全文获取类型
收费全文 | 487篇 |
免费 | 1篇 |
国内免费 | 3篇 |
专业分类
系统科学 | 2篇 |
理论与方法论 | 2篇 |
现状及发展 | 112篇 |
研究方法 | 38篇 |
综合类 | 331篇 |
自然研究 | 6篇 |
出版年
2018年 | 2篇 |
2015年 | 1篇 |
2014年 | 2篇 |
2013年 | 6篇 |
2012年 | 20篇 |
2011年 | 25篇 |
2010年 | 12篇 |
2009年 | 1篇 |
2008年 | 17篇 |
2007年 | 17篇 |
2006年 | 19篇 |
2005年 | 24篇 |
2004年 | 32篇 |
2003年 | 19篇 |
2002年 | 11篇 |
2001年 | 13篇 |
2000年 | 16篇 |
1999年 | 8篇 |
1994年 | 1篇 |
1992年 | 8篇 |
1991年 | 5篇 |
1990年 | 6篇 |
1989年 | 3篇 |
1988年 | 3篇 |
1987年 | 6篇 |
1986年 | 13篇 |
1985年 | 8篇 |
1984年 | 4篇 |
1983年 | 8篇 |
1982年 | 3篇 |
1981年 | 2篇 |
1980年 | 3篇 |
1979年 | 11篇 |
1978年 | 12篇 |
1977年 | 8篇 |
1976年 | 7篇 |
1975年 | 9篇 |
1974年 | 13篇 |
1973年 | 11篇 |
1972年 | 12篇 |
1971年 | 12篇 |
1970年 | 18篇 |
1969年 | 8篇 |
1968年 | 14篇 |
1967年 | 14篇 |
1966年 | 11篇 |
1965年 | 8篇 |
1963年 | 1篇 |
1959年 | 1篇 |
1958年 | 1篇 |
排序方式: 共有491条查询结果,搜索用时 31 毫秒
171.
Genomic profiling of drug sensitivities via induced haploinsufficiency 总被引:20,自引:0,他引:20
Giaever G Shoemaker DD Jones TW Liang H Winzeler EA Astromoff A Davis RW 《Nature genetics》1999,21(3):278-283
Lowering the dosage of a single gene from two copies to one copy in diploid yeast results in a heterozygote that is sensitized to any drug that acts on the product of this gene. This haploinsufficient phenotype thereby identifies the gene product of the heterozygous locus as the likely drug target. We exploited this finding in a genomic approach to drug-target identification. Genome sequence information was used to generate molecularly tagged heterozygous yeast strains that were pooled, grown competitively in drug and analysed for drug sensitivity using high-density oligonucleotide arrays. Individual heterozygous strain analysis verified six known drug targets. Parallel analysis identified the known target and two hypersensitive loci in a mixed culture of 233 strains in the presence of the drug tunicamycin. Our discovery that both drug target and hypersensitive loci exhibit drug-induced haploinsufficiency may have important consequences in pharmacogenomics and variable drug toxicity observed in human populations. 相似文献
172.
TJ Pugh SD Weeraratne TC Archer DA Pomeranz Krummel D Auclair J Bochicchio MO Carneiro SL Carter K Cibulskis RL Erlich H Greulich MS Lawrence NJ Lennon A McKenna J Meldrim AH Ramos MG Ross C Russ E Shefler A Sivachenko B Sogoloff P Stojanov P Tamayo JP Mesirov V Amani N Teider S Sengupta JP Francois PA Northcott MD Taylor F Yu GR Crabtree AG Kautzman SB Gabriel G Getz N Jäger DT Jones P Lichter SM Pfister TM Roberts M Meyerson SL Pomeroy YJ Cho 《Nature》2012,488(7409):106-110
173.
