全文获取类型
收费全文 | 4067篇 |
免费 | 304篇 |
国内免费 | 1篇 |
出版年
2023年 | 42篇 |
2022年 | 75篇 |
2021年 | 143篇 |
2020年 | 111篇 |
2019年 | 114篇 |
2018年 | 137篇 |
2017年 | 133篇 |
2016年 | 168篇 |
2015年 | 232篇 |
2014年 | 270篇 |
2013年 | 301篇 |
2012年 | 361篇 |
2011年 | 316篇 |
2010年 | 200篇 |
2009年 | 187篇 |
2008年 | 216篇 |
2007年 | 225篇 |
2006年 | 164篇 |
2005年 | 173篇 |
2004年 | 178篇 |
2003年 | 124篇 |
2002年 | 143篇 |
2001年 | 36篇 |
2000年 | 19篇 |
1999年 | 32篇 |
1998年 | 27篇 |
1997年 | 40篇 |
1996年 | 20篇 |
1995年 | 21篇 |
1994年 | 17篇 |
1993年 | 15篇 |
1992年 | 8篇 |
1991年 | 6篇 |
1990年 | 10篇 |
1989年 | 9篇 |
1988年 | 5篇 |
1987年 | 9篇 |
1985年 | 6篇 |
1984年 | 12篇 |
1983年 | 5篇 |
1982年 | 9篇 |
1981年 | 10篇 |
1980年 | 3篇 |
1979年 | 3篇 |
1977年 | 9篇 |
1976年 | 5篇 |
1975年 | 3篇 |
1974年 | 3篇 |
1973年 | 2篇 |
1961年 | 3篇 |
排序方式: 共有4372条查询结果,搜索用时 31 毫秒
811.
Fernanda Genre Raquel López-Mejías Mercedes García-Bermúdez Santos Casta?eda Carlos González-Juanatey Javier Llorca Alfonso Corrales Bego?a Ubilla José A. Miranda-Filloy Trinitario Pina Carmen Gómez-Vaquero Luis Rodríguez-Rodríguez Benjamín Fernández-Gutiérrez Alejandro Balsa Dora Pascual-Salcedo Francisco J. López-Longo Patricia Carreira Ricardo Blanco Isidoro González-álvaro Javier Martín Miguel A. González-Gay 《PloS one》2014,9(9)
Introduction
Rheumatoid arthritis is an inflammatory disease with high incidence of cardiovascular disease due to accelerated atherosclerosis. Osteoprotegerin (OPG) has been associated with increased risk of atherosclerotic disease in the general population. Several polymorphisms in the OPG gene with functional effects on cardiovascular disease in non-rheumatic individuals have been described. Therefore, we aimed to analyze the effect of three of these functional OPG polymorphisms on the risk of cardiovascular disease in a large and well-characterized cohort of Spanish patients with rheumatoid arthritis.Methods
Three OPG gene variants (rs3134063, rs2073618 and rs3134069) were genotyped by TaqMan assays in 2027 Spanish patients with rheumatoid arthritis. Anti-cyclic citrullinated peptide (anti-CCP) antibody testing was positive in 997 of 1714 tested. Also, 18.3% of the whole series had experienced cardiovascular events, including 5.4% with cerebrovascular accidents. The relationship between OPG variants and cardiovascular events was assessed using Cox regression.Results
No association between OPG gene variants and cardiovascular disease was observed in the whole group of rheumatoid arthritis patients or in anti-CCP positive patients. Nevertheless, a protective effect of CGA haplotype on the risk of cardiovascular disease in general, and specifically in the risk of cerebrovascular complications after adjusting for sex, age at disease diagnosis and traditional cardiovascular risk factors was disclosed in anti-CCP negative patients (HR = 0.54; 95%CI: 0.31–0.95; p = 0.032 and HR = 0.17; 95%CI: 0.04–0.78; p = 0.022, respectively).Conclusion
Our results indicate a protective effect of the OPG CGA haplotype on cardiovascular risk, mainly due to a protective effect against cerebrovascular events in anti-CCP negative rheumatoid arthritis patients. 相似文献812.
