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Sample records for group b1 sox

  1. B1 SOX coordinate cell specification with patterning and morphogenesis in the early zebrafish embryo.

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    Yuichi Okuda

    2010-05-01

    Full Text Available The B1 SOX transcription factors SOX1/2/3/19 have been implicated in various processes of early embryogenesis. However, their regulatory functions in stages from the blastula to early neurula remain largely unknown, primarily because loss-of-function studies have not been informative to date. In our present study, we systematically knocked down the B1 sox genes in zebrafish. Only the quadruple knockdown of the four B1 sox genes sox2/3/19a/19b resulted in very severe developmental abnormalities, confirming that the B1 sox genes are functionally redundant. We characterized the sox2/3/19a/19b quadruple knockdown embryos in detail by examining the changes in gene expression through in situ hybridization, RT-PCR, and microarray analyses. Importantly, these phenotypic analyses revealed that the B1 SOX proteins regulate the following distinct processes: (1 early dorsoventral patterning by controlling bmp2b/7; (2 gastrulation movements via the regulation of pcdh18a/18b and wnt11, a non-canonical Wnt ligand gene; (3 neural differentiation by regulating the Hes-class bHLH gene her3 and the proneural-class bHLH genes neurog1 (positively and ascl1a (negatively, and regional transcription factor genes, e.g., hesx1, zic1, and rx3; and (4 neural patterning by regulating signaling pathway genes, cyp26a1 in RA signaling, oep in Nodal signaling, shh, and mdkb. Chromatin immunoprecipitation analysis of the her3, hesx1, neurog1, pcdh18a, and cyp26a1 genes further suggests a direct regulation of these genes by B1 SOX. We also found an interesting overlap between the early phenotypes of the B1 sox quadruple knockdown embryos and the maternal-zygotic spg embryos that are devoid of pou5f1 activity. These findings indicate that the B1 SOX proteins control a wide range of developmental regulators in the early embryo through partnering in part with Pou5f1 and possibly with other factors, and suggest that the B1 sox functions are central to coordinating cell fate

  2. SoxB1-driven transcriptional network underlies neural-specific interpretation of morphogen signals.

    Science.gov (United States)

    Oosterveen, Tony; Kurdija, Sanja; Ensterö, Mats; Uhde, Christopher W; Bergsland, Maria; Sandberg, Magnus; Sandberg, Rickard; Muhr, Jonas; Ericson, Johan

    2013-04-30

    The reiterative deployment of a small cadre of morphogen signals underlies patterning and growth of most tissues during embyogenesis, but how such inductive events result in tissue-specific responses remains poorly understood. By characterizing cis-regulatory modules (CRMs) associated with genes regulated by Sonic hedgehog (Shh), retinoids, or bone morphogenetic proteins in the CNS, we provide evidence that the neural-specific interpretation of morphogen signaling reflects a direct integration of these pathways with SoxB1 proteins at the CRM level. Moreover, expression of SoxB1 proteins in the limb bud confers on mesodermal cells the potential to activate neural-specific target genes upon Shh, retinoid, or bone morphogenetic protein signaling, and the collocation of binding sites for SoxB1 and morphogen-mediatory transcription factors in CRMs faithfully predicts neural-specific gene activity. Thus, an unexpectedly simple transcriptional paradigm appears to conceptually explain the neural-specific interpretation of pleiotropic signaling during vertebrate development. Importantly, genes induced in a SoxB1-dependent manner appear to constitute repressive gene regulatory networks that are directly interlinked at the CRM level to constrain the regional expression of patterning genes. Accordingly, not only does the topology of SoxB1-driven gene regulatory networks provide a tissue-specific mode of gene activation, but it also determines the spatial expression pattern of target genes within the developing neural tube.

  3. Genovariation Analysis of Sox11 and CYP1B1 in Patients with Peter's Anormaly%Peters'异常患者Sox11及CYP1B1基因变异分析

    Institute of Scientific and Technical Information of China (English)

    贾秀华; 郭向明

    2013-01-01

    [Objective] To investigate the genovariation of Sox11 and CYP1B1 in Chinese population with Peters' anomaly.[Methods] 13 probands of Peters' anormaly and 100 normal controls were selected from our ocular genetic diseases bank.Cycle sequencing was used to analyze the exons and adjacent introns of Sox11 and CYP1B1.The variation detected was further evaluated in 100 normal controls using the heteroduplex analysis-single strand conformation polymorphism (HA-SSCP) methods.Screening the gene mutation of Sox11 and CYP1B1 in Chinese patients with Peters' anormaly,and the related phenotypes of them.[Results] One synonymous mutation of Sox11 and one missense mutation of CYP1B1 were detected in the 13 patients with Peters' anormaly.No such new mutation was found in 100 normal controls.[Conclusions] To our knowledge,it is the first time of Sox11 gene screening on patients with Peters' anormaly.And our finding support the role of CYP1B1 as a causative gene in Peters' anormaly and expand the mutation spectrum of CYP1B1.Furthermore,it enriches our knowledge of genotype-phenotype relation.Our results may provide basis for the functional and genomic study of this kind of disease.%[目的]研究中国人Peters’异常患者Sox11及CYP1B1基因变异情况.[方法]从眼遗传疾病库中选取13例Peters’异常的先证者以及100例正常对照,采用直接测序的方法分析Sox11及CYP1B1基因的外显子及其相邻内含子基因变异情况;通过测序识别的基因突变,使用HA-SSCP分析的方法,在100例正常对照中做进一步评估.筛查中国人群Peters’异常患者Sox11及CYP1B1基因基因变异,并研究其相关表型.[结果]在13例Peters’异常的患者中检测到一个Sox11同义突变,一个CYP1B1错义突变,在正常对照中未发现此基因突变.[结论]本研究首次对Peters’异常患者进行Sox11进行基因筛查,并验证了CYP1B1是Peters’异常的致病基因之一,进一步扩大了Peters’异常患者CYP1B1基因突变

  4. Formation of the embryonic organizer is restricted by the competitive influences of Fgf signaling and the SoxB1 transcription factors.

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    Cheng-Liang Kuo

    Full Text Available The organizer is one of the earliest structures to be established during vertebrate development and is crucial to subsequent patterning of the embryo. We have previously shown that the SoxB1 transcription factor, Sox3, plays a central role as a transcriptional repressor of zebrafish organizer gene expression. Recent data suggest that Fgf signaling has a positive influence on organizer formation, but its role remains to be fully elucidated. In order to better understand how Fgf signaling fits into the complex regulatory network that determines when and where the organizer forms, the relationship between the positive effects of Fgf signaling and the repressive effects of the SoxB1 factors must be resolved. This study demonstrates that both fgf3 and fgf8 are required for expression of the organizer genes, gsc and chd, and that SoxB1 factors (Sox3, and the zebrafish specific factors, Sox19a and Sox19b can repress the expression of both fgf3 and fgf8. However, we also find that these SoxB1 factors inhibit the expression of gsc and chd independently of their repression of fgf expression. We show that ectopic expression of organizer genes induced solely by the inhibition of SoxB1 function is dependent upon the activation of fgf expression. These data allow us to describe a comprehensive signaling network in which the SoxB1 factors restrict organizer formation by inhibiting Fgf, Nodal and Wnt signaling, as well as independently repressing the targets of that signaling. The organizer therefore forms only where Nodal-induced Fgf signaling overlaps with Wnt signaling and the SoxB1 proteins are absent.

  5. A Model for Dimerization of the SOX Group E Transcription Factor Family.

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    Ramsook, Sarah N; Ni, Joyce; Shahangian, Shokofeh; Vakiloroayaei, Ana; Khan, Naveen; Kwan, Jamie J; Donaldson, Logan W

    2016-01-01

    Group E members of the SOX transcription factor family include SOX8, SOX9, and SOX10. Preceding the high mobility group (HMG) domain in each of these proteins is a thirty-eight amino acid region that supports the formation of dimers on promoters containing tandemly inverted sites. The purpose of this study was to obtain new structural insights into how the dimerization region functions with the HMG domain. From a mutagenic scan of the dimerization region, the most essential amino acids of the dimerization region were clustered on the hydrophobic face of a single, predicted amphipathic helix. Consistent with our hypothesis that the dimerization region directly contacts the HMG domain, a peptide corresponding to the dimerization region bound a preassembled HMG-DNA complex. Sequence conservation among Group E members served as a basis to identify two surface exposed amino acids in the HMG domain of SOX9 that were necessary for dimerization. These data were combined to make a molecular model that places the dimerization region of one SOX9 protein onto the HMG domain of another SOX9 protein situated at the opposing site of a tandem promoter. The model provides a detailed foundation for assessing the impact of mutations on SOX Group E transcription factors.

  6. 26 CFR 1.414(b)-1 - Controlled group of corporations.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Controlled group of corporations. 1.414(b)-1... Controlled group of corporations. (a) Defintion of controlled group of corporations. For purposes of this section, the term “controlled group of corporations” has the same meaning as is assigned to the term...

  7. Sox genes in grass carp (Ctenopharyngodon idella with their implications for genome duplication and evolution

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    Tong Jingou

    2006-11-01

    Full Text Available Abstract The Sox gene family is found in a broad range of animal taxa and encodes important gene regulatory proteins involved in a variety of developmental processes. We have obtained clones representing the HMG boxes of twelve Sox genes from grass carp (Ctenopharyngodon idella, one of the four major domestic carps in China. The cloned Sox genes belong to group B1, B2 and C. Our analyses show that whereas the human genome contains a single copy of Sox4, Sox11 and Sox14, each of these genes has two co-orthologs in grass carp, and the duplication of Sox4 and Sox11 occurred before the divergence of grass carp and zebrafish, which support the "fish-specific whole-genome duplication" theory. An estimation for the origin of grass carp based on the molecular clock using Sox1, Sox3 and Sox11 genes as markers indicates that grass carp (subfamily Leuciscinae and zebrafish (subfamily Danioninae diverged approximately 60 million years ago. The potential uses of Sox genes as markers in revealing the evolutionary history of grass carp are discussed.

  8. Sox9

    DEFF Research Database (Denmark)

    Seymour, Philip A

    2014-01-01

    Over the last decade, it has been discovered that the transcription factor Sox9 plays several critical roles in governing the development of the embryonic pancreas and the homeostasis of the mature organ. While analysis of pancreata from patients affected by the Sox9 haploinsufficiency syndrome...... tracing mouse models. Also, current controversies regarding Sox9 function in healthy and injured adult pancreas and unanswered questions and avenues of future study are discussed....

  9. High mobility group B1 levels in sepsis and Disseminated Intravascular Coagulation.

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    Eskici, Zeynep M; Açıkgöz, Şerefden; Pişkin, Nihal; Mungan, Görkem; Can, Murat; Güven, Berrak; Köktürk, Fürüzan

    2012-01-01

    Cytokines trigger coagulant and fibrinolytic systems in sepsis to result in Disseminated Intravascular Coagulation (DIC) that is an important complication and leads to disseminated hemorrhages and multi-organ failure. High Mobility Group B1 DNA Binding (HMGB1) protein is a cytokine taking part in systemic inflammatory response. The objective of this study was to investigate HMGB1 levels in groups of septic patients with and without DIC.Twenty-one septic patients without DIC and 12 septic patients with DIC from the Intensive Care Unit (ICU) were included in the study. In addition, 20 patients admitted to the ICU without sepsis or DIC and 20 healthy volunteers served as controls. Levels of HMGB1, prothrombin time, activated partial thromboplastin time, fibrinogen, D-dimer, protein C, protein S, anti-thrombin III (ATIII), platelet (thrombocyte) and leukocyte count were determined. Levels of fibrinogen, protein C, ATIII and platelet count were significantly lower and D-dimer was significantly higher in the group with sepsis plus DIC compared to the group with sepsis without DIC. Levels of HMGB1 were higher in the group with sepsis and DIC compared to the group with sepsis; however, the difference was not statistically significant and the levels of HGMB1 of both groups were significantly higher compared to ICU and healthy control groups. HMGB1 levels were not significantly different in survivor and non survivor patients. HMGB1 levels did not differ in lower respiratory tract infection (LRTI) and urinary tract infection (UTI) in regard to the etiology of sepsis.

  10. Extracellular roles of high-mobility-group B1%高迁移率族蛋白B1的细胞核外作用

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    王忠堂; 姚咏明; 盛志勇

    2004-01-01

    High-mobility-group B1 (HMGB1), an abundant, highly conserved cellular protein, is widely known as a nuclear DNA - binding protein that stabilizes nucleosome formation, and facilitates gene transcription. Recent studies suggested that HMGBI could be overexpressed and released from cellular nucleosome upon endotoxin and cytokine stimulation, or other stress challenge including bums, shock, as well as infection.Therefore, extracellular HMGB1 might be involved in the pathogenesis of sepsis and subsequent multiple organ dysfunction syndrome. Moreover, experimental data showedextracellular HMGB1 might play vital roles in nerves development, tumor metastasis, atherosclerosis and restenosis after vascular damage.

  11. High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity

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    Yang Runkuan

    2012-05-01

    Full Text Available Abstract Background Acetaminophen (APAP overdose induces massive hepatocyte necrosis. Necrotic tissue releases high mobility group B1 (HMGB1, and HMGB1 contributes to liver injury. Even though blockade of HMGB1 does not protect against APAP-induced acute liver injury (ALI at 9 h time point, the later time points are not studied and the role of HMGB1 in APAP overdose is unknown, it is possible that neutralization of HMGB1 might improve hepatocyte regeneration. This study aims to test whether blockade of HMGB1 improves hepatocyte regeneration after APAP overdose. Methods Male C57BL/6 mice were treated with a single dose of APAP (350 mg/kg. 2 hrs after APAP administration, the APAP challenged mice were randomized to receive treatment with either anti-HMGB1 antibody (400 μg per dose or non-immune (sham IgG every 24 hours for a total of 2 doses. Results 24 hrs after APAP injection, anti-HMGB1 therapy instead of sham IgG therapy significantly improved hepatocyte regeneration microscopically; 48 hrs after APAP challenge, the sham IgG treated mice showed 14.6% hepatic necrosis; in contrast, blockade of HMGB1 significantly decreased serum transaminases (ALT and AST, markedly reduced the number of hepatic inflammatory cells infiltration and restored liver structure to nearly normal; this beneficial effect was associated with enhanced hepatic NF-κB DNA binding and increased the expression of cyclin D1, two important factors related to hepatocyte regeneration. Conclusion HMGB1 impairs hepatocyte regeneration after APAP overdose; Blockade of HMGB1 enhances liver recovery and may present a novel therapy to treat APAP overdose.

  12. 高迁移率族蛋白 B1与缺血性卒中%High-mobility group protein B1 and ischemic stroke

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    曹翔; 徐运

    2016-01-01

    High mobility group protein box 1 (HMGB1) is a typical nonhistone chromosomal protein. It has many celular functions in nucleus. Studies in recent years have showed that HMGB1 can be released to the outside of cels to exert a wide range of cytological effects. Ischemic stroke is one of the diseases with the highest morbidity and disability. More and more evidence has shown that HMGB1 plays a variety of important roles in the occurrence and development process of ischemic stroke. This article reviews the roles of HMGB1 in ischemic stroke.%高迁移率族蛋白 B1(high mobility group protein box 1, HMGB1)是一种典型的非组蛋白,在细胞核内具有多种功能。近年来的研究表明,HMGB1可释放到细胞外发挥广泛的细胞学效应。缺血性卒中是发病率和致残率最高的疾病之一。越来越多的证据表明,HMGB1在缺血性卒中的发生和发展过程中起到多种重要作用。文章就 HMGB1在缺血性卒中中的作用进行了综述。

  13. The bacterial SoxAX cytochromes.

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    Kappler, Ulrike; Maher, Megan J

    2013-03-01

    SoxAX cytochromes are heme-thiolate proteins that play a key role in bacterial thiosulfate oxidation, where they initiate the reaction cycle of a multi-enzyme complex by catalyzing the attachment of sulfur substrates such as thiosulfate to a conserved cysteine present in a carrier protein. SoxAX proteins have a wide phylogenetic distribution and form a family with at least three distinct types of SoxAX protein. The types of SoxAX cytochromes differ in terms of the number of heme groups present in the proteins (there are diheme and triheme versions) as well as in their subunit structure. While two of the SoxAX protein types are heterodimers, the third group contains an additional subunit, SoxK, that stabilizes the complex of the SoxA and SoxX proteins. Crystal structures are available for representatives of the two heterodimeric SoxAX protein types and both of these have shown that the cysteine ligand to the SoxA active site heme carries a modification to a cysteine persulfide that implicates this ligand in catalysis. EPR studies of SoxAX proteins have also revealed a high complexity of heme dependent signals associated with this active site heme; however, the exact mechanism of catalysis is still unclear at present, as is the exact number and types of redox centres involved in the reaction.

  14. Remarkable evolutionary conservation of SOX14 orthologues

    Indian Academy of Sciences (India)

    Jelena Popovic; Milena Stevanovic

    2009-04-01

    SOX proteins constitute a large family of diverse, well-conserved transcription factors present in vertebrates and invertebrates, and also implicated in control of many developmental processes. Our objectives have been to identify Sox14 gene of goat (Capra hircus), cow (Bos taurus) and rat (Rattus norvegicus), and to perform comparative analyses and mapping of SOX14 orthologues from numerous vertebrate species. PCR based approach was used to identify Sox14 of goat, cow and rat, while nucleotide and amino acid sequence alignments and mapping were performed using information currently available in public database. Comparative sequence analysis revealed remarkable identity among Sox14 orthologues and helped us to identify highly conserved motifs that represent molecular signatures of SOX14 protein that might have structural or functional significance. Further, we determined chromosomal locations of numerous predicted group B Sox genes and their neighbouring genes using currently available genome database. In conclusion, our study has not only supported the proposed model of group B Sox genes evolution in chicken and mammals, but has also revealed that additional evolutionary events split Sox B genes into different chromosomes in some mammals. Mapping data presented in this study could help in refining the understanding of the evolution of group B Sox genes in vertebrates.

  15. Isolation and sequencing of the HMG domain of ten Sox genes from Odorrana schmackeri (Amphibia: Anura

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    Ning Wang

    2009-03-01

    Full Text Available Sox (SRY-related HMG-box genes encode a family of transcriptional regulators, which are characterized by a conserved 79-amino acid domain known as HMG-box. They play essential roles in a diverse range of processes including sex determination and the development of the central nervous system (CNS, neural crest and endoderm. In this paper, the HMG domain of ten distinct Sox gene family members (os-Sox2, os-Sox3a, os-Sox3b, os-Sox4, os-Sox11a, os-Sox11b, os-Sox14a, os-Sox14b, os-Sox21a, os-Sox21b were isolated from both male and female Odorrana schmackeri (Boettger, 1892 using PCR, and no sexual differences were found. Molecular phylogenetic analysis of the HMG domain suggested that these ten Sox genes are members of the SoxB and SoxC groups. In addition, sequence analysis suggested that four Sox genes (os-Sox3, os-Sox11, os-Sox14, os-Sox21 were duplicated. The duplication-degeneration-complementation model should be implied to explain the evolution and diversity of the Sox gene family in O. schmackeri.

  16. VDBP, CYP27B1, and 25-Hydroxyvitamin D Gene Polymorphism Analyses in a Group of Sicilian Multiple Sclerosis Patients.

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    Agnello, L; Scazzone, C; Lo Sasso, B; Bellia, C; Bivona, G; Realmuto, S; Brighina, F; Schillaci, R; Ragonese, P; Salemi, G; Ciaccio, Marcello

    2017-04-01

    Multiple sclerosis (MS) is a chronic demyelinating disease of central nervous system regarded as one of the most common causes of neurological disability in young adults. The exact etiology of MS is not yet known, although epidemiological data indicate that both genetic susceptibility and environmental exposure are involved. A poor vitamin D status has been proposed as the most attractive environmental factor. Several evidence have highlighted the importance of mutations in vitamin D-regulating genes for vitamin D status. The purpose of our study was to assess the genetic variants of VDBP and CYP27B1 in MS patients and in a control group. A total of 192 subjects, including 100 MS patients and 92 healthy controls, were genotyped by polymerase chain reaction followed by restriction fragment length polymorphism analyses. Serum 25-hydroxyvitamin D levels were measured in MS patients and controls by high-performance liquid chromatography. We did not observe any statically significant difference in the distribution of genotypic VDBP variants between the study groups. 25(OH)D plasma levels were significantly higher in the control group versus MS patients; MS patients who carried Gc2 showed lower 25(OH)D plasma levels and those who carried Gc1f showed higher levels. We observed only wild-type allele for CYP27B1 mutations analyzed both in MS patients and in the control group. In conclusion, our findings do not support a role of an independent effect of the investigated vitamin D-related gene variants, VDBP and CYP27B1, in the risk of MS.

  17. SOX15 regulates proliferation and migration of endometrial cancer cells.

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    Rui, Xiaohui; Xu, Yun; Jiang, Xiping; Guo, Caixia; Jiang, Jingting

    2017-08-18

    The study aimed to investigate the effects of SOX15 on proliferation and migration of endometrial cancer (EC) cells. Immunohistochemistry was applied to determine the expression of SOX15 in EC tissues and adjacent tissues. We used cell transfection method to construct the HEC-1-A and Ishikawa cell lines with stable overexpression and low-expression SOX15 Reverse transcription quantitative real-time PCR (RT-qPCR) and western blot were performed to examine expression of SOX15 mRNA and SOX15 protein respectively. By conducting a series of cell proliferation assay and migration assay, we analyzed the influence of SOX15 overexpression or low-expression on EC cell proliferation and migration. The expression of SOX15 mRNA and protein in EC tissues was significantly lower than that in adjacent tissues. After lentivirus-transfecting SOX15 , the expression level of SOX15 mRNA and protein was significantly increased in cells of SOX15 group, and decreased in sh- SOX15 group. Overexpression of SOX15 could suppress cell proliferation, while downregulation of SOX15 increased cell proliferation. Flow cytometry results indicated that overexpression of SOX15 induced the ratio of cell cycle arrest in G1 stage. In addition, transwell migration assay results showed that SOX15 overexpression significantly inhibited cell migration, and also downregulation of SOX15 promoted the migration. As a whole, SOX15 could regulate the proliferation and migration of EC cells and upregulation of SOX15 could be valuable for EC treatment. ©2017 The Author(s).

  18. Frequencies of two functionally significant SNPs and their haplotypes of organic anion transporting polypeptide 1B1 SLCO1B1 gene in six ethnic groups of Pakistani population

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    Tausif Ahmed Rajput

    2014-06-01

    Full Text Available Objective(s:Organic anion transporter polypeptide 1B1 (OATP1B1 encoded by solute carrier organic transporter 1B1 (SLCO1B1 gene; a transporter involved in the uptake of drugs and endogenous compounds is present in hepatocyte sinusoidal membrane. Aim of this study was to investigate the frequencies of functionally significant SNPs (388A>G and 521T>C and their haplotypes in 6 ethnic groups of Pakistani population through the development of rapid and efficient Tetra amplification refractory mutation system (T. ARMS genotyping assay. Materials and Methods: Frequencies of alleles, genotype, and haplotypes of two functionally significant Single nucleotide polymorphism in 180 healthy Pakistani subjects and distributions in six ethnic groups by using a single step T. ARMS genotyping assay. Results: The allelic frequency for 388A>G SNP was 50% in total Pakistani population with distributions of 9.7%, 15.1%, 19.4%, 16.1%, 18.3%, and 21.5% in Punjabi, Sindhi, Balouchi, Pathan, Kashmiri and Hazara/Baltistan groups respectively; and for 521T>C SNP it was 23.9% in total Pakistani population with distributions of 11.1%, 8.9%, 15.6%, 11.1%, 31.1% and 22.2% in Punjabi, Sindhi, Balouchi, Pathan, Kashmiri, and Hazara/Baltistan groups. Both functionally significant SNPs occurred in four major haplotypes with a frequency of 35.5% for 388A/521T (*1A, 40.5% for 388G/521T (*1B, 14.4% for 388A/521C (*5, and 9.4% for 388G/521C (*15 with varying distributions among six ethnic groups. Conclusion: The 388A>G and 521T>C genotypes and corresponding haplotypes are present at varying frequencies in various ethnic groups of Pakistani population. Pharmacokinetic and pharmacodynamic

  19. Artificial induction of Sox21 regulates sensory cell formation in the embryonic chicken inner ear.

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    Stephen D Freeman

    Full Text Available During embryonic development, hair cells and support cells in the sensory epithelia of the inner ear derive from progenitors that express Sox2, a member of the SoxB1 family of transcription factors. Sox2 is essential for sensory specification, but high levels of Sox2 expression appear to inhibit hair cell differentiation, suggesting that factors regulating Sox2 activity could be critical for both processes. Antagonistic interactions between SoxB1 and SoxB2 factors are known to regulate cell differentiation in neural tissue, which led us to investigate the potential roles of the SoxB2 member Sox21 during chicken inner ear development. Sox21 is normally expressed by sensory progenitors within vestibular and auditory regions of the early embryonic chicken inner ear. At later stages, Sox21 is differentially expressed in the vestibular and auditory organs. Sox21 is restricted to the support cell layer of the auditory epithelium, while it is enriched in the hair cell layer of the vestibular organs. To test Sox21 function, we used two temporally distinct gain-of-function approaches. Sustained over-expression of Sox21 from early developmental stages prevented prosensory specification, and abolished the formation of both hair cells and support cells. However, later induction of Sox21 expression at the time of hair cell formation in organotypic cultures of vestibular epithelia inhibited endogenous Sox2 expression and Notch activity, and biased progenitor cells towards a hair cell fate. Interestingly, Sox21 did not promote hair cell differentiation in the immature auditory epithelium, which fits with the expression of endogenous Sox21 within mature support cells in this tissue. These results suggest that interactions among endogenous SoxB family transcription factors may regulate sensory cell formation in the inner ear, but in a context-dependent manner.

  20. Sox2 uses multiple domains to associate with proteins present in Sox2-protein complexes.

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    Jesse L Cox

    Full Text Available Master regulators, such as Sox2, Oct4 and Nanog, control complex gene networks necessary for the self-renewal and pluripotency of embryonic stem cells (ESC. These master regulators associate with co-activators and co-repressors to precisely control their gene targets. Recent studies using proteomic analysis have identified a large, diverse group of co-activators and co-repressors that associate with master regulators, including Sox2. In this report, we examined the size distribution of nuclear protein complexes containing Sox2 and its associated proteins HDAC1, Sall4 and Lin28. Interestingly, we determined that Sox2 and HDAC1 associate with protein complexes that vary greatly in size; whereas, Lin28 primarily associates with smaller complexes, and Sall4 primarily associates with larger complexes. Additionally, we examined the domains of Sox2 necessary to mediate its association with its partner proteins Sall4, HDAC1 and HDAC2. We determined that Sox2 uses multiple and distinct domains to associate with its partner proteins. We also examined the domains of Sox2 necessary to mediate its self-association, and we determined that Sox2 self-association is mediated through multiple domains. Collectively, these studies provide novel insights into how Sox2 is able to associate with a wide array of nuclear proteins that control gene transcription.

  1. Proinflammatory effect of high-mobility group protein B1 on keratinocytes: an autocrine mechanism underlying psoriasis development.

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    Zhang, Weigang; Guo, Sen; Li, Bing; Liu, Lin; Ge, Rui; Cao, Tianyu; Wang, Huina; Gao, Tianwen; Wang, Gang; Li, Chunying

    2017-02-01

    Psoriasis is an autoimmune skin disease, in which keratinocytes play a crucial pathogenic role. High-mobility group protein B1 (HMGB1) is an inflammatory factor that can be released from keratinocyte nuclei in psoriatic lesions. We aimed to investigate the proinflammatory effect of HMGB1 on keratinocytes and the contribution of HMGB1 to psoriasis development. Normal human keratinocytes were treated with recombinant human HMGB1, and the production of inflammatory factors and the intermediary signalling pathways were examined. Furthermore, the imiquimod-induced psoriasis-like mouse model was used to investigate the role of HMGB1 in psoriasis development in vivo. A total of 11 inflammatory factors were shown to be upregulated by HMGB1 in keratinocytes, among which interleukin (IL)-18 showed the greatest change. We then found that activation of the nuclear factor-κB signalling pathway and inflammasomes accounted for HMGB1-induced IL-18 expression and secretion. Moreover, HMGB1 and downstream IL-18 contributed to the development of psoriasiform dermatitis in the imiquimod-treated mice. In addition, T-helper 17 immune response in the psoriasis-like mouse model could be inhibited by both HMGB1 and IL-18 blockade. Our findings indicate that HMGB1 secreted from keratinocytes can facilitate the production and secretion of inflammatory factors such as IL-18 in keratinocytes in an autocrine way, thus promoting the development of psoriasis. Blocking the proinflammatory function of the HMGB1-IL-18 axis may be useful for psoriasis treatment in the future. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  2. A Systematic Survey and Characterization of Enhancers that Regulate Sox3 in Neuro-Sensory Development in Comparison with Sox2 Enhancers

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    Hisato Kondoh

    2012-11-01

    Full Text Available Development of neural and sensory primordia at the early stages of embryogenesis depends on the activity of two B1 Sox transcription factors, Sox2 and Sox3. The embryonic expression patterns of the Sox2 and Sox3 genes are similar, yet they show gene-unique features. We screened for enhancers of the 231-kb genomic region encompassing Sox3 of chicken, and identified 13 new enhancers that showed activity in different domains of the neuro-sensory primordia. Combined with the three Sox3-proximal enhancers determined previously, at least 16 enhancers were involved in Sox3 regulation. Starting from the NP1 enhancer, more enhancers with different specificities are activated in sequence, resulting in complex overlapping patterns of enhancer activities. NP1 was activated in the caudal lateral epiblast adjacent to the posterior growing end of neural plate, and by the combined action of Wnt and Fgf signaling, similar to the Sox2 N1 enhancer involved in neural/mesodermal dichotomous cell lineage segregation. The Sox3 D5 enhancer and Sox2 N3 enhancer were also activated similarly in the diencephalon, optic vesicle and lens placode, suggesting analogies in their regulation. In general, however, the specificities of the enhancers were not identical between Sox3 and Sox2, including the cases of the NP1 and D5 enhancers.

  3. A Systematic Survey and Characterization of Enhancers that Regulate Sox3 in Neuro-Sensory Development in Comparison with Sox2 Enhancers.

    Science.gov (United States)

    Nishimura, Naoko; Kamimura, Yoshifumi; Ishida, Yoshiko; Takemoto, Tatsuya; Kondoh, Hisato; Uchikawa, Masanori

    2012-11-22

    Development of neural and sensory primordia at the early stages of embryogenesis depends on the activity of two B1 Sox transcription factors, Sox2 and Sox3. The embryonic expression patterns of the Sox2 and Sox3 genes are similar, yet they show gene-unique features. We screened for enhancers of the 231-kb genomic region encompassing Sox3 of chicken, and identified 13 new enhancers that showed activity in different domains of the neuro-sensory primordia. Combined with the three Sox3-proximal enhancers determined previously, at least 16 enhancers were involved in Sox3 regulation. Starting from the NP1 enhancer, more enhancers with different specificities are activated in sequence, resulting in complex overlapping patterns of enhancer activities. NP1 was activated in the caudal lateral epiblast adjacent to the posterior growing end of neural plate, and by the combined action of Wnt and Fgf signaling, similar to the Sox2 N1 enhancer involved in neural/mesodermal dichotomous cell lineage segregation. The Sox3 D5 enhancer and Sox2 N3 enhancer were also activated similarly in the diencephalon, optic vesicle and lens placode, suggesting analogies in their regulation. In general, however, the specificities of the enhancers were not identical between Sox3 and Sox2, including the cases of the NP1 and D5 enhancers.

  4. Homologues of sox8 and sox10 in the orange-spotted grouper Epinephelus coioides: sequences, expression patterns, and their effects on cyp19a1a promoter activities in vitro.

    Science.gov (United States)

    Liu, Qiongyou; Lu, Huijie; Zhang, Lihong; Xie, Jun; Shen, Wenying; Zhang, Weimin

    2012-09-01

    Sox8 and Sox10 are members of group E Sox proteins involved in a wide range of developmental processes including sex determination and neurogenesis in vertebrates. The orange-spotted grouper sox8a and sox10a homologues were isolated and characterized in the present study. Both sox8a and sox10a genes contain three exons and two introns, and encode putative proteins with typical structures of group E Sox. Sox8a was expressed in diverse tissues including the central nervous system and some peripheral tissues. In contrast, sox10a mRNA was detected primarily in the central nervous system. During embryogenesis, sox8a mRNA seemed to be de novo synthesized in the embryos from otic vesicle stage. However, sox10a mRNA was only detectable in juvenile fish 35 days post hatching and thereafter. The mRNA levels of sox8a in the gonads were not significantly different among ovarian developmental stages but increased in the testis. In vitro transfection assays showed that the Sox10a but not Sox8a up-regulated cyp19a1a promoter activities. Taken together, these results suggested that the sox8a may play roles in diverse tissues and during embryogenesis, whereas sox10a may be mainly involved in the neural regulation of juvenile and adult fish, and that certain Sox homologues may regulate the orange-spotted grouper cyp19a1a promoter.

  5. SoxE function in vertebrate nervous system development.

    Science.gov (United States)

    Stolt, C Claus; Wegner, Michael

    2010-03-01

    Sox8, Sox9, and Sox10 as transcription factors of subgroup E of the Sox protein family are essential for many aspects of nervous system development. These SoxE proteins are already required for the initial neural crest induction, but also guarantee survival and maintenance of pluripotency in migrating neural crest stem cells. SoxE proteins are furthermore key regulators of glial specification in both the peripheral and the central nervous systems. At later stages of development, Sox10 plays crucial roles in Schwann cells and oligodendrocytes for terminal differentiation and myelin formation. In both glial cell types, Sox10 controls directly the expression of genes encoding the major myelin proteins. SoxE proteins are well-integrated components of regulatory networks and as such modulated in their activity by cooperating or antagonistic transcription factors such as SoxD or various bHLH proteins. The multiple functions in peripheral and central nervous system development also link SoxE proteins to various human diseases and identify these proteins as promising targets of future therapeutic approaches.

  6. Sox7, Sox17, and Sox18 Cooperatively Regulate Vascular Development in the Mouse Retina.

    Directory of Open Access Journals (Sweden)

    Yulian Zhou

    Full Text Available Vascular development and maintenance are controlled by a complex transcriptional program, which integrates both extracellular and intracellular signals in endothelial cells. Here we study the roles of three closely related SoxF family transcription factors-Sox7, Sox17, and Sox18 -in the developing and mature mouse vasculature using targeted gene deletion on a mixed C57/129/CD1 genetic background. In the retinal vasculature, each SoxF gene exhibits a distinctive pattern of expression in different classes of blood vessels. On a mixed genetic background, vascular endothelial-specific deletion of individual SoxF genes has little or no effect on vascular architecture or differentiation, a result that can be explained by overlapping function and by reciprocal regulation of gene expression between Sox7 and Sox17. By contrast, combined deletion of Sox7, Sox17, and Sox18 at the onset of retinal angiogenesis leads to a dense capillary plexus with a nearly complete loss of radial arteries and veins, whereas the presence of a single Sox17 allele largely restores arterial identity, as determined by vascular smooth muscle cell coverage. In the developing retina, expression of all three SoxF genes is reduced in the absence of Norrin/Frizzled4-mediated canonical Wnt signaling, but SoxF gene expression is unaffected by reduced VEGF signaling in response to deletion of Neuropilin1 (Npn1. In adulthood, Sox7, Sox17, and Sox18 act in a largely redundant manner to maintain blood vessel function, as adult onset vascular endothelial-specific deletion of all three SoxF genes leads to massive edema despite nearly normal vascular architecture. These data reveal critical and partially redundant roles for Sox7, Sox17 and Sox18 in vascular growth, differentiation, and maintenance.

  7. ompW is cooperatively upregulated by MarA and SoxS in response to menadione.

    Science.gov (United States)

    Collao, B; Morales, E H; Gil, F; Calderón, I L; Saavedra, C P

    2013-04-01

    OmpW is a minor porin whose biological function has not been clearly defined. Evidence obtained in our laboratory indicates that in Salmonella enterica serovar Typhimurium the expression of OmpW is activated by SoxS upon exposure to paraquat and it is required for resistance. SoxS belongs to the AraC family of transcriptional regulators, like MarA and Rob. Due to their high structural similarity, the genes under their control have been grouped in the mar/sox/rob regulon, which presents a DNA-binding consensus sequence denominated the marsox box. In this work, we evaluated the role of the transcription factors MarA, SoxS and Rob of S. enterica serovar Typhimurium in regulating ompW expression in response to menadione. We determined the transcript and protein levels of OmpW in different genetic backgrounds; in the wild-type and Δrob strains ompW was upregulated in response to menadione, while in the ΔmarA and ΔsoxS strains the induction was abolished. In a double marA soxS mutant, ompW transcript levels were lowered after exposure to menadione, and only complementation in trans with both genes restored the positive regulation. Using transcriptional fusions and electrophoretic mobility shift assays with mutant versions of the promoter region we demonstrated that two of the predicted sites were functional. Additionally, we demonstrated that MarA increases the affinity of SoxS for the ompW promoter region. In conclusion, our study shows that ompW is upregulated in response to menadione in a cooperative manner by MarA and SoxS through a direct interaction with the promoter region.

  8. Cloning and sequence analysis of Sox genes in a tetraploid cyprinid fish, Tor douronensis

    Institute of Scientific and Technical Information of China (English)

    GUO BaoCheng; LI JunBing; TONG ChaoBo; HE ShunPing

    2008-01-01

    A PCR survey for Sox genes in a young tetraploid fish Tor douronensis (Teleostei: Cyprinidae) was per-formed to access the evolutionary fates of important functional genes after genome duplication caused by polyploidization event. Totally 13 Sox genes were obtained in Tor douronensis, which represent SoxB, SoxC and SoxE groups. Phylogenetic analysis of Sox genes in Tor douronensis provided evidence for fish-specific genome duplication, and suggested that Sox19 might be a teleost specific Sox gene member. Sequence analysis revealed most of the nucleotide substitutions between duplicated copies of Sox genes caused by tetraploidization event or their orthologues in other species are silent substitutions. It would appear that the sequences are under purifying selective pressure, strongly suggesting that they repre- sent functional genes and supporting selection against all null allele at either of two duplicated loci of Sox4a, Sox9a and Sox9b. Surprising variations of the intron length and similarities of two duplicated copies of Sox9a and Sox9b, suggest that Tor douronensis might be an allotetraploidy.

  9. 鳙Sox基因克隆及序列进化分析%CLONING AND SEQUENCE EVOLUTION ANALYSIS OF SOX GENES IN BIGHEAD CARP (ARISTICHTHYS NOBILIS)

    Institute of Scientific and Technical Information of China (English)

    郭稳杰; 俞小牧; 童金苟

    2014-01-01

    To amplify Sox genes from bighead carp genome, two pairs of degenerate primers (SoxN and Sox9) were de-signed for PCR amplification that were utilized for sequencing and analysis of sequence homology and phylogenetic relationships. The results showed that 15 distinct Sox genes encoding the HMG domains were identified in bighead carp, which were assigned to group B, C and E. According to their homology to orthologs of zebrafish, 15 Sox genes were designated as Sox1a, Sox1b, Sox2, Sox3, Sox4a, Sox4b, Sox9a, Sox9b, Sox10, Sox11b, Sox12, Sox14a, Sox14b, Sox19 and Sox21a, respectively. Phylogenetic tree of Sox1, Sox4 and Sox9 nucleotide sequences indicated that the duplication of these three Sox genes occurred before the divergence of bighead carp and zebrafish, and this observation supported the“fish-specific whole-genome duplication” theory. Using Sox1a, Sox1b and Sox4 as molecular clock markers in phy-logenetic analysis, the estimation of the divergence time between bighead carp and zebrafish demonstrated that in origi-nal Danioninae, a common ancestor appeared approximately 63.7 million years ago for bighead carp and zebrafish, both of which belong to Cyprinidae. This study would provide important information for further studies of Sox gene replica-tion and genome evolution in fish.%利用简并引物SoxN和Sox9在鳙基因组DNA中进行PCR扩增和产物克隆测序,并对序列进行同源性比较和系统进化分析。结果表明本文鉴定出鳙15个Sox基因HMG盒序列,分别属于 SoxB、SoxC和 SoxE组,依据斑马鱼同源基因将其分别命名为Sox1a、Sox1b、Sox2、Sox3、Sox4a、Sox4b、Sox9a、Sox9b、Sox10、Sox11b、Sox12、Sox14a、Sox14b、Sox19和Sox21a。基于鳙和斑马鱼 Sox1、Sox4和Sox9基因核苷酸序列构建的系统进化树显示这3个Sox基因的复制时间发生在鳙和斑马鱼的分化之前,结果支持了鱼类特异的基因组复制假说。以Sox1a、Sox1b和Sox4基因为分子钟标记构建系统

  10. Molecular analysis of the distribution and phylogeny of the soxB gene among sulfur-oxidizing bacteria - evolution of the Sox sulfur-oxidizing enzyme system

    OpenAIRE

    Meyer, Birte; Imhoff, Johannes F.; Kuever, Jan

    2007-01-01

    The soxB gene encodes the SoxB component of the periplasmic thiosulfate-oxidizing Sox enzyme complex, which has been proposed to be widespread among the various phylogenetic groups of sulfur-oxidizing bacteria (SOB) that convert thiosulfate to sulfate with and without the formation of sulfur globules as intermediate. Indeed, the comprehensive genetic and genomic analyses presented in the present study identified the soxB gene in 121 phylogenetically and physiologically divergent SOB, includin...

  11. Research Progress of Intervention Strategies of High Mobility Group Protein B1 in Sepsis%脓毒症时高迁移率族蛋白B1干预策略的研究进展

    Institute of Scientific and Technical Information of China (English)

    王文江

    2012-01-01

    A certain progress has been made in the molecular mechanism , expression , release regularity and drug suppression of high mobility group protein Bl( HMGBl )as a new potential " late" inflammatory mediators involved in the pathogenesis of sepsis, which makes it possible for early intervention of sepsis and uncontrolled inflammatory response for clinicians. Besides, detection of serum HMGBl levels may become a new means to determine the condition of patients with sepsis.%高迁移率族蛋白B1(HMGB1)作为新的潜在"晚期"炎性介质参与脓毒症的发病过程,在揭示HMGB1作用的分子机制、HMGB1表达、释放规律及药物抑制方面已经取得了一定进展,给临床医师提供了对脓毒症和失控炎性反应实施早期干预的可能.同时,检测血清HMGB1水平也可能成为预测和判断脓毒症患者病情的一种新手段.

  12. [The CYP1B1 and CYP2F1 genes polymorphisms frequency in three ethnic groups of Bashkortostan and chronic obstructive pulmonary disease patients].

    Science.gov (United States)

    Korytina, G F; Akhmadishina, L Z; Viktorova, T V

    2010-01-01

    Chronic obstructive pulmonary disease is a multifactorial respiratory disorder. Members of the cytochrome P450 family catalyze the oxidative metabolism of exogenous chemicals and activate their substrates into reactive intermediates that may initiate lung injury. The aim of this study was to learn interethnic variation in frequency distribution patterns of CYP1B1 and CYP2F1 genes polymorphic markers and to analyse its association withchronic obstructive pulmonary disease. The polymorphic markers Leu432Val(CYP1B1) and c.14_15insC(CYP2F1) were studied at chronic obstructive pulmonary disease patients (Russian (N=169), Tatar (N=137)) and cases of healthy individuals (Russian (N=191), Tatar (N=198) and Bashkir (N=78)), residents of Bashkortostan by PCR-RFLP method. It was shown that the CYP2F1 gene genotype frequency distribution patterns differed between three ethnic groups (chi2 = 21.29, df=4, P = 0.0001), because of high frequency of c.14_15insC/c.14_15insC genotype in Tatars (6.38%). On the other hand, high frequency (39.74%) of normal/ c.14_15insC genotype was appeared in Bashkirs. Association analysis of CYP2F1 geneinsertion variant with chronic obstructive pulmonary disease have shown high frequency (87.5%) of normal allele in Tatars patients with very severe stage and manifestation of chronic obstructive pulmonary disease after 55 years (chi2 = 3.964, df=1, P = 0.046; OR = = 2.268). It was shown that allele and genotype frequency distribution of Leu432ValCYP1B1 gene not differed between Russian, Tatar and Bashkir ethnic groups. We did not find any association of Leu432Val CYP1B1 gene with chronic obstructive pulmonary disease.

  13. SOX sensitivity study

    Energy Technology Data Exchange (ETDEWEB)

    Martyn, Johann [Johannes Gutenberg-Universitaet, Mainz (Germany); Collaboration: BOREXINO-Collaboration

    2016-07-01

    To this day most experimental results on neutrino oscillations can be explained in the standard three neutrino model. There are however a few experiments that show anomalous behaviour at a very short baselines. These anomalies can hypothetically be explained with the existence of one or additional more light neutrino states that do not take part in weak interactions and are thus called sterile. Although the anomalies only give a hint that such sterile neutrinos could exist the prospect for physics beyond the standard model is a major motivation to investigate the neutrino oscillations in new very short baseline experiments. The SOX (Short distance Oscillations in BoreXino) experiment will use the Borexino detector and a {sup 144}Ce source to search for sterile neutrinos via the occurance of an oscillation pattern at a baseline of several meters. This talk examines the impact of the Borexino detector systematics on the experimental sensitivity of SOX.

  14. Triage of Atypical Glandular Cell by SOX1 and POU4F3 Methylation: A Taiwanese Gynecologic Oncology Group (TGOG Study.

    Directory of Open Access Journals (Sweden)

    Cheng-Chang Chang

    Full Text Available Invasive procedures including loop electrosurgical excision, cervical conization, and endometrial sampling are often recommended when atypical glandular cells (AGC are detected on Pap smear with unsatisfactory colposcopy. These invasive procedures may result in patient anxiety, increased medical expense, and increasing the risk of preterm delivery in subsequent pregnancies. This study was performed to assess methylation biomarkers in the triage of AGC on Pap smear for invasive procedures.We conducted a multicenter study in 13 medical centers in Taiwan from May 2012 to May 2014. A total of 55 samples diagnosed "AGC not otherwise specified" (AGC-NOS were included. All patients with AGC underwent colposcopy, cervical biopsy, endometrial sampling, and conization if indicated. Multiplex quantitative methylation-specific polymerase chain reaction (QMSPCR was performed. Sensitivity, specificity, and accuracy were calculated for detecting CIN3+ and endometrial complex hyperplasia.In 55 patients with AGC, the sensitivity for methylated (m SOX1m, PAX1 m, ZNF582m,PTPRRm, AJAP1m, HS3ST2m, and POU4F3m for detecting CIN3+ and endometrial complex hyperplasia lesions was 100, 86, 71, 86, 86, 57, and 100%; specificity was 67, 79, 85, 50, 52, 96, and 52%, respectively. Testing for high risk-HPV had a sensitivity of 57% and specificity of 75% for CIN3+ and endometrial complex hyperplasia lesions.Methylated (m SOX1m and POU4F3m could be new methylation biomarkers for detection of CIN3+ and endometrial complex hyperplasia in AGC. Women with AGC and positive SOX1m / POU4F3m, colposcopy, cervical conization or endometrial sampling should be considered.

  15. SOX genes: architects of development.

    Science.gov (United States)

    Prior, H M; Walter, M A

    1996-07-01

    Development in higher organisms involves complex genetic regulation at the molecular level. The emerging picture of development control includes several families of master regulatory genes which can affect the expression of down-stream target genes in developmental cascade pathways. One new family of such development regulators is the SOX gene family. The SOX genes are named for a shared motif called the SRY box a region homologous to the DNA-binding domain of SRY, the mammalian sex determining gene. Like SRY, SOX genes play important roles in chordate development. At least a dozen human SOX genes have been identified and partially characterized (Tables 1 and 2). Mutations in SOX9 have recently been linked to campomelic dysplasia and autosomal sex reversal, and other SOX genes may also be associated with human disease.

  16. SoxC transcription factors in retinal development and regeneration

    Directory of Open Access Journals (Sweden)

    Kun-Che Chang

    2017-01-01

    Full Text Available Glaucoma and other optic neuropathies result in optic nerve degeneration and the loss of retinal ganglion cells (RGCs through complex signaling pathways. Although the mechanisms that regulate RGC development remain unclear, uncovering novel developmental pathways may support new strategies to regenerate the optic nerve or replace RGCs. Here we review recent studies that provide strong evidence that the Sry-related high-mobility-group C (SoxC subfamily of transcription factors (TFs are necessary and sufficient for axon guidance and RGC fate specification. These findings also uncover novel SoxC-dependent mechanisms that serve as master regulators during important steps of RGC development. For example, we review work showing that SoxC TFs regulate RGC axon guidance and direction through the optic chiasm towards their appropriate targets in the brain. We also review work demonstrating that Sox11 subcellular localization is, in part, controlled through small ubiquitin-like post-translational modifier (SUMO and suggest compensatory cross-talk between Sox4 and Sox11. Furthermore, Sox4 overexpression is shown to positively drive RGC differentiation in human induced pluripotent stem cells (hiPSCs. Finally, we discuss how these findings may contribute to the advancement of regenerative and cell-based therapies to treat glaucoma and other optic nerve neuropathies.

  17. Molecular analysis of the distribution and phylogeny of the soxB gene among sulfur-oxidizing bacteria - evolution of the Sox sulfur oxidation enzyme system.

    Science.gov (United States)

    Meyer, Birte; Imhoff, Johannes F; Kuever, Jan

    2007-12-01

    The soxB gene encodes the SoxB component of the periplasmic thiosulfate-oxidizing Sox enzyme complex, which has been proposed to be widespread among the various phylogenetic groups of sulfur-oxidizing bacteria (SOB) that convert thiosulfate to sulfate with and without the formation of sulfur globules as intermediate. Indeed, the comprehensive genetic and genomic analyses presented in the present study identified the soxB gene in 121 phylogenetically and physiologically divergent SOB, including several species for which thiosulfate utilization has not been reported yet. In first support of the previously postulated general involvement of components of the Sox enzyme complex in the thiosulfate oxidation process of sulfur-storing SOB, the soxB gene was detected in all investigated photo- and chemotrophic species that form sulfur globules during thiosulfate oxidation (Chromatiaceae, Chlorobiaceae, Ectothiorhodospiraceae, Thiothrix, Beggiatoa, Thiobacillus, invertebrate symbionts and free-living relatives). The SoxB phylogeny reflected the major 16S rRNA gene-based phylogenetic lineages of the investigated SOB, although topological discrepancies indicated several events of lateral soxB gene transfer among the SOB, e.g. its independent acquisition by the anaerobic anoxygenic phototrophic lineages from different chemotrophic donor lineages. A putative scenario for the proteobacterial origin and evolution of the Sox enzyme system in SOB is presented considering the phylogenetic, genomic (sox gene cluster composition) and geochemical data.

  18. Sox genes in the coral Acropora millepora: divergent expression patterns reflect differences in developmental mechanisms within the Anthozoa.

    Science.gov (United States)

    Shinzato, Chuya; Iguchi, Akira; Hayward, David C; Technau, Ulrich; Ball, Eldon E; Miller, David J

    2008-11-12

    Sox genes encode transcription factors that function in a wide range of developmental processes across the animal kingdom. To better understand both the evolution of the Sox family and the roles of these genes in cnidarians, we are studying the Sox gene complement of the coral, Acropora millepora (Class Anthozoa). Based on overall domain structures and HMG box sequences, the Acropora Sox genes considered here clearly fall into four of the five major Sox classes. AmSoxC is expressed in the ectoderm during development, in cells whose morphology is consistent with their assignment as sensory neurons. The expression pattern of the Nematostella ortholog of this gene is broadly similar to that of AmSoxC, but there are subtle differences--for example, expression begins significantly earlier in Acropora than in Nematostella. During gastrulation, AmSoxBb and AmSoxB1 transcripts are detected only in the presumptive ectoderm while AmSoxE1 transcription is restricted to the presumptive endoderm, suggesting that these Sox genes might play roles in germ layer specification. A third type B Sox gene, AmSoxBa, and a Sox F gene AmSoxF also have complex and specific expression patterns during early development. Each of these genes has a clear Nematostella ortholog, but in several cases the expression pattern observed in Acropora differs significantly from that reported in Nematostella. These differences in expression patterns between Acropora and Nematostella largely reflect fundamental differences in developmental processes, underscoring the diversity of mechanisms within the anthozoan Sub-Class Hexacorallia (Zoantharia).

  19. Vitamin B1

    Science.gov (United States)

    ... Prize Alfred Nobel's Life and Work Teachers' Questionnaire Vitamin B1 - About The Chicken Farm educational game and ... the game window. Reading: "Christian Eijkman, Beriberi and Vitamin B1" - Who was Eijkman and why did he ...

  20. Vitamin B1

    Science.gov (United States)

    ... Prize Alfred Nobel's Life and Work Teachers' Questionnaire Vitamin B1 - About The Chicken Farm educational game and ... the game window. Reading: "Christian Eijkman, Beriberi and Vitamin B1" - Who was Eijkman and why did he ...

  1. Sox2, a key factor in the regulation of pluripotency and neural differentiation

    Institute of Scientific and Technical Information of China (English)

    Shuchen; Zhang; Wei; Cui

    2014-01-01

    Sex determining region Y-box 2(Sox2), a member of the SoxB1 transcription factor family, is an important transcriptional regulator in pluripotent stem cells(PSCs). Together with octamer-binding transcription factor 4 and Nanog, they co-operatively control gene expression in PSCs and maintain their pluripotency. Furthermore, Sox2 plays an essential role in somatic cell reprogram-ming, reversing the epigenetic configuration of differ-entiated cells back to a pluripotent embryonic state. In addition to its role in regulation of pluripotency, Sox2 is also a critical factor for directing the differentiation of PSCs to neural progenitors and for maintaining the properties of neural progenitor stem cells. Here, we review recent findings concerning the involvement of Sox2 in pluripotency, somatic cell reprogramming and neural differentiation as well as the molecular mecha-nisms underlying these roles.

  2. Expression of Sox genes in tooth development.

    Science.gov (United States)

    Kawasaki, Katsushige; Kawasaki, Maiko; Watanabe, Momoko; Idrus, Erik; Nagai, Takahiro; Oommen, Shelly; Maeda, Takeyasu; Hagiwara, Nobuko; Que, Jianwen; Sharpe, Paul T; Ohazama, Atsushi

    2015-01-01

    Members of the Sox gene family play roles in many biological processes including organogenesis. We carried out comparative in situ hybridization analysis of seventeen sox genes (Sox1-14, 17, 18, 21) during murine odontogenesis from the epithelial thickening to the cytodifferentiation stages. Localized expression of five Sox genes (Sox6, 9, 13, 14 and 21) was observed in tooth bud epithelium. Sox13 showed restricted expression in the primary enamel knots. At the early bell stage, three Sox genes (Sox8, 11, 17 and 21) were expressed in pre-ameloblasts, whereas two others (Sox5 and 18) showed expression in odontoblasts. Sox genes thus showed a dynamic spatio-temporal expression during tooth development.

  3. Expression of Sox genes in tooth development

    Science.gov (United States)

    KAWASAKI, KATSUSHIGE; KAWASAKI, MAIKO; WATANABE, MOMOKO; IDRUS, ERIK; NAGAI, TAKAHIRO; OOMMEN, SHELLY; MAEDA, TAKEYASU; HAGIWARA, NOBUKO; QUE, JIANWEN; SHARPE, PAUL T.; OHAZAMA, ATSUSHI

    2017-01-01

    Members of the Sox gene family play roles in many biological processes including organogenesis. We carried out comparative in situ hybridization analysis of seventeen sox genes (Sox1-14, 17, 18, 21) during murine odontogenesis from the epithelial thickening to the cytodifferentiation stages. Localized expression of five Sox genes (Sox6, 9, 13, 14 and 21) was observed in tooth bud epithelium. Sox13 showed restricted expression in the primary enamel knots. At the early bell stage, three Sox genes (Sox8, 11, 17 and 21) were expressed in pre-ameloblasts, whereas two others (Sox5 and 18) showed expression in odontoblasts. Sox genes thus showed a dynamic spatio-temporal expression during tooth development. PMID:26864488

  4. 高迁移率族蛋白B1与胃癌的关系研究进展%Relationship Between High Mobility Group Protein B1 and Stomach Cancer

    Institute of Scientific and Technical Information of China (English)

    胡宏波; 陈贤华

    2016-01-01

    高迁移率族蛋白是一种高度保守的DNA结合蛋白,广泛存在于哺乳动物体内。在核内参与核小体的构建和稳定,调节基因的转录。在核外可介导炎症反应、促进细胞分化及肿瘤生长等。其释放途径主要为主动分泌和被动释放,通过与RAGE、TLR等受体结合,激活相应信号传导途径。近来研究发现,HMGB1与胃癌发生发展、转移、侵袭和靶向治疗密切相关,本文就此作一综述。%High-mobility group box 1(HMGB1),a highly conserved DNA-binding protein,plays an important role in maintaining nucleosome structures, transcription,inflammation,cel differentiation and tumor growth. It can also be released extracelularly and intracelularly. In addition,HMGB1 also participates in other physiological processes,such as cel proliferation,differentiation and apoptosis by binding with RAGE,TLR and other receptors. HMGB1 is recently discovered to closely relate to genesis,development,metastasis and targeted therapy of gastric carcinoma. This article reviewed and summarized the progress in relating research on screening of HMGB1 and gastric cancer.

  5. Effects of mutations in active site heme ligands on the spectroscopic and catalytic properties of SoxAX cytochromes.

    Science.gov (United States)

    Kilmartin, James R; Bernhardt, Paul V; Dhouib, Rabeb; Hanson, Graeme R; Riley, Mark J; Kappler, Ulrike

    2016-09-01

    By attaching a sulfur substrate to a conserved cysteine of the SoxYZ carrier protein SoxAX cytochromes initiate the reaction cycle of the Sox (sulfur oxidation) multienzyme complex, which is the major pathway for microbial reoxidation of sulfur compounds in the environment. Despite their important role in this process, the reaction mechanism of the SoxAX cytochromes has not been fully elucidated. Here we report the effects of several active site mutations on the spectroscopic and enzymatic properties of the type II SoxAX protein from Starkeya novella, which in addition to two heme groups also contains a Cu redox centre. All substituted proteins contained these redox centres except for His231Ala which was unable to bind Cu(II). Substitution of the SoxA active site heme cysteine ligand with histidine resulted in increased microheterogeneity around the SoxA heme as determined by CW-EPR, while a SnSoxAX(C236A) substituted protein revealed a completely new, nitrogenous SoxA heme ligand. The same novel ligand was present in SnSoxAX(H231A) CW-EPR spectra, the first time that a ligand switch of the SoxA heme involving a nearby amino acid has been demonstrated. Kinetically, SnSoxAX(C236A) and SnSoxAX(C236H) showed reduced turnover, and in assays containing SoxYZ these mutants retained only ~25% of the wildtype activity. Together, these data indicate that the Cu redox centre can mediate a low level of activity, and that a possible ligand switch can occur during catalysis. It also appears that the SoxA heme cysteine ligand (and possibly the low redox potential) is important for an efficient reaction with SnSoxYZ/thiosulfate. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Clinical and biochemical function of polymorphic NR0B1 GGAA-microsatellites in Ewing sarcoma: a report from the Children's Oncology Group.

    Directory of Open Access Journals (Sweden)

    Michael J Monument

    Full Text Available The genetics involved in Ewing sarcoma susceptibility and prognosis are poorly understood. EWS/FLI and related EWS/ETS chimeras upregulate numerous gene targets via promoter-based GGAA-microsatellite response elements. These microsatellites are highly polymorphic in humans, and preliminary evidence suggests EWS/FLI-mediated gene expression is highly dependent on the number of GGAA motifs within the microsatellite.Here we sought to examine the polymorphic spectrum of a GGAA-microsatellite within the NR0B1 promoter (a critical EWS/FLI target in primary Ewing sarcoma tumors, and characterize how this polymorphism influences gene expression and clinical outcomes.A complex, bimodal pattern of EWS/FLI-mediated gene expression was observed across a wide range of GGAA motifs, with maximal expression observed in constructs containing 20-26 GGAA motifs. Relative to white European and African controls, the NR0B1 GGAA-microsatellite in tumor cells demonstrated a strong bias for haplotypes containing 21-25 GGAA motifs suggesting a relationship between microsatellite function and disease susceptibility. This selection bias was not a product of microsatellite instability in tumor samples, nor was there a correlation between NR0B1 GGAA-microsatellite polymorphisms and survival outcomes.These data suggest that GGAA-microsatellite polymorphisms observed in human populations modulate EWS/FLI-mediated gene expression and may influence disease susceptibility in Ewing sarcoma.

  7. SOX4 expression in bladder carcinoma

    DEFF Research Database (Denmark)

    Aaboe, Mads; Birkenkamp-Demtroder, Karin; Wiuf, Carsten;

    2006-01-01

    The human transcription factor SOX4 was 5-fold up-regulated in bladder tumors compared with normal tissue based on whole-genome expression profiling of 166 clinical bladder tumor samples and 27 normal urothelium samples. Using a SOX4-specific antibody, we found that the cancer cells expressed...... strongly impaired cell viability and promoted apoptosis. To characterize downstream target genes and SOX4-induced pathways, we used a time-course global expression study of the overexpressed SOX4. Analysis of the microarray data showed 130 novel SOX4-related genes, some involved in signal transduction (MAP......2K5), angiogenesis (NRP2), and cell cycle arrest (PIK3R3) and others with unknown functions (CGI-62). Among the genes regulated by SOX4, 25 contained at least one SOX4-binding motif in the promoter sequence, suggesting a direct binding of SOX4. The gene set identified in vitro was analyzed...

  8. Expression of multiple Sox genes through embryonic development in the ctenophore Mnemiopsis leidyi is spatially restricted to zones of cell proliferation.

    Science.gov (United States)

    Schnitzler, Christine E; Simmons, David K; Pang, Kevin; Martindale, Mark Q; Baxevanis, Andreas D

    2014-01-01

    The Sox genes, a family of transcription factors characterized by the presence of a high mobility group (HMG) box domain, are among the central groups of developmental regulators in the animal kingdom. They are indispensable in progenitor cell fate determination, and various Sox family members are involved in managing the critical balance between stem cells and differentiating cells. There are 20 mammalian Sox genes that are divided into five major groups (B, C, D, E, and F). True Sox genes have been identified in all animal lineages but not outside Metazoa, indicating that this gene family arose at the origin of the animals. Whole-genome sequencing of the lobate ctenophore Mnemiopsis leidyi allowed us to examine the full complement and expression of the Sox gene family in this early-branching animal lineage. Our phylogenetic analyses of the Sox gene family were generally in agreement with previous studies and placed five of the six Mnemiopsis Sox genes into one of the major Sox groups: SoxB (MleSox1), SoxC (MleSox2), SoxE (MleSox3, MleSox4), and SoxF (MleSox5), with one unclassified gene (MleSox6). We investigated the expression of five out of six Mnemiopsis Sox genes during early development. Expression patterns determined through in situ hybridization generally revealed spatially restricted Sox expression patterns in somatic cells within zones of cell proliferation, as determined by EdU staining. These zones were located in the apical sense organ, upper tentacle bulbs, and developing comb rows in Mnemiopsis, and coincide with similar zones identified in the cydippid ctenophore Pleurobrachia. Our results are consistent with the established role of multiple Sox genes in the maintenance of stem cell pools. Both similarities and differences in juvenile cydippid stage expression patterns between Mnemiopsis Sox genes and their orthologs from Pleurobrachia highlight the importance of using multiple species to characterize the evolution of development within a given

  9. Genome-wide analysis of the sox family in the calcareous sponge Sycon ciliatum: multiple genes with unique expression patterns

    Directory of Open Access Journals (Sweden)

    Fortunato Sofia

    2012-07-01

    Full Text Available Abstract Background Sox genes are HMG-domain containing transcription factors with important roles in developmental processes in animals; many of them appear to have conserved functions among eumetazoans. Demosponges have fewer Sox genes than eumetazoans, but their roles remain unclear. The aim of this study is to gain insight into the early evolutionary history of the Sox gene family by identification and expression analysis of Sox genes in the calcareous sponge Sycon ciliatum. Methods Calcaronean Sox related sequences were retrieved by searching recently generated genomic and transcriptome sequence resources and analyzed using variety of phylogenetic methods and identification of conserved motifs. Expression was studied by whole mount in situ hybridization. Results We have identified seven Sox genes and four Sox-related genes in the complete genome of Sycon ciliatum. Phylogenetic and conserved motif analyses showed that five of Sycon Sox genes represent groups B, C, E, and F present in cnidarians and bilaterians. Two additional genes are classified as Sox genes but cannot be assigned to specific subfamilies, and four genes are more similar to Sox genes than to other HMG-containing genes. Thus, the repertoire of Sox genes is larger in this representative of calcareous sponges than in the demosponge Amphimedon queenslandica. It remains unclear whether this is due to the expansion of the gene family in Sycon or a secondary reduction in the Amphimedon genome. In situ hybridization of Sycon Sox genes revealed a variety of expression patterns during embryogenesis and in specific cell types of adult sponges. Conclusions In this study, we describe a large family of Sox genes in Sycon ciliatum with dynamic expression patterns, indicating that Sox genes are regulators in development and cell type determination in sponges, as observed in higher animals. The revealed differences between demosponge and calcisponge Sox genes repertoire highlight the need to

  10. SOX11 and TP53 add prognostic information to MIPI in a homogenously treated cohort of mantle cell lymphoma--a Nordic Lymphoma Group study

    DEFF Research Database (Denmark)

    Nordström, Lena; Sernbo, Sandra; Eden, Patrik;

    2014-01-01

    Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma, where survival has been remarkably improved by use of protocols including high dose cytarabine, rituximab and autologous stem cell transplantation, such as the Nordic MCL2/3 protocols. In 2008, a MCL international prognostic index (MIPI......) was created to enable stratification of the clinical diverse MCL patients into three risk groups. So far, use of the MIPI in clinical routine has been limited, as it has been shown that it inadequately separates low and intermediate risk group patients. To improve outcome and minimize treatment...

  11. Targeting SOX2 as a therapeutic strategy in glioblastoma

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    Ander Matheu

    2016-10-01

    Full Text Available Glioblastoma is the most common and malignant brain cancer in adults. Current therapy consisting of surgery followed by radiation and temozolomide therapy has moderate success rate and the tumor reappears. Among the features that a cancer cell must have to survive the therapeutic treatment and reconstitute the tumor is the ability to self-renewal. Therefore, it is vital to identify the molecular mechanisms that regulate this activity.SOX2 is a transcription factor whose activity has been associated with the maintenance of the undifferentiated state of cancer stem cells in several tissues including the brain. Several groups have detected SOX2 levels increased in biopsies of glioblastoma patients, with highest levels associated to poor outcome. Therefore, SOX2 silencing might be a novel therapeutic approach to combat cancer and particularly brain tumors.In this review, we will summarize the current knowledge about SOX2 in glioblastoma and recapitulate several strategies, which have been recently described targeting SOX2 in this malignancy.

  12. Zebrafish Sox7 and Sox18 function together to control arterial-venous identity.

    Science.gov (United States)

    Pendeville, Hélène; Winandy, Marie; Manfroid, Isabelle; Nivelles, Olivier; Motte, Patrick; Pasque, Vincent; Peers, Bernard; Struman, Ingrid; Martial, Joseph A; Voz, Marianne L

    2008-05-15

    Sox7 and Sox18 are members of the F-subgroup of Sox transcription factors family and are mostly expressed in endothelial compartments. In humans, dominant mutations in Sox18 are the underlying cause of the severe hypotrichosis-lymphedema-telangiectasia disorder characterized by vascular defects. However little is known about which vasculogenic processes Sox7 and Sox18 regulate in vivo. We cloned the orthologs of Sox7 and Sox18 in zebrafish, analysed their expression pattern and performed functional analyses. Both genes are expressed in the lateral plate mesoderm during somitogenesis. At later stages, Sox18 is expressed in all axial vessels whereas Sox7 expression is mainly restricted to the dorsal aorta. Knockdown of Sox7 or Sox18 alone failed to reveal any phenotype. In contrast, blocking the two genes simultaneously led to embryos displaying dysmorphogenesis of the proximal aorta and arteriovenous shunts, all of which can account for the lack of circulation observed in the trunk and tail. Gene expression analyses performed with general endothelial markers on double morphants revealed that Sox7 and Sox18 are dispensable for the initial specification and positioning of the major trunk vessels. However, morphants display ectopic expression of the venous Flt4 marker in the dorsal aorta and a concomitant reduction of the artery-specific markers EphrinB2a and Gridlock. The striking similarities between the phenotype of Sox7/Sox18 morphants and Gridlock mutants strongly suggest that Sox7 and Sox18 control arterial-venous identity by regulating Gridlock expression.

  13. Molecular cloning and characterization of SoxB2 gene from Zhikong scallop Chlamys farreri

    Science.gov (United States)

    He, Yan; Bao, Zhenmin; Guo, Huihui; Zhang, Yueyue; Zhang, Lingling; Wang, Shi; Hu, Jingjie; Hu, Xiaoli

    2013-11-01

    The Sox proteins play critical roles during the development of animals, including sex determination and central nervous system development. In this study, the SoxB2 gene was cloned from a mollusk, the Zhikong scallop ( Chlamys farreri), and characterized with respect to phylogeny and tissue distribution. The full-length cDNA and genomic DNA sequences of C. farreri SoxB2 ( Cf SoxB2) were obtained by rapid amplification of cDNA ends and genome walking, respectively, using a partial cDNA fragment from the highly conserved DNA-binding domain, i.e., the High Mobility Group (HMG) box. The full-length cDNA sequence of Cf SoxB2 was 2 048 bp and encoded 268 amino acids protein. The genomic sequence was 5 551 bp in length with only one exon. Several conserved elements, such as the TATA-box, GC-box, CAAT-box, GATA-box, and Sox/sry-sex/testis-determining and related HMG box factors, were found in the promoter region. Furthermore, real-time quantitative reverse transcription PCR assays were carried out to assess the mRNA expression of Cf SoxB 2 in different tissues. SoxB2 was highly expressed in the mantle, moderately in the digestive gland and gill, and weakly expressed in the gonad, kidney and adductor muscle. In male and female gonads at different developmental stages of reproduction, the expression levels of Cf SoxB2 were similar. Considering the specific expression and roles of SoxB 2 in other animals, in particular vertebrates, and the fact that there are many pallial nerves in the mantle, cerebral ganglia in the digestive gland and gill nerves in gill, we propose a possible essential role in nervous tissue function for Sox B 2 in C. farreri.

  14. B1 Aerogels

    DEFF Research Database (Denmark)

    Duer, Karsten; Svendsen, Sv Aa Højgaard

    1996-01-01

    , engineering and architectural basis which will support the appropriate use of aerogels in windows, solar collectors and passive solar applications, with the aim of saving or producing thermal energy for use in buildings".This objective is in very good agreement with the general scope of task 18 but where Task...... carried out as part of the A2/A3 project.The B1 Aerogel project has been carried out with partition of the following nations: Denmark, Finland, France, Germany, Japan, Norway, Sweden and the United Kingdom....

  15. Expression of Sox4 and Sox11 is regulated by multiple mechanisms during retinal development.

    Science.gov (United States)

    Usui, Ayumi; Iwagawa, Toshiro; Mochizuki, Yujin; Iida, Atsumi; Wegner, Michael; Murakami, Akira; Watanabe, Sumiko

    2013-02-14

    Sox11 and Sox4 play critical roles in retinal development, during which they display specific and unique expression patterns. The expression of Sox11 and Sox4 is temporally sequential, albeit spatially overlapping in some retinal subtypes. Gain-of-function and loss-of-function analyses suggested that Notch signaling suppresses Sox4 expression in the early developing retina but not during the later period of development. The levels of histone H3-acetylation and H3-lysine 4 tri-methylation at the Sox11 locus declined during development, as did the levels of Sox11. A similar but less marked change was seen for Sox4. For both genes, histone H3-lysine 27 methylation was low during development and increased markedly in the adult.

  16. [SOX2 defect and anophthalmia and microphthalmia].

    Science.gov (United States)

    Ye, Fu-xiang; Fan, Xian-qun

    2012-11-01

    As a severe congenital developmental disorder, anophthalmia and microphthalmia are usually accompanied with vision impairment and hypoevolutism of the orbit in the affected side. Many genes are involved in anophthalmia and microphthalmia, in which, SOX2 is an important one. The defect of SOX2 causes multiple system disorders, including anophthalmia and microphthalmia. We describe the relationship between the SOX2 defect and anophthalmia/microphthalmia, in order to offer some proposals for the differential diagnosis, treatment and research of anophthalmia and microphthalmia.

  17. Sox transcription in sarcosine utilization is controlled by Sigma(54) and SoxR in Bacillus thuringiensis HD73.

    Science.gov (United States)

    Peng, Qi; Liu, Chunxia; Wang, Bo; Yang, Min; Wu, Jianbo; Zhang, Jie; Song, Fuping

    2016-07-12

    Sarcosine oxidase catalyzes the oxidative demethylation of sarcosine to yield glycine, formaldehyde, and hydrogen peroxide. In this study, we analyzed the transcription and regulation of the sox locus, including the sarcosine oxidase-encoding genes in Bacillus thuringiensis (Bt). RT-PCR analysis revealed that the sox locus forms two opposing transcriptional units: soxB (soxB/E/F/G/H/I) and soxR (soxR/C/D/A). The typical -12/-24 consensus sequence was located 15 bp and 12 bp from the transcriptional start site (TSS) of soxB and soxC, respectively. Promoter-lacZ fusion assays showed that the soxB promoter is controlled by the Sigma(54) factor and is activated by the Sigma(54)-dependent transcriptional regulator SoxR. SoxR also inhibits its own expression. Expression from the PsoxCR promoter, which is responsible for the transcription of soxC, soxD, and soxA, is Sigma(54)-dependent and requires SoxR. An 11-bp inverted repeat sequence was identified as SoxR binding site upstream of the soxB TSS. Purified SoxR specifically bound a DNA fragment containing this region. Mutation or deletion of this sequence abolished the transcriptional activities of soxB and soxC. Thus, SoxR binds to the same sequence to activate the transcription of soxB and soxC. Sarcosine utilization was abolished in soxB and soxR mutants, suggesting that the sox locus is essential for sarcosine utilization.

  18. Sox transcription in sarcosine utilization is controlled by Sigma54 and SoxR in Bacillus thuringiensis HD73

    Science.gov (United States)

    Peng, Qi; Liu, Chunxia; Wang, Bo; Yang, Min; Wu, Jianbo; Zhang, Jie; Song, Fuping

    2016-01-01

    Sarcosine oxidase catalyzes the oxidative demethylation of sarcosine to yield glycine, formaldehyde, and hydrogen peroxide. In this study, we analyzed the transcription and regulation of the sox locus, including the sarcosine oxidase-encoding genes in Bacillus thuringiensis (Bt). RT-PCR analysis revealed that the sox locus forms two opposing transcriptional units: soxB (soxB/E/F/G/H/I) and soxR (soxR/C/D/A). The typical −12/−24 consensus sequence was located 15 bp and 12 bp from the transcriptional start site (TSS) of soxB and soxC, respectively. Promoter-lacZ fusion assays showed that the soxB promoter is controlled by the Sigma54 factor and is activated by the Sigma54-dependent transcriptional regulator SoxR. SoxR also inhibits its own expression. Expression from the PsoxCR promoter, which is responsible for the transcription of soxC, soxD, and soxA, is Sigma54-dependent and requires SoxR. An 11-bp inverted repeat sequence was identified as SoxR binding site upstream of the soxB TSS. Purified SoxR specifically bound a DNA fragment containing this region. Mutation or deletion of this sequence abolished the transcriptional activities of soxB and soxC. Thus, SoxR binds to the same sequence to activate the transcription of soxB and soxC. Sarcosine utilization was abolished in soxB and soxR mutants, suggesting that the sox locus is essential for sarcosine utilization. PMID:27404799

  19. B1 Aerogels

    DEFF Research Database (Denmark)

    Duer, Karsten; Svendsen, Sv Aa Højgaard

    1996-01-01

    , engineering and architectural basis which will support the appropriate use of aerogels in windows, solar collectors and passive solar applications, with the aim of saving or producing thermal energy for use in buildings".This objective is in very good agreement with the general scope of task 18 but where Task......The report summarizes the work that has been carried out within the project "B1 AEROGELS" as a part of the IEA SH&CP Task 18 "Advanced Glazing and Associated Materials For Solar And Building Applications".By providing at the same time thermal insulation and transparency the silica aerogel is a very...... of aerogel as a material for window applications. It was not a part of the project to make a further development of the aerogel material.The project was carried out in three main steps:1. Collection of information on aerogel production methods2. Measurements and evaluation of optical and thermal properties...

  20. aflatoxina b1

    Directory of Open Access Journals (Sweden)

    A. Valdivia

    2004-01-01

    Full Text Available Con el objetivo de probar que la suplementación dietética de ácido elágico (AE o N-Acetilcisteína (NAC en pollos de engorda, atenúa los efectos de una intoxicación aguda por la aflatoxina B1 (AFB1, se intoxicaron con AFB1 pura, tres grupos de diez pollos cada uno (3.0 mb/kg pc, IP. Otros tres grupos recibieron solamente el vehículo (aceite de maíz 2.0 ml/kg pc, IP. Cuatro días antes se administró un alimento testigo, o bien, la misma dieta adicionada con AE (2.5 g/kg o NAC (200 mg/kg pc/6 h. A las 24 horas de la administración de AFB1, se cuantificaron las concentraciones hepáticas de glutatión (GSH, de actividad enzimática específica de la transferasa de glutatión (GST, alanina aminotransferasa, aspartato aminotransferasa y de proteínas hepáticas totales. Los resultados mostraron que NAC atenúa el impacto negativo de la AFB1 sobre el crecimiento corporal y al igual que AE, incrementa la GST y revierte parcialmente los efectos de AFB1 sobre GSH, lo cual sugiere que ambas sustancias pudieran conferir un efecto protector de las aves

  1. Sox31 is involved in central nervous system anteroposterior regionalization through regulating the organizer activity in zebrafish

    Institute of Scientific and Technical Information of China (English)

    Shengnan Hu; Zhili Wu; Yuanchang Yan; Yiping Li

    2011-01-01

    Sox superfamily proteins are DNA-binding transcriptional factors that contain highly conserved high-mobility group (HMG) box and take part in various development process.Sox31 is a maternal factor supplied in the oocyte and starts its zygotic expression during mid-blastula transition (MBT)From gastrulation stage, it mainly resides in neural tissue.Ectopically expression of Sox31 mRNA leads to cyclopia fusion eyes or totally loss of anterior head structure, in accompany with severe notochord defects. Molecular markers indicate that forebrain tissue reduces sharply while the posterior neural tissue expands anteriorly. In addition organizer specification is also suppressed. Oppositely, an antisense morpholino designed functionally knockdown Sox31 causes typically dorsalized phenotype and reversed central nervous system (CNS) anteroposterior (AP) patterning. Gain of function with chimeric construct, where Sox31 HMG DNA binding domain is fused to a transcription activation domain (VP16) or transcnption suppression domain (EnR), suggests that Sox31 acts as a transcriptional suppressor in vivo. The expression of Bozozok (Dharma), a direct target gene of pre-MBT Wnt/p-catenin signal is suppressed by Sox31 Thus, to unveil the relationship between Sox31 and β-catenin-related transcriptional activity, we designed Top/Fop luciferase assay in HEK293T cells, and found that Sox31 could indeed suppress Tcf/Lef-dependent transcriptional activity without influencing the stability of β-catenin.Moreover, post-MBT Wnt signal was reduced in Sox31 morphants corresponding to the suppressed hindbrain structure, while phenotypic defects caused by excessive Sox31 could be rescued by Wnt antagonist dkkl. Taken together, Sox31 functions as an essential CNS AP patterning determinant and coordinates the CNS AP patterning process with organizer specification.

