全文获取类型
收费全文 | 619篇 |
免费 | 70篇 |
出版年
2023年 | 5篇 |
2022年 | 14篇 |
2021年 | 23篇 |
2020年 | 5篇 |
2019年 | 11篇 |
2018年 | 13篇 |
2017年 | 17篇 |
2016年 | 23篇 |
2015年 | 43篇 |
2014年 | 53篇 |
2013年 | 56篇 |
2012年 | 66篇 |
2011年 | 47篇 |
2010年 | 32篇 |
2009年 | 29篇 |
2008年 | 34篇 |
2007年 | 33篇 |
2006年 | 35篇 |
2005年 | 30篇 |
2004年 | 23篇 |
2003年 | 25篇 |
2002年 | 11篇 |
2001年 | 4篇 |
2000年 | 2篇 |
1999年 | 4篇 |
1998年 | 3篇 |
1997年 | 3篇 |
1996年 | 3篇 |
1995年 | 1篇 |
1994年 | 2篇 |
1993年 | 3篇 |
1992年 | 2篇 |
1991年 | 1篇 |
1989年 | 3篇 |
1988年 | 3篇 |
1986年 | 2篇 |
1984年 | 2篇 |
1983年 | 4篇 |
1982年 | 5篇 |
1981年 | 1篇 |
1978年 | 1篇 |
1976年 | 1篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1971年 | 1篇 |
1970年 | 1篇 |
1969年 | 2篇 |
1968年 | 1篇 |
1963年 | 1篇 |
1962年 | 1篇 |
排序方式: 共有689条查询结果,搜索用时 0 毫秒
11.
Astrocytes mediate either constriction or dilation of local brain arterioles in response to synaptic activity. Recent work
indicates that the directionality of this response may be dictated by ambient oxygen levels. 相似文献
12.
13.
14.
Bindu S. Mayi Jillian A. Leibowitz Arden T. Woods Katherine A. Ammon Alphonse E. Liu Aarti Raja 《PLoS pathogens》2021,17(1)
Neuropilin-1 (NRP-1), a member of a family of signaling proteins, was shown to serve as an entry factor and potentiate SARS Coronavirus 2 (SARS-CoV-2) infectivity in vitro. This cell surface receptor with its disseminated expression is important in angiogenesis, tumor progression, viral entry, axonal guidance, and immune function. NRP-1 is implicated in several aspects of a SARS-CoV-2 infection including possible spread through the olfactory bulb and into the central nervous system and increased NRP-1 RNA expression in lungs of severe Coronavirus Disease 2019 (COVID-19). Up-regulation of NRP-1 protein in diabetic kidney cells hint at its importance in a population at risk of severe COVID-19. Involvement of NRP-1 in immune function is compelling, given the role of an exaggerated immune response in disease severity and deaths due to COVID-19. NRP-1 has been suggested to be an immune checkpoint of T cell memory. It is unknown whether involvement and up-regulation of NRP-1 in COVID-19 may translate into disease outcome and long-term consequences, including possible immune dysfunction. It is prudent to further research NRP-1 and its possibility of serving as a therapeutic target in SARS-CoV-2 infections. We anticipate that widespread expression, abundance in the respiratory and olfactory epithelium, and the functionalities of NRP-1 factor into the multiple systemic effects of COVID-19 and challenges we face in management of disease and potential long-term sequelae. 相似文献
15.
Throughout their global range, oak‐dominated ecosystems have undergone state changes in stand structure and composition. Land managers face an especially acute challenge in restoring oak ecosystems and promoting oak regeneration in urban–exurban areas, where high‐intensity silvicultural treatments are often not feasible. To investigate low‐intensity management alternatives which could be widely applied in urban–exurban forests, a large‐scale adaptive management experiment was implemented in Lake County, IL, in 2012. Five canopy manipulation treatments of varying intensity, timing, and spatial aggregation were replicated across three study areas and oak seedlings were under‐planted into treatment units following management. Responses of understory light environment, shrub and groundlayer plant communities, and survival and growth of underplanted oak seedlings were evaluated. Understory light availability, canopy openness, total groundlayer plant cover, and groundlayer species diversity all differed among treatments. However, although understory light availability was significantly increased by canopy manipulation, groundlayer communities and oak seedling survival and growth did not differ among treatments. High overall seedling survival rates suggest current conditions are amenable to oak regeneration, but long‐term monitoring will be needed to assess the potential for seedlings to transition to the sapling and canopy layers. Early results demonstrate that canopy‐focused silvicultural treatments can affect the understory light environment and, to some degree, groundlayer plant communities. However, underplanting of oak seedlings paired with subcanopy thinning may be sufficient to restore an oak seedling layer, and (when necessary or preferred) canopy manipulation could potentially be deferred until later in the restoration timeline to promote oak recruitment. 相似文献
16.
