全文获取类型
收费全文 | 1935篇 |
免费 | 147篇 |
国内免费 | 5篇 |
专业分类
2087篇 |
出版年
2023年 | 7篇 |
2022年 | 39篇 |
2021年 | 66篇 |
2020年 | 47篇 |
2019年 | 57篇 |
2018年 | 61篇 |
2017年 | 52篇 |
2016年 | 78篇 |
2015年 | 90篇 |
2014年 | 130篇 |
2013年 | 115篇 |
2012年 | 167篇 |
2011年 | 145篇 |
2010年 | 108篇 |
2009年 | 84篇 |
2008年 | 136篇 |
2007年 | 133篇 |
2006年 | 118篇 |
2005年 | 93篇 |
2004年 | 108篇 |
2003年 | 80篇 |
2002年 | 73篇 |
2001年 | 10篇 |
2000年 | 13篇 |
1999年 | 10篇 |
1998年 | 17篇 |
1997年 | 14篇 |
1996年 | 5篇 |
1995年 | 3篇 |
1994年 | 4篇 |
1993年 | 2篇 |
1992年 | 6篇 |
1991年 | 2篇 |
1989年 | 1篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1983年 | 2篇 |
1979年 | 1篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1959年 | 1篇 |
排序方式: 共有2087条查询结果,搜索用时 0 毫秒
1.
New material ofTrischizolagus dumitrescuae from Moldova and Ukraine is described. The variation of p3 inTrischizolagus shows the gradual shift of morphotype frequencies from the ‘Hypolagus’ pattern in Turolian through the mixture of three patterns (including ‘Nekrolagus’ morphotype) in Early Ruscinian to the dominant ‘Alilepus’ pattern in the Late Ruscinian samples. These transformations took place parallel to that of the North AmericanNekrolagus. Probably North AmericanSylvilagus, Brachylagus, andRomerolagus had an North American origin fromNekrolagus, whereas Eurasiatic and AfricanOryctolagus, Caprolagus, Nesolagus, andPoelagus could have originated in the Old World fromTrischizolagus. 相似文献
2.
David Houle Alexey S Kondrashov 《Proceedings. Biological sciences / The Royal Society》2002,269(1486):97-104
Females often choose their mates, instead of mating at random, even when a father contributes nothing but genes to his offspring. Costly female preferences for males with exaggerated traits that reduce viability, such as the peacock's tail, are particularly puzzling. Such preferences can evolve if directly favoured by natural selection or when the exaggerated trait, although maladaptive per se, indicates high overall quality of the male's genotype. Two recent analyses suggested that the advantage to mate choice based on genetic quality is too weak to explain extreme cases of exaggeration of display traits and the corresponding preferences. We studied coevolution of a female mate-preference function and a genotype-dependent male display function where mutation supplies variation in genotype quality and mate preference is costly. Preference readily evolves, often causing extreme exaggeration of the display. Mate choice and trait expression can approach an equilibrium, or a limit cycle, or exaggeration can proceed forever, eventually causing extinction. 相似文献
3.
Formaldehyde fixation of cells is routinely used to study DNA-protein interactions in vivo. In these studies, DNA is often analyzed using a polymerase chain reaction technique. Although it is known that formaldehyde can damage DNA, no studies have been performed so far to compare the efficiency of DNA amplification between normal and fixed cells. Here we show that formaldehyde fixation results in a 15% to 20% reduction in the ability to amplify cellular DNA. The loss of amplifiability is independent of the length of the amplification region and the degree to which DNA is compacted on packaging into chromatin. 相似文献
4.
Alexey F. Bochkov Vladimir N. Chernetsky Nikolay K. Kochetkov 《Carbohydrate research》1975,43(1):35-41
Cationic polymerisation of 3-O-acetyl-β-L-arabinofuranose 1,2,5-orthobenzoate initiated by either triphenylcarbonium tetrafluoroborate or benzoylium perchlorate has been studied. The existence of living chains was demonstrated by termination of polymerisation with tritium-labelled 1-butanol. The number of growing chains reached a maximum after ≈10 min and then decreased. 相似文献
5.
