全文获取类型
收费全文 | 1495篇 |
免费 | 99篇 |
专业分类
1594篇 |
出版年
2024年 | 6篇 |
2023年 | 8篇 |
2022年 | 24篇 |
2021年 | 37篇 |
2020年 | 20篇 |
2019年 | 27篇 |
2018年 | 34篇 |
2017年 | 23篇 |
2016年 | 37篇 |
2015年 | 70篇 |
2014年 | 77篇 |
2013年 | 92篇 |
2012年 | 98篇 |
2011年 | 102篇 |
2010年 | 84篇 |
2009年 | 57篇 |
2008年 | 80篇 |
2007年 | 80篇 |
2006年 | 63篇 |
2005年 | 48篇 |
2004年 | 64篇 |
2003年 | 53篇 |
2002年 | 29篇 |
2001年 | 29篇 |
2000年 | 26篇 |
1999年 | 9篇 |
1998年 | 9篇 |
1997年 | 11篇 |
1996年 | 18篇 |
1995年 | 15篇 |
1994年 | 19篇 |
1993年 | 18篇 |
1992年 | 23篇 |
1991年 | 20篇 |
1990年 | 11篇 |
1989年 | 12篇 |
1988年 | 9篇 |
1987年 | 9篇 |
1985年 | 16篇 |
1984年 | 8篇 |
1983年 | 6篇 |
1982年 | 8篇 |
1981年 | 6篇 |
1979年 | 10篇 |
1976年 | 11篇 |
1975年 | 6篇 |
1974年 | 8篇 |
1973年 | 13篇 |
1972年 | 6篇 |
1971年 | 7篇 |
排序方式: 共有1594条查询结果,搜索用时 0 毫秒
1.
Sander Stroobants Inge Van Molle Queen Saidi Karl Jonckheere Dominique Maes Eveline Peeters 《Acta Crystallographica. Section F, Structural Biology Communications》2019,75(6):428-434
Aerobic thermoacidophilic archaea belonging to the genus Sulfolobus harbor peroxiredoxins, thiol‐dependent peroxidases that assist in protecting the cells from oxidative damage. Here, the crystal structure of the 1‐Cys peroxiredoxin from Sulfolobus islandicus, named 1‐Cys SiPrx, is presented. A 2.75 Å resolution data set was collected from a crystal belonging to space group P212121, with unit‐cell parameters a = 86.8, b = 159.1, c = 189.3 Å, α = β = γ = 90°. The structure was solved by molecular replacement using the homologous Aeropyrum pernix peroxiredoxin (ApPrx) structure as a search model. In the crystal structure, 1‐Cys SiPrx assembles into a ring‐shaped decamer composed of five homodimers. This quaternary structure corresponds to the oligomeric state of the protein in solution, as observed by size‐exclusion chromatography. 1‐Cys SiPrx harbors only a single cysteine, which is the peroxidatic cysteine, and lacks both of the cysteines that are highly conserved in the C‐terminal arm domain in other archaeal Prx6‐subfamily proteins such as ApPrx and that are involved in the association of dimers into higher‐molecular‐weight decamers and dodecamers. It is thus concluded that the Sulfolobus Prx6‐subfamily protein undergoes decamerization independently of arm‐domain cysteines. 相似文献
2.
Speciation with gene flow is greatly facilitated when traits subject to divergent selection also contribute to non-random mating. Such traits have been called 'magic traits', which could be interpreted to imply that they are rare, special, or unrealistic. Here, we question this assumption by illustrating that magic traits can be produced by a variety of mechanisms, including ones in which reproductive isolation arises as an automatic by-product of adaptive divergence. We also draw upon the theoretical literature to explore whether magic traits have a unique role in speciation or can be mimicked in their effects by physically linked trait-complexes. We conclude that magic traits are more frequent than previously perceived, but further work is needed to clarify their importance. 相似文献
3.
Alaedini A Okamoto H Briani C Wollenberg K Shill HA Bushara KO Sander HW Green PH Hallett M Latov N 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(10):6590-6595
Celiac disease is an immune-mediated disorder triggered by ingestion of wheat gliadin and related proteins in genetically susceptible individuals. In addition to the characteristic enteropathy, celiac disease is associated with various extraintestinal manifestations, including neurologic complications such as neuropathy, ataxia, seizures, and neurobehavioral changes. The cause of the neurologic manifestations is unknown, but autoimmunity resulting from molecular mimicry between gliadin and nervous system proteins has been proposed to play a role. In this study, we sought to investigate the immune reactivity of the anti-gliadin Ab response toward neural proteins. We characterized the binding of affinity-purified anti-gliadin Abs from immunized animals to brain proteins by one- and two-dimensional gel electrophoresis, immunoblotting, and peptide mass mapping. The major immunoreactive protein was identified as synapsin I. Anti-gliadin Abs from patients with celiac disease also bound to the protein. Such cross-reactivity may provide clues into the pathogenic mechanism of the neurologic deficits that are associated with gluten sensitivity. 相似文献
4.
