全文获取类型
收费全文 | 731篇 |
免费 | 41篇 |
国内免费 | 1篇 |
出版年
2022年 | 10篇 |
2021年 | 8篇 |
2020年 | 6篇 |
2019年 | 12篇 |
2018年 | 16篇 |
2017年 | 15篇 |
2016年 | 18篇 |
2015年 | 30篇 |
2014年 | 38篇 |
2013年 | 52篇 |
2012年 | 72篇 |
2011年 | 65篇 |
2010年 | 42篇 |
2009年 | 28篇 |
2008年 | 48篇 |
2007年 | 42篇 |
2006年 | 34篇 |
2005年 | 41篇 |
2004年 | 27篇 |
2003年 | 22篇 |
2002年 | 35篇 |
2001年 | 6篇 |
2000年 | 2篇 |
1999年 | 4篇 |
1998年 | 7篇 |
1997年 | 3篇 |
1996年 | 5篇 |
1995年 | 3篇 |
1994年 | 4篇 |
1993年 | 3篇 |
1992年 | 5篇 |
1991年 | 6篇 |
1990年 | 2篇 |
1987年 | 5篇 |
1985年 | 5篇 |
1984年 | 6篇 |
1983年 | 6篇 |
1982年 | 5篇 |
1981年 | 6篇 |
1980年 | 6篇 |
1979年 | 3篇 |
1978年 | 4篇 |
1977年 | 3篇 |
1976年 | 1篇 |
1975年 | 2篇 |
1970年 | 2篇 |
1968年 | 2篇 |
1967年 | 1篇 |
1966年 | 2篇 |
1961年 | 1篇 |
排序方式: 共有773条查询结果,搜索用时 15 毫秒
161.
Naazneen Khan Aniruddha Sasmal Zahra Khedri Patrick Secrest Andrea Verhagen Saurabh Srivastava Nissi Varki Xi Chen Hai Yu Travis Beddoe Adrienne W. Paton James C. Paton Ajit Varki 《The Journal of biological chemistry》2022,298(5)
Many pathogenic bacteria secrete AB5 toxins that can be virulence factors. Cytotoxic A subunits are delivered to the cytosol following B subunit binding to specific host cell surface glycans. Some B subunits are not associated with A subunits, for example, YpeB of Yersinia pestis, the etiologic agent of plague. Plague cannot be eradicated because of Y. pestis'' adaptability to numerous hosts. We previously showed selective binding of other B5 pentamers to a sialoglycan microarray, with sialic acid (Sia) preferences corresponding to those prominently expressed by various hosts, for example, N-acetylneuraminic acid (Neu5Ac; prominent in humans) or N-glycolylneuraminic acid (Neu5Gc; prominent in ruminant mammals and rodents). Here, we report that A subunit phylogeny evolved independently of B subunits and suggest a future B subunit nomenclature based on bacterial species names. We also found via phylogenetic analysis of B subunits, which bind Sias, that homologous molecules show poor correlation with species phylogeny. These data indicate ongoing lateral gene transfers between species, including mixing of A and B subunits. Consistent with much broader host range of Y. pestis, we show that YpeB recognizes all mammalian Sia types, except for 4-O-acetylated ones. Notably, YpeB alone causes dose-dependent cytotoxicity, which is abolished by a mutation (Y77F) eliminating Sia recognition, suggesting that cell proliferation and death are promoted via lectin-like crosslinking of cell surface sialoglycoconjugates. These findings help explain the host range of Y. pestis and could be important for pathogenesis. Overall, our data indicate ongoing rapid evolution of both host Sias and pathogen toxin-binding properties. 相似文献
162.
Yusei Miyazaki Rui Li Ayman Rezk Hétoum Misirliyan Craig Moore Nasr Farooqi Mayra Solis Lorna Galleguillos Goiry Omar de Faria Junior Van Duc Dang David Colman Ajit Singh Dhaunchak Jack Antel Jennifer Gommerman Alexandre Prat Simon Fillatreau Amit Bar-Or 《PloS one》2014,9(8)
Clinical trial results demonstrating that B-cell depletion substantially reduces new relapses in patients with multiple sclerosis (MS) have established that B cells play a role in the pathophysiology of MS relapses. The same treatment appears not to impact antibodies directed against the central nervous system, which underscores the contribution of antibody-independent functions of B cells to disease activity. One mechanism by which B cells are now thought to contribute to MS activity is by over-activating T cells, including through aberrant expression of B cell pro-inflammatory cytokines. However, the mechanisms underlying the observed B cell cytokine dysregulation in MS remain unknown. We hypothesized that aberrant expression of particular microRNAs might be involved in the dysregulated pro-inflammatory cytokine responses of B cells of patients with MS. Through screening candidate microRNAs in activated B cells of MS patients and matched healthy subjects, we discovered that abnormally increased secretion of lymphotoxin and tumor necrosis factor α by MS B cells is associated with abnormally increased expression of miR-132. Over-expression of miR-132 in normal B cells significantly enhanced their production of lymphotoxin and tumor necrosis factor α. The over-expression of miR-132 also suppressed the miR-132 target, sirtuin-1. We confirmed that pharmacological inhibition of sirtuin-1 in normal B cells induces exaggerated lymphotoxin and tumor necrosis factor α production, while the abnormal production of these cytokines by MS B cells can be normalized by resveratrol, a sirtuin-1 activator. These results define a novel miR-132-sirtuin-1 axis that controls pro-inflammatory cytokine secretion by human B cells, and demonstrate that a dysregulation of this axis underlies abnormal pro-inflammatory B cell cytokine responses in patients with MS. 相似文献
163.
