全文获取类型
收费全文 | 798篇 |
免费 | 35篇 |
国内免费 | 2篇 |
专业分类
耳鼻咽喉 | 9篇 |
儿科学 | 15篇 |
妇产科学 | 7篇 |
基础医学 | 242篇 |
口腔科学 | 6篇 |
临床医学 | 100篇 |
内科学 | 128篇 |
皮肤病学 | 5篇 |
神经病学 | 64篇 |
特种医学 | 36篇 |
外科学 | 70篇 |
综合类 | 2篇 |
一般理论 | 1篇 |
预防医学 | 24篇 |
眼科学 | 5篇 |
药学 | 63篇 |
中国医学 | 1篇 |
肿瘤学 | 57篇 |
出版年
2022年 | 4篇 |
2021年 | 7篇 |
2020年 | 4篇 |
2019年 | 4篇 |
2018年 | 7篇 |
2017年 | 5篇 |
2016年 | 6篇 |
2015年 | 15篇 |
2014年 | 19篇 |
2013年 | 19篇 |
2012年 | 43篇 |
2011年 | 43篇 |
2010年 | 22篇 |
2009年 | 24篇 |
2008年 | 43篇 |
2007年 | 34篇 |
2006年 | 60篇 |
2005年 | 51篇 |
2004年 | 43篇 |
2003年 | 53篇 |
2002年 | 58篇 |
2001年 | 20篇 |
2000年 | 20篇 |
1999年 | 15篇 |
1998年 | 18篇 |
1997年 | 20篇 |
1996年 | 10篇 |
1995年 | 5篇 |
1994年 | 6篇 |
1993年 | 4篇 |
1992年 | 12篇 |
1991年 | 8篇 |
1990年 | 6篇 |
1989年 | 4篇 |
1988年 | 6篇 |
1987年 | 8篇 |
1986年 | 5篇 |
1985年 | 8篇 |
1983年 | 6篇 |
1982年 | 6篇 |
1981年 | 5篇 |
1976年 | 3篇 |
1975年 | 6篇 |
1972年 | 6篇 |
1971年 | 4篇 |
1970年 | 3篇 |
1969年 | 3篇 |
1968年 | 7篇 |
1967年 | 13篇 |
1966年 | 5篇 |
排序方式: 共有835条查询结果,搜索用时 31 毫秒
121.
Hillen N Mester G Lemmel C Weinzierl AO Müller M Wernet D Hennenlotter J Stenzl A Rammensee HG Stevanović S 《European journal of immunology》2008,38(11):2993-3003
Human leukocyte antigens (HLA) have long been grouped into supertypes to facilitate peptide-based immunotherapy. Analysis of several hundreds of peptides presented by all nine antigens of the HLA-B44 supertype (HLA-B*18, B*37, B*40, B*41, B*44, B*45, B*47, B*49 and B*50) revealed unique peptide motifs for each of them. Taking all supertype members into consideration only 25 out of 670 natural ligands were found on more than one HLA molecule. Further direct comparisons by two mass spectrometric methods--isotope labeling as well as a label-free approach--consistently demonstrated only minute overlaps of below 3% between the ligandomes of different HLA antigens. In addition, T cell reactions of healthy donors against immunodominant HLA-B*44 and HLA-B*40 epitopes from EBV lacked promiscuous T-cell recognition within the HLA-B44 supertype. Taken together, these results challenge the common paradigm of broadly presented epitopes within this supertype. 相似文献
122.
Kozísek M Henke S Sasková KG Jacobs GB Schuch A Buchholz B Müller V Kräusslich HG Rezácová P Konvalinka J Bodem J 《Antimicrobial agents and chemotherapy》2012,56(8):4320-4330
During the last few decades, the treatment of HIV-infected patients by highly active antiretroviral therapy, including protease inhibitors (PIs), has become standard. Here, we present results of analysis of a patient-derived, multiresistant HIV-1 CRF02_AG recombinant strain with a highly mutated protease (PR) coding sequence, where up to 19 coding mutations have accumulated in the PR. The results of biochemical analysis in vitro showed that the patient-derived PR is highly resistant to most of the currently used PIs and that it also exhibits very poor catalytic activity. Determination of the crystal structure revealed prominent changes in the flap elbow region and S1/S1' active site subsites. While viral loads in the patient were found to be high, the insertion of the patient-derived PR into a HIV-1 subtype B backbone resulted in reduction of infectivity by 3 orders of magnitude. Fitness compensation was not achieved by elevated polymerase (Pol) expression, but the introduction of patient-derived gag and pol sequences in a CRF02_AG backbone rescued viral infectivity to near wild-type (wt) levels. The mutations that accumulated in the vicinity of the processing sites spanning the p2/NC, NC/p1, and p6pol/PR proteins lead to much more efficient hydrolysis of corresponding peptides by patient-derived PR in comparison to the wt enzyme. This indicates a very efficient coevolution of enzyme and substrate maintaining high viral loads in vivo under constant drug pressure. 相似文献
123.
