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991.
Emilie Sundqvist Dorothea Buck Clemens Warnke Eva Albrecht Christian Gieger Mohsen Khademi Izaura Lima Bomfim Anna Fogdell-Hahn Jenny Link Lars Alfredsson Helle Bach S?ndergaard Jan Hillert International Multiple Sclerosis Genetics Consortium Annette B. Oturai Bernhard Hemme Ingrid Kockum Tomas Olsson 《PLoS pathogens》2014,10(4)
JC polyomavirus (JCV) carriers with a compromised immune system, such as in HIV, or subjects on immune-modulating therapies, such as anti VLA-4 therapy may develop progressive multifocal leukoencephalopathy (PML) which is a lytic infection of oligodendrocytes in the brain. Serum antibodies to JCV mark infection occur only in 50–60% of infected individuals, and high JCV-antibody titers seem to increase the risk of developing PML. We here investigated the role of human leukocyte antigen (HLA), instrumental in immune defense in JCV antibody response. Anti-JCV antibody status, as a surrogate for JCV infection, were compared to HLA class I and II alleles in 1621 Scandinavian persons with MS and 1064 population-based Swedish controls and associations were replicated in 718 German persons with MS. HLA-alleles were determined by SNP imputation, sequence specific (SSP) kits and a reverse PCR sequence-specific oligonucleotide (PCR-SSO) method. An initial GWAS screen displayed a strong HLA class II region signal. The HLA-DRB1*15 haplotype was strongly negatively associated to JCV sero-status in Scandinavian MS cases (OR = 0.42, p = 7×10−15) and controls (OR = 0.53, p = 2×10−5). In contrast, the DQB1*06:03 haplotype was positively associated with JCV sero-status, in Scandinavian MS cases (OR = 1.63, p = 0.006), and controls (OR = 2.69, p = 1×10−5). The German dataset confirmed these findings (OR = 0.54, p = 1×10−4 and OR = 1.58, p = 0.03 respectively for these haplotypes). HLA class II restricted immune responses, and hence CD4+ T cell immunity is pivotal for JCV infection control. Alleles within the HLA-DR1*15 haplotype are associated with a protective effect on JCV infection. Alleles within the DQB1*06:03 haplotype show an opposite association. These associations between JC virus antibody response and human leucocyte antigens supports the notion that CD4+ T cells are crucial in the immune defence to JCV and lays the ground for risk stratification for PML and development of therapy and prevention. 相似文献
992.
Simon Cauchemez Neil M. Ferguson Annette Fox Le Quynh Mai Le Thi Thanh Pham Quang Thai Dang Dinh Thoang Tran Nhu Duong Le Nguyen Minh Hoa Nguyen Tran Hien Peter Horby 《PLoS pathogens》2014,10(8)
To guide control policies, it is important that the determinants of influenza transmission are fully characterized. Such assessment is complex because the risk of influenza infection is multifaceted and depends both on immunity acquired naturally or via vaccination and on the individual level of exposure to influenza in the community or in the household. Here, we analyse a large household cohort study conducted in 2007–2010 in Vietnam using innovative statistical methods to ascertain in an integrative framework the relative contribution of variables that influence the transmission of seasonal (H1N1, H3N2, B) and pandemic H1N1pdm09 influenza. Influenza infection was diagnosed by haemagglutination-inhibition (HI) antibody assay of paired serum samples. We used a Bayesian data augmentation Markov chain Monte Carlo strategy based on digraphs to reconstruct unobserved chains of transmission in households and estimate transmission parameters. The probability of transmission from an infected individual to another household member was 8% (95% CI, 6%, 10%) on average, and varied with pre-season titers, age and household size. Within households of size 3, the probability of transmission from an infected member to a child with low pre-season HI antibody titers was 27% (95% CI 21%–35%). High pre-season HI titers were protective against infection, with a reduction in the hazard of infection of 59% (95% CI, 44%–71%) and 87% (95% CI, 70%–96%) for intermediate (1∶20–1∶40) and high (≥1∶80) HI titers, respectively. Even after correcting for pre-season HI titers, adults had half the infection risk of children. Twenty six percent (95% CI: 21%, 30%) of infections may be attributed to household transmission. Our results highlight the importance of integrated analysis by influenza sub-type, age and pre-season HI titers in order to infer influenza transmission risks in and outside of the household. 相似文献
993.
