全文获取类型
收费全文 | 152篇 |
免费 | 1篇 |
国内免费 | 3篇 |
专业分类
系统科学 | 3篇 |
理论与方法论 | 5篇 |
现状及发展 | 25篇 |
研究方法 | 27篇 |
综合类 | 90篇 |
自然研究 | 6篇 |
出版年
2021年 | 1篇 |
2019年 | 2篇 |
2018年 | 4篇 |
2017年 | 2篇 |
2016年 | 2篇 |
2015年 | 1篇 |
2014年 | 2篇 |
2013年 | 2篇 |
2012年 | 13篇 |
2011年 | 19篇 |
2010年 | 6篇 |
2009年 | 3篇 |
2008年 | 10篇 |
2007年 | 9篇 |
2006年 | 14篇 |
2005年 | 11篇 |
2004年 | 16篇 |
2003年 | 5篇 |
2002年 | 15篇 |
2000年 | 4篇 |
1997年 | 1篇 |
1996年 | 1篇 |
1993年 | 1篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1986年 | 4篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1974年 | 1篇 |
1970年 | 1篇 |
1969年 | 1篇 |
排序方式: 共有156条查询结果,搜索用时 171 毫秒
71.
72.
Guryev V Saar K Adamovic T Verheul M van Heesch SA Cook S Pravenec M Aitman T Jacob H Shull JD Hubner N Cuppen E 《Nature genetics》2008,40(5):538-545
The abundance and dynamics of copy number variants (CNVs) in mammalian genomes poses new challenges in the identification of their impact on natural and disease phenotypes. We used computational and experimental methods to catalog CNVs in rat and found that they share important functional characteristics with those in human. In addition, 113 one-to-one orthologous genes overlap CNVs in both human and rat, 80 of which are implicated in human disease. CNVs are nonrandomly distributed throughout the genome. Chromosome 18 is a cold spot for CNVs as well as evolutionary rearrangements and segmental duplications, suggesting stringent selective mechanisms underlying CNV genesis or maintenance. By exploiting gene expression data available for rat recombinant inbred lines, we established the functional relationship of CNVs underlying 22 expression quantitative trait loci. These characteristics make the rat an excellent model for studying phenotypic effects of structural variation in relation to human complex traits and disease. 相似文献
73.
Patricia J. Lardone Amalia Rubio Isabel Cerrillo Araceli G��mez-Corvera Antonio Carrillo-Vico Marina Sanchez-Hidalgo Juan M. Guerrero Patricia Fernandez-Riejos Victor Sanchez-Margalet Patrocinio Molinero 《Cellular and molecular life sciences : CMLS》2010,67(18):3163-3172
Melatonin has been proposed as regulating the immune system by affecting cytokine production in immunocompetent cells, enhancing
the production of several T helper (Th)1 cytokines. To further investigate the melatonin’s role in IL-2/IL-2R system, we established
an inducible T-REx expression system in Jurkat cells in which the protein levels of HIOMT enzyme or MT1 receptor were significantly down-regulated upon tetracycline incubation. We found that T-REx Jurkat cells with lower levels
of HIOMT activity, and consequently lower content of endogenous melatonin, showed IL-2 production decrease after activation
with lectin. Likewise, tetracycline-inducible stable cell line expressing MT1 antisense produced decreased amounts of IL-2 (mRNA and protein levels) after stimulation. Moreover, in T-Rex-MT1 cells incubated with tetracycline, a sub-optimal PHA dose failed to induce the early activation marker CD25 on the cell surface.
The results shown here support the relevance of endogenous melatonin and its signaling in T cell activation. 相似文献
74.
Andrea Venerando Oriano Marin Giorgio Cozza Victor H. Bustos Stefania Sarno Lorenzo Alberto Pinna 《Cellular and molecular life sciences : CMLS》2010,67(7):1105-1118
The ability of three isoforms of protein kinase CK1 (α, γ1, and δ) to phosphorylate the N-terminal region of p53 has been assessed using either recombinant p53 or a synthetic peptide
reproducing its 1–28 sequence. Both substrates are readily phosphoylated by CK1δ and CK1α, but not by the γ isoform. Affinity
of full size p53 for CK1 is 3 orders of magnitude higher than that of its N-terminal peptide (K
m 0.82 μM vs 1.51 mM). The preferred target is S20, whose phosphorylation critically relies on E17, while S6 is unaffected
despite displaying the same consensus (E-x-x-S). Our data support the concept that non-primed phosphorylation of p53 by CK1
is an isoform-specific reaction preferentially affecting S20 by a mechanism which is grounded both on a local consensus and
on a remote docking site mapped to the K221RQK224 loop according to modeling and mutational analysis. 相似文献
75.
