全文获取类型
收费全文 | 2499篇 |
免费 | 269篇 |
国内免费 | 1篇 |
出版年
2023年 | 17篇 |
2022年 | 26篇 |
2021年 | 69篇 |
2020年 | 53篇 |
2019年 | 44篇 |
2018年 | 54篇 |
2017年 | 49篇 |
2016年 | 72篇 |
2015年 | 156篇 |
2014年 | 147篇 |
2013年 | 175篇 |
2012年 | 219篇 |
2011年 | 213篇 |
2010年 | 100篇 |
2009年 | 102篇 |
2008年 | 145篇 |
2007年 | 152篇 |
2006年 | 139篇 |
2005年 | 127篇 |
2004年 | 97篇 |
2003年 | 89篇 |
2002年 | 79篇 |
2001年 | 26篇 |
2000年 | 24篇 |
1999年 | 36篇 |
1998年 | 20篇 |
1997年 | 15篇 |
1996年 | 13篇 |
1994年 | 10篇 |
1992年 | 9篇 |
1991年 | 16篇 |
1990年 | 13篇 |
1989年 | 11篇 |
1988年 | 18篇 |
1987年 | 10篇 |
1985年 | 8篇 |
1984年 | 11篇 |
1983年 | 17篇 |
1982年 | 8篇 |
1981年 | 11篇 |
1978年 | 10篇 |
1977年 | 14篇 |
1975年 | 7篇 |
1974年 | 12篇 |
1973年 | 12篇 |
1972年 | 8篇 |
1971年 | 10篇 |
1970年 | 9篇 |
1969年 | 8篇 |
1968年 | 8篇 |
排序方式: 共有2769条查询结果,搜索用时 852 毫秒
951.
Inducing cellular dedifferentiation: a potential method for enhancing endogenous regeneration in mammals 总被引:8,自引:0,他引:8
Odelberg SJ 《Seminars in cell & developmental biology》2002,13(5):335-343
Salamanders have the remarkable ability to regenerate lost body parts and injured organs. This regenerative ability requires fully-differentiated cells in the vicinity of the injury to dedifferentiate, proliferate, and then redifferentiate to form the specialized cells that comprise the regenerated structure or organ. The dedifferentiation stage plays a crucial role in the regenerative response and distinguishes the salamander from other vertebrates with more limited regenerative abilities. Recently, several investigators have shown that certain mammalian cell types can be induced to dedifferentiate to progenitor cells when stimulated with the appropriate signals. This discovery opens the possibility that researchers might one day enhance the endogenous regenerative capacity of mammals by inducing cellular dedifferentiation in vivo. 相似文献
952.
Aurora B family kinases play an essential role in chromosome segregation and cytokinesis. Recent work suggests that the kinase activity is required for bipolar chromosome orientation, kinetochore assembly, spindle checkpoint and microtubule dynamics. Aurora B also has additional functions in chromosome condensation and cohesion. 相似文献
953.
Gundry RL Riordon DR Tarasova Y Chuppa S Bhattacharya S Juhasz O Wiedemeier O Milanovich S Noto FK Tchernyshyov I Raginski K Bausch-Fluck D Tae HJ Marshall S Duncan SA Wollscheid B Wersto RP Rao S Van Eyk JE Boheler KR 《Molecular & cellular proteomics : MCP》2012,11(8):303-316
Induction of a pluripotent state in somatic cells through nuclear reprogramming has ushered in a new era of regenerative medicine. Heterogeneity and varied differentiation potentials among induced pluripotent stem cell (iPSC) lines are, however, complicating factors that limit their usefulness for disease modeling, drug discovery, and patient therapies. Thus, there is an urgent need to develop nonmutagenic rapid throughput methods capable of distinguishing among putative iPSC lines of variable quality. To address this issue, we have applied a highly specific chemoproteomic targeting strategy for de novo discovery of cell surface N-glycoproteins to increase the knowledge-base of surface exposed proteins and accessible epitopes of pluripotent stem cells. We report the identification of 500 cell surface proteins on four embryonic stem cell and iPSCs lines and demonstrate the biological significance of this resource on mouse fibroblasts containing an oct4-GFP expression cassette that is active in reprogrammed cells. These results together with immunophenotyping, cell sorting, and functional analyses demonstrate that these newly identified surface marker panels are useful for isolating iPSCs from heterogeneous reprogrammed cultures and for isolating functionally distinct stem cell subpopulations. 相似文献
954.
