全文获取类型
收费全文 | 4044篇 |
免费 | 283篇 |
国内免费 | 2篇 |
专业分类
4329篇 |
出版年
2023年 | 13篇 |
2022年 | 20篇 |
2021年 | 39篇 |
2020年 | 31篇 |
2019年 | 43篇 |
2018年 | 64篇 |
2017年 | 54篇 |
2016年 | 88篇 |
2015年 | 195篇 |
2014年 | 166篇 |
2013年 | 221篇 |
2012年 | 289篇 |
2011年 | 281篇 |
2010年 | 213篇 |
2009年 | 162篇 |
2008年 | 230篇 |
2007年 | 270篇 |
2006年 | 255篇 |
2005年 | 240篇 |
2004年 | 221篇 |
2003年 | 233篇 |
2002年 | 211篇 |
2001年 | 40篇 |
2000年 | 35篇 |
1999年 | 57篇 |
1998年 | 62篇 |
1997年 | 49篇 |
1996年 | 52篇 |
1995年 | 45篇 |
1994年 | 36篇 |
1993年 | 50篇 |
1992年 | 38篇 |
1991年 | 26篇 |
1990年 | 17篇 |
1989年 | 31篇 |
1988年 | 13篇 |
1987年 | 27篇 |
1986年 | 18篇 |
1985年 | 13篇 |
1984年 | 22篇 |
1983年 | 26篇 |
1982年 | 15篇 |
1981年 | 23篇 |
1980年 | 15篇 |
1979年 | 10篇 |
1978年 | 11篇 |
1976年 | 6篇 |
1975年 | 7篇 |
1974年 | 9篇 |
1973年 | 7篇 |
排序方式: 共有4329条查询结果,搜索用时 0 毫秒
221.
Michard E Lacombe B Porée F Mueller-Roeber B Sentenac H Thibaud JB Dreyer I 《The Journal of general physiology》2005,126(6):605-617
Among all voltage-gated K+ channels from the model plant Arabidopsis thaliana, the weakly rectifying K+ channel (K(weak) channel) AKT2 displays unique gating properties. AKT2 is exceptionally regulated by phosphorylation: when nonphosphorylated AKT2 behaves as an inward-rectifying potassium channel; phosphorylation of AKT2 abolishes inward rectification by shifting its activation threshold far positive (>200 mV) so that it closes only at voltages positive of +100 mV. In its phosphorylated form, AKT2 is thus locked in the open state in the entire physiological voltage range. To understand the molecular grounds of this unique gating behavior, we generated chimeras between AKT2 and the conventional inward-rectifying channel KAT1. The transfer of the pore from KAT1 to AKT2 altered the permeation properties of the channel. However, the gating properties were unaffected, suggesting that the pore region of AKT2 is not responsible for the unique K(weak) gating. Instead, a lysine residue in S4, highly conserved among all K(weak) channels but absent from other plant K+ channels, was pinpointed in a site-directed mutagenesis approach. Substitution of the lysine by serine or aspartate abolished the "open-lock" characteristic and converted AKT2 into an inward-rectifying channel. Interestingly, phosphoregulation of the mutant AKT2-K197S appeared to be similar to that of the K(in) channel KAT1: as suggested by mimicking the phosphorylated and dephosphorylated states, phosphorylation induced a shift of the activation threshold of AKT2-K197S by about +50 mV. We conclude that the lysine residue K197 sensitizes AKT2 to phosphoregulation. The phosphorylation-induced reduction of the activation energy in AKT2 is approximately 6 kT larger than in the K197S mutant. It is discussed that this hypersensitive response of AKT2 to phosphorylation equips a cell with the versatility to establish a potassium gradient and to make efficient use of it. 相似文献
222.
Identification and characterization of antigenic determinants on proteins has received considerable attention utilizing both, experimental as well as computational methods. For computational routines mostly structural as well as physicochemical parameters have been utilized for predicting the antigenic propensity of protein sites. However, the performance of computational routines has been low when compared to experimental alternatives. Here we describe the construction of machine learning based classifiers to enhance the prediction quality for identifying linear B-cell epitopes on proteins. Our approach combines several parameters previously associated with antigenicity, and includes novel parameters based on frequencies of amino acids and amino acid neighborhood propensities. We utilized machine learning algorithms for deriving antigenicity classification functions assigning antigenic propensities to each amino acid of a given protein sequence. We compared the prediction quality of the novel classifiers with respect to established routines for epitope scoring, and tested prediction accuracy on experimental data available for HIV proteins. The major finding is that machine learning classifiers clearly outperform the reference classification systems on the HIV epitope validation set. 相似文献
223.
