全文获取类型
收费全文 | 2837篇 |
免费 | 371篇 |
国内免费 | 32篇 |
出版年
2022年 | 18篇 |
2021年 | 34篇 |
2020年 | 25篇 |
2019年 | 19篇 |
2018年 | 39篇 |
2017年 | 30篇 |
2016年 | 51篇 |
2015年 | 101篇 |
2014年 | 89篇 |
2013年 | 96篇 |
2012年 | 153篇 |
2011年 | 162篇 |
2010年 | 96篇 |
2009年 | 93篇 |
2008年 | 132篇 |
2007年 | 135篇 |
2006年 | 129篇 |
2005年 | 135篇 |
2004年 | 109篇 |
2003年 | 119篇 |
2002年 | 115篇 |
2001年 | 135篇 |
2000年 | 100篇 |
1999年 | 101篇 |
1998年 | 45篇 |
1997年 | 44篇 |
1996年 | 44篇 |
1995年 | 32篇 |
1994年 | 30篇 |
1993年 | 23篇 |
1992年 | 68篇 |
1991年 | 53篇 |
1990年 | 54篇 |
1989年 | 55篇 |
1988年 | 39篇 |
1987年 | 47篇 |
1986年 | 33篇 |
1985年 | 32篇 |
1984年 | 35篇 |
1982年 | 23篇 |
1981年 | 17篇 |
1980年 | 25篇 |
1979年 | 40篇 |
1978年 | 23篇 |
1977年 | 19篇 |
1975年 | 18篇 |
1974年 | 17篇 |
1973年 | 19篇 |
1972年 | 18篇 |
1970年 | 18篇 |
排序方式: 共有3240条查询结果,搜索用时 531 毫秒
991.
Koch PJ de Viragh PA Scharer E Bundman D Longley MA Bickenbach J Kawachi Y Suga Y Zhou Z Huber M Hohl D Kartasova T Jarnik M Steven AC Roop DR 《The Journal of cell biology》2000,151(2):389-400
The epidermal cornified cell envelope (CE) is a complex protein-lipid composite that replaces the plasma membrane of terminally differentiated keratinocytes. This lamellar structure is essential for the barrier function of the skin and has the ability to prevent the loss of water and ions and to protect from environmental hazards. The major protein of the epidermal CE is loricrin, contributing approximately 70% by mass. We have generated mice that are deficient for this protein. These mice showed a delay in the formation of the skin barrier in embryonic development. At birth, homozygous mutant mice weighed less than control littermates and showed skin abnormalities, such as congenital erythroderma with a shiny, translucent skin. Tape stripping experiments suggested that the stratum corneum stability was reduced in newborn Lor(-/-) mice compared with wild-type controls. Isolated mutant CEs were more easily fragmented by sonication in vitro, indicating a greater susceptibility to mechanical stress. Nevertheless, we did not detect impaired epidermal barrier function in these mice. Surprisingly, the skin phenotype disappeared 4-5 d after birth. At least one of the compensatory mechanisms preventing a more severe skin phenotype in newborn Lor(-/-) mice is an increase in the expression of other CE components, such as SPRRP2D and SPRRP2H, members of the family of "small proline rich proteins", and repetin, a member of the "fused gene" subgroup of the S100 gene family. 相似文献
992.
Both calmodulin and the unconventional myosin Myr4 regulate membrane trafficking along the recycling pathway of MDCK cells 总被引:4,自引:0,他引:4
Huber LA Fialka I Paiha K Hunziker W Sacks DB Bähler M Way M Gagescu R Gruenberg J 《Traffic (Copenhagen, Denmark)》2000,1(6):494-503
In epithelial cells, endocytosed transferrin and its receptor, which cycle basolaterally, have been shown to transit through recycling endosomes which can also be accessed by markers internalized from the apical surface. In this work, we have used an in vitro assay to follow transfer of an endocytosed marker from apical or basolateral early endosomes to recycling endosomes labeled with transferrin. We show that calmodulin (CaM) function is necessary for transfer and identified myr4, a member of the unconventional myosin superfamily known to use CaM as a light chain, as a possible target protein for CaM. Since myr4 is believed to act as an actin-based mechanoenzyme, we tested the role of polymerized actin in the assay. Our data show that conditions which either prevent actin polymerization or induce the breakdown of existing filaments strongly inhibit interactions between recycling endosomes and either set of early endosomes. Altogether, our data indicate that trafficking at early steps of the endocytic pathway in Madin–Darby Canine Kidney cells depends on the actin-based mechanoenzyme myr4, its light chain CaM, and polymerized actin. 相似文献
993.
994.
Flexibility, conformational diversity and two dimerization modes in complexes of ribosomal protein L12 下载免费PDF全文
Protein L12, the only multicopy component of the ribosome, is presumed to be involved in the binding of translation factors, stimulating factor-dependent GTP hydrolysis. Crystal structures of L12 from Thermotogamaritima have been solved in two space groups by the multiple anomalous dispersion method and refined at 2.4 and 2.0 A resolution. In both crystal forms, an asymmetric unit comprises two full-length L12 molecules and two N-terminal L12 fragments that are associated in a specific, hetero-tetrameric complex with one non-crystallographic 2-fold axis. The two full-length proteins form a tight, symmetric, parallel dimer, mainly through their N-terminal domains. Each monomer of this central dimer additionally associates in a different way with an N-terminal L12 fragment. Both dimerization modes are unlike models proposed previously and suggest that similar complexes may occur in vivo and in situ. The structures also display different L12 monomer conformations, in accord with the suggested dynamic role of the protein in the ribosomal translocation process. The structures have been submitted to the Protein Databank (http://www.rcsb.org/pdb) under accession numbers 1DD3 and 1DD4. 相似文献
995.