Rucavado A Escalante T Shannon JD Ayala-Castro CN Villalta M Gutiérrez JM Fox JW 《Journal of proteome research》2012,11(1):292-305
Proteomic analysis of wound exudates represents a valuable tool to investigate tissue pathology and to assess the therapeutic success of various interventions. In this study, the ability of horse-derived IgG and F(ab')(2) antivenoms to neutralize local pathological effects induced by the venom of the snake Bothrops asper in mouse muscle was investigated by the proteomic analysis of exudates collected in the vicinity of affected tissue. In experiments involving the incubation of venom and antivenom prior to injection in mice, hemorrhagic activity was completely abolished and local muscle-damaging activity was significantly reduced by the antivenoms. In these conditions, the relative amounts of several intracellular and extracellular matrix proteins were reduced by the action of antivenoms, whereas the relative amounts of various plasma proteins were not modified. Because not all intracellular proteins were reduced, it is likely that there is a residual cytotoxicity not neutralized by antivenoms. In experiments designed to more closely reproduce the actual circumstances of envenoming, that is, when antivenom is administered after envenomation, the number of proteins whose amounts in exudates were reduced by antivenoms decreased, underscoring the difficulty in neutralizing local pathology due to the very rapid onset of venom-induced pathology. In these experiments, IgG antivenom was more efficient than F(ab')(2) antivenom when administered after envenomation, probably as a consequence of differences in their pharmacokinetic profiles. 相似文献
955.
956.
Paulo H. Rodrigues Leticia Reyes Amandeep S. Chadda Myriam Bélanger Shannon M. Wallet Debra Akin William Dunn Jr Ann Progulske-Fox 《PloS one》2012,7(12)
Both epidemiologic and experimental findings suggest that infection with Porphyromonas gingivalis exacerbates progression of atherosclerosis. As P. gingivalis exhibits significant strain variation, it is reasonable that different strains possess different capabilities and/or mechanisms by which they promote atherosclerosis. Using P. gingivalis strains that have been previously evaluated in the ApoE null atherosclerosis model, we assessed the ability of W83, A7436, 381, and 33277 to adhere, invade, and persist in human coronary artery endothelial (HCAE) cells. W83 and 381 displayed an equivalent ability to adhere to HCAE cells, which was significantly greater than both A7436 and 33277 (P<0.01). W83, 381, and 33277 were more invasive than A7436 (P<0.0001). However, only W83 and A7436 were able to remain viable up to 48 hours in HCAE cell cultures, whereas 381 was cleared by 48 hours and 33277 was cleared by 24 hours. These differences in persistence were in part due to strain specific differences in intracellular trafficking. Both W83 and 381 trafficked through the autophagic pathway, but not A7436 or 33277. Internalized 381 was the only strain that was dependent upon the autophagic pathway for its survival. Finally, we assessed the efficacy of these strains to activate HCAE cells as defined by production of IL-6, IL-8, IL-12p40, MCP-1, RANTES, TNF-α, and soluble adhesion molecules (sICAM-1, sVCAM-1, and sE-selectin). Only moderate inflammation was observed in cells infected with either W83 or A7436, whereas cells infected with 381 exhibited the most profound inflammation, followed by cells infected with 33277. These results demonstrate that virulence mechanisms among different P. gingivalis strains are varied and that pathogenic mechanisms identified for one strain are not necessarily applicable to other strains. 相似文献
957.
Erika Kague Michael Gallagher Sally Burke Michael Parsons Tamara Franz-Odendaal Shannon Fisher 《PloS one》2012,7(11)
The neural crest (NC) is a major contributor to the vertebrate craniofacial skeleton, detailed in model organisms through embryological and genetic approaches, most notably in chick and mouse. Despite many similarities between these rather distant species, there are also distinct differences in the contribution of the NC, particularly to the calvariae of the skull. Lack of information about other vertebrate groups precludes an understanding of the evolutionary significance of these differences. Study of zebrafish craniofacial development has contributed substantially to understanding of cartilage and bone formation in teleosts, but there is currently little information on NC contribution to the zebrafish skeleton. Here, we employ a two–transgene system based on Cre recombinase to genetically label NC in the zebrafish. We demonstrate NC contribution to cells in the cranial ganglia and peripheral nervous system known to be NC–derived, as well as to a subset of myocardial cells. The indelible labeling also enables us to determine NC contribution to late–forming bones, including the calvariae. We confirm suspected NC origin of cartilage and bones of the viscerocranium, including cartilages such as the hyosymplectic and its replacement bones (hymandibula and symplectic) and membranous bones such as the opercle. The cleithrum develops at the border of NC and mesoderm, and as an ancestral component of the pectoral girdle was predicted to be a hybrid bone composed of both NC and mesoderm tissues. However, we find no evidence of a NC contribution to the cleithrum. Similarly, in the vault of the skull, the parietal bones and the caudal portion of the frontal bones show no evidence of NC contribution. We also determine a NC origin for caudal fin lepidotrichia; the presumption is that these are derived from trunk NC, demonstrating that these cells have the ability to form bone during normal vertebrate development. 相似文献
958.
