全文获取类型
收费全文 | 1000篇 |
免费 | 10篇 |
国内免费 | 28篇 |
专业分类
系统科学 | 20篇 |
丛书文集 | 2篇 |
教育与普及 | 3篇 |
理论与方法论 | 13篇 |
现状及发展 | 206篇 |
研究方法 | 133篇 |
综合类 | 635篇 |
自然研究 | 26篇 |
出版年
2020年 | 5篇 |
2019年 | 5篇 |
2018年 | 14篇 |
2017年 | 12篇 |
2016年 | 8篇 |
2015年 | 13篇 |
2014年 | 18篇 |
2013年 | 19篇 |
2012年 | 68篇 |
2011年 | 98篇 |
2010年 | 38篇 |
2009年 | 24篇 |
2008年 | 54篇 |
2007年 | 67篇 |
2006年 | 52篇 |
2005年 | 64篇 |
2004年 | 41篇 |
2003年 | 65篇 |
2002年 | 54篇 |
2001年 | 40篇 |
2000年 | 43篇 |
1999年 | 20篇 |
1992年 | 10篇 |
1991年 | 7篇 |
1990年 | 4篇 |
1989年 | 10篇 |
1988年 | 9篇 |
1987年 | 9篇 |
1986年 | 5篇 |
1985年 | 9篇 |
1984年 | 3篇 |
1983年 | 3篇 |
1982年 | 6篇 |
1981年 | 7篇 |
1980年 | 8篇 |
1979年 | 8篇 |
1978年 | 7篇 |
1977年 | 10篇 |
1976年 | 5篇 |
1975年 | 9篇 |
1974年 | 5篇 |
1973年 | 9篇 |
1972年 | 3篇 |
1971年 | 9篇 |
1970年 | 9篇 |
1969年 | 7篇 |
1968年 | 5篇 |
1967年 | 7篇 |
1966年 | 5篇 |
1965年 | 7篇 |
排序方式: 共有1038条查询结果,搜索用时 156 毫秒
991.
Lee YA Wahn U Kehrt R Tarani L Businco L Gustafsson D Andersson F Oranje AP Wolkertstorfer A v Berg A Hoffmann U Küster W Wienker T Rüschendorf F Reis A 《Nature genetics》2000,26(4):470-473
Atopic dermatitis (eczema) is a chronic inflammatory skin disease with onset mainly in early childhood It is commonly the initial clinical manifestation of allergic disease, often preceding the onset of respiratory allergies. Along with asthma and allergic rhinitis, atopic dermatitis is an important manifestation of atopy that is characterized by the formation of allergy antibodies (IgE) to environmental allergens. In the developed countries, the prevalence of atopic dermatitis is approximately 15%, with a steady increase over the past decades. Genetic and environmental factors interact to determine disease susceptibility and expression, and twin studies indicate that the genetic contribution is substantial. To identify susceptibility loci for atopic dermatitis, we ascertained 199 families with at least two affected siblings based on established diagnostic criteria. A genome-wide linkage study revealed highly significant evidence for linkage on chromosome 3q21 (Zall=4.31, P= 8.42 10(-6)). Moreover, this locus provided significant evidence for linkage of allergic sensitization under the assumption of paternal imprinting (hlod=3.71,alpha=44%), further supporting the presence of an atopy gene in this region. Our findings indicate that distinct genetic factors contribute to susceptibility to atopic dermatitis and that the study of this disease opens new avenues to dissect the genetics of atopy. 相似文献
992.
Tong ZB Gold L Pfeifer KE Dorward H Lee E Bondy CA Dean J Nelson LM 《Nature genetics》2000,26(3):267-268
Maternal effect genes produce mRNA or proteins that accumulate in the egg during oogenesis. We show here that Mater, a mouse oocyte protein dependent on the maternal genome, is essential for embryonic development beyond the two-cell stage. Females lacking the maternal effect gene Mater are sterile. Null males are fertile. 相似文献
993.
