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41.
The effect of pH on the extent of binding of cyclic AMP was evaluated by membrane filtration, charcoal exclusion and Sephadex G-25 chromatography. The amount of binding activity found in hemolysates of rat erythrocytes and 105,000 × g supernatants of rat thigh muscle homogenates varies appreciably with pH and method of measurement. Measurements of binding activity in a muscle extract by exclusion from Sephadex G-25 indicated the presence of two pH optima, one at pH 4.5 and the other at pH 7.4 or higher. The filtration method gave higher values than the charcoal method at pH 4.5 while the reverse was true at pH 7.4. With the erythrocyte preparation no binding was evident above pH 5.0 by either procedure except in the presence of 0.8 M KCl. Hypertonic KCl raised the pH of optimum binding to 5–5.5 for both tissues as indicated by both the filtration and charcoal methods. It is apparent from these results that the determination of cyclic AMP binding proteins from various tissues requires that more attention be paid to the role of ionic strength, pH and the mode of collection of the bound complex. 相似文献
42.
J C Woodrow C A Clarke W T Donohow R Finn R B McConnell P M Sheppard D Lehane F M Roberts T M Gimlette 《BMJ (Clinical research ed.)》1975,2(5962):57-59
The mechanism by which Rh immunization is prevented by IgG anti-D was investigated by studying the specificity of immunosuppression. 62 D-negative Kell(K)-negative male volunteers were given two successive stimuli of 1 ml D-positive K-positive red cells. Thirty-one of the volunteers were also given 13-14 mug of IgG anti-K immediately after each stimulus, the others acting as controls. Anti-D developed in 11 of the 31 controls and in one of the 31 volunteers who had received anti-K. This marked suppression of the anti-D response by IgG anti-K was accompanied by the rapid clearance of the injected red cells to the spleen. This shows that the predominant mechanism that must be operating when IgG anti-D prevents Rh immunization is not antigen specific but is one that must involve the whole red cell, probably through destruction within splenic macrophages. 相似文献
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Maria Davern Noel E. Donlon Andrew Sheppard Fiona O’ Connell Conall Hayes Anshul Bhardwaj Emma Foley Dermot O’ Toole Niamh Lynam-Lennon Narayanasamy Ravi John V. Reynolds Stephen G. Maher Joanne Lysaght 《Translational oncology》2021,14(6):101062
Use of immune checkpoint inhibitors (ICIs) with chemotherapy to enhance responses in oesophageal adenocarcinoma (OAC) is an attractive approach. We identified subpopulations of OAC cells expressing inhibitory immune checkpoint (IC) ligands (PD-L1, PD-L2 and CD160) and receptors (PD-1, TIGIT, TIM-3, LAG-3 and A2aR) in vitro and in ex vivo biopsies. Combination chemotherapy regimens FLOT and CROSS promote a more immune-resistant phenotype through upregulation of IC ligands and receptors on OAC cells in vitro. Importantly, this study investigated if OAC cells, enriched for ICs exhibited a more stem-like and senescent-like phentoype. FLOT preferentially upregulates PD-L1 on a stem-like OAC cell phenotype, defined by ALDH activity. Expression of senescence-associated β-galactosidase is induced in a subpopulation of OAC cells following FLOT and CROSS chemotherapy treatment, along with enhanced expression of TIM-3 and A2aR ICs. Blockade of PD-1 signalling in OAC cells induced apoptosis and enhanced FLOT and CROSS chemotherapy toxicity in vitro. Upregulation of ICs on OAC cells following chemotherapy may represent potential mechanisms of chemo-immune resistance. Combination ICIs may be required to enhance the efficacy of chemotherapy and immunotherapy in OAC patients. 相似文献
46.
