全文获取类型
收费全文 | 336篇 |
免费 | 0篇 |
专业分类
系统科学 | 5篇 |
理论与方法论 | 2篇 |
现状及发展 | 50篇 |
研究方法 | 62篇 |
综合类 | 193篇 |
自然研究 | 24篇 |
出版年
2018年 | 5篇 |
2017年 | 4篇 |
2016年 | 3篇 |
2015年 | 1篇 |
2014年 | 3篇 |
2013年 | 3篇 |
2012年 | 20篇 |
2011年 | 45篇 |
2010年 | 11篇 |
2008年 | 23篇 |
2007年 | 21篇 |
2006年 | 21篇 |
2005年 | 19篇 |
2004年 | 37篇 |
2003年 | 21篇 |
2002年 | 14篇 |
2001年 | 6篇 |
2000年 | 11篇 |
1999年 | 4篇 |
1997年 | 1篇 |
1996年 | 2篇 |
1993年 | 1篇 |
1992年 | 2篇 |
1990年 | 3篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1986年 | 4篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 2篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1979年 | 5篇 |
1978年 | 1篇 |
1976年 | 3篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1973年 | 4篇 |
1972年 | 5篇 |
1971年 | 3篇 |
1970年 | 2篇 |
1969年 | 4篇 |
1968年 | 1篇 |
1967年 | 2篇 |
1966年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有336条查询结果,搜索用时 46 毫秒
91.
Parkhill J Sebaihia M Preston A Murphy LD Thomson N Harris DE Holden MT Churcher CM Bentley SD Mungall KL Cerdeño-Tárraga AM Temple L James K Harris B Quail MA Achtman M Atkin R Baker S Basham D Bason N Cherevach I Chillingworth T Collins M Cronin A Davis P Doggett J Feltwell T Goble A Hamlin N Hauser H Holroyd S Jagels K Leather S Moule S Norberczak H O'Neil S Ormond D Price C Rabbinowitsch E Rutter S Sanders M Saunders D Seeger K Sharp S Simmonds M Skelton J Squares R Squares S Stevens K 《Nature genetics》2003,35(1):32-40
Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica are closely related Gram-negative beta-proteobacteria that colonize the respiratory tracts of mammals. B. pertussis is a strict human pathogen of recent evolutionary origin and is the primary etiologic agent of whooping cough. B. parapertussis can also cause whooping cough, and B. bronchiseptica causes chronic respiratory infections in a wide range of animals. We sequenced the genomes of B. bronchiseptica RB50 (5,338,400 bp; 5,007 predicted genes), B. parapertussis 12822 (4,773,551 bp; 4,404 genes) and B. pertussis Tohama I (4,086,186 bp; 3,816 genes). Our analysis indicates that B. parapertussis and B. pertussis are independent derivatives of B. bronchiseptica-like ancestors. During the evolution of these two host-restricted species there was large-scale gene loss and inactivation; host adaptation seems to be a consequence of loss, not gain, of function, and differences in virulence may be related to loss of regulatory or control functions. 相似文献
92.
Adaptation of core mechanisms to generate cell polarity 总被引:34,自引:0,他引:34
Cell polarity is defined as asymmetry in cell shape, protein distributions and cell functions. It is characteristic of single-cell organisms, including yeast and bacteria, and cells in tissues of multi-cell organisms such as epithelia in worms, flies and mammals. This diversity raises several questions: do different cell types use different mechanisms to generate polarity, how is polarity signalled, how do cells react to that signal, and how is structural polarity translated into specialized functions? Analysis of evolutionarily diverse cell types reveals that cell-surface landmarks adapt core pathways for cytoskeleton assembly and protein transport to generate cell polarity. 相似文献
93.
94.
Arterial dilations in response to calcitonin gene-related peptide involve activation of K+ channels 总被引:21,自引:0,他引:21
Calcitonin gene-related peptide (CGRP) is a 37-amino-acid peptide produced by alternative processing of messenger RNA from the calcitonin gene. CGRP is one of the most potent vasodilators known. It occurs in and is released from perivascular nerves and has been detected in the blood stream, suggesting that it is important in the control of blood flow. The mechanism by which it dilates arteries is not known. Here, we report that arterial dilations in response to CGRP are partially reversed by blockers of the ATP-sensitive potassium channel (K(ATP)), glibenclamide and barium. We also show that CGRP hyperpolarizes arterial smooth muscle and that blockers of K(ATP) channels reverse this hyperpolarization. Finally, we show that CGRP opens single K+ channels in patches on single smooth muscle cells from the same arteries. We propose that activation of K(ATP) channels underlies a substantial part of the relaxation produced by CGRP. 相似文献
95.