  2. mTOR inhibition decreases SOX2-SOX9 mediated glioma stem cell activity and temozolomide resistance

    Science.gov (United States)

    Garros-Regulez, Laura; Aldaz, Paula; Arrizabalaga, Olatz; Moncho-Amor, Veronica; Carrasco-Garcia, Estefania; Manterola, Lorea; Moreno-Cugnon, Leire; Barrena, Cristina; Villanua, Jorge; Ruiz, Irune; Pollard, Steven; Lovell-Badge, Robin; Sampron, Nicolas; Garcia, Idoia; Matheu, Ander

    2016-01-01

    ABSTRACT Background: SOX2 and SOX9 are commonly overexpressed in glioblastoma, and regulate the activity of glioma stem cells (GSCs). Their specific and overlapping roles in GSCs and glioma treatment remain unclear. Methods: SOX2 and SOX9 levels were examined in human biopsies. Gain and loss of function determined the impact of altering SOX2 and SOX9 on cell proliferation, senescence, stem cell activity, tumorigenesis and chemoresistance. Results: SOX2 and SOX9 expression correlates positively in glioma cells and glioblastoma biopsies. High levels of SOX2 bypass cellular senescence and promote resistance to temozolomide. Mechanistic investigations revealed that SOX2 acts upstream of SOX9. mTOR genetic and pharmacologic (rapamycin) inhibition decreased SOX2 and SOX9 expression, and reversed chemoresistance. Conclusions: Our findings reveal SOX2-SOX9 as an oncogenic axis that regulates stem cell properties and chemoresistance. We identify that rapamycin abrogate SOX protein expression and provide evidence that a combination of rapamycin and temozolomide inhibits tumor growth in cells with high SOX2/SOX9. PMID:26878385

  3. Molecular Cloning, Promoter Analysis and Expression Profiles of the sox3 Gene in Japanese Flounder, Paralichthys olivaceus

    Directory of Open Access Journals (Sweden)

    Jinning Gao

    2015-11-01

    Full Text Available Sox3, which belongs to the SoxB1 subgroup, plays major roles in neural and gonadal development. In the present study, Japanese flounder Paralichthys olivaceus sox3 gene (Posox3 and its promoter sequence were isolated and characterized. The deduced PoSox3 protein contained 298 amino acids with a characteristic HMG-box domain. Alignment and phylogenetic analyses indicated that PoSox3 shares highly identical sequence with Sox3 homologues from different species. The promoter region of Posox3 has many potential transcription factor (TF binding sites. The expression profiles of Posox3 in different developmental stages and diverse adult tissues were analyzed by quantitative real-time RT-PCR (qRT-PCR. Posox3 mRNA was maternally inherited, and maintained at a considerably high expression level between the blastula stage and the hatching stage during embryonic development. Posox3 was abundantly expressed in the adult brain and showed sexually dimorphic expression pattern. In situ hybridization (ISH was carried out to investigate the cellular distribution of Posox3 in the ovary, and results showed the uniform distribution of Posox3 throughout the cytoplasm of oogonia and stage I–III oocytes. These results indicate that Posox3 has potentially vital roles in embryonic and neural development and may be involved in the oogenesis process. Our work provides a fundamental understanding of the structure and potential functions of Sox3 in Paralichthys olivaceus.

  4. Sox2 promotes malignancy in glioblastoma by regulating plasticity and astrocytic differentiation.

    Science.gov (United States)

    Berezovsky, Artem D; Poisson, Laila M; Cherba, David; Webb, Craig P; Transou, Andrea D; Lemke, Nancy W; Hong, Xin; Hasselbach, Laura A; Irtenkauf, Susan M; Mikkelsen, Tom; deCarvalho, Ana C

    2014-03-01

    The high-mobility group-box transcription factor sex-determining region Y-box 2 (Sox2) is essential for the maintenance of stem cells from early development to adult tissues. Sox2 can reprogram differentiated cells into pluripotent cells in concert with other factors and is overexpressed in various cancers. In glioblastoma (GBM), Sox2 is a marker of cancer stemlike cells (CSCs) in neurosphere cultures and is associated with the proneural molecular subtype. Here, we report that Sox2 expression pattern in GBM tumors and patient-derived mouse xenografts is not restricted to a small percentage of cells and is coexpressed with various lineage markers, suggesting that its expression extends beyond CSCs to encompass more differentiated neoplastic cells across molecular subtypes. Employing a CSC derived from a patient with GBM and isogenic differentiated cell model, we show that Sox2 knockdown in the differentiated state abolished dedifferentiation and acquisition of CSC phenotype. Furthermore, Sox2 deficiency specifically impaired the astrocytic component of a biphasic gliosarcoma xenograft model while allowing the formation of tumors with sarcomatous phenotype. The expression of genes associated with stem cells and malignancy were commonly downregulated in both CSCs and serum-differentiated cells on Sox2 knockdown. Genes previously shown to be associated with pluripontency and CSCs were only affected in the CSC state, whereas embryonic stem cell self-renewal genes and cytokine signaling were downregulated, and the Wnt pathway activated in differentiated Sox2-deficient cells. Our results indicate that Sox2 regulates the expression of key genes and pathways involved in GBM malignancy, in both cancer stemlike and differentiated cells, and maintains plasticity for bidirectional conversion between the two states, with significant clinical implications. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Cellular Reprogramming Employing Recombinant Sox2 Protein

    Directory of Open Access Journals (Sweden)

    Marc Thier

    2012-01-01

    Full Text Available Induced pluripotent stem (iPS cells represent an attractive option for the derivation of patient-specific pluripotent cells for cell replacement therapies as well as disease modeling. To become clinically meaningful, safe iPS cells need to be generated exhibiting no permanent genetic modifications that are caused by viral integrations of the reprogramming transgenes. Recently, various experimental strategies have been applied to accomplish transgene-free derivation of iPS cells, including the use of nonintegrating viruses, episomal expression, or excision of transgenes after reprogramming by site-specific recombinases or transposases. A straightforward approach to induce reprogramming factors is the direct delivery of either synthetic mRNA or biologically active proteins. We previously reported the generation of cell-permeant versions of Oct4 (Oct4-TAT and Sox2 (Sox2-TAT proteins and showed that Oct4-TAT is reprogramming-competent, that is, it can substitute for Oct4-encoding virus. Here, we explore conditions for enhanced Sox2-TAT protein stabilization and functional delivery into somatic cells. We show that cell-permeant Sox2 protein can be stabilized by lipid-rich albumin supplements in serum replacement or low-serum-supplemented media. Employing optimized conditions for protein delivery, we demonstrate that Sox2-TAT protein is able to substitute for viral Sox2. Sox2-piPS cells express pluripotency-associated markers and differentiate into all three germ layers.

  6. SOX10 regulates an alternative promoter at the Charcot-Marie-Tooth disease locus MTMR2.

    Science.gov (United States)

    Fogarty, Elizabeth A; Brewer, Megan H; Rodriguez-Molina, Jose F; Law, William D; Ma, Ki H; Steinberg, Noah M; Svaren, John; Antonellis, Anthony

    2016-09-15

    Schwann cells are the myelinating glia of the peripheral nervous system and dysfunction of these cells causes motor and sensory peripheral neuropathy. The transcription factor SOX10 is critical for Schwann cell development and maintenance, and many SOX10 target genes encode proteins required for Schwann cell function. Loss-of-function mutations in the gene encoding myotubularin-related protein 2 (MTMR2) cause Charcot-Marie-Tooth disease type 4B1 (CMT4B1), a severe demyelinating peripheral neuropathy characterized by myelin outfoldings along peripheral nerves. Previous reports indicate that MTMR2 is ubiquitously expressed making it unclear how loss of this gene causes a Schwann cell-specific phenotype. To address this, we performed computational and functional analyses at MTMR2 to identify transcriptional regulatory elements important for Schwann cell expression. Through these efforts, we identified an alternative, SOX10-responsive promoter at MTMR2 that displays strong regulatory activity in immortalized rat Schwann (S16) cells. This promoter directs transcription of a previously unidentified MTMR2 transcript that is enriched in mouse Schwann cells compared to immortalized mouse motor neurons (MN-1), and is predicted to encode an N-terminally truncated protein isoform. The expression of the endogenous transcript is induced in a heterologous cell line by ectopically expressing SOX10, and is nearly ablated in Schwann cells by impairing SOX10 function. Intriguingly, overexpressing the two MTMR2 protein isoforms in HeLa cells revealed that both localize to nuclear puncta and the shorter isoform displays higher nuclear localization compared to the longer isoform. Combined, our data warrant further investigation of the truncated MTMR2 protein isoform in Schwann cells and in CMT4B1 pathogenesis. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  7. Ectopic expression and knockdown of a zebrafish sox21 reveal its role as a transcriptional repressor in early development.

    Science.gov (United States)

    Argenton, Francesco; Giudici, Simona; Deflorian, Gianluca; Cimbro, Simona; Cotelli, Franco; Beltrame, Monica

    2004-02-01

    Sox proteins are DNA-binding proteins belonging to the HMG box superfamily and they play key roles in animal embryonic development. Zebrafish Sox21a is part of group B Sox proteins and its chicken and mouse orthologs have been described as transcriptional repressor and activator, respectively, in two different target gene contexts. Zebrafish sox21a is present as a maternal transcript in the oocyte and is mainly expressed at the developing midbrain-hindbrain boundary from the onset of neurulation. In order to understand its role in vivo, we ectopically expressed sox21a by microinjection. Ectopic expression of full length sox21a leads to dorsalization of the embryos. A subset of the dorsalized embryos shows a partial axis splitting, and hence an ectopic neural tube, as an additional phenotype. At gastrulation, injected embryos show expansion of the expression domains of organizer-specific genes, such as chordin and goosecoid. Molecular markers used in somitogenesis highlight that sox21a-injected embryos have shortened AP axis, undulating axial structures, enlarged or even radialized paraxial territory. The developmental abnormalities caused by ectopic expression of sox21a are suggestive of defects in convergence-extension morphogenetic movements. Antisense morpholino oligonucleotides, designed to functionally knockdown sox21a, cause ventralization of the embryos. Moreover, gain-of-function experiments with chimeric constructs, where Sox21a DNA-binding domain is fused to a transcriptional activator (VP16) or repressor (EnR) domain, suggests that zebrafish Sox21a acts as a repressor in dorso-ventral patterning.

  8. Genetics Home Reference: SOX2 anophthalmia syndrome

    Science.gov (United States)

    ... Kherani F, Katowitz J, Schimmenti LA, Hummel M, Fitzpatrick DR, Young TL. Familial recurrence of SOX2 anophthalmia ... Nov 5. Review. Citation on PubMed Verma AS, Fitzpatrick DR. Anophthalmia and microphthalmia. Orphanet J Rare Dis. ...

  9. Mesoderm-specific Stat3 deletion affects expression of Sox9 yielding Sox9-dependent phenotypes

    Science.gov (United States)

    Hall, Michael D.; Murray, Caroline A.; Perantoni, Alan O.

    2017-01-01

    To date, mutations within the coding region and translocations around the SOX9 gene both constitute the majority of genetic lesions underpinning human campomelic dysplasia (CD). While pathological coding-region mutations typically result in a non-functional SOX9 protein, little is known about what mechanism(s) controls normal SOX9 expression, and subsequently, which signaling pathways may be interrupted by alterations occurring around the SOX9 gene. Here, we report the identification of Stat3 as a key modulator of Sox9 expression in nascent cartilage and developing chondrocytes. Stat3 expression is predominant in tissues of mesodermal origin, and its conditional ablation using mesoderm-specific TCre, in vivo, causes dwarfism and skeletal defects characteristic of CD. Specifically, Stat3 loss results in the expansion of growth plate hypertrophic chondrocytes and deregulation of normal endochondral ossification in all bones examined. Conditional deletion of Stat3 with a Sox9Cre driver produces palate and tracheal irregularities similar to those described in Sox9+/- mice. Furthermore, mesodermal deletion of Stat3 causes global embryonic down regulation of Sox9 expression and function in vivo. Mechanistic experiments ex vivo suggest Stat3 can directly activate the expression of Sox9 by binding to its proximal promoter following activation. These findings illuminate a novel role for Stat3 in chondrocytes during skeletal development through modulation of a critical factor, Sox9. Importantly, they further provide the first evidence for the modulation of a gene product other than Sox9 itself which is capable of modeling pathological aspects of CD and underscore a potentially valuable therapeutic target for patients with the disorder. PMID:28166224

  10. Over-expression of Sox4 and β-catenin is associated with a less favorable prognosis of osteosarcoma.

    Science.gov (United States)

    Bao, Zheng-Qi; Zhang, Chang-chun; Xiao, Yu-zhou; Zhou, Jian-sheng; Tao, Yi-sheng; Chai, Da-min

    2016-04-01

    The purpose of this study was to examine the association of the expression of Sox4 and β-catenin with the prognosis of osteosarcoma. A total of 108 cases of conventional osteosarcoma were involved in this study and 28 cases of osteochondroma served as controls. The expression of Sox4 and β-catenin was detected by using immunohistochemical staining and Western blotting. The results showed that Sox4 and β-catenin were over-expressed in 67 (62.03%) and 62 (57.41%) of 108 osteosarcoma cases, while in only 3 (10.71%) and 5 (17.86%) of 28 controls, respectively (Posteosarcoma (Posteosarcoma patients with Sox4 and β-catenin over-expressed were significantly reduced as compared with those in Sox4 and β-catenin low-expression group (Posteosarcoma (Posteosarcoma.

  11. Regeneration of hyaline-like cartilage in situ with SOX9 stimulation of bone marrow-derived mesenchymal stem cells.

    Science.gov (United States)

    Zhang, Xiaowei; Wu, Shili; Naccarato, Ty; Prakash-Damani, Manan; Chou, Yuan; Chu, Cong-Qiu; Zhu, Yong

    2017-01-01

    Microfracture, a common procedure for treatment of cartilage injury, induces fibrocartilage repair by recruiting bone marrow derived mesenchymal stem cells (MSC) to the site of cartilage injury. However, fibrocartilage is inferior biomechanically to hyaline cartilage. SRY-type high-mobility group box-9 (SOX9) is a master regulator of chondrogenesis by promoting proliferation and differentiation of MSC into chondrocytes. In this study we aimed to test the therapeutic potential of cell penetrating recombinant SOX9 protein in regeneration of hyaline cartilage in situ at the site of cartilage injury. We generated a recombinant SOX9 protein which was fused with super positively charged green fluorescence protein (GFP) (scSOX9) to facilitate cell penetration. scSOX9 was able to induce chondrogenesis of bone marrow derived MSC in vitro. In a rabbit cartilage injury model, scSOX9 in combination with microfracture significantly improved quality of repaired cartilage as shown by macroscopic appearance. Histological analysis revealed that the reparative tissue induced by microfracture with scSOX9 had features of hyaline cartilage; and collagen type II to type I ratio was similar to that in normal cartilage. This short term in vivo study demonstrated that when administered at the site of microfracture, scSOX9 was able to induce reparative tissue with features of hyaline cartilage.

  12. Functional constraints on SoxE proteins in neural crest development: The importance of differential expression for evolution of protein activity.

    Science.gov (United States)

    Lee, Eric M; Yuan, Tian; Ballim, Reyna D; Nguyen, Kristy; Kelsh, Robert N; Medeiros, Daniel M; McCauley, David W

    2016-10-01

    Vertebrate SoxE genes (Sox8, 9, and 10) are key regulators of neural crest cell (NCC) development. These genes arose by duplication from a single SoxE gene in the vertebrate ancestor. Although SoxE paralogs are coexpressed early in NCC development, later, Sox9 is restricted to skeletogenic lineages in the head, and Sox10 to non-skeletogenic NCC in the trunk and head. When this subfunctionalization evolved and its possible role in the evolution of the neural crest are unknown. Sea lampreys are basal vertebrates that also possess three SoxE genes, while only a single SoxE is present in the cephalochordate amphioxus. In order to address the functional divergence of SoxE genes, and to determine if differences in their biochemical functions may be linked to changes in neural crest developmental potential, we examined the ability of lamprey and amphioxus SoxE genes to regulate differentiation of NCC derivatives in zebrafish colourless (cls) mutants lacking expression of sox10. Our findings suggest that the proto-vertebrate SoxE gene possessed both melanogenic and neurogenic capabilities prior to SoxE gene duplication. Following the agnathan-gnathostome split, lamprey SoxE1 and SoxE3 largely lost their melanogenic and/or enteric neurogenic properties, while gnathostome SoxE paralogs have retained functional conservation. We posit that this difference in protein subfunctionalization is a direct consequence of the independent regulation of SoxE paralog expression between the two lineages. Specifically, we propose that the overlapping expression of gnathostome SoxE paralogs in early neural crest largely constrained the function of gnathostome SoxE proteins. In contrast, the largely non-overlapping expression of lamprey SoxE paralogs allowed them to specialize with regard to their DNA-binding and/or protein interaction properties. Restriction of developmental potential among cranial and trunk neural crest in lampreys may be related to constraints on SoxE activity among

  13. 76 FR 4724 - Catawba Sox, LLC Formerly Known as Catawba Sox, Inc. Including Workers Whose Unemployment...

    Science.gov (United States)

    2011-01-26

    ... of Catawba Sox, LLC, formerly known as Catawba Sox, Inc., Newton, North Carolina. The notice was published in the Federal Register on August 2, 2010 (75 FR 45162). At the request of the State agency, the... Whose Unemployment Insurance UI) Wages Are Paid Through Ellis Hosiery Mill, LLC, Newton, NC;...

  14. Genome-Wide Identification and Transcriptome-Based Expression Profiling of the Sox Gene Family in the Nile Tilapia (Oreochromis niloticus).

    Science.gov (United States)

    Wei, Ling; Yang, Chao; Tao, Wenjing; Wang, Deshou

    2016-02-23

    The Sox transcription factor family is characterized with the presence of a Sry-related high-mobility group (HMG) box and plays important roles in various biological processes in animals, including sex determination and differentiation, and the development of multiple organs. In this study, 27 Sox genes were identified in the genome of the Nile tilapia (Oreochromis niloticus), and were classified into seven groups. The members of each group of the tilapia Sox genes exhibited a relatively conserved exon-intron structure. Comparative analysis showed that the Sox gene family has undergone an expansion in tilapia and other teleost fishes following their whole genome duplication, and group K only exists in teleosts. Transcriptome-based analysis demonstrated that most of the tilapia Sox genes presented stage-specific and/or sex-dimorphic expressions during gonadal development, and six of the group B Sox genes were specifically expressed in the adult brain. Our results provide a better understanding of gene structure and spatio-temporal expression of the Sox gene family in tilapia, and will be useful for further deciphering the roles of the Sox genes during sex determination and gonadal development in teleosts.

  15. Progress in relationship between high mobility group box 1 protein and cardiovascular diseases%高迁移率族蛋白B1与心血管疾病相关性的研究进展

    Institute of Scientific and Technical Information of China (English)

    刘宇; 曹清心

    2012-01-01

    High mobility group box 1 protein (HMGB1) is a kind of nucleoprotein. It is secreted by necrosis cells and activated immunocytes into the extracellular environment, which has the activity of a cytokine, and thereby initiates immune responses and cause inflammatory reactions. It has been confirmed by numerous studies that HMGB1 is closely related to heart failure, myocardial ischemia reperfusion injury, atherosclerosis, heart infarction, etc. Studying the mechanism of HMGB1 in the development of angiocardiopathy will find a new target for curing cardiovascular diseases clinically.%高迁移率族蛋白B1(high mobility group box1 protein,HMGB1)是一种核蛋白质,其可由坏死细胞以及活化的免疫细胞释放至细胞外而具有细胞因子的活性,继之启动免疫反应和引发炎性反应.近年来,大量研究证实HMGB1与心力衰竭( heart failure,HF)、心肌缺血-再灌注(ischemia/reperfusion,I/R)损伤、动脉粥样硬化(atherosclerosis,AS)、心肌梗死(myocardial infarction,MI)等疾病有密切关系,通过研究HMGB1在心血管疾病发生发展过程中的机制,可为心血管疾病的临床治疗找到新靶点.

  16. Sox2 in Embryonic Stem Cells and Lung Development

    NARCIS (Netherlands)

    C.G. Pardo (Cristina Gontan)

    2009-01-01

    markdownabstract__Abstract__ Sox2 is a fascinating transcription factor with multiple roles during embryonic development. In early embryonic development, Sox2 is one of the key transcription factors in the maintenance of the pluripotent status of the cells of the inner cell mass (ICM). Sox2 is also

  17. 高迁移率族蛋白B1对心肌缺血再灌注损伤保护作用的初步临床研究%Cardioprotective effect of high mobility group protein B1 against myocardial ischemia-reperfusion injury in acute myocardial infarction patients

    Institute of Scientific and Technical Information of China (English)

    刘宇; 曹清心; 张燕; 赵仙先

    2012-01-01

    目的 随着急性心肌梗死(acute myocardial infarction,AMI)发病率的不断增加,以及再灌注治疗的广泛开展,缺血再灌注损伤(ischemical reperfusion injury,IRI)已经引起了广泛关注,但尚未找到一种能有效减轻IRI的治疗方法.近年来,国内外基于动物模型的研究发现:高迁移率族蛋白B1(high mobility group box 1 protein,HMGB1)可能在IRI过程中发挥着中枢作用,并且目前有关AMI患者经经皮冠状动脉内介入术(percutaneous coronary intervention,PCI)血浆中HMGB1浓度变化及其机制的研究还鲜见报道.文中初步探讨HMGB1是否参与AMI患者PCI中心肌IRI过程,及其在此过程中产生的心肌保护作用和可能机制.方法 采用酶联免疫吸附法,分别测定17例经冠状动脉造影术(coronary arteriography,CAG)检查正常的健康志愿者(对照组),41例AMI经急诊PCI治疗患者(AMI手术组)术前即刻、术后24h和48h血浆中HMGB1和血管内皮生长因子(vascular endothelial growth factor,VEGF)变化水平,并记录AMI手术组梗死相关血管(infarction related artery,IRA)开通即刻出现的再灌注心律失常(reperfusion arrhythmia,RA)类型、术后24h脑钠肽(brain natriuretic peptide,BNP)水平、住院期间不良临床事件(心力衰竭、心源性猝死)及其他基本临床数据.结果 AMI手术组患者在IRA开通即刻均观察到RA;术后24h HMGB1水平明显高于术前即刻及术后48h(P<0.05),并且各时间点HMGB1水平与VEGF水平呈正相关(P<0.05);AMI手术组院内出现不良临床事件与无不良事件的患者相比较,各时间点HMGB1水平明显降低(P<0.05).结论 HMGB1参与了AMI患者行PCI手术中IRI的过程;HMGB1水平对于AMI患者的远期预后有一定预测作用;HMGB1可能通过促进VEGF的分泌而参与梗死后心肌的修复过程,并可能通过此作用对改善心功能、保护心肌细胞产生一定作用.%Objective With the increasing incidence of acute myocardial infarction

  18. CRISPR reveals a distal super-enhancer required for Sox2 expression in mouse embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Yan Li

    Full Text Available The pluripotency of embryonic stem cells (ESCs is maintained by a small group of master transcription factors including Oct4, Sox2 and Nanog. These core factors form a regulatory circuit controlling the transcription of a number of pluripotency factors including themselves. Although previous studies have identified transcriptional regulators of this core network, the cis-regulatory DNA sequences required for the transcription of these key pluripotency factors remain to be defined. We analyzed epigenomic data within the 1.5 Mb gene-desert regions around the Sox2 gene and identified a 13kb-long super-enhancer (SE located 100kb downstream of Sox2 in mouse ESCs. This SE is occupied by Oct4, Sox2, Nanog, and the mediator complex, and physically interacts with the Sox2 locus via DNA looping. Using a simple and highly efficient double-CRISPR genome editing strategy we deleted the entire 13-kb SE and characterized transcriptional defects in the resulting monoallelic and biallelic deletion clones with RNA-seq. We showed that the SE is responsible for over 90% of Sox2 expression, and Sox2 is the only target gene along the chromosome. Our results support the functional significance of a SE in maintaining the pluripotency transcription program in mouse ESCs.

  19. Constitutive SoxS expression in a fluoroquinolone-resistant strain with a truncated SoxR protein and identification of a new member of the marA-soxS-rob regulon, mdtG.

    Science.gov (United States)

    Fàbrega, Anna; Martin, Robert G; Rosner, Judah L; Tavio, M Mar; Vila, Jordi

    2010-03-01

    Elevated levels of fluoroquinolone resistance are frequently found among Escherichia coli clinical isolates. This study investigated the antibiotic resistance mechanisms of strain NorE5, derived in vitro by exposing an E. coli clinical isolate, PS5, to two selection steps with increasing concentrations of norfloxacin. In addition to the amino acid substitution in GyrA (S83L) present in PS5, NorE5 has an amino acid change in ParC (S80R). Furthermore, we now find by Western blotting that NorE5 has a multidrug resistance phenotype resulting from the overexpression of the antibiotic resistance efflux pump AcrAB-TolC. Microarray and gene fusion analyses revealed significantly increased expression in NorE5 of soxS, a transcriptional activator of acrAB and tolC. The high soxS activity is attributable to a frameshift mutation that truncates SoxR, rendering it a constitutive transcriptional activator of soxS. Furthermore, microarray and reverse transcription-PCR analyses showed that mdtG (yceE), encoding a putative efflux pump, is overexpressed in the resistant strain. SoxS, MarA, and Rob activated an mdtG::lacZ fusion, and SoxS was shown to bind to the mdtG promoter, showing that mdtG is a member of the marA-soxS-rob regulon. The mdtG marbox sequence is in the backward or class I orientation within the promoter, and its disruption resulted in a loss of inducibility by MarA, SoxS, and Rob. Thus, chromosomal mutations in parC and soxR are responsible for the increased antibiotic resistance of NorE5.

  20. MicroRNA-25 suppresses proliferation, migration, and invasion of osteosarcoma by targeting SOX4.

    Science.gov (United States)

    Chen, Bingpeng; Liu, Jingjing; Qu, Ji; Song, Yang; Li, Yuxiang; Pan, Su

    2017-07-01

    Altered expression of the miR-25 has been implicated in many human malignant progression as oncogene or tumor suppressor. However, the precise role of miR-25 in osteosarcoma progression remains largely unclear. This study aimed to investigate the role and underlying mechanism of miR-25 in osteosarcoma. In this study, we demonstrated that miR-25 was significantly downregulated in osteosarcoma cell lines and tissues and that lower miR-25 was associated with advanced tumor-node-metastasis stage and lymph node metastasis. Then, we found that introduction of miR-25 significantly suppressed the proliferation, colony formation, migration, and invasion of osteosarcoma cells in vitro and retarded tumor growth in vivo. Further studies indicated that the epithelial-mesenchymal transition-related transcription factor, SOX4 (SRY-related high-mobility group box 4), was a direct target gene of miR-25, evidenced by bioinformatics analysis predicted and luciferase reporter assay. Furthermore, miR-25 could decrease the expression of SOX4 levels and inhibited epithelial-mesenchymal transition process. The levels of miR-25 were inversely correlated with those of SOX4 expression in osteosarcoma tissues. SOX4 overexpression rescued miR-25-induced suppression of proliferation, migration, and invasion of osteosarcoma cells. Taken together, these results suggest that miR-25 functions as a tumor suppressor in the progression of osteosarcoma by repressing SOX4.

  1. Genome duplication, subfunction partitioning, and lineage divergence: Sox9 in stickleback and zebrafish.

    Science.gov (United States)

    Cresko, William A; Yan, Yi-Lin; Baltrus, David A; Amores, Angel; Singer, Amy; Rodríguez-Marí, Adriana; Postlethwait, John H

    2003-11-01

    Teleosts are the most species-rich group of vertebrates, and a genome duplication (tetraploidization) event in ray-fin fish appears to have preceded this remarkable explosion of biodiversity. What is the relationship of the ray-fin genome duplication to the teleost radiation? Genome duplication may have facilitated lineage divergence by partitioning different ancestral gene subfunctions among co-orthologs of tetrapod genes in different teleost lineages. To test this hypothesis, we investigated gene expression patterns for Sox9 gene duplicates in stickleback and zebrafish, teleosts whose lineages diverged early in Euteleost evolution. Most expression domains appear to have been partitioned between Sox9a and Sox9b before the divergence of stickleback and zebrafish lineages, but some ancestral expression domains were distributed differentially in each lineage. We conclude that some gene subfunctions, as represented by lineage-specific expression domains, may have assorted differently in separate lineages and that these may have contributed to lineage diversification during teleost evolution.

  2. Co-motif discovery identifies an Esrrb-Sox2-DNA ternary complex as a mediator of transcriptional differences between mouse embryonic and epiblast stem cells.

    Science.gov (United States)

    Hutchins, Andrew Paul; Choo, Siew Hua; Mistri, Tapan Kumar; Rahmani, Mehran; Woon, Chow Thai; Ng, Calista Keow Leng; Jauch, Ralf; Robson, Paul

    2013-02-01

    Transcription factors (TF) often bind in heterodimeric complexes with each TF recognizing a specific neighboring cis element in the regulatory region of the genome. Comprehension of this DNA motif grammar is opaque, yet recent developments have allowed the interrogation of genome-wide TF binding sites. We reasoned that within this data novel motif grammars could be identified that controlled distinct biological programs. For this purpose, we developed a novel motif-discovery tool termed fexcom that systematically interrogates ChIP-seq data to discover spatially constrained TF-TF composite motifs occurring over short DNA distances. We applied this to the extensive ChIP-seq data available from mouse embryonic stem cells (ESCs). In addition to the well-known and most prevalent sox-oct motif, we also discovered a novel constrained spacer motif for Esrrb and Sox2 with a gap of between 2 and 8 bps that Essrb and Sox2 cobind in a selective fashion. Through the use of knockdown experiments, we argue that the Esrrb-Sox2 complex is an arbiter of gene expression differences between ESCs and epiblast stem cells (EpiSC). A number of genes downregulated upon dual Esrrb/Sox2 knockdown (e.g., Klf4, Klf5, Jam2, Pecam1) are similarly downregulated in the ESC to EpiSC transition and contain the esrrb-sox motif. The prototypical Esrrb-Sox2 target gene, containing an esrrb-sox element conserved throughout eutherian and metatherian mammals, is Nr0b1. Through positive regulation of this transcriptional repressor, we argue the Esrrb-Sox2 complex promotes the ESC state through inhibition of the EpiSC transcriptional program and the same trio may also function to maintain trophoblast stem cells.

  3. Testis development in the absence of SRY: chromosomal rearrangements at SOX9 and SOX3.

    Science.gov (United States)

    Vetro, Annalisa; Dehghani, Mohammad Reza; Kraoua, Lilia; Giorda, Roberto; Beri, Silvana; Cardarelli, Laura; Merico, Maurizio; Manolakos, Emmanouil; Parada-Bustamante, Alexis; Castro, Andrea; Radi, Orietta; Camerino, Giovanna; Brusco, Alfredo; Sabaghian, Marjan; Sofocleous, Crystalena; Forzano, Francesca; Palumbo, Pietro; Palumbo, Orazio; Calvano, Savino; Zelante, Leopoldo; Grammatico, Paola; Giglio, Sabrina; Basly, Mohamed; Chaabouni, Myriam; Carella, Massimo; Russo, Gianni; Bonaglia, Maria Clara; Zuffardi, Orsetta

    2015-08-01

    Duplications in the ~2 Mb desert region upstream of SOX9 at 17q24.3 may result in familial 46,XX disorders of sex development (DSD) without any effects on the XY background. A balanced translocation with its breakpoint falling within the same region has also been described in one XX DSD subject. We analyzed, by conventional and molecular cytogenetics, 19 novel SRY-negative unrelated 46,XX subjects both familial and sporadic, with isolated DSD. One of them had a de novo reciprocal t(11;17) translocation. Two cases carried partially overlapping 17q24.3 duplications ~500 kb upstream of SOX9, both inherited from their normal fathers. Breakpoints cloning showed that both duplications were in tandem, whereas the 17q in the reciprocal translocation was broken at ~800 kb upstream of SOX9, which is not only close to a previously described 46,XX DSD translocation, but also to translocations without any effects on the gonadal development. A further XX male, ascertained because of intellectual disability, carried a de novo cryptic duplication at Xq27.1, involving SOX3. CNVs involving SOX3 or its flanking regions have been reported in four XX DSD subjects. Collectively in our cohort of 19 novel cases of SRY-negative 46,XX DSD, the duplications upstream of SOX9 account for ~10.5% of the cases, and are responsible for the disease phenotype, even when inherited from a normal father. Translocations interrupting this region may also affect the gonadal development, possibly depending on the chromatin context of the recipient chromosome. SOX3 duplications may substitute SRY in some XX subjects.

  4. Emerging role of long non-coding RNA SOX2OT in SOX2 regulation in breast cancer.

    Directory of Open Access Journals (Sweden)

    Marjan E Askarian-Amiri

    Full Text Available The transcription factor SOX2 is essential for maintaining pluripotency in a variety of stem cells. It has important functions during embryonic development, is involved in cancer stem cell maintenance, and is often deregulated in cancer. The mechanism of SOX2 regulation has yet to be clarified, but the SOX2 gene lies in an intron of a long multi-exon non-coding RNA called SOX2 overlapping transcript (SOX2OT. Here, we show that the expression of SOX2 and SOX2OT is concordant in breast cancer, differentially expressed in estrogen receptor positive and negative breast cancer samples and that both are up-regulated in suspension culture conditions that favor growth of stem cell phenotypes. Importantly, ectopic expression of SOX2OT led to an almost 20-fold increase in SOX2 expression, together with a reduced proliferation and increased breast cancer cell anchorage-independent growth. We propose that SOX2OT plays a key role in the induction and/or maintenance of SOX2 expression in breast cancer.

  5. Combination of null alleles with 7+9 allelic pair at Glu-B1 locus on the long arm of group 1 chromosome improves wheat dough functionality for tortillas

    Science.gov (United States)

    Deletion of one or more high molecular weight glutenin subunit (HMW-GS) alleles reduces gluten strength in a way that may be beneficial for tortilla quality. Wheat lines in which one or more of the HMW-GS alleles were absent from Glu-A1, Glu-B1 or Glu-D1 locus (deletion lines) were compared with non...

  6. Sox17 promotes cell cycle progression and inhibits TGF-beta/Smad3 signaling to initiate progenitor cell behavior in the respiratory epithelium.

    Directory of Open Access Journals (Sweden)

    Alexander W Lange

    Full Text Available The Sry-related high mobility group box transcription factor Sox17 is required for diverse developmental processes including endoderm formation, vascular development, and fetal hematopoietic stem cell maintenance. Expression of Sox17 in mature respiratory epithelial cells causes proliferation and lineage respecification, suggesting that Sox17 can alter adult lung progenitor cell fate. In this paper, we identify mechanisms by which Sox17 influences lung epithelial progenitor cell behavior and reprograms cell fate in the mature respiratory epithelium. Conditional expression of Sox17 in epithelial cells of the adult mouse lung demonstrated that cell cluster formation and respecification of alveolar progenitor cells toward proximal airway lineages were rapidly reversible processes. Prolonged expression of Sox17 caused the ectopic formation of bronchiolar-like structures with diverse respiratory epithelial cell characteristics in alveolar regions of lung. During initiation of progenitor cell behavior, Sox17 induced proliferation and increased the expression of the progenitor cell marker Sca-1 and genes involved in cell cycle progression. Notably, Sox17 enhanced cyclin D1 expression in vivo and activated cyclin D1 promoter activity in vitro. Sox17 decreased the expression of transforming growth factor-beta (TGF-beta-responsive cell cycle inhibitors in the adult mouse lung, including p15, p21, and p57, and inhibited TGF-beta1-mediated transcriptional responses in vitro. Further, Sox17 interacted with Smad3 and blocked Smad3 DNA binding and transcriptional activity. Together, these data show that a subset of mature respiratory epithelial cells retains remarkable phenotypic plasticity and that Sox17, a gene required for early endoderm formation, activates the cell cycle and reinitiates multipotent progenitor cell behavior in mature lung cells.

  7. Differential expression of the transcription factors MarA, Rob, and SoxS of Salmonella Typhimurium in response to sodium hypochlorite: down-regulation of rob by MarA and SoxS.

    Science.gov (United States)

    Collao, B; Morales, E H; Gil, F; Polanco, R; Calderón, I L; Saavedra, C P

    2012-11-01

    To survive, Salmonella enterica serovar Typhimurium (S. Typhimurium) must sense signals found in phagocytic cells and modulate gene expression. In the present work, we evaluated the expression and cross-regulation of the transcription factors MarA, Rob, and SoxS in response to NaOCl. We generated strains ΔsoxS and ΔmarA, which were 20 times more sensitive to NaOCl as compared to the wild-type strain; while Δrob only 5 times. Subsequently, we determined that marA and soxS transcript and protein levels were increased while those of rob decreased in a wild-type strain treated with NaOCl. To assess if changes in S. Typhimurium after exposure to NaOCl were due to a cross-regulation, as in Escherichia coli, we evaluated the expression of marA, soxS, and rob in the different genetic backgrounds. The positive regulation observed in the wild-type strain of marA and soxS was retained in the Δrob strain. As in the wild-type strain, rob was down-regulated in the ΔmarA and ΔsoxS treated with NaOCl; however, this effect was decreased. Since rob was down-regulated by both factors, we generated a ΔmarA ΔsoxS strain finding that the negative regulation was abolished, confirming our hypothesis. Electrophoretic mobility shift assays using MarA and SoxS confirmed an interaction with the promoter of rob.

  8. Characterization of SoxB2 and SoxC genes in Amphioxus (Branchiostoma belcheri): Implications for their evolutionary conservation

    Institute of Scientific and Technical Information of China (English)

    LIN YuShuang; CHEN DongYan; FAN QiuSheng; ZHANG HongWei

    2009-01-01

    Most Sox genes directly affect cell fate determination and differentiation. In this study, we isolated two Sox genes: SoxB2 and SoxC from amphioxus (Branchiostoma belcheri), the closest living invertebrate relative of the vertebrates. Alignments of SoxB2 and SoxC protein sequences and their vertebrate homologs show high conservation of their HMG domains. Phylogenic analysis shows that amphioxus SoxB2 and SoxC fall out of the vertebrate branches, suggesting that vertebrate homologs might arise from gene duplications during evolution. The two genes possess similar spatial and temporal expression patterns during embryogenesis and in adults. They are both maternally inherited. During neurulation, they are expressed in the neural ectoderm and archenterons. In adults, they are expressed not only in the nerve cord, but also in the gut, midgut diverticulum, gill and oocytes. These results suggest that amphioxus SoxB2 and SoxC might co-function and have conserved functions in the nervous sys-tem and gonads as their vertebrate homologs.

  9. Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication.

    Science.gov (United States)

    Kaufhold, Samantha; Garbán, Hermes; Bonavida, Benjamin

    2016-05-25

    The transcription factor Yin Yang 1 (YY1) is frequently overexpressed in cancerous tissues compared to normal tissues and has regulatory roles in cell proliferation, cell viability, epithelial-mesenchymal transition, metastasis and drug/immune resistance. YY1 shares many properties with cancer stem cells (CSCs) that drive tumorigenesis, metastasis and drug resistance and are regulated by overexpression of certain transcription factors, including SOX2, OCT4 (POU5F1), BMI1 and NANOG. Based on these similarities, it was expected that YY1 expression would be associated with SOX2, OCT4, BMI1, and NANOG's expressions and activities. Data mining from the proteomic tissue-based datasets from the Human Protein Atlas were used for protein expression patterns of YY1 and the four CSC markers in 17 types of cancer, including both solid and hematological malignancies. A close association was revealed between the frequency of expressions of YY1 and SOX2 as well as SOX2 and OCT4 in all cancers analyzed. Two types of dynamics were identified based on the nature of their association, namely, inverse or direct, between YY1 and SOX2. These two dynamics define distinctive patterns of BMI1 and OCT4 expressions. The relationship between YY1 and SOX2 expressions as well as the expressions of BMI1 and OCT4 resulted in the classification of four groups of cancers with distinct molecular signatures: (1) Prostate, lung, cervical, endometrial, ovarian and glioma cancers (YY1(lo)SOX2(hi)BMI1(hi)OCT4(hi)) (2) Skin, testis and breast cancers (YY1(hi)SOX2(lo)BMI1(hi)OCT4(hi)) (3) Liver, stomach, renal, pancreatic and urothelial cancers (YY1(lo)SOX2(lo)BMI1(hi)OCT4(hi)) and (4) Colorectal cancer, lymphoma and melanoma (YY1(hi)SOX2(hi)BMI1(lo)OCT4(hi)). A regulatory loop is proposed consisting of the cross-talk between the NF-kB/PI3K/AKT pathways and the downstream inter-regulation of target gene products YY1, OCT4, SOX2 and BMI1.

  10. FCC DeSOx and DeNOx additive technology

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The fluid catalytic cracking(FCC) is the principal gasoline-producing process in the refinery. Considerable amounts of harmful sulfur oxides and nitrogen oxides (SOx and NOx ) are generated with the FCC operation. Impacted by strengthening environmental regulations and the current global emphasis on environmental protection and pollution abatement, refiners have been meaning to look for effective ways to control and reduce SOx and NOx emissions. FCC DeSOx and DeNOx additives is the most promising measure. The present paper reviews the developments in FCC DeSOx and DeNOx additive technology based on the respective authors' works, the future directions of the technology are also discussed.

  11. Sry and SoxE genes: How they participate in mammalian sex determination and gonadal development?

    Science.gov (United States)

    She, Zhen-Yu; Yang, Wan-Xi

    2017-03-01

    In mammals, sex determination defines the differentiation of the bipotential genital ridge into either testes or ovaries. Sry, the mammalian Y-chromosomal testis-determining gene, is a master regulator of male sex determination. It acts to switch the undifferentiated genital ridge towards testis development, triggering the adoption of a male fate. Sry initiates a cascade of gene networks through the direct regulation of Sox9 expression and promotes supporting cell differentiation, Leydig cell specification, vasculature formation and testis cord development. In the absence of Sry, alternative genetic cascades, including female sex-determining genes RSPO1, Wnt4/β-catenin and Foxl2, are involved in the formation of female genitalia and the maintenance of female ovarian development. The mutual antagonisms between male and female sex-determining pathways are crucial in not just the initiation but also the maintenance of the somatic sex of the gonad throughout the organism's lifetime. Any imbalances in above sex-determining genes can cause disorders of sex development in humans and mice. In this review, we provide a detailed summary of the expression profiles, biochemical properties and developmental functions of Sry and SoxE genes in embryonic testis development and adult gonadal development. We also briefly summarize the dedicate balances between male and female sex-determining genes in mammalian sex development, with particular highlights on the molecular actions of Sry and Sox9 transcription factors.

  12. Sox17-dependent gene expression and early heart and gut development in Sox17-deficient mouse embryos.

    Science.gov (United States)

    Pfister, Sabine; Jones, Vanessa J; Power, Melinda; Truisi, Germaine L; Khoo, Poh-Lynn; Steiner, Kirsten A; Kanai-Azuma, Masami; Kanai, Yoshiakira; Tam, Patrick P L; Loebel, David A F

    2011-01-01

    Sox17 is a transcription factor that is required for maintenance of the definitive endoderm in mouse embryos. By expression profiling of wild-type and mutant embryos and Sox17-overexpressing hepatoma cells, we identified genes with Sox17-dependent expression. Among the genes that were up-regulated in Sox17-null embryos and down-regulated by Sox17 expressing HepG2 cells is a set of genes that are expressed in the developing liver, suggesting that one function of Sox17 is the repression of liver gene expression, which is compatible with a role for Sox17 in maintaining the definitive endoderm in a progenitor state. Consistent with these findings, Sox17(-/-) cells display a diminished capacity to contribute to the definitive endoderm when transplanted into wild-type hosts. Analysis of gene ontology further revealed that many genes related to heart development were downregulated in Sox17-null embryos. This is associated with the defective development of the heart in the mutant embryos, which is accompanied by localised loss of Myocd-expressing cardiogenic progenitors and the malformation of the anterior intestinal portal.

  13. MAN1B1 deficiency: an unexpected CDG-II.

    Directory of Open Access Journals (Sweden)

    Daisy Rymen

    Full Text Available Congenital disorders of glycosylation (CDG are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. In the present study, exome sequencing was used to identify MAN1B1 as the culprit gene in an unsolved CDG-II patient. Subsequently, 6 additional cases with MAN1B1-CDG were found. All individuals presented slight facial dysmorphism, psychomotor retardation and truncal obesity. Generally, MAN1B1 is believed to be an ER resident alpha-1,2-mannosidase acting as a key factor in glycoprotein quality control by targeting misfolded proteins for ER-associated degradation (ERAD. However, recent studies indicated a Golgi localization of the endogenous MAN1B1, suggesting a more complex role for MAN1B1 in quality control. We were able to confirm that MAN1B1 is indeed localized to the Golgi complex instead of the ER. Furthermore, we observed an altered Golgi morphology in all patients' cells, with marked dilatation and fragmentation. We hypothesize that part of the phenotype is associated to this Golgi disruption. In conclusion, we linked mutations in MAN1B1 to a Golgi glycosylation disorder. Additionally, our results support the recent findings on MAN1B1 localization. However, more work is needed to pinpoint the exact function of MAN1B1 in glycoprotein quality control, and to understand the pathophysiology of its deficiency.

  14. Coexistence of an MHC chromosomal segment marked by HLA B17,BfS,C4A6,B1,DR7, and DQw9 in different ethnic groups.

    Science.gov (United States)

    Kay, P H; Dawkins, R L; Williamson, J; Tokunaga, K; Christiansen, F T; Charoenwong, P

    1988-09-01

    Previously we have shown that the supratype HLA B17 BfS C4A6 B1 DR7 (17 6 1 7) carrying a C4/Bgl II RFLP correlating with C4A6 coexists in whites and Thai/Chinese. Using conventional and PFGE/Southern blotting with class II, class III, and TNF probes as well as serologic DQ subtyping, we have extended these comparisons and now report that four examples each of white and Oriental 17 6 1 7 bear DQw9, as well as an approximately 10kb fragment hybridizing with a DR beta probe following digestion of genomic DNA with Hind III. Furthermore, Oriental and white 17 6 1 7 share a genomic insertion of some 70kb close to the class II region. These data suggest that 17 6 1 7 may mark a highly conserved chromosomal segment which provides new insights into the biology and evolution of the major histocompatibility complex.

  15. The 144Ce source for SOX

    Science.gov (United States)

    Durero, M.; Vivier, M.; Agostini, M.; Altenmüller, K.; Appel, S.; Bellini, G.; Benziger, J.; Berton, N.; Bick, D.; Bonfini, G.; Bravo, D.; Caccianiga, B.; Calaprice, F.; Caminata, A.; Cavalcante, P.; Chepurnov, A.; Choi, K.; Cribier, M.; D'Angelo, D.; Davini, S.; Derbin, A.; Di Noto, L.; Drachnev, I.; Etenko, A.; Farinon, S.; Fischer, V.; Fomenko, K.; Franco, D.; Gabriele, F.; Gaffiot, J.; Galbiati, C.; Ghiano, C.; Giammarchi, M.; Goeger-Neff, M.; Goretti, A.; Gromov, M.; Hagner, C.; Houdy, T.; Hungerford, E.; Ianni, Aldo; Ianni, Andrea; Jonqueres, N.; Jedrzejczak, K.; Kaiser, M.; Kobychev, V.; Korablev, D.; Korga, G.; Kornoukhov; Kryn, D.; Lachenmaier, T.; Lasserre, T.; Laubenstein, M.; Lehnert, B.; Link, J.; Litvinovich, E.; Lombardi, F.; Lombardi, P.; Ludhova, L.; Lukyanchenko, G.; Machulin, I.; Manecki, S.; Maneschg, W.; Marcocci, S.; Maricic, J.; Mention, G.; Meroni, E.; Meyer, M.; Miramonti, L.; Misiaszek, M.; Montuschi, M.; Muratova, V.; Musenich, R.; Neumair, B.; Oberauer, L.; Obolensky, M.; Ortica, F.; Pallavicini, M.; Papp, L.; Perasso, L.; Pocar, A.; Ranucci, G.; Razeto, A.; Re, A.; Romani, A.; Roncin, R.; Rossi, N.; Schönert, S.; Scola, L.; Semenov, D.; Simgen, H.; Skorokhvatov, M.; Smirnov, O.; Sotnikov, A.; Sukhotin, S.; Suvorov; Tartaglia, R.; Testera, G.; Thurn, J.; Toropova, M.; Veyssiére, C.; Unzhakov, E.; Vogelaar, R. B.; von Feilitzsch, F.; Wang, H.; Weinz, S.; Winter, J.; Wojcik, M.; Wurm, M.; Yokley, Z.; Zaimidoroga, O.; Zavatarelli, S.; Zuber, K.; Zuzel, G.

    2016-02-01

    The SOX (Short distance neutrino Oscillations with BoreXino) project aims at testing the light sterile neutrino hypothesis. To do so, two artificials sources of antineutrinos and neutrinos respectively will be consecutively deployed at the Laboratori Nazionali del Gran Sasso (LNGS) in close vicinity to Borexino, a large liquid scintillator detector. This document reports on the source production and transportation. The source should exhibit a long lifetime and a high decay energy, a requirement fullfilled by the 144Ce-144Pr pair at secular equilibrium. It will be produced at FSUE “Mayak” PA using spent nuclear fuel. It will then be shielded and packed according to international regulation and shipped to LNGS across Europe. Knowledge of the Cerium antineutrino generator (CeANG) parameters is crucial for SOX as it can strongly impact the experiment sensitivity. Several apparatuses are being used or designed to characterize CeANG activity, radioactive emission and content. An overview of the measurements performed so far is presented here.

  16. On Products of Property b1

    Institute of Scientific and Technical Information of China (English)

    Jianjun WANG; Peiyong ZHU

    2012-01-01

    In this note,we present that:(1) Let X=σ{Xα:α ∈ A} be |A|-paracompact (resp.,hereditarily |A|-paracompact).If every finite subproduct of {Xα:α ∈ A} has property b1 (resp.,hereditarily property b1),then so is X.(2) Let X be a P-space and Y a metric space.Then,X × Y has property b1 iff X has property b1.(3) Let X be a strongly zero-dimensional and compact space.Then,X × Y has property b1 iff Y has property b1.

  17. SOX9 drives WNT pathway activation in prostate cancer.

    Science.gov (United States)

    Ma, Fen; Ye, Huihui; He, Housheng Hansen; Gerrin, Sean J; Chen, Sen; Tanenbaum, Benjamin A; Cai, Changmeng; Sowalsky, Adam G; He, Lingfeng; Wang, Hongyun; Balk, Steven P; Yuan, Xin

    2016-05-02

    The transcription factor SOX9 is critical for prostate development, and dysregulation of SOX9 is implicated in prostate cancer (PCa). However, the SOX9-dependent genes and pathways involved in both normal and neoplastic prostate epithelium are largely unknown. Here, we performed SOX9 ChIP sequencing analysis and transcriptome profiling of PCa cells and determined that SOX9 positively regulates multiple WNT pathway genes, including those encoding WNT receptors (frizzled [FZD] and lipoprotein receptor-related protein [LRP] family members) and the downstream β-catenin effector TCF4. Analyses of PCa xenografts and clinical samples both revealed an association between the expression of SOX9 and WNT pathway components in PCa. Finally, treatment of SOX9-expressing PCa cells with a WNT synthesis inhibitor (LGK974) reduced WNT pathway signaling in vitro and tumor growth in murine xenograft models. Together, our data indicate that SOX9 expression drives PCa by reactivating the WNT/β-catenin signaling that mediates ductal morphogenesis in fetal prostate and define a subgroup of patients who would benefit from WNT-targeted therapy.

  18. Synthesis of 4"-benzyloxyimino-4"-deoxyavermectin B1a derivatives

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Six new 4"-benzyloxyimino-4"-deoxyavermectin B1a derivatives were synthesized from avermectin B1a by the selective protection of C-5-hydroxy group, oxidation of C-4"-hydroxy group, and deprotection followed by reaction with O-substituted hydroxylamine hydrochlorides. Their structures were confirmed by IR, 1H NMR, 13C NMR and MS. Insecticidal activities of the derivatives against Phopalosiphum pseudobrassicae, Spodoptera exigua and Pluteua xylosteua were evaluated.

  19. SOX9基因判断前列腺癌恶性程度及生化复发的预测%SOX9 gene for judgment of malignancy and prediction of biochemical relapse of prostate cancer

    Institute of Scientific and Technical Information of China (English)

    秦国强; 江福能; 毕学成; 韩兆冬; 何慧婵; 钟惟德

    2012-01-01

    Objective:To investigate the role of SOX9 gene for judgment of malignancy and prediction of biochemical relapse of prostate cancer after castration. Methods: Inquiry of SOX9 expression in prostate cancer tissues was conducted in Oncomine,the public Database. Expression of SOX9 in DU145,LNCap and PC3, cell lines of prostate cancer, and RWPE-1, the normal prostate cell line, was detected using reverse transcription-quantitative polymerase chain reaction ( RT-QPCR). Immunohistochemical assay was employed to detect SOX9 expression in 106 prostate cancer tissues and adjacent tissues for further clinical analysis of pathologic parameters. Surgical SD rat castration models were constructed to detect SOX9 expression in prostate tissues. Results: Marked SOX9 expression was presented in prostate cancer tissues. The PC3 cell line was noted as having considerably higher S0X9 expression than RWPE-1 (P =0.004). Of 106 tissues,prostate cancer tissues yielded significantly higher level of S0X9 positive expression (n = 62 ) than adjacent cancerous tissues ( n =26) ( P = 0. 000). Intense SOX9 expression was positively correlated with serum PSA ( P = 0. 007 ) , Gleason score (P =0.034) and tumor TNM stage (P =0.004) ,but not with age (P=0. 179). The distinction in the number of SD rats with SOX9 positively stained prostate cancer tissues between control group ( n = 2 ) and model group ( n = 9) reached statistical significance (P < 0. 05 ). Conclusion; Intense SOX9 expression is correlated with malignancy of prostate cancer. In addition to predicting the progress of biochemical relapse, it is possible to offer early diagnosis and judgment of malignancy via determination of SOX9 expression and serum PSA concentration.%目的:探讨SOX9基因在判断前列腺癌恶性程度及预测前列腺癌去势后生化复发的作用.方法:通过Oncomine公共数据库查询SOX9基因在前列腺癌中的表达情况;RT-QPCR法检测SOX9基因在前列腺癌细胞株DU145、LNCap、PC3和

  20. SOX7与SOX9在鉴别前列腺癌与前列腺增生中的作用%The role of SOX7 and SOX9 in differentiating prostate cancer from benign prostatic hyperplasia

    Institute of Scientific and Technical Information of China (English)

    许礼伟; 叶燕霞; 叶显明; 江福能; 秦国强; 钟惟德

    2014-01-01

    目的 探讨SOX7和SOX9在鉴别前列腺癌与前列腺增生中的临床意义.方法 收集147例前列腺癌与28例前列腺增生患者病理组织及临床资料,运用免疫组化实验分析SOX7与SOX9的表达及其作用.结果 SOX7在前列腺癌组织中表现为低表达(P=0.025),而SOX9为高表达(P=0.043),SOX7与SOX9呈负相关(r=-0.263,P=0.001).将SOX7与SOX9免疫组化评分与前列腺癌病理参数相结合进行分析,发现SOX7在血清PSA水平<10 ng/ml(P=0.048)、Gleason评分<7(P=0.018)、肿瘤TNM分期<T2a(P<0.001)和病理分期T2a~T2c(P=0.002)前列腺癌患者中有较高的表达,而SOX9在Gleason评分≥7(P=0.001)和肿瘤TNM分期≥T2a(P=0.005)的前列腺癌患者中有较高的表达,差异有统计学意义.结论 通过检测SOX7和SOX9的水平可鉴别前列腺癌与前列腺增生,并可以初步判断前列腺癌的恶性程度.

  1. Characterization, phylogeny, alternative splicing and expression of Sox30 gene

    Directory of Open Access Journals (Sweden)

    Huang Baofeng

    2010-12-01

    Full Text Available Abstract Background Members of the Sox gene family isolated from both vertebrates and invertebrates have been proved to participate in a wide variety of developmental processes, including sex determination and differentiation. Among these members, Sox30 had been considered to exist only in mammals since its discovery, and its exact function remains unclear. Results Sox30 cDNA was cloned from the Nile tilapia by RT-PCR and RACE. Screening of available genome and EST databases and phylogenetic analysis showed that Sox30 also exists in non-mammalian vertebrates and invertebrates, which was further supported by synteny analyses. Tissue expression in human, mouse and tilapia suggested that Sox30 was probably a gonad-specific gene, which was also supported by the fact that Sox30 EST sequences were obtained from gonads of the animal species. In addition, four alternatively spliced isoforms were isolated from tilapia gonad. Their temporal and spatial expression patterns during normal and sex reversed gonadal development were investigated by RT-PCR and in situ hybridization. Our data suggest that expressions of Sox30 isoforms are related to stage and phenotypic-sex, observed in the germ cells of male gonad and in somatic cells of the female gonad. Conclusions Sox30 is not a gene only existed in mammals, but exists widely throughout the animal kingdom as supported by our bioinformatic, phylogenetic and syntenic analyses. It is very likely that Sox30 is expressed exclusively in gonads. Expression analyses revealed that Sox30 may be involved in female and male gonadal development at different stages by alternative splicing.

  2. Delivery of the Sox9 gene promotes chondrogenic differentiation of human umbilical cord blood-derived mesenchymal stem cells in an in vitro model

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Z.H. [Department of Otolaryngology - Head and Neck Surgery, The Second Hospital, Xi' an Jiaotong University, Xi' an (China); Li, X.L. [Department of Dermatology, The Second Hospital, Xi' an Jiaotong University, Xi' an (China); He, X.J. [Department of Orthopedics, The Second Hospital, Xi' an Jiaotong University, Xi' an (China); Wu, B.J.; Xu, M. [Department of Otolaryngology - Head and Neck Surgery, The Second Hospital, Xi' an Jiaotong University, Xi' an (China); Chang, H.M. [Department of Otolaryngology - Head and Neck Surgery, Affiliated Hospital of Xi' an Medical University, Xi' an (China); Zhang, X.H. [Department of Otolaryngology - Head and Neck Surgery, The Second Hospital, Xi' an Jiaotong University, Xi' an (China); Xing, Z. [Department of Clinical Dentistry, Faculty of Dentistry, Center for Clinical Dental Research, University of Bergen, Bergen (Norway); Jing, X.H.; Kong, D.M.; Kou, X.H.; Yang, Y.Y. [Department of Otolaryngology - Head and Neck Surgery, The Second Hospital, Xi' an Jiaotong University, Xi' an (China)

    2014-03-18

    SRY-related high-mobility-group box 9 (Sox9) gene is a cartilage-specific transcription factor that plays essential roles in chondrocyte differentiation and cartilage formation. The aim of this study was to investigate the feasibility of genetic delivery of Sox9 to enhance chondrogenic differentiation of human umbilical cord blood-derived mesenchymal stem cells (hUC-MSCs). After they were isolated from human umbilical cord blood within 24 h after delivery of neonates, hUC-MSCs were untreated or transfected with a human Sox9-expressing plasmid or an empty vector. The cells were assessed for morphology and chondrogenic differentiation. The isolated cells with a fibroblast-like morphology in monolayer culture were positive for the MSC markers CD44, CD105, CD73, and CD90, but negative for the differentiation markers CD34, CD45, CD19, CD14, or major histocompatibility complex class II. Sox9 overexpression induced accumulation of sulfated proteoglycans, without altering the cellular morphology. Immunocytochemistry demonstrated that genetic delivery of Sox9 markedly enhanced the expression of aggrecan and type II collagen in hUC-MSCs compared with empty vector-transfected counterparts. Reverse transcription-polymerase chain reaction analysis further confirmed the elevation of aggrecan and type II collagen at the mRNA level in Sox9-transfected cells. Taken together, short-term Sox9 overexpression facilitates chondrogenesis of hUC-MSCs and may thus have potential implications in cartilage tissue engineering.

  3. 34 CFR 5b.1 - Definitions.

    Science.gov (United States)

    2010-07-01

    ... maintained by the Department, including but not limited to the individual's education, financial transactions... 34 Education 1 2010-07-01 2010-07-01 false Definitions. 5b.1 Section 5b.1 Education Office of the Secretary, Department of Education PRIVACY ACT REGULATIONS § 5b.1 Definitions. As used in this part:...

  4. 18 CFR 1b.1 - Definitions.

    Science.gov (United States)

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Definitions. 1b.1 Section 1b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES RULES RELATING TO INVESTIGATIONS § 1b.1 Definitions. For purposes of this part—...

  5. Effect of SOX13 antibody on islet β cell function in ketosis-prone diabetes%SOX13抗体对酮症倾向糖尿病患者胰岛功能的影响

    Institute of Scientific and Technical Information of China (English)

    李莉蓉; 上官海燕; 沈山梅; 胡云; 黄干; 周智广; 朱大龙

    2010-01-01

    further determine the characteristics of autoimmune response of SOX13-Ab in ketosis-prone diabetes(KPD). Methods During the period from January 2005 to November 2009, the 245 KPD patients (male:138, female:107; age:33(1.0 to 80.0)years) who visited a doctor in Department of Endocrinology at Nanjing Drum Tower Hospital were recruited and screened for SOX13-Ab,GDA-Ab and IA-2A. Then according to SOX13-Ab, GAD-Ab and IA-2A starus, the diabetes were divided into SOX13-Ab, GAD-Ab, IA-2A positive groups and antibody-negative group. The effect of SOX13-Ab on islet β cell function was evaluated by comparison of C-peptide levels among the four subgroups. The mean levels of C-peptide in different subgroups were expressed as median(IQR), then analysed with ANOVA after being In-transformed. Results The fasting C-peptide(FCP) and/or postprandial C-peptide(PCP) levels in SOX13-Ab or GAD-Ab positive groups were significantly lower than that in antibody-negative group among female KPD ( FCP: 166.0 (300.0) vs 287.5 ( 302.7 ) pmol/L, 166.5 ( 159.3 ) vs 287.5 ( 302.7 ) pmol/L;PCP: 285.0 ( 527.0) vs 528.0 ( 774.0 ) pmol/L, 231.0 ( 502.5 ) vs 528.0 ( 774.0 ) pmol/L, all P < 0.05 ) or KPD patients with age-onset ≤40 years ( FCP: 166.0 ( 56.0) vs 228.0 ( 250.0 ) pmol/L, 166.0 ( 241.8 ) vs 228.0 (250.0) pmol/L, all P < 0.05 ) or duration ≤ 5 years ( FCP: 191.0 ( 137.5 ) vs 324.0 ( 340.0 )pmol/L, 167.1(223.1) vs 324.0 (340.0) pmol/L,all P<0.05). While among patients with duration >5 years,the levels of FCP in GAD-Ab positive group were significantly lower than that in SOX13-Ab positive group ( 130.0(458.8 ) vs 189.5 ( 357.7 ) pmol/L, P < 0.05 ). The comparison of β cell function among groups with different islet antibody status was made using an ANOVA model, which showed that no significant difference in FCP and PCP levels between SOX13-Ab positive and antibody-negative group, while the difference in FCP levels was significant between GAD-Ab/SOX13-Ab positive and antibody

  6. Study of systematics for the SOX experiment

    Energy Technology Data Exchange (ETDEWEB)

    Neumair, Birgit [Technische Univ. Muenchen, Garching bei Muenchen (Germany); Collaboration: BOREXINO-Collaboration

    2016-07-01

    In the last years, several neutrino oscillation experiments reported results not compatible within the 3-neutrino model, which hint at the existence of light sterile neutrinos. To test this hypothesis, the SOX (Short distance neutrino Oscillations in BoreXino) experiment will search for oscillations from active to sterile neutrinos by placing radioactive electron (anti-)neutrino sources underneath the Borexino detector. Oscillations will be observed via a reduction of the detected interaction rate of the electron(anti-)neutrinos and an oscillatory pattern as a function of the neutrino energy and travelled distance. The talk gives an overview of the experiment with the focus on the systematics and their impact on the sensitivity for a 100kCi {sup 144}Ce source.

  7. SOX6 attenuates glucose-stimulated insulin secretion by repressing PDX1 transcriptional activity and is down-regulated in hyperinsulinemic obese mice.

    Science.gov (United States)

    Iguchi, Haruhisa; Ikeda, Yukio; Okamura, Masashi; Tanaka, Toshiya; Urashima, Yasuyo; Ohguchi, Hiroto; Takayasu, Shinobu; Kojima, Noriaki; Iwasaki, Satoshi; Ohashi, Riuko; Jiang, Shuying; Hasegawa, Go; Ioka, Ryoichi X; Magoori, Kenta; Sumi, Koichi; Maejima, Takashi; Uchida, Aoi; Naito, Makoto; Osborne, Timothy F; Yanagisawa, Masashi; Yamamoto, Tokuo T; Kodama, Tatsuhiko; Sakai, Juro

    2005-11-11

    In obesity-related insulin resistance, pancreatic islets compensate for insulin resistance by increasing secretory capacity. Here, we report the identification of sex-determining region Y-box 6 (SOX6), a member of the high mobility group box superfamily of transcription factors, as a co-repressor for pancreatic-duodenal homeobox factor-1 (PDX1). SOX6 mRNA levels were profoundly reduced by both a long term high fat feeding protocol in normal mice and in genetically obese ob/ob mice on a normal chow diet. Interestingly, we show that SOX6 is expressed in adult pancreatic insulin-producing beta-cells and that overexpression of SOX6 decreased glucose-stimulated insulin secretion, which was accompanied by decreased ATP/ADP ratio, Ca(2+) mobilization, proinsulin content, and insulin gene expression. In a complementary fashion, depletion of SOX6 by small interfering RNAs augmented glucose-stimulated insulin secretion in insulinoma mouse MIN6 and rat INS-1E cells. These effects can be explained by our mechanistic studies that show SOX6 acts to suppress PDX1 stimulation of the insulin II promoter through a direct protein/protein interaction. Furthermore, SOX6 retroviral expression decreased acetylation of histones H3 and H4 in chromatin from the promoter for the insulin II gene, suggesting that SOX6 may decrease PDX1 stimulation through changes in chromatin structure at specific promoters. These results suggest that perturbations in transcriptional regulation that are coordinated through SOX6 and PDX1 in beta-cells may contribute to the beta-cell adaptation in obesity-related insulin resistance.

  8. RAR agonists stimulate SOX9 gene expression in breast cancer cell lines: evidence for a role in retinoid-mediated growth inhibition.

    Science.gov (United States)

    Afonja, Olubunmi; Raaka, Bruce M; Huang, Ambrose; Das, Sharmistha; Zhao, Xinyu; Helmer, Elizabeth; Juste, Dominique; Samuels, Herbert H

    2002-11-01

    Retinoic acid receptors (RARs) are ligand-dependent transcription factors which are members of the steroid/thyroid hormone receptor gene family. RAR-agonists inhibit the proliferation of many human breast cancer cell lines, particularly those whose growth is stimulated by estradiol (E2) or growth factors. PCR-amplified subtractive hybridization was used to identify candidate retinoid-regulated genes that may be involved in growth inhibition. One candidate gene identified was SOX9, a member of the high mobility group (HMG) box gene family of transcription factors. SOX9 gene expression is rapidly stimulated by RAR-agonists in T-47D cells and other retinoid-inhibited breast cancer cell lines. In support of this finding, a database search indicates that SOX9 is expressed as an EST in breast tumor cells. SOX9 is known to be expressed in chondrocytes where it regulates the transcription of type II collagen and in testes where it plays a role in male sexual differentiation. RAR pan-agonists and the RARalpha-selective agonist Am580, but not RXR agonists, stimulate the expression of SOX9 in a wide variety of retinoid-inhibited breast cancer cell lines. RAR-agonists did not stimulate SOX9 in breast cancer cell lines which were not growth inhibited by retinoids. Expression of SOX9 in T-47D cells leads to cycle changes similar to those found with RAR-agonists while expression of a dominant negative form of SOX9 blocks RA-mediated cell cycle changes, suggesting a role for SOX9 in retinoid-mediated growth inhibition.

  9. Sox11 Reduces Caspase-6 Cleavage and Activity.

    Directory of Open Access Journals (Sweden)

    Elaine Waldron-Roby

    Full Text Available The apoptotic cascade is an orchestrated event, whose final stages are mediated by effector caspases. Regulatory binding proteins have been identified for caspases such as caspase-3, -7, -8, and -9. Many of these proteins belong to the inhibitor of apoptosis (IAP family. By contrast, caspase-6 is not believed to be influenced by IAPs, and little is known about its regulation. We therefore performed a yeast-two-hybrid screen using a constitutively inactive form of caspase-6 for bait in order to identify novel regulators of caspase-6 activity. Sox11 was identified as a potential caspase-6 interacting protein. Sox11 was capable of dramatically reducing caspase-6 activity, as well as preventing caspase-6 self- cleavage. Several regions, including amino acids 117-214 and 362-395 within sox11 as well as a nuclear localization signal (NLS all contributed to the reduction in caspase-6 activity. Furthermore, sox11 was also capable of decreasing other effector caspase activity but not initiator caspases -8 and -9. The ability of sox11 to reduce effector caspase activity was also reflected in its capacity to reduce cell death following toxic insult. Interestingly, other sox proteins also had the ability to reduce caspase-6 activity but to a lesser extent than sox11.

  10. Clinicopathological significance of SOX4 expression in primary gallbladder carcinoma

    Directory of Open Access Journals (Sweden)

    Wang Chengguo

    2012-04-01

    Full Text Available Abstract Aim SOX4, as a member of the SRY-related HMG-box (SOX transcription factor family, has been demonstrated to be involved in tumorigenesis of many human malignancies; however, its role in primary gallbladder carcinoma (PGC is still largely unknown. The aim of this study was to investigate SOX4 expression in PGC and its prognostic significance. Methods From 1997 to 2006, 136 patients underwent resection for PGC. The median follow-up was 12.8 months. Immunostainings for SOX4 were performed on these archival tissues. The correlation of SOX4 expression with clinicopathological features including survival was analyzed. Results SOX4 was expressed in 75.0% (102/136 of PGC but not in the normal epithelium of the gallbladder. In addition, the over-expression of SOX4 was significantly associated with low histologic grade (P = 0.02, low pathologic T stage (P = 0.02, and early clinical stage (P = 0.03. The levels of SOX4 immunostainings in PGC tissues with positive nodal metastasis were also significantly lower than those without (P = 0.01. Moreover, Kaplan-Meier curves showed that SOX4 over-expression was significantly related to better overall (P = 0.008 and disease-free survival (P = 0.01. Furthermore, multivariate analyses showed that SOX4 expression was an independent risk factor for both overall (P = 0.03, hazard ratio, 3.682 and disease-free survival (P = 0.04, hazard ratio, 2.215. Conclusion Our data indicate for the first time that the over-expression of SOX4 in PGC was significantly correlated with favorable clinicopathologic features and was an independent prognostic factor for better overall and disease-free survival in patients. Therefore, SOX4 might be an auxiliary parameter for predicting malignant behavior for PGC. Virtual slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1534825818694957.

  11. Clinical application of serum high mobility group box 1in patients with severe pneumonia%重症肺炎患者血清高迁移率族蛋白B1检测的临床应用

    Institute of Scientific and Technical Information of China (English)

    刘洁; 胡志刚; 陈国千

    2011-01-01

    OBJECTIVE To investigate the change and the clinical significance of serum HMGB1 level of severe pneumonia . METHODS Serum HMGBland CRP and WBC levels were determined in 27 healthy individuals and 35 patients of common pneumonia and 25 patients of severe pneumonia. The correlation between serum HMGB1 level and serum C-reactive protein level or white blood cell count in acute pancreatitis were analyzed. RESULTS The level of Serum HMGB1 and CRP and WBC were significantly higher in patients with severe pneumonia and the patients with common pneumonia than the healthy matched control (P<0. 01). Serum HMGB1 level of the patients of severe pneumonia(16. 8±11. 2)ng/ml were significantly above the patients of common pneumonia(6. 2 ±3. 8)ng/ml (P<0. 01). There have significant difference of CRP and WBC between the patients of severe pneumonia and the patients of common pneumonia (P<0. 05). Serum HMGB1 level of the patients of severe pneumonia after post-treatment(6. 8±3. 9)ng/ml were significantly below the patients of pretherapy(16. 8±11. 2) ng/ml (P < 0.01). Serum HMGB1 level of the patients of severe pneumonia after post-treatment were significantly above the healthy matched control(P<0. 01). CONCLUSION Serum HMGBl level is significantly elevated in the patients with pneumonia. The level measurement of the serum HMGBl is a valid index sign which evaluates pneumonia pathological changes and respond degree of inflammatory reaction.%目的 调查重症肺炎患者高迁移率族蛋白B1(HMGB1)、C-反应蛋白(CRP)、白细胞计数(WBC)水平的变化及其临床意义.方法 检测27例健康对照者、35例普通肺炎患者和25例重症肺炎患者的血清HMGB1水平及c-反应蛋白、白细胞计数;分析血清HMGB1水平与C-反应蛋白、白细胞计数等与肺炎的关系.结果 重症肺炎、普通肺炎患者血清HMGB1、CRP、WBC水平显著性高于健康对照组(P<0.01);重症肺炎患者血清HMGB1水平(16.8士11.2)ng/ml,显著

  12. Cyclin B1 Vaccine Delays Spontaneous Tumors

    Science.gov (United States)

    Laura A, Vella; Min, Yu; Amy, Phillips; Olivera J, Finn

    2012-01-01

    We previously identified cyclin B1-specific T cells and antibodies in cancer patients with cyclin B1+ tumors and also in some healthy individuals. We also demonstrated that these responses may be important in cancer immunosurveillance by showing that vaccination against cyclin B1 prevents growth of transplantable cyclin B1+ tumors in mice. Constitutive overexpression of cyclin B1 was determined to correlate with the lack of p53 function. This allowed us to use p53−/− mice as a model that better approximates human disease. p53−/− mice spontaneously develop cyclin B1+ tumors. At 5–6 weeks of age, when the mice were still healthy with no evidence of tumor, they received the cyclin B1 vaccine and were then observed for tumor growth. We demonstrate that cyclin B1 vaccination can delay spontaneous cyclin B1+ tumor growth and increases median survival of tumor bearing p53−/− mice. PMID:19769738

  13. SuFEx Click: New Materials from SOx F and Silyl Ethers.

    Science.gov (United States)

    Yatvin, Jeremy; Brooks, Karson; Locklin, Jason

    2016-11-07

    New forms of click chemistry present new opportunities in materials science. Sulfur(VI) fluoride exchange (SuFEx) is a recently discovered click reaction between molecules containing SOx F groups and silyl ethers, two functionalities that are orthogonal to all other known click chemistries, that generates sulfate or sulfonate connections upon the addition of certain organobases or fluoride sources. SuFEx also has several important advantages over other click reactions in that it is insensitive to ambient oxygen and water, and its precursor materials, especially SOx F, are chemically, UV, and thermally inert. This Concept article focuses on the unique reactivity of SuFEx and its relation to building high molecular weight polymers and surface coatings, both of which make it a powerful new tool for materials science.

  14. SOX9 Is a Progressive Factor in Prostate Cancer

    Science.gov (United States)

    2013-09-01

    implicated in supporting stem cells in small intestine and hair follicle (52–54). Recent lineage tracing studies found that SOX9 marks the adult stem cell... target . 15. SUBJECT TERMS SOX9, caner stem cells 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF...proliferate despite the castration level of circulating testosterone. Although enthusiasm for androgen receptor targeting approaches remains high

  15. MarA, SoxS and Rob function as virulence factors in an Escherichia coli murine model of ascending pyelonephritis.

    Science.gov (United States)

    Casaz, Paul; Garrity-Ryan, Lynne K; McKenney, David; Jackson, Caroline; Levy, Stuart B; Tanaka, S Ken; Alekshun, Michael N

    2006-12-01

    MarA, SoxS and Rob are transcription factors belonging to the AraC family. While these proteins have been associated historically with control of multiple antibiotic resistance, and tolerance to oxidative stress agents and organic solvents, only a paucity of experimental data support a role in regulating virulence. Clinical Escherichia coli isolates, and isogenic strains lacking marA, soxS and rob, were studied in a murine model of ascending pyelonephritis, which is a clinically relevant model of urinary tract infection. Organisms lacking all three transcription factors (triple knockouts) were significantly less virulent than parental strains, and complementation studies demonstrated that the addition of marA, soxS and rob individually restored wild-type virulence in the triple-knockout strain. Deletion of soxS or rob alone was more detrimental than the removal of marA. Thus, all three proteins contribute to virulence in vivo.

  16. Sox2 promotes tamoxifen resistance in breast cancer cells

    Science.gov (United States)

    Piva, Marco; Domenici, Giacomo; Iriondo, Oihana; Rábano, Miriam; Simões, Bruno M; Comaills, Valentine; Barredo, Inmaculada; López-Ruiz, Jose A; Zabalza, Ignacio; Kypta, Robert; Vivanco, Maria d M

    2014-01-01

    Development of resistance to therapy continues to be a serious clinical problem in breast cancer management. Cancer stem/progenitor cells have been shown to play roles in resistance to chemo- and radiotherapy. Here, we examined their role in the development of resistance to the oestrogen receptor antagonist tamoxifen. Tamoxifen-resistant cells were enriched for stem/progenitors and expressed high levels of the stem cell marker Sox2. Silencing of the SOX2 gene reduced the size of the stem/progenitor cell population and restored sensitivity to tamoxifen. Conversely, ectopic expression of Sox2 reduced tamoxifen sensitivity in vitro and in vivo. Gene expression profiling revealed activation of the Wnt signalling pathway in Sox2-expressing cells, and inhibition of Wnt signalling sensitized resistant cells to tamoxifen. Examination of patient tumours indicated that Sox2 levels are higher in patients after endocrine therapy failure, and also in the primary tumours of these patients, compared to those of responders. Together, these results suggest that development of tamoxifen resistance is driven by Sox2-dependent activation of Wnt signalling in cancer stem/progenitor cells. PMID:24178749

  17. 18 CFR 3b.1 - Purpose.

    Science.gov (United States)

    2010-04-01

    ... 18 Conservation of Power and Water Resources 1 2010-04-01 2010-04-01 false Purpose. 3b.1 Section 3b.1 Conservation of Power and Water Resources FEDERAL ENERGY REGULATORY COMMISSION, DEPARTMENT OF ENERGY GENERAL RULES COLLECTION, MAINTENANCE, USE, AND DISSEMINATION OF RECORDS OF IDENTIFIABLE...

  18. Profiling spermatogenic failure in adult testes bearing Sox9-deficient Sertoli cells identifies genes involved in feminization, inflammation and stress

    Directory of Open Access Journals (Sweden)

    Barrionuevo Francisco

    2010-12-01

    Full Text Available Abstract Background Sox9 (Sry box containing gene 9 is a DNA-binding transcription factor involved in chondrocyte development and sex determination. The protein's absence in testicular Sertoli nurse cells has been shown to disrupt testicular function in adults but little is known at the genome-wide level about molecular events concomitant with testicular break-down. Methods To determine the genome-wide effect on mRNA concentrations triggered by the absence of Sox9 in Sertoli cells we analysed adult testicular tissue from wild-type versus mutant mice with high-density oligonucleotide microarrays and integrated the output of this experiment with regulatory motif predictions and protein-protein network data. Results We report the genome-wide mRNA signature of adult testes lacking Sox9 in Sertoli cells before and after the onset of late spermatogenic failure as compared to fertile controls. The GeneChip data integrated with evolutionarily conserved Sox9 DNA binding motifs and regulatory network data identified genes involved in feminization, stress response and inflammation. Conclusions Our results extend previous observations that genes required for female gonadogenesis are up-regulated in the absence of Sox9 in fetal Sertoli cells to the adult stage. Importantly, we identify gene networks involved in immunological processes and stress response which is reminiscent of a phenomenon occurring in a sub-group of infertile men. This suggests mice lacking Sox9 in their Sertoli cells to be a potentially useful model for adult human testicular failure.

