全文获取类型
收费全文 | 3132篇 |
免费 | 26篇 |
国内免费 | 37篇 |
专业分类
系统科学 | 60篇 |
丛书文集 | 70篇 |
教育与普及 | 164篇 |
理论与方法论 | 10篇 |
现状及发展 | 306篇 |
研究方法 | 524篇 |
综合类 | 2059篇 |
自然研究 | 2篇 |
出版年
2021年 | 6篇 |
2017年 | 6篇 |
2016年 | 9篇 |
2014年 | 12篇 |
2013年 | 9篇 |
2012年 | 239篇 |
2011年 | 317篇 |
2010年 | 70篇 |
2009年 | 18篇 |
2008年 | 250篇 |
2007年 | 226篇 |
2006年 | 224篇 |
2005年 | 217篇 |
2004年 | 194篇 |
2003年 | 209篇 |
2002年 | 175篇 |
2001年 | 123篇 |
2000年 | 185篇 |
1999年 | 59篇 |
1998年 | 12篇 |
1997年 | 8篇 |
1996年 | 13篇 |
1995年 | 6篇 |
1994年 | 7篇 |
1993年 | 11篇 |
1992年 | 13篇 |
1991年 | 18篇 |
1990年 | 13篇 |
1989年 | 23篇 |
1988年 | 14篇 |
1987年 | 12篇 |
1986年 | 18篇 |
1985年 | 15篇 |
1984年 | 18篇 |
1983年 | 14篇 |
1982年 | 18篇 |
1981年 | 17篇 |
1980年 | 10篇 |
1979年 | 11篇 |
1971年 | 15篇 |
1970年 | 24篇 |
1966年 | 11篇 |
1960年 | 6篇 |
1959年 | 30篇 |
1958年 | 62篇 |
1957年 | 43篇 |
1956年 | 43篇 |
1955年 | 49篇 |
1954年 | 35篇 |
1948年 | 17篇 |
排序方式: 共有3195条查询结果,搜索用时 890 毫秒
841.
Ahmed ZM Masmoudi S Kalay E Belyantseva IA Mosrati MA Collin RW Riazuddin S Hmani-Aifa M Venselaar H Kawar MN Tlili A van der Zwaag B Khan SY Ayadi L Riazuddin SA Morell RJ Griffith AJ Charfedine I Caylan R Oostrik J Karaguzel A Ghorbel A Riazuddin S Friedman TB Ayadi H Kremer H 《Nature genetics》2008,40(11):1335-1340
842.
Large-scale production of functional membrane proteins 总被引:2,自引:0,他引:2
Junge F Schneider B Reckel S Schwarz D Dötsch V Bernhard F 《Cellular and molecular life sciences : CMLS》2008,65(11):1729-1755
The preparation of sufficient amounts of high-quality samples is still the major bottleneck for the characterization of membrane proteins by in vitro approaches. The hydrophobic nature, the requirement for complicated transport and modification pathways, and the often observed negative effects on membrane properties are intrinsic features of membrane proteins that frequently cause significant problems in overexpression studies. Establishing efficient protocols for the production of functionally folded membrane proteins is therefore a challenging task, and numerous specific characteristics have to be considered. In addition, a variety of expression systems have been developed, and choice of appropriate techniques could strongly depend on the desired target membrane proteins as well as on their intended applications. The production of membrane proteins is a highly dynamic field and new or modified approaches are frequently emerging. The review will give an overview of currently established processes for the production of functionally folded membrane proteins. 相似文献
843.
Gonzalez MR Bischofberger M Pernot L van der Goot FG Frêche B 《Cellular and molecular life sciences : CMLS》2008,65(3):493-507
Pore-forming toxins (PFTs) are the most common class of bacterial protein toxins and constitute important bacterial virulence
factors. The mode of action of PFT is starting to be better understood. In contrast, little is known about the cellular response
to this threat. Recent studies reveal that cells do not just swell and lyse, but are able to sense and react to pore formation,
mount a defense, even repair the damaged membrane and thus survive. These responses involve a variety of signal-transduction
pathways and sophisticated cellular mechanisms such as the pathway regulating lipid metabolism. In this review we discuss
the different classes of bacterial PFTs and their modes of action, and provide examples of how the different bacteria use
PFTs. Finally, we address the more recent field dealing with the eukaryotic cell response to PFT-induced damage.