Müller A Ulm H Reder-Christ K Sahl HG Schneider T 《Microbial drug resistance (Larchmont, N.Y.)》2012,18(3):261-270
Lantibiotics are a unique group within the antimicrobial peptides characterized by the presence of thioether amino acids (lanthionine and methyllanthionine). These peptides are produced by and primarily act on Gram-positive bacteria exerting multiple activities at the cytoplasmic membrane of susceptible strains. Previously, the cell wall precursor lipid II was identified as the molecular target for the prototype lantibiotic nisin. Binding and sequestration of lipid II blocks the incorporation of the central cell wall precursor into the growing peptidoglycan network, thereby inhibiting the formation of a functional cell wall. Additionally, nisin combines this activity with a unique target-mediated pore formation, using lipid II as a docking molecule. The interaction with the pyrophosphate moiety of lipid II is crucial for nisin binding. We show that, besides binding to lipid II, nisin interacts with the lipid intermediates lipid III (undecaprenol-pyrophosphate-N-acetyl-glucosamine) and lipid IV (undecaprenol-pyrophosphate-N-acetyl-glucosamine-N-acetyl-mannosamine) of the wall teichoic acid (WTA) biosynthesis pathway. Binding of nisin to the precursors was observed at a stoichiometry of 2:1. The specific interaction with WTA precursors further promoted target-mediated pore formation in artificial lipid bilayers. Specific interactions with lipid III and lipid IV could also be demonstrated for related type A lantibiotics, for example, gallidermin, containing the conserved lipid-II-binding motif. 相似文献
124.
125.
Multiple genetic and environmental factors underlie the etiology of type 2 diabetes. To evaluate the influence of the relationship between dietary fat intake and single nucleotide polymorphisms (SNPs) in genes involved in fat assimilation on disease susceptibility, a 2-step approach using an exploratory case-control study (n = 192/384) and an independent, confirmatory case-cohort study (n = 614/2248) taken from the same prospective study population (European Prospective Investigation into Cancer and Nutrition-Potsdam) was used. Sixty-three SNPs in 32 genes were initially analyzed. Total intake of fat and fatty acid intake were calculated from validated baseline FFQ. The SNP × nutrient interaction was tested in multivariate adjusted regression models. The initial screening step revealed evidence that, for 4 SNPs (CAV2 rs2270188, DBI rs2084202, PPARG rs1801282, and SREBF1 rs2297508), disease susceptibility might depend on the amount and quality of fat intake. The insulin receptor regulator CAV2 rs2270188 G > T SNP was found to interact with dietary fat in the confirmatory case-cohort study. Using pooled data, homozygous individuals of the rare T-allele showed a 100% greater risk of type 2 diabetes if daily fat intake was increased from 30 to 40 % energy. An increase in dietary SFA from 10 to 20 % energy predicted an ~200% greater risk of type 2 diabetes. We found preliminary evidence that CAV2 rs2270188 interacts with dietary fat to affect risk of type 2 diabetes. 相似文献
126.
Richter F Bauer R Ebersberger A Lehmenkühler A Schaible HG 《Journal of cerebral blood flow and metabolism》2012,32(8):1535-1545
The brainstem of the adult rat is relatively resistant to spreading depolarization (SD) but after enhancement of excitability SD can be evoked by local application of KCl. In the present experiments, we observed that the enhanced excitability even triggers prolonged periods of repetitive depolarizations (RDs), which elicit significant cardiovascular changes. In contrast to KCl-evoked SDs with amplitudes of ∼24 mV and spreading velocity of 4 mm/min, spontaneous RDs had amplitudes of 7 to 12 mV, propagated up to 30 times faster than KCl-evoked SDs, and depolarized larger brainstem areas including the contralateral side. Similarly as SD, RDs depended on glutamatergic neurotransmission and were blocked by MK-801 or by the calcium channel blocker agatoxin. They depended on sodium channels and were blocked by tetrodotoxin. Functionally, the invasion of RDs into the spinal trigeminal and other nuclei evoked bursts of action potentials, indicating that specific neuronal systems are affected. In fact, during episodes of RDs the blood pressure and the local blood flow at the surface of the brainstem and the cortex increased substantially. Brainstem RDs did not propagate into the cerebral cortex. We propose to consider brainstem RPs as a pathophysiological mechanism whose significance for brainstem disease states should be further explored. 相似文献
127.