  19. Dual lineage-specific expression of Sox17 during mouse embryogenesis

    DEFF Research Database (Denmark)

    Choi, Eunyoung; Kraus, Marine R C; Lemaire, Laurence A

    2012-01-01

    Sox17 is essential for both endoderm development and fetal hematopoietic stem cell (HSC) maintenance. While endoderm-derived organs are well known to originate from Sox17-expressing cells, it is less certain whether fetal HSCs also originate from Sox17-expressing cells. By generating a Sox17(GFPCre......) allele and using it to assess the fate of Sox17-expressing cells during embryogenesis, we confirmed that both endodermal and a part of definitive hematopoietic cells are derived from Sox17-positive cells. Prior to E9.5, the expression of Sox17 is restricted to the endoderm lineage. However, at E9.5 Sox17...... is expressed in the endothelial cells (ECs) at the para-aortic splanchnopleural region that contribute to the formation of HSCs at a later stage. The identification of two distinct progenitor cell populations that express Sox17 at E9.5 was confirmed using fluorescence-activated cell sorting together with RNA...

  20. Pseudomonas aeruginosa SoxR does not conform to the archetypal paradigm for SoxR-dependent regulation of the bacterial oxidative stress adaptive response.

    Science.gov (United States)

    Palma, Marco; Zurita, Juan; Ferreras, Julian A; Worgall, Stefan; Larone, Davise H; Shi, Lei; Campagne, Fabien; Quadri, Luis E N

    2005-05-01

    SoxR is a transcriptional regulator that controls an oxidative stress response in Escherichia coli. The regulator is primarily activated by superoxide anion-dependent oxidation. Activated SoxR turns on transcription of a single gene, soxS, which encodes a transcriptional regulator that activates a regulon that includes dozens of oxidative stress response genes. SoxR homologues have been identified in many bacterial species, including the opportunistic pathogen Pseudomonas aeruginosa. However, the expected SoxR partner, SoxS, has not been found in P. aeruginosa. Thus, the primary gene target(s) of P. aeruginosa SoxR is unknown and the involvement of this regulator in the oxidative stress response of the bacterium remains unclear. We utilized transcriptome profiling to identify the P. aeruginosa SoxR regulon and constructed and characterized an unmarked P. aeruginosa DeltasoxR mutant. We provide evidence indicating that P. aeruginosa SoxR activates a six-gene regulon in response to O(2)(.-)-induced stress. The regulon includes three transcriptional units: (i) the recently identified mexGHI-ompD four-gene operon, which encodes a multidrug efflux pump system involved in quorum-sensing signal homeostasis; (ii) gene PA3718, encoding a probable efflux pump; and (iii) gene PA2274, encoding a probable monooxygenase. We also demonstrate that P. aeruginosa SoxR is not a key regulatory player in the oxidative stress response. Finally, we show that P. aeruginosa SoxR is required for virulence in a mouse model of intrapulmonary infection. These results demonstrate that the E. coli-based SoxRS paradigm does not hold in P. aeruginosa and foster new hypotheses for the possible physiological role of P. aeruginosa SoxR.

  1. Study of Microflares through SOXS Mission

    Indian Academy of Sciences (India)

    Rajmal Jain; Vishal Joshi; Yoichiro Hanaoka; T. Sakurai; Nipa Upadhyay

    2006-06-01

    We present a study of 10 microflares observed in 4–30 keV by SOXS mission simultaneously with H observations made at NAOJ, Japan during the interval between February and August 2004. The X-ray and H light curves showed that the lifetime of microflares varies between 4 and 25 min. We found that the X-ray emission in all microflares under study in the dynamic energy range of 4–30 keV can be fitted by thermal plus non-thermal components. The thermal spectrum appeared to start from almost 4 keV, low level discriminator (LLD) of both Si and CZT detectors, however it ends below 8 keV. We also observed the Fe line complex features at 6.7 keV in some microflares and attempted to fit this line by isothermal temperature assumption. The temperature of isothermal plasma of microflares varies in the range between 8.6 and 10.1 MK while emission measure between 0.5 and 2 × 1049 cm-3. Non-thermal (NT) emission appeared in the energy range 7–15 keV with exponent -6.8 ≤ ≤ -4.8. Our study of microflares that had occurred on 25 February 2004 showed that sometimes a given active region produces recurrent microflare activity of a similar nature.We concluded from X-ray and simultaneous H observations that the microflares are perhaps the result of the interaction of low lying loops. It appears that the electrons that accelerated during reconnection heat the ambient coronal plasma as well as interact with material while moving down along the loops and thereby produce H bright kernels.

  2. Observation of B Meson decays to b1pi and b1K.

    Science.gov (United States)

    Aubert, B; Bona, M; Boutigny, D; Karyotakis, Y; Lees, J P; Poireau, V; Prudent, X; Tisserand, V; Zghiche, A; Tico, J Garra; Grauges, E; Lopez, L; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Pegna, D Lopes; Lynch, G; Mir, L M; Orimoto, T J; Osipenkov, I L; Ronan, M T; Tackmann, K; Tanabe, T; Wenzel, W A; Del Amo Sanchez, P; Hawkes, C M; Watson, A T; Held, T; Koch, H; Pelizaeus, M; Schroeder, T; Steinke, M; Walker, D; Asgeirsson, D J; Cuhadar-Donszelmann, T; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Barrett, M; Khan, A; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Liu, F; Long, O; Shen, B C; Zhang, L; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Schalk, T; Schumm, B A; Seiden, A; Wilson, M G; Winstrom, L O; Chen, E; Cheng, C H; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Gabareen, A M; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Klose, V; Kobel, M J; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Lombardo, V; Thiebaux, Ch; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Watson, J E; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Franchini, P; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Santoro, V; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; de Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Dauncey, P D; Flack, R L; Nash, J A; Vazquez, W Panduro; Tibbetts, M; Behera, P K; Chai, X; Charles, M J; Mallik, U; Ziegler, V; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Lae, C K; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Béquilleux, J; D'Orazio, A; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F; Lutz, A M; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Burke, J P; Chavez, C A; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; George, K A; Di Lodovico, F; Menges, W; Sacco, R; Cowan, G; Flaecher, H U; Hopkins, D A; Paramesvaran, S; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Salvati, E; Saremi, S; Cowan, R; Dujmic, D; Fisher, P H; Koeneke, K; Sciolla, G; Sekula, S J; Spitznagel, M; Taylor, F; Yamamoto, R K; Zhao, M; Zheng, Y; McLachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; De Nardo, G; Fabozzi, F; Lista, L; Monorchio, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; Losecco, J M; Benelli, G; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Wong, Q K; Blount, N L; Brau, J; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gagliardi, N; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Ben-Haim, E; Briand, H; Calderini, G; Chauveau, J; David, P; Del Buono, L; de la Vaissière, Ch; Hamon, O; Leruste, Ph; Malclès, J; Ocariz, J; Perez, A; Prendki, J; Gladney, L; Biasini, M; Covarelli, R; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Carpinelli, M; Cenci, R; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Haire, M; Biesiada, J; Elmer, P; Lau, Y P; Lu, C; Olsen, J; Smith, A J S; Telnov, A V; Baracchini, E; Bellini, F; Cavoto, G; Del Re, D; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Gioi, L Li; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Castelli, G; Franek, B; Olaiya, E O; Ricciardi, S; Roethel, W; Wilson, F F; Emery, S; Escalier, M; Gaidot, A; Ganzhur, S F; de Monchenault, G Hamel; Kozanecki, W; Vasseur, G; Yèche, Ch; Zito, M; Chen, X R; Liu, H; Park, W; Purohit, M V; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Berger, N; Claus, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Grenier, P; Hast, C; Hryn'ova, T; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Luitz, S; Luth, V; Lynch, H L; Macfarlane, D B; Marsiske, H; Messner, R; Muller, D R; O'Grady, C P; Ofte, I; Perazzo, A; Perl, M; Pulliam, T; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Stelzer, J; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Va'vra, J; van Bakel, N; Wagner, A P; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Burchat, P R; Edwards, A J; Majewski, S A; Petersen, B A; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Jain, V; Pan, B; Saeed, M A; Wappler, F R; Zain, S B; Krishnamurthy, M; Spanier, S M; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Izen, J M; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martinez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Hamano, K; Kowalewski, R; Nugent, I M; Roney, J M; Sobie, R J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Dasu, S; Flood, K T; Hollar, J J; Kutter, P E; Pan, Y; Pierini, M; Prepost, R; Wu, S L; Neal, H

    2007-12-14

    We present the results of searches for decays of B mesons to final states with a b1 meson and a charged pion or kaon. The data, collected with the BABAR detector at the Stanford Linear Accelerator Center, represent 382x10(6) BB[over ] pairs produced in e+e- annihilation. The results for the branching fractions are, in units of 10(-6), B(B+-->b1(0)pi+)=6.7+/-1.7+/-1.0, B(B+-->b1(0)K+)=9.1+/-1.7+/-1.0, B(B0-->b1(-/+)pi(+/-))=10.9+/-1.2+/-0.9, and B(B0-->b1(-)K+)=7.4+/-1.0+/-1.0, with the assumption that B(b1-->omega pi)=1. We also measure charge and flavor asymmetries A(ch)(B+-->b1(0)pi+)=0.05+/-0.16+/-0.02, Ach(B+-->b1(0)K+)=-0.46+/-0.20+/-0.02, A(ch)(B0-->b1(-/+)pi(+/-))=-0.05+/-0.10+/-0.02, C(B0-->b1(-/+)pi(+/-))=-0.22+/-0.23+/-0.05, DeltaC(B0-->b1(-/+)pi(+/-))=-1.04+/-0.23+/-0.08, and A(ch)(B0-->b1(-)K+)=-0.07+/-0.12+/-0.02. The first error quoted is statistical, and the second systematic.

  3. Study of impact of reduced Sox4 expression levels in homeostasis, cancer and ageing

    OpenAIRE

    Foronda Álvaro, Miguel

    2014-01-01

    Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 12-05-2014 Sox4 belongs to the SoxC class of transcription factors (encompassing Sox4, Sox11 and Sox12) within the Sry-related HMG box-containing superfamily of proteins. Sox4 expression peaks during embryonic development in neural crest and mesenchyme, where it regulates the differentiation and survival of mesenchymal and neural progeni...

  4. SOX10 mutation is relevant to inner ear malformation in patients with Waardenburg syndrome%SOX10基因突变对Waardenburg综合征患者内耳发育的影响

    Institute of Scientific and Technical Information of China (English)

    徐广雨; 郝青青; 钟玲玲; 任巍; 闫艳; 刘日渊; 李佳楠; 郭维维; 赵辉

    2016-01-01

    目的 通过对SOX10基因突变Waardenburg综合征(Waardenburg syndrome,WS)患者的内耳影像学分析和分子遗传学分析,研究SOX10基因突变与WS患者发生内耳畸形的相关性.方法 收集2001-2015年解放军总医院耳鼻咽喉头颈外科收治的WS患者36例的临床资料.通过颞骨高分辨率CT、头颅MRI、内听道磁共振水成像等影像学检查,全面评估每位患者内耳发育情况.并对每位患者筛查WS常见致病基因SOX10、MITF、PAX3的突变情况.按SOX10基因是否突变分为2组,以Fisher精确检验法比较两组间内耳畸形发生率的差异.结果 36例WS患者中,共发现12例内耳畸形(33.3%),其中后半规管畸形发生率最高(12例),可合并前庭扩大及耳蜗畸形.36例患者中9例检出SOX10基因杂合突变,其中6例出现双侧内耳畸形.36例患者中27例无SOX10基因突变,其中6例出现双侧内耳畸形.Fisher精确检验法比较SOX10基因突变组与非SOX10基因突变组间内耳畸形发生率差异有统计学意义(P =0.036).结论 WS患者中如为SOX10基因突变,则出现内耳畸形的可能性较大,并且趋向于双侧耳蜗、前庭及半规管同时畸形.%Objective To determine the relevance between the SOX10 mutation and Waardenburg syndrome (WS) accompanied with inner ear abnormality by analyzing the inner ear imaging results and molecular and genetic results of the WS patients with the SOX10 mutation.Methods This study included 36 WS in patients during 2001 and 2015 in the department of otorhinolaryngology head and neck surgery,Chinese Peoples's Liberation Army General Hospital.The condition of the inner ear of each patient was assessed by analyzing HRCT scans of the temporal bone and MRI scans of the brain and internal auditory canal.Meanwhile,the possible pathogenic genes of WS,including SOX10,MITF,and PAX3,were also screened.Patients were divided into two groups according to SOX10 mutation.The Fisher accuracy test was used to determine

  5. The Function of HMG-Box Transcription Factors Sox4a and Sox4b in Zebrafish Bone Development and Homeostasis

    Science.gov (United States)

    Aceto, J.; Motte, P.; Martial, J. A.; Muller, M.

    2008-06-01

    In mammals, the Sox4 gene is involved in development of endocardial crests, the brain, the lung, teeth, gonads and lymphocytes. Recently, Sox4 was shown to control bone mass and mineralization in mice. In zebrafish, two homologs for the mammalian Sox4 are present, sox4a and sox4b. Here we investigate the function of the sox4a and sox4b genes in cartilage and bone development in zebrafish. Therefore, we focus our attention on the first bone structures to be formed, the head skeleton and more precisely the pharyngeal cartilage. We show that both genes are expressed in the pharyngeal region, albeit at different time points during development. Double in situ hybridization experiments are used to exactly define the particular tissues where they are expressed. Furthermore, microinjection experiments of antisense oligonucleotides are used to block translation of these specific genes and to define their precise function during cartilage and bone development.

  6. Observation of h_b(1P)->eta_b(1S)gamma

    CERN Document Server

    ,

    2011-01-01

    We report the first observation of the radiative transition h_b(1P)->eta_b(1S)gamma, where the h_b(1P) is produced in Upsilon(5S)->h_b(1P)pi+pi- dipion transitions. We measure the eta_b(1S) mass to be (9401.0+-1.9+1.4-2.4)MeV/c^2 with a width of (12.4+5.5-4.6+11.5-3.4)MeV and a decay branching fraction of BF[h_b(1P)->eta_b(1S)gamma]=(49.8+-6.8+10.9-5.2)%. The measured eta_b(1S) mass corresponds to a hyperfine splitting of (59.3+-1.9+2.4-1.4)MeV/c^2. This value deviates significantly from the current world average obtained from measurements of Upsilon(3S)->eta_b(1S)gamma and Upsilon(2S)->eta_b(1S)gamma reactions. We also report updated results for the h_b(1P) mass (9899.0+-0.4+-1.0)MeV/c^2 and its hyperfine splitting (0.8+-1.1)MeV/c^2. These measurements are performed using a 121.4fb^-1 data sample collected at the peak of the Upsilon(5S) resonance with the Belle detector at the KEKB asymmetric-energy e+e- collider.

  7. Cervical cancer cells with positive Sox2 expression exhibit the properties of cancer stem cells.

    Directory of Open Access Journals (Sweden)

    Xiao-Fang Liu

    Full Text Available BACKGROUND: Although Sox2 expression has been found in several types of cancer, it has not yet been used to identify or isolate CSCs in somatic carcinoma. METHODS: SiHa and C33A cells stably transfected with a plasmid containing human Sox2 transcriptional elements driving the enhanced green fluorescent protein (EGFP reporter were sorted into the Sox2-positive and the Sox2-negative populations by FACS, and Sox2 expression was detected by western blot and immunohistochemistry. The differentiation, self-renewal and tumor formation abilities, as well as the expression of the stemness and the EMT related genes of the Sox2-positive and the Sox2-negative cervical cancer cells were characterized in vitro and in vivo. RESULTS: A pSox2/EGFP system was used to separate the Sox2-positive and the Sox2-negative cells from cervical cancer cell lines, SiHa and C33A cells. Compared with the Sox2-negative cells, the Sox2-positive SiHa and C33A cells exhibited greater capacities for self-renewal, differentiation and tumor formation. Furthermore, Sox2-positive SiHa and C33A cells expressed higher levels of stemness-related genes, such as Sox2/Bmi-1/Oct4/ALDH1, and EMT-related genes, such as vimentin/snail/β-catenin. Taken together, all these results indicated that cells expressing endogenous Sox2 are CSCs in cervical carcinomas. CONCLUSION: This study is the first to establish a functional link between endogenous Sox2 expression and CSCs in cervical carcinomas. Additionally, this study demonstrated that it is feasible to develop a tool to isolate CSCs from somatic tumors based on the expression of the endogenous nuclear protein Sox2 instead of cell surface markers.

  8. SOX9 is a novel cancer stem cell marker surrogated by osteopontin in human hepatocellular carcinoma

    Science.gov (United States)

    Kawai, Takayuki; Yasuchika, Kentaro; Ishii, Takamichi; Miyauchi, Yuya; Kojima, Hidenobu; Yamaoka, Ryoya; Katayama, Hokahiro; Yoshitoshi, Elena Yukie; Ogiso, Satoshi; Kita, Sadahiko; Yasuda, Katsutaro; Fukumitsu, Ken; Komori, Junji; Hatano, Etsuro; Kawaguchi, Yoshiya; Uemoto, Shinji

    2016-01-01

    The current lack of cancer stem cell (CSC) markers that are easily evaluated by blood samples prevents the establishment of new therapeutic strategies in hepatocellular carcinoma (HCC). Herein, we examined whether sex determining region Y-box 9 (SOX9) represents a new CSC marker, and whether osteopontin (OPN) can be used as a surrogate marker of SOX9 in HCC. In HCC cell lines transfected with a SOX9 promoter-driven enhanced green fluorescence protein gene, FACS-isolated SOX9+ cells were capable of self-renewal and differentiation into SOX9− cells, and displayed high proliferation capacity in vitro. Xenotransplantation experiments revealed that SOX9+ cells reproduced, differentiated into SOX9− cells, and generated tumors at a high frequency in vivo. Moreover, SOX9+ cells were found to be involved in epithelial-mesenchymal transition (EMT) and activation of TGFb/Smad signaling. Gain/loss of function experiments showed that SOX9 regulates Wnt/beta-catenin signaling, including cyclin D1 and OPN. Immunohistochemistry of 166 HCC surgical specimens and serum OPN measurements showed that compared to SOX9− patients, SOX9+ patients had significantly poorer recurrence-free survival, stronger venous invasion, and higher serum OPN levels. In conclusion, SOX9 is a novel HCC-CSC marker regulating the Wnt/beta-catenin pathway and its downstream target, OPN. OPN is a useful surrogate marker of SOX9 in HCC. PMID:27457505

  9. Histone Acetylation Influences the Activity of Sox9-related Transcriptional Complex

    Directory of Open Access Journals (Sweden)

    Furumatsu,Takayuki

    2010-12-01

    Full Text Available Chondrocyte differentiation is the fundamental process in skeletal development. From the mesenchymal condensation of chondroprogenitors to the hypertrophic maturation of chondrocytes, chondrogenesis is sequentially regulated by cross-talk among transcription factors, growth factors, and chromatin structure. The master transcription factor Sry-type HMG box (Sox 9 has an essential role in the expression of chondrogenic genes through the association with Sox9-binding sites on its target genes. Several transcription factors and coactivators, such as Scleraxis/E47 and p300, cooperatively modulate the Sox9-dependent transcription by interacting with Sox9. The Sox9-related transcriptional apparatus activates its target gene expression through p300-mediated histone acetylation on chromatin. The transforming growth factor (TGF-β superfamily also plays a key role in chondrocyte differentiation. The TGF-β-regulated Smad3/4 complex activates Sox9-dependent transcription on chromatin by associating with Sox9 itself, and by recruiting p300 onto Sox9. These findings suggest that the epigenetic status including histone modification and chromatin structure, directly influences Sox9-regulated chondrocyte differentiation. In this article, we review the regulators of Sox9 expression itself, modulators of posttranslational Sox9 function, and Sox9-associating factors in the Sox9-dependent epigenetic regulation during chondrogenesis.

  10. SOXE neofunctionalization and elaboration of the neural crest during chordate evolution

    Science.gov (United States)

    Tai, Andrew; Cheung, Martin; Huang, Yong-Heng; Jauch, Ralf; Bronner, Marianne E.; Cheah, Kathryn S. E.

    2016-01-01

    During chordate evolution, two genome-wide duplications facilitated acquisition of vertebrate traits, including emergence of neural crest cells (NCCs), in which neofunctionalization of the duplicated genes are thought to have facilitated development of craniofacial structures and the peripheral nervous system. How these duplicated genes evolve and acquire the ability to specify NC and their derivatives are largely unknown. Vertebrate SoxE paralogues, most notably Sox9/10, are essential for NC induction, delamination and lineage specification. In contrast, the basal chordate, amphioxus, has a single SoxE gene and lacks NC-like cells. Here, we test the hypothesis that duplication and divergence of an ancestral SoxE gene may have facilitated elaboration of NC lineages. By using an in vivo expression assay to compare effects of AmphiSoxE and vertebrate Sox9 on NC development, we demonstrate that all SOXE proteins possess similar DNA binding and homodimerization properties and can induce NCCs. However, AmphiSOXE is less efficient than SOX9 in transactivation activity and in the ability to preferentially promote glial over neuronal fate, a difference that lies within the combined properties of amino terminal and transactivation domains. We propose that acquisition of AmphiSoxE expression in the neural plate border led to NCC emergence while duplication and divergence produced advantageous mutations in vertebrate homologues, promoting elaboration of NC traits. PMID:27734831

  11. A new SOx simulation model of coal combustion

    Energy Technology Data Exchange (ETDEWEB)

    Li Yonghua; Chen Hongwei; Zhen Zhi; Feng Zhaoxing; Dong Jianxun [North China Electric Power University, Baoding (China)

    2003-07-01

    It is very important to study the emission of pollutants from a coal combustion device, and we consider the best way is to use numerical simulation for such a study. By using a mathematical model with a post-processing method and based on combustion simulation, this paper reports the calculation of the SOx distribution in a power plant boiler furnace. For the formation of SOx, a conventional chemical reaction model is adopted, and according to the principles of reaction dynamics, a model for the SOx formation is also put forward. It is the first time the calculation and on-site testing an 800MW-unit boiler have been combined in China. The test and calculation results show that the model is reasonable, and such a study will be valuable as a reference for boiler design and clean operation. 5 refs., 1 fig., 3 tabs.

  12. Fumonisin B(1): a neurotoxic mycotoxin.

    Science.gov (United States)

    Domijan, Ana-Marija

    2012-12-01

    Fumonisin B(1) (FB(1)) is a mycotoxin produced by Fusarium spp. moulds that contaminate crop, predominantly maize, all around the world. More than 15 types of fumonisins have been indentified so far, but FB(1) is the most abundant and toxicologically the most significant one. FB(1) has a wide range of toxic effects, depending on animal species. In horses FB(1) causes equine leukoencephalomalacia (ELEM), in pigs pulmonary oedema and in experimental rodents nephrotoxicity and hepatotoxicity. In humans exposure to FB(1) is linked with higher incidence of primary liver cancer and oesophageal cancer, which are frequent in certain regions of the world (such as Transkei region in South Africa) where maize is staple food. The occurrence of neural tube defect in children in some countries of Central America (such as Mexico and Honduras) is connected with the consumption of FB(1)-contaminated maize-based food. However, possible involvement of FB(1) in the development of human diseases is not clear. Nevertheless, the International Agency for Research on Cancer (IARC) has classified FB(1) as a possible carcinogen to humans (group 2B). FB(1) is a causative agent of ELEM, a brain disorder in equines, indicating that brain is a target organ of FB(1) toxicity. Several studies on experimental animals or on cell cultures of neural origin have established that FB(1) has a neurodegenerative potential, although the mechanism of its neurotoxicity is still vague. The aim of this article is to give an overview of available literature on FB(1) neurotoxicity and involved mechanisms, and to offer a new perspective for future studies.

  13. EXPRESSION OF THE SOX2 GENE IN DIFFERENT TISSUES AND DIFFERENT MONTHS ON TESTIS OF HYRIOPSIS SCHLEGELII%池蝶蚌Sox2基因在不同组织及不同月龄精巢中的表达

    Institute of Scientific and Technical Information of China (English)

    曾柳根; 徐灵; 王军花; 盛军庆; 辜清; 彭扣; 洪一江

    2012-01-01

    The Sox genes family comprises several transcription factors that share a highly conserved HMG (High-Mobility-Group) box and has been studied in many species, including a variety of vertebrates and several of invertebrates such as fruit fly, nematode and Portunustrituberculatus. But there are only few reports on Sox gene family of freshwater bivalve so far, which have important value in evolution and production. H. Schlegelii, which originated from Lake Biwa in Japan and was introduced into China in 1998, is one of the representative freshwater pearl mussels. It has been widely applied in the Chinese freshwater pearl industry for its high quality pearl bearing ability. In order to know the function of Sox genes in this mussel, a degenerate PCR, referred to the HMG box of human SRY gene, was used to amplify the conserved sequence of HMG domains of Sox genes. Two different HMG sequences were got from DNA and the testis cDNA, named DNA-HMG1, DNA-HMG2 and cDNA-HMG. Amino acids sequences analysis showed that those HMG sequences had high homology with the Sox1, Sox2, Sox3 and Sox 14 genes from other animals including human being. But there showed no difference between the male and female. A partial cDNA sequence of Sox2 gene (refereed as hs-Sox2) with 1774 bp including partial ORF and complete 3' untranslated region (UTR) was cloned from the testis cDNA by RACE-PCR methods. DNA sequences analysis showed that it had high homology with the SoxB gene in Patella vulgata and the Soxl gene in human being. The putative 249 amino acid sequence contained one conserved HMG box like the human SYR gene, and exhibited 98% homology with human, mouse, chicken and zebrafish. For further know the expression level of Sox2 gene, real-time PCR method was used to examine its mRNA level in different tissues and different months on testis of H. Schlegelii. Results showed that the hs-Soxl mRNA was ubiquitously expressed in all the tissues, with the highest in kidney, followed by intestine

  14. Effect of microRNA-101 on apoptosis of rabbit condylar cartilage cells by inhibiting target gene SOX9

    Institute of Scientific and Technical Information of China (English)

    Xin Li; Zi-Xin Wang; Zi-Sheng Wang; Quan-Fang Li

    2015-01-01

    Objective:To explore the effect of microRNA-101 on apoptosis of condylar cartilage cells and the specific mechanism of molecular biology. Methods: IL-1 was used to stimulate and establish the model of apoptosis of condylar cartilage cells. The expression change of miR-101 in control group was compared with that in IL-1 stimulation group by qRT-PCR. Overexpression and down-regulation models of miR-101 were established by transfecting Mimics and Inhibitor and verified by qRT-PCR. Flow cytometry was used to detect the effect of miR-101 overexpression and down-regulation on apoptosis. Target gene of miR-101 was analyzed and calculated through bioinformatics. Western blot and Luciferase report assay were used to detect whether Sox9 could become the target gene of miR-101. Results:qRT-PCR results showed that IL-1 stimulation could cause the increase of miR-101 expression. After the transfection of rabbit condylar cartilage cells by Mimics and Inhibitor, qRT-PCR results confirmed the significant effect of miR-101 overexpression and down-regulation. It was confirmed by flow cytometry that overexpression of miR-101 could promote the apoptosis of condylar cartilage cells, and down-regulation of miR-101 could reduce the apoptosis. It was confirmed by Western blot and Luciferase report assay that Sox9 was the target gene of miR-101, and miR-101 inhibited SOX9 expression through complementary pairing with 3’UTR of Sox9 mRNA. Conclusions:miR-101 can promote the apoptosis of condylar cartilage cells through inhibiting the protein level of target gene SOX9.

  15. Genome-wide mapping of Sox6 binding sites in skeletal muscle reveals both direct and indirect regulation of muscle terminal differentiation by Sox6

    Directory of Open Access Journals (Sweden)

    An Chung-Il

    2011-10-01

    Full Text Available Abstract Background Sox6 is a multi-faceted transcription factor involved in the terminal differentiation of many different cell types in vertebrates. It has been suggested that in mice as well as in zebrafish Sox6 plays a role in the terminal differentiation of skeletal muscle by suppressing transcription of slow fiber specific genes. In order to understand how Sox6 coordinately regulates the transcription of multiple fiber type specific genes during muscle development, we have performed ChIP-seq analyses to identify Sox6 target genes in mouse fetal myotubes and generated muscle-specific Sox6 knockout (KO mice to determine the Sox6 null muscle phenotype in adult mice. Results We have identified 1,066 Sox6 binding sites using mouse fetal myotubes. The Sox6 binding sites were found to be associated with slow fiber-specific, cardiac, and embryonic isoform genes that are expressed in the sarcomere as well as transcription factor genes known to play roles in muscle development. The concurrently performed RNA polymerase II (Pol II ChIP-seq analysis revealed that 84% of the Sox6 peak-associated genes exhibited little to no binding of Pol II, suggesting that the majority of the Sox6 target genes are transcriptionally inactive. These results indicate that Sox6 directly regulates terminal differentiation of muscle by affecting the expression of sarcomere protein genes as well as indirectly through influencing the expression of transcription factors relevant to muscle development. Gene expression profiling of Sox6 KO skeletal and cardiac muscle revealed a significant increase in the expression of the genes associated with Sox6 binding. In the absence of the Sox6 gene, there was dramatic upregulation of slow fiber-specific, cardiac, and embryonic isoform gene expression in Sox6 KO skeletal muscle and fetal isoform gene expression in Sox6 KO cardiac muscle, thus confirming the role Sox6 plays as a transcriptional suppressor in muscle development

  16. Characterization of SoxB2 and SoxC genes in Amphi-oxus (Branchiostoma belcheri):Implications for their evolutionary conservation

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Most Sox genes directly affect cell fate determination and differentiation. In this study,we isolated two Sox genes:SoxB2 and SoxC from amphioxus (Branchiostoma belcheri),the closest living invertebrate relative of the vertebrates. Alignments of SoxB2 and SoxC protein sequences and their vertebrate homologs show high conservation of their HMG domains. Phylogenic analysis shows that amphioxus SoxB2 and SoxC fall out of the vertebrate branches,suggesting that vertebrate homologs might arise from gene duplications during evolution. The two genes possess similar spatial and temporal expression patterns during embryogenesis and in adults. They are both maternally inherited. During neurulation,they are expressed in the neural ectoderm and archenterons. In adults,they are expressed not only in the nerve cord,but also in the gut,midgut diverticulum,gill and oocytes. These results suggest that amphioxus SoxB2 and SoxC might co-function and have conserved functions in the nervous system and gonads as their vertebrate homologs.

  17. Activation of SoxR-dependent transcription in vitro by noncatalytic or NifS-mediated assembly of [2Fe-2S] clusters into apo-SoxR.

    Science.gov (United States)

    Hidalgo, E; Demple, B

    1996-03-29

    SoxR is a transcriptional activator that senses superoxide and nitric oxide stress in Escherichia coli. The active protein isolated from E. coli contains a pair of [2Fe-2S] clusters per SoxR dimer. We previously demonstrated that the iron-free protein (apo-SoxR), isolated during purification in thiol-containing buffers, binds soxS promoter DNA with an affinity equal to that of the metalloprotein (Fe-SoxR), but lacks significant ability to activate transcription in vitro. Here we demonstrate the reversibility of this process: the full transcriptional activity of SoxR can be restored by in vitro assembly of iron-sulfur clusters into the apoprotein. Two methods were used to synthesize the metallocenters of SoxR: (i) nonenzymatic, in which apo-SoxR, incubated in the presence of iron, inorganic sulfide, and a reducing agent, regained full transcriptional activity in 5-6 h; (ii) enzymatic, in which NifS protein of Azotobacter vinelandii regenerated active Fe-SoxR in as little as 2 min. Analysis by electron paramagnetic resonance spectroscopy indicated that binuclear [2Fe-2S] clusters were restored by both the enzymatic and nonenzymatic reconstitutions. A mutant SoxR protein missing one of its four cysteine residues failed to undergo either transcriptional activation or the formation of [2Fe-2S] centers, even in the presence of NifS. Thus, only the presence of an iron-sulfur center is required to restore transcriptional activity to apo-SoxR. Moreover, the catalytic generation of [2Fe-2S] centers extends the known specificity of this enzyme beyond that already shown for [4Fe-4S] centers. Catalytic generation of [2Fe-2S]-containing SoxR could allow for rapid activation of this transcription factor in vivo.

  18. The FCC Flue Gas SOx Transfer Additive RFS Developed by RIPP

    Institute of Scientific and Technical Information of China (English)

    Chen Beiyan; Jiang Wenbin; Song Haitao; Shen Ningyuan; Tian Huiping; He Mingyuan

    2007-01-01

    The present paper introduces the development of FCC flue gas SOx transfer additives by RIPP with a brief discussion of SOx transfer mechanism. The second-generation SOx transfer additives of the RFS series are RIPP's proprietary additives with significantly improved performances. The results of commercial tests indicate that the RFS additive can effectively control SOx emission of the FCC regenerator while maintaining product yields and product quality when the additive is used in a proper concentration range.

  19. Observation of B-meson decays to b_1 pi and b_1 K

    CERN Document Server

    Aubert, B; Boutigny, D; Karyotakis, Yu; Lees, J P; Poireau, V; Prudent, X; Tisserand, V; Zghiche, A; Garra Tico, J; Graugès-Pous, E; López, L; Palano, A; Pappagallo, M; Eigen, G; Stugu, B; Sun, L; Abrams, G S; Battaglia, M; Brown, D N; Button-Shafer, J; Cahn, R N; Groysman, Y; Jacobsen, R G; Kadyk, J A; Kerth, L T; Kolomensky, Yu G; Kukartsev, G; Lopes-Pegna, D; Lynch, G; Mir, L M; Orimoto, T J; Osipenkov, I L; Ronan, M T; Tackmann, K; Tanabé, T; Wenzel, W A; Del Amo-Sánchez, P; Hawkes, C M; Watson, A T; Held, T; Koch, H; Pelizaeus, M; Schröder, T; Steinke, M; Walker, D; Asgeirsson, D J; Çuhadar-Dönszelmann, T; Fulsom, B G; Hearty, C; Mattison, T S; McKenna, J A; Khan, A; Saleem, M; Teodorescu, L; Blinov, V E; Bukin, A D; Druzhinin, V P; Golubev, V B; Onuchin, A P; Serednyakov, S I; Skovpen, Yu I; Solodov, E P; Todyshev, K Yu; Bondioli, M; Curry, S; Eschrich, I; Kirkby, D; Lankford, A J; Lund, P; Mandelkern, M; Martin, E C; Stoker, D P; Abachi, S; Buchanan, C; Foulkes, S D; Gary, J W; Liu, F; Long, O; Shen, B C; Zhang, L; Paar, H P; Rahatlou, S; Sharma, V; Berryhill, J W; Campagnari, C; Cunha, A; Dahmes, B; Hong, T M; Kovalskyi, D; Richman, J D; Beck, T W; Eisner, A M; Flacco, C J; Heusch, C A; Kroseberg, J; Lockman, W S; Schalk, T; Schumm, B A; Seiden, A; Wilson, M G; Winstrom, L O; Chen, E; Cheng, C H; Fang, F; Hitlin, D G; Narsky, I; Piatenko, T; Porter, F C; Andreassen, R; Mancinelli, G; Meadows, B T; Mishra, K; Sokoloff, M D; Blanc, F; Bloom, P C; Chen, S; Ford, W T; Hirschauer, J F; Kreisel, A; Nagel, M; Nauenberg, U; Olivas, A; Smith, J G; Ulmer, K A; Wagner, S R; Zhang, J; Gabareen, A M; Soffer, A; Toki, W H; Wilson, R J; Winklmeier, F; Altenburg, D D; Feltresi, E; Hauke, A; Jasper, H; Merkel, J; Petzold, A; Spaan, B; Wacker, K; Klose, V; Kobel, M J; Lacker, H M; Mader, W F; Nogowski, R; Schubert, J; Schubert, K R; Schwierz, R; Sundermann, J E; Volk, A; Bernard, D; Bonneaud, G R; Latour, E; Lombardo, V; Thiebaux, C; Verderi, M; Clark, P J; Gradl, W; Muheim, F; Playfer, S; Robertson, A I; Watson, J E; Xie, Y; Andreotti, M; Bettoni, D; Bozzi, C; Calabrese, R; Cecchi, A; Cibinetto, G; Franchini, P; Luppi, E; Negrini, M; Petrella, A; Piemontese, L; Prencipe, E; Santoro, V; Anulli, F; Baldini-Ferroli, R; Calcaterra, A; De Sangro, R; Finocchiaro, G; Pacetti, S; Patteri, P; Peruzzi, I M; Piccolo, M; Rama, M; Zallo, A; Buzzo, A; Contri, R; Lo Vetere, M; Macri, M M; Monge, M R; Passaggio, S; Patrignani, C; Robutti, E; Santroni, A; Tosi, S; Chaisanguanthum, K S; Morii, M; Wu, J; Dubitzky, R S; Marks, J; Schenk, S; Uwer, U; Bard, D J; Dauncey, P D; Flack, R L; Nash, J A; Panduro-Vazquez, W; Tibbetts, M; Behera, P K; Chai, X; Charles, M J; Mallik, U; Ziegler, V; Cochran, J; Crawley, H B; Dong, L; Eyges, V; Meyer, W T; Prell, S; Rosenberg, E I; Rubin, A E; Gao, Y Y; Gritsan, A V; Guo, Z J; Lae, C K; Denig, A G; Fritsch, M; Schott, G; Arnaud, N; Bequilleux, J; D'Orazio, A; Davier, M; Grosdidier, G; Höcker, A; Lepeltier, V; Le Diberder, F; Lutz, A M; Pruvot, S; Rodier, S; Roudeau, P; Schune, M H; Serrano, J; Sordini, V; Stocchi, A; Wang, W F; Wormser, G; Lange, D J; Wright, D M; Bingham, I; Burke, J P; Chavez, C A; Forster, I J; Fry, J R; Gabathuler, E; Gamet, R; Hutchcroft, D E; Payne, D J; Schofield, K C; Touramanis, C; Bevan, A J; George, K A; Di Lodovico, F; Menges, W; Sacco, R; Cowan, G; Flächer, H U; Hopkins, D A; Paramesvaran, S; Salvatore, F; Wren, A C; Brown, D N; Davis, C L; Allison, J; Barlow, N R; Barlow, R J; Chia, Y M; Edgar, C L; Lafferty, G D; West, T J; Yi, J I; Anderson, J; Chen, C; Jawahery, A; Roberts, D A; Simi, G; Tuggle, J M; Blaylock, G; Dallapiccola, C; Hertzbach, S S; Li, X; Moore, T B; Salvati, E; Saremi, S; Cowan, R; Dujmic, D; Fisher, P H; Koeneke, K; Sciolla, G; Sekula, S J; Spitznagel, M; Taylor, F; Yamamoto, R K; Zhao, M; Zheng, Y; Mclachlin, S E; Patel, P M; Robertson, S H; Lazzaro, A; Palombo, F; Bauer, J M; Cremaldi, L; Eschenburg, V; Godang, R; Kroeger, R; Sanders, D A; Summers, D J; Zhao, H W; Brunet, S; Côté, D; Simard, M; Taras, P; Viaud, F B; Nicholson, H; De Nardo, Gallieno; Fabozzi, F; Lista, L; Monorchio, D; Sciacca, C; Baak, M A; Raven, G; Snoek, H L; Jessop, C P; Knoepfel, K J; LoSecco, J M; Benelli, G; Corwin, L A; Honscheid, K; Kagan, H; Kass, R; Morris, J P; Rahimi, A M; Regensburger, J J; Wong, Q K; Blount, N L; Brau, J E; Frey, R; Igonkina, O; Kolb, J A; Lu, M; Rahmat, R; Sinev, N B; Strom, D; Strube, J; Torrence, E; Gagliardi, N; Gaz, A; Margoni, M; Morandin, M; Pompili, A; Posocco, M; Rotondo, M; Simonetto, F; Stroili, R; Voci, C; Ben-Haim, E; Briand, H; Calderini, G; Chauveau, J; David, P; Del Buono, L; De La Vaissière, C; Hamon, O; Leruste, P; Malcles, J; Ocariz, J; Pérez, A; Prendki, J; Gladney, L; Biasini, M; Covarelli, R; Manoni, E; Angelini, C; Batignani, G; Bettarini, S; Carpinelli, M; Cenci, R; Cervelli, A; Forti, F; Giorgi, M A; Lusiani, A; Marchiori, G; Mazur, M A; Morganti, M; Neri, N; Paoloni, E; Rizzo, G; Walsh, J J; Haire, M; Biesiada, J; Elmer, P; Lau, Y P; Lü, C; Olsen, J; Smith, A J S; Telnov, A V; Baracchini, E; Bellini, F; Cavoto, G; Del Re, D; Di Marco, E; Faccini, R; Ferrarotto, F; Ferroni, F; Gaspero, M; Jackson, P D; Li Gioi, L; Mazzoni, M A; Morganti, S; Piredda, G; Polci, F; Renga, F; Voena, C; Ebert, M; Hartmann, T; Schröder, H; Waldi, R; Adye, T; Castelli, G; Franek, B; Olaiya, E O; Ricciardi, S; Röthel, W; Wilson, F F; Emery, S; Escalier, M; Gaidot, A; Ganzhur, S F; Hamel de Monchenault, G; Kozanecki, W; Vasseur, G; Yéche, C; Zito, M; Chen, X R; Liu, H; Park, W; Purohit, M V; Wilson, J R; Allen, M T; Aston, D; Bartoldus, R; Bechtle, P; Berger, N; Claus, R; Coleman, J P; Convery, M R; Dingfelder, J C; Dorfan, J; Dubois-Felsmann, G P; Dunwoodie, W; Field, R C; Glanzman, T; Gowdy, S J; Graham, M T; Grenier, P; Hast, C; Hrynóva, T; Innes, W R; Kaminski, J; Kelsey, M H; Kim, H; Kim, P; Kocian, M L; Leith, D W G S; Li, S; Luitz, S; Lüth, V; Lynch, H L; MacFarlane, D B; Marsiske, H; Messner, R; Müller, D R; O'Grady, C P; Ofte, I; Perazzo, A; Perl, M; Pulliam, T; Ratcliff, B N; Roodman, A; Salnikov, A A; Schindler, R H; Schwiening, J; Snyder, A; Stelzer, J; Su, D; Sullivan, M K; Suzuki, K; Swain, S K; Thompson, J M; Vavra, J; Van Bakel, N; Wagner, A P; Weaver, M; Wisniewski, W J; Wittgen, M; Wright, D H; Yarritu, A K; Yi, K; Young, C C; Burchat, P R; Edwards, A J; Majewski, S A; Petersen, B A; Wilden, L; Ahmed, S; Alam, M S; Bula, R; Ernst, J A; Jain, V; Pan, B; Saeed, M A; Wappler, F R; Zain, S B; Krishnamurthy, M; Spanier, S M; Eckmann, R; Ritchie, J L; Ruland, A M; Schilling, C J; Schwitters, R F; Izen, J M; Lou, X C; Ye, S; Bianchi, F; Gallo, F; Gamba, D; Pelliccioni, M; Bomben, M; Bosisio, L; Cartaro, C; Cossutti, F; Della Ricca, G; Lanceri, L; Vitale, L; Azzolini, V; Lopez-March, N; Martínez-Vidal, F; Milanes, D A; Oyanguren, A; Albert, J; Banerjee, Sw; Bhuyan, B; Hamano, K; Kowalewski, R; Nugent, I M; Roney, J M; Sobie, R J; Harrison, P F; Ilic, J; Latham, T E; Mohanty, G B; Band, H R; Chen, X; Dasu, S; Flood, K T; Hollar, J J; Kutter, P E; Pan, Y; Pierini, M; Prepost, R; Wu, S L; Neal, H

    2007-01-01

    We present the results of searches for decays of B mesons to final states with a b_1 meson and a charged pion or kaon. The data, collected with the BaBar detector at the Stanford Linear Accelerator Center, represent 382 million B-Bbar pairs produced in e+e- annihilation. The results for the branching fractions are, in units of 10^{-6}, B(B+ -> b1^0 pi+) = 6.7 +/- 1.7 +/- 1.0 (4.0 sigma), B(B+ -> b1^0 K+ = 9.1+/- 1.7+/- 1.0 (5.3 sigma), B(B0 -> b1^-/+ pi^+/-) = 10.9 +/- 1.2 +/- 0.9 (8.9 sigma), and B(B0 -> b1^-K+) = 7.4 +/- 1.0 +/- 1.0 (6.1 sigma), with the assumption that B(b_1 -> omega pi)=1. We also measure charge and flavor asymmetries Ach(B+ -> b1^0 pi+) = 0.05 +/- 0.16 +/- 0.02, Ach(B+ -> b1^0 K+ = -0.46 +/- 0.20 +/- 0.02, Ach(B0 -> b1^-/+ pi^+/-) = -0.05 +/- 0.10 +/- 0.02, C(B0 -> b1^-/+ pi^+/-) = -0.22 +/- 0.23 +/- 0.05, deltaC(B0 -> b1^-/+ pi^+/-) = -1.04 +/- 0.23 +/- 0.08, and Ach(B0 -> b1^-K+) = -0.07 +/- 0.12 +/- 0.02, The first error quoted is statistical, the second systematic, and for the branch...

  20. Sox2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice

    NARCIS (Netherlands)

    Arnold, K.; Sarkar, A.; Yram, M.A.; Polo, J.M.; Bronson, R.; Sengupta, S.; Seandel, M.; Geijsen, N.; Hochedlinger, K.

    2011-01-01

    The transcription factor Sox2 maintains the pluripotency of early embryonic cells and regulates the formation of several epithelia during fetal development. Whether Sox2 continues to play a role in adult tissues remains largely unknown. We show here that Sox2 marks adult cells in several epithelial

  1. The HMG box transcription factor Sox4 contributes to the development of the endocrine pancreas.

    NARCIS (Netherlands)

    Wilson, M.E.; Yang, K.Y.; Kalousova, A.; Janet, L.; Kosaka, Y.; Lynn, F.C.; Wang, J.; Mrejen, C.; Episkopou, V.; Clevers, J.C.; German, M.S.

    2005-01-01

    To investigate the role of the Sry/hydroxymethylglutaryl box (Sox) transcription factors in the development of the pancreas, we determined the expression pattern of Sox factors in the developing mouse pancreas. By RT-PCR, we detected the presence of multiple Sox family members in both the developing

  2. SOX17 Regulates Cholangiocyte Differentiation and Acts as a Tumor Suppressor in Cholangiocarcinoma

    DEFF Research Database (Denmark)

    Merino-Azpitarte, M; Lozano, E; Perugorria, M J

    2017-01-01

    BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a biliary malignancy linked to genetic and epigenetic abnormalities, such as hypermethylation of SOX17 promoter. Here, the role of SOX17 in cholangiocyte differentiation and cholangiocarcinogenesis was studied. METHODS: SOX17 expression/function was ...

  3. Sox9 expression in canine epithelial skin tumors

    Directory of Open Access Journals (Sweden)

    E. Fantinato

    2015-07-01

    Full Text Available Sox9 is a master regulatory gene involved in developmental processes, stem cells maintenance and tumorigenesis. This gene is expressed in healthy skin but even in several skin neoplasms, where its expression patterns often resembles those of the developing hair follicle. In this study, samples from eleven different types of canine skin neoplasms (squamous papilloma, squamous cell carcinoma, infundibular keratinizing acanthoma, inferior tricholemmoma, isthmic tricholemmoma, trichoblastoma, trichoepitelioma, malignant trichoepitelioma, pilomatricoma, subungual keratoacanthoma, subungual squamous cell carcinoma were immunohistochemically stained and evaluated for Sox9 with the aim to correlate tumor phenotype with molecular characteristics that may help to better define tumor development, contribute to its diagnosis and clinical management. Keratoacanthoma excluded, all the skin neoplasms examined showed a variable positivity to Sox9, especially in the basal layers, but with major intensity in neoplasms developing from the bulge region of the hair follicle, as trichoblastoma. According to our results, Sox9 could be employed as a stem cell marker to better assess the role of stem cells in canine epidermal and follicular tumors.

  4. SOX: search for short baseline neutrino oscillations with Borexino

    Science.gov (United States)

    Vivier, M.; Agostini, M.; Altenmüller, K.; Appel, S.; Bellini, G.; Benziger, J.; Berton, N.; Bick, D.; Bonfini, G.; Bravo, D.; Caccianiga, B.; Calaprice, F.; Caminata, A.; Cavalcante, P.; Chepurnov, A.; Choi, K.; Cribier, M.; D'Angelo, D.; Davini, S.; Derbin, A.; Di Noto, L.; Drachnev, I.; Durero, M.; Etenko, A.; Farinon, S.; Fischer, V.; Fomenko, K.; Franco, D.; Gabriele, F.; Gaffliot, J.; Galbiati, C.; Ghiano, C.; Giammarchi, M.; Goeger-Neff, M.; Goretti, A.; Gromov, M.; Hagner, C.; Houdy, T.; Hungerford, E.; Ianni, Aldo; Ianni, Andrea; Jonquàres, N.; Jedrzejczak, K.; Kaiser, M.; Kobychev, V.; Korablev, D.; Korga, G.; Kornoukhov, V.; Kryn, D.; Lachenmaier, T.; Lasserre, T.; Laubenstein, M.; Lehnert, B.; Link, J.; Litvinovich, E.; Lombardi, F.; Lombardi, P.; Ludhova, L.; Lukyanchenko, G.; Machulin, I.; Manecki, S.; Maneschg, W.; Marcocci, S.; Maricic, J.; Mention, G.; Meroni, E.; Meyer, M.; Miramonti, L.; Misiaszek, M.; Montuschi, M.; Mosteiro, P.; Muratova, V.; Musenich, R.; Neumair, B.; Oberauer, L.; Obolensky, M.; Ortica, F.; Pallavicini, M.; Papp, L.; Perasso, L.; Pocar, A.; Ranucci, G.; Razeto, A.; Re, A.; Romani, A.; Roncin, R.; Rossi, N.; Schönert, S.; Scola, L.; Semenov, D.; Skorokhvatov, M.; Smirnov, O.; Sotnikov, A.; Sukhotin, S.; Suvorov, Y.; Tartaglia, R.; Testera, G.; Thurn, J.; Toropova, M.; Veyssiére, C.; Unzhakov, E.; Vogelaar, R. B.; von Feilitzsch, F.; Wang, H.; Weinz, S.; Winter, J.; Wojcik, M.; Wurm, M.; Yokley, Z.; Zaimidoroga, O.; Zavatarelli, S.; Zuber, K.; Zuzel, G.; Borexino Collaboration

    2016-05-01

    The Borexino detector has convincingly shown its outstanding performances in the low energy regime through its accomplishments in the observation and study of the solar and geo neutrinos. It is then an ideal tool to perform a state of the art source-based experiment for testing the longstanding hypothesis of a fourth sterile neutrino with ~ eV2 mass, as suggested by several anomalies accumulated over the past three decades in source, reactor, and accelerator-based experiments. The SOX project aims at successively deploying two intense radioactive sources, made of Cerium (antineutrino) and Chromium (neutrino), respectively, in a dedicated pit located beneath the detector. The existence of such an ~ eV2 sterile neutrino would then show up as an unambiguous spatial and energy distortion in the count rate of neutrinos interacting within the active detector volume. This article reports on the latest developments about the first phase of the SOX experiment, namely CeSOX, and gives a realistic projection of CeSOX sensitivity to light sterile neutrinos in a simple (3+1) model.

  5. Sequential EMT-MET induces neuronal conversion through Sox2.

    Science.gov (United States)

    He, Songwei; Chen, Jinlong; Zhang, Yixin; Zhang, Mengdan; Yang, Xiao; Li, Yuan; Sun, Hao; Lin, Lilong; Fan, Ke; Liang, Lining; Feng, Chengqian; Wang, Fuhui; Zhang, Xiao; Guo, Yiping; Pei, Duanqing; Zheng, Hui

    2017-01-01

    Direct neuronal conversion can be achieved with combinations of small-molecule compounds and growth factors. Here, by studying the first or induction phase of the neuronal conversion induced by defined 5C medium, we show that the Sox2-mediated switch from early epithelial-mesenchymal transition (EMT) to late mesenchymal-epithelial transition (MET) within a high proliferation context is essential and sufficient for the conversion from mouse embryonic fibroblasts (MEFs) to TuJ(+) cells. At the early stage, insulin and basic fibroblast growth factor (bFGF)-induced cell proliferation, early EMT, the up-regulation of Stat3 and Sox2, and the subsequent activation of neuron projection. Up-regulated Sox2 then induced MET and directed cells towards a neuronal fate at the late stage. Inhibiting either stage of this sequential EMT-MET impaired the conversion. In addition, Sox2 could replace sequential EMT-MET to induce a similar conversion within a high proliferation context, and its functions were confirmed with other neuronal conversion protocols and MEFs reprogramming. Therefore, the critical roles of the sequential EMT-MET were implicated in direct cell fate conversion in addition to reprogramming, embryonic development and cancer progression.

  6. Nestin-positive/SOX2-negative cells mediate adult neurogenesis of nigral dopaminergic neurons in mice.

    Science.gov (United States)

    Albright, Joshua E; Stojkovska, Iva; Rahman, Abir A; Brown, Connor J; Morrison, Brad E

    2016-02-26

    The primary clinical motor symptoms of Parkinson's disease (PD) result from loss of dopaminergic (DA) neurons in the substantia nigra (SN). Consequently, neurogenesis of this group of neurons in the adult brain has drawn considerable interest for the purpose of harnessing endogenous neurogenerative potential as well as devising better strategies for stem cell therapy for PD. However, the existence of adult neurogenesis for DA neurons within the SN remains controversial. To overcome technical and design limitations associated with previous studies, our group has developed a novel genetic mouse model for assessing adult nigral DA neurogenesis. This system utilizes transgenic mice that express a tamoxifen-activatable Cre recombinase (Cre(ERT2)) under the control of the neuronal progenitor cell promoters nestin or Sox2 leading to suppression of the DA neuron marker tyrosine hydroxylase (TH) via excision of exon 1 by flanking loxP sites in adult animals. This study reports that six months following initiation of a six week treatment with tamoxifen mice with nestin-mediated Th excision displayed a significant reduction in TH+ neurons in the SN. This finding indicates that nestin-expressing cells regenerate DA neurons within the SN of adult animals. Interestingly, no reduction was observed in TH+ cells following Sox2-mediated Th excision suggesting that a nestin+/SOX2- precursor cell population drives DA neurogenesis in the adult SN. This information represents a substantial leap in current knowledge of adult DA neurogenesis, will enable improved in vitro and in vivo modeling, as well as facilitate the harnessing of this process for therapeutic intervention for PD. Published by Elsevier Ireland Ltd.

  7. The role of SOX10 in the pathogenesis of Hirschsprung's disease associated enterocolitis%SOX10在先天性巨结肠相关性小肠结肠炎发病中的作用

    Institute of Scientific and Technical Information of China (English)

    郑辉明; 向磊; 李宁; 韦佳; 郑帅玉; 邱银荣; 冯杰雄

    2011-01-01

    目的 探讨SOX10、潘氏细胞发育及分泌防御素-5与先天性巨结肠相关性小肠结肠炎的关系.方法 收集50例先天性巨结肠病变肠管,根据术前是否发生小肠结肠炎分为HAFC组(n=14)和HD组(n=36),并以20例正常结肠标本作对照组.采用免疫组织化学方法观察结肠中防御素-5蛋白质表达、潘氏细胞发育情况以及SOX10蛋白质表达情况.采用实时荧光定量PCR技术检测防御素-5 mRNA及Sox 10 mRNA表达情况.结果 防御素-5在正常肠管中不表达,HAEC组和HD组在肠腺隐窝基底处呈不同程度阳性表达.但前者阳性区域平均光密度值明显增高(0.33±0.039比0.10±0.031,P<0.05),HAEC组防御素-5mRNA亦呈显著增高趋势(2.72±0.80比0.78±0.21,P<0.05).对结肠组织同层切片进行潘氏细胞特异性产物溶菌酶免疫组化染色发现,对照组肠管中除1例存在弱阳性外其他均无阳性表达.HD组和HAEC组结肠中同样在隐窝基底处存在溶菌酶阳性细胞,可鉴别为化生的潘氏细胞,但HAEC组在发生率(78.6%)和细胞个数(2.97±0.80)明显高于HD组(27.8%,0.43±0.85)(P<0.05).SOX10免疫产物主要在结肠神经节细胞膜及胞浆中表达,对照组、HAEC组、HD组阳性区域的平均光密度值递减(0.75±0.041,0.61±0.048,0.35±0.025),差异具有统计学意义(P<0.05),同时RT-PCR检测显示Sox10 mRNA在各组中的表达与蛋白质水平呈平行结果.结论 SOX10可能通过影响潘氏细胞发育及分泌防御素-5在先天性巨结肠相关性小肠结肠炎的发生发展中起一定作用.%Objective To study the expression of SOX10 and Human α-defensins-5(HD-5 )in Hirschsprung's disease associated enterocolitis(HAEC) and expore the possible relationship between SOX10 and HAEC.Methods Fifty pathological colons of Hirschsprung's disease (HD) were divided into HAEC group (n = 14) and HD group(n = 36) according to the presence of preoperative enterocolitis,Twenty normal colons as control

  8. Sox9基因的结构、功能及进化%Sox9 gene: structure, function and evolution

    Institute of Scientific and Technical Information of China (English)

    陈维; 王昌留; 王磊

    2012-01-01

    Sox9 is the first member of Sox gene family which has intron fragments after the discovery of SRY gene. About 671 Sox9 gene sequences are recorded in the Genebank, which are widely distributed in many species from mammals and bird to coelenterate. Sox9 is a multifunctional gene which takes part in sex determination, chondrogenesis, formation of nervous system and pancreas. Furthermore, this gene can also play roles in oncogenesis. This paper reviews the research progress of the structure, function and evolution of Sox9,to provide references for further study on Sox9 gene.%Sox9基因是继SRY基因之后人们发现的第一个具有内含子的Sox家族成员.在Genebank中可查的Sox9基因序列共671个,广泛分布于哺乳动物和鸟类直至水母等低等动物.近年来的研究发现,Sox9基因的功能呈现多样性,该基因在发育过程中参与性别的决定、软骨的形成以及神经系统和胰腺的形成,另外Sox9基因在肿瘤发生中也有一定的作用.本文从Sox9基因的结构、功能以及进化等方面进行了综述,为进一步研究Sox9基因提供参考资料.

  9. Crystallization and X-ray diffraction analysis of the HMG domain of the chondrogenesis master regulator Sox9 in complex with a ChIP-Seq-identified DNA element

    Energy Technology Data Exchange (ETDEWEB)

    Vivekanandan, Saravanan; Moovarkumudalvan, Balasubramanian; Lescar, Julien; Kolatkar, Prasanna R.

    2015-10-30

    Sox9 is a fundamental sex-determining gene and the master regulator of chondrogenesis, and is involved in the development of various vital organs such as testes, kidney, heart and brain, and in skeletal development. Similar to other known Sox transcription factors, Sox9 recognizes and binds DNA with the consensus sequence C(T/A)TTG(T/A)(T/A) through the highly conserved HMG domain. Nonetheless, the molecular basis of the functional specificity of Sox9 in key developmental processes is still unclear. As an initial step towards a mechanistic understanding of Sox9 transcriptional regulation, the current work describes the details of the purification of the mouse Sox9 HMG domain (mSox9HMG), its crystallization in complex with a ChIP-Seq-identified FOXP2 promoter DNA element and the X-ray diffraction data analysis of this complex. The mSox9HMG–FOXP2 promoter DNA complex was crystallized by the hanging-drop vapour-diffusion method using 20% PEG 3350 in 200 mMsodium/potassium phosphate with 100 mMbis-tris propane at pH 8.5. The crystals diffracted to 2.7 Å resolution and the complex crystallized in the tetragonal space groupP41212, with unit-cell parametersa=b= 99.49,c= 45.89 Å. Crystal-packing parameters revealed that asymmetric unit contained one mSox9HMG–FOXP2 promoter DNA complex with an estimated solvent content of 64%.

  10. Crystallization and X-ray diffraction analysis of the HMG domain of the chondrogenesis master regulator Sox9 in complex with a ChIP-Seq-identified DNA element.

    Science.gov (United States)

    Vivekanandan, Saravanan; Moovarkumudalvan, Balasubramanian; Lescar, Julien; Kolatkar, Prasanna R

    2015-11-01

    Sox9 is a fundamental sex-determining gene and the master regulator of chondrogenesis, and is involved in the development of various vital organs such as testes, kidney, heart and brain, and in skeletal development. Similar to other known Sox transcription factors, Sox9 recognizes and binds DNA with the consensus sequence C(T/A)TTG(T/A)(T/A) through the highly conserved HMG domain. Nonetheless, the molecular basis of the functional specificity of Sox9 in key developmental processes is still unclear. As an initial step towards a mechanistic understanding of Sox9 transcriptional regulation, the current work describes the details of the purification of the mouse Sox9 HMG domain (mSox9HMG), its crystallization in complex with a ChIP-Seq-identified FOXP2 promoter DNA element and the X-ray diffraction data analysis of this complex. The mSox9HMG-FOXP2 promoter DNA complex was crystallized by the hanging-drop vapour-diffusion method using 20% PEG 3350 in 200 mM sodium/potassium phosphate with 100 mM bis-tris propane at pH 8.5. The crystals diffracted to 2.7 Å resolution and the complex crystallized in the tetragonal space group P41212, with unit-cell parameters a = b = 99.49, c = 45.89 Å. Crystal-packing parameters revealed that asymmetric unit contained one mSox9HMG-FOXP2 promoter DNA complex with an estimated solvent content of 64%.

  11. SOX9 Expression Predicts Relapse of Stage II Colon Cancer Patients

    DEFF Research Database (Denmark)

    Espersen, Maiken Lise Marcker; Linnemann, Dorte; Alamili, Mahdi;

    2016-01-01

    The aim of this study was to investigate if the protein expression of Sex-determining region y-box 9 (SOX9) in primary tumors could predict relapse of stage II colon cancer patients.144 patients with stage II primary colon cancer were retrospectively enrolledin the study. SOX9 expression...... high levels of SOX9 of primary stage II colon tumors predict low riskof relapse whereas low levels of SOX9 predict high risk of relapse. SOX9 may have an important value as a biomarker when evaluating risk of relapse for personalized treatment....

  12. MarA, SoxS and Rob of Escherichia coli - Global regulators of multidrug resistance, virulence and stress response.

    Science.gov (United States)

    Duval, Valérie; Lister, Ida M

    2013-01-01

    Bacteria have a great capacity for adjusting their metabolism in response to environmental changes by linking extracellular stimuli to the regulation of genes by transcription factors. By working in a co-operative manner, transcription factors provide a rapid response to external threats, allowing the bacteria to survive. This review will focus on transcription factors MarA, SoxS and Rob in Escherichia coli, three members of the AraC family of proteins. These homologous proteins exemplify the ability to respond to multiple threats such as oxidative stress, drugs and toxic compounds, acidic pH, and host antimicrobial peptides. MarA, SoxS and Rob recognize similar DNA sequences in the promoter region of more than 40 regulatory target genes. As their regulons overlap, a finely tuned adaptive response allows E. coli to survive in the presence of different assaults in a co-ordinated manner. These regulators are well conserved amongst Enterobacteriaceae and due to their broad involvement in bacterial adaptation in the host, have recently been explored as targets to develop new anti-virulence agents. The regulators are also being examined for their roles in novel technologies such as biofuel production.

  13. SoxS Increases the Expression of the Zinc Uptake System ZnuACB in an Escherichia coli Murine Pyelonephritis Model

    OpenAIRE

    Warner, Douglas M; Levy, Stuart B.

    2012-01-01

    Paralogous transcriptional regulators MarA, Rob, and SoxS act individually and together to control expression of more than 80 Escherichia coli genes. Deletion of marA, rob, and soxS from an E. coli clinical isolate prevents persistence beyond 2 days postinfection in a mouse model of pyelonephritis. We used microarray analysis to identify 242 genes differentially expressed between the triple deletion mutant and its parent strain at 2 days postinfection in the kidney. One of these, znuC of the ...

  14. SOX9 accelerates ESC differentiation to three germ layer lineages by repressing SOX2 expression through P21 (WAF1/CIP1).

    Science.gov (United States)

    Yamamizu, Kohei; Schlessinger, David; Ko, Minoru S H

    2014-11-01

    Upon removal of culture conditions that maintain an undifferentiated state, mouse embryonic stem cells (ESCs) differentiate into various cell types. Differentiation can be facilitated by forced expression of certain transcription factors (TFs), each of which can generally specify a particular developmental lineage. We previously established 137 mouse ESC lines, each of which carried a doxycycline-controllable TF. Among them, Sox9 has unique capacity: its forced expression accelerates differentiation of mouse ESCs into cells of all three germ layers. With the additional use of specific culture conditions, overexpression of Sox9 facilitated the generation of endothelial cells, hepatocytes and neurons from ESCs. Furthermore, Sox9 action increases formation of p21 (WAF1/CIP1), which then binds to the SRR2 enhancer of pluripotency marker Sox2 and inhibits its expression. Knockdown of p21 abolishes inhibition of Sox2 and Sox9-accelerated differentiation, and reduction of Sox2 2 days after the beginning of ESC differentiation can comparably accelerate mouse ESC formation of cells of three germ layers. These data implicate the involvement of the p21-Sox2 pathway in the mechanism of accelerated ESC differentiation by Sox9 overexpression. The molecular cascade could be among the first steps to program ESC differentiation.

  15. Selective influence of Sox2 on POU transcription factor binding in embryonic and neural stem cells.

    Science.gov (United States)

    Mistri, Tapan Kumar; Devasia, Arun George; Chu, Lee Thean; Ng, Wei Ping; Halbritter, Florian; Colby, Douglas; Martynoga, Ben; Tomlinson, Simon R; Chambers, Ian; Robson, Paul; Wohland, Thorsten

    2015-09-01

    Embryonic stem cell (ESC) identity is orchestrated by co-operativity between the transcription factors (TFs) Sox2 and the class V POU-TF Oct4 at composite Sox/Oct motifs. Neural stem cells (NSCs) lack Oct4 but express Sox2 and class III POU-TFs Oct6, Brn1 and Brn2. This raises the question of how Sox2 interacts with POU-TFs to transcriptionally specify ESCs versus NSCs. Here, we show that Oct4 alone binds the Sox/Oct motif and the octamer-containing palindromic MORE equally well. Sox2 binding selectively increases the affinity of Oct4 for the Sox/Oct motif. In contrast, Oct6 binds preferentially to MORE and is unaffected by Sox2. ChIP-Seq in NSCs shows the MORE to be the most enriched motif for class III POU-TFs, including MORE subtypes, and that the Sox/Oct motif is not enriched. These results suggest that in NSCs, co-operativity between Sox2 and class III POU-TFs may not occur and that POU-TF-driven transcription uses predominantly the MORE cis architecture. Thus, distinct interactions between Sox2 and POU-TF subclasses distinguish pluripotent ESCs from multipotent NSCs, providing molecular insight into how Oct4 alone can convert NSCs to pluripotency.

  16. SOX9: a stem cell transcriptional regulator of secreted niche signaling factors.

    Science.gov (United States)

    Kadaja, Meelis; Keyes, Brice E; Lin, Mingyan; Pasolli, H Amalia; Genander, Maria; Polak, Lisa; Stokes, Nicole; Zheng, Deyou; Fuchs, Elaine

    2014-02-15

    Hair follicles (HFs) undergo cyclical periods of growth, which are fueled by stem cells (SCs) at the base of the resting follicle. HF-SC formation occurs during HF development and requires transcription factor SOX9. Whether and how SOX9 functions in HF-SC maintenance remain unknown. By conditionally targeting Sox9 in adult HF-SCs, we show that SOX9 is essential for maintaining them. SOX9-deficient HF-SCs still transition from quiescence to proliferation and launch the subsequent hair cycle. However, once activated, bulge HF-SCs begin to differentiate into epidermal cells, which naturally lack SOX9. In addition, as HF-SC numbers dwindle, outer root sheath production is not sustained, and HF downgrowth arrests prematurely. Probing the mechanism, we used RNA sequencing (RNA-seq) to identify SOX9-dependent transcriptional changes and chromatin immunoprecipitation (ChIP) and deep sequencing (ChIP-seq) to identify SOX9-bound genes in HF-SCs. Intriguingly, a large cohort of SOX9-sensitive targets encode extracellular factors, most notably enhancers of Activin/pSMAD2 signaling. Moreover, compromising Activin signaling recapitulates SOX9-dependent defects, and Activin partially rescues them. Overall, our findings reveal roles for SOX9 in regulating adult HF-SC maintenance and suppressing epidermal differentiation in the niche. In addition, our studies expose a role for SCs in coordinating their own behavior in part through non-cell-autonomous signaling within the niche.

  17. Organogenesis relies on SoxC transcription factors for the survival of neural and mesenchymal progenitors.

    Science.gov (United States)

    Bhattaram, Pallavi; Penzo-Méndez, Alfredo; Sock, Elisabeth; Colmenares, Clemencia; Kaneko, Kotaro J; Vassilev, Alex; Depamphilis, Melvin L; Wegner, Michael; Lefebvre, Véronique

    2010-04-12

    During organogenesis, neural and mesenchymal progenitor cells give rise to many cell lineages, but their molecular requirements for self-renewal and lineage decisions are incompletely understood. In this study, we show that their survival critically relies on the redundantly acting SoxC transcription factors Sox4, Sox11 and Sox12. The more SoxC alleles that are deleted in mouse embryos, the more severe and widespread organ hypoplasia is. SoxC triple-null embryos die at midgestation unturned and tiny, with normal patterning and lineage specification, but with massively dying neural and mesenchymal progenitor cells. Specific inactivation of SoxC genes in neural and mesenchymal cells leads to selective apoptosis of these cells, suggesting SoxC cell-autonomous roles. Tead2 functionally interacts with SoxC genes in embryonic development, and is a direct target of SoxC proteins. SoxC genes therefore ensure neural and mesenchymal progenitor cell survival, and function in part by activating this transcriptional mediator of the Hippo signalling pathway.

  18. Patients with Multiple Myeloma Develop SOX2-Specific Autoantibodies after Allogeneic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Sebastian Kobold

    2011-01-01

    Full Text Available The occurrence of SOX2-specific autoantibodies seems to be associated with an improved prognosis in patients with monoclonal gammopathy of undetermined significance (MGUS. However, it is unclear if SOX2-specific antibodies also develop in established multiple myeloma (MM. Screening 1094 peripheral blood (PB sera from 196 MM patients and 100 PB sera from healthy donors, we detected SOX2-specific autoantibodies in 7.7% and 2.0% of patients and donors, respectively. We identified SOX2211–230 as an immunodominant antibody-epitope within the full protein sequence. SOX2 antigen was expressed in most healthy tissues and its expression did not correlate with the number of BM-resident plasma cells. Accordingly, anti-SOX2 immunity was not related to SOX2 expression levels or tumor burden in the patients’ BM. The only clinical factor predicting the development of anti-SOX2 immunity was application of allogeneic stem cell transplantation (alloSCT. Anti-SOX2 antibodies occurred more frequently in patients who had received alloSCT (n=74. Moreover, most SOX2-seropositive patients had only developed antibodies after alloSCT. This finding indicates that alloSCT is able to break tolerance towards this commonly expressed antigen. The questions whether SOX2-specific autoantibodies merely represent an epiphenomenon, are related to graft-versus-host effects or participate in the immune control of myeloma needs to be answered in prospective studies.

  19. 血清高迁移率蛋白B1检测在急性阑尾炎诊断中的应用%Application of serum high mobility group box protein-1 level detection in diagnosis of acute appendicitis

    Institute of Scientific and Technical Information of China (English)

    张希儒; 张广文; 杨栋文; 李成利; 杨香玲

    2012-01-01

    目的:探讨急性阑尾炎患者血清中高迁移率蛋白B1( HMGB1)水平及其对急性阑尾炎诊断的意义.方法:采用ELISA定量试剂盒检测40例健康体检者(A组)和129例拟诊为急性阑尾炎患者血清HMGB1水平,同时检测白细胞(WBC)和C反应蛋白(CRP)水平.根据手术和病理结果将129例拟诊患者分为:B组(非阑尾炎15例),C组(急性单纯性阑尾炎63例),D组(急性化脓性、坏疽性、穿孔性急性阑尾炎及阑尾周围脓肿51例),比较上述指标在各组中的差异并采用受试者工作曲线( ROC)分析各指标对急性阑尾炎的诊断效率.结果:与A,B组比较,C,D组患者WBC,血清CRP及HMGB1均明显升高,差异均有统计学意义(均P<0.05),且D组各项指标均明显高于C组(均P<0.05);ROC曲线分析显示,WBC,CRP和HMGB1的曲线下面积(AUG)分别为0.729,0.811和0.850,HMGB1的诊断效率最高(均P<0.05).结论:急性阑尾炎患者血清HMGB1水平明显升高,血清HMGB1水平可望作为评价急性阑尾炎病变和炎症反应程度的辅助指标.%The serum HMGBl levels of 40 subjects undergoing health maintenance examination (group A) and 129 suspected acute appendicitis patients were detected by using quantitative ELISA kit, and their white blood cell (WBC) count and C-reactive protein (CRP) level were also determined. According to the surgical findings and postoperative pathological results, the 129 suspected cases were distinguished into group B (15 cases without appendicitis), group C (63 cases of simple acute appendicitis) and group D (51 cases of acute suppurative , gangrenous, perforated appendicitis or periappendiceal abscess). The differences in above mentioned indexes among the groups were compared and the receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic efficiency of each index for acute appendicitis. Results: The WBC count, serum level of HMGB1 and CRP markedly increased in group C and group D compared

  20. Effects of SOX2 on Proliferation, Migration and Adhesion of Human Dental Pulp Stem Cells.

    Science.gov (United States)

    Liu, Pengfei; Cai, Jinglei; Dong, Delu; Chen, Yaoyu; Liu, Xiaobo; Wang, Yi; Zhou, Yulai

    2015-01-01

    As a key factor for cell pluripotent and self-renewing phenotypes, SOX2 has attracted scientists' attention gradually in recent years. However, its exact effects in dental pulp stem cells (DPSCs) are still unclear. In this study, we mainly investigated whether SOX2 could affect some biological functions of DPSCs. DPSCs were isolated from the dental pulp of human impacted third molar. SOX2 overexpressing DPSCs (DPSCs-SOX2) were established through retroviral infection. The effect of SOX2 on cell proliferation, migration and adhesion ability was evaluated with CCK-8, trans-well system and fibronectin-induced cell attachment experiment respectively. Whole genome expression of DPSCs-SOX2 was analyzed with RNA microarray. Furthermore, a rescue experiment was performed with SOX2-siRNA in DPSC-SOX2 to confirm the effect of SOX2 overexpression in DPSCs. We found that SOX2 overexpression could result in the enhancement of cell proliferation, migration, and adhesion in DPSCs obviously. RNA microarray analysis indicated that some key genes in the signal pathways associated with cell cycle, migration and adhesion were upregulated in different degree, and the results were further confirmed with qPCR and western-blot. Finally, DPSC-SOX2 transfected with SOX2-siRNA showed a decrease of cell proliferation, migration and adhesion ability, which further confirmed the biological effect of SOX2 in human DPSCs. This study indicated that SOX2 could improve the cell proliferation, migration and adhesion ability of DPSCs through regulating gene expression about cell cycle, migration and adhesion, and provided a novel strategy to develop seed cells with strong proliferation, migration and adhesion ability for tissue engineering.

  1. Effects of SOX2 on Proliferation, Migration and Adhesion of Human Dental Pulp Stem Cells.

    Directory of Open Access Journals (Sweden)

    Pengfei Liu

    Full Text Available As a key factor for cell pluripotent and self-renewing phenotypes, SOX2 has attracted scientists' attention gradually in recent years. However, its exact effects in dental pulp stem cells (DPSCs are still unclear. In this study, we mainly investigated whether SOX2 could affect some biological functions of DPSCs. DPSCs were isolated from the dental pulp of human impacted third molar. SOX2 overexpressing DPSCs (DPSCs-SOX2 were established through retroviral infection. The effect of SOX2 on cell proliferation, migration and adhesion ability was evaluated with CCK-8, trans-well system and fibronectin-induced cell attachment experiment respectively. Whole genome expression of DPSCs-SOX2 was analyzed with RNA microarray. Furthermore, a rescue experiment was performed with SOX2-siRNA in DPSC-SOX2 to confirm the effect of SOX2 overexpression in DPSCs. We found that SOX2 overexpression could result in the enhancement of cell proliferation, migration, and adhesion in DPSCs obviously. RNA microarray analysis indicated that some key genes in the signal pathways associated with cell cycle, migration and adhesion were upregulated in different degree, and the results were further confirmed with qPCR and western-blot. Finally, DPSC-SOX2 transfected with SOX2-siRNA showed a decrease of cell proliferation, migration and adhesion ability, which further confirmed the biological effect of SOX2 in human DPSCs. This study indicated that SOX2 could improve the cell proliferation, migration and adhesion ability of DPSCs through regulating gene expression about cell cycle, migration and adhesion, and provided a novel strategy to develop seed cells with strong proliferation, migration and adhesion ability for tissue engineering.

  2. Aflatoxin B1: Mechanism of mutagenesis

    Directory of Open Access Journals (Sweden)

    Regina M. Santella

    2007-02-01

    Full Text Available

    Aflatoxins are a group of toxic and carcinogenic fungal metabolites that frequently contaminate corn, peanuts and other products. Aflatoxin B1 (AFB1, the most potent of these, is metabolized by the cytochrome P450 system into a number of hydroxylated metabolites and glutathione conjugates in the process of conversion to more hydrophilic forms for urinary excretion. Unfortunately, one of these metabolites is the aflatoxin-8,9-epoxide that is produced in two forms, endo and exo. Glutathione S-transferases (GST are able to conjugate and detoxify this reactive intermediate. Species differences in susceptibility to the effects of AFB1 are partially related to differences in expression of specific GSTs that are able to conjugate the epoxide to glutathione. The exo epoxide is able to intercalate into DNA and this is followed by reaction of the C8 position of the epoxide with the N7 position of guanine.

    NMR studies of oligonucleotide duplexes containing the adduct have demonstrated that the adduct exists with the aromatic portion intercalated on the 5' face of the guanine residue with Watson-Crick base pairing maintained.

    However, this covalent adduct is chemically unstable due to the charge on the ribose ring. As a result, the guanine can be released from the DNA leaving an apurinic site. This released guanine adduct can be detected in the urine and serves as a biomarker of exposure to AFB1. Alternatively, the ribose ring opens forming a stable formamidopyrimidine (FAPY adduct. This adduct somewhat stabilizes the DNA duplex. Time course studies in animals have demonstrated that the N7 adduct is rapidly removed, probably because it causes more distortion in the helix, while the FAPY adduct is more

  3. Expression of SOX2 in gastric carcinoma tissues and its clinicopathologic significance%SOX2在胃癌组织中的表达与临床意义

    Institute of Scientific and Technical Information of China (English)

    陈淑贞; 许玲; 刘凤军; 宋燕燕; 薛凤华; 张建平

    2012-01-01

    Objective:To investigate the expression of SO×2 in gastric carcinoma and analyze its relationship with clinicopathologic characteristics. Methods:Tissue microarray and immunohis-tochemical methods were performed to detect the expression of SO×2 in 130 cases of gastric carcinoma and 20 cases normal gastric mucosa. Results:The positive expression rate of SO×2 in gastric carcinoma (67.7%) was obviously down regulated than in normal gastric mucosa (90.0%). The expression of SOX2 was not related to the age and sex of the patients, but significantly associated with histological type, differentiation, depth of invasion, lymph node metastasis and TNM stage of the tumor. The statistical significance in the each group was assessed by P<0.05. Conclusion: The results suggest the expression of SO×2 is closely related to the genesis, invasion and metastasis of gastric carcinoma, and may provide a potential role for prognosis.%目的:探讨SOX2在胃癌组织中的表达情况及与临床病理特征的关系.方法:应用组织芯片技术及免疫组织化学PV-9000通用二步法检测130例胃癌组织及20例正常胃黏膜中SOX2的表达情况.结果:SOX2在胃癌组织中的阳性表达率(67.7%)低于较正常胃黏膜阳性率(90.0%,P<0.05).SOX2的表达与患者的年龄、性别无关,与肿瘤的组织学类型、分化程度、浸润深度、淋巴结转移及TNM分期相关,差异均有统计学意义(P<0.05).结论:SOX2与胃癌的发生、浸润和转移过程有密切关系,可为胃癌早期诊断、治疗、预后判断提供依据.

