全文获取类型
收费全文 | 14770篇 |
免费 | 1413篇 |
国内免费 | 10篇 |
出版年
2024年 | 16篇 |
2023年 | 113篇 |
2022年 | 268篇 |
2021年 | 597篇 |
2020年 | 270篇 |
2019年 | 335篇 |
2018年 | 400篇 |
2017年 | 346篇 |
2016年 | 605篇 |
2015年 | 953篇 |
2014年 | 956篇 |
2013年 | 1086篇 |
2012年 | 1401篇 |
2011年 | 1340篇 |
2010年 | 798篇 |
2009年 | 641篇 |
2008年 | 877篇 |
2007年 | 823篇 |
2006年 | 817篇 |
2005年 | 649篇 |
2004年 | 593篇 |
2003年 | 530篇 |
2002年 | 490篇 |
2001年 | 114篇 |
2000年 | 75篇 |
1999年 | 94篇 |
1998年 | 105篇 |
1997年 | 56篇 |
1996年 | 68篇 |
1995年 | 35篇 |
1994年 | 47篇 |
1993年 | 52篇 |
1992年 | 62篇 |
1991年 | 48篇 |
1990年 | 51篇 |
1989年 | 53篇 |
1988年 | 19篇 |
1987年 | 29篇 |
1986年 | 24篇 |
1985年 | 35篇 |
1984年 | 36篇 |
1983年 | 21篇 |
1982年 | 18篇 |
1981年 | 19篇 |
1980年 | 13篇 |
1979年 | 24篇 |
1978年 | 23篇 |
1977年 | 19篇 |
1975年 | 14篇 |
1973年 | 20篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
951.
Marie‐Catherine Boisselier‐Dubayle Raphaël Leblois Sarah Samadi Josie Lambourdière Corinne Sarthou 《Ecography》2010,33(1):175-184
Inselbergs are isolated granitic rock outcrops that provide distinctive ecological conditions. In northern South America they rise above the surrounding rainforest. Among inselberg specialists, Pitcairnia geyskesii (Bromeliaceae) is restricted to these habitats in French Guiana. We studied populations from 12 inselbergs using 7 microsatellite loci to give a "reverse image" of the reduction-expansion of the rainforest in the context of the refuge hypothesis. Our analyses showed that populations are fragmented with dispersal occurring only over very short distances. Genetic diversity was higher in northern French Guiana, whereas specific alleles were observed in the south. The results point to the occurrence of a dry corridor in the north, as hypothesized by Tardy (1998) based on charcoal analyses, whereas de Granville's (1982) hypothesis of a unique past refuge is not confirmed. Moreover, our data suggests the importance of Oyapock River as a pathway for range expansion, arguing against the potential role of the Inini-Camopi Mountains as a physical barrier. Finally, in spite of a strongly argued scenario in favour of a north-to-south migration history, a clear genetic isolation of P. geyskesii populations living on inselbergs of the Mitaraka archipelago suggests a distinct ancestry of the most southern populations. 相似文献
952.
Deep brain stimulation (DBS) of the subthlamic nucleus (STN) represents an effective treatment for medically refractory Parkinson’s
disease; however, understanding of its effects on basal ganglia network activity remains limited. We constructed a computational
model of the subthalamopallidal network, trained it to fit in vivo recordings from parkinsonian monkeys, and evaluated its response to STN DBS. The network model was created with synaptically
connected single compartment biophysical models of STN and pallidal neurons, and stochastically defined inputs driven by cortical
beta rhythms. A least mean square error training algorithm was developed to parameterize network connections and minimize
error when compared to experimental spike and burst rates in the parkinsonian condition. The output of the trained network
was then compared to experimental data not used in the training process. We found that reducing the influence of the cortical
beta input on the model generated activity that agreed well with recordings from normal monkeys. Further, during STN DBS in
the parkinsonian condition the simulations reproduced the reduction in GPi bursting found in existing experimental data. The
model also provided the opportunity to greatly expand analysis of GPi bursting activity, generating three major predictions.
