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Sample records for b1 sox coordinate

  1. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  3. EphrinB1/EphB3b Coordinate Bidirectional Epithelial-Mesenchymal Interactions Controlling Liver Morphogenesis and Laterality

    DEFF Research Database (Denmark)

    Cayuso, Jordi; Dzementsei, Aliaksandr; Fischer, Johanna C

    2016-01-01

    Positioning organs in the body often requires the movement of multiple tissues, yet the molecular and cellular mechanisms coordinating such movements are largely unknown. Here, we show that bidirectional signaling between EphrinB1 and EphB3b coordinates the movements of the hepatic endoderm...... and adjacent lateral plate mesoderm (LPM), resulting in asymmetric positioning of the zebrafish liver. EphrinB1 in hepatoblasts regulates directional migration and mediates interactions with the LPM, where EphB3b controls polarity and movement of the LPM. EphB3b in the LPM concomitantly repels hepatoblasts...

  4. 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...... endocrine differentiation and maintaining pancreatic ductal identity, and it has recently been unveiled as a key player in the initiation of pancreatic cancer. These functions of Sox9 are discussed in this article, with special emphasis on the knowledge gained from various loss-of-function and lineage...

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

    Directory of Open Access Journals (Sweden)

    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.

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

    OpenAIRE

    Zhong , Lei; Yu , Xiaomu; Tong , Jingou

    2006-01-01

    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 h...

  7. SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas.

    Science.gov (United States)

    Watanabe, Hideo; Ma, Qiuping; Peng, Shouyong; Adelmant, Guillaume; Swain, Danielle; Song, Wenyu; Fox, Cameron; Francis, Joshua M; Pedamallu, Chandra Sekhar; DeLuca, David S; Brooks, Angela N; Wang, Su; Que, Jianwen; Rustgi, Anil K; Wong, Kwok-kin; Ligon, Keith L; Liu, X Shirley; Marto, Jarrod A; Meyerson, Matthew; Bass, Adam J

    2014-04-01

    The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. Conserved genomic organisation of Group B Sox genes in insects.

    Directory of Open Access Journals (Sweden)

    Woerfel Gertrud

    2005-05-01

    Full Text Available Abstract Background Sox domain containing genes are important metazoan transcriptional regulators implicated in a wide rage of developmental processes. The vertebrate B subgroup contains the Sox1, Sox2 and Sox3 genes that have early functions in neural development. Previous studies show that Drosophila Group B genes have been functionally conserved since they play essential roles in early neural specification and mutations in the Drosophila Dichaete and SoxN genes can be rescued with mammalian Sox genes. Despite their importance, the extent and organisation of the Group B family in Drosophila has not been fully characterised, an important step in using Drosophila to examine conserved aspects of Group B Sox gene function. Results We have used the directed cDNA sequencing along with the output from the publicly-available genome sequencing projects to examine the structure of Group B Sox domain genes in Drosophila melanogaster, Drosophila pseudoobscura, Anopheles gambiae and Apis mellifora. All of the insect genomes contain four genes encoding Group B proteins, two of which are intronless, as is the case with vertebrate group B genes. As has been previously reported and unusually for Group B genes, two of the insect group B genes, Sox21a and Sox21b, contain introns within their DNA-binding domains. We find that the highly unusual multi-exon structure of the Sox21b gene is common to the insects. In addition, we find that three of the group B Sox genes are organised in a linked cluster in the insect genomes. By in situ hybridisation we show that the pattern of expression of each of the four group B genes during embryogenesis is conserved between D. melanogaster and D. pseudoobscura. Conclusion The DNA-binding domain sequences and genomic organisation of the group B genes have been conserved over 300 My of evolution since the last common ancestor of the Hymenoptera and the Diptera. Our analysis suggests insects have two Group B1 genes, SoxN and

  10. Remarkable evolutionary conservation of SOX14 orthologues

    Indian Academy of Sciences (India)

    similar amino acid residues are shaded grey. N: N- terminus of SOX14, specific for B2 group of SOX proteins; HMG domain: High Mobility Group binding domain; GBHR: Group B Homology Region; B, C, E, F and G, SOX14 specific regions; A, h1, h2 and h3, SOX14/SOX21 homology regions. 1. SOX14 Homo sapiens, 2.

  11. Sox1 marks an activated neural stem/progenitor cell in the hippocampus

    OpenAIRE

    Venere, Monica; Han, Young-Goo; Bell, Robert; Song, Jun S.; Alvarez-Buylla, Arturo; Blelloch, Robert

    2012-01-01

    The dentate gyrus of the hippocampus continues generating new neurons throughout life. These neurons originate from radial astrocytes within the subgranular zone (SGZ). Here, we find that Sox1, a member of the SoxB1 family of transcription factors, is expressed in a subset of radial astrocytes. Lineage tracing using Sox1-tTA;tetO-Cre;Rosa26 reporter mice shows that the Sox1-expressing cells represent an activated neural stem/progenitor population that gives rise to most if not all newly born ...

  12. Unravelling pathways downstream Sox6 induction in K562 erythroid cells by proteomic analysis

    KAUST Repository

    Barbarani, Gloria

    2017-10-20

    The Sox6 transcription factor is crucial for terminal maturation of definitive red blood cells. Sox6-null mouse fetuses present misshapen and nucleated erythrocytes, due to impaired actin assembly and cytoskeleton stability. These defects are accompanied with a reduced survival of Sox6-/- red blood cells, resulting in a compensated anemia. Sox6-overexpression in K562 cells and in human primary ex vivo erythroid cultures enhances erythroid differentiation and leads to hemoglobinization, the hallmark of erythroid maturation. To obtain an overview on processes downstream to Sox6 expression, we performed a differential proteomic analysis on human erythroid K562 cells overexpressing Sox6. Sox6-overexpression induces dysregulation of 64 proteins, involved in cytoskeleton remodeling and in protein synthesis, folding and trafficking, key processes for erythroid maturation. Moreover, 43 out of 64 genes encoding for differentially expressed proteins contain within their proximal regulatory regions sites that are bound by SOX6 according to ENCODE ChIP-seq datasets and are possible direct SOX6 targets. SAR1B, one of the most induced proteins upon Sox6 overexpression, shares a conserved regulatory module, composed by a double SOX6 binding site and a GATA1 consensus, with the adjacent SEC24 A gene. Since both genes encode for COPII components, this element could concur to the coordinated expression of these proteins during erythropoiesis.

  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. 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

  15. 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 ...

  16. Parallel Expansions of Sox Transcription Factor Group B Predating the Diversifications of the Arthropods and Jawed Vertebrates

    Science.gov (United States)

    Zhong, Lei; Wang, Dengqiang; Gan, Xiaoni; Yang, Tong; He, Shunping

    2011-01-01

    Group B of the Sox transcription factor family is crucial in embryo development in the insects and vertebrates. Sox group B, unlike the other Sox groups, has an unusually enlarged functional repertoire in insects, but the timing and mechanism of the expansion of this group were unclear. We collected and analyzed data for Sox group B from 36 species of 12 phyla representing the major metazoan clades, with an emphasis on arthropods, to reconstruct the evolutionary history of SoxB in bilaterians and to date the expansion of Sox group B in insects. We found that the genome of the bilaterian last common ancestor probably contained one SoxB1 and one SoxB2 gene only and that tandem duplications of SoxB2 occurred before the arthropod diversification but after the arthropod-nematode divergence, resulting in the basal repertoire of Sox group B in diverse arthropod lineages. The arthropod Sox group B repertoire expanded differently from the vertebrate repertoire, which resulted from genome duplications. The parallel increases in the Sox group B repertoires of the arthropods and vertebrates are consistent with the parallel increases in the complexity and diversification of these two important organismal groups. PMID:21305035

  17. Genetics Home Reference: SOX2 anophthalmia syndrome

    Science.gov (United States)

    ... Twitter Home Health Conditions SOX2 anophthalmia syndrome SOX2 anophthalmia syndrome Printable PDF Open All Close All Enable ... to view the expand/collapse boxes. Description SOX2 anophthalmia syndrome is a rare disorder characterized by abnormal ...

  18. 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.

  19. Rhodium. Suppl. Vol. B1

    International Nuclear Information System (INIS)

    Griffith, W.P.; Jehn, H.; McCleverty, J.A.; Raub, C.J.; Robinson, S.D.

    1982-01-01

    The present rhodium vol. B1 is concerned largely with linary compounds and coordination complexes of this important metal, which is used either alone or in alloy form for fabrication of other materials or for heterogeneous catalysis. In first two chapters are devoted for hydrides, oxides, ternary and quaternary oxorhodates. Third chapter is on different type of complexes with nitrogen. From chapter four to seven is on halogen complexes with this metal. Next chapters are on sulphides, sulphoxide and sulphito complexes, sulphates and sulphato complexes, selenides and tellurides, borides, borane complexes, carbides, carbonato, cyno, fulminato and thiocyanato complexes. Finally, silicide, phosphides, phosphito and arsenides are treated over here. (AB)

  20. CYP7B1

    DEFF Research Database (Denmark)

    Roos, P; Svenstrup, K; Danielsen, E R

    2014-01-01

    UNLABELLED: The SPG5A subtype of Hereditary Spastic Paraplegia (HSP) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the CYP7B1 gene, which encodes a steroid cytochrome P450 7α-hydroxylase. This enzyme provides the primary metabolic route for neurosteroids. Clinica......UNLABELLED: The SPG5A subtype of Hereditary Spastic Paraplegia (HSP) is a rare autosomal recessive neurodegenerative disorder caused by mutations in the CYP7B1 gene, which encodes a steroid cytochrome P450 7α-hydroxylase. This enzyme provides the primary metabolic route for neurosteroids.......945_947 dupGGC p.A316AA). CONCLUSION: SPG5A could be characterized as a predominantly pure HSP. MRS showing elevated mI/Cr ratio in the white matter may be indicative of SPG5A....

  1. SOX2 anophthalmia syndrome and dental anomalies.

    Science.gov (United States)

    Chacon-Camacho, Oscar Francisco; Fuerte-Flores, Bertha Irene; Ricardez-Marcial, Edgar F; Zenteno, Juan Carlos

    2015-11-01

    SOX2 anophthalmia syndrome is an uncommon autosomal dominant syndrome caused by mutations in the SOX2 gene and clinically characterized by severe eye malformations (anophthalmia/microphthalmia) and extraocular anomalies mainly involving brain, esophagus, and genitalia. In this work, a patient with the SOX2 anophthalmia syndrome and exhibiting a novel dental anomaly is described. SOX2 genotyping in this patient revealed an apparently de novo c.70del20 deletion, a commonly reported SOX2 mutation. A review of the phenotypic variation observed in patients carrying the recurrent SOX2 c.70del20 mutation is presented. Although dental anomalies are uncommonly reported in the SOX2 anophthalmia syndrome, we suggest that a dental examination should be performed in patients with SOX2 mutations. © 2015 Wiley Periodicals, Inc.

  2. Electroporation-mediated transfer of SOX trio genes (SOX-5, SOX-6, and SOX-9) to enhance the chondrogenesis of mesenchymal stem cells.

    Science.gov (United States)

    Kim, Hye-Joung; Im, Gun-Il

    2011-12-01

    The purpose of this study was to test the hypothesis that the SOX trio genes (SOX-5, SOX-6, and SOX-9) have a lower level of expression during the chondrogenic differentiation of mesenchymal stem cells (MSCs) compared with chondrocytes and that the electroporation-mediated gene transfer of SOX trio promotes chondrogenesis from human MSCs. An in vitro pellet culture was carried out using MSCs or chondrocytes at passage 3 and analyzed after 7 and 21 days. Then, MSCs were transfected with SOX trio genes and analyzed for the expression of chondrogenic markers after 21 days of in vitro culture. Without transforming growth factor-β1, the untransfected MSCs had a lower level of SOX trio gene and protein expression than chondrocytes. However, the level of SOX-9 gene expression increased in MSCs when treated with transforming growth factor-β1. GAG level significantly increased 7-fold in MSCs co-transfected with SOX trio, which was corroborated by Safranin-O staining. SOX trio co-transfection significantly increased COL2A1 gene and protein and decreased COL10A1 protein in MSCs. It is concluded that the SOX trio have a significantly lower expression in human MSCs than in chondrocytes and that the electroporation-mediated co-transfection of SOX trio enhances chondrogenesis and suppresses hypertrophy of human MSCs.

  3. 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...... in the clinical bladder material and a small subset of the genes showed a high correlation to SOX4 expression. The present data suggest a role of SOX4 in the bladder cancer disease....... the SOX4 protein and, thus, did an evaluation of SOX4 protein expression in 2,360 bladder tumors using a tissue microarray with clinical annotation. We found a correlation (P bladder cell line HU609, SOX4...

  4. 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...... of aerogel as a material for window applications3. Construction of an aerogel DGU and measurement of key performance parameters. The goal for the aerogel DGU was to reach a Total Solar Energy Transmittance above 0.75 and a U-value below 0.5 W/m²K. These are values that can not be simultaneously reached......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...

  5. 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

  6. Cross-species functional analyses reveal shared and separate roles for Sox11 in frog primary neurogenesis and mouse cortical neuronal differentiation

    Directory of Open Access Journals (Sweden)

    Chao Chen

    2016-04-01

    Full Text Available A well-functioning brain requires production of the correct number and types of cells during development; cascades of transcription factors are essential for cellular coordination. Sox proteins are transcription factors that affect various processes in the development of the nervous system. Sox11, a member of the SoxC family, is expressed in differentiated neurons and supports neuronal differentiation in several systems. To understand how generalizable the actions of Sox11 are across phylogeny, its function in the development of the frog nervous system and the mouse cerebral cortex were compared. Expression of Sox11 is largely conserved between these species; in the developing frog, Sox11 is expressed in the neural plate, neural tube and throughout the segmented brain, while in the mouse cerebral cortex, Sox11 is expressed in differentiated zones, including the preplate, subplate, marginal zone and cortical plate. In both frog and mouse, data demonstrate that Sox11 supports a role in promoting neuronal differentiation, with Sox11-positive cells expressing pan-neural markers and becoming morphologically complex. However, frog and mouse Sox11 cannot substitute for one another; a functional difference likely reflected in sequence divergence. Thus, Sox11 appears to act similarly in subserving neuronal differentiation but is species-specific in frog neural development and mouse corticogenesis.

  7. Redundant roles of Sox17 and Sox18 in early cardiovascular development of mouse embryos

    International Nuclear Information System (INIS)

    Sakamoto, Youhei; Hara, Kenshiro; Kanai-Azuma, Masami; Matsui, Toshiyasu; Miura, Yutaroh; Tsunekawa, Naoki; Kurohmaru, Masamichi; Saijoh, Yukio; Koopman, Peter; Kanai, Yoshiakira

    2007-01-01

    Sox7, -17 and -18 constitute the Sox subgroup F (SoxF) of HMG box transcription factor genes, which all are co-expressed in developing vascular endothelial cells in mice. Here we characterized cardiovascular phenotypes of Sox17/Sox18-double and Sox17-single null embryos during early-somite stages. Whole-mount PECAM staining demonstrated the aberrant heart looping, enlarged cardinal vein and mild defects in anterior dorsal aorta formation in Sox17 single-null embryos. The Sox17/Sox18 double-null embryos showed more severe defects in formation of anterior dorsal aorta and head/cervical microvasculature, and in some cases, aberrant differentiation of endocardial cells and defective fusion of the endocardial tube. However, the posterior dorsal aorta and allantoic microvasculature was properly formed in all of the Sox17/Sox18 double-null embryos. The anomalies in both anterior dorsal aorta and head/cervical vasculature corresponded with the weak Sox7 expression sites. This suggests the region-specific redundant activities of three SoxF members along the anteroposterior axis of embryonic vascular network

  8. [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.

  9. SoxB2 in sea urchin development: implications in neurogenesis, ciliogenesis and skeletal patterning.

    Science.gov (United States)

    Anishchenko, Evgeniya; Arnone, Maria Ina; D'Aniello, Salvatore

    2018-01-01

    Current studies in evolutionary developmental biology are focused on the reconstruction of gene regulatory networks in target animal species. From decades, the scientific interest on genetic mechanisms orchestrating embryos development has been increasing in consequence to the fact that common features shared by evolutionarily distant phyla are being clarified. In 2011, a study across eumetazoan species showed for the first time the existence of a highly conserved non-coding element controlling the SoxB2 gene, which is involved in the early specification of the nervous system. This discovery raised several questions about SoxB2 function and regulation in deuterostomes from an evolutionary point of view. Due to the relevant phylogenetic position within deuterostomes, the sea urchin Strongylocentrotus purpuratus represents an advantageous animal model in the field of evolutionary developmental biology. Herein, we show a comprehensive study of SoxB2 functions in sea urchins, in particular its expression pattern in a wide range of developmental stages, and its co-localization with other neurogenic markers, as SoxB1 , SoxC and Elav . Moreover, this work provides a detailed description of the phenotype of sea urchin SoxB2 knocked-down embryos, confirming its key function in neurogenesis and revealing, for the first time, its additional roles in oral and aboral ectoderm cilia and skeletal rod morphology. We concluded that SoxB2 in sea urchins has a neurogenic function; however, this gene could have multiple roles in sea urchin embryogenesis, expanding its expression in non-neurogenic cells. We showed that SoxB2 is functionally conserved among deuterostomes and suggested that in S. purpuratus this gene acquired additional functions, being involved in ciliogenesis and skeletal patterning.

  10. Sox2 Suppresses Gastric Tumorigenesis in Mice

    Directory of Open Access Journals (Sweden)

    Abby Sarkar

    2016-08-01

    Full Text Available Sox2 expression marks gastric stem and progenitor cells, raising important questions regarding the genes regulated by Sox2 and the role of Sox2 itself during stomach homeostasis and disease. By using ChIP-seq analysis, we have found that the majority of Sox2 targets in gastric epithelial cells are tissue specific and related to functions such as endoderm development, Wnt signaling, and gastric cancer. Unexpectedly, we found that Sox2 itself is dispensable for gastric stem cell and epithelial self-renewal, yet Sox2+ cells are highly susceptible to tumorigenesis in an Apc/Wnt-driven mouse model. Moreover, Sox2 loss enhances, rather than impairs, tumor formation in Apc-deficient gastric cells in vivo and in vitro by inducing Tcf/Lef-dependent transcription and upregulating intestinal metaplasia-associated genes, providing a mechanistic basis for the observed phenotype. Together, these data identify Sox2 as a context-dependent tumor suppressor protein that is dispensable for normal tissue regeneration but restrains stomach adenoma formation through modulation of Wnt-responsive and intestinal genes.

  11. Hyperphagia, mild developmental delay but apparently no structural brain anomalies in a boy without SOX3 expression.

    Science.gov (United States)

    Helle, Johan Robert; Barøy, Tuva; Misceo, Doriana; Braaten, Øivind; Fannemel, Madeleine; Frengen, Eirik

    2013-05-01

    The transcription factor SOX3 is widely expressed in early vertebrate brain development. In humans, duplication of SOX3 and polyalanine expansions at its C-terminus may cause intellectual disability and hypopituitarism. Sox3 knock-out mice show a variable phenotype including structural and functional anomalies affecting the branchial arches and midline cerebral structures such as the optic chiasm and the hypothalamo-pituitary axis. SOX3 is claimed to be required in normal brain development and function in mice and humans, as well as in pituitary and craniofacial development. We report on an 8-year-old boy with a 2.1 Mb deletion in Xq27.1q27.2, which was found to be inherited from his healthy mother. To our knowledge, this is the smallest deletion including the entire SOX3 gene in a male reported to date. He is mildly intellectually disabled with language delay, dysarthria, behavior problems, minor facial anomalies, and hyperphagia. Hormone levels including growth, adrenocorticotropic and thyroid stimulating hormones are normal. Magnetic resonance imaging (MRI) at age 6 years showed no obvious brain anomalies. Genetic redundancy between the three members of the B1 subfamily of SOX proteins during early human brain development likely explains the apparently normal development of brain structures in our patient who is nullisomic for SOX3. Copyright © 2012 Wiley Periodicals, Inc.

  12. 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.

  13. Cloning and analysis of the HMG domains of ten Sox genes from ...

    African Journals Online (AJOL)

    Sox is a large gene family which encodes Sry-related transcription factors and contains a HMG box that is responsible for the sequence-specific DNA binding. In this paper, we obtained ten clones representing HMG box-containing Sox genes (BmSox1a, BmSox1b, BmSox3a, BmSox3b, BmSox3c, BmSox11a, BmSox11b, ...

  14. 76 FR 4724 - Catawba Sox, LLC Formerly Known as Catawba Sox, Inc. Including Workers Whose Unemployment...

    Science.gov (United States)

    2011-01-26

    ... Known as Catawba Sox, Inc. Including Workers Whose Unemployment Insurance UI) Wages Are Paid Through...., had their wages reported under a separated unemployment insurance (UI) tax account under the name..., LLC, formerly known as Catawba Sox, Inc., including workers whose unemployment insurance (UI) wages...

  15. Zinc finger protein 219-like (ZNF219L) and Sox9a regulate synuclein-γ2 (sncgb) expression in the developing notochord of zebrafish.

    Science.gov (United States)

    Lien, Huang-Wei; Yang, Chung-Hsiang; Cheng, Chia-Hsiung; Liao, Yung-Feng; Han, Yu-San; Huang, Chang-Jen

    2013-12-13

    Zebrafish synuclein-γ2 (sncgb) has been reported to be expressed specifically in the notochord. However, the mechanism by which the sncgb gene promoter is regulated has not been described. In this paper, we demonstrate that Zinc finger protein 219-like (ZNF219L) and sox9a are involved in the regulation of sncgb gene expression. Furthermore, we observed that over-expression of both ZNF219L and Sox9a resulted in increased sncgb expression. In addition, ZNF219L is physically associated with Sox9a, and simultaneous morpholino knockdown of znf219L and sox9a caused a synergistic decrease of sncgb expression in the notochord. Taken together, our results reveal that coordination of ZNF219L with Sox9a is involved in the regulation of notochord-specific expression of sncgb. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

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

    Science.gov (United States)

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

    2017-10-31

    The study aimed to investigate the effects of Sry-like high mobility group box 15 ( SOX15 ) on proliferation and migration of endometrial cancer (EC) cells. Immunohistochemistry (IHC) 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 down-regulation of SOX15 increased cell proliferation. Flow cytometry results indicated that overexpression of SOX15 induced the ratio of cell-cycle arrest in G 1 stage. In addition, Transwell migration assay results showed that SOX15 overexpression significantly inhibited cell migration, and also down-regulation of SOX15 promoted the migration. As a whole, SOX15 could regulate the proliferation and migration of EC cells and up- regulation of SOX15 could be valuable for EC treatment. © 2017 The Author(s).

  17. SOX1 links the function of neural patterning and Notch signalling in the ventral spinal cord during the neuron-glial fate switch

    Energy Technology Data Exchange (ETDEWEB)

    Genethliou, Nicholas; Panayiotou, Elena [The Cyprus Institute of Neurology and Genetics, Airport Avenue, No. 6, Agios Dometios, 2370 Nicosia (Cyprus); Department of Biological Sciences, University of Cyprus, P.O. Box 20537, 1678 Nicosia (Cyprus); Panayi, Helen; Orford, Michael; Mean, Richard; Lapathitis, George; Gill, Herman; Raoof, Sahir [The Cyprus Institute of Neurology and Genetics, Airport Avenue, No. 6, Agios Dometios, 2370 Nicosia (Cyprus); Gasperi, Rita De; Elder, Gregory [James J. Peters VA Medical Center, Research and Development (3F22), 130 West Kingsbridge Road, Bronx, NY 10468 (United States); Kessaris, Nicoletta; Richardson, William D. [Wolfson Institute for Biomedical Research and Research Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT (United Kingdom); Malas, Stavros, E-mail: smalas@cing.ac.cy [The Cyprus Institute of Neurology and Genetics, Airport Avenue, No. 6, Agios Dometios, 2370 Nicosia (Cyprus); Department of Biological Sciences, University of Cyprus, P.O. Box 20537, 1678 Nicosia (Cyprus)

    2009-12-25

    During neural development the transition from neurogenesis to gliogenesis, known as the neuron-glial ({Nu}/G) fate switch, requires the coordinated function of patterning factors, pro-glial factors and Notch signalling. How this process is coordinated in the embryonic spinal cord is poorly understood. Here, we demonstrate that during the N/G fate switch in the ventral spinal cord (vSC) SOX1 links the function of neural patterning and Notch signalling. We show that, SOX1 expression in the vSC is regulated by PAX6, NKX2.2 and Notch signalling in a domain-specific manner. We further show that SOX1 regulates the expression of Hes1 and that loss of Sox1 leads to enhanced production of oligodendrocyte precursors from the pMN. Finally, we show that Notch signalling functions upstream of SOX1 during this fate switch and is independently required for the acquisition of the glial fate perse by regulating Nuclear Factor I A expression in a PAX6/SOX1/HES1/HES5-independent manner. These data integrate functional roles of neural patterning factors, Notch signalling and SOX1 during gliogenesis.

  18. Two-stage gene regulation of the superoxide stress response soxRS system in Escherichia coli.

    Science.gov (United States)

    Nunoshiba, T

    1996-01-01

    All organisms have adapted to environmental changes by acquiring various functions controlled by gene regulation. In bacteria, a number of specific responses have been found to confer cell survival in various nutrient-limited conditions, and under physiological stresses such as high or low temperature, extreme pH, radiation, and oxidation (for review, see Neidhardt et al., 1987). In this article, I introduce an Escherichia coli (E. coli) global response induced by superoxide stress, the soxRS regulon. The functions controlled by this system consist of a wide variety of enzymes such as manganese-containing SOD (Mn-SOD); glucose 6-phosphate dehydrogenase (G6PD), the DNA repair enzyme endonuclease IV, fumarase C, NADPH:ferredoxin oxidoreductase, and aconitase. This response is positively regulated by a two-stage control system in which SoxR iron-sulfur protein senses exposure to superoxide and nitric oxide, and then activates transcription of the soxS gene, whose product stimulates the expression of the regulon genes. Our recent finding indicates that soxS transcription is initiated in a manner dependent on the rpoS gene encoding RNA polymerase sigma factor, theta s, in response to entering the stationary phase of growth. With this information, mechanisms for prokaryotic coordinating gene expression in response to superoxide stress and in stationary phase are discussed.

  19. Sox9 induces testis development in XX transgenic mice

    NARCIS (Netherlands)

    Vidal, V. P.; Chaboissier, M. C.; de rooij, D. G.; Schedl, A.

    2001-01-01

    Mutations in SOX9 are associated with male-to-female sex reversal in humans. To analyze Sox9 function during sex determination, we ectopically expressed this gene in XX gonads. Here, we show that Sox9 is sufficient to induce testis formation in mice, indicating that it can substitute for the

  20. (SOXS) Mission Amish B. Shah , NM

    Indian Academy of Sciences (India)

    to estimate correct thresholds for flare detection. Memory check-out and read out modes are usable for on-board diagnosis. 2.4 Data communication. This package provides a common interface to all SOXS packages with spacecraft bus. It minimizes the chance of damage of mainframe bus because of anomaly in packages.

  1. Sox6 directly silences epsilon globin expression in definitive erythropoiesis.

    Directory of Open Access Journals (Sweden)

    2006-02-01

    Full Text Available Sox6 is a member of the Sox transcription factor family that is defined by the conserved high mobility group (HMG DNA binding domain, first described in the testis determining gene, Sry. Previous studies have suggested that Sox6 plays a role in the development of the central nervous system, cartilage, and muscle. In the Sox6-deficient mouse, p100H, epsilony globin is persistently expressed, and increased numbers of nucleated red cells are present in the fetal circulation. Transfection assays in GM979 (erythroleukemic cells define a 36-base pair region of the epsilony proximal promoter that is critical for Sox6 mediated repression. Electrophoretic mobility shift assay (EMSA and chromatin immunoprecipitation (ChIP assays demonstrate that Sox6 acts as a repressor by directly binding to the epsilony promoter. The normal expression of Sox6 in wild-type fetal liver and the ectopic expression of epsilony in p100H homozygous fetal liver demonstrate that Sox6 functions in definitive erythropoiesis. The present study shows that Sox6 is required for silencing of epsilony globin in definitive erythropoiesis and suggests a role for Sox6 in erythroid cell maturation. Thus, Sox6 regulation of epsilony globin might provide a novel therapeutical target in the treatment of hemoglobinopathies such as sickle cell anemia and thalassemia.

  2. 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.

  3. Generation of a human iPSC line from a patient with congenital glaucoma caused by mutation in CYP1B1 gene

    Directory of Open Access Journals (Sweden)

    Arantxa Bolinches-Amorós

    2018-04-01

    Full Text Available The human iPSC cell line, GLC-FiPS4F1 (ESi047-A, derived from dermal fibroblast from the patient with congenital glaucoma caused by the mutation of the gene CYP1B1, was generated by non-integrative reprogramming technology using OCT3/4, SOX2, CMYC and KLF4 reprogramming factors.

  4. Molecular basis for the genome engagement by Sox proteins.

    Science.gov (United States)

    Hou, Linlin; Srivastava, Yogesh; Jauch, Ralf

    2017-03-01

    The Sox transcription factor family consists of 20 members in the human genome. Many of them are key determinants of cellular identities and possess the capacity to reprogram cell fates by pioneering the epigenetic remodeling of the genome. This activity is intimately tied to their ability to specifically bind and bend DNA alone or with other proteins. Here we discuss our current knowledge on how Sox transcription factors such as Sox2, Sox17, Sox18 and Sox9 'read' the genome to find and regulate their target genes and highlight the roles of partner factors including Pax6, Nanog, Oct4 and Brn2. We integrate insights from structural and biochemical studies as well as high-throughput assays to probe DNA specificity in vitro as well as in cells and tissues. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  5. 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: (a...

  6. 7 CFR 15b.1 - Purpose.

    Science.gov (United States)

    2010-01-01

    ... FEDERAL FINANCIAL ASSISTANCE General Provisions § 15b.1 Purpose. The purpose of this part is to implement... 7 Agriculture 1 2010-01-01 2010-01-01 false Purpose. 15b.1 Section 15b.1 Agriculture Office of the... receiving Federal financial assistance. ...

  7. 15 CFR 8b.1 - Purpose.

    Science.gov (United States)

    2010-01-01

    ... of handicap in any program or activity receiving Federal financial assistance. The purpose of this... 15 Commerce and Foreign Trade 1 2010-01-01 2010-01-01 false Purpose. 8b.1 Section 8b.1 Commerce... HANDICAPPED IN FEDERALLY ASSISTED PROGRAMS OPERATED BY THE DEPARTMENT OF COMMERCE General Provisions § 8b.1...

  8. The dark side of SOX2: cancer - a comprehensive overview.

    Science.gov (United States)

    Wuebben, Erin L; Rizzino, Angie

    2017-07-04

    The pluripotency-associated transcription factor SOX2 is essential during mammalian embryogenesis and later in life, but SOX2 expression can also be highly detrimental. Over the past 10 years, SOX2 has been shown to be expressed in at least 25 different cancers. This review provides a comprehensive overview of the roles of SOX2 in cancer and focuses on two broad topics. The first delves into the expression and function of SOX2 in cancer focusing on the connection between SOX2 levels and tumor grade as well as patient survival. As part of this discussion, we address the developing connection between SOX2 expression and tumor drug resistance. We also call attention to an under-appreciated property of SOX2, its levels in actively proliferating tumor cells appear to be optimized to maximize tumor growth - too little or too much SOX2 dramatically alters tumor growth. The second topic of this review focuses on the exquisite array of molecular mechanisms that control the expression and transcriptional activity of SOX2. In addition to its complex regulation at the transcriptional level, SOX2 expression and activity are controlled carefully by microRNAs, long non-coding RNAs, and post-translational modifications. In the Conclusion and Future Perspectives section, we point out that there are still important unanswered questions. Addressing these questions is expected to lead to new insights into the functions of SOX2 in cancer, which will help design novels strategies for more effectively treating some of the most deadly cancers.

  9. Time for a second look at SOX compliance.

    Science.gov (United States)

    Bigalke, John T; Burrill, Stephen J

    2007-08-01

    Incentives for tax-exempt healthcare organizations to comply with the Sarbanes-Oxley Act (SOX) abound from many quarters, including government, various associations, and the capital markets. New proposals from the Securities and Exchange Commission and the Public Company Accountability Oversight Board will streamline the processes of SOX compliance, even as the cost of compliance is dropping. Voluntary SOX compliance can best be achieved by adopting a four-phased control rationalization approach to implementation and maintenance.

  10. SOX9 regulates ERBB signalling in pancreatic cancer development.

    Science.gov (United States)

    Grimont, Adrien; Pinho, Andreia V; Cowley, Mark J; Augereau, Cécile; Mawson, Amanda; Giry-Laterrière, Marc; Van den Steen, Géraldine; Waddell, Nicola; Pajic, Marina; Sempoux, Christine; Wu, Jianmin; Grimmond, Sean M; Biankin, Andrew V; Lemaigre, Frédéric P; Rooman, Ilse; Jacquemin, Patrick

    2015-11-01

    The transcription factor SOX9 was recently shown to stimulate ductal gene expression in pancreatic acinar-to-ductal metaplasia and to accelerate development of premalignant lesions preceding pancreatic ductal adenocarcinoma (PDAC). Here, we investigate how SOX9 operates in pancreatic tumourigenesis. We analysed genomic and transcriptomic data from surgically resected PDAC and extended the expression analysis to xenografts from PDAC samples and to PDAC cell lines. SOX9 expression was manipulated in human cell lines and mouse models developing PDAC. We found genetic aberrations in the SOX9 gene in about 15% of patient tumours. Most PDAC samples strongly express SOX9 protein, and SOX9 levels are higher in classical PDAC. This tumour subtype is associated with better patient outcome, and cell lines of this subtype respond to therapy targeting epidermal growth factor receptor (EGFR/ERBB1) signalling, a pathway essential for pancreatic tumourigenesis. In human PDAC, high expression of SOX9 correlates with expression of genes belonging to the ERBB pathway. In particular, ERBB2 expression in PDAC cell lines is stimulated by SOX9. Inactivating Sox9 expression in mice confirmed its role in PDAC initiation; it demonstrated that Sox9 stimulates expression of several members of the ERBB pathway and is required for ERBB signalling activity. By integrating data from patient samples and mouse models, we found that SOX9 regulates the ERBB pathway throughout pancreatic tumourigenesis. Our work opens perspectives for therapy targeting tumourigenic mechanisms. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  11. Deciphering the Sox-Oct partner code by quantitative cooperativity measurements.

    Science.gov (United States)

    Ng, Calista K L; Li, Noel X; Chee, Sheena; Prabhakar, Shyam; Kolatkar, Prasanna R; Jauch, Ralf

    2012-06-01

    Several Sox-Oct transcription factor (TF) combinations have been shown to cooperate on diverse enhancers to determine cell fates. Here, we developed a method to quantify biochemically the Sox-Oct cooperation and assessed the pairing of the high-mobility group (HMG) domains of 11 Sox TFs with Oct4 on a series of composite DNA elements. This way, we clustered Sox proteins according to their dimerization preferences illustrating that Sox HMG domains evolved different propensities to cooperate with Oct4. Sox2, Sox14, Sox21 and Sox15 strongly cooperate on the canonical element but compete with Oct4 on a recently discovered compressed element. Sry also cooperates on the canonical element but binds additively to the compressed element. In contrast, Sox17 and Sox4 cooperate more strongly on the compressed than on the canonical element. Sox5 and Sox18 show some cooperation on both elements, whereas Sox8 and Sox9 compete on both elements. Testing rationally mutated Sox proteins combined with structural modeling highlights critical amino acids for differential Sox-Oct4 partnerships and demonstrates that the cooperativity correlates with the efficiency in producing induced pluripotent stem cells. Our results suggest selective Sox-Oct partnerships in genome regulation and provide a toolset to study protein cooperation on DNA.

  12. 45 CFR 73b.1 - Scope.

    Science.gov (United States)

    2010-10-01

    ... 45 Public Welfare 1 2010-10-01 2010-10-01 false Scope. 73b.1 Section 73b.1 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION DEBARMENT OR SUSPENSION OF FORMER EMPLOYEES... officer or employee of the Department, including former and retired officers of the commissioned corps of...

  13. Sox21 deletion in mice causes postnatal growth deficiency without physiological disruption of hypothalamic-pituitary endocrine axes.

    Science.gov (United States)

    Cheung, Leonard Y M; Okano, Hideyuki; Camper, Sally A

    2017-01-05

    The hypothalamic-pituitary axes are the coordinating centers for multiple endocrine gland functions and physiological processes. Defects in the hypothalamus or pituitary gland can cause reduced growth and severe short stature, affecting approximately 1 in 4000 children, and a large percentage of cases of pituitary hormone deficiencies do not have an identified genetic cause. SOX21 is a protein that regulates hair, neural, and trophoblast stem cell differentiation. Mice lacking Sox21 have reduced growth, but the etiology of this growth defect has not been described. We studied the expression of Sox21 in hypothalamic-pituitary development and examined multiple endocrine axes in these mice. We find no evidence of reduced intrauterine growth, food intake, or physical activity, but there is evidence for increased energy expenditure in mutants. In addition, despite changes in pituitary hormone expression, hypothalamic-pituitary axes appear to be functional. Therefore, SOX21 variants may be a cause of non-endocrine short stature in humans. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. 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.

  15. 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.

  16. 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(GFPC...

  17. De novo SOX11 mutations cause Coffin-Siris syndrome.

    Science.gov (United States)

    Tsurusaki, Yoshinori; Koshimizu, Eriko; Ohashi, Hirofumi; Phadke, Shubha; Kou, Ikuyo; Shiina, Masaaki; Suzuki, Toshifumi; Okamoto, Nobuhiko; Imamura, Shintaro; Yamashita, Michiaki; Watanabe, Satoshi; Yoshiura, Koh-ichiro; Kodera, Hirofumi; Miyatake, Satoko; Nakashima, Mitsuko; Saitsu, Hirotomo; Ogata, Kazuhiro; Ikegawa, Shiro; Miyake, Noriko; Matsumoto, Naomichi

    2014-06-02

    Coffin-Siris syndrome (CSS) is a congenital disorder characterized by growth deficiency, intellectual disability, microcephaly, characteristic facial features and hypoplastic nails of the fifth fingers and/or toes. We previously identified mutations in five genes encoding subunits of the BAF complex, in 55% of CSS patients. Here we perform whole-exome sequencing in additional CSS patients, identifying de novo SOX11 mutations in two patients with a mild CSS phenotype. sox11a/b knockdown in zebrafish causes brain abnormalities, potentially explaining the brain phenotype of CSS. SOX11 is the downstream transcriptional factor of the PAX6-BAF complex, highlighting the importance of the BAF complex and SOX11 transcriptional network in brain development.

  18. MR fingerprinting with simultaneous B1 estimation.

    Science.gov (United States)

    Buonincontri, Guido; Sawiak, Stephen J

    2016-10-01

    MR fingerprinting (MRF) can be used for quantitative estimation of physical parameters in MRI. Here, we extend the method to incorporate B1 estimation. The acquisition is based on steady state free precession MR fingerprinting with a Cartesian trajectory. To increase the sensitivity to the B1 profile, abrupt changes in flip angle were introduced in the sequence. Slice profile and B1 effects were included in the dictionary and the results from two- and three-dimensional (3D) acquisitions were compared. Acceleration was demonstrated using retrospective undersampling in the phase encode directions of 3D data exploiting redundancy between MRF frames at the edges of k-space. Without B1 estimation, T2 and B1 were inaccurate by more than 20%. Abrupt changes in flip angle improved B1 maps. T1 and T2 values obtained with the new MRF methods agree with classical spin echo measurements and are independent of the B1 field profile. When using view sharing reconstruction, results remained accurate (error Reson Med 76:1127-1135, 2016. © 2015 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2015 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.

  19. SOX2 regulates acinar cell development in the salivary gland

    Science.gov (United States)

    Emmerson, Elaine; May, Alison J; Nathan, Sara; Cruz-Pacheco, Noel; Lizama, Carlos O; Maliskova, Lenka; Zovein, Ann C; Shen, Yin; Muench, Marcus O; Knox, Sarah M

    2017-01-01

    Acinar cells play an essential role in the secretory function of exocrine organs. Despite this requirement, how acinar cells are generated during organogenesis is unclear. Using the acini-ductal network of the developing human and murine salivary gland, we demonstrate an unexpected role for SOX2 and parasympathetic nerves in generating the acinar lineage that has broad implications for epithelial morphogenesis. Despite SOX2 being expressed by progenitors that give rise to both acinar and duct cells, genetic ablation of SOX2 results in a failure to establish acini but not ducts. Furthermore, we show that SOX2 targets acinar-specific genes and is essential for the survival of acinar but not ductal cells. Finally, we illustrate an unexpected and novel role for peripheral nerves in the creation of acini throughout development via regulation of SOX2. Thus, SOX2 is a master regulator of the acinar cell lineage essential to the establishment of a functional organ. DOI: http://dx.doi.org/10.7554/eLife.26620.001 PMID:28623666

  20. Structural basis for the SOX-dependent genomic redistribution of OCT4 in stem cell differentiation.

    Science.gov (United States)

    Merino, Felipe; Ng, Calista Keow Leng; Veerapandian, Veeramohan; Schöler, Hans Robert; Jauch, Ralf; Cojocaru, Vlad

    2014-09-02

    In pluripotent cells, OCT4 associates with SOX2 to maintain pluripotency or with SOX17 to induce primitive endoderm commitment. The OCT4-SOX2 and OCT4-SOX17 combinations bind mutually exclusive to two distinct composite DNA elements, known as the "canonical" and "compressed" motifs, respectively. The structural basis for the OCT4-SOX17 cooperativity is unknown. Whereas SOX17 has been engineered to replace SOX2 in the pluripotency circuitry, all generated SOX2 mutants have failed to act like SOX17. From molecular simulations, we revealed the OCT4-SOX17 interaction interface and elucidated the SOX-dependent motif preference of OCT4. Moreover, we designed a SOX2 mutant that we predicted and confirmed experimentally to bind cooperatively with OCT4 to the compressed motif. Ultimately, we found a strong correlation between the experimental and calculated relative cooperative-binding free energies of 12 OCT4-SOX-DNA complexes. Therefore, we validated the OCT4-SOX interfaces and demonstrated that in silico design of DNA-binding cooperativity is suitable for altering transcriptional circuitries. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Identification and characterization of the human SOX6 promoter

    International Nuclear Information System (INIS)

    Ikeda, Toshiyuki; Saito, Taku; Ushita, Masahiro; Yano, Fumiko; Kan, Akinori; Itaka, Keiji; Moro, Toru; Nakamura, Kozo; Kawaguchi, Hiroshi; Chung, Ung-il

    2007-01-01

    The present study attempted to identify and characterize the embryonic promoter of Sox6, a determinant regulator of chondrogenic differentiation. A common transcription start region for human and mouse Sox6 was initially identified, which contained a highly conserved sequence, A-box. Tandem repeats of A-box had a strong transcriptional activity both at the basal level and in response to Sox9. Cells carrying the 4xA-box-DsRed2 reporter fluoresced only upon chondrogenic differentiation. The 46-bp core enhancer region (CES6) was then identified in the 3' half of A-box, within which a C/EBP-binding motif was identified. Overexpressed C/EBPβ activated the Sox6 promoter, and mutant 4xCES6 constructs lacking the C/EBP motif lost their basal activity. CES6 and nuclear extracts formed a specific complex, which was supershifted by anti-C/EBPβ antibody, and in vitro translated C/EBPβ specifically bound to CES6. Thus, we successfully identified the Sox6 promoter and its core enhancer and characterized the interactions with regulatory transcription factors

  2. Evolutionarily Conserved, Growth Plate Zone-Specific Regulation of the Matrilin-1 Promoter: L-Sox5/Sox6 and Nfi Factors Bound near TATA Finely Tune Activation by Sox9 ▿

    Science.gov (United States)

    Nagy, Andrea; Kénesi, Erzsébet; Rentsendorj, Otgonchimeg; Molnár, Annamária; Szénási, Tibor; Sinkó, Ildikó; Zvara, Ágnes; Thottathil Oommen, Sajit; Barta, Endre; Puskás, László G.; Lefebvre, Veronique; Kiss, Ibolya

    2011-01-01

    To help uncover the mechanisms underlying the staggered expression of cartilage-specific genes in the growth plate, we dissected the transcriptional mechanisms driving expression of the matrilin-1 gene (Matn1). We show that a unique assembly of evolutionarily conserved cis-acting elements in the Matn1 proximal promoter restricts expression to the proliferative and prehypertrophic zones of the growth plate. These elements functionally interact with distal elements and likewise are capable of restricting the domain of activity of a pancartilaginous Col2a1 enhancer. The proximal elements include a Pe1 element binding the chondrogenic L-Sox5, Sox6, and Sox9 proteins, a SI element binding Nfi proteins, and an initiator Ine element binding the Sox trio and other factors. Sox9 binding to Pe1 is indispensable for functional interaction with the distal promoter. Binding of L-Sox5/Sox6 to Ine and Nfib to SI modulates Sox9 transactivation in a protein dose-dependent manner, possibly to enhance Sox9 activity in early stages of chondrogenesis and repress it at later stages. Hence, our data suggest a novel model whereby Sox and Nfi proteins bind to conserved Matn1 proximal elements and functionally interact with each other to finely tune gene expression in specific zones of the cartilage growth plate. PMID:21173167

  3. 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

  4. SOXs in human prostate cancer: implication as progression and prognosis factors

    International Nuclear Information System (INIS)

    Zhong, Wei-de; Chen, Xi-bin; Lin, Zhuo-yuan; Deng, Ye-han; Wu, Shu-lin; He, Hui-chan; Wu, Chin-lee; Qin, Guo-qiang; Dai, Qi-shan; Han, Zhao-dong; Chen, Shan-ming; Ling, Xiao-hui; Fu, Xin; Cai, Chao; Chen, Jia-hong

    2012-01-01

    SOX genes play an important role in a number of developmental processes. Potential roles of SOXs have been demonstrated in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. The aim of this study was to investigate the involvement of SOXs in the progression and prognosis of human prostate cancer (PCa). The gene expression changes of SOXs in human PCa tissues compared with non-cancerous prostate tissues was detected using gene expression microarray, and confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) analysis and immunohositochemistry. The roles of these genes in castration resistance were investigated in LNCaP xenograft model of PCa. The microarray analysis identified three genes (SOX7, SOX9 and SOX10) of SOX family that were significantly dis-regulated in common among four PCa specimens. Consistent with the results of the microarray, differential mRNA and protein levels of three selected genes were found in PCa tissues by QRT-PCR analysis and immunohistochemistry. Additionally, we found that the immunohistochemical staining scores of SOX7 in PCa tissues with higher serum PSA level (P = 0.02) and metastasis (P = 0.03) were significantly lower than those with lower serum PSA level and without metastasis; the increased SOX9 protein expression was frequently found in PCa tissues with higher Gleason score (P = 0.02) and higher clinical stage (P < 0.0001); the down-regulation of SOX10 tend to be found in PCa tissues with higher serum PSA levels (P = 0.03) and advanced pathological stage (P = 0.01). Moreover, both univariate and multivariate analyses showed that the down-regulation of SOX7 and the up-regulation of SOX9 were independent predictors of shorter biochemical recurrence-free survival. Furthermore, we discovered that SOX7 was significantly down-regulated and SOX9 was significantly up-regulated during the progression to castration resistance. Our data offer the convince

  5. Aflatoxin B1 use in radioimmunoassay

    International Nuclear Information System (INIS)

    Liu Yinkun; Zhang Xiaying; Chen Ruiqun; Gu Tianjue

    1987-01-01

    Antibodies against Aflatoxin B 1 (AFB 1 ) were obtained after multiple-site injections of bovine serum albumin-AFB 1 conjugate into rabbits. The greatest specific binding effciency of antibody for AFB 1 is 70∼80%. The sensitivity of radioimmunoassay (RIA) for AFB 1 is between 0.46∼2.3 ng. The retrievel rate of AFB 1 by RIA from intentionally contaminated serum and rice is between 70∼80%. Detailed methods for the preparation of conjugate, immune serum, and methods for antibody titer determination are described

  6. Structure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction.

    Science.gov (United States)

    Klaus, Miriam; Prokoph, Nina; Girbig, Mathias; Wang, Xuecong; Huang, Yong-Heng; Srivastava, Yogesh; Hou, Linlin; Narasimhan, Kamesh; Kolatkar, Prasanna R; Francois, Mathias; Jauch, Ralf

    2016-05-05

    The transcription factor (TF) SOX18 drives lymphatic vessel development in both embryogenesis and tumour-induced neo-lymphangiogenesis. Genetic disruption of Sox18 in a mouse model protects from tumour metastasis and established the SOX18 protein as a molecular target. Here, we report the crystal structure of the SOX18 DNA binding high-mobility group (HMG) box bound to a DNA element regulating Prox1 transcription. The crystals diffracted to 1.75Å presenting the highest resolution structure of a SOX/DNA complex presently available revealing water structure, structural adjustments at the DNA contact interface and non-canonical conformations of the DNA backbone. To explore alternatives to challenging small molecule approaches for targeting the DNA-binding activity of SOX18, we designed a set of five decoys based on modified Prox1-DNA. Four decoys potently inhibited DNA binding of SOX18 in vitro and did not interact with non-SOX TFs. Serum stability, nuclease resistance and thermal denaturation assays demonstrated that a decoy circularized with a hexaethylene glycol linker and terminal phosphorothioate modifications is most stable. This SOX decoy also interfered with the expression of a luciferase reporter under control of a SOX18-dependent VCAM1 promoter in COS7 cells. Collectively, we propose SOX decoys as potential strategy for inhibiting SOX18 activity to disrupt tumour-induced neo-lymphangiogenesis. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  7. THRAP3 interacts with and inhibits the transcriptional activity of SOX9 during chondrogenesis.

    Science.gov (United States)

    Sono, Takashi; Akiyama, Haruhiko; Miura, Shigenori; Deng, Jian Min; Shukunami, Chisa; Hiraki, Yuji; Tsushima, Yu; Azuma, Yoshiaki; Behringer, Richard R; Matsuda, Shuichi

    2018-07-01

    Sex-determining region Y (Sry)-box (Sox)9 is required for chondrogenesis as a transcriptional activator of genes related to chondrocyte proliferation, differentiation, and cartilage-specific extracellular matrix. Although there have been studies investigating the Sox9-dependent transcriptional complexes, not all their components have been identified. In the present study, we demonstrated that thyroid hormone receptor-associated protein (THRAP)3 is a component of a SOX9 transcriptional complex by liquid chromatography mass spectrometric analysis of FLAG-tagged Sox9-binding proteins purified from FLAG-HA-tagged Sox9 knock-in mice. Thrap3 knockdown in ATDC5 chondrogenic cells increased the expression of Collagen type II alpha 1 chain (Col2a1) without affecting Sox9 expression. THRAP3 and SOX9 overexpression reduced Col2a1 levels to a greater degree than overexpression of SOX9 alone. The negative regulation of SOX9 transcriptional activity by THRAP3 was mediated by interaction between the proline-, glutamine-, and serine-rich domain of SOX9 and the innominate domain of THRAP3. These results indicate that THRAP3 negatively regulates SOX9 transcriptional activity as a cofactor of a SOX9 transcriptional complex during chondrogenesis.

  8. Small-Molecule Inhibitors of the SOX18 Transcription Factor.

    Science.gov (United States)

    Fontaine, Frank; Overman, Jeroen; Moustaqil, Mehdi; Mamidyala, Sreeman; Salim, Angela; Narasimhan, Kamesh; Prokoph, Nina; Robertson, Avril A B; Lua, Linda; Alexandrov, Kirill; Koopman, Peter; Capon, Robert J; Sierecki, Emma; Gambin, Yann; Jauch, Ralf; Cooper, Matthew A; Zuegg, Johannes; Francois, Mathias

    2017-03-16

    Pharmacological modulation of transcription factors (TFs) has only met little success over the past four decades. This is mostly due to standard drug discovery approaches centered on blocking protein/DNA binding or interfering with post-translational modifications. Recent advances in the field of TF biology have revealed a central role of protein-protein interaction in their mode of action. In an attempt to modulate the activity of SOX18 TF, a known regulator of vascular growth in development and disease, we screened a marine extract library for potential small-molecule inhibitors. We identified two compounds, which inspired a series of synthetic SOX18 inhibitors, able to interfere with the SOX18 HMG DNA-binding domain, and to disrupt HMG-dependent protein-protein interaction with RBPJ. These compounds also perturbed SOX18 transcriptional activity in a cell-based reporter gene system. This approach may prove useful in developing a new class of anti-angiogenic compounds based on the inhibition of TF activity. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Study of Microflares through SOXS Mission Rajmal Jain , Vishal ...

    Indian Academy of Sciences (India)

    Abstract. We present a study of 10 microflares observed in 4–30 keV by SOXS mission simultaneously with Hα observations made at NAOJ,. Japan during the interval between February and August 2004. The X-ray and Hα light curves showed that the lifetime of microflares varies between. 4 and 25 min. We found that the ...

  10. 118-B-1 excavation treatability test plan

    International Nuclear Information System (INIS)

    1994-07-01

    The Hanford 118-B-1 Burial Ground Treatability Study has been required by milestone change request number-sign M-15-93-04, dated September 30, 1993. The change request requires that a treatability test be conducted at the 100-B Area to obtain additional engineering information for remedial design of burial grounds receiving waste from 100 Area removal actions. This treatability study has two purposes: (1) to support development of the Proposed Plan (PP) and Record of Decision (ROD), which will identify the approach to be used for burial ground remediation, and (2) to provide specific engineering information for receiving waste generated from the 100 Area removal actions. Data generated from this test also will provide critical performance and cost information necessary for remedy evaluation in the detailed analysis of alternatives during preparation of the focused feasibility study (FFS). This treatability testing supports the following 100 Area alternatives: (1) excavation and disposal, and (2) excavation, sorting, (treatment), and disposal

  11. 118-B-1 excavation treatability test procedures

    International Nuclear Information System (INIS)

    Frain, J.M.

    1994-01-01

    This treatability study has two purposes: to support development of the approach to be used for burial ground remediation, and to provide specific engineering information for the design of burial grounds receiving waste generated from the 100 Area removal actions. Data generated from this test will also provide performance and cost information necessary for detailed analysis of alternatives for burial ground remediation. Further details on the test requirements, milestones and data quality objectives are described in detail in the 118-B-1 Excavation Treatability Test Plan (DOE/RL-94-43). These working procedures are intended for use by field personnel to implement the requirements of the milestone. A copy of the detailed Test Plan will be kept on file at the on-site field support trailer, and will be available for review by field personnel

  12. Observation of Cleft Palate in an Individual with SOX11 Mutation: Indication of a Role for SOX11 in Human Palatogenesis.

    Science.gov (United States)

    Khan, Umair; Study, Ddd; Baker, Eleanor; Clayton-Smith, Jill

    2018-03-01

    Point mutations and deletions within the SOX11 gene have recently been described in individuals with a rare variant of Coffin-Siris syndrome, OMIM 615866, an intellectual disability syndrome with associated features of nail hypoplasia, microcephaly, and characteristic facial features including a wide mouth and prominent lips. We describe a further patient with a mutation in SOX11 and phenotype resembling mild Coffin-Siris syndrome. This boy had a cleft palate, a feature not previously seen in other patients with SOX11 mutations. We discuss This adds to the current evidence that SOX11 is a gene involved in palatogenesis.

