全文获取类型
收费全文 | 409篇 |
免费 | 51篇 |
国内免费 | 1篇 |
出版年
2023年 | 2篇 |
2022年 | 3篇 |
2021年 | 15篇 |
2020年 | 5篇 |
2019年 | 12篇 |
2018年 | 13篇 |
2017年 | 12篇 |
2016年 | 17篇 |
2015年 | 34篇 |
2014年 | 30篇 |
2013年 | 32篇 |
2012年 | 42篇 |
2011年 | 41篇 |
2010年 | 24篇 |
2009年 | 24篇 |
2008年 | 39篇 |
2007年 | 26篇 |
2006年 | 12篇 |
2005年 | 19篇 |
2004年 | 16篇 |
2003年 | 6篇 |
2002年 | 3篇 |
2001年 | 3篇 |
2000年 | 2篇 |
1999年 | 1篇 |
1998年 | 3篇 |
1997年 | 1篇 |
1996年 | 2篇 |
1994年 | 3篇 |
1991年 | 3篇 |
1989年 | 1篇 |
1986年 | 2篇 |
1985年 | 2篇 |
1979年 | 3篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1971年 | 1篇 |
1962年 | 1篇 |
1940年 | 1篇 |
1910年 | 1篇 |
排序方式: 共有461条查询结果,搜索用时 333 毫秒
91.
Pavel V. Belichenko Rime Madani Lorianne Rey-Bellet Maria Pihlgren Ann Becker Adeline Plassard Stephanie Vuillermot Valérie Giriens Rachel L. Nosheny Alexander M. Kleschevnikov Janice S. Valletta Sara K. S. Bengtsson Gordon R. Linke Michael T. Maloney David T. Hickman Pedro Reis Anne Granet Dorin Mlaki Maria Pilar Lopez-Deber Long Do Nishant Singhal Eliezer Masliah Matthew L. Pearn Andrea Pfeifer Andreas Muhs William C. Mobley 《PloS one》2016,11(3)
In Down syndrome (DS) or trisomy of chromosome 21, the β-amyloid (Aβ) peptide product of the amyloid precursor protein (APP) is present in excess. Evidence points to increased APP gene dose and Aβ as playing a critical role in cognitive difficulties experienced by people with DS. Particularly, Aβ is linked to the late-life emergence of dementia as associated with neuropathological markers of Alzheimer’s disease (AD). At present, no treatment targets Aβ–related pathogenesis in people with DS. Herein we used a vaccine containing the Aβ 1–15 peptide embedded into liposomes together with the adjuvant monophosphoryl lipid A (MPLA). Ts65Dn mice, a model of DS, were immunized with the anti-Aβ vaccine at 5 months of age and were examined for cognitive measures at 8 months of age. The status of basal forebrain cholinergic neurons and brain levels of APP and its proteolytic products were measured. Immunization of Ts65Dn mice resulted in robust anti-Aβ IgG titers, demonstrating the ability of the vaccine to break self-tolerance. The vaccine-induced antibodies reacted with Aβ without detectable binding to either APP or its C-terminal fragments. Vaccination of Ts65Dn mice resulted in a modest, but non-significant reduction in brain Aβ levels relative to vehicle-treated Ts65Dn mice, resulting in similar levels of Aβ as diploid (2N) mice. Importantly, vaccinated Ts65Dn mice showed resolution of memory deficits in the novel object recognition and contextual fear conditioning tests, as well as reduction of cholinergic neuron atrophy. No treatment adverse effects were observed; vaccine did not result in inflammation, cellular infiltration, or hemorrhage. These data are the first to show that an anti-Aβ immunotherapeutic approach may act to target Aβ-related pathology in a mouse model of DS. 相似文献
92.
Odile Ozier-Kalogeropoulos Franco Fasiolo Marie-Therèse Adeline Jocelyne Collin Fran?ois Lacroute 《Molecular & general genetics : MGG》1991,231(1):7-16
Summary The URA7 gene of Saccharomyces cerevisiae encodes CTP synthetase (EC 6.3.4.2) which catalyses the conversion of uridine 5-triphosphate to cytidine 5-triphosphate, the last step of the pyrimidine biosynthetic pathway. We have cloned and sequenced the URA 7 gene. The coding region is 1710 by long and the deduced protein sequence shows a strong degree of homology with bacterial and human CTP synthetases. Gene disruption shows that URA7 is not an essential gene: the level of the intracellular CTP pool is roughly the same in the deleted and the wild-type strains, suggesting that an alternative pathway for CTP synthesis exists in yeast. This could involve either a divergent duplicated gene or a different route beginning with the amination of uridine mono- or diphosphate. 相似文献
93.
The literature is full of examples of inbreeding avoidance, while recent mathematical models predict that inbreeding tolerance or even inbreeding preference should be expected under several realistic conditions like e.g. polygyny. We investigated male and female mate preferences with respect to relatedness in the fruit fly D. melanogaster. Experiments offered the choice between a first order relative (full-sibling or parent) and an unrelated individual with the same age and mating history. We found that females significantly preferred mating with their brothers, thus supporting inbreeding preference. Moreover, females did not avoid mating with their fathers, and males did not avoid mating with their sisters, thus supporting inbreeding tolerance. Our experiments therefore add empirical evidence for inbreeding preference, which strengthens the prediction that inbreeding tolerance and preference can evolve under specific circumstances through the positive effects on inclusive fitness. 相似文献
94.
