全文获取类型
收费全文 | 236篇 |
免费 | 18篇 |
国内免费 | 6篇 |
专业分类
260篇 |
出版年
2023年 | 3篇 |
2022年 | 1篇 |
2021年 | 6篇 |
2020年 | 1篇 |
2019年 | 6篇 |
2018年 | 10篇 |
2017年 | 10篇 |
2016年 | 7篇 |
2015年 | 9篇 |
2014年 | 12篇 |
2013年 | 18篇 |
2012年 | 14篇 |
2011年 | 23篇 |
2010年 | 24篇 |
2009年 | 12篇 |
2008年 | 15篇 |
2007年 | 9篇 |
2006年 | 12篇 |
2005年 | 7篇 |
2004年 | 7篇 |
2003年 | 8篇 |
2002年 | 3篇 |
2000年 | 2篇 |
1999年 | 2篇 |
1998年 | 6篇 |
1997年 | 4篇 |
1996年 | 4篇 |
1995年 | 1篇 |
1994年 | 2篇 |
1993年 | 4篇 |
1992年 | 3篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 4篇 |
1985年 | 3篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1975年 | 1篇 |
1972年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有260条查询结果,搜索用时 0 毫秒
41.
Wu LY Anderson MO Toriyabe Y Maung J Campbell TY Tajon C Kazak M Moser J Berkman CE 《Bioorganic & medicinal chemistry》2007,15(23):7434-7443
To identify the pharmacophore of a phosphoramidate peptidomimetic inhibitor of prostate-specific membrane antigen (PSMA), a small analog library was designed and screened for inhibitory potency against PSMA. The design of the lead inhibitor was based upon N-acyl derivatives of endogenous substrate folyl-gamma-Glu and incorporates a phosphoramidate group to interact with the PSMA catalytic zinc atoms. The scope of the analog library was designed to test the importance of various functional groups to the inhibitory potency of the lead phosphoramidate. The IC(50) for the lead phosphoramidate inhibitor was 35 nM while the IC(50) values for the analog library presented a range from 0.86 nM to 4.1 microM. Computational docking, utilizing a recently solved X-ray crystal structure of the recombinant protein, along with enzyme inhibition data, was used to propose a pharmacophore model for the PSMA active site. 相似文献
42.
Cristiana Iosef Claudio M. Martin Marat Slessarev Carolina GillioMeina Gediminas Cepinskas Victor K. M. Han Douglas D. Fraser 《Journal of cellular and molecular medicine》2023,27(1):141
Coronavirus disease 2019 (COVID‐19) is a systemic inflammatory condition with high mortality that may benefit from personalized medicine and high‐precision approaches. COVID‐19 patient plasma was analysed with targeted proteomics of 1161 proteins. Patients were monitored from Days 1 to 10 of their intensive care unit (ICU) stay. Age‐ and gender‐matched COVID‐19‐negative sepsis ICU patients and healthy subjects were examined as controls. Proteomic data were resolved using both cell‐specific annotation and deep‐analysis for functional enrichment. COVID‐19 caused extensive remodelling of the plasma microenvironment associated with a relative immunosuppressive milieu between ICU Days 3–7, and characterized by extensive organ damage. COVID‐19 resulted in (1) reduced antigen presentation and B/T‐cell function, (2) increased repurposed neutrophils and M1‐type macrophages, (3) relatively immature or disrupted endothelia and fibroblasts with a defined secretome, and (4) reactive myeloid lines. Extracellular matrix changes identified in COVID‐19 plasma could represent impaired immune cell homing and programmed cell death. The major functional modules disrupted in COVID‐19 were exaggerated in patients with fatal outcome. Taken together, these findings provide systems‐level insight into the mechanisms of COVID‐19 inflammation and identify potential prognostic biomarkers. Therapeutic strategies could be tailored to the immune response of severely ill patients. 相似文献
43.
44.
Marat R. Sadykov Bo Zhang Steven Halouska Jennifer L. Nelson Lauren W. Kreimer Yefei Zhu Robert Powers Greg A. Somerville 《The Journal of biological chemistry》2010,285(47):36616-36624
Staphylococcus epidermidis is a skin-resident bacterium and a major cause of biomaterial-associated infections. The transition from residing on the skin to residing on an implanted biomaterial is accompanied by regulatory changes that facilitate bacterial survival in the new environment. These regulatory changes are dependent upon the ability of bacteria to “sense” environmental changes. In S. epidermidis, disparate environmental signals can affect synthesis of the biofilm matrix polysaccharide intercellular adhesin (PIA). Previously, we demonstrated that PIA biosynthesis is regulated by tricarboxylic acid (TCA) cycle activity. The observations that very different environmental signals result in a common phenotype (i.e. increased PIA synthesis) and that TCA cycle activity regulates PIA biosynthesis led us to hypothesize that S. epidermidis is “sensing” disparate environmental signals through the modulation of TCA cycle activity. In this study, we used NMR metabolomics to demonstrate that divergent environmental signals are transduced into common metabolomic changes that are “sensed” by metabolite-responsive regulators, such as CcpA, to affect PIA biosynthesis. These data clarify one mechanism by which very different environmental signals cause common phenotypic changes. In addition, due to the frequency of the TCA cycle in diverse genera of bacteria and the intrinsic properties of TCA cycle enzymes, it is likely the TCA cycle acts as a signal transduction pathway in many bacteria. 相似文献
45.