  13. 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.

  14. Identification of SOX3 as an XX male sex reversal gene in mice and humans.

    Science.gov (United States)

    Sutton, Edwina; Hughes, James; White, Stefan; Sekido, Ryohei; Tan, Jacqueline; Arboleda, Valerie; Rogers, Nicholas; Knower, Kevin; Rowley, Lynn; Eyre, Helen; Rizzoti, Karine; McAninch, Dale; Goncalves, Joao; Slee, Jennie; Turbitt, Erin; Bruno, Damien; Bengtsson, Henrik; Harley, Vincent; Vilain, Eric; Sinclair, Andrew; Lovell-Badge, Robin; Thomas, Paul

    2011-01-01

    Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome-linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box-containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.

  15. Identification of SOX3 as an XX male sex reversal gene in mice and humans

    Science.gov (United States)

    Sutton, Edwina; Hughes, James; White, Stefan; Sekido, Ryohei; Tan, Jacqueline; Arboleda, Valerie; Rogers, Nicholas; Knower, Kevin; Rowley, Lynn; Eyre, Helen; Rizzoti, Karine; McAninch, Dale; Goncalves, Joao; Slee, Jennie; Turbitt, Erin; Bruno, Damien; Bengtsson, Henrik; Harley, Vincent; Vilain, Eric; Sinclair, Andrew; Lovell-Badge, Robin; Thomas, Paul

    2010-01-01

    Sex in mammals is genetically determined and is defined at the cellular level by sex chromosome complement (XY males and XX females). The Y chromosome–linked gene sex-determining region Y (SRY) is believed to be the master initiator of male sex determination in almost all eutherian and metatherian mammals, functioning to upregulate expression of its direct target gene Sry-related HMG box–containing gene 9 (SOX9). Data suggest that SRY evolved from SOX3, although there is no direct functional evidence to support this hypothesis. Indeed, loss-of-function mutations in SOX3 do not affect sex determination in mice or humans. To further investigate Sox3 function in vivo, we generated transgenic mice overexpressing Sox3. Here, we report that in one of these transgenic lines, Sox3 was ectopically expressed in the bipotential gonad and that this led to frequent complete XX male sex reversal. Further analysis indicated that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a similar mechanism to Sry. Importantly, we also identified genomic rearrangements within the SOX3 regulatory region in three patients with XX male sex reversal. Together, these data suggest that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad. PMID:21183788

  16. 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

    /function was evaluated along the differentiation of human induced pluripotent stem cells (iPSC) into cholangiocytes, in the dedifferentiation process of normal human cholangiocytes (NHC) in culture and in cholangiocarcinogenesis. Lentiviruses for SOX17 overexpression or knock-down were used. Gene expression and DNA......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...... methylation profiling were performed. RESULTS: SOX17 expression is induced in the last stage of cholangiocyte differentiation from iPSC and regulates the acquisition of biliary markers. SOX17 becomes downregulated in NHC undergoing dedifferentiation; experimental SOX17 knock-down in differentiated NHC...

  17. Inhibition of DNA binding of Sox2 by the SUMO conjugation

    International Nuclear Information System (INIS)

    Tsuruzoe, Shu; Ishihara, Ko; Uchimura, Yasuhiro; Watanabe, Sugiko; Sekita, Yoko; Aoto, Takahiro; Saitoh, Hisato; Yuasa, Yasuhito; Niwa, Hitoshi; Kawasuji, Michio; Baba, Hideo; Nakao, Mitsuyoshi

    2006-01-01

    Sox2 is a member of the high mobility group (HMG) domain DNA-binding proteins for transcriptional control and chromatin architecture. The HMG domain of Sox2 binds the DNA to facilitate transactivation by the cooperative transcription factors such as Oct3/4. We report that mouse Sox2 is modified by SUMO at lysine 247. Substitution of the target lysine to arginine lost the sumoylation but little affected transcriptional potential or nuclear localization of Sox2. By contrast with the unmodified form, Sox2 fused to SUMO-1 did not augment transcription via the Fgf4 enhancer in the presence of Oct3/4. Further, SUMO-1-conjugated Sox2 at the lysine 247 or at the carboxyl terminus reduced the binding to the Fgf4 enhancer. These indicate that Sox2 sumoylation negatively regulates its transcriptional role through impairing the DNA binding

  18. Conversion of Sox17 into a pluripotency reprogramming factor by reengineering its association with Oct4 on DNA.

    Science.gov (United States)

    Jauch, Ralf; Aksoy, Irene; Hutchins, Andrew Paul; Ng, Calista Keow Leng; Tian, Xian Feng; Chen, Jiaxuan; Palasingam, Paaventhan; Robson, Paul; Stanton, Lawrence W; Kolatkar, Prasanna R

    2011-06-01

    Very few proteins are capable to induce pluripotent stem (iPS) cells and their biochemical uniqueness remains unexplained. For example, Sox2 cooperates with other transcription factors to generate iPS cells, but Sox17, despite binding to similar DNA sequences, cannot. Here, we show that Sox2 and Sox17 exhibit inverse heterodimerization preferences with Oct4 on the canonical versus a newly identified compressed sox/oct motif. We can swap the cooperativity profiles of Sox2 and Sox17 by exchanging single amino acids at the Oct4 interaction interface resulting in Sox2KE and Sox17EK proteins. The reengineered Sox17EK now promotes reprogramming of somatic cells to iPS, whereas Sox2KE has lost this potential. Consistently, when Sox2KE is overexpressed in embryonic stem cells it forces endoderm differentiation similar to wild-type Sox17. Together, we demonstrate that strategic point mutations that facilitate Sox/Oct4 dimer formation on variant DNA motifs lead to a dramatic swap of the bioactivities of Sox2 and Sox17. Copyright © 2011 AlphaMed Press.

  19. 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.

  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 prolonged oral administration of fumonisin B1 and aflatoxin B1 in rats.

    Science.gov (United States)

    Pozzi, C R; Corrêa, B; Xavier, J G; Direito, G M; Orsi, R B; Matarazzo, S V

    2001-01-01

    The effects of prolonged oral administration (21 days) of fumonisin B1 (FB1) and aflatoxin B1 (AFB1) were evaluated on male Wistar rats. The animals were housed in individual metabolic cages and submitted to the following treatments: 1-0 microg AFB1 + 0 mg FB1/100g bw.; 2-72 microg AFB1+ 0 mg FB1/100 g bw; 3-0 microg AFB1 + 0.5 mg FB1 g bw; 4-0 microg AFB1 + 1.5 mg FB1/100 g bw; 5-72 microg AFB1 + 0.5 mg FB1/100g bw; 6-72 microgAFB1 + 1.5 mg FB1/100g bw. On day 21, the rats were sacrificed for evaluation. The results showed that treated animals presented differences in body weight and absolute/relative weights of liver and kidney as well as altered hepatic function and cholesterol blood levels. Rats fed with the greatest doses of AFB1 and FB1 gained less weight (2.79 g/day) at the end of the experimental period; their blood concentrations of liver enzymes aspartate aminotransferase (AST) and alkaline phosphatase (AP) were above control levels (130.35 micro/l and 471.00 micro/l, respectively). Blood cholesterol increased in the groups treated with the highest dose of FB1 or FB1 associated with AFB1. Histopathology revealed the occurrence of apoptosis in the liver of rats exposed to FB1. The association of aflatoxin B1 with fumonisin B1 at higher dose probably potentiated the effects of the higher dose of fumonisin B1 acting singly.

  2. 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.

  3. CD25+ B-1a Cells Express Aicda

    Directory of Open Access Journals (Sweden)

    Hiroaki Kaku

    2017-06-01

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

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

    International Nuclear Information System (INIS)

    Pei, Xin-Hong; Lv, Xin-Quan; Li, Hui-Xiang

    2014-01-01

    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

  5. 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.

  6. Parent-of-origin effects in SOX2 anophthalmia syndrome.

    Science.gov (United States)

    Osborne, Robert J; Kurinczuk, Jennifer J; Ragge, Nicola K

    2011-01-01

    Sex determining region Y (SRY)-box 2 (SOX2) anophthalmia syndrome is an autosomal dominant disorder manifesting as severe developmental eye malformations associated with brain, esophageal, genital, and kidney abnormalities. The syndrome is usually caused by de novo mutations or deletions in the transcription factor SOX2. To investigate any potential parental susceptibility factors, we set out to determine the parent of origin of the mutations or deletions, and following this, to determine if birth order or parental age were significant factors, as well as whether mutation susceptibility was related to any sequence variants in cis with the mutant allele. We analyzed 23 cases of de novo disease to determine the parental origin of SOX2 mutations and deletions using informative single nucleotide polymorphisms and a molecular haplotyping approach. We examined parental ages for SOX2 mutation and deletion cases, compared these with the general population, and adjusted for birth order. Although the majority of subjects had mutations or deletions that arose in the paternal germline (5/7 mutation and 5/8 deletion cases), there was no significant paternal bias for new mutations (binomial test, p=0.16) or deletions (binomial test, p=0.22). For both mutation and deletion cases, there was no significant association between any single nucleotide polymorphism allele and the mutant chromosome (p>0.05). Parents of the subjects with mutations were on average older at the birth of the affected child than the general population by 3.8 years (p=0.05) for mothers and 3.3 years (p=0.66) for fathers. Parents of the subjects with deletions were on average younger than the general population by 3.0 years (p=0.17) for mothers and 2.1 years (p=0.19) for fathers. Combining these data, the difference in pattern of parental age between the subjects with deletions and mutations was evident, with a difference of 6.5 years for mothers (p=0.05) and 5.0 years for fathers (p=0.22), with the mothers and

  7. [Molecular pathogenesis of Waardenburg syndrome type II resulting from SOX10 gene mutation].

    Science.gov (United States)

    Zhang, Hua; Chen, Hongsheng; Feng, Yong; Qian, Minfei; Li, Jiping; Liu, Jun; Zhang, Chun

    2016-08-01

    To explore the molecular mechanism of Waardenburg syndrome type II (WS2) resulting from SOX10 gene mutation E248fs through in vitro experiment. 293T cells were transiently transfected with wild type (WT) SOX10 and mutant type (MT) E248fs plasmids. The regulatory effect of WT/MT SOX10 on the transcriptional activity of MITF gene and influence of E248fs on WT SOX10 function were determined with a luciferase activity assay. The DNA binding capacity of the WT/MT SOX10 with the promoter of the MITF gene was determined with a biotinylated double-stranded oligonucleotide probe containing the SOX10 binding sequence cattgtc to precipitate MITF and E248fs, respectively. The stability of SOX10 and E248fs were also analyzed. As a loss-of-function mutation, the E248fs mutant failed to transactivate the MITF promoter as compared with the WT SOX10 (P<0.01), which also showed a dominant-negative effect on WT SOX10. The WT SOX10 and E248fs mutant were also able to bind specifically to the cattgtc motif in the MITF promoter, whereas E248fs had degraded faster than WT SOX10. Despite the fact that the E248fs has a dominant-negative effect on SOX10, its reduced stability may down-regulate the transcription of MITF and decrease the synthesis of melanin, which may result in haploinsufficiency of SOX10 protein and cause the milder WS2 phenotype.

  8. Sox2 promotes survival of satellite glial cells in vitro

    International Nuclear Information System (INIS)

    Koike, Taro; Wakabayashi, Taketoshi; Mori, Tetsuji; Hirahara, Yukie; Yamada, Hisao

    2015-01-01

    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

  9. Sox2 Is an Androgen Receptor-Repressed Gene That Promotes Castration-Resistant Prostate Cancer

    Science.gov (United States)

    Kregel, Steven; Kiriluk, Kyle J.; Rosen, Alex M.; Cai, Yi; Reyes, Edwin E.; Otto, Kristen B.; Tom, Westin; Paner, Gladell P.; Szmulewitz, Russell Z.; Vander Griend, Donald J.

    2013-01-01

    Despite advances in detection and therapy, castration-resistant prostate cancer continues to be a major clinical problem. The aberrant activity of stem cell pathways, and their regulation by the Androgen Receptor (AR), has the potential to provide insight into novel mechanisms and pathways to prevent and treat advanced, castrate-resistant prostate cancers. To this end, we investigated the role of the embryonic stem cell regulator Sox2 [SRY (sex determining region Y)-box 2] in normal and malignant prostate epithelial cells. In the normal prostate, Sox2 is expressed in a portion of basal epithelial cells. Prostate tumors were either Sox2-positive or Sox2-negative, with the percentage of Sox2-positive tumors increasing with Gleason Score and metastases. In the castration-resistant prostate cancer cell line CWR-R1, endogenous expression of Sox2 was repressed by AR signaling, and AR chromatin-IP shows that AR binds the enhancer element within the Sox2 promoter. Likewise, in normal prostate epithelial cells and human embryonic stem cells, increased AR signaling also decreases Sox2 expression. Resistance to the anti-androgen MDV3100 results in a marked increase in Sox2 expression within three prostate cancer cell lines, and in the castration-sensitive LAPC-4 prostate cancer cell line ectopic expression of Sox2 was sufficient to promote castration-resistant tumor formation. Loss of Sox2 expression in the castration-resistant CWR-R1 prostate cancer cell line inhibited cell growth. Up-regulation of Sox2 was not associated with increased CD133 expression but was associated with increased FGF5 (Fibroblast Growth Factor 5) expression. These data propose a model of elevated Sox2 expression due to loss of AR-mediated repression during castration, and consequent castration-resistance via mechanisms not involving induction of canonical embryonic stem cell pathways. PMID:23326489

  10. 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.

  11. 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

  12. Na2SO4-based solid electrolytes for SOx sensors

    DEFF Research Database (Denmark)

    Rao, N.; Schoonman, J.; Toft Sørensen, O.

    1992-01-01

    on the phases present and the structure of the specimens. From a point of view of practical application as SOx sensor material, the Na2SO4 + 5 mol% Y2(SO4)3 + Na2WO4 and Na2SO4+ 4 mol% La2(SO4)3 + Na2WO4 materials are better than undoped Na2SO4 because of their higher conductivity, and absence of a phase...

  13. The C. elegans SoxC protein SEM-2 opposes differentiation factors to promote a proliferative blast cell fate in the postembryonic mesoderm

    Science.gov (United States)

    Tian, Chenxi; Shi, Herong; Colledge, Clark; Stern, Michael; Waterston, Robert; Liu, Jun

    2011-01-01

    The proper development of multicellular organisms requires precise regulation and coordination of cell fate specification, cell proliferation and differentiation. Abnormal regulation and coordination of these processes could lead to disease, including cancer. We have examined the function of the sole C. elegans SoxC protein, SEM-2, in the M lineage, which produces the postembryonic mesoderm. We found that SEM-2/SoxC is both necessary and sufficient to promote a proliferating blast cell fate, the sex myoblast fate, over a differentiated striated bodywall muscle fate. A number of factors control the specific expression of sem-2 in the sex myoblast precursors and their descendants. This includes direct control of sem-2 expression by a Hox-PBC complex. The crucial nature of the HOX/PBC factors in directly enhancing expression of this proliferative factor in the C. elegans M lineage suggests a possible more general link between Hox-PBC factors and SoxC proteins in regulating cell proliferation. PMID:21307099

  14. 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.

  15. Embryonic transcription factor SOX9 drives breast cancer endocrine resistance.

    Science.gov (United States)

    Jeselsohn, Rinath; Cornwell, MacIntosh; Pun, Matthew; Buchwalter, Gilles; Nguyen, Mai; Bango, Clyde; Huang, Ying; Kuang, Yanan; Paweletz, Cloud; Fu, Xiaoyong; Nardone, Agostina; De Angelis, Carmine; Detre, Simone; Dodson, Andrew; Mohammed, Hisham; Carroll, Jason S; Bowden, Michaela; Rao, Prakash; Long, Henry W; Li, Fugen; Dowsett, Mitchell; Schiff, Rachel; Brown, Myles

    2017-05-30

    The estrogen receptor (ER) drives the growth of most luminal breast cancers and is the primary target of endocrine therapy. Although ER blockade with drugs such as tamoxifen is very effective, a major clinical limitation is the development of endocrine resistance especially in the setting of metastatic disease. Preclinical and clinical observations suggest that even following the development of endocrine resistance, ER signaling continues to exert a pivotal role in tumor progression in the majority of cases. Through the analysis of the ER cistrome in tamoxifen-resistant breast cancer cells, we have uncovered a role for an RUNX2-ER complex that stimulates the transcription of a set of genes, including most notably the stem cell factor SOX9, that promote proliferation and a metastatic phenotype. We show that up-regulation of SOX9 is sufficient to cause relative endocrine resistance. The gain of SOX9 as an ER-regulated gene associated with tamoxifen resistance was validated in a unique set of clinical samples supporting the need for the development of improved ER antagonists.

  16. 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

  17. 77 FR 42707 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-07-20

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-35] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... Force (DAY) [[Page 42709

  18. Long noncoding RNA lnc-sox5 modulates CRC tumorigenesis by unbalancing tumor microenvironment.

    Science.gov (United States)

    Wu, Kaiming; Zhao, Zhenxian; Liu, Kuanzhi; Zhang, Jian; Li, Guanghua; Wang, Liang

    2017-07-03

    Long non-coding RNAs (LncRNAs) have been recently regarded as systemic regulators in multiple biologic processes including tumorigenesis. In this study, we observed the expression of lncRNA lnc-sox5 was significantly increased in colorectal cancer (CRC). Despite the CRC cell growth, cell cycle and cell apoptosis was not affected by lnc-sox5 knock-down, lnc-sox5 knock-down suppressed CRC cell migration and invasion. In addition, xenograft animal model suggested that lnc-sox5 knock-down significantly suppressed the CRC tumorigenesis. Our results also showed that the expression of indoleamine 2,3-dioxygenase 1 (IDO1) was significantly reduced by lnc-sox5 knock-down and therefore modulated the infiltration and cytotoxicity of CD3 + CD8 + T cells. Taken together, these results suggested that lnc-sox5 unbalances tumor microenvironment to regulate colorectal cancer progression.

  19. 26 CFR 31.3306(b)-1 - Wages.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Wages. 31.3306(b)-1 Section 31.3306(b)-1... Unemployment Tax Act (Chapter 23, Internal Revenue Code of 1954) § 31.3306(b)-1 Wages. (a) Applicable law and... after 1938 constitutes wages is determined under section 3306(b). Accordingly, only remuneration paid...

  20. 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...

  1. 26 CFR 1.267(b)-1 - Relationships.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 3 2010-04-01 2010-04-01 false Relationships. 1.267(b)-1 Section 1.267(b)-1...) INCOME TAXES Items Not Deductible § 1.267(b)-1 Relationships. (a) In general. (1) The persons referred to... partnership separately. Therefore, if the other person and a partner are within any one of the relationships...

  2. 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

  3. Risk assessment of fumonisin B1 in the Netherlands

    NARCIS (Netherlands)

    Bakker MI; Speijers GJA; Paulsch WE; van Egmond HP; SIR; ARO

    2004-01-01

    Fumonisine B1 is een mycotoxine, dat kan worden gevormd door bepaalde Fusarium schimmels. Het toxine wordt vooral in mais (-producten) aangetroffen, maar het kan ook voorkomen in tarwe (-producten). De inname van fumonisine B1 in de Nederlandse populatie is geschat door fumonisine B1 concentraties

  4. An evolutionarily conserved intronic region controls the spatiotemporal expression of the transcription factor Sox10

    Directory of Open Access Journals (Sweden)

    Pavan William J

    2008-10-01

    Full Text Available Abstract Background A major challenge lies in understanding the complexities of gene regulation. Mutation of the transcription factor SOX10 is associated with several human diseases. The disease phenotypes reflect the function of SOX10 in diverse tissues including the neural crest, central nervous system and otic vesicle. As expected, the SOX10 expression pattern is complex and highly dynamic, but little is known of the underlying mechanisms regulating its spatiotemporal pattern. SOX10 expression is highly conserved between all vertebrates characterised. Results We have combined in vivo testing of DNA fragments in zebrafish and computational comparative genomics to identify the first regulatory regions of the zebrafish sox10 gene. Both approaches converged on the 3' end of the conserved 1st intron as being critical for spatial patterning of sox10 in the embryo. Importantly, we have defined a minimal region crucial for this function. We show that this region contains numerous binding sites for transcription factors known to be essential in early neural crest induction, including Tcf/Lef, Sox and FoxD3. We show that the identity and relative position of these binding sites are conserved between zebrafish and mammals. A further region, partially required for oligodendrocyte expression, lies in the 5' region of the same intron and contains a putative CSL binding site, consistent with a role for Notch signalling in sox10 regulation. Furthermore, we show that β-catenin, Notch signalling and Sox9 can induce ectopic sox10 expression in early embryos, consistent with regulatory roles predicted from our transgenic and computational results. Conclusion We have thus identified two major sites of sox10 regulation in vertebrates and provided evidence supporting a role for at least three factors in driving sox10 expression in neural crest, otic epithelium and oligodendrocyte domains.

  5. Silencing of the Drosophila ortholog of SOX5 leads to abnormal neuronal development and behavioral impairment.

    Science.gov (United States)

    Li, Airong; Hooli, Basavaraj; Mullin, Kristina; Tate, Rebecca E; Bubnys, Adele; Kirchner, Rory; Chapman, Brad; Hofmann, Oliver; Hide, Winston; Tanzi, Rudolph E

    2017-04-15

    SOX5 encodes a transcription factor that is expressed in multiple tissues including heart, lung and brain. Mutations in SOX5 have been previously found in patients with amyotrophic lateral sclerosis (ALS) and developmental delay, intellectual disability and dysmorphic features. To characterize the neuronal role of SOX5, we silenced the Drosophila ortholog of SOX5, Sox102F, by RNAi in various neuronal subtypes in Drosophila. Silencing of Sox102F led to misorientated and disorganized michrochaetes, neurons with shorter dendritic arborization (DA) and reduced complexity, diminished larval peristaltic contractions, loss of neuromuscular junction bouton structures, impaired olfactory perception, and severe neurodegeneration in brain. Silencing of SOX5 in human SH-SY5Y neuroblastoma cells resulted in a significant repression of WNT signaling activity and altered expression of WNT-related genes. Genetic association and meta-analyses of the results in several large family-based and case-control late-onset familial Alzheimer's disease (LOAD) samples of SOX5 variants revealed several variants that show significant association with AD disease status. In addition, analysis for rare and highly penetrate functional variants revealed four novel variants/mutations in SOX5, which taken together with functional prediction analysis, suggests a strong role of SOX5 causing AD in the carrier families. Collectively, these findings indicate that SOX5 is a novel candidate gene for LOAD with an important role in neuronal function. The genetic findings warrant further studies to identify and characterize SOX5 variants that confer risk for AD, ALS and intellectual disability. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. XX male sex reversal with genital abnormalities associated with a de novo SOX3 gene duplication.

    Science.gov (United States)

    Moalem, Sharon; Babul-Hirji, Riyana; Stavropolous, Dmitri J; Wherrett, Diane; Bägli, Darius J; Thomas, Paul; Chitayat, David

    2012-07-01

    Differentiation of the bipotential gonad into testis is initiated by the Y chromosome-linked gene SRY (Sex-determining Region Y) through upregulation of its autosomal direct target gene SOX9 (Sry-related HMG box-containing gene 9). Sequence and chromosome homology studies have shown that SRY most probably evolved from SOX3, which in humans is located at Xq27.1. Mutations causing SOX3 loss-of-function do not affect the sex determination in mice or humans. However, transgenic mouse studies have shown that ectopic expression of Sox3 in the bipotential gonad results in upregulation of Sox9, resulting in testicular induction and XX male sex reversal. However, the mechanism by which these rearrangements cause sex reversal and the frequency with which they are associated with disorders of sex development remains unclear. Rearrangements of the SOX3 locus were identified recently in three cases of human XX male sex reversal. We report on a case of XX male sex reversal associated with a novel de novo duplication of the SOX3 gene. These data provide additional evidence that SOX3 gain-of-function in the XX bipotential gonad causes XX male sex reversal and further support the hypothesis that SOX3 is the evolutionary antecedent of SRY. Copyright © 2012 Wiley Periodicals, Inc.

  7. Sox2 marks epithelial competence to generate teeth in mammals and reptiles

    Science.gov (United States)

    Juuri, Emma; Jussila, Maria; Seidel, Kerstin; Holmes, Scott; Wu, Ping; Richman, Joy; Heikinheimo, Kristiina; Chuong, Cheng-Ming; Arnold, Katrin; Hochedlinger, Konrad; Klein, Ophir; Michon, Frederic; Thesleff, Irma

    2013-01-01

    Tooth renewal is initiated from epithelium associated with existing teeth. The development of new teeth requires dental epithelial cells that have competence for tooth formation, but specific marker genes for these cells have not been identified. Here, we analyzed expression patterns of the transcription factor Sox2 in two different modes of successional tooth formation: tooth replacement and serial addition of primary teeth. We observed specific Sox2 expression in the dental lamina that gives rise to successional teeth in mammals with one round of tooth replacement as well as in reptiles with continuous tooth replacement. Sox2 was also expressed in the dental lamina during serial addition of mammalian molars, and genetic lineage tracing indicated that Sox2+ cells of the first molar give rise to the epithelial cell lineages of the second and third molars. Moreover, conditional deletion of Sox2 resulted in hyperplastic epithelium in the forming posterior molars. Our results indicate that the Sox2+ dental epithelium has competence for successional tooth formation and that Sox2 regulates the progenitor state of dental epithelial cells. The findings imply that the function of Sox2 has been conserved during evolution and that tooth replacement and serial addition of primary teeth represent variations of the same developmental process. The expression patterns of Sox2 support the hypothesis that dormant capacity for continuous tooth renewal exists in mammals. PMID:23462476

  8. SOX4 regulates gonad morphogenesis and promotes male germ cell differentiation in mice.

    Science.gov (United States)

    Zhao, Liang; Arsenault, Michel; Ng, Ee Ting; Longmuss, Enya; Chau, Tevin Chui-Ying; Hartwig, Sunny; Koopman, Peter

    2017-03-01

    The group C SOX transcription factors SOX4, -11 and -12 play important and mutually overlapping roles in development of a number of organs. Here, we examined the role of SoxC genes during gonadal development in mice. All three genes were expressed in developing gonads of both sexes, predominantly in somatic cells, with Sox4 being most strongly expressed. Sox4 deficiency resulted in elongation of both ovaries and testes, and an increased number of testis cords. While female germ cells entered meiosis normally, male germ cells showed reduced levels of differentiation markers Nanos2 and Dnmt3l and increased levels of pluripotency genes Cripto and Nanog, suggesting that SOX4 may normally act to restrict the pluripotency period of male germ cells and ensure their proper differentiation. Finally, our data reveal that SOX4 (and, to a lesser extent, SOX11 and -12) repressed transcription of the sex-determining gene Sox9 via an upstream testis-specific enhancer core (TESCO) element in fetal gonads, raising the possibility that SOXC proteins may function as transcriptional repressors in a context-dependent manner. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Coffin-Siris syndrome and cardiac anomaly with a novel SOX11 mutation.

    Science.gov (United States)

    Okamoto, Nobuhiko; Ehara, Eiji; Tsurusaki, Yoshinori; Miyake, Noriko; Matsumoto, Naomichi

    2017-08-08

    Coffin-Siris syndrome (CSS) is characterized by growth deficiency, intellectual disability, microcephaly, dysmorphic features, and hypoplastic nails of the fifth fingers and/or toes. Variants in the genes encoding subunits of the BAF complex as well as in SOX11 encoding the transcriptional factor under the control of BAF complex are associated with CSS. We report a new patient with a novel SOX11 mutation. He showed the CSS phenotype and coarctation of the aorta. Sox11 is known to be associated with cardiac outflow development in mouse studies. Therefore, cardiac anomalies might be an important complication in patients with SOX11 mutations. © 2017 Japanese Teratology Society.

  10. Sox9b is a key regulator of pancreaticobiliary ductal system development.

    Directory of Open Access Journals (Sweden)

    Marion Delous

    Full Text Available The pancreaticobiliary ductal system connects the liver and pancreas to the intestine. It is composed of the hepatopancreatic ductal (HPD system as well as the intrahepatic biliary ducts and the intrapancreatic ducts. Despite its physiological importance, the development of the pancreaticobiliary ductal system remains poorly understood. The SRY-related transcription factor SOX9 is expressed in the mammalian pancreaticobiliary ductal system, but the perinatal lethality of Sox9 heterozygous mice makes loss-of-function analyses challenging. We turned to the zebrafish to assess the role of SOX9 in pancreaticobiliary ductal system development. We first show that zebrafish sox9b recapitulates the expression pattern of mouse Sox9 in the pancreaticobiliary ductal system and use a nonsense allele of sox9b, sox9b(fh313, to dissect its function in the morphogenesis of this structure. Strikingly, sox9b(fh313 homozygous mutants survive to adulthood and exhibit cholestasis associated with hepatic and pancreatic duct proliferation, cyst formation, and fibrosis. Analysis of sox9b(fh313 mutant embryos and larvae reveals that the HPD cells appear to mis-differentiate towards hepatic and/or pancreatic fates, resulting in a dysmorphic structure. The intrahepatic biliary cells are specified but fail to assemble into a functional network. Similarly, intrapancreatic duct formation is severely impaired in sox9b(fh313 mutants, while the embryonic endocrine and acinar compartments appear unaffected. The defects in the intrahepatic and intrapancreatic ducts of sox9b(fh313 mutants worsen during larval and juvenile stages, prompting the adult phenotype. We further show that Sox9b interacts with Notch signaling to regulate intrahepatic biliary network formation: sox9b expression is positively regulated by Notch signaling, while Sox9b function is required to maintain Notch signaling in the intrahepatic biliary cells. Together, these data reveal key roles for SOX9 in the

  11. Spinal cord regeneration in Xenopus tadpoles proceeds through activation of Sox2-positive cells

    Science.gov (United States)

    2012-01-01

    Background In contrast to mammals, amphibians, such as adult urodeles (for example, newts) and anuran larvae (for example, Xenopus) can regenerate their spinal cord after injury. However, the cellular and molecular mechanisms involved in this process are still poorly understood. Results Here, we report that tail amputation results in a global increase of Sox2 levels and proliferation of Sox2+ cells. Overexpression of a dominant negative form of Sox2 diminished proliferation of spinal cord resident cells affecting tail regeneration after amputation, suggesting that spinal cord regeneration is crucial for the whole process. After spinal cord transection, Sox2+ cells are found in the ablation gap forming aggregates. Furthermore, Sox2 levels correlated with regenerative capabilities during metamorphosis, observing a decrease in Sox2 levels at non-regenerative stages. Conclusions Sox2+ cells contribute to the regeneration of spinal cord after tail amputation and transection. Sox2 levels decreases during metamorphosis concomitantly with the lost of regenerative capabilities. Our results lead to a working hypothesis in which spinal cord damage activates proliferation and/or migration of Sox2+ cells, thus allowing regeneration of the spinal cord after tail amputation or reconstitution of the ependymal epithelium after spinal cord transection. PMID:22537391

  12. Effects of oral administration of aflatoxin B1 and fumonisin B1 in rabbits (Oryctolagus cuniculus).

    Science.gov (United States)

    Orsi, R B; Oliveira, C A F; Dilkin, P; Xavier, J G; Direito, G M; Corrêa, B

    2007-12-15

    The effects of prolonged oral administration (21 days) of fumonisin B(1) (FB(1)) and aflatoxin B(1) (AFB(1)) were studied in male New Zealand rabbits by clinical, pathological, biochemical and sphingolipid analyses. Twenty-four animals were randomly divided into the following four experimental groups: (A) 0 mg FB(1)+0 microg AFB(1)/(kg body weight(bw)day) (control); (B) 0 mg FB(1)+30 microg AFB(1)/(kg bw day); (C) 1.5 mg FB(1)/(kg bw day)+30 microg AFB(1)/(kg bw day); (D) 1.5 mg FB(1)/(kg bw day)+0 microg AFB(1). Animals from group B and principally from group C presented clinical signs of intoxication. Rabbits from group C presented a lower body weight gain than controls. Differences were observed between intoxicated rabbits and controls with respect to absolute and relative liver and kidney weight, hepatic function, serum urea and creatinine levels and Sa/So ratio. The most frequent hepatic and renal injuries were vacuolar degeneration of the liver and kidney as shown by the histopathological and serum biochemical results. Combined administration of AFB(1) and FB(1) resulted in synergistic toxic effects both in the liver and in the kidney, but hepatic injuries were more marked.

  13. Functional analysis of Waardenburg syndrome-associated PAX3 and SOX10 mutations: report of a dominant-negative SOX10 mutation in Waardenburg syndrome type II.

    Science.gov (United States)

    Zhang, Hua; Chen, Hongsheng; Luo, Hunjin; An, Jing; Sun, Lin; Mei, Lingyun; He, Chufeng; Jiang, Lu; Jiang, Wen; Xia, Kun; Li, Jia-Da; Feng, Yong

    2012-03-01

    Waardenburg syndrome (WS) is an auditory-pigmentary disorder resulting from melanocyte defects, with varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four subtypes (WS1-WS4) based on additional symptoms. PAX3 and SOX10 are two transcription factors that can activate the expression of microphthalmia-associated transcription factor (MITF), a critical transcription factor for melanocyte development. Mutations of PAX3 are associated with WS1 and WS3, while mutations of SOX10 cause WS2 and WS4. Recently, we identified some novel WS-associated mutations in PAX3 and SOX10 in a cohort of Chinese WS patients. Here, we further identified an E248fsX30 SOX10 mutation in a family of WS2. We analyzed the subcellular distribution, expression and in vitro activity of two PAX3 mutations (p.H80D, p.H186fsX5) and four SOX10 mutations (p.E248fsX30, p.G37fsX58, p.G38fsX69 and p.R43X). Except H80D PAX3, which retained partial activity, the other mutants were unable to activate MITF promoter. The H80D PAX3 and E248fsX30 SOX10 were localized in the nucleus as wild type (WT) proteins, whereas the other mutant proteins were distributed in both cytoplasm and nucleus. Furthermore, E248fsX30 SOX10 protein retained the DNA-binding activity and showed dominant-negative effect on WT SOX10. However, E248fsX30 SOX10 protein seems to decay faster than the WT one, which may underlie the mild WS2 phenotype caused by this mutation.

  14. 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.

  15. 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.

  16. B1 -sensitivity analysis of quantitative magnetization transfer imaging.

    Science.gov (United States)

    Boudreau, Mathieu; Stikov, Nikola; Pike, G Bruce

    2018-01-01

    To evaluate the sensitivity of quantitative magnetization transfer (qMT) fitted parameters to B 1 inaccuracies, focusing on the difference between two categories of T 1 mapping techniques: B 1 -independent and B 1 -dependent. The B 1 -sensitivity of qMT was investigated and compared using two T 1 measurement methods: inversion recovery (IR) (B 1 -independent) and variable flip angle (VFA), B 1 -dependent). The study was separated into four stages: 1) numerical simulations, 2) sensitivity analysis of the Z-spectra, 3) healthy subjects at 3T, and 4) comparison using three different B 1 imaging techniques. For typical B 1 variations in the brain at 3T (±30%), the simulations resulted in errors of the pool-size ratio (F) ranging from -3% to 7% for VFA, and -40% to > 100% for IR, agreeing with the Z-spectra sensitivity analysis. In healthy subjects, pooled whole-brain Pearson correlation coefficients for F (comparing measured double angle and nominal flip angle B 1 maps) were ρ = 0.97/0.81 for VFA/IR. This work describes the B 1 -sensitivity characteristics of qMT, demonstrating that it varies substantially on the B 1 -dependency of the T 1 mapping method. Particularly, the pool-size ratio is more robust against B 1 inaccuracies if VFA T 1 mapping is used, so much so that B 1 mapping could be omitted without substantially biasing F. Magn Reson Med 79:276-285, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

  17. [SOX10 mutation is relevant to inner ear malformation in patients with Waardenburg syndrome].

    Science.gov (United States)

    Xu, G Y; Hao, Q Q; Zhong, L L; Ren, W; Yan, Y; Liu, R Y; Li, J N; Guo, W W; Zhao, H; Yang, S M

    2016-11-07

    Objective: To determine the relevance between the SOX 10 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 SOX 10 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 PAX 3, were also screened. Patients were divided into two groups according to SOX 10 mutation.The Fisher accuracy test was used to determine statistical difference of inner ear deformation incidence between the two groups. Results: Among all 36 patients, 12 were found to have inner ear abnormality. Most abnormalities were posterior semicircular canal deformations, some accompanied with cochlear deformation and an enlarged vestibule. Among all patients, 9 patients were SOX 10 heterozygous mutation carriers, among which six showed bilateral inner ear abnormality. Fisher accuracy test results suggested a significant correlation between the SOX 10 mutation and inner ear abnormality in WS patients ( P =0.036). Conclusion: This study found that WS patients with the SOX 10 mutation are more likely to have deformed inner ears when compared to WS patients without the SOX 10 mutation.

  18. 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.

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

    Directory of Open Access Journals (Sweden)

    Sarah N Ramsook

    Full Text Available 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.

  20. 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

  1. Unravelling pathways downstream Sox6 induction in K562 erythroid cells by proteomic analysis

    KAUST Repository

    Barbarani, Gloria; Ronchi, Antonella; Ruoppolo, Margherita; Santorelli, Lucia; Steinfelder, Robert; Elangovan, Sudharshan; Fugazza, Cristina; Caterino, Marianna

    2017-01-01

    are accompanied with a reduced survival of Sox6-/- red blood cells, resulting in a compensated anemia. Sox6-overexpression in K562 cells and in human primary ex vivo erythroid cultures enhances erythroid differentiation and leads to hemoglobinization, the hallmark

  2. Solar X-ray Spectrometer (SOXS) Mission – Low Energy Payload ...

    Indian Academy of Sciences (India)

    Solar X-ray Spectrometer (SOXS)' mission, which was launched onboard GSAT-2 Indian spacecraft on 08 May 2003 by GSLV-D2 rocket to study the solar flares. The SOXS Low Energy Detector (SLD) payload was designed, developed and ...

  3. Solar X-ray Spectrometer (SOXS) Mission – Low Energy Payload

    Indian Academy of Sciences (India)

    2016-01-27

    Jan 27, 2016 ... We present the first results from the 'Low Energy Detector' payload of 'Solar X-ray Spectrometer (SOXS)' mission, which was launched onboard GSAT-2 Indian spacecraft on 08 May 2003 by GSLV-D2 rocket to study the solar flares. The SOXS Low Energy Detector (SLD) payload was designed, developed ...

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

    International Nuclear Information System (INIS)

    Hiraoka, Koji; Hayashi, Tomoatsu; Kaneko, Ryusuke; Nasu-Nishimura, Yukiko; Koyama-Nasu, Ryo; Kawasaki, Yoshihiro; Akiyama, Tetsu

    2015-01-01

    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

  5. 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.

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

    DEFF Research Database (Denmark)

    Espersen, Maiken Lise Marcker; Linnemann, Dorte; Christensen, Ib Jarle

    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...

  7. Conserved regulatory modules in the Sox9 testis-specific enhancer predict roles for SOX, TCF/LEF, Forkhead, DMRT, and GATA proteins in vertebrate sex determination.

    Science.gov (United States)

    Bagheri-Fam, Stefan; Sinclair, Andrew H; Koopman, Peter; Harley, Vincent R

    2010-03-01

    While the primary sex determining switch varies between vertebrate species, a key downstream event in testicular development, namely the male-specific up-regulation of Sox9, is conserved. To date, only two sex determining switch genes have been identified, Sry in mammals and the Dmrt1-related gene Dmy (Dmrt1bY) in the medaka fish Oryzias latipes. In mice, Sox9 expression is evidently up-regulated by SRY and maintained by SOX9 both of which directly activate the core 1.3 kb testis-specific enhancer of Sox9 (TESCO). How Sox9 expression is up-regulated and maintained in species without Sry (i.e. non-mammalian species) is not understood. In this study, we have undertaken an in-depth comparative genomics approach and show that TESCO contains an evolutionarily conserved region (ECR) of 180 bp which is present in marsupials, monotremes, birds, reptiles and amphibians. The ECR contains highly conserved modules that predict regulatory roles for SOX, TCF/LEF, Forkhead, DMRT, and GATA proteins in vertebrate sex determination/differentiation. Our data suggest that tetrapods share common aspects of Sox9 regulation in the testis, despite having different sex determining switch mechanisms. They also suggest that Sox9 autoregulation is an ancient mechanism shared by all tetrapods, raising the possibility that in mammals, SRY evolved by mimicking this regulation. The validation of ECR regulatory sequences conserved from human to frogs will provide new insights into vertebrate sex determination. Copyright 2009 Elsevier Ltd. All rights reserved.

  8. Supernumerary impacted teeth in a patient with SOX2 anophthalmia syndrome.

    Science.gov (United States)

    Numakura, Chikahiko; Kitanaka, Sachiko; Kato, Mitsuhiro; Ishikawa, Shigeo; Hamamoto, Yoshioki; Katsushima, Yuriko; Kimura, Toshiyuki; Hayasaka, Kiyoshi

    2010-09-01

    SOX2 anophthalmia syndrome characteristically presents as anophthalmia or microphthalmia, with various extraocular symptoms, such as hypogonadotropic hypogonadism, brain anomaly, and esophageal abnormalities. In this report, we describe a patient with SOX2 anophthalmia syndrome complicated with a dental anomaly, multiple supernumerary impacted teeth, and persistence of deciduous teeth. Multiple supernumerary teeth are usually not solitary symptoms, but indicate systemic syndrome such as cleidocranial dysplasia. In odontogenesis, many transcriptional factors, such as BMPs, FGFs, and Wnts, play significant roles and SOX2 is known to interact with some of them. The role of SOX2 in dental development remains unknown, however, multiple supernumerary teeth can be considered as extraocular symptoms of SOX2 anophthalmia syndrome, rather than the coincidence of two rare diseases.

  9. [A Case of Rhabdomyolysis Related to SOX Therapy for Liver Metastasis of Gastric Cancer].

    Science.gov (United States)

    Sato, Kei; Akiyama, Hirotoshi; Kogure, Yuu; Suwa, Yusuke; Momiyama, Masashi; Ishibe, Atsushi; Endo, Itaru

    2017-04-01

    We report a case of rhabdomyolysis related to S-1 plus oxaliplatin(SOX)therapy for liver metastasis of gastric cancer. A 76- year-old man who had received SOX therapy for metastatic gastric cancer was admitted to our hospital for a chief complaint of fatigue and weakness. He diagnosed with rhabdomyolysis related to SOX therapy because of his symptoms and because his laboratory studies showed significant elevation of his serum creatine kinase(CK)level. The symptoms disappeared and the CK level normalized following large-volume transfusions. Rhabdomyolysis following SOX therapy is a very rare, but severe adverse event. This is the first detailed case report of rhabdomyolysis related to SOX therapy.

  10. 26 CFR 1.280B-1 - Demolition of structures.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 3 2010-04-01 2010-04-01 false Demolition of structures. 1.280B-1 Section 1... (CONTINUED) INCOME TAXES Items Not Deductible § 1.280B-1 Demolition of structures. (a) In general. Section 280B provides that, in the case of the demolition of any structure, no deduction otherwise allowable...

  11. Determination of aflatoxin B1 in food products in Thailand ...

    African Journals Online (AJOL)

    Aflatoxin B1 is generally found in feed and food stuff, such as cereal and all products derived from cereals, including processed cereals since it has been proven to be at least partly resistant to food processing methods. Hence, the aim of this study was to determine the possibility of contamination of aflatoxin B1 in food ...

  12. 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.

  13. 26 CFR 301.6226(b)-1 - 5-percent group.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false 5-percent group. 301.6226(b)-1 Section 301.6226... ADMINISTRATION PROCEDURE AND ADMINISTRATION Assessment In General § 301.6226(b)-1 5-percent group. (a) In general. All members of a 5-percent group shall join in filing any petition for judicial review. The...

  14. 26 CFR 301.6223(b)-1 - Notice group.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Notice group. 301.6223(b)-1 Section 301.6223(b... ADMINISTRATION PROCEDURE AND ADMINISTRATION Assessment In General § 301.6223(b)-1 Notice group. (a) In general. If a group of partners having in the aggregate a 5 percent or more interest in the profits of a...

  15. Risk assessment of fumonisin B1 in the Netherlands

    NARCIS (Netherlands)

    Bakker MI; Speijers GJA; Paulsch WE; Egmond HP van; SIR; ARO

    2004-01-01

    Fumonisin B1 is a mycotoxin that can be produced by certain Fusarium species. The toxin is found, in particular, in maize and maize products, but occurrence in boeth wheat and wheat products, and rice and rice products, has also been reported. The intake of fumonisin B1 by the population in the

  16. OECD 28-days oral toxicity study on fumonisin B1

    NARCIS (Netherlands)

    Nijs M de; Egmond HP van; Jong WH de; Loveren H van; LPI; ARO; MGB

    1999-01-01

    Het beschreven experiment werd uitgevoerd om inzicht te verkrijgen over effecten van lage doseringen fumonisine B1 op target organen en het immuunsysteem. Mannelijke ratten van drie weken oud werden oraal via maagsonde behandeld met 0, 0,19, 0,75 of 3 mg/kg lichaamsgewicht fumonisine B1,

  17. 78 FR 46579 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-08-01

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-30] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...: FMS case YAD-$22M-16Jan10. (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None...

  18. 76 FR 17111 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-03-28

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-10] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  19. 78 FR 62590 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-10-22

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-43] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None (vii) Sensitivity of...

  20. 76 FR 37071 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-06-24

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-03] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  1. 75 FR 60424 - 36(b)(1) Arms Sales Notifications

    Science.gov (United States)

    2010-09-30

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-28 and 10-30] 36(b)(1) Arms Sales Notifications AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of two section 36(b)(1) arms sales notifications to...

  2. 78 FR 78939 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-12-27

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-68] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...-$98M (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: N/A (vii) Sensitivity of...

  3. 76 FR 37075 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-06-24

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-77] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  4. 76 FR 43659 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-07-21

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-28] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  5. 78 FR 78941 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-12-27

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-70] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... any: FMS Case GAC--$82M--12Mar10 (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid...

  6. 76 FR 27026 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-05-10

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-13] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, Department of Defense. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  7. 76 FR 37078 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-06-24

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-68] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  8. 77 FR 42709 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-07-20

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-24] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... Cases, if any: None (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None (vii...

  9. 77 FR 60384 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-10-03

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-54] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This is...

  10. 76 FR 43662 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-07-21

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-15] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...) Military Department: Navy (AAR) (v) Prior Related Cases, if any: None (vi) Sales Commission, Fee, etc...

  11. 75 FR 61440 - 36(b)(1) Arms Sales Notifications

    Science.gov (United States)

    2010-10-05

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-47, 10-48, and 10-51] 36(b)(1) Arms Sales Notifications AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of three section 36(b)(1) arms sales notifications...

  12. 77 FR 37884 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-06-25

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-19] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... Department: Navy (LAN). (v) Prior Related Cases, if any: None. (vi) Sales Commission, Fee, etc., Paid...

  13. 76 FR 72686 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-11-25

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-47] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This..., if any: FMS Case FAL-$73M-6Apr11 (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed To Be...

  14. 75 FR 29998 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-05-28

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal No. 10-22] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification to fulfill the...

  15. 76 FR 29212 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-05-20

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-75] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, Department of Defense. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  16. 78 FR 26324 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-05-06

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-20] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... Gasoline). (v) Prior Related Cases, if any: Numerous cases dating back to 1995. (vi) Sales Commission, Fee...

  17. 75 FR 48646 - 36(b)(1) Arms Sales Notifications

    Science.gov (United States)

    2010-08-11

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-27, 10-31 and 10-41] 36(b)(1) Arms Sales Notifications AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of three section 36(b)(1) arms sales notifications...

  18. 75 FR 23247 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-05-03

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal No. 10-08] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification to fulfill the...

  19. 76 FR 60461 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-09-29

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-27] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... any: FMS Case JAH-$402 million-11Dec91. FMS Case ZUF-$375 million-22Dec08. (vi) Sales Commission, Fee...

  20. 78 FR 76114 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-12-16

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-66] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None (vii) Sensitivity of Technology...

  1. 77 FR 42711 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-07-20

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-20] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This..., Amd 3). (v) Prior Related Cases, if any: FMS case ULJ-$46M-15Jan10. (vi) Sales Commission, Fee, etc...

  2. 75 FR 27314 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-05-14

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal No. 10-19] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification to fulfill the...

  3. 75 FR 11865 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-03-12

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal No. 10-12] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification to fulfill the...

  4. 78 FR 76112 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-12-16

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-63] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... case LAJ-$22M--8Mar07 FMS case GAU-$45M--25Jul08 FMS case LAL-$293M--5Jan09 (vi) Sales Commission, Fee...

  5. 78 FR 42051 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-07-15

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-26] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... any: None (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None (vii...

  6. 75 FR 76418 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-12-08

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-65] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  7. 75 FR 76415 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-12-08

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-72] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, Department of Defense. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  8. 78 FR 32632 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-05-31

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-28] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...-31Dec06. FMS case NZU-$93 million-19Aug10. (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to...

  9. 75 FR 74011 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-30

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-24] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  10. 78 FR 26326 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-05-06

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-09] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...-20Feb08. (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None. (vii) Sensitivity of...

  11. 78 FR 62600 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-10-22

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-47] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...: None (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed To Be Paid: None (vii) Sensitivity of...

  12. 75 FR 76412 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-12-08

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-69] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, Department of Defense. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  13. 77 FR 60391 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-10-03

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-32] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This is...

  14. 76 FR 60455 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-09-29

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-71] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... support. (iv) Military Department: Army (UJT). (v) Prior Related Cases, if any: None. (vi) Sales...

  15. 75 FR 74014 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-11-30

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-49] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  16. 76 FR 27022 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-05-10

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-12] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, Department of Defense. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  17. 77 FR 60387 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-10-03

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-26] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, DoD. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This is...

  18. 77 FR 51780 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-08-27

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-42] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... support. (iv) Military Department: Air Force (QAZ). (v) Prior Related Cases, if any: None. (vi) Sales...

  19. 78 FR 26328 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-05-06

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-06] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...) Prior Related Cases, if any: FMS case QAA-$301M-3Dec08. (vi) Sales Commission, Fee, etc., Paid, Offered...

  20. 77 FR 70151 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-11-23

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-56] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...: Army (UAK). (v) Prior Related Cases, if any: None. (vi) Sales Commission, Fee, etc., Paid, Offered, or...

  1. 77 FR 13564 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-03-07

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-53] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This..., if any: None (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None (vii...

  2. 78 FR 62588 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-10-22

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-53] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None (vii) Sensitivity of Technology...

  3. 77 FR 12037 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-02-28

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-11] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... support. (iv) Military Department: Navy (SAF). (v) Prior Related Cases, if any: None. (vi) Sales...

  4. 76 FR 60459 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-09-29

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-19] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...-$280 million-29Nov07. (vi) Sales Commission, Fee, etc., Paid, Offered, or Agreed to be Paid: None. (vii...

  5. 75 FR 76408 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2010-12-08

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-73] 36(b)(1) Arms Sales Notification AGENCY: Defense Security Cooperation Agency, Department of Defense. ACTION: Notice. SUMMARY: The Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...

  6. 77 FR 46417 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-08-03

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-39] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...: USA (UAF) (v) Prior Related Cases, if any: FMS case UAD-$95M-23Jan12 (vi) Sales Commission, Fee, etc...

  7. 76 FR 60467 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2011-09-29

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 11-34] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...: a Foreign Military Sales Order II (FMSO II) to provide funds for blanket order requisitions, under...

  8. 78 FR 69073 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-11-18

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-59] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...) Military Department: Air Force (QAH) (v) Prior Related Cases: None (vi) Sales Commission, Fee, etc., Paid...

  9. 78 FR 54242 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-09-03

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-38] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...--$54.3M--5May04 FMS case QZX--$62.4M--24Dec03 FMS case CCZ--$48.4M--12Aug02 [[Page 54244

  10. SOXE transcription factors form selective dimers on non-compact DNA motifs through multifaceted interactions between dimerization and high-mobility group domains.

    Science.gov (United States)

    Huang, Yong-Heng; Jankowski, Aleksander; Cheah, Kathryn S E; Prabhakar, Shyam; Jauch, Ralf

    2015-05-27

    The SOXE transcription factors SOX8, SOX9 and SOX10 are master regulators of mammalian development directing sex determination, gliogenesis, pancreas specification and neural crest development. We identified a set of palindromic SOX binding sites specifically enriched in regulatory regions of melanoma cells. SOXE proteins homodimerize on these sequences with high cooperativity. In contrast to other transcription factor dimers, which are typically rigidly spaced, SOXE group proteins can bind cooperatively at a wide range of dimer spacings. Using truncated forms of SOXE proteins, we show that a single dimerization (DIM) domain, that precedes the DNA binding high mobility group (HMG) domain, is sufficient for dimer formation, suggesting that DIM : HMG rather than DIM:DIM interactions mediate the dimerization. All SOXE members can also heterodimerize in this fashion, whereas SOXE heterodimers with SOX2, SOX4, SOX6 and SOX18 are not supported. We propose a structural model where SOXE-specific intramolecular DIM:HMG interactions are allosterically communicated to the HMG of juxtaposed molecules. Collectively, SOXE factors evolved a unique mode to combinatorially regulate their target genes that relies on a multifaceted interplay between the HMG and DIM domains. This property potentially extends further the diversity of target genes and cell-specific functions that are regulated by SOXE proteins.

