全文获取类型
收费全文 | 3707篇 |
免费 | 322篇 |
国内免费 | 1篇 |
专业分类
4030篇 |
出版年
2023年 | 16篇 |
2022年 | 40篇 |
2021年 | 70篇 |
2020年 | 52篇 |
2019年 | 50篇 |
2018年 | 48篇 |
2017年 | 41篇 |
2016年 | 94篇 |
2015年 | 142篇 |
2014年 | 182篇 |
2013年 | 209篇 |
2012年 | 314篇 |
2011年 | 305篇 |
2010年 | 182篇 |
2009年 | 193篇 |
2008年 | 244篇 |
2007年 | 198篇 |
2006年 | 190篇 |
2005年 | 213篇 |
2004年 | 209篇 |
2003年 | 188篇 |
2002年 | 178篇 |
2001年 | 18篇 |
2000年 | 22篇 |
1999年 | 28篇 |
1998年 | 38篇 |
1997年 | 27篇 |
1996年 | 29篇 |
1995年 | 29篇 |
1994年 | 36篇 |
1993年 | 23篇 |
1992年 | 18篇 |
1991年 | 11篇 |
1990年 | 11篇 |
1989年 | 16篇 |
1988年 | 16篇 |
1987年 | 14篇 |
1985年 | 15篇 |
1984年 | 34篇 |
1983年 | 21篇 |
1982年 | 20篇 |
1981年 | 14篇 |
1980年 | 28篇 |
1979年 | 15篇 |
1978年 | 25篇 |
1977年 | 27篇 |
1976年 | 15篇 |
1975年 | 14篇 |
1974年 | 22篇 |
1973年 | 16篇 |
排序方式: 共有4030条查询结果,搜索用时 0 毫秒
991.
Alpha-catenin functions to anchor adherens junctions to the filamentous actin (F-actin) cytoskeleton, through direct and indirect binding mechanisms. When truncated at amino acid 865, alpha-catenin exhibited a markedly reduced F-actin binding affinity compared to wild-type. Expression of the truncated mutant in the alpha-catenin deficient colon carcinoma cell line, Clone A, could not restore an adhesive phenotype when compared. Furthermore, the truncated alpha-catenin fusion protein failed to concentrate at sites of cell-cell contact, to promote morphological changes associated with epithelial monolayers, and to stimulate resistance to shearing forces in a hanging drop aggregation assay. Subsequent attempts to isolate single residues governing the direct F-actin interaction, using neutralizing charge or reverse charge mutations of basic residues within a homology modeled alpha-catenin C-terminal 5-helix bundle, had no effect on F-actin cosedimentation. We conclude that direct attachment of alpha-catenin to F-actin is required to promote cadherin-mediated contact formation and strong cell-cell adhesive states. 相似文献
992.
Silencing viral infection 总被引:1,自引:0,他引:1
993.
Lymphocyte transcellular migration occurs through recruitment of endothelial ICAM-1 to caveola- and F-actin-rich domains 总被引:16,自引:0,他引:16
During inflammation, leukocytes bind to the adhesion receptors ICAM-1 and VCAM-1 on the endothelial surface before undergoing transendothelial migration, also called diapedesis. ICAM-1 is also involved in transendothelial migration, independently of its role in adhesion, but the molecular basis of this function is poorly understood. Here we demonstrate that, following clustering, apical ICAM-1 translocated to caveolin-rich membrane domains close to the ends of actin stress fibres. In these F-actin-rich areas, ICAM-1 was internalized and transcytosed to the basal plasma membrane through caveolae. Human T-lymphocytes extended pseudopodia into endothelial cells in caveolin- and F-actin-enriched areas, induced local translocation of ICAM-1 and caveolin-1 to the endothelial basal membrane and transmigrated through transcellular passages formed by a ring of F-actin and caveolae. Reduction of caveolin-1 levels using RNA interference (RNAi) specifically decreased lymphocyte transcellular transmigration. We propose that the translocation of ICAM-1 to caveola- and F-actin-rich domains links the sequential steps of lymphocyte adhesion and transendothelial migration and facilitates lymphocyte migration through endothelial cells from capillaries into surrounding tissue. 相似文献
994.
