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排序方式: 共有372条查询结果,搜索用时 156 毫秒
11.
Rotem Kadir Tamar Harel Barak Markus Yonatan Perez Anna Bakhrat Idan Cohen Michael Volodarsky Miora Feintsein-Linial Elana Chervinski Joel Zlotogora Sara Sivan Ramon Y. Birnbaum Uri Abdu Stavit Shalev Ohad S. Birk 《PLoS genetics》2016,12(3)
Primary microcephaly is a congenital neurodevelopmental disorder of reduced head circumference and brain volume, with fewer neurons in the cortex of the developing brain due to premature transition between symmetrical and asymmetrical cellular division of the neuronal stem cell layer during neurogenesis. We now show through linkage analysis and whole exome sequencing, that a dominant mutation in ALFY, encoding an autophagy scaffold protein, causes human primary microcephaly. We demonstrate the dominant effect of the mutation in drosophila: transgenic flies harboring the human mutant allele display small brain volume, recapitulating the disease phenotype. Moreover, eye-specific expression of human mutant ALFY causes rough eye phenotype. In molecular terms, we demonstrate that normally ALFY attenuates the canonical Wnt signaling pathway via autophagy-dependent removal specifically of aggregates of DVL3 and not of Dvl1 or Dvl2. Thus, autophagic attenuation of Wnt signaling through removal of Dvl3 aggregates by ALFY acts in determining human brain size. 相似文献
12.
Methanogenesis, the microbial methane (CH4) production, is traditionally thought to anchor the mineralization of organic matter as the ultimate respiratory process in deep sediments, despite the presence of oxidized mineral phases, such as iron oxides. This process is carried out by archaea that have also been shown to be capable of reducing iron in high levels of electron donors such as hydrogen. The current pure culture study demonstrates that methanogenic archaea (Methanosarcina barkeri) rapidly switch from methanogenesis to iron‐oxide reduction close to natural conditions, with nitrogen atmosphere, even when faced with substrate limitations. Intensive, biotic iron reduction was observed following the addition of poorly crystalline ferrihydrite and complex organic matter and was accompanied by inhibition of methane production. The reaction rate of this process was of the first order and was dependent only on the initial iron concentrations. Ferrous iron production did not accelerate significantly with the addition of 9,10‐anthraquinone‐2,6‐disulfonate (AQDS) but increased by 11–28% with the addition of phenazine‐1‐carboxylate (PCA), suggesting the possible role of methanophenazines in the electron transport. The coupling between ferrous iron and methane production has important global implications. The rapid transition from methanogenesis to reduction of iron–oxides close to the natural conditions in sediments may help to explain the globally‐distributed phenomena of increasing ferrous concentrations below the traditional iron reduction zone in the deep ‘methanogenic’ sediment horizon, with implications for metabolic networking in these subsurface ecosystems and in past geological settings. 相似文献
13.
Platelets, which play a central role in thrombosis and hemostasis, develop from megakaryocytes. Signal transduction originated from the megakaryocyte growth and development factor, the Mpl ligand, which leads to megakaryocyte differentiation, polyploidization, and maturation, has been gradually characterized. In this study, we report the inducibility of Mst1, a recently described serine/threonine kinase, by Mpl ligand and the effect of its induced expression on megakaryocyte differentiation. The steady-state level of mst1 message and Mst1-associated kinase activity increased in response to Mpl ligand. Ectopic expression of human mst1 in a mouse megakaryocytic cell line resulted in a drastic increase in DNA content per cell. Elevated expression of megakaryocyte differentiation markers, such as acetylcholine esterase, PF4, and GPIIb was also observed in hmst1-expressing cells. Activation of p38 MAPK, a known downstream effector of Mst1, was shown to be required for polyploidization, but not for enhanced expression of differentiation markers. Our study thus designates Mst1 as a Mpl ligand-responsive signaling molecule that promotes induction of lineage-specific cellular programming. 相似文献
14.
