof techniques offered by the extant body of papers and books. In addition to covering the history and development of this area, the book offers conjectures and discusses open problems. It also includes numerous explanatory figures that enable readers to progressively and intuitively understand the most important notions and proofs in the area of factors and factorization.

  13. Development of a human vasopressin V-1a-receptor antagonist from an evolutionary-related insect neuropeptide

    Czech Academy of Sciences Publication Activity Database

    Di Giglio, M. G.; Muttenthaler, M.; Harpsoe, K.; Liutkeviciute, Z.; Keov, P.; Eder, T.; Rattei, T.; Arrowsmith, S.; Wray, S.; Marek, Aleš; Elbert, Tomáš; Alewood, P. F.; Gloriam, D. E.; Gruber, C. W.

    2017-01-01

    Roč. 7, Feb 1 (2017), č. článku 41002. ISSN 2045-2322 Institutional support: RVO:61388963 Keywords : neuropeptide * inotocin * V1aR-antagonist Subject RIV: CE - Biochemistry OBOR OECD: Biochemistry and molecular biology Impact factor: 4.259, year: 2016 https://www.nature.com/articles/srep41002

  14. Musical Aptitude Is Associated with AVPR1A-Haplotypes

    Science.gov (United States)

    Ukkola, Liisa T.; Onkamo, Päivi; Raijas, Pirre; Karma, Kai; Järvelä, Irma

    2009-01-01

    Artistic creativity forms the basis of music culture and music industry. Composing, improvising and arranging music are complex creative functions of the human brain, which biological value remains unknown. We hypothesized that practicing music is social communication that needs musical aptitude and even creativity in music. In order to understand the neurobiological basis of music in human evolution and communication we analyzed polymorphisms of the arginine vasopressin receptor 1A (AVPR1A), serotonin transporter (SLC6A4), catecol-O-methyltranferase (COMT), dopamin receptor D2 (DRD2) and tyrosine hydroxylase 1 (TPH1), genes associated with social bonding and cognitive functions in 19 Finnish families (n = 343 members) with professional musicians and/or active amateurs. All family members were tested for musical aptitude using the auditory structuring ability test (Karma Music test; KMT) and Carl Seashores tests for pitch (SP) and for time (ST). Data on creativity in music (composing, improvising and/or arranging music) was surveyed using a web-based questionnaire. Here we show for the first time that creative functions in music have a strong genetic component (h2 = .84; composing h2 = .40; arranging h2 = .46; improvising h2 = .62) in Finnish multigenerational families. We also show that high music test scores are significantly associated with creative functions in music (pmusic test scores (COMB) (p = 0.0056; corrected p = 0.0006). AVPR1A haplotype AVR+RS1 further suggested a positive association with ST (p = 0.0038; corrected p = 0.00184) and COMB (p = 0.0083; corrected p = 0.0040) using haplotype-based association test HBAT. The results suggest that the neurobiology of music perception and production is likely to be related to the pathways affecting intrinsic attachment behavior. PMID:19461995

  15. Musical aptitude is associated with AVPR1A-haplotypes.

    Science.gov (United States)

    Ukkola, Liisa T; Onkamo, Päivi; Raijas, Pirre; Karma, Kai; Järvelä, Irma

    2009-05-20

    Artistic creativity forms the basis of music culture and music industry. Composing, improvising and arranging music are complex creative functions of the human brain, which biological value remains unknown. We hypothesized that practicing music is social communication that needs musical aptitude and even creativity in music. In order to understand the neurobiological basis of music in human evolution and communication we analyzed polymorphisms of the arginine vasopressin receptor 1A (AVPR1A), serotonin transporter (SLC6A4), catecol-O-methyltranferase (COMT), dopamin receptor D2 (DRD2) and tyrosine hydroxylase 1 (TPH1), genes associated with social bonding and cognitive functions in 19 Finnish families (n = 343 members) with professional musicians and/or active amateurs. All family members were tested for musical aptitude using the auditory structuring ability test (Karma Music test; KMT) and Carl Seashores tests for pitch (SP) and for time (ST). Data on creativity in music (composing, improvising and/or arranging music) was surveyed using a web-based questionnaire. Here we show for the first time that creative functions in music have a strong genetic component (h(2) = .84; composing h(2) = .40; arranging h(2) = .46; improvising h(2) = .62) in Finnish multigenerational families. We also show that high music test scores are significantly associated with creative functions in music (pmusic test scores (COMB) (p = 0.0056; corrected p = 0.0006). AVPR1A haplotype AVR+RS1 further suggested a positive association with ST (p = 0.0038; corrected p = 0.00184) and COMB (p = 0.0083; corrected p = 0.0040) using haplotype-based association test HBAT. The results suggest that the neurobiology of music perception and production is likely to be related to the pathways affecting intrinsic attachment behavior.

  16. CYP1A1 Genetic Polymorphisms in Ecuador, South America

    Directory of Open Access Journals (Sweden)

    César Paz-y-Miño

    2005-01-01

    Full Text Available A total of 108 individuals from the Ecuadorian population from rural and urban places were analyzed for two CYP1A1 gene polymorphisms. The frequency of the val allele at codon 462 was 0.50, while the frequency of the Msp I restriction site, m2 allele at the T6235C position was 0.70. These polymorphisms in Ecuador have higher frequencies if we compare with others around the world, with the exception of some South American population in Brazil and Chile.

  17. Musical aptitude is associated with AVPR1A-haplotypes.

    Directory of Open Access Journals (Sweden)

    Liisa T Ukkola

    Full Text Available Artistic creativity forms the basis of music culture and music industry. Composing, improvising and arranging music are complex creative functions of the human brain, which biological value remains unknown. We hypothesized that practicing music is social communication that needs musical aptitude and even creativity in music. In order to understand the neurobiological basis of music in human evolution and communication we analyzed polymorphisms of the arginine vasopressin receptor 1A (AVPR1A, serotonin transporter (SLC6A4, catecol-O-methyltranferase (COMT, dopamin receptor D2 (DRD2 and tyrosine hydroxylase 1 (TPH1, genes associated with social bonding and cognitive functions in 19 Finnish families (n = 343 members with professional musicians and/or active amateurs. All family members were tested for musical aptitude using the auditory structuring ability test (Karma Music test; KMT and Carl Seashores tests for pitch (SP and for time (ST. Data on creativity in music (composing, improvising and/or arranging music was surveyed using a web-based questionnaire. Here we show for the first time that creative functions in music have a strong genetic component (h(2 = .84; composing h(2 = .40; arranging h(2 = .46; improvising h(2 = .62 in Finnish multigenerational families. We also show that high music test scores are significantly associated with creative functions in music (p<.0001. We discovered an overall haplotype association with AVPR1A gene (markers RS1 and RS3 and KMT (p = 0.0008; corrected p = 0.00002, SP (p = 0.0261; corrected p = 0.0072 and combined music test scores (COMB (p = 0.0056; corrected p = 0.0006. AVPR1A haplotype AVR+RS1 further suggested a positive association with ST (p = 0.0038; corrected p = 0.00184 and COMB (p = 0.0083; corrected p = 0.0040 using haplotype-based association test HBAT. The results suggest that the neurobiology of music perception and production is likely to be related to the pathways affecting intrinsic attachment

  18. LR1: a candidate RNA virus of Leishmania.

    OpenAIRE

    Tarr, P I; Aline, R F; Smiley, B L; Scholler, J; Keithly, J; Stuart, K

    1988-01-01

    Although viruses are important biological agents and useful molecular tools, little is known about the viruses of parasites. We report here the discovery of a candidate for an RNA virus in a kinetoplastid parasite. This potential virus, which we term LR1, is present in the promastigote form of the human pathogen Leishmania braziliensis guyanensis CUMC1-1A but not in 11 other stocks of Leishmania that were examined nor in Trypanosoma brucei. The candidate viral RNA has a size of approximately ...

  19. The epigenetic regulation of HIF-1α by SIRT1 in MPP{sup +} treated SH-SY5Y cells

    Energy Technology Data Exchange (ETDEWEB)

    Dong, Su-Yan; Guo, Yan-Jie; Feng, Ya; Cui, Xin-Xin [Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080 (China); Kuo, Sheng-Han [Department of Neurology, College of Physicians and Surgeons, Columbia University, New York (United States); Liu, Te, E-mail: liute1979@126.com [Shanghai Geriatric Institute of Chinese Medicine, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200031 (China); Wu, Yun-Cheng, E-mail: yunchw@medmail.com.cn [Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080 (China)

    2016-02-05

    Both silent information regulator 1 (SIRT1) and hypoxia inducible factor 1 (HIF-1) have been found to play important roles in the pathophysiology of Parkinson's disease (PD). However, their mechanisms and their relationship still require further study. In the present study, we focused on the change and relationship of SIRT1 and HIF-1α in PD. PD cell models were established by using methyl-4-phenylpyridinium (MPP{sup +}), which induced inhibition of cell proliferation, cell cycle arrest and apoptosis. We found that the expression of HIF-1α and its target genes VEGFA and LDHA increased and that SIRT1 expression was inhibited in MPP{sup +} treated cells. With further analysis, we found that the acetylation of H3K14 combined with the HIF-1α promoter was dramatically increased in cells treated with MPP{sup +}, which resulted in the transcriptional activation of HIF-1α. Moreover, the acetylation of H3K14 and the expression of HIF-1α increased when SIRT1 was knocked down, suggesting that SIRT1 was involved in the epigenetic regulation of HIF-1α. At last, phenformin, another mitochondrial complex1 inhibitor, was used to testify that the increased HIF-1a was not due to off target effects of MPP{sup +}. Therefore, our results support a link between PD and SIRT1/HIF-1α signaling, which may serve as a clue for understanding PD.

  20. Edaravone Improves Septic Cardiac Function by Inducing an HIF-1α/HO-1 Pathway

    Directory of Open Access Journals (Sweden)

    Chao He

    2018-01-01

    Full Text Available Septic myocardial dysfunction remains prevalent and raises mortality rate in patients with sepsis. During sepsis, tissues undergo tremendous oxidative stress which contributes critically to organ dysfunction. Edaravone, a potent radical scavenger, has been proved beneficial in ischemic injuries involving hypoxia-inducible factor- (HIF- 1, a key regulator of a prominent antioxidative protein heme oxygenase- (HO- 1. However, its effect in septic myocardial dysfunction remains unclarified. We hypothesized that edaravone may prevent septic myocardial dysfunction by inducing the HIF-1/HO-1 pathway. Rats were subjected to cecal ligation and puncture (CLP with or without edaravone infusion at three doses (50, 100, or 200 mg/kg, resp. before CLP and intraperitoneal injection of the HIF-1α antagonist, ME (15 mg/kg, after CLP. After CLP, rats had cardiac dysfunction, which was associated with deformed myocardium, augmented lipid peroxidation, and increased myocardial apoptosis and inflammation, along with decreased activities of catalase, HIF-1α, and HO-1 in the myocardium. Edaravone pretreatment dose-dependently reversed the changes, of which high dose most effectively improved cardiac function and survival rate of septic rats. However, inhibition of HIF-1α by ME demolished the beneficial effects of edaravone at high dose, reducing the survival rate of the septic rats without treatments. Taken together, edaravone, by inducing the HIF-1α/HO-1 pathway, suppressed oxidative stress and protected the heart against septic myocardial injury and dysfunction.

  1. HIF- and Non-HIF-Regulated Hypoxic Responses Require the Estrogen-Related Receptor in Drosophila melanogaster

    Science.gov (United States)

    Li, Yan; Padmanabha, Divya; Gentile, Luciana B.; Dumur, Catherine I.; Beckstead, Robert B.; Baker, Keith D.

    2013-01-01

    Low-oxygen tolerance is supported by an adaptive response that includes a coordinate shift in metabolism and the activation of a transcriptional program that is driven by the hypoxia-inducible factor (HIF) pathway. The precise contribution of HIF-1a in the adaptive response, however, has not been determined. Here, we investigate how HIF influences hypoxic adaptation throughout Drosophila melanogaster development. We find that hypoxic-induced transcriptional changes are comprised of HIF-dependent and HIF-independent pathways that are distinct and separable. We show that normoxic set-points of carbohydrate metabolites are significantly altered in sima mutants and that these animals are unable to mobilize glycogen in hypoxia. Furthermore, we find that the estrogen-related receptor (dERR), which is a global regulator of aerobic glycolysis in larvae, is required for a competent hypoxic response. dERR binds to dHIFa and participates in the HIF-dependent transcriptional program in hypoxia. In addition, dERR acts in the absence of dHIFa in hypoxia and a significant portion of HIF-independent transcriptional responses can be attributed to dERR actions, including upregulation of glycolytic transcripts. These results indicate that competent hypoxic responses arise from complex interactions between HIF-dependent and -independent mechanisms, and that dERR plays a central role in both of these programs. PMID:23382692

  2. A Distinct Inhibitory Function for miR-18a in Th17 Cell Differentiation.

    Science.gov (United States)

    Montoya, Misty M; Maul, Julia; Singh, Priti B; Pua, Heather H; Dahlström, Frank; Wu, Nanyan; Huang, Xiaozhu; Ansel, K Mark; Baumjohann, Dirk

    2017-07-15

    Th17 cell responses orchestrate immunity against extracellular pathogens but also underlie autoimmune disease pathogenesis. In this study, we uncovered a distinct and critical role for miR-18a in limiting Th17 cell differentiation. miR-18a was the most dynamically upregulated microRNA of the miR-17-92 cluster in activated T cells. miR-18a deficiency enhanced CCR6 + RAR-related orphan receptor (ROR)γt + Th17 cell differentiation in vitro and increased the number of tissue Th17 cells expressing CCR6, RORγt, and IL-17A in airway inflammation models in vivo. Sequence-specific miR-18 inhibitors increased CCR6 and RORγt expression in mouse and human CD4 + T cells, revealing functional conservation. miR-18a directly targeted Smad4 , Hif1a , and Rora , all key transcription factors in the Th17 cell gene-expression program. These findings indicate that activating signals influence the outcome of Th cell differentiation via differential regulation of mature microRNAs within a common cluster. Copyright © 2017 by The American Association of Immunologists, Inc.

  3. PRMT5 regulates IRES-dependent translation via methylation of hnRNP A1

    Science.gov (United States)

    Gao, Guozhen; Dhar, Surbhi

    2017-01-01

    Abstract The type II arginine methyltransferase PRMT5 is responsible for the symmetric dimethylation of histone to generate the H3R8me2s and H4R3me2s marks, which correlate with the repression of transcription. However, the protein level of a number of genes (MEP50, CCND1, MYC, HIF1a, MTIF and CDKN1B) are reported to be downregulated by the loss of PRMT5, while their mRNA levels remain unchanged, which is counterintuitive for PRMT5's proposed role as a transcription repressor. We noticed that the majority of the genes regulated by PRMT5, at the posttranscriptional level, express mRNA containing an internal ribosome entry site (IRES). Using an IRES-dependent reporter system, we established that PRMT5 facilitates the translation of a subset of IRES-containing genes. The heterogeneous nuclear ribonucleoprotein, hnRNP A1, is an IRES transacting factor (ITAF) that regulates the IRES-dependent translation of Cyclin D1 and c-Myc. We showed that hnRNP A1 is methylated by PRMT5 on two residues, R218 and R225, and that this methylation facilitates the interaction of hnRNP A1 with IRES RNA to promote IRES-dependent translation. This study defines a new role for PRMT5 regulation of cellular protein levels, which goes beyond the known functions of PRMT5 as a transcription and splicing regulator. PMID:28115626

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Ghrelin receptor (GHS-R1A) agonists show potential as interventive agents during aging.

    Science.gov (United States)

    Smith, Roy G; Sun, Yuxiang; Jiang, Hong; Albarran-Zeckler, Rosie; Timchenko, Nikolai

    2007-11-01

    Administration of an orally active agonist (MK-0677) of the growth hormone secretagogue receptor (GHS-R1a) to elderly subjects restored the amplitude of endogenous episodic growth hormone (GH) release to that of young adults. Functional benefits include increased lean mass and bone density and modest improvements in strength. In old mice, a similar agonist partially restored function to the thymus and reduced tumor cell growth and metastasis. Treatment of old mice with the endogenous GHS-R1a agonist ghrelin restored a young liver phenotype. The mechanism involves inhibition of cyclin D3:cdk4/cdk6 activity and increased protein phosphatase-2A (PP2A) activity in liver nuclei, which stabilizes the dephosphorylated form of the transcription factor C/EBPalpha preventing the age-dependent formation of the C/EBPalpha-Rb-E2F4-Brm nuclear complex. By inhibiting formation of this complex, repression of E2F target genes is de-repressed and C/EBPalpha regulated expression of Pepck, a regulator of gluconeogenesis, is normalized, thereby restoring a young liver phenotype. In the brain, aging is associated with decline in dopamine function. We investigated the potential neuromodulatory role of GHS-R1a on dopamine action. Neurons were identified in the hippocampus, cortex, substantia nigra, and ventral tegmental areas that coexpressed GHS-R1a and dopamine receptor subtype-1 (D1R). Cell culture studies showed that, in the presence of ghrelin and dopamine, GHS-R and D1R form heterodimers, which modified G-protein signal transduction resulting in amplification of dopamine signaling. We speculate that aging is associated with deficient endogenous ghrelin signaling that can be rescued by intervention with GHS-R1a agonists to improve quality of life and maintain independence.

  6. eEF1A Mediates the Nuclear Export of SNAG-Containing Proteins via the Exportin5-Aminoacyl-tRNA Complex

    Directory of Open Access Journals (Sweden)

    José Manuel Mingot

    2013-11-01

    Full Text Available Exportin5 mediates the nuclear export of double-stranded RNAs, including pre-microRNAs, adenoviral RNAs, and tRNAs. When tRNAs are aminoacylated, the Exportin5-aminoacyl (aa-tRNA complex recruits and coexports the translation elongation factor eEF1A. Here, we show that eEF1A binds to Snail transcription factors when bound to their main target, the E-cadherin promoter, facilitating their export to the cytoplasm in association with the aa-tRNA-Exportin5 complex. Snail binds to eEF1A through the SNAG domain, a protein nuclear export signal present in several transcription factor families, and this binding is regulated by phosphorylation. Thus, we describe a nuclear role for eEF1A and provide a mechanism for protein nuclear export that attenuates the activity of SNAG-containing transcription factors.

  7. Effect of acid-sensing ion channel 1a on the process of liver fibrosis under hyperglycemia

    International Nuclear Information System (INIS)

    Wang, Huan; Wang, Ying-hong; Yang, Feng; Li, Xiao-feng; Tian, Yuan-yao; Ni, Ming-ming; Zuo, Long-quan; Meng, Xiao-Ming; Huang, Yan

    2015-01-01

    Metabolic syndrome characterized by hyperglycemia contributes to nonalcoholic steatohepatitis-associated liver fibrosis. This study was to investigate the effects of Acid-sensing ion Channel 1a (ASIC1a) on the process of liver fibrosis under hyperglycemia. Results showed that high glucose significantly worsen the pathology of liver fibrosis in vivo. In vitro, high glucose stimulated proliferation, activation and extracellular matrix (ECM) production in HSCs, and enhanced the effect of PDGF-BB on the activation and proliferation of HSCs. These effects could be attenuated by ASIC1a specific inhibitor Psalmotoxin-1(PcTx1) or specific ShRNA for ASIC1a through Notch1/Hes-1 pathways. These data indicate that ASIC1a plays an important role in diabetes complication liver fibrosis. - Highlights: • Hyperglycemia is a risk factor for the process of liver fibrosis. • ASIC1a may be a key factor linking between high glucose and liver fibrosis. • Notch1/Hes-1 may involve to the process of liver fibrosis under hyperglycemia.