First, its reduction was proportional to the volume of STN activated by DBS. Second, GPi bursting decreased in a stimulation
frequency dependent manner, saturating at values consistent with clinically therapeutic DBS. And third, ablating STN neurons,
reported to generate similar therapeutic outcomes as STN DBS, also reduced GPi bursting. Our theoretical analysis of stimulation
induced network activity suggests that regularization of GPi firing is dependent on the volume of STN tissue activated and
a threshold level of burst reduction may be necessary for therapeutic effect. 相似文献
953.
Helen K. Graham Nigel W. Hodson Judith A. Hoyland Sarah J. Millward-Sadler David Garrod Anthea Scothern Christopher E.M. Griffiths Rachel E.B. Watson Thomas R. Cox Janine T. Erler Andrew W. Trafford Michael J. Sherratt 《Matrix biology》2010,29(4):254-260
Conventional approaches for ultrastructural high-resolution imaging of biological specimens induce profound changes in bio-molecular structures. By combining tissue cryo-sectioning with non-destructive atomic force microscopy (AFM) imaging we have developed a methodology that may be applied by the non-specialist to both preserve and visualize bio-molecular structures (in particular extracellular matrix assemblies) in situ. This tissue section AFM technique is capable of: i) resolving nm–µm scale features of intra- and extracellular structures in tissue cryo-sections; ii) imaging the same tissue region before and after experimental interventions; iii) combining ultrastructural imaging with complimentary microscopical and micromechanical methods. Here, we employ this technique to: i) visualize the macro-molecular structures of unstained and unfixed fibrillar collagens (in skin, cartilage and intervertebral disc), elastic fibres (in aorta and lung), desmosomes (in nasal epithelium) and mitochondria (in heart); ii) quantify the ultrastructural effects of sequential collagenase digestion on a single elastic fibre; iii) correlate optical (auto fluorescent) with ultrastructural (AFM) images of aortic elastic lamellae. 相似文献
954.
Sarah McPhee Lynn D. Hodges Paul F.A. Wright Paul M. Wynne Nicolette Kalafatis Theodore A. Macrides 《Prostaglandins, leukotrienes, and essential fatty acids》2010,82(2-3):97-103
Lipid-rich fractions from the flesh tissue of Mytilus edulis were obtained by solvent extraction and chromatographic separation, and tested for anti-inflammatory (AI) activity in vitro and in vivo. Inhibition of leukotriene production by isolated human neutrophils in response to calcium ionophore stimulation in the presence of exogenous arachidonic acid substrate was demonstrated for the hydrolysed triglyceride fraction of the crude lipid extract. This fraction was subsequently tested for in vivo AI activity using the mycobacterial adjuvant-induced polyarthritis rat model. The hydrolysed triglyceride fraction showed significant AI activity when dosed therapeutically (10 mg/kg BW/day, p.o., for 6 days from the onset of arthritis), decreasing body weight loss by 55% and hind paw swelling by 65% compared to the arthritic control. The (non-hydrolysed) crude lipid extract was effective when dosed prophylactically (30 mg/kg BW/day, p.o., for 16 days starting on day ?2 of arthritigen inoculation). Structural analysis by GC and GC–MS revealed in the extracts an abundance of EPA (20:5n-3) and DHA (22:6n-3) (37% of total fatty acids), along with a small quantity of a rare anti-inflammatory n-3 analogue of arachidonic acid, namely 7, 11, 14, 17-eicosatetraenoic acid (20:4n-3). 相似文献
955.
956.
957.
Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents
Saleem Ahmad Khehyong Ngu Keith J. Miller Ginger Wu Chen-pin Hung Sarah Malmstrom Ge Zhang Eva O’Tanyi William J. Keim Mary Jane Cullen Kenneth W. Rohrbach Michael Thomas Thao Ung Qinling Qu Jinping Gan Rangaraj Narayanan Mary Ann Pelleymounter Jeffrey A. Robl 《Bioorganic & medicinal chemistry letters》2010,20(3):1128-1133
Agonists of the 5-HT2C receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT2B receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT2C agonists with no detectable agonism of the 5-HT2B receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing. 相似文献
958.
