全文获取类型
收费全文 | 895篇 |
免费 | 93篇 |
专业分类
988篇 |
出版年
2022年 | 9篇 |
2021年 | 9篇 |
2018年 | 12篇 |
2017年 | 12篇 |
2016年 | 16篇 |
2015年 | 29篇 |
2014年 | 34篇 |
2013年 | 45篇 |
2012年 | 60篇 |
2011年 | 45篇 |
2010年 | 34篇 |
2009年 | 30篇 |
2008年 | 41篇 |
2007年 | 33篇 |
2006年 | 35篇 |
2005年 | 33篇 |
2004年 | 27篇 |
2003年 | 37篇 |
2002年 | 25篇 |
2001年 | 24篇 |
2000年 | 29篇 |
1999年 | 26篇 |
1998年 | 14篇 |
1997年 | 17篇 |
1996年 | 7篇 |
1995年 | 10篇 |
1994年 | 12篇 |
1993年 | 7篇 |
1992年 | 19篇 |
1991年 | 15篇 |
1990年 | 20篇 |
1989年 | 17篇 |
1988年 | 21篇 |
1987年 | 20篇 |
1986年 | 10篇 |
1985年 | 6篇 |
1984年 | 15篇 |
1983年 | 7篇 |
1982年 | 9篇 |
1981年 | 5篇 |
1980年 | 7篇 |
1979年 | 10篇 |
1977年 | 6篇 |
1976年 | 8篇 |
1975年 | 7篇 |
1974年 | 5篇 |
1973年 | 6篇 |
1972年 | 7篇 |
1971年 | 6篇 |
1970年 | 9篇 |
排序方式: 共有988条查询结果,搜索用时 15 毫秒
891.
Congenital amusia (commonly known as “tone deafness”) is a lifelong impairment of music perception that affects 4% of the population. To estimate whether congenital amusia can be genetically transmitted, its prevalence was quantified by direct auditory testing of 71 members of 9 large families of amusic probands, as well as of 75 members of 10 control families. The results confirm that congenital amusia is expressed by a deficit in processing musical pitch but not musical time and also show that the pitch disorder has a hereditary component. In amusic families, 39% of first-degree relatives have the same cognitive disorder, whereas only 3% have it in the control families. The identification of multiplex families with a high relative risk of experiencing a musical pitch deficit (λs=10.8; 95% confidence interval 8–13.5) enables the mapping of genetic loci for hereditary amusia. 相似文献
892.
The new field of functional glycomics encompasses information about both glycan structure and recognition by carbohydrate-binding proteins (CBPs) and is now being explored through glycan array technology. Glycan array construction, however, is limited by the complexity of efficiently generating derivatives of free, reducing glycans with primary amines for conjugation. Here we describe a straightforward method to derivatize glycans with 2,6-diaminopyridine (DAP) to generate fluorescently labeled glycans (glycan-DAP conjugates or GDAPs) that contain a primary amine for further conjugation. We converted a wide variety of glycans, including milk sugars, N-glycans, glycosaminoglycans and chitin-derived glycans, to GDAPs, as verified by HPLC and mass spectrometry. We covalently conjugated GDAPs to N-hydroxysuccinimide (NHS)-activated glass slides, maleimide-activated protein, carboxylated microspheres and NHS-biotin to provide quantifiable fluorescent derivatives. All types of conjugated glycans were well-recognized by appropriate CBPs. Thus, GDAP derivatives provide versatile new tools for biologists to quantify and covalently capture minute quantities of glycans for exploring their structures and functions and generating new glycan arrays from naturally occurring glycans. 相似文献
893.
