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   10264篇
  免费   944篇
  国内免费   5篇
  11213篇
  2023年   89篇
  2022年   203篇
  2021年   368篇
  2020年   207篇
  2019年   267篇
  2018年   291篇
  2017年   232篇
  2016年   397篇
  2015年   704篇
  2014年   718篇
  2013年   726篇
  2012年   1021篇
  2011年   933篇
  2010年   511篇
  2009年   380篇
  2008年   539篇
  2007年   569篇
  2006年   441篇
  2005年   397篇
  2004年   394篇
  2003年   305篇
  2002年   292篇
  2001年   52篇
  2000年   40篇
  1999年   47篇
  1998年   73篇
  1997年   33篇
  1996年   36篇
  1995年   26篇
  1994年   29篇
  1993年   34篇
  1992年   42篇
  1991年   36篇
  1990年   37篇
  1989年   29篇
  1988年   26篇
  1987年   26篇
  1986年   21篇
  1985年   41篇
  1984年   34篇
  1983年   34篇
  1982年   31篇
  1981年   31篇
  1980年   32篇
  1979年   25篇
  1978年   32篇
  1977年   25篇
  1976年   34篇
  1975年   24篇
  1974年   35篇
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
101.
Infectious microbes face an unwelcoming environment in their mammalian hosts, which have evolved elaborate multicelluar systems for recognition and elimination of invading pathogens. A common strategy used by pathogenic bacteria to establish infection is to secrete protein factors that block intracellular signalling pathways essential for host defence. Some of these proteins also act as toxins, directly causing pathology associated with disease. Bacillus anthracis, the bacterium that causes anthrax, secretes two plasmid-encoded enzymes, LF (lethal factor) and EF (oedema factor), that are delivered into host cells by a third bacterial protein, PA (protective antigen). The two toxins act on a variety of cell types, disabling the immune system and inevitably killing the host. LF is an extraordinarily selective metalloproteinase that site-specifically cleaves MKKs (mitogen-activated protein kinase kinases). Cleavage of MKKs by LF prevents them from activating their downstream MAPK (mitogen-activated protein kinase) substrates by disrupting a critical docking interaction. Blockade of MAPK signalling functionally impairs cells of both the innate and adaptive immune systems and induces cell death in macrophages. EF is an adenylate cyclase that is activated by calmodulin through a non-canonical mechanism. EF causes sustained and potent activation of host cAMP-dependent signalling pathways, which disables phagocytes. Here I review recent progress in elucidating the mechanisms by which LF and EF influence host signalling and thereby contribute to disease.  相似文献   
102.
103.
104.
The surface potential of the purple membrane was measured by a novel method by using an artificial bacteriorhodopsin whose chromophore was 13-CF3 retinal instead of retinal. When attached to the apoprotein by a Schiff base, the intrinsic pK of the 13-CF3 chromophore is around 7.3. The apparent pK of this pigment depends on the surface potential and thus on the electrolyte concentration. This allowed us to determine the surface charge density using the Gouy-Chapman equation. The surface charge density was found to be −1.65 ± 0.15 × 10−3 electronic charges per Å2 or about 2 negative charges/bacteriorhodopsin. This large value for the surface potential probably explains both part of the strong apparent association of divalent cations with the membrane and the effect of low salt concentrations on light-induced proton release from the purple membrane.  相似文献   
105.
Post-translational modifications (PTMs) of histones play an important role in many cellular processes, notably gene regulation. Using a combination of mass spectrometric and immunobiochemical approaches, we show that the PTM profile of histone H3 differs significantly among the various model organisms examined. Unicellular eukaryotes, such as Saccharomyces cerevisiae (yeast) and Tetrahymena thermophila (Tet), for example, contain more activation than silencing marks as compared with mammalian cells (mouse and human), which are generally enriched in PTMs more often associated with gene silencing. Close examination reveals that many of the better-known modified lysines (Lys) can be either methylated or acetylated and that the overall modification patterns become more complex from unicellular eukaryotes to mammals. Additionally, novel species-specific H3 PTMs from wild-type asynchronously grown cells are also detected by mass spectrometry. Our results suggest that some PTMs are more conserved than previously thought, including H3K9me1 and H4K20me2 in yeast and H3K27me1, -me2, and -me3 in Tet. On histone H4, methylation at Lys-20 showed a similar pattern as H3 methylation at Lys-9, with mammals containing more methylation than the unicellular organisms. Additionally, modification profiles of H4 acetylation were very similar among the organisms examined.  相似文献   
106.