  4. Feasibility Study B-1 Power Controller.

    Science.gov (United States)

    1979-11-01

    Study performed by the Autonetics Strategic Systems Division ( ASSD ) of Rockwell International on Contract N62269-79-C-0294. The objective of this study...Modify the design of the ASSD B-1 SSPC, Part Number 12880-507-1, to be a 115 Vac quadruple SSPC unit, with a SOSTEL compatible interface. 3.1.2 115 Vac...Primary Power Modifications. The ASSD SSPC Unit, Appendix A, contains four identical PC’s operating from 230 Vac primary power. Referring to Figure 1

  5. Genetic and Epigenetic Modifications of Sox2 Contribute to the Invasive Phenotype of Malignant Gliomas

    Science.gov (United States)

    Alonso, Marta M.; Diez-Valle, Ricardo; Manterola, Lorea; Rubio, Angel; Liu, Dan; Cortes-Santiago, Nahir; Urquiza, Leire; Jauregi, Patricia; de Munain, Adolfo Lopez; Sampron, Nicolás; Aramburu, Ander; Tejada-Solís, Sonia; Vicente, Carmen; Odero, María D.; Bandrés, Eva; García-Foncillas, Jesús; Idoate, Miguel A.; Lang, Frederick F.; Fueyo, Juan; Gomez-Manzano, Candelaria

    2011-01-01

    We undertook this study to understand how the transcription factor Sox2 contributes to the malignant phenotype of glioblastoma multiforme (GBM), the most aggressive primary brain tumor. We initially looked for unbalanced genomic rearrangements in the Sox2 locus in 42 GBM samples and found that Sox2 was amplified in 11.5% and overexpressed in all the samples. These results prompted us to further investigate the mechanisms involved in Sox2 overexpression in GBM. We analyzed the methylation status of the Sox2 promoter because high CpG density promoters are associated with key developmental genes. The Sox2 promoter presented a CpG island that was hypomethylated in all the patient samples when compared to normal cell lines. Treatment of Sox2-negative glioma cell lines with 5-azacitidine resulted in the re-expression of Sox2 and in a change in the methylation status of the Sox2 promoter. We further confirmed these results by analyzing data from GBM cases generated by The Cancer Genome Atlas project. We observed Sox2 overexpression (86%; N = 414), Sox2 gene amplification (8.5%; N = 492), and Sox 2 promoter hypomethylation (100%; N = 258), suggesting the relevance of this factor in the malignant phenotype of GBMs. To further explore the role of Sox2, we performed in vitro analysis with brain tumor stem cells (BTSCs) and established glioma cell lines. Downmodulation of Sox2 in BTSCs resulted in the loss of their self-renewal properties. Surprisingly, ectopic expression of Sox2 in established glioma cells was not sufficient to support self-renewal, suggesting that additional factors are required. Furthermore, we observed that ectopic Sox2 expression was sufficient to induce invasion and migration of glioma cells, and knockdown experiments demonstrated that Sox2 was essential for maintaining these properties. Altogether, our data underscore the importance of a pleiotropic role of Sox2 and suggest that it could be used as a therapeutic target in GBM. PMID:22069467

  6. Genetic and epigenetic modifications of Sox2 contribute to the invasive phenotype of malignant gliomas.

    Directory of Open Access Journals (Sweden)

    Marta M Alonso

    Full Text Available We undertook this study to understand how the transcription factor Sox2 contributes to the malignant phenotype of glioblastoma multiforme (GBM, the most aggressive primary brain tumor. We initially looked for unbalanced genomic rearrangements in the Sox2 locus in 42 GBM samples and found that Sox2 was amplified in 11.5% and overexpressed in all the samples. These results prompted us to further investigate the mechanisms involved in Sox2 overexpression in GBM. We analyzed the methylation status of the Sox2 promoter because high CpG density promoters are associated with key developmental genes. The Sox2 promoter presented a CpG island that was hypomethylated in all the patient samples when compared to normal cell lines. Treatment of Sox2-negative glioma cell lines with 5-azacitidine resulted in the re-expression of Sox2 and in a change in the methylation status of the Sox2 promoter. We further confirmed these results by analyzing data from GBM cases generated by The Cancer Genome Atlas project. We observed Sox2 overexpression (86%; N = 414, Sox2 gene amplification (8.5%; N = 492, and Sox 2 promoter hypomethylation (100%; N = 258, suggesting the relevance of this factor in the malignant phenotype of GBMs. To further explore the role of Sox2, we performed in vitro analysis with brain tumor stem cells (BTSCs and established glioma cell lines. Downmodulation of Sox2 in BTSCs resulted in the loss of their self-renewal properties. Surprisingly, ectopic expression of Sox2 in established glioma cells was not sufficient to support self-renewal, suggesting that additional factors are required. Furthermore, we observed that ectopic Sox2 expression was sufficient to induce invasion and migration of glioma cells, and knockdown experiments demonstrated that Sox2 was essential for maintaining these properties. Altogether, our data underscore the importance of a pleiotropic role of Sox2 and suggest that it could be used as a therapeutic target in GBM.

  7. SOX9 duplication linked to intersex in deer.

    Directory of Open Access Journals (Sweden)

    Regina Kropatsch

    Full Text Available A complex network of genes determines sex in mammals. Here, we studied a European roe deer with an intersex phenotype that was consistent with a XY genotype with incomplete male-determination. Whole genome sequencing and quantitative real-time PCR analyses revealed a triple dose of the SOX9 gene, allowing insights into a new genetic defect in a wild animal.

  8. Molecular cloning and expression analysis of dmrt1 and sox9 during gonad development and male reproductive cycle in the lambari fish, astyanax altiparanae

    NARCIS (Netherlands)

    Adolfi, Mateus C.; Carreira, Ana C O; Jesus, Lázaro W O; Bogerd, Jan; Funes, Rejane M.; Schartl, Manfred; Sogayar, Mari C.; Borella, Maria I.

    2015-01-01

    Background: The dmrt1 and sox9 genes have a well conserved function related to testis formation in vertebrates, and the group of fish presents a great diversity of species and reproductive mechanisms. The lambari fish (Astyanax altiparanae) is an important Neotropical species, where studies on molec

  9. Molecular cloning and expression analysis of dmrt1 and sox9 during gonad development and male reproductive cycle in the lambari fish, astyanax altiparanae

    NARCIS (Netherlands)

    Adolfi, Mateus C.; Carreira, Ana C O; Jesus, Lázaro W O; Bogerd, Jan|info:eu-repo/dai/nl/098250531; Funes, Rejane M.; Schartl, Manfred; Sogayar, Mari C.; Borella, Maria I.

    2015-01-01

    Background: The dmrt1 and sox9 genes have a well conserved function related to testis formation in vertebrates, and the group of fish presents a great diversity of species and reproductive mechanisms. The lambari fish (Astyanax altiparanae) is an important Neotropical species, where studies on

  10. Effectiveness of compression stockings to prevent the post-thrombotic syndrome (The SOX Trial and Bio-SOX biomarker substudy: a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Rodger Marc A

    2007-07-01

    Full Text Available Abstract Background Post thrombotic syndrome (PTS is a burdensome and costly complication of deep venous thrombosis (DVT that develops in 20–40% of patients within 1–2 years after symptomatic DVT. Affected patients have chronic leg pain and swelling and may develop ulcers. Venous valve disruption from the thrombus itself or thrombus-associated mediators of inflammation is considered to be a key initiating event for the development of venous hypertension that often underlies PTS. As existing treatments for PTS are extremely limited, strategies that focus on preventing the development of PTS in patients with DVT are more likely to be effective and cost-effective in reducing its burden. Elastic compression stockings (ECS could be helpful in preventing PTS; however, data on their effectiveness are scarce and conflicting. Methods/Design The SOX Trial is a randomized, allocation concealed, double-blind multicenter clinical trial. The objective of the study is to evaluate ECS to prevent PTS. A total of 800 patients with proximal DVT will be randomized to one of 2 treatment groups: ECS or placebo (inactive stockings worn on the DVT-affected leg daily for 2 years. The primary outcome is the incidence of PTS during follow-up. Secondary outcomes are severity of PTS, venous thromboembolism (VTE recurrence, death from VTE, quality of life and cost-effectiveness. Outcomes will be evaluated during 6 clinic visits and 2 telephone follow ups. At baseline, 1 and 6 months, blood samples will be obtained to evaluate the role of inflammatory mediators and genetic markers of thrombophilia in the development of PTS (Bio-SOX substudy. Discussion The SOX Trial will be the largest study and the first with a placebo control to evaluate the effectiveness of ECS to prevent PTS. It is designed to provide definitive data on the effects of ECS on the occurrence and severity of PTS, as well as DVT recurrence, cost-effectiveness and quality of life. This study will also

  11. Sox2 acts as a rheostat of epithelial to mesenchymal transition during neural crest development

    Directory of Open Access Journals (Sweden)

    Nikolaos eMandalos

    2014-09-01

    Full Text Available Precise control of self-renewal and differentiation of progenitor cells into the cranial neural crest (CNC pool ensures proper head development, guided by signaling pathways such as BMPs, FGFs, Shh and Notch. Here, we show that murine Sox2 plays an essential role in controlling progenitor cell behavior during craniofacial development. A Conditional by Inversion Sox2 allele (Sox2COIN has been employed to generate an epiblast ablation of Sox2 function (Sox2EpINV. Sox2EpINV/+(H haploinsufficient and conditional (Sox2EpINV/mosaic mutant embryos proceed beyond gastrulation and die around E11. These mutant embryos exhibit severe anterior malformations, with hydrocephaly and frontonasal truncations, which could be attributed to the deregulation of CNC progenitor cells during their epithelial to mesenchymal transition. This irregularity results in an exacerbated and aberrant migration of Sox10+ NCC in the branchial arches and frontonasal process of the Sox2 mutant embryos. These results suggest a novel role for Sox2 as a regulator of the epithelial to mesenchymal transitions that are important for the cell flow in the developing head.

  12. The stem cell factor SOX2 regulates the tumorigenic potential in human gastric cancer cells.

    Science.gov (United States)

    Hütz, Katharina; Mejías-Luque, Raquel; Farsakova, Katarina; Ogris, Manfred; Krebs, Stefan; Anton, Martina; Vieth, Michael; Schüller, Ulrich; Schneider, Marlon R; Blum, Helmut; Wagner, Ernst; Jung, Andreas; Gerhard, Markus

    2014-04-01

    Gastric cancer (GC) is still one of the most common causes of cancer-related death worldwide, which is mainly attributable to late diagnosis and poor treatment options. Infection with Helicobacter pylori, different environmental factors and genetic alterations are known to influence the risk of developing gastric tumors. However, the molecular mechanisms involved in gastric carcinogenesis are still not fully understood, making it difficult to design targeted therapeutic approaches. Aberrant expression of the specific gastric differentiation marker SOX2 has been observed in stomach cancer. However, the role of SOX2 in gastric tumors has not been well established to date. To elucidate the role of SOX2 in gastric tumorigenesis, SOX2 transcriptional activity was blocked in AZ-521 cells. Interestingly, inhibition of SOX2 reduced cell proliferation and migration, increased apoptosis and induced changes in cell cycle. Blocking of SOX2 also reduced the tumorigenic potential of AZ-521 cells in vivo. In addition, correlation of SOX2 expression and proliferation was observed in a subset of human gastric tumors. Finally, target genes of SOX2 were for the first time identified by RNA microarray in GC cells. Taken together, the results presented here indicate that SOX2 controls several aspects related to GC development and progression by regulating the expression of members of important signaling pathways. These findings could provide new therapeutic options for a subset of GCs exhibiting SOX2 deregulation.

  13. Decreased expression of SOX17 is associated with tumor progression and poor prognosis in breast cancer.

    Science.gov (United States)

    Fu, De-Yuan; Tan, Hao-Sheng; Wei, Jin-Li; Zhu, Chang-Ren; Jiang, Ji-Xin; Zhu, Yu-Xiang; Cai, Feng-Lin; Chong, Mei-Hong; Ren, Chuan-Li

    2015-09-01

    The SOX17 (SRY-related HMG-box) transcription factor is involved in a variety of biological processes and is related to the tumorigenesis and progression of multiple tumors. However, the clinical application of SOX17 for breast cancer prognosis is currently limited. The aim of this study was to investigate the clinicopathologic and prognostic significance of SOX17 expression in human breast cancer. qPCR and western blot assays were performed to measure the expression of SOX17 in breast cancer cell lines and 30 matched pairs of breast cancer and corresponding noncancerous tissues. A SOX17 overexpression cell model was used to examine changes in cell growth in vitro. Immunohistochemical analyses were performed to retrospectively examine the prognostic impact of SOX17 expression in 187 additional breast cancer patients. Our results showed that SOX17 expression was decreased at both the messenger RNA (mRNA) and protein levels in the breast cancer cell lines and tissues, and that SOX17 overexpression could strongly suppress cell growth in vitro. Furthermore, the lack of SOX17 protein expression was strongly correlated with higher tumor grade (P = 0.002), lymph node metastasis (P breast cancer. Our findings indicate that SOX17 expression is a useful prognostic biomarker for breast cancer.

  14. SOX9 is expressed in normal stomach, intestinal metaplasia, and gastric carcinoma in humans.

    Science.gov (United States)

    Sashikawa Kimura, Miho; Mutoh, Hiroyuki; Sugano, Kentaro

    2011-11-01

    SOX9 is a marker for stem cells in the intestine and overexpression of SOX9 is found in some types of cancer. However, the expression of SOX9 in normal stomach, precancerous intestinal metaplasia, and gastric carcinoma has not yet been clarified. This study aimed to investigate SOX9 expression in the corpus and pyloric regions of the normal human stomach, premalignant intestinal metaplasia, and gastric carcinoma by using immunohistochemistry. We evaluated SOX9 expression in 46 clinical samples (early gastric well-differentiated adenocarcinoma including surrounding intestinal metaplasia) resected under esophagogastroduodenoscopy. A small amount of SOX9 was expressed in the neck/isthmus of the corpus region and SOX9 expression was predominantly restricted to the neck/isthmus of the pyloric region in normal human stomach. In the intestinal metaplastic mucosa, SOX9- and PCNA-positive cells were located at the base of the intestinal metaplastic mucosa. Almost all of the gastric carcinoma cells expressed SOX9. SOX9 is expressed in intestinal metaplasia and gastric carcinoma in humans.

  15. Sox4 Links Tumor Suppression to Accelerated Aging in Mice by Modulating Stem Cell Activation

    Directory of Open Access Journals (Sweden)

    Miguel Foronda

    2014-07-01

    Full Text Available Sox4 expression is restricted in mammals to embryonic structures and some adult tissues, such as lymphoid organs, pancreas, intestine, and skin. During embryogenesis, Sox4 regulates mesenchymal and neural progenitor survival, as well as lymphocyte and myeloid differentiation, and contributes to pancreas, bone, and heart development. Aberrant Sox4 expression is linked to malignant transformation and metastasis in several types of cancer. To understand the role of Sox4 in the adult organism, we first generated mice with reduced whole-body Sox4 expression. These mice display accelerated aging and reduced cancer incidence. To specifically address a role for Sox4 in adult stem cells, we conditionally deleted Sox4 (Sox4cKO in stratified epithelia. Sox4cKO mice show increased skin stem cell quiescence and resistance to chemical carcinogenesis concomitantly with downregulation of cell cycle, DNA repair, and activated hair follicle stem cell pathways. Altogether, these findings highlight the importance of Sox4 in regulating adult tissue homeostasis and cancer.

  16. Sox5 induces epithelial to mesenchymal transition by transactivation of Twist1

    Energy Technology Data Exchange (ETDEWEB)

    Pei, Xin-Hong [Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan (China); Department of Pathology, The Basic Medical College of Zhengzhou University, Zhengzhou, Henan (China); Lv, Xin-Quan [Department of Pathology, The Basic Medical College of Zhengzhou University, Zhengzhou, Henan (China); Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan (China); Li, Hui-Xiang, E-mail: Lihuixiang1955@163.com [Department of Pathology, The Basic Medical College of Zhengzhou University, Zhengzhou, Henan (China); Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan (China)

    2014-03-28

    Highlights: • Depletion of Sox5 inhibits breast cancer proliferation, migration, and invasion. • Sox5 transactivates Twist1 expression. • Sox5 induces epithelial to mesenchymal transition through transactivation of Twist1 expression. - Abstract: The epithelial to mesenchymal transition (EMT), a highly conserved cellular program, plays an important role in normal embryogenesis and cancer metastasis. Twist1, a master regulator of embryonic morphogenesis, is overexpressed in breast cancer and contributes to metastasis by promoting EMT. In exploring the mechanism underlying the increased Twist1 in breast cancer cells, we found that the transcription factor SRY (sex-determining region Y)-box 5(Sox5) is up-regulation in breast cancer cells and depletion of Sox5 inhibits breast cancer cell proliferation, migration, and invasion. Furthermore, depletion of Sox5 in breast cancer cells caused a dramatic decrease in Twist1 and chromosome immunoprecipitation assay showed that Sox5 can bind directly to the Twist1 promoter, suggesting that Sox5 transactivates Twist1 expression. We further demonstrated that knockdown of Sox5 up-regulated epithelial phenotype cell biomarker (E-cadherin) and down-regulated mesenchymal phenotype cell biomarkers (N-cadherin, Vimentin, and Fibronectin 1), resulting in suppression of EMT. Our study suggests that Sox5 transactivates Twist1 expression and plays an important role in the regulation of breast cancer progression.

  17. Sox2 expression in breast tumours and activation in breast cancer stem cells.

    Science.gov (United States)

    Leis, O; Eguiara, A; Lopez-Arribillaga, E; Alberdi, M J; Hernandez-Garcia, S; Elorriaga, K; Pandiella, A; Rezola, R; Martin, A G

    2012-03-15

    The cancer stem cell (CSC) model does not imply that tumours are generated from transformed tissue stem cells. The target of transformation could be a tissue stem cell, a progenitor cell, or a differentiated cell that acquires self-renewal ability. The observation that induced pluripotency reprogramming and cancer are related has lead to the speculation that CSCs may arise through a reprogramming-like mechanism. Expression of pluripotency genes (Oct4, Nanog and Sox2) was tested in breast tumours by immunohistochemistry and it was found that Sox2 is expressed in early stage breast tumours. However, expression of Oct4 or Nanog was not found. Mammosphere formation in culture was used to reveal stem cell properties, where expression of Sox2, but not Oct4 or Nanog, was induced. Over-expression of Sox2 increased mammosphere formation, effect dependent on continuous Sox2 expression; furthermore, Sox2 knockdown prevented mammosphere formation and delayed tumour formation in xenograft tumour initiation models. Induction of Sox2 expression was achieved through activation of the distal enhancer of Sox2 promoter upon sphere formation, the same element that controls Sox2 transcription in pluripotent stem cells. These findings suggest that reactivation of Sox2 represents an early step in breast tumour initiation, explaining tumour heterogeneity by placing the tumour-initiating event in any cell along the axis of mammary differentiation.

  18. Sox2 promotes survival of satellite glial cells in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Koike, Taro, E-mail: koiket@hirakata.kmu.ac.jp; Wakabayashi, Taketoshi; Mori, Tetsuji; Hirahara, Yukie; Yamada, Hisao

    2015-08-14

    Sox2 is a transcriptional factor expressed in neural stem cells. It is known that Sox2 regulates cell differentiation, proliferation and survival of the neural stem cells. Our previous study showed that Sox2 is expressed in all satellite glial cells of the adult rat dorsal root ganglion. In this study, to examine the role of Sox2 in satellite glial cells, we establish a satellite glial cell-enriched culture system. Our culture method succeeded in harvesting satellite glial cells with the somata of neurons in the dorsal root ganglion. Using this culture system, Sox2 was downregulated by siRNA against Sox2. The knockdown of Sox2 downregulated ErbB2 and ErbB3 mRNA at 2 and 4 days after siRNA treatment. MAPK phosphorylation, downstream of ErbB, was also inhibited by Sox2 knockdown. Because ErbB2 and ErbB3 are receptors that support the survival of glial cells in the peripheral nervous system, apoptotic cells were also counted. TUNEL-positive cells increased at 5 days after siRNA treatment. These results suggest that Sox2 promotes satellite glial cell survival through the MAPK pathway via ErbB receptors. - Highlights: • We established satellite glial cell culture system. • Function of Sox2 in satellite glial cell was examined using siRNA. • Sox2 knockdown downregulated expression level of ErbB2 and ErbB3 mRNA. • Sox2 knockdown increased apoptotic satellite glial cell. • Sox2 promotes satellite glial cell survival through ErbB signaling.

  19. Establishment and initial characterization of SOX2-overexpressing NT2/D1 cell clones.

    Science.gov (United States)

    Drakulic, D; Krstic, A; Stevanovic, M

    2012-05-15

    SOX2, a universal marker of pluripotent stem cells, is a transcription factor that helps control embryonic development in vertebrates; its expression persists in neural stem/progenitor cells into adulthood. Considering the critical role of the SOX2 transcription factor in the regulation of genes required for self-renewal and pluripotency of stem cells, we developed and characterized SOX2-overexpressing NT2/D1 cell clones. Using Southern blot and semi-quantitative RT-PCR, we confirmed integration and expression of exogenous SOX2 in three NT2/D1 cell clones. Overexpression of the SOX2 gene was detected in two of these clones. SOX2 overexpression in NT2/D1 cell clones resulted in altered expression of key pluripotency genes OCT4 and NANOG. Furthermore, SOX2-overexpressing NT2/D1 cell clones entered into retinoic acid-dependent neural differentiation, even when there was elevated SOX2 expression. After 21 days of induction by retinoic acid, expression of neural markers (neuroD1 and synaptophysin) was higher in induced cell clones than in induced parental cells. The cell clone with SOX2 overexpression had an approximately 1.3-fold higher growth rate compared to parental cells. SOX2 overexpression did not increase the population of cells undergoing apoptosis. Taken together, we developed two SOX2-overexpressing cell clones, with constitutive SOX2 expression after three weeks of retinoic acid treatment. SOX2 overexpression resulted in altered expression of pluripotency-related genes, increased proliferation, and altered expression of neural markers after three weeks of retinoic acid treatment.

  20. The Role of Sox Genes in Lung Morphogenesis and Cancer

    Directory of Open Access Journals (Sweden)

    Yongzhao Zhu

    2012-11-01

    Full Text Available The human lung consists of multiple cell types derived from early embryonic compartments. The morphogenesis of the lung, as well as the injury repair of the adult lung, is tightly controlled by a network of signaling pathways with key transcriptional factors. Lung cancer is the third most cancer-related death in the world, which may be developed due to the failure of regulating the signaling pathways. Sox (sex-determining region Y (Sry box-containing family transcriptional factors have emerged as potent modulators in embryonic development, stem cells maintenance, tissue homeostasis, and cancerogenesis in multiple processes. Recent studies demonstrated that the members of the Sox gene family played important roles in the development and maintenance of lung and development of lung cancer. In this context, we summarize our current understanding of the role of Sox family transcriptional factors in the morphogenesis of lung, their oncogenic potential in lung cancer, and their potential impact in the diagnosis, prognosis, and targeted therapy of lung cancer.

  1. Sox17 regulates liver lipid metabolism and adaptation to fasting.

    Science.gov (United States)

    Rommelaere, Samuel; Millet, Virginie; Vu Manh, Thien-Phong; Gensollen, Thomas; Andreoletti, Pierre; Cherkaoui-Malki, Mustapha; Bourges, Christophe; Escalière, Bertrand; Du, Xin; Xia, Yu; Imbert, Jean; Beutler, Bruce; Kanai, Yoshiakira; Malissen, Bernard; Malissen, Marie; Tailleux, Anne; Staels, Bart; Galland, Franck; Naquet, Philippe

    2014-01-01

    Liver is a major regulator of lipid metabolism and adaptation to fasting, a process involving PPARalpha activation. We recently showed that the Vnn1 gene is a PPARalpha target gene in liver and that release of the Vanin-1 pantetheinase in serum is a biomarker of PPARalpha activation. Here we set up a screen to identify new regulators of adaptation to fasting using the serum Vanin-1 as a marker of PPARalpha activation. Mutagenized mice were screened for low serum Vanin-1 expression. Functional interactions with PPARalpha were investigated by combining transcriptomic, biochemical and metabolic approaches. We characterized a new mutant mouse in which hepatic and serum expression of Vanin-1 is depressed. This mouse carries a mutation in the HMG domain of the Sox17 transcription factor. Mutant mice display a metabolic phenotype featuring lipid abnormalities and inefficient adaptation to fasting. Upon fasting, a fraction of the PPARα-driven transcriptional program is no longer induced and associated with impaired fatty acid oxidation. The transcriptional phenotype is partially observed in heterozygous Sox17+/- mice. In mutant mice, the fasting phenotype but not all transcriptomic signature is rescued by the administration of the PPARalpha agonist fenofibrate. These results identify a novel role for Sox17 in adult liver as a modulator of the metabolic adaptation to fasting.

  2. Sox17 regulates liver lipid metabolism and adaptation to fasting.

    Directory of Open Access Journals (Sweden)

    Samuel Rommelaere

    Full Text Available Liver is a major regulator of lipid metabolism and adaptation to fasting, a process involving PPARalpha activation. We recently showed that the Vnn1 gene is a PPARalpha target gene in liver and that release of the Vanin-1 pantetheinase in serum is a biomarker of PPARalpha activation. Here we set up a screen to identify new regulators of adaptation to fasting using the serum Vanin-1 as a marker of PPARalpha activation. Mutagenized mice were screened for low serum Vanin-1 expression. Functional interactions with PPARalpha were investigated by combining transcriptomic, biochemical and metabolic approaches. We characterized a new mutant mouse in which hepatic and serum expression of Vanin-1 is depressed. This mouse carries a mutation in the HMG domain of the Sox17 transcription factor. Mutant mice display a metabolic phenotype featuring lipid abnormalities and inefficient adaptation to fasting. Upon fasting, a fraction of the PPARα-driven transcriptional program is no longer induced and associated with impaired fatty acid oxidation. The transcriptional phenotype is partially observed in heterozygous Sox17+/- mice. In mutant mice, the fasting phenotype but not all transcriptomic signature is rescued by the administration of the PPARalpha agonist fenofibrate. These results identify a novel role for Sox17 in adult liver as a modulator of the metabolic adaptation to fasting.

  3. Differential expression of ID4 and its association with TP53 mutation, SOX2, SOX4 and OCT-4 expression levels.

    Directory of Open Access Journals (Sweden)

    Thais Fernanda de Almeida Galatro

    Full Text Available Inhibitor of DNA Binding 4 (ID4 is a member of the helix-loop-helix ID family of transcription factors, mostly present in the central nervous system during embryonic development, that has been associated with TP53 mutation and activation of SOX2. Along with other transcription factors, ID4 has been implicated in the tumorigenic process of astrocytomas, contributing to cell dedifferentiation, proliferation and chemoresistance. In this study, we aimed to characterize the ID4 expression pattern in human diffusely infiltrative astrocytomas of World Health Organization (WHO grades II to IV of malignancy (AGII-AGIV; to correlate its expression level to that of SOX2, SOX4, OCT-4 and NANOG, along with TP53 mutational status; and to correlate the results with the clinical end-point of overall survival among glioblastoma patients. Quantitative real time PCR (qRT-PCR was performed in 130 samples of astrocytomas for relative expression, showing up-regulation of all transcription factors in tumor cases. Positive correlation was found when comparing ID4 relative expression of infiltrative astrocytomas with SOX2 (r = 0.50; p<0.005, SOX4 (r = 0.43; p<0.005 and OCT-4 (r = 0.39; p<0.05. The results from TP53 coding exon analysis allowed comparisons between wild-type and mutated status only in AGII cases, demonstrating significantly higher levels of ID4, SOX2 and SOX4 in mutated cases (p<0.05. This pattern was maintained in secondary GBM and further confirmed by immunohistochemistry, suggesting a role for ID4, SOX2 and SOX4 in early astrocytoma tumorigenesis. Combined hyperexpression of ID4, SOX4 and OCT-4 conferred a much lower (6 months median survival than did hypoexpression (18 months. Because both ID4 alone and a complex of SOX4 and OCT-4 activate SOX2 transcription, it is possible that multiple activation of SOX2 impair the prognosis of GBM patients. These observational results of associated expression of ID4 with SOX4 and OCT-4 may be used as a

  4. Preparation of Polyclonal Anti-Sox2 Antibody in Capra hircus%山羊SOX2多克隆抗体制备

    Institute of Scientific and Technical Information of China (English)

    刘平; 张明; 张昀; 郑喜邦; 李恭贺; 岑小妹; 岳磊磊; 宗自杰; 卢晟盛; 卢克焕

    2012-01-01

    [Objective] The present study was to construct a prokaryotic expression vector of Capra hircus Sox2 gene, pRSET-Sox2, to induce expression and purification of His-Sox2 fusion protein, which was used to immunize New Zeland white rabbits to prepare polyclonal anti-Sox2 antibody. [Method] Removed from plasmid pMD18-Sox2 by double digestion of BamH I and Xho I, Sox2 fragment was subcloned to pRSET-A vector to construct recombinant plasmid pRSET-Sox2. The plasmid was transformed into E. coli BL 21 (DE3), and His-Sox2 fusion protein was induced to expess with 1 mrnol·L-1 IPTG at 37℃ for 4 h, which was identified with SDS-PAGE analysis and Western blotting. In the same way, large volume of expressing culture was prepared to purify His-Sox2 fusion protein with NI-NTA argrose under denaturing condition. The refolded fusion protein in vitro was injected subcutaneously into New Zeland white rabbits for four times at intervals of 2-3 weeks. Seven days after the last injection, blood samples were collected, serum was isolated, and specificity of polyclonal anti-Sox2 antibody was determined by Western blotting assay. [Result] The prokaryotic expression vector pRSET-Sox2 was expressed efficiently in E. coli. BL21. The purified His-Sox2 was qualified for preparation of polyclonal antibody. The polyclonal anti-Sox2 antibody was prepared, and it could bind His-Sox2 fusion protein specifically, which was illustrated by Western blotting assay. [Conclusion] The polyclonal anti-Sox2 antibody with strong specificity was prepared, which will lay a solid biological foundation for study of Sox2, and for its application in detection of Capra hircus iPS cells (induced pluripotent stem cells).%[目的]构建山羊Sox2原核表达载体—pRSET-Sox2,并将诱导表达、纯化的His-Sox2融合蛋白免疫新西兰大白兔,制备Sox2多克隆抗体.[方法]从pMD18T-Sox2载体上以BamHI和XhoI双酶切截取Sox2 片段,然后将其亚克隆到pRSET-A表达载体上,获得pRSET-Sox2重组质粒.转化了pRSET-Sox

  5. Mechanism of thiosulfate oxidation in the SoxA family of cysteine-ligated cytochromes.

    Science.gov (United States)

    Grabarczyk, Daniel B; Chappell, Paul E; Eisel, Bianca; Johnson, Steven; Lea, Susan M; Berks, Ben C

    2015-04-03

    Thiosulfate dehydrogenase (TsdA) catalyzes the oxidation of two thiosulfate molecules to form tetrathionate and is predicted to use an unusual cysteine-ligated heme as the catalytic cofactor. We have determined the structure of Allochromatium vinosum TsdA to a resolution of 1.3 Å. This structure confirms the active site heme ligation, identifies a thiosulfate binding site within the active site cavity, and reveals an electron transfer route from the catalytic heme, through a second heme group to the external electron acceptor. We provide multiple lines of evidence that the catalytic reaction proceeds through the intermediate formation of a S-thiosulfonate derivative of the heme cysteine ligand: the cysteine is reactive and is accessible to electrophilic attack; cysteine S-thiosulfonate is formed by the addition of thiosulfate or following the reverse reaction with tetrathionate; the S-thiosulfonate modification is removed through catalysis; and alkylating the cysteine blocks activity. Active site amino acid residues required for catalysis were identified by mutagenesis and are inferred to also play a role in stabilizing the S-thiosulfonate intermediate. The enzyme SoxAX, which catalyzes the first step in the bacterial Sox thiosulfate oxidation pathway, is homologous to TsdA and can be inferred to use a related catalytic mechanism. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  6. Activated WNT signaling in postnatal SOX2-positive dental stem cells can drive odontoma formation.

    Science.gov (United States)

    Xavier, Guilherme M; Patist, Amanda L; Healy, Chris; Pagrut, Ankita; Carreno, Gabriela; Sharpe, Paul T; Martinez-Barbera, Juan Pedro; Thavaraj, Selvam; Cobourne, Martyn T; Andoniadou, Cynthia L

    2015-09-28

    In common with most mammals, humans form only two dentitions during their lifetime. Occasionally, supernumerary teeth develop in addition to the normal complement. Odontoma represent a small group of malformations containing calcified dental tissues of both epithelial and mesenchymal origin, with varying levels of organization, including tooth-like structures. The specific cell type responsible for the induction of odontoma, which retains the capacity to re-initiate de novo tooth development in postnatal tissues, is not known. Here we demonstrate that aberrant activation of WNT signaling by expression of a non-degradable form of β-catenin specifically in SOX2-positive postnatal dental epithelial stem cells is sufficient to generate odontoma containing multiple tooth-like structures complete with all dental tissue layers. Genetic lineage-tracing confirms that odontoma form in a similar manner to normal teeth, derived from both the mutation-sustaining epithelial stem cells and adjacent mesenchymal tissues. Activation of the WNT pathway in embryonic SOX2-positive progenitors results in ectopic expression of secreted signals that promote odontogenesis throughout the oral cavity. Significantly, the inductive potential of epithelial dental stem cells is retained in postnatal tissues, and up-regulation of WNT signaling specifically in these cells is sufficient to promote generation and growth of ectopic malformations faithfully resembling human odontoma.

  7. Evaluation of SOX2 as a potential marker for ameloblastic carcinoma.

    Science.gov (United States)

    Lei, Yu; Jaradat, Jumana M; Owosho, Adepitan; Adebiyi, Kehinde E; Lybrand, Kelley S; Neville, Brad W; Müller, Susan; Bilodeau, Elizabeth A

    2014-05-01

    Ameloblastic carcinoma often poses diagnostic challenges in its separation from benign ameloblastoma with atypical cytologic features or an unusual clinical course. This study aimed to determine whether SOX2 (sex determining region-Y-related high mobility group box 2), a protein expressed in the epithelial basal proliferative zone in dentigerous cysts, is a marker for ameloblastic carcinoma as well as for high-grade transformation in ameloblastic neoplasms. Immunoperoxidase stains were performed according to a standard protocol. Immunostains were interpreted independently by 3 pathologists, and scores were recorded based on the percentage of staining and intensity of staining in the cells of interest. The diffuse strong nuclear staining pattern has 86.4% specificity (19 of 22) to indicate the presence of high-grade features and has 76.9% sensitivity (10 of 13) in comparison with benign counterparts (P = .0021). Although previously shown as a marker for ameloblastic neoplasms, calretinin is weakly positive in a few cells in 50% (5 of 10) of ameloblastic carcinoma and 43% (3 of 7) of benign ameloblastic neoplasms, with little value in highlighting the high-grade change (P = .36). The diffuse nuclear staining pattern of SOX2 is suggestive of a high-grade process in ameloblastic neoplasms. Numerous aggregates of cells harboring dense nuclear stain should raise concern for a malignancy. Copyright © 2014 Elsevier Inc. All rights reserved.

  8. Activated WNT signaling in postnatal SOX2-positive dental stem cells can drive odontoma formation

    Science.gov (United States)

    Xavier, Guilherme M.; Patist, Amanda L.; Healy, Chris; Pagrut, Ankita; Carreno, Gabriela; Sharpe, Paul T.; Pedro Martinez-Barbera, Juan; Thavaraj, Selvam; Cobourne, Martyn T.; Andoniadou, Cynthia L.

    2015-01-01

    In common with most mammals, humans form only two dentitions during their lifetime. Occasionally, supernumerary teeth develop in addition to the normal complement. Odontoma represent a small group of malformations containing calcified dental tissues of both epithelial and mesenchymal origin, with varying levels of organization, including tooth-like structures. The specific cell type responsible for the induction of odontoma, which retains the capacity to re-initiate de novo tooth development in postnatal tissues, is not known. Here we demonstrate that aberrant activation of WNT signaling by expression of a non-degradable form of β-catenin specifically in SOX2-positive postnatal dental epithelial stem cells is sufficient to generate odontoma containing multiple tooth-like structures complete with all dental tissue layers. Genetic lineage-tracing confirms that odontoma form in a similar manner to normal teeth, derived from both the mutation-sustaining epithelial stem cells and adjacent mesenchymal tissues. Activation of the WNT pathway in embryonic SOX2-positive progenitors results in ectopic expression of secreted signals that promote odontogenesis throughout the oral cavity. Significantly, the inductive potential of epithelial dental stem cells is retained in postnatal tissues, and up-regulation of WNT signaling specifically in these cells is sufficient to promote generation and growth of ectopic malformations faithfully resembling human odontoma. PMID:26411543

  9. The beta-catenin/VegT-regulated early zygotic gene Xnr5 is a direct target of SOX3 regulation.

    Science.gov (United States)

    Zhang, Chi; Basta, Tamara; Jensen, Eric D; Klymkowsky, M W

    2003-12-01

    In Xenopus laevis, beta-catenin-mediated dorsal axis formation can be suppressed by overexpression of the HMG-box transcription factor XSOX3. Mutational analysis indicates that this effect is due not to the binding of XSOX3 to beta-catenin nor to its competition with beta-catenin-regulated TCF-type transcription factors for specific DNA binding sites, but rather to SOX3 binding to sites within the promoter of the early VegT- and beta-catenin-regulated dorsal-mesoderm-inducing gene Xnr5. Although B1-type SOX proteins, such as XSOX3, are commonly thought to act as transcriptional activators, XSOX3 acts as a transcriptional repressor of Xnr5 in both the intact embryo and animal caps injected with VegT RNA. Expression of a chimeric polypeptide composed of XSOX3 and a VP16 transcriptional activation domain or morpholino-induced decrease in endogenous XSOX3 polypeptide levels lead to an increase in Xnr5 expression, as does injection of an anti-XSOX3 antibody that inhibits XSOX3 DNA binding. These observations indicate that maternal XSOX3 acts in a novel manner to restrict Xnr5 expression to the vegetal hemisphere.

  10. Expression Detection of DMRTs and Two sox9 Genes in Takifugu rubripes (Tetraodontidae,Vertebrata)

    Institute of Scientific and Technical Information of China (English)

    SHEN Xueyan; CUI Jianzhou; YANG Guanpin; GONG Qingli; GU Qianqun

    2007-01-01

    Sex determination and sex differentiation are important phenomena in fish, but the mechanisms of sex determination in Takifugu rubripes are poorly understood. In our study, the expression patterns of genes for DMRTs (DMRT1, DMRT2 and DMRT3),sox9a and sox9b in T. rubripes tissues were verified with the Reverse Transcription (RT)-PCR detection. It is showed that DMRT1 expressions in testis and ovaries were much lower, and no expressions were fotmd in muscle, blood and tailfin. However, expressions for DMRT2 and DMRT3 were not found in the tissues stated above. Transcripts of sox9a were detected in muscle, fin, ovary and testis, but not in blood, whereas sox9b expression was only detected in ovary. The expression patterns of DMRTs, sox9a and sox9b in T. rubripes gonads suggest that these genes may not be sex-specific.

  11. Quiescent Sox2+ Cells Drive Hierarchical Growth and Relapse in Sonic Hedgehog Subgroup Medulloblastoma

    Science.gov (United States)

    Vanner, Robert J.; Remke, Marc; Gallo, Marco; Selvadurai, Hayden J.; Coutinho, Fiona; Lee, Lilian; Kushida, Michelle; Head, Renee; Morrissy, Sorana; Zhu, Xueming; Aviv, Tzvi; Voisin, Veronique; Clarke, Ian D.; Li, Yisu; Mungall, Andrew J.; Moore, Richard A.; Ma, Yussanne; Jones, Steven J.M.; Marra, Marco A.; Malkin, David; Northcott, Paul A.; Kool, Marcel; Pfister, Stefan M.; Bader, Gary; Hochedlinger, Konrad; Korshunov, Andrey; Taylor, Michael D.; Dirks, Peter B.

    2015-01-01

    SUMMARY Functional heterogeneity within tumors presents a significant therapeutic challenge. Here we show that quiescent, therapy-resistant Sox2+ cells propagate sonic hedgehog subgroup medulloblastoma by a mechanism that mirrors a neurogenic program. Rare Sox2+ cells produce rapidly cycling doublecortin+ progenitors that, together with their postmitotic progeny expressing NeuN, comprise tumor bulk. Sox2+ cells are enriched following anti-mitotic chemotherapy and Smoothened inhibition, creating a reservoir for tumor regrowth. Lineage traces from Sox2+ cells increase following treatment, suggesting that this population is responsible for relapse. Targeting Sox2+ cells with the antineoplastic mithramycin abrogated tumor growth. Addressing functional heterogeneity and eliminating Sox2+ cells presents a promising therapeutic paradigm for treatment of sonic hedgehog subgroup medulloblastoma. PMID:24954133

  12. Clinical and molecular characterization of a Brazilian cohort of campomelic dysplasia patients, and identification of seven new SOX9 mutations

    Directory of Open Access Journals (Sweden)

    Eduardo P. Mattos

    2015-03-01

    Full Text Available Campomelic dysplasia (CD is an autosomal, dominantly inherited, skeletal abnormality belonging to the subgroup of bent bone dysplasias. In addition to bowed lower limbs, CD typically includes the following: disproportionate short stature, flat face, micrognathia, cleft palate, bell-shaped thorax, and club feet. Up to three quarters of 46, XY individuals may be sex-reversed. Radiological signs include scapular and pubic hypoplasia, narrow iliac wings, spaced ischia, and bowed femora and tibiae. Lethal CD is usually due to heterozygous mutations in SOX9, a major regulator of chondrocytic development. We present a detailed clinical and molecular characterization of nine Brazilian CD patients. Infants were either stillborn (n = 2 or died shortly after birth and presented similar phenotypes. Sex-reversal was observed in one of three chromosomally male patients. Sequencing of SOX9 revealed new heterozygous mutations in seven individuals. Six patients had mutations that resulted in premature transcriptional termination, while one infant had a single-nucleotide substitution at the conserved splice-site acceptor of intron 1. No clear genotype-phenotype correlations were observed. This study highlights the diversity of SOX9 mutations leading to lethal CD, and expands the group of known genetic alterations associated with this skeletal dysplasia.

  13. Induction and selection of Sox17-expressing endoderm cells generated from murine embryonic stem cells.

    Science.gov (United States)

    Schroeder, Insa S; Sulzbacher, Sabine; Nolden, Tobias; Fuchs, Joerg; Czarnota, Judith; Meisterfeld, Ronny; Himmelbauer, Heinz; Wobus, Anna M

    2012-01-01

    Embryonic stem (ES) cells offer a valuable source for generating insulin-producing cells. However, current differentiation protocols often result in heterogeneous cell populations of various developmental stages. Here we show the activin A-induced differentiation of mouse ES cells carrying a homologous dsRed-IRES-puromycin knock-in within the Sox17 locus into the endoderm lineage. Sox17-expressing cells were selected by fluorescence-assisted cell sorting (FACS) and characterized at the transcript and protein level. Treatment of ES cells with high concentrations of activin A for 10 days resulted in up to 19% Sox17-positive cells selected by FACS. Isolated Sox17-positive cells were characterized by defini- tive endoderm-specific Sox17/Cxcr4/Foxa2 transcripts, but lacked pluripotency-associated Oct4 mRNA and protein. The Sox17-expressing cells showed downregulation of extraembryonic endoderm (Sox7, Afp, Sdf1)-, mesoderm (Foxf1, Meox1)- and ectoderm (Pax6, NeuroD6)-specific transcripts. The presence of Hnf4α, Hes1 and Pdx1 mRNA demonstrated the expression of primitive gut/foregut cell-specific markers. Ngn3, Nkx6.1 and Nkx2.2 transcripts in Sox17-positive cells were determined as properties of pancreatic endocrine progenitors. Immunocytochemistry of activin A-induced Sox17-positive embryoid bodies revealed coexpression of Cxcr4 and Foxa2. Moreover, the histochemical demonstration of E-cadherin-, Cxcr4-, Sox9-, Hnf1β- and Ngn3-positive epithelial-like structures underlined the potential of Sox17-positive cells to further differentiate into the pancreatic lineage. By reducing the heterogeneity of the ES cell progeny, Sox17-expressing cells are a suitable model to evaluate the effects of growth and differentiation factors and of culture conditions to delineate the differentiation process for the generation of pancreatic cells in vitro.

  14. Study on Mg/Fe Mixed Oxides Derived from Hydrotalite as De—SOx Catalyst

    Institute of Scientific and Technical Information of China (English)

    GuangLanZHUO; YinFeiCHEN; 等

    2002-01-01

    A novel class of desulfurization agent derived from hydrotalcite has been developed and its activity for SOx uptake have been investigated. The results showed that the Mg/Fe mixed oxide having high SOx uptake ability at a broad reaction temperature (e.g.673K-973K). The Mg/Fe ratio of the mixed oxide strongly affect the desulfurization role of the material and it can be used repeatly without much loss of SOx uptake ability.

  15. Study on Mg/Fe Mixed Oxides Derived from Hydrotalcite as De-SOx Catalyst

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    A novel class of desulfurization agent derived from hydrotalcite has been developed and its activity for Sox uptake have been investigated. The results showed that the Mg/Fe mixed oxide having high Sox uptake ability at a broad reaction temperature (e.g. 673K ~ 973K). The Mg/Fe ratio of the mixed oxide strongly affect the desulfurization role of the material and it can be used repeatly without much loss of Sox uptake ability.

  16. SOX2 overexpression affects neural differentiation of human pluripotent NT2/D1 cells.

    Science.gov (United States)

    Klajn, A; Drakulic, D; Tosic, M; Pavkovic, Z; Schwirtlich, M; Stevanovic, M

    2014-11-01

    SOX2 is one of the key transcription factors involved in maintenance of neural progenitor identity. However, its function during the process of neural differentiation, including phases of lineage-specification and terminal differentiation, is still poorly understood. Considering growing evidence indicating that SOX2 expression level must be tightly controlled for proper neural development, the aim of this research was to analyze the effects of constitutive SOX2 overexpression on outcome of retinoic acid-induced neural differentiation of pluripotent NT2/D1 cells. We demonstrated that in spite of constitutive SOX2 overexpression, NT2/D1 cells were able to reach final phases of neural differentiation yielding both neuronal and glial cells. However, SOX2 overexpression reduced the number of mature MAP2-positive neurons while no difference in the number of GFAP-positive astrocytes was detected. In-depth analysis at single-cell level showed that SOX2 downregulation was in correlation with both neuronal and glial phenotype acquisitions. Interestingly, while in mature neurons SOX2 was completely downregulated, astrocytes with low level of SOX2 expression were detected. Nevertheless, cells with high level of SOX2 expression were incapable of entering in either of two differentiation pathways, neurogenesis or gliogenesis. Accordingly, our results indicate that fine balance between undifferentiated state and neural differentiation depends on SOX2 expression level. Unlike neurons, astrocytes could maintain low level of SOX2 expression after they acquired glial fate. Further studies are needed to determine whether differences in the level of SOX2 expression in GFAP-positive astrocytes are in correlation with their self-renewal capacity, differentiation status, and/or their phenotypic characteristics.

  17. [Enhanced chemosensitivity of Hep-2 through down-regulating expression of SOX2 by RNAi].

    Science.gov (United States)

    Yang, Ning; Hui, Lian; Yang, Huijun; Jiang, Xuejun

    2014-08-01

    To investigate the effect of SOX2 on chemotherapy sensitivity of human laryngeal epithelial cells Hep-2. We designed and synthesized RNAis for silencing the expression of SOX2 in Hep-2 cells and selected the most effective RNAi by Western blot analysis. Then the recombinant plasmids of pGCsi-H1-SOX2 and pGCsi-H1-NC were constructed and transfected into Hep-2 cells to build cell lines of psiSOX2-Hep-2 and psiNC-Hep-2. CCK-8 assay had been used to test the sensitivity of Hep-2 cells to 5-FU and PTX after silencing SOX2 expression. Hoechst staining had been used to exam the changes of Hep-2 cells apoptosis treatment by 5-FU and PTX after silencing SOX2 expression. Furthermore, the changes of apoptosis-related genes expressions were detected by Western blotting. The cell lines of psiSOX2-Hep-2 and psiNC-Hep-2 were successfully established, and the expression of SOX2 protein was decreased 78% in psiSOX2-Hep-2 cells compared with psiNC-Hep-2 cells. After reducing SOX2 expression, the sensitivity of Hep-2 cells to 5-FU and PTX were increased and the IC50 values for 48 h were decreased to 8.12 μg/ml and 5.16 μg/ml. Meanwhile, the apoptosis rate and the expression of apoptotic gene Bax and cleaved caspase-3 expression were dramatically increased and anti-apoptotic genes survivin and Bcl-2 were significantly decreased in psiSOX2-Hep-2 cells compared with psiNC-Hep-2 cells. Down-regulating the protein expression of SOX2 by RNAi will significantly enhance the sensitivity of human laryngeal epithelial cells Hep-2 to 5-FU and PTX.

  18. SOX2 functions as a molecular rheostat to control the growth, tumorigenicity and drug responses of pancreatic ductal adenocarcinoma cells

    Science.gov (United States)

    Wuebben, Erin L.; Wilder, Phillip J.; Cox, Jesse L.; Grunkemeyer, James A.; Caffrey, Thomas; Hollingsworth, Michael A.; Rizzino, Angie

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is a highly deadly malignancy. Expression of the stem cell transcription factor SOX2 increases during progression of PDAC. Knockdown of SOX2 in PDAC cell lines decreases growth in vitro; whereas, stable overexpression of SOX2 in one PDAC cell line reportedly increases growth in vitro. Here, we reexamined the role of SOX2 in PDAC cells, because inducible SOX2 overexpression in other tumor cell types inhibits growth. In this study, four PDAC cell lines were engineered for inducible overexpression of SOX2 or inducible knockdown of SOX2. Remarkably, inducible overexpression of SOX2 in PDAC cells inhibits growth in vitro and reduces tumorigenicity. Additionally, inducible knockdown of SOX2 in PDAC cells reduces growth in vitro and in vivo. Thus, growth and tumorigenicity of PDAC cells is highly dependent on the expression of optimal levels of SOX2 – a hallmark of molecular rheostats. We also determined that SOX2 alters the responses of PDAC cells to drugs used in PDAC clinical trials. Increasing SOX2 reduces growth inhibition mediated by MEK and AKT inhibitors; whereas knockdown of SOX2 further reduces growth when PDAC cells are treated with these inhibitors. Thus, targeting SOX2, or its mode of action, could improve the treatment of PDAC. PMID:27145457

  19. Data Acquisition, Control, Communication and Computation System of Solar X-ray Spectrometer (SOXS) Mission

    Indian Academy of Sciences (India)

    Amish B. Shah; N. M. Vadher; Rajmal Jain; Hemant Dave; Vishal Shah; K. S. B. Manian; Satish Kayasth; Vinod Patel; Girish Ubale; Kirit Shah; Chirag Solanki; M. R. Deshpande; Ramkrishna Sharma; C. N. Umapathy; N. Viswanath; Ravi Kulkarni; P. S. Kumar

    2006-06-01

    The Solar X-ray Spectrometer (SOXS) mission onboard GSAT-2 Indian Spacecraft was launched on 08 May 2003 using GSLV–D2 rocket by Indian Space Research Organization (ISRO). SOXS aims to study solar flares, which are the most violent and energetic phenomena in the solar system, in the energy range of 4–56 keV with high spectral and temporal resolution. SOXS employs state-of-the-art semiconductor devices, viz., Si-Pin and CZT detectors to achieve sub-keV energy resolution requirements. In this paper, we present an overview of data acquisition, control, communication and computation of low energy payload of the SOXS mission.

  20. SOX10 transactivates S100B to suppress Schwann cell proliferation and to promote myelination.

    Directory of Open Access Journals (Sweden)

    Sayaka Fujiwara

    Full Text Available Schwann cells are an important cell source for regenerative therapy for neural disorders. We investigated the role of the transcription factor sex determining region Y (SRY-box 10 (SOX10 in the proliferation and myelination of Schwann cells. SOX10 is predominantly expressed in rat sciatic nerve-derived Schwann cells and is induced shortly after birth. Among transcription factors known to be important for the differentiation of Schwann cells, SOX10 potently transactivates the S100B promoter. In cultures of Schwann cells, overexpressing SOX10 dramatically induces S100B expression, while knocking down SOX10 with shRNA suppresses S100B expression. Here, we identify three core response elements of SOX10 in the S100B promoter and intron 1 with a putative SOX motif. Knockdown of either SOX10 or S100B enhances the proliferation of Schwann cells. In addition, using dissociated cultures of dorsal root ganglia, we demonstrate that suppressing S100B with shRNA impairs myelination of Schwann cells. These results suggest that the SOX10-S100B signaling axis critically regulates Schwann cell proliferation and myelination, and therefore is a putative therapeutic target for neuronal disorders.

  1. High levels of SOX5 decrease proliferative capacity of human B cells, but permit plasmablast differentiation.

    Directory of Open Access Journals (Sweden)

    Mirzokhid Rakhmanov

    Full Text Available Currently very little is known about the differential expression and function of the transcription factor SOX5 during B cell maturation. We identified two new splice variants of SOX5 in human B cells, encoding the known L-SOX5B isoform and a new shorter isoform L-SOX5F. The SOX5 transcripts are highly expressed during late stages of B-cell differentiation, including atypical memory B cells, activated CD21low B cells and germinal center B cells of tonsils. In tonsillar sections SOX5 expression was predominantly polarized to centrocytes within the light zone. After in vitro stimulation, SOX5 expression was down-regulated during proliferation while high expression levels were permissible for plasmablast differentiation. Overexpression of L-SOX5F in human primary B lymphocytes resulted in reduced proliferation, less survival of CD138neg B cells, but comparable numbers of CD138+CD38hi plasmablasts compared to control cells. Thus, our findings describe for the first time a functional role of SOX5 during late B cell development reducing the proliferative capacity and thus potentially affecting the differentiation of B cells during the germinal center response.

  2. Transcriptional regulation of Sox2 by the retinoblastoma family of pocket proteins.

    Science.gov (United States)

    Vilas, Jéssica M; Ferreirós, Alba; Carneiro, Carmen; Morey, Lluis; Da Silva-Álvarez, Sabela; Fernandes, Tânia; Abad, María; Di Croce, Luciano; García-Caballero, Tomás; Serrano, Manuel; Rivas, Carmen; Vidal, Anxo; Collado, Manuel

    2015-02-20

    Cellular reprogramming to iPSCs has uncovered unsuspected links between tumor suppressors and pluripotency factors. Using this system, it was possible to identify tumor suppressor p27 as a repressor of Sox2 during differentiation. This led to the demonstration that defects in the repression of Sox2 can contribute to tumor development. The members of the retinoblastoma family of pocket proteins, pRb, p107 and p130, are negative regulators of the cell cycle with tumor suppressor activity and with roles in differentiation. In this work we studied the relative contribution of the retinoblastoma family members to the regulation of Sox2 expression. We found that deletion of Rb or p130 leads to impaired repression of Sox2, a deffect amplified by inactivation of p53. We also identified binding of pRb and p130 to an enhancer with crucial regulatory activity on Sox2 expression. Using cellular reprogramming we tested the impact of the defective repression of Sox2 and confirmed that Rb deficiency allows the generation of iPSCs in the absence of exogenous Sox2. Finally, partial depletion of Sox2 positive cells reduced the pituitary tumor development initiated by Rb loss in vivo. In summary, our results show that Sox2 repression by pRb is a relevant mechanism of tumor suppression.

  3. Stringent comparative sequence analysis reveals SOX10 as a putative inhibitor of glial cell differentiation.

    Science.gov (United States)

    Gopinath, Chetna; Law, William D; Rodríguez-Molina, José F; Prasad, Arjun B; Song, Lingyun; Crawford, Gregory E; Mullikin, James C; Svaren, John; Antonellis, Anthony

    2016-11-07

    The transcription factor SOX10 is essential for all stages of Schwann cell development including myelination. SOX10 cooperates with other transcription factors to activate the expression of key myelin genes in Schwann cells and is therefore a context-dependent, pro-myelination transcription factor. As such, the identification of genes regulated by SOX10 will provide insight into Schwann cell biology and related diseases. While genome-wide studies have successfully revealed SOX10 target genes, these efforts mainly focused on myelinating stages of Schwann cell development. We propose that less-biased approaches will reveal novel functions of SOX10 outside of myelination. We developed a stringent, computational-based screen for genome-wide identification of SOX10 response elements. Experimental validation of a pilot set of predicted binding sites in multiple systems revealed that SOX10 directly regulates a previously unreported alternative promoter at SOX6, which encodes a transcription factor that inhibits glial cell differentiation. We further explored the utility of our computational approach by combining it with DNase-seq analysis in cultured Schwann cells and previously published SOX10 ChIP-seq data from rat sciatic nerve. Remarkably, this analysis enriched for genomic segments that map to loci involved in the negative regulation of gliogenesis including SOX5, SOX6, NOTCH1, HMGA2, HES1, MYCN, ID4, and ID2. Functional studies in Schwann cells revealed that: (1) all eight loci are expressed prior to myelination and down-regulated subsequent to myelination; (2) seven of the eight loci harbor validated SOX10 binding sites; and (3) seven of the eight loci are down-regulated upon repressing SOX10 function. Our computational strategy revealed a putative novel function for SOX10 in Schwann cells, which suggests a model where SOX10 activates the expression of genes that inhibit myelination during non-myelinating stages of Schwann cell development. Importantly, the

  4. Transcriptional regulation of Sox2 by the retinoblastoma family of pocket proteins

    Science.gov (United States)

    Carneiro, Carmen; Morey, Lluis; Silva-Álvarez, Sabela Da; Fernandes, Tânia; Abad, María; Croce, Luciano Di; García-Caballero, Tomás; Serrano, Manuel; Rivas, Carmen; Vidal, Anxo; Collado, Manuel

    2015-01-01

    Cellular reprogramming to iPSCs has uncovered unsuspected links between tumor suppressors and pluripotency factors. Using this system, it was possible to identify tumor suppressor p27 as a repressor of Sox2 during differentiation. This led to the demonstration that defects in the repression of Sox2 can contribute to tumor development. The members of the retinoblastoma family of pocket proteins, pRb, p107 and p130, are negative regulators of the cell cycle with tumor suppressor activity and with roles in differentiation. In this work we studied the relative contribution of the retinoblastoma family members to the regulation of Sox2 expression. We found that deletion of Rb or p130 leads to impaired repression of Sox2, a deffect amplified by inactivation of p53. We also identified binding of pRb and p130 to an enhancer with crucial regulatory activity on Sox2 expression. Using cellular reprogramming we tested the impact of the defective repression of Sox2 and confirmed that Rb deficiency allows the generation of iPSCs in the absence of exogenous Sox2. Finally, partial depletion of Sox2 positive cells reduced the pituitary tumor development initiated by Rb loss in vivo. In summary, our results show that Sox2 repression by pRb is a relevant mechanism of tumor suppression. PMID:25576924

  5. LncSox4 promotes the self-renewal of liver tumour-initiating cells through Stat3-mediated Sox4 expression

    Science.gov (United States)

    Chen, Zhen-zhen; Huang, Lan; Wu, Ya-hong; Zhai, Wen-jie; Zhu, Ping-ping; Gao, Yan-feng

    2016-01-01

    Liver cancer has a tendency to develop asymptomatically in patients, so most patients are diagnosed at a later stage. Accumulating evidence implicates that liver tumour-initiating cells (TICs) as being responsible for liver cancer initiation and recurrence. However, the molecular mechanism of liver TIC self-renewal is poorly understood. Here we discover that a long noncoding RNA (lncRNA) termed LncSox4 is highly expressed in hepatocellular carcinoma (HCC) tissues and in liver TICs. We find that LncSox4 is required for liver TIC self-renewal and tumour initiation. LncSox4 interacts with and recruits Stat3 to the Sox4 promoter to initiate the expression of Sox4, which is highly expressed in liver TICs and required for liver TIC self-renewal. The expression level of Sox4 correlates with HCC development, clinical severity and prognosis of patients. Altogether, we find that LncSox4 is highly expressed in liver TICs and is required for their self-renewal. PMID:27553854

  6. 高迁移率族蛋白B1与急性胰腺炎肠黏膜屏障损伤关系的研究%Study on the Relationship between High Mobility Group Box 1 and Intestinal Mucosal Barrier Injury in Acute Pancreatitis

    Institute of Scientific and Technical Information of China (English)

    张伟杰; 徐桂芳; 田志强; 吴国忠; 邹晓平

    2012-01-01

    背景:急性胰腺炎(AP)是临床常见的急腹症,肠黏膜屏障损伤引起继发感染是AP患者死亡的主要原因之一.近年动物模型研究发现高迁移率族蛋白B1(HMGB1)在AP肠黏膜屏障损伤中发挥重要作用.目的:研究HMGB1与AP患者肠黏膜屏障损伤的关系.方法:纳入2007年12月~2009年3月南京大学医学院附属鼓楼医院和中国人民解放军第101医院收治、确诊的AP患者80例,其中重症急性胰腺炎(SAP) 38例,轻症急性胰腺炎(MAP) 42例,选取30名同期健康体检者作为正常对照组.检测患者血清HMGB1含量,分析其与AP病情严重程度、血清内毒素含量、二胺氧化酶(DAO)含量、尿液乳果糖/甘露醇(L/M)比值的关系.结果:SAP组和MAP组血清HMGB1含量、内毒素含量、DAO含量和尿液L/M比值与对照组相比显著升高(P<0.05).患者血清HMGB1含量与血清内毒素含量、DAO含量、尿液L/M比值以及Ranson评分、24 h APACHEⅡ评分、Balthazar CT评分均呈正相关(P<0.001).结论:血清HMGB1含量可反映AP病情严重程度,并可作为判断AP患者肠黏膜屏障损伤的参考指标.%Background: Acute pancreatitis (AP) is a common acute abdomen of digestive system, secondary infection induced by intestinal mucosal barrier injury is one of the main causes of death in AP. Recent experimental studies have shown that high mobility group box 1 ( HMGB1) plays an important role in the intestinal mucosal barrier injury of AP. Aims: To define the relationship between HMGB1 and intestinal mucosal barrier injury of AP patients. Methods: A total of 80 AP patients from Dec. 2007 to Mar. 2009 at Drum Tower Hospital of Nanjing University Medical School and 101th Hospital of People's Liberation Army were enrolled, 38 cases were severe acute pancreatitis (SAP) and 42 were mild acute pancreatitis (MAP). Thirty healthy subjects were served as controls. Serum levels of HMGB1, endotoxin, diamine oxidase (DAO) and urine lactose/mannitol ( L

  7. AraC/XylS family stress response regulators Rob, SoxS, PliA, and OpiA in the fire blight pathogen Erwinia amylovora.

    Science.gov (United States)

    Pletzer, Daniel; Schweizer, Gabriel; Weingart, Helge

    2014-09-01

    Transcriptional regulators of the AraC/XylS family have been associated with multidrug resistance, organic solvent tolerance, oxidative stress, and virulence in clinically relevant enterobacteria. In the present study, we identified four homologous AraC/XylS regulators, Rob, SoxS, PliA, and OpiA, from the fire blight pathogen Erwinia amylovora Ea1189. Previous studies have shown that the regulators MarA, Rob, and SoxS from Escherichia coli mediate multiple-antibiotic resistance, primarily by upregulating the AcrAB-TolC efflux system. However, none of the four AraC/XylS regulators from E. amylovora was able to induce a multidrug resistance phenotype in the plant pathogen. Overexpression of rob led to a 2-fold increased expression of the acrA gene. However, the rob-overexpressing strain showed increased resistance to only a limited number of antibiotics. Furthermore, Rob was able to induce tolerance to organic solvents in E. amylovora by mechanisms other than efflux. We demonstrated that SoxS from E. amylovora is involved in superoxide resistance. A soxS-deficient mutant of Ea1189 was not able to grow on agar plates supplemented with the superoxide-generating agent paraquat. Furthermore, expression of soxS was induced by redox cycling agents. We identified two novel members of the AraC/XylS family in E. amylovora. PliA was highly upregulated during the early infection phase in apple rootstock and immature pear fruits. Multiple compounds were able to induce the expression of pliA, including apple leaf extracts, phenolic compounds, redox cycling agents, heavy metals, and decanoate. OpiA was shown to play a role in the regulation of osmotic and alkaline pH stress responses.

  8. The new SOXS instrument for the ESO NTT

    CERN Document Server

    Schipani, P; Campana, S; Baruffolo, A; Basa, S; Basso, S; Cappellaro, E; Cascone, E; Cosentino, R; DAlessio, F; De Caprio, V; Della Valle, M; Postigo, A de Ugarte; DOrsi, S; Franzen, R; Fynbo, J; Gal-Yam, A; Gardiol, D; Giro, E; Hamuy, M; Iuzzolino, M; Loreggia, D; Mattila, S; Munari, M; Pignata, G; Riva, M; Savarese, S; Schmidt, B; Scuderi, S; Smartt, S; Vitali, F

    2016-01-01

    SOXS (Son Of X-Shooter) will be a unique spectroscopic facility for the ESO-NTT 3.5-m telescope in La Silla (Chile), able to cover the optical/NIR band (350-1750 nm). The design foresees a high-efficiency spectrograph with a resolution-slit product of ~4,500, capable of simultaneously observing the complete spectral range 350 - 1750 nm with a good sensitivity, with light imaging capabilities in the visible band. This paper outlines the status of the project.

  9. The search for sterile neutrinos with SOX-Borexino

    Energy Technology Data Exchange (ETDEWEB)

    Altenmüller, K., E-mail: konrad.altenmueller@ph.tum.de; Agostini, M.; Appel, S. [Technische Universität München, Physik-Department and Excellence Cluster Universe (Germany); Bellini, G. [Università degli Studi e INFN, Dipartimento di Fisica (Italy); Benziger, J. [Princeton University, Chemical Engineering Department (United States); Berton, N. [Centre de Saclay, IRFU, Commissariat a l’Energie Atomique et aux Energies Alternatives (France); Bick, D. [Universität Hamburg, Institut für Experimentalphysik (Germany); Bonfini, G. [INFN Laboratori Nazionali del Gran Sasso (Italy); Bravo, D. [Virginia Polytechnic Institute and State University, Physics Department (United States); Caccianiga, B. [Università degli Studi e INFN, Dipartimento di Fisica (Italy); Calaprice, F. [Princeton University, Physics Department (United States); Caminata, A. [Università degli Studi e INFN, Dipartimento di Fisica (Italy); Cavalcante, P. [INFN Laboratori Nazionali del Gran Sasso (Italy); Chepurnov, A. [Moscow State University Skobeltsyn Institute of Nuclear Physics (Russian Federation); Cribier, M. [Centre de Saclay, IRFU, Commissariat a l’Energie Atomique et aux Energies Alternatives (France); D’Angelo, D. [Università degli Studi e INFN, Dipartimento di Fisica (Italy); Davini, S. [Gran Sasso Science Institute (INFN) (Italy); Derbin, A. [St. Petersburg Nuclear Physics Institute (Russian Federation); Noto, L. di [Università degli Studi e INFN, Dipartimento di Fisica (Italy); Drachnev, I. [Gran Sasso Science Institute (INFN) (Italy); and others

    2016-12-15

    The aim of the SOX-Borexino project is to verify or falsify the existence of eV-scale sterile neutrinos. The existence of sterile neutrinos is suspected because of several anomalies, which were observed in previous experiments. A ~3.7 PBq electron antineutrino source made of {sup 144}Ce will be installed below the Borexino detector at LNGS, Italy, to search for short-baseline oscillations of active-to-sterile neutrinos within the detector volume. Source delivery and beginning of data acquisition is planned for end of 2016, preliminary results are expected already in 2017.

  10. The search for sterile neutrinos with SOX-Borexino

    Science.gov (United States)

    Altenmüller, K.; Agostini, M.; Appel, S.; Bellini, G.; Benziger, J.; Berton, N.; Bick, D.; Bonfini, G.; Bravo, D.; Caccianiga, B.; Calaprice, F.; Caminata, A.; Cavalcante, P.; Chepurnov, A.; Cribier, M.; D'Angelo, D.; Davini, S.; Derbin, A.; di Noto, L.; Drachnev, I.; Durero, M.; Empl, A.; Etenko, A.; Farinon, S.; Fischer, V.; Fomenko, K.; Franco, D.; Gabriele, F.; Gaffiot, J.; Galbiati, C.; Ghiano, C.; Giammarchi, M.; Göger-Neff, M.; Goretti, A.; Gromov, M.; Hagner, C.; Houdy, Th.; Hungerford, E.; Ianni, Aldo; Ianni, Andrea; Jonqures, N.; Kaiser, M.; Kobychev, V.; Korablev, D.; Korga, G.; Kryn, D.; Lachenmaier, T.; Lasserre, T.; Laubenstein, M.; Lehnert, B.; Link, J.; Litvinovich, E.; Lombardi, F.; Lombardi, P.; Ludhova, L.; Lukyanchenko, G.; Machulin, I.; Maneschg, W.; Marcocci, S.; Maricic, J.; Mention, G.; Meroni, E.; Meyer, M.; Miramonti, L.; Misiaszek, M.; Montuschi, M.; Muratova, V.; Musenich, R.; Neumair, B.; Oberauer, L.; Obolensky, M.; Ortica, F.; Pagani, L.; Pallavicini, M.; Papp, L.; Perasso, L.; Pocar, A.; Ranucci, G.; Razeto, A.; Re, A.; Roncin, R.; Romani, A.; Rossi, N.; Schönert, S.; Scola, L.; Semenov, D.; Simgen, H.; Skorokhvatov, M.; Smirnov, O.; Sotnikov, A.; Sukhotin, S.; Suvorov, Y.; Tartaglia, R.; Testera, G.; Toropova, M.; Unzhakov, E.; Veyssière, C.; Vivier, M.; Vogelaar, R. B.; von Feilitzsch, F.; Wang, H.; Winter, J.; Wojcik, M.; Wurm, M.; Yokley, Z.; Zaimidoroga, O.; Zavatarelli, S.; Zuber, K.; Zuzel, G.

    2016-12-01

    The aim of the SOX-Borexino project is to verify or falsify the existence of eV-scale sterile neutrinos. The existence of sterile neutrinos is suspected because of several anomalies, which were observed in previous experiments. A 3.7 PBq electron antineutrino source made of 144Ce will be installed below the Borexino detector at LNGS, Italy, to search for short-baseline oscillations of active-to-sterile neutrinos within the detector volume. Source delivery and beginning of data acquisition is planned for end of 2016, preliminary results are expected already in 2017.

  11. Effects of Penehyclidine Hydrochloride Pretreatment on Expression of High Mobility Group Box 1 in Lung Tissue in Septic Rats%盐酸戊乙奎醚预先给药对脓毒症大鼠肺组织高迁移率族蛋白 B1表达的影响

    Institute of Scientific and Technical Information of China (English)

    尧云; 李学平; 査本俊

    2016-01-01

    ABSTRACT:Objective To investigate the effects of penehyclidine hydrochloride pretreatment on the expression of high mobility group box 1(HMGB1)in the lung tissue in septic rats.Methods One hundred and eight male SD rats weighting 300-350 g(4-5 months old)were randomly divided into three groups:sham operation group(group S),sepsis group(group CLP)and penehyclidine hydrochloride treatment group(group PH),with 36 rats in each group.Sepsis was induced by ce-cal ligation and puncture(CLP)in groups CLP and PH.Rats in group PH were intravenously in-jected with 0.1 mg/kg penehyclidine hydrochloride 1 hour before CLP.Rats in groups S and CLP were given the same volume of normal saline.Six animals in each group were killed 2 hours before CLP and 2,12,24,48 and 72 hours after CIP,respectively.Bronchoalveolar lavage fluid(BALF) was collected to examine the protein content.The lung tissue samples were collected to examine the lung wet/dry weight ratio.Myeloperoxidase(MPO)activity in the lung tissue was determined by spectrophptometry.Protein and mRNA expression of HMGB1 in the lung tissue was detected by ELISA and real-time PCR,respectively.Results Compared with group S,the lung wet/dry weight ratio,BALF protein content,MPO activity,and HMGB1 protein and mRNA expression significantly increased in group CLP(P < 0.05).Compared with group CLP,the lung wet/dry weight ratio,BALF protein content,MPO activity,and HMGB1 protein and mRNA expression significantly decreased in group PH(P <0.05).Conclusion PHC pretreatment can attenuate the lung injury induced by sepsis in rats through down-regulating the expression of HMGB1.%目的:评价盐酸戊乙奎醚预先给药对脓毒症大鼠肺组织高迁移率族蛋白 B1(HMGB1)表达的影响。方法健康雄性SD 大鼠108只,4~5月龄,体质量300~350 g,采用随机数字表法分为:假手术组(S 组)、脓毒症模型组(CLP 组)和盐酸戊乙奎醚+脓毒症模型组(PH 组),每组36只。CLP

  12. Sox2 is not required for melanomagenesis, melanoma growth and melanoma metastasis in vivo.

    Science.gov (United States)

    Cesarini, V; Guida, E; Todaro, F; Di Agostino, S; Tassinari, V; Nicolis, S; Favaro, R; Caporali, S; Lacal, P M; Botti, E; Costanzo, A; Rossi, P; Jannini, E A; Dolci, S

    2017-08-01

    Melanoma is a dangerous form of skin cancer derived from the malignant transformation of melanocytes. The transcription factor SOX2 is not expressed in melanocytes, however, it has been shown to be differentially expressed between benign nevi and malignant melanomas and to be essential for melanoma stem cell maintenance and expansion in vitro and in xenograft models. By using a mouse model in which BRaf(V600E) mutation cooperates with Pten loss to induce the development of metastatic melanoma, we investigated if Sox2 is required during the process of melanomagenesis, melanoma growth and metastasis and in the acquisition of resistance to BRAF inhibitors (BRAFi) treatments. We found that deletion of Sox2 specifically in Pten null and BRafV600E-expressing melanocytes did not prevent tumor formation and did not modify the temporal kinetics of melanoma occurrence compared to Sox2 wt mice. In addition, tumor growth was similar between Sox2 wt and Sox2 deleted (del) melanomas. By querying publicly available databases, we did not find statistically significant differences in SOX2 expression levels between benign nevi and melanomas, and analysis on two melanoma patient cohorts confirmed that Sox2 levels did not significantly change between primary and metastatic melanomas. Melanoma cell lines derived from both Sox2 genotypes showed a similar sensitivity to vemurafenib treatment and the same ability to develop vemurafenib resistance in long-term cultures. Development of vemurafenib resistance was not dependent on SOX2 expression also in human melanoma cell lines in vitro. Our findings exclude an oncogenic function for Sox2 during melanoma development and do not support a role for this transcription factor in the acquisition of resistance to BRAFi treatments.

  13. RNA-Seq analysis reveals a six-gene SoxR regulon in Streptomyces coelicolor.

    Directory of Open Access Journals (Sweden)

    Nawar Naseer

    Full Text Available The redox-regulated transcription factor SoxR is conserved in diverse bacteria, but emerging studies suggest that this protein plays distinct physiological roles in different bacteria. SoxR regulates a global oxidative stress response (involving > 100 genes against exogenous redox-cycling drugs in Escherichia coli and related enterics. In the antibiotic producers Streptomyces coelicolor and Pseudomonas aeruginosa, however, SoxR regulates a smaller number of genes that encode membrane transporters and proteins with homology to antibiotic-tailoring enzymes. In both S. coelicolor and P. aeruginosa, SoxR-regulated genes are expressed in stationary phase during the production of endogenously-produced redox-active antibiotics. These observations suggest that SoxR evolved to sense endogenous secondary metabolites and activate machinery to process and transport them in antibiotic-producing bacteria. Previous bioinformatics analysis that searched the genome for SoxR-binding sites in putative promoters defined a five-gene SoxR regulon in S. coelicolor including an ABC transporter, two oxidoreductases, a monooxygenase and an epimerase/dehydratase. Since this in silico screen may have missed potential SoxR-targets, we conducted a whole genome transcriptome comparison of wild type S. coelicolor and a soxR-deficient mutant in stationary phase using RNA-Seq. Our analysis revealed a sixth SoxR-regulated gene in S. coelicolor that encodes a putative quinone oxidoreductase. Knowledge of the full complement of genes regulated by SoxR will facilitate studies to elucidate the function of this regulatory molecule in antibiotic producers.

  14. Sox11 is required to maintain proper levels of Hedgehog signaling during vertebrate ocular morphogenesis.

    Directory of Open Access Journals (Sweden)

    Lakshmi Pillai-Kastoori

    2014-07-01

    Full Text Available Ocular coloboma is a sight-threatening malformation caused by failure of the choroid fissure to close during morphogenesis of the eye, and is frequently associated with additional anomalies, including microphthalmia and cataracts. Although Hedgehog signaling is known to play a critical role in choroid fissure closure, genetic regulation of this pathway remains poorly understood. Here, we show that the transcription factor Sox11 is required to maintain specific levels of Hedgehog signaling during ocular development. Sox11-deficient zebrafish embryos displayed delayed and abnormal lens formation, coloboma, and a specific reduction in rod photoreceptors, all of which could be rescued by treatment with the Hedgehog pathway inhibitor cyclopamine. We further demonstrate that the elevated Hedgehog signaling in Sox11-deficient zebrafish was caused by a large increase in shha transcription; indeed, suppressing Shha expression rescued the ocular phenotypes of sox11 morphants. Conversely, over-expression of sox11 induced cyclopia, a phenotype consistent with reduced levels of Sonic hedgehog. We screened DNA samples from 79 patients with microphthalmia, anophthalmia, or coloboma (MAC and identified two novel heterozygous SOX11 variants in individuals with coloboma. In contrast to wild type human SOX11 mRNA, mRNA containing either variant failed to rescue the lens and coloboma phenotypes of Sox11-deficient zebrafish, and both exhibited significantly reduced transactivation ability in a luciferase reporter assay. Moreover, decreased gene dosage from a segmental deletion encompassing the SOX11 locus resulted in microphthalmia and related ocular phenotypes. Therefore, our study reveals a novel role for Sox11 in controlling Hedgehog signaling, and suggests that SOX11 variants contribute to pediatric eye disorders.

  15. cDNA cloning and expression analysis of two distinct Sox8 genes in Paramisgurnus dabryanus (Cypriniformes).

    Science.gov (United States)

    Xia, Xiaohua; Zhao, Jie; Du, Qiyan; Chang, Zhongjie

    2010-08-01

    The Sox9 gene attracts a lot of attention because of its connection with gonadal development and differentiation. However, Sox8, belonging to the same subgroup SoxE, has rarely been studied. To investigate the function as well as the evolutionary origin of SOXE subgroup, we amplified the genomic DNA of Paramisgurnus dabryanu using a pair of degenerate primers. Using rapid amplification of the cDNA ends (RACE), it was discovered that P. dabryanu has two duplicates: Sox8a and Sox8b. Each has an intron of different length in the conserved HMG-box region. The overall sequence similarity of the deduced amino acid of PdSox8a and PdSox8b was 46.26%, and only two amino acids changed in the HMG-box. This is the first evidence showing that there are two distinct duplications of Sox8 genes in Cypriniformes. Southern blot analysis showed only one hybrid band, with lengths 7.4 or 9.2 kb. Both semi-quantitative RT-PCR and real-time quantitative PCR assay displayed that both PdSox8a and PdSox8b are downregulated during early embryonic development. In adult tissues, the two Sox8 genes expressed ubiquitously, and expression levels are particularly high in the gonads and brain. In gonads, both PdSox8a and PdSox8b are expressed at a higher level in the tesis than in the ovary. PdSox8a and PdSox8b may have functional overlaps and are essential for the neuronal development and differentiation of gonads.

