全文获取类型
收费全文 | 506篇 |
免费 | 42篇 |
专业分类
548篇 |
出版年
2024年 | 1篇 |
2023年 | 6篇 |
2022年 | 9篇 |
2021年 | 15篇 |
2020年 | 14篇 |
2019年 | 15篇 |
2018年 | 17篇 |
2017年 | 14篇 |
2016年 | 15篇 |
2015年 | 33篇 |
2014年 | 41篇 |
2013年 | 44篇 |
2012年 | 42篇 |
2011年 | 52篇 |
2010年 | 32篇 |
2009年 | 26篇 |
2008年 | 35篇 |
2007年 | 12篇 |
2006年 | 26篇 |
2005年 | 12篇 |
2004年 | 20篇 |
2003年 | 16篇 |
2002年 | 15篇 |
2001年 | 9篇 |
2000年 | 1篇 |
1999年 | 2篇 |
1998年 | 2篇 |
1997年 | 2篇 |
1996年 | 1篇 |
1995年 | 1篇 |
1993年 | 3篇 |
1992年 | 4篇 |
1991年 | 2篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1979年 | 1篇 |
1977年 | 1篇 |
1974年 | 3篇 |
1957年 | 2篇 |
排序方式: 共有548条查询结果,搜索用时 15 毫秒
41.
42.
Cyclin D1, a key regulator of the cell cycle, acts as an oncogene when over-expressed in several types of cancer. In some B-chronic lymphoproliferative disorders, the over-expression of cyclin D1 protein is thought to confer a proliferative phenotype. We have generated BaF3 pro-B cell derivatives in which cyclin D1 can be induced rapidly and reversibly in a dose-dependent manner by the hormone muristerone A. When non-expressing clones displayed the same proliferative capacity as the parental cell line, in the sub-clones, a moderate induction of cyclin D1 lengthened the proliferation rate. The over-expression of cyclin D1 had the same effects on cell proliferation but also led ultimately to cell death by apoptosis. The induction of cyclin D1 in growth factor-deprived cells as well as in anticancer drug-treated cells also reinforced the magnitude of apoptosis. Thus, the expression of cyclin D1 in lymphoid cells does not confer a proliferative advantage but rather alters the response of cells towards apoptotic stimuli in a p53-independent manner. 相似文献
43.
44.
Dendritic cells (DC) promote natural killer (NK) cell functions: dynamics of the human DC/NK cell cross talk 总被引:7,自引:0,他引:7
Fernandez NC Flament C Crépineau F Angevin E Vivier E Zitvogel L 《European cytokine network》2002,13(1):17-27
Dendritic cells (DC) were originally found critical in the setting of cognate immune responses. We first demonstrated that DC can also induce mouse NK cell activation and NK cell dependent-antitumor effects in mice. Here we analyzed the dynamics between DC and NK cells in human in vitro model systems. In the absence of LPS, DC do not trigger resting NK cells. Conversely, in the presence of LPS, resting bulk NK cells interacting with DC acquire CD25 and CD69 surface expression, produce high levels of IFN-gamma and lyse DAUDI cells. On activated IL-2 dependent NK cell lines, regardless of their differentiation stage, DC maintain or enhance NK cell proliferation and effector functions in the absence of exogenous cytokines. While IL-12, IL-15 and IL-18 are not critical, a direct cell-to-cell contact is mandatory for NK activation by DC and required for optimal proliferation. These data imply that DC also modulate human NK cell innate effector functions. 相似文献
45.
Transcriptional silencing of the TFPI-2 gene by promoter hypermethylation in choriocarcinoma cells 总被引:7,自引:0,他引:7
Hubé F Reverdiau P Iochmann S Rollin J Cherpi-Antar C Gruel Y 《Biological chemistry》2003,384(7):1029-1034
46.
Claser C Malleret B Gun SY Wong AY Chang ZW Teo P See PC Howland SW Ginhoux F Rénia L 《PloS one》2011,6(4):e18720
Background
Infection with Plasmodium berghei ANKA (PbA) in susceptible mice induces a syndrome called experimental cerebral malaria (ECM) with severe pathologies occurring in various mouse organs. Immune mediators such as T cells or cytokines have been implicated in the pathogenesis of ECM. Red blood cells infected with PbA parasites have been shown to accumulate in the brain and other tissues during infection. This accumulation is thought to be involved in PbA–induced pathologies, which mechanisms are poorly understood.Methods and Findings
Using transgenic PbA parasites expressing the luciferase protein, we have assessed by real-time in vivo imaging the dynamic and temporal contribution of different immune factors in infected red blood cell (IRBC) accumulation and distribution in different organs during PbA infection. Using deficient mice or depleting antibodies, we observed that CD8+ T cells and IFN-γ drive the rapid increase in total parasite biomass and accumulation of IRBC in the brain and in different organs 6–12 days post-infection, at a time when mice develop ECM. Other cells types like CD4+ T cells, monocytes or neutrophils or cytokines such as IL-12 and TNF-α did not influence the early increase of total parasite biomass and IRBC accumulation in different organs.Conclusions
CD8+ T cells and IFN-γ are the major immune mediators controlling the time-dependent accumulation of P. berghei-infected red blood cells in tissues. 相似文献47.