Thomas Mailund Gerth S Brodal Rolf Fagerberg Christian NS Pedersen Derek Phillips 《BMC bioinformatics》2006,7(1):29-8
Background
The neighbor-joining method by Saitou and Nei is a widely used method for constructing phylogenetic trees. The formulation of the method gives rise to a canonical Θ(n 3) algorithm upon which all existing implementations are based. 相似文献995.
For many years, the ant subfamily Ponerinae was hypothesized to contain the basal (early branching) lineages of ants. Recently the Ponerinae were reclassified into six poneromorph subfamilies based on morphological analysis. We evaluate this new poneromorph classification using 1240 base pairs of DNA sequence data obtained from 28S rRNA gene sequences of 68 terminal taxa. The molecular tree supported the monophyly of the ant family Formicidae, with 100% parsimony bootstrap (PB) support and posterior probabilities (PP) of 1.00, with the ant subfamily Leptanillinae as a sister group to all other ants (PB=62, PP=93). However, our analyses strongly support the polyphyly of the Poneromorph subfamilies (sensu Bolton). The Ectatomminae and Heteroponerinae are more closely related to the Formicoid subfamilies than to the rest of the poneromophs (PB=96, PP=100). The Amblyoponinae (PB=52, PP=96), Paraponerinae (PB=100, PP=100), Ponerinae (PB<50, PP=71), and Proceratiinae (PB=98, PP=100) appear as distinct lineages at the base of the tree and are identified as a poneroid grade. Monophyletic origins for the poneroid subfamilies Amblyoponinae, Paraponerinae, Ponerinae and Proceratiinae are supported in our analysis. However, the genus Platythyrea forms a distinct sister group to the Ponerini within the Ponerinae. The Heteroponerinae, based on our sample of Heteroponera, are associated with the subfamily Ectatomminae (PB=98, PP=100). Furthermore, our data indicate the genus Probolomyrmex belongs to the Proceratiinae as suggested by recent morphological analysis (PB=98, PP=100). 相似文献
996.
Lisi AJ O'Neill CW Lindsey DP Cooperstein R Cooperstein E Zucherman JF 《Journal of applied biomechanics》2006,22(3):234-239
This paper presents the first reported measurements of lumbar intervertebral disc pressure in vivo during spinal manipulation. A pressure transducer was inserted into the nucleus pulposus of one normal-appearing lumbar disc in an asymptomatic adult volunteer. Pressures were recorded during several body positions and maneuvers, then during spinal manipulation, and lastly during a repetition of the preintervention body positions. Baseline pressures in the prone and side-lying positions measured 110 kPa and 150 kPa, respectively. During the manipulation, pressure rose to a peak of 890 kPa over 250 ms. Immediately following, pressures in the prone and side-lying positions measured 150 kPa and 165 kPa, respectively. These data do not support the hypotheses that manipulation can reduce a herniation by decreasing intradiscal pressure, or cause a herniation by raising pressure to failure levels. Further work may lead to a better understanding of this treatment method. 相似文献
997.
Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer 总被引:18,自引:0,他引:18
Thomas GV Tran C Mellinghoff IK Welsbie DS Chan E Fueger B Czernin J Sawyers CL 《Nature medicine》2006,12(1):122-127
Inhibitors of the kinase mammalian target of rapamycin (mTOR) have shown sporadic activity in cancer trials, leading to confusion about the appropriate clinical setting for their use. Here we show that loss of the Von Hippel-Lindau tumor suppressor gene (VHL) sensitizes kidney cancer cells to the mTOR inhibitor CCI-779 in vitro and in mouse models. Growth arrest caused by CCI-779 correlates with a block in translation of mRNA encoding hypoxia-inducible factor (HIF1A), and is rescued by expression of a VHL-resistant HIF1A cDNA lacking the 5' untranslated region. VHL-deficient tumors show increased uptake of the positron emission tomography (PET) tracer fluorodeoxyglucose (FDG) in an mTOR-dependent manner. Our findings provide preclinical rationale for prospective, biomarker-driven clinical studies of mTOR inhibitors in kidney cancer and suggest that FDG-PET scans may have use as a pharmacodynamic marker in this setting. 相似文献
998.
Bioinspired fibrous materials that span the nano-to-meso scales have potentially broad applications in nanobiotechnology; for instance, as scaffolds in 3D cell culture and tissue engineering, and as templates for the assembly of other polymer and inorganic materials. The field is burgeoning, and this review is necessarily focused. It centres on recent developments in the design of peptide-based fibres and particularly those using the alpha-helix and the collagen triple helix as building blocks for self-assembly. Advances include new designs in both categories, the assembly of more-complex topologies using fibres themselves as building blocks, and the decoration of the assembled materials with functional moieties. 相似文献
999.