  8. Effect of acid-sensing ion channel 1a on the process of liver fibrosis under hyperglycemia

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Huan, E-mail: wanghuan7@126.com [School of Pharmacy, Anhui Medical University, Hefei, 230032 (China); Institute for Liver Diseases of Anhui Medical University (AMU), Anhui Medical University, Hefei, 230032 (China); Wang, Ying-hong; Yang, Feng; Li, Xiao-feng; Tian, Yuan-yao; Ni, Ming-ming; Zuo, Long-quan; Meng, Xiao-Ming [School of Pharmacy, Anhui Medical University, Hefei, 230032 (China); Institute for Liver Diseases of Anhui Medical University (AMU), Anhui Medical University, Hefei, 230032 (China); Huang, Yan, E-mail: aydhy@126.com [School of Pharmacy, Anhui Medical University, Hefei, 230032 (China); Institute for Liver Diseases of Anhui Medical University (AMU), Anhui Medical University, Hefei, 230032 (China)

    2015-12-25

    Metabolic syndrome characterized by hyperglycemia contributes to nonalcoholic steatohepatitis-associated liver fibrosis. This study was to investigate the effects of Acid-sensing ion Channel 1a (ASIC1a) on the process of liver fibrosis under hyperglycemia. Results showed that high glucose significantly worsen the pathology of liver fibrosis in vivo. In vitro, high glucose stimulated proliferation, activation and extracellular matrix (ECM) production in HSCs, and enhanced the effect of PDGF-BB on the activation and proliferation of HSCs. These effects could be attenuated by ASIC1a specific inhibitor Psalmotoxin-1(PcTx1) or specific ShRNA for ASIC1a through Notch1/Hes-1 pathways. These data indicate that ASIC1a plays an important role in diabetes complication liver fibrosis. - Highlights: • Hyperglycemia is a risk factor for the process of liver fibrosis. • ASIC1a may be a key factor linking between high glucose and liver fibrosis. • Notch1/Hes-1 may involve to the process of liver fibrosis under hyperglycemia.

  9. CC2D1A Regulates Human Intellectual and Social Function as well as NF-κB Signaling Homeostasis

    Directory of Open Access Journals (Sweden)

    M. Chiara Manzini

    2014-08-01

    Full Text Available Autism spectrum disorder (ASD and intellectual disability (ID are often comorbid, but the extent to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive “founder” mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB. Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intracellular signaling. Cc2d1a knockdown in neurons reduces dendritic complexity and increases NF-κB activity, and the effects of Cc2d1a depletion can be rescued by inhibiting NF-κB activity. Homeostatic regulation of neuronal signaling pathways provides a mechanism whereby common founder mutations could manifest diverse symptoms in different patients.

  10. Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer’s disease

    Science.gov (United States)

    Janel, N; Alexopoulos, P; Badel, A; Lamari, F; Camproux, A C; Lagarde, J; Simon, S; Feraudet-Tarisse, C; Lamourette, P; Arbones, M; Paul, J L; Dubois, B; Potier, M C; Sarazin, M; Delabar, J M

    2017-01-01

    Early identification of Alzheimer’s disease (AD) risk factors would aid development of interventions to delay the onset of dementia, but current biomarkers are invasive and/or costly to assess. Validated plasma biomarkers would circumvent these challenges. We previously identified the kinase DYRK1A in plasma. To validate DYRK1A as a biomarker for AD diagnosis, we assessed the levels of DYRK1A and the related markers brain-derived neurotrophic factor (BDNF) and homocysteine in two unrelated AD patient cohorts with age-matched controls. Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers. These results associate a decreased level of DYRK1A with AD and challenge the use of DYRK1A inhibitors in peripheral tissues as treatment. These measures will be useful for diagnosis purposes. PMID:28632203

  11. Amplification factor variable amplifier

    NARCIS (Netherlands)

    Akitsugu, Oshita; Nauta, Bram

    2007-01-01

    PROBLEM TO BE SOLVED: To provide an amplification factor variable amplifier capable of achieving temperature compensation of an amplification factor over a wide variable amplification factor range. ; SOLUTION: A Gilbert type amplification factor variable amplifier 11 amplifies an input signal and

  12. Amplification factor variable amplifier

    NARCIS (Netherlands)

    Akitsugu, Oshita; Nauta, Bram

    2010-01-01

    PROBLEM TO BE SOLVED: To provide an amplification factor variable amplifier capable of achieving temperature compensation of an amplification factor over a wide variable amplification factor range. ;SOLUTION: A Gilbert type amplification factor variable amplifier 11 amplifies an input signal and can

  13. Foundations of factor analysis

    CERN Document Server

    Mulaik, Stanley A

    2009-01-01

    Introduction Factor Analysis and Structural Theories Brief History of Factor Analysis as a Linear Model Example of Factor AnalysisMathematical Foundations for Factor Analysis Introduction Scalar AlgebraVectorsMatrix AlgebraDeterminants Treatment of Variables as Vectors Maxima and Minima of FunctionsComposite Variables and Linear Transformations Introduction Composite Variables Unweighted Composite VariablesDifferentially Weighted Composites Matrix EquationsMulti

  14. Blood coagulation factor VIII

    Indian Academy of Sciences (India)

    Factor VIII (FVIII) functions as a co-factor in the blood coagulation cascade for the proteolytic activation of factor X by factor IXa. Deficiency of FVIII causes hemophilia A, the most commonly inherited bleeding disorder. This review highlights current knowledge on selected aspects of FVIII in which both the scientist and the ...

  15. Constructivism, Factoring, and Beliefs.

    Science.gov (United States)

    Rauff, James V.

    1994-01-01

    Discusses errors made by remedial intermediate algebra students in factoring polynomials in light of student definitions of factoring. Found certain beliefs about factoring to logically imply many of the errors made. Suggests that belief-based teaching can be successful in teaching factoring. (16 references) (Author/MKR)

  16. Sentinel-1A/B Combined Product Geolocation Accuracy

    Directory of Open Access Journals (Sweden)

    Adrian Schubert

    2017-06-01

    Full Text Available Sentinel-1A and -1B are twin spaceborne synthetic aperture radar (SAR sensors developed and operated by the European Space Agency under the auspices of the Copernicus Earth observation programme. Launched in April 2014 and April 2016, Sentinel-1A and -1B are currently operating in tandem, in a common orbital configuration to provide an increased revisit frequency. In-orbit commissioning was completed for each unit within months of their respective launches, and level-1 SAR products generated by the operational SAR processor have been geometrically calibrated. In order to compare and monitor the geometric characteristics of the level-1 products from both units, as well as to investigate potential improvements, products from both satellites have been monitored since their respective commissioning phases. In this study, we present geolocation accuracy estimates for both Sentinel-1 units based on the time series of level-1 products collected thus far. While both units were demonstrated to be performing consistently, and providing SAR data products according to the nominal product specifications, a subtle beam- and mode-dependent azimuth bias common to the data from both units was identified. A method for removing the bias is proposed, and the corresponding improvement to the geometric accuracies is demonstrated and quantified.

  17. RICE CROP MAPPING USING SENTINEL-1A PHENOLOGICAL METRICS

    Directory of Open Access Journals (Sweden)

    C. F. Chen

    2016-06-01

    Full Text Available Rice is the most important food crop in Vietnam, providing food more than 90 million people and is considered as an essential source of income for majority of rural populations. Monitoring rice-growing areas is thus important to developing successful strategies for food security in the country. This paper aims to develop an approach for crop acreage estimation from multi-temporal Sentinel-1A data. We processed the data for two main cropping seasons (e.g., winter–spring, summer–autumn in the Mekong River Delta (MRD, Vietnam through three main steps: (1 data pre-processing, (3 rice classification based on crop phenological metrics, and (4 accuracy assessment of the mapping results. The classification results compared with the ground reference data indicated the overall accuracy of 86.2% and Kappa coefficient of 0.72. These results were reaffirmed by close correlation between the government’s rice area statistics for such crops (R2 > 0.95. The values of relative error in area obtained for the winter–spring and summer–autumn were -3.6% and 6.7%, respectively. This study demonstrates the potential application of multi-temporal Sentinel-1A data for rice crop mapping using information of crop phenology in the study region.

  18. Histone demethylase JMJD1A promotes alternative splicing of AR variant 7 (AR-V7) in prostate cancer cells.

    Science.gov (United States)

    Fan, Lingling; Zhang, Fengbo; Xu, Songhui; Cui, Xiaolu; Hussain, Arif; Fazli, Ladan; Gleave, Martin; Dong, Xuesen; Qi, Jianfei

    2018-05-15

    Formation of the androgen receptor splicing variant 7 (AR-V7) is one of the major mechanisms by which resistance of prostate cancer to androgen deprivation therapy occurs. The histone demethylase JMJD1A (Jumonji domain containing 1A) functions as a key coactivator for AR by epigenetic regulation of H3K9 methylation marks. Here, we describe a role for JMJD1A in AR-V7 expression. While JMJD1A knockdown had no effect on full-length AR (AR-FL), it reduced AR-V7 levels in prostate cancer cells. Reexpression of AR-V7 in the JMJD1A-knockdown cells elevated expression of select AR targets and partially rescued prostate cancer cell growth in vitro and in vivo. The AR-V7 protein level correlated positively with JMJD1A in a subset of human prostate cancer specimens. Mechanistically, we found that JMJD1A promoted alternative splicing of AR-V7 through heterogeneous nuclear ribonucleoprotein F (HNRNPF), a splicing factor known to regulate exon inclusion. Knockdown of JMJD1A or HNRNPF inhibited splicing of AR-V7, but not AR-FL, in a minigene reporter assay. JMJD1A was found to interact with and promote the recruitment of HNRNPF to a cryptic exon 3b on AR pre-mRNA for the generation of AR-V7. Taken together, the role of JMJD1A in AR-FL coactivation and AR-V7 alternative splicing highlights JMJD1A as a potentially promising target for prostate cancer therapy.

  19. Cytokine-Like Protein 1(Cytl1: A Potential Molecular Mediator in Embryo Implantation.

    Directory of Open Access Journals (Sweden)

    Zhichao Ai

    Full Text Available Cytokine-like protein 1 (Cytl1, originally described as a protein expressed in CD34+ cells, was recently identified as a functional secreted protein involved in chondrogenesis and cartilage development. However, our knowledge of Cytl1 is still limited. Here, we determined the Cytl1 expression pattern regulated by ovarian hormones at both the mRNA and protein levels. We found that the endometrial expression of Cytl1 in mice was low before or on the first day of gestation, significantly increased during embryo implantation, and then decreased at the end of implantation. We investigated the effects of Cytl1 on endometrial cell proliferation, and the effects on the secretion of leukemia inhibitory factor (LIF and heparin-binding epidermal growth factor (HB-EGF. We also explored the effect of Cytl1 on endometrial adhesion properties in cell-cell adhesion assays. Our findings demonstrated that Cytl1 is an ovarian hormone-dependent protein expressed in the endometrium that enhances the proliferation of HEC-1-A and RL95-2 cells, stimulates endometrial secretion of LIF and HB-EGF, and enhances the adhesion of HEC-1-A and RL95-2 cells to JAR spheroids. This study suggests that Cytl1 plays an active role in the regulation of embryo implantation.

  20. Prevalence of Retinopathy in Adult Patients with GCK-MODY and HNF1A-MODY.

    Science.gov (United States)

    Szopa, M; Wolkow, J; Matejko, B; Skupien, J; Klupa, T; Wybrańska, I; Trznadel-Morawska, I; Kiec-Wilk, B; Borowiec, M; Malecki, M T

    2015-10-01

    We aimed to assess the prevalence of diabetic retinopathy (DR) in adult patients with GCK-MODY and HNF1A-MODY in Poland and to identify biochemical and clinical risk factors associated with its occurrence.We examined 74 GCK mutation carriers, 51 with diabetes and 23 with prediabetes, respectively, and 63 patients with HNF1A-MODY. Retinal photographs, 12 for each patient, were done by a fundus camera. Signs of DR were graded according to the DR disease severity scale. Statistical tests were performed to assess differences between the groups and logistic regression was done for the association with DR.The mean age at examination was 34.5±14.8 and 39.9±15.2 in the GCK-MODY and HNF1A-MODY groups, respectively. Mild nonproliferative DR (NPDR) was found in one patient with the GCK mutation and likely concomitant type 1 diabetes, whereas DR was diagnosed in 15 HNF1A-MODY patients: 9 with proliferative, 3 with moderate NPDR and 2 with mild NPDR. In univariate logistic regression analysis in the HNF1A-MODY group, significant results were found for diabetes duration, fasting glycemia, HbA1c, arterial hypertension, age at the examination, and eGFR. The strongest independent predictors of DR in HNF1A-MODY were markers of glucose control: HbA1c (OR: 2.05, CL%95: 1.2-3.83, p=0.01) and glucose (p=0.006, OR: 1.40, CL%95: 1.12-1.83) analyzed in 2 separated models. Additionally, arterial hypertension independently predicted DR (OR: 9.06, CL%95: 1.19-98.99, p=0.04) in the model with HbA1c as glycaemic control marker.In conclusion, DR of any degree was not present in our GCK-MODY group, while in spite of young age almost every fourth subject with HNF1A-MODY showed signs of this complication. © Georg Thieme Verlag KG Stuttgart · New York.

  1. Targeting the CACNA1A IRES as a Treatment for Spinocerebellar Ataxia Type 6.

    Science.gov (United States)

    Pastor, Parviz Daniel Hejazi; Du, Xiaofei; Fazal, Sarah; Davies, Andre N; Gomez, Christopher M

    2018-02-01

    We have discovered that the P/Q-type voltage-gated Ca 2+ channel (VGCC) gene, CACNA1A, encodes both the α1A (Cav2.1) subunit and a newly recognized transcription factor, α1ACT, by means of a novel internal ribosomal entry site (IRES) within the α1A C-terminal coding region. α1ACT, when mutated with an expansion of the polyglutamine tract in the C-terminus, gives rise to spinocerebellar ataxia type 6 (SCA6). Because silencing of the entire CACNA1A gene would result in the loss of the essential Cav2.1 channel, the IRES controlling α1ACT expression is an excellent target for selective silencing of α1ACT as a therapeutic intervention for SCA6. We performed a high-throughput screen of FDA-approved small molecules using a dual luciferase reporter system and identified ten hits able to selectively inhibit the IRES. We identified four main candidates that showed selective suppression of α1ACT relative to α1A in HEK cells expressing a native CACNA1A vector. We previously pursued another avenue of molecular intervention through miRNA silencing. We studied three human miRNAs (miRNA-711, -3191-5p, -4786) that would potentially bind to sequences within the CACNA1A IRES region, based on an miRNA prediction program. Only miRNA-3191-5p was found to selectively inhibit the translation of α1ACT in cells. We developed a hyperacute model of SCA6 in mice by injecting a pathogenic form of the IRES-mediated α1ACT (AAV9-α1ACTQ33). Finally, we tested the effectiveness of the miRNA therapy by co-expressing either control miRNA or miRNA-3191-5p and found that miRNA-3191-5p decreased the levels of α1ACTQ33 and prevented the hyperacute disease in mice. These studies provide the proof of principle that a therapy directed at selectively preventing α1ACT expression could be used to treat SCA6.

  2. Visualisation of serotonin-1A (5-HT{sub 1A}) receptors in the central nervous system

    Energy Technology Data Exchange (ETDEWEB)

    Passchier, J.; Waarde, A. van [PET Center, University Hospital Groningen (Netherlands)

    2001-01-01

    The 5-HT{sub 1A} subtype of receptors for the neurotransmitter serotonin is predominantly located in the limbic forebrain and is involved in the modulation of emotion and the function of the hypothalamus. Since 5-HT{sub 1A} receptors are implicated in the pathogenesis of anxiety, depression, hallucinogenic behaviour, motion sickness and eating disorders, they are an important target for drug therapy. Here, we review the radioligands which are available for visualisation and quantification of this important neuroreceptor in the human brain, using positron emission tomography (PET) or single-photon emission tomography (SPET). More than 20 compounds have been labelled with carbon-11 (half-life 20 min), fluorine-18 (half-life 109.8 min) or iodine-123 (half-life 13.2 h): structural analogues of the agonist, 8-OH-DPAT, structural analogues of the antagonist, WAY 100635, and apomorphines. The most successful radioligands thus far are [carbonyl-{sup 11}C] WAY-100635 (WAY), [carbonyl-{sup 11}C]desmethyl-WAY-100635 (DWAY), p-[{sup 18}F]MPPF and [{sup 11}C]robalzotan (NAD-299). The high-affinity ligands WAY and DWAY produce excellent images of 5-HT{sub 1A} receptor distribution in the brain (even the raphe nuclei are visualised), but they cannot be distributed to remote facilities and they probably cannot be used to measure changes in endogenous serotonin. Binding of the moderate-affinity ligands MPPF and NAD-299 may be more sensitive to serotonin competition and MPPF can be distributed to PET centres within a flying distance of a few hours. Future research should be directed towards: (a) improvement of the metabolic stability in primates; (b) development of a fluorinated radioligand which can be produced in large quantities and (c) production of a radioiodinated or technetium-labelled ligand for SPET. (orig.)

  3. Factors affecting construction performance: exploratory factor analysis

    Science.gov (United States)

    Soewin, E.; Chinda, T.

    2018-04-01

    The present work attempts to develop a multidimensional performance evaluation framework for a construction company by considering all relevant measures of performance. Based on the previous studies, this study hypothesizes nine key factors, with a total of 57 associated items. The hypothesized factors, with their associated items, are then used to develop questionnaire survey to gather data. The exploratory factor analysis (EFA) was applied to the collected data which gave rise 10 factors with 57 items affecting construction performance. The findings further reveal that the items constituting ten key performance factors (KPIs) namely; 1) Time, 2) Cost, 3) Quality, 4) Safety & Health, 5) Internal Stakeholder, 6) External Stakeholder, 7) Client Satisfaction, 8) Financial Performance, 9) Environment, and 10) Information, Technology & Innovation. The analysis helps to develop multi-dimensional performance evaluation framework for an effective measurement of the construction performance. The 10 key performance factors can be broadly categorized into economic aspect, social aspect, environmental aspect, and technology aspects. It is important to understand a multi-dimension performance evaluation framework by including all key factors affecting the construction performance of a company, so that the management level can effectively plan to implement an effective performance development plan to match with the mission and vision of the company.

  4. Music genetics research: Association with musicality of a polymorphism in the AVPR1A gene.

    Science.gov (United States)

    Mariath, Luiza Monteavaro; Silva, Alexandre Mauat da; Kowalski, Thayne Woycinck; Gattino, Gustavo Schulz; Araujo, Gustavo Andrade de; Figueiredo, Felipe Grahl; Tagliani-Ribeiro, Alice; Roman, Tatiana; Vianna, Fernanda Sales Luiz; Schuler-Faccini, Lavínia; Schuch, Jaqueline Bohrer

    2017-01-01

    Musicality is defined as a natural tendency, sensibility, knowledge, or talent to create, perceive, and play music. Musical abilities involve a great range of social and cognitive behaviors, which are influenced by both environmental and genetic factors. Although a number of studies have yielded insights into music genetics research, genes and biological pathways related to these traits are not fully understood. Our hypothesis in the current study is that genes associated with different behaviors could also influence the musical phenotype. Our aim was to investigate whether polymorphisms in six genes (AVPR1A, SLC6A4, ITGB3, COMT, DRD2 and DRD4) related to social and cognitive traits are associated with musicality in a sample of children. Musicality was assessed through an individualized music therapy assessment profile (IMTAP) which has been validated in Brazil to measure musical ability. We show here that the RS1 microsatellite of the AVPR1A gene is nominally associated with musicality, corroborating previous results linking AVPR1A with musical activity. This study is one of the first to investigate musicality in a comprehensive way, and it contributes to better understand the genetic basis underlying musical ability.

