首页 | 本学科首页   官方微博 | 高级检索  
文章检索
  按 检索   检索词:      
出版年份:   被引次数:   他引次数: 提示:输入*表示无穷大
  收费全文   2059篇
  免费   140篇
  国内免费   2篇
  2201篇
  2023年   16篇
  2022年   41篇
  2021年   72篇
  2020年   37篇
  2019年   45篇
  2018年   54篇
  2017年   56篇
  2016年   78篇
  2015年   105篇
  2014年   126篇
  2013年   172篇
  2012年   170篇
  2011年   169篇
  2010年   83篇
  2009年   88篇
  2008年   123篇
  2007年   93篇
  2006年   92篇
  2005年   90篇
  2004年   84篇
  2003年   73篇
  2002年   53篇
  2001年   30篇
  2000年   22篇
  1999年   20篇
  1998年   12篇
  1997年   11篇
  1996年   11篇
  1995年   13篇
  1994年   8篇
  1993年   7篇
  1992年   5篇
  1991年   12篇
  1990年   6篇
  1989年   6篇
  1988年   8篇
  1987年   6篇
  1986年   9篇
  1985年   7篇
  1984年   12篇
  1983年   4篇
  1981年   7篇
  1980年   11篇
  1979年   9篇
  1974年   4篇
  1973年   4篇
  1971年   4篇
  1970年   5篇
  1969年   4篇
  1968年   5篇
排序方式: 共有2201条查询结果,搜索用时 15 毫秒
61.
62.
Toxoplasma gondii causes retinitis and encephalitis. Avoiding targeting by autophagosomes is key for its survival because T. gondii cannot withstand lysosomal degradation. During invasion of host cells, T. gondii triggers epidermal growth factor receptor (EGFR) signalling enabling the parasite to avoid initial autophagic targeting. However, autophagy is a constitutive process indicating that the parasite may also use a strategy operative beyond invasion to maintain blockade of autophagic targeting. Finding that such a strategy exists would be important because it could lead to inhibition of host cell signalling as a novel approach to kill the parasite in previously infected cells and treat toxoplasmosis. We report that T. gondii induced prolonged EGFR autophosphorylation. This effect was mediated by PKCα/PKCβ ? Src because T. gondii caused prolonged activation of these molecules and their knockdown or incubation with inhibitors of PKCα/PKCβ or Src after host cell invasion impaired sustained EGFR autophosphorylation. Addition of EGFR tyrosine kinase inhibitor (TKI) to previously infected cells led to parasite entrapment by LC3 and LAMP‐1 and pathogen killing dependent on the autophagy proteins ULK1 and Beclin 1 as well as lysosomal enzymes. Administration of gefitinib (EGFR TKI) to mice with ocular and cerebral toxoplasmosis resulted in disease control that was dependent on Beclin 1. Thus, T. gondii promotes its survival through sustained EGFR signalling driven by PKCα/β ? Src, and inhibition of EGFR controls pre‐established toxoplasmosis.  相似文献   
63.
Locovei S  Scemes E  Qiu F  Spray DC  Dahl G 《FEBS letters》2007,581(3):483-488
The purinergic receptor P2X(7) is part of a complex signaling mechanism participating in a variety of physiological and pathological processes. Depending on the activation scheme, P2X(7) receptors in vivo are non-selective cation channels or form large pores that can mediate apoptotic cell death. Expression of P2X(7)R in Xenopus oocytes results exclusively in formation of a non-selective cation channel. However, here we show that co-expression of P2X(7)R with pannexin1 in oocytes leads to the complex response seen in many mammalian cells, including cell death with prolonged ATP application. While the cation channel activity is resistant to carbenoxolone treatment, this gap junction and hemichannel blocking drug suppressed the currents induced by ATP in pannexin1/P2X(7)R co-expressing cells. Thus, pannexin1 appears to be the molecular substrate for the permeabilization pore (or death receptor channel) recruited into the P2X(7)R signaling complex.  相似文献   
64.
65.
Monosomy 7 arises as a recurrent chromosome aberration in donor cell leukemia after hematopoietic stem cell transplantation. We report a new case of donor cell leukemia with monosomy 7 following HLA-identical allogenic bone marrow transplantation for severe aplastic anemia (SAA). The male patient received a bone marrow graft from his sister, and monosomy 7 was detected only in the XX donor cells, 34 months after transplantation. The patient’s bone marrow microenvironment may have played a role in the leukemic transformation of the donor hematopoietic cells.  相似文献   
66.
