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Stefan Thiem Moritz F. Eissmann Emma Stuart Joachim Elzer Anna Jonas Michael Buchert Matthias Ernst 《Genesis (New York, N.Y. : 2000)》2016,54(12):626-635
Temporal and spatial regulation of genes mediated by tissue‐specific promoters and conditional gene expression systems provide a powerful tool to study gene function in health, disease, and during development. Although transgenic mice expressing the Cre recombinase in the gastric epithelium have been reported, there is a lack of models that allow inducible and reversible gene modification in the stomach. Here, we exploited the gastrointestinal epithelium‐specific expression pattern of the three trefoil factor (Tff) genes and bacterial artificial chromosome transgenesis to generate a novel mouse strain that expresses the CreERT2 recombinase and the reverse tetracycline transactivator (rtTA). The Tg(Tff1‐CreERT2;Tff2‐rtTA;Tff3‐Luc) strain confers tamoxifen‐inducible irreversible somatic recombination and allows simultaneous doxycycline‐dependent reversible gene activation in the gastric epithelium of developing and adult mice. This strain also confers luciferase activity to the intestinal epithelium to enable in vivo bioluminescence imaging. Using fluorescent reporters as conditional alleles, we show Tff1‐CreERT2 and Tff2‐rtTA transgene activity in a partially overlapping subset of long‐term regenerating gastric stem/progenitor cells. Therefore, the Tg(Tff1‐CreERT2;Tff2‐rtTA;Tff3‐Luc) strain can confer intermittent transgene expression to gastric epithelial cells that have undergone previous gene modification, and may be suitable to genetically model therapeutic intervention during development, tumorigenesis, and other genetically tractable diseases. Birth Defects Research (Part A) 106:626–635, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
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Emma E. M. Knowles Samuel R. Mathias Josephine Mollon Amanda Rodrigue Marinka M. G. Koenis Thomas D. Dyer Harald H. H. Goring Joanne E. Curran Rene L. Olvera Ravi Duggirala Laura Almasy John Blangero David C. Glahn 《Genes, Brain & Behavior》2019,18(4)
Processing speed is a psychological construct that refers to the speed with which an individual can perform any cognitive operation. Processing speed correlates strongly with general cognitive ability, declines sharply with age and is impaired across a number of neurological and psychiatric disorders. Thus, identifying genes that influence processing speed will likely improve understanding of the genetics of intelligence, biological aging and the etiologies of numerous disorders. Previous genetics studies of processing speed have relied on simple phenotypes (eg, mean reaction time) derived from single tasks. This strategy assumes, erroneously, that processing speed is a unitary construct. In the present study, we aimed to characterize the genetic architecture of processing speed by using a multidimensional model applied to a battery of cognitive tasks. Linkage and QTL‐specific association analyses were performed on the factors from this model. The randomly ascertained sample comprised 1291 Mexican‐American individuals from extended pedigrees. We found that performance on all three distinct processing‐speed factors (Psychomotor Speed; Sequencing and Shifting and Verbal Fluency) were moderately and significantly heritable. We identified a genome‐wide significant quantitative trait locus (QTL) on chromosome 3q23 for Psychomotor Speed (LOD = 4.83). Within this locus, we identified a plausible and interesting candidate gene for Psychomotor Speed (Z = 2.90, P = 1.86 × 10?03). 相似文献
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Emma Sherratt Felicity J. Coutts Arne R. Rasmussen Kate L. Sanders 《Evolution & development》2019,21(3):135-144
Snakes exhibit a diverse array of body shapes despite their characteristically simplified morphology. The most extreme shape changes along the precloacal axis are seen in fully aquatic sea snakes (Hydrophiinae): “microcephalic” sea snakes have tiny heads and dramatically reduced forebody girths that can be less than a third of the hindbody girth. This morphology has evolved repeatedly in sea snakes that specialize in hunting eels in burrows, but its developmental basis has not previously been examined. Here, we infer the developmental mechanisms underlying body shape changes in sea snakes by examining evolutionary patterns of changes in vertebral number and postnatal ontogenetic growth. Our results show that microcephalic species develop their characteristic shape via changes in both the embryonic and postnatal stages. Ontogenetic changes cause the hindbodies of microcephalic species to reach greater sizes relative to their forebodies in adulthood, suggesting heterochronic shifts that may be linked to homeotic effects (axial regionalization). However, microcephalic species also have greater numbers of vertebrae, especially in their forebodies, indicating that somitogenetic effects also contribute to evolutionary changes in body shape. Our findings highlight sea snakes as an excellent system for studying the development of segment number and regional identity in the snake precloacal axial skeleton. 相似文献
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Gemma V. White Emma V. Edgar Duncan S. Holmes Xiao Qing Lewell John Liddle Oxana Polyakova Kathrine J. Smith James H. Thorpe Ann L. Walker Yichen Wang Robert J. Young Alain Hovnanian 《Bioorganic & medicinal chemistry letters》2019,29(6):821-825
Netherton syndrome (NS) is a rare and debilitating severe autosomal recessive genetic skin disease with high mortality rates particularly in neonates. NS is caused by loss-of-function SPINK5 mutations leading to unregulated kallikrein 5 (KLK5) and kallikrein 7 (KLK7) activity. Furthermore, KLK5 inhibition has been proposed as a potential therapeutic treatment for NS. Identification of potent and selective KLK5 inhibitors would enable further exploration of the disease biology and could ultimately lead to a treatment for NS. This publication describes how fragmentation of known trypsin-like serine protease (TLSP) inhibitors resulted in the identification of a series of phenolic amidine-based KLK5 inhibitors 1. X-ray crystallography was used to find alternatives to the phenol interaction leading to identification of carbonyl analogues such as lactam 13 and benzimidazole 15. These reversible inhibitors, with selectivity over KLK1 (10–100 fold), provided novel starting points for the guided growth towards suitable tool molecules for the exploration of KLK5 biology. 相似文献
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Emma Strother 《Arts Education Policy Review》2019,120(1):1-10
An expansive movement comprised of UN Millennium Development Goals, international banks, and hundreds of programs worldwide promotes access to the arts as a creative means of social change. Often grounded in cognitive science and inspired by the model of youth orchestras in Venezuela known as El Sistema, this movement contends that arts training—which can foster empathy, collaboration, academic achievement, and self-esteem—helps alleviate poverty and combat inequality. In contrast to the majority of the literature on public arts programs—impact studies that often assume arts engagement creates social change through universal mechanisms—this study examines the influence of political economy on the implementation of public arts programs. Through a comparative study of youth orchestras with social inclusion goals in Venezuela (1974–2015) and Chile (1964–2015), the scope and intensity of government control, social welfare policy, and competition for public funds are found to shape public arts programs' social goals, daily operations, definitions of success, and impact study procedures. Therefore, scholars, practitioners, and policy makers must reexamine their understanding of arts programs as a development model. Future global efforts to combat inequality should avoid over-standardization. This article offers a new Arts for Social Change Context Framework that places input variables at the center of analysis, with policy implications. 相似文献