全文获取类型
收费全文 | 209篇 |
免费 | 2篇 |
专业分类
系统科学 | 2篇 |
教育与普及 | 2篇 |
理论与方法论 | 1篇 |
现状及发展 | 55篇 |
研究方法 | 23篇 |
综合类 | 124篇 |
自然研究 | 4篇 |
出版年
2017年 | 3篇 |
2016年 | 1篇 |
2015年 | 1篇 |
2014年 | 1篇 |
2013年 | 4篇 |
2012年 | 13篇 |
2011年 | 16篇 |
2010年 | 4篇 |
2009年 | 3篇 |
2008年 | 13篇 |
2007年 | 13篇 |
2006年 | 14篇 |
2005年 | 7篇 |
2004年 | 13篇 |
2003年 | 9篇 |
2002年 | 12篇 |
2001年 | 6篇 |
2000年 | 4篇 |
1999年 | 5篇 |
1998年 | 1篇 |
1994年 | 2篇 |
1992年 | 5篇 |
1991年 | 4篇 |
1990年 | 1篇 |
1989年 | 1篇 |
1988年 | 2篇 |
1987年 | 4篇 |
1986年 | 3篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1982年 | 3篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 1篇 |
1977年 | 3篇 |
1976年 | 1篇 |
1975年 | 5篇 |
1974年 | 4篇 |
1973年 | 2篇 |
1972年 | 2篇 |
1971年 | 5篇 |
1970年 | 3篇 |
1969年 | 4篇 |
1967年 | 2篇 |
1966年 | 2篇 |
1965年 | 1篇 |
1946年 | 1篇 |
排序方式: 共有211条查询结果,搜索用时 31 毫秒
101.
Mills RE Walter K Stewart C Handsaker RE Chen K Alkan C Abyzov A Yoon SC Ye K Cheetham RK Chinwalla A Conrad DF Fu Y Grubert F Hajirasouliha I Hormozdiari F Iakoucheva LM Iqbal Z Kang S Kidd JM Konkel MK Korn J Khurana E Kural D Lam HY Leng J Li R Li Y Lin CY Luo R Mu XJ Nemesh J Peckham HE Rausch T Scally A Shi X Stromberg MP Stütz AM Urban AE Walker JA Wu J Zhang Y Zhang ZD Batzer MA Ding L Marth GT McVean G Sebat J Snyder M Wang J Ye K Eichler EE Gerstein MB Hurles ME Lee C McCarroll SA 《Nature》2011,470(7332):59-65
Genomic structural variants (SVs) are abundant in humans, differing from other forms of variation in extent, origin and functional impact. Despite progress in SV characterization, the nucleotide resolution architecture of most SVs remains unknown. We constructed a map of unbalanced SVs (that is, copy number variants) based on whole genome DNA sequencing data from 185 human genomes, integrating evidence from complementary SV discovery approaches with extensive experimental validations. Our map encompassed 22,025 deletions and 6,000 additional SVs, including insertions and tandem duplications. Most SVs (53%) were mapped to nucleotide resolution, which facilitated analysing their origin and functional impact. We examined numerous whole and partial gene deletions with a genotyping approach and observed a depletion of gene disruptions amongst high frequency deletions. Furthermore, we observed differences in the size spectra of SVs originating from distinct formation mechanisms, and constructed a map of SV hotspots formed by common mechanisms. Our analytical framework and SV map serves as a resource for sequencing-based association studies. 相似文献
102.
Dorner M Horwitz JA Robbins JB Barry WT Feng Q Mu K Jones CT Schoggins JW Catanese MT Burton DR Law M Rice CM Ploss A 《Nature》2011,474(7350):208-211
Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin comprise the minimal human factors required to render mouse cells permissive to HCV entry in vitro, we attempted murine humanization via a genetic approach. Here we show that expression of two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We establish a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class I for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as showing that a recombinant vaccinia virus vector induces humoral immunity and confers partial protection against heterologous challenge. This system recapitulates a portion of the HCV life cycle in an immunocompetent rodent for the first time, opening opportunities for studying viral pathogenesis and immunity and comprising an effective platform for testing HCV entry inhibitors in vivo. 相似文献
103.
Walter Riofrio 《Foundations of Science》2012,17(3):277-289
Lately there has been a growing interest in evolutionary studies concerning how the regularities and patterns found in the living cell could have emerged spontaneously by way of self-assembly and self-organization. It is reasonable to postulate that the chemical compounds found in the primitive Earth would have mostly been very simple in nature, and would have been immersed in the natural dynamics of the physical world, some of which would have involved self-organization. It seems likely that some molecular processes self-organized spontaneously into a hierarchy of complex behaviours. Our conceptual search herein reaches back to the time when prebiotic phenomena began to take shape. This was before the origin of life, so in this paper we hope to shed new light on some of the theoretical issues that surround the ways in which cellular organization might have evolved without the aid of replicated information. 相似文献
104.
我们对柏拉图之前的希腊情况知之甚少,然而公元前6世纪出现的一种特殊文学样式留下了宝贵的历史资料。在这个时期曾经有一些视野较为宽阔的关于宇宙及其起源的书籍问世,它们在特殊的环境中获得繁荣。这些书籍主要由两条支流——思想和文学汇集而成,它们超越了狭小的地域边界,广为流传的是:智慧的宣言和宇宙开创的神话。到目前为止,我们没有理由将希腊人——荷马,赫西俄德或俄耳甫斯神话的宇宙发生论从其东方副本(极相似的人或物)中分离出来。很明显,它们出自同一个家庭,而且有不少证据显示出前苏格拉底的哲学家们依然在步东方宇宙发生论的后尘。 相似文献
105.
