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Chan CS Guzman JN Ilijic E Mercer JN Rick C Tkatch T Meredith GE Surmeier DJ 《Nature》2007,447(7148):1081-1086
Why dopamine-containing neurons of the brain's substantia nigra pars compacta die in Parkinson's disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Ca(v)1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as juvenile dopamine-containing neurons in the substantia nigra pars compacta use pacemaking mechanisms common to neurons not affected in Parkinson's disease. These mechanisms remain latent in adulthood, and blocking Ca(v)1.3 Ca2+ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking ('rejuvenation') protects these neurons in both in vitro and in vivo models of Parkinson's disease, pointing to a new strategy that could slow or stop the progression of the disease. 相似文献
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Janich P Pascual G Merlos-Suárez A Batlle E Ripperger J Albrecht U Cheng HY Obrietan K Di Croce L Benitah SA 《Nature》2011,480(7376):209-214
Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis. 相似文献
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VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism 总被引:49,自引:0,他引:49
Gerber HP Malik AK Solar GP Sherman D Liang XH Meng G Hong K Marsters JC Ferrara N 《Nature》2002,417(6892):954-958
Vascular endothelial growth factor (VEGF) is a principal regulator of blood vessel formation and haematopoiesis, but the mechanisms by which VEGF differentially regulates these processes have been elusive. Here we describe a regulatory loop by which VEGF controls survival of haematopoietic stem cells (HSCs). We observed a reduction in survival, colony formation and in vivo repopulation rates of HSCs after ablation of the VEGF gene in mice. Intracellularly acting small-molecule inhibitors of VEGF receptor (VEGFR) tyrosine kinase dramatically reduced colony formation of HSCs, thus mimicking deletion of the VEGF gene. However, blocking VEGF by administering a soluble VEGFR-1, which acts extracellularly, induced only minor effects. These findings support the involvement in HSC survival of a VEGF-dependent internal autocrine loop mechanism (that is, the mechanism is resistant to inhibitors that fail to penetrate the intracellular compartment). Not only ligands selective for VEGF and VEGFR-2 but also VEGFR-1 agonists rescued survival and repopulation of VEGF-deficient HSCs, revealing a function for VEGFR-1 signalling during haematopoiesis. 相似文献
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Lopez-Castejón G Baroja-Mazo A Pelegrín P 《Cellular and molecular life sciences : CMLS》2011,68(18):3095-3107
Plasticity is a well-known property of macrophages that is controlled by different changes in environmental signals. Macrophage
polarization is regarded as a spectrum of activation phenotypes adjusted from one activation extreme, the classic (M1), to
the other, the alternative (M2) activation. Here we show, in vitro and in vivo, that both M1 and M2 macrophage phenotypes
are tightly coupled to specific patterns of gene expression. Novel M2-associated markers were characterized and identified
as genes controlling the extracellular metabolism of ATP to generate pyrophosphates (PPi). Stimulation of M1 macrophages with
PPi dampens both NLR and TLR signaling and thus mediates cytokine production. In this context extracellular PPi enhanced the
resolution phase of a murine peritonitis model via a decrease in pro-inflammatory cytokine production. Therefore, our study
reveals an additional level of plasticity modulating the resolution of inflammation. 相似文献
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Summary A quasi-valence number of less than 3.20 was reported to be significant in correlating carcinogenicity. This criterion has no meaningful relationship since such a large proportion of organic compounds fall in this group, that it provides no selectivity.Acknowledgment. The authors express appreciation to the American Cancer Society (CH-57), the National Institute of Environmental Health Sciences (1-RO1-ES01975-01 PTHB) and the Robert A. Welch Foundation (B-702) for financial assistance of projects related to this paper. 相似文献
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Riassunto Cellule embrionali diD. melanogaster, coltivate in vitro fino a 120 h, presentano un progressivo aumento delle variazioni dei numeri cromosomici interessanti principalmente il I e il IV paio di cromosomi. 相似文献
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Mutation in myosin heavy chain 6 causes atrial septal defect 总被引:23,自引:0,他引:23
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