全文获取类型
收费全文 | 2626篇 |
免费 | 266篇 |
国内免费 | 1篇 |
出版年
2021年 | 69篇 |
2020年 | 43篇 |
2019年 | 39篇 |
2018年 | 42篇 |
2017年 | 42篇 |
2016年 | 59篇 |
2015年 | 130篇 |
2014年 | 133篇 |
2013年 | 133篇 |
2012年 | 154篇 |
2011年 | 174篇 |
2010年 | 96篇 |
2009年 | 89篇 |
2008年 | 112篇 |
2007年 | 155篇 |
2006年 | 112篇 |
2005年 | 106篇 |
2004年 | 92篇 |
2003年 | 96篇 |
2002年 | 81篇 |
2001年 | 39篇 |
2000年 | 34篇 |
1999年 | 23篇 |
1998年 | 27篇 |
1997年 | 24篇 |
1995年 | 19篇 |
1992年 | 17篇 |
1991年 | 25篇 |
1990年 | 21篇 |
1989年 | 25篇 |
1987年 | 13篇 |
1986年 | 27篇 |
1985年 | 16篇 |
1984年 | 21篇 |
1983年 | 18篇 |
1982年 | 22篇 |
1981年 | 16篇 |
1979年 | 13篇 |
1978年 | 22篇 |
1977年 | 19篇 |
1976年 | 21篇 |
1974年 | 29篇 |
1973年 | 19篇 |
1972年 | 16篇 |
1971年 | 14篇 |
1970年 | 16篇 |
1969年 | 20篇 |
1968年 | 15篇 |
1964年 | 16篇 |
1963年 | 13篇 |
排序方式: 共有2893条查询结果,搜索用时 250 毫秒
991.
992.
Kasper G Taudien S Staub E Mennerich D Rieder M Hinzmann B Dahl E Schwidetzky U Rosenthal A Rump A 《Gene》2002,295(1):27-32
Encephalopsin, also called Panopsin, is a recently discovered extraretinal photoreceptor, which may play a role in non-visual photic processes such as the entrainment of circadian rhythm or the regulation of pineal melatonin production. Based on RT-PCR data and comparative genomic sequence analysis, we show that the human OPN3 gene consists of six exons and expresses various splice variants, while the murine homologue contains four exons and produces just one splice form. Furthermore, the human OPN3 gene overlaps with the neighboring KMO gene on a genomic as well as on an RNA level, whereas the corresponding genes in mouse lie close together but do not overlap. This finding is of particular interest, since differences in gene organization between man and mouse, that have been reported so far, occur within gene clusters, i.e. the number of genes within a certain cluster may differ between man and mouse. OPN3 provides an exception to this rule, since it is positionally uncoupled from other genes of the opsin family. 相似文献
993.
994.
995.
Roxane Simeone Alexandre Bobard Juliane Lippmann Wilbert Bitter Laleh Majlessi Roland Brosch Jost Enninga 《PLoS pathogens》2012,8(2)
Survival within macrophages is a central feature of Mycobacterium tuberculosis pathogenesis. Despite significant advances in identifying new immunological parameters associated with mycobacterial disease, some basic questions on the intracellular fate of the causative agent of human tuberculosis in antigen-presenting cells are still under debate. To get novel insights into this matter, we used a single-cell fluorescence resonance energy transfer (FRET)-based method to investigate the potential cytosolic access of M. tuberculosis and the resulting cellular consequences in an unbiased, quantitative way. Analysis of thousands of THP-1 macrophages infected with selected wild-type or mutant strains of the M. tuberculosis complex unambiguously showed that M. tuberculosis induced a change in the FRET signal after 3 to 4 days of infection, indicating phagolysosomal rupture and cytosolic access. These effects were not seen for the strains M. tuberculosisΔRD1 or BCG, both lacking the ESX-1 secreted protein ESAT-6, which reportedly shows membrane-lysing properties. Complementation of these strains with the ESX-1 secretion system of M. tuberculosis restored the ability to cause phagolysosomal rupture. In addition, control experiments with the fish pathogen Mycobacterium marinum showed phagolysosomal translocation only for ESX-1 intact strains, further validating our experimental approach. Most importantly, for M. tuberculosis as well as for M. marinum we observed that phagolysosomal rupture was followed by necrotic cell death of the infected macrophages, whereas ESX-1 deletion- or truncation-mutants that remained enclosed within phagolysosomal compartments did not induce such cytotoxicity. Hence, we provide a novel mechanism how ESX-1 competent, virulent M. tuberculosis and M. marinum strains induce host cell death and thereby escape innate host defenses and favor their spread to new cells. In this respect, our results also open new research directions in relation with the extracellular localization of M. tuberculosis inside necrotic lesions that can now be tackled from a completely new perspective. 相似文献
996.