Received 19 September 2007; received after revision 18 October 2007; accepted 23 October 2007 相似文献
844.
Identification of ten loci associated with height highlights new biological pathways in human growth 总被引:1,自引:0,他引:1
Lettre G Jackson AU Gieger C Schumacher FR Berndt SI Sanna S Eyheramendy S Voight BF Butler JL Guiducci C Illig T Hackett R Heid IM Jacobs KB Lyssenko V Uda M;Diabetes Genetics Initiative;FUSION;KORA;Prostate Lung Colorectal Ovarian Cancer Screening Trial;Nurses' Health Study;SardiNIA Boehnke M Chanock SJ Groop LC Hu FB Isomaa B Kraft P Peltonen L Salomaa V Schlessinger D Hunter DJ Hayes RB Abecasis GR Wichmann HE Mohlke KL Hirschhorn JN 《Nature genetics》2008,40(5):584-591
Height is a classic polygenic trait, reflecting the combined influence of multiple as-yet-undiscovered genetic factors. We carried out a meta-analysis of genome-wide association study data of height from 15,821 individuals at 2.2 million SNPs, and followed up the strongest findings in >10,000 subjects. Ten newly identified and two previously reported loci were strongly associated with variation in height (P values from 4 x 10(-7) to 8 x 10(-22)). Together, these 12 loci account for approximately 2% of the population variation in height. Individuals with < or =8 height-increasing alleles and > or =16 height-increasing alleles differ in height by approximately 3.5 cm. The newly identified loci, along with several additional loci with strongly suggestive associations, encompass both strong biological candidates and unexpected genes, and highlight several pathways (let-7 targets, chromatin remodeling proteins and Hedgehog signaling) as important regulators of human stature. These results expand the picture of the biological regulation of human height and of the genetic architecture of this classical complex trait. 相似文献
845.
Rosendahl J Witt H Szmola R Bhatia E Ozsvári B Landt O Schulz HU Gress TM Pfützer R Löhr M Kovacs P Blüher M Stumvoll M Choudhuri G Hegyi P te Morsche RH Drenth JP Truninger K Macek M Puhl G Witt U Schmidt H Büning C Ockenga J Kage A Groneberg DA Nickel R Berg T Wiedenmann B Bödeker H Keim V Mössner J Teich N Sahin-Tóth M 《Nature genetics》2008,40(1):78-82
Chronic pancreatitis is a persistent inflammatory disease of the pancreas, in which the digestive protease trypsin has a fundamental pathogenetic role. Here we have analyzed the gene encoding the trypsin-degrading enzyme chymotrypsin C (CTRC) in German subjects with idiopathic or hereditary chronic pancreatitis. Two alterations in this gene, p.R254W and p.K247_R254del, were significantly overrepresented in the pancreatitis group, being present in 30 of 901 (3.3%) affected individuals but only 21 of 2,804 (0.7%) controls (odds ratio (OR) = 4.6; confidence interval (CI) = 2.6-8.0; P = 1.3 x 10(-7)). A replication study identified these two variants in 10 of 348 (2.9%) individuals with alcoholic chronic pancreatitis but only 3 of 432 (0.7%) subjects with alcoholic liver disease (OR = 4.2; CI = 1.2-15.5; P = 0.02). CTRC variants were also found in 10 of 71 (14.1%) Indian subjects with tropical pancreatitis but only 1 of 84 (1.2%) healthy controls (OR = 13.6; CI = 1.7-109.2; P = 0.0028). Functional analysis of the CTRC variants showed impaired activity and/or reduced secretion. The results indicate that loss-of-function alterations in CTRC predispose to pancreatitis by diminishing its protective trypsin-degrading activity. 相似文献
846.
