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Many cellular processes are carried out by molecular 'machines'-assemblies of multiple differentiated proteins that physically interact to execute biological functions. Despite much speculation, strong evidence of the mechanisms by which these assemblies evolved is lacking. Here we use ancestral gene resurrection and manipulative genetic experiments to determine how the complexity of an essential molecular machine--the hexameric transmembrane ring of the eukaryotic V-ATPase proton pump--increased hundreds of millions of years ago. We show that the ring of Fungi, which is composed of three paralogous proteins, evolved from a more ancient two-paralogue complex because of a gene duplication that was followed by loss in each daughter copy of specific interfaces by which it interacts with other ring proteins. These losses were complementary, so both copies became obligate components with restricted spatial roles in the complex. Reintroducing a single historical mutation from each paralogue lineage into the resurrected ancestral proteins is sufficient to recapitulate their asymmetric degeneration and trigger the requirement for the more elaborate three-component ring. Our experiments show that increased complexity in an essential molecular machine evolved because of simple, high-probability evolutionary processes, without the apparent evolution of novel functions. They point to a plausible mechanism for the evolution of complexity in other multi-paralogue protein complexes. 相似文献
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Boris Strilić Tomáš Kučera Eckhard Lammert 《Cellular and molecular life sciences : CMLS》2010,67(19):3209-3218
The cardiovascular system developed early in evolution and is pivotal for the transport of oxygen, nutrients, and waste products
within the organism. It is composed of hollow tubular structures and has a high level of complexity in vertebrates. This complexity
is, at least in part, due to the endothelial cell lining of vertebrate blood vessels. However, vascular lumen formation by
endothelial cells is still controversially discussed. For example, it has been suggested that the lumen mainly forms via coalescence
of large intracellular vacuoles generated by pinocytosis. Alternatively, it was proposed that the vascular lumen initiates
extracellularly between adjacent apical endothelial cell surfaces. Here we discuss invertebrate and vertebrate cardiovascular
lumen formation and highlight the possible modes of blood vessel formation. Finally, we point to the importance of a better
understanding of vascular lumen formation for treating human pathologies, including cancer and coronary heart disease. 相似文献
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Ellinghaus E Ellinghaus D Stuart PE Nair RP Debrus S Raelson JV Belouchi M Fournier H Reinhard C Ding J Li Y Tejasvi T Gudjonsson J Stoll SW Voorhees JJ Lambert S Weidinger S Eberlein B Kunz M Rahman P Gladman DD Gieger C Wichmann HE Karlsen TH Mayr G Albrecht M Kabelitz D Mrowietz U Abecasis GR Elder JT Schreiber S Weichenthal M Franke A 《Nature genetics》2010,42(11):991-995
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Hunt KA Smyth DJ Balschun T Ban M Mistry V Ahmad T Anand V Barrett JC Bhaw-Rosun L Bockett NA Brand OJ Brouwer E Concannon P Cooper JD Dias KR van Diemen CC Dubois PC Edkins S Fölster-Holst R Fransen K Glass DN Heap GA Hofmann S Huizinga TW Hunt S Langford C Lee J Mansfield J Marrosu MG Mathew CG Mein CA Müller-Quernheim J Nutland S Onengut-Gumuscu S Ouwehand W Pearce K Prescott NJ Posthumus MD Potter S Rosati G Sambrook J Satsangi J Schreiber S Shtir C Simmonds MJ Sudman M Thompson SD Toes R 《Nature genetics》2012,44(1):3-5
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Thye T Owusu-Dabo E Vannberg FO van Crevel R Curtis J Sahiratmadja E Balabanova Y Ehmen C Muntau B Ruge G Sievertsen J Gyapong J Nikolayevskyy V Hill PC Sirugo G Drobniewski F van de Vosse E Newport M Alisjahbana B Nejentsev S Ottenhoff TH Hill AV Horstmann RD Meyer CG 《Nature genetics》2012,44(3):257-259
After imputation of data from the 1000 Genomes Project into a genome-wide dataset of Ghanaian individuals with tuberculosis and controls, we identified a resistance locus on chromosome 11p13 downstream of the WT1 gene (encoding Wilms tumor 1). The strongest signal was obtained at the rs2057178 SNP (P = 2.63 × 10(-9)). Replication in Gambian, Indonesian and Russian tuberculosis case-control study cohorts increased the significance level for the association with this SNP to P = 2.57 × 10(-11). 相似文献
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Pansuriya TC van Eijk R d'Adamo P van Ruler MA Kuijjer ML Oosting J Cleton-Jansen AM van Oosterwijk JG Verbeke SL Meijer D van Wezel T Nord KH Sangiorgi L Toker B Liegl-Atzwanger B San-Julian M Sciot R Limaye N Kindblom LG Daugaard S Godfraind C Boon LM Vikkula M Kurek KC Szuhai K French PJ Bovée JV 《Nature genetics》2011,43(12):1256-1261
Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation. 相似文献
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