The resistive work of breathing against an external load during inspiration (WRI) was measured at the mouth, during sub-maximal exercise in healthy participants. This measure (which excludes the elastic work component) allows the relationship between resistive work and power, ventilation and exercise modality to be explored. A total of 45 adult participants with healthy lung function took part in a series of exercise protocols, in which the relationship between WRI, power of breathing, PRI and minute ventilation, were assessed during rest, while treadmill walking or ergometer cycling, over a range of exercise intensities (up to 150 Watts) and ventilation rates (up to 48 L min−1) with applied constant resistive loads of 0.75 and 1.5 kPa.L.sec−1. Resting WRI was 0.12 JL−1 and PRI was 0.9 W. At each resistive load, independent of the breathing pattern or exercise mode, the WRI increased in a linear fashion at 20 mJ per litre of , while PRI increased exponentially. With increasing resistive load the work and power at any given increased exponentially. Calculation of the power to work ratio during loaded breathing suggests that loads above 1.5 kPa.L.sec−1 make the work of resistive breathing become inhibitive at even a moderate (>30 L sec−1). The relationship between work done and power generated while breathing against resistive loads is independent of the exercise mode (cycling or walking) and that ventilation is limited by the work required to breathe, rather than an inability to maintain or generate power. 相似文献
997.
Thomas F. Benkert Lena Dietz Elena M. Hartmann Ellen Leich Andreas Rosenwald Edgar Serfling Mathias Buttmann Friederike Berberich-Siebelt 《PloS one》2012,7(12)
Natalizumab is a recombinant monoclonal antibody raised against integrin alpha-4 (CD49d). It is approved for the treatment of patients with multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the CNS. While having shown high therapeutic efficacy, treatment by natalizumab has been linked to progressive multifocal leukoencephalopathy (PML) as a serious adverse effect. Furthermore, drug cessation sometimes induces rebound disease activity of unknown etiology. Here we investigated whether binding of this adhesion-blocking antibody to T lymphocytes could modulate their phenotype by direct induction of intracellular signaling events. Primary CD4+ T lymphocytes either from healthy donors and treated with natalizumab in vitro or from MS patients receiving their very first dose of natalizumab were analyzed. Natalizumab induced a mild upregulation of IL-2, IFN-γ and IL-17 expression in activated primary human CD4+ T cells propagated ex vivo from healthy donors, consistent with a pro-inflammatory costimulatory effect on lymphokine expression. Along with this, natalizumab binding triggered rapid MAPK/ERK phosphorylation. Furthermore, it decreased CD49d surface expression on effector cells within a few hours. Sustained CD49d downregulation could be attributed to integrin internalization and degradation. Importantly, also CD4+ T cells from some MS patients receiving their very first dose of natalizumab produced more IL-2, IFN-γ and IL-17 already 24 h after infusion. Together these data indicate that in addition to its adhesion-blocking mode of action natalizumab possesses mild direct signaling capacities, which can support a pro-inflammatory phenotype of peripheral blood T lymphocytes. This might explain why a rebound of disease activity or IRIS is observed in some MS patients after natalizumab cessation. 相似文献
998.
Attila Kristóf Zoltán Husti István Koncz Zsófia Kohajda Tamás Szél Viktor Juhász Péter Biliczki Norbert Jost István Baczkó Julius Gy Papp András Varró László Virág 《PloS one》2012,7(12)
Background
The aim of the present work was to characterize the electrophysiological effects of the non-steroidal anti-inflammatory drug diclofenac and to study the possible proarrhythmic potency of the drug in ventricular muscle.Methods
Ion currents were recorded using voltage clamp technique in canine single ventricular cells and action potentials were obtained from canine ventricular preparations using microelectrodes. The proarrhythmic potency of the drug was investigated in an anaesthetized rabbit proarrhythmia model.Results
Action potentials were slightly lengthened in ventricular muscle but were shortened in Purkinje fibers by diclofenac (20 µM). The maximum upstroke velocity was decreased in both preparations. Larger repolarization prolongation was observed when repolarization reserve was impaired by previous BaCl2 application. Diclofenac (3 mg/kg) did not prolong while dofetilide (25 µg/kg) significantly lengthened the QTc interval in anaesthetized rabbits. The addition of diclofenac following reduction of repolarization reserve by dofetilide further prolonged QTc. Diclofenac alone did not induce Torsades de Pointes ventricular tachycardia (TdP) while TdP incidence following dofetilide was 20%. However, the combination of diclofenac and dofetilide significantly increased TdP incidence (62%). In single ventricular cells diclofenac (30 µM) decreased the amplitude of rapid (IKr) and slow (IKs) delayed rectifier currents thereby attenuating repolarization reserve. L-type calcium current (ICa) was slightly diminished, but the transient outward (Ito) and inward rectifier (IK1) potassium currents were not influenced.Conclusions
Diclofenac at therapeutic concentrations and even at high dose does not prolong repolarization markedly and does not increase the risk of arrhythmia in normal heart. However, high dose diclofenac treatment may lengthen repolarization and enhance proarrhythmic risk in hearts with reduced repolarization reserve. 相似文献999.
The different morphological stages of microglial activation have not yet been described in detail. We transected the olfactory bulb of rats and examined the activation of the microglial system histologically. Six stages of bidirectional microglial activation (A) and deactivation (R) were observed: from stage 1A to 6A, the cell body size increased, the cell process number decreased, and the cell processes retracted and thickened, orienting toward the direction of the injury site; until stage 6A, when all processes disappeared. In contrast, in deactivation stages 6R to 1R, the microglia returned to the original site exhibiting a stepwise retransformation to the original morphology. Thin highly branched processes re-formed in stage 1R, similar to those in stage 1A. This reverse transformation mirrored the forward transformation except in stages 6R to 1R: cells showed multiple nuclei which were slowly absorbed. Our findings support a morphologically defined stepwise activation and deactivation of microglia cells. 相似文献
1000.