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排序方式: 共有174条查询结果,搜索用时 62 毫秒
101.
Uddipta Biswas Cornelia Wetzker Julian Lange Eleni G. Christodoulou Michael Seifert Andreas Beyer Rolf Jessberger 《PLoS genetics》2013,9(12)
Cohesin subunit SMC1β is specific and essential for meiosis. Previous studies showed functions of SMC1β in determining the axis-loop structure of synaptonemal complexes (SCs), in providing sister chromatid cohesion (SCC) in metaphase I and thereafter, in protecting telomere structure, and in synapsis. However, several central questions remained unanswered and concern roles of SMC1β in SCC and synapsis and processes related to these two processes. Here we show that SMC1β substantially supports prophase I SCC at centromeres but not along chromosome arms. Arm cohesion and some of centromeric cohesion in prophase I are provided by non-phosphorylated SMC1α. Besides supporting synapsis of autosomes, SMC1β is also required for synapsis and silencing of sex chromosomes. In absence of SMC1β, the silencing factor γH2AX remains associated with asynapsed autosomes and fails to localize to sex chromosomes. Microarray expression studies revealed up-regulated sex chromosome genes and many down-regulated autosomal genes. SMC1β is further required for non-homologous chromosome associations observed in absence of SPO11 and thus of programmed double-strand breaks. These breaks are properly generated in Smc1β−/− spermatocytes, but their repair is delayed on asynapsed chromosomes. SMC1α alone cannot support non-homologous associations. Together with previous knowledge, three main functions of SMC1β have emerged, which have multiple consequences for spermatocyte biology: generation of the loop-axis architecture of SCs, homologous and non-homologous synapsis, and SCC starting in early prophase I. 相似文献
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104.
SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells 总被引:3,自引:0,他引:3
Haigis MC Mostoslavsky R Haigis KM Fahie K Christodoulou DC Murphy AJ Valenzuela DM Yancopoulos GD Karow M Blander G Wolberger C Prolla TA Weindruch R Alt FW Guarente L 《Cell》2006,126(5):941-954
Sir2 is an NAD-dependent deacetylase that connects metabolism with longevity in yeast, flies, and worms. Mammals have seven Sir2 homologs (SIRT1-7). We show that SIRT4 is a mitochondrial enzyme that uses NAD to ADP-ribosylate and downregulate glutamate dehydrogenase (GDH) activity. GDH is known to promote the metabolism of glutamate and glutamine, generating ATP, which promotes insulin secretion. Loss of SIRT4 in insulinoma cells activates GDH, thereby upregulating amino acid-stimulated insulin secretion. A similar effect is observed in pancreatic beta cells from mice deficient in SIRT4 or on the dietary regimen of calorie restriction (CR). Furthermore, GDH from SIRT4-deficient or CR mice is insensitive to phosphodiesterase, an enzyme that cleaves ADP-ribose, suggesting the absence of ADP-ribosylation. These results indicate that SIRT4 functions in beta cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR. 相似文献
105.
Gsponer J Christodoulou J Cavalli A Bui JM Richter B Dobson CM Vendruscolo M 《Structure (London, England : 1993)》2008,16(5):736-746
We used nuclear magnetic resonance data to determine ensembles of conformations representing the structure and dynamics of calmodulin (CaM) in the calcium-bound state (Ca(2+)-CaM) and in the state bound to myosin light chain kinase (CaM-MLCK). These ensembles reveal that the Ca(2+)-CaM state includes a range of structures similar to those present when CaM is bound to MLCK. Detailed analysis of the ensembles demonstrates that correlated motions within the Ca(2+)-CaM state direct the structural fluctuations toward complex-like substates. This phenomenon enables initial ligation of MLCK at the C-terminal domain of CaM and induces a population shift among the substates accessible to the N-terminal domain, thus giving rise to the cooperativity associated with binding. Based on these results and the combination of modern free energy landscape theory with classical allostery models, we suggest that a coupled equilibrium shift mechanism controls the efficient binding of CaM to a wide range of ligands. 相似文献
106.
Reading requires the extraction of letter shapes from a complex background of text, and an impairment in visual shape extraction would cause difficulty in reading. To investigate the neural mechanisms of visual shape extraction in dyslexia, we used functional magnetic resonance imaging (fMRI) to examine brain activation while adults with or without dyslexia responded to the change of an arrow’s direction in a complex, relative to a simple, visual background. In comparison to adults with typical reading ability, adults with dyslexia exhibited opposite patterns of atypical activation: decreased activation in occipital visual areas associated with visual perception, and increased activation in frontal and parietal regions associated with visual attention. These findings indicate that dyslexia involves atypical brain organization for fundamental processes of visual shape extraction even when reading is not involved. Overengagement in higher-order association cortices, required to compensate for underengagment in lower-order visual cortices, may result in competition for top-down attentional resources helpful for fluent reading. 相似文献
107.
Christian Lehmann Yao-Zhong Xu Chris Christodoulou Michael J. Gait Luc Van Meervelt Madeleine Moore 《Nucleosides, nucleotides & nucleic acids》2013,32(7):1599-1614
Abstract X-ray structure analysis of the more laevorotatory isomers of 2′-O-tetrahydropyranyl-4N-benzoylcytidine (4b) and of 2′-O-tetrahydropyranyluridine (5b) confirmed their chirality at the satellite anomeric centre C2″ to be S. The other diastereomers (4a resp. 5a) exhibited an unexpected reversal of 3′/5′-regio-selectivity when treated with 9-fluorenylmethoxycarbonyl chloride in pyridine. The X-ray crystallographic results form the basis for a mechanistic proposal. 相似文献
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109.
Minal J. Menezes Lisa G. Riley John Christodoulou 《Biochimica et Biophysica Acta (BBA)/General Subjects》2014
Background
Mitochondrial respiratory chain disorders (MRCDs) are some of the most common metabolic disorders presenting in childhood, however because of it clinical heterogeneity, diagnosis is often challenging. Being a multisystemic disorder with variable and non-specific presentations, definitive diagnosis requires a combination of investigative approaches, and is often a laborious process.Scope of review
In this review we provide a broad overview of the clinical presentations of MRCDs in childhood, evaluating the different diagnostic approaches and treatment options, and highlighting the recent research advances in this area.Major conclusions
Extensive research over the years has significantly increased the frequency with which accurate diagnosis is being made, including the identification of new biomarkers and next generation sequencing (NGS) technologies. NGS has provided a breakthrough in unravelling the genetic basis of MRCDs, especially considering the complexity of mitochondrial genetics with its dual genetic contributions.General significance
With an increased understanding of the pathophysiology of this group of disorders, clinical trials are now being established using a number of different therapeutic approaches, with the hope of changing the focus of treatment from being largely supportive to potentially having a positive effect on the natural history of the disorder.This article is part of a Special Issue entitled: Special Issue: Frontiers of Mitochondria IG000218. 相似文献110.