Susan Thrane Christoph M. Janitzek Mette ?. Agerb?k Sisse B. Ditlev Mafalda Resende Morten A. Nielsen Thor G. Theander Ali Salanti Adam F. Sander 《PloS one》2015,10(11)
Placental malaria caused by Plasmodium falciparum is a major cause of mortality and severe morbidity. Clinical testing of a soluble protein-based vaccine containing the parasite ligand, VAR2CSA, has been initiated. VAR2CSA binds to the human receptor chondroitin sulphate A (CSA) and is responsible for sequestration of Plasmodium falciparum infected erythrocytes in the placenta. It is imperative that a vaccine against malaria in pregnancy, if administered to women before they become pregnant, can induce a strong and long lasting immune response. While most soluble protein-based vaccines have failed during clinical testing, virus-like particle (VLP) based vaccines (e.g., the licensed human papillomavirus vaccines) have demonstrated high efficacy, suggesting that the spatial assembly of the vaccine antigen is a critical parameter for inducing an optimal long-lasting protective immune response. We have developed a VLP vaccine display platform by identifying regions of the HPV16 L1 coat protein where a biotin acceptor site (AviTagTM) can be inserted without compromising VLP-assembly. Subsequent biotinylation of Avi-L1 VLPs allow us to anchor monovalent streptavidin (mSA)-fused proteins to the biotin, thereby obtaining a dense and repetitive VLP-display of the vaccine antigen. The mSA-VAR2CSA antigen was delivered on the Avi-L1 VLP platform and tested in C57BL/6 mice in comparison to two soluble protein-based vaccines consisting of naked VAR2CSA and mSA-VAR2CSA. The mSA-VAR2CSA Avi-L1 VLP and soluble mSA-VAR2CSA vaccines induced higher antibody titers than the soluble naked VAR2CSA vaccine after three immunizations. The VAR2CSA Avi-L1 VLP vaccine induced statistically significantly higher endpoint titres compared to the soluble mSA-VAR2CSA vaccine, after 1st and 2nd immunization; however, this difference was not statistically significant after 3rd immunization. Importantly, the VLP-VAR2CSA induced antibodies were functional in inhibiting the binding of parasites to CSA. This study demonstrates that the described Avi-L1 VLP-platform may serve as a versatile system for facilitating optimal VLP-display of large and complex vaccine antigens. 相似文献
5.
Sander Barnhoorn Lieneke M. Uittenboogaard Dick Jaarsma Wilbert P. Vermeij Maria Tresini Michael Weymaere Hervé Menoni Renata M. C. Brandt Monique C. de Waard Sander M. Botter Altaf H. Sarker Nicolaas G. J. Jaspers Gijsbertus T. J. van der Horst Priscilla K. Cooper Jan H. J. Hoeijmakers Ingrid van der Pluijm 《PLoS genetics》2014,10(10)
As part of the Nucleotide Excision Repair (NER) process, the endonuclease XPG is involved in repair of helix-distorting DNA lesions, but the protein has also been implicated in several other DNA repair systems, complicating genotype-phenotype relationship in XPG patients. Defects in XPG can cause either the cancer-prone condition xeroderma pigmentosum (XP) alone, or XP combined with the severe neurodevelopmental disorder Cockayne Syndrome (CS), or the infantile lethal cerebro-oculo-facio-skeletal (COFS) syndrome, characterized by dramatic growth failure, progressive neurodevelopmental abnormalities and greatly reduced life expectancy. Here, we present a novel (conditional) Xpg−/− mouse model which -in a C57BL6/FVB F1 hybrid genetic background- displays many progeroid features, including cessation of growth, loss of subcutaneous fat, kyphosis, osteoporosis, retinal photoreceptor loss, liver aging, extensive neurodegeneration, and a short lifespan of 4–5 months. We show that deletion of XPG specifically in the liver reproduces the progeroid features in the liver, yet abolishes the effect on growth or lifespan. In addition, specific XPG deletion in neurons and glia of the forebrain creates a progressive neurodegenerative phenotype that shows many characteristics of human XPG deficiency. Our findings therefore exclude that both the liver as well as the neurological phenotype are a secondary consequence of derailment in other cell types, organs or tissues (e.g. vascular abnormalities) and support a cell-autonomous origin caused by the DNA repair defect itself. In addition they allow the dissection of the complex aging process in tissue- and cell-type-specific components. Moreover, our data highlight the critical importance of genetic background in mouse aging studies, establish the Xpg−/− mouse as a valid model for the severe form of human XPG patients and segmental accelerated aging, and strengthen the link between DNA damage and aging. 相似文献
6.
