全文获取类型
收费全文 | 1097篇 |
免费 | 100篇 |
出版年
2023年 | 22篇 |
2022年 | 29篇 |
2021年 | 51篇 |
2020年 | 39篇 |
2019年 | 45篇 |
2018年 | 43篇 |
2017年 | 30篇 |
2016年 | 51篇 |
2015年 | 86篇 |
2014年 | 85篇 |
2013年 | 80篇 |
2012年 | 106篇 |
2011年 | 95篇 |
2010年 | 49篇 |
2009年 | 33篇 |
2008年 | 57篇 |
2007年 | 39篇 |
2006年 | 38篇 |
2005年 | 23篇 |
2004年 | 29篇 |
2003年 | 37篇 |
2002年 | 21篇 |
2001年 | 6篇 |
2000年 | 2篇 |
1999年 | 7篇 |
1998年 | 6篇 |
1997年 | 5篇 |
1996年 | 5篇 |
1994年 | 3篇 |
1993年 | 4篇 |
1992年 | 5篇 |
1991年 | 7篇 |
1990年 | 2篇 |
1988年 | 5篇 |
1987年 | 2篇 |
1986年 | 3篇 |
1985年 | 2篇 |
1980年 | 4篇 |
1979年 | 3篇 |
1976年 | 3篇 |
1974年 | 8篇 |
1973年 | 5篇 |
1972年 | 4篇 |
1971年 | 3篇 |
1968年 | 3篇 |
1967年 | 4篇 |
1965年 | 1篇 |
1964年 | 1篇 |
1962年 | 1篇 |
1938年 | 1篇 |
排序方式: 共有1197条查询结果,搜索用时 31 毫秒
921.
Recent work in motor control demonstrates that humans take their own motor uncertainty into account, adjusting the timing and goals of movement so as to maximize expected gain. Visual sensitivity varies dramatically with retinal location and target, and models of optimal visual search typically assume that the visual system takes retinal inhomogeneity into account in planning eye movements. Such models can then use the entire retina rather than just the fovea to speed search. Using a simple decision task, we evaluated human ability to compensate for retinal inhomogeneity. We first measured observers'' sensitivity for targets, varying contrast and eccentricity. Observers then repeatedly chose between targets differing in eccentricity and contrast, selecting the one they would prefer to attempt: e.g., a low contrast target at 2° versus a high contrast target at 10°. Observers knew they would later attempt some of their chosen targets and receive rewards for correct classifications. We evaluated performance in three ways. Equivalence: Do observers'' judgments agree with their actual performance? Do they correctly trade off eccentricity and contrast and select the more discriminable target in each pair? Transitivity: Are observers'' choices self-consistent? Dominance: Do observers understand that increased contrast improves performance? Decreased eccentricity? All observers exhibited patterned failures of equivalence, and seven out of eight observers failed transitivity. There were significant but small failures of dominance. All these failures together reduced their winnings by 10%–18%. 相似文献
922.
Ravinesh A. Kumar Christian R. Marshall Judith A. Badner Timothy D. Babatz Zohar Mukamel Kimberly A. Aldinger Jyotsna Sudi Camille W. Brune Gerald Goh Samer KaraMohamed James S. Sutcliffe Edwin H. Cook Daniel H. Geschwind William B. Dobyns Stephen W. Scherer Susan L. Christian 《PloS one》2009,4(2)
Background
Autism is a complex childhood neurodevelopmental disorder with a strong genetic basis. Microdeletion or duplication of a ∼500–700-kb genomic rearrangement on 16p11.2 that contains 24 genes represents the second most frequent chromosomal disorder associated with autism. The role of common and rare 16p11.2 sequence variants in autism etiology is unknown.Methodology/Principal Findings
To identify common 16p11.2 variants with a potential role in autism, we performed association studies using existing data generated from three microarray platforms: Affymetrix 5.0 (777 families), Illumina 550 K (943 families), and Affymetrix 500 K (60 families). No common variants were identified that were significantly associated with autism. To look for rare variants, we performed resequencing of coding and promoter regions for eight candidate genes selected based on their known expression patterns and functions. In total, we identified 26 novel variants in autism: 13 exonic (nine non-synonymous, three synonymous, and one untranslated region) and 13 promoter variants. We found a significant association between autism and a coding variant in the seizure-related gene SEZ6L2 (12/1106 autism vs. 3/1161 controls; p = 0.018). Sez6l2 expression in mouse embryos was restricted to the spinal cord and brain. SEZ6L2 expression in human fetal brain was highest in post-mitotic cortical layers, hippocampus, amygdala, and thalamus. Association analysis of SEZ6L2 in an independent sample set failed to replicate our initial findings.Conclusions/Significance
We have identified sequence variation in at least one candidate gene in 16p11.2 that may represent a novel genetic risk factor for autism. However, further studies are required to substantiate these preliminary findings. 相似文献923.