Karla J. Helbig Jillian M. Carr Julie K. Calvert Satiya Wati Jennifer N. Clarke Nicholas S. Eyre Sumudu K. Narayana Guillaume N. Fiches Erin M. McCartney Michael R. Beard 《PLoS neglected tropical diseases》2013,7(4)
The host protein viperin is an interferon stimulated gene (ISG) that is up-regulated during a number of viral infections. In this study we have shown that dengue virus type-2 (DENV-2) infection significantly induced viperin, co-incident with production of viral RNA and via a mechanism requiring retinoic acid-inducible gene I (RIG-I). Viperin did not inhibit DENV-2 entry but DENV-2 RNA and infectious virus release was inhibited in viperin expressing cells. Conversely, DENV-2 replicated to higher tires earlier in viperin shRNA expressing cells. The anti-DENV effect of viperin was mediated by residues within the C-terminal 17 amino acids of viperin and did not require the N-terminal residues, including the helix domain, leucine zipper and S-adenosylmethionine (SAM) motifs known to be involved in viperin intracellular membrane association. Viperin showed co-localisation with lipid droplet markers, and was co-localised and interacted with DENV-2 capsid (CA), NS3 and viral RNA. The ability of viperin to interact with DENV-2 NS3 was associated with its anti-viral activity, while co-localisation of viperin with lipid droplets was not. Thus, DENV-2 infection induces viperin which has anti-viral properties residing in the C-terminal region of the protein that act to restrict early DENV-2 RNA production/accumulation, potentially via interaction of viperin with DENV-2 NS3 and replication complexes. These anti-DENV-2 actions of viperin show both contrasts and similarities with other described anti-viral mechanisms of viperin action and highlight the diverse nature of this unique anti-viral host protein. 相似文献
17.
Robert Bronstein Luisa Torres Jillian C. Nissen Stella E. Tsirka 《Journal of visualized experiments : JoVE》2013,(78)
Microglia are the resident macrophage-like cells of the central nervous system (CNS) and, as such, have critically important roles in physiological and pathological processes such as CNS maturation in development, multiple sclerosis, and spinal cord injury. Microglia can be activated and recruited to action by neuronal injury or stimulation, such as axonal damage seen in MS or ischemic brain trauma resulting from stroke. These immunocompetent members of the CNS are also thought to have roles in synaptic plasticity under non-pathological conditions. We employ protocols for culturing microglia from the neonatal and adult tissues that are aimed to maximize the viable cell numbers while minimizing confounding variables, such as the presence of other CNS cell types and cell culture debris. We utilize large and easily discernable CNS components (e.g. cortex, spinal cord segments), which makes the entire process feasible and reproducible. The use of adult cells is a suitable alternative to the use of neonatal brain microglia, as many pathologies studied mainly affect the postnatal spinal cord. These culture systems are also useful for directly testing the effect of compounds that may either inhibit or promote microglial activation. Since microglial activation can shape the outcomes of disease in the adult CNS, there is a need for in vitro systems in which neonatal and adult microglia can be cultured and studied. 相似文献
18.
Géraldine De Muylder Sylvie Daulouède Laurence Lecordier Pierrick Uzureau Yannick Morias Jan Van Den Abbeele Guy Caljon Michel Hérin Philippe Holzmuller Silla Semballa Pierrette Courtois Luc Vanhamme Beno?t Stijlemans Patrick De Baetselier Michael P. Barrett Jillian L. Barlow Andrew N. J. McKenzie Luke Barron Thomas A. Wynn Alain Beschin Philippe Vincendeau Etienne Pays 《PLoS pathogens》2013,9(10)
Background
In order to promote infection, the blood-borne parasite Trypanosoma brucei releases factors that upregulate arginase expression and activity in myeloid cells.Methodology/Principal findings
By screening a cDNA library of T. brucei with an antibody neutralizing the arginase-inducing activity of parasite released factors, we identified a Kinesin Heavy Chain isoform, termed TbKHC1, as responsible for this effect. Following interaction with mouse myeloid cells, natural or recombinant TbKHC1 triggered SIGN-R1 receptor-dependent induction of IL-10 production, resulting in arginase-1 activation concomitant with reduction of nitric oxide (NO) synthase activity. This TbKHC1 activity was IL-4Rα-independent and did not mirror M2 activation of myeloid cells. As compared to wild-type T. brucei, infection by TbKHC1 KO parasites was characterized by strongly reduced parasitaemia and prolonged host survival time. By treating infected mice with ornithine or with NO synthase inhibitor, we observed that during the first wave of parasitaemia the parasite growth-promoting effect of TbKHC1-mediated arginase activation resulted more from increased polyamine production than from reduction of NO synthesis. In late stage infection, TbKHC1-mediated reduction of NO synthesis appeared to contribute to liver damage linked to shortening of host survival time.Conclusion
A kinesin heavy chain released by T. brucei induces IL-10 and arginase-1 through SIGN-R1 signaling in myeloid cells, which promotes early trypanosome growth and favors parasite settlement in the host. Moreover, in the late stage of infection, the inhibition of NO synthesis by TbKHC1 contributes to liver pathogenicity. 相似文献19.
