全文获取类型
收费全文 | 3036篇 |
免费 | 256篇 |
国内免费 | 2篇 |
专业分类
3294篇 |
出版年
2023年 | 9篇 |
2022年 | 14篇 |
2021年 | 20篇 |
2020年 | 14篇 |
2019年 | 34篇 |
2018年 | 45篇 |
2017年 | 30篇 |
2016年 | 49篇 |
2015年 | 90篇 |
2014年 | 95篇 |
2013年 | 145篇 |
2012年 | 211篇 |
2011年 | 187篇 |
2010年 | 142篇 |
2009年 | 129篇 |
2008年 | 165篇 |
2007年 | 193篇 |
2006年 | 199篇 |
2005年 | 197篇 |
2004年 | 186篇 |
2003年 | 176篇 |
2002年 | 154篇 |
2001年 | 43篇 |
2000年 | 25篇 |
1999年 | 33篇 |
1998年 | 51篇 |
1997年 | 34篇 |
1996年 | 36篇 |
1995年 | 47篇 |
1994年 | 33篇 |
1993年 | 43篇 |
1992年 | 40篇 |
1991年 | 22篇 |
1990年 | 27篇 |
1989年 | 34篇 |
1988年 | 20篇 |
1987年 | 13篇 |
1986年 | 17篇 |
1985年 | 20篇 |
1984年 | 26篇 |
1983年 | 25篇 |
1982年 | 26篇 |
1981年 | 19篇 |
1980年 | 23篇 |
1979年 | 11篇 |
1978年 | 25篇 |
1977年 | 16篇 |
1976年 | 13篇 |
1974年 | 12篇 |
1973年 | 7篇 |
排序方式: 共有3294条查询结果,搜索用时 15 毫秒
121.
122.
Păunescu V Deak E Herman D Siska IR Tănasie G Bunu C Anghel S Tatu CA Oprea TI Henschler R Rüster B Bistrian R Seifried E 《Journal of cellular and molecular medicine》2007,11(3):502-508
Our study examined whether human bone marrow-derived MSCs are able to differentiate, in vitro, into functional epithelial-like cells. MSCs were isolated from the sternum of 8 patients with different hematological disorders. The surface phenotype of these cells was characterized.To induce epithelial differentiation, MSCs were cultured using Epidermal Growth Factor, Keratinocyte Growth Factor, Hepatocyte Growth Factor and Insulin-like growth Factor-II. Differentiated cells were further characterized both morphologically and functionally by their capacity to express markers with specificity for epithelial lineage. The expression of cytokeratin 19 was assessed by immunocytochemistry, and cytokeratin 18 was evaluated by quantitative RT-PCR (Taq-man). The data demonstrate that human MSCs isolated from human bone marrow can differentiate into epithelial-like cells and may thus serve as a cell source for tissue engineering and cell therapy of epithelial tissue. 相似文献
123.
Robbins SH Bessou G Cornillon A Zucchini N Rupp B Ruzsics Z Sacher T Tomasello E Vivier E Koszinowski UH Dalod M 《PLoS pathogens》2007,3(8):e123
Understanding the mechanisms that help promote protective immune responses to pathogens is a major challenge in biomedical research and an important goal for the design of innovative therapeutic or vaccination strategies. While natural killer (NK) cells can directly contribute to the control of viral replication, whether, and how, they may help orchestrate global antiviral defense is largely unknown. To address this question, we took advantage of the well-defined molecular interactions involved in the recognition of mouse cytomegalovirus (MCMV) by NK cells. By using congenic or mutant mice and wild-type versus genetically engineered viruses, we examined the consequences on antiviral CD8 T cell responses of specific defects in the ability of the NK cells to control MCMV. This system allowed us to demonstrate, to our knowledge for the first time, that NK cells accelerate CD8 T cell responses against a viral infection in vivo. Moreover, we identify the underlying mechanism as the ability of NK cells to limit IFN-alpha/beta production to levels not immunosuppressive to the host. This is achieved through the early control of cytomegalovirus, which dramatically reduces the activation of plasmacytoid dendritic cells (pDCs) for cytokine production, preserves the conventional dendritic cell (cDC) compartment, and accelerates antiviral CD8 T cell responses. Conversely, exogenous IFN-alpha administration in resistant animals ablates cDCs and delays CD8 T cell activation in the face of NK cell control of viral replication. Collectively, our data demonstrate that the ability of NK cells to respond very early to cytomegalovirus infection critically contributes to balance the intensity of other innate immune responses, which dampens early immunopathology and promotes optimal initiation of antiviral CD8 T cell responses. Thus, the extent to which NK cell responses benefit the host goes beyond their direct antiviral effects and extends to the prevention of innate cytokine shock and to the promotion of adaptive immunity. 相似文献
124.
125.
PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties 总被引:1,自引:0,他引:1
Bouhlel MA Derudas B Rigamonti E Dièvart R Brozek J Haulon S Zawadzki C Jude B Torpier G Marx N Staels B Chinetti-Gbaguidi G 《Cell metabolism》2007,6(2):137-143
Th1 cytokines promote monocyte differentiation into proatherogenic M1 macrophages, while Th2 cytokines lead to an "alternative" anti-inflammatory M2 macrophage phenotype. Here we show that in human atherosclerotic lesions, the expression of M2 markers and PPARgamma, a nuclear receptor controlling macrophage inflammation, correlate positively. Moreover, PPARgamma activation primes primary human monocytes into M2 differentiation, resulting in a more pronounced anti-inflammatory activity in M1 macrophages. However, PPARgamma activation does not influence M2 marker expression in resting or M1 macrophages, nor does PPARgamma agonist treatment influence the expression of M2 markers in atherosclerotic lesions, indicating that only native monocytes can be primed by PPARgamma activation to an enhanced M2 phenotype. Furthermore, PPARgamma activation significantly increases expression of the M2 marker MR in circulating peripheral blood mononuclear cells. These data demonstrate that PPARgamma activation skews human monocytes toward an anti-inflammatory M2 phenotype. 相似文献
126.
