全文获取类型
收费全文 | 189篇 |
免费 | 0篇 |
专业分类
系统科学 | 9篇 |
丛书文集 | 1篇 |
理论与方法论 | 1篇 |
现状及发展 | 42篇 |
研究方法 | 36篇 |
综合类 | 96篇 |
自然研究 | 4篇 |
出版年
2021年 | 1篇 |
2020年 | 1篇 |
2019年 | 3篇 |
2018年 | 1篇 |
2017年 | 2篇 |
2016年 | 4篇 |
2015年 | 1篇 |
2014年 | 1篇 |
2013年 | 3篇 |
2012年 | 20篇 |
2011年 | 29篇 |
2010年 | 9篇 |
2008年 | 9篇 |
2007年 | 12篇 |
2006年 | 14篇 |
2005年 | 13篇 |
2004年 | 18篇 |
2003年 | 13篇 |
2002年 | 11篇 |
1992年 | 1篇 |
1986年 | 3篇 |
1985年 | 8篇 |
1984年 | 8篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1977年 | 2篇 |
排序方式: 共有189条查询结果,搜索用时 449 毫秒
101.
Feedback repression is required for mammalian circadian clock function 总被引:13,自引:0,他引:13
Sato TK Yamada RG Ukai H Baggs JE Miraglia LJ Kobayashi TJ Welsh DK Kay SA Ueda HR Hogenesch JB 《Nature genetics》2006,38(3):312-319
102.
Nicholas AK Khurshid M Désir J Carvalho OP Cox JJ Thornton G Kausar R Ansar M Ahmad W Verloes A Passemard S Misson JP Lindsay S Gergely F Dobyns WB Roberts E Abramowicz M Woods CG 《Nature genetics》2010,42(11):1010-1014
Autosomal recessive primary microcephaly (MCPH) is a disorder of neurodevelopment resulting in a small brain. We identified WDR62 as the second most common cause of MCPH after finding homozygous missense and frame-shifting mutations in seven MCPH families. In human cell lines, we found that WDR62 is a spindle pole protein, as are ASPM and STIL, the MCPH7 and MCHP7 proteins. Mutant WDR62 proteins failed to localize to the mitotic spindle pole. In human and mouse embryonic brain, we found that WDR62 expression was restricted to neural precursors undergoing mitosis. These data lend support to the hypothesis that the exquisite control of the cleavage furrow orientation in mammalian neural precursor cell mitosis, controlled in great part by the centrosomes and spindle poles, is critical both in causing MCPH when perturbed and, when modulated, generating the evolutionarily enlarged human brain. 相似文献
103.
Molecular coupling of Tsix regulation and pluripotency 总被引:1,自引:0,他引:1
Navarro P Oldfield A Legoupi J Festuccia N Dubois A Attia M Schoorlemmer J Rougeulle C Chambers I Avner P 《Nature》2010,468(7322):457-460
104.
Song MS Salmena L Carracedo A Egia A Lo-Coco F Teruya-Feldstein J Pandolfi PP 《Nature》2008,455(7214):813-817
Nuclear exclusion of the PTEN (phosphatase and tensin homologue deleted in chromosome 10) tumour suppressor has been associated with cancer progression. However, the mechanisms leading to this aberrant PTEN localization in human cancers are currently unknown. We have previously reported that ubiquitinylation of PTEN at specific lysine residues regulates its nuclear-cytoplasmic partitioning. Here we show that functional promyelocytic leukaemia protein (PML) nuclear bodies co-ordinate PTEN localization by opposing the action of a previously unknown PTEN-deubiquitinylating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), and that the integrity of this molecular framework is required for PTEN to be able to enter the nucleus. We find that PTEN is aberrantly localized in acute promyelocytic leukaemia, in which PML function is disrupted by the PML-RARalpha fusion oncoprotein. Remarkably, treatment with drugs that trigger PML-RARalpha degradation, such as all-trans retinoic acid or arsenic trioxide, restore nuclear PTEN. We demonstrate that PML opposes the activity of HAUSP towards PTEN through a mechanism involving the adaptor protein DAXX (death domain-associated protein). In support of this paradigm, we show that HAUSP is overexpressed in human prostate cancer and is associated with PTEN nuclear exclusion. Thus, our results delineate a previously unknown PML-DAXX-HAUSP molecular network controlling PTEN deubiquitinylation and trafficking, which is perturbed by oncogenic cues in human cancer, in turn defining a new deubiquitinylation-dependent model for PTEN subcellular compartmentalization. 相似文献
105.