  11. SOXE transcription factors form selective dimers on non-compact DNA motifs through multifaceted interactions between dimerization and high-mobility group domains

    Science.gov (United States)

    Huang, Yong-Heng; Jankowski, Aleksander; Cheah, Kathryn S. E.; Prabhakar, Shyam; Jauch, Ralf

    2015-01-01

    The SOXE transcription factors SOX8, SOX9 and SOX10 are master regulators of mammalian development directing sex determination, gliogenesis, pancreas specification and neural crest development. We identified a set of palindromic SOX binding sites specifically enriched in regulatory regions of melanoma cells. SOXE proteins homodimerize on these sequences with high cooperativity. In contrast to other transcription factor dimers, which are typically rigidly spaced, SOXE group proteins can bind cooperatively at a wide range of dimer spacings. Using truncated forms of SOXE proteins, we show that a single dimerization (DIM) domain, that precedes the DNA binding high mobility group (HMG) domain, is sufficient for dimer formation, suggesting that DIM : HMG rather than DIM:DIM interactions mediate the dimerization. All SOXE members can also heterodimerize in this fashion, whereas SOXE heterodimers with SOX2, SOX4, SOX6 and SOX18 are not supported. We propose a structural model where SOXE-specific intramolecular DIM:HMG interactions are allosterically communicated to the HMG of juxtaposed molecules. Collectively, SOXE factors evolved a unique mode to combinatorially regulate their target genes that relies on a multifaceted interplay between the HMG and DIM domains. This property potentially extends further the diversity of target genes and cell-specific functions that are regulated by SOXE proteins. PMID:26013289

  12. SOX2 regulates self-renewal and tumorigenicity of human melanoma-initiating cells.

    Science.gov (United States)

    Santini, R; Pietrobono, S; Pandolfi, S; Montagnani, V; D'Amico, M; Penachioni, J Y; Vinci, M C; Borgognoni, L; Stecca, B

    2014-09-18

    Melanoma is one of the most aggressive types of human cancer, characterized by enhanced heterogeneity and resistance to conventional therapy at advanced stages. We and others have previously shown that HEDGEHOG-GLI (HH-GLI) signaling is required for melanoma growth and for survival and expansion of melanoma-initiating cells (MICs). Recent reports indicate that HH-GLI signaling regulates a set of genes typically expressed in embryonic stem cells, including SOX2 (sex-determining region Y (SRY)-Box2). Here we address the function of SOX2 in human melanomas and MICs and its interaction with HH-GLI signaling. We find that SOX2 is highly expressed in melanoma stem cells. Knockdown of SOX2 sharply decreases self-renewal in melanoma spheres and in putative melanoma stem cells with high aldehyde dehydrogenase activity (ALDH(high)). Conversely, ectopic expression of SOX2 in melanoma cells enhances their self-renewal in vitro. SOX2 silencing also inhibits cell growth and induces apoptosis in melanoma cells. In addition, depletion of SOX2 progressively abrogates tumor growth and leads to a significant decrease in tumor-initiating capability of ALDH(high) MICs upon xenotransplantation, suggesting that SOX2 is required for tumor initiation and for continuous tumor growth. We show that SOX2 is regulated by HH signaling and that the transcription factors GLI1 and GLI2, the downstream effectors of HH-GLI signaling, bind to the proximal promoter region of SOX2 in primary melanoma cells. In functional studies, we find that SOX2 function is required for HH-induced melanoma cell growth and MIC self-renewal in vitro. Thus SOX2 is a critical factor for self-renewal and tumorigenicity of MICs and an important mediator of HH-GLI signaling in melanoma. These findings could provide the basis for novel therapeutic strategies based on the inhibition of SOX2 for the treatment of a subset of human melanomas.

  13. 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

  14. A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle.

    Science.gov (United States)

    Dutton, Kirsten; Abbas, Leila; Spencer, Joanne; Brannon, Claire; Mowbray, Catriona; Nikaido, Masataka; Kelsh, Robert N; Whitfield, Tanya T

    2009-01-01

    In humans, mutations in the SOX10 gene are a cause of the auditory-pigmentary disorder Waardenburg syndrome type IV (WS4) and related variants. SOX10 encodes an Sry-related HMG box protein essential for the development of the neural crest; deafness in WS4 and other Waardenburg syndromes is usually attributed to loss of neural-crest-derived melanocytes in the stria vascularis of the cochlea. However, SOX10 is strongly expressed in the developing otic vesicle and so direct roles for SOX10 in the otic epithelium might also be important. Here, we examine the otic phenotype of zebrafish sox10 mutants, a model for WS4. As a cochlea is not present in the fish ear, the severe otic phenotype in these mutants cannot be attributed to effects on this tissue. In zebrafish sox10 mutants, we see abnormalities in all otic placodal derivatives. Gene expression studies indicate deregulated expression of several otic genes, including fgf8, in sox10 mutants. Using a combination of mutant and morphant data, we show that the three sox genes belonging to group E (sox9a, sox9b and sox10) provide a link between otic induction pathways and subsequent otic patterning: they act redundantly to maintain sox10 expression throughout otic tissue and to restrict fgf8 expression to anterior macula regions. Single-cell labelling experiments indicate a small and transient neural crest contribution to the zebrafish ear during normal development, but this is unlikely to account for the strong defects seen in the sox10 mutant. We discuss the implication that the deafness in WS4 patients with SOX10 mutations might reflect a haploinsufficiency for SOX10 in the otic epithelium, resulting in patterning and functional abnormalities in the inner ear.

  15. Wind tunnel tests of Risø-B1-18 and Risø-B1-24

    DEFF Research Database (Denmark)

    Fuglsang, P.; Bak, Christian; Gaunaa, Mac

    2003-01-01

    This report contains 2D measurements of the Risø-B1-18 and Risø-B1-24 airfoils. The aerodynamic properties were derived from pressure measurements on the airfoil surface and in the wake. The measurements were conducted in the VELUX open jet wind tunnel,which has a background turbulence intensity...

  16. Poisson Coordinates.

    Science.gov (United States)

    Li, Xian-Ying; Hu, Shi-Min

    2013-02-01

    Harmonic functions are the critical points of a Dirichlet energy functional, the linear projections of conformal maps. They play an important role in computer graphics, particularly for gradient-domain image processing and shape-preserving geometric computation. We propose Poisson coordinates, a novel transfinite interpolation scheme based on the Poisson integral formula, as a rapid way to estimate a harmonic function on a certain domain with desired boundary values. Poisson coordinates are an extension of the Mean Value coordinates (MVCs) which inherit their linear precision, smoothness, and kernel positivity. We give explicit formulas for Poisson coordinates in both continuous and 2D discrete forms. Superior to MVCs, Poisson coordinates are proved to be pseudoharmonic (i.e., they reproduce harmonic functions on n-dimensional balls). Our experimental results show that Poisson coordinates have lower Dirichlet energies than MVCs on a number of typical 2D domains (particularly convex domains). As well as presenting a formula, our approach provides useful insights for further studies on coordinates-based interpolation and fast estimation of harmonic functions.

  17. Familial recurrence of SOX2 anophthalmia syndrome: phenotypically normal mother with two affected daughters.

    Science.gov (United States)

    Schneider, Adele; Bardakjian, Tanya M; Zhou, Jie; Hughes, Nkecha; Keep, Rosanne; Dorsainville, Darnelle; Kherani, Femida; Katowitz, James; Schimmenti, Lisa A; Hummel, Marybeth; Fitzpatrick, David R; Young, Terri L

    2008-11-01

    The SOX2 anophthalmia syndrome is emerging as a clinically recognizable disorder that has been identified in 10-15% of individuals with bilateral anophthalmia. Extra-ocular anomalies are common. The majority of SOX2 mutations identified appear to arise de novo in probands ascertained through the presence of anophthalmia or microphthalmia. In this report, we describe two sisters with bilateral anophthalmia/microphthalmia, brain anomalies and a novel heterozygous SOX2 gene single-base pair nucleotide deletion, c.551delC, which predicts p.Pro184ArgfsX19. The hypothetical protein product is predicted to lead to haploinsufficient SOX2 function. Mosaicism for this mutation in the SOX2 gene was also identified in their clinically unaffected mother in peripheral blood DNA. Thus it cannot be assumed that all SOX2 mutations in individuals with anophthalmia/microphthalmia are de novo. Testing of parents is indicated when a SOX2 mutation is identified in a proband. Copyright 2008 Wiley-Liss, Inc.

  18. Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia.

    Science.gov (United States)

    Schneider, Adele; Bardakjian, Tanya; Reis, Linda M; Tyler, Rebecca C; Semina, Elena V

    2009-12-01

    SOX2 represents a High Mobility Group domain containing transcription factor that is essential for normal development in vertebrates. Mutations in SOX2 are known to result in a spectrum of severe ocular phenotypes in humans, also typically associated with other systemic defects. Ocular phenotypes include anophthalmia/microphthalmia (A/M), optic nerve hypoplasia, ocular coloboma and other eye anomalies. We screened 51 unrelated individuals with A/M and identified SOX2 mutations in the coding region of the gene in 10 individuals. Seven of the identified mutations are novel alterations, while the remaining three individuals carry the previously reported recurrent 20-nucleotide deletion in SOX2, c.70del20. Among the SOX2-positive cases, seven patients had bilateral A/M and mutations resulting in premature termination of the normal protein sequence (7/38; 18% of all bilateral cases), one patient had bilateral A/M associated with a single amino acid insertion (1/38; 3% of bilateral cases), and the final two patients demonstrated unilateral A/M associated with missense mutations (2/13; 15% of all unilateral cases). These findings and review of previously reported cases suggest a potential genotype/phenotype correlation for SOX2 mutations with missense changes generally leading to less severe ocular defects. In addition, we report a new familial case of affected siblings with maternal mosaicism for the identified SOX2 mutation, which further underscores the importance of parental testing to provide accurate genetic counseling to families.

  19. Dissecting the role of distinct OCT4-SOX2 heterodimer configurations in pluripotency

    Science.gov (United States)

    Tapia, Natalia; MacCarthy, Caitlin; Esch, Daniel; Gabriele Marthaler, Adele; Tiemann, Ulf; Araúzo-Bravo, Marcos J.; Jauch, Ralf; Cojocaru, Vlad; Schöler, Hans R.

    2015-01-01

    The transcription factors OCT4 and SOX2 are required for generating induced pluripotent stem cells (iPSCs) and for maintaining embryonic stem cells (ESCs). OCT4 and SOX2 associate and bind to DNA in different configurations depending on the arrangement of their individual DNA binding elements. Here we have investigated the role of the different OCT4-SOX2-DNA assemblies in regulating and inducing pluripotency. To this end, we have generated SOX2 mutants that interfere with specific OCT4-SOX2 heterodimer configurations and assessed their ability to generate iPSCs and to rescue ESC self-renewal. Our results demonstrate that the OCT4-SOX2 configuration that dimerizes on a Hoxb1-like composite, a canonical element with juxtaposed individual binding sites, plays a more critical role in the induction and maintenance of pluripotency than any other OCT4-SOX2 configuration. Overall, the results of this study provide new insight into the protein interactions required to establish a de novo pluripotent network and to maintain a true pluripotent cell fate. PMID:26314899

  20. Prolonged Sox4 expression in oligodendrocytes interferes with normal myelination in the central nervous system.

    Science.gov (United States)

    Potzner, Michaela R; Griffel, Carola; Lütjen-Drecoll, Elke; Bösl, Michael R; Wegner, Michael; Sock, Elisabeth

    2007-08-01

    The highly related transcription factors Sox4 and Sox11 are both expressed in oligodendrocyte precursors. Yet whether they have a function in oligodendrocyte development is unknown. By overexpressing Sox4 under the control of 3.1 kb of 5' flanking sequences of the myelin basic protein gene in transgenic mice, we extended Sox4 expression in the oligodendrocyte lineage from oligodendrocyte precursors to cells undergoing terminal differentiation. As a consequence of transgene expression, mice develop the full spectrum of phenotypic traits associated with a severe hypomyelination during the first postnatal weeks. Myelin gene expression was severely reduced, and myelin dramatically thinned in several central nervous system (CNS) regions. Despite these disturbances in CNS myelination, the number of oligodendrocytic cells remained unaltered. Considering that apoptosis rates were normal and proliferation only slightly increased, oligodendrocytes likely persist in a premyelinating to early myelinating state. This shows that prolonged Sox4 expression in cells of the oligodendrocyte lineage is incompatible with the acquisition of a fully mature phenotype and argues that the presence of Sox4, and possibly Sox11, in oligodendrocyte precursors may normally prevent premature differentiation.

  1. Prolonged Sox4 Expression in Oligodendrocytes Interferes with Normal Myelination in the Central Nervous System▿ †

    Science.gov (United States)

    Potzner, Michaela R.; Griffel, Carola; Lütjen-Drecoll, Elke; Bösl, Michael R.; Wegner, Michael; Sock, Elisabeth

    2007-01-01

    The highly related transcription factors Sox4 and Sox11 are both expressed in oligodendrocyte precursors. Yet whether they have a function in oligodendrocyte development is unknown. By overexpressing Sox4 under the control of 3.1 kb of 5′ flanking sequences of the myelin basic protein gene in transgenic mice, we extended Sox4 expression in the oligodendrocyte lineage from oligodendrocyte precursors to cells undergoing terminal differentiation. As a consequence of transgene expression, mice develop the full spectrum of phenotypic traits associated with a severe hypomyelination during the first postnatal weeks. Myelin gene expression was severely reduced, and myelin dramatically thinned in several central nervous system (CNS) regions. Despite these disturbances in CNS myelination, the number of oligodendrocytic cells remained unaltered. Considering that apoptosis rates were normal and proliferation only slightly increased, oligodendrocytes likely persist in a premyelinating to early myelinating state. This shows that prolonged Sox4 expression in cells of the oligodendrocyte lineage is incompatible with the acquisition of a fully mature phenotype and argues that the presence of Sox4, and possibly Sox11, in oligodendrocyte precursors may normally prevent premature differentiation. PMID:17515609

  2. The Sox2 high mobility group transcription factor inhibits mature osteoblast function in transgenic mice

    Science.gov (United States)

    Holmes, Greg; Bromage, Timothy G.; Basilico, Claudio

    2011-01-01

    We have previously shown that in osteoblasts Sox2 expression can be induced by Fgfs, and can inhibit Wnt signaling and differentiation. Furthermore, in mice in which Sox2 is conditionally deleted in the osteoblastic lineage, bones are osteopenic, and Sox2 inactivation in cultured osteoblasts leads to a loss of proliferative ability with a senescent phenotype. To help understand the role of Sox2 in osteoblast development we have specifically expressed Sox2 in bone from a Col1α1 promoter, which extended Sox2 expression into more mature osteoblasts. In long bones, trabecular cartilage remodeling was delayed and the transition from endochondral to cortical bone was disrupted, resulting in porous and undermineralized cortical bone. Collagen deposition was disorganized, and patterns of osteoclast activity were altered. Calvarial bones were thinner and parietal bones failed to develop the diploic space. Microarray analysis showed significant up- or downregulation of a variety of genes coding for non-collagenous extracellular matrix proteins, with a number of genes typical of mature osteoblasts being downregulated. Our results position Sox2 as a negative regulator of osteoblast maturation in vivo. PMID:21703370

  3. Wnt signaling in ovarian development inhibits Sf1 activation of Sox9 via the Tesco enhancer.

    Science.gov (United States)

    Bernard, Pascal; Ryan, Janelle; Sim, Helena; Czech, Daniel P; Sinclair, Andrew H; Koopman, Peter; Harley, Vincent R

    2012-02-01

    Genome analysis of patients with disorders of sex development, and gain- and loss-of-function studies in mice indicate that gonadal development is regulated by opposing signals. In females, the Wnt/β-catenin canonical pathway blocks testicular differentiation by repressing the expression of the Sertoli cell-specific gene Sox9 by an unknown mechanism. Using cell and embryonic gonad culture models, we show that activation of the Wnt/β-catenin pathway inhibits the expression of Sox9 and Amh, whereas mRNA and protein levels of Sry and steroidogenic factor 1 (Sf1), two key transcriptional regulators of Sox9, are not altered. Ectopic activation of Wnt/β-catenin signaling in male gonads led to a loss of Sf1 binding to the Tesco enhancer and absent Sox9 expression that we also observed in wild-type ovaries. Moreover, ectopic Wnt/β-catenin signaling induced the expression of the female somatic cell markers, Bmp2 and Rspo1, as a likely consequence of Sox9 loss. Wnt/β-catenin signaling in XY gonads did not, however, affect gene expression of the steroidogenic Leydig cell Sf1 target gene, Cyp11a1, or Sf1 binding to the Cyp11a1 promoter. Our data support a model in ovary development whereby activation of β-catenin prevents Sf1 binding to the Sox9 enhancer, thereby inhibiting Sox9 expression and Sertoli cell differentiation.

  4. Risk assessment of fumonisin B1 in the Netherlands

    OpenAIRE

    Bakker MI; Speijers GJA; Paulsch WE; van Egmond HP; SIR; ARO

    2004-01-01

    Fumonisin B1 is a mycotoxin that can be produced by certain Fusarium species. The toxin is found, in particular, in maize and maize products, but occurrence in boeth wheat and wheat products, and rice and rice products, has also been reported. The intake of fumonisin B1 by the population in the Netherlands was estimated in an exposure assessment using data on concentrations of fumonisin B1 in different food products combined with the consumption rate of these products. From the (limited) resu...

  5. Characterisation and expression of Sox9 in the Leopard gecko, Eublepharis macularius.

    Science.gov (United States)

    Valleley, E M; Cartwright, E J; Croft, N J; Markham, A F; Coletta, P L

    2001-04-15

    Since the discovery of the sex-determining gene, Sry, a number of genes have been identified which are involved in sex determination and gonadogenesis in mammals. Although Sry is known to be the testis-determining factor in mammals, this is not the case in non-mammalian vertebrates. Sox9 is another gene that has been shown to have a male-specific role in sex determination, but, unlike Sry, Sox9 has been shown to be involved in sex determination in mammals, birds, and reptiles. This is the first gene to be described that has a conserved role in sex determination in species with either chromosomal or environmental sex-determining mechanisms. Many reptiles do not have sex chromosomes but exhibit temperature-dependent sex determination (TSD). Sox9 has been shown to be expressed in both turtle and alligator during gonadogenesis. To determine if Sox9 also has a role in a gecko species with TSD, we studied gonadal expression of Sox9 during embryonic development of the Leopard gecko (Eublepharis macularius). Gecko Sox9 was found to be highly conserved at the nucleotide level when compared to other vertebrate species including human, chick, alligator, and turtle. Sox9 was found to be expressed in embryos incubated at the male-producing temperature (32.5 degrees C) as well as in embryos incubated at the female-producing temperatures (26 and 34 degrees C), Northern blot analysis showed that Sox9 was expressed at both temperatures from morphological stages 31 to 37. mRNA in situ hybridisation on isolated urogenital systems showed expression at both female- and male-producing temperatures up to stage 36. After this stage, no expression was seen in the female gonads but expression remained in the male. These data provide further evidence that Sox9 is an essential component of a testis-determining pathway that is conserved in species with differing sex-determining mechanisms.

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

    Directory of Open Access Journals (Sweden)

    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.

  7. SOX4 expression is associated with treatment failure and chemoradioresistance in oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Yoon, Tae Mi; Kim, Sun-Ae; Cho, Wan Seok; Lee, Dong Hoon; Lee, Joon Kyoo; Park, Young-Lan; Lee, Kyung-Hwa; Lee, Jae Hyuk; Kweon, Sun-Seog; Chung, Ik-Joo; Lim, Sang Chul; Joo, Young-Eun

    2015-01-01

    In humans, sex-determining region-Y (SRY) related high-mobility-group box 4 (SOX4) is linked to development and tumorigenesis. SOX4 is over-expressed in several cancers and has prognostic significance. This study evaluated whether SOX4 affects oncogenic behavior and chemoradiotherapy response in head and neck squamous cell carcinoma (HNSCC) cells, and documented the relationship between its expression and prognosis in oral squamous cell carcinoma (OSCC). We used small interfering RNA in HNSCC cells to evaluate the effect of SOX4 on cell proliferation, apoptosis, chemoradiation-induced apoptosis, invasion, and migration. SOX4 expression in OSCC tissues was investigated by immunohistochemistry. SOX4 knockdown (KO) decreased cell proliferation and induced apoptosis by activating caspases-3 and −7, and poly-ADP ribose polymerase and suppressing X-linked inhibitor of apoptosis protein in HNSCC cells; it also enhanced radiation/cisplatin-induced apoptosis; and suppressed tumor cell invasion and migration. Immunostaining showed SOX4 protein was significantly increased in OSCC tissues compared with adjacent normal mucosa. SOX4 expression was observed in 51.8 % of 85 OSCC tissues, and was significantly correlated with treatment failure (P = 0.032) and shorter overall survival (P = 0.036) in patients with OSCC. SOX4 may contribute to oncogenic phenotypes of HNSCC cells by promoting cell survival and causing chemoradioresistance. It could be a potential prognostic marker for OSCC. The online version of this article (doi:10.1186/s12885-015-1875-8) contains supplementary material, which is available to authorized users

  8. Suppression of SOX18 by siRNA inhibits cell growth and invasion of breast cancer cells.

    Science.gov (United States)

    Zhang, Jianxiang; Ma, Yanmei; Wang, Shoujun; Chen, Fu; Gu, Yuanting

    2016-06-01

    Breast cancer is the most common malignancy in women around the world, and its incidence and mortality rates are still rising. An increasing number of studies have reported that SOX18 plays an important role in various cancers. However, the role of SOX18 in breast cancer remains poorly understood. In this study, we aimed to investigate the biological role and potential molecular mechanism of SOX18 in breast cancer. We found that the mRNA and protein expression levels of SOX18 were prevalently and significantly overexpressed in human breast cancer cell lines. Next, we performed loss-of-function experiments by transfection of two breast cancer cell lines, BT-474 and MCF-7, with SOX18 small interfering RNAs (siRNA). Results showed that SOX18 siRNA transfection significantly suppressed mRNA and protein expression of SOX18 in breast cancer cells. Furthermore, knockdown of SOX18 significantly inhibited cell proliferation and invasion, but promoted apoptosis in breast cancer cells. Importantly, several oncogenic proteins, including the Ras homolog gene family member A (RhoA), platelet-derived growth factor B (PDGFB), Insulin-like growth factor 1 receptor (IGF-1R), and matrix metalloproteinase-7 (MMP-7), were markedly decreased by SOX18 siRNA. Taken together, the results of our study suggest that knockdown of SOX18 inhibits breast cancer cell growth and invasion, possibly by downregulating downstream oncogenic proteins, providing novel insights into the development of breast cancer therapy through targeting of SOX18.

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

    Directory of Open Access Journals (Sweden)

    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

  10. The role of Sox6 in zebrafish muscle fiber type specification.

    Science.gov (United States)

    Jackson, Harriet E; Ono, Yosuke; Wang, Xingang; Elworthy, Stone; Cunliffe, Vincent T; Ingham, Philip W

    2015-01-01

    The transcription factor Sox6 has been implicated in regulating muscle fiber type-specific gene expression in mammals. In zebrafish, loss of function of the transcription factor Prdm1a results in a slow to fast-twitch fiber type transformation presaged by ectopic expression of sox6 in slow-twitch progenitors. Morpholino-mediated Sox6 knockdown can suppress this transformation but causes ectopic expression of only one of three slow-twitch specific genes assayed. Here, we use gain and loss of function analysis to analyse further the role of Sox6 in zebrafish muscle fiber type specification. The GAL4 binary misexpression system was used to express Sox6 ectopically in zebrafish embryos. Cis-regulatory elements were characterized using transgenic fish. Zinc finger nuclease mediated targeted mutagenesis was used to analyse the effects of loss of Sox6 function in embryonic, larval and adult zebrafish. Zebrafish transgenic for the GCaMP3 Calcium reporter were used to assay Ca2+ transients in wild-type and mutant muscle fibres. Ectopic Sox6 expression is sufficient to downregulate slow-twitch specific gene expression in zebrafish embryos. Cis-regulatory elements upstream of the slow myosin heavy chain 1 (smyhc1) and slow troponin c (tnnc1b) genes contain putative Sox6 binding sites required for repression of the former but not the latter. Embryos homozygous for sox6 null alleles expressed tnnc1b throughout the fast-twitch muscle whereas other slow-specific muscle genes, including smyhc1, were expressed ectopically in only a subset of fast-twitch fibers. Ca2+ transients in sox6 mutant fast-twitch fibers were intermediate in their speed and amplitude between those of wild-type slow- and fast-twitch fibers. sox6 homozygotes survived to adulthood and exhibited continued misexpression of tnnc1b as well as smaller slow-twitch fibers. They also exhibited a striking curvature of the spine. The Sox6 transcription factor is a key regulator of fast-twitch muscle fiber differentiation

  11. Osmotic stress upregulates the transcription of thiamine (vitamin B1 ...

    African Journals Online (AJOL)

    Osmotic stress upregulates the transcription of thiamine (vitamin B1) ... Oil palm's responses in terms of the expression profiles of these two thiamine biosynthesis genes to an osmotic stress inducer, polyethylene glycol ... from 32 Countries:.

  12. ACTH Regulation of Adrenal SR-B1

    Directory of Open Access Journals (Sweden)

    Wen-Jun eShen

    2016-05-01

    Full Text Available The adrenal gland is one of the prominent sites for steroid hormone synthesis. Lipoprotein-derived cholesterol esters delivered via scavenger receptor, class B type 1 (SR-B1 constitute the dominant source of cholesterol for steroidogenesis, particularly in rodents. ACTH stimulates steroidogenesis through downstream actions on multiple components involved in steroidogenesis. Both acute and chronic ACTH treatment can modulate SR-B1 function including its transcription, its post transcriptional stability, its phosphorylation and dimerization status, as well as its interaction with other protein partners; all of which result in changes in the ability of SR-B1 to mediate HDL-cholesterol ester uptake and the supply of cholesterol for conversion to steroids. Here we provide a review of the recent findings on the regulation of adrenal SR-B1 function by ACTH.

  13. Overexpression of SOX18 correlates with accelerated cell growth and poor prognosis in human pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Wang, Yazhou; Guo, Huahu; Zhang, Dafang; Yu, Xin; Leng, Xisheng; Li, Shu; Zhu, Weihua

    2016-01-01

    Transcription factor SOX18 has been proved to play a significant role in carcinogenesis. However, no investigation was performed about the expression of SOX18 in pancreatic ductal adenocarcinoma (PDAC). In our work, we found that the PDAC tissues had higher level of SOX18 mRNA and protein expression than matched non-tumor pancreatic tissues and high level of SOX18 protein indicated poor prognosis for PDAC patients. After knockdown of SOX18 gene in PANC-1 and SW1990 cell lines, which showed higher expression level of SOX18 among five PDAC cell lines, the abilities of proliferation, migration and invasion were inhibited and the tumor growth was suppressed in vivo. In addition, the flow cytometry results indicated that down-regulation of SOX18 induced G1/S phase arrest. Furthermore, we found that the expression of cyclin D1, c-myc and MMP-7, three tumorigenesis promoters, was inhabited with downregulation of SOX18. In conclusion, our study reveals that SOX18 plays a significant role in promoting the growth of PDAC, and might serve as a promising target for PDAC therapy. - Highlights: • Overexpression of SOX18 correlates with poor prognosis for pancreatic cancer. • SOX18 promotes pancreatic cancer cell growth in vitro and in vivo. • SOX18 promotes pancreatic cancer cell migration and invasion. • Knockdown of SOX18 induces G1/S phase arrest. • Knockdown of SOX18 induces decrease of cyclin D1, c-myc and MMP-7.

  14. On a generalization of B1( ) on C∗ -algebras

    Indian Academy of Sciences (India)

    Introduction. Let Ж be a complex and separable Hilbert space and let 多 (Ж ) be the set of bounded linear operators on Ж . Let be a open connected subset of complex plane C. A class of Cowen–Douglas operator with index one: B1( ) is defined as follows [6]: B1( ) =: {T ∈ 多 (Ж ): (i). ⊂ σ (T ) =: {λ ∈ C : T − λI is not invertible ...

  15. 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... elapsed and receives the remainder at the end of the week, the payroll period is still the calendar week...

  16. 77 FR 46413 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-08-03

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-29] 36(b)(1) Arms Sales... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This...-$131.7M-15Jun10 FMS case ZUM-$32.1M-15Jun10 FMS case ULU-$150.3M-20Oct10 (vi) Sales Commission, Fee...

  17. [Analysis of SOX10 gene mutation in a family affected with Waardenburg syndrome type II].

    Science.gov (United States)

    Zheng, Lei; Yan, Yousheng; Chen, Xue; Zhang, Chuan; Zhang, Qinghua; Feng, Xuan; Hao, Shen

    2018-02-10

    OBJECTIVE To detect potential mutation of SOX10 gene in a pedigree affected with Warrdenburg syndrome type II. METHODS Genomic DNA was extracted from peripheral blood samples of the proband and his family members. Exons and flanking sequences of MITF, PAX3, SOX10, SNAI2, END3 and ENDRB genes were analyzed by chip capturing and high throughput sequencing. Suspected mutations were verified with Sanger sequencing. RESULTS A c.127C>T (p.R43X) mutation of the SOX10 gene was detected in the proband, for which both parents showed a wild-type genotype. CONCLUSION The c.127C>T (p.R43X) mutation of SOX10 gene probably underlies the ocular symptoms and hearing loss of the proband.

  18. A novel heterozygous SOX2 mutation causing congenital bilateral anophthalmia, hypogonadotropic hypogonadism and growth hormone deficiency.

    Science.gov (United States)

    Macchiaroli, Annamaria; Kelberman, Daniel; Auriemma, Renata Simona; Drury, Suzanne; Islam, Lily; Giangiobbe, Sara; Ironi, Gabriele; Lench, Nicholas; Sowden, Jane C; Colao, Annamaria; Pivonello, Rosario; Cavallo, Luciano; Gasperi, Maurizio; Faienza, Maria Felicia

    2014-01-25

    Heterozygous de novo mutations in SOX2 have been reported in approximately 10-20% of patients with unilateral or bilateral anophthalmia or microphthalmia. An additional phenotype of hypopituitarism, with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, has been reported in patients carrying SOX2 alterations. We report a novel heterozygous mutation in the SOX2 gene in a male affected with congenital bilateral anophthalmia, hypogonadotrophic hypogonadism and growth hormone deficiency. The mutation we describe is a cytosine deletion in position 905 (c905delC) which causes frameshift and an aberrant C-terminal domain. Our report highlights the fact that subjects affected with eye anomalies and harboring SOX2 mutations are at high risk for gonadotropin deficiency, which has important implications for their clinical management. Copyright © 2013 Elsevier B.V. All rights reserved.

  19. Sox17 drives functional engraftment of endothelium converted from non-vascular cells.

    Science.gov (United States)

    Schachterle, William; Badwe, Chaitanya R; Palikuqi, Brisa; Kunar, Balvir; Ginsberg, Michael; Lis, Raphael; Yokoyama, Masataka; Elemento, Olivier; Scandura, Joseph M; Rafii, Shahin

    2017-01-16

    Transplanting vascular endothelial cells (ECs) to support metabolism and express regenerative paracrine factors is a strategy to treat vasculopathies and to promote tissue regeneration. However, transplantation strategies have been challenging to develop, because ECs are difficult to culture and little is known about how to direct them to stably integrate into vasculature. Here we show that only amniotic cells could convert to cells that maintain EC gene expression. Even so, these converted cells perform sub-optimally in transplantation studies. Constitutive Akt signalling increases expression of EC morphogenesis genes, including Sox17, shifts the genomic targeting of Fli1 to favour nearby Sox consensus sites and enhances the vascular function of converted cells. Enforced expression of Sox17 increases expression of morphogenesis genes and promotes integration of transplanted converted cells into injured vessels. Thus, Ets transcription factors specify non-vascular, amniotic cells to EC-like cells, whereas Sox17 expression is required to confer EC function.

  20. Effect of an esterified glucomannan on laying hens exposed to combined mycotoxins (aflatoxin B1, zearalenone and fumonisin B1)

    OpenAIRE

    A. Zaghini; A. Altafini; M. Simioli; L. Rizzi

    2011-01-01

    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...

  1. Novel kinin B1 receptor agonists with improved pharmacological profiles.

    Science.gov (United States)

    Côté, Jérôme; Savard, Martin; Bovenzi, Veronica; Bélanger, Simon; Morin, Josée; Neugebauer, Witold; Larouche, Annie; Dubuc, Céléna; Gobeil, Fernand

    2009-04-01

    There is some evidence to suggest that inducible kinin B1 receptors (B1R) may play beneficial and protecting roles in cardiovascular-related pathologies such as hypertension, diabetes, and ischemic organ diseases. Peptide B1R agonists bearing optimized pharmacological features (high potency, selectivity and stability toward proteolysis) hold promise as valuable therapeutic agents in the treatment of these diseases. In the present study, we used solid-phase methodology to synthesize a series of novel peptide analogues based on the sequence of Sar[dPhe(8)]desArg(9)-bradykinin, a relatively stable peptide agonist with moderate affinity for the human B1R. We evaluated the pharmacological properties of these peptides using (1) in vitro competitive binding experiments on recombinant human B1R and B2R (for index of selectivity determination) in transiently transfected human embryonic kidney 293 cells (HEK-293T cells), (2) ex vivo vasomotor assays on isolated human umbilical veins expressing endogenous human B1R, and (3) in vivo blood pressure tests using anesthetized lipopolysaccharide-immunostimulated rabbits. Key chemical modifications at the N-terminus, the positions 3 and 5 on Sar[dPhe(8)]desArg(9)-bradykinin led to potent analogues. For example, peptides 18 (SarLys[Hyp(3),Cha(5), dPhe(8)]desArg(9)-bradykinin) and 20 (SarLys[Hyp(3),Igl(5), dPhe(8)]desArg(9)-bradykinin) outperformed the parental molecule in terms of affinity, functional potency and duration of action in vitro and in vivo. These selective agonists should be valuable in future animal and human studies to investigate the potential benefits of B1R activation.

  2. Mutations in SOX17 are Associated with Congenital Anomalies of the Kidney and the Urinary Tract

    Science.gov (United States)

    Gimelli, Stefania; Caridi, Gianluca; Beri, Silvana; McCracken, Kyle; Bocciardi, Renata; Zordan, Paola; Dagnino, Monica; Fiorio, Patrizia; Murer, Luisa; Benetti, Elisa; Zuffardi, Orsetta; Giorda, Roberto; Wells, James M; Gimelli, Giorgio; Ghiggeri, Gian Marco

    2010-01-01

    Congenital anomalies of the kidney and the urinary tract (CAKUT) represent a major source of morbidity and mortality in children. Several factors (PAX, SOX,WNT, RET, GDFN, and others) play critical roles during the differentiation process that leads to the formation of nephron epithelia. We have identified mutations in SOX17, an HMG-box transcription factor and Wnt signaling antagonist, in eight patients with CAKUT (seven vesico-ureteric reflux, one pelvic obstruction). One mutation, c.775T>A (p.Y259N), recurred in six patients. Four cases derived from two small families; renal scars with urinary infection represented the main symptom at presentation in all but two patients. Transfection studies indicated a 5–10-fold increase in the levels of the mutant protein relative to wild-type SOX17 in transfected kidney cells. Moreover we observed a corresponding increase in the ability of SOX17 p.Y259N to inhibit Wnt/β-catenin transcriptional activity, which is known to regulate multiple stages of kidney and urinary tract development. In conclusion, SOX17 p.Y259N mutation is recurrent in patients with CAKUT. Our data shows that this mutation correlates with an inappropriate accumulation of SOX17-p.Y259N protein and inhibition of the β-catenin/Wnt signaling pathway. These data indicate a role of SOX17 in human kidney and urinary tract development and implicate the SOX17–p.Y259N mutation as a causative factor in CAKUT. Hum Mutat 31:1352–1359, 2010. © 2010 Wiley-Liss, Inc. PMID:20960469

  3. 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.

  4. B1 gradient coherence selection using a tapered stripline.

    Science.gov (United States)

    van Meerten, S G J; Tijssen, K C H; van Bentum, P J M; Kentgens, A P M

    2018-01-01

    Pulsed-field gradients are common in modern liquid state NMR pulse sequences. They are often used instead of phase cycles for the selection of coherence pathways, thereby decreasing the time required for the NMR experiment. Soft off-resonance pulses with a B 1 gradient result in a spatial encoding similar to that created by pulsed-field (B 0 ) gradients. In this manuscript we show that pulse sequences with pulsed-field gradients can easily be converted to one which uses off-resonance B 1 field gradient (OFFBEAT) pulses. The advantage of B 1 gradient pulses for coherence selection is that the chemical shift evolution during the pulses is (partially) suppressed. Therefore no refocusing echos are required to correct for evolution during the gradient pulses. A tapered stripline is shown to be a convenient tool for creating a well-defined gradient in the B 1 field strength. B 1 gradient coherence selection using a tapered stripline is a simple and cheap alternative to B 0 pulsed-field gradients. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  5. The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner

    International Nuclear Information System (INIS)

    Yano, Fumiko; Kugimiya, Fumitaka; Ohba, Shinsuke; Ikeda, Toshiyuki; Chikuda, Hirotaka; Ogasawara, Toru; Ogata, Naoshi; Takato, Tsuyoshi; Nakamura, Kozo; Kawaguchi, Hiroshi; Chung, Ung-il

    2005-01-01

    To better understand the role of the canonical Wnt signaling pathway in cartilage development, we adenovirally expressed a constitutively active (Canada) or a dominant negative (dn) form of lymphoid enhancer factor-1 (LEF-1), the main nuclear effector of the pathway, in undifferentiated mesenchymal cells, chondrogenic cells, and primary chondrocytes, and examined the expression of markers for chondrogenic differentiation and hypertrophy. caLEF-1 and LiCl, an activator of the canonical pathway, promoted both chondrogenic differentiation and hypertrophy, whereas dnLEF-1 and the gene silencing of β-catenin suppressed LiCl-promoted effects. To investigate whether these effects were dependent on Sox9, a master regulator of cartilage development, we stimulated Sox9-deficient ES cells with the pathway. caLEF-1 and LiCl promoted both chondrogenic differentiation and hypertrophy in wild-type, but not in Sox9-deficient, cells. The response of Sox9-deficient cells was restored by the adenoviral expression of Sox9. Thus, the canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner

  6. A Korean boy with 46,XX testicular disorder of sex development caused by SOX9 duplication.

    Science.gov (United States)

    Lee, Gyung Min; Ko, Jung Min; Shin, Choong Ho; Yang, Sei Won

    2014-06-01

    The 46,XX testicular disorder of sex development (DSD), also known as 46,XX male syndrome, is a rare form of DSD and clinical phenotype shows complete sex reversal from female to male. The sex-determining region Y (SRY) gene can be identified in most 46,XX testicular DSD patients; however, approximately 20% of patients with 46,XX testicular DSD are SRY-negative. The SRY-box 9 (SOX9) gene has several important functions during testis development and differentiation in males, and overexpression of SOX9 leads to the male development of 46,XX gonads in the absence of SRY. In addition, SOX9 duplication has been found to be a rare cause of 46,XX testicular DSD in humans. Here, we report a 4.2-year-old SRY-negative 46,XX boy with complete sex reversal caused by SOX9 duplication for the first time in Korea. He showed normal external and internal male genitalia except for small testes. Fluorescence in situ hybridization and polymerase chain reaction (PCR) analyses failed to detect the presence of SRY, and SOX9 intragenic mutation was not identified by direct sequencing analysis. Therefore, we performed real-time PCR analyses with specific primer pairs, and duplication of the SOX9 gene was revealed. Although SRY-negative 46,XX testicular DSD is a rare condition, an effort to make an accurate diagnosis is important for the provision of proper genetic counseling and for guiding patients in their long-term management.

  7. Sox5 Functions as a Fate Switch in Medaka Pigment Cell Development

    Science.gov (United States)

    Nagao, Yusuke; Suzuki, Takao; Shimizu, Atsushi; Kimura, Tetsuaki; Seki, Ryoko; Adachi, Tomoko; Inoue, Chikako; Omae, Yoshihiro; Kamei, Yasuhiro; Hara, Ikuyo; Taniguchi, Yoshihito; Naruse, Kiyoshi; Wakamatsu, Yuko; Kelsh, Robert N.; Hibi, Masahiko; Hashimoto, Hisashi

    2014-01-01

    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). PMID:24699463

  8. 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.

  9. Disrupted SOX10 function causes spongiform neurodegeneration in gray tremor mice

    Science.gov (United States)

    Anderson, Sarah R.; Lee, Inyoul; Ebeling, Christine; Stephenson, Dennis A.; Schweitzer, Kelsey M.; Baxter, David; Moon, Tara M.; LaPierre, Sarah; Jaques, Benjamin; Silvius, Derek; Wegner, Michael; Hood, Leroy E.; Carlson, George; Gunn, Teresa M.

    2014-01-01

    Mice homozygous for the gray tremor (gt) mutation have a pleiotropic phenotype that includes pigmentation defects, megacolon, whole body tremors, sporadic seizures, hypo- and dysmyelination of the CNS and PNS, vacuolation of the CNS, and early death. Vacuolation similar to that caused by prions was originally reported to be transmissible, but subsequent studies showed the inherited disease was not infectious. The gt mutation mapped to distal mouse chromosome 15, to the same region as Sox10, which encodes a transcription factor with essential roles in neural crest survival and differentiation. As dominant mutations in mouse or human SOX10 cause white spotting and intestinal aganglionosis, we screened the Sox10 coding region for mutations in gt/gt DNA. An adenosine to guanine transversion was identified in exon 2 that changes a highly conserved glutamic acid residue in the SOX10 DNA binding domain to glycine. This mutant allele was not seen in wildtype mice, including the related GT/Le strain, and failed to complement a Sox10 null allele. Gene expression analysis revealed significant down-regulation of genes involved in myelin lipid biosynthesis pathways in gt/gt brains. Knockout mice for some of these genes develop CNS vacuolation and/or myelination defects, suggesting that their down-regulation may contribute to these phenotypes in gt mutants and could underlie the neurological phenotypes associated with Peripheral demyelinating neuropathy-Central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung (PCWH) disease, caused by mutations in human SOX10. PMID:25399070

  10. Long-range activation of Sox9 in Odd Sex (Ods) mice.

    Science.gov (United States)

    Qin, Yangjun; Kong, Ling-kun; Poirier, Christophe; Truong, Cavatina; Overbeek, Paul A; Bishop, Colin E

    2004-06-15

    The Odd Sex mouse mutation arose in a transgenic line of mice carrying a tyrosinase minigene driven by the dopachrome tautomerase (Dct) promoter region. The minigene integrated 0.98 Mb upstream of Sox9 and was accompanied by a deletion of 134 kb. This mutation causes female to male sex reversal in XX Ods/+ mice, and a characteristic eye phenotype of microphthalmia with cataracts in all mice carrying the transgene. Ods causes sex reversal in the absence of Sry by upregulating Sox9 expression and maintaining a male pattern of Sox9 expression in XX Ods/+ embryonic gonads. This expression, which begins at E11.5, triggers downstream events leading to the formation of a testis. We report here that the 134 kb deletion, in itself, is insufficient to cause sex reversal. We demonstrate that in Ods, the Dct promoter is capable of acting over a distance of 1 Mb to induce inappropriate expression of Sox9 in the retinal pigmented epithelium of the eye, causing the observed microphthalmia. In addition, it induces Sox9 expression in the melanocytes where it causes pigmentation defects. We propose that Ods sex reversal is due to the Dct promoter element interacting with gonad-specific enhancer elements to produce the observed male pattern expression of Sox9 in the embryonic gonads.

  11. Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4.

    Science.gov (United States)

    Bondurand, Nadege; Dastot-Le Moal, Florence; Stanchina, Laure; Collot, Nathalie; Baral, Viviane; Marlin, Sandrine; Attie-Bitach, Tania; Giurgea, Irina; Skopinski, Laurent; Reardon, William; Toutain, Annick; Sarda, Pierre; Echaieb, Anis; Lackmy-Port-Lis, Marilyn; Touraine, Renaud; Amiel, Jeanne; Goossens, Michel; Pingault, Veronique

    2007-12-01

    Waardenburg syndrome (WS) is an auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair and skin. Depending on additional symptoms, WS is classified into four subtypes, WS1-WS4. Absence of additional features characterizes WS2. The association of facial dysmorphic features defines WS1 and WS3, whereas the association with Hirschsprung disease (aganglionic megacolon) characterizes WS4, also called "Waardenburg-Hirschsprung disease." Mutations within the genes MITF and SNAI2 have been identified in WS2, whereas mutations of EDN3, EDNRB, and SOX10 have been observed in patients with WS4. However, not all cases are explained at the molecular level, which raises the possibility that other genes are involved or that some mutations within the known genes are not detected by commonly used genotyping methods. We used a combination of semiquantitative fluorescent multiplex polymerase chain reaction and fluorescent in situ hybridization to search for SOX10 heterozygous deletions. We describe the first characterization of SOX10 deletions in patients presenting with WS4. We also found SOX10 deletions in WS2 cases, making SOX10 a new gene of WS2. Interestingly, neurological phenotypes reminiscent of that observed in WS4 (PCWH syndrome [peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, WS, and Hirschsprung disease]) were observed in some WS2-affected patients with SOX10 deletions. This study further characterizes the molecular complexity and the close relationship that links the different subtypes of WS.

  12. Labelling aflatoxine-B1 by radioactive iodine

    International Nuclear Information System (INIS)

    Kim, Y.S.; Park, K.B.; Sung, H.K.; Ryu, Y.W.

    1977-01-01

    Labelling aflatoxines, the potential carcinogenic compounds, by radioactive iodine has been studied. The auflatoxine-B 1 , which is known to be the most abundant components of auflatoxines in the nature, was labelled by radioactive iodine-125 through an acid catalyst chloroamine-T procedure. The radiochemical yield was amounted to 63.6%. The chemical structure of the labelled product was proved to be 6-iodo 5-methoxy coumarine structure of auflatoxine-B 1 molecule by means of I.R. and N.M.R. spectroscopy. The labelled product was orally administered in a test animal (rat) and examined the accumulation of radioactivity in the body at the definite time interval. The accumulation of the radioactivity was pronounced at the blood and the liver. There was no indication of the decomposition of auflatoxine-B 1 - 125 I in the organs of the test animal. (author)

  13. Coordination cycles

    Czech Academy of Sciences Publication Activity Database

    Steiner, Jakub

    -, č. 274 (2005), s. 1-26 ISSN 1211-3298 Institutional research plan: CEZ:AV0Z70850503 Keywords : coordination * crises * cycles and fluctuations Subject RIV: AH - Economics http://www.cerge-ei.cz/pdf/wp/Wp274.pdf

  14. Coordination cycles

    Czech Academy of Sciences Publication Activity Database

    Steiner, Jakub

    2008-01-01

    Roč. 63, č. 1 (2008), s. 308-327 ISSN 0899-8256 Institutional research plan: CEZ:AV0Z70850503 Keywords : global games * coordination * crises * cycles and fluctuations Subject RIV: AH - Economics Impact factor: 1.333, year: 2008

  15. Seasonal behaviour of B0 and B1

    International Nuclear Information System (INIS)

    Mosert Gonzalez, M. de; Radicella, S.M.

    1997-01-01

    A preliminary analysis of the thickness parameter B0 and the shape parameter B1 is presented. Noon electron density profiles recorded at five ionospheric stations during different seasonal and solar activity conditions are used in the study. The results show that both parameters present a seasonal trend with minimum value for B0 during the local winter and maximum during the local summer. This behaviour is inverted for B1. Discrepancies with IRI-90 model are found. (author). 8 refs, 4 figs, 2 tabs

  16. Variability in equatorial B0 and B1

    International Nuclear Information System (INIS)

    Adeniyi, J.O.; Radicella, S.M.

    2002-01-01

    Variability of ionospheric profile parameters B0 and B1, below the F2 peak is investigated for an equatorial station at two levels of solar activities. The whole 24 hours of the day and the four seasons of the year are covered. Absolute and relative variability indices were utilized in the study. Some evidences of correlations of variability index and profiles parameters were observed. Daytime values of relative variability in B1 at solar minimum were found to be greater than those of solar maximum. (author)

  17. RIA determination of aflatoxin B1 in food

    International Nuclear Information System (INIS)

    Bludovsky, R.

    1986-01-01

    The possibility was tested of the application of a commercial RIA kit in determining aflatoxin B 1 in foodstuffs. Stability, sensitivity, specificity and the effect of interfering materials were studied. Alternative methods were tested of sample preparation and a technique was proposed usable for food analysis. The kit was found to be mainly suitable for screening and for the determination of aflatoxin B 1 in concentrations exceedings 1 μg/kg. Lipids were found to cause a systematic positive error and should thus be removed by extraction prior to analysis. (author). 10 tabs., 15 refs

  18. Adsorption of SOX and NOX in activated viscose fibers

    Directory of Open Access Journals (Sweden)

    Ana Carolina O. Plens

    2015-06-01

    Full Text Available SOx and NOx are emissions resulting from combustion processes and are the main agents that contribute to the formation of acid rain, which causes harm to humans and the environment. Several techniques for removing these pollutants are applied in i.e. oil refineries, thermoelectric that use petroleum oils and vehicular pollution. Among these, highlight the adsorption of contaminants by the usage of activated carbon fibers and activated carbon, which are characterized by high surface area and uniform distribution of pores, providing appropriate conditions for application in processes of removing environmental contaminants. In the present work, activated viscose fibers (AVF were prepared and applied in adsorption experiments of NO and SO2. The materials produced showed high values of surface area, with a predominance of micro pores with diameters in the range of 1.0 nm. The AVF had satisfactory performance in the removal of contaminants and are compatible with other synthetic fibers. Thus, the formation of active sites of carbon provides contaminants adsorption, demonstrating that carbon fibers cloth can be applied for the removal of pollutants.

  19. 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

  20. The early human germ cell lineage does not express SOX2 during in vivo development or upon in vitro culture

    DEFF Research Database (Denmark)

    Perrett, Rebecca M; Turnpenny, Lee; Eckert, Judith J

    2008-01-01

    NANOG, POU5F1, and SOX2 are required by the inner cell mass of the blastocyst and act cooperatively to maintain pluripotency in both mouse and human embryonic stem cells. Inadequacy of any one of them causes loss of the undifferentiated state. Mouse primordial germ cells (PGCs), from which...... pluripotent embryonic germ cells (EGCs) are derived, also express POU5F1, NANOG, and SOX2. Thus, a similar expression profile has been predicted for human PGCs. Here we show by RT-PCR, immunoblotting, and immunohistochemistry that human PGCs express POU5F1 and NANOG but not SOX2, with no evidence...... of redundancy within the group B family of human SOX genes. Although lacking SOX2, proliferative human germ cells can still be identified in situ during early development and are capable of culture in vitro. Surprisingly, with the exception of FGF4, many stem cell-restricted SOX2 target genes remained detected...

  1. Osmotic stress upregulates the transcription of thiamine (vitamin B1 ...

    African Journals Online (AJOL)

    Syamimi Mimi

    2016-07-20

    Jul 20, 2016 ... damage tolerance when subjected to abiotic stress. (Machado et al. ... µg/µl of total RNA, 4 µl of 5× Reverse Transcriptase Buffer, 1 µl of 10 mM ..... facilitate vitamin B1 biofortification of plants by genetic engineering;. Front.

  2. 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 a...

  3. 26 CFR 1.269B-1 - Stapled foreign corporations.

    Science.gov (United States)

    2010-04-01

    ... avoidance of U.S. income tax. A stapling of interests may have a principal purpose of tax avoidance even though the tax avoidance purpose is outweighed by other purposes when taken together. (3) Example. The....269B-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX...

  4. 77 FR 68742 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-11-16

    ... missile defense capability, strengthen its homeland defense, and deter regional threats. The proposed sale... Defense System continues to hold a significant technology lead over other surface-to-air missile systems... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-58] 36(b)(1) Arms Sales...

  5. 78 FR 48426 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-08-08

    ... of Technology: 1. The AN/FPS-132 Block 5 supports Missile Defense, Space Situational Awareness, and... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 13-33] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The...

  6. 77 FR 40028 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-07-06

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 12-18] 36(b)(1) Arms Sales Notification AGENCY: Department of Defense, Defense Security Cooperation Agency. ACTION: Notice. SUMMARY: The... proposed sale will require travel of U.S. Government or contractor representatives to Kuwait on a temporary...

  7. 78 FR 26332 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2013-05-06

    ... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... type of mission. 2. The AN/ALE-47 Counter-Measures Dispensing System (CMDS) is an integrated, threat... multiple Optical Sensor Converter (OSC) units, a Computer Processor (CP) and a Control Indicator (CI). The...

  8. 77 FR 27202 - 36(b)(1) Arms Sales Notification

    Science.gov (United States)

    2012-05-09

    ... Department of Defense is publishing the unclassified text of a section 36(b)(1) arms sales notification. This... airframe/outer mold line, Pratt and Whitney engine, radar, integrated core processor central computer... amounts and types of stores, fuel, and other supplies or equipment needed to quickly turn the aircraft for...

  9. 75 FR 41820 - 36(b)(1) Arms Sales Notifications

    Science.gov (United States)

    2010-07-19

    ... DEPARTMENT OF DEFENSE Office of the Secretary [Transmittal Nos. 10-05, 10-11, 10-18, 10-21 and 10-29] 36(b)(1) Arms Sales Notifications AGENCY: Defense Security Cooperation Agency, DoD. ACTION...) arms sales notifications to fulfill the requirements of section 155 of Public Law 104-164, dated 21...

  10. TECHNICAL COORDINATION

    CERN Multimedia

    A. Ball

    Overview From a technical perspective, CMS has been in “beam operation” state since 6th November. The detector is fully closed with all components operational and the magnetic field is normally at the nominal 3.8T. The UXC cavern is normally closed with the radiation veto set. Access to UXC is now only possible during downtimes of LHC. Such accesses must be carefully planned, documented and carried out in agreement with CMS Technical Coordination, Experimental Area Management, LHC programme coordination and the CCC. Material flow in and out of UXC is now strictly controlled. Access to USC remains possible at any time, although, for safety reasons, it is necessary to register with the shift crew in the control room before going down.It is obligatory for all material leaving UXC to pass through the underground buffer zone for RP scanning, database entry and appropriate labeling for traceability. Technical coordination (notably Stephane Bally and Christoph Schaefer), the shift crew and run ...

  11. SOX9 as a Predictor for Neurogenesis Potentiality of Amniotic Fluid Stem Cells

    Science.gov (United States)

    Wei, Pei-Cih; Chao, Angel; Peng, Hsiu-Huei; Chao, An-Shine; Chang, Yao-Lung; Chang, Shuenn-Dyh; Wang, Hsin-Shih; Chang, Yu-Jen; Tsai, Ming-Song; Sieber, Martin; Chen, Hua-Chien; Chen, Shu-Jen; Lee, Yun-Shien

    2014-01-01

    Preclinical studies of amniotic fluid-derived cell therapy have been successful in the research of neurodegenerative diseases, peripheral nerve injury, spinal cord injury, and brain ischemia. Transplantation of human amniotic fluid stem cells (AFSCs) into rat brain ventricles has shown improvement in symptoms of Parkinson's disease and also highlighted the minimal immune rejection risk of AFSCs, even between species. Although AFSCs appeared to be a promising resource for cell-based regenerative therapy, AFSCs contain a heterogeneous pool of distinct cell types, rendering each preparation of AFSCs unique. Identification of predictive markers for neuron-prone AFSCs is necessary before such stem cell-based therapeutics can become a reality. In an attempt to identify markers of AFSCs to predict their ability for neurogenesis, we performed a two-phase study. In the discovery phase of 23 AFSCs, we tested ZNF521/Zfp521, OCT6, SOX1, SOX2, SOX3, and SOX9 as predictive markers of AFSCs for neural differentiation. In the validation phase, the efficacy of these predictive markers was tested in independent sets of 18 AFSCs and 14 dental pulp stem cells (DPSCs). We found that high expression of SOX9 in AFSCs is associated with good neurogenetic ability, and these positive correlations were confirmed in independent sets of AFSCs and DPSCs. Furthermore, knockdown of SOX9 in AFSCs inhibited their neuronal differentiation. In conclusion, the discovery of SOX9 as a predictive marker for neuron-prone AFSCs could expedite the selection of useful clones for regenerative medicine, in particular, in neurological diseases and injuries. PMID:25154783

  12. 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.