Guillaume Fouché Thomas Michel Anaïs Lalève Nick X. Wang David H. Young Brigitte Meunier Danièle Debieu Sabine Fillinger Anne-Sophie Walker 《Environmental microbiology》2022,24(3):1117-1132
Acquired resistance is a threat to antifungal efficacy in medicine and agriculture. The diversity of possible resistance mechanisms and highly adaptive traits of pathogens make it difficult to predict evolutionary outcomes of treatments. We used directed evolution as an approach to assess the resistance risk to the new fungicide fenpicoxamid in the wheat pathogenic fungus Zymoseptoria tritici. Fenpicoxamid inhibits complex III of the respiratory chain at the ubiquinone reduction site (Qi site) of the mitochondrially encoded cytochrome b, a different site than the widely used strobilurins which inhibit the same complex at the ubiquinol oxidation site (Qo site). We identified the G37V change within the cytochrome b Qi site as the most likely resistance mechanism to be selected in Z. tritici. This change triggered high fenpicoxamid resistance and halved the enzymatic activity of cytochrome b, despite no significant penalty for in vitro growth. We identified negative cross-resistance between isolates harbouring G37V or G143A, a Qo site change previously selected by strobilurins. Double mutants were less resistant to both QiIs and quinone outside inhibitors compared to single mutants. This work is a proof of concept that experimental evolution can be used to predict adaptation to fungicides and provides new perspectives for the management of QiIs. 相似文献
127.
Marvin Gohrbandt Andr Lipski James W Grimshaw Jessica A Buttress Zunera Baig Brigitte Herkenhoff Stefan Walter Rainer Kurre Gabriele DeckersHebestreit Henrik Strahl 《The EMBO journal》2022,41(5)
All living organisms adapt their membrane lipid composition in response to changes in their environment or diet. These conserved membrane‐adaptive processes have been studied extensively. However, key concepts of membrane biology linked to regulation of lipid composition including homeoviscous adaptation maintaining stable levels of membrane fluidity, and gel‐fluid phase separation resulting in domain formation, heavily rely upon in vitro studies with model membranes or lipid extracts. Using the bacterial model organisms Escherichia coli and Bacillus subtilis, we now show that inadequate in vivo membrane fluidity interferes with essential complex cellular processes including cytokinesis, envelope expansion, chromosome replication/segregation and maintenance of membrane potential. Furthermore, we demonstrate that very low membrane fluidity is indeed capable of triggering large‐scale lipid phase separation and protein segregation in intact, protein‐crowded membranes of living cells; a process that coincides with the minimal level of fluidity capable of supporting growth. Importantly, the in vivo lipid phase separation is not associated with a breakdown of the membrane diffusion barrier function, thus explaining why the phase separation process induced by low fluidity is biologically reversible. 相似文献
128.
Hartmut Arndt Maria Krocker Brigitte Nixdorf Antje Khler 《International Review of Hydrobiology》1993,78(3):379-402
Annual changes of rotifers, copepods, cladocerans, the ciliate Epistylis rotans, and larvae of Dreissena polymorpha were analysed for the period 1908–1990. Though food resources increased 6–10 fold in the course of eutrophication, only rotifers and Epistylis increased accordingly. Probably as a result of increased predation pressure crustaceans increased only twice. The seasonal pattern of metazoans and protozoans (flagellates, sarcodines, ciliates) were analysed for 12 and 3 years, resp. During winter and spring, large heterotrophic flagellates and ciliates dominated the zooplankton and were responsible for a pronounced - formerly underestimated - grazing pressure on phytoplankton. In early summer, metazoan filter-feeders were often able to cause a significant reduction of phyto- and protozooplankton. However, during some years, phytoplankton declined in the absence of a pronounced grazing pressure. Field data and experiments revealed that predators were able to regulate the density of cladocerans in early summer (mainly cyclopoids) and summer (mainly Leptodora, smelt and fish juveniles). 相似文献
129.
130.
Jorge D García-García Kristen Van Gelder Jaya Joshi Ulschan Bathe Bryan J Leong Steven D Bruner Chang C Liu Andrew D Hanson 《Plant physiology》2022,188(2):971
Continuous directed evolution of enzymes and other proteins in microbial hosts is capable of outperforming classical directed evolution by executing hypermutation and selection concurrently in vivo, at scale, with minimal manual input. Provided that a target enzyme’s activity can be coupled to growth of the host cells, the activity can be improved simply by selecting for growth. Like all directed evolution, the continuous version requires no prior mechanistic knowledge of the target. Continuous directed evolution is thus a powerful way to modify plant or non-plant enzymes for use in plant metabolic research and engineering. Here, we first describe the basic features of the yeast (Saccharomyces cerevisiae) OrthoRep system for continuous directed evolution and compare it briefly with other systems. We then give a step-by-step account of three ways in which OrthoRep can be deployed to evolve primary metabolic enzymes, using a THI4 thiazole synthase as an example and illustrating the mutational outcomes obtained. We close by outlining applications of OrthoRep that serve growing demands (i) to change the characteristics of plant enzymes destined for return to plants, and (ii) to adapt (“plantize”) enzymes from prokaryotes—especially exotic prokaryotes—to function well in mild, plant-like conditions.Continuous directed evolution using the yeast OrthoRep system is a powerful way to improve enzymes for use in plant engineering as illustrated by “plantizing” a bacterial thiamin synthesis enzyme. 相似文献