全文获取类型
收费全文 | 12398篇 |
免费 | 1082篇 |
国内免费 | 3篇 |
专业分类
13483篇 |
出版年
2023年 | 43篇 |
2022年 | 128篇 |
2021年 | 253篇 |
2020年 | 147篇 |
2019年 | 169篇 |
2018年 | 231篇 |
2017年 | 182篇 |
2016年 | 317篇 |
2015年 | 577篇 |
2014年 | 568篇 |
2013年 | 729篇 |
2012年 | 992篇 |
2011年 | 1038篇 |
2010年 | 633篇 |
2009年 | 539篇 |
2008年 | 860篇 |
2007年 | 860篇 |
2006年 | 769篇 |
2005年 | 718篇 |
2004年 | 764篇 |
2003年 | 632篇 |
2002年 | 647篇 |
2001年 | 109篇 |
2000年 | 69篇 |
1999年 | 106篇 |
1998年 | 165篇 |
1997年 | 115篇 |
1996年 | 110篇 |
1995年 | 97篇 |
1994年 | 84篇 |
1993年 | 76篇 |
1992年 | 57篇 |
1991年 | 65篇 |
1990年 | 43篇 |
1989年 | 41篇 |
1988年 | 43篇 |
1987年 | 39篇 |
1986年 | 52篇 |
1985年 | 42篇 |
1984年 | 44篇 |
1983年 | 45篇 |
1982年 | 40篇 |
1981年 | 37篇 |
1980年 | 35篇 |
1979年 | 25篇 |
1978年 | 23篇 |
1977年 | 19篇 |
1976年 | 24篇 |
1974年 | 16篇 |
1973年 | 13篇 |
排序方式: 共有10000条查询结果,搜索用时 0 毫秒
921.
922.
Timothy J. Gawne 《Journal of computational neuroscience》2010,29(3):615-623
The Local Field Potential (LFP) is the analog signal recorded from a microelectrode inserted into cortex, typically in the
frequency band of approximately 1 to 200 Hz. Here visual stimuli were flashed on in the receptive fields of primary visual
cortical neurons in awake behaving macaques, and both isolated single units (neurons) and the LFP signal were recorded from
the same unipolar microelectrode. The fall-off of single unit activity as a visual stimulus was moved from near the center
to near the edge of the receptive field paralleled the fall-off of the stimulus-locked (evoked) LFP response. This suggests
that the evoked LFP strongly reflects local neuronal activity. However, the evoked LFP could be significant even when the
visual stimulus was completely outside the receptive field and the single unit response had fallen to zero, although this
phenomenon was variable. Some of the non-local components of the LFP may be related to the slow distributed, or non-retinotopic,
LFP signal previously observed in anesthetized animals. The induced (not time-locked to stimulus onset) component of the LFP
showed significant increases only for stimuli within the receptive field of the single units. While the LFP primarily reflects
local neuronal activity, it can also reflect neuronal activity at more distant sites, although these non-local components
are typically more variable, slower, and weaker than the local components. 相似文献
923.
Jared J. Heymann Mario Gabričević Timothy A. Mietzner Alvin L. Crumbliss 《Journal of biological inorganic chemistry》2010,15(2):237-248
The bacterial transferrin ferric binding protein A (FbpA) requires an exogenous anion to facilitate iron sequestration, and
subsequently to shuttle the metal across the periplasm to the cytoplasmic membrane. In the diverse conditions of the periplasm,
numerous anions are known to be present. Prior in vitro experiments have demonstrated the ability of multiple anions to fulfill
the synergistic iron-binding requirement, and the identity of the bound anion has been shown to modulate important physicochemical
properties of iron-bound FbpA (FeFbpA). Here we address the kinetics and mechanism of anion exchange for the FeFbpA–nitrilotriacetate
(NTA) assembly with several biologically relevant anions (citrate, oxalate, phosphate, and pyrophosphate), with nonphysiologic
NTA serving as a representative synergistic anion/chelator. The kinetic data are consistent with an anion-exchange process
that occurs in multiple steps, dependent on the identity of both the entering anion and the leaving anion. The exchange mechanism
may proceed either as a direct substitution or through an intermediate FeFbpA–X* assembly based on anion (X) identity. Our
kinetic results further develop an understanding of exogenous anion lability in the periplasm, as well as address the final
step of the iron-free FbpA (apo-FbpA)/Fe3+ sequestration mechanism. Our results highlight the kinetic significance of the FbpA anion binding site, demonstrating a correlation
between apo-FbpA/anion affinity and the FeFbpA rate of anion exchange, further supporting the requirement of an exogenous
anion to complete tight sequestration of iron by FbpA, and developing a mechanism for anion exchange within FeFbpA that is
dependent on the identity of both the entering anion and the leaving anion. 相似文献
924.
