全文获取类型
收费全文 | 1000篇 |
免费 | 2篇 |
国内免费 | 3篇 |
专业分类
系统科学 | 13篇 |
教育与普及 | 5篇 |
理论与方法论 | 7篇 |
现状及发展 | 224篇 |
研究方法 | 149篇 |
综合类 | 588篇 |
自然研究 | 19篇 |
出版年
2021年 | 3篇 |
2018年 | 5篇 |
2017年 | 7篇 |
2016年 | 16篇 |
2015年 | 11篇 |
2014年 | 17篇 |
2013年 | 13篇 |
2012年 | 69篇 |
2011年 | 102篇 |
2010年 | 28篇 |
2009年 | 7篇 |
2008年 | 63篇 |
2007年 | 67篇 |
2006年 | 59篇 |
2005年 | 66篇 |
2004年 | 53篇 |
2003年 | 59篇 |
2002年 | 70篇 |
2001年 | 12篇 |
2000年 | 16篇 |
1999年 | 17篇 |
1998年 | 4篇 |
1996年 | 3篇 |
1994年 | 4篇 |
1992年 | 6篇 |
1991年 | 7篇 |
1990年 | 6篇 |
1989年 | 8篇 |
1988年 | 4篇 |
1987年 | 7篇 |
1986年 | 8篇 |
1985年 | 6篇 |
1983年 | 4篇 |
1982年 | 4篇 |
1980年 | 2篇 |
1979年 | 12篇 |
1978年 | 13篇 |
1977年 | 11篇 |
1976年 | 6篇 |
1975年 | 7篇 |
1974年 | 9篇 |
1973年 | 11篇 |
1972年 | 7篇 |
1971年 | 14篇 |
1970年 | 18篇 |
1969年 | 13篇 |
1968年 | 8篇 |
1967年 | 17篇 |
1966年 | 6篇 |
1965年 | 5篇 |
排序方式: 共有1005条查询结果,搜索用时 15 毫秒
971.
Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations 总被引:20,自引:0,他引:20
Hong SE Shugart YY Huang DT Shahwan SA Grant PE Hourihane JO Martin ND Walsh CA 《Nature genetics》2000,26(1):93-96
Normal development of the cerebral cortex requires long-range migration of cortical neurons from proliferative regions deep in the brain. Lissencephaly ("smooth brain," from "lissos," meaning smooth, and "encephalos," meaning brain) is a severe developmental disorder in which neuronal migration is impaired, leading to a thickened cerebral cortex whose normally folded contour is simplified and smooth. Two identified lissencephaly genes do not account for all known cases, and additional lissencephaly syndromes have been described. An autosomal recessive form of lissencephaly (LCH) associated with severe abnormalities of the cerebellum, hippocampus and brainstem maps to chromosome 7q22, and is associated with two independent mutations in the human gene encoding reelin (RELN). The mutations disrupt splicing of RELN cDNA, resulting in low or undetectable amounts of reelin protein. LCH parallels the reeler mouse mutant (Reln(rl)), in which Reln mutations cause cerebellar hypoplasia, abnormal cerebral cortical neuronal migration and abnormal axonal connectivity. RELN encodes a large (388 kD) secreted protein that acts on migrating cortical neurons by binding to the very low density lipoprotein receptor (VLDLR), the apolipoprotein E receptor 2 (ApoER2; refs 9-11 ), alpha3beta1 integrin and protocadherins. Although reelin was previously thought to function exclusively in brain, some humans with RELN mutations show abnormal neuromuscular connectivity and congenital lymphoedema, suggesting previously unsuspected functions for reelin in and outside of the brain. 相似文献
972.
Vertebrate limb development depends on signals from the apical ectodermal ridge (AER), which rims the distal tip of the limb bud. Removal of the AER in chick results in limbs lacking distal skeletal elements. Fibroblast growth factor (FGF) proteins can substitute for the AER (refs 4-7), suggesting that FGF signalling mediates AER activity. Of the four mouse Fgf genes (Fgf4 , Fgf8, Fgf9, Fgf17) known to display AER-specific expression domains within the limb bud (AER-Fgfs), only Fgf8 is expressed throughout the AER. Moreover, Fgf8 expression precedes that of other AER-Fgfs (refs 8-13), suggesting that Fgf8 may perform unique functions early in limb development. In mice, loss of function of Fgf4 (refs 13,14), Fgf9 (D. Ornitz, pers. comm.) or Fgf17 (ref. 15) has no effect on limb formation. We report here that inactivating Fgf8 in early limb ectoderm causes a substantial reduction in limb-bud size, a delay in Shh expression, misregulation of Fgf4 expression, and hypoplasia or aplasia of specific skeletal elements. Our data identify Fgf8 as the only known AER-Fgf individually necessary for normal limb development, and provide insight into the function of Fgf signalling from the AER in the normal outgrowth and patterning of the limb. 相似文献
973.
974.
975.
