全文获取类型
收费全文 | 3232篇 |
免费 | 283篇 |
出版年
2022年 | 9篇 |
2021年 | 33篇 |
2020年 | 39篇 |
2019年 | 46篇 |
2018年 | 57篇 |
2017年 | 53篇 |
2016年 | 61篇 |
2015年 | 135篇 |
2014年 | 144篇 |
2013年 | 182篇 |
2012年 | 207篇 |
2011年 | 219篇 |
2010年 | 150篇 |
2009年 | 138篇 |
2008年 | 169篇 |
2007年 | 198篇 |
2006年 | 186篇 |
2005年 | 171篇 |
2004年 | 216篇 |
2003年 | 167篇 |
2002年 | 135篇 |
2001年 | 44篇 |
2000年 | 32篇 |
1999年 | 43篇 |
1998年 | 52篇 |
1997年 | 31篇 |
1996年 | 29篇 |
1995年 | 19篇 |
1994年 | 36篇 |
1993年 | 31篇 |
1992年 | 25篇 |
1991年 | 27篇 |
1990年 | 27篇 |
1989年 | 25篇 |
1988年 | 26篇 |
1987年 | 40篇 |
1986年 | 25篇 |
1985年 | 28篇 |
1984年 | 19篇 |
1983年 | 23篇 |
1982年 | 17篇 |
1981年 | 16篇 |
1980年 | 10篇 |
1979年 | 17篇 |
1978年 | 17篇 |
1977年 | 9篇 |
1976年 | 13篇 |
1975年 | 13篇 |
1974年 | 14篇 |
1973年 | 18篇 |
排序方式: 共有3515条查询结果,搜索用时 15 毫秒
1.
Philipp Rausch Natalie Steck Abdulhadi Suwandi Janice A. Seidel Sven Künzel Kirandeep Bhullar Marijana Basic Andre Bleich Jill M. Johnsen Bruce A. Vallance John F. Baines Guntram A. Grassl 《PLoS pathogens》2015,11(7)
Glycans play important roles in host-microbe interactions. Tissue-specific expression patterns of the blood group glycosyltransferase β-1,4-N-acetylgalactosaminyltransferase 2 (B4galnt2) are variable in wild mouse populations, and loss of B4galnt2 expression is associated with altered intestinal microbiota. We hypothesized that variation in B4galnt2 expression alters susceptibility to intestinal pathogens. To test this, we challenged mice genetically engineered to express different B4galnt2 tissue-specific patterns with a Salmonella Typhimurium infection model. We found B4galnt2 intestinal expression was strongly associated with bacterial community composition and increased Salmonella susceptibility as evidenced by increased intestinal inflammatory cytokines and infiltrating immune cells. Fecal transfer experiments demonstrated a crucial role of the B4galnt2-dependent microbiota in conferring susceptibility to intestinal inflammation, while epithelial B4galnt2 expression facilitated epithelial invasion of S. Typhimurium. These data support a critical role for B4galnt2 in gastrointestinal infections. We speculate that B4galnt2-specific differences in host susceptibility to intestinal pathogens underlie the strong signatures of balancing selection observed at the B4galnt2 locus in wild mouse populations. 相似文献
2.
Understanding the processes underlying speciation has long been a challenge to evolutionary biologists. This spurs from difficulties teasing apart the various mechanisms that contribute to the evolution of barriers to reproduction. The study by Rafati et al. ( 2018 ) in this issue of Molecular Ecology combines spatially explicit whole‐genome resequencing with evaluation of differential gene expression across individuals with mixed ancestry to associate the genomic architecture of reproductive barriers with expression of reproductive incompatibilities. In a natural hybrid zone between rabbit subspecies, Oryctolagus cuniculus cuniculus and O. c. algirus (Figure 1 ), Rafati et al. ( 2018 ) use landscape‐level patterns of allele frequency variation to identify potential candidate regions of the genome associated with reproductive isolation. These candidate regions are used to test predictions associated with the genomic architecture of reproductive barriers, including the role of structural rearrangements, enrichment of functional categories associated with incompatibilities, and the contribution of protein‐coding versus regulatory changes. A lack of structural rearrangements and limited protein‐coding changes in candidate regions point towards the importance of regulatory variation as major contributors to genetic incompatibilities, while functional enrichments indicate overrepresentation of genes associated with male infertility. To quantify phenotypic expression of proposed incompatibilities, the authors assess gene expression of experimental crosses. Extensive misregulation of gene expression within the testes of backcross hybrids relative to F1 and parental individuals provides an important link between genotype and phenotype, validating hypotheses developed from assessment of genomic architectures. Together, this work shows how pairing natural hybrid zones with experimental crosses can be used to link observations in nature to mechanistic underpinnings that may be tested experimentally. 相似文献
3.
