全文获取类型
收费全文 | 255篇 |
免费 | 1篇 |
国内免费 | 1篇 |
专业分类
系统科学 | 2篇 |
丛书文集 | 2篇 |
教育与普及 | 1篇 |
理论与方法论 | 1篇 |
现状及发展 | 64篇 |
研究方法 | 59篇 |
综合类 | 118篇 |
自然研究 | 10篇 |
出版年
2019年 | 1篇 |
2018年 | 12篇 |
2017年 | 3篇 |
2016年 | 8篇 |
2015年 | 5篇 |
2014年 | 7篇 |
2013年 | 5篇 |
2012年 | 18篇 |
2011年 | 46篇 |
2010年 | 13篇 |
2009年 | 4篇 |
2008年 | 15篇 |
2007年 | 21篇 |
2006年 | 19篇 |
2005年 | 17篇 |
2004年 | 15篇 |
2003年 | 17篇 |
2002年 | 17篇 |
2000年 | 1篇 |
1998年 | 2篇 |
1995年 | 1篇 |
1993年 | 1篇 |
1991年 | 1篇 |
1979年 | 3篇 |
1976年 | 1篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1972年 | 2篇 |
排序方式: 共有257条查询结果,搜索用时 15 毫秒
101.
Julie Lecomte Krystel Louis Benoit Detry Silvia Blacher Vincent Lambert Sandrine Bekaert Carine Munaut Jenny Paupert Pierre Blaise Jean-Michel Foidart Jean-Marie Rakic Stephen M. Krane Agn��s Noel 《Cellular and molecular life sciences : CMLS》2011,68(4):677-686
In this study, we evaluate the potential involvement of collagenase-3 (MMP13), a matrix metalloproteinase (MMP) family member, in the exudative form of age-related macular degeneration characterized by a neovascularisation into the choroid. RT-PCR analysis revealed that human neovascular membranes issued from patients with AMD expressed high levels of Mmp13. The contribution of MMP13 in choroidal neovascularization (CNV) formation was explored by using a murine model of laser-induced CNV and applying it to wild-type mice (WT) and Mmp13-deficient mice (Mmp13 ?/? mice). Angiogenic and inflammatory reactions were explored by immunohistochemistry. The implication of bone marrow (BM)-derived cells was determined by BM engraftment into irradiated mice and by injecting mesenchymal stem cells (MSC) isolated from WT BM. The deficiency of Mmp13 impaired CNV formation which was fully restored by WT BM engraftment and partially rescued by several injections of WT MSC. The present study sheds light on a novel function of MMP13 during BM-dependent choroidal vascularization and provides evidence for a role for MSC in the pathogenesis of CNV. 相似文献
102.
103.
Relativism is one of the most problematic terms associated with philosophical discourse, with Feyerabend considered among the most important twentieth century theorists subscribing to it. This paper provides a detailed overview of relativist positions advanced in Feyerabend's mid-to-late work and investigates the associated epistemic and political applications. Emphasis is placed on how Feyerabend supported certain aspects of relativism, and at what stage he rejected others. It is noted that Feyerabend had already imposed limitations on relativism in Farewell to Reason, in which he entertained the possibility of epistemic definition within stable contexts, and advanced the notion that opportunities and equality associated with political and cultural units could only be valid within a democratic system. In Conquest of Abundance, political relativism is largely discarded, while epistemological relativism is increasingly treated as an appeal for diversity in all areas.In this re-reading of his work, it becomes clear that Feyerabend was already advocating a moderate form of epistemic and political relativism in the middle of his career, which he subsequently developed in the direction of “ontological pluralism” in his later work. This paper thus shows that Feyerabend's relativism should not be completely rejected, but rather that it continues to offer interesting food for thought. 相似文献
104.
Prediction of central nervous system embryonal tumour outcome based on gene expression. 总被引:75,自引:0,他引:75
Scott L Pomeroy Pablo Tamayo Michelle Gaasenbeek Lisa M Sturla Michael Angelo Margaret E McLaughlin John Y H Kim Liliana C Goumnerova Peter M Black Ching Lau Jeffrey C Allen David Zagzag James M Olson Tom Curran Cynthia Wetmore Jaclyn A Biegel Tomaso Poggio Shayan Mukherjee Ryan Rifkin Andrea Califano Gustavo Stolovitzky David N Louis Jill P Mesirov Eric S Lander Todd R Golub 《Nature》2002,415(6870):436-442
Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated, and patients' response to therapy is difficult to predict. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis. 相似文献
105.
106.
Morin RD Mendez-Lago M Mungall AJ Goya R Mungall KL Corbett RD Johnson NA Severson TM Chiu R Field M Jackman S Krzywinski M Scott DW Trinh DL Tamura-Wells J Li S Firme MR Rogic S Griffith M Chan S Yakovenko O Meyer IM Zhao EY Smailus D Moksa M Chittaranjan S Rimsza L Brooks-Wilson A Spinelli JJ Ben-Neriah S Meissner B Woolcock B Boyle M McDonald H Tam A Zhao Y Delaney A Zeng T Tse K Butterfield Y Birol I Holt R Schein J Horsman DE Moore R Jones SJ Connors JM Hirst M Gascoyne RD Marra MA 《Nature》2011,476(7360):298-303
Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis. 相似文献
107.