  13. Sox2 is translationally activated by eukaryotic initiation factor 4E in human glioma-initiating cells

    Energy Technology Data Exchange (ETDEWEB)

    Ge, Yuqing; Zhou, Fengbiao; Chen, Hong; Cui, Chunhong; Liu, Dan [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Li, Qiuping [Zhongshan Hospital of Fudan University, Shanghai 200032 (China); Yang, Zhiyuan; Wu, Guoqiang [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Sun, Shuhui [Key Laboratory of Medical Molecular Virology, Ministry of Education and Health, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Gu, Jianxin [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Institutes of Biomedical Sciences of Fudan University, Shanghai 200032 (China); Wei, Yuanyan, E-mail: yywei@fudan.edu.cn [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Jiang, Jianhai, E-mail: jianhaijiang@fudan.edu.cn [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China)

    2010-07-09

    Sox2, a master transcription factor, contributes to the generation of induced pluripotent stem cells and plays significant roles in sustaining the self-renewal of neural stem cells and glioma-initiating cells. Understanding the functional differences of Sox2 between glioma-initiating cells and normal neural stem cells would contribute to therapeutic approach for treatment of brain tumors. Here, we first demonstrated that Sox2 could contribute to the self-renewal and proliferation of glioma-initiating cells. The following experiments showed that Sox2 was activated at translational level in a subset of human glioma-initiating cells compared with the normal neural stem cells. Further investigation revealed there was a positive correlation between Sox2 and eukaryotic initiation factor 4E (eIF4E) in glioma tissues. Down-regulation of eIF4E decreased Sox2 protein level without altering its mRNA level in glioma-initiating cells, indicating that Sox2 was activated by eIF4E at translational level. Furthermore, eIF4E was presumed to regulate the expression of Sox2 by its 5' untranslated region (5' UTR) sequence. Our results suggest that the eIF4E-Sox2 axis is a novel mechanism of unregulated self-renewal of glioma-initiating cells, providing a potential therapeutic target for glioma.

  14. Sox2 is translationally activated by eukaryotic initiation factor 4E in human glioma-initiating cells

    International Nuclear Information System (INIS)

    Ge, Yuqing; Zhou, Fengbiao; Chen, Hong; Cui, Chunhong; Liu, Dan; Li, Qiuping; Yang, Zhiyuan; Wu, Guoqiang; Sun, Shuhui; Gu, Jianxin; Wei, Yuanyan; Jiang, Jianhai

    2010-01-01

    Sox2, a master transcription factor, contributes to the generation of induced pluripotent stem cells and plays significant roles in sustaining the self-renewal of neural stem cells and glioma-initiating cells. Understanding the functional differences of Sox2 between glioma-initiating cells and normal neural stem cells would contribute to therapeutic approach for treatment of brain tumors. Here, we first demonstrated that Sox2 could contribute to the self-renewal and proliferation of glioma-initiating cells. The following experiments showed that Sox2 was activated at translational level in a subset of human glioma-initiating cells compared with the normal neural stem cells. Further investigation revealed there was a positive correlation between Sox2 and eukaryotic initiation factor 4E (eIF4E) in glioma tissues. Down-regulation of eIF4E decreased Sox2 protein level without altering its mRNA level in glioma-initiating cells, indicating that Sox2 was activated by eIF4E at translational level. Furthermore, eIF4E was presumed to regulate the expression of Sox2 by its 5' untranslated region (5' UTR) sequence. Our results suggest that the eIF4E-Sox2 axis is a novel mechanism of unregulated self-renewal of glioma-initiating cells, providing a potential therapeutic target for glioma.

  15. Sox9 is required for precursor cell expansion and extracellular matrix organization during mouse heart valve development.

    Science.gov (United States)

    Lincoln, Joy; Kist, Ralf; Scherer, Gerd; Yutzey, Katherine E

    2007-05-01

    Heart valve structures derived from mesenchymal cells of the endocardial cushions (ECs) are composed of highly organized cell lineages and extracellular matrix. Sox9 is a transcription factor required for both early and late stages of cartilage formation that is also expressed in the developing valves of the heart. The requirements for Sox9 function during valvulogenesis and adult valve homeostasis in mice were examined by conditional inactivation of Sox9 using Tie2-cre and Col2a1-cre transgenes. Sox9(flox/flox);Tie2-cre mice die before E14.5 with hypoplastic ECs, reduced cell proliferation and altered extracellular matrix protein (ECM) deposition. Sox9(flox/flox);Col2a1-cre mice die at birth with thickened heart valve leaflets, reduced expression of cartilage-associated proteins and abnormal ECM patterning. Thickened valve leaflets and calcium deposits, characteristic of valve disease, are observed in heterozygous adult Sox9(flox/+);Col2a1-cre mice. Therefore, Sox9 is required early in valve development for expansion of the precursor cell population and later is required for normal expression and distribution of valvular ECM proteins. These data indicate that Sox9 is required for early and late stages of valvulogenesis and identify a potential role for Sox9 in valve disease mechanisms.

  16. Identification and functional analysis of SOX10 missense mutations in different subtypes of Waardenburg syndrome.

    Science.gov (United States)

    Chaoui, Asma; Watanabe, Yuli; Touraine, Renaud; Baral, Viviane; Goossens, Michel; Pingault, Veronique; Bondurand, Nadege

    2011-12-01

    Waardenburg syndrome (WS) is a rare disorder characterized by pigmentation defects and sensorineural deafness, classified into four clinical subtypes, WS1-S4. Whereas the absence of additional features characterizes WS2, association with Hirschsprung disease defines WS4. WS is genetically heterogeneous, with six genes already identified, including SOX10. About 50 heterozygous SOX10 mutations have been described in patients presenting with WS2 or WS4, with or without myelination defects of the peripheral and central nervous system (PCWH, Peripheral demyelinating neuropathy-Central dysmyelinating leukodystrophy-Waardenburg syndrome-Hirschsprung disease, or PCW, PCWH without HD). The majority are truncating mutations that most often remove the main functional domains of the protein. Only three missense mutations have been thus far reported. In the present study, novel SOX10 missense mutations were found in 11 patients and were examined for effects on SOX10 characteristics and functions. The mutations were associated with various phenotypes, ranging from WS2 to PCWH. All tested mutations were found to be deleterious. Some mutants presented with partial cytoplasmic redistribution, some lost their DNA-binding and/or transactivation capabilities on various tissue-specific target genes. Intriguingly, several mutants were redistributed in nuclear foci. Whether this phenomenon is a cause or a consequence of mutation-associated pathogenicity remains to be determined, but this observation could help to identify new SOX10 modes of action. © 2011 Wiley-Liss, Inc.

  17. 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.

  18. Duplication of SOX9 associated with 46,XX ovotesticular disorder of sex development.

    Science.gov (United States)

    López-Hernández, Berenice; Méndez, Juan Pablo; Coral-Vázquez, Ramón Mauricio; Benítez-Granados, Jesús; Zenteno, Juan Carlos; Villegas-Ruiz, Vanessa; Calzada-León, Raúl; Soderlund, Daniela; Canto, Patricia

    2018-04-04

    The purpose of the present study was to investigate whether ten unrelated SRY-negative individuals with this sex differentiation disorder presented a double dose of SOX9 as the cause of their disease. Ten unrelated SRY-negative 46,XX ovotesticular disorder of sexual development (DSD) subjects were molecularly studied. Multiplex-ligation dependent probe amplification (MLPA) and quantitative real-time PCR analysis (qRT-PCR) for SOX9 were performed. The MLPA analysis demonstrated that one patient presented a heterozygous duplication of the entire SOX9 coding region (above 1.3 value of peak ratio), as well as at least a ~ 483 kb upstream duplication. Moreover, no duplication of other SOX9 probes was observed corresponding to the region between -1007 and -1500 kb upstream. A qRT-PCR analysis showed a duplication of at least -581 kb upstream and ~1.63 kb of the coding region that encompasses exon 3. The limits of the duplication were mapped approximately from ~71539762 to 72122741 of Chr17. No molecular abnormalities were found in the remaining nine patients. This study is thought to be the first report regarding a duplication of SOX9 that is associated with the presence of 46,XX ovotesticular DSD, encompassing at least -581 kb upstream, and the almost entire coding region of the gene. Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  19. Identification of a polyoxometalate inhibitor of the DNA binding activity of Sox2.

    Science.gov (United States)

    Narasimhan, Kamesh; Pillay, Shubhadra; Bin Ahmad, Nor Rizal; Bikadi, Zsolt; Hazai, Eszter; Yan, Li; Kolatkar, Prasanna R; Pervushin, Konstantin; Jauch, Ralf

    2011-06-17

    Aberrant expression of transcription factors is a frequent cause of disease, yet drugs that modulate transcription factor protein-DNA interactions are presently unavailable. To this end, the chemical tractability of the DNA binding domain of the stem cell inducer and oncogene Sox2 was explored in a high-throughput fluorescence anisotropy screen. The screening revealed a Dawson polyoxometalate (K(6)[P(2)Mo(18)O(62)]) as a direct and nanomolar inhibitor of the DNA binding activity of Sox2. The Dawson polyoxometalate (Dawson-POM) was found to be selective for Sox2 and related Sox-HMG family members when compared to unrelated paired and zinc finger DNA binding domains. [(15)N,(1)H]-Transverse relaxation optimized spectroscopy (TROSY) experiments coupled with docking studies suggest an interaction site of the POM on the Sox2 surface that enabled the rationalization of its inhibitory activity. The unconventional molecular scaffold of the Dawson-POM and its inhibitory mode provides strategies for the development of drugs that modulate transcription factors.

  20. Coordinating controls

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    1986-07-15

    While physics Laboratories are having to absorb cuts in resources, the machines they rely on are becoming more and more complex, requiring increasingly sophisticated systems. Rather than being a resourceful engineer or physicist able to timber together solutions in his 'backyard', the modern controls specialist has become a professional in his own right. Because of possible conflicts between increasing sophistication on one hand and scarcer resources on the other, there was felt a need for more contacts among controls specialists to exchange experiences, coordinate development and discuss 'family problems', away from meetings where the main interest is on experimental physics.

  1. Coordinated unbundling

    DEFF Research Database (Denmark)

    Timmermans, Bram; Zabala-Iturriagagoitia, Jon Mikel

    2013-01-01

    Public procurement for innovation is a matter of using public demand to trigger innovation. Empirical studies have demonstrated that demand-based policy instruments can be considered to be a powerful tool in stimulating innovative processes among existing firms; however, the existing literature has...... not focused on the role this policy instrument can play in the promotion of (knowledge-intensive) entrepreneurship. This paper investigates this link in more detail and introduces the concept of coordinated unbundling as a strategy that can facilitate this purpose. We also present a framework on how...

  2. Coordinating controls

    International Nuclear Information System (INIS)

    Anon.

    1986-01-01

    While physics Laboratories are having to absorb cuts in resources, the machines they rely on are becoming more and more complex, requiring increasingly sophisticated systems. Rather than being a resourceful engineer or physicist able to timber together solutions in his 'backyard', the modern controls specialist has become a professional in his own right. Because of possible conflicts between increasing sophistication on one hand and scarcer resources on the other, there was felt a need for more contacts among controls specialists to exchange experiences, coordinate development and discuss 'family problems', away from meetings where the main interest is on experimental physics

  3. 26 CFR 1.367(b)-1 - Other transfers.

    Science.gov (United States)

    2010-04-01

    ... its successor in interest) that the shareholder is making the election described in § 1.367(b)-3(c)(3... paragraph (c)(2)— (i) A shareholder described in § 1.367(b)-3(b)(1) that realizes income in a transaction described in § 1.367(b)-3(a); (ii) A shareholder that makes the election described in § 1.367(b)-3(c)(3...

  4. CobB1 deacetylase activity in Streptomyces coelicolor

    Czech Academy of Sciences Publication Activity Database

    Mikulík, Karel; Felsberg, Jürgen; Kudrnáčová, E.; Bezoušková, Silvia; Šetinová, Dita; Stodůlková, Eva; Zídková, J.; Zídek, Václav

    2012-01-01

    Roč. 90, č. 2 (2012), s. 179-187 ISSN 0829-8211 R&D Projects: GA AV ČR(CZ) IAA500110805; GA ČR GA303/09/0475 Institutional research plan: CEZ:AV0Z50110509; CEZ:AV0Z50200510 Keywords : sirtuin * NAD(+)dependent deacetylation activity CobB1 * Streptomyces coeliocolor Subject RIV: EE - Microbiology, Virology Impact factor: 2.915, year: 2012

  5. Biochemical characterization of the GM2 gangliosidosis B1 variant

    Directory of Open Access Journals (Sweden)

    Tutor J.C.

    2004-01-01

    Full Text Available The deficiency of the A isoenzyme of ß-hexosaminidase (Hex produced by different mutations of the gene that codes for the alpha subunit (Tay-Sachs disease has two variants with enzymological differences: the B variant consists of the absence of Hex A isoenzyme and the B1 variant produces an inactive Hex A isoenzyme for the hydrolysis of the GM2 ganglioside and synthetic substrates with negative charge. In contrast to the early childhood form of the B variant, the B1 variant appears at a later clinical stage (3 to 7 years of age with neurodegenerative symptoms leading to the death of the patient in the second decade of life. The most frequent mutation responsible for the GM2 gangliosidosis B1 variant is R178H, which has a widespread geographic and ethnic distribution. The highest incidence has been described in Portugal, which has been suggested as the point of origin of this mutation. Biochemical characterization of this lysosomal disease is carried out using negatively charged synthetic alpha subunit-specific sulfated substrates, since Hex A isoenzyme heat-inactivation assays are not applicable. However, the determination of the apparent activation energy of Hex using the neutral substrate 3,3'-dichlorophenolsulfonphthaleinyl N-acetyl-ß-D-glucosaminide, may offer a valid alternative. The presence of an alpha subunit in the alphaß heterodimer Hex A means that its activation energy (41.8 kJ/mol is significantly lower than that of the ßß homodimer Hex B (75.1 kJ/mol; however, as mutation inactivates the alpha subunit, the Hex A of the B1 variant presents an activation energy that is similar to that of the Hex B isoenzyme.

  6. Analysis of SOX10 mutations identified in Waardenburg-Hirschsprung patients: Differential effects on target gene regulation.

    Science.gov (United States)

    Chan, Kwok Keung; Wong, Corinne Kung Yen; Lui, Vincent Chi Hang; Tam, Paul Kwong Hang; Sham, Mai Har

    2003-10-15

    SOX10 is a member of the SOX gene family related by homology to the high-mobility group (HMG) box region of the testis-determining gene SRY. Mutations of the transcription factor gene SOX10 lead to Waardenburg-Hirschsprung syndrome (Waardenburg-Shah syndrome, WS4) in humans. A number of SOX10 mutations have been identified in WS4 patients who suffer from different extents of intestinal aganglionosis, pigmentation, and hearing abnormalities. Some patients also exhibit signs of myelination deficiency in the central and peripheral nervous systems. Although the molecular bases for the wide range of symptoms displayed by the patients are still not clearly understood, a few target genes for SOX10 have been identified. We have analyzed the impact of six different SOX10 mutations on the activation of SOX10 target genes by yeast one-hybrid and mammalian cell transfection assays. To investigate the transactivation activities of the mutant proteins, three different SOX target binding sites were introduced into luciferase reporter gene constructs and examined in our series of transfection assays: consensus HMG domain protein binding sites; SOX10 binding sites identified in the RET promoter; and Sox10 binding sites identified in the P0 promoter. We found that the same mutation could have different transactivation activities when tested with different target binding sites and in different cell lines. The differential transactivation activities of the SOX10 mutants appeared to correlate with the intestinal and/or neurological symptoms presented in the patients. Among the six mutant SOX10 proteins tested, much reduced transactivation activities were observed when tested on the SOX10 binding sites from the RET promoter. Of the two similar mutations X467K and 1400del12, only the 1400del12 mutant protein exhibited an increase of transactivation through the P0 promoter. While the lack of normal SOX10 mediated activation of RET transcription may lead to intestinal aganglionosis

  7. Wind tunel tests of Risoe-B1-18 and Risoe-B1-24

    Energy Technology Data Exchange (ETDEWEB)

    Fuglsang, P.; Bak, C.; Gaunaa, M.; Antoniou, I.

    2003-01-01

    This report contains 2D measurements of the Risoe-B1-18 and Risoe-B1-24 airfoils. The aerodynamic properties were derived from pressure measurements on the airfoil surface and in the wake. The measurements were conducted in the VELUX open jet wind tunnel, which has a background turbulence intensity of 1%, and an inlet flow velocity of 42 m/s. The airfoil sections had a chord of 0.600 m giving a Reynolds number of 1.6Oe106. The span was 1.9 m and end plates were used to minimize 3D flow effects. The measurements comprised both static and dynamic inflow. Static inflow covered angles of attack from 5o to 30 deg. Dynamic inflow was obtained by pitching the airfoil in a harmonic motion around various mean angles of attack. The test matrix involved smooth flow, various kinds of leading edge roughness, stall strips, vortex generators and Gurney flaps in different combinations. The quality of the measurements was good and the agreement between measurements and numerical CFD predictions with EllipSys2D was good. For both airfoils predictions with turbulent flow captured very well the shapes of lift and drag curves as well as the magnitude of maximum lift. Measurements of Risoe-B1-18 showed that the maximum lift coefficient was 1.64 at an angle of attack of approximately 13 deg. The airfoil was not very sensitive to leading edge roughness despite its high maximum lift. Measurements with stall strips showed that stall strips could control the level of maximum lift. The Risoe-B1-24 measurements showed that the maximum lift coefficient was 1.62 at an angle of attack of approximately 14 deg. The airfoil was only little sensitive to leading edge roughness despite its high relative thickness and high maximum lift. Measurements with delta wing shaped vortex generators increased the maximum lift coefficient to 2.02 and measurements with Gurney flaps increased the maximum lift coefficient to 1.85. Measurements with combination of vortex generators and Gurney flaps showed a maximum

  8. TECHNICAL COORDINATION

    CERN Multimedia

    A. Ball

    2010-01-01

    Operational Experience At the end of the first full-year running period of LHC, CMS is established as a reliable, robust and mature experiment. In particular common systems and infrastructure faults accounted for <0.6 % CMS downtime during LHC pp physics. Technical operation throughout the entire year was rather smooth, the main faults requiring UXC access being sub-detector power systems and rack-cooling turbines. All such problems were corrected during scheduled technical stops, in the shadow of tunnel access needed by the LHC, or in negotiated accesses or access extensions. Nevertheless, the number of necessary accesses to the UXC averaged more than one per week and the technical stops were inevitably packed with work packages, typically 30 being executed within a few days, placing a high load on the coordination and area management teams. It is an appropriate moment for CMS Technical Coordination to thank all those in many CERN departments and in the Collaboration, who were involved in CMS techni...

  9. 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

  10. 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...

  11. A novel heterozygous SOX2 mutation causing anophthalmia/microphthalmia with genital anomalies.

    Science.gov (United States)

    Pedace, Lucia; Castori, Marco; Binni, Francesco; Pingi, Alberto; Grammatico, Barbara; Scommegna, Salvatore; Majore, Silvia; Grammatico, Paola

    2009-01-01

    Anophthalmia/microphthalmia is a rare developmental craniofacial defect, which recognizes a wide range of causes, including chromosomal abnormalities, single-gene mutations as well as environmental factors. Heterozygous mutations in the SOX2 gene are the most common monogenic form of anophthalmia/microphthalmia, as they are reported in up to 10-15% cases. Here, we describe a sporadic patient showing bilateral anophthalmia/microphthalmia and micropenis caused by a novel mutation (c.59_60insGG) in the SOX2 gene. Morphological and endocrinological evaluations excluded any anomaly of the hypothalamus-pituitary axis. Our finding supports the hypothesis that SOX2 is particularly prone to slipped-strand mispairing, which results in a high frequency of point deletions/insertions.

  12. Recurrent SOX9 deletion campomelic dysplasia due to somatic mosaicism in the father.

    Science.gov (United States)

    Smyk, M; Obersztyn, E; Nowakowska, B; Bocian, E; Cheung, S W; Mazurczak, T; Stankiewicz, P

    2007-04-15

    Haploinsufficiency of SOX9, a master gene in chondrogenesis and testis development, leads to the semi-lethal skeletal malformation syndrome campomelic dysplasia (CD), with or without XY sex reversal. We report on two children with CD and a phenotypically normal father, a carrier of a somatic mosaic SOX9 deletion. This is the first report of a mosaic deletion of SOX9; few familial CD cases with germline and somatic mutation mosaicism have been described. Our findings confirm the utility of aCGH and indicate that for a more accurate estimate of the recurrence risk for a completely penetrant autosomal dominant disorder, parental somatic mosaicism should be considered in healthy parents. Copyright 2007 Wiley-Liss, Inc.

  13. A family with X-linked anophthalmia: exclusion of SOX3 as a candidate gene.

    Science.gov (United States)

    Slavotinek, Anne; Lee, Stephen S; Hamilton, Steven P

    2005-10-01

    We report on a four-generation family with X-linked anophthalmia in four affected males and show that this family has LOD scores consistent with linkage to Xq27, the third family reported to be linked to the ANOP1 locus. We sequenced the SOX3 gene at Xq27 as a candidate gene for the X-linked anophthalmia based on the high homology of this gene to SOX2, a gene previously mutated in bilateral anophthlamia. However, no amino acid sequence alterations were identified in SOX3. We have improved the definition of the phenotype in males with anophthalmia linked to the ANOP1 locus, as microcephaly, ocular colobomas, and severe renal malformations have not been described in families linked to ANOP1. (c) 2005 Wiley-Liss, Inc.

  14. A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease.

    Science.gov (United States)

    Sznajer, Yves; Coldéa, Cristina; Meire, Françoise; Delpierre, Isabelle; Sekhara, Tayeb; Touraine, Renaud L

    2008-04-15

    Type 4 Waardenburg syndrome represents a well define entity caused by neural crest derivatives anomalies (melanocytes, intrinsic ganglion cells, central, autonomous and peripheral nervous systems) leading, with variable expressivity, to pigmentary anomalies, deafness, mental retardation, peripheral neuropathy, and Hirschsprung disease. Autosomal dominant mode of inheritance is prevalent when Sox10 gene mutation is identified. We report the natural history of a child who presented with synophrys, vivid blue eye, deafness, bilateral complete semicircular canals agenesis with mental retardation, subtle signs for peripheral neuropathy and lack of Hirschsprung disease. SOX10 gene sequencing identified "de novo" splice site mutation (c.698-2A > C). The present phenotype and the genotype findings underline the wide spectrum of SOX10 gene implication in unusual type 4 Waardenburg syndrome patient. Copyright 2008 Wiley-Liss, Inc.

  15. The epigenetic regulation of SOX9 by miR-145 in human chondrosarcoma.

    Science.gov (United States)

    Mak, Isabella W Y; Singh, Shalini; Turcotte, Robert; Ghert, Michelle

    2015-01-01

    Chondrosarcoma is the most common primary bone malignancy in the adult population with a high rate of pulmonary metastasis. Chondrosarcoma is managed with surgical excision as the tumors do not respond well to conventional chemotherapy or radiation therapy. Thus, there exists a dire need to develop systemic treatment options to target chondrosarcoma cells for metastatic spread. We hypothesized that the expression of miR-145 is low in chondrosarcoma, leading to decreased transcriptional control of SOX9 (the master regulator of chondrogenesis), and downstream activation of the transcription factor ETV5. We have previously shown that ETV5 activates MMP-2 expression in chondrosarcoma, which in turn increases local bone matrix resorption. In this study, we confirm high expression of SOX9 in human chondrosarcoma using real-time PCR, Western blotting, and immunofluorescence. An ETV5 promoter-reporter plasmid was transfected into chondrosarcoma cells to determine if SOX9 directly regulates the expression of ETV5. Co-transfection of the ETV5 promoter-plasmid with SOX9 lentivirus significantly increased the luciferase activity derived from the ETV5 promoter, from which the regulatory relationship between SOX9 and ETV5 is established. MiR-145 was found to be down-regulated in chondrosarcoma cell lines, patient samples, and further confirmed with a public sarcoma database. After stable miR-145 lentiviral transfection, the subsequent mRNA expression levels of SOX9, ETV5, and MMP-2 were significantly decreased in chondrosarcoma cells. The results generated by this study may have important clinical significance in the treatment of patients with chondrosarcoma in that targeted miRNA may have the potential to downregulate the upstream activators of proteases such as MMP-2. © 2014 Wiley Periodicals, Inc.

  16. Podoplanin and SOX2 Expression in CIN 3-like Squamous Cell Carcinoma of the Cervix.

    Science.gov (United States)

    Stewart, Colin J R; Crook, Maxine L

    2018-01-01

    Squamous cell carcinoma (SCC) of the uterine cervix occasionally demonstrates a deceptive growth pattern that mimics endocervical crypt involvement by cervical intraepithelial neoplasia, grade 3 (CIN 3). Such CIN 3-like SCCs may be misinterpreted as noninvasive or minimally invasive leading to delays in diagnosis. Little is known of the factors that influence the growth patterns of cervical SCC but we suggested recently that CIN 3-like tumors might demonstrate "collective cellular invasion," which is characterized by a retained epithelial phenotype. This contrasts with the more overtly infiltrative growth of conventional SCC, which exhibits features suggestive of epithelial-mesenchymal transition. In the current study we investigated podoplanin (PP) and SOX2 expression in normal squamous epithelium, in CIN 3 and in 16 CIN 3-like SCCs 11 of which also showed a conventional invasive component. Compared with normal epithelium, CIN 3 often showed a focal loss of basal PP staining and most cases showed increased, typically diffuse, SOX2 expression. Although the immunohistochemical findings were not uniform, they generally supported collective cellular invasion in CIN 3-like tumor areas as these were often PP positive and showed diffuse SOX2 expression. In contrast, most conventional SCCs showed only focal SOX2 staining and they were typically negative, or only focally positive, for PP. The staining patterns did not reliably distinguish CIN 3 from CIN 3-like SCC. Small infiltrative tumor nests around the margins of CIN 3 or deeply invasive CIN 3-like SCC often showed a localized reduction in SOX2 expression suggesting SOX2 downregulation during the transition to invasive growth.

  17. Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness.

    Science.gov (United States)

    Pingault, Veronique; Bodereau, Virginie; Baral, Viviane; Marcos, Severine; Watanabe, Yuli; Chaoui, Asma; Fouveaut, Corinne; Leroy, Chrystel; Vérier-Mine, Odile; Francannet, Christine; Dupin-Deguine, Delphine; Archambeaud, Françoise; Kurtz, François-Joseph; Young, Jacques; Bertherat, Jérôme; Marlin, Sandrine; Goossens, Michel; Hardelin, Jean-Pierre; Dodé, Catherine; Bondurand, Nadege

    2013-05-02

    Transcription factor SOX10 plays a role in the maintenance of progenitor cell multipotency, lineage specification, and cell differentiation and is a major actor in the development of the neural crest. It has been implicated in Waardenburg syndrome (WS), a rare disorder characterized by the association between pigmentation abnormalities and deafness, but SOX10 mutations cause a variable phenotype that spreads over the initial limits of the syndrome definition. On the basis of recent findings of olfactory-bulb agenesis in WS individuals, we suspected SOX10 was also involved in Kallmann syndrome (KS). KS is defined by the association between anosmia and hypogonadotropic hypogonadism due to incomplete migration of neuroendocrine gonadotropin-releasing hormone (GnRH) cells along the olfactory, vomeronasal, and terminal nerves. Mutations in any of the nine genes identified to date account for only 30% of the KS cases. KS can be either isolated or associated with a variety of other symptoms, including deafness. This study reports SOX10 loss-of-function mutations in approximately one-third of KS individuals with deafness, indicating a substantial involvement in this clinical condition. Study of SOX10-null mutant mice revealed a developmental role of SOX10 in a subpopulation of glial cells called olfactory ensheathing cells. These mice indeed showed an almost complete absence of these cells along the olfactory nerve pathway, as well as defasciculation and misrouting of the nerve fibers, impaired migration of GnRH cells, and disorganization of the olfactory nerve layer of the olfactory bulbs. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  18. 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.

  19. Expression of SRY-related HMG Box Transcription Factors (Sox) 2 and 9 in Craniopharyngioma Subtypes and Surrounding Brain Tissue.

    Science.gov (United States)

    Thimsen, Vivian; John, Nora; Buchfelder, Michael; Flitsch, Jörg; Fahlbusch, Rudolf; Stefanits, Harald; Knosp, Engelbert; Losa, Marco; Buslei, Rolf; Hölsken, Annett

    2017-11-20

    Stem cells have been discovered as key players in the genesis of different neoplasms including craniopharyngioma (CP), a rare tumour entity in the sellar region. Sox2 and Sox9 are well-known stem cell markers involved in pituitary development. In this study we analysed the expression of both transcription factors using immunohistochemistry in a large cohort of 64 adamantinomatous (aCP) and 9 papillary CP (pCP) and quantitative PCR in 26 aCP and 7 pCP. Whereas immunohistochemically Sox2+ cells were verifiable in only five aCP (7.8%) and in 39.1% of the respective surrounding cerebral tissue, pCP specimens appeared always negative. In contrast, Sox9 was detectable in all tumours with a significantly higher expression in aCP compared to pCP (protein, p < 0.0001; mRNA p = 0.0484) This was also true for the respective tumour adjacent CNS where 63 aCP (98.4%) and six pCP (66.7%) showed Sox9+ cells. We further confirmed absence of Sox9 expression in nuclear β-catenin accumulating cells of aCP. Our results point to the conclusion that Sox2 and Sox9, seem to play essential roles not only in the specific formation of aCP, but also in processes involving the cerebral tumour environment, which needs to be illuminated in the future.

  20. The promotion of cartilage defect repair using adenovirus mediated Sox9 gene transfer of rabbit bone marrow mesenchymal stem cells.

    Science.gov (United States)

    Cao, Lei; Yang, Fei; Liu, Guangwang; Yu, Degang; Li, Huiwu; Fan, Qiming; Gan, Yaokai; Tang, Tingting; Dai, Kerong

    2011-06-01

    Although Sox9 is essential for chondrogenic differentiation and matrix production, its application in cartilage tissue engineering has been rarely reported. In this study, the chondrogenic effect of Sox9 on bone marrow mesenchymal stem cells (BMSCs) in vitro and its application in articular cartilage repair in vivo were evaluated. Rabbit BMSCs were transduced with adenoviral vector containing Sox9. Toluidine blue, safranin O staining and real-time PCR were performed to check chondrogenic differentiation. The results showed that Sox9 could induce chondrogenesis of BMSCs both in monolayer and on PGA scaffold effectively. The rabbit model with full-thickness cartilage defects was established and then repaired by PGA scaffold and rabbit BMSCs with or without Sox9 transduction. HE, safranin O staining and immunohistochemistry were used to assess the repair of defects by the complex. Better repair, including more newly-formed cartilage tissue and hyaline cartilage-specific extracellular matrix and greater expression of several chondrogenesis marker genes were observed in PGA scaffold and BMSCs with Sox9 transduction, compared to that without transduction. Our findings defined the important role of Sox9 in the repair of cartilage defects in vivo and provided evidence that Sox9 had the potential and advantage in the application of tissue engineering. Copyright © 2011 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Xiaowei Zhang

    Full Text Available 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.

  2. 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.

  3. Continuous hydrostatic pressure induces differentiation phenomena in chondrocytes mediated by changes in polycystins, SOX9, and RUNX2.

    Science.gov (United States)

    Karamesinis, Konstantinos; Spyropoulou, Anastasia; Dalagiorgou, Georgia; Katsianou, Maria A; Nokhbehsaim, Marjan; Memmert, Svenja; Deschner, James; Vastardis, Heleni; Piperi, Christina

    2017-01-01

    The present study aimed to investigate the long-term effects of hydrostatic pressure on chondrocyte differentiation, as indicated by protein levels of transcription factors SOX9 and RUNX2, on transcriptional activity of SOX9, as determined by pSOX9 levels, and on the expression of polycystin-encoding genes Pkd1 and Pkd2. ATDC5 cells were cultured in insulin-supplemented differentiation medium (ITS) and/or exposed to 14.7 kPa of hydrostatic pressure for 12, 24, 48, and 96 h. Cell extracts were assessed for SOX9, pSOX9, and RUNX2 using western immunoblotting. The Pkd1 and Pkd2 mRNA levels were detected by real-time PCR. Hydrostatic pressure resulted in an early drop in SOX9 and pSOX9 protein levels at 12 h followed by an increase from 24 h onwards. A reverse pattern was followed by RUNX2, which reached peak levels at 24 h of hydrostatic pressure-treated chondrocytes in ITS culture. Pkd1 and Pkd2 mRNA levels increased at 24 h of combined hydrostatic pressure and ITS treatment, with the latter remaining elevated up to 96 h. Our data indicate that long periods of continuous hydrostatic pressure stimulate chondrocyte differentiation through a series of molecular events involving SOX9, RUNX2, and polycystins-1, 2, providing a theoretical background for functional orthopedic mechanotherapies.

  4. 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.

  5. MicroRNA-320 suppresses colorectal cancer by targeting SOX4, FOXM1, and FOXQ1

    DEFF Research Database (Denmark)

    Vishnubalaji, Radhakrishnan; Hamam, Rimi; Yue, Shijun

    2016-01-01

    gene targets for the miR-320 family. Inverse correlation between the expression of miR-320 members with SOX4, FOXM1, and FOXQ1 was observed in primary CRC patients' specimens, suggesting that these genes are likely bona fide targets for the miR-320 family. Interestingly, interrogation of the expression...... for the miR-320/SOX4/FOXM1/FOXQ1 axes in promoting CRC development and progression and suggest targeting those networks as potential therapeutic strategy for CRC....

  6. Mutations of the SRY-responsive enhancer of SOX9 are uncommon in XY gonadal dysgenesis.

    Science.gov (United States)

    Georg, I; Bagheri-Fam, S; Knower, K C; Wieacker, P; Scherer, Gerd; Harley, V R

    2010-01-01

    During mouse sex determination, SRY upregulates the core testis-specific enhancer of Sox9, TESCO. Mutations in human SRY are found in one third of cases with XY pure gonadal dysgenesis (XY GD; Swyer syndrome), while two thirds remain unexplained. Heterozygous SOX9 mutations can cause XY GD in association with the skeletal malformation syndrome campomelic dysplasia. We hypothesized that human TESCO mutations could cause isolated XY GD. Sixty-six XY GD cases with an intact SRY were analyzed for TESCO point mutations or deletions. No mutations were identified. We conclude that TESCO mutations are not a common cause of XY GD. Copyright © 2010 S. Karger AG, Basel.

  7. A search for cyanopolyynes in L1157-B1

    Science.gov (United States)

    Mendoza, Edgar; Lefloch, B.; Ceccarelli, C.; Kahane, C.; Jaber, A. A.; Podio, L.; Benedettini, M.; Codella, C.; Viti, S.; Jimenez-Serra, I.; Lepine, J. R. D.; Boechat-Roberty, H. M.; Bachiller, R.

    2018-04-01

    We present here a systematic search for cyanopolyynes in the shock region L1157-B1 and its associated protostar L1157-mm in the framework of the Large Program`Astrochemical Surveys At IRAM' (ASAI), dedicated to chemical surveys of solar-type star-forming regions with the IRAM 30-m telescope. Observations of the millimeter windows between 72 and 272 GHz permitted the detection of HC3N and its 13C isotopologues, and HC5N (for the first time in a protostellar shock region). In the shock, the analysis of the line profiles shows that the emission arises from the outflow cavities associated with L1157-B1 and L1157-B2. Molecular abundances and excitation conditions were obtained from the analysis of the Spectral Line Energy Distributions under the assumption of Local Thermodynamical Equilibrium or using a radiative transfer code in the Large Velocity Gradient approximation. Towards L1157 mm, the HC3N emission arises from the cold envelope (T_rot=10K) and a higher-excitation region (Trot = 31K) of smaller extent around the protostar. We did not find any evidence of 13C or D fractionation enrichment towards L1157-B1. We obtain a relative abundance ratio HC3N/HC5N of 3.3 in the shocked gas. We find an increase by a factor of 30 of the HC3N abundance between the envelope of L1157-mm and the shock region itself. Altogether, these results are consistent with a scenario in which the bulk of HC3N was produced by means of gas phase reactions in the passage of the shock. This scenario is supported by the predictions of a parametric shock code coupled with the chemical model UCL_CHEM.

  8. Regulation by SoxR of mfsA, Which Encodes a Major Facilitator Protein Involved in Paraquat Resistance in Stenotrophomonas maltophilia.

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    Kriangsuk Srijaruskul

    Full Text Available Stenotrophomonas maltophilia MfsA (Smlt1083 is an efflux pump in the major facilitator superfamily (MFS. Deletion of mfsA renders the strain more susceptible to paraquat, but no alteration in the susceptibility levels of other oxidants is observed. The expression of mfsA is inducible upon challenge with redox cycling/superoxide-generating drug (paraquat, menadione and plumbagin treatments and is directly regulated by SoxR, which is a transcription regulator and sensor of superoxide-generating agents. Analysis of mfsA expression patterns in wild-type and a soxR mutant suggests that oxidized SoxR functions as a transcription activator of the gene. soxR (smlt1084 is located in a head-to-head fashion with mfsA, and these genes share the -10 motif of their promoter sequences. Purified SoxR specifically binds to the putative mfsA promoter motifs that contain a region that is highly homologous to the consensus SoxR binding site, and mutation of the SoxR binding site abolishes binding of purified SoxR protein. The SoxR box is located between the putative -35 and -10 promoter motifs of mfsA; and this position is typical for a promoter in which SoxR acts as a transcriptional activator. At the soxR promoter, the SoxR binding site covers the transcription start site of the soxR transcript; thus, binding of SoxR auto-represses its own transcription. Taken together, our results reveal for the first time that mfsA is a novel member of the SoxR regulon and that SoxR binds and directly regulates its expression.

  9. MicroRNA-29b-1 impairs in vitro cell proliferation, self‑renewal and chemoresistance of human osteosarcoma 3AB-OS cancer stem cells.

    Science.gov (United States)

    Di Fiore, Riccardo; Drago-Ferrante, Rosa; Pentimalli, Francesca; Di Marzo, Domenico; Forte, Iris Maria; D'Anneo, Antonella; Carlisi, Daniela; De Blasio, Anna; Giuliano, Michela; Tesoriere, Giovanni; Giordano, Antonio; Vento, Renza

    2014-11-01

    Osteosarcoma (OS) is the most common type of bone cancer, with a peak incidence in the early childhood. Emerging evidence suggests that treatments targeting cancer stem cells (CSCs) within a tumor can halt cancer and improve patient survival. MicroRNAs (miRNAs) have been implicated in the maintenance of the CSC phenotype, thus, identification of CSC-related miRNAs would provide information for a better understanding of CSCs. Downregulation of miRNA-29 family members (miR-29a/b/c; miR‑29s) was observed in human OS, however, little is known about the functions of miR-29s in human OS CSCs. Previously, during the characterization of 3AB-OS cells, a CSC line selected from human OS MG63 cells, we showed a potent downregulation of miR-29b. In this study, after stable transfection of 3AB-OS cells with miR-29b-1, we investigated the role of miR-29b-1 in regulating cell proliferation, sarcosphere-forming ability, clonogenic growth, chemosensitivity, migration and invasive ability of 3AB-OS cells, in vitro. We found that, miR-29b-1 overexpression consistently reduced both, 3AB-OS CSCs growth in two- and three-dimensional culture systems and their sarcosphere- and colony-forming ability. In addition, while miR-29b-1 overexpression sensitized 3AB-OS cells to chemotherapeutic drug-induced apoptosis, it did not influence their migratory and invasive capacities, thus suggesting a context-depending role of miR-29b-1. Using publicly available databases, we proceeded to identify potential miR-29b target genes, known to play a role in the above reported functions. Among these targets we analyzed CD133, N-Myc, CCND2, E2F1 and E2F2, Bcl-2 and IAP-2. We also analyzed the most important stemness markers as Oct3/4, Sox2 and Nanog. Real-time RT-PCR and western-blot analyses showed that miR-29b-1 negatively regulated the expression of these markers. Overall, the results show that miR-29b-1 suppresses stemness properties of 3AB-OS CSCs and suggest that developing miR-29b-1 as a novel

  10. Duplication of SOX9 is not a common cause of 46,XX testicular or 46,XX ovotesticular DSD.

    Science.gov (United States)

    Seeherunvong, Tossaporn; Ukarapong, Supamit; McElreavey, Kenneth; Berkovitz, Gary D; Perera, Erasmo M

    2012-01-01

    Translocation of the SRY gene to the paternal X chromosome is the explanation for testis development in the majority of subjects with 46,XX testicular disorder of sexual development (DSD). However, nearly all subjects with 46,XX ovotesticular DSD and up to one third of subjects with 46,XX testicular DSD lack SRY. SRY-independent expression of SOX9 has been implicated in the etiology of testis development in some individuals. We amplified microsatellite markers in the region of SOX9 from a cohort of 30 subjects with either 46,XX testicular or 46,XX ovotesticular DSD to detect SOX9 duplications. Duplication of the SOX9 region in 17q was not detected in any subject. Duplication in the region of 17q that contains SOX9 is not a common cause of testis development in subjects with SRY-negative 46,XX testicular or ovotesticular DSD.

  11. Sox17-Mediated XEN Cell Conversion Identifies Dynamic Networks Controlling Cell-Fate Decisions in Embryo-Derived Stem Cells

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    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.

  12. Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin–Siris syndrome

    Science.gov (United States)

    Hempel, Annmarie; Pagnamenta, Alistair T; Blyth, Moira; Mansour, Sahar; McConnell, Vivienne; Kou, Ikuyo; Ikegawa, Shiro; Tsurusaki, Yoshinori; Matsumoto, Naomichi; Lo-Castro, Adriana; Plessis, Ghislaine; Albrecht, Beate; Battaglia, Agatino; Taylor, Jenny C; Howard, Malcolm F; Keays, David; Sohal, Aman Singh; Kühl, Susanne J; Kini, Usha; McNeill, Alisdair

    2016-01-01

    Background SOX11 is a transcription factor proposed to play a role in brain development. The relevance of SOX11 to human developmental disorders was suggested by a recent report of SOX11 mutations in two patients with Coffin–Siris syndrome. Here we further investigate the role of SOX11 variants in neurodevelopmental disorders. Methods We used array based comparative genomic hybridisation and trio exome sequencing to identify children with intellectual disability who have deletions or de novo point mutations disrupting SOX11. The pathogenicity of the SOX11 mutations was assessed using an in vitro gene expression reporter system. Loss-of-function experiments were performed in xenopus by knockdown of Sox11 expression. Results We identified seven individuals with chromosome 2p25 deletions involving SOX11. Trio exome sequencing identified three de novo SOX11 variants, two missense (p.K50N; p.P120H) and one nonsense (p.C29*). The biological consequences of the missense mutations were assessed using an in vitro gene expression system. These individuals had microcephaly, developmental delay and shared dysmorphic features compatible with mild Coffin–Siris syndrome. To further investigate the function of SOX11, we knocked down the orthologous gene in xenopus. Morphants had significant reduction in head size compared with controls. This suggests that SOX11 loss of function can be associated with microcephaly. Conclusions We thus propose that SOX11 deletion or mutation can present with a Coffin–Siris phenotype. PMID:26543203

  13. 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.

  14. 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.

  15. Rapid Immunoenzyme Assay of Aflatoxin B1 Using Magnetic Nanoparticles

    Directory of Open Access Journals (Sweden)

    Alexandr E. Urusov

    2014-11-01

    Full Text Available The main limitations of microplate-based enzyme immunoassays are the prolonged incubations necessary to facilitate heterogeneous interactions, the complex matrix and poorly soluble antigens, and the significant sample dilutions often required because of the presence of organic extractants. This study presents the use of antibody immobilization on the surface of magnetic particles to overcome these limitations in the detection of the mycotoxin, aflatoxin B1. Features of the proposed system are a high degree of nanoparticle dispersion and methodologically simple immobilization of the antibodies by adsorption. Reactions between the immobilized antibodies with native and labeled antigens are conducted in solution, thereby reducing the interaction period to 5 min without impairing the analytical outcome. Adsorption of immunoglobulins on the surface of magnetic nanoparticles increases their stability in aqueous-organic media, thus minimizing the degree of sample dilution required. Testing barley and maize extracts demonstrated a limit of aflatoxin B1 detection equal to 20 pg/mL and total assay duration of 20 min. Using this method, only the 3-fold dilution of the initial methanol/water (60/40 extraction mixture in the microplate wells is necessary. The proposed pseudo-homogeneous approach could be applied toward immunodetection of a wide range of compounds.

  16. 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...

  17. Silencing of the Drosophila ortholog of SOX5 in heart leads to cardiac dysfunction as detected by optical coherence tomography.

    Science.gov (United States)

    Li, Airong; Ahsen, Osman O; Liu, Jonathan J; Du, Chuang; McKee, Mary L; Yang, Yan; Wasco, Wilma; Newton-Cheh, Christopher H; O'Donnell, Christopher J; Fujimoto, James G; Zhou, Chao; Tanzi, Rudolph E

    2013-09-15

    The SRY-related HMG-box 5 (SOX5) gene encodes a member of the SOX family of transcription factors. Recently, genome-wide association studies have implicated SOX5 as a candidate gene for susceptibility to four cardiac-related endophenotypes: higher resting heart rate (HR), the electrocardiographic PR interval, atrial fibrillation and left ventricular mass. We have determined that human SOX5 has a highly conserved Drosophila ortholog, Sox102F, and have employed transgenic Drosophila models to quantitatively measure cardiac function in adult flies. For this purpose, we have developed a high-speed and ultrahigh-resolution optical coherence tomography imaging system, which enables rapid cross-sectional imaging of the heart tube over various cardiac cycles for the measurement of cardiac structural and dynamical parameters such as HR, dimensions and areas of heart chambers, cardiac wall thickness and wall velocities. We have found that the silencing of Sox102F resulted in a significant decrease in HR, heart chamber size and cardiac wall velocities, and a significant increase in cardiac wall thickness that was accompanied by disrupted myofibril structure in adult flies. In addition, the silencing of Sox102F in the wing led to increased L2, L3 and wing marginal veins and increased and disorganized expression of wingless, the central component of the Wnt signaling pathway. Collectively, the silencing of Sox102F resulted in severe cardiac dysfunction and structural defects with disrupted Wnt signaling transduction in flies. This implicates an important functional role for SOX5 in heart and suggests that the alterations in SOX5 levels may contribute to the pathogenesis of multiple cardiac diseases or traits.

  18. During development intense Sox2 expression marks not only Prox1-expressing taste bud cell but also perigemmal cell lineages.

    Science.gov (United States)

    Nakayama, Ayumi; Miura, Hirohito; Ooki, Makoto; Harada, Shuitsu

    2015-03-01

    Sox2 is proposed to regulate the differentiation of bipotential progenitor cells into taste bud cells. However, detailed expression of Sox2 remains unclear. In this report, Sox2 expression during taste bud development in the fungiform (FF), circumvallate (CV) and soft palate (SP) areas is examined together with Prox1. First, we immunohistochemically checked Prox1 expression in adults and found that almost all taste bud cells are Prox1-positive. During FF development, intense Sox2 expression was restricted to taste bud primordia expressing Prox1 at E12.5. However, at E14.5, Sox2 was intensely expressed outside the developing taste buds resolving to perigemmal Sox2 expression in adults. In the SP, at E14.5, taste bud primordia emerged as Prox1-expressing cell clusters. However, intense Sox2 expression was not restricted to taste bud primordia but was detected widely in the epithelium. During development, Sox2 expression outside developing taste buds was generally down-regulated but was retained in the perigemmal region similarly to that in the FF. In the CV, the initial stage of taste bud development remained unclear because of the lack of taste bud primordia comparable to that in the FF and SP. Here, we show that Prox1-expressing cells appear in the apical epithelium at E12.5, in the inner trench wall at E17.5 and in the outer trench wall at E18.5. Sox2 was again not restricted to developing taste bud cells expressing Prox1 during CV development. The expression patterns support that Sox2 does not serve as a cell fate selector between taste bud cells and surrounding keratinocytes but rather may contribute to them both.

  19. RUN COORDINATION

    CERN Multimedia

    Christophe Delaere

    2013-01-01

    The focus of Run Coordination during LS1 is to monitor closely the advance of maintenance and upgrade activities, to smooth interactions between subsystems and to ensure that all are ready in time to resume operations in 2015 with a fully calibrated and understood detector. After electricity and cooling were restored to all equipment, at about the time of the last CMS week, recommissioning activities were resumed for all subsystems. On 7 October, DCS shifts began 24/7 to allow subsystems to remain on to facilitate operations. That culminated with the Global Run in November (GriN), which   took place as scheduled during the week of 4 November. The GriN has been the first centrally managed operation since the beginning of LS1, and involved all subdetectors but the Pixel Tracker presently in a lab upstairs. All nights were therefore dedicated to long stable runs with as many subdetectors as possible. Among the many achievements in that week, three items may be highlighted. First, the Strip...

  20. RUN COORDINATION

    CERN Multimedia

    C. Delaere

    2013-01-01

    Since the LHC ceased operations in February, a lot has been going on at Point 5, and Run Coordination continues to monitor closely the advance of maintenance and upgrade activities. In the last months, the Pixel detector was extracted and is now stored in the pixel lab in SX5; the beam pipe has been removed and ME1/1 removal has started. We regained access to the vactank and some work on the RBX of HB has started. Since mid-June, electricity and cooling are back in S1 and S2, allowing us to turn equipment back on, at least during the day. 24/7 shifts are not foreseen in the next weeks, and safety tours are mandatory to keep equipment on overnight, but re-commissioning activities are slowly being resumed. Given the (slight) delays accumulated in LS1, it was decided to merge the two global runs initially foreseen into a single exercise during the week of 4 November 2013. The aim of the global run is to check that we can run (parts of) CMS after several months switched off, with the new VME PCs installed, th...

  1. Sox4 is a key oncogenic target in C/EBP alpha mutant acute myeloid leukemia

    Czech Academy of Sciences Publication Activity Database

    Zhang, H.; Alberich-Jorda, Meritxell; Amabile, G.; Yang, H.; Staber, P.B.; DiRuscio, A.; Welner, R.S.; Ebralidze, A.; Zhang, J.; Levantini, E.; Lefebvre, V.; Valk, P.J.; Delwel, R.; Hoogenkamp, M.; Nerlov, C.; Cammenga, J.; Saez, B.; Scadden, D.T.; Bonifer, C.; Ye, M.; Tenen, D.G.

    2013-01-01

    Roč. 24, č. 5 (2013), s. 575-588 ISSN 1535-6108 R&D Projects: GA MŠk LK21307 Institutional support: RVO:68378050 Keywords : Sox4 * C/EBP alpha * acute myeloid leukemia Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 23.893, year: 2013

  2. Screening of MITF and SOX10 regulatory regions in Waardenburg syndrome type 2.

    Directory of Open Access Journals (Sweden)

    Viviane Baral

    Full Text Available Waardenburg syndrome (WS is a rare auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and pigmentation defects. Four subtypes are clinically defined based on the presence or absence of additional symptoms. WS type 2 (WS2 can result from mutations within the MITF or SOX10 genes; however, 70% of WS2 cases remain unexplained at the molecular level, suggesting that other genes might be involved and/or that mutations within the known genes escaped previous screenings. The recent identification of a deletion encompassing three of the SOX10 regulatory elements in a patient presenting with another WS subtype, WS4, defined by its association with Hirschsprung disease, led us to search for deletions and point mutations within the MITF and SOX10 regulatory elements in 28 yet unexplained WS2 cases. Two nucleotide variations were identified: one in close proximity to the MITF distal enhancer (MDE and one within the U1 SOX10 enhancer. Functional analyses argued against a pathogenic effect of these variations, suggesting that mutations within regulatory elements of WS genes are not a major cause of this neurocristopathy.

  3. Screening of MITF and SOX10 Regulatory Regions in Waardenburg Syndrome Type 2

    Science.gov (United States)

    Baral, Viviane; Chaoui, Asma; Watanabe, Yuli; Goossens, Michel; Attie-Bitach, Tania; Marlin, Sandrine; Pingault, Veronique; Bondurand, Nadege

    2012-01-01

    Waardenburg syndrome (WS) is a rare auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and pigmentation defects. Four subtypes are clinically defined based on the presence or absence of additional symptoms. WS type 2 (WS2) can result from mutations within the MITF or SOX10 genes; however, 70% of WS2 cases remain unexplained at the molecular level, suggesting that other genes might be involved and/or that mutations within the known genes escaped previous screenings. The recent identification of a deletion encompassing three of the SOX10 regulatory elements in a patient presenting with another WS subtype, WS4, defined by its association with Hirschsprung disease, led us to search for deletions and point mutations within the MITF and SOX10 regulatory elements in 28 yet unexplained WS2 cases. Two nucleotide variations were identified: one in close proximity to the MITF distal enhancer (MDE) and one within the U1 SOX10 enhancer. Functional analyses argued against a pathogenic effect of these variations, suggesting that mutations within regulatory elements of WS genes are not a major cause of this neurocristopathy. PMID:22848661

  4. 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.

  5. Cloning and analysis of the HMG domains of ten Sox genes from ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-04-20

    Apr 20, 2009 ... Sox is a large gene family which encodes Sry-related transcription factors and ..... Gene orthology are boxed drawing by straight line and dotted line. .... HMG Box Functions as a Kinetic Clamp to Augment DNA Bending. J. Mol.

  6. 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.

  7. Screening of MITF and SOX10 regulatory regions in Waardenburg syndrome type 2.

    Science.gov (United States)

    Baral, Viviane; Chaoui, Asma; Watanabe, Yuli; Goossens, Michel; Attie-Bitach, Tania; Marlin, Sandrine; Pingault, Veronique; Bondurand, Nadege

    2012-01-01

    Waardenburg syndrome (WS) is a rare auditory-pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and pigmentation defects. Four subtypes are clinically defined based on the presence or absence of additional symptoms. WS type 2 (WS2) can result from mutations within the MITF or SOX10 genes; however, 70% of WS2 cases remain unexplained at the molecular level, suggesting that other genes might be involved and/or that mutations within the known genes escaped previous screenings. The recent identification of a deletion encompassing three of the SOX10 regulatory elements in a patient presenting with another WS subtype, WS4, defined by its association with Hirschsprung disease, led us to search for deletions and point mutations within the MITF and SOX10 regulatory elements in 28 yet unexplained WS2 cases. Two nucleotide variations were identified: one in close proximity to the MITF distal enhancer (MDE) and one within the U1 SOX10 enhancer. Functional analyses argued against a pathogenic effect of these variations, suggesting that mutations within regulatory elements of WS genes are not a major cause of this neurocristopathy.

  8. The tumour suppressor SOX11 is associated with improved survival among high grade epithelial ovarian cancers and is regulated by reversible promoter methylation

    International Nuclear Information System (INIS)

    Sernbo, Sandra; Gustavsson, Elin; Brennan, Donal J; Gallagher, William M; Rexhepaj, Elton; Rydnert, Frida; Jirström, Karin; Borrebaeck, Carl AK; Ek, Sara

    2011-01-01

    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. SOX11 expression and clinicopathological data was compared using χ 2 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. 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. 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. 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.

