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341.
The sleep of healthy people--a diary study 总被引:4,自引:0,他引:4
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K Niimi DR Harding AR Holmes E Lamping M Niimi JD Tyndall RD Cannon BC Monk 《Molecular microbiology》2012,85(4):747-767
Overexpression of the Candida albicans ATP‐binding cassette transporter CaCdr1p causes clinically significant resistance to azole drugs including fluconazole (FLC). Screening of a ~ 1.89 × 106 member d ‐octapeptide combinatorial library that concentrates library members at the yeast cell surface identified RC21v3, a 4‐methoxy‐2,3,6‐trimethylbenzenesulphonyl derivative of the d ‐octapeptide d ‐NH2‐FFKWQRRR‐CONH2, as a potent and stereospecific inhibitor of CaCdr1p. RC21v3 chemosensitized Saccharomyces cerevisiae strains overexpressing CaCdr1p but not other fungal ABC transporters, the C. albicans MFS transporter CaMdr1p or the azole target enzyme CaErg11p, to FLC. RC21v3 also chemosensitized clinical C. albicans isolates overexpressing CaCDR1 to FLC, even when CaCDR2 was overexpressed. Specific targeting of CaCdr1p by RC21v3 was confirmed by spontaneous RC21v3 chemosensitization‐resistant suppressor mutants of S. cerevisiae expressing CaCdr1p. The suppressor mutations introduced a positive charge beside, or within, extracellular loops 1, 3, 4 and 6 of CaCdr1p or an aromatic residue near the extracytoplasmic end of transmembrane segment 5. The mutations did not affect CaCdr1p localization or CaCdr1p ATPase activity but some increased susceptibility to the CaCdr1p substrates FLC, rhodamine 6G, rhodamine 123 and cycloheximide. The suppressor mutations showed that the drug‐like CaCdr1p inhibitors FK506, enniatin, milbemycin α11 and milbemycin β9 have modes of action similar to RC21v3. 相似文献
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Mehner Thomas Rapp Tobias Monk Christopher T. Beck Mara E. Trudeau Ashley Kiljunen Mikko Hilt Sabine Arlinghaus Robert 《Ecosystems》2019,22(2):346-362
Ecosystems - It is well documented that aquatic ecosystems may be subsidized by naturally derived terrestrial carbon sources. In contrast, the intentional or unintentional subsidy of animal... 相似文献
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Ortega Roldan JL Romero Romero ML Ora A Ab E Lopez Mayorga O Azuaga AI van Nuland NA 《Journal of biomolecular NMR》2007,39(4):331-336
CD2 associated protein (CD2AP) is an adaptor protein that plays an important role in cell to cell union needed for the kidney
function. CD2AP interacts, as an adaptor protein, with different natural targets, such as CD2, nefrin, c-Cbl and podocin.
These proteins are believed to interact to one of the three SH3 domains that are positioned in the N-terminal region of CD2AP.
To understand the network of interactions between the natural targets and the three SH3 domains (SH3-A, B and C), we have
started to determine the structures of the individual SH3 domains. Here we present the high-resolution structure of the SH3-C
domain derived from NMR data. Full backbone and side-chain assignments were obtained from triple-resonance spectra. The structure
was determined from distance restraints derived from high-resolution 600 and 800 MHz NOESY spectra, together with phi and psi torsion angle restraints based on the analysis of 1HN, 15N, 1Hα, 13Cα, 13CO and 13Cβ chemical shifts. Structures were calculated using CYANA and refined in water using RECOORD. The three-dimensional structure
of CD2AP SH3-C contains all the features that are typically found in other SH3 domains, including the general binding site
for the recognition of polyproline sequences. 相似文献
347.
