全文获取类型
收费全文 | 8438篇 |
免费 | 614篇 |
国内免费 | 5篇 |
专业分类
9057篇 |
出版年
2023年 | 43篇 |
2022年 | 93篇 |
2021年 | 195篇 |
2020年 | 130篇 |
2019年 | 123篇 |
2018年 | 181篇 |
2017年 | 149篇 |
2016年 | 281篇 |
2015年 | 401篇 |
2014年 | 461篇 |
2013年 | 570篇 |
2012年 | 693篇 |
2011年 | 712篇 |
2010年 | 439篇 |
2009年 | 379篇 |
2008年 | 495篇 |
2007年 | 515篇 |
2006年 | 504篇 |
2005年 | 417篇 |
2004年 | 382篇 |
2003年 | 302篇 |
2002年 | 333篇 |
2001年 | 77篇 |
2000年 | 55篇 |
1999年 | 58篇 |
1998年 | 89篇 |
1997年 | 36篇 |
1996年 | 51篇 |
1995年 | 52篇 |
1994年 | 49篇 |
1993年 | 48篇 |
1992年 | 40篇 |
1991年 | 40篇 |
1990年 | 32篇 |
1989年 | 36篇 |
1988年 | 32篇 |
1987年 | 43篇 |
1986年 | 29篇 |
1985年 | 39篇 |
1984年 | 36篇 |
1983年 | 46篇 |
1982年 | 34篇 |
1981年 | 35篇 |
1980年 | 23篇 |
1979年 | 23篇 |
1978年 | 19篇 |
1977年 | 34篇 |
1976年 | 20篇 |
1973年 | 14篇 |
1964年 | 14篇 |
排序方式: 共有9057条查询结果,搜索用时 15 毫秒
151.
152.
Jye-Lin Hsu Dick J. H. van den Boomen Peter Tomasec Michael P. Weekes Robin Antrobus Richard J. Stanton Eva Ruckova Daniel Sugrue Gavin S. Wilkie Andrew J. Davison Gavin W. G. Wilkinson Paul J. Lehner 《PLoS pathogens》2015,11(4)
Human cytomegalovirus (HCMV) US2, US3, US6 and US11 act in concert to prevent immune recognition of virally infected cells by CD8+ T-lymphocytes through downregulation of MHC class I molecules (MHC-I). Here we show that US2 function goes far beyond MHC-I degradation. A systematic proteomic study using Plasma Membrane Profiling revealed US2 was unique in downregulating additional cellular targets, including: five distinct integrin α-chains, CD112, the interleukin-12 receptor, PTPRJ and thrombomodulin. US2 recruited the cellular E3 ligase TRC8 to direct the proteasomal degradation of all its targets, reminiscent of its degradation of MHC-I. Whereas integrin α-chains were selectively degraded, their integrin β1 binding partner accumulated in the ER. Consequently integrin signaling, cell adhesion and migration were strongly suppressed. US2 was necessary and sufficient for degradation of the majority of its substrates, but remarkably, the HCMV NK cell evasion function UL141 requisitioned US2 to enhance downregulation of the NK cell ligand CD112. UL141 retained CD112 in the ER from where US2 promoted its TRC8-dependent retrotranslocation and degradation. These findings redefine US2 as a multifunctional degradation hub which, through recruitment of the cellular E3 ligase TRC8, modulates diverse immune pathways involved in antigen presentation, NK cell activation, migration and coagulation; and highlight US2’s impact on HCMV pathogenesis. 相似文献
153.
154.
