全文获取类型
收费全文 | 804篇 |
免费 | 95篇 |
国内免费 | 3篇 |
出版年
2022年 | 5篇 |
2021年 | 9篇 |
2019年 | 11篇 |
2017年 | 7篇 |
2016年 | 13篇 |
2015年 | 27篇 |
2014年 | 21篇 |
2013年 | 39篇 |
2012年 | 68篇 |
2011年 | 60篇 |
2010年 | 34篇 |
2009年 | 22篇 |
2008年 | 36篇 |
2007年 | 53篇 |
2006年 | 27篇 |
2005年 | 27篇 |
2004年 | 42篇 |
2003年 | 25篇 |
2002年 | 30篇 |
2001年 | 41篇 |
2000年 | 18篇 |
1999年 | 14篇 |
1997年 | 8篇 |
1996年 | 12篇 |
1995年 | 7篇 |
1994年 | 9篇 |
1993年 | 7篇 |
1992年 | 9篇 |
1991年 | 14篇 |
1990年 | 12篇 |
1989年 | 19篇 |
1988年 | 11篇 |
1987年 | 9篇 |
1986年 | 8篇 |
1985年 | 9篇 |
1984年 | 5篇 |
1983年 | 8篇 |
1982年 | 7篇 |
1981年 | 7篇 |
1980年 | 5篇 |
1979年 | 12篇 |
1978年 | 6篇 |
1976年 | 12篇 |
1975年 | 6篇 |
1974年 | 5篇 |
1973年 | 6篇 |
1972年 | 10篇 |
1970年 | 7篇 |
1968年 | 4篇 |
1966年 | 5篇 |
排序方式: 共有902条查询结果,搜索用时 125 毫秒
51.
Dombroski MA Letavic MA McClure KF Barberia JT Carty TJ Cortina SR Csiki C Dipesa AJ Elliott NC Gabel CA Jordan CK Labasi JM Martin WH Peese KM Stock IA Svensson L Sweeney FJ Yu CH 《Bioorganic & medicinal chemistry letters》2004,14(4):919-923
The synthesis and in vitro p38 alpha activity of a novel series of benzimidazolone inhibitors is described. The p38 alpha SAR is consistent with a mode of binding wherein the benzimidazolone carbonyl serves as the H-bond acceptor to Met109 of p38 alpha in a manner analogous to the pyridine nitrogen of prototypical pyridylimidazole p38 inhibitors. Potent p38 alpha activity comparable to that of several previously reported p38 inhibitors is observed for this novel chemotype. 相似文献
52.
53.
Saccharomyces cerevisiae and its close congener S. paradoxus are typically indistinguishable by the phenotypic criteria of classical yeast taxonomy, but they are evolutionarily distinct as indicated by hybrid spore inviability and genomic sequence divergence. Previous work has shown that these two species coexist in oak-associated microhabitats at natural woodland sites in North America. Here, we show that sympatric populations of S. cerevisiae and S. paradoxus from a single natural site are phenotypically differentiated in their growth rate responses to temperature. Our main finding is that the S. cerevisiae population exhibits a markedly higher growth rate at 37 degrees C than the S. paradoxus population; we also find possible differences in growth rate between these populations at two lower temperatures. We discuss the implications of our results for the coexistence of these yeasts in natural environments, and we suggest that thermal growth response may be an evolutionarily labile feature of these organisms that could be analyzed using genomic approaches. 相似文献
54.
Practical aspects of using the microbatch method in screening conditions for protein crystallization
The microbatch technique is a simple and efficient method for screening for protein crystallization conditions both by hand and using automated systems. Many of the problems associated with more commonly used methods such as vapour diffusion can be overcome using this method. Despite its promise microbatch has not been widely utilized as a viable screening procedure. This review aims to describe the method from a practical point of view with an emphasis on screening crystallization conditions, outlining current progress and discussion of the advantages compared to other methods. 相似文献
55.