Quantitative proteomics suggests decrease in the secretogranin‐1 cerebrospinal fluid levels during the disease course of multiple sclerosis 下载免费PDF全文
Ann C. Kroksveen Jacob D. Jaffe Elise Aasebø Harald Barsnes Yngvild Bjørlykke Diego Franciotta Hasmik Keshishian Kjell‐Morten Myhr Jill A. Opsahl Vincent van Pesch Charlotte E. Teunissen Øivind Torkildsen Rune J. Ulvik Heidrun Vethe Steven A. Carr Frode S. Berven 《Proteomics》2015,15(19):3361-3369
Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS with unknown cause. Proteins with different abundance in the cerebrospinal fluid (CSF) from relapsing‐remitting MS (RRMS) patients and neurological controls could give novel insight to the MS pathogenesis and be used to improve diagnosis, predict prognosis and disease course, and guide in therapy decisions. We combined iTRAQ labeling and Orbitrap mass spectrometry to discover proteins with different CSF abundance between six RRMS patients and 18 neurological disease controls. From 777 quantified proteins seven were selected as biomarker candidates, namely chitinase‐3‐like protein 1, secretogranin‐1 (Sg1), cerebellin‐1, neuroserpin, cell surface glycoprotein MUC18, testican‐2 and glutamate receptor 4. An independent sample set of 13 early‐MS patients, 13 RRMS patients and 13 neurological controls was used in a multiple reaction monitoring verification study. We found the intracellular calcium binding protein Sg1 to be increased in early‐MS patients compared to RRMS and neurological controls. Sg1 should be included in further studies to elucidate its role in the early phases of MS pathogenesis and its potential as a biomarker for this disease. 相似文献
4.
EV Rosenfeld 《European biophysics journal : EBJ》2012,41(9):733-753
The cross-bridge working stroke is regarded as a continuous (without jumps) change of myosin head internal state under the action of a force exerted within the nucleotide-binding site. Involvement of a concept of continuous cross-bridge conformation enables discussion of the nature of the force propelling muscle, and the Coulomb repulsion of like-charged adenosine triphosphate (ATP) fragments ADP(2-) and P (i) (2-) can quite naturally be considered as the source of this force. Two entirely different types of working stroke termination are considered. Along with the fluctuation mechanism, which controls the working stroke duration t (w) at isometric contraction, another interrupt mechanism is initially taken into account. It is triggered when the lever arm shift amounts to the maximal value S?≈?11?nm, the back door opens, and P(i) crashes out. As a result, t (w) becomes inversely proportional to the velocity v of sliding filaments t (w)?≈?S/v for a wide range of values of v. Principal features of the experimentally observed dependences of force, efficiency, and rate of heat production on velocity and ATP concentration can then be reproduced by fitting a single parameter: the velocity-independent time span t (r) between the termination of the last and beginning of the next working stroke. v becomes the principal variable of the model, and the muscle force changes under external load are determined by variations in v rather than in the tension of filaments. The Boltzmann equation for an ensemble of cross-bridges is obtained, and some collective effects are discussed. 相似文献
5.
T cell exhaustion and loss of memory potential occur during many chronic viral infections and cancer. We investigated when during chronic viral infection virus-specific CD8 T cells lose the potential to form memory. Virus-specific CD8 T cells from established chronic infection were unable to become memory CD8 T cells if removed from infection. However, at earlier stages of chronic infection, these virus-specific CD8 T cells retained the potential to partially or fully revert to a memory differentiation program after transfer to infection-free mice. Conversely, effector CD8 T cells primed during acute infection were not protected from exhaustion if transferred to a chronic infection. We also tested whether memory and exhausted CD8 T cells arose from different subpopulations of effector CD8 T cells and found that only the KLRG1(lo) memory precursor subset gave rise to exhausted CD8 T cells. Together, these studies demonstrate that CD8 T cell exhaustion is a progressive developmental process. Early during chronic infection, the fate of virus-specific CD8 T cells remains plastic, while later, exhausted CD8 T cells become fixed in their differentiation state. Moreover, exhausted CD8 T cells arise from the memory precursor and not the terminally differentiated subset of effector CD8 T cells. These studies have implications for our understanding of senescence versus exhaustion and for therapeutic interventions during chronic infection. 相似文献
6.
