全文获取类型
收费全文 | 2480篇 |
免费 | 233篇 |
国内免费 | 1篇 |
出版年
2023年 | 14篇 |
2022年 | 30篇 |
2021年 | 102篇 |
2020年 | 46篇 |
2019年 | 66篇 |
2018年 | 67篇 |
2017年 | 55篇 |
2016年 | 88篇 |
2015年 | 141篇 |
2014年 | 172篇 |
2013年 | 206篇 |
2012年 | 231篇 |
2011年 | 215篇 |
2010年 | 120篇 |
2009年 | 130篇 |
2008年 | 162篇 |
2007年 | 149篇 |
2006年 | 117篇 |
2005年 | 109篇 |
2004年 | 59篇 |
2003年 | 69篇 |
2002年 | 68篇 |
2001年 | 33篇 |
2000年 | 24篇 |
1999年 | 24篇 |
1998年 | 14篇 |
1997年 | 10篇 |
1996年 | 5篇 |
1995年 | 11篇 |
1994年 | 11篇 |
1993年 | 12篇 |
1992年 | 11篇 |
1991年 | 14篇 |
1990年 | 14篇 |
1989年 | 10篇 |
1988年 | 10篇 |
1987年 | 5篇 |
1986年 | 9篇 |
1985年 | 6篇 |
1982年 | 4篇 |
1981年 | 4篇 |
1978年 | 4篇 |
1977年 | 5篇 |
1976年 | 5篇 |
1974年 | 4篇 |
1973年 | 9篇 |
1972年 | 4篇 |
1970年 | 4篇 |
1969年 | 7篇 |
1968年 | 4篇 |
排序方式: 共有2714条查询结果,搜索用时 515 毫秒
61.
62.
63.
Adam K. A. Wright Mathieu Bangert Jenna F. Gritzfeld Daniela M. Ferreira Kondwani C. Jambo Angela D. Wright Andrea M. Collins Stephen B. Gordon 《PLoS pathogens》2013,9(3)
Pneumococcal carriage is both immunising and a pre-requisite for mucosal and systemic disease. Murine models of pneumococcal colonisation show that IL-17A-secreting CD4+ T-cells (Th-17 cells) are essential for clearance of pneumococci from the nasopharynx. Pneumococcal-responding IL-17A-secreting CD4+ T-cells have not been described in the adult human lung and it is unknown whether they can be elicited by carriage and protect the lung from pneumococcal infection. We investigated the direct effect of experimental human pneumococcal nasal carriage (EHPC) on the frequency and phenotype of cognate CD4+ T-cells in broncho-alveolar lavage and blood using multi-parameter flow cytometry. We then examined whether they could augment ex vivo alveolar macrophage killing of pneumococci using an in vitro assay. We showed that human pneumococcal carriage leads to a 17.4-fold (p = 0.007) and 8-fold (p = 0.003) increase in the frequency of cognate IL-17A+ CD4+ T-cells in BAL and blood, respectively. The phenotype with the largest proportion were TNF+/IL-17A+ co-producing CD4+ memory T-cells (p<0.01); IFNγ+ CD4+ memory T-cells were not significantly increased following carriage. Pneumococci could stimulate large amounts of IL-17A protein from BAL cells in the absence of carriage but in the presence of cognate CD4+ memory T-cells, IL-17A protein levels were increased by a further 50%. Further to this we then show that alveolar macrophages, which express IL-17A receptors A and C, showed enhanced killing of opsonised pneumococci when stimulated with rhIL-17A (p = 0.013). Killing negatively correlated with RC (r = −0.9, p = 0.017) but not RA expression. We conclude that human pneumococcal carriage can increase the proportion of lung IL-17A-secreting CD4+ memory T-cells that may enhance innate cellular immunity against pathogenic challenge. These pathways may be utilised to enhance vaccine efficacy to protect the lung against pneumonia. 相似文献
64.
Potential for Virus Endogenization in Humans through Testicular Germ Cell Infection: the Case of HIV
65.
66.
Karin Rybka Siobhan E. Toal Daniel J. Verbaro Daniel Mathieu Harald Schwalbe Reinhard Schweitzer‐Stenner 《Proteins》2013,81(6):968-983
In the preceding paper, we found that ensembles of tripeptides with long or bulky chains can include up to 20% of various turns. Here, we determine the structural and thermodynamic characteristics of GxG peptides with short polar and/or ionizable central residues (D, N, C), whose conformational distributions exhibit higher than average percentage (>20%) of turn conformations. To probe the side‐chain conformations of these peptides, we determined the 3J(Hα,Hβ) coupling constants and derived the population of three rotamers with χ1‐angles of ?60°, 180° and 60°, which were correlated with residue propensities by DFT‐calculations. For protonated GDG, the rotamer distribution provides additional evidence for asx‐turns. A comparison of vibrational spectra and NMR coupling constants of protonated GDG, ionized GDG, and the protonated aspartic acid dipeptide revealed that side chain protonation increases the pPII content at the expense of turn populations. The charged terminal groups, however, have negligible influence on the conformational properties of the central residue. Like protonated GDG, cationic GCG samples asx‐turns to a significant extent. The temperature dependence of the UVCD spectra and 3J(HNHα) constants suggest that the turn populations of GDG and GNG are practically temperature‐independent, indicating enthalpic and entropic stabilization. The temperature‐independent J‐coupling and UVCD spectra of GNG require a three‐state model. Our results indicate that short side chains with hydrogen bonding capability in GxG segments of proteins may serve as hinge regions for establishing compact structures of unfolded proteins and peptides. Proteins 2013. © 2012 Wiley Periodicals, Inc. 相似文献
67.