Correlation between In Vivo Biofilm Formation and Virulence Gene Expression in Escherichia coli O104:H4 总被引:1,自引:0,他引:1
The emergence of novel pathogens poses a major public health threat causing widespread epidemics in susceptible populations. The Escherichia coli O104:H4 strain implicated in a 2011 outbreak in northern Germany caused the highest frequency of hemolytic uremic syndrome (HUS) and death ever recorded in a single E. coli outbreak. Therefore, it has been suggested that this strain is more virulent than other pathogenic E. coli (e.g., E. coli O157:H7). The E. coli O104:H4 outbreak strain possesses multiple virulence factors from both Shiga toxin (Stx)-producing E. coli (STEC) and enteroaggregative E. coli (EAEC), though the mechanism of pathogenesis is not known. Here, we demonstrate that E. coli O104:H4 produces a stable biofilm in vitro and that in vivo virulence gene expression is highest when E. coli O104:H4 overexpresses genes required for aggregation and exopolysaccharide production, a characteristic of bacterial cells residing within an established biofilm. Interrupting exopolysaccharide production and biofilm formation may therefore represent effective strategies for combating future E. coli O104:H4 infections. 相似文献
959.
Brown JC Huedo-Medina TB Pescatello LS Ryan SM Pescatello SM Moker E LaCroix JM Ferrer RA Johnson BT 《PloS one》2012,7(1):e30955
Introduction
The purpose of this meta-analysis was to examine the efficacy of exercise to reduce depressive symptoms among cancer survivors. In addition, we examined the extent to which exercise dose and clinical characteristics of cancer survivors influence the relationship between exercise and reductions in depressive symptoms.Methods
We conducted a systematic search identifying randomized controlled trials of exercise interventions among adult cancer survivors, examining depressive symptoms as an outcome. We calculated effect sizes for each study and performed weighted multiple regression moderator analysis.Results
We identified 40 exercise interventions including 2,929 cancer survivors. Diverse groups of cancer survivors were examined in seven exercise interventions; breast cancer survivors were examined in 26; prostate cancer, leukemia, and lymphoma were examined in two; and colorectal cancer in one. Cancer survivors who completed an exercise intervention reduced depression more than controls, d + = −0.13 (95% CI: −0.26, −0.01). Increases in weekly volume of aerobic exercise reduced depressive symptoms in dose-response fashion (β = −0.24, p = 0.03), a pattern evident only in higher quality trials. Exercise reduced depressive symptoms most when exercise sessions were supervised (β = −0.26, p = 0.01) and when cancer survivors were between 47–62 yr (β = 0.27, p = 0.01).Conclusion
Exercise training provides a small overall reduction in depressive symptoms among cancer survivors but one that increased in dose-response fashion with weekly volume of aerobic exercise in high quality trials. Depressive symptoms were reduced to the greatest degree among breast cancer survivors, among cancer survivors aged between 47–62 yr, or when exercise sessions were supervised. 相似文献960.
McAuley EZ Scimone A Tiwari Y Agahi G Mowry BJ Holliday EG Donald JA Weickert CS Mitchell PB Schofield PR Fullerton JM 《PloS one》2012,7(5):e38172
We previously identified a significant bipolar spectrum disorder linkage peak on 15q25-26 using 35 extended families with a broad clinical phenotype, including bipolar disorder (types I and II), recurrent unipolar depression and schizoaffective disorder. However, the specific gene(s) contributing to this signal had not been identified. By a fine mapping association study in an Australian case-control cohort (n?=?385), we find that the sialyltransferase 8B (ST8SIA2) gene, coding for an enzyme that glycosylates proteins involved in neuronal plasticity which has previously shown association to both schizophrenia and autism, is associated with increased risk to bipolar spectrum disorder. Nominal single point association was observed with SNPs in ST8SIA2 (rs4586379, P?=?0.0043; rs2168351, P?=?0.0045), and a specific risk haplotype was identified (frequency: bipolar vs controls?=?0.41 vs 0.31; χ(2)?=?6.46, P?=?0.011, OR?=?1.47). Over-representation of the specific risk haplotype was also observed in an Australian schizophrenia case-control cohort (n?=?256) (χ(2)?=?8.41, P?=?0.004, OR?=?1.82). Using GWAS data from the NIMH bipolar disorder (n?=?2055) and NIMH schizophrenia (n?=?2550) cohorts, the equivalent haplotype was significantly over-represented in bipolar disorder (χ(2)?=?5.91, P?=?0.015, OR?=?1.29), with the same direction of effect in schizophrenia, albeit non-significant (χ(2)?=?2.3, P?=?0.129, OR?=?1.09). We demonstrate marked down-regulation of ST8SIA2 gene expression across human brain development and show a significant haplotype×diagnosis effect on ST8SIA2 mRNA levels in adult cortex (ANOVA: F(1,87)?=?6.031, P?=?0.016). These findings suggest that variation the ST8SIA2 gene is associated with increased risk to mental illness, acting to restrict neuronal plasticity and disrupt early neuronal network formation, rendering the developing and adult brain more vulnerable to secondary genetic or environmental insults. 相似文献