  10. Competition for vitamin B1 (thiamin) structures numerous ecological interactions.

    Science.gov (United States)

    Kraft, Clifford E; Angert, Esther R

    2017-06-01

    Thiamin (vitamin B1) is a cofactor required for essential biochemical reactions in all living organisms, yet free thiamin is scarce in the environment. The diversity of biochemical pathways involved in the acquisition, degradation, and synthesis of thiamin indicates that organisms have evolved numerous ecological strategies for meeting this nutritional requirement. In this review we synthesize information from multiple disciplines to show how the complex biochemistry of thiamin influences ecological outcomes of interactions between organisms in environments ranging from the open ocean and the Australian outback to the gastrointestinal tract of animals. We highlight population and ecosystem responses to the availability or absence of thiamin. These include widespread mortality of fishes, birds, and mammals, as well as the thiamin-dependent regulation of ocean productivity. Overall, we portray thiamin biochemistry as the foundation for molecularly mediated ecological interactions that influence survival and abundance of a vast array of organisms.

  11. Waardenburg syndrome type 4: report of two new cases caused by SOX10 mutations in Spain.

    Science.gov (United States)

    Fernández, Raquel M; Núñez-Ramos, Raquel; Enguix-Riego, M Valle; Román-Rodríguez, Francisco José; Galán-Gómez, Enrique; Blesa-Sánchez, Emilio; Antiñolo, Guillermo; Núñez-Núñez, Ramón; Borrego, Salud

    2014-02-01

    Shah-Waardenburg syndrome or Waardenburg syndrome type 4 (WS4) is a neurocristopathy characterized by the association of deafness, depigmentation and Hirschsprung disease. Three disease-causing genes have been identified so far for WS4: EDNRB, EDN3, and SOX10. SOX10 mutations, found in 45-55% of WS4 patients, are inherited in autosomal dominant way. In addition, mutations in SOX10 are also responsible for an extended syndrome involving peripheral and central neurological phenotypes, referred to as PCWH (peripheral demyelinating neuropathy, central dysmyelinating leucodystrophy, Waardenburg syndrome, Hirschsprung disease). Such mutations are mostly private, and a high intra- and inter-familial variability exists. In this report, we present a patient with WS4 and a second with PCWH due to SOX10 mutations supporting again the genetic and phenotypic heterogeneity of these syndromes. Interestingly, the WS4 family carries an insertion of 19 nucleotides in exon 5 of SOX10, which results in distinct phenotypes along three different generations: hypopigmentation in the maternal grandmother, hearing loss in the mother, and WS4 in the proband. Since mosaicism cannot explain the three different related-WS features observed in this family, we propose as the most plausible explanation the existence of additional molecular events, acting in an additive or multiplicative fashion, in genes or regulatory regions unidentified so far. On the other hand, the PCWH case was due to a de novo deletion in exon 5 of the gene. Efforts should be devoted to unravel the mechanisms underlying the intrafamilial phenotypic variability observed in the families affected, and to identify new genes responsible for the still unsolved WS4 cases. © 2013 Wiley Periodicals, Inc.

  12. Andrographolide Induces Cell Cycle Arrest and Apoptosis of Chondrosarcoma by Targeting TCF-1/SOX9 Axis.

    Science.gov (United States)

    Zhang, Huan-Tian; Yang, Jie; Liang, Gui-Hong; Gao, Xue-Juan; Sang, Yuan; Gui, Tao; Liang, Zu-Jian; Tam, Man-Seng; Zha, Zhen-Gang

    2017-12-01

    Chondrosarcoma is the second most malignant bone tumor with poor prognosis and limited treatment options. Thus, development of more effective treatments has become urgent. Recently, natural compounds derived from medicinal plants have emerged as promising therapeutic options via targeting multiple key cellular molecules. Andrographolide (Andro) is such a compound, which has previously been shown to induce cell cycle arrest and apoptosis in several human cancers. However, the molecular mechanism through which Andro exerts its anti-cancer effect on chondrosarcoma remains to be elucidated. In the present study, we showed that Andro-induced G2/M cell cycle arrest of chondrosarcoma by fine-tuning the expressions of several cell cycle regulators such as p21, p27, and Cyclins, and that prolonged treatment of cells with Andro caused pronounced cell apoptosis. Remarkably, we found that SOX9 was highly expressed in poor-differentiated chondrosarcoma, and that knockdown of SOX9 suppressed chondrosarcoma cell growth. Further, our results showed that Andro dose-dependently down-regulated SOX9 expression in chondrosarcoma cells. Concomitantly, an inhibition of T cell factor 1 (TCF-1) mRNA expression and an enhancement of TCF-1 protein degradation by Andro were observed. In contrast, the expression and subcellular localization of β-catenin were not altered upon the treatment of Andro, suggesting that β-catenin might not function as the primary target of Andro. Additionally, we provided evidence that there was a mutual regulation between TCF-1 and SOX9 in chondrosarcoma cells. In conclusion, these results highlight the potential therapeutic effects of Andro in treatment of chondrosarcoma via targeting the TCF-1/SOX9 axis. J. Cell. Biochem. 118: 4575-4586, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  13. SOX10-Nano-Lantern Reporter Human iPS Cells; A Versatile Tool for Neural Crest Research.

    Directory of Open Access Journals (Sweden)

    Tomoko Horikiri

    Full Text Available The neural crest is a source to produce multipotent neural crest stem cells that have a potential to differentiate into diverse cell types. The transcription factor SOX10 is expressed through early neural crest progenitors and stem cells in vertebrates. Here we report the generation of SOX10-Nano-lantern (NL reporter human induced pluripotent stem cells (hiPS by using CRISPR/Cas9 systems, that are beneficial to investigate the generation and maintenance of neural crest progenitor cells. SOX10-NL positive cells are produced transiently from hiPS cells by treatment with TGFβ inhibitor SB431542 and GSK3 inhibitor CHIR99021. We found that all SOX10-NL-positive cells expressed an early neural crest marker NGFR, however SOX10-NL-positive cells purified from differentiated hiPS cells progressively attenuate their NL-expression under proliferation. We therefore attempted to maintain SOX10-NL-positive cells with additional signaling on the plane and sphere culture conditions. These SOX10-NL cells provide us to investigate mass culture with neural crest cells for stem cell research.

  14. Heterozygous deletion at the SOX10 gene locus in two patients from a Chinese family with Waardenburg syndrome type II.

    Science.gov (United States)

    Wenzhi, He; Ruijin, Wen; Jieliang, Li; Xiaoyan, Ma; Haibo, Liu; Xiaoman, Wang; Jiajia, Xian; Shaoying, Li; Shuanglin, Li; Qing, Li

    2015-10-01

    Waardenburg syndrome (WS) is a rare disease characterized by sensorineural deafness and pigment disturbance. To date, almost 100 mutations have been reported, but few reports on cases with SOX10 gene deletion. The inheritance pattern of SOX10 gene deletion is still unclear. Our objective was to identify the genetic causes of Waardenburg syndrome type II in a two-generation Chinese family. Clinical evaluations were conducted in both of the patients. Microarray analysis and multiplex ligation-dependent probe amplification (MLPA) were performed to identify disease-related copy number variants (CNVs). DNA sequencing of the SOX10, MITF and SNAI2 genes was performed to identify the pathogenic mutation responsible for WS2. A 280kb heterozygous deletion at the 22q13.1 chromosome region (including SOX10) was detected in both of the patients. No mutation was found in the patients, unaffected family members and 30 unrelated healthy controls. This report is the first to describe SOX10 heterozygous deletions in Chinese WS2 patients. Our result conform the thesis that heterozygous deletions at SOX10 is an important pathogenicity for WS, and present as autosomal dominant inheritance. Nevertheless, heterozygous deletion of the SOX10 gene would be worth investigating to understand their functions and contributions to neurologic phenotypes. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  15. De novo dominant mutation of SOX10 gene in a Chinese family with Waardenburg syndrome type II.

    Science.gov (United States)

    Chen, Kaitian; Zong, Ling; Liu, Min; Zhan, Yuan; Wu, Xuan; Zou, Wenting; Jiang, Hongyan

    2014-06-01

    Waardenburg syndrome is a rare genetic disorder, inherited as an autosomal dominant trait. The condition is characterized by sensorineural hearing loss and pigment disturbances of the hair, skin, and iris. The de novo mutation in the SOX10 gene, responsible for Waardenburg syndrome type II, is rarely seen. The present study aimed to identify the genetic causes of Waardenburg syndrome type II in a Chinese family. Clinical and molecular evaluations were conducted in a Chinese family with Waardenburg syndrome type II. A novel SOX10 heterozygous c.259-260delCT mutation was identified. Heterozygosity was not observed in the parents and sister of the proband, indicating that the mutation has arisen de novo. The novel frameshift mutation, located in exon 3 of the SOX10 gene, disrupted normal amino acid coding from Leu87, leading to premature termination at nucleotide 396 (TGA). The high mobility group domain of SOX10 was inferred to be partially impaired. The novel heterozygous c.259-260delCT mutation in the SOX10 gene was considered to be the cause of Waardenburg syndrome in the proband. The clinical and genetic characterization of this family would help elucidate the genetic heterogeneity of SOX10 in Waardenburg syndrome type II. Moreover, the de novo pattern expanded the mutation data of SOX10. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  16. Arid5b facilitates chondrogenesis by recruiting the histone demethylase Phf2 to Sox9-regulated genes

    Science.gov (United States)

    Hata, Kenji; Takashima, Rikako; Amano, Katsuhiko; Ono, Koichiro; Nakanishi, Masako; Yoshida, Michiko; Wakabayashi, Makoto; Matsuda, Akio; Maeda, Yoshinobu; Suzuki, Yutaka; Sugano, Sumio; Whitson, Robert H.; Nishimura, Riko; Yoneda, Toshiyuki

    2013-11-01

    Histone modification, a critical step for epigenetic regulation, is an important modulator of biological events. Sox9 is a transcription factor critical for endochondral ossification; however, proof of its epigenetic regulation remains elusive. Here we identify AT-rich interactive domain 5b (Arid5b) as a transcriptional co-regulator of Sox9. Arid5b physically associates with Sox9 and synergistically induces chondrogenesis. Growth of Arid5b-/- mice is retarded with delayed endochondral ossification. Sox9-dependent chondrogenesis is attenuated in Arid5b-deficient cells. Arid5b recruits Phf2, a histone lysine demethylase, to the promoter region of Sox9 target genes and stimulates H3K9me2 demethylation of these genes. In the promoters of chondrogenic marker genes, H3K9me2 levels are increased in Arid5b-/- chondrocytes. Finally, we show that Phf2 knockdown inhibits Sox9-induced chondrocyte differentiation. Our findings establish an epigenomic mechanism of skeletal development, whereby Arid5b promotes chondrogenesis by facilitating Phf2-mediated histone demethylation of Sox9-regulated chondrogenic gene promoters.

  17. 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.

  18. SOX2 co-occupies distal enhancer elements with distinct POU factors in ESCs and NPCs to specify cell state.

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    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.

  19. Enteric Neuron Imbalance and Proximal Dysmotility in Ganglionated Intestine of the Sox10Dom/+ Hirschsprung Mouse ModelSummary

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    Melissa A. Musser

    2015-01-01

    Full Text Available Background & Aims: In Hirschsprung disease (HSCR, neural crest-derived progenitors (NCPs fail to completely colonize the intestine so that the enteric nervous system is absent from distal bowel. Despite removal of the aganglionic region, many HSCR patients suffer from residual intestinal dysmotility. To test the hypothesis that inappropriate lineage segregation of NCPs in proximal ganglionated regions of the bowel could contribute to such postoperative disease, we investigated neural crest (NC-derived lineages and motility in ganglionated, postnatal intestine of the Sox10Dom/+ HSCR mouse model. Methods: Cre-mediated fate-mapping was applied to evaluate relative proportions of NC-derived cell types. Motility assays were performed to assess gastric emptying and small intestine motility while colonic inflammation was assessed by histopathology for Sox10Dom/+ mutants relative to wild-type controls. Results: Sox10Dom/+ mice showed regional alterations in neuron and glia proportions as well as calretinin+ and neuronal nitric oxide synthase (nNOS+ neuronal subtypes. In the colon, imbalance of enteric NC derivatives correlated with the extent of aganglionosis. All Sox10Dom/+ mice exhibited reduced small intestinal transit at 4 weeks of age; at 6 weeks of age, Sox10Dom/+ males had increased gastric emptying rates. Sox10Dom/+ mice surviving to 6 weeks of age had little or no colonic inflammation when compared with wild-type littermates, suggesting that these changes in gastrointestinal motility are neurally mediated. Conclusions: The Sox10Dom mutation disrupts the balance of NC-derived lineages and affects gastrointestinal motility in the proximal, ganglionated intestine of adult animals. This is the first report identifying alterations in enteric neuronal classes in Sox10Dom/+ mutants, which suggests a previously unrecognized role for Sox10 in neuronal subtype specification. Keywords: Aganglionosis, Enteric Nervous System, Neural Crest

  20. SOX2 plays a critical role in EGFR-mediated self-renewal of human prostate cancer stem-like cells.

    Science.gov (United States)

    Rybak, Adrian P; Tang, Damu

    2013-12-01

    SOX2 is an essential transcription factor for stem cells and plays a role in tumorigenesis, however its role in prostate cancer stem cells (PCSCs) remains unclear. We report here a significant upregulation of SOX2 at both mRNA and protein levels in DU145 PCSCs propagated as suspension spheres in vitro. The expression of SOX2 in DU145 PCSCs is positively regulated by epidermal growth factor receptor (EGFR) signaling. Activation of EGFR signaling, following the addition of epidermal growth factor (EGF) or ectopic expression of a constitutively-active EGFR mutant (EGFRvIII), increased SOX2 expression and the self-renewal of DU145 PCSCs. Conversely, a small molecule EGFR inhibitor (AG1478) blocked EGFR activation, reduced SOX2 expression and inhibited PCSC self-renewal activity, implicating SOX2 in mediating EGFR-dependent self-renewal of PCSCs. In line with this notion, ectopic SOX2 expression enhanced EGF-induced self-renewal of DU145 PCSCs, while SOX2 knockdown reduced PCSC self-renewal with EGF treatment no longer capable of enhancing their propagation. Furthermore, SOX2 knockdown reduced the capacity of DU145 PCSCs to grow under anchorage-independent conditions. Finally, DU145 PCSCs generated xenograft tumors more aggressively with elevated levels of SOX2 expression compared to xenograft tumors derived from non-PCSCs. Collectively, we provide evidence that SOX2 plays a critical role in EGFR-mediated self-renewal of DU145 PCSCs. © 2013.

  1. 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...

  2. B-1 cell immunoglobulin directed against oxidation-specific epitopes

    Directory of Open Access Journals (Sweden)

    Dimitrios eTsiantoulas

    2013-01-01

    Full Text Available Natural antibodies (NAbs are pre-existing antibodies with germline origin that arise in the absence of previous exposure to foreign antigens. NAbs are produced by B-1 lymphocytes and are primarily of the IgM isotype. There is accumulating evidence that - in addition to their role in antimicrobial host defense - NAbs exhibit important housekeeping functions by facilitating the non-immunogenic clearance of apoptotic cells as well as the removal of (neo-self antigens. These properties are largely mediated by the ability of NAbs to recognize highly conserved and endogenously generated structures, which are exemplified by so-called oxidation-specific epitopes (OSEs that are products of lipid peroxidation. The generation of OSEs as well as their interaction with the immune system have been studied extensively in the context of atherosclerosis, a chronic inflammatory disease of the vascular wall that is characterized by the accumulation of cellular debris and oxidized low-density lipoproteins (OxLDL. Both apoptotic cells as well as OxLDL carry OSEs that are targeted by NAbs. Therefore, OSEs represent stress-induced neo-self structures that mediate recognition of metabolic waste (e.g. cellular debris by NAbs, allowing its safe disposal, which has fundamental implications in health and disease.

  3. Identification of New Aflatoxin B1-Degrading Bacteria from Iran

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    Fahimeh Sangi

    2018-04-01

    Full Text Available Background: Aflatoxin B1 (AFB1 is a mutagenic and carcinogenic compound mainly produced by the Aspergillus parasiticus, A. flavus, A. nomius, A. tamari, and A. pseudotamarii. AFB1 biodegradation is the most important strategy for reducing AFB1 in plant tissues. Bacteria can deactivate and biodegrade AFB1 for effective detoxification of contaminated products. The present study investigated the efficiency of AFB1 degradation by soil bacteria from the Southern Khorasan Province in Eastern Iran by thin-layer and high-performance liquid chromatography during 2014–2015. Methods: DNA was extracted from AFB1-degrading isolates by the cetyltrimethylammonium bromide method and the 16S rRNA gene was amplified with the 27f and 1492r general bacterial primers and the sequences were used to identify the isolates based on their similarity to Gene Bank sequences of known bacterial species. Results: We isolated five strains from four species of AFB1-degrading bacteria from Birjand plain, including Bacillus pumilus, two isolates of Ochrobactrum pseudogrigonens, Pseudomonas aeruginosa, and Enterobacter cloace, which had AFB1-degrading activities of 88%, 78%, 61%, 58%, and 51%, respectively. Conclusion: We provide the first demonstration of AFB1 degradation by B. pumilus in from Iran and the first report identifying O. pseudogrigonens and E. cloace species as having AFB1-degrading activity.

  4. Solvent-dependent transformation of aflatoxin B1 in soil.

    Science.gov (United States)

    Starr, James M; Rushing, Blake R; Selim, Mustafa I

    2017-08-01

    To date, all studies of aflatoxin B 1 (AFB 1 ) transformation in soil or in purified mineral systems have identified aflatoxins B 2 (AFB 2 ) and G 2 (AFG 2 ) as the primary transformation products. However, identification in these studies was made using thin layer chromatography which has relatively low resolution, and these studies did not identify a viable mechanism by which such transformations would occur. Further, the use of methanol as the solvent delivery vehicle in these studies may have contributed to formation of artifactual transformation products. In this study, we investigated the role of the solvent vehicle in the transformation of AFB 1 in soil. To do this, we spiked soils with AFB 1 dissolved in water (93:7, water/methanol) or methanol and used HPLC-UV and HPLC-MS to identify the transformation products. Contrasting previous published reports, we did not detect AFB 2 or AFG 2 . In an aqueous-soil environment, we identified aflatoxin B 2a (AFB 2a ) as the single major transformation product. We propose that AFB 2a is formed from hydrolysis of AFB 1 with the soil acting as an acid catalyst. Alternatively, when methanol was used, we identified methoxy aflatoxin species likely formed via acid-catalyzed addition of methanol to AFB 1 . These results suggest that where soil moisture is adequate, AFB 1 is hydrolyzed to AFB 2a and that reactive organic solvents should be avoided when replicating natural conditions to study the fate of AFB 1 in soil.

  5. Decomposition and detoxification of aflatoxin B1 by lactic acid.

    Science.gov (United States)

    Aiko, Visenuo; Edamana, Prasad; Mehta, Alka

    2016-04-01

    A degradation study of aflatoxin B1 (AFB1) was carried out using a combination of physical and chemical methods. AFB1 was heated at 80 °C in the presence of acetic, citric and lactic acids for various time periods. The cytotoxicity of the degraded AFB1 and its products were determined by MTT assay. The results showed that among the three organic acids lactic acid was most efficient in degrading AFB1. Although complete degradation was not observed, up to 85% degradation of AFB1 was obtained when heated for 120 min. Degradation of AFB1 was confirmed by the reduced toxicity on HeLa cells using MTT assay. Treatment with lactic acid resulted in the conversion of AFB1 into two degradation products. These products were observed at lower retention factors of 0.63 and 0.38, which were identified as AFB2 and AFB2a, respectively. The cytotoxicity of AFB2a exhibited much reduced toxicity on HeLa cells compared to that of AFB1. The results have shown the efficiency of lactic acid in degrading AFB1. This study suggest that lactic acid may be considered for use in the food and feed industry since it is present naturally in food and is considered safe. © 2015 Society of Chemical Industry.

  6. Amide temperature coefficients in the protein G B1 domain

    International Nuclear Information System (INIS)

    Tomlinson, Jennifer H.; Williamson, Mike P.

    2012-01-01

    Temperature coefficients have been measured for backbone amide 1 H and 15 N nuclei in the B1 domain of protein G (GB1), using temperatures in the range 283–313 K, and pH values from 2.0 to 9.0. Many nuclei display pH-dependent coefficients, which were fitted to one or two pK a values. 1 H coefficients showed the expected behaviour, in that hydrogen-bonded amides have less negative values, but for those amides involved in strong hydrogen bonds in regular secondary structure there is a negative correlation between strength of hydrogen bond and size of temperature coefficient. The best correlation to temperature coefficient is with secondary shift, indicative of a very approximately uniform thermal expansion. The largest pH-dependent changes in coefficient are for amides in loops adjacent to sidechain hydrogen bonds rather than the amides involved directly in hydrogen bonds, indicating that the biggest determinant of the temperature coefficient is temperature-dependent loss of structure, not hydrogen bonding. Amide 15 N coefficients have no clear relationship with structure.

  7. Predominant porB1A and porB1B genotypes and correlation of gene mutations with drug resistance in Neisseria gonorrhoeae isolates in Eastern China

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    Tang Renxian

    2010-11-01

    Full Text Available Abstract Background Variations of porB1A and porB1B genes and their serotypes exist in Neisseria gonorrhoeae isolates from different geographical areas, and some site mutations in the porB1B gene correlate with drug resistance. Methods The β-lactamase production of N. gonorrhoeae isolates was determined by paper acidometric test and nitrocefin discs. The porB1A and porB1B genes of 315 non-penicillinase-producting N. gonorrhoeae (non-PPNG strains were amplified by PCR for sequencing to determine serotypes and site mutations. A duplex PCR was designed to simultaneously detect both porB1A and porB1B genes. Penicillin and tetracycline resistance was assessed by an in vitro drug sensitivity test. Results Of the N. gonorrhoeae isolates, 31.1% tested positive for porB1A and 68.9% for porB1B genes. All the 98 porB1A+ isolates belonging to IA6 serotype with either no mutation at the 120 and 121 sites (88.8% or a D120G (11.2% mutation and were no resistance to both penicillin and tetracycline. Among the 217 porB1B+ isolates, 26.7%, 22.6% and 11.5% belonged to IB3, IB3/6 and IB4 serotypes, respectively. Particularly, two novel chimeric serotypes, IB3/6-IB2 and IB2-IB4-IB2, were found in 77 and 8 porB1B+ isolates. Two hundred and twelve (97.7% of the porB1B+ isolates were presented G120 and/or A121 mutations with 163 (76.9% at both sites. Interestingly, within the 77 porB1B+ isolates belonging to IB3/6-IB2 serotype, 15 were discovered to possess novel deletions at both A121 and N122 sites. All the replacement mutations at these sites in PorB1B were correlated with resistance and the deletion mutation showed the highest resistance. Conclusion N. gonorrhoeae isolates circulating in Eastern China include a sole PorB1A serotype (IA6 and five PorB1B serotypes. Multiple mutations in porB1B genes, including novel A121 and N122 deletions, are correlated with high levels of penicillin and tetracycline resistance.

  8. SLC9B1 methylation predicts fetal intolerance of labor.

    Science.gov (United States)

    Knight, Anna K; Conneely, Karen N; Kilaru, Varun; Cobb, Dawayland; Payne, Jennifer L; Meilman, Samantha; Corwin, Elizabeth J; Kaminsky, Zachary A; Dunlop, Anne L; Smith, Alicia K

    2018-01-01

    Fetal intolerance of labor is a common indication for delivery by Caesarean section. Diagnosis is based on the presence of category III fetal heart rate tracing, which is an abnormal heart tracing associated with increased likelihood of fetal hypoxia and metabolic acidemia. This study analyzed data from 177 unique women who, during their prenatal visits (7-15 weeks and/or 24-32 weeks) to Atlanta area prenatal care clinics, consented to provide blood samples for DNA methylation (HumanMethylation450 BeadChip) and gene expression (Human HT-12 v4 Expression BeadChip) analyses. We focused on 57 women aged 18-36 (mean 25.4), who had DNA methylation data available from their second prenatal visit. DNA methylation patterns at CpG sites across the genome were interrogated for associations with fetal intolerance of labor. Four CpG sites (P value intolerance of labor. DNA methylation and gene expression were negatively associated when examined longitudinally during pregnancy using a linear mixed-effects model. Positive predictive values of methylation of these four sites ranged from 0.80 to 0.89, while negative predictive values ranged from 0.91 to 0.92. The four CpG sites were also associated with fetal intolerance of labor in an independent cohort (the Johns Hopkins Prospective PPD cohort). Therefore, fetal intolerance of labor could be accurately predicted from maternal blood samples obtained between 24-32 weeks gestation. Fetal intolerance of labor may be accurately predicted from maternal blood samples obtained between 24-32 weeks gestation by assessing DNA methylation patterns of SLC9B1. The identification of pregnant women at elevated risk for fetal intolerance of labor may allow for the development of targeted treatments or management plans.

  9. Aflatoxin B1 Degradation by a Pseudomonas Strain

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    Lancine Sangare

    2014-10-01

    Full Text Available Aflatoxin B1 (AFB1, one of the most potent naturally occurring mutagens and carcinogens, causes significant threats to the food industry and animal production. In this study, 25 bacteria isolates were collected from grain kernels and soils displaying AFB1 reduction activity. Based on its degradation effectiveness, isolate N17-1 was selected for further characterization and identified as Pseudomonas aeruginosa. P. aeruginosa N17-1 could degrade AFB1, AFB2 and AFM1 by 82.8%, 46.8% and 31.9% after incubation in Nutrient Broth (NB medium at 37 °C for 72 h, respectively. The culture supernatant of isolate N17-1 degraded AFB1 effectively, whereas the viable cells and intra cell extracts were far less effective. Factors influencing AFB1 degradation by the culture supernatant were investigated. Maximum degradation was observed at 55 °C. Ions Mn2+ and Cu2+ were activators for AFB1 degradation, however, ions Mg2+, Li+, Zn2+, Se2+, Fe3+ were strong inhibitors. Treatments with proteinase K and proteinase K plus SDS significantly reduced the degradation activity of the culture supernatant. No degradation products were observed based on preliminary LC-QTOF/MS analysis, indicating AFB1 was metabolized to degradation products with chemical properties different from that of AFB1. The results indicated that the degradation of AFB1 by P. aeruginosa N17-1 was enzymatic and could have a great potential in industrial applications. This is the first report indicating that the isolate of P. aeruginosa possesses the ability to degrade aflatoxin.

  10. Determination of fumonisin B1 levels in body fluids and hair from piglets fed fumonisin B1-contaminated diets.

    Science.gov (United States)

    Souto, Pollyana C M C; Jager, Alessandra V; Tonin, Fernando G; Petta, Tânia; Di Gregório, Mayra C; Cossalter, Anne-Marie; Pinton, Philippe; Oswald, Isabelle P; Rottinghaus, George E; Oliveira, Carlos A F

    2017-10-01

    The levels of fumonisin B 1 (FB 1 ) residues in plasma, urine, feces and hair from 24 piglets fed FB 1 -contaminated diets containing 3.1, 6.1 or 9.0 μg FB 1 .g -1 for 28 days were determined using liquid chromatography coupled to mass spectrometry (LC-MS/MS). The levels of FB 1 in plasma, urine, feces and pooled hair (n = 3) samples varied from 0.15 to 1.08 μg.L -1 , 16.09-75.01 μg.L -1 , 1.87-13.89 μg.g -1 and 2.08-8.09 ng.g -1 , respectively. Significant correlations (r = 0.808-0.885; P 14 days). The possibility to evaluate hair as a biomarker of fumonisin exposure was established, although further studies are needed to provide physiologically based toxicokinetics of residual FB 1 in the pig hair. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. SOX10-positive cells emerge in the rat pituitary gland during late embryogenesis and start to express S100β.

    Science.gov (United States)

    Ueharu, Hiroki; Yoshida, Saishu; Kanno, Naoko; Horiguchi, Kotaro; Nishimura, Naoto; Kato, Takako; Kato, Yukio

    2018-04-01

    In the pituitary gland, S100β-positive cells localize in the neurohypophysis and adenohypophysis but the lineage of the two groups remains obscure. S100β is often observed in many neural crest-derived cell types. Therefore, in this study, we investigate the origin of pituitary S100β-positive cells by immunohistochemistry for SOX10, a potent neural crest cell marker, using S100β-green fluorescence protein-transgenic rats. On embryonic day 21.5, a SOX10-positive cell population, which was also positive for the stem/progenitor cell marker SOX2, emerged in the pituitary stalk and posterior lobe and subsequently expanded to create a rostral-caudal gradient on postnatal day 3 (P3). Thereafter, SOX10-positive cells appeared in the intermediate lobe by P15, localizing to the boundary facing the posterior lobe, the gap between the lobule structures and the marginal cell layer, a pituitary stem/progenitor cell niche. Subsequently, there was an increase in SOX10/S100β double-positive cells; some of these cells in the gap between the lobule structures showed extended cytoplasm containing F-actin, indicating a feature of migration activity. The proportion of SOX10-positive cells in the postnatal anterior lobe was lower than 0.025% but about half of them co-localized with the pituitary-specific progenitor cell marker PROP1. Collectively, the present study identified that one of the lineages of S100β-positive cells is a SOX10-positive one and that SOX10-positive cells express pituitary stem/progenitor cell marker genes.

  12. SOX2 anophthalmia syndrome: 12 new cases demonstrating broader phenotype and high frequency of large gene deletions.

    Science.gov (United States)

    Bakrania, P; Robinson, D O; Bunyan, D J; Salt, A; Martin, A; Crolla, J A; Wyatt, A; Fielder, A; Ainsworth, J; Moore, A; Read, S; Uddin, J; Laws, D; Pascuel-Salcedo, D; Ayuso, C; Allen, L; Collin, J R O; Ragge, N K

    2007-11-01

    Developmental eye anomalies, which include anophthalmia (absent eye) or microphthalmia (small eye) are an important cause of severe visual impairment in infants and young children. Heterozygous mutations in SOX2, a SOX1B-HMG box transcription factor, have been found in up to 10% of individuals with severe microphthalmia or anophthalmia and such mutations could also be associated with a range of non-ocular abnormalities. We performed mutation analysis on a new cohort of 120 patients with congenital eye abnormalities, mainly anophthalmia, microphthalmia and coloboma. Multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridisation (FISH) were used to detect whole gene deletion. We identified four novel intragenic SOX2 mutations (one single base deletion, one single base duplication and two point mutations generating premature translational termination codons) and two further cases with the previously reported c.70del20 mutation. Of 52 patients with severe microphthalmia or anophthalmia analysed by MLPA, 5 were found to be deleted for the whole SOX2 gene and 1 had a partial deletion. In two of these, FISH studies identified sub-microscopic deletions involving a minimum of 328 Kb and 550 Kb. The SOX2 phenotypes include a patient with anophthalmia, oesophageal abnormalities and horseshoe kidney, and a patient with a retinal dystrophy implicating SOX2 in retinal development. Our results provide further evidence that SOX2 haploinsufficiency is a common cause of severe developmental ocular malformations and that background genetic variation determines the varying phenotypes. Given the high incidence of whole gene deletion we recommend that all patients with severe microphthalmia or anophthalmia, including unilateral cases be screened by MLPA and FISH for SOX2 deletions.

  13. Efficacy and safety of SOX chemotherapy with or without surgery in AFP-producing advanced gastric cancer

    OpenAIRE

    Li, Zhu; Hou, Xu; Chen, Juan; Sun, Huidong; Mi, Yuetang; Sui, Yongling; Li, Yuhong; Xie, Jiaping; Qiao, Yingli; Lei, Xiaofeng; Che, Xiaoshuang; Liu, Jun

    2017-01-01

    The present study investigated the clinical efficacy of S-1 plus oxaliplatin (SOX) regimen, with or without surgery in ?-fetoprotein-producing gastric cancer (APGC) with liver metastasis. A total of 24 patients with APGC treated at the Liaocheng People's Hospital between January 2011 and December 2013 were retrospectively reviewed. Clinical efficacy and patient safety were compared between the two groups. The median progression-free survival (PFS) and overall survival (OS) in the SOX group we...

  14. Interchromosomal insertional translocation at Xq26.3 alters SOX3 expression in an individual with XX male sex reversal.

    Science.gov (United States)

    Haines, Bryan; Hughes, James; Corbett, Mark; Shaw, Marie; Innes, Josie; Patel, Leena; Gecz, Jozef; Clayton-Smith, Jill; Thomas, Paul

    2015-05-01

    46,XX male sex reversal occurs in approximately 1: 20 000 live births and is most commonly caused by interchromosomal translocations of the Y-linked sex-determining gene, SRY. Rearrangements of the closely related SOX3 gene on the X chromosome are also associated with 46,XX male sex reversal. It has been hypothesized that sex reversal in the latter is caused by ectopic expression of SOX3 in the developing urogenital ridge where it triggers male development by acting as an analog of SRY. However, altered regulation of SOX3 in individuals with XX male sex reversal has not been demonstrated. Here we report a boy with SRY-negative XX male sex reversal who was diagnosed at birth with a small phallus, mixed gonads, and borderline-normal T. Molecular characterization of the affected individual was performed using array comparative genomic hybridization, fluorescent in situ hybridization of metaphase chromosomes, whole-genome sequencing, and RT-PCR expression analysis of lymphoblast cell lines. The affected male carries ∼774-kb insertion translocation from chromosome 1 into a human-specific palindromic sequence 82 kb distal to SOX3. Importantly, robust SOX3 expression was identified in cells derived from the affected individual but not from control XX or XY cells, indicating that the translocation has a direct effect on SOX3 regulation. This is the first demonstration of altered SOX3 expression in an individual with XX male sex reversal and suggests that SOX3 can substitute for SRY to initiate male development in humans.

  15. SOX4 inhibits GBM cell growth and induces G0/G1 cell cycle arrest through Akt-p53 axis.

    Science.gov (United States)

    Zhang, Jing; Jiang, Huawei; Shao, Jiaofang; Mao, Ruifang; Liu, Jie; Ma, Yingying; Fang, Xuefeng; Zhao, Na; Zheng, Shu; Lin, Biaoyang

    2014-11-01

    SOX4 is a transcription factor required for tissue development and differentiation in vertebrates. Overexpression of SOX4 has been reported in many cancers including glioblastoma multiforme (GBM), however, the underlying mechanism of actions has not been studied. In this study, we investigated the role of SOX4 in GBM. Kaplan-Meier analysis was performed to assess the association between SOX4 expression levels and survival times in primary GBM samples. Cre/lox P system was used to generate gain or loss of SOX4 in GBM cells, and microarray analysis uncovered the regulation network of SOX4 in GBM cells. High SOX4 expression was significantly associated with good prognosis of primary GBMs. SOX4 inhibited the growth of GBM cell line LN229, A172G and U87MG, partly via the activation of p53-p21 signaling and down-regulation of phosphorylated AKT1. Gene expression profiling and subsequent gene ontology analysis showed that SOX4 influenced several key pathways including the Wnt/ beta-catenin and TGF-beta signaling pathways. Our study found that SOX4 acts as a tumor suppressor in GBM cells by induce cell cycle arrest and inhibiting cell growth.

  16. Global regulator SoxR is a negative regulator of efflux pump gene expression and affects antibiotic resistance and fitness in Acinetobacter baumannii.

    Science.gov (United States)

    Li, Henan; Wang, Qi; Wang, Ruobing; Zhang, Yawei; Wang, Xiaojuan; Wang, Hui

    2017-06-01

    SoxR is a global regulator contributing to multidrug resistance in Enterobacteriaceae. However, the contribution of SoxR to antibiotic resistance and fitness in Acinetobacter baumannii has not yet been studied. Comparisons of molecular characteristics were performed between 32 multidrug-resistant A. baumannii isolates and 11 susceptible isolates. A soxR overexpression mutant was constructed, and its resistance phenotype was analyzed. The impact of SoxR on efflux pump gene expression was measured at the transcription level. The effect of SoxR on the growth and fitness of A. baumannii was analyzed using a growth rate assay and an in vitro competition assay. The frequency of the Gly39Ser mutation in soxR was higher in multidrug-resistant A. baumannii, whereas the soxS gene was absent in all strains analyzed. SoxR overexpression led to increased susceptibility to chloramphenicol (4-fold), tetracycline (2-fold), tigecycline (2-fold), ciprofloxacin (2-fold), amikacin (2-fold), and trimethoprim (2-fold), but it did not influence imipenem susceptibility. Decreased expression of abeS (3.8-fold), abeM (1.3-fold), adeJ (2.4-fold), and adeG (2.5-fold) were correlated with soxR overexpression (P baumannii.

  17. Waardenburg syndrome: a rare cause of inherited neuropathy due to SOX10 mutation.

    Science.gov (United States)

    Bogdanova-Mihaylova, Petya; Alexander, Michael D; Murphy, Raymond P J; Murphy, Sinéad M

    2017-09-01

    Waardenburg syndrome (WS) is a rare disorder comprising sensorineural deafness and pigmentation abnormalities. Four distinct subtypes are defined based on the presence or absence of additional symptoms. Mutations in six genes have been described in WS. SOX10 mutations are usually associated with a more severe phenotype of WS with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, and Hirschsprung disease. Here we report a 32-year-old man with a novel heterozygous missense variant in SOX10 gene, who presented with congenital deafness, Hirschsprung disease, iris heterochromia, foot deformity, and intermediate conduction velocity length-dependent sensorimotor neuropathy. This case highlights that the presence of other non-neuropathic features in a patient with presumed hereditary neuropathy should alert the clinician to possible atypical rare causes. © 2017 Peripheral Nerve Society.

  18. Isolated hypogonadotropic hypogonadism with SOX2 mutation and anophthalmia/microphthalmia in offspring.

    Science.gov (United States)

    Stark, Zornitza; Storen, Rebecca; Bennetts, Bruce; Savarirayan, Ravi; Jamieson, Robyn V

    2011-07-01

    Isolated hypogonadotropic hypogonadism (IHH) is a genetically heterogeneous condition in which patients frequently require assisted reproduction to achieve fertility. In patients with IHH who are otherwise well, no particular increased risk of congenital anomalies in the resultant offspring has been highlighted. Heterozygous mutations in SOX2 are the commonest single-gene cause of anophthalmia/microphthalmia (A/M) and sometimes result in pituitary abnormalities. We report a family with a novel frameshift mutation in the SOX2 transactivation domain, p.Gly280AlafsX91, resulting in bilateral anophthalmia and subtle endocrinological abnormalities in a male sibling, and unilateral microphthalmia in a female sibling. The mutation is present in their mother who has IHH, but has no eye disorders or other anomalies. She underwent assisted reproduction to achieve fertility. This report has important implications for the evaluation of patients with IHH, particularly in the setting of planned infertility treatment.

  19. 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.

  20. Transcription Factor SOX5 Promotes the Migration and Invasion of Fibroblast-Like Synoviocytes in Part by Regulating MMP-9 Expression in Collagen-Induced Arthritis

    Directory of Open Access Journals (Sweden)

    Yumeng Shi

    2018-04-01

    Full Text Available ObjectivesFibroblast-like synoviocytes (FLS exhibit a unique aggressive phenotype in rheumatoid arthritis (RA. Increased FLS migration and subsequent invasion of the extracellular matrix are essential to joint destruction in RA. Our previous research reported that transcription factor SOX5 was highly expressed in RA-FLS. Here, the effects of SOX5 in RA-FLS migration and invasion will be investigated.MethodsThe migration and invasion of RA-FLS were evaluated using a transwell chamber assay. The expression of several potential SOX5-targeted genes, including matrix metalloproteinases (MMP-1, 2, 3 and 9, chemokines (CCL4, CCL2, CCR5 and CCR2, and pro-inflammatory cytokines (TNF-α and IL-6, were examined in RA-FLS using SOX5 gain- and loss-of-function study. The molecular mechanisms of SOX5-mediated MMP-9 expressions were assayed by luciferase reporter gene and chromatin immunoprecipitation (ChIP studies. The in vivo effect of SOX5 on FLS migration and invasion was examined using collagen-induced arthritis (CIA in DBA/1J mice.ResultsKnockdown SOX5 decreased lamellipodium formation, migration, and invasion of RA-FLS. The expression of MMP-9 was the only gene tested to be concomitantly affected by silencing or overexpressing SOX5. ChIP assay revealed that SOX5 was bound to the MMP-9 promoter in RA-FLS. The overexpression of SOX5 markedly enhanced the MMP-9 promoter activity, and specific deletion of a putative SOX5-binding site in MMP-9 promoter diminished this promoter-driven transcription in FLS. Locally knocked down SOX5 inhibited MMP-9 expression in the joint tissue and reduced pannus migration and invasion into the cartilage in CIA mice.ConclusionSOX5 plays a novel role in mediating migration and invasion of FLS in part by regulating MMP-9 expression in RA.

  1. Transcription Factor SOX5 Promotes the Migration and Invasion of Fibroblast-Like Synoviocytes in Part by Regulating MMP-9 Expression in Collagen-Induced Arthritis.

    Science.gov (United States)

    Shi, Yumeng; Wu, Qin; Xuan, Wenhua; Feng, Xiaoke; Wang, Fang; Tsao, Betty P; Zhang, Miaojia; Tan, Wenfeng

    2018-01-01

    Fibroblast-like synoviocytes (FLS) exhibit a unique aggressive phenotype in rheumatoid arthritis (RA). Increased FLS migration and subsequent invasion of the extracellular matrix are essential to joint destruction in RA. Our previous research reported that transcription factor SOX5 was highly expressed in RA-FLS. Here, the effects of SOX5 in RA-FLS migration and invasion will be investigated. The migration and invasion of RA-FLS were evaluated using a transwell chamber assay. The expression of several potential SOX5-targeted genes, including matrix metalloproteinases (MMP-1, 2, 3 and 9), chemokines (CCL4, CCL2, CCR5 and CCR2), and pro-inflammatory cytokines (TNF-α and IL-6), were examined in RA-FLS using SOX5 gain- and loss-of-function study. The molecular mechanisms of SOX5-mediated MMP-9 expressions were assayed by luciferase reporter gene and chromatin immunoprecipitation (ChIP) studies. The in vivo effect of SOX5 on FLS migration and invasion was examined using collagen-induced arthritis (CIA) in DBA/1J mice. Knockdown SOX5 decreased lamellipodium formation, migration, and invasion of RA-FLS. The expression of MMP-9 was the only gene tested to be concomitantly affected by silencing or overexpressing SOX5. ChIP assay revealed that SOX5 was bound to the MMP-9 promoter in RA-FLS. The overexpression of SOX5 markedly enhanced the MMP-9 promoter activity, and specific deletion of a putative SOX5-binding site in MMP-9 promoter diminished this promoter-driven transcription in FLS. Locally knocked down SOX5 inhibited MMP-9 expression in the joint tissue and reduced pannus migration and invasion into the cartilage in CIA mice. SOX5 plays a novel role in mediating migration and invasion of FLS in part by regulating MMP-9 expression in RA.

  2. LSD1 demethylase and the methyl-binding protein PHF20L1 prevent SET7 methyltransferase-dependent proteolysis of the stem-cell protein SOX2.

    Science.gov (United States)

    Zhang, Chunxiao; Hoang, Nam; Leng, Feng; Saxena, Lovely; Lee, Logan; Alejo, Salvador; Qi, Dandan; Khal, Anthony; Sun, Hong; Lu, Fei; Zhang, Hui

    2018-03-09

    The pluripotency-controlling stem-cell protein SRY-box 2 (SOX2) plays a pivotal role in maintaining the self-renewal and pluripotency of embryonic stem cells and also of teratocarcinoma or embryonic carcinoma cells. SOX2 is monomethylated at lysine 119 (Lys-119) in mouse embryonic stem cells by the SET7 methyltransferase, and this methylation triggers ubiquitin-dependent SOX2 proteolysis. However, the molecular regulators and mechanisms controlling SET7-induced SOX2 proteolysis are unknown. Here, we report that in human ovarian teratocarcinoma PA-1 cells, methylation-dependent SOX2 proteolysis is dynamically regulated by the LSD1 lysine demethylase and a methyl-binding protein, PHD finger protein 20-like 1 (PHF20L1). We found that LSD1 not only removes the methyl group from monomethylated Lys-117 (equivalent to Lys-119 in mouse SOX2), but it also demethylates monomethylated Lys-42 in SOX2, a reaction that SET7 also regulated and that also triggered SOX2 proteolysis. Our studies further revealed that PHF20L1 binds both monomethylated Lys-42 and Lys-117 in SOX2 and thereby prevents SOX2 proteolysis. Down-regulation of either LSD1 or PHF20L1 promoted SOX2 proteolysis, which was prevented by SET7 inactivation in both PA-1 and mouse embryonic stem cells. Our studies also disclosed that LSD1 and PHF20L1 normally regulate the growth of pluripotent mouse embryonic stem cells and PA-1 cells by preventing methylation-dependent SOX2 proteolysis. In conclusion, our findings reveal an important mechanism by which the stability of the pluripotency-controlling stem-cell protein SOX2 is dynamically regulated by the activities of SET7, LSD1, and PHF20L1 in pluripotent stem cells. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Purification, crystallization and preliminary X-ray diffraction analysis of the HMG domain of Sox17 in complex with DNA

    International Nuclear Information System (INIS)

    Ng, Calista Keow Leng; Palasingam, Paaventhan; Venkatachalam, Rajakannan; Baburajendran, Nithya; Cheng, Jason; Jauch, Ralf; Kolatkar, Prasanna R.

    2008-01-01

    Crystals of the Sox17 HMG domain bound to LAMA1 enhancer DNA-element crystals that diffracted to 2.75 Å resolution were obtained. Sox17 is a member of the SRY-related high-mobility group (HMG) of transcription factors that have been shown to direct endodermal differentiation in early mammalian development. The LAMA1 gene encoding the α-chain of laminin-1 has been reported to be directly bound and regulated by Sox17. This paper describes the details of initial crystallization attempts with the HMG domain of mouse Sox17 (mSox17-HMG) with a 16-mer DNA element derived from the LAMA1 enhancer and optimization strategies to obtain a better diffracting crystal. The best diffracting crystal was obtained in a condition containing 0.1 M Tris–HCl pH 7.4, 0.2 M MgCl 2 , 30% PEG 3350 using the hanging-drop vapour-diffusion method. A highly redundant in-house data set was collected to 2.75 Å resolution with 99% completeness. The presence of the mSox17-HMG–DNA complex within the crystals was confirmed and Matthews analysis indicated the presence of one complex per asymmetric unit

  4. A novel luciferase knock-in reporter system for studying transcriptional regulation of the human Sox2 gene.

    Science.gov (United States)

    Xiao, Dan; Zhang, Weifeng; Li, Yan; Liu, Kuan; Zhao, Junli; Sun, Xiaohong; Shan, Linlin; Mao, Qinwen; Xia, Haibin

    2016-02-10

    Sox2 is an important transcriptional factor that has multiple functions in stem cell maintenance and tumorigenesis. To investigate the transcriptional regulation of the Sox2 gene, a luciferase knock-in reporter system was established in HEK293 cells by placing the luciferase gene in the genome under the control of the Sox2 gene promoter using a transcription activator-like effector nuclease (TALEN)-mediated genome editing technique. PCR and Southern blot results confirmed the site-specific integration of a single copy of the exogenous luciferase gene into the genome. To prove the reliability and sensitivity of this novel luciferase knock-in system, a CRISPR/Cas transcription activation system for the Sox2 gene was constructed and applied to the knock-in system. The results indicated that luciferase activity was directly correlated with the activity of the Sox2 endogenous promoter. This novel system will be a useful tool to study the transcriptional regulation of Sox2, and has great potential in medical and industrial applications. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. De novo SOX10 Nonsense Mutation in a Patient with Kallmann Syndrome, Deafness, Iris Hypopigmentation, and Hyperthyroidism.

    Science.gov (United States)

    Wang, Fang; Zhao, Shaoli; Xie, Yanhong; Yang, Wenjun; Mo, Zhaohui

    2018-03-01

    Kallmann syndrome (KS) is a clinically and genetically heterogeneous disorder characterized by hypogonadotropic hypogonadism and olfactory dysfunction. Recently, mutations in SOX10, a well-known causative gene of Waardenburg syndrome (WS), have been identified in a few KS patients with additional developmental defects including hearing loss. However, the understanding of SOX10 mutation associates with KS and other clinical consequences remains fragmentary. A 30-year-old Chinese male patient presented with no pubertal sex development when he was at the age of twelve years. Additionally, he showed anosmia, sensory deafness, and blue irises. Last year, he developed clinical symptoms of hyperthyroidism with a fast heartbeat, heat intolerance and weight loss. Blood examinations revealed low levels of FSH, LH, and testosterone. Thyroid function showed high levels of FT3, FT4 and extremely low level of TSH. Molecular analysis detected a de novo (c.565G>T/p.E189X) mutation in SOX10, which has previously been reported in a patient with WS4 (WS with Hirschsprung). The mutation was predicted to be probably damaging. These results highlight the significance of SOX10 haploinsufficiency as a genetic cause of KS. Importantly, our result implies that the same SOX10 mutation can underlie both typical KS and WS, while the correlation between SOX10 and hyperthyroidism still needs to be clarified in the future. © 2018 by the Association of Clinical Scientists, Inc.

  6. 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. © 2014 Wiley Periodicals, Inc.

  7. 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.

  8. 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.

  9. 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.

  10. Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors.

    Science.gov (United States)

    Narasimhan, Kamesh; Micoine, Kevin; Lacôte, Emmanuel; Thorimbert, Serge; Cheung, Edwin; Hasenknopf, Bernold; Jauch, Ralf

    2014-01-01

    SOX transcription factors constitute an attractive target class for intervention with small molecules as they play a prominent role in the field of regenerative biomedicine and cancer biology. However, rationally engineering specific inhibitors that interfere with transcription factor DNA interfaces continues to be a monumental challenge in the field of transcription factor chemical biology. Polyoxometalates (POMs) are inorganic compounds that were previously shown to target the high-mobility group (HMG) of SOX proteins at nanomolar concentrations. In continuation of this work, we carried out an assessment of the selectivity of a panel of newly synthesized organo-polyoxometalate hybrids in targeting different transcription factor families to enable the usage of polyoxometalates as specific SOX transcription factor drugs. The residual DNA-binding activities of 15 different transcription factors were measured after treatment with a panel of diverse polyoxometalates. Polyoxometalates belonging to the Dawson structural class were found to be more potent inhibitors than the Keggin class. Further, organically modified Dawson polyoxometalates were found to be the most potent in inhibiting transcription factor DNA binding activity. The size of the polyoxometalates and its derivitization were found to be the key determinants of their potency. Polyoxometalates are highly potent, nanomolar range inhibitors of the DNA binding activity of the Sox-HMG family. However, binding assays involving a limited subset of structurally diverse polyoxometalates revealed a low selectivity profile against different transcription factor families. Further progress in achieving selectivity and deciphering structure-activity relationship of POMs require the identification of POM binding sites on transcription factors using elaborate approaches like X-ray crystallography and multidimensional NMR. In summary, our report reaffirms that transcription factors are challenging molecular architectures

  11. miR-126 Functions as a Tumor Suppressor in Osteosarcoma by Targeting Sox2

    Directory of Open Access Journals (Sweden)

    Chenglin Yang

    2013-12-01

    Full Text Available Osteosarcoma (OS is the most common malignant bone tumor in children and young adults, the early symptoms and signs of which are non-specific. The discovery of microRNAs (miRNAs provides a new avenue for the early diagnosis and treatment of OS. miR-126 has been reported to be highly expressed in vascularized tissues, and is recently widely studied in cancers. Herein, we explored the expression and significance of miR-126 in OS. Using TaqMan RT-PCR analysis, we analyzed the expression of miR-126 in 32 paired OS tumor tissues and 4 OS cell lines and found that miR-126 was consistently under-expressed in OS tissues and cell lines compared with normal bone tissues and normal osteoblast cells (NHOst, respectively. As miR-126 is significantly decreased in OS tissues and cell lines, we sought to compensate for its loss through exogenous transfection into MG-63 cells with a miR-126 mimic. Ectopic expression of miR-126 inhibited cell proliferation, migration and invasion, and induced apoptosis of MG-63 cells. Moreover, bioinformatic prediction suggested that the sex-determining region Y-box 2 (Sox2 is a target gene of miR-126. Using mRNA and protein expression analysis, luciferase assays and rescue assays, we demonstrate that restored expression of Sox2 dampened miR-126-mediated suppression of tumor progression, which suggests the important role of miR-126/Sox2 interaction in tumor progression. Taken together, our data indicate that miR-126 functions as a tumor suppressor in OS, which exerts its activity by suppressing the expression of Sox2.

  12. Spectrum of temporal bone abnormalities in patients with Waardenburg syndrome and SOX10 mutations.

    Science.gov (United States)

    Elmaleh-Bergès, M; Baumann, C; Noël-Pétroff, N; Sekkal, A; Couloigner, V; Devriendt, K; Wilson, M; Marlin, S; Sebag, G; Pingault, V

    2013-01-01

    Waardenburg syndrome, characterized by deafness and pigmentation abnormalities, is clinically and genetically heterogeneous, consisting of 4 distinct subtypes and involving several genes. SOX10 mutations have been found both in types 2 and 4 Waardenburg syndrome and neurologic variants. The purpose of this study was to evaluate both the full spectrum and relative frequencies of inner ear malformations in these patients. Fifteen patients with Waardenburg syndrome and different SOX10 mutations were studied retrospectively. Imaging was performed between February 2000 and March 2010 for cochlear implant work-up, diagnosis of hearing loss, and/or evaluation of neurologic impairment. Eleven patients had both CT and MR imaging examinations, 3 had MR imaging only, and 1 had CT only. Temporal bone abnormalities were bilateral. The most frequent pattern associated agenesis or hypoplasia of ≥1 semicircular canal, an enlarged vestibule, and a cochlea with a reduced size and occasionally an abnormal shape, but with normal partition in the 13/15 cases that could be analyzed. Three patients lacked a cochlear nerve, bilaterally in 2 patients. In addition, associated abnormalities were found when adequate MR imaging sequences were available: agenesis of the olfactory bulbs (7/8), hypoplastic or absent lacrimal glands (11/14), hypoplastic parotid glands (12/14), and white matter signal anomalies (7/13). In the appropriate clinical context, bilateral agenesis or hypoplasia of the semicircular canals or both, associated with an enlarged vestibule and a cochlear deformity, strongly suggests a diagnosis of Waardenburg syndrome linked to a SOX10 mutation.

  13. 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. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  14. MicroRNA-320 suppresses colorectal cancer by targeting SOX4, FOXM1, and FOXQ1

    DEFF Research Database (Denmark)

    Vishnubalaji, Radhakrishnan; Hamam, Rimi; Shijun, Yue

    2016-01-01

    Colorectal cancer (CRC) is the third most common cancer causing high mortality rates world-wide. Delineating the molecular mechanisms leading to CRC development and progression, including the role of microRNAs (miRNAs), are currently being unravelled at a rapid rate. Here, we report frequent down...... for the miR-320/SOX4/FOXM1/FOXQ1 axes in promoting CRC development and progression and suggest targeting those networks as potential therapeutic strategy for CRC....... mice. Global gene expression analysis in CRC cells over-expressing miR-320c, combined with in silico prediction identified 84 clinically-relevant potential gene targets for miR-320 in CRC. Using a series of biochemical assays and functional validation, SOX4, FOXM1, and FOXQ1 were validated as novel...... gene targets for the miR-320 family. Inverse correlation between the expression of miR-320 members with SOX4, FOXM1, and FOXQ1 was observed in primary CRC patients' specimens, suggesting that these genes are likely bona fide targets for the miR-320 family. Interestingly, interrogation of the expression...