Kyle JL Cummings CA Parker CT Quiñones B Vatta P Newton E Huynh S Swimley M Degoricija L Barker M Fontanoz S Nguyen K Patel R Fang R Tebbs R Petrauskene O Furtado M Mandrell RE 《Journal of bacteriology》2012,194(8):1885-1896
Enteropathogenic Escherichia coli (EPEC) continues to be a leading cause of mortality and morbidity in children around the world. Two EPEC genomes have been fully sequenced: those of EPEC O127:H6 strain E2348/69 (United Kingdom, 1969) and EPEC O55:H7 strain CB9615 (Germany, 2003). The O55:H7 serotype is a recent precursor to the virulent enterohemorrhagic E. coli O157:H7. To explore the diversity of O55:H7 and better understand the clonal evolution of O157:H7, we fully sequenced EPEC O55:H7 strain RM12579 (California, 1974), which was collected 1 year before the first U.S. isolate of O157:H7 was identified in California. Phage-related sequences accounted for nearly all differences between the two O55:H7 strains. Additionally, O55:H7 and O157:H7 strains were tested for the presence and insertion sites of Shiga toxin gene (stx)-containing bacteriophages. Analysis of non-phage-associated genes supported core elements of previous O157:H7 stepwise evolutionary models, whereas phage composition and insertion analyses suggested a key refinement. Specifically, the placement and presence of lambda-like bacteriophages (including those containing stx) should not be considered stable evolutionary markers or be required in placing O55:H7 and O157:H7 strains within the stepwise evolutionary models. Additionally, we suggest that a 10.9-kb region (block 172) previously believed unique to O55:H7 strains can be used to identify early O157:H7 strains. Finally, we defined two subsets of O55:H7 strains that share an as-yet-unobserved or extinct common ancestor with O157:H7 strains. Exploration of O55:H7 diversity improved our understanding of the evolution of E. coli O157:H7 and suggested a key revision to accommodate existing and future configurations of stx-containing bacteriophages into current models. 相似文献
894.
A major limitation in studying the structures and functions of glycans in glycosphingolipids is the difficulty in releasing free glycans for analysis and derivatization. Here we show that reducing glycans can be released nonenzymatically from glycosphingolipids after a brief treatment with ozone followed by heating in neutral aqueous buffer (pHs 6.0-8.0). The released free reducing glycans are then available for glycomic analyses, including fluorescent labeling, permethylation, and mass spectrometry. This procedure is simple and highly efficient, with no base-catalyzed "peeling" reaction by-products observed. 相似文献
895.
Background
Here we present two new computer tools, PREMIM and EMIM, for the estimation of parental and child genetic effects, based on genotype data from a variety of different child-parent configurations. PREMIM allows the extraction of child-parent genotype data from standard-format pedigree data files, while EMIM uses the extracted genotype data to perform subsequent statistical analysis. The use of genotype data from the parents as well as from the child in question allows the estimation of complex genetic effects such as maternal genotype effects, maternal-foetal interactions and parent-of-origin (imprinting) effects. These effects are estimated by EMIM, incorporating chosen assumptions such as Hardy-Weinberg equilibrium or exchangeability of parental matings as required.Results
In application to simulated data, we show that the inference provided by EMIM is essentially equivalent to that provided by alternative (competing) software packages such as MENDEL and LEM. However, PREMIM and EMIM (used in combination) considerably outperform MENDEL and LEM in terms of speed and ease of execution.Conclusions
Together, EMIM and PREMIM provide easy-to-use command-line tools for the analysis of pedigree data, giving unbiased estimates of parental and child genotype relative risks. 相似文献896.
ABSTRACT: BACKGROUND: The dynamics of viral infections have been studied extensively in a variety of settings, both experimentally and with mathematical models. The majori-ty of mathematical models assumes that only one virus can infect a given cell at a time. It is, however, clear that especially in the context of high viral load, cells can become infected with multiple copies of a virus, a process called coinfection. This has been best demonstrated experimentally for human immunodeficiency virus (HIV), although it is thought to be equally relevant for a number of other viral infections. In a previously explored mathematical model, the viral output from an infected cell does not depend on the number of viruses that reside in the cell, i.e. viral replication is limited by cellular rather than viral factors. In this case, basic virus dynamics properties are not altered by coinfection. Results: Here, we explore the alternative assumption that multiply infected cells are characterized by an increased burst size and find that this can fundamentally alter model predictions. Under this scenario, establishment of infection may not be solely determined by the basic reproductive ratio of the virus, but can depend on the initial virus load. Upon infection, the virus population need not follow straight exponential growth. Instead, the exponential rate of growth can increase over time as virus load becomes larger. Moreover, the model suggests that the ability of anti-viral drugs to suppress the virus population can depend on the virus load upon initiation of therapy. This is because more coinfected cells, which produce more virus, are present at higher virus loads. Hence, the degree of drug resistance is not only determined by the viral genotype, but also by the prevalence of coinfected cells. Conclusions: Our work shows how an increased burst size in multiply infected cells can alter basic infection dynamics. This forms the basis for future experimental testing of model assumptions and predictions that can distinguish between the different scenarios. 相似文献
897.