  16. cDNA cloning and expression analysis of two distinct Sox8 genes in Paramisgurnus dabryanus (Cypriniformes)

    Indian Academy of Sciences (India)

    Xiaohua Xia; Jie Zhao; Qiyan Du; Zhongjie Chang

    2010-08-01

    The Sox9 gene attracts a lot of attention because of its connection with gonadal development and differentiation. However, Sox8, belonging to the same subgroup SoxE, has rarely been studied. To investigate the function as well as the evolutionary origin of SOXE subgroup, we amplified the genomic DNA of Paramisgurnus dabryanu using a pair of degenerate primers. Using rapid amplification of the cDNA ends (RACE), it was discovered that P. dabryanu has two duplicates: Sox8a and Sox8b. Each has an intron of different length in the conserved HMG-box region. The overall sequence similarity of the deduced amino acid of PdSox8a and PdSox8b was 46.26%, and only two amino acids changed in the HMG-box. This is the first evidence showing that there are two distinct duplications of Sox8 genes in Cypriniformes. Southern blot analysis showed only one hybrid band, with lengths 7.4 or 9.2 kb. Both semi-quantitative RT-PCR and real-time quantitative PCR assay displayed that both PdSox8a and PdSox8b are downregulated during early embryonic development. In adult tissues, the two Sox8 genes expressed ubiquitously, and expression levels are particularly high in the gonads and brain. In gonads, both PdSox8a and PdSox8b are expressed at a higher level in the tesis than in the ovary. PdSox8a and PdSox8b may have functional overlaps and are essential for the neuronal development and differentiation of gonads.

  17. 严重烧伤患者外周血高迁移率族蛋白B-1水平的检测及其临床意义%Detection of plasma high mobility group box-1 protein in severely burned patients and its clinical significance

    Institute of Scientific and Technical Information of China (English)

    肖锦华; 王亚萍; 朱华燕; 潘宇红; 黄璇

    2012-01-01

    目的 检测严重烧伤后患者血浆高迁移率族蛋白B-1 (HMGB1)水平的变化并探讨其临床意义.方法 用酶联免疫吸附试验法检测77例严重烧伤患者血浆HMGB1水平,同步检测肿瘤坏死因子-α(TNF-α)含量,并与30名健康对照组进行比较.结果 77例严重烧伤患者按烧伤面积分为3组,A组31例,烧伤总面积30%~49%,B组25例,烧伤总面积50%~69%,C组21例,烧伤总面积70%~95%;烧伤患者血浆HMGB1及TNF-α水平在A组为(22.15±6.34) ng/ml、(89.26±21.41)pg/ml,B组为(26.24±9.71)ng/ml、( 132.45±76.32)pg/ml,C组为(36.45±11.63)ng/ml、(213.61±87.45) pg/ml,对照组为(2.17±1.13)ng/ml、(45.32±13.84)pg/m1,烧伤各组HMGB1及TNF-α水平明显高于对照组(P<0.01);24例特大面积烧伤患者根据预后情况分为生存组和死亡组进行动态观察,两组患者血浆HMGB1水平在伤后第1天即显著升高(P<0.01),在伤后3~21 d,死亡组明显高于生存组(P<0.05),而TNF-α含量在伤后第3~7 d达高峰,以后逐渐下降,到21d时生存组与死亡组相比已差异无统计学意义.结论 严重烧伤后HMGB1的表达异常升高,HMGB1作为重要的晚期炎症介质和TNF-α相互诱生相互作用,参与严重烧伤后全身炎症反应综合征的病理生理过程,动态观察其水平变化有助于烧伤患者病程监测及预后判断.%OBJECTIVE To investigate the changes of plasma high mobility group box-1 protein ( HMGB1) in severely burned patients and its clinical significance. METHODS The plasma HMGB1 and TNF-α levels were measured by enzyme linked immunosorbent assay(ELISA) simultaneously in all patients and were compared with 30 healthy control subjects. RESULTS Totally 77 burned patients were involved in this study, and they were divided into three burn size groups: 30%-49% total body surface area(TBSA) burn(group A, n = 31), 50% - 69% TBSA burn (group B, n = 25) and 70%-95% TBSA burn(group C, n = 21). The levels of HMGB2 and TNF

  18. Novel mutations of PAX3, MITF, and SOX10 genes in Chinese patients with type I or type II Waardenburg syndrome.

    Science.gov (United States)

    Chen, Hongsheng; Jiang, Lu; Xie, Zhiguo; Mei, Lingyun; He, Chufeng; Hu, Zhengmao; Xia, Kun; Feng, Yong

    2010-06-18

    Waardenburg syndrome (WS) is a rare disorder characterized by distinctive facial features, pigment disturbances, and sensorineural deafness. There are four WS subtypes. WS1 is mostly caused by PAX3 mutations, while MITF, SNAI2, and SOX10 mutations are associated with WS2. More than 100 different disease-causing mutations have been reported in many ethnic groups, but the data from Chinese patients with WS remains poor. Herein we report 18 patients from 15 Chinese WS families, in which five cases were diagnosed as WS1 and the remaining as WS2. Clinical evaluation revealed intense phenotypic variability in Chinese WS patients. Heterochromia iridis and sensorineural hearing loss were the most frequent features (100% and 88.9%, respectively) of the two subtypes. Many brown freckles on normal skin could be a special subtype of cutaneous pigment disturbances in Chinese WS patients. PAX3, MITF, SNAI2, and SOX10 genes mutations were screened for in all the patients. A total of nine mutations in 11 families were identified and seven of them were novel. The SOX10 mutations in WS2 were first discovered in the Chinese population, with an estimated frequency similar to that of MITF mutations, implying SOX10 is an important pathogenic gene in Chinese WS2 cases and should be considered for first-step analysis in WS2, as well as MITF.

  19. Differentiation of SOX-9 and GDF-5 co-transfected bone marrow mesenchymal stem cells into nucleus pulposus cells%SOX-9和GDF-5共同转染骨髓间充质干细胞向类髓核细胞的分化

    Institute of Scientific and Technical Information of China (English)

    杜志才; 银和平; 李树文; 武海军; 白明; 曹振华; 孟格东

    2015-01-01

    背景:移植间充质干细胞预防和治疗椎间盘退变是一种可行的方法,将SOX-9和GDF-5共同转染骨髓间充质干细胞,使其向髓核细胞转化,以期获得更大的髓核诱导和促增殖效应.目的:探讨SOX-9和GDF-5基因共同诱导兔骨髓间充质干细胞向类髓核细胞分化的效果.方法:提取、分离、纯化4周龄新西兰大白兔骨髓间充质干细胞,取第3代骨髓间充质干细胞分为5组体外诱导其向类髓核细胞分化,分别为未转染组、空载体转染组、SOX-9转染组、GDF-5转染组、共转染组.转染后第14 天采用RT-PCR检测SOX-9,GDF-5和Ⅱ型胶原的mRNA表达,免疫组化染色法检测髓核细胞标记物KRT19表达.结果与结论:共转染组SOX-9 mRNA表达高于转染SOX-9组,差异有显著性意义(P < 0.05);共转染组GDF-5 mRNA表达高于转染GDF-5组,差异有显著性意义(P < 0.05).共转染组Ⅱ型胶原表达高于转染SOX-9组、转染GDF-5组,差异有显著性意义(P < 0.05).SOX-9转染组及GDF-5转染组KRT19呈阳性表达,共转染组呈强阳性表达,可见被转染的骨髓间充质干细胞向类髓核细胞分化,且双基因转染诱导骨髓间充质干细胞向类髓核细胞分化的能力和分泌细胞外基质的能力明显高于单基因转染.%BACKGROUND:Transplantation of mesenchymal stem cels to prevent and treat degeneration of the intervertebral disc is a feasible method. Mesenchymal stem cels co-transfected by SRY-related high mobility group-box gene 9 (SOX-9) and growth differentiation factor-5 (GDF-5) can differentiate into nucleus pulposus cels, in order to obtain greater effect of induction and proliferation of nucleus pulposus cels. OBJECTIVE:To investigate the effect of SOX-9 and GDF-5 co-transfection on the differentiation of rabbit bone marrow mesenchymal stem cels into nucleus pulposus cels. METHODS: We separated and cultured bone marrow mesenchymal stem cels from the bone marrow of rabbit aged 4 months. Passage 3 cels

  20. Metabolism of aflatoxin B1 and identification of the major aflatoxin B1-DNA adducts formed in cultured human bronchus and colon

    DEFF Research Database (Denmark)

    1979-01-01

    ) with the guanyl group and hydroxy group in trans-position and an adduct which has been tentatively identified by other investigators as 2,3-dihydro-2-(N5-formyl-2',5',6'-triamino-4'-oxo-N5-pyrimidyl)-3-hydroxyaflatoxin B1 (Structure 11). Seventy % of the radioactivity associated with bronchial DNA was found...

  1. Effects of high mobility group box-1 (HMGB1) protein on phenotype of regulatory T cells and functional polarization of T cells in burned rots%高迁移率族蛋白B1对烫伤大鼠调节性T细胞表型及T细胞功能极化的影响

    Institute of Scientific and Technical Information of China (English)

    黄立锋; 姚凤华; 董宁; 张立天; 姚咏明

    2011-01-01

    目的 探讨严重烫伤延迟复苏后脾脏高迁移率族蛋白B1(HMGB1)表达对调节性T细胞(Treg)表型及其介导T淋巴细胞功能性极化的影响.方法 104只Wistar大鼠随机分为正常对照组(8只)、假烫组(32只)、烫伤组(32只)、丙酮酸乙酯(EP)治疗组(32只).后2组大鼠制作30% TBSA三度烫伤模型,伤后6h腹腔注射林格液或EP液延迟复苏抗休克.分别于伤后1、3、5、7d处死各组大鼠,免疫磁珠法分离大鼠脾脏CD4+CD25+ Treg,检测脾组织HMGB1含量及T淋巴细胞上清液中白细胞介素4(IL-4)、干扰素γ(IFN-γ)水平,并采用流式细胞术检测Treg表面标记物叉头翼状螺旋转录因子(Foxp3)表达水平.结果 与假烫组比较,烫伤组大鼠脾组织HMGB1水平在伤后1~7d显著升高(P<0.01),其中第1天时达峰值(46.73±8.27ng/mg),EP干预后HMGB1水平在1~7d显著低于烫伤组(P<0.01).与假烫组比较,烫伤组大鼠伤后1d脾脏Treg表面Foxp3表达逐渐增强,于第3天达峰值(72.46%±11.02%),EP治疗组伤后1~7d Foxp3表达显著低于烫伤组(P<0.01或P<0.05).与假烫组比较,烫伤组脾T淋巴细胞IL-4分泌量明显增高(P<0.01或P<0.05),IFN-γ分泌量明显降低(P<0.01),EP治疗组伤后1~5d IL-4分泌量明显低于烫伤组(P<0.05),伤后1~7d IFN-γ分泌量则明显高于烫伤组(P<0.05).结论 严重烧伤后HMGB1可促进Treg成熟,从而介导T细胞功能亚群从促炎反应优势向抗炎优势转化,诱导机体细胞免疫功能抑制.%Objective To explore the effects of high mobility group box-1 (HMGB1) protein expression on the phenotype of regulatory T cells (Treg) and the functional polarization of splenic T cells in severe burn rata after delayed resuscitation. Methods One hundred and four Wistar rats were involved in present study and randomly divided into normal control group (n=8), sham bum group (n=32), bum group (n=32) and ethyl pyruvate (EP) treatment group (n=32). Thirty percent TBSA full-thickness bum

  2. Goniodysgenesis variability and activity of CYP1B1 genotypes in primary congenital glaucoma

    Science.gov (United States)

    de Hoz, Rosa; Rojas, Blanca; Ramírez, Ana I.; Triviño, Alberto; Aroca-Aguilar, José-Daniel; García-Feijoo, Julián; Escribano, Julio

    2017-01-01

    Mutations in the CYP1B1 gene are currently the main known genetic cause of primary congenital glaucoma (PCG), a leading cause of blindness in children. Here, we analyze for the first time the CYP1B1 genotype activity and the microscopic and clinical phenotypes in human PCG. Surgical pieces from trabeculectomy from patients with PCG (n = 5) and sclerocorneal rims (n = 3) from cadaver donors were processed for transmission electron microscopy. Patients were classified into three groups depending on goniodysgenesis severity, which was influenced by CYP1B1 enzymatic activity. The main histological changes observed in the outflow pathway of patients with PCG and mutations in CYP1B1 were: i) underdeveloped collector channels and the Schlemm’s canal; ii) abnormal insertion of the ciliary muscle; iii) death of the trabecular endothelial cells. Our findings could be useful in improving treatment strategy of PCG associated with CYP1B1 mutations. PMID:28448622

  3. An Evolutionarily Conserved SoxB-Hdac2 Crosstalk Regulates Neurogenesis in a Cnidarian.

    Science.gov (United States)

    Flici, Hakima; Schnitzler, Christine E; Millane, R Cathriona; Govinden, Graham; Houlihan, Amy; Boomkamp, Stephanie D; Shen, Sanbing; Baxevanis, Andreas D; Frank, Uri

    2017-02-07

    SoxB transcription factors and histone deacetylases (HDACs) are each major players in the regulation of neurogenesis, but a functional link between them has not been previously demonstrated. Here, we show that SoxB2 and Hdac2 act together to regulate neurogenesis in the cnidarian Hydractinia echinata during tissue homeostasis and head regeneration. We find that misexpression of SoxB genes modifies the number of neural cells in all life stages and interferes with head regeneration. Hdac2 was co-expressed with SoxB2, and its downregulation phenocopied SoxB2 knockdown. We also show that SoxB2 and Hdac2 promote each other's transcript levels, but Hdac2 counteracts this amplification cycle by deacetylating and destabilizing SoxB2 protein. Finally, we present evidence for conservation of these interactions in human neural progenitors. We hypothesize that crosstalk between SoxB transcription factors and Hdac2 is an ancient feature of metazoan neurogenesis and functions to stabilize the correct levels of these multifunctional proteins.

  4. Sox9 potentiates BMP2-induced chondrogenic differentiation and inhibits BMP2-induced osteogenic differentiation.

    Science.gov (United States)

    Liao, Junyi; Hu, Ning; Zhou, Nian; Lin, Liangbo; Zhao, Chen; Yi, Shixiong; Fan, Tingxu; Bao, Wei; Liang, Xi; Chen, Hong; Xu, Wei; Chen, Cheng; Cheng, Qiang; Zeng, Yongming; Si, Weike; Yang, Zhong; Huang, Wei

    2014-01-01

    Bone morphogenetic protein 2 (BMP2) is one of the key chondrogenic growth factors involved in the cartilage regeneration. However, it also exhibits osteogenic abilities and triggers endochondral ossification. Effective chondrogenesis and inhibition of BMP2-induced osteogenesis and endochondral ossification can be achieved by directing the mesenchymal stem cells (MSCs) towards chondrocyte lineage with chodrogenic factors, such as Sox9. Here we investigated the effects of Sox9 on BMP2-induced chondrogenic and osteogenic differentiation of MSCs. We found exogenous overexpression of Sox9 enhanced the BMP2-induced chondrogenic differentiation of MSCs in vitro. Also, it inhibited early and late osteogenic differentiation of MSCs in vitro. Subcutaneous stem cell implantation demonstrated Sox9 potentiated BMP2-induced cartilage formation and inhibited endochondral ossification. Mouse limb cultures indicated that BMP2 and Sox9 acted synergistically to stimulate chondrocytes proliferation, and Sox9 inhibited BMP2-induced chondrocytes hypertrophy and ossification. This study strongly suggests that Sox9 potentiates BMP2-induced MSCs chondrogenic differentiation and cartilage formation, and inhibits BMP2-induced MSCs osteogenic differentiation and endochondral ossification. Thus, exogenous overexpression of Sox9 in BMP2-induced mesenchymal stem cells differentiation may be a new strategy for cartilage tissue engineering.

  5. The versatile functions of Sox9 in development, stem cells, and human diseases

    Science.gov (United States)

    Jo, Alice; Denduluri, Sahitya; Zhang, Bosi; Wang, Zhongliang; Yin, Liangjun; Yan, Zhengjian; Kang, Richard; Shi, Lewis L.; Mok, James; Lee, Michael J.; Haydon, Rex C.

    2014-01-01

    The transcription factor Sox9 was first discovered in patients with campomelic dysplasia, a haploinsufficiency disorder with skeletal deformities caused by dysregulation of Sox9 expression during chondrogenesis. Since then, its role as a cell fate determiner during embryonic development has been well characterized; Sox9 expression differentiates cells derived from all three germ layers into a large variety of specialized tissues and organs. However, recent data has shown that ectoderm- and endoderm-derived tissues continue to express Sox9 in mature organs and stem cell pools, suggesting its role in cell maintenance and specification during adult life. The versatility of Sox9 may be explained by a combination of post-transcriptional modifications, binding partners, and the tissue type in which it is expressed. Considering its importance during both development and adult life, it follows that dysregulation of Sox9 has been implicated in various congenital and acquired diseases, including fibrosis and cancer. This review provides a summary of the various roles of Sox9 in cell fate specification, stem cell biology, and related human diseases. Ultimately, understanding the mechanisms that regulate Sox9 will be crucial for developing effective therapies to treat disease caused by stem cell dysregulation or even reverse organ damage. PMID:25685828

  6. Sox9 transcriptionally represses Spp1 to prevent matrix mineralization in maturing heart valves and chondrocytes.

    Directory of Open Access Journals (Sweden)

    Jacqueline D Peacock

    Full Text Available Sox9 is an SRY-related transcription factor required for expression of cartilaginous genes in the developing skeletal system and heart valve structures. In contrast to positively regulating cartilaginous matrix, Sox9 also negatively regulates matrix mineralization associated with bone formation. While the transcriptional activation of Sox9 target genes during chondrogenesis has been characterized, the mechanisms by which Sox9 represses osteogenic processes are not so clear. Using ChIP-on-chip and luciferase assays we show that Sox9 binds and represses transactivation of the osteogenic glycoprotein Spp1. In addition, Sox9 knockdown in post natal mouse heart valve explants and rib chondrocyte cultures promotes Spp1 expression and matrix mineralization, while attenuating expression of cartilage genes Type II Collagen and Cartilage Link Protein. Further, we show that Spp1 is required for matrix mineralization induced by Sox9 knockdown. These studies provide insights into the molecular mechanisms by which Sox9 prevents pathologic matrix mineralization in tissues that must remain cartilaginous.

  7. Sox4 mediates Tbx3 transcriptional regulation of the gap junction protein Cx43

    NARCIS (Netherlands)

    Boogerd, C.J.; Wong, L.Y.; van den Boogaard, M.; Bakker, M.A.J.; Tessadori, F.; Bakkers, J.; 't Hoen, P.A.C.; Moorman, A.F.; Christoffels, V.M.; Barnett, P.

    2011-01-01

    Tbx3, a T-box transcription factor, regulates key steps in development of the heart and other organ systems. Here, we identify Sox4 as an interacting partner of Tbx3. Pull-down and nuclear retention assays verify this interaction and in situ hybridization reveals Tbx3 and Sox4 to co-localize

  8. Identification of the Transformational Properties and Transcriptional Targets of the Oncogenic SRY Transcription Factor SOX4

    Science.gov (United States)

    2010-01-01

    January 15, 2009 and BMP-6 (40) to parathyroid hormone and progesterone (8). Previous work has shown that SOX4 directly signals from IL-5Ra (41), and here...stained section of SOX4 knockout mouse prostate (4x). Clear hyperplasia is seen in the uppermost gland however the majority of tissue appears normal. (C

  9. Cloning and study of adult-tissue-specific expression of Sox9 in Cyprinus carpio

    Indian Academy of Sciences (India)

    Du Qi-Yan; Wang Feng-Yu; Hua Hui-Ying; Chang Zhong-Jie

    2007-08-01

    The Sox9 gene is one of the important transcription factors in the development of many tissues and organs, particularly in sex determination and chondrogenesis. We amplified the genomic DNA of Cyprinus carpio using degenerate primers, and found that there were two versions of Sox9 in this species: Sox9a and Sox9b, that differ in having an intron of different length (704 bp and 616 bp, respectively) in the conserved HMG box region that codes for identical amino acid sequences. We used a two-phase rapid amplification of cDNA ends (RACE) for the isolation of full-length cDNA of Sox9b. Sequence analyses revealed a 2447-bp cDNA containing 233-bp 5′ untranslated region, a 927-bp 3′ untranslated region, including poly(A), and a 1287 bp open reading frame (ORF) encoding a protein of 428 amino acids. The HMG box of 79 amino acid motif was confirmed from positions 96–174. Sequence alignment showed that the identity of amino acids of Sox9 among ten animal species, including C. carpio, is 75%, indicating that the Sox9 gene is evolutionarily quite conserved. The expression level of Sox9b gene varied among several organs of adult C. carpio, with the level of expression being highest in the brain and testis.

  10. SOX9-mediated upregulation of LGR5 is important for glioblastoma tumorigenicity

    Energy Technology Data Exchange (ETDEWEB)

    Hiraoka, Koji; Hayashi, Tomoatsu; Kaneko, Ryusuke; Nasu-Nishimura, Yukiko; Koyama-Nasu, Ryo; Kawasaki, Yoshihiro; Akiyama, Tetsu, E-mail: akiyama@iam.u-tokyo.ac.jp

    2015-05-01

    LGR5 plays an important role in the self-renewal of stem cells and is used as a marker identifying self-renewing stem cells in small intestine and hair follicles. Moreover, LGR5 has been reported to be overexpressed in several cancers. SOX9 is a transcription factor that plays a key role in development, differentiation and lineage commitment in various tissues. It has also been reported that SOX9 is overexpressed in a variety of cancers and contributes to their malignant phenotype. Here we show that LGR5 is required for the tumorigenicity of glioblastoma cells. We further show that SOX9 is upregulated in glioblastoma cells and directly enhances the expression of LGR5. We also demonstrate that knockdown of SOX9 suppresses the proliferation and tumorigenicity of glioblastoma cells. These results suggest that SOX9-mediated transcriptional regulation of LGR5 is critical for the tumorigenicity of glioblastoma cells. We speculate that the SOX9-LGR5 pathway could be a potentially promising target for the therapy of glioblastoma. - Highlights: • LGR5 is required for the tumorigenicity of glioblastoma cells. • SOX9 directly enhances the expression of LGR5. • SOX9 is required for the tumorigenicity of glioblastoma cells.

  11. Spontaneous evolution of an unusual cortical malformation in SOX2 anophthalmia syndrome

    Directory of Open Access Journals (Sweden)

    Jay Desai

    2013-01-01

    Full Text Available Brain malformations such as agenesis and dysgenesis of corpus callosum, pituitary hypoplasia, hypothalamic hamartoma, mesial temporal periventricular heterotopia, and abnormally oriented and misshapen hippocampi have been described with SOX2 gene mutations. A neocortical malformation is presented here in association with SOX2 deletion that over time underwent spontaneous evolution and decrease in size.

  12. Analysis of SOX2 expression in developing human testis and germ cell neoplasia

    DEFF Research Database (Denmark)

    Sonne, Si Brask; Perrett, Rebecca M.; Nielsen, John Erik

    2010-01-01

    The transcriptional regulators of pluripotency, POU5F1 (OCT4), NANOG and SOX2, are highly expressed in embryonal carcinoma (EC). In contrast to OCT4 and NANOG, SOX2 has not been demonstrated in the early human germ cell lineage or carcinoma in situ (CIS), the precursor for testicular germ cell tu...

  13. Synthesis of 5-Deoxy-5-Acyloxyiminoavermectin B1 Derivatives

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Four 5-deoxy-5-acyloxyiminoavermectin B1 derivatives 4a~d were synthesized via three steps from avermectin B1 and their biological activities were tested against Heliothis armigera,Laphygma exigua and Musca domestica.

  14. Serum levels and roles of high mobility group box-1 protein in patients with acute suppurative cholangitis%血清高迁移率族蛋白B1在急性化脓性胆管炎发生中的作用及意义研究

    Institute of Scientific and Technical Information of China (English)

    郭继中; 张婷; 谢震雄; 蒋莉莎; 陆国民; 夏敏

    2013-01-01

    Objective To observe the serum levels of high mobility group box-1 protein (HMGB1)in patients with acute cholangitis (AC) and to investigate contributions of HMGB1 in AC.Methods Serum HMGB1 concentrations were determined by an enzyme-linked immunosorbent assay in 30 patients with AC of severe type (ACST) and 42 patients with mild acute cholangitis at the time of admission (within 72 h after the onset).A total of 50 healthy subjects were recruited as the control group.Fluorescent quantitative PCR (FQPCR) was used to detect the HMGB1 mRNA expression and the relationship between serum HMGB1 levels and clinical factors was analyzed.Results The serum HMGB1 levels in healthy control group,mild group and ACST group were (1.82 ± 0.64) μg/L,(10.46 ± 3.75) μg/L,(18.89 ± 6.86) μg/L,respectively.The mean value of serum HMGB1 level in mild group was significantly higher than that in control group,while significantly lower than that in ACST group (P < 0.05).Compared to the control group,the HMGB1 mRNA level in patients of AC increased significantly and the level of ACST group was higher than that of mild group.The serum HMGB1 levels of patients with positive bile or/and blood cultures were higher than that of negative.After emergency endoscopic nasal biliary drainage,the serum HMGB1 levels of patients significantly decreased compared to preoperational (P < 0.05).The HMGB1 levels were significantly positively correlated with white cell counts,C-reactive protein (CRP),total serum bilirubin,direct bilirubin and alkaline phosphatase (ALP).By logistic regression analysis,serum HMGB1 levels had correlation with severity of disease.Conclusion Serum HMGB1 levels significantly increased in patients with AC and the serum concentrations of ACST group were higher than those of mild group.Serum HMGB1 level has a correlation with sepsis.ENBD could lower its serum levels.Serum HMGB1 has predictive value to severity of disease.%目的 检测急性化脓性胆管炎(ASC)患者血清高迁移率族蛋白B

  15. Molecular cloning and evolution analysis of the CaSox4 gene of Alligator sinensis%扬子鳄的CaSox4基因的分子克隆和进化分析

    Institute of Scientific and Technical Information of China (English)

    郑济芳; 朱睦元

    2003-01-01

    The completely identical HMG-box motif of CaSox4 gene from both male and female genomic DNA of the Chinese alligator (alligator sinensis) was cloned and sequenced by degenerate primer PCR.Compared with the human and mouse SRY,CaSox4 revealed 51% and 57% nucleotide homology respectively and 49% and 55% amino acid identity respectively,CaSox4 belongs to subgroup C of the Sox gene family.The GC content is 86% in the HMG-box region of the CaSox4 gene,Blast analysis showed that the CaSox4 gene shares 100 amino acid identity with human Sox4.bird SoxLF4,turtle Sra4 and lizard CvSox4 genes.Casox4 may be orthologous with the human SOx4 gene.This indicates that CaSox4 gene shows the remarkable evolutionary conservation during the evolution of Alligator Sinensis,The extensive sequence conservation of the Sox4 gene between reptiles,mammals and birds suggests major functional constraints[Acta Zoologica Sinica 49(3):404-407,2003].

  16. Sox10 directs neural stem cells toward the oligodendrocyte lineage by decreasing Suppressor of Fused expression

    Science.gov (United States)

    Pozniak, Christine D.; Langseth, Abraham J.; Dijkgraaf, Gerrit J. P.; Choe, Youngshik; Werb, Zena; Pleasure, Samuel J.

    2010-01-01

    Oligodendrocyte precursor cells (OPCs) are lineage-restricted progenitors generally limited in vivo to producing oligodendrocytes. Mechanisms controlling genesis of OPCs are of interest because of their importance in myelin development and their potential for regenerative therapies in multiple sclerosis and dysmyelinating syndromes. We show here that the SoxE transcription factors (comprising Sox8, 9, and 10) induce multipotent neural precursor cells (NPCs) from the early postnatal subventricular zone (SVZ) to become OPCs in an autonomous manner. We performed a chromatin immunoprecipitation-based bioinformatic screen and identified Suppressor of Fused (Sufu) as a direct target of repression by Sox10. In vitro, overexpression of Sufu blocked OPC production, whereas RNAi-mediated inhibition augmented OPC production. Furthermore, mice heterozygous for Sufu have increased numbers of OPCs in the telencephalon during development. We conclude that Sox10 acts to restrict the potential of NPCs toward the oligodendrocyte lineage in part by regulating the expression of Sufu. PMID:21098272

  17. Haploinsufficiency of SOX5, a member of the SOX (SRY-related HMG-box) family of transcription factors is a cause of intellectual disability.

    Science.gov (United States)

    Schanze, Ina; Schanze, Denny; Bacino, Carlos A; Douzgou, Sofia; Kerr, Bronwyn; Zenker, Martin

    2013-02-01

    Intellectual disability (ID) is a clinically and genetically heterogeneous condition; the cause is unknown in most non-specific and sporadic cases. To establish an etiological basis in those patients represents a difficult challenge. Over the last years it has become apparent that chromosomal rearrangements below the detection level of conventional karyotyping contribute significantly to the cause of ID. We present three patients with non-specific intellectual disability who all have overlapping microdeletions in the chromosomal region 12p12.1. De novo occurrence of the deletion could be proven in the two cases from which parental samples were available. All three identified deletions have different breakpoints and range in size from 120 kb to 4.9 Mb. The smallest deletion helps to narrow down the critical region to a genomic segment (chr12:23,924,800-24,041,698, build 37/hg19) encompassing only one gene, SOX5. SOX5 is a member of the SOX (SRY-related HMG-box) family of transcription factors shown to play roles in chondroblast function, oligodendrocyte differentiation and migration, as well as ensuring proper development of specific neuronal cell types. Because of these biological functions, mutations in SOX5 are predicted to cause complex disease syndromes, as it is the case for other SOX genes, but such mutations have not yet been identified. Our findings indicate that haploinsufficiency of SOX5 is a cause of intellectual disability without any striking physical anomalies.

  18. 26 CFR 301.7701(b)-1 - Resident alien.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Resident alien. 301.7701(b)-1 Section 301.7701... ADMINISTRATION PROCEDURE AND ADMINISTRATION Definitions § 301.7701(b)-1 Resident alien. (a) Scope. Section 301.7701(b)-1(b) provides rules for determining whether an alien individual is a lawful permanent resident...

  19. Compound list: aflatoxin B1 [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available aflatoxin B1 AFB1 00165 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in_vitro/aflatoxin..._B1.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/Single/aflatoxin_B1.Rat.in_vivo.Liver.Single.zip ...

  20. Assessment of human exposure to fumonisin B1

    NARCIS (Netherlands)

    Nijs, M. de; Egmond, H.P. van; Nauta, M.; Rombouts, F.M.; Notermans, S.H.W.

    1998-01-01

    Fumonisin B1 is currently regarded as the most significant mycotoxin produced by Fusarium spp. It has carcinogenic properties and may play a role in the etiology of human esophageal cancer. The human population is exposed to fumonisin B1 primarily by intake of fumonisin B1-contaminated maize. Maize

  1. Synthesis of Polyclonal Antibodies against Aflatoxin B1

    Directory of Open Access Journals (Sweden)

    Wiyogo Prio Wicaksono

    2015-09-01

    Full Text Available Polyclonal antibodies of aflatoxin B1 were successfully produced from New Zealand White female rabbits after immunization by the hapten of aflatoxin B1-carboxymethyl hydroxylamine hemihydrochloride (AFB1-CMO conjugated with bovine serum albumin (BSA as the antigen. The hapten was synthesized using the carbodiimide method with CMO as a linker. Absorption peaks at 362, 264, and 218 nm were observed as a result of characterization with UV-Vis spectroscopy, while IR spectroscopy showed peaks at 3448 cm-1 and 1642 cm-1 attributable to the hydroxyl and nitrile groups, respectively. Furthermore, mass spectrometry showed fragmentation at the m/z of 386, 368.2, and 310, which confirms that the hapten of AFB1-CMO was successfully synthesized. The hapten was then conjugated with BSA to serve as an antigen of AFB1 when it was injected into the rabbits. The specificity of the antigen towards its antibody and the confirmation of hapten-BSA conjugation were characterized using the dot blot immunoassay, which showed a BSA concentration of 1.74 mg/mL. Two weeks after the primary immunization by its antigen, agar gel precipitation testing showed that the rabbit blood serum had positive results for polyclonal antibodiest against AFB1 with the highest concentration of antibodiest of 2.19 mg/mL.

  2. Clinical and Prognostic Implications of Transcription Factor SOX4 in Patients with Colon Cancer.

    Directory of Open Access Journals (Sweden)

    Chun-Mao Lin

    Full Text Available Colon cancer is one of the most common malignant cancers worldwide but the current therapeutic approaches for advanced colon cancer are less efficient. This study investigated associations between the expression of nuclear transcription factor SOX4 and various clinicopathologic parameters as well as patients' survival. Expression levels of nuclear SOX4 were analyzed by immunohistochemistry; the data comprised colon tissues from 263 patients with colon cancer. Paired t tests were used to analyze the differences in nuclear SOX4 expression between tumor and non-tumor tissues from each patient. Two-tailed Χ(2 tests were performed to determine whether the differences in nuclear SOX4 expression and clinicopathologic parameters were significant. Time-to-event endpoints for clinicopathologic parameters were plotted using the Kaplan-Meier method, and statistical significance was determined using univariate log-rank tests. Cox proportional hazard model was used for multivariate analysis to determine the independence of prognostic effects of nuclear SOX4 expression. Overexpression of nuclear SOX4 was significantly correlated with depth of invasion (P = 0.0041, distant metastasis (P<0.0001, and stage (P = 0.0001. Patients who displayed high expression levels of nuclear SOX4 achieved a significantly poorer disease-free survival rate, compared with patients with low SOX4 expression levels (P<0.001. Univariate Cox regression analysis showed that overexpression of nuclear SOX4 was a clear prognostic marker for colon cancer (P = 0.001. Overexpression of nuclear SOX4 may be used as a marker to predict the outcome of patients with colon cancer.

  3. Clinical and prognostic association of transcription factor SOX4 in gastric cancer.

    Directory of Open Access Journals (Sweden)

    Chia-Lang Fang

    Full Text Available Gastric cancer (GC is one of the most common malignant cancers worldwide. However, little is known about the molecular process by which this disease develops and progresses. This study investigated correlations between the expression of nuclear transcription factor SOX4 and various clinicopathologic parameters as well as patients' survival. Expression levels of nuclear SOX4 were analyzed by immunohistochemistry; the data comprised gastric tissues from 168 patients with GC. Paired t tests were used to analyze the differences in nuclear SOX4 expression between tumor and non-tumor tissues from each patient. Two-tailed Χ(2 tests were performed to determine whether the differences in nuclear SOX4 expression and clinicopathologic parameters were significant. Time-to-event endpoints for clinicopathologic parameters were plotted using the Kaplan-Meier method, and statistical significance was determined using univariate log-rank tests. Cox proportional hazard model was used for multivariate analysis to determine the independence of prognostic effects of nuclear SOX4 expression. Overexpression of nuclear SOX4 was significantly correlated with depth of invasion (P<0.0001, nodal status (P=0.0055, distant metastasis (P=0.0195, stage (P=0.0003, and vascular invasion (P=0.0383. Patients who displayed high expression levels of nuclear SOX4 achieved a significantly poorer disease-free survival rate, compared with patients with low SOX4 expression levels (P=0.003. Univariate Cox regression analysis showed that overexpression of nuclear SOX4 was a clear prognostic marker for GC (P=0.004. Overexpression of nuclear SOX4 can be used as a marker to predict the outcome of patients with GC.

  4. SOX9 indirectly regulates CEACAM1 expression and immune resistance in melanoma cells.

    Science.gov (United States)

    Ashkenazi, Shira; Ortenberg, Rona; Besser, Michal; Schachter, Jacob; Markel, Gal

    2016-05-24

    As melanoma cells are immunogenic, they instigate an adaptive immune response and production of anti-tumor T-cells. A central factor in this interaction is CEACAM1 (carcinoembryonic antigen cell adhesion molecule 1), a transmembrane glycoprotein previously shown in our lab to protect melanoma cells from T cell-mediated killing. In this study, we examine the role of transcription factor SOX9 in the regulation of CEACAM1 expression and immune resistance in melanoma cells. Knockdown of endogenous SOX9 results in CEACAM1 up-regulation, while its overexpression leads to the opposite effect. We show that SOX9 controls CEACAM1 expression at a transcriptional level, but in an indirect manner, as regulation of the CEACAM1 promoter remains intact even when all eight potential SOX9-binding sites are abolished. A series of promoter truncations localizes the SOX9-controlled area to the proximal 200bp of the promoter. Point mutations in putative Sp1 and ETS1 binding sites identify these transcription factors as the primary SOX9-controlled mediators. Co-immunoprecipitation studies show that SOX9 and Sp1 physically interact in melanoma cells, while silencing of SOX9 down-regulates ETS1, but not Sp1, in the same cells. Finally, knockdown of SOX9 indeed renders melanoma cells resistant to T cell-mediated killing, in line with the increased CEACAM1 expression. In conclusion, we show that SOX9 regulates CEACAM1 expression in melanoma cells, and thereby their immune resistance. As CEACAM1 is a pivotal protein in melanoma biology and immune crosstalk, further understanding of its regulation can provide new insights and contribute to the development of novel approaches to therapy.

  5. Effects of acupuncture on cortical expression of Wnt3a, β-catenin and Sox2 in a rat model of traumatic brain injury.

    Science.gov (United States)

    Zhang, Yi-min; Dai, Qiu-fu; Chen, Wei-hao; Jiang, Shu-ting; Chen, Sheng-xin; Zhang, Yu-juan; Tang, Chun-zhi; Cheng, Shao-bing

    2016-02-01

    To observe the effects of acupuncture treatment on the expression of Wnt/β-catenin signalling pathway-related genes (Wnt3a, β-catenin and Sox2) in the injured cerebral cortex of rats with traumatic brain injury (TBI). A controlled impact model of TBI was established using Feeney's free-drop method. Seventy-eight Sprague-Dawley rats were randomly divided into the following three groups: a normal group (n=18) that was left untreated; a model group (n=30) that received no treatment after TBI; and an acupuncture group (n=30) that received acupuncture (at LI4, GV20, GV26 and GV16) after TBI. Rats in each group were randomly and equally divided into 3-day, 7-day and 14-day subgroups according to the duration of therapy. Real-time fluorescence quantitative PCR (RT-qPCR) was used to measure mRNA expression of Wnt3a, β-catenin and Sox2. Western blots were performed to determine the expression levels of WNT3a, β-Catenin and SOX2. Wnt3a mRNA was upregulated in the 7-day and 14-day acupuncture subgroups compared with the corresponding model subgroups (pacupuncture subgroups compared with the corresponding model subgroups (pacupuncture subgroups, Sox2 expression was significantly higher than that in the normal and model groups (pAcupuncture exerts a regulatory effect on the Wnt/β-catenin signalling pathway, which may in turn influence the proliferation and differentiation of endogenous neural stem cells. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  6. The relationship between high mobility group-B1/receptor for advanced glycation endproducts and Alzheimer's disease%高迁移率组蛋白1/晚期糖基化终末产物受体与阿尔茨海默病

    Institute of Scientific and Technical Information of China (English)

    耿丽颖; 王珊; 王斌斌; 孙雪娇; 张国华

    2016-01-01

    随着时代的发展、科技的进步,人们的物质文化水平也逐步提高,除了对物质的追求之外,对精神方面的享受也更加注重,然而阿尔茨海默病(AD)却大大地影响了人们晚年的生活质量.阿尔茨海默病可能的发病机制包括:Aβ沉积、tau蛋白过度磷酸化、神经血管功能紊乱、细胞周期异常、炎症、氧化应激、线粒体功能障碍.而由Aβ沉积引起的炎性反应在其发病机制中至关重要.高迁移率组蛋白1(HMGB1)及晚期糖基化终末产物受体(RAGE)均可参与Aβ沉积而在阿尔茨海默病中发挥作用,两者结合后也可引起炎症反应等效应,促进阿尔茨海默病的进展.本文就HMGB1/RAGE及其与阿尔茨海默病的相关研究做一综述.%As the development of the times and scientific progress,people's material culture has been enhanced.We pay attention to not only the material pursuing but also spiritual enjoyment.However,Alzheimer's disease affects the quality of late-life significantly.Congnitive disorder is one clinical symptom of Alzheimer's disease,which influences people's later life the most.β-amyloid (Aβ) plaques accumulation,tau protein hyperphosphorylation,nerve vascular dysfunction,abnormal cell cycle,inflammation,oxidative stress,and mitochondrial disorder may be the pathogenesis of Alzheimer's disease.The inflammation of Alzheimer's disease can be caused by the nervous lesions that are generated by the inflammatory mediator released by activated neurogliocyte around Aβ.High mobility group-B1 (HMGB1) and receptor for advanced glycation endproducts (RAGE) are closely related to the inflammation.It may also promote the progresses of Alzheimer;s disease,if HMGB1 is combined with RAGE.This review aims to elaborate the relationship between HMGB1/RAGE and Alzheimer's disease.

  7. Search for B-meson decays to b1ρ and b1K*

    Science.gov (United States)

    Aubert, B.; Karyotakis, Y.; Lees, J. P.; Poireau, V.; Prencipe, E.; Prudent, X.; Tisserand, V.; Garra Tico, J.; Grauges, E.; Martinelli, M.; Palano, A.; Pappagallo, M.; Eigen, G.; Stugu, B.; Sun, L.; Battaglia, M.; Brown, D. N.; Hooberman, B.; Kerth, L. T.; Kolomensky, Yu. G.; Lynch, G.; Osipenkov, I. L.; Tackmann, K.; Tanabe, T.; Hawkes, C. M.; Soni, N.; Watson, A. T.; Koch, H.; Schroeder, T.; Asgeirsson, D. J.; Hearty, C.; Mattison, T. S.; McKenna, J. A.; Barrett, M.; Khan, A.; Randle-Conde, A.; Blinov, V. E.; Bukin, A. D.; Buzykaev, A. R.; Druzhinin, V. P.; Golubev, V. B.; Onuchin, A. P.; Serednyakov, S. I.; Skovpen, Yu. I.; Solodov, E. P.; Todyshev, K. Yu.; Bondioli, M.; Curry, S.; Eschrich, I.; Kirkby, D.; Lankford, A. J.; Lund, P.; Mandelkern, M.; Martin, E. C.; Stoker, D. P.; Atmacan, H.; Gary, J. W.; Liu, F.; Long, O.; Vitug, G. M.; Yasin, Z.; Sharma, V.; Campagnari, C.; Hong, T. M.; Kovalskyi, D.; Mazur, M. A.; Richman, J. D.; Beck, T. W.; Eisner, A. M.; Heusch, C. A.; Kroseberg, J.; Lockman, W. S.; Martinez, A. J.; Schalk, T.; Schumm, B. A.; Seiden, A.; Wang, L.; Winstrom, L. O.; Cheng, C. H.; Doll, D. A.; Echenard, B.; Fang, F.; Hitlin, D. G.; Narsky, I.; Ongmongkolkul, P.; Piatenko, T.; Porter, F. C.; Andreassen, R.; Mancinelli, G.; Meadows, B. T.; Mishra, K.; Sokoloff, M. D.; Bloom, P. C.; Chavez, A.; Ford, W. T.; Gaz, A.; Hirschauer, J. F.; Nagel, M.; Nauenberg, U.; Smith, J. G.; Wagner, S. R.; Ayad, R.; Toki, W. H.; Wilson, R. J.; Feltresi, E.; Hauke, A.; Jasper, H.; Karbach, T. M.; Merkel, J.; Petzold, A.; Spaan, B.; Wacker, K.; Kobel, M. J.; Nogowski, R.; Schubert, K. R.; Schwierz, R.; Bernard, D.; Latour, E.; Verderi, M.; Clark, P. J.; Playfer, S.; Watson, J. E.; Andreotti, M.; Bettoni, D.; Bozzi, C.; Calabrese, R.; Cecchi, A.; Cibinetto, G.; Fioravanti, E.; Franchini, P.; Luppi, E.; Munerato, M.; Negrini, M.; Petrella, A.; Piemontese, L.; Santoro, V.; Baldini-Ferroli, R.; Calcaterra, A.; de Sangro, R.; Finocchiaro, G.; Pacetti, S.; Patteri, P.; Peruzzi, I. M.; Piccolo, M.; Rama, M.; Zallo, A.; Contri, R.; Guido, E.; Lo Vetere, M.; Monge, M. R.; Passaggio, S.; Patrignani, C.; Robutti, E.; Tosi, S.; Chaisanguanthum, K. S.; Morii, M.; Adametz, A.; Marks, J.; Schenk, S.; Uwer, U.; Bernlochner, F. U.; Klose, V.; Lacker, H. M.; Lueck, T.; Volk, A.; Bard, D. J.; Dauncey, P. D.; Tibbetts, M.; Behera, P. K.; Charles, M. J.; Mallik, U.; Cochran, J.; Crawley, H. B.; Dong, L.; Eyges, V.; Meyer, W. T.; Prell, S.; Rosenberg, E. I.; Rubin, A. E.; Gao, Y. Y.; Gritsan, A. V.; Guo, Z. J.; Arnaud, N.; Béquilleux, J.; D'Orazio, A.; Davier, M.; Derkach, D.; Firmino da Costa, J.; Grosdidier, G.; Le Diberder, F.; Lepeltier, V.; Lutz, A. M.; Malaescu, B.; Pruvot, S.; Roudeau, P.; Schune, M. H.; Serrano, J.; Sordini, V.; Stocchi, A.; Wormser, G.; Lange, D. J.; Wright, D. M.; Bingham, I.; Burke, J. P.; Chavez, C. A.; Fry, J. R.; Gabathuler, E.; Gamet, R.; Hutchcroft, D. E.; Payne, D. J.; Touramanis, C.; Bevan, A. J.; Clarke, C. K.; di Lodovico, F.; Sacco, R.; Sigamani, M.; Cowan, G.; Paramesvaran, S.; Wren, A. C.; Brown, D. N.; Davis, C. L.; Denig, A. G.; Fritsch, M.; Gradl, W.; Hafner, A.; Alwyn, K. E.; Bailey, D.; Barlow, R. J.; Jackson, G.; Lafferty, G. D.; West, T. J.; Yi, J. I.; Anderson, J.; Chen, C.; Jawahery, A.; Roberts, D. A.; Simi, G.; Tuggle, J. M.; Dallapiccola, C.; Salvati, E.; Cowan, R.; Dujmic, D.; Fisher, P. H.; Henderson, S. W.; Sciolla, G.; Spitznagel, M.; Yamamoto, R. K.; Zhao, M.; Patel, P. M.; Robertson, S. H.; Schram, M.; Biassoni, P.; Lazzaro, A.; Lombardo, V.; Palombo, F.; Stracka, S.; Cremaldi, L.; Godang, R.; Kroeger, R.; Sonnek, P.; Summers, D. J.; Zhao, H. W.; Simard, M.; Taras, P.; Nicholson, H.; de Nardo, G.; Lista, L.; Monorchio, D.; Onorato, G.; Sciacca, C.; Raven, G.; Snoek, H. L.; Jessop, C. P.; Knoepfel, K. J.; Losecco, J. M.; Wang, W. F.; Corwin, L. A.; Honscheid, K.; Kagan, H.; Kass, R.; Morris, J. P.; Rahimi, A. M.; Sekula, S. J.; Wong, Q. K.; Blount, N. L.; Brau, J.; Frey, R.; Igonkina, O.; Kolb, J. A.; Lu, M.; Rahmat, R.; Sinev, N. B.; Strom, D.; Strube, J.; Torrence, E.; Castelli, G.; Gagliardi, N.; Margoni, M.; Morandin, M.; Posocco, M.; Rotondo, M.; Simonetto, F.; Stroili, R.; Voci, C.; Del Amo Sanchez, P.; Ben-Haim, E.; Bonneaud, G. R.; Briand, H.; Chauveau, J.; Hamon, O.; Leruste, Ph.; Marchiori, G.; Ocariz, J.; Perez, A.; Prendki, J.; Sitt, S.; Gladney, L.; Biasini, M.; Manoni, E.; Angelini, C.; Batignani, G.; Bettarini, S.; Calderini, G.; Carpinelli, M.; Cervelli, A.; Forti, F.; Giorgi, M. A.; Lusiani, A.; Morganti, M.; Neri, N.; Paoloni, E.; Rizzo, G.; Walsh, J. J.; Lopes Pegna, D.; Lu, C.; Olsen, J.; Smith, A. J. S.; Telnov, A. V.; Anulli, F.; Baracchini, E.; Cavoto, G.; Faccini, R.; Ferrarotto, F.; Ferroni, F.; Gaspero, M.; Jackson, P. D.; Li Gioi, L.

    2009-09-01

    We present a search for decays of B mesons to final states with a b1 meson and a ρ or K*(892) meson. The search is based on a data sample consisting of 465 million B Bmacr pairs collected by the BABAR detector at the SLAC National Accelerator Laboratory. We do not observe any statistically significant signal. The upper limits we set on the branching fractions range from 1.4 to 8.0×10-6 at the 90% confidence level, including systematic uncertainties.

  8. Dynamic scenario of membrane binding process of kalata b1.

    Directory of Open Access Journals (Sweden)

    Wanapinun Nawae

    Full Text Available Kalata B1 (kB1, a cyclotide that has been used in medical applications, displays cytotoxicity related to membrane binding and oligomerization. Our molecular dynamics simulation results demonstrate that Trp19 in loop 5 of both monomeric and tetrameric kB1 is a key residue for initial anchoring in the membrane binding process. This residue also facilitates the formation of kB1 tetramers. Additionally, we elucidate that kB1 preferentially binds to the membrane interfacial zone and is unable to penetrate into the membrane. In particular, significant roles of amino acid residues in loop 5 and loop 6 on the localization of kB1 to this membrane-water interface zone are found. This study reveals the roles of amino acid residues in the bioactivity of kB1, which is information that can be useful for designing new therapeutic cyclotides with less toxicity.

  9. SWI/SNF enzymes promote SOX10- mediated activation of myelin gene expression.

    Directory of Open Access Journals (Sweden)

    Himangi G Marathe

    Full Text Available SOX10 is a Sry-related high mobility (HMG-box transcriptional regulator that promotes differentiation of neural crest precursors into Schwann cells, oligodendrocytes, and melanocytes. Myelin, formed by Schwann cells in the peripheral nervous system, is essential for propagation of nerve impulses. SWI/SNF complexes are ATP dependent chromatin remodeling enzymes that are critical for cellular differentiation. It was recently demonstrated that the BRG1 subunit of SWI/SNF complexes activates SOX10 expression and also interacts with SOX10 to activate expression of OCT6 and KROX20, two transcriptional regulators of Schwann cell differentiation. To determine the requirement for SWI/SNF enzymes in the regulation of genes that encode components of myelin, which are downstream of these transcriptional regulators, we introduced SOX10 into fibroblasts that inducibly express dominant negative versions of the SWI/SNF ATPases, BRM or BRG1. Dominant negative BRM and BRG1 have mutations in the ATP binding site and inhibit gene activation events that require SWI/SNF function. Ectopic expression of SOX10 in cells derived from NIH 3T3 fibroblasts led to the activation of the endogenous Schwann cell specific gene, myelin protein zero (MPZ and the gene that encodes myelin basic protein (MBP. Thus, SOX10 reprogrammed these cells into myelin gene expressing cells. Ectopic expression of KROX20 was not sufficient for activation of these myelin genes. However, KROX20 together with SOX10 synergistically activated MPZ and MBP expression. Dominant negative BRM and BRG1 abrogated SOX10 mediated activation of MPZ and MBP and synergistic activation of these genes by SOX10 and KROX20. SOX10 was required to recruit BRG1 to the MPZ locus. Similarly, in immortalized Schwann cells, BRG1 recruitment to SOX10 binding sites at the MPZ locus was dependent on SOX10 and expression of dominant negative BRG1 inhibited expression of MPZ and MBP in these cells. Thus, SWI/SNF enzymes cooperate

  10. SWI/SNF enzymes promote SOX10- mediated activation of myelin gene expression.

    Science.gov (United States)

    Marathe, Himangi G; Mehta, Gaurav; Zhang, Xiaolu; Datar, Ila; Mehrotra, Aanchal; Yeung, Kam C; de la Serna, Ivana L

    2013-01-01

    SOX10 is a Sry-related high mobility (HMG)-box transcriptional regulator that promotes differentiation of neural crest precursors into Schwann cells, oligodendrocytes, and melanocytes. Myelin, formed by Schwann cells in the peripheral nervous system, is essential for propagation of nerve impulses. SWI/SNF complexes are ATP dependent chromatin remodeling enzymes that are critical for cellular differentiation. It was recently demonstrated that the BRG1 subunit of SWI/SNF complexes activates SOX10 expression and also interacts with SOX10 to activate expression of OCT6 and KROX20, two transcriptional regulators of Schwann cell differentiation. To determine the requirement for SWI/SNF enzymes in the regulation of genes that encode components of myelin, which are downstream of these transcriptional regulators, we introduced SOX10 into fibroblasts that inducibly express dominant negative versions of the SWI/SNF ATPases, BRM or BRG1. Dominant negative BRM and BRG1 have mutations in the ATP binding site and inhibit gene activation events that require SWI/SNF function. Ectopic expression of SOX10 in cells derived from NIH 3T3 fibroblasts led to the activation of the endogenous Schwann cell specific gene, myelin protein zero (MPZ) and the gene that encodes myelin basic protein (MBP). Thus, SOX10 reprogrammed these cells into myelin gene expressing cells. Ectopic expression of KROX20 was not sufficient for activation of these myelin genes. However, KROX20 together with SOX10 synergistically activated MPZ and MBP expression. Dominant negative BRM and BRG1 abrogated SOX10 mediated activation of MPZ and MBP and synergistic activation of these genes by SOX10 and KROX20. SOX10 was required to recruit BRG1 to the MPZ locus. Similarly, in immortalized Schwann cells, BRG1 recruitment to SOX10 binding sites at the MPZ locus was dependent on SOX10 and expression of dominant negative BRG1 inhibited expression of MPZ and MBP in these cells. Thus, SWI/SNF enzymes cooperate with SOX10 to

  11. A Novel Regulatory Mechanism of Type II Collagen Expression via a SOX9-dependent Enhancer in Intron 6.

    Science.gov (United States)

    Yasuda, Hideyo; Oh, Chun-do; Chen, Di; de Crombrugghe, Benoit; Kim, Jin-Hoi

    2017-01-13

    Type II collagen α1 is specific for cartilaginous tissues, and mutations in its gene are associated with skeletal diseases. Its expression has been shown to be dependent on SOX9, a master transcription factor required for chondrogenesis that binds to an enhancer region in intron 1. However, ChIP sequencing revealed that SOX9 does not strongly bind to intron 1, but rather it binds to intron 6 and a site 30 kb upstream of the transcription start site. Here, we aimed to determine the role of the novel SOX9-binding site in intron 6. We prepared reporter constructs that contain a Col2a1 promoter, intron 1 with or without intron 6, and the luciferase gene. Although the reporter constructs were not activated by SOX9 alone, the construct that contained both introns 1 and 6 was activated 5-10-fold by the SOX9/SOX5 or the SOX9/SOX6 combination in transient-transfection assays in 293T cells. This enhancement was also observed in rat chondrosarcoma cells that stably expressed the construct. CRISPR/Cas9-induced deletion of intron 6 in RCS cells revealed that a 10-bp region of intron 6 is necessary both for Col2a1 expression and SOX9 binding. Furthermore, SOX9, but not SOX5, binds to this region as demonstrated in an electrophoretic mobility shift assay, although both SOX9 and SOX5 bind to a larger 325-bp fragment of intron 6 containing this small sequence. These findings suggest a novel mechanism of action of SOX5/6; namely, the SOX9/5/6 combination enhances Col2a1 transcription through a novel enhancer in intron 6 together with the enhancer in intron 1. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Search for sterile neutrinos with the SOX experiment

    Science.gov (United States)

    Caminata, A.; Agostini, M.; Altenmüller, K.; Appel, S.; Bellini, G.; Benziger, J.; Berton, N.; Bick, D.; Bonfini, G.; Bravo, D.; Caccianiga, B.; Calaprice, F.; Cavalcante, P.; Chepurnov, A.; Choi, K.; Cribier, M.; D'Angelo, D.; Davini, S.; Derbin, A.; Di Noto, L.; Drachnev, I.; Durero, M.; Empl, A.; Etenko, A.; Farinon, S.; Fischer, V.; Fomenko, K.; Franco, D.; Gabriele, F.; Gaffiot, J.; Galbiati, C.; Ghiano, C.; Giammarchi, M.; Goeger-Neff, M.; Goretti, A.; Gromov, M.; Hagner, C.; Houdy, Th.; Hungerford, E.; Ianni, Aldo; Ianni, Andrea; Jonquères, N.; Jedrzejczak, K.; Kaiser, M.; Kobychev, V.; Korablev, D.; Korga, G.; Kornoukhov, V.; Kryn, D.; Lachenmaier, T.; Lasserre, T.; Laubenstein, M.; Lehnert, B.; Link, J.; Litvinovich, E.; Lombardi, F.; Lombardi, P.; Ludhova, L.; Lukyanchenko, G.; Machulin, I.; Manecki, S.; Maneschg, W.; Marcocci, S.; Maricic, J.; Mention, G.; Meroni, E.; Meyer, M.; Miramonti, L.; Misiaszek, M.; Montuschi, M.; Mosteiro, P.; Muratova, V.; Musenich, R.; Neumair, B.; Oberauer, L.; Obolensky, M.; Ortica, F.; Otis, K.; Pagani, L.; Pallavicini, M.; Papp, L.; Perasso, L.; Pocar, A.; Ranucci, G.; Razeto, A.; Re, A.; Romani, A.; Roncin, R.; Rossi, N.; Schönert, S.; Scola, L.; Semenov, D.; Simgen, H.; Skorokhvatov, M.; Smirnov, O.; Sotnikov, A.; Sukhotin, S.; Suvorov, Y.; Tartaglia, R.; Testera, G.; Thurn, J.; Toropova, M.; Unzhakov, E.; Veyssière, C.; Vivier, M.; Vogelaar, R. B.; von Feilitzsch, F.; Wang, H.; Weinz, S.; Winter, J.; Wojcik, M.; Wurm, M.; Yokley, Z.; Zaimidoroga, O.; Zavatarelli, S.; Zuber, K.; Zuzel, G.

    2016-01-01

    In the recent years, the Borexino detector has proven its outstanding performances in detecting neutrinos and antineutrinos in the low energy regime. Consequently, it is an ideal tool to investigate the existence of sterile neutrinos, whose presence has been suggested by several anomalies over the past two decades. The SOX ( Short distance neutrino Oscillations with boreXino) project will investigate the presence of sterile neutrinos placing a neutrino and an antineutrino sources in a location under the detector foreseen for this purpose since the construction of Borexino. Interacting in the detector active volume, each beam would create a well detectable spatial wave pattern in case of oscillation of neutrino or antineutrino in a sterile state. Otherwise, the experiment will set a very stringent limit on the existence of a sterile state.

  13. Metabolism of aflatoxin B1 and identification of the major aflatoxin B1-DNA adducts formed in cultured human bronchus and colon

    DEFF Research Database (Denmark)

    1979-01-01

    compared to aflatoxin B1, the binding level of benzo(a)pyrene to both bronchial and colonic DNA was generally higher. The major adducts formed in both tissues by the interaction of aflatoxin B1 and DNA were chromatographically identical to 2,3-dihydro-2-(N7-guanyl)-3-hydroxyaflatoxin B1 (Structure 1......) with the guanyl group and hydroxy group in trans-position and an adduct which has been tentatively identified by other investigators as 2,3-dihydro-2-(N5-formyl-2',5',6'-triamino-4'-oxo-N5-pyrimidyl)-3-hydroxyaflatoxin B1 (Structure 11). Seventy % of the radioactivity associated with bronchial DNA was found...... in these two peaks, and the ratio of radioactivity between the peaks was nearly 1. In colonic DNA, the ratio between Structures 1 and 11 was approximately 2. These observations add aflatoxin B1 to the list of chemical procarcinogens metabolized by cultured human tissues and in which the carcinogen-DNA adducts...

  14. Effects of high mobility group box-1 protein on cytokine expreesion in splenic dendritic cells in rats%高迁移率族蛋白B1对大鼠脾脏树突状细胞细胞因子表达的影响

    Institute of Scientific and Technical Information of China (English)

    徐姗; 姚咏明; 姚风华; 董宁; 刘峰; 于燕

    2009-01-01

    目的 观察高迁移率族蛋白B1(HMGB1)对树突状细胞(dendritic cells,DC)细胞因子蛋白合成和基因表达的影响.方法 分离正常Wistar大鼠脾脏DC后置于96孔培养板(1×105/孔),给予重组HMGB1刺激,研究HMGB1刺激与TNF-α,IL-12蛋白合成和基因表达的时间-效应关系,24孔细胞随机分为6组:正常对照24 h组(4孔/组)、正常对照48 h组(4孔/组)、正常对照72 h组(4孔/组)、HMGB1 24 h组(4孔/组)、HMGB1 48 h组(4孔/组)和HMGB1 72 h组(4孔/组),后3组分别以1 μg/mLHMGB1 刺激.刺激相应时间检测TNF-α,IL-12 mRNA的表达和蛋白水平.研究HMGB1刺激与TNF-α,IL-12蛋白合成和基因表达的剂量-效应关系,16孔细胞随机分为4组:正常对照组(4孔/组)、0.1μg/mL组(4孔/组)、1 μg/mL组(4孔/组)和10 μg/mL组(4孔/组),分别以相应剂量HMGB1刺激.刺激后48 h后检测TNF-α、IL-12 mRNA的表达和蛋白水平.应用Promega公司mRNA提取试剂盒裂解收集的DC,提取细胞mRNA.采用SYBR Green real-time(实时荧光定量)PCR技术检测TNF-α mRNA,IL-12mRNA表达水平.以三磷酸甘油脱氢酶(GAPDH)作为内参对照.扩增产物经Fast 7500 real-time PCR仪处理,作相对定量(RQ)分析.以ELISA试剂盒检测各组上清中IL-12,TNF-α蛋白水平.数据进行单因素方差分析,以P<0.05为差异具有统计学意义.结果 1 μg/mL HMGB1 刺激后,脾脏DC IL-12,TNF-α蛋白合成和基因表达均分别于24~72 h明显上调(P<0.05或P<0.01),其中以作用48 h后其表达上调尤为显著(P<0.01);0.1/.μg/mL,1 tcVmL,10μg/mL HMGB1刺激48 h均可诱导DC IL-12、TNF-α蛋白合成和基因表达增强(P<0.01),其中HMGB1浓度在1 μg/mL时,DC IL-12和TNF-α蛋白合成和基因表达表达最明显(P<0.01).结论 HMGB1诱导DC成熟分化过程中能促进DC合成、释放IL-12和TNF-α,从而发挥其免疫调节作用.%Objective To investigate the effect of high mobility group box-1 protein (HMGB1) on cytokine expression in splenic

  15. Rapid modulation of the organic anion transporting polypeptide 2B1 (OATP2B1, SLCO2B1) function by protein kinase C-mediated internalization.

    Science.gov (United States)

    Köck, Kathleen; Koenen, Anna; Giese, Bernd; Fraunholz, Martin; May, Karen; Siegmund, Werner; Hammer, Elke; Völker, Uwe; Jedlitschky, Gabriele; Kroemer, Heyo K; Grube, Markus

    2010-04-09

    Members of the organic anion transporting polypeptide (OATP) family are involved in various pharmacological, pathophysiological, and physiological processes, such as hepatic drug uptake, progress of cancer, or transport of hormones. Although variability in expression and function of OATPs has been investigated in detail, data concerning regulation are rather limited. Here, we report a novel mechanism for rapid regulation of OATP2B1 mediated by protein kinase C (PKC) resulting in significant changes of transport activity. PKC activation by the phorbol ester (phorbol 12-myristate 13-acetate, PMA) resulted in increased phosphorylation of OATP2B1 as well as reduced OATP2B1 transport activity with a decrease in V(max) of E(1)S uptake (288 +/- 21 (control) versus 165 +/- 16 pmol/min/mg of protein (PMA)). This effect was sensitive to the PKC inhibitor bisindolylmaleimide I (BIM-I). Confocal microscopy, fluorescence-based internalization assay, and live-cell imaging using green fluorescent protein-tagged OATP2B1 revealed that transport inhibition was due to internalization of the transporter. Furthermore, colocalization with LAMP-2 and chloroquine-sensitive degradation of OATP2B1 suggest that the internalized protein is targeted to a lysosomal degradation pathway. With regard to the underlying mechanism inhibition of caveolin/lipid raft-mediated endocytosis failed to prevent OATP2B1 internalization, whereas inhibition of clathrin-mediated processes blocked OATP2B1 sequestration. However, small interfering RNA-mediated clathrin knock-down affected general trafficking of OATP2B1 and resulted in intracellular accumulation in the absence of PMA. In conclusion, our data demonstrate that OATP2B1 function is regulated by PKC-mediated, clathrin-dependent internalization and followed by lysosomal degradation. Furthermore, internalization could be shown in an ex vivo placenta perfusion. Our findings represent a new, rapid mechanism in regulation of human OATPs.

  16. Expression of the stem cell marker, SOX2, in ameloblastoma and dental epithelium.

    Science.gov (United States)

    Juuri, Emma; Isaksson, Sanna; Jussila, Maria; Heikinheimo, Kristiina; Thesleff, Irma

    2013-12-01

    Ameloblastomas are locally invasive odontogenic tumors that exhibit a high rate of recurrence and often associate with the third molars. They are suggested to originate from dental epithelium because the tumor cells resemble epithelial cells of developing teeth. Expression of the transcription factor SOX2 has been previously localized in epithelial stem and progenitor cells in developing teeth as well as in various tumors. Here, we show that SOX2 is expressed in the epithelial cells of follicular and plexiform ameloblastomas. SOX2 was localized in the dental lamina of developing human primary molars. It was also expressed in the fragmented dental lamina associated with the third molars and in the epithelium budding from its posterior aspect in mice. However, no SOX2 expression was detected in either Hertwig's epithelial root sheath directing the formation of roots or in the epithelial cell rests of Malassez covering the completed roots. SOX2 was associated with supernumerary tooth formation in odontoma-like tumors induced by Wnt signal activation in mice. We propose that SOX2 functions in maintaining the progenitor state of epithelium in ameloblastomas and that ameloblastomas may originate from SOX2-expressing dental lamina epithelium.

  17. Zebrafish sox9b is crucial for hepatopancreatic duct development and pancreatic endocrine cell regeneration.

    Science.gov (United States)

    Manfroid, Isabelle; Ghaye, Aurélie; Naye, François; Detry, Nathalie; Palm, Sarah; Pan, Luyuan; Ma, Taylur P; Huang, Wei; Rovira, Meritxell; Martial, Joseph A; Parsons, Michael J; Moens, Cecilia B; Voz, Marianne L; Peers, Bernard

    2012-06-15

    Recent zebrafish studies have shown that the late appearing pancreatic endocrine cells are derived from pancreatic ducts but the regulatory factors involved are still largely unknown. Here, we show that the zebrafish sox9b gene is expressed in pancreatic ducts where it labels the pancreatic Notch-responsive cells previously shown to be progenitors. Inactivation of sox9b disturbs duct formation and impairs regeneration of beta cells from these ducts in larvae. sox9b expression in the midtrunk endoderm appears at the junction of the hepatic and ventral pancreatic buds and, by the end of embryogenesis, labels the hepatopancreatic ductal system as well as the intrapancreatic and intrahepatic ducts. Ductal morphogenesis and differentiation are specifically disrupted in sox9b mutants, with the dysmorphic hepatopancreatic ducts containing misdifferentiated hepatocyte-like and pancreatic-like cells. We also show that maintenance of sox9b expression in the extrapancreatic and intrapancreatic ducts requires FGF and Notch activity, respectively, both pathways known to prevent excessive endocrine differentiation in these ducts. Furthermore, beta cell recovery after specific ablation is severely compromised in sox9b mutant larvae. Our data position sox9b as a key player in the generation of secondary endocrine cells deriving from pancreatic ducts in zebrafish. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. Sox9 plays multiple roles in the lung epithelium during branching morphogenesis.

    Science.gov (United States)

    Rockich, Briana E; Hrycaj, Steven M; Shih, Hung Ping; Nagy, Melinda S; Ferguson, Michael A H; Kopp, Janel L; Sander, Maike; Wellik, Deneen M; Spence, Jason R

    2013-11-19

    Lung branching morphogenesis is a highly orchestrated process that gives rise to the complex network of gas-exchanging units in the adult lung. Intricate regulation of signaling pathways, transcription factors, and epithelial-mesenchymal cross-talk are critical to ensuring branching morphogenesis occurs properly. Here, we describe a role for the transcription factor Sox9 during lung branching morphogenesis. Sox9 is expressed at the distal tips of the branching epithelium in a highly dynamic manner as branching occurs and is down-regulated starting at embryonic day 16.5, concurrent with the onset of terminal differentiation of type 1 and type 2 alveolar cells. Using epithelial-specific genetic loss- and gain-of-function approaches, our results demonstrate that Sox9 controls multiple aspects of lung branching. Fine regulation of Sox9 levels is required to balance proliferation and differentiation of epithelial tip progenitor cells, and loss of Sox9 leads to direct and indirect cellular defects including extracellular matrix defects, cytoskeletal disorganization, and aberrant epithelial movement. Our evidence shows that unlike other endoderm-derived epithelial tissues, such as the intestine, Wnt/β-catenin signaling does not regulate Sox9 expression in the lung. We conclude that Sox9 collectively promotes proper branching morphogenesis by controlling the balance between proliferation and differentiation and regulating the extracellular matrix.

  19. SOX7 is involved in aspirin-mediated growth inhibition of human colorectal cancer cells

    Institute of Scientific and Technical Information of China (English)

    Xin Zhou; Shu-Yan Huang; Jing-Xin Feng; Yan-Yan Gao; Li Zhao; Jun Lu; Bai-Qu Huang; Yu Zhang

    2011-01-01

    AIM: To confirm the role of sex-determining region Y-box 7 (Sox7) in aspirin-mediated growth inhibition of COX-independent human colorectal cancer cells.METHODS: The cell survival percentage was examined by MTT (Moto-nuclear cell direc cytotoxicity) assay.SOX7 expression was assessed by using reverse transcription-polymerase chain reaction and Western blotting. SB203580 was used to inhibit the p38MAPK signal pathway. SOX7 promoter activity was detected by Luciferase reporter assay.RESULTS: SOX7 was upregulated by aspirin and was involved in aspirin-mediated growth inhibition of SW480 human colorectal cancer cells. The p38MAPK pathway played a role in aspirin-induced SOX7 expression, during which the AP1 transcription factors c-Jun and c-Fos upregulated SOX7 promoter activities.RESULTS: SOX7 is upregulated by aspirin and is involved in aspirin-mediated growth inhibition of human colorectal cancer SW480 cells.

  20. The role of SOX9 transcription factor in pancreatic and duodenal development.

    Science.gov (United States)

    Belo, Jamie; Krishnamurthy, Mansa; Oakie, Amanda; Wang, Rennian

    2013-11-15

    Progenitor expansion during development is a highly regulated process dictating the final organ size, while expansion of specific progenitor populators can adjust the final cellular composition of the organ. Understanding factors involved in these pathways is required to develop cell-based therapies such as β-cell transplantation for conditions such as diabetes mellitus. One versatile factor controlling both processes as well as a network of other proteins involved in pancreatic and duodenal development is the transcription factor SOX9. This review will focus on a comparison of SOX9 function during progenitor expansion and differentiation in the developing pancreas and duodenum with specific focus on endocrine development. During human pancreatic development, SOX9 functions in a dose-dependent manner to regulate epithelial progenitor expansion and endocrine differentiation. SOX9 expression is eventually limited to a subset of ductal and centroacinar cells, hypothesized to be the pancreatic stem cell compartment. Similarly, during duodenal development, SOX9 is expressed in most early epithelial progenitors and becomes gradually restricted to proliferative progenitors in the lower crypts, as well as mature Paneth and enteroendocrine cells indicating some differences in functional roles. However, in both developmental contexts, SOX9 is involved in pathways responsible for cellular proliferation and differentiation, such as Notch and Wnt. With its adaptable and central function in progenitor control, SOX9 represents an attractive target for manipulation for in vitro progenitor expansion and differentiation meriting further investigation.

  1. Profiling of Sox4-dependent transcriptome in skin links tumour suppression and adult stem cell activation

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    Miguel Foronda

    2015-12-01

    Full Text Available Adult stem cells (ASCs reside in specific niches in a quiescent state in adult mammals. Upon specific cues they become activated and respond by self-renewing and differentiating into newly generated specialised cells that ensure appropriate tissue fitness. ASC quiescence also serves as a tumour suppression mechanism by hampering cellular transformation and expansion (White AC et al., 2014. Some genes restricted to early embryonic development and adult stem cell niches are often potent modulators of stem cell quiescence, and derailed expression of these is commonly associated to cancer (Vervoort SJ et al., 2013. Among them, it has been shown that recommissioned Sox4 expression facilitates proliferation, survival and migration of malignant cells. By generating a conditional Knockout mouse model in stratified epithelia (Sox4cKO mice, we demonstrated a delayed plucking-induced Anagen in the absence of Sox4. Skin global transcriptome analysis revealed a prominent defect in the induction of transcriptional networks that control hair follicle stem cell (HFSC activation such as those regulated by Wnt/Ctnnb1, Shh, Myc or Sox9, cell cycle and DNA damage response-associated pathways. Besides, Sox4cKO mice are resistant to skin carcinogenesis, thus linking Sox4 to both normal and pathological HFSC activation (Foronda M et al., 2014. Here we provide additional details on the analysis of Sox4-regulated transcriptome in Telogen and Anagen skin. The raw and processed microarray data is deposited in GEO under GSE58155.

  2. SOX2 redirects the developmental fate of the intestinal epithelium toward a premature gastric phenotype

    Institute of Scientific and Technical Information of China (English)

    Lalini Raghoebir; Dick Tibboel; Ron Smits; Robbert J. Rottier; Elvira RM. Bakker; Jason C. Mills; Sigrid Swagemakers; Marjon Buscop-van Kempen; Anne Boerema-de Munck; Siska Driegen; Dies Meijer; Frank Grosveld

    2012-01-01

    Various factors play an essential role in patterning the digestive tract.During development,Sox2 and Cdx2 are exclusively expressed in the anterior and the posterior parts of the primitive gut,respectively.However,it is unclear whether these transcription factors influence each other in determining specification of the na(i)ve gut endoderm.We therefore investigated whether Sox2 redirects the fate of the prospective intestinal part of the primitive gut.Ectopic expression of Sox2 in the posterior region of the primitive gut caused anteriorization of the gut toward a gastric-like phenotype.Sox2 activated the foregut transcriptional program,in spite of sustained co-expression of endogenous Cdx2.However,binding of Cdx2 to its genomic targets and thus its transcriptional activity was strongly reduced.Recent findings indicate that endodermal Cdx2 is required to initiate the intestinal program and to suppress anterior cell fate.Our findings suggest that reduced Cdx2 expression by itself is not sufficient to cause anteriorization,but that Sox2 expression is also required.Moreover,it indicates that the balance between Sox2 and Cdx2 function is essential for proper specification of the primitive gut and that Sox2 may overrule the initial patterning of the primitive gut,emphasizing the plasticity of the primitive gut.

  3. Sox9 Activation is Essential for the Recovery of Lung Function after Acute Lung Injury

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    Lei Li

    2015-09-01

    Full Text Available Background/Aims: Acute lung injury (ALI often predisposes acute respiratory distress syndrome (ARDS in humans, and is featured with neutrophilic alveolitis, injury of the alveolar epithelium and endothelium, hyaline membrane formation, and microvascular thrombi. Although the pathogenesis of ALI is relatively well studied, the knowledge on the molecular regulation of the post-ALI lung recovery are poorly understood. Methods: Here, we used a widely applied bleomycin-induced ALI model to study the molecular mechanisms that underlie the post-ALI lung recovery in mice. We analyzed Sox9 expression in mouse lung by RT-qPCR, Western blot and immunohistochemistry. We analyzed miR-101 levels in mouse lung by RT-qPCR. We inhibited Sox9 in mouse lung by expressing either shRNA for Sox9 or miR-101, and analyzed the effects of Sox9 suppression on lung recovery. Results: We detected a significant increase in Sox9 protein but not mRNA, and a signifcant decrease in miR-101 levels in the mouse lung after ALI. MiR-101 was found to target 3'-UTR of Sox9 mRNA to inhibit its expression. Sox9 inhibition by either shRNA for Sox9 or by miR-101 further impaired the functional recovery of the lung after ALI. Conclusion: Our data suggest that Sox9 activation is essential for the recovery of lung function after ALI, which highlights a previously unappreciated mechanism that controls the post-ALI lung recovery.

  4. Sox2 Promotes Malignancy in Glioblastoma by Regulating Plasticity and Astrocytic Differentiation12

    Science.gov (United States)

    Berezovsky, Artem D.; Poisson, Laila M.; Cherba, David; Webb, Craig P.; Transou, Andrea D.; Lemke, Nancy W.; Hong, Xin; Hasselbach, Laura A.; Irtenkauf, Susan M.; Mikkelsen, Tom; deCarvalho, Ana C.

    2014-01-01

    The high-mobility group–box transcription factor sex-determining region Y–box 2 (Sox2) is essential for the maintenance of stem cells from early development to adult tissues. Sox2 can reprogram differentiated cells into pluripotent cells in concert with other factors and is overexpressed in various cancers. In glioblastoma (GBM), Sox2 is a marker of cancer stemlike cells (CSCs) in neurosphere cultures and is associated with the proneural molecular subtype. Here, we report that Sox2 expression pattern in GBM tumors and patient-derived mouse xenografts is not restricted to a small percentage of cells and is coexpressed with various lineage markers, suggesting that its expression extends beyond CSCs to encompass more differentiated neoplastic cells across molecular subtypes. Employing a CSC derived from a patient with GBM and isogenic differentiated cell model, we show that Sox2 knockdown in the differentiated state abolished dedifferentiation and acquisition of CSC phenotype. Furthermore, Sox2 deficiency specifically impaired the astrocytic component of a biphasic gliosarcoma xenograft model while allowing the formation of tumors with sarcomatous phenotype. The expression of genes associated with stem cells and malignancy were commonly downregulated in both CSCs and serum-differentiated cells on Sox2 knockdown. Genes previously shown to be associated with pluripontency and CSCs were only affected in the CSC state, whereas embryonic stem cell self-renewal genes and cytokine signaling were downregulated, and the Wnt pathway activated in differentiated Sox2-deficient cells. Our results indicate that Sox2 regulates the expression of key genes and pathways involved in GBM malignancy, in both cancer stemlike and differentiated cells, and maintains plasticity for bidirectional conversion between the two states, with significant clinical implications. PMID:24726753

  5. Sox2 Promotes Malignancy in Glioblastoma by Regulating Plasticity and Astrocytic Differentiation

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    Artem D. Berezovsky

    2014-03-01

    Full Text Available The high-mobility group–box transcription factor sex-determining region Y–box 2 (Sox2 is essential for the maintenance of stem cells from early development to adult tissues. Sox2 can reprogram differentiated cells into pluripotent cells in concert with other factors and is overexpressed in various cancers. In glioblastoma (GBM, Sox2 is a marker of cancer stemlike cells (CSCs in neurosphere cultures and is associated with the proneural molecular subtype. Here, we report that Sox2 expression pattern in GBM tumors and patient-derived mouse xenografts is not restricted to a small percentage of cells and is coexpressed with various lineage markers, suggesting that its expression extends beyond CSCs to encompass more differentiated neoplastic cells across molecular subtypes. Employing a CSC derived from a patient with GBM and isogenic differentiated cell model, we show that Sox2 knockdown in the differentiated state abolished dedifferentiation and acquisition of CSC phenotype. Furthermore, Sox2 deficiency specifically impaired the astrocytic component of a biphasic gliosarcoma xenograft model while allowing the formation of tumors with sarcomatous phenotype. The expression of genes associated with stem cells and malignancy were commonly downregulated in both CSCs and serum-differentiated cells on Sox2 knockdown. Genes previously shown to be associated with pluripontency and CSCs were only affected in the CSC state, whereas embryonic stem cell self-renewal genes and cytokine signaling were downregulated, and the Wnt pathway activated in differentiated Sox2-deficient cells. Our results indicate that Sox2 regulates the expression of key genes and pathways involved in GBM malignancy, in both cancer stemlike and differentiated cells, and maintains plasticity for bidirectional conversion between the two states, with significant clinical implications.