Ca transients from Ca channel activity in rat cardiac myocytes reveal dynamics of dyad cleft and troponin C Ca binding 总被引:1,自引:0,他引:1
Vadakkadath Meethal S Potter KT Redon D Heisey DM Haworth RA 《American journal of physiology. Cell physiology》2004,286(2):C302-C316
The properties of the dyad cleft can in principle significantly impact excitation-contraction coupling, but these properties are not easily amenable to experimental investigation. We simultaneously measured the time course of the rise in integrated Ca current (ICa) and the rise in concentration of fura 2 with Ca bound ([Ca-fura 2]) with high time resolution in rat myocytes for conditions under which Ca entry is only via L-type Ca channels and sarcoplasmic reticulum (SR) Ca release is blocked, and compared these measurements with predictions from a finite-element model of cellular Ca diffusion. We found that 1) the time course of the rise of [Ca-fura 2] follows the time course of integrated ICa plus a brief delay (1.36 ± 0.43 ms, n = 6 cells); 2) from the model, high-affinity Ca binding sites in the dyad cleft at the level previously envisioned would result in a much greater delay (=" BORDER="0">3 ms) and are therefore unlikely to be present at that level; 3) including ATP in the model promoted Ca efflux from the dyad cleft by a factor of 1.57 when low-affinity cleft Ca binding sites were present; 4) the data could only be fit to the model if myofibrillar troponin C (TnC) Ca binding were low affinity (4.56 µM), like that of soluble troponin C, instead of the high-affinity value usually used (0.38 µM). In a "good model," the rate constants for Ca binding and dissociation were 0.375 times the values for soluble TnC; and 5) consequently, intracellular Ca buffering at the rise of the Ca transient is inferred to be low. excitation-contraction coupling; adenosine triphosphate; fura 2; modeling; fuzzy space 相似文献
15.
Gdalyahu A Ghosh I Levy T Sapir T Sapoznik S Fishler Y Azoulai D Reiner O 《The EMBO journal》2004,23(4):823-832
Mutations in the X-linked gene DCX result in lissencephaly in males, and abnormal neuronal positioning in females, suggesting a role for this gene product during neuronal migration. In spite of several known protein interactions, the involvement of DCX in a signaling pathway is still elusive. Here we demonstrate that DCX is a substrate of JNK and interacts with both c-Jun N-terminal kinase (JNK) and JNK interacting protein (JIP). The localization of this signaling module in the developing brain suggests its functionality in migrating neurons. The localization of DCX at neurite tips is determined by its interaction with JIP and by the interaction of the latter with kinesin. DCX is phosphorylated by JNK in growth cones. DCX mutated in sites phosphorylated by JNK affected neurite outgrowth, and the velocity and relative pause time of migrating neurons. We hypothesize that during neuronal migration, there is a need to regulate molecular motors that are working in the cell in opposite directions: kinesin (a plus-end directed molecular motor) versus dynein (a minus-end directed molecular motor). 相似文献
16.
Trials in the 1990s demonstrated that medical therapy is as effective as invasive therapies for treating single-vessel coronary disease. Yet more recent studies enrolling patients with this condition have focused on evaluating only invasive approaches, namely, stenting versus coronary artery bypass surgery. Several ethical and scientific questions remain unanswered regarding the conduct of these later trials. Were they justified? Why wasn't a medical therapy arm included? Were subjects informed about the availability of medical therapy as an equivalent option? Was optimized medical therapy given prior to randomization? The absence of clear answers to these questions raises the possibility of serious bias in favor of invasive interventions. Considering that medical therapy is underutilized in patients with coronary disease, efforts should focus more on increasing utilization of medical therapy and proper selection of noninvasive interventions. 相似文献
17.