Oefner C Douangamath A D'Arcy A Häfeli S Mareque D Mac Sweeney A Padilla J Pierau S Schulz H Thormann M Wadman S Dale GE 《Journal of molecular biology》2003,332(1):13-21
Methionyl aminopeptidases (MetAPs) represent a unique class of protease that are responsible for removing the N-terminal methionine residue from proteins and peptides. There are two major classes of MetAPs (type I and type II) described and each class can be subdivided into two subclasses. Eukaryotes contain both the type I and type II MetAPs, whereas prokaryotes possess only the type I enzyme. Due to the physiological importance of these enzymes there is considerable interest in inhibitors to be used as antiangiogenic and antimicrobial agents. Here, we describe the 1.15A crystal structure of the Staphylococcus aureus MetAP-I as an apo-enzyme and its complexes with various 1,2,4-triazole-based derivatives at high-resolution. The protein has a typical "pita-bread" fold as observed for the other MetAP structures. The inhibitors bind in the active site with the N1 and N2 atoms of the triazole moiety complexing two divalent ions. The 1,2,4-triazols represent a novel class of potent non-peptidic inhibitors for the MetAP-Is. 相似文献
56.
Sweeney SM DiLullo G Slater SJ Martinez J Iozzo RV Lauer-Fields JL Fields GB San Antonio JD 《The Journal of biological chemistry》2003,278(33):30516-30524
Angiogenesis depends on proper collagen biosynthesis and cross-linking, and type I collagen is an ideal angiogenic scaffold, although its mechanism is unknown. We examined angiogenesis using an assay wherein confluent monolayers of human umbilical vein endothelial cells were overlain with collagen in a serum-free defined medium. Small spaces formed in the cell layer by 2 h, and cells formed net-like arrays by 6-8 h and capillary-like lumens by 24 h. Blocking of alpha2beta1, but not alpha1 or alpha(v)beta3 integrin function halted morphogenesis. We found that a triple-helical, homotrimeric peptide mimetic of a putative alpha2beta1 binding site: alpha1(I)496-507 GARGERGFP*GER (where single-letter amino acid nomenclature is used, P* = hydroxyproline) inhibited tube formation, whereas a peptide carrying another putative site: alpha1(I)127-138 GLP*GERGRP*GAP* or control peptides did not. A chemical inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), SB202190, blocked tube formation, and p38 MAPK activity was increased in collagen-treated cultures, whereas targeting MAPK kinase (MEK), focal adhesion kinase (FAK), or phosphatidylinositol 3-kinase (PI3K) had little effect. Collagen-treated cells had fewer focal adhesions and 3- to 5-fold less activated FAK. Thus capillary morphogenesis requires endothelial alpha2beta1 integrin engagement of a single type I collagen integrin-binding site, possibly signaling via p38 MAPK and focal adhesion disassembly/FAK inactivation. 相似文献
57.
Acute and chronic leptin treatment mediate contrasting effects on signaling,glucose uptake,and GLUT4 translocation in L6-GLUT4myc myotubes 总被引:3,自引:0,他引:3
We have previously shown that in L6-GLUT4myc rat skeletal muscle cells, acute treatment with leptin reduced insulin-stimulated glucose uptake without altering insulin-stimulated GLUT4 translocation. In contrast, we show here that the ability of leptin to increase phosphorylation of its receptor and to reduce insulin-stimulated glucose uptake was lost in cells that were continuously exposed to leptin for 24 h. This desensitization correlated with an increase in expression of suppressor of cytokine signaling-3 (SOCS-3). Time course analysis demonstrated that the transition from acute to chronic effects of leptin occurs after 2 h. The desensitization of leptin action at 24 h was not reversed by 30 min washout period prior to re-exposing cells to leptin. However, despite insulin-stimulated glucose uptake being unaffected upon 24 h preincubation with leptin, a small but significant decrease (37%) in insulin-stimulated GLUT4 translocation and phosphorylation of Akt on T308 was detected. Insulin-stimulated phosphorylation of Akt on S473 or of p38 MAPK were unaffected. These results suggest that the chronic leptin treatment leads to desensitization of leptin signaling yet can simultaneously decrease the ability of insulin to phosphorylate Akt on T308 and translocate GLUT4. However, this does not manifest as a reduction in total glucose uptake into L6 myotubes. 相似文献
58.
