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Guan K Nayernia K Maier LS Wagner S Dressel R Lee JH Nolte J Wolf F Li M Engel W Hasenfuss G 《Nature》2006,440(7088):1199-1203
Embryonic germ cells as well as germline stem cells from neonatal mouse testis are pluripotent and have differentiation potential similar to embryonic stem cells, suggesting that the germline lineage may retain the ability to generate pluripotent cells. However, until now there has been no evidence for the pluripotency and plasticity of adult spermatogonial stem cells (SSCs), which are responsible for maintaining spermatogenesis throughout life in the male. Here we show the isolation of SSCs from adult mouse testis using genetic selection, with a success rate of 27%. These isolated SSCs respond to culture conditions and acquire embryonic stem cell properties. We name these cells multipotent adult germline stem cells (maGSCs). They are able to spontaneously differentiate into derivatives of the three embryonic germ layers in vitro and generate teratomas in immunodeficient mice. When injected into an early blastocyst, SSCs contribute to the development of various organs and show germline transmission. Thus, the capacity to form multipotent cells persists in adult mouse testis. Establishment of human maGSCs from testicular biopsies may allow individual cell-based therapy without the ethical and immunological problems associated with human embryonic stem cells. Furthermore, these cells may provide new opportunities to study genetic diseases in various cell lineages. 相似文献
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Savage DB Agostini M Barroso I Gurnell M Luan J Meirhaeghe A Harding AH Ihrke G Rajanayagam O Soos MA George S Berger D Thomas EL Bell JD Meeran K Ross RJ Vidal-Puig A Wareham NJ O'Rahilly S Chatterjee VK Schafer AJ 《Nature genetics》2002,31(4):379-384
Impaired insulin action is a key feature of type 2 diabetes and is also found, to a more extreme degree, in familial syndromes of insulin resistance. Although inherited susceptibility to insulin resistance may involve the interplay of several genetic loci, no clear examples of interactions among genes have yet been reported. Here we describe a family in which five individuals with severe insulin resistance, but no unaffected family members, were doubly [corrected] heterozygous with respect to frameshift/premature stop mutations in two unlinked genes, PPARG and PPP1R3A these encode peroxisome proliferator activated receptor gamma, which is highly expressed in adipocytes, and protein phosphatase 1, regulatory subunit 3, the muscle-specific regulatory subunit of protein phosphatase 1, which are centrally involved in the regulation of carbohydrate and lipid metabolism, respectively. That mutant molecules primarily involved in either carbohydrate or lipid metabolism can combine to produce a phenotype of extreme insulin resistance provides a model of interactions among genes that may underlie common human metabolic disorders such as type 2 diabetes. 相似文献
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Al-Mayouf SM Sunker A Abdwani R Abrawi SA Almurshedi F Alhashmi N Al Sonbul A Sewairi W Qari A Abdallah E Al-Owain M Al Motywee S Al-Rayes H Hashem M Khalak H Al-Jebali L Alkuraya FS 《Nature genetics》2011,43(12):1186-1188
Systemic lupus erythematosus (SLE) is a complex autoimmune disease that causes substantial morbidity. As is typical for many other multifactorial disorders, much of the heritability of SLE remains unknown. We identified a rare autosomal recessive form of SLE, in which autozygome analysis revealed a null mutation in the DNASE1L3 gene. The DNASE1L3-related SLE we describe was always pediatric in onset and correlated with a high frequency of lupus nephritis. Our findings confirm the critical role of impaired clearance of degraded DNA in SLE pathogenesis. 相似文献
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Iness Charfi Karim Nagi Ouissame Mnie-Filali Dominic Thibault Gianfranco Balboni Peter W. Schiller Louis-Eric Trudeau Graciela Pineyro 《Cellular and molecular life sciences : CMLS》2014,71(8):1529-1546
Signaling bias refers to G protein-coupled receptor ligand ability to preferentially activate one type of signal over another. Bias to evoke signaling as opposed to sequestration has been proposed as a predictor of opioid ligand potential for generating tolerance. Here we measured whether delta opioid receptor agonists preferentially inhibited cyclase activity over internalization in HEK cells. Efficacy (τ) and affinity (KA) values were estimated from functional data and bias was calculated from efficiency coefficients (log τ/KA). This approach better represented the data as compared to alternative methods that estimate bias exclusively from τ values. Log (τ/KA) coefficients indicated that SNC-80 and UFP-512 promoted cyclase inhibition more efficiently than DOR internalization as compared to DPDPE (bias factor for SNC-80: 50 and for UFP-512: 132). Molecular determinants of internalization were different in HEK293 cells and neurons with βarrs contributing to internalization in both cell types, while PKC and GRK2 activities were only involved in neurons. Rank orders of ligand ability to engage different internalization mechanisms in neurons were compared to rank order of E max values for cyclase assays in HEK cells. Comparison revealed a significant reversal in rank order for cyclase E max values and βarr-dependent internalization in neurons, indicating that these responses were ligand-specific. Despite this evidence, and because kinases involved in internalization were not the same across cellular backgrounds, it is not possible to assert if the magnitude and nature of bias revealed by rank orders of maximal responses is the same as the one measured in HEK cells. 相似文献
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p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway 总被引:4,自引:0,他引:4
Hui L Bakiri L Mairhorfer A Schweifer N Haslinger C Kenner L Komnenovic V Scheuch H Beug H Wagner EF 《Nature genetics》2007,39(6):741-749
The mitogen-activated protein kinase (MAPK) p38alpha controls inflammatory responses and cell proliferation. Using mice carrying conditional Mapk14 (also known as p38alpha) alleles, we investigated its function in postnatal development and tumorigenesis. When we specifically deleted Mapk14 in the mouse embryo, fetuses developed to term but died shortly after birth, probably owing to lung dysfunction. Fetal hematopoietic cells and embryonic fibroblasts deficient in p38alpha showed increased proliferation resulting from sustained activation of the c-Jun N-terminal kinase (JNK)-c-Jun pathway. Notably, in chemical-induced liver cancer development, mice with liver-specific deletion of Mapk14 showed enhanced hepatocyte proliferation and tumor development that correlated with upregulation of the JNK-c-Jun pathway. Furthermore, inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells. These results demonstrate a new mechanism whereby p38alpha negatively regulates cell proliferation by antagonizing the JNK-c-Jun pathway in multiple cell types and in liver cancer development. 相似文献
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Mach's views on the nature of time have been unduly neglected. They are both more defensible in their own historical context and more relevant to our own contemporary context than has been appreciated. This essay provides an extended and comprehensive discussion of Mach's writings on time offering novel analysis and interpretation. Contra the prevailing current in the secondary literature, Mach's views on time are shown to be largely vindicated in the context of late nineteenth century physics. Then, building upon this more historical project, we conclude with a critical evaluation of the modern Machian view of time due to Barbour within the context of relativistic chronometry as instantiated via pulsar clocks and atomic clocks. Once more, considered analysis serves to support the Machian view. About time we go back to Mach. 相似文献