首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   465篇
  免费   52篇
  2021年   6篇
  2020年   4篇
  2018年   3篇
  2017年   5篇
  2016年   9篇
  2015年   15篇
  2014年   12篇
  2013年   11篇
  2012年   27篇
  2011年   23篇
  2010年   14篇
  2009年   21篇
  2008年   23篇
  2007年   22篇
  2006年   20篇
  2005年   15篇
  2004年   18篇
  2003年   24篇
  2002年   22篇
  2001年   14篇
  2000年   18篇
  1999年   12篇
  1998年   17篇
  1997年   8篇
  1996年   5篇
  1995年   3篇
  1994年   11篇
  1992年   13篇
  1991年   9篇
  1990年   7篇
  1989年   6篇
  1988年   5篇
  1987年   5篇
  1986年   5篇
  1985年   7篇
  1984年   3篇
  1983年   4篇
  1982年   5篇
  1981年   3篇
  1980年   4篇
  1979年   9篇
  1978年   5篇
  1977年   4篇
  1974年   3篇
  1972年   2篇
  1971年   6篇
  1969年   5篇
  1967年   2篇
  1966年   3篇
  1965年   2篇
排序方式: 共有517条查询结果,搜索用时 343 毫秒
491.
492.
493.
An unresolved question about GPCR function is the role of membrane components in receptor stability and activation. In particular, cholesterol is known to affect the function of membrane proteins, but the details of its effect on GPCRs are still elusive. Here, we describe how cholesterol modulates the behavior of the TM1‐TM2‐TM7‐helix 8(H8) functional network that comprises the highly conserved NPxxY(x)5,6F motif, through specific interactions with the receptor. The inferences are based on the analysis of microsecond length molecular dynamics (MD) simulations of rhodopsin in an explicit membrane environment. Three regions on the rhodopsin exhibit the highest cholesterol density throughout the trajectory: the extracellular end of TM7, a location resembling the high‐density sterol area from the electron microscopy data; the intracellular parts of TM1, TM2, and TM4, a region suggested as the cholesterol binding site in the recent X‐ray crystallography data on β2‐adrenergic GPCR; and the intracellular ends of TM2‐TM3, a location that was categorized as the high cholesterol density area in multiple independent 100 ns MD simulations of the same system. We found that cholesterol primarily affects specific local perturbations of the helical TM domains such as the kinks in TM1, TM2, and TM7. These local distortions, in turn, relate to rigid‐body motions of the TMs in the TM1‐TM2‐TM7‐H8 bundle. The specificity of the effects stems from the nonuniform distribution of cholesterol around the protein. Through correlation analysis we connect local effects of cholesterol on structural perturbations with a regulatory role of cholesterol in the structural rearrangements involved in GPCR function. Proteins 2009. © 2008 Wiley‐Liss, Inc.  相似文献   
494.
A very high percentage (around 70%) of the agronomic area in Switzerland is covered by grasslands at various altitudes where environmental conditions, management, community structure and productivity vary widely. As heat waves and drought are predicted to increase in future climate, survival of plant species in grasslands is a major issue of concern in Central Europe. The effect of summer drought on representative grasslands in Switzerland was studied through drought experiments (using rain-out shelters avoiding natural precipitation) to understand the response of predominant species to changed climatic conditions. The physiological performance (gas exchange, leaf water potential) of selected species was investigated at three locations in Switzerland. The pre-dawn leaf water potential of all species was lower (more negative) under the dryer conditions at the three sites. Net photosynthesis and stomatal conductance of forb and legume species did not show major changes under drought, while grass species showed large decreases at the lowland site. These differences between forb-legume and grass species were not observed at the pre-alpine and alpine site. The apparent drought tolerance of the forb-legume species seems to be due—at least partially—to increased water use efficiency under drought conditions.  相似文献   
495.