Eukaryotic initiation factor eIF1 and the functional C-terminal domain of prokaryotic initiation factor IF3 maintain the fidelity of initiation codon selection in eukaryotes and prokaryotes, respectively, and bind to the same regions of small ribosomal subunits, between the platform and initiator tRNA. Here we report that these nonhomologous factors can bind to the same regions of heterologous subunits and perform their functions in heterologous systems in a reciprocal manner, discriminating against the formation of initiation complexes containing codon-anticodon mismatches. We also show that like IF3, eIF1 can influence initiator tRNA selection, which occurs at the stage of ribosomal subunit joining after eIF5-induced hydrolysis of eIF2-bound GTP. The mechanisms of initiation codon and initiator tRNA selection in prokaryotes and eukaryotes are therefore unexpectedly conserved and likely involve related conformational changes induced in the small ribosomal subunit by factor binding. YciH, a prokaryotic eIF1 homologue, could perform some of IF3's functions, which justifies the possibility that YciH and eIF1 might have a common evolutionary origin as initiation factors, and that IF3 functionally replaced YciH in prokaryotes. 相似文献
46.
Keith W.T.Goulding 《中国科学:生命科学英文版》2005,48(Z2)
The nitrogen (N) cycle is essentially 'leaky'. The losses of small amounts of nitrate to waters and of ammonia and nitrous oxide to the atmosphere are a part of the global biogeo-chemical N cycle. However, intensive agricultural production, industry and vehicle use have more than doubled the amount of 'reactive' N in the environment, resulting in eutrophication, ecosystem change and health concerns. Research has identified agricultural practices that cause large losses of N and, in some cases, developed solutions. This paper discusses the problems of maintaining productivity while reducing N losses, compares conventional with low input (integrated) and organic farming systems, and discusses wider options. It also looks at the need to integrate studies on N with other environmental impacts, set in the context of the whole farm system, to provide truly sustainable agricultural systems. 相似文献
47.
Low temperature 31P and 15N NMR spectroscopy was used to investigate the species forming in the organic layer following the extraction of uranium from nitric acid solutions with di-2-ethylhexyl phosphoric acid. It was found that uranium is extracted from neutral solutions as the 1:2 complex UO2A2 regardless of what anion is present. For dilute nitric acid solutions, the uranium is extracted both as associated and mixed nitrato species. As the nitric acid concentration of the aqueous layer increases, the mixed nitrato complex, UO2(NO3)A·HA, becomes predominant. 相似文献
48.
Ticu C Murataliev M Nechifor R Wilson KS 《The Journal of biological chemistry》2011,286(24):21697-21705
The antibiotic fusidic acid potently inhibits bacterial translation (and cellular growth) by lodging between domains I and III of elongation factor G (EF-G) and preventing release of EF-G from the ribosome. We examined the functions of key amino acid residues near the active site of EF-G that interact with fusidic acid and regulate hydrolysis of GTP. Alanine mutants of these residues spontaneously hydrolyzed GTP in solution, bypassing the normal activating role of the ribosome. A conserved phenylalanine in the switch II element of EF-G was important for suppressing GTP hydrolysis in solution and critical for catalyzing translocation of the ribosome along mRNA. These experimental results reveal the multipurpose roles of an interdomain joint in the heart of an essential translation factor that can both promote and inhibit bacterial translation. 相似文献
49.
ZHENZHEN YI WEIBO SONG THORSTEN STOECK KHALED A. S. AL‐RASHEID ABDULAZIZ A. AL‐KHEDHAIRY JUN GONG HONGWEI MA ZIGUI CHEN 《Zoological Journal of the Linnean Society》2009,157(2):227-236
The morphologically unique ciliate Psammomitra has long been considered as a systematically uncertain stichotrich. This is mainly because of its highly specialized morphology and a lack of either detailed information concerning its ontogenesis, or molecular data. Based on the small subunit rRNA (SSrRNA) gene and alpha‐tubulin gene sequences, we re‐evaluated the phylogenetic position of Psammomitra retractilis using multiple algorithms. Phylogenetic trees inferred from the SSrRNA gene sequences representing a total of 53 spirotrichs demonstrated the closest relationship of Psammomitra was with Holosticha‐like taxa, with strong support, which clearly suggested that Psammomitra should be placed into the order Urostylida although it branched at a rather deep level, and is likely to be closely related to Holostichidae. With consideration to molecular evidence and morphological characters, Psammomitra should be a clearly outlined taxon at about the rank of family, i.e. Psammomitridae stat. nov. , within the order Urostylida. The improved diagnosis for this family is as follows: Urostylida possessing extremely contractile, elongated body which consists of three parts: head, trunk, and slender tail; midventral complex composed of midventral pairs only and restricted to about anterior 1/3 of ventral surface; frontal, frontoterminal, and transverse cirri present; one left and one right marginal rows which commence near proximal end of adoral zone and extend to near rear body end. 相似文献
50.
Carlos García-Estrada Inmaculada Vaca Ricardo V Ullán Marco A van den Berg Roel AL Bovenberg Juan Francisco Martín 《BMC microbiology》2009,9(1):104-15