351 research outputs found
338 Improved life expectancy in cystic fibrosis patients: real progress or reduced measurement bias?
Présentation graphique des caractÚres technologiques des principaux bois tropicaux. Tome 7 : Bois de Martinique
Caractéristiques physiques et mécaniques des bois sous forme de tableaux comparatifs pour la Martiniqu
Variations in dysfunction of sister chromatid cohesion in esco2 mutant zebrafish reflect the phenotypic diversity of Roberts syndrome
Mutations in ESCO2, one of two establishment of cohesion factors necessary for proper sister chromatid cohesion (SCC), cause a spectrum of developmental defects in the autosomal-recessive disorder Roberts syndrome (RBS), warranting in vivo analysis of the consequence of cohesion dysfunction. Through a genetic screen in zebrafish targeting embryonic-lethal mutants that have increased genomic instability, we have identified an esco2 mutant zebrafish. Utilizing the natural transparency of zebrafish embryos, we have developed a novel technique to observe chromosome dynamics within a single cell during mitosis in a live vertebrate embryo. Within esco2 mutant embryos, we observed premature chromatid separation, a unique chromosome scattering, prolonged mitotic delay, and genomic instability in the form of anaphase bridges and micronuclei formation. Cytogenetic studies indicated complete chromatid separation and high levels of aneuploidy within mutant embryos. Amongst aneuploid spreads, we predominantly observed decreases in chromosome number, suggesting that either cells with micronuclei or micronuclei themselves are eliminated. We also demonstrated that the genomic instability leads to p53-dependent neural tube apoptosis. Surprisingly, although many cells required Esco2 to establish cohesion, 10-20% of cells had only weakened cohesion in the absence of Esco2, suggesting that compensatory cohesion mechanisms exist in these cells that undergo a normal mitotic division. These studies provide a unique in vivo vertebrate view of the mitotic defects and consequences of cohesion establishment loss, and they provide a compensation-based model to explain the RBS phenotypes
Présentation graphique des caractÚres technologiques des principaux bois tropicaux. Tome 8 : Bois du Burundi
Caractéristiques physiques et mécaniques des bois sous forme de tableaux comparatifs pour le Burund
Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity
MDM2âMDMX complexes bind the p53 tumor-suppressor protein, inhibiting p53's transcriptional activity and targeting p53 for proteasomal degradation. Inhibitors that disrupt binding between p53 and MDM2 efficiently activate a p53 response, but their use in the treatment of cancers that retain wild-type p53 may be limited by on-target toxicities due to p53 activation in normal tissue. Guided by a novel crystal structure of the MDM2âMDMXâE2(UbcH5B)âubiquitin complex, we designed MDM2 mutants that prevent E2âubiquitin binding without altering the RING-domain structure. These mutants lack MDM2's E3 activity but retain the ability to limit p53âČs transcriptional activity and allow cell proliferation. Cells expressing these mutants respond more quickly to cellular stress than cells expressing wild-type MDM2, but basal p53 control is maintained. Targeting the MDM2 E3-ligase activity could therefore widen the therapeutic window of p53 activation in tumors
Signs of positive selection of somatic mutations in human cancers detected by EST sequence analysis
BACKGROUND: Carcinogenesis typically involves multiple somatic mutations in caretaker (DNA repair) and gatekeeper (tumor suppressors and oncogenes) genes. Analysis of mutation spectra of the tumor suppressor that is most commonly mutated in human cancers, p53, unexpectedly suggested that somatic evolution of the p53 gene during tumorigenesis is dominated by positive selection for gain of function. This conclusion is supported by accumulating experimental evidence of evolution of new functions of p53 in tumors. These findings prompted a genome-wide analysis of possible positive selection during tumor evolution. METHODS: A comprehensive analysis of probable somatic mutations in the sequences of Expressed Sequence Tags (ESTs) from malignant tumors and normal tissues was performed in order to access the prevalence of positive selection in cancer evolution. For each EST, the numbers of synonymous and non-synonymous substitutions were calculated. In order to identify genes with a signature of positive selection in cancers, these numbers were compared to: i) expected numbers and ii) the numbers for the respective genes in the ESTs from normal tissues. RESULTS: We identified 112 genes with a signature of positive selection in cancers, i.e., a significantly elevated ratio of non-synonymous to synonymous substitutions, in tumors as compared to 37 such genes in an approximately equal-sized EST collection from normal tissues. A substantial fraction of the tumor-specific positive-selection candidates have experimentally demonstrated or strongly predicted links to cancer. CONCLUSION: The results of EST analysis should be interpreted with extreme caution given the noise introduced by sequencing errors and undetected polymorphisms. Furthermore, an inherent limitation of EST analysis is that multiple mutations amenable to statistical analysis can be detected only in relatively highly expressed genes. Nevertheless, the present results suggest that positive selection might affect a substantial number of genes during tumorigenic somatic evolution