Ronit Rosenfeld Hadar Marcus Einat Ben-Arie Bat-El Lachmi Adva Mechaly Shaul Reuveny Orit Gat Ohad Mazor Arie Ordentlich 《PloS one》2009,4(7)
Several studies have demonstrated that the passive transfer of protective antigen (PA)-neutralizing antibodies can protect animals against Bacillus anthracis infection. The standard protocol for the isolation of PA-neutralizing monoclonal antibodies is based upon a primary selection of the highest PA-binders by ELISA, and usually yields only few candidates antibodies. We demonstrated that by applying a PA-neutralization functionality-based screen as the primary criterion for positive clones, it was possible to isolate more than 100 PA-neutralizing antibodies, some of which exhibited no measurable anti-PA titers in ELISA. Among the large panel of neutralizing antibodies identified, mAb 29 demonstrated the most potent activity, and was therefore chimerized. The variable region genes of the mAb 29 were fused to human constant region genes, to form the chimeric 29 antibody (cAb 29). Guinea pigs were fully protected against infection by 40LD50
B. anthracis spores following two separate administrations with 10 mg/kg of cAb 29: the first administration was given before the challenge, and a second dose was administered on day 4 following exposure. Moreover, animals that survived the challenge and developed endogenous PA-neutralizing antibodies with neutralizing titers above 100 were fully protected against repeat challenges with 40LD50 of B. anthracis spores. The data presented here emphasize the importance of toxin neutralization-based screens for the efficient isolation of protective antibodies that were probably overlooked in the standard screening protocol. The protective activity of the chimeric cAb 29 demonstrated in this study suggest that it may serve as an effective immunotherapeutic agent against anthrax. 相似文献
7.
8.
Many epithelial tissues expand rapidly during embryonic development while remaining surrounded by a basement membrane. Remodeling of the basement membrane is assumed to occur during branching morphogenesis to accommodate epithelial growth, but how such remodeling occurs is not yet clear. We report that the basement membrane is highly dynamic during branching of the salivary gland, exhibiting both local and global remodeling. At the tip of the epithelial end bud, the basement membrane becomes perforated by hundreds of well-defined microscopic holes at regions of rapid expansion. Locally, this results in a distensible, mesh-like basement membrane for controlled epithelial expansion while maintaining tissue integrity. Globally, the basement membrane translocates rearward as a whole, accumulating around the forming secondary ducts, helping to stabilize them during branching. Both local and global dynamics of the basement membrane require protease and myosin II activity. Our findings suggest that the basement membrane is rendered distensible by proteolytic degradation to allow it to be moved and remodeled by cells through actomyosin contractility to support branching morphogenesis. 相似文献
9.
Jill T. Anderson Cheng‐Ruei Lee Thomas Mitchell‐Olds 《Evolution; international journal of organic evolution》2014,68(1):16-31
Fitness trade‐offs across episodes of selection and environments influence life‐history evolution and adaptive population divergence. Documenting these trade‐offs remains challenging as selection can vary in magnitude and direction through time and space. Here, we evaluate fitness trade‐offs at the levels of the whole organism and the quantitative trait locus (QTL) in a multiyear field study of Boechera stricta (Brassicaceae), a genetically tractable mustard native to the Rocky Mountains. Reciprocal local adaptation was pronounced for viability, but not for reproductive components of fitness. Instead, local genomes had a fecundity advantage only in the high latitude garden. By estimating realized selection coefficients from individual‐level data on viability and reproductive success and permuting the data to infer significance, we examined the genetic basis of fitness trade‐offs. This analytical approach (Conditional Neutrality‐Antagonistic Pleiotropy, CNAP) identified genetic trade‐offs at a flowering phenology QTL (costs of adaptation) and revealed genetic trade‐offs across fitness components (costs of reproduction). These patterns would not have emerged from traditional ANOVA‐based QTL mapping. Our analytical framework can be applied to other systems to investigate fitness trade‐offs. This task is becoming increasingly important as climate change may alter fitness landscapes, potentially disrupting fitness trade‐offs that took many generations to evolve. 相似文献
10.
Etienne Karita Matt A Price Shabir Lakhi William Kilembe Anatoli Kamali Eugene Ruzagira Eric Hunter Paul Farmer Susan Allen Gwynn Stevens Paramesh Chetty Sabrina Welsh Annie Yang Jill Gilmour Pat Fast The IAVI Africa HIV Prevention Partnership 《PloS one》2015,10(8)