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排序方式: 共有95条查询结果,搜索用时 31 毫秒
71.
Efficient generation and mapping of recessive developmental mutations using ENU mutagenesis 总被引:12,自引:0,他引:12
Herron BJ Lu W Rao C Liu S Peters H Bronson RT Justice MJ McDonald JD Beier DR 《Nature genetics》2002,30(2):185-189
Treatment with N-ethyl-N-nitrosourea (ENU) efficiently generates single-nucleotide mutations in mice. Along with the renewed interest in this approach, much attention has been given recently to large screens with broad aims; however, more finely focused studies have proven very productive as well. Here we show how mutagenesis together with genetic mapping can facilitate the rapid characterization of recessive loci required for normal embryonic development. We screened third-generation progeny of mutagenized mice at embryonic day (E) 18.5 for abnormalities of organogenesis. We ascertained 15 monogenic mutations in the 54 families that were comprehensively analyzed. We carried out the experiment as an outcross, which facilitated the genetic mapping of the mutations by haplotype analysis. We mapped seven of the mutations and identified the affected locus in two lines. Using a hierarchical approach, it is possible to maximize the efficiency of this analysis so that it can be carried out easily with modest infrastructure and resources. 相似文献
72.
The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum 总被引:4,自引:0,他引:4
Howard HC Mount DB Rochefort D Byun N Dupré N Lu J Fan X Song L Rivière JB Prévost C Horst J Simonati A Lemcke B Welch R England R Zhan FQ Mercado A Siesser WB George AL McDonald MP Bouchard JP Mathieu J Delpire E Rouleau GA 《Nature genetics》2002,32(3):384-392
Peripheral neuropathy associated with agenesis of the corpus callosum (ACCPN) is a severe sensorimotor neuropathy associated with mental retardation, dysmorphic features and complete or partial agenesis of the corpus callosum. ACCPN is transmitted in an autosomal recessive fashion and is found at a high frequency in the province of Quebec, Canada. ACCPN has been previously mapped to chromosome 15q. The gene SLC12A6 (solute carrier family 12, member 6), which encodes the K+-Cl- transporter KCC3 and maps within the ACCPN candidate region, was screened for mutations in individuals with ACCPN. Four distinct protein-truncating mutations were found: two in the French Canadian population and two in non-French Canadian families. The functional consequence of the predominant French Canadian mutation (2436delG, Thr813fsX813) was examined by heterologous expression of wildtype and mutant KCC3 in Xenopus laevis oocytes; the truncated mutant is appropriately glycosylated and expressed at the cellular membrane, where it is non-functional. Mice generated with a targeted deletion of Slc12a6 have a locomotor deficit, peripheral neuropathy and a sensorimotor gating deficit, similar to the human disease. Our findings identify mutations in SLC12A6 as the genetic lesion underlying ACCPN and suggest a critical role for SLC12A6 in the development and maintenance of the nervous system. 相似文献
73.
74.
Haiman CA Patterson N Freedman ML Myers SR Pike MC Waliszewska A Neubauer J Tandon A Schirmer C McDonald GJ Greenway SC Stram DO Le Marchand L Kolonel LN Frasco M Wong D Pooler LC Ardlie K Oakley-Girvan I Whittemore AS Cooney KA John EM Ingles SA Altshuler D Henderson BE Reich D 《Nature genetics》2007,39(5):638-644
After the recent discovery that common genetic variation in 8q24 influences inherited risk of prostate cancer, we genotyped 2,973 SNPs in up to 7,518 men with and without prostate cancer from five populations. We identified seven risk variants, five of them previously undescribed, spanning 430 kb and each independently predicting risk for prostate cancer (P = 7.9 x 10(-19) for the strongest association, and P < 1.5 x 10(-4) for five of the variants, after controlling for each of the others). The variants define common genotypes that span a more than fivefold range of susceptibility to cancer in some populations. None of the prostate cancer risk variants aligns to a known gene or alters the coding sequence of an encoded protein. 相似文献
75.
76.
基于遗传算法的伺服系统摩擦参数辨识研究 总被引:12,自引:0,他引:12
LuGre摩擦模型能够精确描述摩擦环节的动态特性 ,但由于其高度非线性 ,使得参数辨识非常困难。针对LuGre摩擦模型 ,提出一种新型的基于遗传算法的模型参数两步辨识方法。首先通过Stribeck曲线 ,辨识出摩擦模型中的静态参数 ,然后由系统的稳态极限环振荡响应 ,辨识出摩擦模型的动态参数。在每一步辨识中 ,均采用遗传算法作为优化工具 ,从而避免了采用线性辩识方法时的局部极小问题。对提出的方法进行了数字仿真 ,并通过设计摩擦补偿环节 ,对辨识参数进行验证 ,结果表明了该方法的有效性。 相似文献
77.
