全文获取类型
收费全文 | 492篇 |
免费 | 4篇 |
国内免费 | 1篇 |
专业分类
系统科学 | 7篇 |
教育与普及 | 2篇 |
理论与方法论 | 11篇 |
现状及发展 | 35篇 |
研究方法 | 75篇 |
综合类 | 325篇 |
自然研究 | 42篇 |
出版年
2019年 | 2篇 |
2018年 | 5篇 |
2017年 | 12篇 |
2016年 | 6篇 |
2015年 | 6篇 |
2014年 | 3篇 |
2013年 | 3篇 |
2012年 | 48篇 |
2011年 | 80篇 |
2010年 | 13篇 |
2009年 | 1篇 |
2008年 | 53篇 |
2007年 | 42篇 |
2006年 | 36篇 |
2005年 | 40篇 |
2004年 | 34篇 |
2003年 | 40篇 |
2002年 | 43篇 |
2001年 | 2篇 |
2000年 | 7篇 |
1999年 | 5篇 |
1998年 | 2篇 |
1995年 | 1篇 |
1993年 | 1篇 |
1990年 | 1篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1984年 | 2篇 |
1982年 | 2篇 |
1975年 | 1篇 |
1973年 | 1篇 |
排序方式: 共有497条查询结果,搜索用时 250 毫秒
201.
202.
Tammela T Zarkada G Wallgard E Murtomäki A Suchting S Wirzenius M Waltari M Hellström M Schomber T Peltonen R Freitas C Duarte A Isoniemi H Laakkonen P Christofori G Ylä-Herttuala S Shibuya M Pytowski B Eichmann A Betsholtz C Alitalo K 《Nature》2008,454(7204):656-660
Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is a key process in several pathological conditions, including tumour growth and age-related macular degeneration. Vascular endothelial growth factors (VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells. VEGFR-3 (also known as FLT-4) is present in all endothelia during development, and in the adult it becomes restricted to the lymphatic endothelium. However, VEGFR-3 is upregulated in the microvasculature of tumours and wounds. Here we demonstrate that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting of VEGFR-3 or blocking of VEGFR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR-3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR-2 (also known as KDR or FLK-1) inhibitors, whereas antibodies against VEGFR-3 and VEGFR-2 in combination resulted in additive inhibition of angiogenesis and tumour growth. Furthermore, genetic or pharmacological disruption of the Notch signalling pathway led to widespread endothelial VEGFR-3 expression and excessive sprouting, which was inhibited by blocking VEGFR-3 signals. Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR-2 inhibitors. 相似文献
203.
204.
The impact of microRNAs on protein output 总被引:2,自引:0,他引:2
MicroRNAs are endogenous approximately 23-nucleotide RNAs that can pair to sites in the messenger RNAs of protein-coding genes to downregulate the expression from these messages. MicroRNAs are known to influence the evolution and stability of many mRNAs, but their global impact on protein output had not been examined. Here we use quantitative mass spectrometry to measure the response of thousands of proteins after introducing microRNAs into cultured cells and after deleting mir-223 in mouse neutrophils. The identities of the responsive proteins indicate that targeting is primarily through seed-matched sites located within favourable predicted contexts in 3' untranslated regions. Hundreds of genes were directly repressed, albeit each to a modest degree, by individual microRNAs. Although some targets were repressed without detectable changes in mRNA levels, those translationally repressed by more than a third also displayed detectable mRNA destabilization, and, for the more highly repressed targets, mRNA destabilization usually comprised the major component of repression. The impact of microRNAs on the proteome indicated that for most interactions microRNAs act as rheostats to make fine-scale adjustments to protein output. 相似文献
205.
Dunn CW Hejnol A Matus DQ Pang K Browne WE Smith SA Seaver E Rouse GW Obst M Edgecombe GD Sørensen MV Haddock SH Schmidt-Rhaesa A Okusu A Kristensen RM Wheeler WC Martindale MQ Giribet G 《Nature》2008,452(7188):745-749
Long-held ideas regarding the evolutionary relationships among animals have recently been upended by sometimes controversial hypotheses based largely on insights from molecular data. These new hypotheses include a clade of moulting animals (Ecdysozoa) and the close relationship of the lophophorates to molluscs and annelids (Lophotrochozoa). Many relationships remain disputed, including those that are required to polarize key features of character evolution, and support for deep nodes is often low. Phylogenomic approaches, which use data from many genes, have shown promise for resolving deep animal relationships, but are hindered by a lack of data from many important groups. Here we report a total of 39.9 Mb of expressed sequence tags from 29 animals belonging to 21 phyla, including 11 phyla previously lacking genomic or expressed-sequence-tag data. Analysed in combination with existing sequences, our data reinforce several previously identified clades that split deeply in the animal tree (including Protostomia, Ecdysozoa and Lophotrochozoa), unambiguously resolve multiple long-standing issues for which there was strong conflicting support in earlier studies with less data (such as velvet worms rather than tardigrades as the sister group of arthropods), and provide molecular support for the monophyly of molluscs, a group long recognized by morphologists. In addition, we find strong support for several new hypotheses. These include a clade that unites annelids (including sipunculans and echiurans) with nemerteans, phoronids and brachiopods, molluscs as sister to that assemblage, and the placement of ctenophores as the earliest diverging extant multicellular animals. A single origin of spiral cleavage (with subsequent losses) is inferred from well-supported nodes. Many relationships between a stable subset of taxa find strong support, and a diminishing number of lineages remain recalcitrant to placement on the tree. 相似文献
206.