Genome-wide analysis of single-nucleotide polymorphisms in human expressed sequences 总被引:16,自引:0,他引:16
Single-nucleotide polymorphisms (SNPs) have been explored as a high-resolution marker set for accelerating the mapping of disease genes. Here we report 48,196 candidate SNPs detected by statistical analysis of human expressed sequence tags (ESTs), associated primarily with coding regions of genes. We used Bayesian inference to weigh evidence for true polymorphism versus sequencing error, misalignment or ambiguity, misclustering or chimaeric EST sequences, assessing data such as raw chromatogram height, sharpness, overlap and spacing, sequencing error rates, context-sensitivity and cDNA library origin. Three separate validations-comparison with 54 genes screened for SNPs independently, verification of HLA-A polymorphisms and restriction fragment length polymorphism (RFLP) testing-verified 70%, 89% and 71% of our predicted SNPs, respectively. Our method detects tenfold more true HLA-A SNPs than previous analyses of the EST data. We found SNPs in a large fraction of known disease genes, including some disease-causing mutations (for example, the HbS sickle-cell mutation). Our comprehensive analysis of human coding region polymorphism provides a public resource for mapping of disease genes (available at http://www.bioinformatics.ucla.edu/snp). 相似文献
994.
Functional link between ataxia-telangiectasia and Nijmegen breakage syndrome gene products 总被引:50,自引:0,他引:50
Zhao S Weng YC Yuan SS Lin YT Hsu HC Lin SC Gerbino E Song MH Zdzienicka MZ Gatti RA Shay JW Ziv Y Shiloh Y Lee EY 《Nature》2000,405(6785):473-477
Ataxia-telangiectasia (A-T) and Nijmegen breakage syndrome (NBS) are recessive genetic disorders with susceptibility to cancer and similar cellular phenotypes. The protein product of the gene responsible for A-T, designated ATM, is a member of a family of kinases characterized by a carboxy-terminal phosphatidylinositol 3-kinase-like domain. The NBS1 protein is specifically mutated in patients with Nijmegen breakage syndrome and forms a complex with the DNA repair proteins Rad50 and Mrel1. Here we show that phosphorylation of NBS1, induced by ionizing radiation, requires catalytically active ATM. Complexes containing ATM and NBS1 exist in vivo in both untreated cells and cells treated with ionizing radiation. We have identified two residues of NBS1, Ser 278 and Ser 343 that are phosphorylated in vitro by ATM and whose modification in vivo is essential for the cellular response to DNA damage. This response includes S-phase checkpoint activation, formation of the NBS1/Mrel1/Rad50 nuclear foci and rescue of hypersensitivity to ionizing radiation. Together, these results demonstrate a biochemical link between cell-cycle checkpoints activated by DNA damage and DNA repair in two genetic diseases with overlapping phenotypes. 相似文献
995.
Taguchi A Blood DC del Toro G Canet A Lee DC Qu W Tanji N Lu Y Lalla E Fu C Hofmann MA Kislinger T Ingram M Lu A Tanaka H Hori O Ogawa S Stern DM Schmidt AM 《Nature》2000,405(6784):354-360
The receptor for advanced glycation end products (RAGE), a multi-ligand member of the immunoglobulin superfamily of cell surface molecules, interacts with distinct molecules implicated in homeostasis, development and inflammation, and certain diseases such as diabetes and Alzheimer's disease. Engagement of RAGE by a ligand triggers activation of key cell signalling pathways, such as p21ras, MAP kinases, NF-kappaB and cdc42/rac, thereby reprogramming cellular properties. RAGE is a central cell surface receptor for amphoterin, a polypeptide linked to outgrowth of cultured cortical neurons derived from developing brain. Indeed, the co-localization of RAGE and amphoterin at the leading edge of advancing neurites indicated their potential contribution to cellular migration, and in pathologies such as tumour invasion. Here we demonstrate that blockade of RAGE-amphoterin decreased growth and metastases of both implanted tumours and tumours developing spontaneously in susceptible mice. Inhibition of the RAGE-amphoterin interaction suppressed activation of p44/p42, p38 and SAP/JNK MAP kinases; molecular effector mechanisms importantly linked to tumour proliferation, invasion and expression of matrix metalloproteinases. 相似文献
996.