Grbić M Van Leeuwen T Clark RM Rombauts S Rouzé P Grbić V Osborne EJ Dermauw W Ngoc PC Ortego F Hernández-Crespo P Diaz I Martinez M Navajas M Sucena É Magalhães S Nagy L Pace RM Djuranović S Smagghe G Iga M Christiaens O Veenstra JA Ewer J Villalobos RM Hutter JL Hudson SD Velez M Yi SV Zeng J Pires-daSilva A Roch F Cazaux M Navarro M Zhurov V Acevedo G Bjelica A Fawcett JA Bonnet E Martens C Baele G Wissler L Sanchez-Rodriguez A Tirry L Blais C Demeestere K Henz SR Gregory TR Mathieu J 《Nature》2011,479(7374):487-492
108.
Locke DP Hillier LW Warren WC Worley KC Nazareth LV Muzny DM Yang SP Wang Z Chinwalla AT Minx P Mitreva M Cook L Delehaunty KD Fronick C Schmidt H Fulton LA Fulton RS Nelson JO Magrini V Pohl C Graves TA Markovic C Cree A Dinh HH Hume J Kovar CL Fowler GR Lunter G Meader S Heger A Ponting CP Marques-Bonet T Alkan C Chen L Cheng Z Kidd JM Eichler EE White S Searle S Vilella AJ Chen Y Flicek P Ma J Raney B Suh B Burhans R Herrero J Haussler D Faria R Fernando O Darré F Farré D Gazave E Oliva M 《Nature》2011,469(7331):529-533
'Orang-utan' is derived from a Malay term meaning 'man of the forest' and aptly describes the southeast Asian great apes native to Sumatra and Borneo. The orang-utan species, Pongo abelii (Sumatran) and Pongo pygmaeus (Bornean), are the most phylogenetically distant great apes from humans, thereby providing an informative perspective on hominid evolution. Here we present a Sumatran orang-utan draft genome assembly and short read sequence data from five Sumatran and five Bornean orang-utan genomes. Our analyses reveal that, compared to other primates, the orang-utan genome has many unique features. Structural evolution of the orang-utan genome has proceeded much more slowly than other great apes, evidenced by fewer rearrangements, less segmental duplication, a lower rate of gene family turnover and surprisingly quiescent Alu repeats, which have played a major role in restructuring other primate genomes. We also describe a primate polymorphic neocentromere, found in both Pongo species, emphasizing the gradual evolution of orang-utan genome structure. Orang-utans have extremely low energy usage for a eutherian mammal, far lower than their hominid relatives. Adding their genome to the repertoire of sequenced primates illuminates new signals of positive selection in several pathways including glycolipid metabolism. From the population perspective, both Pongo species are deeply diverse; however, Sumatran individuals possess greater diversity than their Bornean counterparts, and more species-specific variation. Our estimate of Bornean/Sumatran speciation time, 400,000?years ago, is more recent than most previous studies and underscores the complexity of the orang-utan speciation process. Despite a smaller modern census population size, the Sumatran effective population size (N(e)) expanded exponentially relative to the ancestral N(e) after the split, while Bornean N(e) declined over the same period. Overall, the resources and analyses presented here offer new opportunities in evolutionary genomics, insights into hominid biology, and an extensive database of variation for conservation efforts. 相似文献
109.
Gibbs DJ Lee SC Isa NM Gramuglia S Fukao T Bassel GW Correia CS Corbineau F Theodoulou FL Bailey-Serres J Holdsworth MJ 《Nature》2011,479(7373):415-418
110.
DNA double strand breaks (DSBs) in repetitive sequences are a potent source of genomic instability, owing to the possibility of non-allelic homologous recombination (NAHR). Repetitive sequences are especially at risk during meiosis, when numerous programmed DSBs are introduced into the genome to initiate meiotic recombination. In the repetitive ribosomal DNA (rDNA) array of the budding yeast Saccharomyces cerevisiae, meiotic DSB formation is prevented in part through Sir2-dependent heterochromatin formation. Here we show that the edges of the rDNA array are exceptionally susceptible to meiotic DSBs, revealing an inherent heterogeneity in the rDNA array. We find that this localized DSB susceptibility necessitates a border-specific protection system consisting of the meiotic ATPase Pch2 and the origin recognition complex subunit Orc1. Upon disruption of these factors, DSB formation and recombination increased specifically in the outermost rDNA repeats, leading to NAHR and rDNA instability. Notably, the Sir2-dependent heterochromatin of the rDNA itself was responsible for the induction of DSBs at the rDNA borders in pch2Δ cells. Thus, although the activity of Sir2 globally prevents meiotic DSBs in the rDNA, it creates a highly permissive environment for DSB formation at the junctions between heterochromatin and euchromatin. Heterochromatinized repetitive DNA arrays are abundant in most eukaryotic genomes. Our data define the borders of such chromatin domains as distinct high-risk regions for meiotic NAHR, the protection of which may be a universal requirement to prevent meiotic genome rearrangements that are associated with genomic diseases and birth defects. 相似文献