The draft genome of the transgenic tropical fruit tree papaya (Carica papaya Linnaeus) 总被引:1,自引:0,他引:1
Ming R Hou S Feng Y Yu Q Dionne-Laporte A Saw JH Senin P Wang W Ly BV Lewis KL Salzberg SL Feng L Jones MR Skelton RL Murray JE Chen C Qian W Shen J Du P Eustice M Tong E Tang H Lyons E Paull RE Michael TP Wall K Rice DW Albert H Wang ML Zhu YJ Schatz M Nagarajan N Acob RA Guan P Blas A Wai CM Ackerman CM Ren Y Liu C Wang J Wang J Na JK Shakirov EV Haas B Thimmapuram J Nelson D Wang X Bowers JE Gschwend AR Delcher AL Singh R Suzuki JY Tripathi S Neupane K Wei H Irikura B Paidi M Jiang N Zhang W 《Nature》2008,452(7190):991-996
Papaya, a fruit crop cultivated in tropical and subtropical regions, is known for its nutritional benefits and medicinal applications. Here we report a 3x draft genome sequence of 'SunUp' papaya, the first commercial virus-resistant transgenic fruit tree to be sequenced. The papaya genome is three times the size of the Arabidopsis genome, but contains fewer genes, including significantly fewer disease-resistance gene analogues. Comparison of the five sequenced genomes suggests a minimal angiosperm gene set of 13,311. A lack of recent genome duplication, atypical of other angiosperm genomes sequenced so far, may account for the smaller papaya gene number in most functional groups. Nonetheless, striking amplifications in gene number within particular functional groups suggest roles in the evolution of tree-like habit, deposition and remobilization of starch reserves, attraction of seed dispersal agents, and adaptation to tropical daylengths. Transgenesis at three locations is closely associated with chloroplast insertions into the nuclear genome, and with topoisomerase I recognition sites. Papaya offers numerous advantages as a system for fruit-tree functional genomics, and this draft genome sequence provides the foundation for revealing the basis of Carica's distinguishing morpho-physiological, medicinal and nutritional properties. 相似文献
207.
Liu M Duke JL Richter DJ Vinuesa CG Goodnow CC Kleinstein SH Schatz DG 《Nature》2008,451(7180):841-845
Somatic hypermutation introduces point mutations into immunoglobulin genes in germinal centre B cells during an immune response. The reaction is initiated by cytosine deamination by the activation-induced deaminase (AID) and completed by error-prone processing of the resulting uracils by mismatch and base excision repair factors. Somatic hypermutation represents a threat to genome integrity and it is not known how the B cell genome is protected from the mutagenic effects of somatic hypermutation nor how often these protective mechanisms fail. Here we show, by extensive sequencing of murine B cell genes, that the genome is protected by two distinct mechanisms: selective targeting of AID and gene-specific, high-fidelity repair of AID-generated uracils. Numerous genes linked to B cell tumorigenesis, including Myc, Pim1, Pax5, Ocab (also called Pou2af1), H2afx, Rhoh and Ebf1, are deaminated by AID but escape acquisition of most mutations through the combined action of mismatch and base excision repair. However, approximately 25% of expressed genes analysed were not fully protected by either mechanism and accumulated mutations in germinal centre B cells. Our results demonstrate that AID acts broadly on the genome, with the ultimate distribution of mutations determined by a balance between high-fidelity and error-prone DNA repair. 相似文献
208.
Collins PJ Haire LF Lin YP Liu J Russell RJ Walker PA Skehel JJ Martin SR Hay AJ Gamblin SJ 《Nature》2008,453(7199):1258-1261
The potential impact of pandemic influenza makes effective measures to limit the spread and morbidity of virus infection a public health priority. Antiviral drugs are seen as essential requirements for control of initial influenza outbreaks caused by a new virus, and in pre-pandemic plans there is a heavy reliance on drug stockpiles. The principal target for these drugs is a virus surface glycoprotein, neuraminidase, which facilitates the release of nascent virus and thus the spread of infection. Oseltamivir (Tamiflu) and zanamivir (Relenza) are two currently used neuraminidase inhibitors that were developed using knowledge of the enzyme structure. It has been proposed that the closer such inhibitors resemble the natural substrate, the less likely they are to select drug-resistant mutant viruses that retain viability. However, there have been reports of drug-resistant mutant selection in vitro and from infected humans. We report here the enzymatic properties and crystal structures of neuraminidase mutants from H5N1-infected patients that explain the molecular basis of resistance. Our results show that these mutants are resistant to oseltamivir but still strongly inhibited by zanamivir owing to an altered hydrophobic pocket in the active site of the enzyme required for oseltamivir binding. Together with recent reports of the viability and pathogenesis of H5N1 (ref. 7) and H1N1 (ref. 8) viruses with neuraminidases carrying these mutations, our results indicate that it would be prudent for pandemic stockpiles of oseltamivir to be augmented by additional antiviral drugs, including zanamivir. 相似文献
209.
210.
Gonatus onyx is one of the most abundant cephalopods in the Pacific and Atlantic Oceans and is an important prey species for a variety of vertebrate predators, but a full understanding of its life history has been hampered because spawning occurs at great depths, where observation is difficult. Here we describe post-spawning egg care, or brooding, in this deep-sea squid. Our finding is unexpected because this behaviour differs from the reproductive habits of all other known squid species. 相似文献