164.
In this study, the inhibition of molting fluid enzymes from Helicoverpa armigera by an aspartic protease inhibitor, Alkalophilic Thermophilic Bacillus Inhibitor (ATBI) purified from Bacillus sp. is reported. The in vitro experiments showed 80% inhibition (IC50= 48 µM) of hemoglobin hydrolyzing and 95% inhibition (IC50= 35 µM) of chitin hydrolyzing activity from molting fluid by ATBI (IC50 value is the ATBI concentration for 50% inhibition of total enzymatic activity). The treatment of H. armigera larvae with 400 µM ATBI recorded 20% larval mortality, 27.77% deformed pupae and 12.22% deformed adults. The LC50 value (Concentration of ATBI calculated to give 50% mortality) calculated for insect population was found to be 330.06 µM. Similarly, significant variations in mean larval and pupal weight, no. of eggs laid per female and percent hatching of eggs were observed at higher concentrations of ATBI. The results may provide the basis for the selection of non-host inhibitors to develop a H. armigera insecticide formulation. 相似文献
165.
The formation and maintenance of cell-cell junctions, both under physiological and pathological conditions, requires the targeting and trafficking of junctional proteins. Proteins of the syntaxin (Stx)-family localize to a variety of subcellular membranes and contribute to intracellular transport of cargo by regulating vesicle fusion events at these sites. Unlike plasma membrane localized Stxs, the roles of endosome- and Golgi-localized stx proteins in epithelial morphogenesis are less understood. Here we show that Stx16– an endosome- and Golgi-localized target-membrane soluble N-ethylmaleimide attachment protein receptor (t-SNARE) that plays a role in membrane trafficking between these compartments – is essential for lumen development. In cultured Madin Darby Canine Kidney (MDCK) cells, Stx16 was selectively upregulated as sparsely plated cells attained confluency. Stx16-depleted confluent monolayers consistently showed lower transepithelial resistance than control monolayers, and failed to maintain endogenous and ectopically expressed E-cadherin at the adherens junctions due to decreased recycling. We further found that whereas cysts formed by MDCK cells cultured in Matrigel have a single hollow lumen, those formed by stx16-depleted counterparts had multiple lumens, due to abnormal orientiation of the mitotic spindle. Finally, a similar role for stx16 function in vivo is indicated by our analysis of pronephric-duct development in zebrafish expressing the claudinB:lynGFP transgene; lack of stx16 function in this structure (in stx16-morphant embryos) led to the development of enlarged, torturous pronephric ducts with more than one lumen. Taken together, our in vitro and in vivo studies establish a role for Stx16 in maintaining the integrity of cell-cell junctions, and thereby in morphogenesis of the kidney epithelial lumen. 相似文献
166.
167.
168.
169.
Katrina M. Pollock Damien J. Montamat-Sicotte Lisa Grass Graham S. Cooke Moses S. Kapembwa Onn M. Kon Robert D. Sampson Graham P. Taylor Ajit Lalvani 《PloS one》2016,11(1)
HIV co-infection is an important risk factor for tuberculosis (TB) providing a powerful model in which to dissect out defective, protective and dysfunctional Mycobacterium tuberculosis (MTB)-specific immune responses. To identify the changes induced by HIV co-infection we compared MTB-specific CD4+ responses in subjects with active TB and latent TB infection (LTBI), with and without HIV co-infection. CD4+ T-cell subsets producing interferon-gamma (IFN-γ), interleukin-2 (IL-2) and tumour necrosis factor-alpha (TNF-α) and expressing CD279 (PD-1) were measured using polychromatic flow-cytometry. HIV-TB co-infection was consistently and independently associated with a reduced frequency of CD4+ IFN-γ and IL-2-dual secreting T-cells and the proportion correlated inversely with HIV viral load (VL). The impact of HIV co-infection on this key MTB-specific T-cell subset identifies them as a potential correlate of mycobacterial immune containment. The percentage of MTB-specific IFN-γ-secreting T-cell subsets that expressed PD-1 was increased in active TB with HIV co-infection and correlated with VL. This identifies a novel correlate of dysregulated immunity to MTB, which may in part explain the paucity of inflammatory response in the face of mycobacterial dissemination that characterizes active TB with HIV co-infection. 相似文献
170.
Allophanate lyase can be induced by urea or acetamide 20-40-fold within 4 h in NH4 + -deprived cultures of Chlamydomonas reinhardi. In light-synchronized cultures, allophanate lyase induction appeared to be limited to the light phase of the cell cycle, provided that culture samples were induced under ongoing illumination conditions (i.e. light induction of light phase cells and dark induction of dark phase cells). However, when culture samples were induced under constant light conditions this cell cycle pattern was abolished. Light was found to be required for allophanate lyase induction and this was shown to be due, in part, to the light requirement for inducer uptake. The relationship between allophanate lyase induction and gametogenesis is discussed. 相似文献