María J. Barrero Borja Sese Bernd Kuebler Josipa Bilic Stephanie Boue Mercè Martí Juan Carlos Izpisua Belmonte 《Cell reports》2013,3(4):1005-1011
Highlights? Macrohistone variants are regulated during reprogramming and differentiation ? The levels of macrohistone variants modulate the efficiency of reprogramming ? MacroH2A.1 occupies pluripotency and differentiation genes in keratinocytes ? MacroH2A.1 occupancy prevents the gain of H3K4me2 during reprogramming 相似文献
224.
Bernd Richard Knappmann Maria-Regina Kula 《Applied microbiology and biotechnology》1990,33(3):324-329
Summary Several strains of Gram-negative microorganisms were screened for maximum 3-deoxy-d-manno-2-octulosonic acid (KDO) aldolase (EC 4.1.2.23) activity. Although this enzyme has been noted to be inducible on special medium, no induction was found. By centrifugation studies the KDO aldolase was found to be localized in the cell wall or membrane fraction. The enzyme activity was very susceptible to small amounts of detergent in solution.
Offprint requests to: M.-R. Kula 相似文献
225.
Weibezahn J Schlieker C Bukau B Mogk A 《The Journal of biological chemistry》2003,278(35):32608-32617
The AAA+ protein ClpB mediates the solubilization of protein aggregates in cooperation with the DnaK chaperone system (KJE). The order of action of ClpB and KJE on aggregated proteins is unknown. We describe a ClpB variant with mutational alterations in the Walker B motif of both AAA domains (E279A/E678A), which binds but does not hydrolyze ATP. This variant associates in vitro and in vivo in a stable manner with protein substrates, demonstrating direct interaction of ClpB with protein aggregates for the first time. Substrate interaction is strictly dependent on ATP binding to both AAA domains of ClpB. The unique substrate binding properties of the double Walker B variant allowed to dissect the order of ClpB and DnaK action during disaggregation reactions. ClpB-E279A/E678A outcompetes the DnaK system for binding to the model substrate TrfA and inhibits the dissociation of small protein aggregates by DnaK only, indicating that ClpB acts prior to DnaK on protein substrates. 相似文献
226.
Bernd Gröttrup Jens Wiltfang Helmut Heinsen Katrin Marcus Helmut E. Meyer Lea T. Grinberg Young Mok Park 《Proteomics》2013,13(20):2938-2941
The HUPO Brain Proteome Project (HUPO BPP) held its 19th workshop in Dortmund, Germany, from May 22 to 24, 2013. The focus of the spring workshop was on strategies and developments concerning early diagnosis of neurodegenerative diseases 相似文献
227.
Hereditary channelopathies, that is, mutations in channel genes that alter channel function
and are causal for the pathogenesis of the disease, have been described for several members
of the transient receptor potential channel family. Mutations in the TRPV4 gene,
encoding a polymodal Ca2+ permeable channel, are causative for several human
diseases, which affect the skeletal system and the peripheral nervous system, with highly
variable phenotypes. In this review, we describe the phenotypes of TRPV4 channelopathies and
overlapping symptoms. Putative mechanisms to explain the puzzle, and how mutations in the
same region of the channel cause different diseases, are discussed and experimental
approaches to tackle this surprising problem are suggested. 相似文献
228.