  15. 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; De Val, Sarah; 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

  16. NFATc4 Regulates Sox9 Gene Expression in Acinar Cell Plasticity and Pancreatic Cancer Initiation

    Directory of Open Access Journals (Sweden)

    Elisabeth Hessmann

    2016-01-01

    Full Text Available Acinar transdifferentiation toward a duct-like phenotype constitutes the defining response of acinar cells to external stress signals and is considered to be the initial step in pancreatic carcinogenesis. Despite the requirement for oncogenic Kras in pancreatic cancer (PDAC development, oncogenic Kras is not sufficient to drive pancreatic carcinogenesis beyond the level of premalignancy. Instead, secondary events, such as inflammation-induced signaling activation of the epidermal growth factor (EGFR or induction of Sox9 expression, are required for tumor formation. Herein, we aimed to dissect the mechanism that links EGFR signaling to Sox9 gene expression during acinar-to-ductal metaplasia in pancreatic tissue adaptation and PDAC initiation. We show that the inflammatory transcription factor NFATc4 is highly induced and localizes in the nucleus in response to inflammation-induced EGFR signaling. Moreover, we demonstrate that NFATc4 drives acinar-to-ductal conversion and PDAC initiation through direct transcriptional induction of Sox9. Therefore, strategies designed to disrupt NFATc4 induction might be beneficial in the prevention or therapy of PDAC.

  17. EGL-13/SoxD specifies distinct O2 and CO2 sensory neuron fates in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    Jakob Gramstrup Petersen

    2013-05-01

    Full Text Available Animals harbor specialized neuronal systems that are used for sensing and coordinating responses to changes in oxygen (O2 and carbon dioxide (CO2. In Caenorhabditis elegans, the O2/CO2 sensory system comprises functionally and morphologically distinct sensory neurons that mediate rapid behavioral responses to exquisite changes in O2 or CO2 levels via different sensory receptors. How the diversification of the O2- and CO2-sensing neurons is established is poorly understood. We show here that the molecular identity of both the BAG (O2/CO2-sensing and the URX (O2-sensing neurons is controlled by the phylogenetically conserved SoxD transcription factor homolog EGL-13. egl-13 mutant animals fail to fully express the distinct terminal gene batteries of the BAG and URX neurons and, as such, are unable to mount behavioral responses to changes in O2 and CO2. We found that the expression of egl-13 is regulated in the BAG and URX neurons by two conserved transcription factors-ETS-5(Ets factor in the BAG neurons and AHR-1(bHLH factor in the URX neurons. In addition, we found that EGL-13 acts in partially parallel pathways with both ETS-5 and AHR-1 to direct BAG and URX neuronal fate respectively. Finally, we found that EGL-13 is sufficient to induce O2- and CO2-sensing cell fates in some cellular contexts. Thus, the same core regulatory factor, egl-13, is required and sufficient to specify the distinct fates of O2- and CO2-sensing neurons in C. elegans. These findings extend our understanding of mechanisms of neuronal diversification and the regulation of molecular factors that may be conserved in higher organisms.

  18. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis.

    Science.gov (United States)

    Ren, Decheng; Zhou, Yingjiang; Morris, David; Li, Minghua; Li, Zhiqin; Rui, Liangyou

    2007-02-01

    SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (alpha, beta, gamma, and/or delta) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1beta was specifically expressed in neural tissue in SH2B1-transgenic (SH2B1(Tg)) mice. SH2B1(Tg) mice were crossed with SH2B1-knockout (SH2B1(KO)) mice to generate SH2B1(TgKO) mice expressing SH2B1 only in neural tissue but not in other tissues. Systemic deletion of the SH2B1 gene resulted in metabolic disorders in SH2B1(KO) mice, including hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of SH2B1beta not only corrected the metabolic disorders in SH2B1(TgKO) mice, but also improved JAK2-mediated leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Moreover, neuron-specific overexpression of SH2B1 dose-dependently protected against high-fat diet-induced leptin resistance and obesity. These observations suggest that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin sensitivity.

  19. Modelling of three-dimensional structures of cytochromes P450 11B1 and 11B2.

    Science.gov (United States)

    Belkina, N V; Lisurek, M; Ivanov, A S; Bernhardt, R

    2001-12-15

    The final steps of the biosynthesis of glucocorticoids and mineralocorticoids in the adrenal cortex require the action of two different cytochromes P450--CYP11B1 and CYP11B2. Homology modelling of the three-dimensional structures of these cytochromes was performed based on crystallographic coordinates of two bacterial P450s, CYP102 (P450BM-3) and CYP108 (P450terp). Principal attention was given to the modelling of the active sites and a comparison of the active site structures of CYP11B1 and CYP11B2 was performed. It can be demonstrated that key residue contacts within the active site appear to depend on the orientation of the heme. The obtained 3D structures of CYP11B1 and CYP11B2 were used for investigation of structure-function relationships of these enzymes. Previously obtained results on naturally occurring mutants and on mutants obtained by site-directed mutagenesis are discussed.

  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)

    Autrup, Herman; Essigmann, John M.; Croy, Robert G.

    1979-01-01

    Aflatoxin B1 and benzo(a)pyrene were activated by both cultured human bronchus and human colon as measured by binding to cellular DNA and protein. The binding of aflatoxin B1 to DNA was dose dependent, and the level of binding was higher in cultured human bronchus than it was in the colon. When c...

  1. SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression.

    Directory of Open Access Journals (Sweden)

    Victor Y L Leung

    2011-11-01

    Full Text Available Cartilage and endochondral bone development require SOX9 activity to regulate chondrogenesis, chondrocyte proliferation, and transition to a non-mitotic hypertrophic state. The restricted and reciprocal expression of the collagen X gene, Col10a1, in hypertrophic chondrocytes and Sox9 in immature chondrocytes epitomise the precise spatiotemporal control of gene expression as chondrocytes progress through phases of differentiation, but how this is achieved is not clear. Here, we have identified a regulatory element upstream of Col10a1 that enhances its expression in hypertrophic chondrocytes in vivo. In immature chondrocytes, where Col10a1 is not expressed, SOX9 interacts with a conserved sequence within this element that is analogous to that within the intronic enhancer of the collagen II gene Col2a1, the known transactivation target of SOX9. By analysing a series of Col10a1 reporter genes in transgenic mice, we show that the SOX9 binding consensus in this element is required to repress expression of the transgene in non-hypertrophic chondrocytes. Forced ectopic Sox9 expression in hypertrophic chondrocytes in vitro and in mice resulted in down-regulation of Col10a1. Mutation of a binding consensus motif for GLI transcription factors, which are the effectors of Indian hedgehog signaling, close to the SOX9 site in the Col10a1 regulatory element, also derepressed transgene expression in non-hypertrophic chondrocytes. GLI2 and GLI3 bound to the Col10a1 regulatory element but not to the enhancer of Col2a1. In addition to Col10a1, paired SOX9-GLI binding motifs are present in the conserved non-coding regions of several genes that are preferentially expressed in hypertrophic chondrocytes and the occurrence of pairing is unlikely to be by chance. We propose a regulatory paradigm whereby direct concomitant positive and negative transcriptional control by SOX9 ensures differentiation phase-specific gene expression in chondrocytes. Discrimination between

  2. Hurricane Satellite (HURSAT) from International Satellite Cloud Climatology Project (ISCCP) B1, Version 6

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — The Hurricane Satellite (HURSAT) from derived International Satellite Cloud Climatology Project (ISCCP) B1 observations of tropical cyclones worldwide. The B1 data...

  3. Prdm1a and miR-499 act sequentially to restrict Sox6 activity to the fast-twitch muscle lineage in the zebrafish embryo.

    Science.gov (United States)

    Wang, XinGang; Ono, Yosuke; Tan, Swee Chuan; Chai, Ruth JinFen; Parkin, Caroline; Ingham, Philip W

    2011-10-01

    Sox6 has been proposed to play a conserved role in vertebrate skeletal muscle fibre type specification. In zebrafish, sox6 transcription is repressed in slow-twitch progenitors by the Prdm1a transcription factor. Here we identify sox6 cis-regulatory sequences that drive fast-twitch-specific expression in a Prdm1a-dependent manner. We show that sox6 transcription subsequently becomes derepressed in slow-twitch fibres, whereas Sox6 protein remains restricted to fast-twitch fibres. We find that translational repression of sox6 is mediated by miR-499, the slow-twitch-specific expression of which is in turn controlled by Prdm1a, forming a regulatory loop that initiates and maintains the slow-twitch muscle lineage.

  4. Deletions and de novo mutations of SOX11 are associated with a neurodevelopmental disorder with features of Coffin-Siris syndrome.

    Science.gov (United States)

    Hempel, Annmarie; Pagnamenta, Alistair T; Blyth, Moira; Mansour, Sahar; McConnell, Vivienne; Kou, Ikuyo; Ikegawa, Shiro; Tsurusaki, Yoshinori; Matsumoto, Naomichi; Lo-Castro, Adriana; Plessis, Ghislaine; Albrecht, Beate; Battaglia, Agatino; Taylor, Jenny C; Howard, Malcolm F; Keays, David; Sohal, Aman Singh; Kühl, Susanne J; Kini, Usha; McNeill, Alisdair

    2016-03-01

    SOX11 is a transcription factor proposed to play a role in brain development. The relevance of SOX11 to human developmental disorders was suggested by a recent report of SOX11 mutations in two patients with Coffin-Siris syndrome. Here we further investigate the role of SOX11 variants in neurodevelopmental disorders. We used array based comparative genomic hybridisation and trio exome sequencing to identify children with intellectual disability who have deletions or de novo point mutations disrupting SOX11. The pathogenicity of the SOX11 mutations was assessed using an in vitro gene expression reporter system. Loss-of-function experiments were performed in xenopus by knockdown of Sox11 expression. We identified seven individuals with chromosome 2p25 deletions involving SOX11. Trio exome sequencing identified three de novo SOX11 variants, two missense (p.K50N; p.P120H) and one nonsense (p.C29*). The biological consequences of the missense mutations were assessed using an in vitro gene expression system. These individuals had microcephaly, developmental delay and shared dysmorphic features compatible with mild Coffin-Siris syndrome. To further investigate the function of SOX11, we knocked down the orthologous gene in xenopus. Morphants had significant reduction in head size compared with controls. This suggests that SOX11 loss of function can be associated with microcephaly. We thus propose that SOX11 deletion or mutation can present with a Coffin-Siris phenotype. 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/

  5. 26 CFR 48.4161(b)-1 - Imposition and rates of tax; bows and arrows.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 16 2010-04-01 2010-04-01 true Imposition and rates of tax; bows and arrows. 48.4161(b)-1 Section 48.4161(b)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) MISCELLANEOUS EXCISE TAXES MANUFACTURERS AND RETAILERS EXCISE TAXES Sporting Goods § 48.4161(b)-1...

  6. 17 CFR 270.6b-1 - Exemption of employees' securities company pending determination of application.

    Science.gov (United States)

    2010-04-01

    ...' securities company pending determination of application. 270.6b-1 Section 270.6b-1 Commodity and Securities... 1940 § 270.6b-1 Exemption of employees' securities company pending determination of application. Any... Act (54 Stat. 801; 15 U.S.C. 80a-6) shall be exempt, pending final determination of such application...

  7. 17 CFR 240.15b1-1 - Application for registration of brokers or dealers.

    Science.gov (United States)

    2010-04-01

    ... of brokers or dealers. 240.15b1-1 Section 240.15b1-1 Commodity and Securities Exchanges SECURITIES... Rules and Regulations Under the Securities Exchange Act of 1934 Registration of Brokers and Dealers § 240.15b1-1 Application for registration of brokers or dealers. (a) An application for registration of...

  8. 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

  9. Coop-Seq Analysis Demonstrates that Sox2 Evokes Latent Specificities in the DNA Recognition by Pax6.

    Science.gov (United States)

    Hu, Caizhen; Malik, Vikas; Chang, Yiming Kenny; Veerapandian, Veeramohan; Srivastava, Yogesh; Huang, Yong-Heng; Hou, Linlin; Cojocaru, Vlad; Stormo, Gary D; Jauch, Ralf

    2017-11-24

    Sox2 and Pax6 co-regulate genes in neural lineages and the lens by forming a ternary complex likely facilitated allosterically through DNA. We used the quantitative and scalable cooperativity-by-sequencing (Coop-seq) approach to interrogate Sox2/Pax6 dimerization on a DNA library where five positions of the Pax6 half-site were randomized yielding 1024 cooperativity factors. Consensus positions normally required for the high-affinity DNA binding by Pax6 need to be mutated for effective dimerization with Sox2. Out of the five randomized bases, a 5' thymidine is present in most of the top ranking elements. However, this thymidine maps to a region outside of the Pax half site and is not expected to directly interact with Pax6 in known binding modes suggesting structural reconfigurations. Re-analysis of ChIP-seq data identified several genomic regions where the cooperativity promoting sequence pattern is co-bound by Sox2 and Pax6. A highly conserved Sox2/Pax6 bound site near the Sprouty2 locus was verified to promote cooperative dimerization designating Sprouty2 as a potential target reliant on Sox2/Pax6 cooperativity in several neural cell types. Collectively, the functional interplay of Sox2 and Pax6 demands the relaxation of high-affinity binding sites and is enabled by alternative DNA sequences. We conclude that this binding mode evolved to warrant that a subset of target genes is only regulated in the presence of suitable partner factors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus

    Science.gov (United States)

    Suh, Hoonkyo; Consiglio, Antonella; Ray, Jasodhara; Sawai, Toru; D'Amour, Kevin A.; Gage, Fred H.

    2007-01-01

    Summary To characterize the properties of adult neural stem cells (NSCs), we generated and analyzed Sox2-GFP transgenic mice. Sox2-GFP cells in the subgranular zone (SGZ) express markers specific for progenitors, but they represent two morphologically distinct populations that differ in proliferation levels. Lentivirus- and retrovirus-mediated fate tracing studies showed that Sox2+ cells in the SGZ have potential to give rise to neurons and astrocytes, revealing their multipotency at the population as well as a single cell level. More interestingly, a subpopulation of Sox2+ cells gives rise to cells that retain Sox2, highlighting Sox2+ cells as a primary source for adult NSCs. In response to mitotic signals, increased proliferation of Sox2+ cells is coupled with the generation of Sox2+ NSCs as well as neuronal precursors. An asymmetric contribution of Sox2+ NSCs may play an important role in maintaining the constant size of the NSC pool and producing newly born neurons during adult neurogenesis. PMID:18371391

  11. Kinin B1 Receptor Promotes Neurogenic Hypertension Through Activation of Centrally Mediated Mechanisms.

    Science.gov (United States)

    Sriramula, Srinivas; Lazartigues, Eric

    2017-12-01

    Hypertension is associated with increased activity of the kallikrein-kinin system. Kinin B1 receptor (B1R) activation leads to vasoconstriction and inflammation. Despite evidence supporting a role for the B1R in blood pressure regulation, the mechanisms by which B1R could alter autonomic function and participate in the pathogenesis of hypertension remain unidentified. We sought to explore whether B1R-mediated inflammation contributes to hypertension and investigate the molecular mechanisms involved. In this study, we tested the hypothesis that activation of B1R in the brain is involved in the pathogenesis of hypertension, using the deoxycorticosterone acetate-salt model of neurogenic hypertension in wild-type and B1R knockout mice. Deoxycorticosterone acetate-salt treatment in wild-type mice led to significant increases in B1R mRNA and protein levels and bradykinin levels, enhanced gene expression of carboxypeptidase N supporting an increase in the B1R ligand, associated with enhanced blood pressure, inflammation, sympathoexcitation, autonomic dysfunction, and impaired baroreflex sensitivity, whereas these changes were blunted or prevented in B1R knockout mice. B1R stimulation was further shown to involve activation of the ASK1-JNK-ERK1/2 and NF-κB pathways in the brain. To dismiss potential developmental alterations in knockout mice, we further used B1R blockade selectively in the brain of wild-type mice. Supporting the central origin of this mechanism, intracerebroventricular infusion of a specific B1R antagonist, attenuated the deoxycorticosterone acetate-salt-induced increase in blood pressure in wild-type mice. Our data provide the first evidence of a central role for B1R-mediated inflammatory pathways in the pathogenesis of deoxycorticosterone acetate-salt hypertension and offer novel insights into possible B1R-targeted therapies for the treatment of neurogenic hypertension. © 2017 American Heart Association, Inc.

  12. Effect of vitamin B1 and mixtures of B1 with other vitamins on cytostatic efficiency of sanazole under irradiation. A study in vitro

    Science.gov (United States)

    Heinrich, Edith; Getoff, Nikola

    2003-06-01

    Experiments in vitro, using bacteria Escherichia coli (AB 1157) as a biological model, showed that the cytostatic efficiency of sanazole (AK-2123, a nitrotriazole-type radiosensitizer) in radiation treatment can be strongly influenced by the presence of various vitamins. In airfree media the sanazole action is increased by a factor of 2.5 in the presence of vitamin (vit.) B1, vit. C E-acetate and β-carotene, whereas vit. B1 used individually possesses a 2.7-times higher cytostatic activity than sanazole itself. In media containing air the highest increase of sanazole action is observed in the presence of vit. B1 and C, whereas the individual use of vit. B1 shows a radiation protection effect. In media saturated with N 2O the addition of the vit. B1 and C causes a 1.8-times larger sanazole activity, but the application of vit. B1 alone brings about a very high radiation protection. From studies of vit. B1-radiolysis it can be concluded that OH radicals are the major primary transients leading to substrate degradation. The results are of interest for the radiation therapy of cancer.

  13. Effect of vitamin B1 and mixtures of B1 with other vitamins on cytostatic efficiency of sanazole under irradiation. A study in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Heinrich, Edith; Getoff, Nikola E-mail: nikola.getoff@univie.ac.at

    2003-06-01

    Experiments in vitro, using bacteria Escherichia coli (AB 1157) as a biological model, showed that the cytostatic efficiency of sanazole (AK-2123, a nitrotriazole-type radiosensitizer) in radiation treatment can be strongly influenced by the presence of various vitamins. In airfree media the sanazole action is increased by a factor of 2.5 in the presence of vitamin (vit.) B1, vit. C E-acetate and {beta}-carotene, whereas vit. B1 used individually possesses a 2.7-times higher cytostatic activity than sanazole itself. In media containing air the highest increase of sanazole action is observed in the presence of vit. B1 and C, whereas the individual use of vit. B1 shows a radiation protection effect. In media saturated with N{sub 2}O the addition of the vit. B1 and C causes a 1.8-times larger sanazole activity, but the application of vit. B1 alone brings about a very high radiation protection. >From studies of vit. B1-radiolysis it can be concluded that OH radicals are the major primary transients leading to substrate degradation. The results are of interest for the radiation therapy of cancer.

  14. Effect of vitamin B1 and mixtures of B1 with other vitamins on cytostatic efficiency of sanazole under irradiation. A study in vitro

    International Nuclear Information System (INIS)

    Heinrich, Edith; Getoff, Nikola

    2003-01-01

    Experiments in vitro, using bacteria Escherichia coli (AB 1157) as a biological model, showed that the cytostatic efficiency of sanazole (AK-2123, a nitrotriazole-type radiosensitizer) in radiation treatment can be strongly influenced by the presence of various vitamins. In airfree media the sanazole action is increased by a factor of 2.5 in the presence of vitamin (vit.) B1, vit. C E-acetate and β-carotene, whereas vit. B1 used individually possesses a 2.7-times higher cytostatic activity than sanazole itself. In media containing air the highest increase of sanazole action is observed in the presence of vit. B1 and C, whereas the individual use of vit. B1 shows a radiation protection effect. In media saturated with N 2 O the addition of the vit. B1 and C causes a 1.8-times larger sanazole activity, but the application of vit. B1 alone brings about a very high radiation protection. >From studies of vit. B1-radiolysis it can be concluded that OH radicals are the major primary transients leading to substrate degradation. The results are of interest for the radiation therapy of cancer

  15. Sulfolobus Replication Factor C stimulates the activity of DNA Polymerase B1

    DEFF Research Database (Denmark)

    Xing, Xuanxuan; Zhang, Likui; Guo, Li

    2014-01-01

    the hyperthermophilic archaea of the genus Sulfolobus physically interacts with DNA polymerase B1 (PolB1) and enhances both the polymerase and 3'-5' exonuclease activities of PolB1 in an ATP-independent manner. Stimulation of the PolB1 activity by RFC is independent of the ability of RFC to bind DNA but is consistent...... with the ability of RFC to facilitate DNA binding by PolB1 through protein-protein interaction. These results suggest that Sulfolobus RFC may play a role in recruiting DNA polymerase for efficient primer extension, in addition to clamp loading, during DNA replication....

  16. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis

    OpenAIRE

    Ren, Decheng; Zhou, Yingjiang; Morris, David; Li, Minghua; Li, Zhiqin; Rui, Liangyou

    2007-01-01

    SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (α, β, γ, and/or δ) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1β was specifically expressed in neural tissue in SH2B1-tran...

  17. CYP1B1 expression, a potential risk factor for breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Goth-Goldstein, Regine; Erdmann, Christine A.; Russell, Marion

    2001-05-31

    CYP1B1 expression in non-tumor breast tissue from breast cancer patients and cancer-free individuals was determined to test the hypothesis that high CYP1B1 expression is a risk factor for breast cancer. Large interindividual variations in CYP1B1 expression were found with CYP1B1 levels notably higher in breast cancer patients than cancer-free individuals. The results indicate that CYP1B1 might play a role in breast cancer either through increased PAH activation or through metabolism of endogenous estrogen to a carcinogenic derivative.

  18. Microvesicle transfer of kinin B1-receptors is a novel inflammatory mechanism in vasculitis.

    Science.gov (United States)

    Kahn, Robin; Mossberg, Maria; Ståhl, Anne-Lie; Johansson, Karl; Lopatko Lindman, Ingrid; Heijl, Caroline; Segelmark, Mårten; Mörgelin, Matthias; Leeb-Lundberg, L M Fredrik; Karpman, Diana

    2017-01-01

    During vasculitis, activation of the kinin system induces inflammation, whereby the kinin B1-receptor is expressed and activated after ligand binding. Additionally, activated blood cells release microvesicles into the circulation. Here we determined whether leukocyte-derived microvesicles bear B1-kinin receptors during vasculitis, and if microvesicles transfer functional B1-receptors to recipient cells, thus promoting inflammation. By flow cytometry, plasma from patients with vasculitis were found to contain high levels of leukocyte-derived microvesicles bearing B1-receptors. Importantly, renal biopsies from two patients with vasculitis showed leukocyte-derived microvesicles bearing B1-receptors docking on glomerular endothelial cells providing in vivo relevance. Microvesicles derived from B1-receptor-transfected human embryonic kidney cells transferred B1-receptors to wild-type human embryonic kidney cells, lacking the receptor, and to glomerular endothelial cells. The transferred B1-receptors induced calcium influx after B1-receptor agonist stimulation: a response abrogated by a specific B1-receptor antagonist. Microvesicles derived from neutrophils also transferred B1-receptors to wild-type human embryonic kidney cells and induced calcium influx after stimulation. Thus, we found a novel mechanism by which microvesicles transfer functional receptors and promote kinin-associated inflammation. Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  19. Porcine SOX9 Gene Expression Is Influenced by an 18 bp Indel in the 5'-Untranslated Region.

    Directory of Open Access Journals (Sweden)

    Bertram Brenig

    Full Text Available Sex determining region Y-box 9 (SOX9 is an important regulator of sex and skeletal development and is expressed in a variety of embryonal and adult tissues. Loss or gain of function resulting from mutations within the coding region or chromosomal aberrations of the SOX9 locus lead to a plethora of detrimental phenotypes in humans and animals. One of these phenotypes is the so-called male-to-female or female-to-male sex-reversal which has been observed in several mammals including pig, dog, cat, goat, horse, and deer. In 38,XX sex-reversal French Large White pigs, a genome-wide association study suggested SOX9 as the causal gene, although no functional mutations were identified in affected animals. However, besides others an 18 bp indel had been detected in the 5'-untranslated region of the SOX9 gene by comparing affected animals and controls. We have identified the same indel (Δ18 between position +247 bp and +266 bp downstream the transcription start site of the porcine SOX9 gene in four other pig breeds; i.e., German Large White, Laiwu Black, Bamei, and Erhualian. These animals have been genotyped in an attempt to identify candidate genes for porcine inguinal and/or scrotal hernia. Because the 18 bp segment in the wild type 5'-UTR harbours a highly conserved cAMP-response element (CRE half-site, we analysed its role in SOX9 expression in vitro. Competition and immunodepletion electromobility shift assays demonstrate that the CRE half-site is specifically recognized by CREB. Both binding of CREB to the wild type as well as the absence of the CRE half-site in Δ18 reduced expression efficiency in HEK293T, PK-15, and ATDC5 cells significantly. Transfection experiments of wild type and Δ18 SOX9 promoter luciferase constructs show a significant reduction of RNA and protein levels depending on the presence or absence of the 18 bp segment. Hence, the data presented here demonstrate that the 18 bp indel in the porcine SOX9 5'-UTR is of functional

  20. ROCK inhibition stimulates SOX9/Smad3-dependent COL2A1 expression in inner meniscus cells.

    Science.gov (United States)

    Furumatsu, Takayuki; Maehara, Ami; Ozaki, Toshifumi

    2016-07-01

    Proper functioning of the meniscus depends on the composition and organization of its fibrocartilaginous extracellular matrix. We previously demonstrated that the avascular inner meniscus has a more chondrocytic phenotype compared with the outer meniscus. Inhibition of the Rho family GTPase ROCK, the major regulator of the actin cytoskeleton, stimulates the chondrogenic transcription factor Sry-type HMG box (SOX) 9-dependent α1(II) collagen (COL2A1) expression in inner meniscus cells. However, the crosstalk between ROCK inhibition, SOX9, and other transcription modulators on COL2A1 upregulation remains unclear in meniscus cells. The aim of this study was to investigate the role of SOX9-related transcriptional complex on COL2A1 expression under the inhibition of ROCK in human meniscus cells. Human inner and outer meniscus cells were prepared from macroscopically intact lateral menisci. Cells were cultured in the presence or absence of ROCK inhibitor (ROCKi, Y27632). Gene expression, collagen synthesis, and nuclear translocation of SOX9 and Smad2/3 were analyzed. Treatment of ROCKi increased the ratio of type I/II collagen double positive cells derived from the inner meniscus. In real-time PCR analyses, expression of SOX9 and COL2A1 genes was stimulated by ROCKi treatment in inner meniscus cells. ROCKi treatment also induced nuclear translocation of SOX9 and phosphorylated Smad2/3 in immunohistological analyses. Complex formation between SOX9 and Smad3 was increased by ROCKi treatment in inner meniscus cells. Chromatin immunoprecipitation analyses revealed that association between SOX9/Smad3 transcriptional complex with the COL2A1 enhancer region was increased by ROCKi treatment. This study demonstrated that ROCK inhibition stimulated SOX9/Smad3-dependent COL2A1 expression through the immediate nuclear translocation of Smad3 in inner meniscus cells. Our results suggest that ROCK inhibition can stimulates type II collagen synthesis through the cooperative activation

  1. Thyroid Hormones Are Transport Substrates and Transcriptional Regulators of Organic Anion Transporting Polypeptide 2B1.

    Science.gov (United States)

    Meyer Zu Schwabedissen, Henriette E; Ferreira, Celio; Schaefer, Anima M; Oufir, Mouhssin; Seibert, Isabell; Hamburger, Matthias; Tirona, Rommel G

    2018-07-01

    Levothyroxine replacement therapy forms the cornerstone of hypothyroidism management. Variability in levothyroxine oral absorption may contribute to the well-recognized large interpatient differences in required dose. Moreover, levothyroxine-drug pharmacokinetic interactions are thought to be caused by altered oral bioavailability. Interestingly, little is known regarding the mechanisms contributing to levothyroxine absorption in the gastrointestinal tract. Here, we aimed to determine whether the intestinal drug uptake transporter organic anion transporting polypeptide 2B1 (OATP2B1) may be involved in facilitating intestinal absorption of thyroid hormones. We also explored whether thyroid hormones regulate OATP2B1 gene expression. In cultured Madin-Darby Canine Kidney II/OATP2B1 cells and in OATP2B1-transfected Caco-2 cells, thyroid hormones were found to inhibit OATP2B1-mediated uptake of estrone-3-sulfate. Competitive counter-flow experiments evaluating the influence on the cellular accumulation of estrone-3-sulfate in the steady state indicated that thyroid hormones were substrates of OATP2B1. Additional evidence that thyroid hormones were OATP2B1 substrates was provided by OATP2B1-dependent stimulation of thyroid hormone receptor activation in cell-based reporter assays. Bidirectional transport studies in intestinal Caco-2 cells showed net absorptive flux of thyroid hormones, which was attenuated by the presence of the OATP2B1 inhibitor, atorvastatin. In intestinal Caco-2 and LS180 cells, but not in liver Huh-7 or HepG2 cells, OATP2B1 expression was induced by treatment with thyroid hormones. Reporter gene assays revealed thyroid hormone receptor α -mediated transactivation of the SLCO2B1 1b and the SLCO2B1 1e promoters. We conclude that thyroid hormones are substrates and transcriptional regulators of OATP2B1. These insights provide a potential mechanistic basis for oral levothyroxine dose variability and drug interactions. Copyright © 2018 by The American

  2. Shah-Waardenburg syndrome and PCWH associated with SOX10 mutations: a case report and review of the literature.

    Science.gov (United States)

    Verheij, Johanna B G M; Sival, Deborah A; van der Hoeven, Johannes H; Vos, Yvonne J; Meiners, Linda C; Brouwer, Oebele F; van Essen, Anthonie J

    2006-01-01

    Shah-Waardenburg syndrome is a rare congenital disorder with variable clinical expression, characterised by aganglionosis of the rectosigmoïd (Hirschsprung disease), and abnormal melanocyte migration, resulting in pigmentary abnormalities and sensorineural deafness (Waardenburg syndrome). Mutations in the EDN, EDNRB and SOX10 genes can be found in patients with this syndrome. SOX10 mutations are specifically associated with a more severe phenotype called PCWH: peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease. Neuronal expression of SOX10 occurs in neural crest cells during early embryonic development and in glial cells of the peripheral and central nervous systems during late embryonic development and in adults. We present a 4-year-old girl with the PCWH phenotype associated with a de novo nonsense mutation (S384X) in SOX10. Main clinical features were mental retardation, peripheral neuropathy, deafness, Hirschsprung disease, distal arthrogryposis, white hairlock, and growth retardation. She presented with hypotonia, developmental delay, reduced peripheral nerve conduction velocities, and radiologically assessed central hypomyelination. Subsequently, the formation of abnormal myelin within the central and peripheral nervous system was functionally and radiologically assessed. Children presenting with features of Waardenburg syndrome and neurological dysfunction should be tested for mutations in the SOX10 gene to enable diagnosis and counselling.

  3. Transcriptional role of androgen receptor in the expression of long non-coding RNA Sox2OT in neurogenesis.

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    Valentina Tosetti

    Full Text Available The complex architecture of adult brain derives from tightly regulated migration and differentiation of precursor cells generated during embryonic neurogenesis. Changes at transcriptional level of genes that regulate migration and differentiation may lead to neurodevelopmental disorders. Androgen receptor (AR is a transcription factor that is already expressed during early embryonic days. However, AR role in the regulation of gene expression at early embryonic stage is yet to be determinate. Long non-coding RNA (lncRNA Sox2 overlapping transcript (Sox2OT plays a crucial role in gene expression control during development but its transcriptional regulation is still to be clearly defined. Here, using Bicalutamide in order to pharmacologically inactivated AR, we investigated whether AR participates in the regulation of the transcription of the lncRNASox2OTat early embryonic stage. We identified a new DNA binding region upstream of Sox2 locus containing three androgen response elements (ARE, and found that AR binds such a sequence in embryonic neural stem cells and in mouse embryonic brain. Our data suggest that through this binding, AR can promote the RNA polymerase II dependent transcription of Sox2OT. Our findings also suggest that AR participates in embryonic neurogenesis through transcriptional control of the long non-coding RNA Sox2OT.

  4. Growth factors and medium hyperglycemia induce Sox9+ ductal cell differentiation into β cells in mice with reversal of diabetes

    Science.gov (United States)

    Zhang, Mingfeng; Lin, Qing; Qi, Tong; Wang, Tiankun; Chen, Ching-Cheng; Riggs, Arthur D.; Zeng, Defu

    2016-01-01

    We previously reported that long-term administration of a low dose of gastrin and epidermal growth factor (GE) augments β-cell neogenesis in late-stage diabetic autoimmune mice after eliminating insulitis by induction of mixed chimerism. However, the source of β-cell neogenesis is still unknown. SRY (sex-determining region Y)-box 9+ (Sox9+) ductal cells in the adult pancreas are clonogenic and can give rise to insulin-producing β cells in an in vitro culture. Whether Sox9+ ductal cells in the adult pancreas can give rise to β cells in vivo remains controversial. Here, using lineage-tracing with genetic labeling of Insulin- or Sox9-expressing cells, we show that hyperglycemia (>300 mg/dL) is required for inducing Sox9+ ductal cell differentiation into insulin-producing β cells, and medium hyperglycemia (300–450 mg/dL) in combination with long-term administration of low-dose GE synergistically augments differentiation and is associated with normalization of blood glucose in nonautoimmune diabetic C57BL/6 mice. Short-term administration of high-dose GE cannot augment differentiation, although it can augment preexisting β-cell replication. These results indicate that medium hyperglycemia combined with long-term administration of low-dose GE represents one way to induce Sox9+ ductal cell differentiation into β cells in adult mice. PMID:26733677

  5. The Impact of SOX Adoption on the Compensation of Non-US Companies’ Boards: The Case of Canadian Companies

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    Nadejda SERDIUC

    2015-11-01

    Full Text Available The purpose of this article is to study the relationship between the adoption of the Sarbanes-Oxley Act (SOX and the compensation of the board of directors of Canadian companies listed on US stock markets. The SOX act, promulgated on 30 July 2002 and the rules adopted by the Securities and Exchange Commission (SEC require, among furthermore, a majority of independent directors on boards. The literature focuses on two main differences between US companies and Canadian companies: more concentrated ownership and the smaller market capitalization of Canadian companies. Therefore, a consistent application of SOX on all the companies that differ at the base, in their size and structure, may have a different impact on the costs of compliance. Using a sample of 17 Canadian companies listed on US stock exchanges from 2001 to 2004, our analysis show that there is a link between the adoption of SOX and the increased in the cash compensation of the board of directors. The results also show that the effect of SOX is different depending on the company’s size.

  6. Direct Reprogramming of Adult Human Somatic Stem Cells Into Functional Neurons Using Sox2, Ascl1, and Neurog2

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    Jessica Alves de Medeiros Araújo

    2018-06-01

    Full Text Available Reprogramming of somatic cells into induced pluripotent stem cells (iPS or directly into cells from a different lineage, including neurons, has revolutionized research in regenerative medicine in recent years. Mesenchymal stem cells are good candidates for lineage reprogramming and autologous transplantation, since they can be easily isolated from accessible sources in adult humans, such as bone marrow and dental tissues. Here, we demonstrate that expression of the transcription factors (TFs SRY (sex determining region Y-box 2 (Sox2, Mammalian achaete-scute homolog 1 (Ascl1, or Neurogenin 2 (Neurog2 is sufficient for reprogramming human umbilical cord mesenchymal stem cells (hUCMSC into induced neurons (iNs. Furthermore, the combination of Sox2/Ascl1 or Sox2/Neurog2 is sufficient to reprogram up to 50% of transfected hUCMSCs into iNs showing electrical properties of mature neurons and establishing synaptic contacts with co-culture primary neurons. Finally, we show evidence supporting the notion that different combinations of TFs (Sox2/Ascl1 and Sox2/Neurog2 may induce multiple and overlapping neuronal phenotypes in lineage-reprogrammed iNs, suggesting that neuronal fate is determined by a combination of signals involving the TFs used for reprogramming but also the internal state of the converted cell. Altogether, the data presented here contribute to the advancement of techniques aiming at obtaining specific neuronal phenotypes from lineage-converted human somatic cells to treat neurological disorders.

  7. Transcription factor Sox4 is required for PUMA-mediated apoptosis induced by histone deacetylase inhibitor, TSA.

    Science.gov (United States)

    Jang, Sang-Min; Kang, Eun-Jin; Kim, Jung-Woong; Kim, Chul-Hong; An, Joo-Hee; Choi, Kyung-Hee

    2013-08-23

    PUMA is a crucial regulator of apoptotic cell death mediated by p53-dependent and p53-independent mechanisms. In many cancer cells, PUMA expression is induced in response to DNA-damaging reagent in a p53-dependent manner. However, few studies have investigated transcription factors that lead to the induction of PUMA expression via p53-independent apoptotic signaling. In this study, we found that the transcription factor Sox4 increased PUMA expression in response to trichostatin A (TSA), a histone deacetylase inhibitor in the p53-null human lung cancer cell line H1299. Ectopic expression of Sox4 led to the induction of PUMA expression at the mRNA and protein levels, and TSA-mediated up-regulation of PUMA transcription was repressed by the knockdown of Sox4. Using luciferase assays and chromatin immunoprecipitation, we also determined that Sox4 recruits p300 on the PUMA promoter region and increases PUMA gene expression in response to TSA treatment. Taken together, these results suggest that Sox4 is required for p53-independent apoptotic cell death mediated by PUMA induction via TSA treatment. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

  8. In depth analysis of the Sox4 gene locus that consists of sense and natural antisense transcripts

    Science.gov (United States)

    Ling, King-Hwa; Brautigan, Peter J.; Moore, Sarah; Fraser, Rachel; Leong, Melody Pui-Yee; Leong, Jia-Wen; Zainal Abidin, Shahidee; Lee, Han-Chung; 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.

    2016-01-01

    SRY (Sex Determining Region Y)-Box 4 or Sox4 is an important regulator of the pan-neuronal gene expression during post-mitotic cell differentiation within the mammalian brain. Sox4 gene locus has been previously characterized with multiple sense and overlapping natural antisense transcripts [1], [2]. Here we provide accompanying data on various analyses performed and described in Ling et al. [2]. The data include a detail description of various features found at Sox4 gene locus, additional experimental data derived from RNA-Fluorescence in situ Hybridization (RNA-FISH), Western blotting, strand-specific reverse-transcription quantitative polymerase chain reaction (RT-qPCR), gain-of-function and in situ hybridization (ISH) experiments. All the additional data provided here support the existence of an endogenous small interfering- or PIWI interacting-like small RNA known as Sox4_sir3, which origin was found within the overlapping region consisting of a sense and a natural antisense transcript known as Sox4ot1. PMID:26958646

  9. Quantitative profiling of selective Sox/POU pairing on hundreds of sequences in parallel by Coop-seq.

    Science.gov (United States)

    Chang, Yiming K; Srivastava, Yogesh; Hu, Caizhen; Joyce, Adam; Yang, Xiaoxiao; Zuo, Zheng; Havranek, James J; Stormo, Gary D; Jauch, Ralf

    2017-01-25

    Cooperative binding of transcription factors is known to be important in the regulation of gene expression programs conferring cellular identities. However, current methods to measure cooperativity parameters have been laborious and therefore limited to studying only a few sequence variants at a time. We developed Coop-seq (cooperativity by sequencing) that is capable of efficiently and accurately determining the cooperativity parameters for hundreds of different DNA sequences in a single experiment. We apply Coop-seq to 12 dimer pairs from the Sox and POU families of transcription factors using 324 unique sequences with changed half-site orientation, altered spacing and discrete randomization within the binding elements. The study reveals specific dimerization profiles of different Sox factors with Oct4. By contrast, Oct4 and the three neural class III POU factors Brn2, Brn4 and Oct6 assemble with Sox2 in a surprisingly indistinguishable manner. Two novel half-site configurations can support functional Sox/Oct dimerization in addition to known composite motifs. Moreover, Coop-seq uncovers a nucleotide switch within the POU half-site when spacing is altered, which is mirrored in genomic loci bound by Sox2/Oct4 complexes. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  10. In depth analysis of the Sox4 gene locus that consists of sense and natural antisense transcripts

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    King-Hwa Ling

    2016-06-01

    Full Text Available SRY (Sex Determining Region Y-Box 4 or Sox4 is an important regulator of the pan-neuronal gene expression during post-mitotic cell differentiation within the mammalian brain. Sox4 gene locus has been previously characterized with multiple sense and overlapping natural antisense transcripts [1,2]. Here we provide accompanying data on various analyses performed and described in Ling et al. [2]. The data include a detail description of various features found at Sox4 gene locus, additional experimental data derived from RNA-Fluorescence in situ Hybridization (RNA-FISH, Western blotting, strand-specific reverse-transcription quantitative polymerase chain reaction (RT-qPCR, gain-of-function and in situ hybridization (ISH experiments. All the additional data provided here support the existence of an endogenous small interfering- or PIWI interacting-like small RNA known as Sox4_sir3, which origin was found within the overlapping region consisting of a sense and a natural antisense transcript known as Sox4ot1.

  11. Differential Expression of Sox11 and Bdnf mRNA Isoforms in the Injured and Regenerating Nervous Systems

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    Felix L. Struebing

    2017-11-01

    Full Text Available In both the central nervous system (CNS and the peripheral nervous system (PNS, axonal injury induces changes in neuronal gene expression. In the PNS, a relatively well-characterized alteration in transcriptional activation is known to promote axonal regeneration. This transcriptional cascade includes the neurotrophin Bdnf and the transcription factor Sox11. Although both molecules act to facilitate successful axon regeneration in the PNS, this process does not occur in the CNS. The present study examines the differential expression of Sox11 and Bdnf mRNA isoforms in the PNS and CNS using three experimental paradigms at different time points: (i the acutely injured CNS (retina after optic nerve crush and PNS (dorsal root ganglion after sciatic nerve crush, (ii a CNS regeneration model (retina after optic nerve crush and induced regeneration; and (iii the retina during a chronic form of central neurodegeneration (the DBA/2J glaucoma model. We find an initial increase of Sox11 in both PNS and CNS after injury; however, the expression of Bdnf isoforms is higher in the PNS relative to the CNS. Sustained upregulation of Sox11 is seen in the injured retina following regeneration treatment, while the expression of two Bdnf mRNA isoforms is suppressed. Furthermore, two isoforms of Sox11 with different 3′UTR lengths are present in the retina, and the long isoform is specifically upregulated in later stages of glaucoma. These results provide insight into the molecular cascades active during axonal injury and regeneration in mammalian neurons.

  12. Toxic responses of Sox2 gene in the regeneration of the earthworm Eisenia foetida exposed to Retnoic acid.

    Science.gov (United States)

    Tao, Jing; Rong, Wei; Diao, Xiaoping; Zhou, Hailong

    2018-01-01

    Exogenous retinoic acid delays and disturbs the regeneration of Eisenia foetida. The stem cell pluripotency factor, Sox2, can play a crucial role in cell reprogramming and dedifferentiation. In this study, we compared the regeneration of Eisenia foetida in different segments after amputation and the effects of retinoic acid on the regeneration of different segments. The results showed that the regeneration speed of the head and tail was slightly faster than the middle part, and retinoic acid disrupted and delayed the regeneration of the earthworm. The qRT-PCR and Western blot analysis showed that the expression of the Sox2 gene and Sox2 protein was highest on the seventh day in different segments (pregeneration of earthworms and the formation of blastema are related to the expression of the Sox2 gene and protein. Retinoic acid delays and interferes with the regeneration of the earthworm by affecting the expression levels of the Sox2 gene and protein. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Activation of Sox3 Gene by Thyroid Hormone in the Developing Adult Intestinal Stem Cell During Xenopus Metamorphosis

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    Sun, Guihong; Fu, Liezhen; Wen, Luan

    2014-01-01

    The maturation of the intestine into the adult form involves the formation of adult stem cells in a thyroid hormone (T3)-dependent process in vertebrates. In mammals, this takes place during postembryonic development, a period around birth when the T3 level peaks. Due to the difficulty of manipulating late-stage, uterus-enclosed embryos, very little is known about the development of the adult intestinal stem cells. Interestingly, the remodeling of the intestine during the T3-dependent amphibian metamorphosis mimics the maturation of mammalian intestine. Our earlier microarray studies in Xenopus laevis revealed that the transcription factor SRY (sex-determining region Y)-box 3 (Sox3), well known for its involvement in neural development, was upregulated in the intestinal epithelium during metamorphosis. Here, we show that Sox3 is highly and specifically expressed in the developing adult intestinal progenitor/stem cells. We further show that its induction by T3 is independent of new protein synthesis, suggesting that Sox3 is directly activated by liganded T3 receptor. Thus, T3 activates Sox3 as one of the earliest changes in the epithelium, and Sox3 in turn may facilitate the dedifferentiation of the larval epithelial cells into adult stem cells. PMID:25211587

  14. XPC Promotes Pluripotency of Human Dental Pulp Cells through Regulation of Oct-4/Sox2/c-Myc

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    Lu Liu

    2016-01-01

    Full Text Available Introduction. Xeroderma pigmentosum group C (XPC, essential component of multisubunit stem cell coactivator complex (SCC, functions as the critical factor modulating pluripotency and genome integrity through interaction with Oct-4/Sox2. However, its specific role in regulating pluripotency and multilineage differentiation of human dental pulp cells (DPCs remains unknown. Methods. To elucidate the functional role XPC played in pluripotency and multilineage differentiation of DPCs, expressions of XPC in DPCs with long-term culture were examined by real-time PCR and western blot. DPCs were transfected with lentiviral-mediated human XPC gene; then transfection rate was investigated by real-time PCR and western blot. Cell cycle, apoptosis, proliferation, senescence, multilineage differentiation, and expression of Oct-4/Sox2/c-Myc in transfected DPCs were examined. Results. XPC, Oct-4, Sox2, and c-Myc were downregulated at P7 compared with P3 in DPCs with long-term culture. XPC genes were upregulated in DPCs at P2 after transfection and maintained high expression level at P3 and P7. Cell proliferation, PI value, and telomerase activity were enhanced, whereas apoptosis was suppressed in transfected DPCs. Oct-4/Sox2/c-Myc were significantly upregulated, and multilineage differentiation in DPCs with XPC overexpression was enhanced after transfection. Conclusions. XPC plays an essential role in the modulation of pluripotency and multilineage differentiation of DPCs through regulation of Oct-4/Sox2/c-Myc.

  15. XPC Promotes Pluripotency of Human Dental Pulp Cells through Regulation of Oct-4/Sox2/c-Myc.

    Science.gov (United States)

    Liu, Lu; Peng, Zhengjun; Xu, Zhezhen; Wei, Xi

    2016-01-01

    Introduction. Xeroderma pigmentosum group C (XPC), essential component of multisubunit stem cell coactivator complex (SCC), functions as the critical factor modulating pluripotency and genome integrity through interaction with Oct-4/Sox2. However, its specific role in regulating pluripotency and multilineage differentiation of human dental pulp cells (DPCs) remains unknown. Methods. To elucidate the functional role XPC played in pluripotency and multilineage differentiation of DPCs, expressions of XPC in DPCs with long-term culture were examined by real-time PCR and western blot. DPCs were transfected with lentiviral-mediated human XPC gene; then transfection rate was investigated by real-time PCR and western blot. Cell cycle, apoptosis, proliferation, senescence, multilineage differentiation, and expression of Oct-4/Sox2/c-Myc in transfected DPCs were examined. Results. XPC, Oct-4, Sox2, and c-Myc were downregulated at P7 compared with P3 in DPCs with long-term culture. XPC genes were upregulated in DPCs at P2 after transfection and maintained high expression level at P3 and P7. Cell proliferation, PI value, and telomerase activity were enhanced, whereas apoptosis was suppressed in transfected DPCs. Oct-4/Sox2/c-Myc were significantly upregulated, and multilineage differentiation in DPCs with XPC overexpression was enhanced after transfection. Conclusions. XPC plays an essential role in the modulation of pluripotency and multilineage differentiation of DPCs through regulation of Oct-4/Sox2/c-Myc.

  16. Observations and light curve solutions of the eclipsing binaries USNO-B1.0 1395-0370184 and USNO-B1.0 1395-0370731

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    Kjurkchieva D.

    2016-01-01

    Full Text Available We present follow-up photometric observations in Sloan filters g', i' of the newly discovered eclipsing stars USNO-B1.0 1395-0370184 and USNO-B1.0 1395-0370731. Our data revealed that their orbital periods are considerably bigger than the previous values. This result changed the classification of USNO-B1.0 1395-0370184 from ultrashort-period binary (P=0.197 d to short-period system (P=0.251 d. The light curve solutions of our observations revealed that USNOB1.0 1395-0370184 and USNO-B1.0 1395-0370731 are overcontact binaries in which components are K dwarfs, close in masses and radii. The light curve distortions were reproduced by cool spots with angular radius of around 20°.

  17. NOAA Climate Data Record (CDR) of Gridded Satellite Data from ISCCP B1 (GridSat-B1) Infrared Channel Brightness Temperature, Version 2

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    National Oceanic and Atmospheric Administration, Department of Commerce — The Gridded Satellite (GridSat-B1) data provides a uniform set of quality controlled geostationary satellite observations for the visible, infrared window and...

  18. P53-miR-191-SOX4 regulatory loop affects apoptosis in breast cancer.

    Science.gov (United States)

    Sharma, Shivani; Nagpal, Neha; Ghosh, Prahlad C; Kulshreshtha, Ritu

    2017-08-01

    miRNAs have emerged as key participants of p53 signaling pathways because they regulate or are regulated by p53. Here, we provide the first study demonstrating direct regulation of an oncogenic miRNA, miR-191-5p, by p53 and existence of a regulatory feedback loop. Using a combination of qRT-PCR, promoter-luciferase, and chromatin-immunoprecipitation assays, we show that p53 brings about down-regulation of miR-191-5p in breast cancer. miR-191-5p overexpression brought about inhibition of apoptosis in breast cancer cell lines (MCF7 and ZR-75) as demonstrated by reduction in annexin-V stained cells and caspase 3/7 activity, whereas miR-191-5p down-regulation showed the opposite. We further unveiled that SOX4 was a direct target of miR-191-5p. SOX4 overexpression was shown to increase p53 protein levels in MCF7 cells. miR-191-5p overexpression brought about down-regulation of SOX4 and thus p53 levels, suggesting the existence of a regulatory feedback loop. Breast cancer treatment by doxorubicin, an anti-cancer drug, involves induction of apoptosis by p53; we thus wanted to check whether miR-191-5p affects doxorubicin sensitivity. Interestingly, Anti-miR-191 treatment significantly decreased the IC50 of the doxorubicin drug and thus sensitized breast cancer cells to doxorubicin treatment by promoting apoptosis. Overall, this work highlights the importance of the p53-miR-191- SOX4 axis in the regulation of apoptosis and drug resistance in breast cancer and offers a preclinical proof-of-concept for use of an Anti-miR-191 and doxorubicin combination as a rational approach to pursue for better breast cancer treatment. © 2017 Sharma et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.

  19. Exploring the utility of organo-polyoxometalate hybrids to inhibit SOX transcription factors

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    Kamesh Narasimhan

    2014-01-01

    Conclusion: Polyoxometalates are highly potent, nanomolar range inhibitors of the DNA binding activity of the Sox-HMG family. However, binding assays involving a limited subset of structurally diverse polyoxometalates revealed a low selectivity profile against different transcription factor families. Further progress in achieving selectivity and deciphering structure-activity relationship of POMs require the identification of POM binding sites on transcription factors using elaborate approaches like X-ray crystallography and multidimensional NMR. In summary, our report reaffirms that transcription factors are challenging molecular architectures and that future polyoxometalate chemistry must consider further modification strategies, to address the substantial challenges involved in achieving target selectivity.

  20. Lamb–Shaffer syndrome, deferred outside not described by SOX5 mutation

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    I. V. Sharkova

    2018-01-01

    Full Text Available Clinical and genetic characteristics of a patient with Lamb–Shaffer syndrome due to the newly discovered heterozygous missense mutation p.1868A>C in the 14 exon of the SOX5 gene are presented in the next generation sequencing of exom. It is shown that, in contrast to the previously described patients due to the presence of a deletion in the region of the gene or segment of chromosome 12p12.1, in the presence of missense mutation, the intellectual deficit and the dysmorphic features of the structure are not pronounced sharply and there is no anomaly in the development of other organs and systems.

  1. Cell stress promotes the association of phosphorylated HspB1 with F-actin.

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    Joseph P Clarke

    Full Text Available Previous studies have suggested that the small heat shock protein, HspB1, has a direct influence on the dynamics of cytoskeletal elements, in particular, filamentous actin (F-actin polymerization. In this study we have assessed the influence of HspB1 phosphorylation on its interaction(s with F-actin. We first determined the distribution of endogenous non-phosphorylated HspB1, phosphorylated HspB1 and F-actin in neuroendocrine PC12 cells by immunocytochemistry and confocal microscopy. We then investigated a potential direct interaction between HspB1 with F-actin by precipitating F-actin directly with biotinylated phalloidin followed by Western analyses; the reverse immunoprecipitation of HspB1 was also carried out. The phosphorylation influence of HspB1 in this interaction was investigated by using pharmacologic inhibition of p38 MAPK. In control cells, HspB1 interacts with F-actin as a predominantly non-phosphorylated protein, but subsequent to stress there is a redistribution of HspB1 to the cytoskeletal fraction and a significantly increased association of pHspB1 with F-actin. Our data demonstrate HspB1 is found in a complex with F-actin both in phosphorylated and non-phosphorylated forms, with an increased association of pHspB1 with F-actin after heat stress. Overall, our study combines both cellular and biochemical approaches to show cellular localization and direct demonstration of an interaction between endogenous HspB1 and F-actin using methodolgy that specifically isolates F-actin.

  2. Enhancer Analysis Unveils Genetic Interactions between TLX and SOX2 in Neural Stem Cells and In Vivo Reprogramming.

    Science.gov (United States)

    Islam, Mohammed M; Smith, Derek K; Niu, Wenze; Fang, Sanhua; Iqbal, Nida; Sun, Guoqiang; Shi, Yanhong; Zhang, Chun-Li

    2015-11-10

    The orphan nuclear receptor TLX is a master regulator of postnatal neural stem cell (NSC) self-renewal and neurogenesis; however, it remains unclear how TLX expression is precisely regulated in these tissue-specific stem cells. Here, we show that a highly conserved cis-element within the Tlx locus functions to drive gene expression in NSCs. We demonstrate that the transcription factors SOX2 and MYT1 specifically interact with this genomic element to directly regulate Tlx enhancer activity in vivo. Knockdown experiments further reveal that SOX2 dominantly controls endogenous expression of TLX, whereas MYT1 only plays a modulatory role. Importantly, TLX is essential for SOX2-mediated in vivo reprogramming of astrocytes and itself is also sufficient to induce neurogenesis in the adult striatum. Together, these findings unveil functional genetic interactions among transcription factors that are critical to NSCs and in vivo cell reprogramming.