Eva Rothmeier Gudrun Pfaffinger Christine Hoffmann Christopher F. Harrison Heinrich Grabmayr Urska Repnik Mandy Hannemann Stefan W?lke Andreas Bausch Gareth Griffiths Annette Müller-Taubenberger Aymelt Itzen Hubert Hilbi 《PLoS pathogens》2013,9(9)
The causative agent of Legionnaires'' disease, Legionella pneumophila, uses the Icm/Dot type IV secretion system (T4SS) to form in phagocytes a distinct “Legionella-containing vacuole” (LCV), which intercepts endosomal and secretory vesicle trafficking. Proteomics revealed the presence of the small GTPase Ran and its effector RanBP1 on purified LCVs. Here we validate that Ran and RanBP1 localize to LCVs and promote intracellular growth of L. pneumophila. Moreover, the L. pneumophila protein LegG1, which contains putative RCC1 Ran guanine nucleotide exchange factor (GEF) domains, accumulates on LCVs in an Icm/Dot-dependent manner. L. pneumophila wild-type bacteria, but not strains lacking LegG1 or a functional Icm/Dot T4SS, activate Ran on LCVs, while purified LegG1 produces active Ran(GTP) in cell lysates. L. pneumophila lacking legG1 is compromised for intracellular growth in macrophages and amoebae, yet is as cytotoxic as the wild-type strain. A downstream effect of LegG1 is to stabilize microtubules, as revealed by conventional and stimulated emission depletion (STED) fluorescence microscopy, subcellular fractionation and Western blot, or by microbial microinjection through the T3SS of a Yersinia strain lacking endogenous effectors. Real-time fluorescence imaging indicates that LCVs harboring wild-type L. pneumophila rapidly move along microtubules, while LCVs harboring ΔlegG1 mutant bacteria are stalled. Together, our results demonstrate that Ran activation and RanBP1 promote LCV formation, and the Icm/Dot substrate LegG1 functions as a bacterial Ran activator, which localizes to LCVs and promotes microtubule stabilization, LCV motility as well as intracellular replication of L. pneumophila. 相似文献
994.
Merel A. W. Oortveld Shivakumar Keerthikumar Martin Oti Bonnie Nijhof Ana Clara Fernandes Korinna Kochinke Anna Castells-Nobau Eva van Engelen Thijs Ellenkamp Lilian Eshuis Anne Galy Hans van Bokhoven Bianca Habermann Han G. Brunner Christiane Zweier Patrik Verstreken Martijn A. Huynen Annette Schenck 《PLoS genetics》2013,9(10)
Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules. 相似文献
995.
Alan Gray Peter E. Levy Mark D. A. Cooper Timothy Jones Jenny Gaiawyn Sarah R. Leeson Susan E. Ward Kerry J. Dinsmore Julia Drewer Lucy J. Sheppard Nick J. Ostle Chris D. Evans Annette Burden Piotr Zieliński 《Global Change Biology》2013,19(4):1141-1150
Previous studies have shown a correspondence between the abundance of particular plant species and methane flux. Here, we apply multivariate analyses, and weighted averaging, to assess the suitability of vegetation composition as a predictor of methane flux. We developed a functional classification of the vegetation, in terms of a number of plant traits expected to influence methane production and transport, and compared this with a purely taxonomic classification at species level and higher. We applied weighted averaging and indirect and direct ordination approaches to six sites in the United Kingdom, and found good relationships between methane flux and vegetation composition (classified both taxonomically and functionally). Plant species and functional groups also showed meaningful responses to management and experimental treatments. In addition to the United Kingdom, we applied the functional group classification across different geographical regions (Canada and the Netherlands) to assess the generality of the method. Again, the relationship appeared good at the site level, suggesting some general applicability of the functional classification. The method seems to have the potential for incorporation into large‐scale (national) greenhouse gas accounting programmes (in relation to peatland condition/management) using vegetation mapping schemes. The results presented here strongly suggest that robust predictive models can be derived using plant species data (for use in national‐scale studies). For trans‐national‐scale studies, where the taxonomic assemblage of vegetation differs widely between study sites, a functional classification of plant species data provides an appropriate basis for predictive models of methane flux. 相似文献
996.