In the past there were doubts about the existence of a especialmoult after the release of an anomopod embryo from the maternalbrood pouch. This moult occurs in all studied anomopods and marksthe beginning of the first juvenile instar. The term neonata (orneanate) must be applied to the unexpanded animal (the terminalphase of embryogenesis) before this moult, and not to the earlyphase of the first postembryonic instar. The latter is the nextstage of development. Using knowledge of the presence of thismoult, it is possible to understand and explain the contradictionsin the periodization of postembryonic development as described bydifferent authors. Under normal conditions males of bosminids andevolutionarily advanced chydorids have only two juvenile instars(with specific morphology) in the course of development. This is anadditional argument to support the idea of close relationship ofthe families Chydoridae and Bosminidae. 相似文献
6.
Valter Bergant Shintaro Yamada Vincent Grass Yuta Tsukamoto Teresa Lavacca Karsten Krey MariaTeresa Mühlhofer Sabine Wittmann Armin Ensser Alexandra Herrmann Anja vom Hemdt Yuriko Tomita Shutoku Matsuyama Takatsugu Hirokawa Yiqi Huang Antonio Piras Constanze A Jakwerth Madlen Oelsner Susanne Thieme Alexander Graf Stefan Krebs Helmut Blum Beate M Kümmerer Alexey Stukalov Carsten B SchmidtWeber Manabu Igarashi Thomas Gramberg Andreas Pichlmair Hiroki Kato 《The EMBO journal》2022,41(17)
The SARS‐CoV‐2 infection cycle is a multistage process that relies on functional interactions between the host and the pathogen. Here, we repurposed antiviral drugs against both viral and host enzymes to pharmaceutically block methylation of the viral RNA 2''‐O‐ribose cap needed for viral immune escape. We find that the host cap 2''‐O‐ribose methyltransferase MTr1 can compensate for loss of viral NSP16 methyltransferase in facilitating virus replication. Concomitant inhibition of MTr1 and NSP16 efficiently suppresses SARS‐CoV‐2 replication. Using in silico target‐based drug screening, we identify a bispecific MTr1/NSP16 inhibitor with anti‐SARS‐CoV‐2 activity in vitro and in vivo but with unfavorable side effects. We further show antiviral activity of inhibitors that target independent stages of the host SAM cycle providing the methyltransferase co‐substrate. In particular, the adenosylhomocysteinase (AHCY) inhibitor DZNep is antiviral in in vitro, in ex vivo, and in a mouse infection model and synergizes with existing COVID‐19 treatments. Moreover, DZNep exhibits a strong immunomodulatory effect curbing infection‐induced hyperinflammation and reduces lung fibrosis markers ex vivo. Thus, multispecific and metabolic MTase inhibitors constitute yet unexplored treatment options against COVID‐19. 相似文献
7.
Jacob L. Jordan Joseph W. Arndt Karl Hanf Guohui Li Janine Hall Stephen Demarest Flora Huang Xiufeng Wu Brian Miller Scott Glaser Erik J. Fernandez Deping Wang Alexey Lugovskoy 《Proteins》2009,77(4):832-841
Bispecific immunoglobulin‐like antibodies capable of engaging multiple antigens represent a promising new class of therapeutic agents. Engineering of these molecules requires optimization of the molecular properties of one of the domain components. Here, we present a detailed crystallographic and computational characterization of the stabilization patterns in the lymphotoxin‐beta receptor (LTβR) binding Fv domain of an anti‐LTβR/anti‐TNF‐related apoptosis inducing ligand receptor‐2 (TRAIL‐R2) bispecific immunoglobulin‐like antibody. We further describe a new hierarchical structure‐guided approach toward engineering of antibody‐like molecules to enhance their thermal and chemical stability. Proteins 2009. © 2009 Wiley‐Liss, Inc. 相似文献
8.