Case Study research is characterized by the employment of multiple data gathering methods. In this paper, I examine the concurrent use of participant observation and qualitative interviews. The question I examine is: what is the rationale behind their combination in case study research? In the literature on case study research, the two most common reasons for using multiple methods appeal to comprehensiveness and convergent confirmation respectively. I argue that there is a third significant, yet overlooked, way to motivate the joint use of participant observation and qualitative interviews: the methods may generate complementary evidence and this puts the researcher in a better position to confirm that her data manifest central epistemic values and so are suitable as a basis for providing an adequate answer to her research question. I refer to this as the rationale of “blended epistemic value validation”. 相似文献
106.
Reysenbach AL Liu Y Banta AB Beveridge TJ Kirshtein JD Schouten S Tivey MK Von Damm KL Voytek MA 《Nature》2006,442(7101):444-447
Deep-sea hydrothermal vents are important in global biogeochemical cycles, providing biological oases at the sea floor that are supported by the thermal and chemical flux from the Earth's interior. As hot, acidic and reduced hydrothermal fluids mix with cold, alkaline and oxygenated sea water, minerals precipitate to form porous sulphide-sulphate deposits. These structures provide microhabitats for a diversity of prokaryotes that exploit the geochemical and physical gradients in this dynamic ecosystem. It has been proposed that fluid pH in the actively venting sulphide structures is generally low (pH < 4.5), yet no extreme thermoacidophile has been isolated from vent deposits. Culture-independent surveys based on ribosomal RNA genes from deep-sea hydrothermal deposits have identified a widespread euryarchaeotal lineage, DHVE2 (deep-sea hydrothermal vent euryarchaeotic 2). Despite the ubiquity and apparent deep-sea endemism of DHVE2, cultivation of this group has been unsuccessful and thus its metabolism remains a mystery. Here we report the isolation and cultivation of a member of the DHVE2 group, which is an obligate thermoacidophilic sulphur- or iron-reducing heterotroph capable of growing from pH 3.3 to 5.8 and between 55 and 75 degrees C. In addition, we demonstrate that this isolate constitutes up to 15% of the archaeal population, providing evidence that thermoacidophiles may be key players in the sulphur and iron cycling at deep-sea vents. 相似文献
107.
A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response 总被引:1,自引:0,他引:1
L Kruidenier CW Chung Z Cheng J Liddle K Che G Joberty M Bantscheff C Bountra A Bridges H Diallo D Eberhard S Hutchinson E Jones R Katso M Leveridge PK Mander J Mosley C Ramirez-Molina P Rowland CJ Schofield RJ Sheppard JE Smith C Swales R Tanner P Thomas A Tumber G Drewes U Oppermann DJ Patel K Lee DM Wilson 《Nature》2012,488(7411):404-408
108.
