全文获取类型
收费全文 | 1808篇 |
免费 | 191篇 |
国内免费 | 2篇 |
专业分类
2001篇 |
出版年
2024年 | 4篇 |
2023年 | 8篇 |
2022年 | 25篇 |
2021年 | 55篇 |
2020年 | 26篇 |
2019年 | 39篇 |
2018年 | 49篇 |
2017年 | 56篇 |
2016年 | 71篇 |
2015年 | 128篇 |
2014年 | 135篇 |
2013年 | 140篇 |
2012年 | 151篇 |
2011年 | 151篇 |
2010年 | 104篇 |
2009年 | 76篇 |
2008年 | 129篇 |
2007年 | 124篇 |
2006年 | 94篇 |
2005年 | 76篇 |
2004年 | 77篇 |
2003年 | 76篇 |
2002年 | 79篇 |
2001年 | 8篇 |
2000年 | 5篇 |
1999年 | 19篇 |
1998年 | 20篇 |
1997年 | 10篇 |
1996年 | 14篇 |
1995年 | 8篇 |
1994年 | 5篇 |
1993年 | 2篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1987年 | 2篇 |
1986年 | 2篇 |
1985年 | 4篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1981年 | 4篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1972年 | 1篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1969年 | 2篇 |
排序方式: 共有2001条查询结果,搜索用时 0 毫秒
41.
Kristen L. Leslie Gyun Jee Song Stacey Barrick Vanessa L. Wehbi Jean-Pierre Vilardaga Philip M. Bauer Alessandro Bisello 《The Journal of biological chemistry》2013,288(51):36426-36436
The interaction between vascular cells and macrophages is critical during vascular remodeling. Here we report that the scaffolding protein, ezrin-binding phosphoprotein 50 (EBP50), is a central regulator of macrophage and vascular smooth muscle cells (VSMC) function. EBP50 is up-regulated in intimal VSMC following endoluminal injury and promotes neointima formation. However, the mechanisms underlying these effects are not fully understood. Because of the fundamental role that inflammation plays in vascular diseases, we hypothesized that EBP50 mediates macrophage activation and the response of vessels to inflammation. Indeed, EBP50 expression increased in primary macrophages and VSMC, and in the aorta of mice, upon treatment with LPS or TNFα. This increase was nuclear factor-κB (NF-κB)-dependent. Conversely, activation of NF-κB was impaired in EBP50-null VSMC and macrophages. We found that inflammatory stimuli promote the formation of an EBP50-PKCζ complex at the cell membrane that induces NF-κB signaling. Macrophage activation and vascular inflammation after acute LPS treatment were reduced in EBP50-null cells and mice as compared with WT. Furthermore, macrophage recruitment to vascular lesions was significantly reduced in EBP50 knock-out mice. Thus, EBP50 and NF-κB participate in a feed-forward loop leading to increased macrophage activation and enhanced response of vascular cells to inflammation. 相似文献
42.
Olivier Escaffre Cyril Le Nou?n Michel Amelot Xavier Ambroggio Kristen M. Ogden Olivier Guionie Didier Toquin Hermann Müller Mohammed R. Islam Nicolas Eterradossi 《Journal of virology》2013,87(5):2767-2780
Infectious bursal disease virus (IBDV) causes an economically significant disease of chickens worldwide. Very virulent IBDV (vvIBDV) strains have emerged and induce as much as 60% mortality. The molecular basis for vvIBDV pathogenicity is not understood, and the relative contributions of the two genome segments, A and B, to this phenomenon are not known. Isolate 94432 has been shown previously to be genetically related to vvIBDVs but exhibits atypical antigenicity and does not cause mortality. Here the full-length genome of 94432 was determined, and a reverse genetics system was established. The molecular clone was rescued and exhibited the same antigenicity and reduced pathogenicity as isolate 94432. Genetically modified viruses derived from 94432, whose vvIBDV consensus nucleotide sequence was restored in segment A and/or B, were produced, and their pathogenicity was assessed in specific-pathogen-free chickens. We found that a valine (position 321) that modifies the most exposed part of the capsid protein VP2 critically modified the antigenicity and partially reduced the pathogenicity of 94432. However, a threonine (position 276) located in the finger domain of the virus polymerase (VP1) contributed even more significantly to attenuation. This threonine is partially exposed in a hydrophobic groove on the VP1 surface, suggesting possible interactions between VP1 and another, as yet unidentified molecule at this amino acid position. The restored vvIBDV-like pathogenicity was associated with increased replication and lesions in the thymus and spleen. These results demonstrate that both genome segments influence vvIBDV pathogenicity and may provide new targets for the attenuation of vvIBDVs. 相似文献
43.