Structure and mechanism of the aberrant ba(3)-cytochrome c oxidase from thermus thermophilus 下载免费PDF全文
Cytochrome c oxidase is a respiratory enzyme catalysing the energy-conserving reduction of molecular oxygen to water. The crystal structure of the ba(3)-cytochrome c oxidase from Thermus thermophilus has been determined to 2.4 A resolution using multiple anomalous dispersion (MAD) phasing and led to the discovery of a novel subunit IIa. A structure-based sequence alignment of this phylogenetically very distant oxidase with the other structurally known cytochrome oxidases leads to the identification of sequence motifs and residues that seem to be indispensable for the function of the haem copper oxidases, e.g. a new electron transfer pathway leading directly from Cu(A) to Cu(B). Specific features of the ba(3)-oxidase include an extended oxygen input channel, which leads directly to the active site, the presence of only one oxygen atom (O(2-), OH(-) or H(2)O) as bridging ligand at the active site and the mainly hydrophobic character of the interactions that stabilize the electron transfer complex between this oxidase and its substrate cytochrome c. New aspects of the proton pumping mechanism could be identified. 相似文献
996.
Crystal structure of the human alpha-thrombin-haemadin complex: an exosite II-binding inhibitor 下载免费PDF全文
Richardson JL Kröger B Hoeffken W Sadler JE Pereira P Huber R Bode W Fuentes-Prior P 《The EMBO journal》2000,19(21):5650-5660
The serine proteinase alpha-thrombin plays a pivotal role in the regulation of blood fluidity, and therefore constitutes a primary target in the treatment of various haemostatic disorders. Haemadin is a slow tight- binding thrombin inhibitor from the land-living leech Haemadipsa sylvestris. Here we present the 3.1 A crystal structure of the human alpha-thrombin- haemadin complex. The N-terminal segment of haemadin binds to the active site of thrombin, forming a parallel beta-strand with residues Ser214-Gly216 of the proteinase. This mode of binding is similar to that observed in another leech-derived inhibitor, hirudin. In contrast to hirudin, however, the markedly acidic C-terminal peptide of haemadin does not bind the fibrinogen-recognition exosite, but interacts with the heparin-binding exosite of thrombin. Thus, haemadin binds to thrombin according to a novel mechanism, despite an overall structural similarity with hirudin. Haemadin inhibits both free and thrombomodulin-bound alpha-thrombin, but not intermediate activation forms such as meizothrombin. This specific anticoagulant ability of haemadin makes it an ideal candidate for an antithrombotic agent, as well as a starting point for the design of novel antithrombotics. 相似文献
997.
Abreu IA Saraiva LM Carita J Huber H Stetter KO Cabelli D Teixeira M 《Molecular microbiology》2000,38(2):322-334
Archaeoglobus fulgidus is a hyperthermophilic sulphate-reducing archaeon. It has an optimum growth temperature of 83 degrees C and is described as a strict anaerobe. Its genome lacks any homologue of canonical superoxide (O2.-) dismutases. In this work, we show that neelaredoxin (Nlr) is the main O2.- scavenger in A. fulgidus, by studying both the wild-type and recombinant proteins. Nlr is a 125-amino-acid blue-coloured protein containing a single iron atom/molecule, which in the oxidized state is high spin ferric. This iron centre has a reduction potential of +230 mV at pH 7.0. Nitroblue tetrazolium-stained gel assays of cell-soluble extracts show that Nlr is the main protein from A. fulgidus which is reactive towards O2.-. Furthermore, it is shown that Nlr is able to both reduce and dismutate O2.-, thus having a bifunctional reactivity towards O2.-. Kinetic and spectroscopic studies indicate that Nlr's superoxide reductase activity may allow the cell to eliminate O2.- quickly in a NAD(P)H-dependent pathway. On the other hand, Nlr's superoxide dismutation activity will allow the cell to detoxify O2.- independently of the cell redox status. Its superoxide dismutase activity was estimated to be 59 U mg-1 by the xanthine/xanthine oxidase assay at 25 degrees C. Pulse radiolysis studies with the isolated and reduced Nlr proved unambiguously that it has superoxide dismutase activity; at pH 7.1 and 83 degrees C, the rate constant is 5 x 106 M-1 s-1. Besides the superoxide dismutase activity, soluble cell extracts of A. fulgidus also exhibit catalase and NAD(P)H/oxygen oxidoreductase activities. By putting these findings together with the entire genomic data available, a possible oxygen detoxification mechanism in A. fulgidus is discussed. 相似文献
998.
999.
Huber JL da Silva KB Bates WR Swalla BJ 《Seminars in cell & developmental biology》2000,11(6):419-426
Ascidians are urochordates, marine invertebrates with non-feeding motile chordate tadpole larvae, except in the family Molgulidae. Urodele, or tailed, Molgulids have typical ascidian chordate tadpole larvae possessing tails with muscle cells, a notochord, and a dorsal hollow nerve cord. In contrast, anural (or tail-less) Molgulids lack a tail and defining chordate features. Molecular phylogenies generated with 18S and 28S ribosomal sequences indicate that Molgulid species fall into at least four distinct clades, three of which have multiple anural members. This refined and expanded phylogeny allows careful examination of the factors that may have influenced the evolution of tail-less ascidians. 相似文献
1000.