Phenology, the study of annually recurring life cycle events such as the timing of migrations and flowering, can provide particularly sensitive indicators of climate change. Changes in phenology may be important to ecosystem function because the level of response to climate change may vary across functional groups and multiple trophic levels. The decoupling of phenological relationships will have important ramifications for trophic interactions, altering food-web structures and leading to eventual ecosystem-level changes. Temperate marine environments may be particularly vulnerable to these changes because the recruitment success of higher trophic levels is highly dependent on synchronization with pulsed planktonic production. Using long-term data of 66 plankton taxa during the period from 1958 to 2002, we investigated whether climate warming signals are emergent across all trophic levels and functional groups within an ecological community. Here we show that not only is the marine pelagic community responding to climate changes, but also that the level of response differs throughout the community and the seasonal cycle, leading to a mismatch between trophic levels and functional groups. 相似文献
976.
Gross O Gewies A Finger K Schäfer M Sparwasser T Peschel C Förster I Ruland J 《Nature》2006,442(7103):651-656
Fungal infections are increasing worldwide due to the marked rise in immunodeficiencies including AIDS; however, immune responses to fungi are poorly understood. Dectin-1 is the major mammalian pattern recognition receptor for the fungal component zymosan. Dectin-1 represents the prototype of innate non-Toll-like receptors (TLRs) containing immunoreceptor tyrosine-based activation motifs (ITAMs) related to those of adaptive antigen receptors. Here we identify Card9 as a key transducer of Dectin-1 signalling. Although being dispensable for TLR/MyD88-induced responses, Card9 controls Dectin-1-mediated myeloid cell activation, cytokine production and innate anti-fungal immunity. Card9 couples to Bcl10 and regulates Bcl10-Malt1-mediated NF-kappaB activation induced by zymosan. Yet, Card9 is dispensable for antigen receptor signalling that uses Carma1 as a link to Bcl10-Malt1. Thus, our results define a novel innate immune pathway and indicate that evolutionarily distinct ITAM receptors in innate and adaptive immune cells use diverse adaptor proteins to engage selectively the conserved Bcl10-Malt1 module. 相似文献
977.
Faelber K Posor Y Gao S Held M Roske Y Schulze D Haucke V Noé F Daumke O 《Nature》2011,477(7366):556-560
Dynamin is a mechanochemical GTPase that oligomerizes around the neck of clathrin-coated pits and catalyses vesicle scission in a GTP-hydrolysis-dependent manner. The molecular details of oligomerization and the mechanism of the mechanochemical coupling are currently unknown. Here we present the crystal structure of human dynamin 1 in the nucleotide-free state with a four-domain architecture comprising the GTPase domain, the bundle signalling element, the stalk and the pleckstrin homology domain. Dynamin 1 oligomerized in the crystals via the stalks, which assemble in a criss-cross fashion. The stalks further interact via conserved surfaces with the pleckstrin homology domain and the bundle signalling element of the neighbouring dynamin molecule. This intricate domain interaction rationalizes a number of disease-related mutations in dynamin 2 and suggests a structural model for the mechanochemical coupling that reconciles previous models of dynamin function. 相似文献
978.
979.
The conserved Polycomb repressive complex 2 (PRC2) generates trimethylation of histone 3 lysine 27 (H3K27me3), a modification associated with stable epigenetic silencing. Much is known about PRC2-induced silencing but key questions remain concerning its nucleation and stability. Vernalization, the perception and memory of winter in plants, is a classic epigenetic process that, in Arabidopsis, involves PRC2-based silencing of the floral repressor FLC. The slow dynamics of vernalization, taking place over weeks in the cold, generate a level of stable silencing of FLC in the subsequent warm that depends quantitatively on the length of the prior cold. These features make vernalization an ideal experimental system to investigate both the maintenance of epigenetic states and the switching between them. Here, using mathematical modelling, chromatin immunoprecipitation and an FLC:GUS reporter assay, we show that the quantitative nature of vernalization is generated by H3K27me3-mediated FLC silencing in the warm in a subpopulation of cells whose number depends on the length of the prior cold. During the cold, H3K27me3 levels progressively increase at a tightly localized nucleation region within FLC. At the end of the cold, numerical simulations predict that such a nucleation region is capable of switching the bistable epigenetic state of an individual locus, with the probability of overall FLC coverage by silencing H3K27me3 marks depending on the length of cold exposure. Thus, the model predicts a bistable pattern of FLC gene expression in individual cells, a prediction we verify using the FLC:GUS reporter system. Our proposed switching mechanism, involving the local nucleation of an opposing histone modification, is likely to be widely relevant in epigenetic reprogramming. 相似文献
980.
Dynamic molecular processes mediate cellular mechanotransduction 总被引:1,自引:0,他引:1
Cellular responses to mechanical forces are crucial in embryonic development and adult physiology, and are involved in numerous diseases, including atherosclerosis, hypertension, osteoporosis, muscular dystrophy, myopathies and cancer. These responses are mediated by load-bearing subcellular structures, such as the plasma membrane, cell-adhesion complexes and the cytoskeleton. Recent work has demonstrated that these structures are dynamic, undergoing assembly, disassembly and movement, even when ostensibly stable. An emerging insight is that transduction of forces into biochemical signals occurs within the context of these processes. This framework helps to explain how forces of varying strengths or dynamic characteristics regulate distinct signalling pathways. 相似文献