Eric Morello Adeline Mallet Yoan Konto-Ghiorghi Thibault Chaze Michel-Yves Mistou Giulia Oliva Liliana Oliveira Anne-Marie Di Guilmi Patrick Trieu-Cuot Shaynoor Dramsi 《PloS one》2015,10(9)
Streptococcus agalactiae (or Group B Streptococcus, GBS) is a commensal bacterium present in the intestinal and urinary tracts of approximately 30% of humans. We and others previously showed that the PI-2a pilus polymers, made of the backbone pilin PilB, the tip adhesin PilA and the cell wall anchor protein PilC, promote adhesion to host epithelia and biofilm formation. Affinity-purified PI-2a pili from GBS strain NEM316 were recognized by N-acetylneuraminic acid (NeuNAc, also known as sialic acid) specific lectins such as Elderberry Bark Lectin (EBL) suggesting that pili are sialylated. Glycan profiling with twenty different lectins combined with monosaccharide composition by HPLC suggested that affinity-purified PI-2a pili are modified by N-glycosylation and decorated with sialic acid attached to terminal galactose. Analysis of various relevant mutants in the PI-2a pilus operon by flow-cytometry and electron microscopy analyses pointed to PilA as the pilus subunit modified by glycosylation. Double labeling using PilB antibody and EBL lectin, which specifically recognizes N-acetylneuraminic acid attached to galactose in α-2, 6, revealed a characteristic binding of EBL at the tip of the pilus structures, highly reminiscent of PilA localization. Expression of a secreted form of PilA using an inducible promoter showed that this recombinant PilA binds specifically to EBL lectin when produced in the native GBS context. In silico search for potentially glycosylated asparagine residues in PilA sequence pointed to N427 and N597, which appear conserved and exposed in the close homolog RrgA from S. pneumoniae, as likely candidates. Conversion of these two asparagyl residues to glutamyl resulted in a higher instability of PilA. Our results provide the first evidence that the tip PilA adhesin can be glycosylated, and suggest that this modification is critical for PilA stability and may potentially influence interactions with the host. 相似文献
95.
96.
Burlak C Hammer CH Robinson MA Whitney AR McGavin MJ Kreiswirth BN Deleo FR 《Cellular microbiology》2007,9(5):1172-1190
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a threat to human health worldwide. Although progress has been made, mechanisms of CA-MRSA pathogenesis are poorly understood and a comprehensive analysis of CA-MRSA exoproteins has not been conducted. To address that deficiency, we used proteomics to identify exoproteins made by MW2 (USA400) and LAC (USA300) during growth in vitro. Two hundred and fifty unique exoproteins were identified by 2-dimensional gel electrophoresis coupled with automated direct infusion-tandem mass spectrometry (ADI-MS/MS) analysis. Eleven known virulence-related exoproteins differed in abundance between the strains, including alpha-haemolysin (Hla), collagen adhesin (Cna), staphylokinase (Sak), coagulase (Coa), lipase (Lip), enterotoxin C3 (Sec3), enterotoxin Q (Seq), V8 protease (SspA) and cysteine protease (SspB). Mice infected with MW2 or LAC produced antibodies specific for known or putative virulence factors, such as autolysin (Atl), Cna, Ear, ferritin (Ftn), Lip, 1-phosphatidylinositol phosphodiesterase (Plc), Sak, Sec3 and SspB, indicating the exoproteins are made during infection in vivo. We used confocal microscopy to demonstrate aureolysin (Aur), Hla, SspA and SspB are produced following phagocytosis by human neutrophils, thereby linking exoprotein production in vitro with that during host-pathogen interaction. We conclude that the exoproteins identified herein likely account in part for the success of CA-MRSA as a human pathogen. 相似文献
97.
Gilles Darcis Anna Kula Sophie Bouchat Koh Fujinaga Francis Corazza Amina Ait-Ammar Nadège Delacourt Adeline Melard Kabamba Kabeya Caroline Vanhulle Benoit Van Driessche Jean-Stéphane Gatot Thomas Cherrier Luiz F. Pianowski Lucio Gama Christian Schwartz Jorge Vila Arsène Burny Nathan Clumeck Michel Moutschen Stéphane De Wit B. Matija Peterlin Christine Rouzioux Olivier Rohr Carine Van Lint 《PLoS pathogens》2015,11(7)
98.