  6. The change of high mobility group box-1 protein expression in the moose model with acute hepatic failure%高迁移率族蛋白B1在急性肝功能衰竭小鼠中的表达变化

    Institute of Scientific and Technical Information of China (English)

    刘婷; 贺永文

    2010-01-01

    目的 阐明高迁移率族蛋白B1(HMGB1)在小鼠急性肝功能衰竭模型肝组织中的表达模式、动态变化及其与TNF-α、IL-1β的相互作用.方法 D-氨基半乳糖和脂多糖制备小鼠急性肝功能衰竭模型,免疫组织化学SABC法检测肝组织内HMGB1在6个时间点的表达变化,ELISA测定血清中TNF-α、IL-1β的含量.配对t检验分析数据差异.结果 造模后2 h肝内即可观察到HMGB1的表达,并随时间的延长而呈现出明显的增长趋势,直至24 h;血清中TNF-α、IL-1β造模后即出现上升,分别于8 h、2 h达到峰值,TNF-α 8 h为(473.42±22.99)pg/mL,IL-1β2 h为(724.49士34.24)pg/mL.后缓慢下降,其中IL-1β于24 h恢复正常为(51.49士36.87)pg/mL.结论 HMGB1是急性肝功能衰竭的重要参与因子,早期可促进TNF-α、IL-1β的分泌,中晚期则在炎性因子的作用下大量表达,加速肝脏损伤,并与肝功能衰竭的发展及严重程度存在正相关.%Objective To study the expression-mode and dynamic transmutation of high mobility group box-1 (HMGB1) in hepatocytes of the mouse model with acute hepatic failure and to study the interaction beween HMGB1 and tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β). Methods The mouse model of acute hepatic failure was established by injecting D-galactosamine (D-GalN) and lipopolysaccharide(LPS). Immunohistochemistry SABC method was used to detect the HMGB1 expression at 6 time points. The enzyme linked immunosorbent assay (ELISA) was used to determine serum TNF-α. IL-1β levels. Paired t test was used for statistical analysis. Results The HMGB1 expression was detectable at 2 hours after injection, which dramatically increased over time and peaked at 24 hours after injection. The serum TNF-a level and IL-1β level increased right after injection. The TNF-a level peaked at 8 hours after injection with a maximum value of (473.42±22. 99) pg/mL. The IL-1β level peaked at 2 hours after injection with a maximum value of

  7. [Microdeletion 12p12 involving SOX5 gene: a new syndrome with developmental delay].

    Science.gov (United States)

    Arroyo-Carrera, Ignacio; de Zaldívar-Tristancho, M Solo; Martín-Fernández, Rebeca; Hernández-Martín, Raquel; López-Lafuente, Amparo; Rodríguez-Revenga, Laia

    2015-05-16

    Introduccion. El gen SOX5 codifica un factor de transcripcion implicado en la regulacion de la condrogenia y el desarrollo del sistema nervioso. Caso clinico. Niña de 10 anos con discapacidad intelectual, alteracion conductual y malformaciones menores de este nuevo sindrome con alteracion en el neurodesarrollo, con una delecion 12p12 que incluye el gen SOX5. Conclusiones. Se revisan los casos publicados tanto de deleciones intragenicas de SOX5 como de deleciones mas grandes que incluyen este gen, y se analizan las correlaciones genotipo-fenotipo y los genes implicados en esta paciente.

  8. Sox10 expressing cells in the lateral wall of the aged mouse and human cochlea.

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    Xinping Hao

    Full Text Available Age-related hearing loss (presbycusis is a common human disorder, affecting one in three Americans aged 60 and over. Previous studies have shown that presbyacusis is associated with a loss of non-sensory cells in the cochlear lateral wall. Sox10 is a transcription factor crucial to the development and maintenance of neural crest-derived cells including some non-sensory cell types in the cochlea. Mutations of the Sox10 gene are known to cause various combinations of hearing loss and pigmentation defects in humans. This study investigated the potential relationship between Sox10 gene expression and pathological changes in the cochlear lateral wall of aged CBA/CaJ mice and human temporal bones from older donors. Cochlear tissues prepared from young adult (1-3 month-old and aged (2-2.5 year-old mice, and human temporal bone donors were examined using quantitative immunohistochemical analysis and transmission electron microscopy. Cells expressing Sox10 were present in the stria vascularis, outer sulcus and spiral prominence in mouse and human cochleas. The Sox10(+ cell types included marginal and intermediate cells and outer sulcus cells, including those that border the scala media and those extending into root processes (root cells in the spiral ligament. Quantitative analysis of immunostaining revealed a significant decrease in the number of Sox10(+ marginal cells and outer sulcus cells in aged mice. Electron microscopic evaluation revealed degenerative alterations in the surviving Sox10(+ cells in aged mice. Strial marginal cells in human cochleas from donors aged 87 and older showed only weak immunostaining for Sox10. Decreases in Sox10 expression levels and a loss of Sox10(+ cells in both mouse and human aged ears suggests an important role of Sox10 in the maintenance of structural and functional integrity of the lateral wall. A loss of Sox10(+ cells may also be associated with a decline in the repair capabilities of non-sensory cells in the

  9. Construction of HEK293 cells stably expressing wild-type organic anion transporting polypeptide 1B1 (OATP1B1*1a) and variant OATP1B1*1b and OATP1B1*15.

    Science.gov (United States)

    Chen, M; Qu, B X; Chen, X L; Hu, H H; Jiang, H D; Yu, L S; Zhou, Q; Zeng, S

    2016-06-01

    A transgenic cell line stably expressing the human organic anion transporting polypeptide (OATP1B1) was established. Human Embryonic Kidney 293 (HEK293) cell line stably expressing OATP1B1*1a sequence was amplified through PCR with the extracted total RNA as templates from human liver, then subcloned into the plasmid pMD19-T and verified by sequencing. OATP1B1*1b/OATP1B1*15 mutant sequences were obtained by site-directed mutation PCR with pMD19-T/ OATP1B1*1a as templates. The plasmids pcDNA3.1(+)/OATP1B1*1a, *1b and *15 were constructed and transfected into HEK293 cell line using Lipofectamine 2000 transfection reagent. Several stable transfected clones were obtained after selection with G418. Using rosuvastatin as a probe substrate of OATP1B1, the intracellular rosuvastatin accumulation in HEK293 and HEK-OATP1B1*1a, *1b and *15 monoclone cells were validated by a ultra-performance liquid chromatography-tandem mass spectrometry. OATP1B1 mRNA and protein expression were detected by RT-PCR and Western blot, respectively. The results from RT-PCR, rosuvastatin uptake and Western blot assay indicated that human OATP1B1 was highly expressed in transfected cells compared with controls. The HEK-293 cell lines stably expressing human OATP1B1-wild and variant (HEK-OATP1B1, *1b and *15) are potential models to study drug transport in vitro.

  10. Visualized gene network reveals the novel target transcripts Sox2 and Pax6 of neuronal development in trans-placental exposure to bisphenol A.

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    Chung-Wei Yang

    Full Text Available Bisphenol A (BPA is a ubiquitous endocrine disrupting chemical in our daily life, and its health effect in response to prenatal exposure is still controversial. Early-life BPA exposure may impact brain development and contribute to childhood neurological disorders. The aim of the present study was to investigate molecular target genes of neuronal development in trans-placental exposure to BPA.A meta-analysis of three public microarray datasets was performed to screen for differentially expressed genes (DEGs in exposure to BPA. The candidate genes of neuronal development were identified from gene ontology analysis in a reconstructed neuronal sub-network, and their gene expressions were determined using real-time PCR in 20 umbilical cord blood samples dichotomized into high and low BPA level groups upon the median 16.8 nM.Among 36 neuronal transcripts sorted from DAVID ontology clusters of 457 DEGs using the analysis of Bioconductor limma package, we found two neuronal genes, sex determining region Y-box 2 (Sox2 and paired box 6 (Pax6, had preferentially down-regulated expression (Bonferroni correction p-value <10(-4 and log2-transformed fold change ≤-1.2 in response to BPA exposure. Fetal cord blood samples had the obviously attenuated gene expression of Sox2 and Pax6 in high BPA group referred to low BPA group. Visualized gene network of Cytoscape analysis showed that Sox2 and Pax6 which were contributed to neural precursor cell proliferation and neuronal differentiation might be down-regulated through sonic hedgehog (Shh, vascular endothelial growth factor A (VEGFA and Notch signaling.These results indicated that trans-placental BPA exposure down-regulated gene expression of Sox2 and Pax6 potentially underlying the adverse effect on childhood neuronal development.

  11. Hydroxysteroid sulfotransferase SULT2B1b promotes hepatocellular carcinoma cells proliferation in vitro and in vivo.

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    Xiaoming Yang

    Full Text Available Hydroxysteroid sulfotransferase 2B1b (SULT2B1b is highly selective for the addition of sulfate groups to 3β-hydroxysteroids. Although previous reports have suggested that SULT2B1b is correlated with cell proliferation of hepatocytes, the relationship between SULT2B1b and the malignant phenotype of hepatocarcinoma cells was not clear. In the present study, we found that SULT2B1 was comparatively higher in the human hepatocarcinoma tumorous tissues than their adjacent tissues. Besides, SULT2B1b overexpression promoted the growth of the mouse hepatocarcinoma cell line Hepa1-6, while Lentivirus-mediated SULT2B1b interference inhibited growth as assessed by the CCK-8 assay. Likewise, inhibition of SULT2B1b expression induced cell-cycle arrest and apoptosis in Hepa1-6 cells by upregulating the expression of FAS, downregulating the expression of cyclinB1, BCL2 and MYC in vitro and in vivo at both the transcript and protein levels. Knock-down of SULT2B1b expression significantly suppressed tumor growth in nude mouse xenografts. Moreover, proliferation rates and SULT2B1b expression were highly correlated in the human hepatocarcinoma cell lines Huh-7, Hep3B, SMMC-7721 and BEL-7402 cells. Knock-down of SULT2B1b inhibited cell growth and cyclinB1 levels in human hepatocarcinoma cells and suppressed xenograft growth in vivo. In conclusion, SULT2B1b expression promotes proliferation of hepatocellular carcinoma cells in vitro and in vivo, which may contribute to the progression of HCC.

  12. The human SOX18 gene: Expression analysis and characterization of its 5’ flanking region

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    Petrović Isidora

    2007-01-01

    Full Text Available The aim of this study was to establish an adequate in vitro model system for studying transcriptional regulation of the human SOX18 gene. The paper presents an analysis of expression of this gene in cultured cell lines and characterization of its 5' flanking region. Using RT-PCR, Northern and Western blot analysis, we demonstrated SOX18 expression in HeLa cells, indicating that this cell line provides a suitable model system for studying transcriptional regulation of the given gene. We also cloned, sequenced and for the first time characterized the human SOX18 5’ flanking region. It is shown that the region 892 bp in size immediately upstream from the start codone harbors regulatory elements sufficient for transcription and represents an SOX18 promoter region.

  13. Understanding the detector behavior through Montecarlo and calibration studies in view of the SOX measurement

    Science.gov (United States)

    Caminata, A.; Agostini, M.; Altenmüller, K.; Appel, S.; Bellini, G.; Benziger, J.; Berton, N.; Bick, D.; Bonfini, G.; Bravo, D.; Caccianiga, B.; Calaprice, F.; Cavalcante, P.; Chepurnov, A.; Choi, K.; Cribier, M.; D'Angelo, D.; Davini, S.; Derbin, A.; Di Noto, L.; Drachnev, I.; Durero, M.; Empl, A.; Etenko, A.; Farinon, S.; Fischer, V.; Fomenko, K.; Franco, D.; Gabriele, F.; Gaffiot, J.; Galbiati, C.; Ghiano, C.; Giammarchi, M.; Goeger-Neff, M.; Goretti, A.; Gromov, M.; Hagner, C.; Houdy, T.; Hungerford, E.; Ianni, Aldo; Ianni, Andrea; Jonquères, N.; Jedrzejczak, K.; Kaiser, M.; Kobychev, V.; Korablev, D.; Korga, G.; Kornoukhov, V.; Kryn, D.; Lachenmaier, T.; Lasserre, T.; Laubenstein, M.; Lehnert, B.; Link, J.; Litvinovich, E.; Lombardi, F.; Lombardi, P.; Ludhova, L.; Lukyanchenko, G.; Machulin, I.; Manecki, S.; Maneschg, W.; Marcocci, S.; Maricic, J.; Mention, G.; Meroni, E.; Meyer, M.; Miramonti, L.; Misiaszek, M.; Montuschi, M.; Mosteiro, P.; Muratova, V.; Musenich, R.; Neumair, B.; Oberauer, L.; Obolensky, M.; Ortica, F.; Pallavicini, M.; Papp, L.; Perasso, L.; Pocar, A.; Ranucci, G.; Razeto, A.; Re, A.; Romani, A.; Roncin, R.; Rossi, N.; Schönert, S.; Scola, L.; Semenov, D.; Simgen, H.; Skorokhvatov, M.; Smirnov, O.; Sotnikov, A.; Sukhotin, S.; Suvorov, Y.; Tartaglia, R.; Testera, G.; Thurn, J.; Toropova, M.; Unzhakov, E.; Veyssiere, C.; Vishneva, A.; Vivier, M.; Vogelaar, R. B.; von Feilitzsch, F.; Wang, H.; Weinz, S.; Winter, J.; Wojcik, M.; Wurm, M.; Yokley, Z.; Zaimidoroga, O.; Zavatarelli, S.; Zuber, K.; Zuzel, G.

    2016-02-01

    Borexino is an unsegmented neutrino detector operating at LNGS in central Italy. The experiment has shown its performances through its unprecedented accomplishments in the solar and geoneutrino detection. These performances make it an ideal tool to accomplish a state- of-the-art experiment able to test the existence of sterile neutrinos (SOX experiment). For both the solar and the SOX analysis, a good understanding of the detector response is fundamental. Consequently, calibration campaigns with radioactive sources have been performed over the years. The calibration data are of extreme importance to develop an accurate Monte Carlo code. This code is used in all the neutrino analyses. The Borexino-SOX calibration techniques and program and the advances on the detector simulation code in view of the start of the SOX data taking are presented. 1

  14. HMG-box sequences from microbats homologous to the human SOX30 HMG-box.

    Science.gov (United States)

    Bullejos, M; Díaz de la Guardia, R; Barragán, M J; Sánchez, A

    2000-01-01

    SOX genes are a family of genes that encode for proteins which are characterised by the presence of a HMG-domain related to that of the mammalian sex-determining gene (SRY). By definition, the DNA binding domain of SOX genes is at least 50% identical to the 79 amino acid HMG domain of the SRY gene. We report here two HMG-box sequences from two microbat species (R. ferrumequinum and P. Pipistrellus) which were PCR amplified using a primer pair specific to the mouse Sry HMG-box. The high percentage of identity of this sequences with the human and mouse SOX30 HMG-box suggests that they are the SOX30 HMG-box for these two bat species.

  15. An excretory function for the Escherichia coli outer membrane pore TolC: upregulation of marA and soxS transcription and Rob activity due to metabolites accumulated in tolC mutants.

    Science.gov (United States)

    Rosner, Judah L; Martin, Robert G

    2009-08-01

    Efflux pumps function to rid bacteria of xenobiotics, including antibiotics, bile salts, and organic solvents. TolC, which forms an outer membrane channel, is an essential component of several efflux pumps in Escherichia coli. We asked whether TolC has a role during growth in the absence of xenobiotics. Because tolC transcription is activated by three paralogous activators, MarA, SoxS, and Rob, we examined the regulation of these activators in tolC mutants. Using transcriptional fusions, we detected significant upregulation of marRAB and soxS transcription and Rob protein activity in tolC mutants. Three mechanisms could be distinguished: (i) activation of marRAB transcription was independent of marRAB, soxR, and rob functions; (ii) activation of soxS transcription required SoxR, a sensor of oxidants; and (iii) Rob protein was activated posttranscriptionally. This mechanism is similar to the mechanisms of upregulation of marRAB, soxS, and Rob by treatment with certain phenolics, superoxides, and bile salts, respectively. The transcription of other marA/soxS/rob regulon promoters, including tolC itself, was also elevated in tolC mutants. We propose that TolC is involved in the efflux of certain cellular metabolites, not only xenobiotics. As these metabolites accumulate during growth, they trigger the upregulation of MarA, SoxS, and Rob, which in turn upregulate tolC and help rid the bacteria of these metabolites, thereby restoring homeostasis.

  16. Analysis of the zebrafish sox9b promoter: Identification of elements that recapitulate organ-specific expression of sox9b.

    Science.gov (United States)

    Burns, Felipe R; Lanham, Kevin A; Xiong, Kong M; Gooding, Alex J; Peterson, Richard E; Heideman, Warren

    2016-03-10

    The SRY-related high-mobility box 9 (SOX9) gene is expressed in many different tissues. To better understand the DNA elements that control tissue-specific expression, we cloned and sequenced a 2.5 kb fragment lying 5' to the zebrafish sox9b gene transcriptional start site. Three regions of this clone contained stable secondary structures that hindered cloning, sequencing, and amplification. This segment and smaller fragmentswere inserted 5' of an EGFP reporter and transgenic fish were raised with the different reporters. Reporter expression was also observed in embryos directly injected with the constructs to transiently express the reporter. Heart expression required only a very short 5' sequence, as a 0.6 kb sox9b fragment produced reporter expression in heart in transgenic zebrafish, and transient experiments showed heart expression from a minimal sox9b promoter region containing a conserved TATA box and an EGR2 element (-74/+29 bp). Reporter expression in transgenic skeletal muscle was consistently lower than in other tissues. Jaw, brain, and notochord expression was strong with the full-length clone, but was dramatically reduced as the size of the fragment driving the reporter decreased from approximately 1.8 to 0.9 kb. The 2.5 kb region 5' of the sox9b contained 7 conserved non-coding elements (CNEs) that included putative hypoxia inducible factor 1α (HIF1α), CAAT box (CCAAT), early growth response protein 2 (EGR2), and core promoter elements. While a synthetic fragment containing all 7 CNEs produced some degree of reporter expression in muscle, jaw, heart and brain, the degree of reporter expression was considerably lower than that produced by the full length clone. These results can account for the tissue-specific expression of sox9b in the developing zebrafish.

  17. Isolation and expression analysis of Sox10 gene relating body color variation in Oujiang color common carp%瓯江彩鲤体色相关基因Sox10的分离与表达分析

    Institute of Scientific and Technical Information of China (English)

    李康乐; 胡建尊; 颜标; 王成辉

    2013-01-01

    The numerous and diverse body color of fish was not only excellent materials to study the molecular mechanism of body color and body color inherence, body color evolution, and it was also an ideal model to diagnosis disease. Now, five basic and stable body color patterns have existed in Oujiang color common carp (Cyprinus carpio var. color), namely“Quanhong”,“Dahua”,“Mahua”,“Fenyu”and“Fenhua”, respectively. This fish can be a very good model and material for studying body color inheritance. At the melanin synthesis signaling pathway, skin color was regulated by a small group genes. Sox10 gene plays an important role in the formation of melanin, it regulates the birth, migration and differentiation of melanin. However, the effect of Sox10 gene on body color has not been reported. Four healthy lines of Oujiang color carp (“Quanhong”, “Dahua”, “Fenyu”,“Fenhua”) were collected from the provincial farm of the Zhejiang. Then the skin, muscle, eye, gill, kidney, swim bladder, heart, and liver were taken out, furthermore, the black skin and red skin were sampled separately of“Dahua”, the same with black skin and white skin of“fenhua”. Total RNA was extracted using Trizol, and reverse transcribed into the First-strand cDNA. Primers were designed by Primer5 program, and the right products were purified and sequenced. The obtained sequence was analyzed by Bioedit, Clustalw, Mega and other bioinformatics softwares. The total length of Sox10 gene cloned in Oujiang color common carp is 2 830 bp which contains 9 bp 5’ untranslated regions (UTR) and 1 375 bp 3’-UTR, and 1 446 bp open reading frame (ORF) encoding 481 amino acids. The phylogenetic analyses showed that there were 59%−94%similarities in amino acid sequence with some of previously reported other species. RT-PCR analysis revealed that the gene was highly expressed in skin, muscle, eyes and swim bladder, weakly expressed in gill and heart and no expression were found in

  18. 26 CFR 11.410(b)-1 - Minimum coverage requirements.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 14 2010-04-01 2010-04-01 false Minimum coverage requirements. 11.410(b)-1 Section 11.410(b)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) TEMPORARY INCOME TAX REGULATIONS UNDER THE EMPLOYEE RETIREMENT INCOME SECURITY ACT...

  19. 26 CFR 1.7702B-1 - Consumer protection provisions.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 13 2010-04-01 2010-04-01 false Consumer protection provisions. 1.7702B-1 Section 1.7702B-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME...-Term Care Insurance Model Act (Model Act) and Long-Term Care Insurance Model Regulation...

  20. SerpinB1 Promotes Pancreatic β Cell Proliferation

    Energy Technology Data Exchange (ETDEWEB)

    El Ouaamari, Abdelfattah; Dirice, Ercument; Gedeon, Nicholas; Hu, Jiang; Zhou, Jian-Ying; Shirakawa, Jun; Hou, Lifei; Goodman, Jessica; Karampelias, Christos; Qiang, Guifeng; Boucher, Jeremie; Martinez, Rachael; Gritsenko, Marina A.; De Jesus, Dario F.; Kahraman, Sevim; Bhatt, Shweta; Smith, Richard D.; Beer, Hans-Dietmar; Jungtrakoon, Prapaporn; Gong, Yanping; Goldfine, Allison B.; Liew, Chong Wee; Doria, Alessandro; Andersson, Olov; Qian, Wei-Jun; Remold-O’Donnell, Eileen; Kulkarni, Rohit N.

    2016-01-01

    Compensatory β-cell growth in response to insulin resistance is a common feature in diabetes. We recently reported that liver-derived factors participate in this compensatory response in the liver insulin receptor knockout (LIRKO) mouse, a model of significant islet hyperplasia. Here we show that serpinB1 is a liver-derived secretory protein that controls β-cell proliferation. SerpinB1 is abundant in the hepatocyte secretome and sera derived from LIRKO mice. SerpinB1 and small molecule compounds that partially mimic serpinB1 activity enhanced proliferation of zebrafish, mouse and human β-cells. We report that serpinB1-induced β-cell replication requires protease inhibition activity and mice lacking serpinB1 exhibit attenuated β-cell replication in response to insulin resistance. Finally, SerpinB1-treatment of islets modulated signaling proteins in growth and survival pathways such as MAPK, PKA and GSK3. Together, these data implicate SerpinB1 as a protein that can potentially be harnessed to enhance functional β-cell mass in patients with diabetes.

  1. 26 CFR 301.269B-1 - Stapled foreign corporations.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Stapled foreign corporations. 301.269B-1....269B-1 Stapled foreign corporations. In accordance with section 269B(a)(1), a stapled foreign corporation is subject to the same taxes that apply to a domestic corporation under Title 26 of the...

  2. 26 CFR 1.269B-1 - Stapled foreign corporations.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 3 2010-04-01 2010-04-01 false Stapled foreign corporations. 1.269B-1 Section 1... (CONTINUED) INCOME TAXES Items Not Deductible § 1.269B-1 Stapled foreign corporations. (a) Treatment as a domestic corporation—(1) General rule. Except as otherwise provided, if a foreign corporation is a...

  3. 77 FR 52698 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-08-30

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... of a section 36(b)(1) arms sales notification. This is published to fulfill the requirements of...: 18 AGM-65K2 MAVERICK All-Up- Round Missiles, 36 TGM-65K2 Captive Air Training Missiles, 3...

  4. Sox9 Modulates Proliferation and Expression of Osteogenic Markers of Adipose-Derived Stem Cells (ASC

    Directory of Open Access Journals (Sweden)

    Sabine Stöckl

    2013-05-01

    Full Text Available Background: Mesenchymal stem cells (MSC are promising tools for tissue-engineering and musculoskeletal regeneration. They reside within various tissues, like adipose tissue, periosteum, synovia, muscle, dermis, blood and bone marrow, latter being the most common tissue used for MSC isolation. A promising alternative source for MSC is adipose tissue due to better availability and higher yield of MSC in comparison to bone marrow. A drawback is the yet fragmentary knowledge of adipose-derived stem cell (ASC physiology in order to make them a safe tool for in vivo application. Methods/Results: Here, we identified Sox9 as a highly expressed and crucial transcription factor in undifferentiated rat ASC (rASC. In comparison to rat bone marrow-derived stem cells (rBMSC, mRNA and protein levels of Sox9 were significantly higher in rASC. To study the role of Sox9 in detail, we silenced Sox9 with shRNA in rASC and examined proliferation, apoptosis and the expression of osteogenic differentiation markers. Our results clearly point to a difference in the expression profile of osteogenic marker genes between undifferentiated rASC and rBMSC in early passages. Sox9 silencing induced the expression of osteocalcin, Vegfα and Mmp13, and decreased rASC proliferation accompanied with an induction of p21 and cyclin D1 expression and delayed S-phase entry. Conclusions: We suggest a pro-proliferative role for Sox9 in undifferentiated rASC which may explain the higher proliferation rate of rASC compared to rBMSC. Moreover, we propose an osteogenic differentiation delaying role of Sox9 in rASC which suggests that Sox9 expression is needed to maintain rASC in an undifferentiated, proliferative state.

  5. Monte Carlo simulations in neutrino physics: the example of the SOX experiment

    OpenAIRE

    Caminata, A.; Agostini, M.; Caccianiga, B.; Toropova, M.; Veyssiere, C.; Vivier, M.; Unzhakov, E.; Vogelaar, R. B.; Feilitzsch, F. von; Wang, H.; Weinz, S.; Winter, J.; Wojcik, M.; Calaprice, F.; Wurm, M.

    2016-01-01

    The SOX project aims to test the existence of light sterile neutrinos. A solid signal would mean the discovery of the first particles beyond the Standard Electroweak Model and would have profound implications in our understanding of the Universe and of fundamental particle physics. In case of a negative result, it is able to close a long standing debate about the reality of the neutrino anomalies. The SOX experiment will use a \\mbox{$^{144}$Ce-$^{144}$Pr} antineutrino generator placed at shor...

  6. High expression of Sox10 correlates with tumor aggressiveness and poor prognosis in human nasopharyngeal carcinoma

    Directory of Open Access Journals (Sweden)

    Zhao Y

    2016-03-01

    Full Text Available Yu Zhao,1,* Zhi-gang Liu,1,* Jiao Tang,1 Ren-fang Zou,1 Xiao-yan Chen,2 Guan-min Jiang,3 Yan-fang Qiu,1 Hui Wang11Key Laboratory of Translational Radiation Oncology, Department of Radiation Oncology, 2Department of Pathology, 3Department of Clinical Laboratory, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China*These authors contributed equally to this workPurpose: The aim of the study was to detect the expression of Sox10 in human nasopharyngeal carcinoma (NPC and investigate the relationship between its expression and the clinicopathological characteristics of NPC patients.Patients and methods: Tumor specimens (n=105 were retrospectively collected from patients with NPC diagnosed between 2004 and 2005 who presented at Hunan Cancer Hospital. Immunohistochemistry analyses were performed to characterize the expression of Sox10 in NPC. Kaplan–Meier survival and Cox regression analyses were employed to evaluate the prognosis of 105 NPC patients.Results: The results showed that Sox10 was markedly overexpressed in human NPC tissues. Analysis of clinicopathological parameters showed that high Sox10 expression was significantly correlated with the clinical stage (P=0.032, T classification (P=0.034, and lymph node metastasis (P=0.03. Cox regression analyses further showed that Sox10 expression was an independent prognostic factor for overall survival (P=0.005. This is the first time Sox10 has shown its importance in predicting NPC progressiveness and survival outcomes.Conclusion: Sox10 serves as a potential biomarker for NPC patients. It may hopefully become a novel therapeutic target for NPC patients.Keywords: Sox10, NPC, prognosis

  7. CYP1B1 and hormone-induced cancer.

    Science.gov (United States)

    Gajjar, Ketan; Martin-Hirsch, Pierre L; Martin, Francis L

    2012-11-01

    Cancers in hormone-responsive tissues (e.g., breast, ovary, endometrium, prostate) occur at high incidence rates worldwide. However, their genetic basis remains poorly understood. Studies to date suggest that endogenous/exogenous oestrogen and environmental carcinogens may play a role in development and/or progression of hormone-induced cancers via oxidative oestrogen metabolism. Cytochrome P450 1B1 is a key enzyme in its oestrogen metabolism pathway, giving rise to hydroxylation and conjugation. Although CYP1B1 is expressed in many cancers, particularly high levels of expression are observed in oestrogen-mediated disease. CYP1B1 is more readily found in tumour tissue compared to normal. Given the role of CYP1B1 in pro-carcinogen and oestrogen metabolism, polymorphisms in CYP1B1 could result in modifications in its enzyme activity and subsequently lead to hormone-mediated carcinogenesis. CYP1B1 may also be involved in progression of the disease by altering the tissue response to hormones and clinical response to chemotherapy. The exact mechanism behind these events is complex and unclear. Only a few functional single nucleotide polymorphisms of CYP1B1 are known to result in amino acid substitutions and have been extensively investigated. Studies examining the contribution of different CYP1B1 alleles to hormone-mediated cancer risks are inconsistent. The main focus of this review is to appraise the available studies linking the pathogenesis of the hormone-induced cancers to various CYP1B1 polymorphisms. Additionally, we explore the role of a neuronal protein, γ-synuclein, in CYP1B1-mediated pathogenesis.

  8. Silencing of SOX12 by shRNA suppresses migration, invasion and proliferation of breast cancer cells

    Science.gov (United States)

    Ding, Hanzhi; Quan, Hong; Yan, Weiguo; Han, Jing

    2016-01-01

    Sex determining region Y-box protein 12 (SOX12) is essential for embryonic development and cell-fate determination. The role of SOX12 in tumorigenesis of breast cancer is not well-understood. Here, we found that SOX12 mRNA expression was up-regulated in human breast cancer tissues. To clarify the roles of SOX12 in breast cancer, we used lentiviral shRNAs to suppress its expression in two breast cancer cells with relatively higher expression of SOX12 (BT474 and MCF-7). Our findings strongly suggested that SOX12 was critical for cell migration and invasion of breast cancer cells. We found that silencing of SOX12 significantly decreased the mRNA and protein levels of MMP9 and Twist, while notably increased E-cadherin. Moreover, SOX12 knockdown significantly inhibited the proliferation of breast cancer cells in vitro and the growth of xenograft tumours in vivo. Flow cytometry analysis revealed that breast cancer cells with SOX12 knockdown showed cell cycle arrest and decreased mRNA and protein levels of proliferating cell nuclear antigen (PCNA), CDK2 and Cyclin D1. Taken together, SOX12 plays an important role in growth inhibition through cell-cycle arrest, as well as migration and invasion of breast cancer cells. PMID:27582508

  9. Sox2-positive dermal papilla cells specify hair follicle type in mammalian epidermis.

    Science.gov (United States)

    Driskell, Ryan R; Giangreco, Adam; Jensen, Kim B; Mulder, Klaas W; Watt, Fiona M

    2009-08-01

    The dermal papilla comprises the specialised mesenchymal cells at the base of the hair follicle. Communication between dermal papilla cells and the overlying epithelium is essential for differentiation of the hair follicle lineages. We report that Sox2 is expressed in all dermal papillae at E16.5, but from E18.5 onwards expression is confined to a subset of dermal papillae. In postnatal skin, Sox2 is only expressed in the dermal papillae of guard/awl/auchene follicles, whereas CD133 is expressed both in guard/awl/auchene and in zigzag dermal papillae. Using transgenic mice that express GFP under the control of the Sox2 promoter, we isolated Sox2(+) (GFP(+)) CD133(+) cells and compared them with Sox2(-) (GFP(-)) CD133(+) dermal papilla cells. In addition to the 'core' dermal papilla gene signature, each subpopulation expressed distinct sets of genes. GFP(+) CD133(+) cells had upregulated Wnt, FGF and BMP pathways and expressed neural crest markers. In GFP(-) CD133(+) cells, the hedgehog, IGF, Notch and integrin pathways were prominent. In skin reconstitution assays, hair follicles failed to form when dermis was depleted of both GFP(+) CD133(+) and GFP(-) CD133(+) cells. In the absence of GFP(+) CD133(+) cells, awl/auchene hairs failed to form and only zigzag hairs were found. We have thus demonstrated a previously unrecognised heterogeneity in dermal papilla cells and shown that Sox2-positive cells specify particular hair follicle types.

  10. SOX2–LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors

    Science.gov (United States)

    Cimadamore, Flavio; Amador-Arjona, Alejandro; Chen, Connie; Huang, Chun-Teng; Terskikh, Alexey V.

    2013-01-01

    The transcription factor SRY (sex-determining region)-box 2 (SOX2) is an important functional marker of neural precursor cells (NPCs) and plays a critical role in self-renewal and neuronal differentiation; however, the molecular mechanisms underlying its functions are poorly understood. Using human embryonic stem cell-derived NPCs to model neurogenesis, we found that SOX2 is required to maintain optimal levels of LIN28, a well-characterized suppressor of let-7 microRNA biogenesis. Exogenous LIN28 expression rescued the NPC proliferation deficit, as well as the early but not the late stages of the neurogenic deficit associated with the loss of SOX2. We found that SOX2 binds to a proximal site in the LIN28 promoter region and regulates LIN28 promoter acetylation, likely through interactions with the histone acetyltransferase complex. Misexpression of let-7 microRNAs in NPCs reduced proliferation and inhibited neuronal differentiation, phenocopying the loss of SOX2. In particular, we identified let-7i as a novel and potent inhibitor of neuronal differentiation that targets MASH1 and NGN1, two well-characterized proneural genes. In conclusion, we discovered the SOX2–LIN28/let-7 pathway as a unique molecular mechanism governing NPC proliferation and neurogenic potential. PMID:23884650

  11. SOX2-LIN28/let-7 pathway regulates proliferation and neurogenesis in neural precursors.

    Science.gov (United States)

    Cimadamore, Flavio; Amador-Arjona, Alejandro; Chen, Connie; Huang, Chun-Teng; Terskikh, Alexey V

    2013-08-06

    The transcription factor SRY (sex-determining region)-box 2 (SOX2) is an important functional marker of neural precursor cells (NPCs) and plays a critical role in self-renewal and neuronal differentiation; however, the molecular mechanisms underlying its functions are poorly understood. Using human embryonic stem cell-derived NPCs to model neurogenesis, we found that SOX2 is required to maintain optimal levels of LIN28, a well-characterized suppressor of let-7 microRNA biogenesis. Exogenous LIN28 expression rescued the NPC proliferation deficit, as well as the early but not the late stages of the neurogenic deficit associated with the loss of SOX2. We found that SOX2 binds to a proximal site in the LIN28 promoter region and regulates LIN28 promoter acetylation, likely through interactions with the histone acetyltransferase complex. Misexpression of let-7 microRNAs in NPCs reduced proliferation and inhibited neuronal differentiation, phenocopying the loss of SOX2. In particular, we identified let-7i as a novel and potent inhibitor of neuronal differentiation that targets MASH1 and NGN1, two well-characterized proneural genes. In conclusion, we discovered the SOX2-LIN28/let-7 pathway as a unique molecular mechanism governing NPC proliferation and neurogenic potential.

  12. Dynamics of SOX2 and CDX2 Expression in Barrett’s Mucosa

    Directory of Open Access Journals (Sweden)

    Rita Barros

    2016-01-01

    Full Text Available Barrett’s esophagus (BE is the replacement of the normal esophageal squamous epithelium by a columnar lining epithelium. It is a premalignant condition for the development of adenocarcinoma of the esophagus and esophagogastric junction. BE is associated with gastroesophageal reflux which might change the expression profile of key transcription factors involved in the establishment of tissue differentiation, namely, SOX2 (associated with esophageal and gastric differentiation and CDX2 (associated with intestinal differentiation. Here, we sought to characterize the expression profile of SOX2 and CDX2 in the sequential alterations of the esophageal mucosa towards adenocarcinoma and compare it with the well-established gastric and intestinal mucin profiles (MUC5AC, MUC6, and MUC2. We observed that SOX2 and CDX2 expression correlates with gastric and intestinal differentiation in BE, defined by morphological parameters and mucin expression. We show the presence of a complete intestinal profile in BE, without gastric mucins and without SOX2, and we observed an evolutionary modulation of the metaplastic phenotype by SOX2 and CDX2. We observed that adenocarcinomas harbor more frequently a mixed gastric and intestinal phenotype. In conclusion, our study establishes a role for transcription factors SOX2 and CDX2 in the progression from gastric to gastrointestinal differentiation in Barrett’s metaplasia.

  13. Sox5 functions as a fate switch in medaka pigment cell development.

    Directory of Open Access Journals (Sweden)

    Yusuke Nagao

    2014-04-01

    Full Text Available Mechanisms generating diverse cell types from multipotent progenitors are crucial for normal development. Neural crest cells (NCCs are multipotent stem cells that give rise to numerous cell-types, including pigment cells. Medaka has four types of NCC-derived pigment cells (xanthophores, leucophores, melanophores and iridophores, making medaka pigment cell development an excellent model for studying the mechanisms controlling specification of distinct cell types from a multipotent progenitor. Medaka many leucophores-3 (ml-3 mutant embryos exhibit a unique phenotype characterized by excessive formation of leucophores and absence of xanthophores. We show that ml-3 encodes sox5, which is expressed in premigratory NCCs and differentiating xanthophores. Cell transplantation studies reveal a cell-autonomous role of sox5 in the xanthophore lineage. pax7a is expressed in NCCs and required for both xanthophore and leucophore lineages; we demonstrate that Sox5 functions downstream of Pax7a. We propose a model in which multipotent NCCs first give rise to pax7a-positive partially fate-restricted intermediate progenitors for xanthophores and leucophores; some of these progenitors then express sox5, and as a result of Sox5 action develop into xanthophores. Our results provide the first demonstration that Sox5 can function as a molecular switch driving specification of a specific cell-fate (xanthophore from a partially-restricted, but still multipotent, progenitor (the shared xanthophore-leucophore progenitor.

  14. Loss of SOX9 Expression Is Associated with PSA Recurrence in ERG-Positive and PTEN Deleted Prostate Cancers.

    Directory of Open Access Journals (Sweden)

    Christoph Burdelski

    Full Text Available The transcription factor SOX9 plays a crucial role in normal prostate development and has been suggested to drive prostate carcinogenesis in concert with PTEN inactivation. To evaluate the clinical impact of SOX9 and its relationship with key genomic alterations in prostate cancer, SOX9 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21 and 6q15 were available from earlier studies. SOX9 expression levels were comparable in luminal cells of normal prostate glands (50% SOX9 positive and 3,671 cancers lacking TMPRSS2:ERG fusion (55% SOX9 positive, but was markedly increased in 3,116 ERG-fusion positive cancers (81% SOX9 positive, p<0.0001. While no unequivocal changes in the SOX9 expression levels were found in different stages of ERG-negative cancers, a gradual decrease of SOX9 paralleled progression to advanced stage, high Gleason grade, metastatic growth, and presence of PTEN deletions in ERG-positive cancers (p<0.0001 each. SOX9 levels were unrelated to deletions of 3p, 5q, and 6q. Down-regulation of SOX9 expression was particularly strongly associated with PSA recurrence in ERG-positive tumors harboring PTEN deletions (p=0.001, but had no significant effect in ERG-negative cancers or in tumors with normal PTEN copy numbers. In summary, the results of our study argue against a tumor-promoting role of SOX9 in prostate cancer, but demonstrate that loss of SOX9 expression characterizes a particularly aggressive subset of ERG positive cancers harboring PTEN deletions.

  15. Ablation of the Sox11 Gene Results in Clefting of the Secondary Palate Resembling the Pierre Robin Sequence.

    Science.gov (United States)

    Huang, Huarong; Yang, Xiaojuan; Bao, Meiling; Cao, Huanhuan; Miao, Xiaoping; Zhang, Xiaoyun; Gan, Lin; Qiu, Mengsheng; Zhang, Zunyi

    2016-03-25

    Mouse gene inactivation has shown that the transcription factor Sox11 is required for mouse palatogenesis. However, whether Sox11 is primarily involved in the regulation of palatogenesis still remains elusive. In this study, we explored the role ofSox11in palatogenesis by analyzing the developmental mechanism in cleft palate formation in mutants deficient in Sox11. Sox11 is expressed both in the developing palatal shelf and in the surrounding structures, including the mandible. We found that cleft palate occurs only in the mutant in which Sox11is directly deleted. As in the wild type, the palatal shelves in the Sox11 mutant undergo outgrowth in a downward direction and exhibit potential for fusion and elevation. However, mutant palatal shelves encounter clefting, which is associated with a malpositioned tongue that results in physical obstruction of palatal shelf elevation at embryonic day 14.5 (E14.5). We found that loss of Sox11led to reduced cell proliferation in the developing mandibular mesenchyme via Cyclin D1, leading to mandibular hypoplasia, which blocks tongue descent. Extensive analyses of gene expression inSox11 deficiency identified FGF9 as a potential candidate target of Sox11 in the modulation of cell proliferation both in the mandible and the palatal shelf between E12.5 and E13.5. Finally we show, using in vitro assays, that Sox11 directly regulates the expression of Fgf9 and that application of FGF9 protein to Sox11-deficient palatal shelves restores the rate of BrdU incorporation. Taken together, the palate defects presented in the Sox11 loss mutant mimic the clefting in the Pierre Robin sequence in humans.

  16. Expression of high mobility group box 1 protein and the receptor for advanced glycation end products in patients with primary gouty arthritis%高迁移率族蛋白B1及其糖基化终产物受体在原发性痛风性关节炎患者的变化及其临床意义

    Institute of Scientific and Technical Information of China (English)

    潘舒月; 周京国; 青玉凤; 张梦云; 蒲梦君; 谢文光

    2014-01-01

    be involved in the regulation of the lipid metabolism of gout.%目的 探讨高迁移率族蛋白B1(HMGB1)及其糖基化终产物受体(RAGE)在原发性痛风性关节炎(GA)发病中可能的作用.方法 采用ELISA检测68例急性GA(AG)患者、48例间歇期痛风(QG)患者和45名健康体检者血浆HMGB1水平;实时荧光定量RT-qPCR检测68例AG、48例QG和94名健康体检者PBMCs HMGB1及其RAGE转录水平.组间差异采用方差分析或秩和检验,进一步LSD法两两比较;变量间相关关系采用Spearman相关分析.结果 血浆HMGB1、PBMCs HMGB1mRNA、RAGEmRNA表达水平在AG组[(222±178) ng/ml,0.235±0.954,0.001 5±0.003 5]和QG组[(107±176) ng/ml,0.044±0.117,0.001 3±0.000 9]均显著高于健康体检者组[(24±34) ng/ml,0.019±0.029,0.000 5±0.000 3](P均<0.05),血浆HMGB1、PBMCs HMGB1 mRNA在AG组均高于QG组(P均<0.05),而RAGE mRNA表达水平在AG和QG差异无统计学意义(P>0.05).痛风患者血浆HMGB1浓度与白细胞、中性粒细胞、单个核细胞、ESR呈正相关(r=0.34,0.44,0.39,0.33;P均<0.01),与载脂蛋白A1呈负相关(r=-0.28,P<0.01);HMGB1mRNA与RAGE mRNA、淋巴细胞计数、总胆固醇、低密度脂蛋白、载脂蛋白B100呈正相关(r=0.29,0.36,0.26,0.28,0.29;P均<0.05),与高密度脂蛋白呈负相关(r=-0.30,P<0.01);RAGE转录水平与淋巴细胞计数、TC、载脂蛋白B100呈正相关(r=0.35,0.35,0.44;P均<0.01).结论 HMGB1及其信号通路可能在GA发生发展中发挥重要作用,其可能还参与痛风的脂代谢调节.

  17. Sox10 contributes to the balance of fate choice in dorsal root ganglion progenitors

    Science.gov (United States)

    Madelaine, Romain; Busolin, Giorgia; Nikaido, Masataka; Colanesi, Sarah; Camargo-Sosa, Karen; Toppo, Stefano; Blader, Patrick; Tiso, Natascia; Kelsh, Robert N.

    2017-01-01

    The development of functional peripheral ganglia requires a balance of specification of both neuronal and glial components. In the developing dorsal root ganglia (DRGs), these components form from partially-restricted bipotent neuroglial precursors derived from the neural crest. Work in mouse and chick has identified several factors, including Delta/Notch signaling, required for specification of a balance of these components. We have previously shown in zebrafish that the Sry-related HMG domain transcription factor, Sox10, plays an unexpected, but crucial, role in sensory neuron fate specification in vivo. In the same study we described a novel Sox10 mutant allele, sox10baz1, in which sensory neuron numbers are elevated above those of wild-types. Here we investigate the origin of this neurogenic phenotype. We demonstrate that the supernumerary neurons are sensory neurons, and that enteric and sympathetic neurons are almost absent just as in classical sox10 null alleles; peripheral glial development is also severely abrogated in a manner similar to other sox10 mutant alleles. Examination of proliferation and apoptosis in the developing DRG reveals very low levels of both processes in wild-type and sox10baz1, excluding changes in the balance of these as an explanation for the overproduction of sensory neurons. Using chemical inhibition of Delta-Notch-Notch signaling we demonstrate that in embryonic zebrafish, as in mouse and chick, lateral inhibition during the phase of trunk DRG development is required to achieve a balance between glial and neuronal numbers. Importantly, however, we show that this mechanism is insufficient to explain quantitative aspects of the baz1 phenotype. The Sox10(baz1) protein shows a single amino acid substitution in the DNA binding HMG domain; structural analysis indicates that this change is likely to result in reduced flexibility in the HMG domain, consistent with sequence-specific modification of Sox10 binding to DNA. Unlike other Sox10

  18. SOX2 and SOX2-MYC Reprogramming Process of Fibroblasts to the Neural Stem Cells Compromised by Senescence.

    Directory of Open Access Journals (Sweden)

    Marta Winiecka-Klimek

    Full Text Available Tumorigenic potential of induced pluripotent stem cells (iPSCs infiltrating population of induced neural stem cells (iNSCs generated from iPSCs may limit their medical applications. To overcome such a difficulty, direct reprogramming of adult somatic cells into iNSCs was proposed. The aim of this study was the systematic comparison of induced neural cells (iNc obtained with different methods-direct reprogramming of human adult fibroblasts with either SOX2 (SiNSc-like or SOX2 and c-MYC (SMiNSc-like and induced pluripotent stem cells differentiation to ebiNSc-in terms of gene expression profile, differentiation potential as well as proliferation properties. Immunocytochemistry and real-time PCR analyses were used to evaluate gene expression profile and differentiation potential of various iNc types. Bromodeoxyuridine (BrdU incorporation and senescence-associated beta-galactosidase (SA-β-gal assays were used to estimate proliferation potential. All three types of iNc were capable of neuronal differentiation; however, astrocytic differentiation was possible only in case of ebiNSc. Contrary to ebiNSc generation, the direct reprogramming was rarely a propitious process, despite 100% transduction efficiency. The potency of direct iNSCs-like cells generation was lower as compared to iNSCs obtained by iPSCs differentiation, and only slightly improved when c-MYC was added. Directly reprogrammed iNSCs-like cells were lacking the ability to differentiate into astrocytic cells and characterized by poor efficiency of neuronal cells formation. Such features indicated that these cells could not be fully reprogrammed, as confirmed mainly with senescence detection. Importantly, SiNSc-like and SMiNSc-like cells were unable to achieve the long-term survival and became senescent, which limits their possible therapeutic applicability. Our results suggest that iNSCs-like cells, generated in the direct reprogramming attempts, were either not fully reprogrammed or

  19. CYP1B1: a unique gene with unique characteristics.

    Science.gov (United States)

    Faiq, Muneeb A; Dada, Rima; Sharma, Reetika; Saluja, Daman; Dada, Tanuj

    2014-01-01

    CYP1B1, a recently described dioxin inducible oxidoreductase, is a member of the cytochrome P450 superfamily involved in the metabolism of estradiol, retinol, benzo[a]pyrene, tamoxifen, melatonin, sterols etc. It plays important roles in numerous physiological processes and is expressed at mRNA level in many tissues and anatomical compartments. CYP1B1 has been implicated in scores of disorders. Analyses of the recent studies suggest that CYP1B1 can serve as a universal/ideal cancer marker and a candidate gene for predictive diagnosis. There is plethora of literature available about certain aspects of CYP1B1 that have not been interpreted, discussed and philosophized upon. The present analysis examines CYP1B1 as a peculiar gene with certain distinctive characteristics like the uniqueness in its chromosomal location, gene structure and organization, involvement in developmentally important disorders, tissue specific, not only expression, but splicing, potential as a universal cancer marker due to its involvement in key aspects of cellular metabolism, use in diagnosis and predictive diagnosis of various diseases and the importance and function of CYP1B1 mRNA in addition to the regular translation. Also CYP1B1 is very difficult to express in heterologous expression systems, thereby, halting its functional studies. Here we review and analyze these exceptional and startling characteristics of CYP1B1 with inputs from our own experiences in order to get a better insight into its molecular biology in health and disease. This may help to further understand the etiopathomechanistic aspects of CYP1B1 mediated diseases paving way for better research strategies and improved clinical management.

  20. Genotoxicity of aflatoxin B1 and its ammonium derivatives.

    Science.gov (United States)

    Márquez Márquez, R; Tejada de Hernandez, I; Madrigal Bujaidar, E

    1995-01-01

    Aflatoxin (AF) B1 is a main contaminant in diverse agricultural products. In an attempt to reduce this problem and the hazards to human health, an AFB1 inactivating system with ammonia has been developed. In this work we evaluated the efficiency of the system in mice using micronucleus (MN) and sister chromatid exchange (SCE) analysis. Four groups of animals were fed for 8 weeks with a special diet mainly composed of maize: (1) uncontaminated; (2) uncontaminated/inactivated; (3) contaminated/inactivated; and (4) contaminated. We evaluated MN at weekly intervals in peripheral blood, and in weeks 4 and 8 SCE frequencies were quantified in bone marrow cells. The results shows that animals fed with AFB1 contaminated/inactivated maize had a 45% lower level of induced cytogenetic damage than those animals fed with AFB1 contaminated but not inactivated maize. A residual amount of AFB1 after the inactivating treatment and reconversion back to AFB1 in the organism may account for the remaining increased levels of SCE and MN.

  1. Context-dependent wiring of Sox2 regulatory networks for self-renewal of embryonic and trophoblast stem cells.

    Science.gov (United States)

    Adachi, Kenjiro; Nikaido, Itoshi; Ohta, Hiroshi; Ohtsuka, Satoshi; Ura, Hiroki; Kadota, Mitsutaka; Wakayama, Teruhiko; Ueda, Hiroki R; Niwa, Hitoshi

    2013-11-07

    Sox2 is a transcription factor required for the maintenance of pluripotency. It also plays an essential role in different types of multipotent stem cells, raising the possibility that Sox2 governs the common stemness phenotype. Here we show that Sox2 is a critical downstream target of fibroblast growth factor (FGF) signaling, which mediates self-renewal of trophoblast stem cells (TSCs). Sustained expression of Sox2 together with Esrrb or Tfap2c can replace FGF dependency. By comparing genome-wide binding sites of Sox2 in embryonic stem cells (ESCs) and TSCs combined with inducible knockout systems, we found that, despite the common role in safeguarding the stem cell state, Sox2 regulates distinct sets of genes with unique functions in these two different yet developmentally related types of stem cells. Our findings provide insights into the functional versatility of transcription factors during embryogenesis, during which they can be recursively utilized in a variable manner within discrete network structures.

  2. Master regulator for chondrogenesis, Sox9, regulates transcriptional activation of the endoplasmic reticulum stress transducer BBF2H7/CREB3L2 in chondrocytes.

    Science.gov (United States)

    Hino, Kenta; Saito, Atsushi; Kido, Miori; Kanemoto, Soshi; Asada, Rie; Takai, Tomoko; Cui, Min; Cui, Xiang; Imaizumi, Kazunori

    2014-05-16

    The endoplasmic reticulum (ER) stress transducer, box B-binding factor 2 human homolog on chromosome 7 (BBF2H7), is a basic leucine zipper (bZIP) transmembrane transcription factor. This molecule is activated in response to ER stress during chondrogenesis. The activated BBF2H7 accelerates cartilage matrix protein secretion through the up-regulation of Sec23a, which is responsible for protein transport from the ER to the Golgi apparatus and is a target of BBF2H7. In the present study, we elucidated the mechanisms of the transcriptional activation of Bbf2h7 in chondrocytes. The transcription of Bbf2h7 is regulated by Sex determining region Y-related high-mobility group box 9 (Sox9), a critical factor for chondrocyte differentiation that facilitates the expression of one of the major cartilage matrix proteins Type II collagen (Col2), through binding to the Sox DNA-binding motif in the Bbf2h7 promoter. BBF2H7 is activated as a transcription factor in response to physiological ER stress caused by abundant synthesis of cartilage matrix proteins, and consequently regulates the secretion of cartilage matrix proteins. Taken together, our findings demonstrate novel regulatory mechanisms of Sox9 for controlling the secretion of cartilage matrix proteins through the activation of BBF2H7-Sec23a signaling during chondrogenesis.

  3. Development and Characterization of an Electroless Plated Silver/Cysteine Sensor Platform for the Electrochemical Determination of Aflatoxin B1

    Directory of Open Access Journals (Sweden)

    Alex Paul Wacoo

    2016-01-01

    Full Text Available An electroless plated silver/cysteine sensor platform [Glass|silver|cysteine|aflatoxin B1|horseradish peroxidase] for the Electrochemical detection of aflatoxin B1 was developed and characterized. This involved four major steps: (1 an electroless deposition of silver (plating onto a glass slide, (2 immobilization of cysteine; (3 conjugation of aflatoxin B1 to cysteine groups; and (4 blocking of free cysteine groups with horseradish peroxidase (HRP. The binding of cysteine to the silver was demonstrated by the disappearance of thiol (S-H groups at 2500 cm−1 using Fourier transmittance infrared spectra (FT-IR, while the subsequent steps in the assembly of sensor platform were monitored using both FT-IR and cyclic voltammetry, respectively. The sensor platform exhibited a broadened nonsymmetrical redox couple as indicated by cyclic voltammetry. The platform was further characterized for sensitivity and limit of detection. The indirect competitive immunoassay format, whereby free and immobilized aflatoxin B1 on the sensor competed for the binding site of free anti-aflatoxin B1 antibody, was used at various concentrations of aflatoxin B1. The sensor generated differential staircase voltammogram that was inversely proportional to the concentration of aflatoxin B1 and aflatoxin B1 in the range of 0.06–1.1 ng/mL with a detection limit of 0.08 ng/mL could be detected.

  4. Analysis of CYP27B1 in multiple sclerosis

    Science.gov (United States)

    Ross, Jay P; Bernales, Cecily Q; Lee, Joshua D; Sadovnick, A Dessa; Traboulsee, Anthony L; Vilariño-Güell, Carles

    2016-01-01

    The analysis of genetic variability in CYP27B1 and its effect on risk of multiple sclerosis (MS) has yielded conflicting results. Here we describe a study to genetically characterize CYP27B1 and elucidate its role on MS risk in the Canadian population. Sequencing CYP27B1 failed to identify mutations known to cause loss of enzymatic activity, however genotyping of p.R389H in cases and controls identified the mutation in one multi-incident family (allele frequency = 0.03%) in which the p.R389H mutation segregates with disease in five family members diagnosed with MS, thus providing additional support for CYP27B1 p.R389H in the pathogenicity of MS. PMID:24308945

  5. Supercritical Fluid Extraction of Aflatoxin B 1 from Soil

    Science.gov (United States)

    This research describes the development of a Supercritical Fluid Extraction (SFE) method to recover aflatoxin B1 from fortified soil. The effects of temperature, pressure, modifier (identity and percentage), and extraction type were assessed. Using the optimized SFE conditions, ...

  6. SERUM TRANSFORMING GROWTH FACTOR B1 AND PROSTATE

    African Journals Online (AJOL)

    tein expression associated with fibrotic condi- ... TGF—B1 AND PSA AS MARKERS OF PROSTATE CANCER ..... transforming growth factor-beta is significantly the cell surface in tumor progression ... growth factor for clear cell renal carcinoma.

  7. Inhibition of Fungal Aflatoxin B1 Biosynthesis by Diverse Botanically ...

    African Journals Online (AJOL)

    effects on A. flavus growth and AFB1 production. Fungal spores were cultured ... Keywords: Polyphenols, Quercetin, Aflatoxin B1, Inhibition, Antioxidation. Tropical Journal of ..... agents used in animal feed or food processing areas. However,.

  8. Supercritical Fluid Extraction of Aflatoxin B 1 from Soil

    Science.gov (United States)

    This research describes the development of a Supercritical Fluid Extraction (SFE) method to recover aflatoxin B1 from fortified soil. The effects of temperature, pressure, modifier (identity and percentage), and extraction type were assessed. Using the optimized SFE conditions, ...

  9. B-1 cells as a source of IgA.

    Science.gov (United States)

    Meyer-Bahlburg, Almut

    2015-12-01

    Immunoglobulin A (IgA) is the most abundantly produced immunoglobulin found primarily on mucosal surfaces. The generation of IgA and its involvement in mucosal immune responses have been intensely studied over the past years. IgA can be generated in T cell-dependent and T cell-independent pathways, and it has an important impact on maintaining homeostasis within the mucosal immune system. There is good evidence that B-1 cells contribute substantially to the production of mucosal IgA and thus play an important role in regulating commensal microbiota. However, whether B-1 cells produce antigen-specific or only nonspecific IgA remains to be determined. This review will discuss what is currently known about IgA production by B-1 cells and the functional relevance of B-1 cell-derived IgA both in vitro and in vivo.

  10. Structural Stability, Transitions, and Interactions within SoxYZCD-Thiosulphate from Sulfurimonas denitrificans: An In Silico Molecular Outlook for Maintaining Environmental Sulphur Cycle

    Science.gov (United States)

    Banerjee, Arundhati

    2016-01-01

    Thiosulphate oxidation (an essential mechanism) serves to maintain the global sulphur cycle. Earlier experimental and computational studies dealt with environmental thiosulphate oxidation but none dealt with thiosulphate oxidation from deep ocean belts. Wet-laboratory experimental research shows that epsilon-proteobacteria Sulfurimonas denitrificans possess sox (sulphur-oxidizing) operon and perform thiosulphate oxidation efficiently underneath the oceans. From this specific sox operon, SoxCD complex recycles the thiosulphate-bound SoxY from SoxYZ complex to balance the environmental sulphur cycle. So, four chief proteins were variedly modeled and relevant simulated interactive structures were obtained. The final simulated tetraprotein complex (SoxYZCD) from docked SoxYZ and SoxCD complexes was disclosed to be a highly interactive one with predominant ionic residues. Free energy of folding, solvent accessibility, and conformational shifts (coil-like conformation to helices and sheets) were observed in SoxYZ complex after interacting with SoxCD. The stability of the complex (SoxYZCD) after simulation was also observed through the electrostatic surface potential values. These evaluations were rationalized via biostatistics. This aids SoxCD for recycling SoxY along with thiosulphate, which remains interconnected by four H-bonds with SoxY. Therefore, this novel exploration is endowed with the detailed molecular viewpoint for maintaining the sulphur cycle (globally) including the ocean belts. PMID:27777586

  11. Identification of direct regulatory targets of the transcription factor Sox10 based on function and conservation

    Directory of Open Access Journals (Sweden)

    Lee Sanghyuk

    2008-09-01

    Full Text Available Abstract Background Sox10, a member of the Sry-related HMG-Box gene family, is a critical transcription factor for several important cell lineages, most notably the neural crest stem cells and the derivative peripheral glial cells and melanocytes. Thus far, only a handful of direct target genes are known for this transcription factor limiting our understanding of the biological network it governs. Results We describe identification of multiple direct regulatory target genes of Sox10 through a procedure based on function and conservation. By combining RNA interference technique and DNA microarray technology, we have identified a set of genes that show significant down-regulation upon introduction of Sox10 specific siRNA into Schwannoma cells. Subsequent comparative genomics analyses led to potential binding sites for Sox10 protein conserved across several mammalian species within the genomic region proximal to these genes. Multiple sites belonging to 4 different genes (proteolipid protein, Sox10, extracellular superoxide dismutase, and pleiotrophin were shown to directly interact with Sox10 by chromatin immunoprecipitation assay. We further confirmed the direct regulation through the identified cis-element for one of the genes, extracellular superoxide dismutase, using electrophoretic mobility shift assay and reporter assay. Conclusion In sum, the process of combining differential expression profiling and comparative genomics successfully led to further defining the role of Sox10, a critical transcription factor for the development of peripheral glia. Our strategy utilizing relatively accessible techniques and tools should be applicable to studying the function of other transcription factors.

  12. CIAE Signs Contract on B1/B2 Project

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    CIAE signed Contract on Design,Commissioning and Technology Service for B1/B2 Project of Birine Reactor with CZEC in December,2015.The B1/B2 project which was won over by CZEC is PhaseⅠand PhaseⅡof an Algeria project which aimed to upgrade and rebuild Algeria Birine Nuclear Research Center.According to the contract with total fund amounting to 110million Yuan,CIAE will provide

  13. 26 CFR 31.3401(b)-1 - Payroll period.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Payroll period. 31.3401(b)-1 Section 31.3401(b... Collection of Income Tax at Source § 31.3401(b)-1 Payroll period. (a) The term payroll period means the period of service for which a payment of wages is ordinarily made to an employee by his employer. It is...

  14. CYP1B1-mediated Pathobiology of Primary Congenital Glaucoma.

    Science.gov (United States)

    Faiq, Muneeb A; Dada, Rima; Qadri, Rizwana; Dada, Tanuj

    2015-01-01

    CYP1B1 is a dioxin-inducible enzyme belonging to the cytochrome P450 superfamily. It has been observed to be important in a variety of developmental processes including in utero development of ocular structures. Owing to its role in the developmental biology of eye, its dysfunction can lead to ocular developmental defects. This has been found to be true and CYP1B1 mutations have been observed in a majority of primary congenital glaucoma (PCG) patients from all over the globe. Primary congenital glaucoma is an irreversibly blinding childhood disorder (onset at birth or early infancy) typified by anomalous development of trabecular meshwork (TM). How CYP1B1 causes PCG is not known; however, some basic investigations have been reported. Understanding the CYP1B1 mediated etiopathomechanism of PCG is very important to identify targets for therapy and preventive management. In this perspective, we will make an effort to reconstruct the pathomechanism of PCG in the light of already reported information about the disease and the CYP1B1 gene. How to cite this article: Faiq MA, Dada R, Qadri R, Dada T. CYP1 B1-mediated Pathobiology of Primary Congenital Glaucoma. J Curr Glaucoma Pract 2015;9(3):77-80.

  15. SOX2 defect and anophthalmia and microphthalmia%SOX2基因缺陷与先天性小眼球和无眼球

    Institute of Scientific and Technical Information of China (English)

    叶福相; 范先群

    2012-01-01

    As a severe congenital developmental disorder,anophthalmia and microphthalmia are usually accompanied with vision impairment and hypoevolutism of the orbit in the affected side.Many genes are involved in anophthalmia and microphthalmia,in which,SOX2 is an important one.The defect of SOX2 causes multiple system disorders,including anophthalmia and microphthalmia.We describe the relationship between the SOX2 defect and anophthalmia/microphthalmia,in order to offer some proposals for the differential diagnosis,treatment and research of anophthalmia and microphthalmia.%先天性小眼球和无眼球是一种严重眼球先天性发育疾病,患侧通常有严重的视力障碍,同时伴有患侧眼眶发育迟缓.先天性小眼球和无眼球的发病与诸多基因相关,其中,较为重要的是SOX2基因,其缺陷可导致包括先天性无眼球和小眼球在内的多系统异常.本文对SOX2基因缺陷与先天性小眼球和无眼球之间的关系进行简要综述,为先天性小眼球和无眼球的鉴别、诊治和研究提供一定的参考.

  16. Pluripotency transcription factor Sox2 is strongly adsorbed by heparin but requires a protein transduction domain for cell internalization

    Energy Technology Data Exchange (ETDEWEB)

    Albayrak, Cem [Department of Chemical Engineering, Stanford University, 381 North-South Mall, Stanford, CA 94305 (United States); Yang, William C. [Department of Bioengineering, Stanford University, 318 Campus Drive, Stanford, CA 94305 (United States); Swartz, James R., E-mail: jswartz@stanford.edu [Department of Chemical Engineering, Stanford University, 381 North-South Mall, Stanford, CA 94305 (United States); Department of Bioengineering, Stanford University, 318 Campus Drive, Stanford, CA 94305 (United States)

    2013-02-15

    Highlights: ► Both R9Sox2 and Sox2 bind heparin with comparable affinity. ► Both R9Sox2 and Sox2 bind to fibroblasts, but only R9Sox2 is internalized. ► Internalization efficiency of R9Sox2 is 0.3% of the administered protein. ► Heparan sulfate adsorption may be part of a mechanism for managing cell death. -- Abstract: The binding of protein transduction domain (PTD)-conjugated proteins to heparan sulfate is an important step in cellular internalization of macromolecules. Here, we studied the pluripotency transcription factor Sox2, with or without the nonaarginine (R9) PTD. Unexpectedly, we observed that Sox2 is strongly adsorbed by heparin and by the fibroblasts without the R9 PTD. However, only the R9Sox2 fusion protein is internalized by the cells. These results collectively show that binding to heparan sulfate is not sufficient for cellular uptake, thereby supporting a recent hypothesis that other proteins play a role in cell internalization of PTD-conjugated proteins.

  17. TG-interacting Factor (TGIF) Downregulates SOX3 Gene Expression in the NT2/D1 Cell Line

    Institute of Scientific and Technical Information of China (English)

    Marija Mojsin; Jelena Popovic; Natasa Kovacevic Gruiicic; Milena Stevanovic

    2012-01-01

    SOX3 is a member of the Sox gene family implicated in brain formation and cognitive function.It is considered to be one of the earliest neural markers in vertebrates,playing a role in specifying neuronal fate.Recently,we have established the first link between TALE (threeamino-acid loop extension) proteins,PBX1 (pre-B-cell leukemia homeobox 1) and MEIS1 (myeloid ecotropic viral integration site 1homologue),and the expression of the human SOX3 gene.Here we present the evidence that TGIF (TG-interacting factor) is an additional TALE superfamily member involved in the regulation of human SOX3 gene expression in NT2/D1 cells by direct interaction with the consensus binding site that is conserved in primate orthologue promoters.Functional analysis demonstrated that mutation of the TGIF binding site resulted in the activation of SOX3 promoter.TGIF overexpression downregulates SOX3 promoter activity and decreases endogenous SOX3 protein expression in both uninduced and refinoic acid (RA)-induced NT2/D1 cells.Up to now,this is the first transcription factor identified as a negative regulator of SOX3 gene expression.The obtained results further underscore the significance of TALE proteins as important transcriptional regulators of SOX3 gene expression.

  18. Cloning and function analysis of high mobility group box 1(HMGB1)protein of Schistosoma japonicum(Mainland strain)%日本血吸虫高速泳动家族B1蛋白基因的克隆表达与功能分析

    Institute of Scientific and Technical Information of China (English)

    姚媛; 许永良; 杨静; 余传信; 宋丽君; 殷旭仁; 王玠; 金一; 沈双; 张伟; 高玒

    2014-01-01

    to both supercoiled DNA and linear DNA,and the recombinant protein immu-nized mice produced high titers of antiserum IgG. Western bloting indicated that the recombinant SjHMGB1 protein was recognized specifically by the S. japonicum-infected mice serum. Above results showed that the recombinant SjHMGB1 protein possessed both functional activity and immunogenicity as the natural protein. RT-PCR and Western blot results showed that SjHMGB1 was abun-dantly expressed in the adult and egg stages whereas barely detectable in the cercaria stage. The immune protection experiment showed that the recombinant SjHMGB1 induced mice to produce high titers of specific antibody IgG but failed to conduct an effec-tive immune protection against S. japonicum. Conclusion The gene encoding HMGB1 from S. japonicum and the soluble recombi-nant SjHMGB1 protein with natural functional activity are obtained,and the recombinant SjHMGB1 has a high immunogenicity but is not able to induce an effective immune protection against S. japonicum.%目的:克隆、表达日本血吸虫高速泳动家族B1蛋白(SjHMGB1),并研究其功能特性。方法利用逆转录PCR (RT-PCR)技术从日本血吸虫成虫mRNA中反转录扩增出编码SjHMGB1的完整开放阅读框DNA片段,然后将其亚克隆至原核表达载体质粒pET28a(+)中,构建重组表达质粒SjHMGB1-pET28a。将重组表达质粒转化大肠埃希菌BL21(DE3),含重组质粒的转化子细菌经异丙基硫代半乳糖苷(IPTG)诱导以表达重组SjHMGB1蛋白。通过镍螯合琼脂糖亲和胶亲和层析法制备纯化的重组SjHMGB1蛋白。通过DNA迟滞实验和动物免疫鉴定重组SjHMGB1的DNA结合和免疫学特性。通过免疫印迹试验(Western blotting)和RT-PCR确定SjHMGB1分子在日本血吸虫不同发育阶段的表达情况。以重组SjH-MGB1为抗原免疫小鼠,3次免疫后每只小鼠感染45±2条血吸虫尾蚴,42 d后剖杀,计算减虫率与减卵率,

  19. Cytochrome P450 1B1 Contributes to the Development of Atherosclerosis and Hypertension in Apolipoprotein E-Deficient Mice.

    Science.gov (United States)

    Song, Chi Young; Ghafoor, Khuzema; Ghafoor, Hafiz U; Khan, Nayaab S; Thirunavukkarasu, Shyamala; Jennings, Brett L; Estes, Anne M; Zaidi, Sahar; Bridges, Dave; Tso, Patrick; Gonzalez, Frank J; Malik, Kafait U

    2016-01-01

    Cytochrome P450 (CYP) 1B1 contributes to vascular smooth muscle cell growth and hypertension in male mice. This study was conducted to determine the contribution of CYP1B1 to the development of atherosclerosis and hypertension and associated pathogenesis in 8-week-old male apolipoprotein E-deficient (ApoE(-/-)/Cyp1b1(+/+)), and ApoE- and CYP1B1-deficient (ApoE(-/-)/Cyp1b1(-/-)) mice fed a normal or atherogenic diet for 12 weeks. A separate group of ApoE(-/-)/Cyp1b1(+/+) mice on an atherogenic diet was injected every third day with the CYP1B1 inhibitor, 2,3',4,5'-tetramethoxystilbene (300 μg/kg), or its vehicle, dimethyl sulfoxide (30 μL, IP); systolic blood pressure was measured by the tail cuff method. After 12 weeks, mice were euthanized, blood collected for lipid analysis, and aortas harvested for measuring lesions and remodeling, and for infiltration of inflammatory cells by histological and immunohistochemical analysis, respectively, and for reactive oxygen species production. Blood pressure, areas of lipids and collagen deposition, elastin breaks, infiltration of macrophages and T lymphocytes, reactive oxygen species generation in the aorta, and plasma lipid levels were increased in ApoE(-/-)/Cyp1b1(+/+) mice on an atherogenic diet; these changes were minimized in mice given 2,3',4,5'-tetramethoxystilbene, and in ApoE(-/-)/Cyp1b1(-/-) mice on an atherogenic diet; absorption/production of lipids remained unaltered in these mice. These data suggest that aortic lesions, hypertension, and associated pathogenesis in ApoE(-/-)/Cyp1b1(+/+) mice on an atherogenic diet are most likely dependent on CYP1B1-generated oxidative stress and increased plasma lipid levels independent of blood pressure and absorption of lipids. CYP1B1 could serve as a novel target for developing drugs to treat atherosclerosis and hypertension caused by hypercholesterolemia.

  20. Mir-21–Sox2 Axis Delineates Glioblastoma Subtypes with Prognostic Impact

    Science.gov (United States)

    Sathyan, Pratheesh; Zinn, Pascal O.; Marisetty, Anantha L.; Liu, Bin; Kamal, Mohamed Mostafa; Singh, Sanjay K.; Bady, Pierre; Lu, Li; Wani, Khalida M.; Veo, Bethany L.; Gumin, Joy; Kassem, Dina Hamada; Robinson, Frederick; Weng, Connie; Baladandayuthapani, Veerabhadran; Suki, Dima; Colman, Howard; Bhat, Krishna P.; Sulman, Erik P.; Aldape, Ken; Colen, Rivka R.; Verhaak, Roel G.W.; Lu, Zhimin; Fuller, Gregory N.; Huang, Suyun; Lang, Frederick F.; Sawaya, Raymond; Hegi, Monika

    2015-01-01

    Glioblastoma (GBM) is the most aggressive human brain tumor. Although several molecular subtypes of GBM are recognized, a robust molecular prognostic marker has yet to be identified. Here, we report that the stemness regulator Sox2 is a new, clinically important target of microRNA-21 (miR-21) in GBM, with implications for prognosis. Using the MiR-21–Sox2 regulatory axis, approximately half of all GBM tumors present in the Cancer Genome Atlas (TCGA) and in-house patient databases can be mathematically classified into high miR-21/low Sox2 (Class A) or low miR-21/high Sox2 (Class B) subtypes. This classification reflects phenotypically and molecularly distinct characteristics and is not captured by existing classifications. Supporting the distinct nature of the subtypes, gene set enrichment analysis of the TCGA dataset predicted that Class A and Class B tumors were significantly involved in immune/inflammatory response and in chromosome organization and nervous system development, respectively. Patients with Class B tumors had longer overall survival than those with Class A tumors. Analysis of both databases indicated that the Class A/Class B classification is a better predictor of patient survival than currently used parameters. Further, manipulation of MiR-21–Sox2 levels in orthotopic mouse models supported the longer survival of the Class B subtype. The MiR-21–Sox2 association was also found in mouse neural stem cells and in the mouse brain at different developmental stages, suggesting a role in normal development. Therefore, this mechanism-based classification suggests the presence of two distinct populations of GBM patients with distinguishable phenotypic characteristics and clinical outcomes. SIGNIFICANCE STATEMENT Molecular profiling-based classification of glioblastoma (GBM) into four subtypes has substantially increased our understanding of the biology of the disease and has pointed to the heterogeneous nature of GBM. However, this classification is not

  1. Long-Term Expandable SOX9+ Chondrogenic Ectomesenchymal Cells from Human Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Katsutsugu Umeda

    2015-04-01

    Full Text Available Here we report the successful generation and long-term expansion of SOX9-expressing CD271+PDGFRα+CD73+ chondrogenic ectomesenchymal cells from the PAX3/SOX10/FOXD3-expressing MIXL1−CD271hiPDGFRαloCD73− neural crest-like progeny of human pluripotent stem cells in a chemically defined medium supplemented with Nodal/Activin/transforming growth factorβ (TGFβ inhibitor and fibroblast growth factor (FGF. When “primed” with TGFβ, such cells efficiently formed translucent cartilage particles, which were completely mineralized in 12 weeks in immunocompromized mice. The ectomesenchymal cells were expandable without loss of chondrogenic potential for at least 16 passages. They maintained normal karyotype for at least 10 passages and expressed genes representing embryonic progenitors (SOX4/12, LIN28A/B, cranial mesenchyme (ALX1/3/4, and chondroprogenitors (SOX9, COL2A1 of neural crest origin (SOX8/9, NGFR, NES. Ectomesenchyme is a source of many craniofacial bone and cartilage structures. The method we describe for obtaining a large quantity of human ectomesenchymal cells will help to model craniofacial disorders in vitro and potentially provide cells for the repair of craniofacial damage.

  2. Interplay between SOX7 and RUNX1 regulates hemogenic endothelial fate in the yolk sac.

    Science.gov (United States)

    Lilly, Andrew J; Costa, Guilherme; Largeot, Anne; Fadlullah, Muhammad Z H; Lie-A-Ling, Michael; Lacaud, Georges; Kouskoff, Valerie

    2016-12-01

    Endothelial to hematopoietic transition (EHT) is a dynamic process involving the shutting down of endothelial gene expression and switching on of hematopoietic gene transcription. Although the factors regulating EHT in hemogenic endothelium (HE) of the dorsal aorta have been relatively well studied, the molecular regulation of yolk sac HE remains poorly understood. Here, we show that SOX7 inhibits the expression of RUNX1 target genes in HE, while having no effect on RUNX1 expression itself. We establish that SOX7 directly interacts with RUNX1 and inhibits its transcriptional activity. Through this interaction we demonstrate that SOX7 hinders RUNX1 DNA binding as well as the interaction between RUNX1 and its co-factor CBFβ. Finally, we show by single-cell expression profiling and immunofluorescence that SOX7 is broadly expressed across the RUNX1(+) yolk sac HE population compared with SOX17. Collectively, these data demonstrate for the first time how direct protein-protein interactions between endothelial and hematopoietic transcription factors regulate contrasting transcriptional programs during HE differentiation and EHT. © 2016. Published by The Company of Biologists Ltd.

  3. Differential Nucleosome Occupancies across Oct4-Sox2 Binding Sites in Murine Embryonic Stem Cells.

    Directory of Open Access Journals (Sweden)

    Amy Sebeson

    Full Text Available The binding sequence for any transcription factor can be found millions of times within a genome, yet only a small fraction of these sequences encode functional transcription factor binding sites. One of the reasons for this dichotomy is that many other factors, such as nucleosomes, compete for binding. To study how the competition between nucleosomes and transcription factors helps determine a functional transcription factor site from a predicted transcription factor site, we compared experimentally-generated in vitro nucleosome occupancy with in vivo nucleosome occupancy and transcription factor binding in murine embryonic stem cells. Using a solution hybridization enrichment technique, we generated a high-resolution nucleosome map from targeted regions of the genome containing predicted sites and functional sites of Oct4/Sox2 regulation. We found that at Pax6 and Nes, which are bivalently poised in stem cells, functional Oct4 and Sox2 sites show high amounts of in vivo nucleosome displacement compared to in vitro. Oct4 and Sox2, which are active, show no significant displacement of in vivo nucleosomes at functional sites, similar to nonfunctional Oct4/Sox2 binding. This study highlights a complex interplay between Oct4 and Sox2 transcription factors and nucleosomes among different target genes, which may result in distinct patterns of stem cell gene regulation.

  4. Sox10 Regulates Stem/Progenitor and Mesenchymal Cell States in Mammary Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Christopher Dravis

    2015-09-01

    Full Text Available To discover mechanisms that mediate plasticity in mammary cells, we characterized signaling networks that are present in the mammary stem cells responsible for fetal and adult mammary development. These analyses identified a signaling axis between FGF signaling and the transcription factor Sox10. Here, we show that Sox10 is specifically expressed in mammary cells exhibiting the highest levels of stem/progenitor activity. This includes fetal and adult mammary cells in vivo and mammary organoids in vitro. Sox10 is functionally relevant, as its deletion reduces stem/progenitor competence whereas its overexpression increases stem/progenitor activity. Intriguingly, we also show that Sox10 overexpression causes mammary cells to undergo a mesenchymal transition. Consistent with these findings, Sox10 is preferentially expressed in stem- and mesenchymal-like breast cancers. These results demonstrate a signaling mechanism through which stem and mesenchymal states are acquired in mammary cells and suggest therapeutic avenues in breast cancers for which targeted therapies are currently unavailable.