Molecular Evolution of the Two-Component System BvgAS Involved in Virulence Regulation in Bordetella
Julien Herrou Anne-Sophie Debrie Eve Willery Geneviève Renaud-Mongénie Camille Locht Frits Mooi Fran?oise Jacob-Dubuisson Rudy Antoine 《PloS one》2009,4(9)
The whooping cough agent Bordetella pertussis is closely related to Bordetella bronchiseptica, which is responsible for chronic respiratory infections in various mammals and is occasionally found in humans, and to Bordetella parapertussis, one lineage of which causes mild whooping cough in humans and the other ovine respiratory infections. All three species produce similar sets of virulence factors that are co-regulated by the two-component system BvgAS. We characterized the molecular diversity of BvgAS in Bordetella by sequencing the two genes from a large number of diverse isolates. The response regulator BvgA is virtually invariant, indicating strong functional constraints. In contrast, the multi-domain sensor kinase BvgS has evolved into two different types. The pertussis type is found in B. pertussis and in a lineage of essentially human-associated B. bronchiseptica, while the bronchiseptica type is associated with the majority of B. bronchiseptica and both ovine and human B. parapertussis. BvgS is monomorphic in B. pertussis, suggesting optimal adaptation or a recent population bottleneck. The degree of diversity of the bronchiseptica type BvgS is markedly different between domains, indicating distinct evolutionary pressures. Thus, absolute conservation of the putative solute-binding cavities of the two periplasmic Venus Fly Trap (VFT) domains suggests that common signals are perceived in all three species, while the external surfaces of these domains vary more extensively. Co-evolution of the surfaces of the two VFT domains in each type and domain swapping experiments indicate that signal transduction in the periplasmic region may be type-specific. The two distinct evolutionary solutions for BvgS confirm that B. pertussis has emerged from a specific B. bronchiseptica lineage. The invariant regions of BvgS point to essential parts for its molecular mechanism, while the variable regions may indicate adaptations to different lifestyles. The repertoire of BvgS sequences will pave the way for functional analyses of this prototypic system. 相似文献
924.
Holly G. Prigerson Mardi J. Horowitz Selby C. Jacobs Colin M. Parkes Mihaela Aslan Karl Goodkin Beverley Raphael Samuel J. Marwit Camille Wortman Robert A. Neimeyer George Bonanno Susan D. Block David Kissane Paul Boelen Andreas Maercker Brett T. Litz Jeffrey G. Johnson Michael B. First Paul K. Maciejewski 《PLoS medicine》2009,6(8)
Background
Bereavement is a universal experience, and its association with excess morbidity and mortality is well established. Nevertheless, grief becomes a serious health concern for a relative few. For such individuals, intense grief persists, is distressing and disabling, and may meet criteria as a distinct mental disorder. At present, grief is not recognized as a mental disorder in the DSM-IV or ICD-10. The goal of this study was to determine the psychometric validity of criteria for prolonged grief disorder (PGD) to enhance the detection and potential treatment of bereaved individuals at heightened risk of persistent distress and dysfunction.Methods and Findings
A total of 291 bereaved respondents were interviewed three times, grouped as 0–6, 6–12, and 12–24 mo post-loss. Item response theory (IRT) analyses derived the most informative, unbiased PGD symptoms. Combinatoric analyses identified the most sensitive and specific PGD algorithm that was then tested to evaluate its psychometric validity. Criteria require reactions to a significant loss that involve the experience of yearning (e.g., physical or emotional suffering as a result of the desired, but unfulfilled, reunion with the deceased) and at least five of the following nine symptoms experienced at least daily or to a disabling degree: feeling emotionally numb, stunned, or that life is meaningless; experiencing mistrust; bitterness over the loss; difficulty accepting the loss; identity confusion; avoidance of the reality of the loss; or difficulty moving on with life. Symptoms must be present at sufficiently high levels at least six mo from the death and be associated with functional impairment.Conclusions
The criteria set for PGD appear able to identify bereaved persons at heightened risk for enduring distress and dysfunction. The results support the psychometric validity of the criteria for PGD that we propose for inclusion in DSM-V and ICD-11. Please see later in the article for Editors'' Summary 相似文献925.