  5. Music genetics research: Association with musicality of a polymorphism in the AVPR1A gene

    Directory of Open Access Journals (Sweden)

    Luiza Monteavaro Mariath

    2017-05-01

    Full Text Available Abstract Musicality is defined as a natural tendency, sensibility, knowledge, or talent to create, perceive, and play music. Musical abilities involve a great range of social and cognitive behaviors, which are influenced by both environmental and genetic factors. Although a number of studies have yielded insights into music genetics research, genes and biological pathways related to these traits are not fully understood. Our hypothesis in the current study is that genes associated with different behaviors could also influence the musical phenotype. Our aim was to investigate whether polymorphisms in six genes (AVPR1A, SLC6A4, ITGB3, COMT, DRD2 and DRD4 related to social and cognitive traits are associated with musicality in a sample of children. Musicality was assessed through an individualized music therapy assessment profile (IMTAP which has been validated in Brazil to measure musical ability. We show here that the RS1 microsatellite of the AVPR1A gene is nominally associated with musicality, corroborating previous results linking AVPR1A with musical activity. This study is one of the first to investigate musicality in a comprehensive way, and it contributes to better understand the genetic basis underlying musical ability.

  6. Bee venom processes human skin lipids for presentation by CD1a.

    Science.gov (United States)

    Bourgeois, Elvire A; Subramaniam, Sumithra; Cheng, Tan-Yun; De Jong, Annemieke; Layre, Emilie; Ly, Dalam; Salimi, Maryam; Legaspi, Annaliza; Modlin, Robert L; Salio, Mariolina; Cerundolo, Vincenzo; Moody, D Branch; Ogg, Graham

    2015-02-09

    Venoms frequently co-opt host immune responses, so study of their mode of action can provide insight into novel inflammatory pathways. Using bee and wasp venom responses as a model system, we investigated whether venoms contain CD1-presented antigens. Here, we show that venoms activate human T cells via CD1a proteins. Whereas CD1 proteins typically present lipids, chromatographic separation of venoms unexpectedly showed that stimulatory factors partition into protein-containing fractions. This finding was explained by demonstrating that bee venom-derived phospholipase A2 (PLA2) activates T cells through generation of small neoantigens, such as free fatty acids and lysophospholipids, from common phosphodiacylglycerides. Patient studies showed that injected PLA2 generates lysophospholipids within human skin in vivo, and polyclonal T cell responses are dependent on CD1a protein and PLA2. These findings support a previously unknown skin immune response based on T cell recognition of CD1a proteins and lipid neoantigen generated in vivo by phospholipases. The findings have implications for skin barrier sensing by T cells and mechanisms underlying phospholipase-dependent inflammatory skin disease. © 2015 Bourgeois et al.

  7. Working group 1A - basis for the standard-safety

    International Nuclear Information System (INIS)

    Whipple, C.

    1993-01-01

    This paper presents a summary of the progress made by working group 1A (Basis for the Safety Standard) during the Electric Power Research Institute's EPRI Workshop on the technical basis of EPA HLW Disposal Criteria, March 1993. This group discussed the semantics of terms within the standard 40 CFR Part 191, the implementation of this standard, the advanced notice of rulemaking, the issue of emitting carbon-14 through a gaseous pathway, the strategy of dealing with standards for contamination of drinking water and groundwater, the 100,000 year time frame, and the analysis of specific comments. The specific comments dealt with the cost effectiveness of the standard, the dose histogram for populations and individuals, groundwater definition and the underlying technology driver for this standard

  8. HEXIM1, a New Player in the p53 Pathway

    Energy Technology Data Exchange (ETDEWEB)

    Lew, Qiao Jing; Chu, Kai Ling; Chia, Yi Ling; Cheong, Nge [Expression Engineering Group, Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), 20 Biopolis Way, #06-01, Singapore 138668 (Singapore); Chao, Sheng-Hao, E-mail: jimmy_chao@bti.a-star.edu.sg [Expression Engineering Group, Bioprocessing Technology Institute, A*STAR (Agency for Science, Technology and Research), 20 Biopolis Way, #06-01, Singapore 138668 (Singapore); Department of Microbiology, National University of Singapore, Singapore 117597 (Singapore)

    2013-07-04

    Hexamethylene bisacetamide-inducible protein 1 (HEXIM1) is best known as the inhibitor of positive transcription elongation factor b (P-TEFb), which controls transcription elongation of RNA polymerase II and Tat transactivation of human immunodeficiency virus. Besides P-TEFb, several proteins have been identified as HEXIM1 binding proteins. It is noteworthy that more than half of the HEXIM1 binding partners are involved in cancers. P53 and two key regulators of the p53 pathway, nucleophosmin (NPM) and human double minute-2 protein (HDM2), are among the factors identified. This review will focus on the functional importance of the interactions between HEXIM1 and p53/NPM/HDM2. NPM and the cytoplasmic mutant of NPM, NPMc+, were found to regulate P-TEFb activity and RNA polymerase II transcription through the interaction with HEXIM1. Importantly, more than one-third of acute myeloid leukemia (AML) patients carry NPMc+, suggesting the involvement of HEXIM1 in tumorigenesis of AML. HDM2 was found to ubiquitinate HEXIM1. The HDM2-mediated ubiquitination of HEXIM1 did not lead to protein degradation of HEXIM1 but enhanced its inhibitory activity on P-TEFb. Recently, HEXIM1 was identified as a novel positive regulator of p53. HEXIM1 prevented p53 ubiquitination by competing with HDM2 in binding to p53. Taken together, the new evidence suggests a role of HEXIM1 in regulating the p53 pathway and tumorigenesis.

  9. The joy of factoring

    CERN Document Server

    Wagstaff, Samuel S

    2013-01-01

    This book is about the theory and practice of integer factorization presented in a historic perspective. It describes about twenty algorithms for factoring and a dozen other number theory algorithms that support the factoring algorithms. Most algorithms are described both in words and in pseudocode to satisfy both number theorists and computer scientists. Each of the ten chapters begins with a concise summary of its contents. The book starts with a general explanation of why factoring integers is important. The next two chapters present number theory results that are relevant to factoring. Further on there is a chapter discussing, in particular, mechanical and electronic devices for factoring, as well as factoring using quantum physics and DNA molecules. Another chapter applies factoring to breaking certain cryptographic algorithms. Yet another chapter is devoted to practical vs. theoretical aspects of factoring. The book contains more than 100 examples illustrating various algorithms and theorems. It also co...

  10. Menadione Suppresses Benzo(αpyrene-Induced Activation of Cytochromes P450 1A: Insights into a Possible Molecular Mechanism.

    Directory of Open Access Journals (Sweden)

    Yulia A Sidorova

    Full Text Available Oxidative reactions that are catalyzed by cytochromes P450 1A (CYP1A lead to formation of carcinogenic derivatives of arylamines and polycyclic aromatic hydrocarbons (PAHs, such as the widespread environmental pollutant benzo(αpyrene (BP. These compounds upregulate CYP1A at the transcriptional level via an arylhydrocarbon receptor (AhR-dependent signaling pathway. Because of the involvement of AhR-dependent genes in chemically induced carcinogenesis, suppression of this signaling pathway could prevent tumor formation and/or progression. Here we show that menadione (a water-soluble analog of vitamin K3 inhibits BP-induced expression and enzymatic activity of both CYP1A1 and CYP1A2 in vivo (in the rat liver and BP-induced activity of CYP1A1 in vitro. Coadministration of BP and menadione reduced DNA-binding activity of AhR and increased DNA-binding activity of transcription factors Oct-1 and CCAAT/enhancer binding protein (C/EBP, which are known to be involved in negative regulation of AhR-dependent genes, in vivo. Expression of another factor involved in downregulation of CYP1A-pAhR repressor (AhRR-was lower in the liver of the rats treated with BP and menadione, indicating that the inhibitory effect of menadione on CYP1A is not mediated by this protein. Furthermore, menadione was well tolerated by the animals: no signs of acute toxicity were detected by visual examination or by assessment of weight gain dynamics or liver function. Taken together, our results suggest that menadione can be used in further studies on animal models of chemically induced carcinogenesis because menadione may suppress tumor formation and possibly progression.

  11. Menadione Suppresses Benzo(α)pyrene-Induced Activation of Cytochromes P450 1A: Insights into a Possible Molecular Mechanism.

    Science.gov (United States)

    Sidorova, Yulia A; Perepechaeva, Maria L; Pivovarova, Elena N; Markel, Arkady L; Lyakhovich, Vyacheslav V; Grishanova, Alevtina Y

    2016-01-01

    Oxidative reactions that are catalyzed by cytochromes P450 1A (CYP1A) lead to formation of carcinogenic derivatives of arylamines and polycyclic aromatic hydrocarbons (PAHs), such as the widespread environmental pollutant benzo(α)pyrene (BP). These compounds upregulate CYP1A at the transcriptional level via an arylhydrocarbon receptor (AhR)-dependent signaling pathway. Because of the involvement of AhR-dependent genes in chemically induced carcinogenesis, suppression of this signaling pathway could prevent tumor formation and/or progression. Here we show that menadione (a water-soluble analog of vitamin K3) inhibits BP-induced expression and enzymatic activity of both CYP1A1 and CYP1A2 in vivo (in the rat liver) and BP-induced activity of CYP1A1 in vitro. Coadministration of BP and menadione reduced DNA-binding activity of AhR and increased DNA-binding activity of transcription factors Oct-1 and CCAAT/enhancer binding protein (C/EBP), which are known to be involved in negative regulation of AhR-dependent genes, in vivo. Expression of another factor involved in downregulation of CYP1A-pAhR repressor (AhRR)-was lower in the liver of the rats treated with BP and menadione, indicating that the inhibitory effect of menadione on CYP1A is not mediated by this protein. Furthermore, menadione was well tolerated by the animals: no signs of acute toxicity were detected by visual examination or by assessment of weight gain dynamics or liver function. Taken together, our results suggest that menadione can be used in further studies on animal models of chemically induced carcinogenesis because menadione may suppress tumor formation and possibly progression.

  12. UDP glucuronosyltransferase (UGT) 1A6 pharmacogenetics: I. Identification of polymorphisms in the 5'-regulatory and exon 1 regions, and association with human liver UGT1A6 gene expression and glucuronidation.

    Science.gov (United States)

    Krishnaswamy, Soundararajan; Hao, Qin; Al-Rohaimi, Abdul; Hesse, Leah M; von Moltke, Lisa L; Greenblatt, David J; Court, Michael H

    2005-06-01

    UDP glucuronosyltransferase (UGT) 1A6 is a major isoform in human liver that glucuronidates numerous drugs, toxins, and endogenous substrates with high interindividual variability. The molecular basis for this variability remains unknown, although it likely involves genetic and environmental factors. Phenotype-genotype studies were conducted using a well characterized human liver bank (n = 54) and serotonin glucuronidation as a UGT1A6-specific phenotype marker. A positive moderate-to-heavy alcohol use history (>14 drinks per week) was the only demographic factor examined that correlated with phenotype and was associated with 2-fold higher serotonin glucuronidation (p g, -1310del5, and -652g-->a). Initial univariate analyses did not identify any significant phenotype-genotype associations. However, in livers without substantial alcohol exposure, 50% lower UGT1A6 mRNA levels (p = 0.026) were found in carriers of the linked S7A-enhancer polymorphisms compared with noncarriers but without significant effect on UGT1A6 protein content or glucuronidation activities. Three major haplotypes, including (*)1A (reference), (*)1B (-1535g-->a and -427g-->c), and (*)2 (-1710c-->g, -1310del5, -652g-->a, S7A, T181A, and R184S), were identified, accounting for 90% of alleles. No association of haplotype with any of the phenotype measures could be discerned. In conclusion, although the identified UGT1A6 polymorphisms did not explain the observed glucuronidation variability, there does seem to be a significant role for environmental factors associated with alcohol consumption.

  13. FOXM1: A novel drug target in gastroenteropancreatic neuroendocrine tumors

    Science.gov (United States)

    Briest, Franziska; Berg, Erika; Grass, Irina; Freitag, Helma; Kaemmerer, Daniel; Lewens, Florentine; Christen, Friederike; Arsenic, Ruza; Altendorf-Hofmann, Annelore; Kunze, Almut; Sänger, Jörg; Knösel, Thomas; Siegmund, Britta; Hummel, Michael; Grabowski, Patricia

    2015-01-01

    Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are heterogeneous tumors that need to be molecularly defined to obtain novel therapeutic options. Forkheadbox protein M1 (FOXM1) is a crucial transcription factor in neoplastic cells and has been associated with differentiation and proliferation. We found that FOXM1 is strongly associated with tumor differentiation and occurrence of metastases in gastrointestinal NENs. In vitro inhibition by the FOXM1 inhibitor siomycin A led to down-regulation of mitotic proteins and resulted in a strong inhibitory effect. Siomycin A decreased mitosis rate, induced apoptosis in GEP-NEN cell lines and exerts synergistic effects with chemotherapy. FOXM1 is associated with clinical outcome and FOXM1 inhibition impairs survival in vitro. We therefore propose FOXM1 as novel therapeutic target in GEP-NENs. PMID:25797272

  14. Stable SREBP-1a knockdown decreases the cell proliferation rate in human preadipocyte cells without inducing senescence

    International Nuclear Information System (INIS)

    Alvarez, María Soledad; Fernandez-Alvarez, Ana; Cucarella, Carme; Casado, Marta

    2014-01-01

    Highlights: • SGBS cells mostly expressed SREBP-1a variant. • SREBP-1a knockdown decreased the proliferation of SGBS cells without inducing senescence. • We have identified RBBP8 and CDKN3 genes as potential SREBP-1a targets. - Abstract: Sterol regulatory element binding proteins (SREBP), encoded by the Srebf1 and Srebf2 genes, are important regulators of genes involved in cholesterol and fatty acid metabolism. Whereas SREBP-2 controls the cholesterol synthesis, SREBP-1 proteins (-1a and -1c) function as the central hubs in lipid metabolism. Despite the key function of these transcription factors to promote adipocyte differentiation, the roles of SREBP-1 proteins during the preadipocyte state remain unknown. Here, we evaluate the role of SREBP-1 in preadipocyte proliferation using RNA interference technology. Knockdown of the SREBP-1a gene decreased the proliferation rate in human SGBS preadipocyte cell strain without inducing senescence. Furthermore, our data identified retinoblastoma binding protein 8 and cyclin-dependent kinase inhibitor 3 genes as new potential SREBP-1 targets, in addition to cyclin-dependent kinase inhibitor 1A which had already been described as a gene regulated by SREBP-1a. These data suggested a new role of SREBP-1 in adipogenesis via regulation of preadipocyte proliferation

  15. Opposing function of MYBBP1A in proliferation and migration of head and neck squamous cell carcinoma cells

    International Nuclear Information System (INIS)

    Acuña Sanhueza, Gustavo A; Simon, Christian; Hess, Jochen; Faller, Leonie; George, Babitha; Koffler, Jennifer; Misetic, Vinko; Flechtenmacher, Christa; Dyckhoff, Gerhard; Plinkert, Peter P; Angel, Peter

    2012-01-01

    Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent and lethal cancers worldwide and mortality mostly results from loco-regional recurrence and metastasis. Despite its significance, our knowledge on molecular, cellular and environmental mechanisms that drive disease pathogenesis remains largely elusive, and there are limited therapeutic options, with only negligible clinical benefit. We applied global gene expression profiling with samples derived from a recently established mouse model for oral cancer recurrence and identified a list of genes with differential expression between primary and recurrent tumors. One differentially expressed gene codes for Myb-binding protein 1a (MYBBP1A), which is known as a transcriptional co-regulator that physically interacts with nuclear transcription factors, such as NFκB and p53. We confirmed significantly reduced MYBBP1A protein levels on tissue sections of recurrent mouse tumors compared to primary tumors by immunohistochemistry, and found aberrant MYBBP1A protein levels also in tumor samples of HNSCC patients. Interestingly, silencing of MYBBP1A expression in murine SCC7 and in human HNSCC cell lines elicited increased migration but decreased cell growth. We provide experimental evidence that MYBBP1A is an important molecular switch in the regulation of tumor cell proliferation versus migration in HNSCC and it will be a major challenge for the future to proof the concept whether regulation MYBBP1A expression and/or function could serve as a novel option for anti-cancer therapy

  16. Stable SREBP-1a knockdown decreases the cell proliferation rate in human preadipocyte cells without inducing senescence

    Energy Technology Data Exchange (ETDEWEB)

    Alvarez, María Soledad [Instituto de Biomedicina de Valencia (IBV-CSIC), Jaime Roig 11, E-46010 Valencia (Spain); Fernandez-Alvarez, Ana [Fundación Instituto Leloir, IIBBA-CONICET, Av. Patricias Argentinas 435, Ciudad Autónoma de Buenos Aires C1405BWE (Argentina); Cucarella, Carme [Instituto de Biomedicina de Valencia (IBV-CSIC), Jaime Roig 11, E-46010 Valencia (Spain); Casado, Marta, E-mail: mcasado@ibv.csic.es [Instituto de Biomedicina de Valencia (IBV-CSIC), Jaime Roig 11, E-46010 Valencia (Spain)

    2014-04-25

    Highlights: • SGBS cells mostly expressed SREBP-1a variant. • SREBP-1a knockdown decreased the proliferation of SGBS cells without inducing senescence. • We have identified RBBP8 and CDKN3 genes as potential SREBP-1a targets. - Abstract: Sterol regulatory element binding proteins (SREBP), encoded by the Srebf1 and Srebf2 genes, are important regulators of genes involved in cholesterol and fatty acid metabolism. Whereas SREBP-2 controls the cholesterol synthesis, SREBP-1 proteins (-1a and -1c) function as the central hubs in lipid metabolism. Despite the key function of these transcription factors to promote adipocyte differentiation, the roles of SREBP-1 proteins during the preadipocyte state remain unknown. Here, we evaluate the role of SREBP-1 in preadipocyte proliferation using RNA interference technology. Knockdown of the SREBP-1a gene decreased the proliferation rate in human SGBS preadipocyte cell strain without inducing senescence. Furthermore, our data identified retinoblastoma binding protein 8 and cyclin-dependent kinase inhibitor 3 genes as new potential SREBP-1 targets, in addition to cyclin-dependent kinase inhibitor 1A which had already been described as a gene regulated by SREBP-1a. These data suggested a new role of SREBP-1 in adipogenesis via regulation of preadipocyte proliferation.

  17. Accurate measurement of gene copy number for human alpha-defensin DEFA1A3.

    Science.gov (United States)

    Khan, Fayeza F; Carpenter, Danielle; Mitchell, Laura; Mansouri, Omniah; Black, Holly A; Tyson, Jess; Armour, John A L

    2013-10-20

    Multi-allelic copy number variants include examples of extensive variation between individuals in the copy number of important genes, most notably genes involved in immune function. The definition of this variation, and analysis of its impact on function, has been hampered by the technical difficulty of large-scale but accurate typing of genomic copy number. The copy-variable alpha-defensin locus DEFA1A3 on human chromosome 8 commonly varies between 4 and 10 copies per diploid genome, and presents considerable challenges for accurate high-throughput typing. In this study, we developed two paralogue ratio tests and three allelic ratio measurements that, in combination, provide an accurate and scalable method for measurement of DEFA1A3 gene number. We combined information from different measurements in a maximum-likelihood framework which suggests that most samples can be assigned to an integer copy number with high confidence, and applied it to typing 589 unrelated European DNA samples. Typing the members of three-generation pedigrees provided further reassurance that correct integer copy numbers had been assigned. Our results have allowed us to discover that the SNP rs4300027 is strongly associated with DEFA1A3 gene copy number in European samples. We have developed an accurate and robust method for measurement of DEFA1A3 copy number. Interrogation of rs4300027 and associated SNPs in Genome-Wide Association Study SNP data provides no evidence that alpha-defensin copy number is a strong risk factor for phenotypes such as Crohn's disease, type I diabetes, HIV progression and multiple sclerosis.

