全文获取类型
收费全文 | 49539篇 |
免费 | 131篇 |
国内免费 | 172篇 |
专业分类
系统科学 | 250篇 |
丛书文集 | 1052篇 |
教育与普及 | 108篇 |
理论与方法论 | 271篇 |
现状及发展 | 22218篇 |
研究方法 | 1875篇 |
综合类 | 23310篇 |
自然研究 | 758篇 |
出版年
2013年 | 360篇 |
2012年 | 666篇 |
2011年 | 1423篇 |
2010年 | 302篇 |
2008年 | 843篇 |
2007年 | 934篇 |
2006年 | 918篇 |
2005年 | 941篇 |
2004年 | 969篇 |
2003年 | 871篇 |
2002年 | 904篇 |
2001年 | 1408篇 |
2000年 | 1311篇 |
1999年 | 917篇 |
1992年 | 878篇 |
1991年 | 691篇 |
1990年 | 721篇 |
1989年 | 733篇 |
1988年 | 712篇 |
1987年 | 730篇 |
1986年 | 760篇 |
1985年 | 945篇 |
1984年 | 742篇 |
1983年 | 605篇 |
1982年 | 531篇 |
1981年 | 563篇 |
1980年 | 689篇 |
1979年 | 1546篇 |
1978年 | 1303篇 |
1977年 | 1270篇 |
1976年 | 952篇 |
1975年 | 995篇 |
1974年 | 1469篇 |
1973年 | 1240篇 |
1972年 | 1283篇 |
1971年 | 1510篇 |
1970年 | 2033篇 |
1969年 | 1602篇 |
1968年 | 1437篇 |
1967年 | 1508篇 |
1966年 | 1338篇 |
1965年 | 995篇 |
1964年 | 291篇 |
1959年 | 559篇 |
1958年 | 938篇 |
1957年 | 715篇 |
1956年 | 571篇 |
1955年 | 519篇 |
1954年 | 591篇 |
1948年 | 346篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
841.
Altenhöfer S Kleikers PW Radermacher KA Scheurer P Rob Hermans JJ Schiffers P Ho H Wingler K Schmidt HH 《Cellular and molecular life sciences : CMLS》2012,69(14):2327-2343
Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis. 相似文献
842.
Gleim S Stitham J Tang WH Martin KA Hwa J 《Cellular and molecular life sciences : CMLS》2012,69(20):3361-3380
Cardiovascular disease is the foremost cause of morbidity and mortality in the Western world. Atherosclerosis followed by thrombosis (atherothrombosis) is the pathological process underlying most myocardial, cerebral, and peripheral vascular events. Atherothrombosis is a complex and heterogeneous inflammatory process that involves interactions between many cell types (including vascular smooth muscle cells, endothelial cells, macrophages, and platelets) and processes (including migration, proliferation, and activation). Despite a wealth of knowledge from many recent studies using knockout mouse and human genetic studies (GWAS and candidate approach) identifying genes and proteins directly involved in these processes, traditional cardiovascular risk factors (hyperlipidemia, hypertension, smoking, diabetes mellitus, sex, and age) remain the most useful predictor of disease. Eicosanoids (20 carbon polyunsaturated fatty acid derivatives of arachidonic acid and other essential fatty acids) are emerging as important regulators of cardiovascular disease processes. Drugs indirectly modulating these signals, including COX-1/COX-2 inhibitors, have proven to play major roles in the atherothrombotic process. However, the complexity of their roles and regulation by opposing eicosanoid signaling, have contributed to the lack of therapies directed at the eicosanoid receptors themselves. This is likely to change, as our understanding of the structure, signaling, and function of the eicosanoid receptors improves. Indeed, a major advance is emerging from the characterization of dysfunctional naturally occurring mutations of the eicosanoid receptors. In light of the proven and continuing importance of risk factors, we have elected to focus on the relationship between eicosanoids and cardiovascular risk factors. 相似文献
843.
Primary cilia are singular, cytoskeletal organelles present in the majority of mammalian cell types where they function as coordinating centres for mechanotransduction, Wnt and hedgehog signalling. The length of the primary cilium is proposed to modulate cilia function, governed in part by the activity of intraflagellar transport (IFT). In articular cartilage, primary cilia length is increased and hedgehog signaling activated in osteoarthritis (OA). Here, we examine primary cilia length with exposure to the quintessential inflammatory cytokine interleukin-1 (IL-1), which is up-regulated in OA. We then test the hypothesis that the cilium is involved in mediating the downstream inflammatory response. Primary chondrocytes treated with IL-1 exhibited a 50% increase in cilia length after 3 h exposure. IL-1-induced cilia elongation was also observed in human fibroblasts. In chondrocytes, this elongation occurred via a protein kinase A (PKA)-dependent mechanism. G-protein coupled adenylate cyclase also regulated the length of chondrocyte primary cilia but not downstream of IL-1. Chondrocytes treated with IL-1 exhibit a characteristic increase in the release of the inflammatory chemokines, nitric oxide and prostaglandin E2. However, in cells with a mutation in IFT88 whereby the cilia structure is lost, this response to IL-1 was significantly attenuated and, in the case of nitric oxide, completely abolished. Inhibition of IL-1-induced cilia elongation by PKA inhibition also attenuated the chemokine response. These results suggest that cilia assembly regulates the response to inflammatory cytokines. Therefore, the cilia proteome may provide a novel therapeutic target for the treatment of inflammatory pathologies, including OA. 相似文献
844.
845.
