全文获取类型
收费全文 | 886篇 |
免费 | 58篇 |
国内免费 | 2篇 |
专业分类
946篇 |
出版年
2022年 | 6篇 |
2021年 | 19篇 |
2020年 | 6篇 |
2019年 | 9篇 |
2018年 | 18篇 |
2017年 | 12篇 |
2016年 | 19篇 |
2015年 | 34篇 |
2014年 | 27篇 |
2013年 | 46篇 |
2012年 | 39篇 |
2011年 | 54篇 |
2010年 | 34篇 |
2009年 | 29篇 |
2008年 | 32篇 |
2007年 | 33篇 |
2006年 | 26篇 |
2005年 | 21篇 |
2004年 | 20篇 |
2003年 | 24篇 |
2002年 | 10篇 |
2001年 | 15篇 |
2000年 | 20篇 |
1999年 | 15篇 |
1998年 | 6篇 |
1997年 | 9篇 |
1996年 | 7篇 |
1992年 | 13篇 |
1991年 | 7篇 |
1990年 | 14篇 |
1989年 | 15篇 |
1988年 | 21篇 |
1987年 | 7篇 |
1986年 | 7篇 |
1985年 | 8篇 |
1984年 | 18篇 |
1983年 | 9篇 |
1982年 | 21篇 |
1981年 | 22篇 |
1980年 | 21篇 |
1979年 | 18篇 |
1978年 | 9篇 |
1977年 | 6篇 |
1976年 | 11篇 |
1975年 | 7篇 |
1974年 | 6篇 |
1973年 | 12篇 |
1972年 | 14篇 |
1970年 | 5篇 |
1968年 | 5篇 |
排序方式: 共有946条查询结果,搜索用时 0 毫秒
81.
During normal metaphase in Saccharomyces cerevisiae, chromosomes are captured at the kinetochores by microtubules emanating from the spindle pole bodies at opposite poles of the dividing cell. The balance of forces between the cohesins holding the replicated chromosomes together and the pulling force from the microtubules at the kinetochores result in the biorientation of the sister chromatids before chromosome segregation. The absence of kinetochore–microtubule interactions or loss of cohesion between the sister chromatids triggers the spindle checkpoint which arrests cells in metaphase. We report here that an MEN mutant, cdc15-2, though competent in activating the spindle assembly checkpoint when exposed to Noc, mis-segregated chromosomes during recovery from spindle checkpoint activation. cdc15-2 cells arrested in Noc, although their Pds1p levels did not accumulate as well as in wild-type cells. Genetic analysis indicated that Pds1p levels are lower in a mad2Δ cdc15-2 and bub2Δ cdc15-2 double mutants compared with the single mutants. Chromosome mis-segregation in the mutant was due to premature spindle elongation in the presence of unattached chromosomes, likely through loss of proper control on spindle midzone protein Slk19p and kinesin protein, Cin8p. Our data indicate that a slower rate of transition through the cell division cycle can result in an inadequate level of Pds1p accumulation that can compromise recovery from spindle assembly checkpoint activation. 相似文献
82.
Lake JP Lauder MA Smith NA 《Journal of strength and conditioning research / National Strength & Conditioning Association》2010,24(11):3180-3185
The aim of this study was to examine whether ground reaction force (GRF) side differences were transmitted and related to bar end power output asymmetries during hang power clean (HPC) performance and whether progressive loading would intensify this effect. Differences between the dominant (D) and nondominant (ND) side average GRFs (AGRFs) of both feet and average bar end power outputs were recorded simultaneously from 15 recreationally trained male volunteers at 30, 60, and 90% 1RM using 2 force platforms and 3 high-speed digital cameras, quantifying side dominance from perceived handedness (left- or right-side dominance [LRSD]), GRF side dominance (force side dominance [FSD]), and bar end power output side dominance (barbell side dominance [BSD]). With the exception of the LRSD condition, differences between the D and ND side AGRFs were significant (FSD: 1.8-4.3%; BSD: 5.1-6.4%, p < 0.05). Bar end power output side differences were significant for all conditions (LRSD: 1.5-5.4%; FSD: 0.5-3.4%; BSD: 3.9-5.6%, p < 0.05). Progressive loading did not significantly affect GRF side differences or the FSD average bar power side differences. However, during the LRSD and BSD conditions, the 60 and 90% side average bar power side differences were >the 30% equivalents. Average GRF side differences were not related to bar end power output side differences. Because of the consistent side difference of 4-6% investigators and strength and conditioning practitioners should exercise caution when interpreting changes in bar end power output. 相似文献
83.
Nina Klee Pui Ee Wong Beatriz Baragaña Farah El Mazouni Margaret A. Phillips Michael P. Barrett Ian H. Gilbert 《Bioorganic & medicinal chemistry letters》2010,20(15):4364-4366
Trypanosoma brucei, the parasite that causes human African trypanosomiasis, is auxotrophic for purines and has specialist nucleoside transporters to import these metabolites. In particular, the P2 aminopurine transporter can also selectively accumulate melamine derivatives. In this Letter, we report the coupling of the melamine moiety to 2-hydroxy APA, a potent ornithine decarboxylase inhibitor, with the aim of selectively delivering this compound to the parasite. The best compound described here shows an increased in vitro trypanocidal activity compared with the parent. 相似文献
84.
