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221.
222.
Transmission routes maintaining a viral pathogen of steelhead trout within a complex multi‐host assemblage
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Rachel Breyta Paige Ferguson Gael Kurath Kerry A. Naish Maureen K. Purcell Andrew R. Wargo Shannon LaDeau 《Ecology and evolution》2017,7(20):8187-8200
This is the first comprehensive region wide, spatially explicit epidemiologic analysis of surveillance data of the aquatic viral pathogen infectious hematopoietic necrosis virus (IHNV) infecting native salmonid fish. The pathogen has been documented in the freshwater ecosystem of the Pacific Northwest of North America since the 1950s, and the current report describes the disease ecology of IHNV during 2000–2012. Prevalence of IHNV infection in monitored salmonid host cohorts ranged from 8% to 30%, with the highest levels observed in juvenile steelhead trout. The spatial distribution of all IHNV‐infected cohorts was concentrated in two sub‐regions of the study area, where historic burden of the viral disease has been high. During the study period, prevalence levels fluctuated with a temporal peak in 2002. Virologic and genetic surveillance data were analyzed for evidence of three separate but not mutually exclusive transmission routes hypothesized to be maintaining IHNV in the freshwater ecosystem. Transmission between year classes of juvenile fish at individual sites (route 1) was supported at varying levels of certainty in 10%–55% of candidate cases, transmission between neighboring juvenile cohorts (route 2) was supported in 31%–78% of candidate cases, and transmission from adult fish returning to the same site as an infected juvenile cohort was supported in 26%–74% of candidate cases. The results of this study indicate that multiple specific transmission routes are acting to maintain IHNV in juvenile fish, providing concrete evidence that can be used to improve resource management. Furthermore, these results demonstrate that more sophisticated analysis of available spatio‐temporal and genetic data is likely to yield greater insight in future studies. 相似文献
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Mechanism of type‐III protein secretion: Regulation of FlhA conformation by a functionally critical charged‐residue cluster
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Marc Erhardt Paige Wheatley Eun A Kim Takanori Hirano Yang Zhang Mayukh K. Sarkar Kelly T. Hughes David F. Blair 《Molecular microbiology》2017,104(2):234-249
The bacterial flagellum contains a specialized secretion apparatus in its base that pumps certain protein subunits through the growing structure to their sites of installation beyond the membrane. A related apparatus functions in the injectisomes of gram‐negative pathogens to export virulence factors into host cells. This mode of protein export is termed type‐III secretion (T3S). Details of the T3S mechanism are unclear. It is energized by the proton gradient; here, a mutational approach was used to identify proton‐binding groups that might function in transport. Conserved proton‐binding residues in all the membrane components were tested. The results identify residues R147, R154 and D158 of FlhA as most critical. These lie in a small, well‐conserved cytoplasmic domain of FlhA, located between transmembrane segments 4 and 5. Two‐hybrid experiments demonstrate self‐interaction of the domain, and targeted cross‐linking indicates that it forms a multimeric array. A mutation that mimics protonation of the key acidic residue (D158N) was shown to trigger a global conformational change that affects the other, larger cytoplasmic domain that interacts with the export cargo. The results are discussed in the framework of a transport model based on proton‐actuated movements in the cytoplasmic domains of FlhA. 相似文献
225.