Cummings DE 《Nature medicine》2012,18(5):656-658
Clinicians note that bariatric operations can dramatically resolve type 2 diabetes, often before and out of proportion to postoperative weight loss. Now two randomized controlled trials formally show superior results from surgical compared with medical diabetes care, including among only mildly obese patients. The concept of 'metabolic surgery' to treat diabetes has taken a big step forward. 相似文献
898.
Bhave G Cummings CF Vanacore RM Kumagai-Cresse C Ero-Tolliver IA Rafi M Kang JS Pedchenko V Fessler LI Fessler JH Hudson BG 《Nature chemical biology》2012,8(9):784-790
Collagen IV comprises the predominant protein network of basement membranes, a specialized extracellular matrix, which underlie epithelia and endothelia. These networks assemble through oligomerization and covalent crosslinking to endow mechanical strength and shape cell behavior through interactions with cell-surface receptors. A recently discovered sulfilimine (S=N) bond between a methionine sulfur and hydroxylysine nitrogen reinforces the collagen IV network. We demonstrate that peroxidasin, an enzyme found in basement membranes, catalyzes formation of the sulfilimine bond. Drosophila peroxidasin mutants have disorganized collagen IV networks and torn visceral muscle basement membranes, pointing to a critical role for the enzyme in tissue biogenesis. Peroxidasin generates hypohalous acids as reaction intermediates, suggesting a paradoxically anabolic role for these usually destructive oxidants. This work highlights sulfilimine bond formation as what is to our knowledge the first known physiologic function for peroxidasin, a role for hypohalous oxidants in tissue biogenesis, and a possible role for peroxidasin in inflammatory diseases. 相似文献
899.
WHO-VMI Dengue Vaccine Modeling Group Beatty M Boni MF Brown S Buathong R Burke D Coudeville L Cummings DA Edelman R Farrar J Focks DA Gomes MG Guignard A Halstead S Hombach J Knerer G Koelle K Lam FC Lang J Longini I Medlock J Namgyal P Powell M Recker M Rohani P Standaert B Struchiner C Teyssou R Wearing H 《PLoS neglected tropical diseases》2012,6(3):e1450
900.
Courtenay MD Gilbert JR Jiang L Cummings AC Gallins PJ Caywood L Reinhart-Mercer L Fuzzell D Knebusch C Laux R McCauley JL Jackson CE Pericak-Vance MA Haines JL Scott WK 《Human genetics》2012,131(2):201-208
Avoiding disease, maintaining physical and cognitive function, and continued social engagement in long-lived individuals describe successful aging (SA). Mitochondrial lineages described by patterns of common genetic variants (??haplogroups??) have been associated with increased longevity in different populations. We investigated the influence of mitochondrial haplogroups on SA in an Amish community sample. Cognitively intact volunteers aged ??80?years (n?=?261) were enrolled in a door-to-door survey of Amish communities in Indiana and Ohio. Individuals scoring in the top third for lower extremity function, needing little assistance with self-care tasks, having no depression symptoms, and expressing high life satisfaction were considered SA (n?=?74). The remainder (n?=?187) were retained as controls. These individuals descend from 51 matrilines in a single 13-generation pedigree. Mitochondrial haplogroups were assigned using the ten mitochondrial single nucleotide polymorphisms (mtSNPs) defining the nine most common European haplogroups. An additional 17 mtSNPs from a genome-wide association panel were also investigated. Associations between haplogroups, mtSNPs, and SA were determined by logistic regression models accounting for sex, age, body mass index, and matriline via generalized estimating equations. SA cases were more likely to carry Haplogroup X (OR?=?7.56, p?=?0.0015), and less likely to carry Haplogroup J (OR?=?0.40, p?=?0.0003). Our results represent a novel association of Haplogroup X with SA and suggest that variants in the mitochondrial genome may promote maintenance of both physical and cognitive function in older adults. 相似文献