  18. Differential SLC1A2 Promoter Methylation in Bipolar Disorder With or Without Addiction

    Directory of Open Access Journals (Sweden)

    Yun-Fang Jia

    2017-07-01

    Full Text Available While downregulation of excitatory amino acid transporter 2 (EAAT2, the main transporter removing glutamate from the synapse, has been recognized in bipolar disorder (BD, the underlying mechanisms of downregulation have not been elucidated. BD is influenced by environmental factors, which may, via epigenetic modulation of gene expression, differentially affect illness presentation. This study thus focused on epigenetic DNA methylation regulation of SLC1A2, encoding for EAAT2, in BD with variable environmental influences of addiction. High resolution melting PCR (HRM-PCR and thymine–adenine (TA cloning with sequence analysis were conducted to examine methylation of the promoter region of the SLC1A2. DNA was isolated from blood samples drawn from BD patients (N = 150 with or without addiction to alcohol, nicotine, or food, defined as binge eating, and matched controls (N = 32. In comparison to controls, the SLC1A2 promoter region was hypermethylated in BD without addiction but was hypomethylated in BD with addiction. After adjusting for age and sex, the association of methylation levels with nicotine addiction (p = 0.0009 and binge eating (p = 0.0002 remained significant. Consistent with HRM-PCR, direct sequencing revealed increased methylation in CpG site 6 in BD, but decreased methylation in three CpG sites (6, 48, 156 in BD with alcohol and nicotine addictions. These results suggest that individual point methylation within the SLC1A2 promoter region may be modified by exogenous addiction and may have a potential for developing clinically valuable epigenetic biomarkers for BD diagnosis and monitoring.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Bruno Lemieux

    Full Text Available 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.

  1. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes.

    Science.gov (United States)

    Lal, Dennis; Reinthaler, Eva M; Dejanovic, Borislav; May, Patrick; Thiele, Holger; Lehesjoki, Anna-Elina; Schwarz, Günter; Riesch, Erik; Ikram, M Arfan; van Duijn, Cornelia M; Uitterlinden, Andre G; Hofman, Albert; Steinböck, Hannelore; Gruber-Sedlmayr, Ursula; Neophytou, Birgit; Zara, Federico; Hahn, Andreas; Gormley, Padhraig; Becker, Felicitas; Weber, Yvonne G; Cilio, Maria Roberta; Kunz, Wolfram S; Krause, Roland; Zimprich, Fritz; Lemke, Johannes R; Nürnberg, Peter; Sander, Thomas; Lerche, Holger; Neubauer, Bernd A

    2016-01-01

    The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10-4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.

  2. Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease.

    Science.gov (United States)

    Popat, R A; Van Den Eeden, S K; Tanner, C M; Kamel, F; Umbach, D M; Marder, K; Mayeux, R; Ritz, B; Ross, G W; Petrovitch, H; Topol, B; McGuire, V; Costello, S; Manthripragada, A D; Southwick, A; Myers, R M; Nelson, L M

    2011-05-01

    In 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine animal models of Parkinson's disease (PD), caffeine protects neurons by blocking the adenosine receptor A2A (ADORA2A). Caffeine is primarily metabolized by cytochrome P450 1A2 (CYP1A2). Our objective was to examine whether ADORA2A and CYP1A2 polymorphisms are associated with PD risk or modify the caffeine-PD association. Parkinson's Epidemiology and Genetic Associations Studies in the United States (PEGASUS) included five population-based case-control studies. One laboratory genotyped four ADORA2A and three CYP1A2 polymorphisms in 1325 PD cases and 1735 age- and sex-matched controls. Information regarding caffeine (coffee) consumption and other lifestyle factors came from structured in-person or telephone interviews. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using logistic regression. Two ADORA2A polymorphisms were inversely associated with PD risk - rs71651683, a 5' variant (adjusted allelic OR = 0.51, 95% CI 0.33-0.80, permutation-adjusted P = 0.015) and rs5996696, a promoter region variant (adjusted OR for AC and CC genotypes compared with the AA wild-type genotype were 0.76 (95% CI 0.57-1.02) and 0.37 (95% CI 0.13-1.01), respectively (permutation-adjusted P for trend = 0.04). CYP1A2 polymorphisms were not associated with PD risk; however, the coffee-PD association was strongest among subjects homozygous for either variant allele rs762551 (P(interaction) = 0.05) or rs2470890 (P(interaction) = 0.04). In this consortium study, two ADORA2A polymorphisms were inversely associated with PD risk, but there was weak evidence of interaction with coffee consumption. In contrast, the coffee-PD association was strongest among slow metabolizers of caffeine who were homozygous carriers of the CYP1A2 polymorphisms. © 2011 The Author(s). European Journal of Neurology © 2011 EFNS.

  3. Factor VII deficiency

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000548.htm Factor VII deficiency To use the sharing features on this page, please enable JavaScript. Factor VII (seven) deficiency is a disorder caused by a ...

  4. Annual Adjustment Factors

    Data.gov (United States)

    Department of Housing and Urban Development — The Department of Housing and Urban Development establishes the rent adjustment factors - called Annual Adjustment Factors (AAFs) - on the basis of Consumer Price...

  5. Stroke - risk factors

    Science.gov (United States)

    ... oxygen. Brain cells can die, causing lasting damage. Risk factors are things that increase your chance of ... a disease or condition. This article discusses the risk factors for stroke and things you can do ...

  6. Bootstrapping the (A1, A2) Argyres-Douglas theory

    Science.gov (United States)

    Cornagliotto, Martina; Lemos, Madalena; Liendo, Pedro

    2018-03-01

    We apply bootstrap techniques in order to constrain the CFT data of the ( A 1 , A 2) Argyres-Douglas theory, which is arguably the simplest of the Argyres-Douglas models. We study the four-point function of its single Coulomb branch chiral ring generator and put numerical bounds on the low-lying spectrum of the theory. Of particular interest is an infinite family of semi-short multiplets labeled by the spin ℓ. Although the conformal dimensions of these multiplets are protected, their three-point functions are not. Using the numerical bootstrap we impose rigorous upper and lower bounds on their values for spins up to ℓ = 20. Through a recently obtained inversion formula, we also estimate them for sufficiently large ℓ, and the comparison of both approaches shows consistent results. We also give a rigorous numerical range for the OPE coefficient of the next operator in the chiral ring, and estimates for the dimension of the first R-symmetry neutral non-protected multiplet for small spin.

  7. RASSF1A and the rs2073498 Cancer Associated SNP

    International Nuclear Information System (INIS)

    Donninger, Howard; Barnoud, Thibaut; Nelson, Nick; Kassler, Suzanna; Clark, Jennifer; Cummins, Timothy D.; Powell, David W.; Nyante, Sarah; Millikan, Robert C.; Clark, Geoffrey J.

    2011-01-01

    RASSF1A is one of the most frequently inactivated tumor suppressors yet identified in human cancer. It is pro-apoptotic and appears to function as a scaffolding protein that interacts with a variety of other tumor suppressors to modulate their function. It can also complex with the Ras oncoprotein and may serve to integrate pro-growth and pro-death signaling pathways. A SNP has been identified that is present in approximately 29% of European populations [rs2073498, A(133)S]. Several studies have now presented evidence that this SNP is associated with an enhanced risk of developing breast cancer. We have used a proteomics based approach to identify multiple differences in the pattern of protein/protein interactions mediated by the wild type compared to the SNP variant protein. We have also identified a significant difference in biological activity between wild type and SNP variant protein. However, we have found only a very modest association of the SNP with breast cancer predisposition.

  8. Load Composition Model Workflow (BPA TIP-371 Deliverable 1A)

    Energy Technology Data Exchange (ETDEWEB)

    Chassin, David P.; Cezar, Gustavo V.; /SLAC

    2017-07-17

    This project is funded under Bonneville Power Administration (BPA) Strategic Partnership Project (SPP) 17-005 between BPA and SLAC National Accelerator Laboratory. The project in a BPA Technology Improvement Project (TIP) that builds on and validates the Composite Load Model developed by the Western Electric Coordinating Council's (WECC) Load Modeling Task Force (LMTF). The composite load model is used by the WECC Modeling and Validation Work Group to study the stability and security of the western electricity interconnection. The work includes development of load composition data sets, collection of load disturbance data, and model development and validation. This work supports reliable and economic operation of the power system. This report was produced for Deliverable 1A of the BPA TIP-371 Project entitled \\TIP 371: Advancing the Load Composition Model". The deliverable documents the proposed work ow for the Composite Load Model, which provides the basis for the instrumentation, data acquisition, analysis and data dissemination activities addressed by later phases of the project.

  9. Mortalidad extrahospitalaria en menores de 1 año

    Directory of Open Access Journals (Sweden)

    Felipa E. García García

    1997-04-01

    Full Text Available Se presenta un estudio retrospectivo de 40 niños menores de 1 año, fallecidos fuera de un centro hospitalario en el período comprendido de enero de 1989 a diciembre de 1990 en Ciudad de La Habana. La muerte natural apareció con mayor frecuencia y dentro de ella las bronconeumonías, cardiopatías y sepsis fueron las 3 primeras causas. El maltrato se presentó en el 40 % de los casos, y se comportó el intencional y la muerte por negligencia de igual forma con el 50 % respectivamente. No se identificó la muerte súbita, aunque sí se hallaron aspectos relacionados con ella, como la edad al morir, sexo y horario de defunciones.It is presented a retrospective study of 40 children under one year old, who died outside a hospital center from January, 1989 to December, 1990, in Havana City. Natural death was the most frequent, and within it bronchopneumonias, cardiopathies, and sepsis were the first three causes. Mistreatment was present in 40 % of the cases; whereas intentional mistreatment and death due to negligence behaved in the same way with 50 %, respectively. Sudden death was not identified, although some aspects connected with it such as age of death, sex, and time of decesse were found.

  10. EVALUATION OF PLEIADES-1A TRIPLET ON TRENTO TESTFIELD

    Directory of Open Access Journals (Sweden)

    D. Poli

    2013-05-01

    Full Text Available The Pleiades mission is part of the French-Italian ORFEO system (Optical and Radar Federated Earth Observation and has the aim to provide very-high resolution optical imagery from space for civilian and military needs. Within the Pleiades evaluation program, the 3DOM Unit at the Bruno Kessler Foundation in Trento (Italy received a triplet by Pleiades-1A over Trento testfield for research purposes. The images composing the triplet were acquired on August 28, 2012 with across-track angles close to nadir and alongtrack angles of 18°, -13° and 13° in average with respect to the flight direction (Fig. 1 and a mean GSD between 0.72 m and 0.78 m. The aim of this paper is to investigate the quality of the Pleiades triplet and derived Digital Surface Model (DSM. The image analysis was conducted by evaluating the radiometric properties of the images (noise characteristics, image artifacts, spilling and the geometric accuracy. After image orientation, three DSMs were generated with advanced image matching algorithms using two image combinations and the triplet. The DSMs were compared to the reference Lidar DSM (1 m grid spacing for quality analysis in areas with different characteristics (land use and cover, topography. Thanks to the availability of other very high resolution satellite imagery in the testfield, the results were compared to those previously obtained using WorldView-2 ad GeoEye-1 stereopairs acquired on the same area.

  11. 77 FR 69568 - Special Conditions: Bombardier Aerospace, Model BD-500-1A10 and BD-500-1A11 Airplanes; Sidestick...

    Science.gov (United States)

    2012-11-20

    ... Aerospace, Model BD-500-1A10 and BD-500-1A11 Airplanes; Sidestick Controllers AGENCY: Federal Aviation... conditions for the Bombardier Aerospace Model BD-500-1A10 and BD-500-1A11 airplanes. These airplanes will... on the comments we receive. Background On December 10, 2009, Bombardier Aerospace applied for a type...

  12. 78 FR 75511 - Special Conditions: Bombardier Inc., Models BD-500-1A10 and BD-500-1A11 Series Airplanes...

    Science.gov (United States)

    2013-12-12

    ... Inc., Models BD-500-1A10 and BD- 500-1A11 Series Airplanes; Electronic Flight Control System: Control... Inc. Models BD-500-1A10 and BD-500-1A11 series airplanes. These airplanes will have a novel or unusual... comments, data, or views. The most helpful comments reference a specific portion of the special conditions...

  13. Up-regulation of eEF1A2 promotes proliferation and inhibits apoptosis in prostate cancer

    International Nuclear Information System (INIS)

    Sun, Yue; Du, Chengli; Wang, Bo; Zhang, Yanling; Liu, Xiaoyan; Ren, Guoping

    2014-01-01

    Highlights: • The expression of eEF1A2 is up-regulated in prostate cancer tissues. • Suppression of eEF1A2 inhibits the proliferation and promotes apoptosis. • Inhibition of eEF1A2 enhances the expression of apoptotic relevant proteins. • The expressions of eEF1A2 and cleavage-caspase3 are inversely correlated. - Abstract: Background: eEF1A2 is a protein translation factor involved in protein synthesis, which possesses important function roles in cancer development. This study aims at investigating the expression pattern of eEF1A2 in prostate cancer and its potential role in prostate cancer development. Methods: We examined the expression level of eEF1A2 in 30 pairs of prostate cancer tissues by using RT-PCR and immunohistochemical staining (IHC). Then we applied siRNA specifically targeting eEF1A2 to down-regulate its expression in DU-145 and PC-3 cells. Flow cytometer was used to explore apoptosis and Western-blot was used to detect the pathway proteins of apoptosis. Results: Our results showed that the expression level of eEF1A2 in prostate cancer tissues was significantly higher compared to their corresponding normal tissues. Reduction of eEF1A2 expression in DU-145 and PC-3 cells led to a dramatic inhibition of proliferation accompanied with enhanced apoptosis rate. Western blot revealed that apoptosis pathway proteins (caspase3, BAD, BAX, PUMA) were significantly up-regulated after suppression of eEF1A2. More importantly, the levels of eEF1A2 and caspase3 were inversely correlated in prostate cancer tissues. Conclusion: Our data suggests that eEF1A2 plays an important role in prostate cancer development, especially in inhibiting apoptosis. So eEF1A2 might serve as a potential therapeutic target in prostate cancer

  14. Human factors in training

    International Nuclear Information System (INIS)

    Dutton, J.W.; Brown, W.R.

    1981-01-01

    The Human Factors concept is a focused effort directed at those activities which require human involvement. Training is, by its nature, an activity totally dependent on the Human Factor. This paper identifies several concerns significant to training situations and discusses how Human Factor awareness can increase the quality of learning. Psychology in the training arena is applied Human Factors. Training is a method of communication represented by sender, medium, and receiver. Two-thirds of this communications model involves the human element directly

  15. Neutron electromagnetic form factors

    International Nuclear Information System (INIS)

    Finn, J.M.; Madey, R.; Eden, T.; Markowitz, P.; Rutt, P.M.; Beard, K.; Anderson, B.D.; Baldwin, A.R.; Keane, D.; Manley, D.M.; Watson, J.W.; Zhang, W.M.; Kowalski, S.; Bertozzi, W.; Dodson, G.; Farkhondeh, M.; Dow, K.; Korsch, W.; Tieger, D.; Turchinetz, W.; Weinstein, L.; Gross, F.; Mougey, J.; Ulmer, P.; Whitney, R.; Reichelt, T.; Chang, C.C.; Kelly, J.J.; Payerle, T.; Cameron, J.; Ni, B.; Spraker, M.; Barkhuff, D.; Lourie, R.; Verst, S.V.; Hyde-Wright, C.; Jiang, W.-D.; Flanders, B.; Pella, P.; Arenhoevel, H.

    1992-01-01

    Nucleon form factors provide fundamental input for nuclear structure and quark models. Current knowledge of neutron form factors, particularly the electric form factor of the neutron, is insufficient to meet these needs. Developments of high-duty-factor accelerators and polarization-transfer techniques permit new experiments that promise results with small sensitivities to nuclear models. We review the current status of the field, our own work at the MIT/Bates linear accelerator, and future experimental efforts

  16. Disconnected electromagnetic form factors

    International Nuclear Information System (INIS)

    Wilcox, Walter

    2001-01-01

    Preliminary results of a calculation of disconnected nucleon electromagnetic factors factors on the lattice are presented. The implementation of the numerical subtraction scheme is outlined. A comparison of results for electric and magnetic disconnected form factors on two lattice sizes with those of the Kentucky group is presented. Unlike previous results, the results found in this calculation are consistent with zero in these sectors

  17. Mesonic Form Factors

    Energy Technology Data Exchange (ETDEWEB)

    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.

  18. Aberrant over-expression of a forkhead family member, FOXO1A, in a brain tumor cell line

    International Nuclear Information System (INIS)

    Dallas, Peter B; Egli, Simone; Terry, Philippa A; Kees, Ursula R

    2007-01-01

    The mammalian FOXO (forkhead box, O subclass) proteins are a family of pleiotropic transcription factors involved in the regulation of a broad range of cellular processes critical for survival. Despite the essential and diverse roles of the FOXO family members in human cells and their involvement in tumor pathogenesis, the regulation of FOXO expression remains poorly understood. We have addressed the mechanisms underlying the high level of expression of the FOXO1A gene in a cell line, PER-453, derived from a primitive neuroectodermal tumor of the central nervous system (CNS-PNET). The status of the FOXO1A locus in the PER-453 CNS-PNET cell line was investigated by Southern blotting and DNA sequence analysis of the proximal promoter, 5'-UTR, open reading frame and 3'-UTR. FOXO1A expression was assessed by conventional and quantitative RT-PCR, Northern and Western blotting. Quantitative real-time RT-PCR (qRT-PCR) data indicated that after normalization to ACTB mRNA levels, canonical FOXO1A mRNA expression in the PER-453 cell line was 124-fold higher than the average level of five other CNS-PNET cell lines tested, 24-fold higher than the level in whole fetal brain, and 3.5-fold higher than the level in fetal brain germinal matrix cells. No mutations within the FOXO1A open reading frame or gross rearrangements of the FOXO1A locus were detected. However, a single nucleotide change within the proximal promoter and several nucleotide changes within the 3'-UTR were identified. In addition, two novel FOXO1A transcripts were isolated that differ from the canonical transcript by alternative splicing within the 3'-UTR. The CNS-PNET cell line, PER-453, expresses FOXO1A at very high levels relative to most normal and cancer cells from a broad range of tissues. The FOXO1A open reading frame is wild type in the PER-453 cell line and the abnormally high FOXO1A mRNA expression is not due to mutations affecting the 5'-UTR or proximal promoter. Over expression

  19. MCPH1: a window into brain development and evolution

    Directory of Open Access Journals (Sweden)

    Jeannette eNardelli

    2015-03-01

    Full Text Available The development of the mammalian cerebral cortex involves a series of mechanisms: from patterning, progenitor cell proliferation and differentiation, to neuronal migration. Many factors influence the development of the cerebral cortex to its normal size and neuronal composition. Of these, the mechanisms that influence the proliferation and differentiation of neural progenitor cells are of particular interest, as they may have the greatest consequence on brain size, not only during development but also in evolution. In this context, causative genes of human autosomal recessive primary microcephaly, such as ASPM and MCPH1, are attractive candidates, as many of them show positive selection during primate evolution. MCPH1 causes microcephaly in mice and humans and is involved in a diverse array of molecular functions beyond brain development, including DNA repair and chromosome condensation. Positive selection of MCPH1 in the primate lineage has led to much insight and discussion of its role in brain size evolution. In this review, we will present an overview of MCPH1 from these multiple angles, and whilst its specific role in brain size regulation during development and evolution remain elusive, the pieces of the puzzle will be discussed with the aim of putting together the full picture of this fascinating gene.

  20. [On the role of selective silencer Freud-1 in the regulation of the brain 5-HT(1A) receptor gene expression].