Epidermal growth factor (EGF) stimulation of prostate metastatic tumor cells results in transient phosphorylation and cellular localization of non-muscle myosin heavy chain II-B (NMHC II-B) with kinetics similar to those seen in chemotaxis. We demonstrate that expression of 18- and 72-kDa fragments derived from the NMHC II-B C terminus that contain EGF-dependent NMHC II-B phosphorylation sites serve as dominant-negative mutations for EGF-dependent NMHC II-B phosphorylation and localization. Both fragments inhibited the EGF-dependent phosphorylation by competing with NMHC II-B on the myosin heavy chain kinase. However, only expression of the 72-kDa fragment resulted in cells with abnormalities in cell shape, focal adhesions, and chemotaxis. We found that the 72-kDa (but not 18-kDa) fragment is capable of self-assembly. To our knowledge, these results provide the first strong evidence that EGF-dependent NMHC II-B phosphorylation is required for the cellular localization of NMHC II-B and that NMHC II-B is required for normal cell attachment and for chemotactic response. 相似文献
18.
Antifibrotic action of Cu/Zn SOD is mediated by TGF-beta1 repression and phenotypic reversion of myofibroblasts 总被引:2,自引:0,他引:2
Vozenin-Brotons MC Sivan V Gault N Renard C Geffrotin C Delanian S Lefaix JL Martin M 《Free radical biology & medicine》2001,30(1):30-42
Skin fibrosis is characterized by the proliferation and accumulation of activated fibroblasts called myofibroblasts. They exhibit specific cytoskeletal differentiation, overexpress the fibrogenic cytokine TGF-beta1, synthesize excess extracellular matrix compounds and exhibit a depleted antioxidant metabolism. Recently, SOD was successfully used as an antifibrotic agent in vivo, thus challenging the postulate of established fibrosis irreversibility. We postulated that myofibroblasts could be a direct target for this therapeutic effect. To test this hypothesis, we used three-dimensional co-culture models of skin, in which specific phenotypes of normal fibroblasts versus myofibroblasts are retained. These 3-D models were treated with liposomal and carrier-free Cu/Zn SOD, and examined for their effects on cell number, cell death, and phenotypic differentiation. The results show that SOD did not induce myofibroblast cell death, whereas it significantly reduced TGF-beta1 expression, thus demonstrating that SOD might be proposed as a potent antagonist of this major fibrogenic growth factor. We also found that SOD significantly lowered the levels of the myofibroblast marker alpha-sm actin, of beta-actin, and of the extracellular matrix components alpha1(I) collagen and tenascin-C. In conclusion, our results suggest that SOD antifibrotic action occurred in vitro through the reversion of myofibroblasts into normal fibroblasts. 相似文献
19.
Induction of apoptosis in granulosa cells by TNF alpha and its attenuation by glucocorticoids involve modulation of Bcl-2 总被引:1,自引:0,他引:1
Sasson R Winder N Kees S Amsterdam A 《Biochemical and biophysical research communications》2002,294(1):51-59
Tumor necrosis factor alpha (TNF alpha) plays a role in mammalian ovarian follicular development, steroidogenesis, ovulation, luteolysis, and atresia, but the exact mechanism of TNF alpha action is not completely understood. Induction of apoptosis and suppression of steroidogenesis by TNF alpha in primary preovulatory rat and human granulosa cells, as well as, in human granulosa cells immortalized by mutated p53, were characterized in the present work. Dexamethasone (Dex) and hydrocortisone efficiently suppressed TNF alpha-induced apoptosis in granulosa cells. TNF alpha dramatically reduced intracellular levels of Bcl-2, while Dex abrogated this reduction. TNF alpha reduced considerably intracellular levels of StAR protein, a key regulating factor in steroidogenesis. This reduction can be explained only in part by elimination of cells through apoptosis, since loss of steroidogenic capacity was much higher and faster than the rate and extent of loss of cell viability induced by TNF alpha, suggesting independent mechanisms for TNF alpha-induction of apoptosis and TNF alpha-suppression of steroidogenesis. 相似文献