Contrasting patterns of early twenty-first-century glacier mass change in the Himalayas 总被引:9,自引:0,他引:9
Glaciers are among the best indicators of terrestrial climate variability, contribute importantly to water resources in many mountainous regions and are a major contributor to global sea level rise. In the Hindu Kush-Karakoram-Himalaya region (HKKH), a paucity of appropriate glacier data has prevented a comprehensive assessment of current regional mass balance. There is, however, indirect evidence of a complex pattern of glacial responses in reaction to heterogeneous climate change signals. Here we use satellite laser altimetry and a global elevation model to show widespread glacier wastage in the eastern, central and south-western parts of the HKKH during 2003-08. Maximal regional thinning rates were 0.66?±?0.09 metres per year in the Jammu-Kashmir region. Conversely, in the Karakoram, glaciers thinned only slightly by a few centimetres per year. Contrary to expectations, regionally averaged thinning rates under debris-mantled ice were similar to those of clean ice despite insulation by debris covers. The 2003-08 specific mass balance for our entire HKKH study region was -0.21?±?0.05?m?yr(-1) water equivalent, significantly less negative than the estimated global average for glaciers and ice caps. This difference is mainly an effect of the balanced glacier mass budget in the Karakoram. The HKKH sea level contribution amounts to one per cent of the present-day sea level rise. Our 2003-08 mass budget of -12.8?±?3.5 gigatonnes (Gt) per year is more negative than recent satellite-gravimetry-based estimates of -5?±?3?Gt?yr(-1) over 2003-10 (ref. 12). For the mountain catchments of the Indus and Ganges basins, the glacier imbalance contributed about 3.5% and about 2.0%, respectively, to the annual average river discharge, and up to 10% for the Upper Indus basin. 相似文献
109.
Mackay TF Richards S Stone EA Barbadilla A Ayroles JF Zhu D Casillas S Han Y Magwire MM Cridland JM Richardson MF Anholt RR Barrón M Bess C Blankenburg KP Carbone MA Castellano D Chaboub L Duncan L Harris Z Javaid M Jayaseelan JC Jhangiani SN Jordan KW Lara F Lawrence F Lee SL Librado P Linheiro RS Lyman RF Mackey AJ Munidasa M Muzny DM Nazareth L Newsham I Perales L Pu LL Qu C Ràmia M Reid JG Rollmann SM Rozas J Saada N Turlapati L Worley KC Wu YQ Yamamoto A Zhu Y Bergman CM Thornton KR 《Nature》2012,482(7384):173-178
A major challenge of biology is understanding the relationship between molecular genetic variation and variation in quantitative traits, including fitness. This relationship determines our ability to predict phenotypes from genotypes and to understand how evolutionary forces shape variation within and between species. Previous efforts to dissect the genotype-phenotype map were based on incomplete genotypic information. Here, we describe the Drosophila melanogaster Genetic Reference Panel (DGRP), a community resource for analysis of population genomics and quantitative traits. The DGRP consists of fully sequenced inbred lines derived from a natural population. Population genomic analyses reveal reduced polymorphism in centromeric autosomal regions and the X chromosome, evidence for positive and negative selection, and rapid evolution of the X chromosome. Many variants in novel genes, most at low frequency, are associated with quantitative traits and explain a large fraction of the phenotypic variance. The DGRP facilitates genotype-phenotype mapping using the power of Drosophila genetics. 相似文献
110.
Scuoppo C Miething C Lindqvist L Reyes J Ruse C Appelmann I Yoon S Krasnitz A Teruya-Feldstein J Pappin D Pelletier J Lowe SW 《Nature》2012,487(7406):244-248
Tumour suppressor genes encode a broad class of molecules whose mutational attenuation contributes to malignant progression. In the canonical situation, the tumour suppressor is completely inactivated through a two-hit process involving a point mutation in one allele and chromosomal deletion of the other. Here, to identify tumour suppressor genes in lymphoma, we screen a short hairpin RNA library targeting genes deleted in human lymphomas. We functionally identify those genes whose suppression promotes tumorigenesis in a mouse lymphoma model. Of the nine tumour suppressors we identified, eight correspond to genes occurring in three physically linked 'clusters', suggesting that the common occurrence of large chromosomal deletions in human tumours reflects selective pressure to attenuate multiple genes. Among the new tumour suppressors are adenosylmethionine decarboxylase 1 (AMD1) and eukaryotic translation initiation factor 5A (eIF5A), two genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, we establish the polyamine-hypusine axis as a new tumour suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas and co-suppression of both genes promotes lymphomagenesis in mice. Thus, some tumour suppressor functions can be disabled through a two-step process targeting different genes acting in the same pathway. 相似文献