Ellenrieder C Bartosch B Lee GY Murphy M Sweeney C Hergersberg M Carrington M Jaussi R Hunt T 《DNA and cell biology》2001,20(7):413-423
We have reinvestigated the long form of cyclin-dependent kinase (CDK)2 that is expressed in many rodent cells. We show that the mRNA encoding CDK2L arises by alternative splicing and that the encoded protein can bind to, and be activated by, cyclins A and E. The complex of CDK2L with cyclin A has about half the specific activity of the equivalent CDK2-cyclin A complex. Also, CDK2L--cyclin A is inhibited to the same extent and by the same concentrations of p21(CIP1) as CDK2--cyclin A. The nucleotide sequences of intron V in the human and murine CDK2 genes, where the sequences encoding the 48-residue insert in CDK2L are located, show very high conservation in the position of the alternatively spliced exon and its surroundings. Despite this, we were not able to detect significant expression of CDK2L in human cell lines, although a low level is expressed in COS-1 cells from monkeys. 相似文献
59.
Eradication of Mycobacterium bovis relies on accurate detection of infected animals, including potential domestic and wildlife reservoirs. Available diagnostic tests lack the sensitivity and specificity necessary for accurate detection, particularly in infected wildlife populations. Recently, an in vitro diagnostic test for cattle which measures plasma interferon-gamma (IFN-gamma) levels in blood following in vitro incubation with M. bovis purified protein derivative has been enveloped. This test appears to have increased sensitivity over traditional testing. Unfortunately, it does not detect IFN-gamma from Cervidae. To begin to address this problem, the IFN-gamma gene from elk (Cervus elaphus) was cloned, sequenced, expressed, and characterized. cDNA was cloned from mitogen stimulated peripheral blood mononuclear cells. The predicted amino acid (aa) sequence was compared to known sequences from cattle, sheep, goats, red deer (Cervus elaphus), humans, and mice. Biological activity of the recombinant elk IFN-gamma (rElkIFN-gamma) was confirmed in a vesicular stomatitis virus cytopathic effect reduction assay. Production of monoclonal antibodies to IFN-gamma epitopes conserved between ruminant species could provide an important tool for the development of reliable, practical diagnostic assays for detection of a delayed type hypersensitivity response to a variety of persistent infectious agents in ruminants, including M. bovis and Brucella abortus. Moreover, development of these reagents will aid investigators in studies to explore immunological responses of elk that are associated with resistance to infectious diseases. 相似文献
60.
The trp (transient receptor potential) gene encodes a Ca2+ channel responsible for the major component of the phospholipase C (PLC) mediated light response in Drosophila. In trp mutants, maintained light leads to response decay and temporary total loss of sensitivity (inactivation). Using genetically targeted PIP2-sensitive inward rectifier channels (Kir2.1) as biosensors, we provide evidence that trp decay reflects depletion of PIP2. Two independent mutations in the PIP2 recycling pathway (rdgB and cds) prevented recovery from inactivation. Abolishing Ca2+ influx in wild-type photoreceptors mimicked inactivation, while raising Ca2+ by blocking Na+/Ca2+ exchange prevented inactivation in trp. The results suggest that Ca2+ influx prevents PIP2 depletion by inhibiting PLC activity and facilitating PIP2 recycling. Without this feedback one photon appears sufficient to deplete the phosphoinositide pool of approximately 4 microvilli. 相似文献