Wenxuan Liu Tatiana V. Danilova Matthew N. Rouse Robert L. Bowden Bernd Friebe Bikram S. Gill Michael O. Pumphrey 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2013,126(5):1167-1177
The emergence of the highly virulent Ug99 race complex of the stem rust fungus (Puccinia graminis Pers. f. sp. tritici Eriks. and Henn.) threatens wheat (Triticum aestivum L.) production worldwide. One of the effective genes against the Ug99 race complex is Sr44, which was derived from Thinopyrum intermedium (Host) Barkworth and D.R. Dewey and mapped to the short arm of 7J (designated 7J#1S) present in the noncompensating T7DS-7J#1L?7J#1S translocation. Noncompensating wheat-alien translocations are known to cause genomic duplications and deficiencies leading to poor agronomic performance, precluding their direct use in wheat improvement. The present study was initiated to produce compensating wheat-Th. intermedium Robertsonian translocations with Sr44 resistance. One compensating RobT was identified consisting of the wheat 7DL arm translocated to the Th. intermedium 7J#1S arm resulting in T7DL?7J#1S. The T7DL?7J#1S stock was designated as TA5657. The 7DL?7J#1S stock carries Sr44 and has resistance to the Ug99 race complex. This compensating RobT with Sr44 resistance may be useful in wheat improvement. In addition, we identified an unnamed stem rust resistance gene located on the 7J#1L arm that confers resistance not only to Ug99, but also to race TRTTF, which is virulent to Sr44. However, the action of the second gene can be modified by the presence of suppressors in the recipient wheat cultivars. 相似文献
229.
When is a native species invasive? Incursion of a novel predatory marsupial detected using molecular and historical data 下载免费PDF全文
Catriona D. Campbell Stephen D. Sarre Dejan Stojanovic Bernd Gruber Kathryn Medlock Stephen Harris Anna J. MacDonald Clare E. Holleley 《Diversity & distributions》2018,24(6):831-840
Aim
Range expansions facilitated by humans or in response to local biotic or abiotic stressors provide the opportunity for species to occupy novel environments. Classifying the status of newly expanded populations can be difficult, particularly when the timing and nature of the range expansion are unclear. Should native species in new habitats be considered invasive pests or actively conserved? Here, we present an analytical framework applied to an Australian marsupial, the sugar glider (Petaurus breviceps), a species that preys upon on an endangered parrot in Tasmania, and whose provenance was uncertain.Location
Tasmania, Australia.Methods
We conducted an extensive search of historical records for sugar glider occurrences in Tasmania. Source material included museum collection data, early European expedition logs, community observation records, and peer‐reviewed and grey literature. To determine the provenance of the Tasmanian population, we sequenced two mitochondrial genes and one nuclear gene in Tasmanian animals (n = 27) and in individuals across the species' native range. We then estimated divergence times between Tasmania and southern Australian populations using phylogenetic and Bayesian analyses.Results
We found no historical evidence of sugar gliders occurring in Tasmania prior to 1835. All Tasmanian individuals (n = 27) were genetically identical at the three genes surveyed here with those individuals being 0.125% divergent from individuals from a population in Victoria. Bayesian analysis of divergence between Tasmanian individuals and southern Australian individuals suggested a recent introduction of sugar gliders into Tasmania from southern Australia.Main conclusions
Molecular and historical data demonstrate that Tasmanian sugar gliders are a recent, post‐European, anthropogenic introduction from mainland Victoria. This result has implications for the management of the species in relation to their impact on an endangered parrot. The analytical framework outlined here can assist environmental managers with the complex task of assessing the status of recently expanded or introduced native species.230.
Protein function is considerably altered by posttranslational modification. In recent years, cycles of acetylation/deacetylation emerged as fundamental regulators adjusting biological activity of many proteins. Particularly, protein deacetylation by Sirtuins, a family of atypical histone deacetylases (HDACs), was demonstrated to regulate fundamental cell biological processes including gene expression, genome stability, mitosis, nutrient metabolism, aging, mitochondrial function and cell motility. Given this wealth of biological functions, perhaps not unexpectedly then, pharmacological compounds targeting Sirtuin activity are now prime therapeutic agents for alleviating severity of major diseases encompassing diabetes, cancer, cardiovascular and neurodegenerative disorders in many organs. In this review, we will focus on the brain and its physiological and pathological processes governed by Sirtuin-mediated deacetylation. Besides discussing Sirtuin function in neurodegenerative diseases, emphasis will be given on the mounting evidence deciphering key developmental brain functions for Sirtuins in neuronal motility, neuroprotection and oligodendrocyte differentiation. In this respect, we will particularly highlight functions of the unconventional family member SIRT2 in post-mitotic neurons and glial cells. 相似文献