Florent Guérin Mathilde Wagner Antoine Liné Magaly Zappa Magali Fasseu Valérie Paradis Valérie Vilgrain Bernard E. Van Beers Josette Legagneux Richard Moreau Philippe Lettéron 《PloS one》2015,10(5)
MethodsWe conducted an experimental study comparing portacaval shunt (PCS), total portal vein ligation (PVL), and sham (S) operated rats. Each group were either sacrificed at 6 weeks (early) or 6 months (late). Arterial liver perfusion was studied in vivo using CT, and histopathological changes were noted. Liver mRNA levels were quantified by RT-QPCR for markers of inflammation (Il10, Tnfa), proliferation (Il6st, Mki67, Hgf, Hnf4a), angiogenesis: (Vegfa, Vegfr 1, 2 and 3; Pgf), oxidative stress (Nos2, and 3, Hif1a), and fibrosis (Tgfb). PCS and PVL were compared to the S group.ResultsPeriportal fibrosis and arterial proliferation was observed in late PCS and PVL groups. CT imaging demonstrated increased arterial liver perfusion in the PCS group. RT-QPCR showed increased inflammatory markers in PCS and PVL early groups. Tnfa and Il10 were increased in PCS and PVL late groups respectively. All proliferative markers increased in the PCS, and Hnf4a in the PVL early groups. Mki67 and Hnf4a were increased in the PCS late group. Nos3 was increased in the early and late PCS groups, and Hif1a was decreased in the PVL groups. Markers of angiogenesis were all increased in the early PCS group, and Vegfr3 and Pgf in the late PCS group. Only Vegfr3 was increased in the PVL groups. Tgf was increased in the PCS groups.ConclusionsPortal deprivation in rats induces a sustained increase in intrahepatic markers of inflammation, angiogenesis, proliferation, and fibrosis. 相似文献
48.
Caroline M. Tucker Tracy Aze Marc W. Cadotte Juan L. Cantalapiedra Chelsea Chisholm Sandra Díaz Richard Grenyer Danwei Huang Florent Mazel William D. Pearse Matthew W. Pennell Marten Winter Arne O. Mooers 《Biological reviews of the Cambridge Philosophical Society》2019,94(5):1740-1760
It is often claimed that conserving evolutionary history is more efficient than species‐based approaches for capturing the attributes of biodiversity that benefit people. This claim underpins academic analyses and recommendations about the distribution and prioritization of species and areas for conservation, but evolutionary history is rarely considered in practical conservation activities. One impediment to implementation is that arguments related to the human‐centric benefits of evolutionary history are often vague and the underlying mechanisms poorly explored. Herein we identify the arguments linking the prioritization of evolutionary history with benefits to people, and for each we explicate the purported mechanism, and evaluate its theoretical and empirical support. We find that, even after 25 years of academic research, the strength of evidence linking evolutionary history to human benefits is still fragile. Most – but not all – arguments rely on the assumption that evolutionary history is a useful surrogate for phenotypic diversity. This surrogacy relationship in turn underlies additional arguments, particularly that, by capturing more phenotypic diversity, evolutionary history will preserve greater ecosystem functioning, capture more of the natural variety that humans prefer, and allow the maintenance of future benefits to humans. A surrogate relationship between evolutionary history and phenotypic diversity appears reasonable given theoretical and empirical results, but the strength of this relationship varies greatly. To the extent that evolutionary history captures unmeasured phenotypic diversity, maximizing the representation of evolutionary history should capture variation in species characteristics that are otherwise unknown, supporting some of the existing arguments. However, there is great variation in the strength and availability of evidence for benefits associated with protecting phenotypic diversity. There are many studies finding positive biodiversity–ecosystem functioning relationships, but little work exists on the maintenance of future benefits or the degree to which humans prefer sets of species with high phenotypic diversity or evolutionary history. Although several arguments link the protection of evolutionary history directly with the reduction of extinction rates, and with the production of relatively greater future biodiversity via increased adaptation or diversification, there are few direct tests. Several of these putative benefits have mismatches between the relevant spatial scales for conservation actions and the spatial scales at which benefits to humans are realized. It will be important for future work to fill in some of these gaps through direct tests of the arguments we define here. 相似文献
49.
Florent Ailloud Tiffany Lowe Gilles Cellier David Roche Caitilyn Allen Philippe Prior 《BMC genomics》2015,16(1)
Background
Ralstonia solanacearum is a vascular soil-borne plant pathogen with an unusually broad host range. This economically destructive and globally distributed bacterium has thousands of distinct lineages within a heterogeneous and taxonomically disputed species complex. Some lineages include highly host-adapted strains (ecotypes), such as the banana Moko disease-causing strains, the cold-tolerant potato brown rot strains (also known as R3bv2) and the recently emerged Not Pathogenic to Banana (NPB) strains.Results
These distinct ecotypes offer a robust model to study host adaptation and the emergence of ecotypes because the polyphyletic Moko strains include lineages that are phylogenetically close to the monophyletic brown rot and NPB strains. Draft genomes of eight new strains belonging to these three model ecotypes were produced to complement the eleven publicly available R. solanacearum genomes. Using a suite of bioinformatics methods, we searched for genetic and evolutionary features that distinguish ecotypes and propose specific hypotheses concerning mechanisms of host adaptation in the R. solanacearum species complex. Genome-wide, few differences were identified, but gene loss events, non-synonymous polymorphisms, and horizontal gene transfer were identified among type III effectors and were associated with host range differences.Conclusions
This extensive comparative genomics analysis uncovered relatively few divergent features among closely related strains with contrasting biological characteristics; however, several virulence factors were associated with the emergence of Moko, NPB and brown rot and could explain host adaptation.Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1474-8) contains supplementary material, which is available to authorized users. 相似文献50.
Xylan has been used as a raw material in the synthesis of butyl, octyl and decyl glycosides. Mixtures of d-xylose-, l-arabinose- and d-glucose-based surfactants were obtained under smooth conditions with high yields in a one-pot process. The surface activities of octyl and decyl glycosides thus obtained have been studied and compared with that of pure alkyl d-xylosides. The results have confirmed that the new synthetic approach described in this paper is a potentially economical and efficient method for the preparation of environmentally friendly surfactants. 相似文献