Sanjay K. Shukla Dane Cook Jacob Meyer Suzanne D. Vernon Thao Le Derek Clevidence Charles E. Robertson Steven J. Schrodi Steven Yale Daniel N. Frank 《PloS one》2015,10(12)
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by intense and debilitating fatigue not due to physical activity that has persisted for at least 6 months, post-exertional malaise, unrefreshing sleep, and accompanied by a number of secondary symptoms, including sore throat, memory and concentration impairment, headache, and muscle/joint pain. In patients with post-exertional malaise, significant worsening of symptoms occurs following physical exertion and exercise challenge serves as a useful method for identifying biomarkers for exertion intolerance. Evidence suggests that intestinal dysbiosis and systemic responses to gut microorganisms may play a role in the symptomology of ME/CFS. As such, we hypothesized that post-exertion worsening of ME/CFS symptoms could be due to increased bacterial translocation from the intestine into the systemic circulation. To test this hypothesis, we collected symptom reports and blood and stool samples from ten clinically characterized ME/CFS patients and ten matched healthy controls before and 15 minutes, 48 hours, and 72 hours after a maximal exercise challenge. Microbiomes of blood and stool samples were examined. Stool sample microbiomes differed between ME/CFS patients and healthy controls in the abundance of several major bacterial phyla. Following maximal exercise challenge, there was an increase in relative abundance of 6 of the 9 major bacterial phyla/genera in ME/CFS patients from baseline to 72 hours post-exercise compared to only 2 of the 9 phyla/genera in controls (p = 0.005). There was also a significant difference in clearance of specific bacterial phyla from blood following exercise with high levels of bacterial sequences maintained at 72 hours post-exercise in ME/CFS patients versus clearance in the controls. These results provide evidence for a systemic effect of an altered gut microbiome in ME/CFS patients compared to controls. Upon exercise challenge, there were significant changes in the abundance of major bacterial phyla in the gut in ME/CFS patients not observed in healthy controls. In addition, compared to controls clearance of bacteria from the blood was delayed in ME/CFS patients following exercise. These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS patients that may account for the profound post-exertional malaise experienced by ME/CFS patients. 相似文献
1000.
Characterization of Enterococcus faecalis Alkaline Phosphatase and Use in Identifying Streptococcus agalactiae Secreted Proteins 下载免费PDF全文
Martin H. Lee Aphakorn Nittayajarn R. Paul Ross Cynthia B. Rothschild Derek Parsonage Al Claiborne Craig E. Rubens 《Journal of bacteriology》1999,181(18):5790-5799
We have identified and characterized an Enterococcus faecalis alkaline phosphatase (AP, encoded by phoZ). The predicted gene product shows homology with alkaline phosphatases from a variety of species; it has especially high similarity with two alkaline phosphatases from Bacillus subtilis. Expression of phoZ in Escherichia coli, E. faecalis, Streptococcus agalactiae (group B streptococcus [GBS]), or Streptococcus pyogenes (group A streptococcus [GAS]) produces a blue-colony phenotype on plates containing a chromogenic substrate, 5-bromo-4-chloro-3-indolylphosphate (XP or BCIP). Two tests were made to determine if the activity of the enzyme is dependent upon the enzyme's subcellular location. First, elimination of the signal sequence reduced AP activity to 3% of the wild-type activity (or less) in three species of gram-positive bacteria. Restoration of export, using the signal sequence from C5a peptidase, restored AP activity to at least 50% of that of the wild type. Second, we engineered two chimeric proteins in which AP was fused to either a periplasmic domain or a cytoplasmic domain of lactose permease (a membrane protein). In E. coli, the periplasmic fusion had 17-fold-higher AP activity than the cytoplasmic fusion. We concluded that AP activity is export dependent. The signal sequence deletion mutant, phoZDeltass, was used to identify random genomic fragments from GBS that encode exported proteins or integral membrane proteins. Included in this set of fragments were genes that exhibited homology with the Rib protein (a cell wall protein from GBS) or with DppB (an integral membrane protein from GAS). AP acts as a reporter enzyme in GBS, GAS, and E. faecalis and is expected to be useful in a variety of gram-positive bacteria. 相似文献