全文获取类型
收费全文 | 1528篇 |
免费 | 136篇 |
国内免费 | 1篇 |
出版年
2024年 | 2篇 |
2023年 | 7篇 |
2022年 | 9篇 |
2021年 | 50篇 |
2020年 | 16篇 |
2019年 | 23篇 |
2018年 | 35篇 |
2017年 | 29篇 |
2016年 | 53篇 |
2015年 | 87篇 |
2014年 | 85篇 |
2013年 | 111篇 |
2012年 | 147篇 |
2011年 | 171篇 |
2010年 | 105篇 |
2009年 | 74篇 |
2008年 | 100篇 |
2007年 | 95篇 |
2006年 | 102篇 |
2005年 | 86篇 |
2004年 | 65篇 |
2003年 | 65篇 |
2002年 | 63篇 |
2001年 | 10篇 |
2000年 | 5篇 |
1999年 | 11篇 |
1998年 | 6篇 |
1997年 | 5篇 |
1996年 | 1篇 |
1995年 | 3篇 |
1994年 | 6篇 |
1993年 | 1篇 |
1992年 | 5篇 |
1991年 | 3篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 3篇 |
1987年 | 1篇 |
1986年 | 4篇 |
1984年 | 2篇 |
1982年 | 1篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1976年 | 2篇 |
1960年 | 1篇 |
1913年 | 1篇 |
排序方式: 共有1665条查询结果,搜索用时 20 毫秒
991.
McLaren CE Garner CP Constantine CC McLachlan S Vulpe CD Snively BM Gordeuk VR Nickerson DA Cook JD Leiendecker-Foster C Beckman KB Eckfeldt JH Barcellos LF Murray JA Adams PC Acton RT Killeen AA McLaren GD 《PloS one》2011,6(3):e17390
The existence of multiple inherited disorders of iron metabolism in man, rodents and other vertebrates suggests genetic contributions to iron deficiency. To identify new genomic locations associated with iron deficiency, a genome-wide association study (GWAS) was performed using DNA collected from white men aged≥25 y and women≥50 y in the Hemochromatosis and Iron Overload Screening (HEIRS) Study with serum ferritin (SF)≤12 μg/L (cases) and iron replete controls (SF>100 μg/L in men, SF>50 μg/L in women). Regression analysis was used to examine the association between case-control status (336 cases, 343 controls) and quantitative serum iron measures and 331,060 single nucleotide polymorphism (SNP) genotypes, with replication analyses performed in a sample of 71 cases and 161 controls from a population of white male and female veterans screened at a US Veterans Affairs (VA) medical center. Five SNPs identified in the GWAS met genome-wide statistical significance for association with at least one iron measure, rs2698530 on chr. 2p14; rs3811647 on chr. 3q22, a known SNP in the transferrin (TF) gene region; rs1800562 on chr. 6p22, the C282Y mutation in the HFE gene; rs7787204 on chr. 7p21; and rs987710 on chr. 22q11 (GWAS observed P<1.51×10(-7) for all). An association between total iron binding capacity and SNP rs3811647 in the TF gene (GWAS observed P=7.0×10(-9), corrected P=0.012) was replicated within the VA samples (observed P=0.012). Associations with the C282Y mutation in the HFE gene also were replicated. The joint analysis of the HEIRS and VA samples revealed strong associations between rs2698530 on chr. 2p14 and iron status outcomes. These results confirm a previously-described TF polymorphism and implicate one potential new locus as a target for gene identification. 相似文献
992.
Streb JW Long X Lee TH Sun Q Kitchen CM Georger MA Slivano OJ Blaner WS Carr DW Gelman IH Miano JM 《PloS one》2011,6(4):e18538
Retinoids are used clinically to treat a number of hyper-proliferative disorders and have been shown in experimental animals to attenuate vascular occlusive diseases, presumably through nuclear receptors bound to retinoic acid response elements (RARE) located in target genes. Here, we show that natural or synthetic retinoids rapidly induce mRNA and protein expression of a specific isoform of A-Kinase Anchoring Protein 12 (AKAP12β) in cultured smooth muscle cells (SMC) as well as the intact vessel wall. Expression kinetics and actinomycin D studies indicate Akap12β is a retinoid-induced, immediate-early gene. Akap12β promoter analyses reveal a conserved RARE mildly induced with atRA in a region that exhibits hyper-acetylation. Immunofluorescence microscopy and protein kinase A (PKA) regulatory subunit overlay assays in SMC suggest a physical association between AKAP12β and PKA following retinoid treatment. Consistent with its designation as a tumor suppressor, inducible expression of AKAP12β attenuates SMC growth in vitro. Further, immunohistochemistry studies establish marked decreases in AKAP12 expression in experimentally-injured vessels of mice as well as atheromatous lesions in humans. Collectively, these results demonstrate a novel role for retinoids in the induction of an AKAP tumor suppressor that blocks vascular SMC growth thus providing new molecular insight into how retiniods may exert their anti-proliferative effects in the injured vessel wall. 相似文献
993.