Anderson BH Kasher PR Mayer J Szynkiewicz M Jenkinson EM Bhaskar SS Urquhart JE Daly SB Dickerson JE O'Sullivan J Leibundgut EO Muter J Abdel-Salem GM Babul-Hirji R Baxter P Berger A Bonafé L Brunstom-Hernandez JE Buckard JA Chitayat D Chong WK Cordelli DM Ferreira P Fluss J Forrest EH Franzoni E Garone C Hammans SR Houge G Hughes I Jacquemont S Jeannet PY Jefferson RJ Kumar R Kutschke G Lundberg S Lourenço CM Mehta R Naidu S Nischal KK Nunes L Ounap K Philippart M Prabhakar P Risen SR 《Nature genetics》2012,44(3):338-342
Coats plus is a highly pleiotropic disorder particularly affecting the eye, brain, bone and gastrointestinal tract. Here, we show that Coats plus results from mutations in CTC1, encoding conserved telomere maintenance component 1, a member of the mammalian homolog of the yeast heterotrimeric CST telomeric capping complex. Consistent with the observation of shortened telomeres in an Arabidopsis CTC1 mutant and the phenotypic overlap of Coats plus with the telomeric maintenance disorders comprising dyskeratosis congenita, we observed shortened telomeres in three individuals with Coats plus and an increase in spontaneous γH2AX-positive cells in cell lines derived from two affected individuals. CTC1 is also a subunit of the α-accessory factor (AAF) complex, stimulating the activity of DNA polymerase-α primase, the only enzyme known to initiate DNA replication in eukaryotic cells. Thus, CTC1 may have a function in DNA metabolism that is necessary for but not specific to telomeric integrity. 相似文献
846.
Golubchik T Brueggemann AB Street T Gertz RE Spencer CC Ho T Giannoulatou E Link-Gelles R Harding RM Beall B Peto TE Moore MR Donnelly P Crook DW Bowden R 《Nature genetics》2012,44(3):352-355
Streptococcus pneumoniae ('pneumococcus') causes an estimated 14.5 million cases of serious disease and 826,000 deaths annually in children under 5 years of age(1). The highly effective introduction of the PCV7 pneumococcal vaccine in 2000 in the United States(2,3) provided an unprecedented opportunity to investigate the response of an important pathogen to widespread, vaccine-induced selective pressure. Here, we use array-based sequencing of 62 isolates from a US national monitoring program to study five independent instances of vaccine escape recombination(4), showing the simultaneous transfer of multiple and often large (up to at least 44 kb) DNA fragments. We show that one such new strain quickly became established, spreading from east to west across the United States. These observations clarify the roles of recombination and selection in the population genomics of pneumococcus and provide proof of principle of the considerable value of combining genomic and epidemiological information in the surveillance and enhanced understanding of infectious diseases. 相似文献
847.
Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas 总被引:1,自引:0,他引:1
Wu G Broniscer A McEachron TA Lu C Paugh BS Becksfort J Qu C Ding L Huether R Parker M Zhang J Gajjar A Dyer MA Mullighan CG Gilbertson RJ Mardis ER Wilson RK Downing JR Ellison DW Zhang J Baker SJ;St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project 《Nature genetics》2012,44(3):251-253
To identify somatic mutations in pediatric diffuse intrinsic pontine glioma (DIPG), we performed whole-genome sequencing of DNA from seven DIPGs and matched germline tissue and targeted sequencing of an additional 43 DIPGs and 36 non-brainstem pediatric glioblastomas (non-BS-PGs). We found that 78% of DIPGs and 22% of non-BS-PGs contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, that caused a p.Lys27Met amino acid substitution in each protein. An additional 14% of non-BS-PGs had somatic mutations in H3F3A causing a p.Gly34Arg alteration. 相似文献
848.
Maize HapMap2 identifies extant variation from a genome in flux 总被引:3,自引:0,他引:3
Chia JM Song C Bradbury PJ Costich D de Leon N Doebley J Elshire RJ Gaut B Geller L Glaubitz JC Gore M Guill KE Holland J Hufford MB Lai J Li M Liu X Lu Y McCombie R Nelson R Poland J Prasanna BM Pyhäjärvi T Rong T Sekhon RS Sun Q Tenaillon MI Tian F Wang J Xu X Zhang Z Kaeppler SM Ross-Ibarra J McMullen MD Buckler ES Zhang G Xu Y Ware D 《Nature genetics》2012,44(7):803-807
Whereas breeders have exploited diversity in maize for yield improvements, there has been limited progress in using beneficial alleles in undomesticated varieties. Characterizing standing variation in this complex genome has been challenging, with only a small fraction of it described to date. Using a population genetics scoring model, we identified 55 million SNPs in 103 lines across pre-domestication and domesticated Zea mays varieties, including a representative from the sister genus Tripsacum. We find that structural variations are pervasive in the Z. mays genome and are enriched at loci associated with important traits. By investigating the drivers of genome size variation, we find that the larger Tripsacum genome can be explained by transposable element abundance rather than an allopolyploid origin. In contrast, intraspecies genome size variation seems to be controlled by chromosomal knob content. There is tremendous overlap in key gene content in maize and Tripsacum, suggesting that adaptations from Tripsacum (for example, perennialism and frost and drought tolerance) can likely be integrated into maize. 相似文献
849.
850.
Yang J Ferreira T Morris AP Medland SE;Genetic Investigation of ANthropometric Traits 《Nature genetics》2012,44(4):369-75, S1-3
We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium. 相似文献