Jones FC Grabherr MG Chan YF Russell P Mauceli E Johnson J Swofford R Pirun M Zody MC White S Birney E Searle S Schmutz J Grimwood J Dickson MC Myers RM Miller CT Summers BR Knecht AK Brady SD Zhang H Pollen AA Howes T Amemiya C;Broad Institute Genome Sequencing Platform & Whole Genome Assembly Team Baldwin J Bloom T Jaffe DB Nicol R Wilkinson J Lander ES Di Palma F Lindblad-Toh K Kingsley DM 《Nature》2012,484(7392):55-61
Marine stickleback fish have colonized and adapted to thousands of streams and lakes formed since the last ice age, providing an exceptional opportunity to characterize genomic mechanisms underlying repeated ecological adaptation in nature. Here we develop a high-quality reference genome assembly for threespine sticklebacks. By sequencing the genomes of twenty additional individuals from a global set of marine and freshwater populations, we identify a genome-wide set of loci that are consistently associated with marine-freshwater divergence. Our results indicate that reuse of globally shared standing genetic variation, including chromosomal inversions, has an important role in repeated evolution of distinct marine and freshwater sticklebacks, and in the maintenance of divergent ecotypes during early stages of reproductive isolation. Both coding and regulatory changes occur in the set of loci underlying marine-freshwater evolution, but regulatory changes appear to predominate in this well known example of repeated adaptive evolution in nature. 相似文献
174.
Barretina J Caponigro G Stransky N Venkatesan K Margolin AA Kim S Wilson CJ Lehár J Kryukov GV Sonkin D Reddy A Liu M Murray L Berger MF Monahan JE Morais P Meltzer J Korejwa A Jané-Valbuena J Mapa FA Thibault J Bric-Furlong E Raman P Shipway A Engels IH Cheng J Yu GK Yu J Aspesi P de Silva M Jagtap K Jones MD Wang L Hatton C Palescandolo E Gupta S Mahan S Sougnez C Onofrio RC Liefeld T MacConaill L Winckler W Reich M Li N Mesirov JP Gabriel SB Getz G Ardlie K Chan V Myer VE Weber BL Porter J 《Nature》2012,483(7391):603-607
The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens. 相似文献
175.
The self-templating conformations of yeast prion proteins act as epigenetic elements of inheritance. Yeast prions might provide a mechanism for generating heritable phenotypic diversity that promotes survival in fluctuating environments and the evolution of new traits. However, this hypothesis is highly controversial. Prions that create new traits have not been found in wild strains, leading to the perception that they are rare 'diseases' of laboratory cultivation. Here we biochemically test approximately 700 wild strains of Saccharomyces for [PSI(+)] or [MOT3(+)], and find these prions in many. They conferred diverse phenotypes that were frequently beneficial under selective conditions. Simple meiotic re-assortment of the variation harboured within a strain readily fixed one such trait, making it robust and prion-independent. Finally, we genetically screened for unknown prion elements. Fully one-third of wild strains harboured them. These, too, created diverse, often beneficial phenotypes. Thus, prions broadly govern heritable traits in nature, in a manner that could profoundly expand adaptive opportunities. 相似文献
176.
Keesing F Belden LK Daszak P Dobson A Harvell CD Holt RD Hudson P Jolles A Jones KE Mitchell CE Myers SS Bogich T Ostfeld RS 《Nature》2010,468(7324):647-652
Current unprecedented declines in biodiversity reduce the ability of ecological communities to provide many fundamental ecosystem services. Here we evaluate evidence that reduced biodiversity affects the transmission of infectious diseases of humans, other animals and plants. In principle, loss of biodiversity could either increase or decrease disease transmission. However, mounting evidence indicates that biodiversity loss frequently increases disease transmission. In contrast, areas of naturally high biodiversity may serve as a source pool for new pathogens. Overall, despite many remaining questions, current evidence indicates that preserving intact ecosystems and their endemic biodiversity should generally reduce the prevalence of infectious diseases. 相似文献
177.