Montonen J Drogan D Joost HG Boeing H Fritsche A Schleicher E Schulze MB Pischon T 《European journal of epidemiology》2011,26(1):29-38
The contribution of different biological pathways to the development of type 2 diabetes was quantified in a case-cohort design
based on circulating blood biomarkers from participants aged 35–65 years in the EPIC–Potsdam Study. The analytic sample included
613 participants with incident diabetes and 1965 participants without diabetes. The proportion that each biomarker contributed
to the risk of diabetes was quantified using effect decomposition method. Summarized risk of each biomarker was estimated
by an index based on quintiles of gamma-glutamyltransferase (GGT), HDL-cholesterol, hs-CRP, and adiponectin. Cox proportional
hazard regression was used to estimate relative risks adjusted for age, sex, body mass index, waist-circumference, education,
sport activity, cycling, occupational activity, smoking, alcohol intake, and consumptions of red meat, coffee and whole grain
bread. Adiponectin explained a total of 32.1% (CI = 16.8, 49.1%) of the risk related to index. For the other biomarkers the
corresponding proportions were 23.5% (CI = 10.1, 37.8%) by HDL-cholesterol, 21.5% (CI = 11.5, 32.8%) by GGT, and 15.5% (CI = 4.44,
27.3%) by hs-CRP. The results support the hypothesis that the different biological pathways reflected by GGT, HDL-cholesterol,
hs-CRP and adiponectin independent from each other contribute to the risk of type 2 diabetes. Of these pathways the highest
contribution was observed for adiponectin which contributed one-third to the risk and that equal proportion was contributed
by GGT and HDL-cholesterol, although the contribution of inflammation was lower. 相似文献
128.
This paper examines access to health care by poorer residents in Chennai, India. It reveals constraining and enabling conditions for impoverished users seeking treatment. We explore patterns of health-seeking behaviour through the reasoning of residents themselves as well as stakeholders involved in providing care for these users. Particular attention is paid to the needy residents' preference for private health care providers despite the costs involved and that free public facilities are available. We address this issue by combining Sen's entitlement approach with Penchansky and Thomas' work on access to health care. Based on data gathered in a qualitative field-based research design including interviews with 14 residents and 58 stakeholders involved in caring for poor people, we argue that the availability of health care facilities within walking distance is a necessary but not sufficient precondition for satisfactory access. Rather, we demonstrate the influence of 'entitlements to health care' which allow poor households that are endowed with resources such as income, knowledge and social networks to realise access. The narratives we present reveal not only experiences of health care, but also feelings about its utilisation. The latter, we contend, are crucial in determining choice of health care facilities. This finding suggests that analyses of affordability and physical access to health care in less developed countries should include a focus on emotional dimensions of utilisation. In other words, there is a need to consider not only effective access to health care, but also affective dimensions of treatment for poorer citizens. 相似文献
129.
130.
Leopold Schmetterer Susanne Dallinger Barbara Bobr Nicole Selenko Hans-Georg Eichler Michael Wolzt 《British journal of pharmacology》1998,124(5):930-934
- Endothelins (ETs) might play a pathophysiological role in a variety of vascular diseases. The aim of the present study was to characterize the effects of BQ-123, a specific ETA receptor antagonist on systemic and renal haemodynamics in healthy subjects. This was done at baseline and during infusion of exogenous ET-1.
- The study was performed in a balanced, randomized, placebo-controlled, double blind 4 way cross-over design in 10 healthy male subjects. Subjects received co-infusions of ET-1 (2.5 ng kg−1 min−1 for 120 min) or placebo and BQ-123 (15 μg min−1 for 60 min and subsequently 60 μg min−1 for 60 min) or placebo. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para-aminohippurate (PAH) and the inulin plasma clearance method, respectively.
- BQ-123 alone had no renal or systemic haemodynamic effect. ET-1 significantly reduced RPF (−24%, P<0.001) and GFR (−12%, P=0.034). These effects were abolished by co-infusion of either dose of BQ-123 (RPF: P=0.0012; GFR: P=0.020).
- BQ-123 reversed the renal haemodynamic effects induced by exogenous ET-1 in vivo. This indicates that vasoconstriction in the kidney provoked by ET-1 is predominantly mediated by the ETA receptor subtype.