The aim of the present paper is to detect two different antigens simultaneously in a single slide. In cryostat sections of human tonsils, B-lymphocytes of follicle mantle-bearing surface IgD were immunostained with the alkaline phosphatase method using monoclonal anti IgD. The subsequent staining for T-lymphocyte subsets (T-helper and T-suppressor lymphocytes) was performed again with the alkaline phosphatase method using one of the monoclonal antibodies OKT 4, OKT 8, Leu 3a, Leu 2a. The best results with the alkaline phosphatase method were achieved using naphthol AS phosphate and Fast Blue BB for the revelation of the first antigen and naphthol AS-BI phosphate and diazotized New Fuchsin for the second.  相似文献   
496.
497.
Mutations in RNA binding proteins (RBPs) and in genes regulating autophagy are frequent causes of familial amyotrophic lateral sclerosis (fALS). The P56S mutation in vesicle-associated membrane protein-associated protein B (VAPB) leads to fALS (ALS8) and spinal muscular atrophy (SMA). While VAPB is primarily involved in the unfolded protein response (UPR), vesicular trafficking and in initial steps of the autophagy pathway, the effect of mutant P56S-VAPB on autophagy regulation in connection with RBP homeostasis has not been explored yet. Examining the muscle biopsy of our index ALS8 patient of European origin revealed globular accumulations of VAPB aggregates co-localised with autophagy markers LC3 and p62 in partially atrophic and atrophic muscle fibres. In line with this skin fibroblasts obtained from the same patient showed accumulation of P56S-VAPB aggregates together with LC3 and p62. Detailed investigations of autophagic flux in cell culture models revealed that P56S-VAPB alters both initial and late steps of the autophagy pathway. Accordingly, electron microscopy complemented with live cell imaging highlighted the impaired fusion of accumulated autophagosomes with lysosomes in cells expressing P56S-VAPB. Consistent with these observations, neuropathological studies of brain and spinal cord of P56S-VAPB transgenic mice revealed signs of neurodegeneration associated with altered protein quality control and defective autophagy. Autophagy and RBP homeostasis are interdependent, as demonstrated by the cytoplasmic mis-localisation of several RBPs including pTDP-43, FUS, Matrin 3 which often sequestered with P56S-VAPB aggregates both in cell culture and in the muscle biopsy of the ALS8 patient. Further confirming the notion that aggregation of the RBPs proceeds through the stress granule (SG) pathway, we found persistent G3BP- and TIAR1-positive SGs in P56S-VAPB expressing cells as well as in the ALS8 patient muscle biopsy. We conclude that P56S-VAPB-ALS8 involves a cohesive pathomechanism of aberrant RBP homeostasis together with dysfunctional autophagy.Subject terms: Mechanisms of disease, Amyotrophic lateral sclerosis  相似文献   
498.
The central‐marginal hypothesis (CMH) posits that range margins exhibit less genetic diversity and greater inter‐population genetic differentiation compared to range cores. CMH predictions are based on long‐held “abundant‐centre” assumptions of a decline in ecological conditions and abundances towards range margins. Although much empirical research has confirmed CMH, exceptions remain almost as common. We contend that mangroves provide a model system to test CMH that alleviates common confounding factors and may help clarify this lack of consensus. Here, we document changes in black mangrove (Avicennia germinans) population genetics with 12 nuclear microsatellite loci along three replicate coastlines in the United States (only two of three conform to underlying “abundant‐centre” assumptions). We then test an implicit prediction of CMH (reduced genetic diversity may constrain adaptation at range margins) by measuring functional traits of leaves associated with cold tolerance, the climatic factor that controls these mangrove distributional limits. CMH predictions were confirmed only along the coastlines that conform to “abundant‐centre” assumptions and, in contrast to theory, range margin A. germinans exhibited functional traits consistent with greater cold tolerance compared to range cores. These findings support previous accounts that CMH may not be a general rule across species and that reduced neutral genetic diversity at range margins may not be a constraint to shifts in functional trait variation along climatic gradients.  相似文献   
499.
500.
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号