Norval J. C. Strachan Ovidiu Rotariu Marion MacRae Samuel K. Sheppard Alison Smith-Palmer John Cowden Martin C. J. Maiden Ken J. Forbes 《PloS one》2013,8(11)
A framework of general factors for infectious disease emergence was made operational for Campylobacter utilising explanatory variables including time series and risk factor data. These variables were generated using a combination of empirical epidemiology, case-case and case-control studies, time series analysis, and microbial sub-typing (source attribution, diversity, genetic distance) to unravel the changing/emerging aetiology of human campylobacteriosis. The study focused on Scotland between 1990–2012 where there was a 75% increase in reported cases that included >300% increase in the elderly and 50% decrease in young children. During this period there were three phases 1990–2000 a 75% rise and a 20% fall to 2006, followed by a 19% resurgence. The rise coincided with expansions in the poultry industry, consumption of chicken, and a shift from rural to urban cases. The post-2000 fall occurred across all groups apart from the elderly and coincided with a drop of the prevalence of Campylobacter in chicken and a higher proportion of rural cases. The increase in the elderly was associated with uptake of proton pump inhibitors. During the resurgence the increase was predominantly in adults and the elderly, again there was increasing use of PPIs and high prevalences in chicken and ruminants. Cases associated with foreign travel during the study also increased from 9% to a peak of 16% in 2006 before falling to an estimated 10% in 2011, predominantly in adults and older children. During all three periods source attribution, genetic distance, and diversity measurements placed human isolates most similar to those in chickens. A combination of emergence factors generic for infectious diseases were responsible for the Campylobacter epidemic. It was possible to use these to obtain a putative explanation for the changes in human disease and the potential to make an informed view of how incidence rates may change in the future. 相似文献
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David Fowler Mhairi Coyle Ute Skiba Mark A. Sutton J. Neil Cape Stefan Reis Lucy J. Sheppard Alan Jenkins Bruna Grizzetti James N. Galloway Peter Vitousek Allison Leach Alexander F. Bouwman Klaus Butterbach-Bahl Frank Dentener David Stevenson Marcus Amann Maren Voss 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2013,368(1621)
Global nitrogen fixation contributes 413 Tg of reactive nitrogen (Nr) to terrestrial and marine ecosystems annually of which anthropogenic activities are responsible for half, 210 Tg N. The majority of the transformations of anthropogenic Nr are on land (240 Tg N yr−1) within soils and vegetation where reduced Nr contributes most of the input through the use of fertilizer nitrogen in agriculture. Leakages from the use of fertilizer Nr contribute to nitrate (NO3−) in drainage waters from agricultural land and emissions of trace Nr compounds to the atmosphere. Emissions, mainly of ammonia (NH3) from land together with combustion related emissions of nitrogen oxides (NOx), contribute 100 Tg N yr−1 to the atmosphere, which are transported between countries and processed within the atmosphere, generating secondary pollutants, including ozone and other photochemical oxidants and aerosols, especially ammonium nitrate (NH4NO3) and ammonium sulfate (NH4)2SO4. Leaching and riverine transport of NO3 contribute 40–70 Tg N yr−1 to coastal waters and the open ocean, which together with the 30 Tg input to oceans from atmospheric deposition combine with marine biological nitrogen fixation (140 Tg N yr−1) to double the ocean processing of Nr. Some of the marine Nr is buried in sediments, the remainder being denitrified back to the atmosphere as N2 or N2O. The marine processing is of a similar magnitude to that in terrestrial soils and vegetation, but has a larger fraction of natural origin. The lifetime of Nr in the atmosphere, with the exception of N2O, is only a few weeks, while in terrestrial ecosystems, with the exception of peatlands (where it can be 102–103 years), the lifetime is a few decades. In the ocean, the lifetime of Nr is less well known but seems to be longer than in terrestrial ecosystems and may represent an important long-term source of N2O that will respond very slowly to control measures on the sources of Nr from which it is produced. 相似文献
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Susan M. Gribble Frances K. Wiseman Stephen Clayton Elena Prigmore Elizabeth Langley Fengtang Yang Sean Maguire Beiyuan Fu Diana Rajan Olivia Sheppard Carol Scott Heidi Hauser Philip J. Stephens Lucy A. Stebbings Bee Ling Ng Tomas Fitzgerald Michael A. Quail Ruby Banerjee Kai Rothkamm Victor L. J. Tybulewicz Elizabeth M. C. Fisher Nigel P. Carter 《PloS one》2013,8(4)
Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype – phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439. 相似文献
50.
Britt McKinnon Seungmi Yang Michael S. Kramer Tracey Bushnik Amanda J. Sheppard Jay S. Kaufman 《CMAJ》2016,188(1):E19-E26