McDole JR Wheeler LW McDonald KG Wang B Konjufca V Knoop KA Newberry RD Miller MJ 《Nature》2012,483(7389):345-349
The intestinal immune system is exposed to a mixture of foreign antigens from diet, commensal flora and potential pathogens. Understanding how pathogen-specific immunity is elicited while avoiding inappropriate responses to the background of innocuous antigens is essential for understanding and treating intestinal infections and inflammatory diseases. The ingestion of protein antigen can induce oral tolerance, which is mediated in part by a subset of intestinal dendritic cells (DCs) that promote the development of regulatory T cells. The lamina propria (LP) underlies the expansive single-cell absorptive villous epithelium and contains a large population of DCs (CD11c(+) CD11b(+) MHCII(+) cells) comprised of two predominant subsets: CD103(+) CX(3)CR1(-) DCs, which promote IgA production, imprint gut homing on lymphocytes and induce the development of regulatory T cells, and CD103(-) CX(3)CR1(+) DCs (with features of macrophages), which promote tumour necrosis factor-α (TNF-α) production, colitis, and the development of T(H)17 T cells. However, the mechanisms by which different intestinal LP-DC subsets capture luminal antigens in vivo remains largely unexplored. Using a minimally disruptive in vivo imaging approach we show that in the steady state, small intestine goblet cells (GCs) function as passages delivering low molecular weight soluble antigens from the intestinal lumen to underlying CD103(+) LP-DCs. The preferential delivery of antigens to DCs with tolerogenic properties implies a key role for this GC function in intestinal immune homeostasis. 相似文献
78.
Adaptive protein evolution at the Adh locus in Drosophila 总被引:75,自引:0,他引:75
Proteins often differ in amino-acid sequence across species. This difference has evolved by the accumulation of neutral mutations by random drift, the fixation of adaptive mutations by selection, or a mixture of the two. Here we propose a simple statistical test of the neutral protein evolution hypothesis based on a comparison of the number of amino-acid replacement substitutions to synonymous substitutions in the coding region of a locus. If the observed substitutions are neutral, the ratio of replacement to synonymous fixed differences between species should be the same as the ratio of replacement to synonymous polymorphisms within species. DNA sequence data on the Adh locus (encoding alcohol dehydrogenase, EC 1.1.1.1) in three species in the Drosophila melanogaster species subgroup do not fit this expectation; instead, there are more fixed replacement differences between species than expected. We suggest that these excess replacement substitutions result from adaptive fixation of selectively advantageous mutations. 相似文献
79.
三轴高精度虚拟仿真转台研究 总被引:3,自引:1,他引:2
提出了三轴虚拟仿真转台系统的基本体系结构及其功能特点。文中着重阐述了虚拟仿真转台系统中的PDIVL,CAD,CAE技术、数据引擎、虚拟装配技术和虚拟样机等技术'同时详细论述了虚拟仿真转台系统的运行方式以及功能结构,其中包括基于PDM技术加以开发、设计转台机械结构并进行图纸管理和生产过程管理;运用OpenGL动画技术和虚拟装配理论实现模型的动态装配;运用虚拟样机技术实现了转台系统的机械结构模型与复杂控制模型的联合分析,实时调节与优化机械结构或控制率来提高系统的机械与控制性能,极大缩短真实转台系统的开发周期。 相似文献
80.
V Labay T Raz D Baron H Mandel H Williams T Barrett R Szargel L McDonald A Shalata K Nosaka S Gregory N Cohen 《Nature genetics》1999,22(3):300-304
Thiamine-responsive megaloblastic anaemia (TRMA), also known as Rogers syndrome, is an early onset, autosomal recessive disorder defined by the occurrence of megaloblastic anaemia, diabetes mellitus and sensorineural deafness, responding in varying degrees to thiamine treatment (MIM 249270). We have previously narrowed the TRMA locus from a 16-cM to a 4-cM interval on chromosomal region 1q23.3 (refs 3,4) and this region has been further refined to a 1.4-cM interval. Previous studies have suggested that deficiency in a high-affinity thiamine transporter may cause this disorder. Here we identify the TRMA gene by positional cloning. We assembled a P1-derived artificial chromosome (PAC) contig spanning the TRMA candidate region. This clarified the order of genetic markers across the TRMA locus, provided 9 new polymorphic markers and narrowed the locus to an approximately 400-kb region. Mutations in a new gene, SLC19A2, encoding a putative transmembrane protein homologous to the reduced folate carrier proteins, were found in all affected individuals in six TRMA families, suggesting that a defective thiamine transporter protein (THTR-1) may underlie the TRMA syndrome. 相似文献