Bryan J. Williams Rui‐Hong Du M. Wade Calcutt Rasul Abdolrasulnia Brian W. Christman Timothy S. Blackwell 《Molecular microbiology》2010,76(1):104-119
Agmatine is the decarboxylation product of arginine and a number of bacteria have devoted enzymatic pathways for its metabolism. Pseudomonas aeruginosa harbours the aguBA operon that metabolizes agmatine to putrescine, which can be subsequently converted into other polyamines or shunted into the TCA cycle for energy production. We discovered an alternate agmatine operon in the P. aeruginosa strain PA14 named agu2ABCA′ that contains two genes for agmatine deiminases (agu2A and agu2A′). This operon was found to be present in 25% of clinical P. aeruginosa isolates. Agu2A′ contains a twin‐arginine translocation signal at its N‐terminus and site‐directed mutagenesis and cell fractionation experiments confirmed this protein is secreted to the periplasm. Analysis of the agu2ABCA′ promoter demonstrates that agmatine induces expression of the operon during the stationary phase of growth and during biofilm growth and agu2ABCA′ provides only weak complementation of aguBA, which is induced during log phase. Biofilm assays of mutants of all three agmatine deiminase genes in PA14 revealed that deletion of agu2ABCA′, specifically its secreted product Agu2A′, reduces biofilm production of PA14 following addition of exogenous agmatine. Together, these findings reveal a novel role for the agu2ABCA′ operon in the biofilm development of P. aeruginosa. 相似文献
925.
926.
Kap‐Hoon Han Yoon‐Hee Chun Bárbara De Castro Pimentel Figueiredo Frederico Marianetti Soriani Marcela Savoldi Agostinho Almeida Fernando Rodrigues Charlie Timothy Cairns Elaine Bignell Jaqueline Moisés Tobal Maria Helena S. Goldman Jong‐Hwan Kim Yong‐Sun Bahn Gustavo Henrique Goldman Márcia Eliana Da Silva Ferreira 《Molecular microbiology》2010,75(6):1372-1388
Carbon dioxide (CO2) and its hydration product bicarbonate (HCO3‐) are essential molecules in various physiological processes of all living organisms. The reversible interconversion between CO2 and HCO3‐ is in equilibrium. This reaction is slow without catalyst, but can be rapidly facilitated by Zn2+‐metalloenzymes named carbonic anhydrases (CAs). To gain an insight into the function of multiple clades of fungal CA, we chose to investigate the filamentous fungi Aspergillus fumigatus and A. nidulans. We identified four and two CAs in A. fumigatus and A. nidulans, respectively, named cafA‐D and canA‐B. The cafA and cafB genes are constitutively, strongly expressed whereas cafC and cafD genes are weakly expressed but CO2‐inducible. Heterologous expression of the A. fumigatus cafB, and A. nidulans canA and canB genes completely rescued the high CO2‐requiring phenotype of a Saccharomyces cerevisiaeΔnce103 mutant. Only the ΔcafAΔcafB and ΔcanB deletion mutants were unable to grow at 0.033% CO2, of which growth defects can be restored by high CO2. Defects in the CAs can affect Aspergilli conidiation. Furthermore, A. fumigatusΔcafA, ΔcafB, ΔcafC, ΔcafD and ΔcafAΔcafB mutant strains are fully virulent in a low‐dose murine infection. 相似文献
927.
Yang Z Fairfax DJ Maeng JH Masih L Usyatinsky A Hassler C Isaacson S Fitzpatrick K DeOrazio RJ Chen J Harding JP Isherwood M Dobritsa S Christensen KL Wierschke JD Bliss BI Peterson LH Beer CM Cioffi C Lynch M Rennells WM Richards JJ Rust T Khmelnitsky YL Cohen ML Manning DD 《Bioorganic & medicinal chemistry letters》2010,20(22):6538-6541
A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D). 相似文献
928.
Bin Ma Kevin M. Guckian Edward Yin-Shiang Lin Wen-Cherng Lee Daniel Scott Gnanasambandam Kumaravel Timothy L. Macdonald Kevin R. Lynch Cheryl Black Sowmya Chollate Kyungmin Hahm Gregg Hetu Ping Jin Yi Luo Ellen Rohde Anthony Rossomando Robert Scannevin Joy Wang Chunhua Yang 《Bioorganic & medicinal chemistry letters》2010,20(7):2264-2269
Modifying FTY720, an immunosuppressant modulator, led to a new series of well phosphorylated tetralin analogs as potent S1P1 receptor agonists. The stereochemistry effect of tetralin ring was probed, and (?)-(R)-2-amino-2-((S)-6-octyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability. 相似文献
929.
Daniel A. Bachovchin Monique R. Wolfe Kim Masuda Steven J. Brown Timothy P. Spicer Virneliz Fernandez-Vega Peter Chase Peter S. Hodder Hugh Rosen Benjamin F. Cravatt 《Bioorganic & medicinal chemistry letters》2010,20(7):2254-2258
We recently described a fluorescence polarization platform for competitive activity-based protein profiling (fluopol-ABPP) that enables high-throughput inhibitor screening for enzymes with poorly characterized biochemical activity. Here, we report the discovery of a class of oxime ester inhibitors for the unannotated serine hydrolase RBBP9 from a full-deck (200,000+ compound) fluopol-ABPP screen conducted in collaboration with the Molecular Libraries Screening Center Network (MLSCN). We show that these compounds covalently inhibit RBBP9 by modifying enzyme’s active site serine nucleophile and, based on competitive ABPP in cell and tissue proteomes, are selective for RBBP9 relative to other mammalian serine hydrolases. 相似文献
930.
Wilna J. Moree Florence Jovic Timothy Coon Jinghua Yu Bin-Feng Li Fabio C. Tucci Dragan Marinkovic Raymond S. Gross Siobhan Malany Margaret J. Bradbury Lisa M. Hernandez Zhihong O’Brien Jianyun Wen Hua Wang Samuel R.J. Hoare Robert E. Petroski Aida Sacaan Ajay Madan Paul D. Crowe Graham Beaton 《Bioorganic & medicinal chemistry letters》2010,20(7):2316-2320
SAR of lead benzothiophene H1-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H1-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound. 相似文献