Melnikov A Galinsky K Rogov P Fennell T Van Tyne D Russ C Daniels R Barnes KG Bochicchio J Ndiaye D Sene PD Wirth DF Nusbaum C Volkman SK Birren BW Gnirke A Neafsey DE 《Genome biology》2011,12(8):R73-9
We have adapted a solution hybrid selection protocol to enrich pathogen DNA in clinical samples dominated by human genetic material. Using mock mixtures of human and Plasmodium falciparum malaria parasite DNA as well as clinical samples from infected patients, we demonstrate an average of approximately 40-fold enrichment of parasite DNA after hybrid selection. This approach will enable efficient genome sequencing of pathogens from clinical samples, as well as sequencing of endosymbiotic organisms such as Wolbachia that live inside diverse metazoan phyla. 相似文献
994.
Adams DJ Berger B Harismendy O Huttenhower C Liu XS Myers CL Oshlack A Rinn JL Walhout AJ 《Genome biology》2011,12(12):137
As we come to the end of 2011, Genome Biology has asked some members of our Editorial Board for their views on the state of play in genomics. What was their favorite paper of 2011? What are the challenges in their particular research area? Who has had the biggest influence on their careers? What advice would they give to young researchers embarking on a career in research? 相似文献
995.
996.
Stewart C Kural D Strömberg MP Walker JA Konkel MK Stütz AM Urban AE Grubert F Lam HY Lee WP Busby M Indap AR Garrison E Huff C Xing J Snyder MP Jorde LB Batzer MA Korbel JO Marth GT; Genomes Project 《PLoS genetics》2011,7(8):e1002236
As a consequence of the accumulation of insertion events over evolutionary time, mobile elements now comprise nearly half of the human genome. The Alu, L1, and SVA mobile element families are still duplicating, generating variation between individual genomes. Mobile element insertions (MEI) have been identified as causes for genetic diseases, including hemophilia, neurofibromatosis, and various cancers. Here we present a comprehensive map of 7,380 MEI polymorphisms from the 1000 Genomes Project whole-genome sequencing data of 185 samples in three major populations detected with two detection methods. This catalog enables us to systematically study mutation rates, population segregation, genomic distribution, and functional properties of MEI polymorphisms and to compare MEI to SNP variation from the same individuals. Population allele frequencies of MEI and SNPs are described, broadly, by the same neutral ancestral processes despite vastly different mutation mechanisms and rates, except in coding regions where MEI are virtually absent, presumably due to strong negative selection. A direct comparison of MEI and SNP diversity levels suggests a differential mobile element insertion rate among populations. 相似文献
997.
Ji-Won Moon Ilia N. Ivanov Chad E. Duty Lonnie J. Love Adam J. Rondinone Wei Wang Yi-Liang Li Andrew S. Madden Jennifer J. Mosher Michael Z. Hu Anil K. Suresh Claudia J. Rawn Hyunsung Jung Robert J. Lauf Tommy J. Phelps 《Journal of industrial microbiology & biotechnology》2013,40(11):1263-1271
We report microbially facilitated synthesis of cadmium sulfide (CdS) nanostructured particles (NP) using anaerobic, metal-reducing Thermoanaerobacter sp. The extracellular CdS crystallites were <10 nm in size with yields of ~3 g/L of growth medium/month with demonstrated reproducibility and scalability up to 24 L. During synthesis, Thermoanaerobacter cultures reduced thiosulfate and sulfite salts to H2S, which reacted with Cd2+ cations to produce thermodynamically favored NP in a single step at 65 °C with catalytic nucleation on the cell surfaces. Photoluminescence (PL) analysis of dry CdS NP revealed an exciton-dominated PL peak at 440 nm, having a narrow full width at half maximum of 10 nm. A PL spectrum of CdS NP produced by dissimilatory sulfur reducing bacteria was dominated by features associated with radiative exciton relaxation at the surface. High reproducibility of CdS NP PL features important for scale-up conditions was confirmed from test tubes to 24 L batches at a small fraction of the manufacturing cost associated with conventional inorganic NP production processes. 相似文献
998.