Reulen SW Brusselaars WW Langereis S Mulder WJ Breurken M Merkx M 《Bioconjugate chemistry》2007,18(2):590-596
Liposomes have become popular drug delivery vehicles and have more recently also been applied as contrast agents for molecular imaging. Most current methods for functionalization of liposomes with targeting proteins rely on reactions of amine or thiol groups at the protein exterior, which generally result in nonspecific conjugation at multiple sites on the protein. In this study, we present native chemical ligation (NCL) as a general method to covalently couple recombinant proteins in a highly specific and chemoselective way to liposomes containing cysteine-functionalized phospholipids. A cysteine-functionalized phospholipid (Cys-PEG-DSPE) was prepared and shown to readily react with the MESNA thioester of EYFP, which was used as a model protein. Characterization of the EYFP-liposomes using fluorescence spectroscopy showed full retention of the fluorescent properties of conjugated EYFP and provides a lower limit of 120 proteins per liposome. The general applicability of NCL was further tested using CNA35, a collagen-binding protein recently applied in fluorescent imaging of collagen. NCL of CNA35 thioester yielded liposomes containing approximately 100 copies of CNA35 per liposome. The CNA35-liposomes were shown to be fully functional and bind collagen with a 150-fold higher affinity compared to CNA35. Our results show that NCL is an attractive addition to existing conjugation methods that allows direct, covalent, and highly specific coupling of recombinant proteins to liposomes and other lipid-based assemblies. 相似文献
7.
Cholesterol regulates activation of sterol regulatory element-binding protein (SREBP) through a classic feedback loop. Walker et al. (2011) extend the regulatory inputs governing SREBP activity to include an independent loop modulated by phosphatidylcholine (PC) and cellular methylation capacity. These findings suggest a link between lipid synthesis and cellular pathways involved in methylation. 相似文献
8.
Servaas A. Morré Ouafae Karimi & Sander Ouburg 《FEMS immunology and medical microbiology》2009,55(2):140-153
The aim of this review is to present a concise overview of all data available on the immunogenetics of Chlamydia trachomatis infections, both sexually transmitted urogenital and ocular infections. Currently, candidate gene approaches are used to identify genes related to the susceptibility to and severity of C. trachomatis infections. The main focus in the review will be on data obtained by the study of human cohorts. 相似文献
9.
Davide Sala Yuanpeng Janet Huang Casey A. Cole David A. Snyder Gaohua Liu Yojiro Ishida G.V.T. Swapna Kelly P. Brock Chris Sander Krzysztof Fidelis Andriy Kryshtafovych Masayori Inouye Roberto Tejero Homayoun Valafar Antonio Rosato Gaetano T. Montelione 《Proteins》2019,87(12):1315-1332
CASP13 has investigated the impact of sparse NMR data on the accuracy of protein structure prediction. NOESY and 15N-1H residual dipolar coupling data, typical of that obtained for 15N,13C-enriched, perdeuterated proteins up to about 40 kDa, were simulated for 11 CASP13 targets ranging in size from 80 to 326 residues. For several targets, two prediction groups generated models that are more accurate than those produced using baseline methods. Real NMR data collected for a de novo designed protein were also provided to predictors, including one data set in which only backbone resonance assignments were available. Some NMR-assisted prediction groups also did very well with these data. CASP13 also assessed whether incorporation of sparse NMR data improves the accuracy of protein structure prediction relative to nonassisted regular methods. In most cases, incorporation of sparse, noisy NMR data results in models with higher accuracy. The best NMR-assisted models were also compared with the best regular predictions of any CASP13 group for the same target. For six of 13 targets, the most accurate model provided by any NMR-assisted prediction group was more accurate than the most accurate model provided by any regular prediction group; however, for the remaining seven targets, one or more regular prediction method provided a more accurate model than even the best NMR-assisted model. These results suggest a novel approach for protein structure determination, in which advanced prediction methods are first used to generate structural models, and sparse NMR data is then used to validate and/or refine these models. 相似文献
10.