Jennifer H Humphreys Jessica AB van Nies Jackie Chipping Tarnya Marshall Annette HM van der Helm-van Mil Deborah PM Symmons Suzanne MM Verstappen 《Arthritis research & therapy》2014,16(6)
Introduction
This study aimed to investigate rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) status and levels as predictors of mortality in two large cohorts of patients with early inflammatory arthritis (EIA).Methods
Data from the Norfolk Arthritis Register (NOAR) and Leiden Early Arthritis Clinic (EAC) cohorts were used. At baseline, patients had demographic data and smoking status recorded; RF, ACPA and inflammatory markers were measured in the local laboratories. Patients were flagged with national death registers until death or censor date. Antibody status was stratified as negative, low or high positive by RF and ACPA levels individually. In addition, patients were grouped as seronegative, RF positive, ACPA positive or double antibody (RF and ACPA) positive. Cox regression models explored associations between antibody status and mortality adjusting for age, sex, smoking status, inflammatory markers and year of enrolment.Results
A total of 4962 patients were included, 64% were female. Median age at onset was 56 (NOAR) and 54 (EAC) years. In NOAR and EAC respectively, 35% and 42% of patients were ACPA/RF positive. When antibody status was stratified as negative, low or high positive, there were no consistent findings between the two cohorts. Double antibody positivity was associated with excess mortality in both cohorts compared to seronegative patients: NOAR and EAC respective adjusted HR (95% confidence interval) 1.35 (1.09 to 1.68) and 1.58 (1.16 to 2.15).Conclusions
Patients with EIA who are seropositive for both RF and ACPA have increased mortality compared to those who are single positive or seronegative. Antibody level in seropositive patients was not consistently associated with excess mortality.Electronic supplementary material
The online version of this article (doi:10.1186/s13075-014-0483-3) contains supplementary material, which is available to authorized users. 相似文献348.
Globally it is estimated that up to 37% of all marine mammals are at a risk of extinction, due in particular to human impacts, including coastal pollution. Dolphins are known to be at risk from anthropogenic contaminants due to their longevity and high trophic position. While it is known that beach-cast animals are often high in contaminants, it has not been possible to determine whether levels may also be high in live animals from the same populations. In this paper we quantitatively assess mercury contamination in the two main populations of a newly described dolphin species from south eastern Australia, Tursiops australis. This species appear to be limited to coastal waters in close proximity to a major urban centre, and as such is likely to be vulnerable to anthropogenic pollution. For the first time, we were able to compare blubber mercury concentrations from biopsy samples of live individuals and necropsies of beach-cast animals and show that beach-cast animals were highly contaminated with mercury, at almost three times the levels found in live animals. Levels in live animals were also high, and are attributable to chronic low dose exposure to mercury from the dolphin''s diet. Measurable levels of mercury were found in a number of important prey fish species. This illustrates the potential for low dose toxins in the environment to pass through marine food webs and potentially contribute to marine mammal deaths. This study demonstrates the potential use of blubber from biopsy samples to make inferences about the health of dolphins exposed to mercury. 相似文献
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Monk KA Siles R Hadimani MB Mugabe BE Ackley JF Studerus SW Edvardsen K Trawick ML Garner CM Rhodes MR Pettit GR Pinney KG 《Bioorganic & medicinal chemistry》2006,14(9):3231-3244
A series of analogs with nitro or serinamide substituents at the C-2'-, C-5'-, or C-6'-position of the combretastatin A-4 (CA4) B-ring was synthesized and evaluated for cytotoxic effects against heart endothelioma cells, blood flow reduction to tumors in SCID mice, and as inhibitors of tubulin polymerization. The synthesis of these analogs typically featured a Wittig reaction between a suitably functionalized arylaldehyde and an arylphosphonium salt followed by separation of the resultant E- and Z-isomers. Several of these nitrogen-modified CA4 derivatives (both amino and nitro) demonstrate significant inhibition of tubulin assembly as well as cytotoxicity and in vivo blood flow reduction. 2'-Aminostilbenoid 7 and 2'-amino-3'-hydroxystilbenoid 29 proved to be the most active in this series. Both compounds, 7 and 29, have the potential for further pro-drug modification and development as vascular disrupting agents for treatment of solid tumor cancers and certain ophthalmological diseases. 相似文献