Michael G Ross Carsten Russ Maura Costello Andrew Hollinger Niall J Lennon Ryan Hegarty Chad Nusbaum David B Jaffe 《Genome biology》2013,14(5):R51
Background
DNA sequencing technologies deviate from the ideal uniform distribution of reads. These biases impair scientific and medical applications. Accordingly, we have developed computational methods for discovering, describing and measuring bias.Results
We applied these methods to the Illumina, Ion Torrent, Pacific Biosciences and Complete Genomics sequencing platforms, using data from human and from a set of microbes with diverse base compositions. As in previous work, library construction conditions significantly influence sequencing bias. Pacific Biosciences coverage levels are the least biased, followed by Illumina, although all technologies exhibit error-rate biases in high- and low-GC regions and at long homopolymer runs. The GC-rich regions prone to low coverage include a number of human promoters, so we therefore catalog 1,000 that were exceptionally resistant to sequencing. Our results indicate that combining data from two technologies can reduce coverage bias if the biases in the component technologies are complementary and of similar magnitude. Analysis of Illumina data representing 120-fold coverage of a well-studied human sample reveals that 0.20% of the autosomal genome was covered at less than 10% of the genome-wide average. Excluding locations that were similar to known bias motifs or likely due to sample-reference variations left only 0.045% of the autosomal genome with unexplained poor coverage.Conclusions
The assays presented in this paper provide a comprehensive view of sequencing bias, which can be used to drive laboratory improvements and to monitor production processes. Development guided by these assays should result in improved genome assemblies and better coverage of biologically important loci. 相似文献999.
Ramakrishna Kommagani Maria M. Szwarc Ertug Kovanci William E. Gibbons Nagireddy Putluri Suman Maity Chad J. Creighton Arun Sreekumar Francesco J. DeMayo John P. Lydon Bert W. O'Malley 《PLoS genetics》2013,9(10)
Early embryo miscarriage is linked to inadequate endometrial decidualization, a cellular transformation process that enables deep blastocyst invasion into the maternal compartment. Although much of the cellular events that underpin endometrial stromal cell (ESC) decidualization are well recognized, the individual gene(s) and molecular pathways that drive the initiation and progression of this process remain elusive. Using a genetic mouse model and a primary human ESC culture model, we demonstrate that steroid receptor coactivator-2 (SRC-2) is indispensable for rapid steroid hormone-dependent proliferation of ESCs, a critical cell-division step which precedes ESC terminal differentiation into decidual cells. We reveal that SRC-2 is required for increasing the glycolytic flux in human ESCs, which enables rapid proliferation to occur during the early stages of the decidualization program. Specifically, SRC-2 increases the glycolytic flux through induction of 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase 3 (PFKFB3), a major rate-limiting glycolytic enzyme. Similarly, acute treatment of mice with a small molecule inhibitor of PFKFB3 significantly suppressed the ability of these animals to exhibit an endometrial decidual response. Together, these data strongly support a conserved mechanism of action by which SRC-2 accelerates the glycolytic flux through PFKFB3 induction to provide the necessary bioenergy and biomass to meet the demands of a high proliferation rate observed in ESCs prior to their differentiation into decidual cells. Because deregulation of endometrial SRC-2 expression has been associated with common gynecological disorders of reproductive-age women, this signaling pathway, involving SRC-2 and PFKFB3, promises to offer new clinical approaches in the diagnosis and/or treatment of a non-receptive uterus in patients presenting idiopathic infertility, recurrent early pregnancy loss, or increased time to pregnancy. 相似文献
1000.
Theoretical models of infection spread on networks predict that targeting vaccination at individuals with a very large number of contacts (superspreaders) can reduce infection incidence by a significant margin. These models generally assume that superspreaders will always agree to be vaccinated. Hence, they cannot capture unintended consequences such as policy resistance, where the behavioral response induced by a new vaccine policy tends to reduce the expected benefits of the policy. Here, we couple a model of influenza transmission on an empirically-based contact network with a psychologically structured model of influenza vaccinating behavior, where individual vaccinating decisions depend on social learning and past experiences of perceived infections, vaccine complications and vaccine failures. We find that policy resistance almost completely undermines the effectiveness of superspreader strategies: the most commonly explored approaches that target a randomly chosen neighbor of an individual, or that preferentially choose neighbors with many contacts, provide at best a relative improvement over their non-targeted counterpart as compared to when behavioral feedbacks are ignored. Increased vaccine coverage in super spreaders is offset by decreased coverage in non-superspreaders, and superspreaders also have a higher rate of perceived vaccine failures on account of being infected more often. Including incentives for vaccination provides modest improvements in outcomes. We conclude that the design of influenza vaccine strategies involving widespread incentive use and/or targeting of superspreaders should account for policy resistance, and mitigate it whenever possible. 相似文献