The selection of an adequate exposure assessment approach is imperative for the quality of epidemiological studies. The use of personal exposimeters turned out to be a reasonable approach to determine exposure profiles, however, certain limitations regarding the absolute values delivered by the devices have to be considered. Apart from the limited dynamic range, it has to be taken into account that these devices give only an approximation of the exposure due to the influence of the body of the person carrying the exposimeter, the receiver characteristics of the exposimeter, as well as the dependence of the measured value on frequency band, channel, slot configuration, and communication traffic. In this study, the relationship between the field strength measured close to the human body at the location of the exposimeter and the exposure, that is, the field strength at the location of the human body without the human body present, is investigated by numerical means using the Visible Human model as an anatomical phantom. Two different scenarios were chosen: (1) For FM, GSM, and UMTS an urban outdoor scenario was examined that included a transmitting antenna mounted on the roof of one of four buildings at a street crossing, (2) For WLAN an indoor scenario was investigated. For GSM the average degree of underestimation by the exposimeter (relation of the average field levels at the location of the exposimeter to the field level averaged over the volume of the human body without the body present) was 0.76, and for UMTS 0.87; for FM no underestimation was found, the ratio was 1. In the case of WLAN the degree of underestimation was more pronounced, the ratio was 0.64. This study clearly suggests that a careful evaluation of correction factors for different scenarios is needed prior to the definition of the study protocol. It has to be noted that the reference scenario used in this study does not allow for final conclusions on general correction factors. Bioelectromagnetics 31:535–545, 2010. © 2010 Wiley‐Liss, Inc.  相似文献   
107.
Decreased antigenicity of cancer cells is a major problem in tumor immunology. This is often acquired by an expression defect in the TAP. However, it has been reported that certain murine Ags appear on the target cell surface upon impairment of TAP expression. In this study, we identified a human CTL epitope belonging to this Ag category. This epitope is derived from preprocalcitonin (ppCT) signal peptide and is generated within the endoplasmic reticulum by signal peptidase and signal peptide peptidase. Lung cancer cells bearing this antigenic peptide displayed low levels of TAP, but restoration of their expression by IFN-γ treatment or TAP1 and TAP2 gene transfer abrogated ppCT Ag presentation. In contrast, TAP upregulation in the same tumor cells increased their recognition by proteasome/TAP-dependent peptide-specific CTLs. Thus, to our knowledge, ppCT(16-25) is the first human tumor epitope whose surface expression requires loss or downregulation of TAP. Lung tumors frequently display low levels of TAP molecules and might thus be ignored by the immune system. Our results suggest that emerging signal peptidase-generated peptides represent alternative T cell targets, which permit CTLs to destroy TAP-impaired tumors and thus overcome tumor escape from CD8(+) T cell immunity.  相似文献   
108.
109.
110.
Maternal transfer of strain-specific immunity in an invertebrate   总被引:10,自引:0,他引:10  
The most celebrated component of the vertebrate immune system is the acquired response in which memory cells established during primary infection enhance the proliferation of antibodies during secondary infection. Additionally, the strength of vertebrate acquired immune responses varies dramatically depending on the infecting pathogen species or on the pathogen genotype within species. Because invertebrates lack the T-cell receptors and Major Histocompatibility Complex (MHC) molecules that mediate vertebrate adaptive immune responses, they are thought to lack adaptive immunity and be relatively unspecific in their interactions with pathogens. With only innate immunity, invertebrate hosts are believed to be nai;ve at each new encounter with pathogens. Nevertheless, some forms of facultative immunity appear to be important in insects; some individuals have enhanced immunity due to population density, and some social insects benefit when their nest-mates have been exposed to a pathogen or pathogen mimic (; see for a predation example.) Here we provide evidence for acquired strain-specific immunity in the crustacean Daphnia magna infected with the pathogenic bacteria Pasteuria ramosa. Specifically, the fitness of hosts was enhanced when challenged with a bacterial strain their mother had experienced relative to cases when mother and offspring were challenged with different strains.  相似文献   
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