  3. Enhancer Analysis Unveils Genetic Interactions between TLX and SOX2 in Neural Stem Cells and In Vivo Reprogramming

    Science.gov (United States)

    Islam, Mohammed M.; Smith, Derek K.; Niu, Wenze; Fang, Sanhua; Iqbal, Nida; Sun, Guoqiang; Shi, Yanhong; Zhang, Chun-Li

    2015-01-01

    Summary The orphan nuclear receptor TLX is a master regulator of postnatal neural stem cell (NSC) self-renewal and neurogenesis; however, it remains unclear how TLX expression is precisely regulated in these tissue-specific stem cells. Here, we show that a highly conserved cis-element within the Tlx locus functions to drive gene expression in NSCs. We demonstrate that the transcription factors SOX2 and MYT1 specifically interact with this genomic element to directly regulate Tlx enhancer activity in vivo. Knockdown experiments further reveal that SOX2 dominantly controls endogenous expression of TLX, whereas MYT1 only plays a modulatory role. Importantly, TLX is essential for SOX2-mediated in vivo reprogramming of astrocytes and itself is also sufficient to induce neurogenesis in the adult striatum. Together, these findings unveil functional genetic interactions among transcription factors that are critical to NSCs and in vivo cell reprogramming. PMID:26607952

  4. Enhancer Analysis Unveils Genetic Interactions between TLX and SOX2 in Neural Stem Cells and In Vivo Reprogramming

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    Mohammed M. Islam

    2015-11-01

    Full Text Available The orphan nuclear receptor TLX is a master regulator of postnatal neural stem cell (NSC self-renewal and neurogenesis; however, it remains unclear how TLX expression is precisely regulated in these tissue-specific stem cells. Here, we show that a highly conserved cis-element within the Tlx locus functions to drive gene expression in NSCs. We demonstrate that the transcription factors SOX2 and MYT1 specifically interact with this genomic element to directly regulate Tlx enhancer activity in vivo. Knockdown experiments further reveal that SOX2 dominantly controls endogenous expression of TLX, whereas MYT1 only plays a modulatory role. Importantly, TLX is essential for SOX2-mediated in vivo reprogramming of astrocytes and itself is also sufficient to induce neurogenesis in the adult striatum. Together, these findings unveil functional genetic interactions among transcription factors that are critical to NSCs and in vivo cell reprogramming.

  5. RepSox improves viability and regulates gene expression in rhesus monkey-pig interspecies cloned embryos.

    Science.gov (United States)

    Zhu, Hai-Ying; Jin, Long; Guo, Qing; Luo, Zhao-Bo; Li, Xiao-Chen; Zhang, Yu-Chen; Xing, Xiao-Xu; Xuan, Mei-Fu; Zhang, Guang-Lei; Luo, Qi-Rong; Wang, Jun-Xia; Cui, Cheng-Du; Li, Wen-Xue; Cui, Zheng-Yun; Yin, Xi-Jun; Kang, Jin-Dan

    2017-05-01

    To investigate the effect of the small molecule, RepSox, on the expression of developmentally important genes and the pre-implantation development of rhesus monkey-pig interspecies somatic cell nuclear transfer (iSCNT) embryos. Rhesus monkey cells expressing the monomeric red fluorescent protein 1 which have a normal (42) chromosome complement, were used as donor cells to generate iSCNT embryos. RepSox increased the expression levels of the pluripotency-related genes, Oct4 and Nanog (p  0.05), this was not significant. RepSox can improve the developmental potential of rhesus monkey-pig iSCNT embryos by regulating the expression of pluripotency-related genes.

  6. FGF signalling controls the specification of hair placode-derived SOX9 positive progenitors to Merkel cells.

    Science.gov (United States)

    Nguyen, Minh Binh; Cohen, Idan; Kumar, Vinod; Xu, Zijian; Bar, Carmit; Dauber-Decker, Katherine L; Tsai, Pai-Chi; Marangoni, Pauline; Klein, Ophir D; Hsu, Ya-Chieh; Chen, Ting; Mikkola, Marja L; Ezhkova, Elena

    2018-06-13

    Merkel cells are innervated mechanosensory cells responsible for light-touch sensations. In murine dorsal skin, Merkel cells are located in touch domes and found in the epidermis around primary hairs. While it has been shown that Merkel cells are skin epithelial cells, the progenitor cell population that gives rise to these cells is unknown. Here, we show that during embryogenesis, SOX9-positive (+) cells inside hair follicles, which were previously known to give rise to hair follicle stem cells (HFSCs) and cells of the hair follicle lineage, can also give rise to Merkel Cells. Interestingly, while SOX9 is critical for HFSC specification, it is dispensable for Merkel cell formation. Conversely, FGFR2 is required for Merkel cell formation but is dispensable for HFSCs. Together, our studies uncover SOX9(+) cells as precursors of Merkel cells and show the requirement for FGFR2-mediated epithelial signalling in Merkel cell specification.

  7. Novel mutations in the SOX10 gene in the first two Chinese cases of type IV Waardenburg syndrome.

    Science.gov (United States)

    Jiang, Lu; Chen, Hongsheng; Jiang, Wen; Hu, Zhengmao; Mei, Lingyun; Xue, Jingjie; He, Chufeng; Liu, Yalan; Xia, Kun; Feng, Yong

    2011-05-20

    We analyzed the clinical features and family-related gene mutations for the first two Chinese cases of type IV Waardenburg syndrome (WS4). Two families were analyzed in this study. The analysis included a medical history, clinical analysis, a hearing test and a physical examination. In addition, the EDNRB, EDN3 and SOX10 genes were sequenced in order to identify the pathogenic mutation responsible for the WS4 observed in these patients. The two WS4 cases presented with high phenotypic variability. Two novel heterozygous mutations (c.254G>A and c.698-2A>T) in the SOX10 gene were detected. The mutations identified in the patients were not found in unaffected family members or in 200 unrelated control subjects. This is the first report of WS4 in Chinese patients. In addition, two novel mutations in SOX10 gene have been identified. Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.

  8. Flavonoids exhibit diverse effects on CYP11B1 expression and cortisol synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Li-Chuan; Li, Lih-Ann, E-mail: lihann@nhri.org.tw

    2012-02-01

    CYP11B1 catalyzes the final step of cortisol biosynthesis. The effects of flavonoids on transcriptional expression and enzyme activity of CYP11B1 were investigated using the human adrenocortical H295R cell model. All tested nonhydroxylated flavones including 3′,4′-dimethoxyflavone, α-naphthoflavone, and β-naphthoflavone upregulated CYP11B1 expression and cortisol production, whereas apigenin and quercetin exhibited potent cytotoxicity and CYP11B1 repression at high concentrations. Nonhydroxylated flavones stimulated CYP11B1-catalyzed cortisol formation at transcriptional level. Resveratrol increased endogenous and substrate-supported cortisol production like nonhydroxylated flavones tested, but it had no effect on CYP11B1 gene expression and enzyme activity. Resveratrol appeared to alter cortisol biosynthesis at an earlier step. The Ad5 element situated in the − 121/− 106 region was required for basal and flavone-induced CYP11B1 expression. Overexpression of COUP-TFI did not improve the responsiveness of Ad5 to nonhydroxylated flavones. Although COUP-TFI overexpression increased CYP11B1 and CYP11B2 promoter activation, its effect was not mediated through the common Ad5 element. Treating cells with PD98059 (a flavone-type MEK1 inhibitor) increased CYP11B1 promoter activity, but not involving ERK signaling because phosphorylation of ERK1/2 remained unvarying throughout the course of treatment. Likewise, AhR was not responsible for the CYP11B1-modulating effects of flavonoids because inconsistency with their effects on AhR activation. 3′,4′-dimethoxyflavone and 8-Br-cAMP additively activated CYP11B1 promoter activity. H-89 reduced 3′,4′-dimethoxyflavone-induced CYP11B1 promoter activation but to a lesser extent as compared to its inhibition on cAMP-induced transactivation. Our data suggest that constant exposure to nonhydroxylated flavones raises a potential risk of high basal and cAMP-induced cortisol synthesis in consequence of increased CYP11B1

  9. Flavonoids exhibit diverse effects on CYP11B1 expression and cortisol synthesis

    International Nuclear Information System (INIS)

    Cheng, Li-Chuan; Li, Lih-Ann

    2012-01-01

    CYP11B1 catalyzes the final step of cortisol biosynthesis. The effects of flavonoids on transcriptional expression and enzyme activity of CYP11B1 were investigated using the human adrenocortical H295R cell model. All tested nonhydroxylated flavones including 3′,4′-dimethoxyflavone, α-naphthoflavone, and β-naphthoflavone upregulated CYP11B1 expression and cortisol production, whereas apigenin and quercetin exhibited potent cytotoxicity and CYP11B1 repression at high concentrations. Nonhydroxylated flavones stimulated CYP11B1-catalyzed cortisol formation at transcriptional level. Resveratrol increased endogenous and substrate-supported cortisol production like nonhydroxylated flavones tested, but it had no effect on CYP11B1 gene expression and enzyme activity. Resveratrol appeared to alter cortisol biosynthesis at an earlier step. The Ad5 element situated in the − 121/− 106 region was required for basal and flavone-induced CYP11B1 expression. Overexpression of COUP-TFI did not improve the responsiveness of Ad5 to nonhydroxylated flavones. Although COUP-TFI overexpression increased CYP11B1 and CYP11B2 promoter activation, its effect was not mediated through the common Ad5 element. Treating cells with PD98059 (a flavone-type MEK1 inhibitor) increased CYP11B1 promoter activity, but not involving ERK signaling because phosphorylation of ERK1/2 remained unvarying throughout the course of treatment. Likewise, AhR was not responsible for the CYP11B1-modulating effects of flavonoids because inconsistency with their effects on AhR activation. 3′,4′-dimethoxyflavone and 8-Br-cAMP additively activated CYP11B1 promoter activity. H-89 reduced 3′,4′-dimethoxyflavone-induced CYP11B1 promoter activation but to a lesser extent as compared to its inhibition on cAMP-induced transactivation. Our data suggest that constant exposure to nonhydroxylated flavones raises a potential risk of high basal and cAMP-induced cortisol synthesis in consequence of increased CYP11B1

  10. Use of methanol as cryoprotectant and its effect on sox genes and proteins in chilled zebrafish embryos.

    Science.gov (United States)

    Desai, Kunjan; Spikings, Emma; Zhang, Tiantian

    2015-08-01

    Methanol is a widely used cryoprotectant (CPA) in cryopreservation of fish embryos, however little is known about its effect at the molecular level. This study investigated the effect of methanol on sox gene and protein expression in zebrafish embryos (50% epiboly) when they were chilled for 3 h and subsequently warmed and cultured to the hatching stages. Initial experiments were carried out to evaluate the chilling tolerance of 50% epiboly embryos which showed no significant differences in hatching rates for up to 6 h chilling in methanol (0.2-, 0.5- and 1 M). Subsequent experiments in embryos that had been chilled for 3 h in 1 M methanol and warmed and cultured up to the hatching stages found that sox2 and sox3 gene expression were increased significantly in hatched embryos that had been chilled compared to non-chilled controls. Sox19a gene expression also remained above control levels in the chilled embryos at all developmental stages tested. Whilst stable sox2 protein expression was observed between non-chilled controls and embryos chilled for 3 h with or without MeOH, a surge in sox19a protein expression was observed in embryos chilled for 3 h in the presence of 1 M MeOH compared to non-chilled controls and then returned to control levels by the hatching stage. The protective effect of MeOH was increased with increasing concentrations. Effect of methanol at molecular level during chilling was reported here first time which could add new parameter in selection of cryoprotectant while designing cryopreservation protocol. Copyright © 2015. Published by Elsevier Inc.

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

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    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.

  12. Phenotypic variability in Waardenburg syndrome resulting from a 22q12.3-q13.1 microdeletion involving SOX10.

    Science.gov (United States)

    Jelena, Brezo; Christina, Lam; Eric, Vilain; Fabiola, Quintero-Rivera

    2014-06-01

    Waardenburg syndrome (WS) is a neurocristopathy characterized by pigmentation abnormalities of the skin, hair, and iris, as well as sensorineural hearing loss. Contiguous gene deletions encompassing SOX10 are rare, which limits conclusions about genotype-phenotype correlation regarding patient prognosis and management. This study adds to the existing body of knowledge by characterizing a 2.4 Mb deletion [arr[hg19] 22q12.3-q13.1 (36467502-38878207)x1] encompassing SOX10 and 53 additional RefSeq genes in a 15-year-old female with atypical WS. The patient presented with developmental delay, profound bilateral sensorineural hearing loss, heterochromia iridis, hypotonia, and bilateral finger contractures. Published genomic and phenotypic profiles of patients with SOX10-encompassing deletions point toward several plausible candidate gene that could account for the considerable clinical heterogeneity. These studies suggest the existence of modifiers among the co-deleted, dosage-sensitive genes (e.g., MYH9) and among genes whose effect may depend on the unmasking of recessive mutations (e.g., PLA2G6). Finally, we highlight evidence illustrating extensive interconnectivity of SOX10-hypothesizing that haploinsufficiency of SOX10 may "unmask" subtler effects on expression or epistasis associated with variants in SOX10 targets (e.g., DHH), in its partners (e.g., PAX3, EGR2), and in genes with functional overlap (e.g., SOX8, SOX9). © 2014 Wiley Periodicals, Inc.

  13. Sox2, a stemness gene, regulates tumor-initiating and drug-resistant properties in CD133-positive glioblastoma stem cells

    Directory of Open Access Journals (Sweden)

    Wen-Shin Song

    2016-10-01

    Conclusion: SOX2 plays a crucial role in regulating tumorigenicity in CD133+ GBM cells. Our results not only revealed the genetic plasticity contributing to drug resistance and stemness but also demonstrated the dominant role of SOX2 in maintenance of GBM CSCs, which may provide a novel therapeutic target to overcome the conundrum of poor survival of brain cancers.

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

    Directory of Open Access Journals (Sweden)

    Ling Wei

    2016-02-01

    Full Text Available 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.

  16. Highly sensitive FRET-based fluorescence immunoassay for aflatoxin B1 using cadmium telluride quantum dots

    International Nuclear Information System (INIS)

    Zekavati, Roya; Bayat, Mansour; Safi, Shahabeddin; Hashemi, Seyed Jamal; Rahmani-Cherati, Tavoos; Tabatabaei, Meisam; Mohsenifar, Afshin

    2013-01-01

    We report on a competitive immunoassay for the determination of aflatoxin B1 using fluorescence resonance energy transfer (FRET) from anti-aflatoxin B1 antibody (immobilized on the shell of CdTe quantum dots) to Rhodamine 123 (Rho 123-labeled aflatoxin B1 bound to albumin). The highly specific immuno reaction between the antibody against aflatoxin B1 on the QDs and the labeled-aflatoxin B1 brings the Rho 123 fluorophore (acting as the acceptor) and the QDs (acting as the donor) in close spatial proximity and causes FRET to occur upon photoexcitation of the QDs. In the absence of unlabeled aflatoxin B1, the antigen-antibody complex is stable, and strong emission resulting from the FRET from QDs to labeled aflatoxin B1 is observed. In the presence of aflatoxin B1, it will compete with the labeled aflatoxin B1-albumin complex for binding to the antibody-QDs conjugate so that FRET will be increasingly suppressed. The reduction in the fluorescence intensity of the acceptor correlates well with the concentration of aflatoxin B1. The feasibility of the method was established by the detection of aflatoxin B1 in spiked human serum. There is a linear relationship between the increased fluorescence intensity of Rho 123 with increasing concentration of aflatoxin B1 in spike human serum, over the range of 0.1–0.6 μmol·mL −1 . The limit of detection is 2 × 10 −11 M. This homogeneous competitive detection scheme is simple, rapid and efficient, and does not require excessive washing and separation steps. (author)

  17. Political economy of low sulfurization and air pollution control policy in Japan : SOx emission reduction by fuel conversion

    OpenAIRE

    Terao, Tadayoshi

    2013-01-01

    In the early stages of the development of Japan’s environmental policy, sulfur oxide (SOx) emissions, which seriously damage health, was the most important air pollution problem. In the second half of the 1960s and the first half of the 1970s, the measures against SOx emissions progressed quickly, and these emissions were reduced drastically. The most important factor of the reduction was the conversion to a low-sulfur fuel for large-scale fuel users, such as the electric power industry. Howe...

  18. Plexin-B1 silencing inhibits ovarian cancer cell migration and invasion

    International Nuclear Information System (INIS)

    Ye, Shuangmei; Chen, Yin; You, Lanying; Zhang, Yiqun; Xu, Gang; Zhou, Jianfeng; Ma, Ding; Wang, Shixuan; Hao, Xing; Zhou, Ting; Wu, Mingfu; Wei, Juncheng; Wang, Yongjun; Zhou, Li; Jiang, Xuefeng; Ji, Li

    2010-01-01

    Elevated Plexin-B1 expression has been found in diverse human cancers and in non-neoplastic tissues, and it mediates diverse biological and pathological activities. However, whether or not Plexin-B1 expression is involved in human ovarian tumors remains unclear. In the present study, Plexin-B1 expression was explored in benign and malignant human ovarian tumor tissues. In addition, the impact of Plexin-B1 expression on ovarian cancer cell proliferation, migration and invasion were investigated in vitro. Plexin-B1 expression was analyzed in normal and benign ovarian tissues and serous ovarian tumors (both borderline and malignant) by immunohistochemical staining, as well as in four human ovarian cancer cell lines (A2780, C13*, SKOV3, and OV2008) by RT-PCR and western blot analyses. Furthermore, endogenous Plexin-B1 expression was suppressed by Plexin-B1 siRNA in SKOV3 cells, which overexpress Plexin-B1. Protein levels of Plexin-B1, AKT and AKT Ser473 were examined by western blot analysis. Cell proliferation, migration and invasion were measured with MTT, wound healing and boyden chamber assays, respectively, and the cytoskeleton was monitored via F-actin staining. Expression levels of Plexin-B1 protein were significantly higher in serous ovarian carcinomas than in normal ovaries or benign ovarian neoplasms, and in the former, Plexin-B1 expression was positively correlated with lymphatic metastasis, and the membrane and cytoplasm of cancer cells stained positively. SKOV3 cells displayed the highest Plexin-B1 expression at both the mRNA and protein levels among the four tested human ovarian cancer cell lines and was selected as a cell model for further in vitro experiments. Plexin-B1 siRNA significantly suppressed phosphorylation of AKT at Ser473 in SKOV3 cells, but it did not alter total AKT expression. In addition, silencing of Plexin-B1 in SKOV3 cells inhibited cell migration and invasion and reorganized the cytoskeleton, whereas cell proliferation was not

  19. Alu-mediated deletion of SOX10 regulatory elements in Waardenburg syndrome type 4.

    Science.gov (United States)

    Bondurand, Nadége; Fouquet, Virginie; Baral, Viviane; Lecerf, Laure; Loundon, Natalie; Goossens, Michel; Duriez, Benedicte; Labrune, Philippe; Pingault, Veronique

    2012-09-01

    Waardenburg syndrome type 4 (WS4) is a rare neural crest disorder defined by the combination of Waardenburg syndrome (sensorineural hearing loss and pigmentation defects) and Hirschsprung disease (intestinal aganglionosis). Three genes are known to be involved in this syndrome, that is, EDN3 (endothelin-3), EDNRB (endothelin receptor type B), and SOX10. However, 15-35% of WS4 remains unexplained at the molecular level, suggesting that other genes could be involved and/or that mutations within known genes may have escaped previous screenings. Here, we searched for deletions within recently identified SOX10 regulatory sequences and describe the first characterization of a WS4 patient presenting with a large deletion encompassing three of these enhancers. Analysis of the breakpoint region suggests a complex rearrangement involving three Alu sequences that could be mediated by a FosTes/MMBIR replication mechanism. Taken together with recent reports, our results demonstrate that the disruption of highly conserved non-coding elements located within or at a long distance from the coding sequences of key genes can result in several neurocristopathies. This opens up new routes to the molecular dissection of neural crest disorders.

  20. Sox9 duplications are a relevant cause of Sry-negative XX sex reversal dogs.

    Science.gov (United States)

    Rossi, Elena; Radi, Orietta; De Lorenzi, Lisa; Vetro, Annalisa; Groppetti, Debora; Bigliardi, Enrico; Luvoni, Gaia Cecilia; Rota, Ada; Camerino, Giovanna; Zuffardi, Orsetta; Parma, Pietro

    2014-01-01

    Sexual development in mammals is based on a complicated and delicate network of genes and hormones that have to collaborate in a precise manner. The dark side of this pathway is represented by pathological conditions, wherein sexual development does not occur properly either in the XX and the XY background. Among them a conundrum is represented by the XX individuals with at least a partial testis differentiation even in absence of SRY. This particular condition is present in various mammals including the dog. Seven dogs characterized by XX karyotype, absence of SRY gene, and testicular tissue development were analysed by Array-CGH. In two cases the array-CGH analysis detected an interstitial heterozygous duplication of chromosome 9. The duplication contained the SOX9 coding region. In this work we provide for the first time a causative mutation for the XXSR condition in the dog. Moreover this report supports the idea that the dog represents a good animal model for the study of XXSR condition caused by abnormalities in the SOX9 locus.

  1. SOX2 Reprograms Resident Astrocytes into Neural Progenitors in the Adult Brain

    Directory of Open Access Journals (Sweden)

    Wenze Niu

    2015-05-01

    Full Text Available Glial cells can be in vivo reprogrammed into functional neurons in the adult CNS; however, the process by which this reprogramming occurs is unclear. Here, we show that a distinct cellular sequence is involved in SOX2-driven in situ conversion of adult astrocytes to neurons. This includes ASCL1+ neural progenitors and DCX+ adult neuroblasts (iANBs as intermediates. Importantly, ASCL1 is required, but not sufficient, for the robust generation of iANBs in the adult striatum. These progenitor-derived iANBs predominantly give rise to calretinin+ interneurons when supplied with neurotrophic factors or the small-molecule valproic acid. Patch-clamp recordings from the induced neurons reveal subtype heterogeneity, though all are functionally mature, fire repetitive action potentials, and receive synaptic inputs. Together, these results show that SOX2-mediated in vivo reprogramming of astrocytes to neurons passes through proliferative intermediate progenitors, which may be exploited for regenerative medicine.

  2. Sox9 duplications are a relevant cause of Sry-negative XX sex reversal dogs.

    Directory of Open Access Journals (Sweden)

    Elena Rossi

    Full Text Available Sexual development in mammals is based on a complicated and delicate network of genes and hormones that have to collaborate in a precise manner. The dark side of this pathway is represented by pathological conditions, wherein sexual development does not occur properly either in the XX and the XY background. Among them a conundrum is represented by the XX individuals with at least a partial testis differentiation even in absence of SRY. This particular condition is present in various mammals including the dog. Seven dogs characterized by XX karyotype, absence of SRY gene, and testicular tissue development were analysed by Array-CGH. In two cases the array-CGH analysis detected an interstitial heterozygous duplication of chromosome 9. The duplication contained the SOX9 coding region. In this work we provide for the first time a causative mutation for the XXSR condition in the dog. Moreover this report supports the idea that the dog represents a good animal model for the study of XXSR condition caused by abnormalities in the SOX9 locus.

  3. Reducing NOx and SOx pollutants in an industrial units using electron accelerator

    Directory of Open Access Journals (Sweden)

    H Nouri

    2017-08-01

    Full Text Available Electron beam accelerators technology has made significant progress in environmental applications in recent years. Including some environmental applications of industrial accelerators, is clearing the air from oxides of nitrogen and sulfur(NOx , SOx produced by industrial facilities. Combustion  of coal, oil, natural gas and other gases that are produced in power plant, refineries and industrial factories, produce high extent of these oxides wshich exceed the limit in most cases. Clearing by irradiation involves adding amounts of ammonia to output gases and irradiation by Electron beam accelerators. Irradiation produces radicals that interact again with  NOx , SOx  and produced the related gases. Due to the ammonia, these acids transform into ammonium sulfate ((NH42SO4 and ammonium nitrate (NH4NO3 are precipitated by electrostatic precipitators, and are used as chemical fertilizer. Cosidering purification process of pollutant  gases by electron beam and the importance of electron accelerator in industrial plants that are polluting the environment in Iran, can be a suitable sollution for this environmental problem

  4. The clinical impact of chromosomal rearrangements with breakpoints upstream of the SOX9 gene: two novel de novo balanced translocations associated with acampomelic campomelic dysplasia.

    Science.gov (United States)

    Fonseca, Ana Carolina S; Bonaldi, Adriano; Bertola, Débora R; Kim, Chong A; Otto, Paulo A; Vianna-Morgante, Angela M

    2013-05-07

    The association of balanced rearrangements with breakpoints near SOX9 [SRY (sex determining region Y)-box 9] with skeletal abnormalities has been ascribed to the presumptive altering of SOX9 expression by the direct disruption of regulatory elements, their separation from SOX9 or the effect of juxtaposed sequences. We report on two sporadic apparently balanced translocations, t(7;17)(p13;q24) and t(17;20)(q24.3;q11.2), whose carriers have skeletal abnormalities that led to the diagnosis of acampomelic campomelic dysplasia (ACD; MIM 114290). No pathogenic chromosomal imbalances were detected by a-CGH. The chromosome 17 breakpoints were mapped, respectively, 917-855 kb and 601-585 kb upstream of the SOX9 gene. A distal cluster of balanced rearrangements breakpoints on chromosome 17 associated with SOX9-related skeletal disorders has been mapped to a segment 932-789 kb upstream of SOX9. In this cluster, the breakpoint of the herein described t(17;20) is the most telomeric to SOX9, thus allowing the redefining of the telomeric boundary of the distal breakpoint cluster region related to skeletal disorders to 601-585 kb upstream of SOX9. Although both patients have skeletal abnormalities, the t(7;17) carrier presents with relatively mild clinical features, whereas the t(17;20) was detected in a boy with severe broncheomalacia, depending on mechanical ventilation. Balanced and unbalanced rearrangements associated with disorders of sex determination led to the mapping of a regulatory region of SOX9 function on testicular differentiation to a 517-595 kb interval upstream of SOX9, in addition to TESCO (Testis-specific enhancer of SOX9 core). As the carrier of t(17;20) has an XY sex-chromosome constitution and normal male development for his age, the segment of chromosome 17 distal to the translocation breakpoint should contain the regulatory elements for normal testis development. These two novel translocations illustrate the clinical variability in carriers of balanced

  5. The Waardenburg Syndrome Type 4 Gene, SOX10, Is a Novel Tumor-associated Antigen Identified in a Patient with a Dramatic Response to Immunotherapy

    Science.gov (United States)

    Khong, Hung T.; Rosenberg, Steven A.

    2008-01-01

    In this study, we have identified, for the first time, the presence of de novo cellular immune reactivity against the transcription factor SOX10, using tumor-infiltrating lymphocytes obtained from a patient who experienced a dramatic clinical response to immunotherapy. SOX10 acts as a critical transactivator of tyrosinase-related protein-2 during melanoblast development and a potent transactivator of micropthalmia-associated transcription factor, which is considered to be a master gene that controls the development and postnatal survival of melanocytes. Mutations in SOX10 result in Waardenburg syndrome type 4. The overlapping epitopes AWISKPPGV and SAWISKPPGV, designated SOX10: 332–340 and SOX10: 331–340, respectively, were recognized by tumor-infiltrating lymphocyte clone M37 in an HLA-A2-restricted fashion. PMID:12036907

  6. Overexpression of microRNA-194 suppresses the epithelial-mesenchymal transition in targeting stem cell transcription factor Sox3 in endometrial carcinoma stem cells.

    Science.gov (United States)

    Gong, Baolan; Yue, Yan; Wang, Renxiao; Zhang, Yi; Jin, Quanfang; Zhou, Xi

    2017-06-01

    The epithelial-mesenchymal transition is the key process driving cancer metastasis. MicroRNA-194 inhibits epithelial-mesenchymal transition in several cancers and its downregulation indicates a poor prognosis in human endometrial carcinoma. Self-renewal factor Sox3 induces epithelial-mesenchymal transition at gastrulation and is also involved epithelial-mesenchymal transition in several cancers. We intended to determine the roles of Sox3 in inducing epithelial-mesenchymal transition in endometrial cancer stem cells and the possible role of microRNA-194 in controlling Sox3 expression. Firstly, we found that Sox3 and microRNA-194 expressions were associated with the status of endometrial cancer stem cells in a panel of endometrial carcinoma tissue, the CD133+ cell was higher in tumorsphere than in differentiated cells, and overexpression of microRNA-194 would decrease CD133+ cell expression. Silencing of Sox3 in endometrial cancer stem cell upregulated the epithelial marker E-cadherin, downregulated the mesenchymal marker vimentin, and significantly reduced cell invasion in vitro; overexpression of Sox3 reversed these phenotypes. Furthermore, we discovered that the expression of Sox3 was suppressed by microRNA-194 through direct binding to the Sox3 3'-untranslated region. Ectopic expression of microRNA-194 in endometrial cancer stem cells induced a mesenchymal-epithelial transition by restoring E-cadherin expression, decreasing vimentin expression, and inhibiting cell invasion in vitro. Moreover, overexpression of microRNA-194 inhibited endometrial cancer stem cell invasion or metastasis in vivo by injection of adenovirus microRNA-194. These findings demonstrate the novel mechanism by which Sox3 contributes to endometrial cancer stem cell invasion and suggest that repression of Sox3 by microRNA-194 may have therapeutic potential to suppress endometrial carcinoma metastasis. The cancer stem cell marker, CD133, might be the surface marker of endometrial cancer stem

  7. Normal Levels of Sox9 Expression in the Developing Mouse Testis Depend on the TES/TESCO Enhancer, but This Does Not Act Alone.

    Science.gov (United States)

    Gonen, Nitzan; Quinn, Alexander; O'Neill, Helen C; Koopman, Peter; Lovell-Badge, Robin

    2017-01-01

    During mouse sex determination, transient expression of the Y-linked gene Sry up-regulates its direct target gene Sox9, via a 3.2 kb testis specific enhancer of Sox9 (TES), which includes a core 1.4 kb element, TESCO. SOX9 activity leads to differentiation of Sertoli cells, rather than granulosa cells from the bipotential supporting cell precursor lineage. Here, we present functional analysis of TES/TESCO, using CRISPR/Cas9 genome editing in mice. Deletion of TESCO or TES reduced Sox9 expression levels in XY fetal gonads to 60 or 45% respectively relative to wild type gonads, and reduced expression of the SOX9 target Amh. Although human patients heterozygous for null mutations in SOX9, which are assumed to have 50% of normal expression, often show XY female sex reversal, mice deleted for one copy of Sox9 do not. Consistent with this, we did not observe sex reversal in either TESCO-/- or TES-/- XY embryos or adult mice. However, embryos carrying both a conditional Sox9 null allele and the TES deletion developed ovotestes. Quantitative analysis of these revealed levels of 23% expression of Sox9 compared to wild type, and a significant increase in the expression of the granulosa cell marker Foxl2. This indicates that the threshold in mice where sex reversal begins to be seen is about half that of the ~50% levels predicted in humans. Our results demonstrate that TES/TESCO is a crucial enhancer regulating Sox9 expression in the gonad, but point to the existence of additional enhancers that act redundantly.

  8. Normal Levels of Sox9 Expression in the Developing Mouse Testis Depend on the TES/TESCO Enhancer, but This Does Not Act Alone.

    Directory of Open Access Journals (Sweden)

    Nitzan Gonen

    2017-01-01

    Full Text Available During mouse sex determination, transient expression of the Y-linked gene Sry up-regulates its direct target gene Sox9, via a 3.2 kb testis specific enhancer of Sox9 (TES, which includes a core 1.4 kb element, TESCO. SOX9 activity leads to differentiation of Sertoli cells, rather than granulosa cells from the bipotential supporting cell precursor lineage. Here, we present functional analysis of TES/TESCO, using CRISPR/Cas9 genome editing in mice. Deletion of TESCO or TES reduced Sox9 expression levels in XY fetal gonads to 60 or 45% respectively relative to wild type gonads, and reduced expression of the SOX9 target Amh. Although human patients heterozygous for null mutations in SOX9, which are assumed to have 50% of normal expression, often show XY female sex reversal, mice deleted for one copy of Sox9 do not. Consistent with this, we did not observe sex reversal in either TESCO-/- or TES-/- XY embryos or adult mice. However, embryos carrying both a conditional Sox9 null allele and the TES deletion developed ovotestes. Quantitative analysis of these revealed levels of 23% expression of Sox9 compared to wild type, and a significant increase in the expression of the granulosa cell marker Foxl2. This indicates that the threshold in mice where sex reversal begins to be seen is about half that of the ~50% levels predicted in humans. Our results demonstrate that TES/TESCO is a crucial enhancer regulating Sox9 expression in the gonad, but point to the existence of additional enhancers that act redundantly.

  9. Targeting cyclin B1 inhibits proliferation and sensitizes breast cancer cells to taxol

    Directory of Open Access Journals (Sweden)

    Strebhardt Klaus

    2008-12-01

    Full Text Available Abstract Background Cyclin B1, the regulatory subunit of cyclin-dependent kinase 1 (Cdk1, is essential for the transition from G2 phase to mitosis. Cyclin B1 is very often found to be overexpressed in primary breast and cervical cancer cells as well as in cancer cell lines. Its expression is correlated with the malignancy of gynecological cancers. Methods In order to explore cyclin B1 as a potential target for gynecological cancer therapy, we studied the effect of small interfering RNA (siRNA on different gynecological cancer cell lines by monitoring their proliferation rate, cell cycle profile, protein expression and activity, apoptosis induction and colony formation. Tumor formation in vivo was examined using mouse xenograft models. Results Downregulation of cyclin B1 inhibited proliferation of several breast and cervical cancer cell lines including MCF-7, BT-474, SK-BR-3, MDA-MB-231 and HeLa. After combining cyclin B1 siRNA with taxol, we observed an increased apoptotic rate accompanied by an enhanced antiproliferative effect in breast cancer cells. Furthermore, control HeLa cells were progressively growing, whereas the tumor growth of HeLa cells pre-treated with cyclin B1 siRNA was strongly inhibited in nude mice, indicating that cyclin B1 is indispensable for tumor growth in vivo. Conclusion Our data support the notion of cyclin B1 being essential for survival and proliferation of gynecological cancer cells. Concordantly, knockdown of cyclin B1 inhibits proliferation in vitro as well as in vivo. Moreover, targeting cyclin B1 sensitizes breast cancer cells to taxol, suggesting that specific cyclin B1 targeting is an attractive strategy for the combination with conventionally used agents in gynecological cancer therapy.

  10. Targeting cyclin B1 inhibits proliferation and sensitizes breast cancer cells to taxol

    International Nuclear Information System (INIS)

    Androic, Ilija; Krämer, Andrea; Yan, Ruilan; Rödel, Franz; Gätje, Regine; Kaufmann, Manfred; Strebhardt, Klaus; Yuan, Juping

    2008-01-01

    Cyclin B1, the regulatory subunit of cyclin-dependent kinase 1 (Cdk1), is essential for the transition from G2 phase to mitosis. Cyclin B1 is very often found to be overexpressed in primary breast and cervical cancer cells as well as in cancer cell lines. Its expression is correlated with the malignancy of gynecological cancers. In order to explore cyclin B1 as a potential target for gynecological cancer therapy, we studied the effect of small interfering RNA (siRNA) on different gynecological cancer cell lines by monitoring their proliferation rate, cell cycle profile, protein expression and activity, apoptosis induction and colony formation. Tumor formation in vivo was examined using mouse xenograft models. Downregulation of cyclin B1 inhibited proliferation of several breast and cervical cancer cell lines including MCF-7, BT-474, SK-BR-3, MDA-MB-231 and HeLa. After combining cyclin B1 siRNA with taxol, we observed an increased apoptotic rate accompanied by an enhanced antiproliferative effect in breast cancer cells. Furthermore, control HeLa cells were progressively growing, whereas the tumor growth of HeLa cells pre-treated with cyclin B1 siRNA was strongly inhibited in nude mice, indicating that cyclin B1 is indispensable for tumor growth in vivo. Our data support the notion of cyclin B1 being essential for survival and proliferation of gynecological cancer cells. Concordantly, knockdown of cyclin B1 inhibits proliferation in vitro as well as in vivo. Moreover, targeting cyclin B1 sensitizes breast cancer cells to taxol, suggesting that specific cyclin B1 targeting is an attractive strategy for the combination with conventionally used agents in gynecological cancer therapy

  11. Explicitly computing geodetic coordinates from Cartesian coordinates

    Science.gov (United States)

    Zeng, Huaien

    2013-04-01

    This paper presents a new form of quartic equation based on Lagrange's extremum law and a Groebner basis under the constraint that the geodetic height is the shortest distance between a given point and the reference ellipsoid. A very explicit and concise formulae of the quartic equation by Ferrari's line is found, which avoids the need of a good starting guess for iterative methods. A new explicit algorithm is then proposed to compute geodetic coordinates from Cartesian coordinates. The convergence region of the algorithm is investigated and the corresponding correct solution is given. Lastly, the algorithm is validated with numerical experiments.

  12. UNC93B1 mediates host resistance to infection with Toxoplasma gondii.

    Directory of Open Access Journals (Sweden)

    Mariane B Melo

    2010-08-01

    Full Text Available UNC93B1 associates with Toll-Like Receptor (TLR 3, TLR7 and TLR9, mediating their translocation from the endoplasmic reticulum to the endolysosome, hence allowing proper activation by nucleic acid ligands. We found that the triple deficient '3d' mice, which lack functional UNC93B1, are hyper-susceptible to infection with Toxoplasma gondii. We established that while mounting a normal systemic pro-inflammatory response, i.e. producing abundant MCP-1, IL-6, TNFα and IFNγ, the 3d mice were unable to control parasite replication. Nevertheless, infection of reciprocal bone marrow chimeras between wild-type and 3d mice with T. gondii demonstrated a primary role of hemopoietic cell lineages in the enhanced susceptibility of UNC93B1 mutant mice. The protective role mediated by UNC93B1 to T. gondii infection was associated with impaired IL-12 responses and delayed IFNγ by spleen cells. Notably, in macrophages infected with T. gondii, UNC93B1 accumulates on the parasitophorous vacuole. Furthermore, upon in vitro infection the rate of tachyzoite replication was enhanced in non-activated macrophages carrying mutant UNC93B1 as compared to wild type gene. Strikingly, the role of UNC93B1 on intracellular parasite growth appears to be independent of TLR function. Altogether, our results reveal a critical role for UNC93B1 on induction of IL-12/IFNγ production as well as autonomous control of Toxoplasma replication by macrophages.

  13. 26 CFR 1.6050B-1 - Information returns by person making unemployment compensation payments.

    Science.gov (United States)

    2010-04-01

    ... unemployment compensation payments. 1.6050B-1 Section 1.6050B-1 Internal Revenue INTERNAL REVENUE SERVICE... Information returns by person making unemployment compensation payments. For taxable years beginning after December 31, 1978, every person who makes payments of unemployment compensation (as defined in section 85...

  14. 26 CFR 1.802(b)-1 - Tax on life insurance companies.

    Science.gov (United States)

    2010-04-01

    .... For the definition of the term “1954 life insurance company taxable income”, see § 1.805-1. (b) The... 26 Internal Revenue 8 2010-04-01 2010-04-01 false Tax on life insurance companies. 1.802(b)-1...) INCOME TAX (CONTINUED) INCOME TAXES Life Insurance Companies § 1.802(b)-1 Tax on life insurance companies...

  15. Immunosuppressive effects of fumonisin B1 in the Trichinella spiralis model

    NARCIS (Netherlands)

    Nijs M de; Egmond HP van; Jong WH de; Loveren H van; LPI; ARO; MGB

    Fumonisin B1 is a mycotoxin produced by Fusarium moniliforme and is found mainly in maize. Fumonisin B1 has been associated with human esophageal cancer, lung edema in pigs and leuko-encephalomalacia in equine species. Adverse effects of this mycotoxin on the immune system can be expected but were

  16. Preparation and application of new fluorescein-labeled fumonisins B1 in fluorescence polarization analysis technique

    Science.gov (United States)

    Objective: To prepare a new fluorescent tracer against common mycotoxins such as fumonisin B1 in order to replace 6-(4,6-Dichlorotriazinyl) aminofluorescein (6-DTAF), an expensive marker, and to develop a technique for quick detection of fumonisin B1 based on the principle of fluorescence polarizati...

  17. Wt-ko_trxB1_Filtered bkg correc transf-norm

    OpenAIRE

    Serrano, L.M.; Molenaar, Douwe; Teusink, Bas; Vos, de, Willem; Smid, Eddy

    2007-01-01

    In this experiment we analyzed the impact of the disruption of trxB1in Lactobacillus plantarum at the transcriptome level. Furthermore we studied the effect of 3.5 mM peroxide effect on both Lactobacillus plantarum wild type (strain WCFS1) and a trxB1 mutant (strain NZ7608).

  18. Production of milk-clotting enzyme by Bacillus subtilis B1 from wheat ...

    African Journals Online (AJOL)

    Three strains, Bacillus subtilis B1, B. subtilis B18 and Bacillus thuringiensis B12, were screened from wheat bran to produce milk-clotting enzyme. Among them, B. subtilis B1 exhibited considerable milkclotting activity with low proteolytic activity. After response surface methodology optimization, milkclotting activity was ...

  19. The use of MR B+1 imaging for validation of FDTD electromagnetic simulations of human anatomies

    International Nuclear Information System (INIS)

    Berg, Cornelis A T van den; Bartels, Lambertus W; Bergen, Bob van den; Kroeze, Hugo; Leeuw, Astrid A C de; Kamer, Jeroen B van de; Lagendijk, Jan J W

    2006-01-01

    In this study, MR B + 1 imaging is employed to experimentally verify the validity of FDTD simulations of electromagnetic field patterns in human anatomies. Measurements and FDTD simulations of the B + 1 field induced by a 3 T MR body coil in a human corpse were performed. It was found that MR B + 1 imaging is a sensitive method to measure the radiofrequency (RF) magnetic field inside a human anatomy with a precision of approximately 3.5%. A good correlation was found between the B + 1 measurements and FDTD simulations. The measured B + 1 pattern for a human pelvis consisted of a global, diagonal modulation pattern plus local B + 1 heterogeneties. It is believed that these local B + 1 field variations are the result of peaks in the induced electric currents, which could not be resolved by the FDTD simulations on a 5 mm 3 simulation grid. The findings from this study demonstrate that B + 1 imaging is a valuable experimental technique to gain more knowledge about the dielectric interaction of RF fields with the human anatomy

  20. Data of evolutionary structure change: 1JJ4B-1R8HE [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available in>B 1JJ4B RLRKH-SDHYR >HGGGG-GGG ...n> RLNDKHRHLFD ture>HHHHH GGG .../pdbID> B 1JJ4B WHWTE-----KTGIL ...> ----- EEE> ATOM 1523 CA TRP B 320 11.497 15.32...1R8HE WHWASPKAPHKHAIV > EEE>

  1. A lattice QCD calculation of the transverse decay constant of the b1(1235) meson

    International Nuclear Information System (INIS)

    Jansen, K.; McNeile, C.; Michael, C.; Urbach, C.

    2009-10-01

    We review various B meson decays that require knowledge of the transverse decay constant of the b 1 (1235) meson. We report on an exploratory lattice QCD calculation of the transverse decay constant of the b 1 meson. The lattice QCD calculations used unquenched gauge configurations, at two lattice spacings, generated with two flavours of sea quarks. The twisted mass formalism is used. (orig.)

  2. Intestinal bile salt absorption in Atp8b1 deficient mice

    NARCIS (Netherlands)

    Groen, Annemiek; Kunne, Cindy; Paulusma, Coen C.; Kramer, Werner; Agellon, Luis B.; Bull, Laura N.; Elferink, Ronald P. J. Oude

    2007-01-01

    BACKGROUND/AIMS: Mutations in the ATP8B1 gene can cause Progressive Familial Intrahepatic Cholestasis type 1. We have previously reported that Atp8b1(G308V/G308V) mice, a model for PFIC1, have slightly, but significantly, higher baseline serum bile salt (BS) concentrations compared to wt mice. Upon

  3. Identification of Ppd-B1 alleles in common wheat cultivars by CAPS marker.

    Science.gov (United States)

    Okoń, S; Kowalczyk, K; Miazga, D

    2012-05-01

    Photoperiod response is a major determinant of the duration of growth stages in common wheat. In common wheat, many genes play a role in determining flowering time, but the Ppd genes located on the homoeologous group 2 play a major role. Of these Ppd-B1 is located on the short arm of 2B. In 107 common wheat cultivars grown in Poland and neighboring countries, the identification of Ppd-B1 alleles using in-del analysis by using a CAPS markers was investigated. 87 cultivars were shown to carry dominant Ppd-B1 alleles. This shows that Ppd-B1 alleles is have been widely used in common wheat breeding programme in these countries. Recessive ppd-B1 alleles were found only in 20 cultivars (12 Polish, 5 former Soviet Union, 2 German, 1 Swedish).

  4. Revaluasi Inventory dengan Menu Standard pada SAP-B1 Sesuaikah dengan IFRS

    Directory of Open Access Journals (Sweden)

    Eka Novianti

    2011-05-01

    Full Text Available Some available standard modules in SAP-B1 can be adapted for changes in accounting rules and regulations. One is the Inventory Revaluation menu of Inventory module. Users can use the menu to make Inventory value adjustments of value in SAP-B1, to be consistent with the values that must be presented in the financial statements. Based on the flexibility provided by SAP-B1menu, should not be too difficult for users of SAP-B1 to manage accounting transactions based on accounting rules that apply today, IFRS. IFRS requirements on inventory adjustment transactions with a value of SAP-B1 could be done more easily.

  5. A study on the possibility of production of aflatoxin B1 in saffron

    Directory of Open Access Journals (Sweden)

    Abbas Mohammadi

    2017-06-01

    Full Text Available Saffron is the most important medicinal plants in the Khorasan Razavi and South Khorasan provinces, Iran. Aspergillus species can infect saffron tissues during harvesting, storage and transportation. Aflatoxin B1 is one of the important carcinogenic mycotoxin which is produced by Aspergillus species in saffron tissues. This study was carried out in order to investigate the production of aflatoxin B1 in saffron tissues from farm to food by TLC chromatography during the year 2015. Wet and dry saffron tissues and rice grains (with and without saffron extract were inoculated with Aspergillus flavus spore suspensions. Production of Aflatoxin B1 in inoculated tissues was investigated by the TLC chromatography method. The results showed that the wet leaves and rice grains were infected with Aspergillus species very quickly. However, this process was very slow in dry tissues. Aflatoxin B1 was detected in all of the tested samples. The amounts of Aflatoxin B1 in the wet saffron tissues and rice grains were more than those found in dry tissues and saffron rice, respectively. The amount of Aflatoxin B1 had a direct correlation with moisture in the environment and the tissues. The contamination of the tissues and production of AflatoxinB1 were increased with increasing the amount of moisture. The results showed that the packaging of saffron before complete drying of its tissue or storing it in conditions with high humidity can increase the risk of infection with the Aspergillus species and production of Aflatoxin B1 in them. Based on our data, saffron can reduce Aspergillus infection and aflatoxin B1 production but not inhibit it. Saffron extract reduces Aspergillus infection and Aflatoxin B1 production in food and grains.

  6. OCT4B1 Regulates the Cellular Stress Response of Human Dental Pulp Cells with Inflammation

    Directory of Open Access Journals (Sweden)

    Lu Liu

    2017-01-01

    Full Text Available Introduction. Infection and apoptosis are combined triggers for inflammation in dental tissues. Octamer-binding transcription factor 4-B1 (OCT4B1, a novel spliced variant of OCT4 family, could respond to the cellular stress and possess antiapoptotic property. However, its specific role in dental pulpitis remains unknown. Methods. To investigate the effect of OCT4B1 on inflammation of dental pulp cells (DPCs, its expression in inflamed dental pulp tissues and DPCs was examined by in situ hybridization, real-time PCR, and FISH assay. OCT4B1 overexpressed DPCs model was established, confirmed by western blot and immunofluorescence staining, and then stimulated with Lipopolysaccharide (LPS. Apoptotic rate was determined by Hoechst/PI staining and FACS. Cell survival rate was calculated by CCK8 assay. Results. In situ hybridization, real-time PCR, and FISH assay revealed that OCT4B1 was extensively expressed in inflamed dental pulp tissues and DPCs with LPS stimulation. Western blot and immunofluorescence staining showed the expression of OCT4B1 and OCT4B increased after OCT4B1 transfection. Hoechst/PI staining and FACS demonstrated that less red/blue fluorescence was detected and apoptotic percentage decreased (3.45% after transfection. CCK8 demonstrated that the survival rate of pCDH-OCT4B1-flag cells increased. Conclusions. OCT4B1 plays an essential role in inflammation and apoptosis of DPCs. OCT4B might operate synergistically with OCT4B1 to reduce apoptosis.

  7. Key role for spinal dorsal horn microglial kinin B1 receptor in early diabetic pain neuropathy

    Directory of Open Access Journals (Sweden)

    Couture Réjean

    2010-06-01

    Full Text Available Abstract Background The pro-nociceptive kinin B1 receptor (B1R is upregulated on sensory C-fibres, astrocytes and microglia in the spinal cord of streptozotocin (STZ-diabetic rat. This study aims at defining the role of microglial kinin B1R in diabetic pain neuropathy. Methods Sprague-Dawley rats were made diabetic with STZ (65 mg/kg, i.p., and 4 days later, two specific inhibitors of microglial cells (fluorocitrate, 1 nmol, i.t.; minocycline, 10 mg/kg, i.p. were administered to assess the impact on thermal hyperalgesia, allodynia and mRNA expression (qRT-PCR of B1R and pro-inflammatory markers. Spinal B1R binding sites ((125I-HPP-desArg10-Hoe 140 were also measured by quantitative autoradiography. Inhibition of microglia was confirmed by confocal microscopy with the specific marker Iba-1. Effects of intrathecal and/or systemic administration of B1R agonist (des-Arg9-BK and antagonists (SSR240612 and R-715 were measured on neuropathic pain manifestations. Results STZ-diabetic rats displayed significant tactile and cold allodynia compared with control rats. Intrathecal or peripheral blockade of B1R or inhibition of microglia reversed time-dependently tactile and cold allodynia in diabetic rats without affecting basal values in control rats. Microglia inhibition also abolished thermal hyperalgesia and the enhanced allodynia induced by intrathecal des-Arg9-BK without affecting hyperglycemia in STZ rats. The enhanced mRNA expression (B1R, IL-1β, TNF-α, TRPV1 and Iba-1 immunoreactivity in the STZ spinal cord were normalized by fluorocitrate or minocycline, yet B1R binding sites were reduced by 38%. Conclusion The upregulation of kinin B1R in spinal dorsal horn microglia by pro-inflammatory cytokines is proposed as a crucial mechanism in early pain neuropathy in STZ-diabetic rats.

  8. SF3B1-initiating mutations in MDS-RSs target lymphomyeloid hematopoietic stem cells.

    Science.gov (United States)

    Mortera-Blanco, Teresa; Dimitriou, Marios; Woll, Petter S; Karimi, Mohsen; Elvarsdottir, Edda; Conte, Simona; Tobiasson, Magnus; Jansson, Monika; Douagi, Iyadh; Moarii, Matahi; Saft, Leonie; Papaemmanuil, Elli; Jacobsen, Sten Eirik W; Hellström-Lindberg, Eva

    2017-08-17

    Mutations in the RNA splicing gene SF3B1 are found in >80% of patients with myelodysplastic syndrome with ring sideroblasts (MDS-RS). We investigated the origin of SF3B1 mutations within the bone marrow hematopoietic stem and progenitor cell compartments in patients with MDS-RS. Screening for recurrently mutated genes in the mononuclear cell fraction revealed mutations in SF3B1 in 39 of 40 cases (97.5%), combined with TET2 and DNMT3A in 11 (28%) and 6 (15%) patients, respectively. All recurrent mutations identified in mononuclear cells could be tracked back to the phenotypically defined hematopoietic stem cell (HSC) compartment in all investigated patients and were also present in downstream myeloid and erythroid progenitor cells. While in agreement with previous studies, little or no evidence for clonal ( SF3B1 mutation) involvement could be found in mature B cells, consistent involvement at the pro-B-cell progenitor stage was established, providing definitive evidence for SF3B1 mutations targeting lymphomyeloid HSCs and compatible with mutated SF3B1 negatively affecting lymphoid development. Assessment of stem cell function in vitro as well as in vivo established that only HSCs and not investigated progenitor populations could propagate the SF3B1 mutated clone. Upon transplantation into immune-deficient mice, SF3B1 mutated MDS-RS HSCs differentiated into characteristic ring sideroblasts, the hallmark of MDS-RS. Our findings provide evidence of a multipotent lymphomyeloid HSC origin of SF3B1 mutations in MDS-RS patients and provide a novel in vivo platform for mechanistically and therapeutically exploring SF3B1 mutated MDS-RS. © 2017 by The American Society of Hematology.