Eleanor Y. Chen Kimberly P. Dobrinski Kim H. Brown Ryan Clagg Elena Edelman Myron S. Ignatius Jin Yun Helen Chen Jillian Brockmann G. Petur Nielsen Sridhar Ramaswamy Charles Keller Charles Lee David M. Langenau 《PLoS genetics》2013,9(8)
Human cancer genomes are highly complex, making it challenging to identify specific drivers of cancer growth, progression, and tumor maintenance. To bypass this obstacle, we have applied array comparative genomic hybridization (array CGH) to zebrafish embryonal rhabdomyosaroma (ERMS) and utilized cross-species comparison to rapidly identify genomic copy number aberrations and novel candidate oncogenes in human disease. Zebrafish ERMS contain small, focal regions of low-copy amplification. These same regions were commonly amplified in human disease. For example, 16 of 19 chromosomal gains identified in zebrafish ERMS also exhibited focal, low-copy gains in human disease. Genes found in amplified genomic regions were assessed for functional roles in promoting continued tumor growth in human and zebrafish ERMS – identifying critical genes associated with tumor maintenance. Knockdown studies identified important roles for Cyclin D2 (CCND2), Homeobox Protein C6 (HOXC6) and PlexinA1 (PLXNA1) in human ERMS cell proliferation. PLXNA1 knockdown also enhanced differentiation, reduced migration, and altered anchorage-independent growth. By contrast, chemical inhibition of vascular endothelial growth factor (VEGF) signaling reduced angiogenesis and tumor size in ERMS-bearing zebrafish. Importantly, VEGFA expression correlated with poor clinical outcome in patients with ERMS, implicating inhibitors of the VEGF pathway as a promising therapy for improving patient survival. Our results demonstrate the utility of array CGH and cross-species comparisons to identify candidate oncogenes essential for the pathogenesis of human cancer. 相似文献
20.
Michael J. Wilkins Kelly C. Wrighton Carrie D. Nicora Kenneth H. Williams Lee Ann McCue Kim M. Handley Chris S. Miller Ludovic Giloteaux Alison P. Montgomery Derek R. Lovley Jillian F. Banfield Philip E. Long Mary S. Lipton 《PloS one》2013,8(3)
While microbial activities in environmental systems play a key role in the utilization and cycling of essential elements and compounds, microbial activity and growth frequently fluctuates in response to environmental stimuli and perturbations. To investigate these fluctuations within a saturated aquifer system, we monitored a carbon-stimulated in situ Geobacter population while iron reduction was occurring, using 16S rRNA abundances and high-resolution tandem mass spectrometry proteome measurements. Following carbon amendment, 16S rRNA analysis of temporally separated samples revealed the rapid enrichment of Geobacter-like environmental strains with strong similarity to G. bemidjiensis. Tandem mass spectrometry proteomics measurements suggest high carbon flux through Geobacter respiratory pathways, and the synthesis of anapleurotic four carbon compounds from acetyl-CoA via pyruvate ferredoxin oxidoreductase activity. Across a 40-day period where Fe(III) reduction was occurring, fluctuations in protein expression reflected changes in anabolic versus catabolic reactions, with increased levels of biosynthesis occurring soon after acetate arrival in the aquifer. In addition, localized shifts in nutrient limitation were inferred based on expression of nitrogenase enzymes and phosphate uptake proteins. These temporal data offer the first example of differing microbial protein expression associated with changing geochemical conditions in a subsurface environment. 相似文献