Abderaouf Damouche Thierry Lazure Véronique Avettand-Fèno?l Nicolas Huot Nathalie Dejucq-Rainsford Anne-Pascale Satie Adeline Mélard Ludivine David Céline Gommet Jade Ghosn Nicolas Noel Guillaume Pourcher Valérie Martinez Stéphane Benoist Véronique Béréziat Antonio Cosma Benoit Favier Bruno Vaslin Christine Rouzioux Jacqueline Capeau Michaela Müller-Trutwin Nathalie Dereuddre-Bosquet Roger Le Grand Olivier Lambotte Christine Bourgeois 《PLoS pathogens》2015,11(9)
Two of the crucial aspects of human immunodeficiency virus (HIV) infection are (i) viral persistence in reservoirs (precluding viral eradication) and (ii) chronic inflammation (directly associated with all-cause morbidities in antiretroviral therapy (ART)-controlled HIV-infected patients). The objective of the present study was to assess the potential involvement of adipose tissue in these two aspects. Adipose tissue is composed of adipocytes and the stromal vascular fraction (SVF); the latter comprises immune cells such as CD4+ T cells and macrophages (both of which are important target cells for HIV). The inflammatory potential of adipose tissue has been extensively described in the context of obesity. During HIV infection, the inflammatory profile of adipose tissue has been revealed by the occurrence of lipodystrophies (primarily related to ART). Data on the impact of HIV on the SVF (especially in individuals not receiving ART) are scarce. We first analyzed the impact of simian immunodeficiency virus (SIV) infection on abdominal subcutaneous and visceral adipose tissues in SIVmac251 infected macaques and found that both adipocytes and adipose tissue immune cells were affected. The adipocyte density was elevated, and adipose tissue immune cells presented enhanced immune activation and/or inflammatory profiles. We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue. We demonstrated that SVF cells (including CD4+ T cells) are infected in ART-controlled HIV-infected patients. Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue. We thus identified adipose tissue as a crucial cofactor in both viral persistence and chronic immune activation/inflammation during HIV infection. These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low-grade chronic inflammation via the modulation of adipose tissue-related pathways. 相似文献
99.
Varrin-Doyer M Nicolle A Marignier R Cavagna S Benetollo C Wattel E Giraudon P 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(3):1222-1233
Recruitment of virus-infected T lymphocytes into the CNS is an essential step in the development of virus-associated neuroinflammatory diseases, notably myelopathy induced by retrovirus human T leukemia virus-1 (HTLV-1). We have recently shown the key role of collapsin response mediator protein 2 (CRMP2), a phosphoprotein involved in cytoskeleton rearrangement, in the control of human lymphocyte migration and in brain targeting in animal models of virus-induced neuroinflammation. Using lymphocytes cloned from infected patients and chronically infected T cells, we found that HTLV-1 affects CRMP2 activity, resulting in an increased migratory potential. Elevated CRMP2 expression accompanies a higher phosphorylation level of CRMP2 and its more pronounced adhesion to tubulin and actin. CRMP2 forms, a full length and a shorter, cleaved one, are also affected. Tax transfection and extinction strategies show the involvement of this viral protein in enhanced full-length and active CRMP2, resulting in prominent migratory rate. A role for other viral proteins in CRMP2 phosphorylation is suspected. Full-length CRMP2 confers a migratory advantage possibly by preempting the negative effect of short CRMP2 we observe on T lymphocyte migration. In addition, HTLV-1-induced migration seems, in part, supported by the ability of infected cell to increase the proteosomal degradation of short CRMP2. Finally, gene expression in CD69(+) cells selected from patients suggests that HTLV-1 has the capacity to influence the CRMP2/PI3K/Akt axis thus to positively control cytoskeleton organization and lymphocyte migration. Our data provide an additional clue to understanding the infiltration of HTLV-1-infected lymphocytes into various tissues and suggest that the regulation of CRMP2 activity by virus infection is a novel aspect of neuroinflammation. 相似文献
100.
Fauconnier M Palomo J Bourigault ML Meme S Szeremeta F Beloeil JC Danneels A Charron S Rihet P Ryffel B Quesniaux VF 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(4):1905-1914
A Th1 response is required for the development of Plasmodium berghei ANKA (PbA)-induced experimental cerebral malaria (ECM). The role of pro-Th1 IL-12 in malaria is complex and controversial. In this study, we addressed the role of IL-12Rβ2 in ECM development. C57BL/6 mice deficient for IL-12Rβ2, IL-12p40, or IL-12p35 were analyzed for ECM development after blood-stage PbA infection in terms of ischemia and blood flow by noninvasive magnetic resonance imaging and angiography, T cell recruitment, and gene expression. Without IL-12Rβ2, no neurologic sign of ECM developed upon PbA infection. Although wild-type mice developed distinct brain microvascular pathology, ECM-resistant, IL-12Rβ2-deficient mice showed unaltered cerebral microcirculation and the absence of ischemia after PbA infection. In contrast, mice deficient for IL-12p40 or IL-12p35 were sensitive to ECM development. The resistance of IL-12Rβ2-deficient mice to ECM correlated with reduced recruitment of activated T cells and impaired overexpression of lymphotoxin-α, TNF-α, and IFN-γ in the brain after PbA infection. Therefore, IL-12Rβ2 signaling is essential for ECM development but independent from IL-12p40 and IL-12p35. We document a novel link between IL-12Rβ2 and lymphotoxin-α, TNF-α, and IFN-γ expression, key cytokines for ECM pathogenesis. 相似文献