María-Belén Bautista-Caro Irene Arroyo-Villa Concepción Castillo-Gallego Eugenio de Miguel Diana Peiteado Chamaida Plasencia-Rodríguez Alejandro Villalba Paloma Sánchez-Mateos Amaya Puig-Kr?ger Emilio Martín-Mola María-Eugenia Miranda-Carús 《PloS one》2014,9(9)
Follicular helper T cells (Tfh), localized in lymphoid organs, promote B cell differentiation and function. Circulating CD4 T cells expressing CXCR5, ICOS and/or PD-1 are counterparts of Tfh. Three subpopulations of circulating CD4+CXCR5+ cells have been described: CXCR3+CCR6- (Tfh-Th1), CXCR3-CCR6+ (Tfh-Th17), and CXCR3-CCR6- (Tfh-Th2). Only Tfh-Th17 and Tfh-Th2 function as B cell helpers. Our objective was to study the frequencies of circulating Tfh (cTfh), cTfh subsets and plasmablasts (CD19+CD20-CD27+CD38high cells), and the function of cTfh cells, in patients with Ankylosing Spondylitis (AS). To this end, peripheral blood was drawn from healthy controls (HC) (n = 50), AS patients naïve for TNF blockers (AS/nb) (n = 25) and AS patients treated with TNF blockers (AS/b) (n = 25). The frequencies of cTfh and plasmablasts were determined by flow cytometry. Cocultures of magnetically sorted CD4+CXCR5+ T cells with autologous CD19+CD27- naïve B cells were established from 3 AS/nb patients and 3 HC, and concentrations of IgG, A and M were measured in supernatants. We obseved that AS/nb but not AS/b patients, demonstrated decreased frequencies of circulating CD4+CXCR5+ICOS+PD-1+ cells and plasmablasts, together with a decreased (Tfh-Th17+Tfh-Th2)/Tfh-Th1 ratio. The amounts of IgG and IgA produced in cocultures of CD4+CXCR5+ T cells with CD19+CD27- B cells of AS/nb patients were significantly lower than observed in cocultures established from HC. In summary, AS/nb but not AS/b patients, demonstrate a decreased frequency of cTfh and plasmablasts, and an underrepresentation of cTfh subsets bearing a B helper phenotype. In addition, peripheral blood CD4+CXCR5+ T cells of AS/nb patients showed a decreased capacity to help B cells ex vivo. 相似文献
813.
Mir-Hossein Moosavi Hamid Katoozian Ali Pashaei Oscar Camara Alejandro F. Frangi 《Computer methods in biomechanics and biomedical engineering》2014,17(7):740-749
Understanding cardiac blood flow patterns has many applications in analysing haemodynamics and for the clinical assessment of heart function. In this study, numerical simulations of blood flow in a patient-specific anatomical model of the left ventricle (LV) and the aortic sinus are presented. The realistic 3D geometry of both LV and aortic sinus is extracted from the processing of magnetic resonance imaging (MRI). Furthermore, motion of inner walls of LV and aortic sinus is obtained from cine-MR image analysis and is used as a constraint to a numerical computational fluid dynamics (CFD) model based on the moving boundary approach. Arbitrary Lagrangian–Eulerian finite element method formulation is used for the numerical solution of the transient dynamic equations of the fluid domain. Simulation results include detailed flow characteristics such as velocity, pressure and wall shear stress for the whole domain. The aortic outflow is compared with data obtained by phase-contrast MRI. Good agreement was found between simulation results and these measurements. 相似文献
814.
Nancy Rivas Ma. Esther Sánchez Espíndola Alejandro D. Camacho Ernesto Ramírez Moreno Ma. Alejandra Rocha‐Gómez Ricardo Alejandre Aguilar 《Journal of vector ecology》2014,39(1):14-20
We studied the morphology and morphometry of scutella from six species of the hemipteran genus Meccus to identify new tools to help solve taxonomic problems in closely related insect species of epidemiological relevance. Scutellum samples were observed by scanning electron microscopy and were subjected to morphometric analysis. The results mainly show differences in central depression shape, posterior process, and vestiture. We found significant dimensional differences in scutellum morphometry and a clear sexual dimorphism among species. A combination of morphology and morphometry can be used to differentiate among species of the genus Meccus. 相似文献
815.
816.
Alejandro Moreno-Domínguez Ahmed F. El-Yazbi Hai-Lei Zhu Olaia Colinas X. Zo? Zhong Emma J. Walsh Dylan M. Cole Gary J. Kargacin Michael P. Walsh William C. Cole 《The Journal of biological chemistry》2014,289(30):20939-20952
Our understanding of the molecular events contributing to myogenic control of diameter in cerebral resistance arteries in response to changes in intravascular pressure, a fundamental mechanism regulating blood flow to the brain, is incomplete. Myosin light chain kinase and phosphatase activities are known to be increased and decreased, respectively, to augment phosphorylation of the 20-kDa regulatory light chain subunits (LC20) of myosin II, which permits cross-bridge cycling and force development. Here, we assessed the contribution of dynamic reorganization of the actin cytoskeleton and thin filament regulation to the myogenic response and serotonin-evoked constriction of pressurized rat middle cerebral arteries. Arterial diameter and the levels of phosphorylated LC20, calponin, caldesmon, cofilin, and HSP27, as well as G-actin content, were determined. A decline in G-actin content was observed following pressurization from 10 mm Hg to between 40 and 120 mm Hg and in three conditions in which myogenic or agonist-evoked constriction occurred in the absence of a detectable change in LC20 phosphorylation. No changes in thin filament protein phosphorylation were evident. Pressurization reduced G-actin content and elevated the levels of cofilin and HSP27 phosphorylation. Inhibitors of Rho-associated kinase and PKC prevented the decline in G-actin; reduced cofilin and HSP27 phosphoprotein content, respectively; and blocked the myogenic response. Furthermore, phosphorylation modulators of HSP27 and cofilin induced significant changes in arterial diameter and G-actin content of myogenically active arteries. Taken together, our findings suggest that dynamic reorganization of the cytoskeleton involving increased actin polymerization in response to Rho-associated kinase and PKC signaling contributes significantly to force generation in myogenic constriction of cerebral resistance arteries. 相似文献
817.