Frank Maldarelli Mary Kearney Sarah Palmer Robert Stephens JoAnn Mican Michael A. Polis Richard T. Davey Joseph Kovacs Wei Shao Diane Rock-Kress Julia A. Metcalf Catherine Rehm Sarah E. Greer Daniel L. Lucey Kristen Danley Harvey Alter John W. Mellors John M. Coffin 《Journal of virology》2013,87(18):10313-10323
HIV infection is characterized by rapid and error-prone viral replication resulting in genetically diverse virus populations. The rate of accumulation of diversity and the mechanisms involved are under intense study to provide useful information to understand immune evasion and the development of drug resistance. To characterize the development of viral diversity after infection, we carried out an in-depth analysis of single genome sequences of HIV pro-pol to assess diversity and divergence and to estimate replicating population sizes in a group of treatment-naive HIV-infected individuals sampled at single (n = 22) or multiple, longitudinal (n = 11) time points. Analysis of single genome sequences revealed nonlinear accumulation of sequence diversity during the course of infection. Diversity accumulated in recently infected individuals at rates 30-fold higher than in patients with chronic infection. Accumulation of synonymous changes accounted for most of the diversity during chronic infection. Accumulation of diversity resulted in population shifts, but the rates of change were low relative to estimated replication cycle times, consistent with relatively large population sizes. Analysis of changes in allele frequencies revealed effective population sizes that are substantially higher than previous estimates of approximately 1,000 infectious particles/infected individual. Taken together, these observations indicate that HIV populations are large, diverse, and slow to change in chronic infection and that the emergence of new mutations, including drug resistance mutations, is governed by both selection forces and drift. 相似文献
44.
Jessica Worthington Wilmer Mitchell Lyons Kristen E. Lee Clive A. McAlpine Frank N. Carrick 《Molecular ecology》2013,22(14):3752-3765
Landscape genetics offers a powerful approach to understanding species' dispersal patterns. However, a central obstacle is to account for ecological processes operating at multiple spatial scales, while keeping research outcomes applicable to conservation management. We address this challenge by applying a novel multilevel regression approach to model landscape drivers of genetic structure at both the resolution of individuals and at a spatial resolution relevant to management (i.e. local government management areas: LGAs) for the koala (Phascolartos cinereus) in Australia. Our approach allows for the simultaneous incorporation of drivers of landscape‐genetic relationships operating at multiple spatial resolutions. Using microsatellite data for 1106 koalas, we show that, at the individual resolution, foliage projective cover (FPC) facilitates high gene flow (i.e. low resistance) until it falls below approximately 30%. Out of six additional land‐cover variables, only highways and freeways further explained genetic distance after accounting for the effect of FPC. At the LGA resolution, there was significant variation in isolation‐by‐resistance (IBR) relationships in terms of their slopes and intercepts. This was predominantly explained by the average resistance distance among LGAs, with a weaker effect of historical forest cover. Rates of recent landscape change did not further explain variation in IBR relationships among LGAs. By using a novel multilevel model, we disentangle the effect of landscape resistance on gene flow at the fine resolution (i.e. among individuals) from effects occurring at coarser resolutions (i.e. among LGAs). This has important implications for our ability to identify appropriate scale‐dependent management actions. 相似文献
45.
Robin L. Dennis Donna B. Schwede Jesse O. Bash Jon E. Pleim John T. Walker Kristen M. Foley 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2013,368(1621)
Reactive nitrogen (Nr) is removed by surface fluxes (air–surface exchange) and wet deposition. The chemistry and physics of the atmosphere result in a complicated system in which competing chemical sources and sinks exist and impact that removal. Therefore, uncertainties are best examined with complete regional chemical transport models that simulate these feedbacks. We analysed several uncertainties in regional air quality model resistance analogue representations of air–surface exchange for unidirectional and bi-directional fluxes and their effect on the continental Nr budget. Model sensitivity tests of key parameters in dry deposition formulations showed that uncertainty estimates of continental total nitrogen deposition are surprisingly small, 5 per cent or less, owing to feedbacks in the chemistry and rebalancing among removal pathways. The largest uncertainties (5%) occur with the change from a unidirectional to a bi-directional NH3 formulation followed by uncertainties in bi-directional compensation points (1–4%) and unidirectional aerodynamic resistance (2%). Uncertainties have a greater effect at the local scale. Between unidirectional and bi-directional formulations, single grid cell changes can be up to 50 per cent, whereas 84 per cent of the cells have changes less than 30 per cent. For uncertainties within either formulation, single grid cell change can be up to 20 per cent, but for 90 per cent of the cells changes are less than 10 per cent. 相似文献
46.