  5. Autophagy and cellular senescence mediated by Sox2 suppress malignancy of cancer cells.

    Directory of Open Access Journals (Sweden)

    Yong-Yeon Cho

    Full Text Available Autophagy is a critical cellular process required for maintaining cellular homeostasis in health and disease states, but the molecular mechanisms and impact of autophagy on cancer is not fully understood. Here, we found that Sox2, a key transcription factor in the regulation of the "stemness" of embryonic stem cells and induced-pluripotent stem cells, strongly induced autophagic phenomena, including intracellular vacuole formation and lysosomal activation in colon cancer cells. The activation occurred through Sox2-mediated ATG10 gene expression and resulted in the inhibition of cell proliferation and anchorage-independent colony growth ex vivo and tumor growth in vivo. Further, we found that Sox2-induced-autophagy enhanced cellular senescence by up-regulating tumor suppressors or senescence factors, including p16(INK4a, p21 and phosphorylated p53 (Ser15. Notably, knockdown of ATG10 in Sox2-expressing colon cancer cells restored cancer cell properties. Taken together, our results demonstrated that regulation of autophagy mediated by Sox2 is a mechanism-driven novel strategy to treat human colon cancers.

  6. The Expression of NP847 and Sox2 after TBI and Its Influence on NSCs

    Science.gov (United States)

    Gu, Jun; Bao, Yifeng; Chen, Jian; Huang, Chuanjun; Zhang, Xinghua; Jiang, Rui; Liu, Qianqian; Liu, Yonghua; Xu, Xide; Shi, Wei

    2016-01-01

    The proliferation and differentiation of neural stem cells (NSCs) is important for neural regeneration after cerebral injury. Here, for the first time, we show that phosphorylated (p)-ser847-nNOS (NP847), rather than nNOS, may play a major role in NSC proliferation after traumatic brain injury (TBI). Western blot results demonstrated that the expression of NP847 and Sox2 in the hippocampus is up-regulated after TBI, and they both peak 3 days after brain injury. In addition, an immunofluorescence experiment indicated that NP847 and Sox2 partly co-localize in the nuclei of NSCs after TBI. Further immunoprecipitation experiments found that NP847 and Sox2 can directly interact with each other in NSCs. Moreover, in an OGD model of NSCs, NP847 expression is decreased, which is followed by the down-regulation of Sox2. Interestingly, in this study, we did not observe changes in the expression of nNOS in the OGD model. Further research data suggest that the NP847-Sox2 complex may play a major role in NSCs through the Shh/Gli signaling pathway in a CaMKII-dependent manner after brain injury. PMID:28066182

  7. Differential Nucleosome Occupancies across Oct4-Sox2 Binding Sites in Murine Embryonic Stem Cells.

    Science.gov (United States)

    Sebeson, Amy; Xi, Liqun; Zhang, Quanwei; Sigmund, Audrey; Wang, Ji-Ping; Widom, Jonathan; Wang, Xiaozhong

    2015-01-01

    The binding sequence for any transcription factor can be found millions of times within a genome, yet only a small fraction of these sequences encode functional transcription factor binding sites. One of the reasons for this dichotomy is that many other factors, such as nucleosomes, compete for binding. To study how the competition between nucleosomes and transcription factors helps determine a functional transcription factor site from a predicted transcription factor site, we compared experimentally-generated in vitro nucleosome occupancy with in vivo nucleosome occupancy and transcription factor binding in murine embryonic stem cells. Using a solution hybridization enrichment technique, we generated a high-resolution nucleosome map from targeted regions of the genome containing predicted sites and functional sites of Oct4/Sox2 regulation. We found that at Pax6 and Nes, which are bivalently poised in stem cells, functional Oct4 and Sox2 sites show high amounts of in vivo nucleosome displacement compared to in vitro. Oct4 and Sox2, which are active, show no significant displacement of in vivo nucleosomes at functional sites, similar to nonfunctional Oct4/Sox2 binding. This study highlights a complex interplay between Oct4 and Sox2 transcription factors and nucleosomes among different target genes, which may result in distinct patterns of stem cell gene regulation.

  8. CO2 , NOx and SOx removal from flue gas via microalgae cultivation: a critical review.

    Science.gov (United States)

    Yen, Hong-Wei; Ho, Shih-Hsin; Chen, Chun-Yen; Chang, Jo-Shu

    2015-06-01

    Flue gas refers to the gas emitting from the combustion processes, and it contains CO2 , NOx , SOx and other potentially hazardous compounds. Due to the increasing concerns of CO2 emissions and environmental pollution, the cleaning process of flue gas has attracted much attention. Using microalgae to clean up flue gas via photosynthesis is considered a promising CO2 mitigation process for flue gas. However, the impurities in the flue gas may inhibit microalgal growth, leading to a lower microalgae-based CO2 fixation rate. The inhibition effects of SOx that contribute to the low pH could be alleviated by maintaining a stable pH level, while NOx can be utilized as a nitrogen source to promote microalgae growth when it dissolves and is oxidized in the culture medium. The yielded microalgal biomass from fixing flue gas CO2 and utilizing NOx and SOx as nutrients would become suitable feedstock to produce biofuels and bio-based chemicals. In addition to the removal of SOx , NOx and CO2 , using microalgae to remove heavy metals from flue gas is also quite attractive. In conclusion, the use of microalgae for simultaneous removal of CO2 , SOx and NOx from flue gas is an environmentally benign process and represents an ideal platform for CO2 reutilization. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Evidence for the eta_b(1S) in the Decay Upsilon(2S)-> gamma eta_b(1S)

    Energy Technology Data Exchange (ETDEWEB)

    Aubert, B.; Bona, M.; Karyotakis, Y.; Lees, J.P.; Poireau, V.; Prencipe, E.; Prudent, X.; Tisserand, V.; /Annecy, LAPP; Garra Tico, J.; Grauges, E.; /Barcelona U., ECM; Lopez, L.; Palano, A.; Pappagallo, M.; /INFN, Bari /Bari U.; Eigen, G.; Stugu, B.; Sun, L.; /Bergen U.; Battaglia, M.; Brown, D.N.; Kerth, L.T.; Kolomensky, Yu.G.; Lynch, G.; /LBL, Berkeley /UC, Berkeley /Birmingham U. /Ruhr U., Bochum /British Columbia U. /Brunel U. /Novosibirsk, IYF /UC, Irvine /UCLA /UC, Riverside /UC, San Diego /UC, Santa Barbara /UC, Santa Cruz /Caltech /Cincinnati U. /Colorado U. /Colorado State U. /Dortmund U. /Dresden, Tech. U. /Ecole Polytechnique /Edinburgh U. /INFN, Ferrara /Ferrara U. /INFN, Ferrara /INFN, Ferrara /Ferrara U. /INFN, Ferrara /INFN, Ferrara /Ferrara U. /Frascati /INFN, Genoa /Genoa U. /INFN, Genoa /INFN, Genoa /Genoa U. /INFN, Genoa /INFN, Genoa /Genoa U. /Harvard U. /Heidelberg U. /Humboldt U., Berlin /Imperial Coll., London /Iowa U. /Iowa State U. /Johns Hopkins U. /Orsay, LAL /LLNL, Livermore /Liverpool U. /Queen Mary, U. of London /Royal Holloway, U. of London /Louisville U. /Karlsruhe U., EKP /Manchester U. /Maryland U. /Massachusetts U., Amherst /MIT, LNS /McGill U. /INFN, Milan /Milan U. /INFN, Milan /INFN, Milan /Milan U. /Mississippi U. /Montreal U. /Mt. Holyoke Coll. /INFN, Naples /Naples U. /INFN, Naples /INFN, Naples /Naples U. /NIKHEF, Amsterdam /Notre Dame U. /Ohio State U. /Oregon U. /INFN, Padua /Padua U. /INFN, Padua /INFN, Padua /Padua U. /Paris U., VI-VII /Pennsylvania U. /INFN, Perugia /Perugia U. /INFN, Pisa /Pisa U. /INFN, Pisa /Pisa, Scuola Normale Superiore /INFN, Pisa /Pisa U. /INFN, Pisa /Princeton U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /INFN, Rome /Rome U. /INFN, Rome /Rostock U. /Rutherford /DSM, DAPNIA, Saclay /South Carolina U. /SLAC /Stanford U., Phys. Dept. /SUNY, Albany /Tennessee U. /Texas U. /Texas U., Dallas /INFN, Turin /Turin U. /INFN, Trieste /Trieste U. /Valencia U., IFIC /Victoria U. /Warwick U. /Wisconsin U., Madison

    2009-12-14

    We have performed a search for the {eta}{sub b}(1S) meson in the radiative decay of the {Upsilon}(2S) resonance using a sample of 91.6 million {Upsilon}(2S) events recorded with the BABAR detector at the PEP-II B factory at the SLAC National Accelerator Laboratory. We observe a peak in the photon energy spectrum at E{sub {gamma}} = 610.5{sub -4.3}{sup +4.5}(stat) {+-} 1.8(syst) MeV, corresponding to an {eta}{sub b}(1S) mass of 9392.9{sub -4.8}{sup +4.6}(stat) {+-} 1.9(syst) MeV/c{sup 2}. The branching fraction for the decay {Upsilon}(2S) {yields} {gamma}{eta}{sub b}(1S) is determined to be (4.2{sub -1.0}{sup +1.1}(stat) {+-} 0.9(syst)) x 10{sup -4}. The ratio {Beta}({Upsilon}(2S) {yields} {gamma}{eta}{sub b}(1S))/{Beta}({Upsilon}(3S) {yields} {gamma}{eta}{sub b}(1S)) = 0.89{sub -0.23}{sup +0.25}(stat){sub -0.16}{sup +0.12}(syst) is consistent with the ratio expected for magnetic dipole transitions to the {eta}{sub b}(1S) meson.

  10. Primary congenital glaucoma and Rieger's anomaly: extended haplotypes reveal founder effects for eight distinct CYP1B1 mutations

    OpenAIRE

    Chavarria-Soley, G.; Michels-Rautenstrauss, K.; Pasutto, F; Flikier, D.; Flikier, P.; Cirak, S; Bejjani, B.; Winters, D.; Lewis, R; Mardin, C.; Reis, A; Rautenstrauss, B.

    2006-01-01

    PURPOSE: Mutations in the cytochrome P450 1B1 (CYP1B1) gene are a frequent cause of primary congenital glaucoma (PCG) in different ethnic groups. Cytochrome P450 proteins are monooxygenases, which catalyze many reactions involved in the metabolism of drugs as well as steroids and other lipids. The repeated occurence of several mutations in various ethnic groups raises the question if founder effects or mutation-prone sites in CYP1B1 are the cause for this observation.METHODS: A total of 30 in...

  11. Association of CYP1B1 with hypersensitivity induced by taxane therapy in breast cancer patients.

    Science.gov (United States)

    Rizzo, Roberta; Spaggiari, Federica; Indelli, Monica; Lelli, Giorgio; Baricordi, Olavio R; Rimessi, Paola; Ferlini, Alessandra

    2010-11-01

    Taxanes represent a group of anticancer drugs with a wide range of activity against breast cancer. Therapy side effects include haematologic toxicity (neutropenia, leucopenia), peripheral neuropathy and hypersensitivity, and demonstrate inter-individual variations. Since it is known that three genes are implicated in taxane turnover, namely ABCB1 in the transport, CYP2C8 in the metabolism and CYP1B1 in the activity, we explored the association among polymorphisms (single nucleotide polymorphisms, SNPs) in these three genes and the occurrence of taxane-induced toxicity. We studied 95 patients affected by breast cancer and under treatment with taxanes as adjuvant, metastatic or neo-adjuvant therapy. We genotyped them for SNPs in the CYP2C8 (alleles *1, *2, *3 and *4), CYP1B1 (alleles *1 and *3) and ABCB1 (1236 C>T; 2677 G>T/A; 3435 C>T) genes by real-time PCR assay. We observed a significant association between the CYP1B1*3 allele and a lower occurrence of hypersensitivity reactions to taxane treatment. We speculate that the highest production of 4-hydroxyestradiol (4-OHE2) metabolite by CYP1B1*3 allele could increase the formation of the 4-OHE2-taxane adduct and possibly inhibit taxane toxicity. We suggest that CYP1B1 might affect taxane hypersensitivity therefore representing, if confirmed in a large cohort of patients, an exploratory hypersensitivity predictive biomarker.

  12. B-1 cells and concomitant immunity in Ehrlich tumour progression.

    Science.gov (United States)

    Azevedo, M C; Palos, M C; Osugui, L; Laurindo, M F; Masutani, D; Nonogaki, S; Bachi, A L L; Melo, F H M; Mariano, M

    2014-05-01

    Concomitant immunity is a phenomenon in which a tumour-bearing host is resistant to the growth of an implanted secondary tumour. Metastases are considered to be secondary tumours that develop spontaneously during primary tumour growth, suggesting the involvement of concomitant immunity in controlling the rise of metastases. It has been demonstrated that B-1 cells, a subset of B-lymphocytes found predominantly in pleural and peritoneal cavities, not only increase the metastatic development of murine melanoma B16F10, but also are capable of differentiating into mononuclear phagocytes, modulating inflammatory responses in wound healing, in oral tolerance and in Paracoccidiose brasiliensis infections. Here, we studied B-1 cells' participation in concomitant immunity during Ehrlich tumour progression. Our results show that B-1 cells obtained from BALB/c mice previously injected with Ehrlich tumour in the footpad were able to protect BALB/c and BALB/Xid mice against Ehrlich tumour challenge. In addition, it was demonstrated that BALB/Xid show faster tumour growth and have lost concomitant immunity, and that this state can be partially restored by reconstituting these animals with B-1 cells. However, further researches are required to establish the mechanism involving B-1 cells in Ehrlich tumour growth. Copyright © 2014 Elsevier GmbH. All rights reserved.

  13. Occurrence of aflatoxin B1 in natural products

    Directory of Open Access Journals (Sweden)

    Guilherme Prado

    2012-12-01

    Full Text Available The media claims for the consumption of natural resource-based food have gradually increased in both developing and developed countries. The interest in the safety of these products is partially due to the possible presence of toxigenic fungi acting as mycotoxin producers, such as aflatoxins produced during the secondary metabolism of Aspergillus flavus, A. parasiticus and A. nomius. Aflatoxins, mainly aflatoxin B1, are directly associated with liver cancer in human beings. This paper is aimed at evaluating the presence of aflatoxin B1 in a few vegetable drugs, dried plant extracts and industrialized products traded in 2010 in the city of Belo Horizonte, State of Minas Gerais, Brazil. The method used for the quantification of aflatoxin B1 was based on extraction through acetone:water (85:15, immunoaffinity column purification followed by separation and detection in high efficiency liquid chromatography. Under the conditions of analysis, the Limits of Detection and Quantification were 0.6 µg kg-1 and 1.0 µg kg-1respectively. The complete sets of analyses were carried out in duplicate. Aflatoxin B1 was noticed in a single sample (< 1.0 µg kg-1. The results revealed low aflatoxin B1contamination in the products under analysis. However, it is required to establish a broad monitoring program in order to obtain additional data and check up on the actual extension of contamination.

  14. SerpinB1 Promotes Pancreatic β Cell Proliferation.

    Science.gov (United States)

    El Ouaamari, Abdelfattah; Dirice, Ercument; Gedeon, Nicholas; Hu, Jiang; Zhou, Jian-Ying; Shirakawa, Jun; Hou, Lifei; Goodman, Jessica; Karampelias, Christos; Qiang, Guifeng; Boucher, Jeremie; Martinez, Rachael; Gritsenko, Marina A; De Jesus, Dario F; Kahraman, Sevim; Bhatt, Shweta; Smith, Richard D; Beer, Hans-Dietmar; Jungtrakoon, Prapaporn; Gong, Yanping; Goldfine, Allison B; Liew, Chong Wee; Doria, Alessandro; Andersson, Olov; Qian, Wei-Jun; Remold-O'Donnell, Eileen; Kulkarni, Rohit N

    2016-01-12

    Although compensatory islet hyperplasia in response to insulin resistance is a recognized feature in diabetes, the factor(s) that promote β cell proliferation have been elusive. We previously reported that the liver is a source for such factors in the liver insulin receptor knockout (LIRKO) mouse, an insulin resistance model that manifests islet hyperplasia. Using proteomics we show that serpinB1, a protease inhibitor, which is abundant in the hepatocyte secretome and sera derived from LIRKO mice, is the liver-derived secretory protein that regulates β cell proliferation in humans, mice, and zebrafish. Small-molecule compounds, that partially mimic serpinB1 effects of inhibiting elastase activity, enhanced proliferation of β cells, and mice lacking serpinB1 exhibit attenuated β cell compensation in response to insulin resistance. Finally, SerpinB1 treatment of islets modulated proteins in growth/survival pathways. Together, these data implicate serpinB1 as an endogenous protein that can potentially be harnessed to enhance functional β cell mass in patients with diabetes.

  15. Glaucoma and Cytochrome P4501B1 Gene Mutations

    Directory of Open Access Journals (Sweden)

    Mukesh Tanwar

    2010-01-01

    Full Text Available Developmental anomalies of the ocular anterior chamber angle may lead to an incomplete development of the structures that form the conventional aqueous outflow pathway. Thus, disorders that present with such dysfunction tend to be associated with glaucoma. Among them, Axenfeld-Rieger (ARS malformation is a rare clinical entity with an estimated prevalence of one in every 200,000 individuals. The changes in eye morphogenesis in ARS are highly penetrant and are associated with 50% risk of development of glaucoma. Mutations in the cytochrome P4501B1 (CYP1B1 gene have been reported to be associated with primary congenital glaucoma and other forms of glaucoma and mutations in pituitary homeobox 2 (PITX2 gene have been identified in ARS in various studies. This case was negative for PITX2 mutations and compound heterozygote for CYP1B1 mutations. Clinical manifestations of this patient include bilateral elevated intraocular pressure (>40 mmHg with increased corneal diameter (>14 mm and corneal opacity. Patient also had iridocorneal adhesions, anteriorly displaced Schwalbe line, anterior insertion of iris, broad nasal bridge and protruding umbilicus. This is the first study from north India reporting CYP1B1 mutations in Axenfeld-Rieger syndrome with bilateral buphthalmos and early onset glaucoma. Result of this study supports the role of CYP1B1 as a causative gene in ASD disorders and its role in oculogenesis.

  16. Clinical significance of SOX9 in human non-small cell lung cancer progression and overall patient survival

    Directory of Open Access Journals (Sweden)

    Zhou Chun-Hui

    2012-03-01

    Full Text Available Abstract Background Sex determining region Y (SRY-related high mobility groupbox 9 (SOX9 is an important transcription factor required for development, which regulates the expression of target genes in the associated pathway. The aim of this study was to describe the expression of SOX9 in human non-small cell lung cancer (NSCLC and to investigate the association between SOX9 expression and progression of NSCLC. Methods SOX9 protein and mRNA expression in normal human pneumonocytes, lung cancer cell lines, and eight pairs of matched lung cancer tissues and their adjacent normal lung tissues were detected by Western blotting and real-time reverse transcription-polymerase chain reaction (RT-PCR. Immunohistochemistry was used to determine SOX9 protein expression in 142 cases of histologically characterized NSCLC. Statistical analyses were applied to test for prognostic and diagnostic associations. Results SOX9 in lung cancer cell lines was upregulated at both mRNA and protein levels, and SOX9 mRNA and protein were also elevated in NSCLC tissues compared with levels in corresponding adjacent non-cancerous lung tissues. Immunohistochemical analysis demonstrated a high expression of SOX9 in 74/142 (52.1% paraffin-embedded archival lung cancer biopsies. Statistical analysis indicated that upregulation of SOX9 was significantly correlated with the histological stage of NSCLC (P = 0.017 and that patients with a high SOX9 level exhibited a shorter survival time (P Conclusions This work shows that SOX9 may serve as a novel and prognostic marker for NSCLC, and play a role during the development and progression of the disease.

  17. Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma.

    Science.gov (United States)

    Liu, Chungang; Liu, Limei; Chen, Xuejiao; Cheng, Jiamin; Zhang, Heng; Shen, Junjie; Shan, Juanjuan; Xu, Yanmin; Yang, Zhi; Lai, Maode; Qian, Cheng

    2016-07-01

    Hepatocellular carcinoma (HCC) is a highly aggressive liver tumor containing cancer stem cells (CSCs) that participate in tumor propagation, resistance to conventional therapy, and promotion of tumor recurrence, causing poor patient outcomes. The protein SRY (sex determining region Y)-box 9 (Sox9) is a transcription factor expressed in some solid tumors, including HCC. However, the molecular mechanisms underlying Sox9 function in liver CSCs remain unclear. Here, we show that Sox9 is highly expressed in liver CSCs and that high levels of Sox9 predict a decreased probability of survival in HCC patients. We demonstrate that Sox9 is required for maintaining proliferation, self-renewal, and tumorigenicity in liver CSCs. Overexpression of exogenous Sox9 in liver non-CSCs restored self-renewal capacity. Additionally, a reduction in the asymmetrical cell division of spheroid-cultured liver CSCs was observed when compared with differentiated cancer cells or liver CSCs with inhibited Notch signaling. Furthermore, we demonstrate that Sox9 is responsible for the asymmetrical-to-symmetrical cell division switch in liver CSCs. Sox9 also negatively regulates Numb expression, contributing to a feedback circuit that maintains Notch activity and directs symmetrical cell division. Clinical analyses revealed that the Sox9(High) Numb(Low) profile is associated with poor prognosis in human HCC patients. We demonstrate that Sox9 plays a critical role in self-renewal and tumor propagation of liver CSCs and identify the molecular mechanisms regulated by Sox9 that link tumor initiation and cell division. (Hepatology 2016;64:117-129). © 2016 by the American Association for the Study of Liver Diseases.

  18. The σ(54)-dependent two-component system regulating sulfur oxidization (Sox) system in Acidithiobacillus caldus and some chemolithotrophic bacteria.

    Science.gov (United States)

    Li, Li-Feng; Fu, Luo-Jie; Lin, Jian-Qun; Pang, Xin; Liu, Xiang-Mei; Wang, Rui; Wang, Zhao-Bao; Lin, Jian-Qiang; Chen, Lin-Xu

    2017-03-01

    The sulfur oxidization (Sox) system is the central sulfur oxidization pathway of phototrophic and chemotrophic sulfur-oxidizing bacteria. Regulation and function of the Sox system in the chemotrophic Paracoccus pantotrophus has been elucidated; however, to date, no information is available on the regulation of this system in the chemolithotrophic Acidithiobacillus caldus, which is widely utilized in bioleaching. We described the novel tspSR-sox-like clusters in A. caldus and other chemolithotrophic sulfur-oxidizing bacteria containing Sox systems. The highly homologous σ(54)-dependent two-component signaling system (TspS/R), upstream of the sox operons in these novel clusters, was identified by phylogenetic analyses. A typical σ(54)-dependent promoter, P1, was identified upstream of soxX-I in the sox-I cluster of A. caldus MTH-04. The transcriptional start site (G) and the -12/-24 regions (GC/GG) of P1 were determined by rapid amplification of cDNA ends (5'RACE), and the upstream activator sequences (UASs; TGTCCCAAATGGGACA) were confirmed by electrophoretic mobility shift assays (EMSAs) in vitro and by UAS-probe-plasmids assays in vivo. Sequence analysis of promoter regions in tspSR-sox-like clusters revealed that there were similar σ(54)-dependent promoters upstream of the soxX genes. Based on our results, we proposed a TspSR-mediated signal transduction and transcriptional regulation pathway for the Sox system in A. caldus. The regulation of σ(54)-dependent two-component systems (TCSs) for Sox pathways were explained for the first time in A. caldus, A. thiooxidans, T. tepidarius, and T. denitrificans, indicating the significance of modulating the sulfur oxidization in these chemolithotrophic sulfur oxidizers.

  19. Craniopharyngiomas express embryonic stem cell markers (SOX2, OCT4, KLF4, and SOX9) as pituitary stem cells but do not coexpress RET/GFRA3 receptors.

    Science.gov (United States)

    Garcia-Lavandeira, Montserrat; Saez, Carmen; Diaz-Rodriguez, Esther; Perez-Romero, Sihara; Senra, Ana; Dieguez, Carlos; Japon, Miguel A; Alvarez, Clara V

    2012-01-01

    Adult stem cells maintain some markers expressed by embryonic stem cells and express other specific markers depending on the organ where they reside. Recently, stem/progenitor cells in the rodent and human pituitary have been characterized as expressing GFRA2/RET, PROP1, and stem cell markers such as SOX2 and OCT4 (GPS cells). Our objective was to detect other specific markers of the pituitary stem cells and to investigate whether craniopharyngiomas (CRF), a tumor potentially derived from Rathke's pouch remnants, express similar markers as normal pituitary stem cells. We conducted mRNA and Western blot studies in pituitary extracts, and immunohistochemistry and immunofluorescence on sections from normal rat and human pituitaries and 20 CRF (18 adamantinomatous and two papillary). Normal pituitary GPS stem cells localized in the marginal zone (MZ) express three key embryonic stem cell markers, SOX2, OCT4, and KLF4, in addition to SOX9 and PROP1 and β-catenin overexpression. They express the RET receptor and its GFRA2 coreceptor but also express the coreceptor GFRA3 that could be detected in the MZ of paraffin pituitary sections. CRF maintain the expression of SOX2, OCT4, KLF4, SOX9, and β-catenin. However, RET and GFRA3 expression was altered in CRF. In 25% (five of 20), both RET and GFRA3 were detected but not colocalized in the same cells. The other 75% (15 of 20) lose the expression of RET, GFRA3, or both proteins simultaneously. Human pituitary adult stem/progenitor cells (GPS) located in the MZ are characterized by expression of embryonic stem cell markers SOX2, OCT4, and KLF4 plus the specific pituitary embryonic factor PROP1 and the RET system. Redundancy in RET coreceptor expression (GFRA2 and GFRA3) suggest an important systematic function in their physiological behavior. CRF share the stem cell markers suggesting a common origin with GPS. However, the lack of expression of the RET/GFRA system could be related to the cell mislocation and deregulated

  20. Sox9 Expression in Amniotes: Species-Specific Differences in the Formation of Digits

    Science.gov (United States)

    Montero, Juan A.; Lorda-Diez, Carlos I.; Francisco-Morcillo, Javier; Chimal-Monroy, Jesus; Garcia-Porrero, Juan A.; Hurle, Juan M.

    2017-01-01

    In tetrapods the digit pattern has evolved to adapt to distinct locomotive strategies. The number of digits varies between species or even between hindlimb and forelimb within the same species. These facts illustrate the plasticity of embryonic limb autopods. Sox9 is a precocious marker of skeletal differentiation of limb mesenchymal cells. Its pattern of expression in the developing limb has been widely studied and reflects the activity of signaling cascades responsible for skeletogenesis. In this assay we stress previously overlooked differences in the pattern of expression of Sox9 in limbs of avian, mouse and turtle embryos which may reflect signaling differences associated with distinct limb skeletal morphologies observed in these species. Furthermore, we show that Sox9 gene expression is higher and maintained in the interdigital region in species with webbed digits in comparison with free digit animals. PMID:28386540

  1. Sox2 transcription network acts as a molecular switch to regulate properties of neural stem cells

    Institute of Scientific and Technical Information of China (English)

    Koji; Shimozaki

    2014-01-01

    Neural stem cells(NSCs) contribute to ontogeny by producing neurons at the appropriate time and location. Neurogenesis from NSCs is also involved in various biological functions in adults. Thus, NSCs continue to exert their effects throughout the lifespan of the organism. The mechanism regulating the core functional properties of NSCs is governed by intra- and extracellular signals. Among the transcription factors that serve as molecular switches, Sox2 is considered a key factor in NSCs. Sox2 forms a core network with partner factors, thereby functioning as a molecular switch. This review discusses how the network of Sox2 partner and target genes illustrates the molecular characteristics of the mechanism underlying the self-renewal and multipotency of NSCs.

  2. Transmission and Demographic Dynamics of Coxsackievirus B1.

    Directory of Open Access Journals (Sweden)

    Pei-Yu Chu

    Full Text Available The infectious activity of coxsackievirus B1 (CV-B1 in Taiwan was high from 2008 to 2010, following an alarming increase in severe neonate disease in the United States (US. To examine the relationship between CV-B1 strains isolated in Taiwan and those from other parts of the world, we performed a phylodynamic study using VP1 and partial 3Dpol (414 nt sequences from 22 strains of CV-B1 isolated in Taiwan (1989-2010 and compared them to sequences from strains isolated worldwide. Phylogenetic trees were constructed by neighbor-joining, maximum likelihood, and Bayesian Monte Carlo Markov Chain methods. Four genotypes (GI-IV in the VP1 region of CV-B1 and three genotypes (GA-C in the 3Dpol region of enterovirus B were identified and had high support values. The phylogenetic analysis indicates that the GI and GIII strains in VP1 were geographically distributed in Taiwan (1993-1994 and in India (2007-2009. On the other hand, the GII and GIV strains appear to have a wider spatiotemporal distribution and ladder-like topology A stair-like phylogeny was observed in the VP1 region indicating that the phylogeny of the virus may be affected by different selection pressures in the specified regions. Further, most of the GI and GII strains in the VP1 tree were clustered together in GA in the 3D tree, while the GIV strains diverged into GB and GC. Taken together, these data provide important insights into the population dynamics of CV-B1 and indicate that incongruencies in specific gene regions may contribute to spatiotemporal patterns of epidemicity for this virus.

  3. Kinin B1 receptors contributes to acute pain following minor surgery in humans

    Directory of Open Access Journals (Sweden)

    Brahim Jaime S

    2010-02-01

    Full Text Available Abstract Background Kinins play an important role in regulation of pain and hyperalgesia after tissue injury and inflammation by activating two types of G-protein-coupled receptors, the kinin B1 and B2 receptors. It is generally accepted that the B2 receptor is constitutively expressed, whereas the B1 receptor is induced in response to inflammation. However, little is known about the regulatory effects of kinin receptors on the onset of acute inflammation and inflammatory pain in humans. The present study investigated the changes in gene expression of kinin receptors and the levels of their endogenous ligands at an early time point following tissue injury and their relation to clinical pain, as well as the effect of COX-inhibition on their expression levels. Results Tissue injury resulted in a significant up-regulation in the gene expression of B1 and B2 receptors at 3 hours post-surgery, the onset of acute inflammatory pain. Interestingly, the up-regulation in the gene expression of B1 and B2 receptors was positively correlated to pain intensity only after ketorolac treatment, signifying an interaction between prostaglandins and kinins in the inflammatory pain process. Further, the gene expression of both B1 and B2 receptors were correlated. Following tissue injury, B1 ligands des-Arg9-BK and des-Arg10-KD were significantly lower at the third hour compared to the first 2 hours in both the placebo and the ketorolac treatment groups but did not differ significantly between groups. Tissue injury also resulted in the down-regulation of TRPV1 gene expression at 3 hours post-surgery with no significant effect by ketorolac treatment. Interestingly, the change in gene expression of TRPV1 was correlated to the change in gene expression of B1 receptor but not B2 receptor. Conclusions These results provide evidence at the transcriptional level in a clinical model of tissue injury that up-regulation of kinin receptors are involved in the development of the

  4. The transcription factor SOX18 regulates the expression of matrix metalloproteinase 7 and guidance molecules in human endothelial cells.

    Directory of Open Access Journals (Sweden)

    Martina Hoeth

    Full Text Available Mutations in the transcription factor SOX18 are responsible for specific cardiovascular defects in humans and mice. In order to gain insight into the molecular basis of its action, we identified target genes of SOX18 and analyzed one, MMP7, in detail.SOX18 was expressed in HUVEC using a recombinant adenoviral vector and the altered gene expression profile was analyzed using microarrays. Expression of several regulated candidate SOX18 target genes was verified by real-time PCR. Knock-down of SOX18 using RNA interference was then used to confirm the effect of the transcription factor on selected genes that included the guidance molecules ephrin B2 and semaphorin 3G. One gene, MMP7, was chosen for further analysis, including detailed promoter studies using reporter gene assays, electrophoretic mobility shift analysis and chromatin-immunoprecipitation, revealing that it responds directly to SOX18. Immunohistochemical analysis demonstrated the co-expression of SOX18 and MMP7 in blood vessels of human skin.The identification of MMP7 as a direct SOX18 target gene as well as other potential candidates including guidance molecules provides a molecular basis for the proposed function of this transcription factor in the regulation of vessel formation.

  5. Elevated Levels of SOX10 in Serum from Vitiligo and Melanoma Patients, Analyzed by Proximity Ligation Assay.

    Directory of Open Access Journals (Sweden)

    Andries Blokzijl

    Full Text Available The diagnosis of malignant melanoma currently relies on clinical inspection of the skin surface and on the histopathological status of the excised tumor. The serum marker S100B is used for prognostic estimates at later stages of the disease, but analyses are marred by false positives and inadequate sensitivity in predicting relapsing disorder.To investigate SOX10 as a potential biomarker for melanoma and vitiligo.In this study we have applied proximity ligation assay (PLA to detect the transcription factor SOX10 as a possible serum marker for melanoma. We studied a cohort of 110 melanoma patients. We further investigated a second cohort of 85 patients with vitiligo, which is a disease that also affects melanocytes.The specificity of the SOX10 assay in serum was high, with only 1% of healthy blood donors being positive. In contrast, elevated serum SOX10 was found with high frequency among vitiligo and melanoma patients. In patients with metastases, lack of SOX10 detection was associated with treatment benefit. In two responding patients, a change from SOX10 positivity to undetectable levels was seen before the response was evident clinically.We show for the first time that SOX10 represents a promising new serum melanoma marker for detection of early stage disease, complementing the established S100B marker. Our findings imply that SOX10 can be used to monitor responses to treatment and to assess if the treatment is of benefit at stages earlier than what is possible radiologically.

  6. Effect of sulfite treatment on total antioxidant capacity, total oxidant status, lipid hydroperoxide, and total free sulfydryl groups contents in normal and sulfite oxidase-deficient rat plasma.

    Science.gov (United States)

    Herken, Emine Nur; Kocamaz, Erdogan; Erel, Ozcan; Celik, Hakim; Kucukatay, Vural

    2009-08-01

    Sulfites, which are commonly used as preservatives, are continuously formed in the body during the metabolism of sulfur-containing amino acids. Sulfite oxidase (SOX) is an essential enzyme in the pathway of the oxidative degradation of sulfite to sulfate protecting cells from sulfite toxicity. This article investigated the effect of sulfite on total antioxidant capacity (TAC), total oxidant status, lipid hydroperoxide (LOOH), and total free sulfydryl groups (-SH) levels in normal and SOX-deficient male albino rat plasma. For this purpose, rats were divided into four groups: control, sulfite-treated, SOX-deficient, and sulfite-treated SOX-deficient groups. SOX deficiency was established by feeding rats a low molybdenum diet and adding to their drinking water 200 ppm tungsten. Sulfite (70 mg/kg) was administered to the animals via their drinking water. SOX deficiency together with sulfite treatment caused a significant increase in the plasma LOOH and total oxidant status levels. -SH content of rat plasma significantly decreased by both sulfite treatment and SOX deficiency compared to the control. There was also a significant decrease in plasma TAC level by sulfite treatment. In conclusion, sulfite treatment affects the antioxidant/oxidant balance of the plasma cells of the rats toward oxidants in SOX-deficient groups.

  7. 78 FR 62600 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-10-22

    ... circuits are classified Secret. The hardware, software, and data identified are classified to protect... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... data, U.S. Government and contractor technical assistance and other related logistics support,...

  8. 77 FR 13564 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-03-07

    .... The hardware, software, and data identified are classified to protect vulnerabilities, design and... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... data, U.S. Government and contractor technical assistance and other related logistics support. \\*\\...

  9. 76 FR 72180 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-11-22

    ... require travel of U.S. Government or contractor representatives to Malaysia on a temporary basis for... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense...

  10. Isolating Barley (Hordeum vulgare L.) B1 Hordein Gene Promoter ...

    African Journals Online (AJOL)

    Yomi

    2012-04-10

    Apr 10, 2012 ... region of B1 hordein gene was isolated from the genomic DNA of Walfajre and Alger barley by ... plasmid DNA extraction kits were provided from Bioneer ... The E. coli competent cells were used for transformation by 5 µL of.

  11. 76 FR 60471 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-09-29

    ... friendly forces on an easy-to-understand relative position display. This proposed system will increase... this additional capability into its Air Force. The proposed sale of this weapon system will not alter... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security...

  12. 78 FR 62592 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-10-22

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... Republic of Singapore to contribute to regional security. Its contributions to counter-piracy...

  13. 78 FR 50045 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-08-16

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... its borders and littoral waters, as well as conduct counter- terrorism/counter-piracy operations....

  14. 26 CFR 1.167(b)-1 - Straight line method.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 2 2010-04-01 2010-04-01 false Straight line method. 1.167(b)-1 Section 1.167(b... Straight line method. (a) In general. Under the straight line method the cost or other basis of the... may be reduced to a percentage or fraction. The straight line method may be used in determining...

  15. 26 CFR 31.3306(b)-1 - Wages.

    Science.gov (United States)

    2010-04-01

    ... Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE EMPLOYMENT TAXES AND COLLECTION OF INCOME TAX AT SOURCE Federal Unemployment Tax Act (Chapter 23, Internal Revenue Code of 1954) § 31.3306(b)-1 Wages. (a) Applicable law...

  16. 78 FR 36534 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-06-18

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... representatives to travel to Thailand for a period of five weeks for equipment de-processing/fielding,...

  17. 78 FR 41040 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-07-09

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF DEFENSE Office of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency.... Government and contractor representatives to travel to the region to support the program. There will be...

  18. 76 FR 61673 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-10-05

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security..., APX-72 Transponder, AN/ARN-147 VOR/ILS, AN/ARN-149 Receiver (ADF), HF-9000 HF Radio, ASN-150 Tactical... RADAR, ARC-210 UHF Radio, APX-72 Transponder, AN/ARN- 147 VOR/ILS, AN/ARN-149 Receiver (ADF), HF-9000...

  19. 78 FR 699 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-01-04

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... goals and national security objectives of the United States by meeting the legitimate security and... dissemination. It can be either fixed or mobile. In addition to the shelter housing the operator...

  20. 77 FR 46417 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-08-03

    ... 155 of Public Law 104-164 dated July 21, 1996. FOR FURTHER INFORMATION CONTACT: Ms. B. English, DSCA... Section 36(b)(1) Of the Arms Export Control Act, as amended (i) Prospective Purchaser: Thailand (ii) Total... 2012 * as defined in Section 47(6) of the Arms Export Control Act. ] Policy Justification Thailand--UH...

  1. βB1-crystallin: thermodynamic profiles of molecular interactions.

    Directory of Open Access Journals (Sweden)

    Monika B Dolinska

    Full Text Available BACKGROUND: β-Crystallins are structural proteins maintaining eye lens transparency and opacification. Previous work demonstrated that dimerization of both βA3 and βB2 crystallins (βA3 and βB2 involves endothermic enthalpy of association (∼8 kcal/mol mediated by hydrophobic interactions. METHODOLOGY/PRINCIPAL FINDINGS: Thermodynamic profiles of the associations of dimeric βA3 and βB1 and tetrameric βB1/βA3 were measured using sedimentation equilibrium. The homo- and heteromolecular associations of βB1 crystallin are dominated by exothermic enthalpy (-13.3 and -24.5 kcal/mol, respectively. CONCLUSIONS/SIGNIFICANCE: Global thermodynamics of βB1 interactions suggest a role in the formation of stable protein complexes in the lens via specific van der Waals contacts, hydrogen bonds and salt bridges whereas those β-crystallins which associate by predominately hydrophobic forces participate in a weaker protein associations.

  2. 78 FR 50047 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-08-16

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... for Purchase: 19 Mobile Troposcatter Radio Systems, 10 Mobile Microwave Radio Systems, spare and... Technology Contained in the Defense Article or Defense Services Proposed to be Sold: None (viii) Date...

  3. 78 FR 15004 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-03-08

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... Representatives, Transmittals 12-60 with attached transmittal, policy justification, and Sensitivity of Technology... RAPISCAN Mobile Eagle High Energy Mobile System Vehicles, 40 M60 RAPISCAN Mobile Eagle High Energy...

  4. 76 FR 66048 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-10-25

    ... Technology: 1. The AVENGER system is a lightweight, highly mobile, and transportable surface-to-air missile... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... Representatives, Transmittals 11-38 with attached transmittal, policy justification, and Sensitivity of...

  5. 78 FR 50043 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-08-16

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency... Representatives, Transmittals 12-67 with attached transmittal, policy justification, and Sensitivity of Technology... Illuminator Radars, 216 MIM-23P HAWK Tactical Missiles, 2 Mobile Battalion Operation Centers (BOC), 3 HAWK...

  6. 78 FR 41036 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-07-09

    ... of the Secretary 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security... Representatives, Transmittal 13-40 with attached transmittal, policy justification, and Sensitivity of Technology... Reaper Remotely Piloted Aircraft 8 Mobile Ground Control Stations 48 Honeywell TPE331-10T...

  7. The Roles of the Stem Cell-Controlling Sox2 Transcription Factor: from Neuroectoderm Development to Alzheimer's Disease?

    Science.gov (United States)

    Sarlak, Golmaryam; Vincent, Bruno

    2016-04-01

    Sox2 is a component of the core transcriptional regulatory network which maintains the totipotency of the cells during embryonic preimplantation period, the pluripotency of embryonic stem cells, and the multipotency of neural stem cells. This maintenance is controlled by internal loops between Sox2 and other transcription factors of the core such as Oct4, Nanog, Dax1, and Klf4, downstream proteins of extracellular ligands, epigenetic modifiers, and miRNAs. As Sox2 plays an important role in the balance between stem cells maintenance and commitment to differentiated lineages throughout the lifetime, it is supposed that Sox2 could regulate stem cells aging processes. In this review, we provide an update concerning the involvement of Sox2 in neurogenesis during normal aging and discuss its possible role in Alzheimer's disease.

  8. Sox17-Mediated XEN Cell Conversion Identifies Dynamic Networks Controlling Cell-Fate Decisions in Embryo-Derived Stem Cells

    Directory of Open Access Journals (Sweden)

    Angela C.H. McDonald

    2014-10-01

    Full Text Available Little is known about the gene regulatory networks (GRNs distinguishing extraembryonic endoderm (ExEn stem (XEN cells from those that maintain the extensively characterized embryonic stem cell (ESC. An intriguing network candidate is Sox17, an essential transcription factor for XEN derivation and self-renewal. Here, we show that forced Sox17 expression drives ESCs toward ExEn, generating XEN cells that contribute to ExEn when placed back into early mouse embryos. Transient Sox17 expression is sufficient to drive this fate change during which time cells transit through distinct intermediate states prior to the generation of functional XEN-like cells. To orchestrate this conversion process, Sox17 acts in autoregulatory and feedforward network motifs, regulating dynamic GRNs directing cell fate. Sox17-mediated XEN conversion helps to explain the regulation of cell-fate changes and reveals GRNs regulating lineage decisions in the mouse embryo.

  9. Aflatoxin B1content in patients with hepatic diseases Aflatoxina B1 en pacientes con enfermedades hepáticas

    Directory of Open Access Journals (Sweden)

    Clara López

    2002-08-01

    Full Text Available Aflatoxins are toxic metabolites of some Aspergillus flavus, A. parasiticus and A. nomius strains that occur in many foods and feeds. There are four major natural occurring aflatoxins: B1, B2, G1 and G2. These toxins can cause illness in human beings and animals. Aflatoxin B1 is the most abundant and toxic member of the family, and it is also the most potent hepatocarcinogen known. In order to estimate the potential human health risk of AFB1, it is useful to measure blood concentration. The presence of aflatoxin B1 in patients was evaluated by high-performance liquid chromatography, in serum samples, obtained from 20 patient volunteers with hepatic disease. Out of the 20 patients, the presence of AFB1 was detected in only one of them, in a concentration of 0.47 ng/cm³. Nevertheless, this result should draw the attention of control organizations in Argentina to the need for a thorough food and feed inspection.Las aflatoxinas son metabolitos tóxicos producidos por cepas de Aspergillus flavus, A. parasiticus y A. nomius, presentes en alimentos y piensos. Las cuatro aflatoxinas principales son: aflatoxina B1, B2, G1 y G2. Dichas toxinas pueden causar enfermedades tanto en seres humanos como en animales. La aflatoxina B1 es la más abundante y la más tóxica del grupo y es también el más potente hepatocarcinógeno conocido. El objetivo de este trabajo fue detectar la presencia de aflatoxina B1 en sangre humana para estimar el riesgo potencial de la salud. La determinación de aflatoxina B1 fue realizada por cromatografía líquida de alto rendimiento, en suero de 20 pacientes voluntarios con enfermedades hepáticas. En sólo uno de estos pacientes se detectó la presencia de aflatoxina B1, en una concentración de 0.47ng/cm³. Estos resultados deberían ser tenidos en cuenta por los responsables de la vigilancia y control de los alimentos en la Argentina.

  10. Effects of Aflatoxin B1 and Fumonisin B1 on the Viability and Induction of Apoptosis in Rat Primary Hepatocytes

    Science.gov (United States)

    Ribeiro, Deise H. B.; Ferreira, Fabiane L.; da Silva, Valéria N.; Aquino, Simone; Corrêa, Benedito

    2010-01-01

    The present study evaluated the effect of aflatoxin B1 (AFB1) and fumonisin B1 (FB1) either alone, or in association, on rat primary hepatocyte cultures. Cell viability was assessed by flow cytometry after propidium iodine intercalation. DNA fragmentation and apoptosis were assessed by agarose gel electrophoresis and acridine orange and ethidium bromide staining. At the concentrations of AFB1 and FB1 used, the toxins did not decrease cell viability, but did induce apoptosis in a concentration and time-dependent manner. PMID:20480051

  11. 5-Azacytidine suppresses EC9706 cell proliferation and metastasis by upregulating the expression of SOX17 and CDH1.

    Science.gov (United States)

    Li, Wenli; Wu, Dan; Niu, Ziyu; Jiang, Dalei; Ma, Huan; He, Heming; Zuo, Xiuli; Xie, Xiangjun; He, Yuanlong

    2016-10-01

    5-Azacytidine is a well-known anticancer drug that is clinically used in the treatment of breast cancer, melanoma and colon cancer. It has been reported that 5-azacytidine suppresses the biological behavior of esophageal cancer cells. However, corresponding mechanisms remain unclear. In this study, using Transwell invasion and cell proliferation assays, we demonstrated that 5-azacytidine significantly inhibited the metastasis and proliferation of EC9706 cells, and upregulated the expression of cadherin 1 (CDH1) and SRY-box containing gene 17 (SOX17). Moreover, the inhibition of the metastasis of the 5-azacytidine-treated EC9706 cells was impaired following transfection with siRNA targeting CDH1 (CDH1 siRNA), and the inhibition of cell proliferation was attenuated following the downregulation of SOX17 by siRNA targeting SOX17 (SOX17 siRNA). Furthermore, 5-azacytidine remarkably reduced the CDH1 and SOX17 promoter methylation levels, suggesting that 5-azacytidine upregulates the expression of SOX17 and CDH1 by inhibiting the methylation of the SOX17 and CDH1 promoter. The findings of our study confirm that 5-azacytidine suppresses the proliferation and metastasis of EC9706 esophageal cancer cells by upregulating the expression of CDH1 and SOX17. The expression levels of CDH1 and SOX17 negatively correlate with the promoter methylation levels. CDH1 and SOX17 are potential indicators of the clinical application of 5-azacytidine.

  12. SOX2 gene regulates the transcriptional network of oncogenes and affects tumorigenesis of human lung cancer cells.

    Directory of Open Access Journals (Sweden)

    Si Chen

    Full Text Available Recent studies demonstrated that cancer stem cells (CSCs have higher tumorigenesis properties than those of differentiated cancer cells and that transcriptional factor-SOX2 plays a vital role in maintaining the unique properties of CSCs; however, the function and underlying mechanism of SOX2 in carcinogenesis of lung cancer are still elusive. This study applied immunohistochemistry to analyze the expression of SOX2 in human lung tissues of normal individuals as well as patients with adenocarcinoma, squamous cell carcinoma, and large cell and small cell carcinoma and demonstrated specific overexpression of SOX2 in all types of lung cancer tissues. This finding supports the notion that SOX2 contributes to the tumorigenesis of lung cancer cells and can be used as a diagnostic probe. In addition, obviously higher expression of oncogenes c-MYC, WNT1, WNT2, and NOTCH1 was detected in side population (SP cells than in non-side population (NSP cells of human lung adenocarcinoma cell line-A549, revealing a possible mechanism for the tenacious tumorigenic potential of CSCs. To further elucidate the function of SOX2 in tumorigenesis of cancer cells, A549 cells were established with expression of luciferase and doxycycline-inducible shRNA targeting SOX2. We found silencing of SOX2 gene reduces the tumorigenic property of A549 cells with attenuated expression of c-MYC, WNT1, WNT2, and NOTCH1 in xenografted NOD/SCID mice. By using the RNA-Seq method, an additional 246 target cancer genes of SOX2 were revealed. These results present evidence that SOX2 may regulate the expression of oncogenes in CSCs to promote the development of human lung cancer.

  13. Aberrant DNA hypermethylation-silenced SOX21-AS1 gene expression and its clinical importance in oral cancer.

    Science.gov (United States)

    Yang, Cheng-Mei; Wang, Tsung-Han; Chen, Hung-Chih; Li, Sung-Chou; Lee, Ming-Chien; Liou, Huei-Han; Liu, Pei-Feng; Tseng, Yu-Kai; Shiue, Yow-Ling; Ger, Luo-Ping; Tsai, Kuo-Wang

    2016-01-01

    Long noncoding RNAs (lncRNAs) are more than 200 nucleotides in length and lack transcriptional ability. The biological function of lncRNAs in oral squamous cell carcinoma (OSCC) remains unclear. The aim of this study was to identify the dysfunction of lncRNA in OSCC. We analyzed the transcriptome profiles of human OSCC tissues and paired adjacent normal tissues from two patients through a next-generation sequencing approach. A total of 14 lncRNAs were upregulated (fold change ≥3) and 13 were downregulated (fold change ≤-3) in OSCC tissues compared with the adjacent normal tissues. SOX21-AS1 was subjected to further analysis, revealing that the expression levels of SOX21-AS1 significantly decreased in OSCC compared with the adjacent normal tissue. The promoter activity of SOX21-AS1 was obviously suppressed by in vitro methylation. The DNA methylation status of the SOX21-AS1 promoter was analyzed using combined bisulfite restriction analysis, revealing that the aberrant promoter hypermethylation of SOX21-AS1 was observed frequently in OSCC tissues. The effects of SOX21-AS1 on cell proliferation and invasion were examined through transient transfection. Our data showed that SOX21-AS1 could significantly suppress oral cancer cell growth and invasion. Furthermore, the low expression level of SOX21-AS1 was significantly correlated with an advanced stage (P = 0.047), large tumor size (P = 0.033), and poor disease-specific survival in OSCC patients (P = 0.002). SOX21-AS1 was identified as susceptible dysfunction correlated with promoter hypermethylation in OSCC. Low SOX21-AS1 expression may be an adverse prognostic biomarker for OSCC.

  14. SOX2 gene regulates the transcriptional network of oncogenes and affects tumorigenesis of human lung cancer cells.

    Science.gov (United States)

    Chen, Si; Xu, Yingxi; Chen, Yanan; Li, Xuefei; Mou, Wenjun; Wang, Lina; Liu, Yanhua; Reisfeld, Ralph A; Xiang, Rong; Lv, Dan; Li, Na

    2012-01-01

    Recent studies demonstrated that cancer stem cells (CSCs) have higher tumorigenesis properties than those of differentiated cancer cells and that transcriptional factor-SOX2 plays a vital role in maintaining the unique properties of CSCs; however, the function and underlying mechanism of SOX2 in carcinogenesis of lung cancer are still elusive. This study applied immunohistochemistry to analyze the expression of SOX2 in human lung tissues of normal individuals as well as patients with adenocarcinoma, squamous cell carcinoma, and large cell and small cell carcinoma and demonstrated specific overexpression of SOX2 in all types of lung cancer tissues. This finding supports the notion that SOX2 contributes to the tumorigenesis of lung cancer cells and can be used as a diagnostic probe. In addition, obviously higher expression of oncogenes c-MYC, WNT1, WNT2, and NOTCH1 was detected in side population (SP) cells than in non-side population (NSP) cells of human lung adenocarcinoma cell line-A549, revealing a possible mechanism for the tenacious tumorigenic potential of CSCs. To further elucidate the function of SOX2 in tumorigenesis of cancer cells, A549 cells were established with expression of luciferase and doxycycline-inducible shRNA targeting SOX2. We found silencing of SOX2 gene reduces the tumorigenic property of A549 cells with attenuated expression of c-MYC, WNT1, WNT2, and NOTCH1 in xenografted NOD/SCID mice. By using the RNA-Seq method, an additional 246 target cancer genes of SOX2 were revealed. These results present evidence that SOX2 may regulate the expression of oncogenes in CSCs to promote the development of human lung cancer.

  15. Construction of recombinant baculovirus Ac-CMV-hSox9 for gene therapy of intervertebral disc degeneration

    Institute of Scientific and Technical Information of China (English)

    LIU Xiao-yun; YANG Shu-hua; LIANG Chang-yong; SONG Jian-hua; LI Kang-hua; CHEN Xin-wen

    2007-01-01

    Objective: To construct the recombinant baculovirus Ac-cytomegalovirus (CMV)-hSox9 for gene therapy of intervertebral disc degeneration. Methods: Bac-to-Bac system was used for the construction of baculovirus Ac-CMV-hSox9. The cDNA of hSox9 was first cloned into a plasmid vector under the control of CMV promotor to generate the donor plasmid pFastBacDul-green fluorescene protein (GFP)-CMV (pFGC)-hSox9.The resultant plasmid was transformed into DH10Bac cells and then the transformation mixture was spread on Luria-Bertani (LB) agarose culture medium containing isopropyl-β-D-thiogalactoside (IPTG), X-gal, gentamicin, kanamycin and tetracycline.The white colonies were selected and cultured for amplification, and the hSox9Bacmid DNA was extracted. After verification, recombinant baculovirus Ac-CMV-hSox9 was obtained through transfecting Sf 21 cells.The expression of hSox9 gene in the intervertebral disc cells in rabbits was determined by Western blotting and immunohistochemical staining.Results: Polymerase chain reaction (PCR) confirmed the presence of hSox9 gene in the recombinant baculovirus and the Sf 21 cells transfected by the baculovirus showed the expression of fluorescence protein.Western blotting and immunohistochemical staining analysis indicated that exogenous hSox9 gene was expressed in the disc cells.Conclusions: The successful construction of the recombinant baculovirus Ac-CMV-hSox9 and the confirmation of the target gene expression provides a novel expression vector system for basic research and clinical treatment of intervertebral degenerative disc disease.

  16. Effect of sox19b gene knockdown on the eyes development in zebra fish%sox19b在斑马鱼胚胎眼睛发育中的作用

    Institute of Scientific and Technical Information of China (English)

    高明; 杨阳; 陈学冉; 史玮; 林浴霜; 郝爱军

    2013-01-01

    Objective To explore the function of sox19b on the eye development in zebrafish by knockdown of sox19b. Methods To inhibit the expression of sox196 by microinjection of soxl9b morpholinos( MO)and then observe the effect of the development of the eyes in zebrafish by RT-PCR and the whole-mount in situ hybridization. Results The development of the eyes was abnormal after knockdown of sox 196, mainly showed small eyes or eye deficiency and the abnormal retina and lens( n = 57/93 ) . The expression of some important genes during the development of the eyes, such as rx3, pax2a and vsx2, was decreased apparently in the sox19b morphant. Conclusion The transcription factor, sox196 is critical for the development of the eyes via the regulation of the important eye-field transcription factors, EFTEs in early zebrafish embryos.%目的 通过抑制sox19b基因的表达,探讨sox19b基因在斑马鱼胚胎眼睛发育和形成中的作用.方法 通过显微注射sox19b吗啉寡聚核苷酸(MO)抑制sox19b基因的表达,观察胚胎发育过程中表型的变化;采用石蜡包埋组织切片及HE染色、RT-PCR和整封原位杂交等方法探讨敲除sox19b后对斑马鱼胚胎眼睛发育的调控机制.结果 敲除sox19b基因后,斑马鱼胚胎眼睛发育受到影响,表现为眼睛变小或缺失,视网膜及晶状体结构发育异常(n=57/93);眼睛发育过程中重要调控基因rx3、pax2a及vsx2等表达明显降低,进而影响眼睛的发育和形成.结论 sox19b基因作为转录调控因子,可以通过调节眼区转录因子的表达进而影响斑马鱼胚胎早期眼睛的发育和形成.

  17. Derivation of an endogenous small RNA from double-stranded Sox4 sense and natural antisense transcripts in the mouse brain.

    Science.gov (United States)

    Ling, King-Hwa; Brautigan, Peter J; Moore, Sarah; Fraser, Rachel; Cheah, Pike-See; Raison, Joy M; Babic, Milena; Lee, Young Kyung; Daish, Tasman; Mattiske, Deidre M; Mann, Jeffrey R; Adelson, David L; Thomas, Paul Q; Hahn, Christopher N; Scott, Hamish S

    2016-03-01

    Natural antisense transcripts (NATs) are involved in cellular development and regulatory processes. Multiple NATs at the Sox4 gene locus are spatiotemporally regulated throughout murine cerebral corticogenesis. In the study, we evaluated the potential functional role of Sox4 NATs at Sox4 gene locus. We demonstrated Sox4 sense and NATs formed dsRNA aggregates in the cytoplasm of brain cells. Over expression of Sox4 NATs in NIH/3T3 cells generally did not alter the level of Sox4 mRNA expression or protein translation. Upregulation of a Sox4 NAT known as Sox4ot1 led to the production of a novel small RNA, Sox4_sir3. Its biogenesis is Dicer1-dependent and has characteristics resemble piRNA. Expression of Sox4_sir3 was observed in the marginal and germinative zones of the developing and postnatal brains suggesting a potential role in regulating neurogenesis. We proposed that Sox4 sense-NATs serve as Dicer1-dependent templates to produce a novel endo-siRNA- or piRNA-like Sox4_sir3.

  18. Targeted 'Next-Generation' sequencing in anophthalmia and microphthalmia patients confirms SOX2, OTX2 and FOXE3 mutations

    Directory of Open Access Journals (Sweden)

    Lopez Jimenez Nelson

    2011-12-01

    Full Text Available Abstract Background Anophthalmia/microphthalmia (A/M is caused by mutations in several different transcription factors, but mutations in each causative gene are relatively rare, emphasizing the need for a testing approach that screens multiple genes simultaneously. We used next-generation sequencing to screen 15 A/M patients for mutations in 9 pathogenic genes to evaluate this technology for screening in A/M. Methods We used a pooled sequencing design, together with custom single nucleotide polymorphism (SNP calling software. We verified predicted sequence alterations using Sanger sequencing. Results We verified three mutations - c.542delC in SOX2, resulting in p.Pro181Argfs*22, p.Glu105X in OTX2 and p.Cys240X in FOXE3. We found several novel sequence alterations and SNPs that were likely to be non-pathogenic - p.Glu42Lys in CRYBA4, p.Val201Met in FOXE3 and p.Asp291Asn in VSX2. Our analysis methodology gave one false positive result comprising a mutation in PAX6 (c.1268A > T, predicting p.X423LeuextX*15 that was not verified by Sanger sequencing. We also failed to detect one 20 base pair (bp deletion and one 3 bp duplication in SOX2. Conclusions Our results demonstrated the power of next-generation sequencing with pooled sample groups for the rapid screening of candidate genes for A/M as we were correctly able to identify disease-causing mutations. However, next-generation sequencing was less useful for small, intragenic deletions and duplications. We did not find mutations in 10/15 patients and conclude that there is a need for further gene discovery in A/M.

  19. Dual lineage-specific expression of Sox17 during mouse embryogenesis

    DEFF Research Database (Denmark)

    Choi, Eunyoung; Kraus, Marine R C; Lemaire, Laurence A

    2012-01-01

    is expressed in the endothelial cells (ECs) at the para-aortic splanchnopleural region that contribute to the formation of HSCs at a later stage. The identification of two distinct progenitor cell populations that express Sox17 at E9.5 was confirmed using fluorescence-activated cell sorting together with RNA-Seq...

  20. Congenital hydrocephalus and abnormal subcommissural organ development in Sox3 transgenic mice.

    Directory of Open Access Journals (Sweden)

    Kristie Lee

    Full Text Available Congenital hydrocephalus (CH is a life-threatening medical condition in which excessive accumulation of CSF leads to ventricular expansion and increased intracranial pressure. Stenosis (blockage of the Sylvian aqueduct (Aq; the narrow passageway that connects the third and fourth ventricles is a common form of CH in humans, although the genetic basis of this condition is unknown. Mouse models of CH indicate that Aq stenosis is associated with abnormal development of the subcommmissural organ (SCO a small secretory organ located at the dorsal midline of the caudal diencephalon. Glycoproteins secreted by the SCO generate Reissner's fibre (RF, a thread-like structure that descends into the Aq and is thought to maintain its patency. However, despite the importance of SCO function in CSF homeostasis, the genetic program that controls SCO development is poorly understood. Here, we show that the X-linked transcription factor SOX3 is expressed in the murine SCO throughout its development and in the mature organ. Importantly, overexpression of Sox3 in the dorsal diencephalic midline of transgenic mice induces CH via a dose-dependent mechanism. Histological, gene expression and cellular proliferation studies indicate that Sox3 overexpression disrupts the development of the SCO primordium through inhibition of diencephalic roof plate identity without inducing programmed cell death. This study provides further evidence that SCO function is essential for the prevention of hydrocephalus and indicates that overexpression of Sox3 in the dorsal midline alters progenitor cell differentiation in a dose-dependent manner.

  1. A mechanism regulating the onset of Sox2 expression in the embryonic neural plate.

    Directory of Open Access Journals (Sweden)

    Costis Papanayotou

    2008-01-01

    Full Text Available In vertebrate embryos, the earliest definitive marker for the neural plate, which will give rise to the entire central nervous system, is the transcription factor Sox2. Although some of the extracellular signals that regulate neural plate fate have been identified, we know very little about the mechanisms controlling Sox2 expression and thus neural plate identity. Here, we use electroporation for gain- and loss-of-function in the chick embryo, in combination with bimolecular fluorescence complementation, two-hybrid screens, chromatin immunoprecipitation, and reporter assays to study protein interactions that regulate expression of N2, the earliest enhancer of Sox2 to be activated and which directs expression to the largest part of the neural plate. We show that interactions between three coiled-coil domain proteins (ERNI, Geminin, and BERT, the heterochromatin proteins HP1alpha and HP1gamma acting as repressors, and the chromatin-remodeling enzyme Brm acting as activator control the N2 enhancer. We propose that this mechanism regulates the timing of Sox2 expression as part of the process of establishing neural plate identity.

  2. Sorting live stem cells based on Sox2 mRNA expression.

    Directory of Open Access Journals (Sweden)

    Hans M Larsson

    Full Text Available While cell sorting usually relies on cell-surface protein markers, molecular beacons (MBs offer the potential to sort cells based on the presence of any expressed mRNA and in principle could be extremely useful to sort rare cell populations from primary isolates. We show here how stem cells can be purified from mixed cell populations by sorting based on MBs. Specifically, we designed molecular beacons targeting Sox2, a well-known stem cell marker for murine embryonic (mES and neural stem cells (NSC. One of our designed molecular beacons displayed an increase in fluorescence compared to a nonspecific molecular beacon both in vitro and in vivo when tested in mES and NSCs. We sorted Sox2-MB(+SSEA1(+ cells from a mixed population of 4-day retinoic acid-treated mES cells and effectively isolated live undifferentiated stem cells. Additionally, Sox2-MB(+ cells isolated from primary mouse brains were sorted and generated neurospheres with higher efficiency than Sox2-MB(- cells. These results demonstrate the utility of MBs for stem cell sorting in an mRNA-specific manner.

  3. Dynamic distribution and stem cell characteristics of Sox1-expressing cells in the cerebellar cortex

    Institute of Scientific and Technical Information of China (English)

    Joelle Alcock; Virginie Sottile

    2009-01-01

    Bergmann glia cells are a discrete radial glia population surrounding Purkinje cells in the cerebellar cortex. Al-though Bergmann glia are essential for the development and correct arborization of Purkinje cells, little is known about the regulation of this cell population after the developmental phase. In an effort to characterize this population at the molecular level, we have analyzed marker expression and established that adult Bergmann glia express Soxl, Sox2 and Sox9, a feature otherwise associated with neural stem cells (NSCs). In the present study, we have further analyzed the developmental pattern of Soxl-expressing cells in the developing cerebellum. We report that before be-coming restricted to the Purkinje cell layer, Soxl-positive cells are present throughout the immature tissue, and that these cells show characteristics of Bergmann glia progenitors. Our study shows that these progenitors express Soxl, Sox2 and Sox9, a signature maintained throughout cerebellar maturation into adulthood. When isolated in culture, the Soxl-expressing cerebellar population exhibited neurosphere-forming ability, NSC-marker characteristics, and demonstrated multipotency at the clonal level. Our results show that the Bergmann glia population expresses Soxl during cerebellar development, and that these cells can be isolated and show stem cell characteristics in vitro, sug-gesting that they could hold a broader potential than previously thought.

  4. Cloning and analysis of the HMG domains of ten Sox genes from ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-04-20

    Apr 20, 2009 ... is responsible for the sequence-specific DNA binding. In this paper, we ... the conservative motif (HMG-box) of the human SRY gene. We want to .... their evolutionary relationships among the ten Sox proteins of B. maxima and ...

  5. Studying the expression patterns of OCT4 and SOX2 proteins in regenerating rabbit ear tissue

    Directory of Open Access Journals (Sweden)

    A. S. Javanmard

    2016-06-01

    Full Text Available Epimorphic regeneration in New Zealand rabbit ear is an interesting example of mammalian wound healing in which blastema formation is involved in replacement of injured tissues. It has been suggested that isolated cells from regenerating rabbit ear possess stem-like properties. In this study, we aimed to determine the expression of stemness markers, OCT4 and SOX2 proteins, in regenerating rabbit tissues by immunohistochemistry. Results indicated that both proteins could be detected in epithelial cells, hair follicle cells and perichondrium cells. Expression pattern analysis of OCT4 and SOX2 proteins showed no clear differences between regenerative and non-regenerative control tissues. According to several reports of OCT4 and SOX2 proteins expression in adult stem cells, it could be proposed that OCT4 and SOX2 expressing cells in regenerating rabbit ear tissues are progenitor/adult stem cells which are resident in these tissues, and other markers should be used for detection of blastema cells.

  6. Temporo-spatial analysis of Osterix, HNK1 and Sox10 during odontogenesis and maxillaries osteogenesis.

    Science.gov (United States)

    Tomazelli, Karin Berria; Modolo, Filipe; Trentin, Andrea Gonçalves; Garcez, Ricardo Castilho; Biz, Michelle Tillmann

    2015-10-01

    Cell differentiation is essential for maxillaries and tooth development. Facial mesenchymal tissue is formed by neural crest cells (NC). These cells are highly migratory, giving rise to various cell types, considered with a high level of plasticity, indicating that they contain progenitor cells with a great power of differentiation. In this study, it was analyzed the presence of NC cell progenitors and mesenchymal stem cells (MSC) during maxillaries osteogenesis and odontogenesis in rats. Histological slides were collected in two phases: embryonic age of 15 and 17 days; 2, 4 and 7 days after birth. Immunohistochemistry for MSC markers (Osterix) and NC cells (Sox10, HNK1) was performed. The results showed positive expression for Osterix and HNK1 in undifferentiated ectomesenchymal cells in early and late stages; Sox10 was present only in early stages in undifferentiated cells. All markers were present in differentiated cells. Although the experiments performed do not allow us to explain a possible role for Osx, HNK1 and Sox10 in both differentiated and undifferentiated cells during osteogenesis and odontogenesis, it had shown important results not yet described: the presence of HNK1 and Sox10 in osteoblasts and odontoblasts in late development stages and in the tooth germ epithelial cells and ameloblasts. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Sixteen additional enhancers associated with the chicken Sox2 locus outside the central 50-kb region.

    Science.gov (United States)

    Okamoto, Ryuji; Uchikawa, Masanori; Kondoh, Hisato

    2015-01-01

    The transcription factor Sox2 plays a central role in the regulation of neuro-sensory development, and many other developmental processes. To gain an in depth understanding of the Sox2 gene regulation, we previously investigated the Sox2-proximal 50-kb region of the chicken genome to determine enhancers based on functional assays using chicken embryo electroporation. We identified 11 enhancers with specificity for neuro-sensory tissues. In this study, we extended the analysis of Sox2 locus-associated enhancers to a 200-kb region and identified 16 additional enhancers with functions in neuro-sensory development. These enhancers roughly correspond to a fraction of the sequence blocks that are highly conserved between chicken and mammalian genomes. The neural enhancers were activated in sequence, thereby creating a complex pattern of functional overlaps in the developing central nervous system (CNS). The variations in the specificities of the sensory enhancers also reflected the intermediate steps of sensory tissue development. This study provides an example where a single transcription factor gene has numerous regulatory elements that allow it to fulfill many functional roles in different biological contexts.

  8. The tumour suppressor SOX11 is associated with improved survival among high grade epithelial ovarian cancers and is regulated by reversible promoter methylation

    LENUS (Irish Health Repository)

    Sernbo, Sandra

    2011-09-24

    Abstract Background The neural transcription factor SOX11 has been described as a prognostic marker in epithelial ovarian cancers (EOC), however its role in individual histological subtypes and tumour grade requires further clarification. Furthermore, methylation-dependent silencing of SOX11 has been reported for B cell lymphomas and indicates that epigenetic drugs may be used to re-express this tumour suppressor, but information on SOX11 promoter methylation in EOC is still lacking. Methods SOX11 expression and clinicopathological data was compared using χ2 test in a cohort of 154 cases of primary invasive EOC. Kaplan-Meier analysis and the log rank test were applied to evaluate ovarian cancer-specific survival (OCSS) and overall survival (OS) in strata, according to SOX11 expression. Also, the methylation status of the SOX11 promoter was determined by sodium bisulfite sequencing and methylation specific PCR (MSP). Furthermore, the effect of ectopic overexpression of SOX11 on proliferation was studied through [3H]-thymidine incorporation. Results SOX11 expression was associated with an improved survival of patients with high grade EOC, although not independent of stage. Further analyses of EOC cell lines showed that SOX11 mRNA and protein were expressed in two of five cell lines, correlating with promoter methylation status. Demethylation was successfully performed using 5\\'-Aza-2\\'deoxycytidine (5-Aza-dC) resulting in SOX11 mRNA and protein expression in a previously negative EOC cell line. Furthermore, overexpression of SOX11 in EOC cell lines confirmed the growth regulatory role of SOX11. Conclusions SOX11 is a functionally associated protein in EOC with prognostic value for high-grade tumours. Re-expression of SOX11 in EOC indicates a potential use of epigenetic drugs to affect cellular growth in SOX11-negative tumours.

  9. 绵羊Sox2基因逆转录病毒载体的构建与检测%Construction and Detection of Retrovirus Vector with Ovine Sox2 Gene

    Institute of Scientific and Technical Information of China (English)

    赵健灵; 安铁洙; 张志人; 王子竹; 朴善花; 王春生

    2012-01-01

    In order to construct the retroviral vector with sheep Sox2 to induce ovine somatic cell to iPS, sheep Sox2 gene was cloned, and then linked with retroviral vector pMXs. 293GP cells were co-transfected by the vector and pVSV-G. Viral supernatant was infected sheep fibroblast cells in order to detect the expression of Sox2. The results were showed as followed. PCR and restriction enzyme digestion revealed that pMXs-Sox2 plasmid was constructed successfully. Expression of Sox2 was detected in sheep fibroblasts cell after being infected by the viral supernatant obtained. The results indicated that the vector obtained could be used to induce sheep somatic cell reprogramming.%为建立利用内源诱导因子诱导绵羊体细胞为多能干细胞(induced pluripotent stem cell,iPS)的方法,对绵羊Sox2基因进行克隆,并与pMXs连接构建逆转录病毒载体,将构建的载体转染293GP细胞以获得假病毒上清,利用假病毒上清侵染绵羊胎儿成纤维细胞以检测细胞中的Sox2表达变化.PCR和酶切鉴定结果显示,成功构建了pMXs-Sox2重组质粒,该质粒具有转染293GP细胞的能力,所获得的假病毒上清侵染绵羊胎儿成纤维细胞后,可诱导细胞表达Sox2基因.本研究为开展绵羊iPS的相关研究提供依据.

  10. Ewing sarcoma ewsa protein regulates chondrogenesis of Meckel's cartilage through modulation of Sox9 in zebrafish.

    Science.gov (United States)

    Merkes, Chris; Turkalo, Timothy K; Wilder, Nicole; Park, Hyewon; Wenger, Luke W; Lewin, Seth J; Azuma, Mizuki

    2015-01-01

    Ewing sarcoma is the second most common skeletal (bone and cartilage) cancer in adolescents, and it is characterized by the expression of the aberrant chimeric fusion gene EWS/FLI1. Wild-type EWS has been proposed to play a role in mitosis, splicing and transcription. We have previously shown that EWS/FLI1 interacts with EWS, and it inhibits EWS activity in a dominant manner. Ewing sarcoma is a cancer that specifically develops in skeletal tissues, and although the above data suggests the significance of EWS, its role in chondrogenesis/skeletogenesis is not understood. To elucidate the function of EWS in skeletal development, we generated and analyzed a maternal zygotic (MZ) ewsa/ewsa line because the ewsa/wt and ewsa/ewsa zebrafish appeared to be normal and fertile. Compared with wt/wt, the Meckel's cartilage of MZ ewsa/ewsa mutants had a higher number of craniofacial prehypertrophic chondrocytes that failed to mature into hypertrophic chondrocytes at 4 days post-fertilization (dpf). Ewsa interacted with Sox9, which is the master transcription factor for chondrogenesis. Sox9 target genes were either upregulated (ctgfa, ctgfb, col2a1a, and col2a1b) or downregulated (sox5, nog1, nog2, and bmp4) in MZ ewsa/ewsa embryos compared with the wt/wt zebrafish embryos. Among these Sox9 target genes, the chromatin immunoprecipitation (ChIP) experiment demonstrated that Ewsa directly binds to ctgfa and ctgfb loci. Consistently, immunohistochemistry showed that the Ctgf protein is upregulated in the Meckel's cartilage of MZ ewsa/ewsa mutants. Together, we propose that Ewsa promotes the differentiation from prehypertrophic chondrocytes to hypertrophic chondrocytes of Meckel's cartilage through inhibiting Sox9 binding site of the ctgf gene promoter. Because Ewing sarcoma specifically develops in skeletal tissue that is originating from chondrocytes, this new role of EWS may provide a potential molecular basis of its pathogenesis.

  11. Ewing sarcoma ewsa protein regulates chondrogenesis of Meckel's cartilage through modulation of Sox9 in zebrafish.

    Directory of Open Access Journals (Sweden)

    Chris Merkes

    Full Text Available Ewing sarcoma is the second most common skeletal (bone and cartilage cancer in adolescents, and it is characterized by the expression of the aberrant chimeric fusion gene EWS/FLI1. Wild-type EWS has been proposed to play a role in mitosis, splicing and transcription. We have previously shown that EWS/FLI1 interacts with EWS, and it inhibits EWS activity in a dominant manner. Ewing sarcoma is a cancer that specifically develops in skeletal tissues, and although the above data suggests the significance of EWS, its role in chondrogenesis/skeletogenesis is not understood. To elucidate the function of EWS in skeletal development, we generated and analyzed a maternal zygotic (MZ ewsa/ewsa line because the ewsa/wt and ewsa/ewsa zebrafish appeared to be normal and fertile. Compared with wt/wt, the Meckel's cartilage of MZ ewsa/ewsa mutants had a higher number of craniofacial prehypertrophic chondrocytes that failed to mature into hypertrophic chondrocytes at 4 days post-fertilization (dpf. Ewsa interacted with Sox9, which is the master transcription factor for chondrogenesis. Sox9 target genes were either upregulated (ctgfa, ctgfb, col2a1a, and col2a1b or downregulated (sox5, nog1, nog2, and bmp4 in MZ ewsa/ewsa embryos compared with the wt/wt zebrafish embryos. Among these Sox9 target genes, the chromatin immunoprecipitation (ChIP experiment demonstrated that Ewsa directly binds to ctgfa and ctgfb loci. Consistently, immunohistochemistry showed that the Ctgf protein is upregulated in the Meckel's cartilage of MZ ewsa/ewsa mutants. Together, we propose that Ewsa promotes the differentiation from prehypertrophic chondrocytes to hypertrophic chondrocytes of Meckel's cartilage through inhibiting Sox9 binding site of the ctgf gene promoter. Because Ewing sarcoma specifically develops in skeletal tissue that is originating from chondrocytes, this new role of EWS may provide a potential molecular basis of its pathogenesis.

  12. Partial Characterization of the Sox2+ Cell Population in an Adult Murine Model of Digit Amputation

    Science.gov (United States)

    Agrawal, Vineet; Siu, Bernard F.; Chao, Hsu; Hirschi, Karen K.; Raborn, Eric; Johnson, Scott A.; Tottey, Stephen; Hurley, Katherine B.; Medberry, Chris J.

    2012-01-01

    Tissue regeneration in response to injury in adult mammals is generally limited to select tissues. Nonmammalian species such as newts and axolotls undergo regeneration of complex tissues such as limbs and digits via recruitment and accumulation of local and circulating multipotent progenitors preprogrammed to recapitulate the missing tissue. Directed recruitment and activation of progenitor cells at a site of injury in adult mammals may alter the default wound-healing response from scar tissue toward regeneration. Bioactive molecules derived from proteolytic degradation of extracellular matrix (ECM) proteins have been shown to recruit a variety of progenitor cells in vitro and in vivo to the site of injury. The present study further characterized the population of cells accumulating at the site of injury after treatment with ECM degradation products in a well-established model of murine digit amputation. After a mid-second phalanx digit amputation in 6–8-week-old adult mice, treatment with ECM degradation products resulted in the accumulation of a heterogeneous population of cells, a subset of which expressed the transcription factor Sox2, a marker of pluripotent and adult progenitor cells. Sox2+ cells were localized lateral to the amputated P2 bone and coexpressed progenitor cell markers CD90 and Sca1. Transgenic Sox2 eGFP/+ and bone marrow chimeric mice showed that the bone marrow and blood circulation did not contribute to the Sox2+ cell population. The present study showed that, in addition to circulating progenitor cells, resident tissue-derived cells also populate at the site of injury after treatment with ECM degradation products. Although future work is necessary to determine the contribution of Sox2+ cells to functional tissue at the site of injury, recruitment and/or activation of local tissue-derived cells may be a viable approach to tissue engineering of more complex tissues in adult mammals. PMID:22530556

  13. Extracellular effect of high mobility group box1 protein and its role in sepsis:an overview%高迁移率族蛋白B1的细胞生物学效应及其与脓毒症的关系

    Institute of Scientific and Technical Information of China (English)

    王松柏; 姚咏明

    2003-01-01

    @@ Goodwin和John早在40多年前就发现了高迁移率族蛋白(high mobility group protein,HMG),证明它是一类典型的非组蛋白(nonhistone chromatin protein,NHCP).NHCP及其他众多核内蛋白质通过与DNA的相互作用,参与了细胞核内诸如转录、复制、重组等复杂有序的功能过程.HMG在细胞核内含量非常丰富并具有广泛功能;细胞核外及血清中也存在一定量的HMGB1.近年来的研究发现,核外HMGB1可能具有"晚期"炎症介质的作用,并日益引起了人们的关注[1-3].在本文中拟重点介绍有关HMGB1的细胞生物学效应及其与脓毒症关系的研究进展.