  9. Cyp26b1 within the growth plate regulates bone growth in juvenile mice

    International Nuclear Information System (INIS)

    Minegishi, Yoshiki; Sakai, Yasuo; Yahara, Yasuhito; Akiyama, Haruhiko; Yoshikawa, Hideki; Hosokawa, Ko; Tsumaki, Noriyuki

    2014-01-01

    Highlights: • Retinoic acid and Cyp26b1 were oppositely localized in growth plate cartilage. • Cyp26b1 deletion in chondrocytes decreased bone growth in juvenile mice. • Cyp26b1 deletion reduced chondrocyte proliferation and growth plate height. • Vitamin A-depletion partially reversed growth plate abnormalities caused by Cyp26b1 deficiency. • Cyp26b1 regulates bone growth by controlling chondrocyte proliferation. - Abstract: Retinoic acid (RA) is an active metabolite of vitamin A and plays important roles in embryonic development. CYP26 enzymes degrade RA and have specific expression patterns that produce a RA gradient, which regulates the patterning of various structures in the embryo. However, it has not been addressed whether a RA gradient also exists and functions in organs after birth. We found localized RA activities in the diaphyseal portion of the growth plate cartilage were associated with the specific expression of Cyp26b1 in the epiphyseal portion in juvenile mice. To disturb the distribution of RA, we generated mice lacking Cyp26b1 specifically in chondrocytes (Cyp26b1 Δchon cKO). These mice showed reduced skeletal growth in the juvenile stage. Additionally, their growth plate cartilage showed decreased proliferation rates of proliferative chondrocytes, which was associated with a reduced height in the zone of proliferative chondrocytes, and closed focally by four weeks of age, while wild-type mouse growth plates never closed. Feeding the Cyp26b1 cKO mice a vitamin A-deficient diet partially reversed these abnormalities of the growth plate cartilage. These results collectively suggest that Cyp26b1 in the growth plate regulates the proliferation rates of chondrocytes and is responsible for the normal function of the growth plate and growing bones in juvenile mice, probably by limiting the RA distribution in the growth plate proliferating zone

  10. Cyp26b1 within the growth plate regulates bone growth in juvenile mice

    Energy Technology Data Exchange (ETDEWEB)

    Minegishi, Yoshiki [Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Department of Plastic and Reconstructive Surgery, University of Fukui Hospital, 23-3 Matsuokashimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui 910-1193 (Japan); Department of Plastic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Sakai, Yasuo [Department of Plastic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Department of Plastic Surgery, Bellland General Hospital, 500-3 Higashiyama Naka-ku, Sakai, Osaka 599-8247 (Japan); Yahara, Yasuhito [Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Akiyama, Haruhiko [Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, 1-1 Yanagito, Gifu 501-1194 (Japan); Yoshikawa, Hideki [Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Hosokawa, Ko [Department of Plastic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Tsumaki, Noriyuki, E-mail: ntsumaki@cira.kyoto-u.ac.jp [Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Japan Science and Technology Agency, CREST, Tokyo 102-0075 (Japan)

    2014-11-07

    Highlights: • Retinoic acid and Cyp26b1 were oppositely localized in growth plate cartilage. • Cyp26b1 deletion in chondrocytes decreased bone growth in juvenile mice. • Cyp26b1 deletion reduced chondrocyte proliferation and growth plate height. • Vitamin A-depletion partially reversed growth plate abnormalities caused by Cyp26b1 deficiency. • Cyp26b1 regulates bone growth by controlling chondrocyte proliferation. - Abstract: Retinoic acid (RA) is an active metabolite of vitamin A and plays important roles in embryonic development. CYP26 enzymes degrade RA and have specific expression patterns that produce a RA gradient, which regulates the patterning of various structures in the embryo. However, it has not been addressed whether a RA gradient also exists and functions in organs after birth. We found localized RA activities in the diaphyseal portion of the growth plate cartilage were associated with the specific expression of Cyp26b1 in the epiphyseal portion in juvenile mice. To disturb the distribution of RA, we generated mice lacking Cyp26b1 specifically in chondrocytes (Cyp26b1{sup Δchon} cKO). These mice showed reduced skeletal growth in the juvenile stage. Additionally, their growth plate cartilage showed decreased proliferation rates of proliferative chondrocytes, which was associated with a reduced height in the zone of proliferative chondrocytes, and closed focally by four weeks of age, while wild-type mouse growth plates never closed. Feeding the Cyp26b1 cKO mice a vitamin A-deficient diet partially reversed these abnormalities of the growth plate cartilage. These results collectively suggest that Cyp26b1 in the growth plate regulates the proliferation rates of chondrocytes and is responsible for the normal function of the growth plate and growing bones in juvenile mice, probably by limiting the RA distribution in the growth plate proliferating zone.

  11. Defects in cardiac outflow tract formation and pro-B-lymphocyte expansion in mice lacking Sox-4

    NARCIS (Netherlands)

    Schilham, M. W.; Oosterwegel, M. A.; Moerer, P.; Ya, J.; de Boer, P. A.; van de Wetering, M.; Verbeek, S.; Lamers, W. H.; Kruisbeek, A. M.; Cumano, A.; Clevers, H.

    1996-01-01

    A striking example of the relationship between regulation of transcription and phenotype is the central role of the Y-chromosomal gene Sry in mammalian sex determination. Sry is the founding member of a large family of so-called Sox genes. During murine embryogenesis, the transcriptional activator

  12. Chronic constipation recognized as a sign of a SOX10 mutation in a patient with Waardenburg syndrome.

    Science.gov (United States)

    Arimoto, Yukiko; Namba, Kazunori; Nakano, Atsuko; Matsunaga, Tatsuo

    2014-05-01

    Waardenburg syndrome is characterized by hearing loss, pigmentation abnormalities, dysmorphologic features, and neurological phenotypes. Waardenburg syndrome consists of four distinct subtypes, and SOX10 mutations have been identified in type II and type IV. Type IV differs from type II owing to the presence of Hirschsprung disease. We identified a de novo nonsense mutation in SOX10 (p.G39X) in a female pediatric patient with Waardenburg syndrome with heterochromia iridis, profound bilateral sensorineural hearing loss, inner ear malformations, and overall hypopigmentation of the hair without dystopia canthorum. This patient has experienced chronic constipation since she was a neonate, but anorectal manometry showed a normal anorectal reflex. Chronic constipation in this patient was likely to be a consequence of a mild intestinal disorder owing to the SOX10 mutation, and this patient was considered to have a clinical phenotype intermediate between type II and type IV of the syndrome. Chronic constipation may be recognized as indicative of a SOX10 mutation in patients with Waardenburg syndrome. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Identification and functional analysis of a novel mutation in the SOX10 gene associated with Waardenburg syndrome type IV.

    Science.gov (United States)

    Wang, Hong-Han; Chen, Hong-Sheng; Li, Hai-Bo; Zhang, Hua; Mei, Ling-Yun; He, Chu-Feng; Wang, Xing-Wei; Men, Mei-Chao; Jiang, Lu; Liao, Xin-Bin; Wu, Hong; Feng, Yong

    2014-03-15

    Waardenburg syndrome type IV (WS4) is a rare genetic disorder, characterized by auditory-pigmentary abnormalities and Hirschsprung disease. Mutations of the EDNRB gene, EDN3 gene, or SOX10 gene are responsible for WS4. In the present study, we reported a case of a Chinese patient with clinical features of WS4. In addition, the three genes mentioned above were sequenced in order to identify whether mutations are responsible for the case. We revealed a novel nonsense mutation, c.1063C>T (p.Q355*), in the last coding exon of SOX10. The same mutation was not found in three unaffected family members or 100 unrelated controls. Then, the function and mechanism of the mutation were investigated in vitro. We found both wild-type (WT) and mutant SOX10 p.Q355* were detected at the expected size and their expression levels are equivalent. The mutant protein also localized in the nucleus and retained the DNA-binding activity as WT counterpart; however, it lost its transactivation capability on the MITF promoter and acted as a dominant-negative repressor impairing function of the WT SOX10. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. A Sox Transcription Factor Is a Critical Regulator of Adult Stem Cell Proliferation in the Drosophila Intestine

    Directory of Open Access Journals (Sweden)

    Fanju W. Meng

    2015-11-01

    Full Text Available Adult organs and their resident stem cells are constantly facing the challenge of adapting cell proliferation to tissue demand, particularly in response to environmental stresses. Whereas most stress-signaling pathways are conserved between progenitors and differentiated cells, stem cells have the specific ability to respond by increasing their proliferative rate, using largely unknown mechanisms. Here, we show that a member of the Sox family of transcription factors in Drosophila, Sox21a, is expressed in intestinal stem cells (ISCs in the adult gut. Sox21a is essential for the proliferation of these cells during both normal epithelium turnover and repair. Its expression is induced in response to tissue damage, downstream of the Jun N-terminal kinase (JNK and extracellular signal-regulated kinase (ERK pathways, to promote ISC proliferation. Although short-lived, Sox21a mutant flies show no developmental defects, supporting the notion that this factor is a specific regulator of adult stem cell proliferation.

  15. SOX6 and PDCD4 enhance cardiomyocyte apoptosis through LPS-induced miR-499 inhibition.

    Science.gov (United States)

    Jia, Zhuqing; Wang, Jiaji; Shi, Qiong; Liu, Siyu; Wang, Weiping; Tian, Yuyao; Lu, Qin; Chen, Ping; Ma, Kangtao; Zhou, Chunyan

    2016-02-01

    Sepsis-induced cardiac apoptosis is one of the major pathogenic factors in myocardial dysfunction. As it enhances numerous proinflammatory factors, lipopolysaccharide (LPS) is considered the principal mediator in this pathological process. However, the detailed mechanisms involved are unclear. In this study, we attempted to explore the mechanisms involved in LPS-induced cardiomyocyte apoptosis. We found that LPS stimulation inhibited microRNA (miR)-499 expression and thereby upregulated the expression of SOX6 and PDCD4 in neonatal rat cardiomyocytes. We demonstrate that SOX6 and PDCD4 are target genes of miR-499, and they enhance LPS-induced cardiomyocyte apoptosis by activating the BCL-2 family pathway. The apoptosis process enhanced by overexpression of SOX6 or PDCD4, was rescued by the cardiac-abundant miR-499. Overexpression of miR-499 protected the cardiomyocytes against LPS-induced apoptosis. In brief, our results demonstrate the existence of a miR-499-SOX6/PDCD4-BCL-2 family pathway in cardiomyocytes in response to LPS stimulation.

  16. SOX9/miR-130a/CTR1 axis modulates DDP-resistance of cervical cancer cell.

    Science.gov (United States)

    Feng, Chenzhe; Ma, Fang; Hu, Chunhong; Ma, Jin-An; Wang, Jingjing; Zhang, Yang; Wu, Fang; Hou, Tao; Jiang, Shun; Wang, Yapeng; Feng, Yeqian

    2018-01-01

    Cisplatin (DDP) -based chemotherapy is a standard strategy for cervical cancer, while chemoresistance remains a huge challenge. Copper transporter protein 1 (CTR1), a copper influx transporter required for high affinity copper (probably reduced Cu I) transport into the cell, reportedly promotes a significant fraction of DDP internalization in tumor cells. In the present study, we evaluated the function of CTR1 in the cell proliferation of cervical cancer upon DDP treatment. MicroRNAs (miRNAs) have been regarded as essential regulators of cell proliferation, apoptosis, migration, as well as chemoresistance. By using online tools, we screened for candidate miRNAs potentially regulate CTR1, among which miR-130a has been proved to promote cervical cancer cell proliferation through targeting PTEN in our previous study. In the present study, we investigated the role of miR-130a in cervical cancer chemoresistance to DDP, and confirmed the binding of miR-130a to CTR1. SOX9 also reportedly act on cancer chemoresistance. In the present study, we revealed that SOX9 inversely regulated miR-130a through direct targeting the promoter of miR-130a. Consistent with previous studies, SOX9 could affect cervical cancer chemoresistance to DDP. Taken together, we demonstrated a SOX9/miR-130a/CTR1 axis which modulated the chemoresistance of cervical cancer cell to DDP, and provided promising targets for dealing with the chemoresistance of cervical cancer.

  17. Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence.

    Science.gov (United States)

    Benko, Sabina; Fantes, Judy A; Amiel, Jeanne; Kleinjan, Dirk-Jan; Thomas, Sophie; Ramsay, Jacqueline; Jamshidi, Negar; Essafi, Abdelkader; Heaney, Simon; Gordon, Christopher T; McBride, David; Golzio, Christelle; Fisher, Malcolm; Perry, Paul; Abadie, Véronique; Ayuso, Carmen; Holder-Espinasse, Muriel; Kilpatrick, Nicky; Lees, Melissa M; Picard, Arnaud; Temple, I Karen; Thomas, Paul; Vazquez, Marie-Paule; Vekemans, Michel; Roest Crollius, Hugues; Hastie, Nicholas D; Munnich, Arnold; Etchevers, Heather C; Pelet, Anna; Farlie, Peter G; Fitzpatrick, David R; Lyonnet, Stanislas

    2009-03-01

    Pierre Robin sequence (PRS) is an important subgroup of cleft palate. We report several lines of evidence for the existence of a 17q24 locus underlying PRS, including linkage analysis results, a clustering of translocation breakpoints 1.06-1.23 Mb upstream of SOX9, and microdeletions both approximately 1.5 Mb centromeric and approximately 1.5 Mb telomeric of SOX9. We have also identified a heterozygous point mutation in an evolutionarily conserved region of DNA with in vitro and in vivo features of a developmental enhancer. This enhancer is centromeric to the breakpoint cluster and maps within one of the microdeletion regions. The mutation abrogates the in vitro enhancer function and alters binding of the transcription factor MSX1 as compared to the wild-type sequence. In the developing mouse mandible, the 3-Mb region bounded by the microdeletions shows a regionally specific chromatin decompaction in cells expressing Sox9. Some cases of PRS may thus result from developmental misexpression of SOX9 due to disruption of very-long-range cis-regulatory elements.

  18. Phenotypic similarities and differences in patients with a p.Met112Ile mutation in SOX10.

    Science.gov (United States)

    Pingault, Veronique; Pierre-Louis, Laurence; Chaoui, Asma; Verloes, Alain; Sarrazin, Elisabeth; Brandberg, Goran; Bondurand, Nadege; Uldall, Peter; Manouvrier-Hanu, Sylvie

    2014-09-01

    Waardenburg syndrome (WS) is characterized by an association of pigmentation abnormalities and sensorineural hearing loss. Four types, defined on clinical grounds, have been delineated, but this phenotypic classification correlates imperfectly with known molecular anomalies. SOX10 mutations have been found in patients with type II and type IV WS (i.e., with Hirschsprung disease), more complex syndromes, and partial forms of the disease. The phenotype induced by SOX10 mutations is highly variable and, except for the neurological forms of the disease, no genotype-phenotype correlation has been characterized to date. There is no mutation hotspot in SOX10 and most cases are sporadic, making it particularly difficult to correlate the phenotypic and genetic variability. This study reports on three independent families with SOX10 mutations predicted to result in the same missense mutation at the protein level (p.Met112Ile), offering a rare opportunity to improve our understanding of the mechanisms underlying phenotypic variability. The pigmentation defects of these patients are very similar, and the neurological symptoms showed a somewhat similar evolution over time, indicating a potential partial genotype-phenotype correlation. However, variability in gastrointestinal symptoms suggests that other genetic factors contribute to the expression of these phenotypes. No correlation between the rs2435357 polymorphism of RET and the expression of Hirschsprung disease was found. In addition, one of the patients has esophageal achalasia, which has rarely been described in WS. © 2014 Wiley Periodicals, Inc.

  19. Sox2-Mediated Conversion of NG2 Glia into Induced Neurons in the Injured Adult Cerebral Cortex

    Directory of Open Access Journals (Sweden)

    Christophe Heinrich

    2014-12-01

    Full Text Available The adult cerebral cortex lacks the capacity to replace degenerated neurons following traumatic injury. Conversion of nonneuronal cells into induced neurons has been proposed as an innovative strategy toward brain repair. Here, we show that retrovirus-mediated expression of the transcription factors Sox2 and Ascl1, but strikingly also Sox2 alone, can induce the conversion of genetically fate-mapped NG2 glia into induced doublecortin (DCX+ neurons in the adult mouse cerebral cortex following stab wound injury in vivo. In contrast, lentiviral expression of Sox2 in the unlesioned cortex failed to convert oligodendroglial and astroglial cells into DCX+ cells. Neurons induced following injury mature morphologically and some acquire NeuN while losing DCX. Patch-clamp recording of slices containing Sox2- and/or Ascl1-transduced cells revealed that a substantial fraction of these cells receive synaptic inputs from neurons neighboring the injury site. Thus, NG2 glia represent a potential target for reprogramming strategies toward cortical repair.

  20. Evidence for increased SOX3 dosage as a risk factor for X-linked hypopituitarism and neural tube defects

    NARCIS (Netherlands)

    Bauters, M.; Frints, S.G.; Esch, H. van; Spruijt, L.; Baldewijns, M.M.; Die-Smulders, C.E.M. de; Fryns, J.P.; Marynen, P.; Froyen, G.

    2014-01-01

    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

  1. Neuronal cell fate decisions:  O2 and CO2 sensing neurons require egl-13/Sox5

    DEFF Research Database (Denmark)

    Gramstrup Petersen, Jakob; Pocock, Roger David John

    2013-01-01

    We recently conducted a study that aimed to describe the differentiation mechanisms used to generate O2 and CO2 sensing neurons in C. elegans. We identified egl-13/Sox5 to be required for the differentiation of both O2 and CO2 sensing neurons. We found that egl-13 functions cell autonomously...

  2. The curvature coordinate system

    DEFF Research Database (Denmark)

    Almegaard, Henrik

    2007-01-01

    The paper describes a concept for a curvature coordinate system on regular curved surfaces from which faceted surfaces with plane quadrangular facets can be designed. The lines of curvature are used as parametric lines for the curvature coordinate system on the surface. A new conjugate set of lin...

  3. Coordinate measuring machines

    DEFF Research Database (Denmark)

    De Chiffre, Leonardo

    This document is used in connection with three exercises of 2 hours duration as a part of the course GEOMETRICAL METROLOGY AND MACHINE TESTING. The exercises concern three aspects of coordinate measuring: 1) Measuring and verification of tolerances on coordinate measuring machines, 2) Traceabilit...... and uncertainty during coordinate measurements, 3) Digitalisation and Reverse Engineering. This document contains a short description of each step in the exercise and schemes with room for taking notes of the results.......This document is used in connection with three exercises of 2 hours duration as a part of the course GEOMETRICAL METROLOGY AND MACHINE TESTING. The exercises concern three aspects of coordinate measuring: 1) Measuring and verification of tolerances on coordinate measuring machines, 2) Traceability...

  4. Wnt/β-catenin signalling regulates Sox17 expression and is essential for organizer and endoderm formation in the mouse.

    Science.gov (United States)

    Engert, Silvia; Burtscher, Ingo; Liao, W Perry; Dulev, Stanimir; Schotta, Gunnar; Lickert, Heiko

    2013-08-01

    Several signalling cascades are implicated in the formation and patterning of the three principal germ layers, but their precise temporal-spatial mode of action in progenitor populations remains undefined. We have used conditional gene deletion of mouse β-catenin in Sox17-positive embryonic and extra-embryonic endoderm as well as vascular endothelial progenitors to address the function of canonical Wnt signalling in cell lineage formation and patterning. Conditional mutants fail to form anterior brain structures and exhibit posterior body axis truncations, whereas initial blood vessel formation appears normal. Tetraploid rescue experiments reveal that lack of β-catenin in the anterior visceral endoderm results in defects in head organizer formation. Sox17 lineage tracing in the definitive endoderm (DE) shows a cell-autonomous requirement for β-catenin in midgut and hindgut formation. Surprisingly, wild-type posterior visceral endoderm (PVE) in midgut- and hindgut-deficient tetraploid chimera rescues the posterior body axis truncation, indicating that the PVE is important for tail organizer formation. Upon loss of β-catenin in the visceral endoderm and DE lineages, but not in the vascular endothelial lineage, Sox17 expression is not maintained, suggesting downstream regulation by canonical Wnt signalling. Strikingly, Tcf4/β-catenin transactivation complexes accumulated on Sox17 cis-regulatory elements specifically upon endoderm induction in an embryonic stem cell differentiation system. Together, these results indicate that the Wnt/β-catenin signalling pathway regulates Sox17 expression for visceral endoderm pattering and DE formation and provide the first functional evidence that the PVE is necessary for gastrula organizer gene induction and posterior axis development.

  5. Slice profile and B1 corrections in 2D magnetic resonance fingerprinting.

    Science.gov (United States)

    Ma, Dan; Coppo, Simone; Chen, Yong; McGivney, Debra F; Jiang, Yun; Pahwa, Shivani; Gulani, Vikas; Griswold, Mark A

    2017-11-01

    The goal of this study is to characterize and improve the accuracy of 2D magnetic resonance fingerprinting (MRF) scans in the presence of slice profile (SP) and B 1 imperfections, which are two main factors that affect quantitative results in MRF. The SP and B 1 imperfections are characterized and corrected separately. The SP effect is corrected by simulating the radiofrequency pulse in the dictionary, and the B 1 is corrected by acquiring a B 1 map using the Bloch-Siegert method before each scan. The accuracy, precision, and repeatability of the proposed method are evaluated in phantom studies. The effects of both SP and B 1 imperfections are also illustrated and corrected in the in vivo studies. The SP and B 1 corrections improve the accuracy of the T 1 and T 2 values, independent of the shape of the radiofrequency pulse. The T 1 and T 2 values obtained from different excitation patterns become more consistent after corrections, which leads to an improvement of the robustness of the MRF design. This study demonstrates that MRF is sensitive to both SP and B 1 effects, and that corrections can be made to improve the accuracy of MRF with only a 2-s increase in acquisition time. Magn Reson Med 78:1781-1789, 2017. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

  6. SR-B1 Is a Silica Receptor that Mediates Canonical Inflammasome Activation

    Directory of Open Access Journals (Sweden)

    Misato Tsugita

    2017-01-01

    Full Text Available The inhalation of silica dust is associated with fibrosis and lung cancer, which are triggered by macrophage inflammatory responses; however, how macrophages recognize silica remains largely unknown. Here, we identify by functional expression cloning the class B scavenger receptor SR-B1 as a silica receptor. Through an extracellular α-helix, both mouse and human SR-B1 specifically recognized amorphous and crystalline silica, but not titanium dioxide nanoparticles, latex nanoparticles, or monosodium urate crystals, although all particles exhibited negative surface potentials. Genetic deletion of SR-B1 and masking of SR-B1 by monoclonal antibodies showed that SR-B1-mediated recognition of silica is associated with caspase-1-mediated inflammatory responses in mouse macrophages and human peripheral blood monocytes. Furthermore, SR-B1 was involved in silica-induced pulmonary inflammation in mice. These results indicate that SR-B1 is a silica receptor associated with canonical inflammasome activation.

  7. 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.

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

    Directory of Open Access Journals (Sweden)

    Z.H. Wang

    2014-04-01

    Full Text Available 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.

  9. Copy number variation in the region harboring SOX9 gene in dogs with testicular/ovotesticular disorder of sex development (78,XX; SRY-negative).

    Science.gov (United States)

    Marcinkowska-Swojak, Malgorzata; Szczerbal, Izabela; Pausch, Hubert; Nowacka-Woszuk, Joanna; Flisikowski, Krzysztof; Dzimira, Stanislaw; Nizanski, Wojciech; Payan-Carreira, Rita; Fries, Ruedi; Kozlowski, Piotr; Switonski, Marek

    2015-10-01

    Although the disorder of sex development in dogs with female karyotype (XX DSD) is quite common, its molecular basis is still unclear. Among mutations underlying XX DSD in mammals are duplication of a long sequence upstream of the SOX9 gene (RevSex) and duplication of the SOX9 gene (also observed in dogs). We performed a comparative analysis of 16 XX DSD and 30 control female dogs, using FISH and MLPA approaches. Our study was focused on a region harboring SOX9 and a region orthologous to the human RevSex (CanRevSex), which was located by in silico analysis downstream of SOX9. Two highly polymorphic copy number variable regions (CNVRs): CNVR1 upstream of SOX9 and CNVR2 encompassing CanRevSex were identified. Although none of the detected copy number variants were specific to either affected or control animals, we observed that the average number of copies in CNVR1 was higher in XX DSD. No copy variation of SOX9 was observed. Our extensive studies have excluded duplication of SOX9 as the common cause of XX DSD in analyzed samples. However, it remains possible that the causative mutation is hidden in highly polymorphic CNVR1.

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

    International Nuclear Information System (INIS)

    Wang, Z.H.; Li, X.L.; He, X.J.; Wu, B.J.; Xu, M.; Chang, H.M.; Zhang, X.H.; Xing, Z.; Jing, X.H.; Kong, D.M.; Kou, X.H.; Yang, Y.Y.

    2014-01-01

    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

  11. Functional analysis of a SOX10 gene mutation associated with Waardenburg syndrome II.

    Science.gov (United States)

    Wang, Xue-Ping; Hao, Zi-Qi; Liu, Ya-Lan; Mei, Ling-Yun; He, Chu-Feng; Niu, Zhi-Jie; Sun, Jie; Zhao, Yu-Lin; Feng, Yong

    2017-11-04

    Waardenburg syndrome (WS) is an autosomal dominant inherited non-syndromic type of hereditary hearing loss characterized by varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair, skin, and inner ear. WS is classified into four subtypes (WS1-WS4) based on additional symptoms. WS2 is characterized by the absence of additional symptoms. Recently, we identified a SOX10 missense mutation c.422T > C (p.L141P) associated with WS2. We performed functional assays and found the mutant loses DNA-binding capacity, shows aberrant cytoplasmic and nuclear localization, and fails to interact with PAX3. Therefore, the mutant cannot transactivate the MITF promoter effectively, inhibiting melanin synthesis and leading to WS2. Our study confirmed haploinsufficiency as the underlying pathogenesis for WS2. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. No significant effect of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid.

    Science.gov (United States)

    Xiang, Xiaoqiang; Vakkilainen, Juha; Backman, Janne T; Neuvonen, Pertti J; Niemi, Mikko

    2011-11-01

    To investigate possible effects of the SLCO1B1 polymorphism on the pharmacokinetics of ursodeoxycholic acid (UDCA) and its metabolites in healthy volunteers. In a crossover study with two phases, 15 healthy volunteers with the SLCO1B1*1A/*1A genotype, seven with the *1B/*1B genotype, and five with the *15/*15 or *5/*15 genotype ingested placebo or a single 150-mg dose of UDCA. Plasma concentrations of bile acids and their biosynthesis marker were determined up to 24 h post-ingestion by liquid chromatography-tandem mass spectrometry. The SLCO1B1 genotype had no significant effect on the pharmacokinetics of UDCA. The geometric mean ratios (95% confidence interval) of UDCA area under the plasma concentration-time curve from 0 to 12 h (AUC(0-12)) in subjects with the SLCO1B1*1B/*1B genotype and in subjects with the SLCO1B1*15/*15 or *5/*15 genotype to the AUC(0-12) in subjects with the SLCO1B1*1A/*1A genotype were 1.07 (0.85, 1.35; P = 0.459) and 0.93 (0.75, 1.15; P = 0.563), respectively. In addition, following either placebo or UDCA administration, the SLCO1B1 polymorphism showed no association with the AUC(0-24) of the glycine and taurine conjugates of UDCA, with endogenous bile acids, or with the incremental AUC(0-24) of a bile acid synthesis marker. Compared with placebo, UDCA ingestion increased the AUC(0-24) of cholic acid, glycochenodeoxycholic acid, glycocholic acid, and glycodeoxycholic acid by 1.5-, 1.1-, 1.2-, and 1.2- fold (P acids.

  13. Contribution of CYP1B1 mutations and founder effect to primary congenital glaucoma in Mexico.

    Science.gov (United States)

    Zenteno, Juan Carlos; Hernandez-Merino, Elena; Mejia-Lopez, Herlinda; Matías-Florentino, Margarita; Michel, Norma; Elizondo-Olascoaga, Celia; Korder-Ortega, Vincent; Casab-Rueda, Homero; Garcia-Ortiz, Jose Elias

    2008-01-01

    The frequency of primary congenital glaucoma (PCG)-causing CYP1B1 mutations varies importantly among distinct populations, ranging from 20% in Indonesians and Japanese to about 100% among the Saudi Arabians and Slovakian Gypsies. Thus, the molecular characterization of large groups of PCG from different ethnic backgrounds is important to establish the actual CYP1B1 contribution in specific populations. In this work, the molecular analysis of the CYP1B1 gene in a group of Mexican PCG patients is reported. Thirty unrelated Mexican patients fulfilling the clinical criteria for PCG were included. Two cases were familial and with proven consanguinity, originating from distinct regions of the country. Polymerase chain reaction amplification and direct automated sequencing of the CYP1B1 coding region was performed in each participating subject. An identical pathogenic CYP1B1 mutation was demonstrated in 2 unrelated PCG subjects. The mutation consisted of a homozygous G to A transition at nucleotide position 1505 in exon 3, which predicted a substitution of glutamic acid for lysine at residue 387 of the protein (E387K). In the remaining 28 PCG subjects, no deleterious mutations were identified. Both subjects with the E387K mutation shared a same haplotype for 5 CYP1B1 intragenic single nucleotide polymorphisms, indicating a common origin of the allele. Mexican patients with PCG are rarely (less than 10%) due to CYP1B1 mutations. Available data indicate that most of the non-Brazilian Latin American PCG patients investigated to date are not due to CYP1B1 defects. Populations with low incidence of CYP1B1 mutations are appropriate candidates for the identification of novel PCG-causing genes.

  14. Diversity in peptide recognition by the SH2 domain of SH2B1.

    Science.gov (United States)

    McKercher, Marissa A; Guan, Xiaoyang; Tan, Zhongping; Wuttke, Deborah S

    2018-02-01

    SH2B1 is a multidomain protein that serves as a key adaptor to regulate numerous cellular events, such as insulin, leptin, and growth hormone signaling pathways. Many of these protein-protein interactions are mediated by the SH2 domain of SH2B1, which recognizes ligands containing a phosphorylated tyrosine (pY), including peptides derived from janus kinase 2, insulin receptor, and insulin receptor substrate-1 and -2. Specificity for the SH2 domain of SH2B1 is conferred in these ligands either by a hydrophobic or an acidic side chain at the +3 position C-terminal to the pY. This specificity for chemically disparate species suggests that SH2B1 relies on distinct thermodynamic or structural mechanisms to bind to peptides. Using binding and structural strategies, we have identified unique thermodynamic signatures for each peptide binding mode, and several SH2B1 residues, including K575 and R578, that play distinct roles in peptide binding. The high-resolution structure of the SH2 domain of SH2B1 further reveals conformationally plastic protein loops that may contribute to the ability of the protein to recognize dissimilar ligands. Together, numerous hydrophobic and electrostatic interactions, in addition to backbone conformational flexibility, permit the recognition of diverse peptides by SH2B1. An understanding of this expanded peptide recognition will allow for the identification of novel physiologically relevant SH2B1/peptide interactions, which can contribute to the design of obesity and diabetes pharmaceuticals to target the ligand-binding interface of SH2B1 with high specificity. © 2017 Wiley Periodicals, Inc.

  15. Aflatoxin B1 adsorption by the natural aluminosilicates - concentrate of montmorillonite and zeolite

    Directory of Open Access Journals (Sweden)

    Marković Marija A.

    2016-01-01

    Full Text Available Aflatoxin B1 adsorption by the concentrate of bentonite clay - montmorillonite and the natural zeolite - clinoptilolite and was investigated at the initial toxin concentration 4 ppm, with different amonunts of solid phase in suspension (10, 5, 2 and 1 mg/10 mL and different pH values - 3, 7 and 9. Results indicated that for both minerals, decreasing the amount of solid phase in suspension, decrease the amount of active sites relevant for adsorption of aflatoxin B1. Thus, for concentrate of montnorillonite, at the lowest level of solid phase in suspension (1 mg/10 mL, aflatoxin B1 adsorption indexes were 97% at pH 3, 88% at pH 7 and 82% at pH 9, while for the natural zeolite, adsorption of toxin was 9% at pH 3 and 7% at pH 7 and 9. Since inorganic cations in minerals are mainly responsible for aflatoxin B1 adsorption, even the natural zeolite - clinoptilite has much higher cation exchange capacity (the content of inorganic exchangeable cations compared to the concentrate of montmorillonite, adsorption of aflatoxin B1 by this mineral is much lower. Comparing the molecular dimensions of aflatoxin B1 molecule with the dimension of channels of clinoptilolite and interlamellar space of montmorillonite it is obvious that this toxin is adsorbed only at the external surface of clinoptilolite while in the montmorillonite all active sites are equally available for its adsorption. Thus, the concentrate of montmorillonite posess by higher adsorption capacity for aflatoxin B1. Results presented in this paper confirmed the fact the differences in the structure of minerals led to their different efficiency for adsorption of aflatoxin B1. Mineralogical and chemical composition, determination of cation exchange capacity, etc., are very important parameters influencing the effectiveness of minerals as aflatoxin B1 adsorbents. [Projekat Ministarstva nauke Republike Srbije, br. 451-03-2802-IP Tip1/142, br. 172018 i br. 34013

  16. C. elegans HIM-8 functions outside of meiosis to antagonize EGL-13 Sox protein function.

    Science.gov (United States)

    Nelms, Brian L; Hanna-Rose, Wendy

    2006-05-15

    egl-13 encodes a Sox domain protein that is required for proper uterine seam cell development in Caenorhabditis elegans. We demonstrate that mutations of the C2H2 zinc fingers encoded by the him-8 (high incidence of males) gene partially suppress the egg-laying and connection-of-gonad morphology defects caused by incompletely penetrant alleles of egl-13. him-8 alleles have previously characterized recessive effects on recombination and segregation of the X chromosome during meiosis due to failure of X chromosome homolog pairing and subsequent synapsis. However, we show that him-8 alleles are semi-dominant suppressors of egl-13, and the semi-dominant effect is due to haplo-insufficiency of the him-8 locus. Thus, we conclude that the wild-type him-8 gene product acts antagonistically to EGL-13. Null alleles of egl-13 cannot be suppressed, suggesting that this antagonistic interaction most likely occurs either upstream of or in parallel with EGL-13. Moreover, we conclude that suppression of egl-13 is due to a meiosis-independent function of him-8 because suppression is observed in mutants that have severely reduced meiotic germ cell populations and suppression does not depend on the function of him-8 in the maternal germ line. We also show that the chromosomal context of egl-13 seems important in the him-8 suppression mechanism. Interactions between these genes can give insight into function of Sox family members, which are important in many aspects of metazoan development, and into functions of him-8 outside of meiosis.

  17. Copy number variation of two separate regulatory regions upstream of SOX9 causes isolated 46,XY or 46,XX disorder of sex development.

    Science.gov (United States)

    Kim, Gwang-Jin; Sock, Elisabeth; Buchberger, Astrid; Just, Walter; Denzer, Friederike; Hoepffner, Wolfgang; German, James; Cole, Trevor; Mann, Jillian; Seguin, John H; Zipf, William; Costigan, Colm; Schmiady, Hardi; Rostásy, Moritz; Kramer, Mildred; Kaltenbach, Simon; Rösler, Bernd; Georg, Ina; Troppmann, Elke; Teichmann, Anne-Christin; Salfelder, Anika; Widholz, Sebastian A; Wieacker, Peter; Hiort, Olaf; Camerino, Giovanna; Radi, Orietta; Wegner, Michael; Arnold, Hans-Henning; Scherer, Gerd

    2015-04-01

    SOX9 mutations cause the skeletal malformation syndrome campomelic dysplasia in combination with XY sex reversal. Studies in mice indicate that SOX9 acts as a testis-inducing transcription factor downstream of SRY, triggering Sertoli cell and testis differentiation. An SRY-dependent testis-specific enhancer for Sox9 has been identified only in mice. A previous study has implicated copy number variations (CNVs) of a 78 kb region 517-595 kb upstream of SOX9 in the aetiology of both 46,XY and 46,XX disorders of sex development (DSD). We wanted to better define this region for both disorders. By CNV analysis, we identified SOX9 upstream duplications in three cases of SRY-negative 46,XX DSD, which together with previously reported duplications define a 68 kb region, 516-584 kb upstream of SOX9, designated XXSR (XX sex reversal region). More importantly, we identified heterozygous deletions in four families with SRY-positive 46,XY DSD without skeletal phenotype, which define a 32.5 kb interval 607.1-639.6 kb upstream of SOX9, designated XY sex reversal region (XYSR). To localise the suspected testis-specific enhancer, XYSR subfragments were tested in cell transfection and transgenic experiments. While transgenic experiments remained inconclusive, a 1.9 kb SRY-responsive subfragment drove expression specifically in Sertoli-like cells. Our results indicate that isolated 46,XY and 46,XX DSD can be assigned to two separate regulatory regions, XYSR and XXSR, far upstream of SOX9. The 1.9 kb SRY-responsive subfragment from the XYSR might constitute the core of the Sertoli-cell enhancer of human SOX9, representing the so far missing link in the genetic cascade of male sex determination. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  18. DISTRIBUTION Of AFLATOXIN B1 FROM POULTRY FEED TO DIFFERENT BODY TISSUES OF BROILERS

    Directory of Open Access Journals (Sweden)

    Farida Begum, A. Rehman1, G. Maliha and J. Nuzhat

    2001-07-01

    Full Text Available This study was carried out to know the distribution of aflatoxin B1 In various edible tissues of broilers from poultry feed at the stage of marketing. For this purpose liver, kidney, dressed meat and poultry feed of the representative flocks were collected and oven dried. The aflatoxin B1 contents of the samples were .e; determined through thin layer chromatography, The data thus collected were statistically analyzed and the results showed that the aflatoxin B1 level was higher (P<0.01 in liver as compared to kidneys and meat.

  19. CYP1B1 Mutations in Individuals With Primary Congenital Glaucoma and Residing in Denmark

    DEFF Research Database (Denmark)

    Grønskov, Karen; Redó-Riveiro, Alba; Sandfeld, Lisbeth

    2016-01-01

    Primary congenital glaucoma (PCG OMIM 231300) can be caused by pathogenic sequence variations in cytochrome P450, subfamily 1, polypeptide 1 (CYP1B1). The purpose of this study was to investigate the contribution of sequence variations in CYP1B1 in a cohort of individuals with PCG residing...... mutations, 5 of which were novel. The frequency of CYP1B1 mutations in this cohort was comparable with other populations. We also detected an individual heterozygous for p.(Tyr81Asn) mutation, previously suggested to cause autosomal dominant primary open-angle glaucoma....

  20. EphB1 as a Novel Drug Target to Combat Pain and Addiction

    Science.gov (United States)

    2016-09-01

    Award Number: W81XWH-14-1-0220 Project Title: EphB1 as a Novel Drug Target to Combat Pain and Addiction Principal Investigator Name: Mark...Pain and Addiction 5a. CONTRACT NUMBER EphB1 as a Novel Drug Target to Combat Pain and Addiction 5b. GRANT NUMBER W81XWH-14-1-0220 5c. PROGRAM...SUBJECT TERMS Chronic neuropathic pain, opioid addiction , synaptic plasticity, EphB1 receptor, ephrin-B2, NMDA receptor, drug discovery 16. SECURITY

  1. Inhibition of SOX2 induces cell apoptosis and G1/S arrest in Ewing's sarcoma through the PI3K/Akt pathway.

    Science.gov (United States)

    Ren, Chongmin; Ren, Tingting; Yang, Kang; Wang, Shidong; Bao, Xing; Zhang, Fan; Guo, Wei

    2016-03-11

    Ewing's sarcoma is an aggressive bone and soft tissue tumor with a high incidence in children and adolescents. Due to its high malignancy and poor prognosis, identification of novel biomarkers for intervention therapies is necessary to improve outcome. The EWS/FLI1 fusion gene is a characteristic of Ewing's sarcoma in most cases. Sex determining region Y-box 2 (SOX2) is a primary target of EWS/FLI1. It has been identified as an oncogene and linked to apoptotic resistance in several types of cancer. However, its role and regulatory mechanisms in Ewing's sarcoma are largely unknown. We systematically investigated the role of SOX2 in Ewing's sarcoma cell lines, human tissue samples and xenograft models. The expression of SOX2 was detected in Ewing's sarcoma samples by WB and IHC. siRNAs were used to knockdown EWS/FLI1 and SOX2 in A673 and RD-ES cell lines with the efficiencies tested by qRT-PCR and WB. The effect of SOX2 on cell cycle and apoptosis was determined by Flow cytometric and TUNEL assays. Akt overexpression was performed with plasmid. The protein expression of the corresponding factors was examined by WB analysis. Inhibition of SOX2 in vivo was performed by siRNA against SOX2 in xenograft models, and the protein expression of the regulators testified in vitro was examined in xenograft tumors by IHC and WB. The results confirmed that SOX2 was highly expressed in Ewing's sarcoma and was the target of EWS/FLI1. SOX2 advanced Ewing's sarcoma cell survival and proliferation by regulating p21, p27 and cyclin-E to facilitate G1/S phase transition and mediating caspase-3, PARP via both extrinsic (Fas and caspase-8) and intrinsic (caspase-9, Bad, Bcl-2 and XIAP) apoptotic pathways to restrain cell apoptosis. Additionally, SOX2 regulated the cell-cycle progression and apoptosis via activation of the PI3K/Akt signaling pathway. The mechanisms were proved both in vitro and in vivo. The results demonstrate that SOX2 played a central role in promoting Ewing's sarcoma

  2. Use of radiolabeled monoclonal anti-B1 antibody for B lymphocyte imaging in Rhesus monkeys

    International Nuclear Information System (INIS)

    Letvin, N.L.; Zalutsky, M.R.; Chalifoux, L.V.; Atkins, H.L.

    1987-01-01

    Imaging tissues rich in B lymphocytes in man using a radiolabeled monoclonal anti-B cell antibody would be extremely useful in the clinical staging of non-Hodgkins lymphomas. Studies were done in rhesus monkeys using radiolabeled monoclonal anti-B1 antibody to determine the feasibility of such an approach. Immunohistologic studies demonstrated that infused monoclonal anti-B1 binds in vivo with specificity to B cells in lymph nodes and spleen. The kinetics of clearance of 131 I-labeled anti-B1 were determined. The B lymphocyte-rich spleen could be readily visualized by gamma camera scanning without significant background and without the need for image intensification or blood background subtraction techniques. These data support the feasibility of using anti-B1 for staging B cell lymphomas in man. (author)

  3. Alternative Thieno[3,2-b][1]benzothiophene Isoindigo Polymers for Solar Cell Applications

    KAUST Repository

    Neophytou, Marios; Bryant, Daniel; Lopatin, Sergei; Chen, Hu; Hallani, Rawad K.; Cater, Lewis; McCulloch, Iain; Yue, Wan

    2018-01-01

    This work reports the synthesis, characterization, photophysical, and photovoltaic properties of five new thieno[3,2-b][1]benzothiophene isoindigo (TBTI)-containing low bandgap donor-acceptor conjugated polymers with a series of comonomers

  4. Potential of lactic acid fermentation in reducing aflatoxin B1 in ...

    African Journals Online (AJOL)

    African Journal of Food, Agriculture, Nutrition and Development ... Although maize is known to be highly susceptible to aflatoxin contamination, and a ... on reduction of aflatoxin B1 in Tanzania maize-based gruel (togwa) by four monocultures ...

  5. Polymorphisms in sh2b1 and spns1 loci are associated with ...

    Indian Academy of Sciences (India)

    SH2B1, which encodes a signal transduction adaptor protein ... Here, we studied the associa- tion of eight single ... Health Study (NSPHS) cohort, consisting of 719 individuals ... mate can lower triglyceride levels, and elevate high-density.

  6. Data of evolutionary structure change: 1EP8B-1FAAA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1EP8B-1FAAA 1EP8 1FAA B A -------------GGSVIVIDSKAAWDAQLAKGKEEHKP...IVVAFTATWCGPCKMIAPLFETLSNDYAGKVIFLKVDVD-AVAAVAEAAGITAMPTFHVYKDGVKADDLVGASQDKLKALVAKHAAA LELALGT.../pdbChain> 1FAAA KLDCNQENKTL EEE HHH 1 1FAA A 1FAAA

  7. Data of evolutionary structure change: 1AY4B-1YAAA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1AY4B-1YAAA 1AY4 1YAA B A ---MLGNLKPQ-----LALMGEFRADPRQGKIDLGVGVY...LPVQTYRYFDAETRGVDFEGMKADLAAAKKGDMVLLHGCCHNPTGANLTLDQWAEIASILEKTGALPLIDLAYQGFGD-GLEEDAAGTRLIASRIP---EVLIAASCS...ntryChain> 1YAA A 1YAAA...ID> A 1YAAA QGFATGDLDKD

  8. Data of evolutionary structure change: 1EP7B-1FAAA [Confc[Archive

    Lifescience Database Archive (English)

    Full Text Available 1EP7B-1FAAA 1EP7 1FAA B A -------------GGSVIVIDSKAAWDAQLAKGKEEHKP...IVVDFTATWCGPCKMIAPLFETLSNDYAGKVIFLKVD-VDAVAAVAEAAGITAMPTFHVYKDGVKADDLVGASQDKLKALVAKHAAA LELALGT...AA A 1FAAA FLKLDCNQENK A 1FAAA VTEVN-KDTFW

  9. CYP1B1 and myocilin gene mutations in Egyptian patients with ...

    African Journals Online (AJOL)

    Mahmoud R. Fassad

    2016-08-09

    Aug 9, 2016 ... Abstract Purpose: Primary congenital glaucoma (PCG) accounts for 26–29% of childhood ... Conclusion: The current study further endorses the role of CYP1B1 mutations in the etiology of ..... There is no conflict of interest.

  10. The role of scavenger receptor B1 in infection with Mycobacterium tuberculosis in a murine model.

    Directory of Open Access Journals (Sweden)

    Georgia Schäfer

    2009-12-01

    Full Text Available The interaction between Mycobacterium tuberculosis (Mtb and host cells is complex and far from being understood. The role of the different receptor(s implicated in the recognition of Mtb in particular remains poorly defined, and those that have been found to have activity in vitro were subsequently shown to be redundant in vivo.To identify novel receptors involved in the recognition of Mtb, we screened a macrophage cDNA library and identified scavenger receptor B class 1 (SR-B1 as a receptor for mycobacteria. SR-B1 has been well-described as a lipoprotein receptor which mediates both the selective uptake of cholesteryl esters and the efflux of cholesterol, and has also recently been implicated in the recognition of other pathogens. We show here that mycobacteria can bind directly to SR-B1 on transfected cells, and that this interaction could be inhibited in the presence of a specific antibody to SR-B1, serum or LDL. We define a variety of macrophage populations, including alveolar macrophages, that express this receptor, however, no differences in the recognition and response to mycobacteria were observed in macrophages isolated from SR-B1(-/- or wild type mice in vitro. Moreover, when wild type and SR-B1(-/- animals were infected with a low dose of Mtb (100 CFU/mouse there were no alterations in survival, bacterial burdens, granuloma formation or cytokine production in the lung. However, significant reduction in the production of TNF, IFNgamma, and IL10 were observed in SR-B1(-/- mice following infection with a high dose of Mtb (1000 CFU/mouse, which marginally affected the size of inflammatory foci but did not influence bacterial burdens. Deficiency of SR-B1 also had no effect on resistance to disease under conditions of varying dietary cholesterol. We did observe, however, that the presence of high levels of cholesterol in the diet significantly enhanced the bacterial burdens in the lung, but this was independent of SR-B1.SR-B1 is involved in

  11. Stability of aflatoxin B1 in animal feed candidate reference materials

    NARCIS (Netherlands)

    Roos, A.H.; Mazijk, van R.J.; Tuinstra, L.G.M.T.; Huf, F.A.

    1991-01-01

    Two candidate reference materials animal feed were stored at a temperature of -18°C, 4 C, 20°C and 37°C. The stability of aflatoxin B1 was studied duringa period of two years. A significant decrease in the aflatoxin B1 content was measured in the samples stared at 20°C and 37°C. In the samples

  12. The Potent of Aspergillus parasiticus to Produce Aflatoxin B1 on the Maize Flour During Storage

    Directory of Open Access Journals (Sweden)

    Agus Selamat Duniaji

    2016-03-01

    Full Text Available Aflatoxin B1 contamination caused by Aspergillus parasiticus and Aspergiluus Aspergillus flavus is a great concern in maize production worldwide. A. parasiticus infection and aflatoxin B1 contamination are usually found in maize and their processed during storage, distribution and processing. Aflatoxin B1 contamination in food and feed can cause the cancer diseases in animal and human. This research was aimed to determinate the potency of A. parasiticus to produce aflatoxin B1 in maize during storage 0, 5, 10 and 15 days. The research methods was using Completed Random Design (CRD with three replicated. The research was investigation of a number of colony A. parasiticus in Petato Dextro Agar (PDA and Aflatoxin B1 content by using Enzym Linked Immunosorbant Assay (ELISA. Result of research showed that A.parasiticus were susceptible to grow in maize flour and produce aflatoxin B1 during storage. The population of A. parasiticus in maize flour were  9.5 x 105 d in primary storage (0 days that was the total colony were increasing  .7 x 106 (storage 5 days, 2.5 x 107 (storage 10 days and 1.5 x 108 cfu/g with storage 15 days A. parasiticus was a potent to produce aflatoxin B1 in myzena flour with total of aflatoxin B1 is  66.50 ppb of mayzena flour during storage 5 days , 46.40 ppb with 10 days storage, 57.00 ppb during storage 15 days and was not found in 0 days.

  13. 26 CFR 1.1402(b)-1 - Self-employment income.

    Science.gov (United States)

    2010-04-01

    ... 26 Internal Revenue 12 2010-04-01 2010-04-01 false Self-employment income. 1.1402(b)-1 Section 1... (CONTINUED) INCOME TAXES Tax on Self-Employment Income § 1.1402(b)-1 Self-employment income. (a) In general... this section, the term “self-employment income” means the net earnings from self-employment derived by...

  14. Transcriptional regulation of male-sterility in 7B-1 male-sterile tomato mutant.

    Directory of Open Access Journals (Sweden)

    Vahid Omidvar

    Full Text Available The 7B-1 tomato (Solanum lycopersicum L. cv Rutgers is a male-sterile mutant with enhanced tolerance to abiotic stress, which makes it a potential candidate for hybrid seed breeding and stress engineering. To underline the molecular mechanism regulating the male-sterility in 7B-1, transcriptomic profiles of the 7B-1 male-sterile and wild type (WT anthers were studied using mRNA sequencing (RNA-Seq. In total, 768 differentially expressed genes (DEGs were identified, including 132 up-regulated and 636 down-regulated transcripts. Gene ontology (GO enrichment analysis of DEGs suggested a general impact of the 7B-1 mutation on metabolic processes, such as proteolysis and carbohydrate catabolic process. Sixteen candidates with key roles in regulation of anther development were subjected to further analysis using qRT-PCR and in situ hybridization. Cytological studies showed several defects associated with anther development in the 7B-1 mutant, including unsynchronized anther maturation, dysfunctional meiosis, arrested microspores, defect in callose degradation and abnormal tapetum development. TUNEL assay showed a defect in programmed cell death (PCD of tapetal cells in 7B-1 anthers. The present study provides insights into the transcriptome of the 7B-1 mutant. We identified several genes with altered expression level in 7B-1 (including beta-1,3 glucanase, GA2oxs, cystatin, cysteine protease, pectinesterase, TA29, and actin that could potentially regulate anther developmental processes, such as meiosis, tapetum development, and cell-wall formation/degradation.

  15. Cloning and tissue expression of cytochrome P450 1B1 and 1C1 ...

    African Journals Online (AJOL)

    Cytochrome P450 1 (CYP1) is widely used as an indicator of exposure to environmental contaminants. In the study, two full-length complementary DNAs encode for CYP1B1 and CYP1C1 were cloned from medaka liver exposed to 500 ppb β-naphthoflavone for 24 h. CYP1B1, having 1984 bp, contains an open reading ...

  16. Code-B-1 for stress/strain calculation for TRISO fuel particle (Contract research)

    International Nuclear Information System (INIS)

    Aihara, Jun; Ueta, Shohei; Shibata, Taiju; Sawa, Kazuhiro

    2011-12-01

    We have developed Code-B-1 for the prediction of the failure probabilities of the coated fuel particles for the high temperature gas-cooled reactors (HTGRs) under operation by modification of an existing code. A finite element method (FEM) is employed for the stress calculation part and Code-B-1 can treat the plastic deformation of the coating layer of the coated fuel particles which the existing code cannot treat. (author)

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

    Science.gov (United States)

    2016-10-01

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

  18. Role of CYP1B1 in PAH-DNA adduct formation and breast cancer risk

    Energy Technology Data Exchange (ETDEWEB)

    Goth-Goldstein, Regine; Russell, Marion L.; Muller, A.P.; Caleffi, M.; Eschiletti, J.; Graudenz, M.; Sohn, Michael D.

    2010-04-01

    This study investigated the hypothesis that increased exposure to polycyclic aromatic hydrocarbons (PAHs) increases breast cancer risk. PAHs are products of incomplete burning of organic matter and are present in cigarette smoke, ambient air, drinking water, and diet. PAHs require metabolic transformation to bind to DNA, causing DNA adducts, which can lead to mutations and are thought to be an important pre-cancer marker. In breast tissue, PAHs appear to be metabolized to their cancer-causing form primarily by the cytochrome P450 enzyme CYP1B1. Because the genotoxic impact of PAH depends on their metabolism, we hypothesized that high CYP1B1 enzyme levels result in increased formation of PAH-DNA adducts in breast tissue, leading to increased development of breast cancer. We have investigated molecular mechanisms of the relationship between PAH exposure, CYP1B1 expression and breast cancer risk in a clinic-based case-control study. We collected histologically normal breast tissue from 56 women (43 cases and 13 controls) undergoing breast surgery and analyzed these specimens for CYP1B1 genotype, PAH-DNA adducts and CYP1B1 gene expression. We did not detect any difference in aromatic DNA adduct levels of cases and controls, only between smokers and non-smokers. CYP1B1 transcript levels were slightly lower in controls than cases, but the difference was not statistically significant. We found no correlation between the levels of CYP1B1 expression and DNA adducts. If CYP1B1 has any role in breast cancer etiology it might be through its metabolism of estrogen rather than its metabolism of PAHs. However, due to the lack of statistical power these results should be interpreted with caution.

  19. LytB1 and LytB2 of Mycobacterium tuberculosis Are Not Genetically Redundant.

    Directory of Open Access Journals (Sweden)

    Amanda Claire Brown

    Full Text Available Mycobacterium tuberculosis synthesises isoprenoid precursors via the MEP/DOXP pathway and at least five enzymes in the pathway (Dxs1, Dxr/IspC, IspD, IspF, and GcpE/IspG are required for growth in vitro. We investigated the role of LytB (IspH in M. tuberculosis; M. tuberculosis is unusual in that it has two homologs-LytB1 and LytB2. We were unable to delete the lytB2 gene unless we provided an additional copy elsewhere, demonstrating that this is the essential homolog. We expressed lytB1 from the lytB2 promoter and confirmed that this could not complement for loss of function of lytB2, despite LytB1 possessing all the previously described conserved critical residues. Interestingly the sole LytB homolog of Mycobacterium smegmatis was able to compensate for loss of LytB2 in M. tuberculosis. We tested translational fusions of LytB1 and LytB2 for functionality in M. tuberculosis, but only a fusion with 90% N-terminal LytB2 and 10% C-terminal LytB1 was functional. In order to identify the key difference between the two proteins, site directed mutagenesis was used to change LytB2 residues into their counterparts in LytB1. None of these amino acid substitutions was essential for function and all lytB2 mutant alleles were functional. In contrast, mutation of the key residues for [Fe4S4] cluster formation, as well as a catalytic residue in LytB1 did not result in functional complementation. Thus, although LytB1 and LytB2 are not genetically redundant, this is not dependent on small amino acid changes, but is likely to be a result of major overall structural differences.

  20. (B1-/sup 125/I-desaminotyrosine)-insulin - A novel homogeneous insulin tracer

    Energy Technology Data Exchange (ETDEWEB)

    Bahrami, S; Zahn, H; Brandenburg, D [Deutsches Wollforschungsinstitut, Aachen (Germany F.R.); Machulla, H -J; Dutschka, K [Institut fuer Medizinische Strahlenphysik und Strahlenbiologie des Universitaetsklinikum, Essen (Germany F.R.)

    1980-10-28

    (B1-/sup 125/I-desaminotyrosine)-insulin (/sup 125/I-MII) was prepared with high specific activities (420 Ci/mmole) by exchanging B1-phenylalanine for /sup 125/I-p-hydroxyphenyl-propionic acid N-hydroxysuccinimide ester (Bolton-Hunter reagent). Overall radiochemical yields were about 8%. Analytical quality control and purification were performed by means of radio high pressure liquid chromatography. The radiochemical purity of /sup 125/I-MII was >99%, and the immunoprecipitability was 97%.