    Science.gov (United States)

    Naumenko, V S; Osipova, D V; Tsybko, A S

    2010-01-01

    Selective 5-HT(1A) receptor silencer (Freud-1) is known to be one of the main factors for transcriptional regulation of brain serotonin 5-HT(1A) receptor. However, there is a lack of data on implication of Freud-1 in the mechanisms underlying genetically determined and experimentally altered 5-HT(1A) receptor system state in vivo. In the present study we have found a difference in the 5-HT(1A) gene expression in the midbrain of AKR and CBA inbred mouse strains. At the same time no distinction in Freud-1 expression was observed. We have revealed 90.3% of homology between mouse and rat 5-HT(1A) receptor DRE-element, whereas there was no difference in DRE-element sequence between AKR and CBA mice. This indicates the absence of differences in Freud-1 binding site in these mouse strains. In the model of 5-HT(1A) receptor desensitization produced by chronic 5-HT(1A) receptor agonist administration, a significant reduction of 5-HT(1A) receptor gene expression together with considerable increase of Freud-1 expression were found. These data allow us to conclude that the selective silencer of 5-HT(1A) receptor, Freud-1, is involved in the compensatory mechanisms that modulate the functional state of brain serotonin system, although it is not the only factor for 5-HT(1A) receptor transcriptional regulation.

  1. The risk factor of thyroid

    International Nuclear Information System (INIS)

    Kusama, Tomoko

    1979-01-01

    For the purposes of radiation protection, the noteworthy risk of thyroid is carcinogenesis. The risk factor which ICRP presented in the publication-26 is 5 x 10 - 6 rem - 1 . This numerical value is based upon the estimated likelihood of inducing fatal thyroid cancer. On the other hand, the risk factor presented by the BEIR report is 4 x 10 - 6 yr - 1 . This value was decided after consideration of the risks of both fatal and non-fatal cancer of thyroid. The following features distinguished thyroid cancer from malignancy of other tissue from medical point of view. 1) A large difference between incidence and mortality in case of thyroid cancer is recognized, because the thyroid cancer could be successfully treated by surgical or radiological treatment. 2) The high prevalence of clinically silent tumor in thyroid gland has been reported. The incidence of thyroid cancer, therefore, is very dependent on methods of medical inspection. The prevalence of radiation induced thyroid cancer is modified by various factors such as age, sex, latency, dose and dose rate. The latent period is very important factors such as ave, sex, latency, dose and dose rate. The latent period is a very important factor in the estimation of accumulated total risk of thyroid malignancy. What is included in the risk caused by thyroid irradiation must be investigated. The risk of non-fatal cancer should be considered in the same way as that of fatal cancer. The dose-equivalent limit of thyroid in non-uniform irradiation caused by radioactive iodine is decided by the limit for non-stochastic effects. Therefore the further consideration of non-stochastic effects of thyroid is necessary. (author)

  2. De-repression of RaRF-mediated RAR repression by adenovirus E1A in the nucleolus.

    Science.gov (United States)

    Um, Soo-Jong; Youn, Hye Sook; Kim, Eun-Joo

    2014-02-21

    Transcriptional activity of the retinoic acid receptor (RAR) is regulated by diverse binding partners, including classical corepressors and coactivators, in response to its ligand retinoic acid (RA). Recently, we identified a novel corepressor of RAR called the retinoic acid resistance factor (RaRF) (manuscript submitted). Here, we report how adenovirus E1A stimulates RAR activity by associating with RaRF. Based on immunoprecipitation (IP) assays, E1A interacts with RaRF through the conserved region 2 (CR2), which is also responsible for pRb binding. The first coiled-coil domain of RaRF was sufficient for this interaction. An in vitro glutathione-S-transferase (GST) pull-down assay was used to confirm the direct interaction between E1A and RaRF. Further fluorescence microscopy indicated that E1A and RaRF were located in the nucleoplasm and nucleolus, respectively. However, RaRF overexpression promoted nucleolar translocation of E1A from the nucleoplasm. Both the RA-dependent interaction of RAR with RaRF and RAR translocation to the nucleolus were disrupted by E1A. RaRF-mediated RAR repression was impaired by wild-type E1A, but not by the RaRF binding-defective E1A mutant. Taken together, our data suggest that E1A is sequestered to the nucleolus by RaRF through a specific interaction, thereby leaving RAR in the nucleoplasm for transcriptional activation. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Decreased expression of Freud-1/CC2D1A, a transcriptional repressor of the 5-HT1A receptor, in the prefrontal cortex of subjects with major depression.

    Science.gov (United States)

    Szewczyk, Bernadeta; Albert, Paul R; Rogaeva, Anastasia; Fitzgibbon, Heidi; May, Warren L; Rajkowska, Grazyna; Miguel-Hidalgo, Jose J; Stockmeier, Craig A; Woolverton, William L; Kyle, Patrick B; Wang, Zhixia; Austin, Mark C

    2010-09-01

    Serotonin1A (5-HT(1A)) receptors are reported altered in the brain of subjects with major depressive disorder (MDD). Recent studies have identified transcriptional regulators of the 5-HT(1A) receptor and have documented gender-specific alterations in 5-HT(1A) transcription factor and 5-HT(1A) receptors in female MDD subjects. The 5' repressor element under dual repression binding protein-1 (Freud-1) is a calcium-regulated repressor that negatively regulates the 5-HT(1A) receptor gene. This study documented the cellular expression of Freud-1 in the human prefrontal cortex (PFC) and quantified Freud-1 protein in the PFC of MDD and control subjects as well as in the PFC of rhesus monkeys chronically treated with fluoxetine. Freud-1 immunoreactivity was present in neurons and glia and was co-localized with 5-HT(1A) receptors. Freud-1 protein level was significantly decreased in the PFC of male MDD subjects (37%, p=0.02) relative to gender-matched control subjects. Freud-1 protein was also reduced in the PFC of female MDD subjects (36%, p=0.18) but was not statistically significant. When the data was combined across genders and analysed by age, the decrease in Freud-1 protein level was greater in the younger MDD subjects (48%, p=0.01) relative to age-matched controls as opposed to older depressed subjects. Similarly, 5-HT(1A) receptor protein was significantly reduced in the PFC of the younger MDD subjects (48%, p=0.01) relative to age-matched controls. Adult male rhesus monkeys administered fluoxetine daily for 39 wk revealed no significant change in cortical Freud-1 or 5-HT(1A) receptor proteins compared to vehicle-treated control monkeys. Reduced protein expression of Freud-1 in MDD subjects may reflect dysregulation of this transcription factor, which may contribute to the altered regulation of 5-HT(1A) receptors observed in subjects with MDD. These data may also suggest that reductions in Freud-1 protein expression in the PFC may be associated with early onset of

  4. The Role of C-SRC Activation in Prostate Tumor Progression

    Science.gov (United States)

    2006-07-01

    cancer cell line PANC -1 and prostrate cancer cell line PC-3 (B2-fold increase relative to control in both cell lines), while the Src inhibitory PP2 blocks...at normoxia in PANC -1 and PC-3 cells, its levels significantly increase in response to hypoxia (B4.5–8-fold induction). Inhibition of endo- genous c...Src activation in PANC -1 and PC-3 cells by PP2 drastically reduced HIF-1a levels to below those levels observed at normoxia (Figure 1a). STAT3 has

  5. demographic factors associated factors associated with malaria

    African Journals Online (AJOL)

    userpc

    .8%) than those in other nce of 35.4% which was actors can predispose alence of malaria in a study were significantly eveloping guidelines and more effective disease endemic areas (Bashar et therefore attempts to rmation on possible demographic factors d out in four selected geria; Major Ibrahim B. Hospital Zaria, Hajiya.

  6. Hereditary mixed polyposis syndrome due to a BMPR1A mutation.

    LENUS (Irish Health Repository)

    O'Riordan, J M

    2010-06-01

    The conditions Juvenile Polyposis Syndrome (JPS) and Hereditary Mixed Polyposis Syndrome (HMPS) are associated with an increased risk of colorectal carcinoma. The genetic mechanisms which explain these conditions have until recently been poorly understood. Recent interest has focused on the transforming growth factor (TGF)-beta signalling pathway and, in particular, on mutations in the SMAD4 gene. However, not all cases of JPS and HMPS have mutations in SMAD4 and focus has now shifted to other components of the TGF-beta pathway to clarify the genetic mechanisms involved in these conditions. In this report, we describe the significance of a bone morphogenetic protein receptor type 1A gene mutation in an Irish family.

  7. Hypoxia/reoxygenation stress signals an increase in organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier: relevance to CNS drug delivery.

    Science.gov (United States)

    Thompson, Brandon J; Sanchez-Covarrubias, Lucy; Slosky, Lauren M; Zhang, Yifeng; Laracuente, Mei-li; Ronaldson, Patrick T

    2014-04-01

    Cerebral hypoxia and subsequent reoxygenation stress (H/R) is a component of several diseases. One approach that may enable neural tissue rescue after H/R is central nervous system (CNS) delivery of drugs with brain protective effects such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (i.e., statins). Our present in vivo data show that atorvastatin, a commonly prescribed statin, attenuates poly (ADP-ribose) polymerase (PARP) cleavage in the brain after H/R, suggesting neuroprotective efficacy. However, atorvastatin use as a CNS therapeutic is limited by poor blood-brain barrier (BBB) penetration. Therefore, we examined regulation and functional expression of the known statin transporter organic anion transporting polypeptide 1a4 (Oatp1a4) at the BBB under H/R conditions. In rat brain microvessels, H/R (6% O2, 60 minutes followed by 21% O2, 10 minutes) increased Oatp1a4 expression. Brain uptake of taurocholate (i.e., Oap1a4 probe substrate) and atorvastatin were reduced by Oatp inhibitors (i.e., estrone-3-sulfate and fexofenadine), suggesting involvement of Oatp1a4 in brain drug delivery. Pharmacological inhibition of transforming growth factor-β (TGF-β)/activin receptor-like kinase 5 (ALK5) signaling with the selective inhibitor SB431542 increased Oatp1a4 functional expression, suggesting a role for TGF-β/ALK5 signaling in Oatp1a4 regulation. Taken together, our novel data show that targeting an endogenous BBB drug uptake transporter (i.e., Oatp1a4) may be a viable approach for optimizing CNS drug delivery for treatment of diseases with an H/R component.

  8. AVPR1a and SLC6A4 Gene Polymorphisms Are Associated with Creative Dance Performance.

    Directory of Open Access Journals (Sweden)

    2005-09-01

    Full Text Available Dancing, which is integrally related to music, likely has its origins close to the birth of Homo sapiens, and throughout our history, dancing has been universally practiced in all societies. We hypothesized that there are differences among individuals in aptitude, propensity, and need for dancing that may partially be based on differences in common genetic polymorphisms. Identifying such differences may lead to an understanding of the neurobiological basis of one of mankind's most universal and appealing behavioral traits-dancing. In the current study, 85 current performing dancers and their parents were genotyped for the serotonin transporter (SLC6A4: promoter region HTTLPR and intron 2 VNTR and the arginine vasopressin receptor 1a (AVPR1a: promoter microsatellites RS1 and RS3. We also genotyped 91 competitive athletes and a group of nondancers/nonathletes (n = 872 subjects from 414 families. Dancers scored higher on the Tellegen Absorption Scale, a questionnaire that correlates positively with spirituality and altered states of consciousness, as well as the Reward Dependence factor in Cloninger's Tridimensional Personality Questionnaire, a measure of need for social contact and openness to communication. Highly significant differences in AVPR1a haplotype frequencies (RS1 and RS3, especially when conditional on both SLC6A4 polymorphisms (HTTLPR and VNTR, were observed between dancers and athletes using the UNPHASED program package (Cocaphase: likelihood ratio test [LRS] = 89.23, p = 0.000044. Similar results were obtained when dancers were compared to nondancers/nonathletes (Cocaphase: LRS = 92.76, p = 0.000024. These results were confirmed using a robust family-based test (Tdtphase: LRS = 46.64, p = 0.010. Association was also observed between Tellegen Absorption Scale scores and AVPR1a (Qtdtphase: global chi-square = 26.53, p = 0.047, SLC6A4 haplotypes (Qtdtphase: chi-square = 2.363, p = 0.018, and AVPR1a conditional on SCL6A4 (Tdtphase: LRS

  9. AVPR1a and SLC6A4 gene polymorphisms are associated with creative dance performance.

    Directory of Open Access Journals (Sweden)

    Rachel Bachner-Melman

    2005-09-01

    Full Text Available Dancing, which is integrally related to music, likely has its origins close to the birth of Homo sapiens, and throughout our history, dancing has been universally practiced in all societies. We hypothesized that there are differences among individuals in aptitude, propensity, and need for dancing that may partially be based on differences in common genetic polymorphisms. Identifying such differences may lead to an understanding of the neurobiological basis of one of mankind's most universal and appealing behavioral traits--dancing. In the current study, 85 current performing dancers and their parents were genotyped for the serotonin transporter (SLC6A4: promoter region HTTLPR and intron 2 VNTR and the arginine vasopressin receptor 1a (AVPR1a: promoter microsatellites RS1 and RS3. We also genotyped 91 competitive athletes and a group of nondancers/nonathletes (n = 872 subjects from 414 families. Dancers scored higher on the Tellegen Absorption Scale, a questionnaire that correlates positively with spirituality and altered states of consciousness, as well as the Reward Dependence factor in Cloninger's Tridimensional Personality Questionnaire, a measure of need for social contact and openness to communication. Highly significant differences in AVPR1a haplotype frequencies (RS1 and RS3, especially when conditional on both SLC6A4 polymorphisms (HTTLPR and VNTR, were observed between dancers and athletes using the UNPHASED program package (Cocaphase: likelihood ratio test [LRS] = 89.23, p = 0.000044. Similar results were obtained when dancers were compared to nondancers/nonathletes (Cocaphase: LRS = 92.76, p = 0.000024. These results were confirmed using a robust family-based test (Tdtphase: LRS = 46.64, p = 0.010. Association was also observed between Tellegen Absorption Scale scores and AVPR1a (Qtdtphase: global chi-square = 26.53, p = 0.047, SLC6A4 haplotypes (Qtdtphase: chi-square = 2.363, p = 0.018, and AVPR1a conditional on SCL6A4 (Tdtphase: LRS

  10. 5,6-Dihydropyrrolo[2,1-a]isoquinolines as Alternative of New Drugs with Cytotoxic Activity

    Czech Academy of Sciences Publication Activity Database

    Chávez-Santos, R. M.; Reyes Gutierrez, Paul Eduardo; Torres-Ochoa, R. O.; Ramírez-Apan, M. T.; Martínez, R.

    2017-01-01

    Roč. 65, č. 10 (2017), s. 973-981 ISSN 0009-2363 Institutional support: RVO:61388963 Keywords : pyrrolo[2,1-a]isoquinoline * synthesis * cytotoxic activity Subject RIV: CC - Organic Chemistry OBOR OECD: Organic chemistry Impact factor: 1.133, year: 2016 https://www.jstage.jst.go.jp/article/cpb/65/10/65_c17-00409/_html/-char/en

  11. A neutron scattering study of the ternary complex EF-Tu.GTP-valyl-tRNAVal1A

    DEFF Research Database (Denmark)

    Österberg, R.; Elias, P.; Kjems, Jørgen

    1986-01-01

    The complex formation between elongation factor Tu (EF-Tu), GTP, and valyl-tRNAVal1A has been investigated in a hepes buffer of "pH" 7.4 and 0.2 M ionic strength using the small-angle neutron scattering method at concentrations of D2O where EF-Tu (42% D2O) and tRNA (71% D2O) are successively...

  12. LONG CARBON-CHAIN MOLECULES AND THEIR ANIONS IN THE STARLESS CORE, LUPUS-1A

    International Nuclear Information System (INIS)

    Sakai, Nami; Shiino, Tatsuya; Yamamoto, Satoshi; Hirota, Tomoya; Sakai, Takeshi

    2010-01-01

    We have recently discovered a new starless core with bright radio emissions of long carbon-chain molecules in the Lupus molecular cloud, which we have named as Lupus-1A. Toward this source, the peak intensities of the C 6 H and C 8 H lines are found to be higher than toward TMC-1 by a factor of 2-3. Even the lines of their anions, C 6 H - and C 8 H - , are also brighter than in TMC-1. Moreover, the line of C 4 H - has been detected for the first time in a starless core. The column densities of these long carbon-chain molecules are almost comparable to those in TMC-1, and hence, this source can be regarded as the second 'TMC-1 like cloud'. TMC-1 has long been an outstanding molecular cloud with rich carbon-chain molecules since its discovery in 1976. In spite of extensive efforts, no comparable sources have been found so far. Lupus-1A will be used for hunting of new interstellar molecules as well as understanding of carbon-chain chemistry through critical comparison of physical and chemical properties with TMC-1. This source is important not only for astronomy but also for molecular science as an ideal spectroscopic laboratory because of narrow line shapes and bright intensities.

  13. Aspects of QCD factorization

    International Nuclear Information System (INIS)

    Neubert, Matthias

    2001-01-01

    The QCD factorization approach provides the theoretical basis for a systematic analysis of nonleptonic decay amplitudes of B mesons in the heavy-quark limit. After recalling the basic ideas underlying this formalism, several tests of QCD factorization in the decays B→D (*) L, B→K * γ, and B→πK, ππ are discussed. It is then illustrated how factorization can be used to obtain new constraints on the parameters of the unitarity triangle

  14. Oversimplifying quantum factoring.

    Science.gov (United States)

    Smolin, John A; Smith, Graeme; Vargo, Alexander

    2013-07-11

    Shor's quantum factoring algorithm exponentially outperforms known classical methods. Previous experimental implementations have used simplifications dependent on knowing the factors in advance. However, as we show here, all composite numbers admit simplification of the algorithm to a circuit equivalent to flipping coins. The difficulty of a particular experiment therefore depends on the level of simplification chosen, not the size of the number factored. Valid implementations should not make use of the answer sought.

  15. Cloning and characterization of GETS-1, a goldfish Ets family member that functions as a transcriptional repressor in muscle.

    Science.gov (United States)

    Goldman, D; Sapru, M K; Stewart, S; Plotkin, J; Libermann, T A; Wasylyk, B; Guan, K

    1998-10-15

    An Ets transcription factor family member, GETS-1, was cloned from a goldfish retina cDNA library. GETS-1 contains a conserved Ets DNA-binding domain at its N-terminus and is most similar to ternary complex factor (TCF) serum-response-factor protein-1a (SAP-1a). GETS-1 is expressed in many tissues, but is enriched in retina and brain. As with the TCFs SAP-1a and ets-related protein (ERP), overexpression of the GETS-1 promoter suppresses nicotinic acetylcholine receptor epsilon-subunit gene expression in cultured muscle cells. A consensus Ets binding site sequence in the promoter of the epsilon-subunit gene is required for GETS-1-mediated repression. GETS-1 repressor activity is abrogated by overexpression of an activated Ras/mitogen-activated protein kinase (MAP kinase) or by mutation of Ser-405, a MAP kinase phosphorylation site in GETS-1. Fusion proteins created between GETS-1 and the Gal4 DNA-binding domain show that, like other TCFs, GETS-1 contains a C-terminal activation domain that is activated by a Ras/MAP kinase signalling cascade. Interestingly, mutation of Ser-405 located within this activation domain abrogated transcriptional activation of the fusion protein.

  16. Dyrk1A-ASF-CaMKIIδ Signaling Is Involved in Valsartan Inhibition of Cardiac Hypertrophy in Renovascular Hypertensive Rats.