In both yeast and mammals, uncapped telomeres activate the DNA damage response (DDR) and undergo end-to-end fusion. Previous work has shown that the Drosophila HOAP protein, encoded by the caravaggio (cav) gene, is required to prevent telomeric fusions. Here we show that HOAP-depleted telomeres activate both the DDR and the spindle assembly checkpoint (SAC). The cell cycle arrest elicited by the DDR was alleviated by mutations in mei-41 (encoding ATR), mus304 (ATRIP), grp (Chk1) and rad50 but not by mutations in tefu (ATM). The SAC was partially overridden by mutations in zw10 (also known as mit(1)15) and bubR1, and also by mutations in mei-41, mus304, rad50, grp and tefu. As expected from SAC activation, the SAC proteins Zw10, Zwilch, BubR1 and Cenp-meta (Cenp-E) accumulated at the kinetochores of cav mutant cells. Notably, BubR1 also accumulated at cav mutant telomeres in a mei-41-, mus304-, rad50-, grp- and tefu-dependent manner. Our results collectively suggest that recruitment of BubR1 by dysfunctional telomeres inhibits Cdc20-APC function, preventing the metaphase-to-anaphase transition. 相似文献
847.
Most heritable traits, including disease susceptibility, are affected by interactions between multiple genes. However, we understand little about how genes interact because very few possible genetic interactions have been explored experimentally. We have used RNA interference in Caenorhabditis elegans to systematically test approximately 65,000 pairs of genes for their ability to interact genetically. We identify approximately 350 genetic interactions between genes functioning in signaling pathways that are mutated in human diseases, including components of the EGF/Ras, Notch and Wnt pathways. Most notably, we identify a class of highly connected 'hub' genes: inactivation of these genes can enhance the phenotypic consequences of mutation of many different genes. These hub genes all encode chromatin regulators, and their activity as genetic hubs seems to be conserved across animals. We propose that these genes function as general buffers of genetic variation and that these hub genes may act as modifier genes in multiple, mechanistically unrelated genetic diseases in humans. 相似文献
848.
A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheep 总被引:38,自引:0,他引:38
Clop A Marcq F Takeda H Pirottin D Tordoir X Bibé B Bouix J Caiment F Elsen JM Eychenne F Larzul C Laville E Meish F Milenkovic D Tobin J Charlier C Georges M 《Nature genetics》2006,38(7):813-818
Texel sheep are renowned for their exceptional meatiness. To identify the genes underlying this economically important feature, we performed a whole-genome scan in a Romanov x Texel F2 population. We mapped a quantitative trait locus with a major effect on muscle mass to chromosome 2 and subsequently fine-mapped it to a chromosome interval encompassing the myostatin (GDF8) gene. We herein demonstrate that the GDF8 allele of Texel sheep is characterized by a G to A transition in the 3' UTR that creates a target site for mir1 and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle. This causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep. Analysis of SNP databases for humans and mice demonstrates that mutations creating or destroying putative miRNA target sites are abundant and might be important effectors of phenotypic variation. 相似文献
849.
A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region 总被引:1,自引:0,他引:1
Smyth DJ Cooper JD Bailey R Field S Burren O Smink LJ Guja C Ionescu-Tirgoviste C Widmer B Dunger DB Savage DA Walker NM Clayton DG Todd JA 《Nature genetics》2006,38(6):617-619
In this study we report convincing statistical support for a sixth type 1 diabetes (T1D) locus in the innate immunity viral RNA receptor gene region IFIH1 (also known as mda-5 or Helicard) on chromosome 2q24.3. We found the association in an interim analysis of a genome-wide nonsynonymous SNP (nsSNP) scan, and we validated it in a case-control collection and replicated it in an independent family collection. In 4,253 cases, 5,842 controls and 2,134 parent-child trio genotypes, the risk ratio for the minor allele of the nsSNP rs1990760 A --> G (A946T) was 0.86 (95% confidence interval = 0.82-0.90) at P = 1.42 x 10(-10). 相似文献
850.
The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells 总被引:45,自引:0,他引:45