85.
Stéphanie Blanchard Anthony D. William Angeline C.-H. Lee Anders Poulsen Ee Ling Teo Weiping Deng Noah Tu Evelyn Tan Kay Lin Goh Wai Chung Ong Chee Pang Ng Kee Chuan Goh Zahid Bonday Eric T. Sun 《Bioorganic & medicinal chemistry letters》2010,20(8):2443-2447
A series of alkenyl indazoles were synthesized and evaluated in Aurora kinase enzyme assays. Several promising leads were optimized for selectivity towards Aurora B. Excellent binding affinity and good selectivity were achieved with optimized compounds in isolated Aurora subfamily assays. 相似文献
86.
Wang YE Park A Lake M Pentecost M Torres B Yun TE Wolf MC Holbrook MR Freiberg AN Lee B 《PLoS pathogens》2010,6(11):e1001186
Paramyxoviruses are known to replicate in the cytoplasm and bud from the plasma membrane. Matrix is the major structural protein in paramyxoviruses that mediates viral assembly and budding. Curiously, the matrix proteins of a few paramyxoviruses have been found in the nucleus, although the biological function associated with this nuclear localization remains obscure. We report here that the nuclear-cytoplasmic trafficking of the Nipah virus matrix (NiV-M) protein and associated post-translational modification play a critical role in matrix-mediated virus budding. Nipah virus (NiV) is a highly pathogenic emerging paramyxovirus that causes fatal encephalitis in humans, and is classified as a Biosafety Level 4 (BSL4) pathogen. During live NiV infection, NiV-M was first detected in the nucleus at early stages of infection before subsequent localization to the cytoplasm and the plasma membrane. Mutations in the putative bipartite nuclear localization signal (NLS) and the leucine-rich nuclear export signal (NES) found in NiV-M impaired its nuclear-cytoplasmic trafficking and also abolished NiV-M budding. A highly conserved lysine residue in the NLS served dual functions: its positive charge was important for mediating nuclear import, and it was also a potential site for monoubiquitination which regulates nuclear export of the protein. Concordantly, overexpression of ubiquitin enhanced NiV-M budding whereas depletion of free ubiquitin in the cell (via proteasome inhibitors) resulted in nuclear retention of NiV-M and blocked viral budding. Live Nipah virus budding was exquisitely sensitive to proteasome inhibitors: bortezomib, an FDA-approved proteasome inhibitor for treating multiple myeloma, reduced viral titers with an IC(50) of 2.7 nM, which is 100-fold less than the peak plasma concentration that can be achieved in humans. This opens up the possibility of using an "off-the-shelf" therapeutic against acute NiV infection. 相似文献
87.
88.
L. Lgdberg E. Kaplan M. Drelich E. Harfeldt H. Gunn P. Ehrlich D. Dottavio P. Lake L.
stberg 《Journal of medical primatology》1994,23(5):285-297
The feasibility to raise nonhuman primate antibodies against selected components of the human immune system was tested. The immunogens were whole cells (human T lymphocytes) or purified, recombinant human proteins (cytokines: TNFα or GM-CSF; soluble forms of cell surface antigens: sCD4 or sCD25). Significant immunizations, yielding functionally relevant antibodies, were readily achieved in rhesus monkeys, but, not surprisingly, may be less frequent in chimpanzees. The results suggest a general strategy for production of therapeutically useful MAB. 相似文献
89.
90.
Kwon YE Park JY No KT Shin JH Lee SK Eun JS Yang JH Shin TY Kim DK Chae BS Leem JY Kim KH 《Bioorganic & medicinal chemistry》2007,15(20):6596-6607
With the goal of developing Alzheimer's disease therapeutics, we have designed and synthesized new piperidine derivatives having dual action of acetylcholinesterase (AChE) and beta-amyloid peptide (Abeta) aggregation inhibition. For binding with the catalytic site of AChE, an ester with aromatic group was designed, and for the peripheral site, another aromatic group was considered. And for intercalating amyloid-beta oligomerization, long and linear conformation with a lipophilic group was considered. The synthetic methods employed for the structure with dual action depended on alcohols with an aromatic ring and the substituted benzoic acids, which are esterificated in the last step of the synthetic pathway. We screened these new derivatives through inhibition tests of acetylcholinesterase, butyrylcholinesterase (BChE), and Abeta(1-42) peptide aggregation, AChE-induced Abeta(1-42) aggregation. Our results displayed that compound 12 showed the best inhibitory potency and selectivity of AChE, and 29 showed the highest selectivity of BChE inhibition. Compounds 15 and 12 had inhibitory activities against Abeta(1-42) aggregation and AChE-induced Abeta aggregation. In the docking model, we confirmed that 4-chlorobenzene of 12 plays the parallel pi-pi stacking against the indole ring of Trp84 in the bottom gorge of AChE. Because the benzyhydryl moiety of 12 covered the peripheral site of AChE in a funnel-like shape, 12 showed good inhibitory potency against AChE and could inhibit AChE-induced Abeta(1-42) peptide aggregation. 相似文献