    Science.gov (United States)

    Yao, Jian; Qin, Xiaotong; Zhu, Jianhua; Sheng, Hongzhuan

    2016-01-01

    It is known that the expression, activity and alternative splicing of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) are dysregulated in the cardiac remodeling process. Recently, we found a further signaling pathway, by which dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) regulates the alternative splicing of CaMKIIδ via the alternative splicing factor (ASF), i.e., Dyrk1A-ASF-CaMKIIδ. In this study, we aimed to investigate whether Dyrk1A-ASF-CaMKIIδ signaling was involved in valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats. Rats were subjected to two kidney-one clip (2K1C) surgery and then treated with valsartan (30 mg/kg/day) for 8 weeks. Hypertrophic parameter analysis was then performed. Western blot analysis was used to determine the protein expression of Dyrk1A and ASF and RT-PCR was used to analyze the alternative splicing of CaMKIIδ in the left ventricular (LV) sample. Valsartan attenuated cardiac hypertrophy in 2K1C rats but without impairment of cardiac systolic function. Increased protein expression of Dyrk1A and decreased protein expression of ASF were observed in the LV sample of 2K1C rats. Treatment of 2K1C rats with valsartan reversed the changes in Dyrk1A and ASF expression in the LV sample. Valsartan adjusted the 2K1C-induced imbalance in alternative splicing of CaMKIIδ by upregulating the mRNA expression of CaMKIIδC and downregulating the mRNA expression of CaMKIIδA and CaMKIIδB. Valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats was mediated, at least partly, by Dyrk1A-ASF-CaMKIIδ signaling. © 2015 S. Karger AG, Basel.

  17. A combination of genomic approaches reveals the role of FOXO1a in regulating an oxidative stress response pathway.

    Directory of Open Access Journals (Sweden)

    Paola de Candia

    2008-02-01

    Full Text Available While many of the phenotypic differences between human and chimpanzee may result from changes in gene regulation, only a handful of functionally important regulatory differences are currently known. As a first step towards identifying transcriptional pathways that have been remodeled in the human lineage, we focused on a transcription factor, FOXO1a, which we had previously found to be up-regulated in the human liver compared to that of three other primate species. We concentrated on this gene because of its known role in the regulation of metabolism and in longevity.Using a combination of expression profiling following siRNA knockdown and chromatin immunoprecipitation in a human liver cell line, we identified eight novel direct transcriptional targets of FOXO1a. This set includes the gene for thioredoxin-interacting protein (TXNIP, the expression of which is directly repressed by FOXO1a. The thioredoxin-interacting protein is known to inhibit the reducing activity of thioredoxin (TRX, thereby hindering the cellular response to oxidative stress and affecting life span.Our results provide an explanation for the repeated observations that differences in the regulation of FOXO transcription factors affect longevity. Moreover, we found that TXNIP is down-regulated in human compared to chimpanzee, consistent with the up-regulation of its direct repressor FOXO1a in humans, and with differences in longevity between the two species.

  18. The Anticancer Effects of Radachlorin-mediated Photodynamic Therapy in the Human Endometrial Adenocarcinoma Cell Line HEC-1-A.

    Science.gov (United States)

    Kim, Su-Mi; Rhee, Yun-Hee; Kim, Jong-Soo

    2017-11-01

    We investigated the effect of photodynamic therapy (PDT) using radachlorin on invasion, vascular formation and apoptosis by targeting epidermal growth factor receptor (EGFR)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling pathways in the HEC-1-A endometrial adenocarcinoma cell line. To investigate the apoptotic pathway, we performed the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, and western blot analysis. We also evaluated the effects of PDT on tubular capillary formation in and invasion by HEC-1-A cells with a tube formation assay, invasion assay, prostaglandin E2 (PGE2) assay, and western blot analysis. PDT had anticancer effects on HEC-1-A through activation of the intrinsic pathway of apoptosis via caspase-9 and poly-(ADP-ribose) polymerase (PARP). PDT also inhibited tubular capillary formation in and invasion by HEC-1-A under VEGF pretreatment, that resulted from down-regulation of VEGFR2, EGFR, Ras homolog gene family/ member A (RhoA) and PGE2. These results are indicative of the specificity of radachlorin-mediated PDT to VEGF. The major advantage of radachlorin-mediated PDT is its selectivity for cancer tissue while maintaining adjacent normal endometrial tissue. Therefore, radachlorin-mediated PDT might offer high anticancer efficacy for endometrial adenocarcinoma and an especially useful modality for preserving fertility. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  19. Radioimmunoassay of human Hageman factor (factor XII)

    International Nuclear Information System (INIS)

    Saito, H.; Ratnoff, O.D.; Pensky, J.

    1976-01-01

    A specific, sensitive, and reproducible radioimmunoassay for human Hageman factor (HF, factor XII) has been developed with purified human HF and monospecific rabbit antibody. Precise measurements of HF antigen were possible for concentrations as low as 0.1 percent of that in normal pooled plasma. A good correlation (correlation coefficient = 0.82) existed between the titers of HF measured by clot-promoting assays and radioimmunoassays among 42 normal adults. Confirming earlier studies, HF antigen was absent in Hageman trait plasma, but other congenital deficient plasmas, including those of individuals with Fletcher trait and Fitzgerald trait, contained normal amounts of HF antigen. HF antigen was reduced in the plasmas of patients with disseminated intravascular coagulation or advanced liver cirrhosis, but it was normal in those of patients with chronic renal failure or patients under treatment with warfarin. HF antigen was detected by this assay in plasmas of primates, but not detectable in plasmas of 11 nonprimate mammalian and one avian species

  20. CROSS-REACTIVITY OF MONOCLONAL ANTIBODIES AGAINST PEPTIDE 277-294 OF RAINBOW TROUT CYP1A1 WITH HEPATIC CYP1A AMONG FISH. (R823881)

    Science.gov (United States)

    AbstractExposure to a variety of xenobiotics, including polychlorinated biphenyls (PCBs) and polycyclic aromatic hydrocarbons (PAHs), results in the induction of CYP1A and related biological activity. Historically, antibodies against purified CYP1A have been raised...

  1. The association between romantic relationship status and 5-HT1A gene in young adults.

    Science.gov (United States)

    Liu, Jinting; Gong, Pingyuan; Zhou, Xiaolin

    2014-11-20

    What factors determine whether or not a young adult will fall in love? Sociological surveys and psychological studies have shown that non-genetic factors, such as socioeconomic status, external appearance, and personality attributes, are crucial components in romantic relationship formation. Here we demonstrate that genetic variants also contribute to romantic relationship formation. As love-related behaviors are associated with serotonin levels in the brain, this study investigated to what extent a polymorphism (C-1019G, rs6295) of 5-HT1A gene is related to relationship status in 579 Chinese Han people. We found that 50.4% of individuals with the CC genotype and 39.0% with CG/GG genotype were in romantic relationship. Logistic regression analysis indicated that the C-1019G polymorphism was significantly associated with the odds of being single both before and after controlling for socioeconomic status, external appearance, religious beliefs, parenting style, and depressive symptoms. These findings provide, for the first time, direct evidence for the genetic contribution to romantic relationship formation.

  2. High fructose consumption induces DNA methylation at PPARα and CPT1A promoter regions in the rat liver

    Energy Technology Data Exchange (ETDEWEB)

    Ohashi, Koji [Department of Clinical Biochemistry, Fujita Health University School of Health Sciences, Toyoake (Japan); Munetsuna, Eiji [Department of Biochemistry, Fujita Health University School of Medicine, Toyoake (Japan); Yamada, Hiroya, E-mail: hyamada@fujita-hu.ac.jp [Department of Hygiene, Fujita Health University School of Medicine, Toyoake (Japan); Ando, Yoshitaka [Department of Joint Research Laboratory of Clinical Medicine, Fujita Health University Hospital, Toyoake (Japan); Yamazaki, Mirai; Taromaru, Nao; Nagura, Ayuri; Ishikawa, Hiroaki [Department of Clinical Biochemistry, Fujita Health University School of Health Sciences, Toyoake (Japan); Suzuki, Koji [Department of Public Health, Fujita Health University School of Health Sciences, Toyoake (Japan); Teradaira, Ryoji [Department of Clinical Biochemistry, Fujita Health University School of Health Sciences, Toyoake (Japan); Hashimoto, Shuji [Department of Hygiene, Fujita Health University School of Medicine, Toyoake (Japan)

    2015-12-04

    DNA methylation status is affected by environmental factors, including nutrition. Fructose consumption is considered a risk factor for the conditions that make up metabolic syndrome such as dyslipidemia. However, the pathogenetic mechanism by which fructose consumption leads to metabolic syndrome is unclear. Based on observations that epigenetic modifications are closely related to induction of metabolic syndrome, we hypothesized that fructose-induced metabolic syndrome is caused by epigenetic alterations. Male SD rats were designated to receive water or 20% fructose solution for 14 weeks. mRNA levels for peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1A (CPT1A) was analyzed using Real-time PCR. Restriction digestion and real-time PCR (qAMP) was used for the analysis of DNA methylation status. Hepatic lipid accumulation was also observed by fructose intake. Fructose feeding also significantly decreased mRNA levels for PPARα and CPT1A. qAMP analysis demonstrated the hypermethylation of promoter regions of PPARα and CTP1A genes. Fructose-mediated attenuated gene expression may be mediated by alterations of DNA methylation status, and pathogenesis of metabolic syndrome induced by fructose relates to DNA methylation status. - Highlights: • No general consensus has been reached regarding the molecular mechanisms of the pathogenesis of fructose-induced diseases. • Significant increase in hepatic total methylation level was observed after fructose-supplemented feeding. • Fructose feeding significantly decreased mRNA levels for PPARα and CPT1A. • qAMP analysis demonstrated the hypermethylation of promoter regions of PPARα and CTP1A genes. • Fructose-mediated attenuated gene expression may be mediated by alterations of DNA methylation status in rat liver.

  3. High fructose consumption induces DNA methylation at PPARα and CPT1A promoter regions in the rat liver

    International Nuclear Information System (INIS)

    Ohashi, Koji; Munetsuna, Eiji; Yamada, Hiroya; Ando, Yoshitaka; Yamazaki, Mirai; Taromaru, Nao; Nagura, Ayuri; Ishikawa, Hiroaki; Suzuki, Koji; Teradaira, Ryoji; Hashimoto, Shuji

    2015-01-01

    DNA methylation status is affected by environmental factors, including nutrition. Fructose consumption is considered a risk factor for the conditions that make up metabolic syndrome such as dyslipidemia. However, the pathogenetic mechanism by which fructose consumption leads to metabolic syndrome is unclear. Based on observations that epigenetic modifications are closely related to induction of metabolic syndrome, we hypothesized that fructose-induced metabolic syndrome is caused by epigenetic alterations. Male SD rats were designated to receive water or 20% fructose solution for 14 weeks. mRNA levels for peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase 1A (CPT1A) was analyzed using Real-time PCR. Restriction digestion and real-time PCR (qAMP) was used for the analysis of DNA methylation status. Hepatic lipid accumulation was also observed by fructose intake. Fructose feeding also significantly decreased mRNA levels for PPARα and CPT1A. qAMP analysis demonstrated the hypermethylation of promoter regions of PPARα and CTP1A genes. Fructose-mediated attenuated gene expression may be mediated by alterations of DNA methylation status, and pathogenesis of metabolic syndrome induced by fructose relates to DNA methylation status. - Highlights: • No general consensus has been reached regarding the molecular mechanisms of the pathogenesis of fructose-induced diseases. • Significant increase in hepatic total methylation level was observed after fructose-supplemented feeding. • Fructose feeding significantly decreased mRNA levels for PPARα and CPT1A. • qAMP analysis demonstrated the hypermethylation of promoter regions of PPARα and CTP1A genes. • Fructose-mediated attenuated gene expression may be mediated by alterations of DNA methylation status in rat liver.

  4. Data of evolutionary structure change: 1A5CA-2QUTD [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available ryChain> 2QUT D 2QUTD ence>LLTADDRVNPC...T D 2QUTD ence>INKCPLLKPWA...1A5CA-2QUTD 1A5C 2QUT A D ------LPADVAEELATTAQKLVQAGKGILAADESTQTI...bID> A 1A5CA ence>LFGTK-GLGKFence> 1 1A5C A 1A5CA

  5. What Are Rare Clotting Factor Deficiencies?

    Science.gov (United States)

    ... Deficiency Factor V Deficiency Combined FV & FVIII Deficiencies Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor ... Deficiency Factor V Deficiency Combined FV & FVIII Deficiencies Factor VII Deficiency Factor X Deficiency Factor XI Deficiency Factor ...

  6. PAYMENT CAPACITY SENSITIVITY FACTORS

    Directory of Open Access Journals (Sweden)

    Daniel BRÎNDESCU – OLARIU

    2014-11-01

    The results of the study facilitate the determination and classification of the main sensitivity factors for the payment capacity at sample level, the establishment of general benchmarks for the payment capacity (as no such benchmarks currently exist in the Romanian literature and the identification of the mechanisms through which the variation of different factors impacts the payment capacity.

  7. Respirator field performance factors

    International Nuclear Information System (INIS)

    Skaggs, B.J.; DeField, J.D.; Strandberg, S.W.; Sutcliffe, C.R.

    1985-01-01

    The Industrial Hygiene Group assisted OSHA and the NRC in measurements of respirator performance under field conditions. They reviewed problems associated with sampling aerosols within the respirator in order to determine fit factors (FFs) or field performance factor (FPF). In addition, they designed an environmental chamber study to determine the effects of temperature and humidity on a respirator wearer

  8. Factors affecting nuclear development

    International Nuclear Information System (INIS)

    Stevens, G.H.; Girouard, P.

    1995-01-01

    Among the factors affecting nuclear development, some depend more or less on public authorities, but many are out of public authorities control (foreign policies, market and deregulation, socials and environmental impacts, public opinion). As far as possible, the following study tries to identify those factors. (D.L.). 2 photos

  9. Soil Forming Factors

    Science.gov (United States)

    It! What is Soil? Chip Off the Old Block Soil Forming Factors Matters of Life and Death Underneath It All Wise Choices A World of Soils Soil Forming Factors 2 A Top to Bottom Guide 3 Making a Soil Monolith 4 Soil Orders 5 State Soil Monoliths 6 Where in the Soil World Are You? >> A Top to

  10. Over-expression of CHAF1A promotes cell proliferation and apoptosis resistance in glioblastoma cells via AKT/FOXO3a/Bim pathway

    International Nuclear Information System (INIS)

    Peng, Honghai; Du, Bin; Jiang, Huili; Gao, Jun

    2016-01-01

    Chromatinassembly factor 1 subunit A (CHAF1A) has been reported to be involved in several human diseases including cancer. However, the biological and clinical significance of CHAF1A in glioblastoma progression remains largely unknown. In this study, we found that up-regulation of CHAF1A happens frequently in glioblastoma tissues and is associated with glioblastoma prognosis. Knockout of CHAF1A by CRISPR/CAS9 technology induce G1 phase arrest and apoptosis in glioblastoma cell U251 and U87. In addition, inhibition of CHAF1A influenced the signal transduction of the AKT/FOXO3a/Bim axis, which is required for glioblastoma cell proliferation. Taken together, these results show that CHAF1A contributes to the proliferation of glioblastoma cells and may be developed as a de novo drug target and prognosis biomarker of glioblastoma.

  11. Over-expression of CHAF1A promotes cell proliferation and apoptosis resistance in glioblastoma cells via AKT/FOXO3a/Bim pathway

    Energy Technology Data Exchange (ETDEWEB)

    Peng, Honghai; Du, Bin [Department of Neurosurgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013 (China); Jiang, Huili [Friendship Nephrology and Blood Purification Center, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013 (China); Gao, Jun, E-mail: gaoj1666@126.com [Department of Neurosurgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013 (China)

    2016-01-22

    Chromatinassembly factor 1 subunit A (CHAF1A) has been reported to be involved in several human diseases including cancer. However, the biological and clinical significance of CHAF1A in glioblastoma progression remains largely unknown. In this study, we found that up-regulation of CHAF1A happens frequently in glioblastoma tissues and is associated with glioblastoma prognosis. Knockout of CHAF1A by CRISPR/CAS9 technology induce G1 phase arrest and apoptosis in glioblastoma cell U251 and U87. In addition, inhibition of CHAF1A influenced the signal transduction of the AKT/FOXO3a/Bim axis, which is required for glioblastoma cell proliferation. Taken together, these results show that CHAF1A contributes to the proliferation of glioblastoma cells and may be developed as a de novo drug target and prognosis biomarker of glioblastoma.

  12. DMPD: IRAK1: a critical signaling mediator of innate immunity. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 17890055 IRAK1: a critical signaling mediator of innate immunity. Gottipati S, Rao ...IRAK1: a critical signaling mediator of innate immunity. PubmedID 17890055 Title IRAK1: a critical signaling mediator

  13. Association of IL1A and IL1B loci with primary open angle glaucoma

    Directory of Open Access Journals (Sweden)

    Mukhopadhyay Indranil

    2010-06-01

    Full Text Available Abstract Background Recent studies suggest that glaucoma is a neurodegenerative disease in which secondary degenerative losses occur after primary insult by raised Intraocular pressure (IOP or by other associated factors. It has been reported that polymorphisms in the IL1A and IL1B genes are associated with Primary Open Angle Glaucoma (POAG. The purpose of our study was to investigate the role of these polymorphisms in eastern Indian POAG patients. Methods The study involved 315 unrelated POAG patients, consisting of 116 High Tension Glaucoma (HTG patients with intra ocular pressure (IOP > 21 mmHg and 199 non-HTG patients (presenting IOP IL1A (-889C/T; rs1800587, IL1B (-511C/T; rs16944 and IL1B (3953C/T; rs1143634. Haplotype frequency was determined by Haploview 4.1 software. The association of individual SNPs and major haplotypes was evaluated using chi-square statistics. The p-value was corrected for multiple tests by Bonferroni method. Results No significant difference was observed in the allele and genotype frequencies for IL1A and IL1B SNPs between total pool of POAG patients and controls. However, on segregating the patient pool to HTG and non-HTG groups, weak association was observed for IL1A polymorphism (-889C/T where -889C allele was found to portray risk (OR = 1.380; 95% CI = 1.041-1.830; p = 0.025 for non-HTG patients. Similarly, 3953T allele of IL1B polymorphism (+3953C/T was observed to confer risk to HTG group (OR = 1.561; 95% CI = 1.022-2.385; p = 0.039. On haplotype analysis it was observed that TTC was significantly underrepresented in non-HTG patients (OR = 0.538; 95% CI = 0.356- 0.815; p = 0.003 while TCT haplotype was overrepresented in HTG patients (OR = 1.784; 95% CI = 1.084- 2.937; p = 0.022 compared to control pool. However, after correction for multiple tests by Bonferroni method, an association of only TTC haplotype with non-HTG cases sustained (pcorrected = 0.015 and expected to confer protection. Conclusion The study

  14. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes.

    Directory of Open Access Journals (Sweden)

    Dennis Lal

    Full Text Available The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic.We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients.We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%. Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1 are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10-4; OR = 0.32, fishers exact test, previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.

  15. Changes in serotoninergic receptors 1A and 2A in the piglet brainstem after intermittent hypercapnic hypoxia (IHH) and nicotine.

    Science.gov (United States)

    Say, Meichien; Machaalani, Rita; Waters, Karen A

    2007-06-04

    We studied the effects of intermittent hypercapnic hypoxia (IHH) and/or nicotine on the immunoreactivity of serotoninergic (5-HT) receptors 1A and 2A in the piglet brainstem. These exposures were developed to mimic two common risk factors for Sudden Infant Death Syndrome (SIDS); prone sleeping (IHH) and cigarette smoke exposure (nicotine). Immunoreactivity for 5-HT(1A)R and 5-HT(2A)R were studied in four nuclei of the caudal medulla. Three exposure groups were compared to controls (n=14): IHH (n=10), nicotine (n=14), and nicotine+IHH (n=14). In control piglets, the immunoreactivity of 5-HT(1A)R was highest in the hypoglossal nucleus (XII), followed by inferior olivary nucleus (ION), nucleus of the solitary tract (NTS) and dorsal motor nucleus of the vagus (DMNV), whereas for 5-HT(2A)R, the immunoreactivity was highest in DMNV/NTS and then ION. Compared to controls, IHH reduced 5-HT(1A)R immunoreactivity in all studied nuclei (pIHH reduced 5-HT(1A)R in DMNV, ION and NTS (pIHH and/or nicotine can reduce 5-HT receptor immunoreactivity within functionally important nuclei of the piglet medulla. The findings support our hypothesis that 5-HT receptor abnormalities may be caused by postnatal exposures to clinically-relevant stimuli such as cigarette smoke exposure and/or prone sleeping.