Tereza Krejcova Miroslava Smelcova Jaroslav Petr Jean-Francois Bodart Marketa Sedmikova Jan Nevoral Marketa Dvorakova Alena Vyskocilova Ivona Weingartova Veronika Kucerova-Chrpova Eva Chmelikova Lenka Tumova Frantisek Jilek 《PloS one》2015,10(1)
Porcine oocytes that have matured in in vitro conditions undergo the process of aging during prolonged cultivation, which is manifested by spontaneous parthenogenetic activation, lysis or fragmentation of aged oocytes. This study focused on the role of hydrogen sulfide (H2S) in the process of porcine oocyte aging. H2S is a gaseous signaling molecule and is produced endogenously by the enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (MPST). We demonstrated that H2S-producing enzymes are active in porcine oocytes and that a statistically significant decline in endogenous H2S production occurs during the first day of aging. Inhibition of these enzymes accelerates signs of aging in oocytes and significantly increases the ratio of fragmented oocytes. The presence of exogenous H2S from a donor (Na2S.9H2O) significantly suppressed the manifestations of aging, reversed the effects of inhibitors and resulted in the complete suppression of oocyte fragmentation. Cultivation of aging oocytes in the presence of H2S donor positively affected their subsequent embryonic development following parthenogenetic activation. Although no unambiguous effects of exogenous H2S on MPF and MAPK activities were detected and the intracellular mechanism underlying H2S activity remains unclear, our study clearly demonstrates the role of H2S in the regulation of porcine oocyte aging. 相似文献
155.
156.
157.
Susanne Diener Sieglinde Bayer Sibylle Sabrautzki Thomas Wieland Birgit Mentrup Gerhard K. H. Przemeck Birgit Rathkolb Elisabeth Graf Wolfgang Hans Helmut Fuchs Marion Horsch Thomas Schwarzmayr Eckhard Wolf Eva Klopocki Franz Jakob Tim M. Strom Martin Hrabě de Angelis Bettina Lorenz-Depiereux 《Mammalian genome》2016,27(3-4):111-121
We performed exome sequencing for mutation discovery of an ENU (N-ethyl-N-nitrosourea)-derived mouse model characterized by significant elevated plasma alkaline phosphatase (ALP) activities in female and male mutant mice, originally named BAP014 (bone screen alkaline phosphatase #14). We identified a novel loss-of-function mutation within the Fam46a (family with sequence similarity 46, member A) gene (NM_001160378.1:c.469G>T, NP_001153850.1:p.Glu157*). Heterozygous mice of this mouse line (renamed Fam46a E157*Mhda) had significantly high ALP activities and apparently no other differences in morphology compared to wild-type mice. In contrast, homozygous Fam46a E157*Mhda mice showed severe morphological and skeletal abnormalities including short stature along with limb, rib, pelvis, and skull deformities with minimal trabecular bone and reduced cortical bone thickness in long bones. ALP activities of homozygous mutants were almost two-fold higher than in heterozygous mice. Fam46a is weakly expressed in most adult and embryonic tissues with a strong expression in mineralized tissues as calvaria and femur. The FAM46A protein is computationally predicted as a new member of the superfamily of nucleotidyltransferase fold proteins, but little is known about its function. Fam46a E157*Mhda mice are the first mouse model for a mutation within the Fam46a gene. 相似文献
158.
159.
Chlamydia pneumoniae is a common human respiratory pathogen, and sera from infected individuals recognize several proteins of C. pneumoniae. We produced C. pneumoniae-specific proteins in a Bacillus subtilis expression system. We then used these recombinant C. pneumoniae proteins and purified C. pneumoniae elementary bodies as antigens in enzyme immunoassays to assess the kinetics and protein specificity of the systemic and mucosal antibody responses induced by C. pneumoniae intranasal infection in BALB/c mice. The systemic antibodies in mice recognized strong 'key' immunogens of Chlamydia, Omp2 and Hsp60, but weakly targeted the MOMP protein, the major immunogen in chlamydial species other than C. pneumoniae. The IgA antibodies in bronchial secretions specifically recognized the putative surface protein of C. pneumoniae, Omp4. Our preliminary observations point to the necessity of further characterization of the mucosal antibody response during C. pneumoniae infection. 相似文献
160.
Cnidarian envenomations cause a burning-pain sensation of which the underlying mechanisms are unknown. Activation of TRPV1, a non-selective cation channel expressed in nociceptive neurons, leads to cell depolarisation and pain. Here, we show in vitro and in vivo evidence for desensitization-dependent TRPV1 activation in cnidarian envenomations. Cnidarian venom induced a nociceptive reactivity, comparable to capsaicin, in laboratory rats, which could be reduced by the selective TRPV1 antagonist, BCTC. These findings are the first to explain at least part of the symptomology of cnidarian envenomations and provide insights into the design of more effective treatments for this global public health problem. 相似文献