Matthew P. Parsons Rujun Kang Caodu Buren Alejandro Dau Amber L. Southwell Crystal N. Doty Shaun S. Sanders Michael R. Hayden Lynn A. Raymond 《The Journal of biological chemistry》2014,289(6):3518-3528
Huntington disease is associated with early alterations in corticostriatal synaptic function that precede cell death, and it is postulated that ameliorating such changes may delay clinical onset and/or prevent neurodegeneration. Although many of these synaptic alterations are thought to be attributable to a toxic gain of function of the mutant huntingtin protein, the role that nonpathogenic huntingtin (HTT) plays in synaptic function is relatively unexplored. Here, we compare the immunocytochemical localization of a major postsynaptic scaffolding protein, PSD-95, in striatal neurons from WT mice and mice overexpressing HTT with 18 glutamine repeats (YAC18, nonpathogenic). We found that HTT overexpression resulted in a palmitoylation- and BDNF-dependent increase in PSD-95 clustering at synaptic sites in striatal spiny projection neurons (SPNs) co-cultured with cortical neurons. Surprisingly, the latter effect was mediated presynaptically, as HTT overexpression in cortical neurons alone was sufficient to increase PSD-95 clustering in the postsynaptic SPNs. In contrast, antisense oligonucleotide knockdown of HTT in WT co-cultures resulted in a significant reduction of PSD-95 clustering in SPNs. Notably, despite these bidirectional changes in PSD-95 clustering, we did not observe an alteration in basal electrophysiological measures of AMPA and NMDA receptors. Thus, unlike in previous studies in the hippocampus, enhanced or decreased PSD-95 clustering alone was insufficient to drive AMPA or NMDA receptors into or out of SPN synapses. In all, our results demonstrate that nonpathogenic HTT can indeed influence synaptic protein localization and uncover a novel role of HTT in PSD-95 distribution. 相似文献
818.
Alejandra Martinez Gonzalo Peluffo Ariel A. Petruk Martín Hugo Dolores Pi?eyro Verónica Demicheli Diego M. Moreno Analía Lima Carlos Batthyány Rosario Durán Carlos Robello Marcelo A. Martí Nicole Larrieux Alejandro Buschiazzo Madia Trujillo Rafael Radi Lucía Piacenza 《The Journal of biological chemistry》2014,289(18):12760-12778
Trypanosoma cruzi, the causative agent of Chagas disease, contains exclusively iron-dependent superoxide dismutases (Fe-SODs) located in different subcellular compartments. Peroxynitrite, a key cytotoxic and oxidizing effector biomolecule, reacted with T. cruzi mitochondrial (Fe-SODA) and cytosolic (Fe-SODB) SODs with second order rate constants of 4.6 ± 0.2 × 104
m−1 s−1 and 4.3 ± 0.4 × 104
m−1 s−1 at pH 7.4 and 37 °C, respectively. Both isoforms are dose-dependently nitrated and inactivated by peroxynitrite. Susceptibility of T. cruzi Fe-SODA toward peroxynitrite was similar to that reported previously for Escherichia coli Mn- and Fe-SODs and mammalian Mn-SOD, whereas Fe-SODB was exceptionally resistant to oxidant-mediated inactivation. We report mass spectrometry analysis indicating that peroxynitrite-mediated inactivation of T. cruzi Fe-SODs is due to the site-specific nitration of the critical and universally conserved Tyr35. Searching for structural differences, the crystal structure of Fe-SODA was solved at 2.2 Å resolution. Structural analysis comparing both Fe-SOD isoforms reveals differences in key cysteines and tryptophan residues. Thiol alkylation of Fe-SODB cysteines made the enzyme more susceptible to peroxynitrite. In particular, Cys83 mutation (C83S, absent in Fe-SODA) increased the Fe-SODB sensitivity toward peroxynitrite. Molecular dynamics, electron paramagnetic resonance, and immunospin trapping analysis revealed that Cys83 present in Fe-SODB acts as an electron donor that repairs Tyr35 radical via intramolecular electron transfer, preventing peroxynitrite-dependent nitration and consequent inactivation of Fe-SODB. Parasites exposed to exogenous or endogenous sources of peroxynitrite resulted in nitration and inactivation of Fe-SODA but not Fe-SODB, suggesting that these enzymes play distinctive biological roles during parasite infection of mammalian cells. 相似文献
819.
820.
Tapan Bhattacharyya Andrew K. Falconar Alejandro O. Luquetti Jaime A. Costales Mario J. Grijalva Michael D. Lewis Louisa A. Messenger Trang T. Tran Juan-David Ramirez Felipe Guhl Hernan J. Carrasco Patricio Diosque Lineth Garcia Sergey V. Litvinov Michael A. Miles 《PLoS neglected tropical diseases》2014,8(5)