  16. Computational modeling on the recognition of the HRE motif by HIF-1: molecular docking and molecular dynamics studies.

    Science.gov (United States)

    Sokkar, Pandian; Sathis, Vani; Ramachandran, Murugesan

    2012-05-01

    Hypoxia inducible factor-1 (HIF-1) is a bHLH-family transcription factor that controls genes involved in glycolysis, angiogenesis, migration, as well as invasion factors that are important for tumor progression and metastasis. HIF-1, a heterodimer of HIF-1α and HIF-1β, binds to the hypoxia responsive element (HRE) present in the promoter regions of hypoxia responsive genes, such as vascular endothelial growth factor (VEGF). Neither the structure of free HIF-1 nor that of its complex with HRE is available. Computational modeling of the transcription factor-DNA complex has always been challenging due to their inherent flexibility and large conformational space. The present study aims to model the interaction between the DNA-binding domain of HIF-1 and HRE. Experiments showed that rigid macromolecular docking programs (HEX and GRAMM-X) failed to predict the optimal dimerization of individually modeled HIF-1 subunits. Hence, the HIF-1 heterodimer was modeled based on the phosphate system positive regulatory protein (PHO4) homodimer. The duplex VEGF-DNA segment containing HRE with flanking nucleotides was modeled in the B form and equilibrated via molecular dynamics (MD) simulation. A rigid docking approach was used to predict the crude binding mode of HIF-1 dimer with HRE, in which the putative contacts were found to be present. An MD simulation (5 ns) of the HIF-1-HRE complex in explicit water was performed to account for its flexibility and to optimize its interactions. All of the conserved amino acid residues were found to play roles in the recognition of HRE. The present work, which sheds light on the recognition of HRE by HIF-1, could be beneficial in the design of peptide or small molecule therapeutics that can mimic HIF-1 and bind with the HRE sequence.

  17. Two-factor authentication

    CERN Document Server

    Stanislav, Mark

    2015-01-01

    During the book, readers will learn about the various technical methods by which two-factor authentication is implemented, security concerns with each type of implementation, and contextual details to frame why and when these technologies should be used. Readers will also be provided with insight about the reasons that two-factor authentication is a critical security control, events in history that have been important to prove why organization and individual would want to use two factor, and core milestones in the progress of growing the market.

  18. Business Intelligence Success Factors

    DEFF Research Database (Denmark)

    Gaardboe, Rikke; Jonasen, Tanja Svarre

    2018-01-01

    Business intelligence (BI) is a strategically important practice in many organizations. Several studies have investigated the factors that contribute to BI success; however, an overview of the critical success factors (CSFs) involved is lacking in the extant literature. We have integrated...... 34 CSFs related to BI success. The distinct CSFs identified in the extant literature relate to project management skills (13 papers), management support (20 papers), and user involvement (11 papers). In the articles with operationalized BI success, we found several distinct factors: system quality...

  19. Human factor reliability program

    International Nuclear Information System (INIS)

    Knoblochova, L.

    2017-01-01

    The human factor's reliability program was at Slovenske elektrarne, a.s. (SE) nuclear power plants. introduced as one of the components Initiatives of Excellent Performance in 2011. The initiative's goal was to increase the reliability of both people and facilities, in response to 3 major areas of improvement - Need for improvement of the results, Troubleshooting support, Supporting the achievement of the company's goals. The human agent's reliability program is in practice included: - Tools to prevent human error; - Managerial observation and coaching; - Human factor analysis; -Quick information about the event with a human agent; -Human reliability timeline and performance indicators; - Basic, periodic and extraordinary training in human factor reliability(authors)

  20. [Human factors in medicine].

    Science.gov (United States)

    Lazarovici, M; Trentzsch, H; Prückner, S

    2017-01-01

    The concept of human factors is commonly used in the context of patient safety and medical errors, all too often ambiguously. In actual fact, the term comprises a wide range of meanings from human-machine interfaces through human performance and limitations up to the point of working process design; however, human factors prevail as a substantial cause of error in complex systems. This article presents the full range of the term human factors from the (emergency) medical perspective. Based on the so-called Swiss cheese model by Reason, we explain the different types of error, what promotes their emergence and on which level of the model error prevention can be initiated.

  1. Therapeutic Mechanism of BET Bromodomain Inhibitor in Breast

    Science.gov (United States)

    2015-12-01

    luminal-like do not disappear on acquisition of resistance. 5 Figure 5. BET bromo- domain inhibition gene expression response. Down-, up- and non...e, Gene tracks depicting Bio-JQ1 and BRD4 with or without JQ1 in SUM159 cells at the HIF1A locus. x-axis, chromosome position with gene structures...JQ1, BRD4, and H3K27ac at the BCL-xL (also known as BCL2L1; f) and SOD2 (g) locus. The x-axis shows position along the chromosome with gene

  2. Distribution of photoperiod-insensitive alleles Ppd-B1a and Ppd-D1a and their effect on heading time in Japanese wheat cultivars.

    Science.gov (United States)

    Seki, Masako; Chono, Makiko; Matsunaka, Hitoshi; Fujita, Masaya; Oda, Shunsuke; Kubo, Katashi; Kiribuchi-Otobe, Chikako; Kojima, Hisayo; Nishida, Hidetaka; Kato, Kenji

    2011-12-01

    The genotypes of photoperiod response genes Ppd-B1 and Ppd-D1 in Japanese wheat cultivars were determined by a PCR-based method, and heading times were compared among genotypes. Most of the Japanese wheat cultivars, except those from the Hokkaido region, carried the photoperiod-insensitive allele Ppd-D1a, and heading was accelerated 10.3 days compared with the Ppd-D1b genotype. Early cultivars with Ppd-D1a may have been selected to avoid damage from preharvest rain. In the Hokkaido region, Ppd-D1a frequency was lower and heading date was late regardless of Ppd-D1 genotype, suggesting another genetic mechanism for late heading in Hokkaido cultivars. In this study, only 11 cultivars proved to carry Ppd-B1a, and all of them carried another photoperiod-insensitive allele, Ppd-D1a. The Ppd-B1a/Ppd-D1a genotype headed 6.7 days earlier than the Ppd-B1b/Ppd-D1a genotype, indicating a significant effect of Ppd-B1a in the genetic background with Ppd-D1a. Early-maturity breeding in Japan is believed to be accelerated by the introduction of the Ppd-B1a allele into medium-heading cultivars carrying Ppd-D1a. Pedigree analysis showed that Ppd-B1a in three extra-early commercial cultivars was inherited from 'Shiroboro 21' by early-heading Chugoku lines bred at the Chugoku Agriculture Experimental Station.

  3. Positron emission tomography study of pindolol occupancy of 5-HT1A receptors in humans: preliminary analyses

    International Nuclear Information System (INIS)

    Martinez, Diana; Mawlawi, Osama; Hwang, Dah-Ren; Kent, Justine; Simpson, Norman; Parsey, Ramin V.; Hashimoto, Tomoki; Slifstein, Mark; Huang Yiyun; Heertum, Ronald van; Abi-Dargham, Anissa; Caltabiano, Stephen; Malizia, Andrea; Cowley, Hugh; Mann, J. John; Laruelle, Marc

    2000-01-01

    Preclinical studies in rodents suggest that augmentation of serotonin reuptake inhibitors (SSRIs) therapy by the 5-hydroxytryptamine 1A (5-HT 1A ) receptor agent pindolol might reduce the delay between initiation of treatment and antidepressant response. This hypothesis is based on the ability of pindolol to potentiate the increase in serotonin (5-HT) transmission induced by SSRIs, an effect achieved by blockade of the 5-HT 1A autoreceptors in the dorsal raphe nuclei (DRN). However, placebo-controlled clinical studies of pindolol augmentation of antidepressant therapy have reported inconsistent results. Here, we evaluated the occupancy of 5-HT 1A receptors following treatment with controlled release pindolol in nine healthy volunteers with positron-emission tomography (PET). Each subject was studied four times: at baseline (scan 1), following 1 week of oral administration of pindolol CR (7.5 mg/day) at peak level, 4 h after the dose (scan 2), and at 10 h following the dose (scan 3), and following one dose of pindolol CR (30 mg) (at peak level, 4 h) (scan 4). Pindolol occupancy of 5-HT 1A receptors was evaluated in the DRN and cortical regions as the decrease in binding potential (BP) of the radiolabelled selective 5-HT 1A antagonist [carbonyl- 11 C]WAY-100635 or [carbonyl- 11 C] N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl) cyclohexanecarboxamide abbreviated as [ 11 C]WAY-100635. Pindolol dose-dependently decreased [ 11 C]WAY-100635 BP. Combining all the regions, occupancy was 20 ± 8% at scan 2, 14 ± 8% at scan 3, and 44 ± 8% at scan 4. The results of this study suggest that at doses used in clinical studies of augmentation of the SSRI effect by pindolol (2.5 mg t.i.d.), the occupancy of 5-HT 1A receptors is moderate and highly variable between subjects. This factor might explain the variable results obtained in clinical studies. On the other hand, at each dose tested, pindolol occupancy of 5-HT 1A receptors was higher in the DRN compared to

  4. CYP1A1 m1 and m2 polymorphisms: genetic susceptibility to lung cancer

    Directory of Open Access Journals (Sweden)

    Paula Mota

    2010-01-01

    Full Text Available Lung cancer is considered an environment-related disease that develops as a consequence of exposure to mutagenic agents, namely those present in tobacco. The CYP1A1 gene codifies the phase I enzyme aryl hydrocarbon hydroxilase (AHH belonging to the cytochrome P450 system that plays a major role in the bio-activation of tobacco procarcinogenes. Two CYP1A1 polymorphisms, m1 (T6235C transition and m2 (A4889G transition, are associated with greater enzymatic activity and have been described as genetic susceptibility factors for lung cancer.The aim of this study was to verify if this association holds true in blood samples of 175 lung cancer patients and 217 non-cancer patients from Portugal's midlands region. The samples were studied by restriction fragment length polymorphism (RFLP assay.The allelic frequencies of the mutant alleles were 0.12 for allele C and 1.14 for allele G in the control population. The results were not statistically different from those alleles in the patient population. There was also no statistically significant difference in genotype distribution in lung cancer patients and controls even when combining high risk genotypes. In our control sample, as in other populations of different ethnic origin, both polymorphisms also seem to be in linkage disequilibrium. We conclude that in this sample of the Portuguese population, CYP1A1 m1 and m2 polymorphisms are too rare to be of clinical relevance, and do not seem to be associated with susceptibility to lung cancer. Resumo: O cancro do pulmão é considerado uma doença relacionada com o meio ambiente, consequência da exposição a agentes mutagénicos, nomeadamente os presentes no fumo do tabaco. O gene CYP1A1 codifica a enzima aril hidrocarboneto hidroxilase (AHH, da fase I, do sistema multienzimático do citocromo P450, que desempenha uma função preponderante na bioactivação dos procarcinogénios do tabaco. Dois polimorfismos do CYP1A1, m1 (transi

  5. Shell Buckling Knockdown Factors

    Data.gov (United States)

    National Aeronautics and Space Administration — The Shell Buckling Knockdown Factor (SBKF) Project, NASA Engineering and Safety Center (NESC) Assessment #: 07-010-E, was established in March of 2007 by the NESC in...

  6. Risk factors for neoplasms

    International Nuclear Information System (INIS)

    Brachner, A.; Grosche, B.

    1991-06-01

    A broad survey is given of risk factors for neoplasms. The main carcinogenic substances (including also ionizing radiation and air pollution) are listed, and are correlated with the risk factors for various cancers most frequently explained and discussed in the literature. The study is intended to serve as a basis for a general assessment of the incidence of neoplasms in children, and of cancer mortality in the entire population of Bavaria in the years 1983-1989, or 1979-1988, respectively, with the principal idea of drawing up an environment-related health survey. The study therefore takes into account not only ionizing radiation as a main risk factor, but also other risk factors detectable within the ecologic context, as e.g. industrial installations and their effects, refuse incineration plants or waste dumps, or the social status. (orig./MG) [de

  7. Factor IX assay

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003679.htm Factor IX assay To use the sharing features on ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  8. Factor VIII assay

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003678.htm Factor VIII assay To use the sharing features on ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  9. Factor II assay

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003674.htm Factor II assay To use the sharing features on ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  10. Factor V deficiency

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000550.htm Factor V deficiency To use the sharing features on ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  11. Rheumatoid factor (RF)

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/003548.htm Rheumatoid factor (RF) To use the sharing features on this ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  12. Factor II deficiency

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000549.htm Factor II deficiency To use the sharing features on ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  13. Factor VII assay

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/003676.htm Factor VII assay To use the sharing features on ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  14. Factor X deficiency

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000553.htm Factor X deficiency To use the sharing features on ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  15. New microbial growth factor

    Science.gov (United States)

    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.

  16. Human factors in aviation

    National Research Council Canada - National Science Library

    Salas, Eduardo; Maurino, Daniel E

    2010-01-01

    .... HFA offers a comprehensive overview of the topic, taking readers from the general to the specific, first covering broad issues, then the more specific topics of pilot performance, human factors...

  17. [Risk factors of schizophrenia].

    Science.gov (United States)

    Suvisaari, Jaana

    2010-01-01

    Schizophrenia is a multifactorial, neurodevelopmental disorder caused by a combination of genetic and environmental risk factors. Disturbances of brain development begin prenatally, while different environmental insults further affect postnatal brain maturation during childhood and adolescence. Genome-wide association studies (GWAS) have succeeded in identifying hundreds of new risk variants for common, multifactorial diseases. In schizophrenia research, GWAS have found several rare copy number variants that considerably increase the risk of schizophrenia, and have shown an association between schizophrenia and the major histocompatibility complex. Research on environmental risk factors in recent years has provided new information particularly on risk factors related to pregnancy and childhood rearing environment. Gene-environment interactions have become a central research topic. There is evidence that genetically susceptible children are more vulnerable to the effects of unstable childhood rearing environment and other environmental risk factors.

  18. Human Factors Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — Purpose: The purpose of the Human Factors Laboratory is to further the understanding of highway user needs so that those needs can be incorporated in roadway design,...

  19. Factors Affecting Wound Healing

    Science.gov (United States)

    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

  20. The stem factor challenge

    International Nuclear Information System (INIS)

    Russell, M.J.; Steele, R. Jr.; DeWall, K.G.; Watkins, J.C.; Bramwell, D.

    1994-01-01

    One of the most important challenges that still needs to be met in the effort to understand the operation of motor-operated, rising-stem valves is the ability to determine stem factor throughout the valve's load range. The stem factor represents the conversion of operator torque to stem thrust. Determining the stem factor is important because some motor-operated valves (MOVs) cannot be tested in the plant at design basis conditions. The ability of these valves to perform their design basis function (typically, to operate against specified flow and pressure loads) must be ensured by analytical methods or by extrapolating from the results of tests conducted at lower loads. Because the stem factor tends to vary in response to friction and lubrication phenomena that occur during loading and wedging, analytical methods and extrapolation methods have been difficult to develop and implement. Early investigations into variability in the stem factor tended to look only at the tip of the iceberg; they focused on what was happening at torque switch trip, which usually occurs at full wedging. In most stems, the stem factor is better (lower) in the wedging transient than before wedging, so working with torque switch trip data alone led many early researchers to false conclusions about the relationship between stem factor and load. However, research at the Idaho National Engineering Laboratory (INEL) has taken a closer look at what happens during the running portion of the closing stroke along with the wedging portion. This shift in focus is important, because functional failure of a valve typically consists of a failure to isolate flow, not a failure to achieve full wedging. Thus, the stem factor that must be determined for a valve's design basis closing requirements is the one that corresponds with the running load before wedging

  1. Factors Affecting Wound Healing

    OpenAIRE

    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 cutane...

  2. Los factores de riesgo

    Directory of Open Access Journals (Sweden)

    Justo Senado Dumoy

    1999-01-01

    Full Text Available Sobre el fundamento filosófico de los conceptos de la Dialéctica Materialista, se presenta un análisis en relación con el concepto e interpretación de los Factores de Riesgo.A analysis on the concept and interpretation of risk factors is presented based on the philosophical foundation of the concepts of materialist dialectics.

  3. Brain derived neurotrophic factor

    DEFF Research Database (Denmark)

    Mitchelmore, Cathy; Gede, Lene

    2014-01-01

    Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin with important functions in neuronal development and neuroplasticity. Accumulating evidence suggests that alterations in BDNF expression levels underlie a variety of psychiatric and neurological disorders. Indeed, BDNF therapies are curre......Brain Derived Neurotrophic Factor (BDNF) is a neurotrophin with important functions in neuronal development and neuroplasticity. Accumulating evidence suggests that alterations in BDNF expression levels underlie a variety of psychiatric and neurological disorders. Indeed, BDNF therapies...

  4. Factors Impacting Knowledge Sharing

    DEFF Research Database (Denmark)

    Schulzmann, David; Slepniov, Dmitrij

    The purpose of this paper is to examine various factors affecting knowledge sharing at the R&D center of a Western MNE in China. The paper employs qualitative methodology and is based on the action research and case study research techniques. The findings of the paper advance our understanding...... about factors that affect knowledge sharing. The main emphasis is given to the discussion on how to improve knowledge sharing in global R&D organizations....

  5. FGF growth factor analogs

    Science.gov (United States)

    Zamora, Paul O [Gaithersburg, MD; Pena, Louis A [Poquott, NY; Lin, Xinhua [Plainview, NY; Takahashi, Kazuyuki [Germantown, MD

    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.

  6. Factorization and pion form factor in QCD

    International Nuclear Information System (INIS)

    Efremov, A.V.; Radyushkin, A.V.

    1979-01-01

    The behaviour of the pion electromagnetic form factor (EMFF) in the framework of quantum chromodynamics (QCD) is discussed. Pion is considered to be a quark-antiquark bound state. It is proposed to use an OPE description of the bound state structure by matrix elements of certain local gauge-invariant operators. Short-distance quark interactions is proved using a direct analysis of perturbation theory in the α-parametric representation of the Feynman diagrams. It is shown that the short-distance parton picture privides a self-consistent description of the large Q 2 momentum behaviour of the pion EMFF in QCD. Pion EMFF asymptotics is expressed in terms of fu fundamental constants of the theory

  7. Radiosensitivity of Saccharomyces cerevisiae W303-1A and BY4741 Strains

    Energy Technology Data Exchange (ETDEWEB)

    Park, Ji Young; Kim, Jin Kyu [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Nili, Mohammad [Dawnesh Radiation Research Institute, Barcelona (Spain)

    2011-05-15

    Saccharomyces cerevisiae, a simple eukaryotic cell, has been widely used as a model for all eukaryotes including humans for the study of fundamental cellular processes such as DNA replication, DNA recombination, cell cycle, cell division and metabolism. Numerous laboratory strains are used in yeast research. Most of the mutants have been derived from the two widely used laboratory strains W303-1A and BY4741. While BY4741 is a derivative of S288C, used in the systematic sequencing of the S. cerevisiae genome, strains with a W303 background serve in many physiological and biochemical studies. It was found in a recent study that W303-1A contains a mutant allele of YBP1, ybp1-1, encoding four amino acid substitutions, that results in increased peroxide sensitivity. Mutation of ybp1-1 is not a complete loss of function allele as it is more resistant to peroxides than the knock-out mutant. Ybp1 is required for oxidation of specific cysteine residues of the transcription factor Yap1p resulting in the nuclear localization of Yap1p in response to stress. Ionizing radiation (IR) can produce highly reactive hydroxyl radicals through the decomposition of cellular water, such as superoxide anion radical, hydrogen peroxide, hydroxyl radical. These reactive oxygen species (ROS) can cause wide-ranging cellular damage, including DNA double-strand breaks (DSBs), lipid peroxidation, and protein modification. Also, ROS produced by IR cause oxidative stress. Detoxification enzymes are activated for ROS scavenging against oxidative stress. Also, antioxidants are used for detoxification of ROS and reduction of oxidative damage. NAC, one of the antioxidants, is a precursor for glutathione (GSH). The aim of the present study was to compare the differences in radiosensitivity associated cell viability between the two strains. Also, effect of NAC against IR on cell protection was investigated

  8. TL1A regulates TCRγδ+ intraepithelial lymphocytes and gut microbial composition

    DEFF Research Database (Denmark)

    Tougaard, Peter; Skov, S.; Pedersen, A. E.