Road track surveys were a poor index of cougar density in southern Utah. The weak relationship we found between track finding frequency and cougar density undoubtedly resulted in part from the fact that available roads do not sample properly from the nonuniformly distributed cougar population. However, the significantly positive relationship ( r 2 = .73) we found between track-finding frequency and number of cougar home ranges crossing the survey road suggested the technique may be of use in monitoring cougar populations where road abundance and location allow the population to be sampled properly. The amount of variance in track-finding frequency unexplained by number of home ranges overlapping survey roads indicates the index may be useful in demonstrating only relatively large changes in cougar population size. 相似文献
106.
Serena Stadler Chi Huu Nguyen Helga Schachner Daniela Milovanovic Silvio Holzner Stefan Brenner Julia Eichsteininger Mira Stadler Daniel Senfter Liselotte Krenn Wolfgang M. Schmidt Nicole Huttary Sigurd Krieger Oskar Koperek Zsuzsanna Bago-Horvath Konstantin Alexander Brendel Brigitte Marian Oliver de Wever Robert M. Mader Benedikt Giessrigl Walter Jäger Helmut Dolznig Georg Krupitza 《Cellular and molecular life sciences : CMLS》2017,74(10):1907-1921
Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca2+ levels were measured and pharmacological- or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca2+, Ca2+-calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca2+ release. Thus, Ca2+ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour–stroma interaction. 相似文献
107.
Knowing how bats select different habitats in response to environmental changes provides a framework for anticipating the likely consequences of changes in climate or vegetation. In this study we assessed the presence of greater horseshoe bats (Rhinolophus ferrumequinum) and their foraging behavior. This study depicts an effective approach for seasonal responses of habitat selection by Chiroptera. 相似文献
108.
Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study 总被引:2,自引:0,他引:2
JA Mattison GS Roth TM Beasley EM Tilmont AM Handy RL Herbert DL Longo DB Allison JE Young M Bryant D Barnard WF Ward W Qi DK Ingram R de Cabo 《Nature》2012,489(7415):318-321
Calorie restriction (CR), a reduction of 10–40% in intake of a nutritious diet, is often reported as the most robust non-genetic mechanism to extend lifespan and healthspan. CR is frequently used as a tool to understand mechanisms behind ageing and age-associated diseases. In addition to and independently of increasing lifespan, CR has been reported to delay or prevent the occurrence of many chronic diseases in a variety of animals. Beneficial effects of CR on outcomes such as immune function, motor coordination and resistance to sarcopenia in rhesus monkeys have recently been reported. We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. Our findings contrast with an ongoing study at the Wisconsin National Primate Research Center (WNPRC), which reported improved survival associated with 30% CR initiated in adult rhesus monkeys (7–14?years) and a preliminary report with a small number of CR monkeys. Over the years, both NIA and WNPRC have extensively documented beneficial health effects of CR in these two apparently parallel studies. The implications of the WNPRC findings were important as they extended CR findings beyond the laboratory rodent and to a long-lived primate. Our study suggests a separation between health effects, morbidity and mortality, and similar to what has been shown in rodents, study design, husbandry and diet composition may strongly affect the life-prolonging effect of CR in a long-lived nonhuman primate. 相似文献
109.
Despite the broad conceptual and applied relevance of how the number of species or endemics changes with area (the species-area and endemics-area relationships (SAR and EAR)), our understanding of universality and pervasiveness of these patterns across taxa and regions has remained limited. The SAR has traditionally been approximated by a power law, but recent theories predict a triphasic SAR in logarithmic space, characterized by steeper increases in species richness at both small and large spatial scales. Here we uncover such universally upward accelerating SARs for amphibians, birds and mammals across the world’s major landmasses. Although apparently taxon-specific and continent-specific, all curves collapse into one universal function after the area is rescaled by using the mean range sizes of taxa within continents. In addition, all EARs approximately follow a power law with a slope close to 1, indicating that for most spatial scales there is roughly proportional species extinction with area loss. These patterns can be predicted by a simulation model based on the random placement of contiguous ranges within a domain. The universality of SARs and EARs after rescaling implies that both total and endemic species richness within an area, and also their rate of change with area, can be estimated by using only the knowledge of mean geographic range size in the region and mean species richness at one spatial scale. 相似文献
110.
Endocytosis functions to recycle plasma membrane components, to regulate cell-surface expression of signalling receptors and to internalize nutrients in all eukaryotic cells. Internalization of proteins, lipids and other cargo can occur by one of several pathways that have different, but often overlapping, molecular requirements. To mediate endocytosis, effectors assemble transiently underneath the plasma membrane, carry out the mechanics of membrane deformation, cargo selection and vesicle internalization, and then disassemble. The mechanism by which endocytosis initiates at particular locations on the plasma membrane has remained unknown. Sites of endocytosis might be formed randomly, induced by stochastic protein and/or lipid clustering. Alternatively, endocytosis might initiate at specific locations. Here we describe large immobile protein assemblies at the plasma membrane in the yeast Saccharomyces cerevisiae that mark endocytic sites. These structures, termed eisosomes (from the Greek 'eis', meaning into or portal, and 'soma', meaning body), are composed primarily of two cytoplasmic proteins, Pil1 and Lsp1. A plasma membrane protein, Sur7, localizes to eisosomes. These structures colocalize with sites of protein and lipid endocytosis, and their components genetically interact with known endocytic effectors. Loss of Pil1 leads to clustering of eisosome remnants and redirects endocytosis and endocytic effector proteins to these clusters. 相似文献