959.
Houman Ashrafian Louise Docherty Vincenzo Leo Christopher Towlson Monica Neilan Violetta Steeples Craig A. Lygate Tertius Hough Stuart Townsend Debbie Williams Sara Wells Dominic Norris Sarah Glyn-Jones John Land Ivana Barbaric Zuzanne Lalanne Paul Denny Dorota Szumska Shoumo Bhattacharya Julian L. Griffin Iain Hargreaves Narcis Fernandez-Fuentes Michael Cheeseman Hugh Watkins T. Neil Dear 《PLoS genetics》2010,6(6)
Mutations in a number of genes have been linked to inherited dilated cardiomyopathy (DCM). However, such mutations account for only a small proportion of the clinical cases emphasising the need for alternative discovery approaches to uncovering novel pathogenic mutations in hitherto unidentified pathways. Accordingly, as part of a large-scale N-ethyl-N-nitrosourea mutagenesis screen, we identified a mouse mutant, Python, which develops DCM. We demonstrate that the Python phenotype is attributable to a dominant fully penetrant mutation in the dynamin-1-like (Dnm1l) gene, which has been shown to be critical for mitochondrial fission. The C452F mutation is in a highly conserved region of the M domain of Dnm1l that alters protein interactions in a yeast two-hybrid system, suggesting that the mutation might alter intramolecular interactions within the Dnm1l monomer. Heterozygous Python fibroblasts exhibit abnormal mitochondria and peroxisomes. Homozygosity for the mutation results in the death of embryos midway though gestation. Heterozygous Python hearts show reduced levels of mitochondria enzyme complexes and suffer from cardiac ATP depletion. The resulting energy deficiency may contribute to cardiomyopathy. This is the first demonstration that a defect in a gene involved in mitochondrial remodelling can result in cardiomyopathy, showing that the function of this gene is needed for the maintenance of normal cellular function in a relatively tissue-specific manner. This disease model attests to the importance of mitochondrial remodelling in the heart; similar defects might underlie human heart muscle disease. 相似文献
960.
McNeela EA Burke A Neill DR Baxter C Fernandes VE Ferreira D Smeaton S El-Rachkidy R McLoughlin RM Mori A Moran B Fitzgerald KA Tschopp J Pétrilli V Andrew PW Kadioglu A Lavelle EC 《PLoS pathogens》2010,6(11):e1001191
Pneumolysin (PLY) is a key Streptococcus pneumoniae virulence factor and potential candidate for inclusion in pneumococcal subunit vaccines. Dendritic cells (DC) play a key role in the initiation and instruction of adaptive immunity, but the effects of PLY on DC have not been widely investigated. Endotoxin-free PLY enhanced costimulatory molecule expression on DC but did not induce cytokine secretion. These effects have functional significance as adoptive transfer of DC exposed to PLY and antigen resulted in stronger antigen-specific T cell proliferation than transfer of DC exposed to antigen alone. PLY synergized with TLR agonists to enhance secretion of the proinflammatory cytokines IL-12, IL-23, IL-6, IL-1β, IL-1α and TNF-α by DC and enhanced cytokines including IL-17A and IFN-γ by splenocytes. PLY-induced DC maturation and cytokine secretion by DC and splenocytes was TLR4-independent. Both IL-17A and IFN-γ are required for protective immunity to pneumococcal infection and intranasal infection of mice with PLY-deficient pneumococci induced significantly less IFN-γ and IL-17A in the lungs compared to infection with wild-type bacteria. IL-1β plays a key role in promoting IL-17A and was previously shown to mediate protection against pneumococcal infection. The enhancement of IL-1β secretion by whole live S. pneumoniae and by PLY in DC required NLRP3, identifying PLY as a novel NLRP3 inflammasome activator. Furthermore, NLRP3 was required for protective immunity against respiratory infection with S. pneumoniae. These results add significantly to our understanding of the interactions between PLY and the immune system. 相似文献