    2015-01-01

    TL1A is a proinflammatory cytokine, which is prevalent in the gut. High TL1A concentrations are present in patients with inflammatory bowel disease (IBD) and in IBD mouse models. However, the role of TL1A during steady‐state conditions is relatively unknown. Here, we used TL1A knockout (KO) mice ...

  9. [Pathological gambling: risk factors].

    Science.gov (United States)

    Bouju, G; Grall-Bronnec, M; Landreat-Guillou, M; Venisse, J-L

    2011-09-01

    In France, consumption of gambling games increased by 148% between 1960 and 2005. In 2004, gamblers lost approximately 0.9% of household income, compared to 0.4% in 1960. This represents approximately 134 Euros per year and per head. In spite of this important increase, the level remains lower than the European average (1%). However, gambling practices may continue to escalate in France in the next few years, particularly with the recent announce of the legalisation of online games and sports betting. With the spread of legalised gambling, pathological gambling rates may increase in France in the next years, in response to more widely available and more attractive gambling opportunities. In this context, there is a need for better understanding of the risk factors that are implicated in the development and maintenance of pathological gambling. This paper briefly describes the major risk factors for pathological gambling by examining the recent published literature available during the first quarter of 2008. This documentary basis was collected by Inserm for the collective expert report procedure on Gambling (contexts and addictions). Seventy-two articles focusing on risk factors for pathological gambling were considered in this review. Only 47 of them were taken into account for analysis. The selection of these 47 publications was based on the guide on literature analysis established by the French National Agency for Accreditation and Assessment in Health (ANAES, 2000). Some publications from more recent literature have also been added, mostly about Internet gambling. We identify three major types of risk factors implicated in gambling problems: some of them are related to the subject (individual factors), others are related to the object of the addiction, here the gambling activity by itself (structural factors), and the last are related to environment (contextual or situational factors). Thus, the development and maintenance of pathological gambling seems to be

  10. Casein Kinase 2 Is a Novel Regulator of the Human Organic Anion Transporting Polypeptide 1A2 (OATP1A2) Trafficking.

    Science.gov (United States)

    Chan, Ting; Cheung, Florence Shin Gee; Zheng, Jian; Lu, Xiaoxi; Zhu, Ling; Grewal, Thomas; Murray, Michael; Zhou, Fanfan

    2016-01-04

    Human organic anion transporting polypeptides (OATPs) mediate the influx of many important drugs into cells. Casein kinase 2 (CK2) is a critical protein kinase that phosphorylates >300 protein substrates and is dysregulated in a number of disease states. Among the CK2 substrates are several transporters, although whether this includes human OATPs has not been evaluated. The current study was undertaken to evaluate the regulation of human OATP1A2 by CK2. HEK-239T cells in which OATP1A2 was overexpressed were treated with CK2 specific inhibitors or transfected with CK2 specific siRNA, and the activity, expression, and subcellular trafficking of OATP1A2 was evaluated. CK2 inhibition decreased the uptake of the prototypic OATP1A2 substrate estrone-3-sulfate (E3S). Kinetic studies revealed that this was due to a decrease in the maximum velocity (Vmax) of E3S uptake, while the Michaelis constant was unchanged. The cell surface expression, but not the total cellular expression of OATP1A2, was impaired by CK2 inhibition and knockdown of the catalytic α-subunits of CK2. CK2 inhibition decreased the internalization of OATP1A2 via a clathrin-dependent pathway, decreased OATP1A2 recycling, and likely impaired OATP1A2 targeting to the cell surface. Consistent with these findings, CK2 inhibition also disrupted the colocalization of OATP1A2 and Rab GTPase (Rab)4-, Rab8-, and Rab9-positive endosomal and secretory vesicles. Taken together, CK2 has emerged as a novel regulator of the subcellular trafficking and stability of OATP1A2. Because OATP1A2 transports many molecules of physiological and pharmacological importance, the present data may inform drug selection in patients with diseases in which CK2 and OATP1A2 are dysregulated.

  11. ANTIBODIES TO BENZO[A]PYRENE AND POLYMORPHISMS OF CYP1A1*2A, CYP1A2*1F, GSTT1, AND GSTM1 GENES IN HEALTHY MEN AND LUNG CANCER PATIENTS

    Directory of Open Access Journals (Sweden)

    A. N. Glushkov

    2016-01-01

    Full Text Available Some genetic polymorphisms of CYP and GST enzymes metabolizing low-molecular weight xenobiotics may represent endogenous risk factors for carcinogenesis. However, possible relationships between the enzyme activities, amounts of carcinogen adducts and synthesis of anticarcinogen antibodies in humans (including cancer patients are still poorly studied. The purpose of this study was to identify possible associations between occurrence of antibodies against benzo[a]pyrene, and frequency of genetic polymorphisms of CYP1A1*2A, CYP1A2*1F, GSTT1, GSTM1 in healthy men and in lung cancer patients. Materials and methods. We have examined 203 men with non-small cell lung cancer and 267 apparently healthy donors without respiratory diseases. A non-competitive solid phase immunoassay of antibodies to benzo[a]pyrene was performed. Analysis of polymorphic loci within CYP1A1 (rs4646903, CYP1A2 (rs762551, GSTP1 (rs1695, rs1138272 was performed by means of real-time PCR using TaqMan technology. Null-alleles of GSTM1 (del, GSTT1 (del genes were detected by multiplex PCR with real-time fluorescent assay. Results. Among the lung cancer patients, the proportion of cases with a high level of IgG antibodies to benzo[a]pyrene in carriers of GSTT1+ and GSTM1+ in conjunction with the CYP1A2*1F C allele was significantly greater than in AA homozygotes CYP1A2*1F. The risk of lung cancer was increased to 5.5 in carriers of CYP1A2*1F C allele combined with GSTT1+ and GSTM1+ at high levels of IgG antibodies to benzo [a] pyrene. In healthy male donors, we have not found differences between the incidence of low and high levels of IgG anti-benzo[a]pyrene antibodies in the carriers of certain CYP1A1*2A, CYP1A2*1F, GSTT1 and GSTM1 genotypes. Conclusions. We have first reported a relationship between CYP1 and GST gene polymorphisms and specific immune response to chemical carcinogens in lung cancer patients. Immunoassays of IgG antibodies to benzo[a]pyrene combined with molecular

  12. Orthosteric Binding of ρ-Da1a, a Natural Peptide of Snake Venom Interacting Selectively with the α1A-Adrenoceptor

    Science.gov (United States)

    Maïga, Arhamatoulaye; Merlin, Jon; Marcon, Elodie; Rouget, Céline; Larregola, Maud; Gilquin, Bernard; Fruchart-Gaillard, Carole; Lajeunesse, Evelyne; Marchetti, Charles; Lorphelin, Alain; Bellanger, Laurent; Summers, Roger J.; Hutchinson, Dana S.; Evans, Bronwyn A.; Servent, Denis; Gilles, Nicolas

    2013-01-01

    ρ-Da1a is a three-finger fold toxin from green mamba venom that is highly selective for the α1A-adrenoceptor. This toxin has atypical pharmacological properties, including incomplete inhibition of 3H-prazosin or 125I-HEAT binding and insurmountable antagonist action. We aimed to clarify its mode of action at the α1A-adrenoceptor. The affinity (pKi 9.26) and selectivity of ρ-Da1a for the α1A-adrenoceptor were confirmed by comparing binding to human adrenoceptors expressed in eukaryotic cells. Equilibrium and kinetic binding experiments were used to demonstrate that ρ-Da1a, prazosin and HEAT compete at the α1A-adrenoceptor. ρ-Da1a did not affect the dissociation kinetics of 3H-prazosin or 125I-HEAT, and the IC50 of ρ-Da1a, determined by competition experiments, increased linearly with the concentration of radioligands used, while the residual binding by ρ-Da1a remained stable. The effect of ρ-Da1a on agonist-stimulated Ca2+ release was insurmountable in the presence of phenethylamine- or imidazoline-type agonists. Ten mutations in the orthosteric binding pocket of the α1A-adrenoceptor were evaluated for alterations in ρ-Da1a affinity. The D1063.32A and the S1885.42A/S1925.46A receptor mutations reduced toxin affinity moderately (6 and 7.6 times, respectively), while the F862.64A, F2886.51A and F3127.39A mutations diminished it dramatically by 18- to 93-fold. In addition, residue F862.64 was identified as a key interaction point for 125I-HEAT, as the variant F862.64A induced a 23-fold reduction in HEAT affinity. Unlike the M1 muscarinic acetylcholine receptor toxin MT7, ρ-Da1a interacts with the human α1A-adrenoceptor orthosteric pocket and shares receptor interaction points with antagonist (F862.64, F2886.51 and F3127.39) and agonist (F2886.51 and F3127.39) ligands. Its selectivity for the α1A-adrenoceptor may result, at least partly, from its interaction with the residue F862.64, which appears to be important also for HEAT binding. PMID:23935897

  13. Identification and functional characterization of a novel bipartite nuclear localization sequence in ARID1A

    Energy Technology Data Exchange (ETDEWEB)

    Bateman, Nicholas W. [Women' s Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, Annandale 22003, VA (United States); The John P. Murtha Cancer Center, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD (United States); Shoji, Yutaka [Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids 49503, MI (United States); Conrads, Kelly A.; Stroop, Kevin D. [Women' s Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, Annandale 22003, VA (United States); Hamilton, Chad A. [Women' s Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, Annandale 22003, VA (United States); The John P. Murtha Cancer Center, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD (United States); Gynecologic Oncology Service, Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, 8901 Wisconsin Ave, MD, Bethesda, 20889 (United States); Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda 20814, MD (United States); Darcy, Kathleen M. [Women' s Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, Annandale 22003, VA (United States); The John P. Murtha Cancer Center, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD (United States); Maxwell, George L. [Department of Obstetrics and Gynecology, Inova Fairfax Hospital, Falls Church, VA 22042 (United States); Risinger, John I. [Department of Obstetrics, Gynecology and Reproductive Biology, Michigan State University, Grand Rapids 49503, MI (United States); and others

    2016-01-01

    AT-rich interactive domain-containing protein 1A (ARID1A) is a recently identified nuclear tumor suppressor frequently altered in solid tumor malignancies. We have identified a bipartite-like nuclear localization sequence (NLS) that contributes to nuclear import of ARID1A not previously described. We functionally confirm activity using GFP constructs fused with wild-type or mutant NLS sequences. We further show that cyto-nuclear localized, bipartite NLS mutant ARID1A exhibits greater stability than nuclear-localized, wild-type ARID1A. Identification of this undescribed functional NLS within ARID1A contributes vital insights to rationalize the impact of ARID1A missense mutations observed in patient tumors. - Highlights: • We have identified a bipartite nuclear localization sequence (NLS) in ARID1A. • Confirmation of the NLS was performed using GFP constructs. • NLS mutant ARID1A exhibits greater stability than wild-type ARID1A.

  14. The Oswestry Disability Index (version 2.1a): validation of a Dutch language version.

    Science.gov (United States)

    van Hooff, Miranda L; Spruit, Maarten; Fairbank, Jeremy C T; van Limbeek, Jacques; Jacobs, Wilco C H

    2015-01-15

    A cross-sectional study on baseline data. To translate the Oswestry Disability Index (ODI) version 2.1a into the Dutch language and to validate its use in a cohort of patients with chronic low back pain in secondary spine care. Patient-reported outcome measures (PROMs) are commonly accepted to evaluate the outcome of spine interventions. Functional status is an important outcome in spine research. The ODI is a recommended condition-specific patient-reported outcome measure used to evaluate functional status in patients with back pain. As yet, no formal translated Dutch version exists. The ODI was translated according to established guidelines. The final version was built into the electronic web-based system in addition with the Roland Morris Disability Questionnaire, the numeric rating scale for pain severity, 36-Item Short Form Health Survey Questionnaire for quality of life, and the hospital anxiety and depression scale. Baseline data were used of 244 patients with chronic low back pain who participated in a combined physical and psychological program. Floor and ceiling effects, internal consistency, and the construct validity were evaluated using quality criteria. The mean ODI (standard deviation) was 39.6 (12.3); minimum 6, maximum 70. Most of the participants (88%) were moderately to severely disabled. Factor analysis determined a 1-factor structure (36% explained variance) and the homogeneity of ODI items is shown (Cronbach α = 0.79). The construct validity is supported as all (6:6) the a priori hypotheses were confirmed. Moreover, the ODI and Roland Morris Disability Questionnaire, showed a strong significant correlation (r = 0.68, P disability among Dutch patients with chronic low back pain. This translated condition-specific patient-reported outcome measure version is recommended for use in future back pain research and to evaluate outcome of back care in the Netherlands.

  15. Induction of cytochromes P450 1A1 and 1A2 suppresses formation of DNA adducts by carcinogenic aristolochic acid I in rats in vivo

    International Nuclear Information System (INIS)

    Dračínská, Helena; Bárta, František; Levová, Kateřina; Hudecová, Alena; Moserová, Michaela; Schmeiser, Heinz H.; Kopka, Klaus; Frei, Eva; Arlt, Volker M.; Stiborová, Marie

    2016-01-01

    Highlights: • Oxidation and reduction of aristolochic acid I (AAI) dictate its (geno)toxicity in vivo. • Cytochrome P450 (CYP) 1A1 and 1A2 are induced in rats treated with Sudan I and AAI. • Induced CYP1A enzyme activity resulted in decreased AAI-DNA adduct levels in vivo. • CYP1A1 and 1A2 mainly detoxify AAI and attenuate its genotoxicity in vivo. - Abstract: Aristolochic acid I (AAI) is a natural plant alkaloid causing aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. One of the most efficient enzymes reductively activating AAI to species forming AAI-DNA adducts is cytosolic NAD(P)H:quinone oxidoreductase 1. AAI is also either reductively activated or oxidatively detoxified to 8-hydroxyaristolochic acid (AAIa) by microsomal cytochrome P450 (CYP) 1A1 and 1A2. Here, we investigated which of these two opposing CYP1A1/2-catalyzed reactions prevails in AAI metabolism in vivo. The formation of AAI-DNA adducts was analyzed in liver, kidney and lung of rats treated with AAI, Sudan I, a potent inducer of CYP1A1/2, or AAI after pretreatment with Sudan I. Compared to rats treated with AAI alone, levels of AAI-DNA adducts determined by the 32 P-postlabeling method were lower in liver, kidney and lung of rats treated with AAI after Sudan I. The induction of CYP1A1/2 by Sudan I increased AAI detoxification to its O-demethylated metabolite AAIa, thereby reducing the actual amount of AAI available for reductive activation. This subsequently resulted in lower AAI-DNA adduct levels in the rat in vivo. Our results demonstrate that CYP1A1/2-mediated oxidative detoxification of AAI is the predominant role of these enzymes in rats in vivo, thereby suppressing levels of AAI-DNA adducts.

  16. Cytochrome P450 1A1 (CYP1A1) protects against nonalcoholic fatty liver disease caused by Western diet containing benzo[a]pyrene in mice.

    Science.gov (United States)

    Uno, Shigeyuki; Nebert, Daniel W; Makishima, Makoto

    2018-03-01

    The Western diet contributes to nonalcoholic fatty liver disease (NAFLD) pathogenesis. Benzo[a]pyrene (BaP), a prototypical environmental pollutant produced by combustion processes, is present in charcoal-grilled meat. Cytochrome P450 1A1 (CYP1A1) metabolizes BaP, resulting in either detoxication or metabolic activation in a context-dependent manner. To elucidate a role of CYP1A1-BaP in NAFLD pathogenesis, we compared the effects of a Western diet, with or without oral BaP treatment, on the development of NAFLD in Cyp1a1(-/-) mice versus wild-type mice. A Western diet plus BaP induced lipid-droplet accumulation in liver of Cyp1a1(-/-) mice, but not wild-type mice. The hepatic steatosis observed in Cyp1a1(-/-) mice was associated with increased cholesterol, triglyceride and bile acid levels. Cyp1a1(-/-) mice fed Western diet plus BaP had changes in expression of genes involved in bile acid and lipid metabolism, and showed no increase in Cyp1a2 expression but did exhibit enhanced Cyp1b1 mRNA expression, as well as hepatic inflammation. Enhanced BaP metabolic activation, oxidative stress and inflammation may exacerbate metabolic dysfunction in liver of Cyp1a1(-/-) mice. Thus, Western diet plus BaP induces NAFLD and hepatic inflammation in Cyp1a1(-/-) mice in comparison to wild-type mice, indicating a protective role of CYP1A1 against NAFLD pathogenesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  17. Type 1a endoleak following Zone 1 and Zone 2 thoracic endovascular aortic repair: effect of bird-beak configuration.

    Science.gov (United States)

    Kudo, Tomoaki; Kuratani, Toru; Shimamura, Kazuo; Sakamoto, Tomohiko; Kin, Keiwa; Masada, Kenta; Shijo, Takayuki; Torikai, Kei; Maeda, Koichi; Sawa, Yoshiki

    2017-10-01

    Type 1a endoleak is one of the most severe complications after thoracic endovascular aortic repair (TEVAR), because it carries the risk of aortic rupture. The association between bird-beak configuration and Type 1a endoleak remains unclear. The purpose of this study was to analyse the predictors of Type 1a endoleak following Zone 1 and Zone 2 TEVAR, with a particular focus on the effect of bird-beak configuration. From April 2008 to July 2015, 105 patients (mean age 68.6 years) who underwent Zone 1 and 2 landing TEVAR were enrolled, with a mean follow-up period of 4.3 years. The patients were categorized into 2 groups, according to the presence (Group B, n = 32) or the absence (Group N, n = 73) of bird-beak configuration on the first postoperative multidetector computed tomography. The Kaplan-Meier event-free rate curve showed that Type 1a endoleak and bird-beak progression occurred less frequently in Group N than in Group B. Five-year freedom from Type 1a endoleak rates were 79.7% and 100% for Groups B and N, respectively (P = 0.007). Multivariable logistic regression analysis showed that dissecting aortic aneurysm (odds ratio 3.72, 95% confidence interval 1.30-11.0; P = 0.014) and shorter radius of inner curvature (odds ratio 1.09, 95% confidence interval 0.85-0.99; P = 0.025) were significant risk factors for bird-beak configuration. Multivariable Cox proportional hazard regression showed that Z-type stent graft (hazard ratio 2.69, 95% confidence interval 1.11-6.51; P = 0.030) was a significant risk factor for bird-beak progression. Appropriate stent grafts need to be chosen carefully to prevent Type 1a endoleak and bird-beak configuration after landing Zone 1 and 2 TEVAR. Patients with bird-beak configuration on early postoperative multidetector computed tomography require closer follow-up to screen for Type 1a endoleak. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio

  18. Expression of the sweetpotato R2R3-type IbMYB1a gene induce