47.
Donna J. Shaver Kristen M. Hart Ikuko Fujisaki Cynthia Rubio Autumn R. Sartain Jaime Peña Patrick M. Burchfield Daniel Gomez Gamez Jaime Ortiz 《Ecology and evolution》2013,3(7):2002-2012
For many marine species, locations of key foraging areas are not well defined. We used satellite telemetry and switching state‐space modeling (SSM) to identify distinct foraging areas used by Kemp's ridley turtles (Lepidochelys kempii) tagged after nesting during 1998–2011 at Padre Island National Seashore, Texas, USA (PAIS; N = 22), and Rancho Nuevo, Tamaulipas, Mexico (RN; N = 9). Overall, turtles traveled a mean distance of 793.1 km (±347.8 SD) to foraging sites, where 24 of 31 turtles showed foraging area fidelity (FAF) over time (N = 22 in USA, N = 2 in Mexico). Multiple turtles foraged along their migratory route, prior to arrival at their “final” foraging sites. We identified new foraging “hotspots” where adult female Kemp's ridley turtles spent 44% of their time during tracking (i.e., 2641/6009 tracking days in foraging mode). Nearshore Gulf of Mexico waters served as foraging habitat for all turtles tracked in this study; final foraging sites were located in water <68 m deep and a mean distance of 33.2 km (±25.3 SD) from the nearest mainland coast. Distance to release site, distance to mainland shore, annual mean sea surface temperature, bathymetry, and net primary production were significant predictors of sites where turtles spent large numbers of days in foraging mode. Spatial similarity of particular foraging sites selected by different turtles over the 13‐year tracking period indicates that these areas represent critical foraging habitat, particularly in waters off Louisiana. Furthermore, the wide distribution of foraging sites indicates that a foraging corridor exists for Kemp's ridleys in the Gulf. Our results highlight the need for further study of environmental and bathymetric components of foraging sites and prey resources contained therein, as well as international cooperation to protect essential at‐sea foraging habitats for this imperiled species. 相似文献
48.
Significant functional impairment of the hand is commonly observed in stroke survivors. Our previous studies suggested that the inability to modulate muscle coordination patterns according to task requirements may be substantial after stroke, but these limitations have not been examined directly. In this study, we aimed to characterize post-stroke impairment in the ability to modulate muscle coordination patterns across tasks and its correlation with hand impairment. Fourteen stroke survivors, divided into a group with severe hand impairment (8 subjects) and a group with moderate hand impairment (6 subjects) according to their clinical functionality score, participated in the experiment. Another four neurologically intact subjects participated in the experiment to serve as a point of comparison. Activation patterns of nine hand and wrist muscles were recorded using surface electromyography while the subjects performed six isometric tasks. Patterns of covariation in muscle activations across tasks, i.e., muscle modules, were extracted from the muscle activation data. Our results showed that the degree of reduction in the inter-task separation of the multi-muscle activation patterns was indicative of the clinical functionality score of the subjects (mean value = 26.2 for severely impaired subjects, 38.1 for moderately impaired subjects). The values for moderately impaired subjects were much closer to those of the impaired subjects (mean value = 46.1). The number of muscle modules extracted from the muscle activation patterns of a subject across six tasks, which represents the degree of motor complexity, was found to be correlated with the clinical functionality score (R = 0.68). Greater impairment was also associated with a change in the muscle module patterns themselves, with greater muscle coactivation. A substantial reduction in the degrees-of-freedom of the multi-muscle coordination post-stroke was apparent, and the extent of the reduction, assessed by the stated metrics, was strongly associated with the level of clinical impairment. 相似文献
49.
David P. Dimmock Michelle M. Clark Mary Gaughran Julie A. Cakici Sara A. Caylor Christina Clarke Michele Feddock Shimul Chowdhury Lisa Salz Cynthia Cheung Lynne M. Bird Charlotte Hobbs Kristen Wigby Lauge Farnaes Cinnamon S. Bloss Stephen F. Kingsmore the RCIGM Investigators 《American journal of human genetics》2020,107(5):942
50.
An allosteric antibody to the leptin receptor reduces body weight and reverses the diabetic phenotype in the Lepob/Lepob mouse 下载免费PDF全文