Polymorphisms in the estrogen receptor 1 and vitamin C and matrix metalloproteinase gene families are associated with susceptibility to lymphoma 总被引:1,自引:0,他引:1
Skibola CF Bracci PM Halperin E Nieters A Hubbard A Paynter RA Skibola DR Agana L Becker N Tressler P Forrest MS Sankararaman S Conde L Holly EA Smith MT 《PloS one》2008,3(7):e2816
Background
Non-Hodgkin lymphoma (NHL) is the fifth most common cancer in the U.S. and few causes have been identified. Genetic association studies may help identify environmental risk factors and enhance our understanding of disease mechanisms.Methodology/Principal Findings
768 coding and haplotype tagging SNPs in 146 genes were examined using Illumina GoldenGate technology in a large population-based case-control study of NHL in the San Francisco Bay Area (1,292 cases 1,375 controls are included here). Statistical analyses were restricted to HIV- participants of white non-Hispanic origin. Genes involved in steroidogenesis, immune function, cell signaling, sunlight exposure, xenobiotic metabolism/oxidative stress, energy balance, and uptake and metabolism of cholesterol, folate and vitamin C were investigated. Sixteen SNPs in eight pathways and nine haplotypes were associated with NHL after correction for multiple testing at the adjusted q<0.10 level. Eight SNPs were tested in an independent case-control study of lymphoma in Germany (494 NHL cases and 494 matched controls). Novel associations with common variants in estrogen receptor 1 (ESR1) and in the vitamin C receptor and matrix metalloproteinase gene families were observed. Four ESR1 SNPs were associated with follicular lymphoma (FL) in the U.S. study, with rs3020314 remaining associated with reduced risk of FL after multiple testing adjustments [odds ratio (OR) = 0.42, 95% confidence interval (CI) = 0.23–0.77) and replication in the German study (OR = 0.24, 95% CI = 0.06–0.94). Several SNPs and haplotypes in the matrix metalloproteinase-3 (MMP3) and MMP9 genes and in the vitamin C receptor genes, solute carrier family 23 member 1 (SLC23A1) and SLC23A2, showed associations with NHL risk.Conclusions/Significance
Our findings suggest a role for estrogen, vitamin C and matrix metalloproteinases in the pathogenesis of NHL that will require further validation. 相似文献226.
Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. 总被引:10,自引:0,他引:10
Claudia Binda Paige Newton-Vinson Frantisek Hubálek Dale E Edmondson Andrea Mattevi 《Nature structural biology》2002,9(1):22-26
Monoamine oxidase B (MAO B) is a mitochondrial outermembrane flavoenzyme that is a well-known target for antidepressant and neuroprotective drugs. We determined the structure of the human enzyme to 3 A resolution. The enzyme binds to the membrane through a C-terminal transmembrane helix and apolar loops located at various positions in the sequence. The electron density shows that pargyline, an analog of the clinically used MAO B inhibitor, deprenyl, binds covalently to the flavin N5 atom. The active site of MAO B consists of a 420 A(3)-hydrophobic substrate cavity interconnected to an entrance cavity of 290 A(3). The recognition site for the substrate amino group is an aromatic cage formed by Tyr 398 and Tyr 435. The structure provides a framework for probing the catalytic mechanism, understanding the differences between the B- and A-monoamine oxidase isoforms and designing specific inhibitors. 相似文献
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228.
ApoE promotes the proteolytic degradation of Abeta 总被引:1,自引:0,他引:1
Jiang Q Lee CY Mandrekar S Wilkinson B Cramer P Zelcer N Mann K Lamb B Willson TM Collins JL Richardson JC Smith JD Comery TA Riddell D Holtzman DM Tontonoz P Landreth GE 《Neuron》2008,58(5):681-693
Apolipoprotein E is associated with age-related risk for Alzheimer's disease and plays critical roles in Abeta homeostasis. We report that ApoE plays a role in facilitating the proteolytic clearance of soluble Abeta from the brain. The endolytic degradation of Abeta peptides within microglia by neprilysin and related enzymes is dramatically enhanced by ApoE. Similarly, Abeta degradation extracellularly by insulin-degrading enzyme is facilitated by ApoE. The capacity of ApoE to promote Abeta degradation is dependent upon the ApoE isoform and its lipidation status. The enhanced expression of lipidated ApoE, through the activation of liver X receptors, stimulates Abeta degradation. Indeed, aged Tg2576 mice treated with the LXR agonist GW3965 exhibited a dramatic reduction in brain Abeta load. GW3965 treatment also reversed contextual memory deficits. These data demonstrate a mechanism through which ApoE facilitates the clearance of Abeta from the brain and suggest that LXR agonists may represent a novel therapy for AD. 相似文献
229.
McComas CC Vu AT Mahaney PE Cohn ST Fensome A Marella MA Nogle L Trybulski EJ Ye F Zhang P Alfinito P Bray J Johnston G Koury E Deecher DC 《Bioorganic & medicinal chemistry letters》2008,18(18):4929-4931
Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters. 相似文献
230.
Dissection of the LXXLL nuclear receptor-coactivator interaction motif using combinatorial peptide libraries: discovery of peptide antagonists of estrogen receptors alpha and beta 总被引:1,自引:0,他引:1
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Chang Cy Norris JD Grøn H Paige LA Hamilton PT Kenan DJ Fowlkes D McDonnell DP 《Molecular and cellular biology》1999,19(12):8226-8239