Anne-Laure Brochet Matthieu Guillemain Camille Lebarbenchon Géraldine Simon Hervé Fritz Andy J. Green François Renaud Frédéric Thomas Michel Gauthier-Clerc 《EcoHealth》2009,6(3):449-457
Waterbirds represent the major natural reservoir for low pathogenic (LP) avian influenza viruses (AIV). Among the wide diversity
of subtypes that have been described, two of them (H5 and H7) may become highly pathogenic (HP) after their introduction into
domestic bird populations and cause severe outbreaks, as is the case for HP H5N1 in South-Eastern Asia. Recent experimental
studies demonstrated that HP H5N1 AIV infection in ducks does not necessarily have significant pathological effects. These
results suggest that wild migratory ducks may asymptomatically carry HP AIV and potentially spread viruses over large geographical
distances. In this study, we investigated the potential spreading distance of HP AIV by common teal (Anas crecca), mallard (A. platyrhynchos), and Eurasian pochard (Aythya ferina). Based on capture-mark-recapture method, we characterized their wintering movements from a western Mediterranean wetland
(Camargue, South of France) and identified the potential distance and direction of virus dispersal. Such data may be crucial
in determining higher-risk areas in the case of HP AIV infection detection in this major wintering quarter, and may serve
as a valuable reference for virus outbreaks elsewhere. 相似文献
926.
A range of conformationally distinct functional states within the T quaternary state of hemoglobin are accessed and probed using a combination of mutagenesis and sol-gel encapsulation that greatly slow or eliminate the T --> R transition. Visible and UV resonance Raman spectroscopy are used to probe the proximal strain at the heme and the status of the alpha(1)beta(2) interface, respectively, whereas CO geminate and bimolecular recombination traces in conjunction with MEM (maximum entropy method) analysis of kinetic populations are used to identify functionally distinct T-state populations. The mutants used in this study are Hb(Nbeta102A) and the alpha99-alpha99 cross-linked derivative of Hb(Wbeta37E). The former mutant, which binds oxygen noncooperatively with very low affinity, is used to access low-affinity ligated T-state conformations, whereas the latter mutant is used to access the high-affinity end of the distribution of T-state conformations. A pattern emerges within the T state in which ligand reactivity increases as both the proximal strain and the alpha(1)beta(2) interface interactions are progressively lessened after ligand binding to the deoxy T-state species. The ligation and effector-dependent interplay between the heme environment and the stability of the Trp beta37 cluster in the hinge region of the alpha(1)beta(2) interface appears to determine the distribution of the ligated T-state species generated upon ligand binding. A qualitative model is presented, suggesting that different T quaternary structures modulate the stability of different alphabeta dimer conformations within the tetramer. 相似文献
927.