Noel Edwards Catriona M. H. Anderson Nichola J. Conlon Andrew K. Watson Rebecca J. Hall Timothy R. Cheek T. Martin Embley David T. Thwaites 《Cellular and molecular life sciences : CMLS》2018,75(5):921-938
Amino acid transporters are essential components of prokaryote and eukaryote cells, possess distinct physiological functions, and differ markedly in substrate specificity. Amino acid transporters can be both drug targets and drug transporters (bioavailability, targeting) with many monogenic disorders resulting from dysfunctional membrane transport. The largest collection of amino acid transporters (including the mammalian SLC6, SLC7, SLC32, SLC36, and SLC38 families), across all kingdoms of life, is within the Amino acid-Polyamine-organoCation (APC) superfamily. The LeuT-fold is a paradigm structure for APC superfamily amino acid transporters and carriers of sugars, neurotransmitters, electrolytes, osmolytes, vitamins, micronutrients, signalling molecules, and organic and fatty acids. Each transporter is specific for a unique sub-set of solutes, specificity being determined by how well a substrate fits into each binding pocket. However, the molecular basis of substrate selectivity remains, by and large, elusive. Using an integrated computational and experimental approach, we demonstrate that a single position within the LeuT-fold can play a crucial role in determining substrate specificity in mammalian and arthropod amino acid transporters within the APC superfamily. Systematic mutation of the amino acid residue occupying the equivalent position to LeuT V104 titrates binding pocket space resulting in dramatic changes in substrate selectivity in exemplar APC amino acid transporters including PAT2 (SLC36A2) and SNAT5 (SLC38A5). Our work demonstrates how a single residue/site within an archetypal structural motif can alter substrate affinity and selectivity within this important superfamily of diverse membrane transporters. 相似文献
96.
97.
Danielle Kamato Partha Mitra Felicity Davis Narin Osman Rebecca Chaplin Peter J. Cabot Rizwana Afroz Walter Thomas Wenhua Zheng Harveen Kaur Margaret Brimble Peter J. Little 《Cellular and molecular life sciences : CMLS》2017,74(8):1379-1390
Seven transmembrane G protein-coupled receptors (GPCRs) have gained much interest in recent years as it is the largest class among cell surface receptors. G proteins lie in the heart of GPCRs signalling and therefore can be therapeutically targeted to overcome complexities in GPCR responses and signalling. G proteins are classified into four families (Gi, Gs, G12/13 and Gq); Gq is further subdivided into four classes. Among them Gαq and Gαq/11 isoforms are most crucial and ubiquitously expressed; these isoforms are almost 88% similar at their amino acid sequence but may exhibit functional divergences. However, uncertainties often arise about Gαq and Gαq/11 inhibitors, these G proteins might also have suitability to the invention of novel-specific inhibitors for each isoforms. YM-254890 and UBO-QIC are discovered as potent inhibitors of Gαq functions and also investigated in thrombin protease-activated receptor (PAR)-1 inhibitors and platelet aggregation inhibition. The most likely G protein involved in PAR-1 stimulates responses is one of the Gαq family isoforms. In this review, we highlight the molecular structures and pharmacological responses of Gαq family which may reflect the biochemical and molecular role of Gαq and Gαq/11. The advanced understanding of Gαq and Gαq/11 role in GPCR signalling may shed light on our understanding on cell biology, cellular physiology and pathophysiology and also lead to the development of novel therapeutic agents for a number of diseases. 相似文献
98.
通过对一百多个星系形成数值模拟和试验的分析,现在可以对引力的树结构算法和平滑粒子流体力学(Smoothed Particle Hydrodynamics,SPH)这两种数值模拟技术的准确性和可靠性做定量的估计。这些结果表明若给SPH方法中使用的平滑半径(h)固定一个下限值,可能会导致数值解的准确性严重下降。若随时调整h的值使得SPH方法计算粒子的邻近粒子数总和保持不变,则可以避免这种有害的影响,使准确性得到提高。结果还表明为了可以准确地模拟原星系的坍缩,小心地选取那些影响引力加速度准确性的参量尤其重要。 相似文献
99.
Tenesa A Farrington SM Prendergast JG Porteous ME Walker M Haq N Barnetson RA Theodoratou E Cetnarskyj R Cartwright N Semple C Clark AJ Reid FJ Smith LA Kavoussanakis K Koessler T Pharoah PD Buch S Schafmayer C Tepel J Schreiber S Völzke H Schmidt CO Hampe J Chang-Claude J Hoffmeister M Brenner H Wilkening S Canzian F Capella G Moreno V Deary IJ Starr JM Tomlinson IP Kemp Z Howarth K Carvajal-Carmona L Webb E Broderick P Vijayakrishnan J Houlston RS Rennert G Ballinger D Rozek L Gruber SB 《Nature genetics》2008,40(5):631-637
In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 x 10(-10)), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 x 10(-26)) and 18q21 (rs4939827; OR = 1.2; P = 7.8 x 10(-28)). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology. 相似文献
100.
Tomlinson IP Webb E Carvajal-Carmona L Broderick P Howarth K Pittman AM Spain S Lubbe S Walther A Sullivan K Jaeger E Fielding S Rowan A Vijayakrishnan J Domingo E Chandler I Kemp Z Qureshi M Farrington SM Tenesa A Prendergast JG Barnetson RA Penegar S Barclay E Wood W Martin L Gorman M Thomas H Peto J Bishop DT Gray R Maher ER Lucassen A Kerr D Evans DG;CORGI Consortium Schafmayer C Buch S Völzke H Hampe J Schreiber S John U Koessler T Pharoah P van Wezel T Morreau H Wijnen JT Hopper JL 《Nature genetics》2008,40(5):623-630
To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition. 相似文献