997.
Gray JE Holroyd GH van der Lee FM Bahrami AR Sijmons PC Woodward FI Schuch W Hetherington AM 《Nature》2000,408(6813):713-716
Stomatal pores on the leaf surface control both the uptake of CO2 for photosynthesis and the loss of water during transpiration. Since the industrial revolution, decreases in stomatal numbers in parallel with increases in atmospheric CO2 concentration have provided evidence of plant responses to changes in CO2 levels caused by human activity. This inverse correlation between stomatal density and CO2 concentration also holds for fossil material from the past 400 million years and has provided clues to the causes of global extinction events. Here we report the identification of the Arabidopsis gene HIC (for high carbon dioxide), which encodes a negative regulator of stomatal development that responds to CO2 concentration. This gene encodes a putative 3-keto acyl coenzyme A synthase--an enzyme involved in the synthesis of very-long-chain fatty acids. Mutant hic plants exhibit up to a 42% increase in stomatal density in response to a doubling of CO2. Our results identify a gene involved in the signal transduction pathway responsible for controlling stomatal numbers at elevated CO2. 相似文献
998.
Despite the status of the eye as an "organ of extreme perfection", theory suggests that complex eyes can evolve very rapidly. The fossil record has, until now, been inadequate in providing insight into the early evolution of eyes during the initial radiation of many animal groups known as the Cambrian explosion. This is surprising because Cambrian Burgess-Shale-type deposits are replete with exquisitely preserved animals, especially arthropods, that possess eyes. However, with the exception of biomineralized trilobite eyes, virtually nothing is known about the details of their optical design. Here we report exceptionally preserved fossil eyes from the Early Cambrian (~ 515 million years ago) Emu Bay Shale of South Australia, revealing that some of the earliest arthropods possessed highly advanced compound eyes, each with over 3,000 large ommatidial lenses and a specialized 'bright zone'. These are the oldest non-biomineralized eyes known in such detail, with preservation quality exceeding that found in the Burgess Shale and Chengjiang deposits. Non-biomineralized eyes of similar complexity are otherwise unknown until about 85 million years later. The arrangement and size of the lenses indicate that these eyes belonged to an active predator that was capable of seeing in low light. The eyes are more complex than those known from contemporaneous trilobites and are as advanced as those of many living forms. They provide further evidence that the Cambrian explosion involved rapid innovation in fine-scale anatomy as well as gross morphology, and are consistent with the concept that the development of advanced vision helped to drive this great evolutionary event. 相似文献
999.
Flynn RL Centore RC O'Sullivan RJ Rai R Tse A Songyang Z Chang S Karlseder J Zou L 《Nature》2011,471(7339):532-536
Maintenance of telomeres requires both DNA replication and telomere 'capping' by shelterin. These two processes use two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomeres 1 (POT1). Although RPA and POT1 each have a critical role at telomeres, how they function in concert is not clear. POT1 ablation leads to activation of the ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase at telomeres, suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. Unexpectedly, we found that purified POT1 and its functional partner TPP1 are unable to prevent RPA binding to telomeric ssDNA efficiently. In cell extracts, we identified a novel activity that specifically displaces RPA, but not POT1, from telomeric ssDNA. Using purified protein, here we show that the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) recapitulates the RPA displacing activity. The RPA displacing activity is inhibited by the telomeric repeat-containing RNA (TERRA) in early S phase, but is then unleashed in late S phase when TERRA levels decline at telomeres. Interestingly, TERRA also promotes POT1 binding to telomeric ssDNA by removing hnRNPA1, suggesting that the re-accumulation of TERRA after S phase helps to complete the RPA-to-POT1 switch on telomeric ssDNA. Together, our data suggest that hnRNPA1, TERRA and POT1 act in concert to displace RPA from telomeric ssDNA after DNA replication, and promote telomere capping to preserve genomic integrity. 相似文献