Maury B Martinand-Mari C Chambon JP Soulé J Degols G Sahuquet A Weill M Berthomieu A Fort P Mangeat P Baghdiguian S 《Developmental biology》2006,289(1):152-165
In Ciona intestinalis, the elimination of extra-embryonic test cells during early stage of development is delayed by a fertilization signal. Test cells undergo a caspase-dependent apoptosis event repressed by thyroxine (T4)-activated NF-kappaB. When apoptosis was experimentally blocked, the hatching stage was delayed. The incubation of unfertilized eggs with a 1-h-fertilized egg extract or purified T4 restored apoptosis in test cells at a similar timing than found in fertilized eggs. Ciona expresses specific genes forming a functional IkappaB/NF-kappaB pathway. One, Ci-p65, was transiently induced upon fertilization via T4 and found to exert its anti-apoptotic role in test cells nuclei as well as in a reconstituted cell system. Blocking NF-kappaB activity by dexamethasone-induced overexpression of Ci-IkappaB abrogated the repression of apoptosis in test cells. Overall, the data are consistent for defining a central coupling role of both T4 and NF-kappaB during early embryo development. 相似文献
928.
929.
A tryptophan-rich motif in the carboxyl terminus of the small envelope protein of hepatitis B virus is central to the assembly of hepatitis delta virus particles 总被引:1,自引:0,他引:1
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The small hepatitis B virus surface antigen (S-HBsAg) is capable of driving the assembly and secretion of hepatitis delta virus (HDV) particles by interacting with the HDV ribonucleoprotein (RNP). Previously, a specific domain of the S-HBsAg protein carboxyl terminus, including a tryptophan residue at position 196 (W196), was proven essential for HDV maturation (S. Jenna and C. Sureau, J. Virol. 73: 3351-3358, 1999). Mutation of W196 to phenylalanine (W196F) was permissive for HBV subviral particle (SVP) secretion but deleterious to HDV virion assembly. Here, the W196F S-HBsAg deficiency was assigned to a loss of its ability for interaction with the large HDV antigen (L-HDAg), a major component of the RNP. Because the overall S-HBsAg carboxyl terminus is particularly rich in tryptophan, an amino acid frequently involved in protein-protein interactions, site-directed mutagenesis was conducted to investigate the function of the S-HBsAg Trp-rich domain in HDV assembly. Single substitutions of tryptophan between positions 163 and 201 with alanine or phenylalanine were tolerated for SVP secretion, but those affecting W196, W199, and W201 were detrimental for HDV assembly. This was proven to result from a reduced capacity of the mutants for interaction with L-HDAg. In addition, a W196S S-HBsAg mutant, which has been described in HBV strains that arose in a few cases of lamivudine-treated HBV-infected patients, was deficient for HDV assembly as a consequence of its impaired capacity for interacting with L-HDAg. Interestingly, the fact that even the most conservative substitution of phenylalanine for tryptophan at positions 196, 199, or 201 was sufficient to ablate interaction of S-HBsAg with L-HDAg suggests that W196, W199, and W201 are located at a binding interface that is central to HDV maturation. 相似文献
930.
Camille Stegen Yordanka Yakova Daniel Henaff Julien Nadjar Johanne Duron Roger Lippé 《PloS one》2013,8(1)
Viruses are strictly dependent on cells to propagate and many incorporate host proteins in their viral particles, but the significance of this incorporation is poorly understood. Recently, we performed the first comprehensive characterization of the mature herpes simplex virus type 1 (HSV-1) in which up to 49 distinct cellular proteins were identified by mass spectrometry. In the present study, we sought to identify if these cellular factors are relevant for the HSV-1 life cycle. To this end, we performed a small interfering RNA functional screen and found that 15 of these host proteins altered HSV-1 proliferation in cell culture, without any significant effect on cell viability. Moreover, the siRNA used had no negative consequences for Adenovirus type 5 propagation (with one exception) indicating that the modulation was specific for HSV-1 and not merely due to unhealthy cells. The positive host proteins include several Rab GTPases and other intracellular transport components as well as proteins involved in signal transduction, gene regulation and immunity. Remarkably, in most cases when virions were depleted for one of the above proteins, they replicated more poorly in subsequent infections in wild type cells. This highlights for the first time that both the cellular and virion-associated pools of many of these proteins actively contribute to viral propagation. Altogether, these findings underscore the power and biological relevance of combining proteomics and RNA interference to identify novel host-pathogen interactions. 相似文献