McKern NM Lawrence MC Streltsov VA Lou MZ Adams TE Lovrecz GO Elleman TC Richards KM Bentley JD Pilling PA Hoyne PA Cartledge KA Pham TM Lewis JL Sankovich SE Stoichevska V Da Silva E Robinson CP Frenkel MJ Sparrow LG Fernley RT Epa VC Ward CW 《Nature》2006,443(7108):218-221
The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14 (ref. 4), grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding. 相似文献
76.
Protein folding is an inherently complex process involving coordination of the intricate networks of weak interactions that stabilize native three-dimensional structures. In the conventional paradigm, simple protein structures are assumed to fold in an all-or-none process that is inaccessible to experiment. Existing experimental methods therefore probe folding mechanisms indirectly. A widely used approach interprets changes in protein stability and/or folding kinetics, induced by engineered mutations, in terms of the structure of the native protein. In addition to limitations in connecting energetics with structure, mutational methods have significant experimental uncertainties and are unable to map complex networks of interactions. In contrast, analytical theory predicts small barriers to folding and the possibility of downhill folding. These theoretical predictions have been confirmed experimentally in recent years, including the observation of global downhill folding. However, a key remaining question is whether downhill folding can indeed lead to the high-resolution analysis of protein folding processes. Here we show, with the use of nuclear magnetic resonance (NMR), that the downhill protein BBL from Escherichia coli unfolds atom by atom starting from a defined three-dimensional structure. Thermal unfolding data on 158 backbone and side-chain protons out of a total of 204 provide a detailed view of the structural events during folding. This view confirms the statistical nature of folding, and exposes the interplay between hydrogen bonding, hydrophobic forces, backbone conformation and side-chain entropy. From the data we also obtain a map of the interaction network in this protein, which reveals the source of folding cooperativity. Our approach can be extended to other proteins with marginal barriers (less than 3RT), providing a new tool for the study of protein folding. 相似文献
77.
Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice 总被引:2,自引:0,他引:2
Wang F Paradkar PN Custodio AO McVey Ward D Fleming MD Campagna D Roberts KA Boyartchuk V Dietrich WF Kaplan J Andrews NC 《Nature genetics》2007,39(8):1025-1032
We undertook a quantitative trait locus (QTL) analysis in mice to identify modifier genes that might influence the severity of human iron disorders. We identified a strong QTL on mouse chromosome 9 that differentially affected macrophage iron burden in C57BL/10J and SWR/J mice. A C57BL/10J missense allele of an evolutionarily conserved gene, Mon1a, cosegregated with the QTL in congenic mouse lines. We present evidence that Mon1a is involved in trafficking of ferroportin, the major mammalian iron exporter, to the surface of iron-recycling macrophages. Differences in amounts of surface ferroportin correlate with differences in cellular iron content. Mon1a is also important for trafficking of cell-surface and secreted molecules unrelated to iron metabolism, suggesting that it has a fundamental role in the mammalian secretory apparatus. 相似文献
78.
针对人类社会发展与地下矿产资源相对短缺的矛盾,阐述了新千年的采矿业必须通过一场新的技术革命,彻底改变传统的生产工艺,合理、有效地利用地下资源,保护环境。同时在分析目前采矿业科技发展现状的基础上,论述了基础理论和实用技术的研究方向。 相似文献
79.
It has often been claimed that Priestley was a skilful experimenter who lacked the capacities to analyze his own experiments and bring them to a theoretical closure. In attempts to revise this view some scholars have alluded to Priestley’s ‘synoptic’ powers while others stressed the contextual role of British Enlightenment in understanding his chemical research. A careful analysis of his pneumatic reports, privileging the dynamics of his experimental practice, uncovers significant yet neglected aspects of Priestley’s science. By focusing on his early experimental conduct and writing on nitrous air, I demonstrate how his methodological and rhetorical devices, far from being consequences of compulsive writing or theoretical naïveté, were deeply entwined with his chemical research. I employ the notion of ‘style of experimental reasoning’ (SER)—derived from A. C. Crombie and I. Hacking—to shed light on the intersection at which Priestley’s unique method, literary style, and epistemology converged to generate scientific knowledge. Establishing Priestley’s SER advances a finer understanding of the interactive character of his pneumatic experimentalism, peculiar dimensions of which have evaded both traditional as well as revisionist scholarship, thus infusing the longstanding historiographic debate over his scientific merits. 相似文献
80.
上世纪70年代以来与微波结构有关的某些计算问题通常是借助共形映射解析解决,且限于一维或二维情形(近年来由于计算机的发展被扩充到三维的某些情形)。本书作者积30多年的经验创立了一种新的方法——基于奇异积分方程(SIE)理论,给出边值问题解的积分表示,从而确定某些二维和三维微波结构的电动力学特性。本书系统全面地论述了这种方法,包括理论基础、用于数值分析的一些算法、以及各种典型应用实例。 相似文献