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Anderson BH Kasher PR Mayer J Szynkiewicz M Jenkinson EM Bhaskar SS Urquhart JE Daly SB Dickerson JE O'Sullivan J Leibundgut EO Muter J Abdel-Salem GM Babul-Hirji R Baxter P Berger A Bonafé L Brunstom-Hernandez JE Buckard JA Chitayat D Chong WK Cordelli DM Ferreira P Fluss J Forrest EH Franzoni E Garone C Hammans SR Houge G Hughes I Jacquemont S Jeannet PY Jefferson RJ Kumar R Kutschke G Lundberg S Lourenço CM Mehta R Naidu S Nischal KK Nunes L Ounap K Philippart M Prabhakar P Risen SR 《Nature genetics》2012,44(3):338-342
Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity. 相似文献
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A single stem cell can recolonize an embryonic thymus, producing phenotypically distinct T-cell populations 总被引:4,自引:0,他引:4
There is much interest in early T-cell development, particularly in relation to the diversification of the T-cell receptor repertoire and the elucidation of the lineage relationships between T-cell populations in the thymus and peripheral lymphoid organs. However, the requirements for the growth of the earliest thymic T-cell precursor in 13-14-day mouse embryo thymus in isolation from the thymic environment are unknown. Proliferation and maturation of such cells are not sustained either in the presence of monolayers of thymic stromal cells or by the addition of interleukin-2 (IL-2), despite the expression of receptors for this growth factor on a proportion of thymocytes displaying the immature Thy 1+ Lyt-2-L3T4- phenotype in the embryonic thymus. In contrast, when maintained within the intact thymic environment in organ cultures, 13-14-day thymic stem cells do show a pattern of surface marker and functional development similar to that seen in vivo, suggesting that short-range growth signals, perhaps necessitating direct contact with organized epithelial cells, are required. We have shown, by exploiting the selective toxicity of deoxyguanosine (dGuo) for early T cells, that this organ culture system can be manipulated to produce alymphoid lobes that can be recolonized from a source of precursors in a transfilter system. We now show that recolonization of alymphoid lobes can also be achieved by association with T-cell precursors in hanging drops, allowing recolonization by exposure to defined numbers of precursors, including a single micromanipulated stem cell. Analysis of T-cell marker expression in these cultures shows that a single thymic stem cell can produce progeny of distinct phenotypes, suggesting that these marker-defined populations are not derived from separate prethymic precursors, but arise within the thymus. 相似文献
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A single micromanipulated stem cell gives rise to multiple T-cell receptor gene rearrangements in the thymus in vitro 总被引:4,自引:0,他引:4
The extensive range of specificities of T-cell receptors is generated, as for immunoglobulins, by rearrangement of genetic information. Much valuable information about rearrangement processes has been inferred by comparing DNA from (monoclonal) lymphoid lines with germ-line DNA and, for B cells, from rearrangements in some Abelson murine leukaemia virus-transformed cell lines. However, because it is difficult to isolate and grow precursor populations, it has not proved possible to study rearrangements occurring in normal untransformed cells in vitro. Here we show that a single T-cell precursor colonizing an alymphoid thymus lobe in organ culture can generate multiple receptor beta-chain gene rearrangements. These observations provide unequivocal evidence for the intra-thymic diversification of the T-cell repertoire. They also offer the possibility of investigating rearrangement and its control in the clonal progeny of a single normal T-cell precursor without the perturbations involved in the use of viral transformation or the production of T-cell hybridomas. 相似文献
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Dibbens LM Tarpey PS Hynes K Bayly MA Scheffer IE Smith R Bomar J Sutton E Vandeleur L Shoubridge C Edkins S Turner SJ Stevens C O'Meara S Tofts C Barthorpe S Buck G Cole J Halliday K Jones D Lee R Madison M Mironenko T Varian J West S Widaa S Wray P Teague J Dicks E Butler A Menzies A Jenkinson A Shepherd R Gusella JF Afawi Z Mazarib A Neufeld MY Kivity S Lev D Lerman-Sagie T Korczyn AD Derry CP Sutherland GR Friend K Shaw M Corbett M Kim HG Geschwind DH Thomas P Haan E Ryan S McKee S 《Nature genetics》2008,40(6):776-781
Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation. 相似文献
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B E Banks C Brown G M Burgess G Burnstock M Claret T M Cocks D H Jenkinson 《Nature》1979,282(5737):415-417
Apamin is a neurotoxic polypeptide of known structure isolated from bee venom. Shuba and coworkers have recently shown that it abolishes the hyperpolarising action of externally-applied ATP on visceral smooth muscle (guinea pig stomach and taenia coli) as well as the hyperpolarisation (inhibitory junction potential) that follows stimulation of the non-adrenergic inhibitory nerve supply to these tissues. As it has been proposed that ATP is the neurotransmitter involved in the latter response, Vladimirova and Shuba tentatively concluded that apamin is a specific postsynaptic blocking agent of this non-adrenergic, possibly 'purinergic', inhibition. We have confirmed the important observation that nanomolar concentrations of apamin reduce inhibition by ATP and by non-adrenergic nerve stimulation, but further experiments suggest that, rather than acting as a specific blocker of ATP receptors, apamin inhibits the increase in potassium permeability caused by a number of agents, including ATP. 相似文献
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Tarpey PS Raymond FL Nguyen LS Rodriguez J Hackett A Vandeleur L Smith R Shoubridge C Edkins S Stevens C O'Meara S Tofts C Barthorpe S Buck G Cole J Halliday K Hills K Jones D Mironenko T Perry J Varian J West S Widaa S Teague J Dicks E Butler A Menzies A Richardson D Jenkinson A Shepherd R Raine K Moon J Luo Y Parnau J Bhat SS Gardner A Corbett M Brooks D Thomas P Parkinson-Lawrence E Porteous ME Warner JP Sanderson T Pearson P Simensen RJ Skinner C Hoganson G Superneau D Wooster R Bobrow M 《Nature genetics》2007,39(9):1127-1133
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Potassium permeability was monitored in human sweat glands and rat submandibular glands. Acetylcholine increased permeability in both tissues and the responses consisted of transient, calcium-independent and sustained, calcium-dependent components. Amiloride, a drug which inhibits Na(+)-H+ countertransport, impaired the regulation of potassium permeability in sweat glands but not in the submandibular gland. It is suggested that the stimulus-permeability coupling process in the sweat gland may be sensitive to the lowering of internal pH. 相似文献