Mathieu Basille Daniel Fortin Christian Dussault Jean‐Pierre Ouellet Réhaume Courtois 《Ecography》2013,36(2):220-229
Species interactions within food webs are driven by multiple constraints, including those imposed by seasonal changes in the environment. Ecologically sound definitions of seasons may therefore be a prerequisite for clarifying predator prey interactions. Most studies define biological seasons based on fixed schedules or on temporal changes in a single movement measurement. We used a novel clustering approach based on homogeneous space‐use patterns of GPS‐collared animals to reveal 7 biological seasons for caribou Rangifer tarandus caribou, and 5 for both moose Alces alces and grey wolves Canis lupus interacting in a boreal ecosystem. Subsequent evaluation of niche overlap showed that, as predicted, wolves had a stronger spatio‐temporal connection with moose, its main prey, than with caribou. Movement constraints and limiting resource distributions similarly affected all species in some instances, but also caused temporal changes in the extent of niche overlap between wolves and its two prey. The risk that caribou faced was not only linked to the niche overlap with wolves, but also to the extent of wolf‐moose niche overlap during the same period. Food‐web properties emerged from the analysis, with temporal changes in relative niche overlap reflecting the strength of trophic interactions during the year. Our study demonstrates how the study of trophic interactions can benefit from comprehensive definitions of biological seasons. 相似文献
68.
Mathieu Mateo Chanakha K. Navaratnarajah Sabriya Syed Roberto Cattaneo 《Journal of virology》2013,87(16):9208-9216
Wild-type measles virus (MV) strains use the signaling lymphocytic activation molecule (SLAM; CD150) and the adherens junction protein nectin-4 (poliovirus receptor-like 4 [PVRL4]) as receptors. Vaccine MV strains have adapted to use ubiquitous membrane cofactor protein (MCP; CD46) in addition. Recently solved cocrystal structures of the MV attachment protein (hemagglutinin [H]) with each receptor indicate that all three bind close to a hydrophobic groove located between blades 4 and 5 (β4-β5 groove) of the H protein β-propeller head. We used this structural information to focus our analysis of the functional footprints of the three receptors on vaccine MV H. We mutagenized this protein and tested the ability of individual mutants to support cell fusion through each receptor. The results highlighted a strong overlap between the functional footprints of nectin-4 and CD46 but not those of SLAM. A soluble form of nectin-4 abolished vaccine MV entry in nectin-4- and CD46-expressing cells but only reduced entry through SLAM. Analyses of the binding kinetics of an H mutant with the three receptors revealed that a single substitution in the β4-β5 groove drastically reduced nectin-4 and CD46 binding while minimally altering SLAM binding. We also generated recombinant viruses and analyzed their infections in cells expressing individual receptors. Introduction of a single substitution into the hydrophobic pocket affected entry through both nectin-4 and CD46 but not through SLAM. Thus, while nectin-4 and CD46 interact functionally with the H protein β4-β5 hydrophobic groove, SLAM merely covers it. This has implications for vaccine and antiviral strategies. 相似文献
69.
Anik Désormeaux Mathieu Coutu Halima Medjahed Beatriz Pacheco Alon Herschhorn Christopher Gu Shi-Hua Xiang Youdong Mao Joseph Sodroski Andrés Finzi 《Journal of virology》2013,87(5):2549-2562
The trimeric envelope glycoprotein (Env) of human immunodeficiency virus type 1 (HIV-1) mediates virus entry into host cells. CD4 engagement with the gp120 exterior envelope glycoprotein subunit represents the first step during HIV-1 entry. CD4-induced conformational changes in the gp120 inner domain involve three potentially flexible topological layers (layers 1, 2, and 3). Structural rearrangements between layer 1 and layer 2 have been shown to facilitate the transition of the envelope glycoprotein trimer from the unliganded to the CD4-bound state and to stabilize gp120-CD4 interaction. However, our understanding of CD4-induced conformational changes in the gp120 inner domain remains incomplete. Here, we report that a highly conserved element of the gp120 inner domain, layer 3, plays a pivot-like role in these allosteric changes. In the unliganded state, layer 3 modulates the association of gp120 with the Env trimer, probably by influencing the relationship of the gp120 inner and outer domains. Importantly, layer 3 governs the efficiency of the initial gp120 interaction with CD4, a function that can also be fulfilled by filling the Phe43 cavity. This work defines the functional importance of layer 3 and completes a picture detailing the role of the gp120 inner domain in CD4-induced conformational transitions in the HIV-1 Env trimer. 相似文献
70.
Magnetic Resonance Elastography (MRE) is an emerging imaging modality for quantifying soft tissue elasticity deduced from displacement measurements within the tissue obtained by phase sensitive Magnetic Resonance Imaging (MRI) techniques. MRE has potential to detect a range of pathologies, diseases and cancer formations, especially tumors. The mechanical model commonly used in MRE is linear viscoelasticity (VE). An alternative Rayleigh damping (RD) model for soft tissue attenuation is used with a subspace-based nonlinear inversion (SNLI) algorithm to reconstruct viscoelastic properties, energy attenuation mechanisms and concomitant damping behavior of the tissue-simulating phantoms. This research performs a thorough evaluation of the RD model in MRE focusing on unique identification of RD parameters, μI and ρI. 相似文献