Aoki SK Diner EJ de Roodenbeke CT Burgess BR Poole SJ Braaten BA Jones AM Webb JS Hayes CS Cotter PA Low DA 《Nature》2010,468(7322):439-442
Bacteria have developed mechanisms to communicate and compete with one another in diverse environments. A new form of intercellular communication, contact-dependent growth inhibition (CDI), was discovered recently in Escherichia coli. CDI is mediated by the CdiB/CdiA two-partner secretion (TPS) system. CdiB facilitates secretion of the CdiA 'exoprotein' onto the cell surface. An additional small immunity protein (CdiI) protects CDI(+) cells from autoinhibition. The mechanisms by which CDI blocks cell growth and by which CdiI counteracts this growth arrest are unknown. Moreover, the existence of CDI activity in other bacteria has not been explored. Here we show that the CDI growth inhibitory activity resides within the carboxy-terminal region of CdiA (CdiA-CT), and that CdiI binds and inactivates cognate CdiA-CT, but not heterologous CdiA-CT. Bioinformatic and experimental analyses show that multiple bacterial species encode functional CDI systems with high sequence variability in the CdiA-CT and CdiI coding regions. CdiA-CT heterogeneity implies that a range of toxic activities are used during CDI. Indeed, CdiA-CTs from uropathogenic E.?coli and the plant pathogen Dickeya dadantii have different nuclease activities, each providing a distinct mechanism of growth inhibition. Finally, we show that bacteria lacking the CdiA-CT and CdiI coding regions are unable to compete with isogenic wild-type CDI(+) cells both in laboratory media and on a eukaryotic host. Taken together, these results suggest that CDI systems constitute an intricate immunity network with an important function in bacterial competition. 相似文献
178.
Shin J Bossenz M Chung Y Ma H Byron M Taniguchi-Ishigaki N Zhu X Jiao B Hall LL Green MR Jones SN Hermans-Borgmeyer I Lawrence JB Bach I 《Nature》2010,467(7318):977-981
Two forms of X-chromosome inactivation (XCI) ensure the selective silencing of female sex chromosomes during mouse embryogenesis. Imprinted XCI begins with the detection of Xist RNA expression on the paternal X?chromosome (Xp) at about the four-cell stage of embryonic development. In the embryonic tissues of the inner cell mass, a random form of XCI occurs in blastocysts that inactivates either Xp or the maternal X?chromosome (Xm). Both forms of XCI require the non-coding Xist RNA that coats the inactive X?chromosome from which it is expressed. Xist has crucial functions in the silencing of X-linked genes, including Rnf12 (refs 3, 4) encoding the ubiquitin ligase RLIM (RING finger LIM-domain-interacting protein). Here we show, by targeting a conditional knockout of Rnf12 to oocytes where RLIM accumulates to high levels, that the maternal transmission of the mutant X?chromosome (Δm) leads to lethality in female embryos as a result of defective imprinted XCI. We provide evidence that in Δm female embryos the initial formation of Xist clouds and Xp silencing are inhibited. In contrast, embryonic stem cells lacking RLIM are able to form Xist clouds and silence at least some X-linked genes during random XCI. These results assign crucial functions to the maternal deposit of Rnf12/RLIM for the initiation of imprinted XCI. 相似文献
179.
Small (c. 1 cm long) terrestrial planarians found in the United Kingdom, the Netherlands and France are described as a new species, Marionfyfea adventor sp. nov. Individuals of the new species have a patchy brown external appearance with small, seemingly random pale blue-ish patches. They have multiple eyes, uniserial around the anterior end, biserial or triserial laterally for a short distance then sparsely uniserial and lateral to the posterior end. The anatomy is characterized by five or six pairs of ventral testes and a single pair of ovaries adjacent to the pharyngeal pouch. The base of each ovary is surrounded by parovarian cells. The penis is of the inverted type with a basal hemispherical seminal vesicle. Two adenodactyls, one ventral, one dorsal, are present in the common antrum. The only other known species of Marionfyfea is recorded only from the Auckland Islands, New Zealand and we assume that the new species has been introduced to Europe.
http://zoobank.org/urn:lsid:zoobank.org:pub:7AC3D565-0BEB-4B67-8BEC-11A13A70D663 相似文献
180.
A tick vector of Thogoto (THO) virus was shown to secrete a factor in saliva which potentiates the transmission of THO virus to uninfected ticks feeding on an apparently non-viraemic host. The effect of the saliva activated transmission (SAT) factor on the virus occurred at the site of inoculation in the skin and was apparent even when the virus was introduced 3 days after the SAT factor. The results suggest that tick saliva can play an important role in disease transmission by virtue of host modification at the site of feeding. 相似文献