«La relation de limitation et dâexception dans le français dâaujourdâhui : exceptĂ©, sauf et hormis comme pivots dâune relation algĂ©brique »
Lâanalyse des emplois prĂ©positionnels et des emplois conjonctifs dâ âexceptĂ©â, de âsaufâ et dâ âhormisâ permet dâenvisager les trois prĂ©positions/conjonctions comme le pivot dâun binĂŽme, comme la plaque tournante dâune structure bipolaire. PlacĂ©es au milieu du binĂŽme, ces prĂ©positions sont forcĂ©es par leur sĂ©mantisme originaire dĂ»ment mĂ©taphorisĂ© de jouer le rĂŽle de marqueurs dâinconsĂ©quence systĂ©matique entre lâĂ©lĂ©ment se trouvant Ă leur gauche et celui qui se trouve Ă leur droite. Lâopposition qui surgit entre les deux Ă©lĂ©ments nâest donc pas une incompatibilitĂ© naturelle, intrinsĂšque, mais extrinsĂšque, induite. Dans la plupart des cas (emplois limitatifs), cette opposition prend la forme dâun rapport entre une « classe » et le « membre (soustrait) de la classe », ou bien entre un « tout » et une « partie » ; dans dâautres (emplois exceptifs), cette opposition se manifeste au contraire comme une attaque de front portĂ©e par un « tout » Ă un autre « tout ». De plus, lâinconsĂ©quence induite mise en place par la prĂ©position/conjonction paraĂźt, en principe, tout Ă fait insurmontable. Dans lâassertion « les Ă©cureuils vivent partout, sauf en Australie » (que lâon peut expliciter par « Les Ă©cureuils vivent partout, sauf [quâils ne vivent pas] en Australie »), la prĂ©position semble en effet capable dâimpliquer le prĂ©dicat principal avec signe inverti, et de bĂątir sur une telle implication une sorte de sous Ă©noncĂ© qui, Ă la rigueur, est totalement inconsĂ©quent avec celui qui le prĂ©cĂšde (si « les Ă©cureuils ne vivent pas en Australie », le fait quâils « vivent partout » est faux). NĂ©anmoins, lâanalyse montre quâalors que certaines de ces oppositions peuvent enfin ĂȘtre dĂ©passĂ©es, dâautres ne le peuvent pas. Câest, respectivement, le cas des relations limitatives et des relations exceptives. La relation limitative, impliquant le rapport « tout » - « partie », permet de rĂ©soudre le conflit dans les termes dâune somme algĂ©brique entre deux sous Ă©noncĂ©s pourvus de diffĂ©rent poids informatif et de signe contraire. Les valeurs numĂ©riques des termes de la somme Ă©tant dĂ©sĂ©quilibrĂ©es, le rĂ©sultat est toujours autre que zĂ©ro. La relation exceptive, au contraire, qui nâimplique pas le rapport « tout » - « partie », nâest pas capable de rĂ©soudre le conflit entre deux sous Ă©noncĂ©s pourvus du mĂȘme poids informatif et en mĂȘme temps de signe contraire : les valeurs numĂ©riques des termes de la somme Ă©tant symĂ©triques et Ă©gales, le rĂ©sultat sera toujours Ă©quivalent Ă zĂ©ro
14-3-3ζ Interacts with Stat3 and Regulates Its Constitutive Activation in Multiple Myeloma Cells
The 14-3-3 proteins are a family of regulatory signaling molecules that interact with other proteins in a phosphorylation-dependent manner and function as adapter or scaffold proteins in signal transduction pathways. One family member, 14-3-3ζ, is believed to function in cell signaling, cycle control, and apoptotic death. A systematic proteomic analysis done in our laboratory has identified signal transducers and activators of transcription 3 (Stat3) as a novel 14-3-3ζ interacting protein. Following our initial finding, in this study, we provide evidence that 14-3-3ζ interacts physically with Stat3. We further demonstrate that phosphorylation of Stat3 at Ser727 is vital for 14-3-3ζ interaction and mutation of Ser727 to Alanine abolished 14-3-3ζ/Stat3 association. Inhibition of 14-3-3ζ protein expression in U266 cells inhibited Stat3 Ser727 phosphorylation and nuclear translocation, and decreased both Stat3 DNA binding and transcriptional activity. Moreover, 14-3-3ζ is involved in the regulation of protein kinase C (PKC) activity and 14-3-3ζ binding to Stat3 protects Ser727 dephosphorylation from protein phosphatase 2A (PP2A). Taken together, our findings support the model that multiple signaling events impinge on Stat3 and that 14-3-3ζ serves as an essential coordinator for different pathways to regulate Stat3 activation and function in MM cells
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