Istem Fer Anthony K. Gardella Alexey N. Shiklomanov Eleanor E. Campbell Elizabeth M. Cowdery Martin G. De Kauwe Ankur Desai Matthew J. Duveneck Joshua B. Fisher Katherine D. Haynes Forrest M. Hoffman Miriam R. Johnston Rob Kooper David S. LeBauer Joshua Mantooth William J. Parton Benjamin Poulter Tristan Quaife Ann Raiho Kevin Schaefer Shawn P. Serbin James Simkins Kevin R. Wilcox Toni Viskari Michael C. Dietze 《Global Change Biology》2021,27(1):13-26
In an era of rapid global change, our ability to understand and predict Earth's natural systems is lagging behind our ability to monitor and measure changes in the biosphere. Bottlenecks to informing models with observations have reduced our capacity to fully exploit the growing volume and variety of available data. Here, we take a critical look at the information infrastructure that connects ecosystem modeling and measurement efforts, and propose a roadmap to community cyberinfrastructure development that can reduce the divisions between empirical research and modeling and accelerate the pace of discovery. A new era of data‐model integration requires investment in accessible, scalable, and transparent tools that integrate the expertise of the whole community, including both modelers and empiricists. This roadmap focuses on five key opportunities for community tools: the underlying foundations of community cyberinfrastructure; data ingest; calibration of models to data; model‐data benchmarking; and data assimilation and ecological forecasting. This community‐driven approach is a key to meeting the pressing needs of science and society in the 21st century. 相似文献
9.
Mitogen-activated protein kinase-activated protein kinase 2-deficient mice show increased susceptibility to Listeria monocytogenes infection 总被引:7,自引:0,他引:7
Lehner MD Schwoebel F Kotlyarov A Leist M Gaestel M Hartung T 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(9):4667-4673
Mitogen-activated protein kinase-activated protein kinase 2 (MK2) is one of several kinases activated through direct phosphorylation by p38 mitogen-activated protein kinase. MK2 regulates LPS-induced TNF mRNA translation, and targeted mutation of the MK2 gene renders mice more resistant to D-galactosamine plus LPS-induced liver damage. In the present study, we investigated the role of MK2 in immune defense against Listeria monocytogenes infection. MK2-deficient mice displayed diminished resistance to L. monocytogenes due to impaired control of bacterial growth. The increase in bacterial load in MK2(-/-) mice was associated with normal levels of IL-1 beta, IL-6, and IFN-gamma, whereas TNF production was strongly attenuated. In line, MK2-deficient bone marrow-derived macrophages showed impaired release of TNF, but not of IL-1 beta, in response to various bacterial stimuli in addition to decreased phagocytosis of fluorescence-labeled bacteria. Furthermore, spleen cells from MK2(-/-) mice displayed diminished IFN-gamma synthesis after stimulation with L. monocytogenes. In contrast, MK2 deficiency had no effect on macrophage generation of NO or on oxidative burst activity in response to L. moocytogenes. These results indicate an essential role of MK2 in host defense against intracellular bacteria probably via regulation of TNF and IFN-gamma production required for activation of antibacterial effector mechanisms. 相似文献
10.
Erpan Ahat Sarah Bui Jianchao Zhang Felipe da Veiga Leprevost Lisa Sharkey Whitney Reid Alexey I. Nesvizhskii Henry L. Paulson Yanzhuang Wang 《The Journal of biological chemistry》2022,298(8)
Recent studies demonstrated that the Golgi reassembly stacking proteins (GRASPs), especially GRASP55, regulate Golgi-independent unconventional secretion of certain cytosolic and transmembrane cargoes; however, the underlying mechanism remains unknown. Here, we surveyed several neurodegenerative disease–related proteins, including mutant huntingtin (Htt-Q74), superoxide dismutase 1 (SOD1), tau, and TAR DNA–binding protein 43 (TDP-43), for unconventional secretion; our results show that Htt-Q74 is most robustly secreted in a GRASP55-dependent manner. Using Htt-Q74 as a model system, we demonstrate that unconventional secretion of Htt is GRASP55 and autophagy dependent and is enhanced under stress conditions such as starvation and endoplasmic reticulum stress. Mechanistically, we show that GRASP55 facilitates Htt secretion by tethering autophagosomes to lysosomes to promote autophagosome maturation and subsequent lysosome secretion and by stabilizing p23/TMED10, a channel for translocation of cytoplasmic proteins into the lumen of the endoplasmic reticulum–Golgi intermediate compartment. Moreover, we found that GRASP55 levels are upregulated by various stresses to facilitate unconventional secretion, whereas inhibition of Htt-Q74 secretion by GRASP55 KO enhances Htt aggregation and toxicity. Finally, comprehensive secretomic analysis identified novel cytosolic cargoes secreted by the same unconventional pathway, including transgelin (TAGLN), multifunctional protein ADE2 (PAICS), and peroxiredoxin-1 (PRDX1). In conclusion, this study defines the pathway of GRASP55-mediated unconventional protein secretion and provides important insights into the progression of Huntington’s disease. 相似文献