Shifeng Cheng Erik van den Bergh Peng Zeng Xiao Zhong Jiajia Xu Xin Liu Johannes Hofberger Suzanne de Bruijn Amey S. Bhide Canan Kuelahoglu Chao Bian Jing Chen Guangyi Fan Kerstin Kaufmann Jocelyn C. Hall Annette Becker Andrea Br?utigam Andreas P.M. Weber Chengcheng Shi Zhijun Zheng Wujiao Li Mingju Lv Yimin Tao Junyi Wang Hongfeng Zou Zhiwu Quan Julian M. Hibberd Gengyun Zhang Xin-Guang Zhu Xun Xu M. Eric Schranz 《The Plant cell》2013,25(8):2813-2830
The Brassicaceae, including Arabidopsis thaliana and Brassica crops, is unmatched among plants in its wealth of genomic and functional molecular data and has long served as a model for understanding gene, genome, and trait evolution. However, genome information from a phylogenetic outgroup that is essential for inferring directionality of evolutionary change has been lacking. We therefore sequenced the genome of the spider flower (Tarenaya hassleriana) from the Brassicaceae sister family, the Cleomaceae. By comparative analysis of the two lineages, we show that genome evolution following ancient polyploidy and gene duplication events affect reproductively important traits. We found an ancient genome triplication in Tarenaya (Th-α) that is independent of the Brassicaceae-specific duplication (At-α) and nested Brassica (Br-α) triplication. To showcase the potential of sister lineage genome analysis, we investigated the state of floral developmental genes and show Brassica retains twice as many floral MADS (for MINICHROMOSOME MAINTENANCE1, AGAMOUS, DEFICIENS and SERUM RESPONSE FACTOR) genes as Tarenaya that likely contribute to morphological diversity in Brassica. We also performed synteny analysis of gene families that confer self-incompatibility in Brassicaceae and found that the critical SERINE RECEPTOR KINASE receptor gene is derived from a lineage-specific tandem duplication. The T. hassleriana genome will facilitate future research toward elucidating the evolutionary history of Brassicaceae genomes. 相似文献
997.
Matthias Lange Svetlana Orashakova Sabrina Lange Rainer Melzer Günter Thei?en David R. Smyth Annette Becker 《The Plant cell》2013,25(2):438-453
The products of B class floral homeotic genes specify petal and stamen identity, and loss of B function results in homeotic conversions of petals into sepals and stamens into carpels. Here, we describe the molecular characterization of seirena-1 (sei-1), a mutant from the basal eudicot California poppy (Eschscholzia californica) that shows homeotic changes characteristic of floral homeotic B class mutants. SEI has been previously described as EScaGLO, one of four B class–related MADS box genes in California poppy. The C terminus of SEI, including the highly conserved PI motif, is truncated in sei-1 proteins. Nevertheless, like the wild-type SEI protein, the sei-1 mutant protein is able to bind CArG-boxes and can form homodimers, heterodimers, and several higher order complexes with other MADS domain proteins. However, unlike the wild type, the mutant protein is not able to mediate higher order complexes consisting of specific B, C, and putative E class related proteins likely involved in specifying stamen identity. Within the PI motif, five highly conserved N-terminal amino acids are specifically required for this interaction. Several families lack this short conserved sequence, including the Brassicaceae, and we propose an evolutionary scenario to explain these functional differences. 相似文献
998.
999.
George M. Savva Annette Pachnio Baksho Kaul Kevin Morgan Felicia A. Huppert Carol Brayne Paul A. H. Moss The Medical Research Council Cognitive Function Ageing Study 《Aging cell》2013,12(3):381-387
Cytomegalovirus (CMV) is a common herpesvirus infection and stimulates the expansion of very large numbers of CMV‐specific T cells that reduce the CD4/CD8 ratio and suppress the number of naïve T cells. CMV infection has been associated with frailty and impaired survival. We investigated the correlates of CMV and the impact of the CMV infection on mortality within a cohort of 511 individuals aged at least 65 years who were followed up for 18 years. The mean age of the participants was 74 years of which 70% were CMV‐seropositive. CMV was strongly linked to socio‐economic status, and CMV infection increased the annual mortality rate by 42% (Hazard ratio = 1.42, 95% CI: 1.11–1.76 after adjusting for age, sex and baseline socio‐economic and health variables) corresponding to 3.7 years lower life expectancy from age 65. Infection was associated with a near doubling of cardiovascular deaths, whereas there was no increase in mortality from other causes. These results show that CMV infection markedly increases the mortality rate in healthy older individuals due to an excess of vascular deaths. These findings may have significant implications for the study of immune senescence and if confirmed more generally could have important implications for measures to optimize the health of the elderly. 相似文献
1000.