  14. Filtration of SOX9 Genes Mutation and Analyses of Its Function in Colorectal Cancer%结直肠癌中SOX9基因突变的筛选及其功能解析

    Institute of Scientific and Technical Information of China (English)

    汪丽佩; 李天一

    2013-01-01

    [目的]观察结直肠癌(colorectalcancer,CRC)中是否存在SOX9基因的突变位点.[方法]通过PCR及直接测序的方法,检测5个结肠癌细胞系DNA(HT29、SW480、SW620、RKO、Hce8693)和20个结肠癌组织DNA中的SOX9基因全部编码区段、启动子、核心区域及增强子区域的突变情况.[结果]在SOX9基因Intron 4的3519bp处发现SNPs位点1个(A/C),包括A/C杂合型、C/C纯合型以及A/A纯合型,但在全部的关键区域未发现突变热点.[结论]SOX9基因在CRC中不存在突变位点,但其在表达水平上明显升高,可推测SOX9基因不是在基因水平上,而是由表达水平的改变直接参与CRC的发生.%[Objective] To find the mutation hot point of SOX9 gene in colorectal cancer. [Methods] Amplification of 5 colorectal cancer cell lines DNA HT29 ,SW480,SW620,RKO,Hce8693 and 20 colorectal cancer tissue DNA through PCR at SOX9's coding region, core region, Promotor and En-hancer.PCR coupled with sequencing was used to detect whether any mutations exist in the sequence of SOX9 gene. [Result] One SNP site was fount at the Intron4(3519bp) of SOX9 gene, including A/C heterozygous type, C/C homozygous type and A/A homozygous type, but no mutation hot point was founc in all the important regions of SOX9.[Conclusion]The mutation hot point didn't exist in the SOX9 gene of colorectal cancer, but its expression was strong in this cancer, which could be deduced that SOX9 doesn't function on colorectal cancer at genomic level, but at expression level.

  15. Cartilage development requires the function of Estrogen-related receptor alpha that directly regulates sox9 expression in zebrafish.

    Science.gov (United States)

    Kim, Yong-Il; No Lee, Joon; Bhandari, Sushil; Nam, In-Koo; Yoo, Kyeong-Won; Kim, Se-Jin; Oh, Gi-Su; Kim, Hyung-Jin; So, Hong-Seob; Choe, Seong-Kyu; Park, Raekil

    2015-12-10

    Estrogen-related receptor alpha (ESRRa) regulates a number of cellular processes including development of bone and muscles. However, direct evidence regarding its involvement in cartilage development remains elusive. In this report, we establish an in vivo role of Esrra in cartilage development during embryogenesis in zebrafish. Gene expression analysis indicates that esrra is expressed in developing pharyngeal arches where genes necessary for cartilage development are also expressed. Loss of function analysis shows that knockdown of esrra impairs expression of genes including sox9, col2a1, sox5, sox6, runx2 and col10a1 thus induces abnormally formed cartilage in pharyngeal arches. Importantly, we identify putative ESRRa binding elements in upstream regions of sox9 to which ESRRa can directly bind, indicating that Esrra may directly regulate sox9 expression. Accordingly, ectopic expression of sox9 rescues defective formation of cartilage induced by the knockdown of esrra. Taken together, our results indicate for the first time that ESRRa is essential for cartilage development by regulating sox9 expression during vertebrate development.

  16. Establishment of testis-specific SOX9 activation requires high-glucose metabolism in mouse sex differentiation.

    Science.gov (United States)

    Matoba, Shogo; Hiramatsu, Ryuji; Kanai-Azuma, Masami; Tsunekawa, Naoki; Harikae, Kyoko; Kawakami, Hayato; Kurohmaru, Masamichi; Kanai, Yoshiakira

    2008-12-01

    In mouse sex differentiation, SRY promotes Sertoli cell differentiation via SOX9 action, resulting in testis formation. SRY/SOX9 also initiates various testis-specific morphogenic events including glycogenesis in pre-Sertoli cells, suggesting the importance of glucose storage for certain SRY/SOX9-downstream events in gonadal sex determination. However, it remains unclear which cell types and what molecular/cellular events require sex-dimorphic high-energy metabolic rate. Here we show that the establishment of SOX9 activation itself is a metabolically active process with sex-dimorphic high-energy requirements in gonadal sex differentiation. The glucose-deprivation and metabolic rescue experiments using genital ridge cultures of the XY/XX-wildtype and XX/Sry transgenic embryos demonstrated that, among the various somatic cell types, pre-Sertoli cells are the most sensitive to glucose starvation despite the differences between XX/Sry and XY genotypes. Moreover, our data showed that, in developing pre-Sertoli cells, the high-glucose metabolic state is required for the establishment of SOX9 expression through an ECM (extracellular matrix)-mediated feed-forward pathway. In contrast, the expression of SRY, SF1/Ad4Bp, GATA4 and WT1, as well as initiation of early SOX9 expression, is properly maintained in the glucose-deprived condition. Therefore, our results imply the metabolic importance of the high-glucose condition for the establishment of SOX9 activation in testis differentiation.

  17. Sox7-sustained expression alters the balance between proliferation and differentiation of hematopoietic progenitors at the onset of blood specification.

    Science.gov (United States)

    Gandillet, Arnaud; Serrano, Alicia G; Pearson, Stella; Lie-A-Ling, Michael; Lacaud, Georges; Kouskoff, Valerie

    2009-11-26

    The molecular mechanisms that regulate the balance between proliferation and differentiation of precursors at the onset of hematopoiesis specification are poorly understood. By using a global gene expression profiling approach during the course of embryonic stem cell differentiation, we identified Sox7 as a potential candidate gene involved in the regulation of blood lineage formation from the mesoderm germ layer. In the present study, we show that Sox7 is transiently expressed in mesodermal precursors as they undergo specification to the hematopoietic program. Sox7 knockdown in vitro significantly decreases the formation of both primitive erythroid and definitive hematopoietic progenitors as well as endothelial progenitors. In contrast, Sox7-sustained expression in the earliest committed hematopoietic precursors promotes the maintenance of their multipotent and self-renewing status. Removal of this differentiation block driven by Sox7-enforced expression leads to the efficient differentiation of hematopoietic progenitors to all erythroid and myeloid lineages. This study identifies Sox7 as a novel and important player in the molecular regulation of the first committed blood precursors. Furthermore, our data demonstrate that the mere sustained expression of Sox7 is sufficient to completely alter the balance between proliferation and differentiation at the onset of hematopoiesis.

  18. Identification of novel craniofacial regulatory domains located far upstream of SOX9 and disrupted in Pierre Robin sequence.

    Science.gov (United States)

    Gordon, Christopher T; Attanasio, Catia; Bhatia, Shipra; Benko, Sabina; Ansari, Morad; Tan, Tiong Y; Munnich, Arnold; Pennacchio, Len A; Abadie, Véronique; Temple, I Karen; Goldenberg, Alice; van Heyningen, Veronica; Amiel, Jeanne; FitzPatrick, David; Kleinjan, Dirk A; Visel, Axel; Lyonnet, Stanislas

    2014-08-01

    Mutations in the coding sequence of SOX9 cause campomelic dysplasia (CD), a disorder of skeletal development associated with 46,XY disorders of sex development (DSDs). Translocations, deletions, and duplications within a ∼2 Mb region upstream of SOX9 can recapitulate the CD-DSD phenotype fully or partially, suggesting the existence of an unusually large cis-regulatory control region. Pierre Robin sequence (PRS) is a craniofacial disorder that is frequently an endophenotype of CD and a locus for isolated PRS at ∼1.2-1.5 Mb upstream of SOX9 has been previously reported. The craniofacial regulatory potential within this locus, and within the greater genomic domain surrounding SOX9, remains poorly defined. We report two novel deletions upstream of SOX9 in families with PRS, allowing refinement of the regions harboring candidate craniofacial regulatory elements. In parallel, ChIP-Seq for p300 binding sites in mouse craniofacial tissue led to the identification of several novel craniofacial enhancers at the SOX9 locus, which were validated in transgenic reporter mice and zebrafish. Notably, some of the functionally validated elements fall within the PRS deletions. These studies suggest that multiple noncoding elements contribute to the craniofacial regulation of SOX9 expression, and that their disruption results in PRS.

  19. Cytochrome P450 1B1 expression in rat esophageal tumorigenesis promoted by gastric and duodenal reflux.

    Science.gov (United States)

    Devlin, Andrea H; McIlroy, Marie; McKeen, Hayley D; Bonde, Pramode; Menezes, A A Carlos; Swarbrick, Christine J; Robson, Tracy; Hirst, David G; Campbell, F Charles; McGuigan, James A; McKeown, Stephanie R

    2009-02-01

    Cytochrome P450 1B1 (CYP1B1) mRNA is constitutively expressed in most normal extra-hepatic tissues; however the protein is not detectable in these tissues but is expressed in a wide variety of tumors. CYP1B1 is responsible for the activation of a number of carcinogens present in tobacco smoke and food. A surgical model of rat esophageal tumorigenesis, promoted by gastric or duodenal reflux was used to determine CYP1B1 expression in premalignant esophageal tissue. Immunohistochemistry was performed using a modified amplified fluorescein tyramide protocol. CYP1B1 was not observed in normal esophageal mucosa, submucosa, or muscularis mucosa. Animals exposed to gastric reflux developed mild hyperplasia. Varying degrees of hyperplasia were observed in the duodenal reflux group. All regions of hyperplasia showed moderate or strong CYP1B1 immunoreactivity. Duodenal reflux induced a small number of premalignant changes: immunoreactivity was absent from the epithelium of squamous dysplasia (0/10), Barrett's esophagus (0/7), and majority of dysplastic Barrett's esophagus (1/4). Moderate or strong immunoreactivity was observed in the majority (7/8) of squamous cell carcinomas (SCCs) in situ. Immunoreactivity was also observed in the lamina propria and submucosa in association with inflammation, regardless of the severity of inflammation. The expression of CYP1B1 in hyperplasia, SCCs in situ, or in association with inflammation may increase the production of carcinogenic metabolites, which may promote esophageal tumorigenesis.

  20. Expression of a Splice Variant of CYP26B1 in Betel Quid-Related Oral Cancer

    Science.gov (United States)

    Lee, Ka-Wo; Hsu, Cheng-Chieh; Chen, Jeff Yi-Fu; Wang, Yan-Hsiung; Wang, Hui-Min David; Huang, Bin

    2014-01-01

    Betel quid (BQ) is a psychostimulant, an addictive substance, and a group 1 carcinogen that exhibits the potential to induce adverse health effects. Approximately, 600 million users chew a variety of BQ. Areca nut (AN) is a necessary ingredient in BQ products. Arecoline is the primary alkaloid in the AN and can be metabolized through the cytochrome P450 (CYP) superfamily by inducing reactive oxygen species (ROS) production. Full-length CYP26B1 is related to the development of oral pharyngeal cancers. We investigated whether a splice variant of CYP26B1 is associated with the occurrence of ROS related oral and pharyngeal cancer. Cytotoxicity assays were used to measure the effects of arecoline on cell viability in a dose-dependent manner. In vitro and in vivo studies were conducted to evaluate the expression of the CYP26B1 splice variant. The CYP26B1 splice variant exhibited lower expression than did full-length CYP26B1 in the human gingival fibroblast-1 and Ca9-22 cell models. Increased expression of the CYP26B1 splice variant was observed in human oral cancer tissue compared with adjacent normal tissue, and increased expression was observed in patients at a late tumor stage. Our results suggested that the CYP26B1 splice variant is associated with the occurrence of BQ-related oral cancer. PMID:25114974

  1. Expression of a Splice Variant of CYP26B1 in Betel Quid-Related Oral Cancer

    Directory of Open Access Journals (Sweden)

    Ping-Ho Chen

    2014-01-01

    Full Text Available Betel quid (BQ is a psychostimulant, an addictive substance, and a group 1 carcinogen that exhibits the potential to induce adverse health effects. Approximately, 600 million users chew a variety of BQ. Areca nut (AN is a necessary ingredient in BQ products. Arecoline is the primary alkaloid in the AN and can be metabolized through the cytochrome P450 (CYP superfamily by inducing reactive oxygen species (ROS production. Full-length CYP26B1 is related to the development of oral pharyngeal cancers. We investigated whether a splice variant of CYP26B1 is associated with the occurrence of ROS related oral and pharyngeal cancer. Cytotoxicity assays were used to measure the effects of arecoline on cell viability in a dose-dependent manner. In vitro and in vivo studies were conducted to evaluate the expression of the CYP26B1 splice variant. The CYP26B1 splice variant exhibited lower expression than did full-length CYP26B1 in the human gingival fibroblast-1 and Ca9-22 cell models. Increased expression of the CYP26B1 splice variant was observed in human oral cancer tissue compared with adjacent normal tissue, and increased expression was observed in patients at a late tumor stage. Our results suggested that the CYP26B1 splice variant is associated with the occurrence of BQ-related oral cancer.

  2. 黄曲霍毒素B1人工抗原的合成及鉴定%Synthesis and Identification of Aflatoxin B1 Artificial Antigen

    Institute of Scientific and Technical Information of China (English)

    伍鑫茹; 杨雪娇; 赵肃清; 张焜

    2013-01-01

    Carboxyl group was introduced to Aflatoxin B1 (aflatoxin B1, AFB1) by derivatization method to synthesis the hapten (AFB1 carboxymethyl activator). And the AFBiO was coupled with BSA by using N-hydroxy-succinimide method to prepare the complete antigen of AFB,. The results of ECI-MS and ultraviolet spectroscopy showed that the target hapten was successfully synthesized. Through combined with ultraviolet spectrophotometry and regression equation, the standard curves of the different concentration hapten and BSA were abtained as follow: y=0.1440x+0.0103 (R2 =0.9986) and y=0.0059x+0.0808 (R2 =0.9889) respectively. The concentrations of AFB1O and BSA in adduct were 186.32 μg/mlL and 6127.46 ng/mL respectively, and the molar ration was 5.13:1.%采用衍生化在黄曲霉毒素B1(aflatoxin B1,AFB1)上引入羧基合成AFB1羧甲基活化物,通过N-羟琥珀酰亚胺酯(N-hydroxy-succinimide NHS)法将AFB1O与牛血清白蛋白(BSA)偶联,制备黄曲霉毒素B1完全抗原AFB1-BSA.ECI-MS和紫外光谱法的鉴定结果表明目标半抗原合成成功.结合紫外分光光度法和回归方程,分别测得不同浓度的半抗原和蛋白质线性曲线为:Y=0.1440X+0.0103,R2=0.9986; Y=0.0059X+0.0808,R2=0.9889.偶联物中半抗原和蛋白质的浓度分别为186.32 μg/mL、6127.46 μg/mL,即求得抗原分子结合比为5.13∶1,从而为制备抗AFB1抗体奠定基础.

  3. Irx3 and Bmp2 Regulate Mouse Mesenchymal Cell Chondrogenic Differentiation in Both a Sox9-Dependent and -Independent Manner.

    Science.gov (United States)

    Tamamura, Yoshihiro; Katsube, Kenichi; Mera, Hisashi; Itokazu, Maki; Wakitani, Shigeyuki

    2017-01-06

    Sox9, a master regulator of cartilage development, controls the cell fate decision to differentiate from mesenchymal to chondrogenic cells. In addition, Sox9 regulates the proliferation and differentiation of chondrocytes, as well as the production of cartilage-specific proteoglycans. The existence of Sox9-independent mechanisms in cartilage development remains to be determined. Here, we attempted to identify genes involved in such putative mechanisms via microarray analysis using a mouse chondrogenic cell line, N1511. We first focused on transcription factors that exhibited upregulated expression following Bmp2 treatment, which was not altered by subsequent treatment with Sox9 siRNA. Among these, we selected positive regulators for chondrogenesis and identified Iroquois-related homeobox 3 (Irx3) as one of the candidate genes. Irx3 expression gradually increased with chondrocyte terminal differentiation in a reciprocal manner to Sox9 expression, and promoted the chondrogenic differentiation of mesenchymal cells upon Bmp2 treatment. Furthermore, Irx3 partially rescued impaired chondrogenesis by upregulating the expression of epiphycan and lumican under reduced Sox9 expression. Finally, Irx3 was shown to act in concert with Bmp2 signaling to activate the p38 MAPK pathway, which in turn stimulated Sox9 expression, as well as the expression of epiphycan and lumican in a Sox9-independent manner. These results indicate that Irx3 represents a novel chondrogenic factor of mesenchymal cells, acts synergistically with Bmp2-mediated signaling, and regulates chondrogenesis independent of the transcriptional machinery associated with Sox9-mediated regulation. This article is protected by copyright. All rights reserved.

  4. SOX2 co-occupies distal enhancer elements with distinct POU factors in ESCs and NPCs to specify cell state.

    Directory of Open Access Journals (Sweden)

    Michael A Lodato

    Full Text Available SOX2 is a master regulator of both pluripotent embryonic stem cells (ESCs and multipotent neural progenitor cells (NPCs; however, we currently lack a detailed understanding of how SOX2 controls these distinct stem cell populations. Here we show by genome-wide analysis that, while SOX2 bound to a distinct set of gene promoters in ESCs and NPCs, the majority of regions coincided with unique distal enhancer elements, important cis-acting regulators of tissue-specific gene expression programs. Notably, SOX2 bound the same consensus DNA motif in both cell types, suggesting that additional factors contribute to target specificity. We found that, similar to its association with OCT4 (Pou5f1 in ESCs, the related POU family member BRN2 (Pou3f2 co-occupied a large set of putative distal enhancers with SOX2 in NPCs. Forced expression of BRN2 in ESCs led to functional recruitment of SOX2 to a subset of NPC-specific targets and to precocious differentiation toward a neural-like state. Further analysis of the bound sequences revealed differences in the distances of SOX and POU peaks in the two cell types and identified motifs for additional transcription factors. Together, these data suggest that SOX2 controls a larger network of genes than previously anticipated through binding of distal enhancers and that transitions in POU partner factors may control tissue-specific transcriptional programs. Our findings have important implications for understanding lineage specification and somatic cell reprogramming, where SOX2, OCT4, and BRN2 have been shown to be key factors.

  5. SOX2 expression is upregulated in adult spinal cord after contusion injury in both oligodendrocyte lineage and ependymal cells.

    Science.gov (United States)

    Lee, Hyun Joon; Wu, Junfang; Chung, Jumi; Wrathall, Jean R

    2013-02-01

    The upregulation of genes normally associated with development may occur in the adult after spinal cord injury (SCI). To test this, we performed real-time RT-PCR array analysis of mouse spinal cord mRNAs comparing embryonic day (E)14.5 spinal cord with intact adult and adult cord 1 week after a clinically relevant standardized contusion SCI. We found significantly increased expression of a large number of neural development- and stem cell-associated genes after SCI. These included Sox2 (sex determining region Y-box 2), a transcription factor that regulates self-renewal and potency of embryonic neural stem cells and is one of only a few key factors needed to induce pluripotency. In adult spinal cord of Sox2-EGFP mice, Sox2-EGFP was found mainly in the ependymal cells of the central canal. After SCI, both mRNA and protein levels of Sox2 were significantly increased at and near the injury site. By 1 day, Sox2 was upregulated in NG2(+) oligodendrocyte progenitor cells (OPC) in the spared white matter. By 3 days, Sox2-EGFP ependymal cells had increased proliferation and begun to form multiple layers and clusters of cells in the central lesion zone of the cord. Expression of Sox2 by NG2(+) cells had declined by 1 week, but increased numbers of other Sox2-expressing cells persisted for at least 4 weeks after SCI in both mouse and rat models. Thus, SCI upregulates many genes associated with development and neural stem cells, including the key transcription factor Sox2, which is expressed in a pool of cells that persists for weeks after SCI.

  6. SOX2 co-occupies distal enhancer elements with distinct POU factors in ESCs and NPCs to specify cell state.

    Directory of Open Access Journals (Sweden)

    Michael A Lodato

    Full Text Available SOX2 is a master regulator of both pluripotent embryonic stem cells (ESCs and multipotent neural progenitor cells (NPCs; however, we currently lack a detailed understanding of how SOX2 controls these distinct stem cell populations. Here we show by genome-wide analysis that, while SOX2 bound to a distinct set of gene promoters in ESCs and NPCs, the majority of regions coincided with unique distal enhancer elements, important cis-acting regulators of tissue-specific gene expression programs. Notably, SOX2 bound the same consensus DNA motif in both cell types, suggesting that additional factors contribute to target specificity. We found that, similar to its association with OCT4 (Pou5f1 in ESCs, the related POU family member BRN2 (Pou3f2 co-occupied a large set of putative distal enhancers with SOX2 in NPCs. Forced expression of BRN2 in ESCs led to functional recruitment of SOX2 to a subset of NPC-specific targets and to precocious differentiation toward a neural-like state. Further analysis of the bound sequences revealed differences in the distances of SOX and POU peaks in the two cell types and identified motifs for additional transcription factors. Together, these data suggest that SOX2 controls a larger network of genes than previously anticipated through binding of distal enhancers and that transitions in POU partner factors may control tissue-specific transcriptional programs. Our findings have important implications for understanding lineage specification and somatic cell reprogramming, where SOX2, OCT4, and BRN2 have been shown to be key factors.

  7. Activation of the Escherichia coli marA/soxS/rob regulon in response to transcriptional activator concentration.

    Science.gov (United States)

    Martin, Robert G; Bartlett, Emily S; Rosner, Judah L; Wall, Michael E

    2008-07-04

    The paralogous transcriptional activators MarA, SoxS, and Rob activate a common set of promoters, the marA/soxS/rob regulon of Escherichia coli, by binding a cognate site (marbox) upstream of each promoter. The extent of activation varies from one promoter to another and is only poorly correlated with the in vitro affinity of the activator for the specific marbox. Here, we examine the dependence of promoter activation on the level of activator in vivo by manipulating the steady-state concentrations of MarA and SoxS in Lon protease mutants and by measuring promoter activation using lacZ transcriptional fusions. We found that: (i) the MarA concentrations needed for half-maximal stimulation varied by at least 19-fold among the 10 promoters tested; (ii) most marboxes were not saturated when there were 24,000 molecules of MarA per cell; (iii) the correlation between the MarA concentration needed for half-maximal promoter activity in vivo and marbox binding affinity in vitro was poor; and (iv) the two activators differed in their promoter activation profiles. The marRAB and sodA promoters could both be saturated by MarA and SoxS in vivo. However, saturation by MarA resulted in greater marRAB and lesser sodA transcription than did saturation by SoxS, implying that the two activators interact with RNA polymerase in different ways at the different promoters. Thus, the concentration and nature of activator determine which regulon promoters are activated, as well as the extent of their activation.

  8. Nematode and arthropod genomes provide new insights into the evolution of class 2 B1 GPCRs.

    Directory of Open Access Journals (Sweden)

    João C R Cardoso

    Full Text Available Nematodes and arthropods are the most speciose animal groups and possess Class 2 B1 G-protein coupled receptors (GPCRs. Existing models of invertebrate Class 2 B1 GPCR evolution are mainly centered on Caenorhabditis elegans and Drosophila melanogaster and a few other nematode and arthropod representatives. The present study reevaluates the evolution of metazoan Class 2 B1 GPCRs and orthologues by exploring the receptors in several nematode and arthropod genomes and comparing them to the human receptors. Three novel receptor phylogenetic clusters were identified and designated cluster A, cluster B and PDF-R-related cluster. Clusters A and B were identified in several nematode and arthropod genomes but were absent from D. melanogaster and Culicidae genomes, whereas the majority of the members of the PDF-R-related cluster were from nematodes. Cluster A receptors were nematode and arthropod-specific but shared a conserved gene environment with human receptor loci. Cluster B members were orthologous to human GCGR, PTHR and Secretin members with which they probably shared a common origin. PDF-R and PDF-R related clusters were present in representatives of both nematodes and arthropods. The results of comparative analysis of GPCR evolution and diversity in protostomes confirm previous notions that C. elegans and D. melanogaster genomes are not good representatives of nematode and arthropod phyla. We hypothesize that at least four ancestral Class 2 B1 genes emerged early in the metazoan radiation, which after the protostome-deuterostome split underwent distinct selective pressures that resulted in duplication and deletion events that originated the current Class 2 B1 GPCRs in nematode and arthropod genomes.

  9. Effect of an esterified glucomannan on laying hens exposed to combined mycotoxins (aflatoxin B1, zearalenone and fumonisin B1

    Directory of Open Access Journals (Sweden)

    A. Zaghini

    2011-03-01

    Full Text Available Mycotoxin toxicity depends on species, exposure time, age, sex, health and possible synergistic effects of other mycotoxins present in feed. In poultry, aflatoxin B1 (AFB1 and fumonisin B1 (FB1 are associated with poor growth performance, lowered feed utilization efficiency, liver damage and immunosuppression; metabolites may persist in tissues and eggs. Exposure of mature hens to zearalenone (ZEN apparently does not cause adverse effects, but ZEN residues and α and β zearalenol persist in liver and muscle (Kuiper-Goodman et al., 1987 and may be transmitted to egg yolk (Dailey et al., 1990. Various treatments and dietary strategies have been tried to reduce mycotoxin levels in contaminated commodities...

  10. SOX9 regulates microRNA miR-202-5p/3p expression during mouse testis differentiation

    DEFF Research Database (Denmark)

    Wainwright, Elanor N; Jorgensen, Joan S; Kim, Youngha;

    2013-01-01

    . Expression of the primary transcript of miR-202-5p/3p remained low in XY gonads in a conditional Sox9-null mouse model, suggesting that pri-miR-202 transcription is downstream of SOX9, a transcription factor that is both necessary and sufficient for male sex determination. We identified the pri-miR-202...... findings indicate that expression of the conserved gonad microRNA, miR-202-5p/3p, is downstream of the testis-determining factor SOX9, suggesting an early role in testis development....

  11. First observation of the hadronic transition $ \\Upsilon(4S) \\to \\eta h_{b}(1P)$ and new measurement of the $h_b(1P)$ and $\\eta_b(1S)$ parameters

    CERN Document Server

    Tamponi, U; Abdesselam, A; Aihara, H; Arinstein, K; Asner, D M; Atmacan, H; Aushev, T; Ayad, R; Badhrees, I; Bakich, A M; Barberio, E; Bhardwaj, V; Bhuyan, B; Biswal, J; Bondar, A; Bonvicini, G; Bozek, A; Bračko, M; Browder, T E; Červenkov, D; Chen, A; Cheon, B G; Cho, K; Chobanova, V; Choi, S -K; Choi, Y; Cinabro, D; Danilov, M; Doležal, Z; Drásal, Z; Drutskoy, A; Eidelman, S; Epifanov, D; Farhat, H; Fast, J E; Ferber, T; Fulsom, B G; Gaur, V; Gabyshev, N; Garmash, A; Getzkow, D; Gillard, R; Goh, Y M; Golob, B; Haba, J; Hayasaka, K; Hayashii, H; He, X H; Hedges, M T; Hou, W -S; Iijima, T; Inami, K; Ishikawa, A; Jaegle, I; Joffe, D; Julius, T; Kato, E; Katrenko, P; Kichimi, H; Kiesling, C; Kim, D Y; Kim, H J; Kim, J H; Kim, K T; Kim, S H; Kinoshita, K; Kodyš, P; Korpar, S; Križan, P; Krokovny, P; Kumita, T; Kuzmin, A; Lange, J S; Lewis, P; Libby, J; Lukin, P; Matvienko, D; Miyabayashi, K; Miyata, H; Mizuk, R; Mohanty, G B; Moll, A; Mori, T; Nakano, E; Nakao, M; Nanut, T; Natkaniec, Z; Nayak, M; Nisar, N K; Nishida, S; Ogawa, S; Okuno, S; Olsen, S L; Ostrowicz, W; Oswald, C; Pakhlova, G; Pal, B; Park, H; Pedlar, T K; Pesántez, L; Pestotnik, R; Petriřc, M; Piilonen, L E; Ribežl, E; Ritter, M; Rostomyan, A; Ryu, S; Sakai, Y; Sandilya, S; Santelj, L; Sanuki, T; Sato, Y; Savinov, V; Schneider, O; Schnell, G; Schwanda, C; Semmler, D; Senyo, K; Sevior, M E; Shapkin, M; Shebalin, V; Shen, C P; Shibata, T -A; Shiu, J -G; Shwartz, B; Sibidanov, A; Simon, F; Sohn, Y -S; Sokolov, A; Starič, M; Steder, M; Stypula, J; Tanida, K; Teramoto, Y; Trabelsi, K; Uchida, M; Uglov, T; Unno, Y; Uno, S; Urquijo, P; Van Hulse, C; Vanhoefer, P; Varner, G; Vinokurova, A; Vossen, A; Wagner, M N; Wang, M -Z; Wang, X L; Watanabe, Y; Williams, K M; Won, E; Yamaoka, J; Yashchenko, S; Zhang, Z P; Zhilich, V; Zhulanov, V; Zupanc, A

    2015-01-01

    Using a sample of $771.6 \\times 10^{6}$ $\\Upsilon(4S)$ decays collected by the Belle experiment at the KEKB $e^+e^-$ collider, we observe for the first time the transition $\\Upsilon(4S) \\to \\eta h_b(1P)$ with the branching fraction ${\\cal B}[\\Upsilon(4S) \\to \\eta h_b(1P)]= (2.18 \\pm 0.11 \\pm 0.18) \\times 10^{-3}$ and we measure the $h_b(1P)$ mass $M_{h_{b}(1P)} = (9899.3 \\pm 0.4 \\pm 1.0)$ MeV/$c^{2}$, corresponding to the hyperfine splitting $\\Delta M_{\\mathrm HF}(1P) = (0.6 \\pm 0.4 \\pm 1.0)$ MeV/$c^{2}$. Using the transition $h_b(1P) \\to \\gamma \\eta_b(1S)$, we measure the $\\eta_b(1S)$ mass $M_{\\eta_{b}(1S)} = (9400.7 \\pm 1.7 \\pm 1.6)$ MeV/$c^{2}$, corresponding to $\\Delta M_{\\mathrm HF}(1S) = (59.6 \\pm 1.7 \\pm 1.6)$ MeV/$c^{2}$, the $\\eta_b(1S)$ width $\\Gamma_{\\eta_{b}(1S)} = (8 ^{+6}_{-5} \\pm 5)$ MeV/$c^{2}$ and the branching fraction ${\\cal B}[h_b(1P) \\to \\gamma \\eta_b(1S)]= (56 \\pm 8 \\pm 4) \\%$.

  12. Genome-wide Reconstruction of OxyR and SoxRS Transcriptional Regulatory Networks under Oxidative Stress in Escherichia coli K-12 MG1655

    DEFF Research Database (Denmark)

    Seo, Sang Woo; Kim, Donghyuk; Szubin, Richard;

    2015-01-01

    Three transcription factors (TFs), OxyR, SoxR, and SoxS, play a critical role in transcriptional regulation of the defense system for oxidative stress in bacteria. However, their full genome-wide regulatory potential is unknown. Here, we perform a genome-scale reconstruction of the OxyR, SoxR, an...

  13. Cytochrome P1B1 (CYP1B1) polymorphisms and ovarian cancer risk: a meta-analysis.

    Science.gov (United States)

    Gajjar, Ketan; Owens, Gemma; Sperrin, Matthew; Martin-Hirsch, Pierre L; Martin, Francis L

    2012-12-16

    CYP1B1 is a key P450 enzyme involved in the metabolism of exogenous and endogenous substrates and plays a key role in hormone-induced carcinogenesis. Risk factors for ovarian cancer are related to hormonal exposure and reproduction, and polymorphisms within genes involved in metabolism of oestrogen and certain xenobiotics may influence the risk of developing ovarian cancer. Current meta-analysis evaluated four CYP1B1 polymorphisms (Leu432Val, Arg48Gly, Ala119Ser and Asn453Ser) for their association with ovarian cancer risk. A search of the MEDLINE bibliographic database for the period up to April 2012 identified five relevant studies. With regards to Leu432Val polymorphism, all of the five studies were eligible (1199 cases and 2596 controls) for analysis, while for Arg48Gly (799 cases and 1169 controls), Ala119Ser (799 cases and 1172 controls) and Asn453Ser (361cases and 1577 controls) only two studies were eligible for analysis. Fixed-effect models were used to estimate pooled odds ratios (OR) with 95% confidence intervals (95% CI) and chi-square based Q-test was used to test for heterogeneity. The pooled OR (95% CI) for CYP1B1_Leu432Val polymorphism were 1.1 (0.84-1.31) for heterozygous subjects and 0.82 (0.57-1.17) for homozygous Val subjects. In a recessive model, homozygous carriers of Leu432Val showed a weak trend towards reduced risk as compared to 'wild type' and heterozygous carriers (OR 0.8, 95% CI; 0.66-0.99); however, this association was of limited significance. Regarding Arg48Gly, the pooled OR (95% CI) were 1.06 (0.89-1.27) for heterozygous and 0.98 (1.72-1.33) for homozygous Gly subjects. With respect to Ala119Ser and Asn453Ser, the pooled OR were 1.06 (0.87-1.29) and 1.24 (0.94-1.63) for heterozygous and 1.1 (0.8-1.52) and 1.09 (0.5-2.34) for homozygous respectively. In conclusion, this meta-analysis suggests that CYP1B1 polymorphisms are not associated with ovarian cancer risk. Studies evaluating CYP1B1_Leu432Val polymorphism are required to

  14. Cytochrome P1B1 (CYP1B1) polymorphisms and cancer risk: a meta-analysis of 52 studies.

    Science.gov (United States)

    Li, Cuiping; Long, Bingshuang; Qin, Xianjing; Li, Weixiong; Zhou, Yang

    2015-01-02

    CYP1B1 plays a critical role in the oxidative metabolism of a variety of exogenous compounds, including carcinogenic compounds, which may be activated during metabolism. There are only a few studies that have examined the association between the two polymorphisms and cancer, and that these studies have been inconclusive. Hence, the aim of the present meta-analysis was to evaluate the relationship between polymorphisms in CYP1B1 G119T and A453G and cancer risk. We performed a detailed search using the PubMed and EMBASE libraries to obtain all relevant published reports on the relationship between the G119T and A453G polymorphisms in CYP1B1 and cancer risk. Combined odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated by Stata version 11.2. We conducted stratified analyses based on cancer types, ethnicity, source of controls, and quality assessments. We also made assessments of heterogeneity tests, sensitivity analyses, and publication bias. There were a total of 25 articles with 15,376 cases and 18,382 controls concerning CYP1B1 G119T and 40 articles with 27,983 cases and 35,839 controls concerning A453G polymorphisms. Regarding G119T, the combined results indicate that the variant genotypes were significantly associated with a slightly increased cancer risk in comparison to the homozygote (TT versus GG: p=0.006, OR=1.231, 95% CI: 1.061-1.428), especially for breast cancer and prostate cancer. Moreover, significantly increased associations with cancer risk were demonstrated in Asians in all genetic models. The combined results indicated no association of A453G with cancer risk; however, an association was observed specifically for prostate cancer. This meta-analysis suggests that the CYP1B1 G119T polymorphism may confer to genetic susceptibility to cancer in Asians, especially to breast cancer and prostate cancer. The A453G polymorphism was found to modify the risk of prostate cancer.

  15. 3B1 beam line and its physical properties

    Science.gov (United States)

    Yi, Futing; Wang, Peiwei; Jin, Ming; Wu, Jianwu

    1995-02-01

    The 3B1 beam line is in the hall of 13# on BSRF, and is used for the lithography, biology and multilayer reflection research. On the line, there are a cylinder mirror system, a vacuum control system, an exposure chamber and a beryllium window for lithography research. The mirror coated with gold receives the synchrotron radiation at a glance angle of 1.5°, and scans in the vertical for lithography. The light, reflected by the scanning mirror and absorbed by the window, produces a spectrum of 4-20 Å and a uniformity spot for the lithography.

  16. Enhancement of neural and thermal vasoconstriction by prostaglandin B1.

    Science.gov (United States)

    Engelbrecht, J A; Greenberg, S; Wilson, W R

    1975-03-01

    The vascular effects of prostaglandin B1 (PGB1) were studied during constant-flow perfusion of the canine hindpaw. The effects of PGB1 (50-200 ng/kg/min ia) on systemic and hindpaw perfusion pressures and on responses to local cooling (4 degrees C for 90 sec) and local heating (45 degrees C for 60 sec) were measured in 15 dogs. PGB1 (50-100 ng/kg/min) decreased perfusion pressure without any significant effect on systemic arterial pressure. Higher concentrations of PGB1 (200 ng/kg/min) elevated perfusion pressure to control values. The pressor responses to local cooling were increased from 11 to 32 mmHg while the dilator responses to local heating and nitroglycerin were reduced during infusions of PGB1. PGB1 also enhanced the pressor responses to norepinephrine or tyramine. These findings support the conclusions that (1) low concentrations of prostaglandin B1 enhance neurotransmitter release with minimal effects on vascular smooth muscle cells and (2) these effects are not secondary to increased perfusion pressures or vascular wall stresses since infusions of PGB1 resulted in vasodilation.

  17. Screening and Initial Binding Assessment of Fumonisin B1 Aptamers

    Directory of Open Access Journals (Sweden)

    Maria C. DeRosa

    2010-11-01

    Full Text Available Fumonisins are mycotoxins produced by Fusarium verticillioides and F. proliferatum, fungi that are ubiquitous in corn (maize. Insect damage and some other environmental conditions result in the accumulation of fumonisins in corn-based products worldwide. Current methods of fumonisin detection rely on the use of immunoaffinity columns and high-performance liquid chromatography (HPLC. The use of aptamers offers a good alternative to the use of antibodies in fumonisin cleanup and detection due to lower costs and improved stability. Aptamers are single-stranded oligonucleotides that are selected using Systematic Evolution of Ligands by EXponential enrichment (SELEX for their ability to bind to targets with high affinity and specificity. Sequences obtained after 18 rounds of SELEX were screened for their ability to bind to fumonisin B1. Six unique sequences were obtained, each showing improved binding to fumonisin B1 compared to controls. Sequence FB1 39 binds to fumonisin with a dissociation constant of 100 ± 30 nM and shows potential for use in fumonisin biosensors and solid phase extraction columns.

  18. Screening and initial binding assessment of fumonisin b(1) aptamers.

    Science.gov (United States)

    McKeague, Maureen; Bradley, Charlotte R; De Girolamo, Annalisa; Visconti, Angelo; Miller, J David; Derosa, Maria C

    2010-01-01

    Fumonisins are mycotoxins produced by Fusarium verticillioides and F. proliferatum, fungi that are ubiquitous in corn (maize). Insect damage and some other environmental conditions result in the accumulation of fumonisins in corn-based products worldwide. Current methods of fumonisin detection rely on the use of immunoaffinity columns and high-performance liquid chromatography (HPLC). The use of aptamers offers a good alternative to the use of antibodies in fumonisin cleanup and detection due to lower costs and improved stability. Aptamers are single-stranded oligonucleotides that are selected using Systematic Evolution of Ligands by EXponential enrichment (SELEX) for their ability to bind to targets with high affinity and specificity. Sequences obtained after 18 rounds of SELEX were screened for their ability to bind to fumonisin B(1). Six unique sequences were obtained, each showing improved binding to fumonisin B(1) compared to controls. Sequence FB(1) 39 binds to fumonisin with a dissociation constant of 100 ± 30 nM and shows potential for use in fumonisin biosensors and solid phase extraction columns.

  19. DELF B1 200 activités

    CERN Document Server

    Bloomfield, Anatole

    2006-01-01

    L'ouvrage est organisé par compétences de réception et de production. Chaque partie propose d'abord une présentation de l'épreuve correspondante, puis les activités de préparation suivies d'épreuves-types et d'une auto-évaluation. Dans le cadre d'une approche actionnelle, les activités fournissent les outils nécessaires à la préparation des examens. Elles donnent des exemples concrets répondant aux attentes des candidats comme à celle des examinateurs. LeNouveau DELF B1 propose des activités précises en vue d'atteindre les compétences nécessaires aux épreuves (oral, écrit, réception, production); sa simplicité et sa pédagogie en font une méthode complète. Dans la tradition de la collection Nouvel Entraînez-vous, cet ouvrage est pratique, didactique et se prête à une utilisation en autonomie ou en classe.Le niveau B1 dit " avancé " évalue un niveau de compétence où l'apprenant peut se considérer comme étant indépendant. Arrivé à ce stade, il est apte de comprendre l'inform...

  20. Sox9基因参与动物性别决定与分化的分子机制%Molecular Mechanisms of Sox9 Gene in Regulating Sex Determination and Differentiation of Animals

    Institute of Scientific and Technical Information of China (English)

    陈维; 王昌留

    2012-01-01

    Sox9基因参与动物多种生理活动的调控,其最主要的功能还是性别决定.笔者通过阅读大量文献,分析不同物种的性别决定分子机制,对Sox9参与动物的性别决定和分化进行了综述,为进一步研究Sox9基因在性别决定和分化中的作用提供参考.%Sox9 gene can take part in many physiological activities of gene regulations.Its most important role is involved in sex determination.The molecular mechanisms of sex determination and differentiation regulated by Sox9 gene in different species are reviewed,which is expected to provide reference materials for further study on sex determination and differentiation of Sox9 gene.

  1. Crystal structure of a KSHV-SOX-DNA complex: insights into the molecular mechanisms underlying DNase activity and host shutoff.

    Science.gov (United States)

    Bagnéris, Claire; Briggs, Louise C; Savva, Renos; Ebrahimi, Bahram; Barrett, Tracey E

    2011-07-01

    The early lytic phase of Kaposi's sarcoma herpesvirus infection is characterized by viral replication and the global degradation (shutoff) of host mRNA. Key to both activities is the virally encoded alkaline exonuclease KSHV SOX. While the DNase activity of KSHV SOX is required for the resolution of viral genomic DNA as a precursor to encapsidation, its exact involvement in host shutoff remains to be determined. We present the first crystal structure of a KSHV SOX-DNA complex that has illuminated the catalytic mechanism underpinning both its endo and exonuclease activities. We further illustrate that KSHV SOX, similar to its Epstein-Barr virus homologue, has an intrinsic RNase activity in vitro that although an element of host shutoff, cannot solely account for the phenomenon.

  2. Argumentative SOX Compliant and Quality Decision Support Intelligent Expert System over the Suppliers Selection Process

    Directory of Open Access Journals (Sweden)

    Jesus Angel Fernandez Canelas

    2013-01-01

    Full Text Available The objective of this paper is to define a decision support system over SOX (Sarbanes-Oxley Act compatibility and quality of the Suppliers Selection Process based on Artificial Intelligence and Argumentation Theory knowledge and techniques. The present SOX Law, in effect nowadays, was created to improve financial government control over US companies. This law is a factor standard out United States due to several factors like present globalization, expansion of US companies, or key influence of US stock exchange markets worldwide. This paper constitutes a novel approach to this kind of problems due to following elements: (1 it has an optimized structure to look for the solution, (2 it has a dynamic learning method to handle court and control gonvernment bodies decisions, (3 it uses fuzzy knowledge to improve its performance, and (4 it uses its past accumulated experience to let the system evolve far beyond its initial state.

  3. Stemness of the organ of Corti relates to the epigenetic status of Sox2 enhancers.

    Directory of Open Access Journals (Sweden)

    Jörg Waldhaus

    Full Text Available In the adult mammalian auditory epithelium, the organ of Corti, loss of sensory hair cells results in permanent hearing loss. The underlying cause for the lack of regenerative response is the depletion of otic progenitors in the cell pool of the sensory epithelium. Here, we show that an increase in the sequence-specific methylation of the otic Sox2 enhancers NOP1 and NOP2 is correlated with a reduced self-renewal potential in vivo and in vitro; additionally, the degree of methylation of NOP1 and NOP2 is correlated with the dedifferentiation potential of postmitotic supporting cells into otic stem cells. Thus, the stemness the organ of Corti is related to the epigenetic status of the otic Sox2 enhancers. These observations validate the continued exploration of treatment strategies for dedifferentiating or reprogramming of differentiated supporting cells into progenitors to regenerate the damaged organ of Corti.

  4. Oct4/Sox2 binding sites contribute to maintaining hypomethylation of the maternal igf2/h19 imprinting control region.

    Directory of Open Access Journals (Sweden)

    David L Zimmerman

    Full Text Available A central question in genomic imprinting is how parental-specific DNA methylation of imprinting control regions (ICR is established during gametogenesis and maintained after fertilization. At the imprinted Igf2/H19 locus, CTCF binding maintains the unmethylated state of the maternal ICR after the blastocyst stage. In addition, evidence from Beckwith-Wiedemann patients and cultured mouse cells suggests that two Sox-Oct binding motifs within the Igf2/H19 ICR also participate in maintaining hypomethylation of the maternal allele. We found that the Sox and octamer elements from both Sox-Oct motifs were required to drive hypomethylation of integrated transgenes in mouse embryonic carcinoma cells. Oct4 and Sox2 showed cooperative binding to the Sox-Oct motifs, and both were present at the endogenous ICR. Using a mouse with mutations in the Oct4 binding sites, we found that maternally transmitted mutant ICRs acquired partial methylation in somatic tissues, but there was little effect on imprinted expression of H19 and Igf2. A subset of mature oocytes also showed partial methylation of the mutant ICR, which suggested that the Sox-Oct motifs provide some protection from methylation during oogenesis. The Sox-Oct motifs, however, were not required for erasure of paternal methylation in primordial germ cells, which indicated that the oocyte methylation was acquired post-natally. Maternally inherited mutant ICRs were unmethylated in blastocysts, which suggested that at least a portion of the methylation in somatic tissues occurred after implantation. These findings provide evidence that Sox-Oct motifs contribute to ICR hypomethylation in post-implantation embryos and maturing oocytes and link imprinted DNA methylation with key stem cell/germline transcription factors.

  5. Identification of novel craniofacial regulatory domains located far upstream ofSOX9and disrupted in Pierre Robin sequence

    OpenAIRE

    2014-01-01

    Mutations in the coding sequence of SOX9 cause campomelic dysplasia (CD), a disorder of skeletal development associated with 46,XY disorders of sex development (DSDs). Translocations, deletions and duplications within a ~2 Mb region upstream of SOX9 can recapitulate the CD-DSD phenotype fully or partially, suggesting the existence of an unusually large cis-regulatory control region. Pierre Robin sequence (PRS) is a craniofacial disorder that is frequently an endophenotype of CD and a locus fo...

  6. Premalignant SOX2 overexpression in the fallopian tubes of ovarian cancer patients: Discovery and validation studies

    Directory of Open Access Journals (Sweden)

    Karin Hellner

    2016-08-01

    Full Text Available Current screening methods for ovarian cancer can only detect advanced disease. Earlier detection has proved difficult because the molecular precursors involved in the natural history of the disease are unknown. To identify early driver mutations in ovarian cancer cells, we used dense whole genome sequencing of micrometastases and microscopic residual disease collected at three time points over three years from a single patient during treatment for high-grade serous ovarian cancer (HGSOC. The functional and clinical significance of the identified mutations was examined using a combination of population-based whole genome sequencing, targeted deep sequencing, multi-center analysis of protein expression, loss of function experiments in an in-vivo reporter assay and mammalian models, and gain of function experiments in primary cultured fallopian tube epithelial (FTE cells. We identified frequent mutations involving a 40 kb distal repressor region for the key stem cell differentiation gene SOX2. In the apparently normal FTE, the region was also mutated. This was associated with a profound increase in SOX2 expression (p < 2−16, which was not found in patients without cancer (n = 108. Importantly, we show that SOX2 overexpression in FTE is nearly ubiquitous in patients with HGSOCs (n = 100, and common in BRCA1-BRCA2 mutation carriers (n = 71 who underwent prophylactic salpingo-oophorectomy. We propose that the finding of SOX2 overexpression in FTE could be exploited to develop biomarkers for detecting disease at a premalignant stage, which would reduce mortality from this devastating disease.

  7. SOx-NOx-Rox Box{trademark} flue gas clean-up demonstration. Final report

    Energy Technology Data Exchange (ETDEWEB)

    NONE

    1995-09-01

    Babcock and Wilcox`s (B and W) SOx-NOx-Rox Box{trademark} process effectively removes SOx, NOx and particulate (Rox) from flue gas generated from coal-fired boilers in a single unit operation, a high temperature baghouse. The SNRB technology utilizes dry sorbent injection upstream of the baghouse for removal of SOx and ammonia injection upstream of a zeolitic selective catalytic reduction (SCR) catalyst incorporated in the baghouse to reduce NOx emissions. Because the SOx and NOx removal processes require operation at elevated gas temperatures (800--900 F) for high removal efficiency, high-temperature fabric filter bags are used in the baghouse. The SNRB technology evolved from the bench and laboratory pilot scale to be successfully demonstrated at the 5-MWe field scale. This report represents the completion of Milestone M14 as specified in the Work Plan. B and W tested the SNRB pollution control system at a 5-MWe demonstration facility at Ohio Edison`s R.E. Burger Plant located near Shadyside, Ohio. The design and operation were influenced by the results from laboratory pilot testing at B and W`s Alliance Research Center. The intent was to demonstrate the commercial feasibility of the SNRB process. The SNRB facility treated a 30,000 ACFM flue gas slipstream from Boiler No. 8. Operation of the facility began in May 1992 and was completed in May 1993. About 2,300 hours of high-temperature operation were achieved. The main emissions control performance goals of: greater than 70% SO{sub 2} removal using a calcium-based sorbent; greater than 90% NOx removal with minimal ammonia slip; and particulate emissions in compliance with the New Source Performance Standards (NSPS) of 0.03 lb/million Btu were exceeded simultaneously in the demonstration program when the facility was operated at optimal conditions. Testing also showed significant reductions in emissions of some hazardous air pollutants.

  8. OCT4 and SOX2 are reliable markers in detecting stem cells in odontogenic lesions

    Directory of Open Access Journals (Sweden)

    Abhishek Banerjee

    2016-01-01

    Full Text Available Context (Background: Stem cells are a unique subpopulation of cells in the human body with a capacity to initiate differentiation into various cell lines. Tumor stem cells (TSCs are a unique subpopulation of cells that possess the ability to initiate a neoplasm and sustain self-renewal. Epithelial stem cell (ESC markers such as octamer-binding transcription factor 4 (OCT4 and sex-determining region Y (SRY-box 2 (SOX2 are capable of identifying these stem cells expressed during the early stages of tooth development. Aims: To detect the expression of the stem cell markers OCT4 and SOX2 in the normal odontogenic tissues and the odontogenic cysts and tumors. Materials and Methods: Paraffin sections of follicular tissue, radicular cyst, dentigerous cyst, odontogenic keratocyst, ameloblastoma, adenomatoid odontogenic tumor, and ameloblastic carcinoma were obtained from the archives. The sections were subjected to immunohistochemical assay by the use of mouse monoclonal antibodies to OCT4 and SOX2. Statistical Analysis: The results were evaluated by descriptive analysis. Results: The results show the presence of stem cells in the normal and lesional tissues with these stem cell identifying markers. SOX2 was found to be more consistent and reliable in the detection of stem cells. Conclusion: The stem cell expressions are maintained in the tumor transformation of tissue and probably suggest that there is no phenotypic change of stem cells in progression from normal embryonic state to its tumor component. The quantification and localization reveals interesting trends that indicate the probable role of the cells in the pathogenesis of the lesions.

  9. The Role of Sox2 in Lung Cancer Initiation and Progression

    Science.gov (United States)

    2013-10-01

    induced tumorigenesis. Our close collaborator Barry Stripp provided re-derived inducible p63-knockout (floxed p63) mouse line from frozen embryos . We set...GFP cells via flow sorting for transplantation into the retroorbital veins of immunodeficient Rag1-/- mice. While our preliminary data demonstrated that...this transplantation led to tumors when the transplant was performed using K-RasG12D-expressing cells, we have not obtained tumors using the Sox2

  10. Comparative analysis between P1 and B1 equations for neutron moderation; Analise comparativa entre os metodos de obtencao e das solucoes das equacoes P1 e B1 para moderacao de neutrons

    Energy Technology Data Exchange (ETDEWEB)

    Martinez, Aquilino Senra; Silva, Fernando Carvalho da; Cardoso, Carlos Eduardo Santos [Universidade Federal, Rio de Janeiro, RJ (Brazil). Coordenacao dos Programas de Pos-graduacao de Engenharia. Programa de Engenharia Nuclear

    2000-07-01

    In order to calculate the neutron flux in nuclear reactors, B1 or P1 equations are solved by numerical methods for several groups of energy. The neutron fluxes obtained from the solutions of the B1 and P1 equations are similar when they are applied to large nuclear power reactors. However, an important difference between the two fluxes is that the system of P1 equations uses one more approximation than the B1 system and then, its flux is less precise. The present work shows the relations between both equations and analyzes for what conditions the two equations systems are equivalent. Furthermore, this equations are numerically solved in 54 groups of energy for a quadrangular arrange. (author)

  11. Sox10 gain-of-function causes XX sex reversal in mice: implications for human 22q-linked disorders of sex development.

    Science.gov (United States)

    Polanco, Juan Carlos; Wilhelm, Dagmar; Davidson, Tara-Lynne; Knight, Deon; Koopman, Peter

    2010-02-01

    Male development in mammals is normally initiated by the Y-linked gene Sry, which activates expression of Sox9, leading to a cascade of gene activity required for testis formation. Although defects in this genetic cascade lead to human disorders of sex development (DSD), only a dozen DSD genes have been identified, and causes of 46,XX DSD (XX maleness) other than SRY translocation are almost completely unknown. Here, we show that transgenic expression of Sox10, a close relative of Sox9, in gonads of XX mice resulted in development of testes and male physiology. The degree of sex reversal correlated with levels of Sox10 expression in different transgenic lines. Sox10 was expressed at low levels in primordial gonads of both sexes during normal mouse development, becoming male-specific during testis differentiation. SOX10 protein was able to activate transcriptional targets of SOX9, explaining at a mechanistic level its ability to direct male development. Because over-expression of SOX10 alone is able to mimic the XX DSD phenotypes associated with duplication of human chromosome 22q13, and given that human SOX10 maps to 22q13.1, our results functionally implicate SOX10 in the etiology of these DSDs.

  12. SOX2 O-GlcNAcylation alters its protein-protein interactions and genomic occupancy to modulate gene expression in pluripotent cells

    Science.gov (United States)

    Myers, Samuel A; Peddada, Sailaja; Chatterjee, Nilanjana; Friedrich, Tara; Tomoda, Kiichrio; Krings, Gregor; Thomas, Sean; Maynard, Jason; Broeker, Michael; Thomson, Matthew; Pollard, Katherine; Yamanaka, Shinya; Burlingame, Alma L; Panning, Barbara

    2016-01-01

    The transcription factor SOX2 is central in establishing and maintaining pluripotency. The processes that modulate SOX2 activity to promote pluripotency are not well understood. Here, we show SOX2 is O-GlcNAc modified in its transactivation domain during reprogramming and in mouse embryonic stem cells (mESCs). Upon induction of differentiation SOX2 O-GlcNAcylation at serine 248 is decreased. Replacing wild type with an O-GlcNAc-deficient SOX2 (S248A) increases reprogramming efficiency. ESCs with O-GlcNAc-deficient SOX2 exhibit alterations in gene expression. This change correlates with altered protein-protein interactions and genomic occupancy of the O-GlcNAc-deficient SOX2 compared to wild type. In addition, SOX2 O-GlcNAcylation impairs the SOX2-PARP1 interaction, which has been shown to regulate ESC self-renewal. These findings show that SOX2 activity is modulated by O-GlcNAc, and provide a novel regulatory mechanism for this crucial pluripotency transcription factor. DOI: http://dx.doi.org/10.7554/eLife.10647.001 PMID:26949256

  13. Evidence for increased SOX3 dosage as a risk factor for X-linked hypopituitarism and neural tube defects.

    Science.gov (United States)

    Bauters, Marijke; Frints, Suzanna G; Van Esch, Hilde; Spruijt, Liesbeth; Baldewijns, Marcella M; de Die-Smulders, Christine E M; Fryns, Jean-Pierre; Marynen, Peter; Froyen, Guy

    2014-08-01

    Genomic duplications of varying lengths at Xq26-q27 involving SOX3 have been described in families with X-linked hypopituitarism. Using array-CGH we detected a 1.1 Mb microduplication at Xq27 in a large family with three males suffering from X-linked hypopituitarism. The duplication was mapped from 138.7 to 139.8 Mb, harboring only two annotated genes, SOX3 and ATP11C, and was shown to be a direct tandem copy number gain. Unexpectedly, the microduplication did not fully segregate with the disease in this family suggesting that SOX3 duplications have variable penetrance for X-linked hypopituitarism. In the same family, a female fetus presenting with a neural tube defect was also shown to carry the SOX3 copy number gain. Since we also demonstrated increased SOX3 mRNA levels in amnion cells derived from an unrelated t(X;22)(q27;q11) female fetus with spina bifida, we propose that increased levels of SOX3 could be a risk factor for neural tube defects.

  14. C-MYC transcriptionally amplifies SOX2 target genes to regulate self-renewal in multipotent otic progenitor cells.

    Science.gov (United States)

    Kwan, Kelvin Y; Shen, Jun; Corey, David P

    2015-01-13

    Sensorineural hearing loss is caused by the loss of sensory hair cells and neurons of the inner ear. Once lost, these cell types are not replaced. Two genes expressed in the developing inner ear are c-Myc and Sox2. We created immortalized multipotent otic progenitor (iMOP) cells, a fate-restricted cell type, by transient expression of C-MYC in SOX2-expressing otic progenitor cells. This activated the endogenous C-MYC and amplified existing SOX2-dependent transcripts to promote self-renewal. RNA-seq and ChIP-seq analyses revealed that C-MYC and SOX2 occupy over 85% of the same promoters. C-MYC and SOX2 target genes include cyclin-dependent kinases that regulate cell-cycle progression. iMOP cells continually divide but retain the ability to differentiate into functional hair cells and neurons. We propose that SOX2 and C-MYC regulate cell-cycle progression of these cells and that downregulation of C-MYC expression after growth factor withdrawal serves as a molecular switch for differentiation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  15. The exonuclease and host shutoff functions of the SOX protein of Kaposi's sarcoma-associated herpesvirus are genetically separable.

    Science.gov (United States)

    Glaunsinger, Britt; Chavez, Leonard; Ganem, Don

    2005-06-01

    The Kaposi's sarcoma-associated herpesvirus (KSHV) SOX protein, encoded by ORF37, promotes shutoff of host cell gene expression during lytic viral replication by dramatically impairing mRNA accumulation. SOX is the KSHV homolog of the alkaline exonuclease of other herpesviruses, which has been shown to function as a DNase involved in processing and packaging the viral genome. Although the exonuclease activity of these proteins is widely conserved across all herpesviruses, the host shutoff activity observed for KSHV SOX is not. We show here that SOX expression sharply reduces the half-life of target mRNAs. Extensive mutational analysis reveals that the DNase and host shutoff activities of SOX are genetically separable. Lesions affecting the DNase activity cluster in conserved regions of the protein, but residues critical for mRNA degradation are not conserved across the viral family. Additionally, we present evidence suggesting that the two different functions of SOX occur within distinct cellular compartments-DNase activity in the nucleus and host shutoff activity in the cytoplasm.

  16. The prognostic value of SOX2 expression in non-small cell lung cancer: a meta-analysis.

    Directory of Open Access Journals (Sweden)

    Yansu Chen

    Full Text Available OBJECTIVE: To investigate the association of SOX2 expression in tumor with clinicopathological features and survival of non-small-cell lung carcinoma (NSCLC patients. METHODS: Publications assessing the clinicopathological characteristics and prognostic significance of SOX2 in NSCLC were identified up to May 2013. A meta-analysis of eligible studies was performed using standard statistical methods to clarify the association between SOX2 expression and these clinical parameters. RESULTS: A total of eight studies met the inclusion criteria. Analysis of these data showed that SOX2 expression was positively associated with squamous histology, (pooled OR = 5.26, 95% CI: 1.08-25.6, P = 0.040. Simultaneously, we also found that SOX2 expression was positively associated with overall survival (pooled HR = 0.65, 95% CI: 0.47-0.89, P = 0.007, random-effect. CONCLUSIONS: SOX2 expression in tumor is a candidate positive prognostic biomarker for NSCLC patients.

  17. The overexpression of SOX2 affects the migration of human teratocarcinoma cell line NT2/D1

    Directory of Open Access Journals (Sweden)

    DANIJELA DRAKULIC

    2015-03-01

    Full Text Available The altered expression of the SOX2 transcription factor is associated with oncogenic or tumor suppressor functions in human cancers. This factor regulates the migration and invasion of different cancer cells. In this study we investigated the effect of constitutive SOX2 overexpression on the migration and adhesion capacity of embryonal teratocarcinoma NT2/D1 cells derived from a metastasis of a human testicular germ cell tumor. We detected that increased SOX2 expression changed the speed, mode and path of cell migration, but not the adhesion ability of NT2/D1 cells. Additionally, we demonstrated that SOX2 overexpression increased the expression of the tumor suppressor protein p53 and the HDM2 oncogene. Our results contribute to the better understanding of the effect of SOX2 on the behavior of tumor cells originating from a human testicular germ cell tumor. Considering that NT2/D1 cells resemble cancer stem cells in many features, our results could contribute to the elucidation of the role of SOX2 in cancer stem cells behavior and the process of metastasis.

  18. The overexpression of SOX2 affects the migration of human teratocarcinoma cell line NT2/D1.

    Science.gov (United States)

    Drakulic, Danijela; Vicentic, Jelena Marjanovic; Schwirtlich, Marija; Tosic, Jelena; Krstic, Aleksandar; Klajn, Andrijana; Stevanovic, Milena

    2015-03-01

    The altered expression of the SOX2 transcription factor is associated with oncogenic or tumor suppressor functions in human cancers. This factor regulates the migration and invasion of different cancer cells. In this study we investigated the effect of constitutive SOX2 overexpression on the migration and adhesion capacity of embryonal teratocarcinoma NT2/D1 cells derived from a metastasis of a human testicular germ cell tumor. We detected that increased SOX2 expression changed the speed, mode and path of cell migration, but not the adhesion ability of NT2/D1 cells. Additionally, we demonstrated that SOX2 overexpression increased the expression of the tumor suppressor protein p53 and the HDM2 oncogene. Our results contribute to the better understanding of the effect of SOX2 on the behavior of tumor cells originating from a human testicular germ cell tumor. Considering that NT2/D1 cells resemble cancer stem cells in many features, our results could contribute to the elucidation of the role of SOX2 in cancer stem cells behavior and the process of metastasis.

  19. Sox2 regulates Müller glia reprogramming and proliferation in the regenerating zebrafish retina via Lin28 and Ascl1a.

    Science.gov (United States)

    Gorsuch, Ryne A; Lahne, Manuela; Yarka, Clare E; Petravick, Michael E; Li, Jingling; Hyde, David R

    2017-08-01

    Sox2 is a well-established neuronal stem cell-associated transcription factor that regulates neural development and adult neurogenesis in vertebrates, and is one of the critical genes used to reprogram differentiated cells into induced pluripotent stem cells. We examined if Sox2 was involved in the early reprogramming-like events that Müller glia undergo as they upregulate many pluripotency- and neural stem cell-associated genes required for proliferation in light-damaged adult zebrafish retinas. In the undamaged adult zebrafish retina, Sox2 is expressed in Müller glia and a subset of amacrine cells, similar to other vertebrates. Following 31 h of light damage, Sox2 expression significantly increased in proliferating Müller glia. Morpholino-mediated knockdown of Sox2 expression resulted in decreased numbers of proliferating Müller glia, while induced overexpression of Sox2 stimulated Müller glia proliferation in the absence of retinal damage. Thus, Sox2 is necessary and sufficient for Müller glia proliferation. We investigated the role of Wnt/β-catenin signaling, which is a known regulator of sox2 expression during vertebrate retinal development. While β-catenin 2, but not β-catenin 1, was necessary for Müller glia proliferation, neither β-catenin paralog was required for sox2 expression following retinal damage. Sox2 expression was also necessary for ascl1a (neurogenic) and lin28a (reprogramming) expression, but not stat3 expression following retinal damage. Furthermore, Sox2 was required for Müller glial-derived neuronal progenitor cell amplification and expression of the pro-neural marker Tg(atoh7:EGFP). Finally, loss of Sox2 expression prevented complete regeneration of cone photoreceptors. This study is the first to identify a functional role for Sox2 during Müller glial-based regeneration of the vertebrate retina. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. The HMG-box transcription factor Sox4b is required for pituitary expression of gata2a and specification of thyrotrope and gonadotrope cells in zebrafish.

    Science.gov (United States)

    Quiroz, Yobhana; Lopez, Mauricio; Mavropoulos, Anastasia; Motte, Patrick; Martial, Joseph A; Hammerschmidt, Matthias; Muller, Marc

    2012-06-01

    The pituitary is a complex gland comprising different cell types each secreting specific hormones. The extensive network of signaling molecules and transcription factors required for determination and terminal differentiation of specific cell types is still not fully understood. The SRY-like HMG-box (SOX) transcription factor Sox4 plays important roles in many developmental processes and has two homologs in zebrafish, Sox4a and Sox4b. We show that the sox4b gene is expressed in the pituitary anlagen starting at 24 h after fertilization (hpf) and later in the entire head region including the pituitary. At 48 hpf, sox4b mRNA colocalizes with that for TSH (tshβ), glycoprotein subunit α (gsuα), and the Zn finger transcription factor Gata2a. Loss of Sox4b function, using morpholino knockdown or expression of a dominant-negative Sox4 mutant, leads to a drastic decrease in tshβ and gsuα expression and reduced levels of gh, whereas other anterior pituitary gland markers including prl, slβ, pomc, and lim3 are not affected. Sox4b is also required for expression of gata2a in the pituitary. Knockdown of gata2a leads to decreased tshβ and gsuα expression at 48 hpf, similar to sox4b morphants. Injection of gata2a mRNA into sox4b morphants rescued tshβ and gsuα expression in thyrotrope cells. Finally, sox4b or gata2a knockdown causes a significant decrease of gonadotropin expression (lhβ and fshβ) at 4 d after fertilization. In summary, our results indicate that Sox4b is expressed in zebrafish during pituitary development and plays a crucial role in the differentiation of thyrotrope and gonadotrope cells through induction of gata2a expression in the developing pituitary.

  1. Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice

    Science.gov (United States)

    Overman, Jeroen; Fontaine, Frank; Moustaqil, Mehdi; Mittal, Deepak; Sierecki, Emma; Sacilotto, Natalia; Zuegg, Johannes; Robertson, Avril AB; Holmes, Kelly; Salim, Angela A; Mamidyala, Sreeman; Butler, Mark S; Robinson, Ashley S; Lesieur, Emmanuelle; Johnston, Wayne; Alexandrov, Kirill; Black, Brian L; Hogan, Benjamin M; Val, Sarah De; Capon, Robert J; Carroll, Jason S; Bailey, Timothy L; Koopman, Peter; Jauch, Ralf; Smyth, Mark J; Cooper, Matthew A; Gambin, Yann; Francois, Mathias

    2017-01-01

    Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics. DOI: http://dx.doi.org/10.7554/eLife.21221.001 PMID:28137359

  2. The lncRNA CASC15 regulates SOX4 expression in RUNX1-rearranged acute leukemia.

    Science.gov (United States)

    Fernando, Thilini R; Contreras, Jorge R; Zampini, Matteo; Rodriguez-Malave, Norma I; Alberti, Michael O; Anguiano, Jaime; Tran, Tiffany M; Palanichamy, Jayanth K; Gajeton, Jasmine; Ung, Nolan M; Aros, Cody J; Waters, Ella V; Casero, David; Basso, Giuseppe; Pigazzi, Martina; Rao, Dinesh S

    2017-07-19

    Long non-coding RNAs (lncRNAs) play a variety of cellular roles, including regulation of transcription and translation, leading to alterations in gene expression. Some lncRNAs modulate the expression of chromosomally adjacent genes. Here, we assess the roles of the lncRNA CASC15 in regulation of a chromosomally nearby gene, SOX4, and its function in RUNX1/AML translocated leukemia. CASC15 is a conserved lncRNA that was upregulated in pediatric B-acute lymphoblastic leukemia (B-ALL) with t (12; 21) as well as pediatric acute myeloid leukemia (AML) with t (8; 21), both of which are associated with relatively better prognosis. Enforced expression of CASC15 led to a myeloid bias in development, and overall, decreased engraftment and colony formation. At the cellular level, CASC15 regulated cellular survival, proliferation, and the expression of its chromosomally adjacent gene, SOX4. Differentially regulated genes following CASC15 knockdown were enriched for predicted transcriptional targets of the Yin and Yang-1 (YY1) transcription factor. Interestingly, we found that CASC15 enhances YY1-mediated regulation of the SOX4 promoter. Our findings represent the first characterization of this CASC15 in RUNX1-translocated leukemia, and point towards a mechanistic basis for its action.

  3. 3D imaging of Sox2 enhancer clusters in embryonic stem cells.

    Science.gov (United States)

    Liu, Zhe; Legant, Wesley R; Chen, Bi-Chang; Li, Li; Grimm, Jonathan B; Lavis, Luke D; Betzig, Eric; Tjian, Robert

    2014-12-24

    Combinatorial cis-regulatory networks encoded in animal genomes represent the foundational gene expression mechanism for directing cell-fate commitment and maintenance of cell identity by transcription factors (TFs). However, the 3D spatial organization of cis-elements and how such sub-nuclear structures influence TF activity remain poorly understood. Here, we combine lattice light-sheet imaging, single-molecule tracking, numerical simulations, and ChIP-exo mapping to localize and functionally probe Sox2 enhancer-organization in living embryonic stem cells. Sox2 enhancers form 3D-clusters that are segregated from heterochromatin but overlap with a subset of Pol II enriched regions. Sox2 searches for specific binding targets via a 3D-diffusion dominant mode when shuttling long-distances between clusters while chromatin-bound states predominate within individual clusters. Thus, enhancer clustering may reduce global search efficiency but enables rapid local fine-tuning of TF search parameters. Our results suggest an integrated model linking cis-element 3D spatial distribution to local-versus-global target search modalities essential for regulating eukaryotic gene transcription.

  4. Helium ion beam lithography (HIBL) using HafSOx as the resist

    Science.gov (United States)

    Luo, Feixiang; Manichev, Viacheslav; Li, Mengjun; Mitchson, Gavin; Yakshinskiy, Boris; Gustafsson, Torgny; Johnson, David; Garfunkel, Eric

    2016-03-01

    Helium ion beam lithography (HIBL) is a novel alternative lithographic technique with the capacity of fabricating highresolution and high-density features. Only limited research has been performed exploring HIBL to date. HafSOx (Hf(OH)4-2x-2y(O2)x(SO4)y·qH2O) is a negative-tone inorganic resist that is one of several candidate resist materials for extreme ultraviolet lithography (EUVL) and e-beam lithography (EBL), and has been demonstrated to show high resolution, moderate sensitivity and low line-edge roughness (LER) in both EUVL and EBL. To date, no ion beam lithography work on HafSOx has been reported. In this study, we tested HafSOx as an HIBL resist and achieved a high sensitivity compared with EBL with a turn-on dose D100 ~ 2-4 μC/cm2. We obtained sub-10 nm line widths with low LER. A simple Monte Carlo simulation suggests that ionizing excitation accounts for most of the incident He ions' energy loss.

  5. SOX2, OTX2 and PAX6 analysis in subjects with anophthalmia and microphthalmia.

    Science.gov (United States)

    Mauri, Lucia; Franzoni, Alessandra; Scarcello, Manuela; Sala, Stefano; Garavelli, Livia; Modugno, Alessandra; Grammatico, Paola; Patrosso, Maria Cristina; Piozzi, Elena; Del Longo, Alessandra; Gesu, Giovanni P; Manfredini, Emanuela; Primignani, Paola; Damante, Giuseppe; Penco, Silvana

    2015-02-01

    Anophthalmia (A) and microphthalmia (M) are rare developmental anomalies that have significant effects on visual activity. In fraction of A/M subjects, single genetic defects have been identified as causative. In this study we analysed 65 Italian A/M patients, 21 of whom are syndromic, for mutations in SOX2, OTX2 and PAX6 genes. In syndromic patients the presence of genome imbalances through array CGH was also investigated. No mutations were found for OTX2 and PAX6 genes. Three causative SOX2 mutations were found in subjects with syndromic A. In a subject with syndromic signs and monolateral M, two de novo 6.26 Mb and 1.37 Mb deletions in 4q13.2q13.3 have been identified. A SOX2 missense (p.Ala161Ser) mutation was found in 1 out of 39 a subject with non-syndromic monolateral M. Alanine at position 161 is conserved along phylogeny and the p.Ala161Ser mutation is estimated pathogenic by in silico analysis. However, this mutation was also present in the unaffected patient's daughter.

  6. The impact of SLCO1B1 genetic polymorphisms on neonatal hyperbilirubinemia: a systematic review with meta-analysis.

    Science.gov (United States)

    Liu, Jiebo; Long, Jun; Zhang, Shaofang; Fang, Xiaoyan; Luo, Yuyuan

    2013-01-01

    To determine whether three variants (388 G>A, 521 T>C, and 463 C>A) of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) are associated with neonatal hyperbilirubinemia. The China National Knowledge Infrastructure and MEDLINE databases were searched. The systematic review with meta-analysis included genetic studies which assessed the association between neonatal hyperbilirubinemia and 388 G>A, 521 T>C, and 463 C>A variants of SLCO1B1 between January of 1980 and December of 2012. Data selection and extraction were performed independently by two reviewers. Ten articles were included in the study. The results revealed that SLCO1B1 388 G>A is associated with an increased risk of neonatal hyperbilirubinemia (OR, 1.39; 95% CI, 1.07-1.82) in Chinese neonates, but not in white, Thai, Latin American, or Malaysian neonates. The SLCO1B1 521 T>C mutation showed a low risk of neonatal hyperbilirubinemia in Chinese neonates, while no significant associations were found in Brazilian, white, Asian, Thai, and Malaysian neonates. There were no significant differences in SLCO1B1 463 C>A between the hyperbilirubinemia and the control group. This study demonstrated that the 388 G>A mutation of the SLCO1B1 gene is a risk factor for developing neonatal hyperbilirubinemia in Chinese neonates, but not in white, Thai, Brazilian, or Malaysian populations; the SLCO1B1 521 T>C mutation provides protection for neonatal hyperbilirubinemia in Chinese neonates, but not in white, Thai, Brazilian, or Malaysian populations. Copyright © 2013 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  7. Screening for coding variants in FTO and SH2B1 genes in Chinese patients with obesity.

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    Zhaojing Zheng

    Full Text Available OBJECTIVE: To investigate potential functional variants in FTO and SH2B1 genes among Chinese children with obesity. METHODS: Sanger sequencing of PCR products of all FTO and SH2B1 exons and their flanking regions were performed in 338 Chinese Han children with obesity and 221 age- and sex-matched lean controls. RESULTS: A total of seven and five rare non-synonymous variants were identified in FTO and SH2B1, respectively. The overall frequencies of FTO and SH2B1 rare non-synonymous variants were similar in obese and lean children (2.37% and 0.90% vs. 1.81% and 1.36%, P>0.05. However, four out of the seven variants in FTO were novel and all were unique to obese children (p>0.05. None of the novel variants was consistently being predicted to be deleterious. Four out of five variants in SH2B1 were novel and one was unique to obese children (p>0.05. One variant (L293R that was consistently being predicted as deleterious in SH2B1 gene was unique to lean control. While rare missense mutations were more frequently detected in girls from obesity as well as lean control than boys, the difference was not statistically significant. In addition, it's shown that the prevalence of rare missense mutations of FTO as well as SH2B1 was similar across different ethnic groups. CONCLUSION: The rare missense mutations of FTO and SH2B1 did not confer risks of obesity in Chinese Han children in our cohort.

  8. Screening for Coding Variants in FTO and SH2B1 Genes in Chinese Patients with Obesity

    Science.gov (United States)

    Huang, Xiaodong; Yang, Peirong; Li, Juan; Ding, Yu; Yao, Ru-en; Geng, Juan; Shen, Yongnian; Shen, Yiping; Fu, Qihua; Yu, Yongguo

    2013-01-01

    Objective To investigate potential functional variants in FTO and SH2B1 genes among Chinese children with obesity. Methods Sanger sequencing of PCR products of all FTO and SH2B1 exons and their flanking regions were performed in 338 Chinese Han children with obesity and 221 age- and sex-matched lean controls. Results A total of seven and five rare non-synonymous variants were identified in FTO and SH2B1, respectively. The overall frequencies of FTO and SH2B1 rare non-synonymous variants were similar in obese and lean children (2.37% and 0.90% vs. 1.81% and 1.36%, P>0.05). However, four out of the seven variants in FTO were novel and all were unique to obese children (p>0.05). None of the novel variants was consistently being predicted to be deleterious. Four out of five variants in SH2B1 were novel and one was unique to obese children (p>0.05). One variant (L293R) that was consistently being predicted as deleterious in SH2B1 gene was unique to lean control. While rare missense mutations were more frequently detected in girls from obesity as well as lean control than boys, the difference was not statistically significant. In addition, it's shown that the prevalence of rare missense mutations of FTO as well as SH2B1 was similar across different ethnic groups. Conclusion The rare missense mutations of FTO and SH2B1 did not confer risks of obesity in Chinese Han children in our cohort. PMID:23825611

  9. Evaluation of Extraction and Degradation Methods to Obtain Chickpeasaponin B1 from Chickpea (Cicer arietinum L.).

    Science.gov (United States)

    Cheng, Kun; Gao, Hua; Wang, Rong-Rong; Liu, Yang; Hou, Yu-Xue; Liu, Xiao-Hong; Liu, Kun; Wang, Wei

    2017-02-21

    The objective of this research is to implement extraction and degradation methods for the obtainment of 3-O-[α-l-rhamnopyranosyl-(1→2)-β-d-galactopyranosyl] soyasapogenol B (chickpeasaponin B1) from chickpea. The effects of microwave-assisted extraction (MAE) processing parameters-such as ethanol concentration, solvent/solid ratio, extraction temperature, microwave irradiation power, and irradiation time-were evaluated. Using 1g of material with 8 mL of 70% aqueous ethanol and an extraction time of 10 min at 70 °C under irradiation power 400W provided optimal extraction conditions. Compared with the conventional extraction techniques, including heat reflux extraction (HRE), Soxhlet extraction (SE), and ultrasonic extraction (UE), MAE produced higher extraction efficiency under a lower extraction time. DDMP (2,3-dihydro-2,5-dihydroxy-6-methyl-4H-pyran-4-one) saponin can be degraded to structurally stable saponin B by the loss of its DDMP group. The influence of pH and the concentration of potassium hydroxide on transformation efficiency of the target compound was investigated. A solution of 0.25 M potassium hydroxide in 75% aqueous ethanol was suitable for converting the corresponding DDMP saponins of chickpeasaponin B1. The implementation by the combining MAE technique and alkaline hydrolysis method for preparing chickpeasaponin B1 provides a convenient technology for future applications.

  10. Evaluation of Extraction and Degradation Methods to Obtain Chickpeasaponin B1 from Chickpea (Cicer arietinum L.

    Directory of Open Access Journals (Sweden)

    Kun Cheng

    2017-02-01

    Full Text Available The objective of this research is to implement extraction and degradation methods for the obtainment of 3-O-[α-l-rhamnopyranosyl-(1→2-β-d-galactopyranosyl] soyasapogenol B (chickpeasaponin B1 from chickpea. The effects of microwave-assisted extraction (MAE processing parameters—such as ethanol concentration, solvent/solid ratio, extraction temperature, microwave irradiation power, and irradiation time—were evaluated. Using 1g of material with 8 mL of 70% aqueous ethanol and an extraction time of 10 min at 70 °C under irradiation power 400W provided optimal extraction conditions. Compared with the conventional extraction techniques, including heat reflux extraction (HRE, Soxhlet extraction (SE, and ultrasonic extraction (UE, MAE produced higher extraction efficiency under a lower extraction time. DDMP (2,3-dihydro-2,5-dihydroxy-6-methyl-4H-pyran-4-one saponin can be degraded to structurally stable saponin B by the loss of its DDMP group. The influence of pH and the concentration of potassium hydroxide on transformation efficiency of the target compound was investigated. A solution of 0.25 M potassium hydroxide in 75% aqueous ethanol was suitable for converting the corresponding DDMP saponins of chickpeasaponin B1. The implementation by the combining MAE technique and alkaline hydrolysis method for preparing chickpeasaponin