We addressed how species number and pair density in guilds of co-existing species is related to habitat structure, and to the abundance and diversity of food resources using the assemblage of seven species of dabbling ducks (genus Anas ) breeding in 60 lakes distributed over six regions in temperate north Europe
Partial correlation and multiple regression revealed that species richness was best predicted by habitat structural diversity as indexed by a principal component analysis based on 18 vegetation and lake characteristics, and by the abundance of aquatic and emergent prey We found no effect of lake size or prey size diversity on species richness Pair density was correlated with the percentage of shoreline with horsetails ( Equisetum ), by habitat structural diversity and by the abundance of emergent invertebrate prey Neither prey size diversity nor abundance of aquatic prey correlated with pair density Species richness and pair density in North European duck guilds vary both with habitat structure and prey availability  相似文献   
67.
118 strains of heterotrophic microorganisms were isolated from goat cheese produced domestically in the IV Region of Northern Chile (Serene, Ovalle, and Illapel) and sold in supermarkets in Valparaíso, Chile. The results of 89 phenotypic tests were numerically analyzed against 17 reference strains, using the simple matching coefficient (SSM). Thirteen phena were found at a 78% similarity level. Five of them (A, B, C, D, and E) were assigned to the family Enterobacteriaceae, phenon F was identified as belonging to the genus Aeromonas and strains of phenon G were assigned to the genus Acinetobacter. The other phena were identified as being members of the genera Bacillus (H, I, and J), Staphylococcus (K), Enterococcus (L), and Micrococcus (M). Approximately 19% of the isolates were Escherichia coli and 27%, Staphylococcus aureus. Received: 20 February 2001 / Accepted: 12 April 2001  相似文献   
68.
Phospholipids are key components of biological membranes and their lipolysis with phospholipase A2 (PLA2) enzymes occurs in different cellular pH environments. Since no studies are available on the effect of pH on PLA2-modified phospholipid membranes, we performed 50-ns atomistic molecular dynamics simulations at three different pH conditions (pH 9.0, 7.5, and 5.5) using a fully PLA2-hydrolyzed phosphatidylcholine (PC) bilayer which consists solely of lysophosphatidylcholine and free fatty acid molecules. We found that a decrease in pH results in lateral squeezing of the membrane, i.e. in decreased surface area per headgroup. Thus, at the decreased pH, the lipid hydrocarbon chains had larger SCD order parameter values, and also enhanced membrane thickness, as seen in the electron density profiles across the membrane. From the lateral pressure profiles, we found that the values of spontaneous curvature of the two opposing monolayers became negative when the pH was decreased. At low pH, protonation of the free fatty acid headgroups reduces their mutual repulsion and accounts for the pH dependence of all the above-mentioned properties. The altered structural characteristics may significantly affect the overall surface properties of biomembranes in cellular vesicles, lipid droplets, and plasma lipoproteins, play an important role in membrane fission and fusion, and modify interactions between membrane lipids and the proteins embedded within them.  相似文献   
69.
BackgroundWe compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression.Methods and findingsATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat.Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups.Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design.ConclusionsIn this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression.Trial registrationClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.

Piero Ruggenenti and co-workers study maintenance immunosuppression in deceased-donor kidney transplantation.  相似文献   
70.
Human immunodeficiency virus type 1 (HIV-1)-infected cells transmit viral products to uninfected CD4+ cells very rapidly. However, the natures of the transmitted viral products and the mechanism of transmission, as well as the relative virological consequences, have not yet been fully clarified. We studied the virological events occurring a few hours after contact between HIV-1-infected and uninfected CD4+ cells using a coculture cell system in which the virus expression in target cells could be monitored through the induction of a green fluorescent protein reporter gene driven by HIV-1 long terminal repeats. Within 16 h of coculture, we observed two phenomena not related to the cell-free virus infection, i.e., the formation of donor-target cell fusions and a fusion-independent internalization of viral particles likely occurring at least in part through intercellular connections. Both events depended on the expression of Env and CD4 in donor and target cells, respectively, whereas the HIV-1 internalization required clathrin activity in target cells. Importantly, both phenomena were also observed in cocultures of primary CD4+ lymphocytes, while primary macrophages supported only HIV-1 endocytosis. By investigating the virological consequences of these events, we noticed that while fused cells released infectious HIV-1 particles, albeit with reduced efficiency compared with donor cells, no virus expression was detectable upon HIV-1 endocytosis in target cells. In sum, the HIV-1 transmission following contact between an HIV-1-infected and an uninfected CD4+ cell can occur through different mechanisms, leading to distinguishable virological outcomes.  相似文献   
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号