全文获取类型
收费全文 | 886篇 |
免费 | 70篇 |
出版年
2022年 | 4篇 |
2021年 | 15篇 |
2020年 | 10篇 |
2019年 | 11篇 |
2018年 | 23篇 |
2017年 | 21篇 |
2016年 | 19篇 |
2015年 | 27篇 |
2014年 | 33篇 |
2013年 | 44篇 |
2012年 | 48篇 |
2011年 | 42篇 |
2010年 | 36篇 |
2009年 | 23篇 |
2008年 | 25篇 |
2007年 | 40篇 |
2006年 | 41篇 |
2005年 | 25篇 |
2004年 | 46篇 |
2003年 | 38篇 |
2002年 | 27篇 |
2001年 | 32篇 |
2000年 | 28篇 |
1999年 | 31篇 |
1998年 | 7篇 |
1997年 | 6篇 |
1996年 | 13篇 |
1995年 | 5篇 |
1994年 | 10篇 |
1993年 | 9篇 |
1992年 | 20篇 |
1991年 | 21篇 |
1990年 | 13篇 |
1989年 | 17篇 |
1988年 | 20篇 |
1987年 | 13篇 |
1986年 | 7篇 |
1985年 | 9篇 |
1984年 | 8篇 |
1983年 | 7篇 |
1980年 | 5篇 |
1979年 | 4篇 |
1978年 | 4篇 |
1977年 | 5篇 |
1975年 | 13篇 |
1973年 | 6篇 |
1972年 | 9篇 |
1970年 | 8篇 |
1969年 | 4篇 |
1966年 | 3篇 |
排序方式: 共有956条查询结果,搜索用时 125 毫秒
91.
The Pot1 (protection of telomeres) protein binds to single-stranded telomeric DNA and is essential for the protection of chromosome ends from degradation and end-to-end fusions. The Pot1 amino-terminal DNA binding domain, Pot1N, adopts an oligonucleotide/oligosaccharide binding fold and binds GGTTAC motifs cooperatively and with exceptionally high sequence specificity. We have now examined DNA binding to naturally occurring telomeric substrates based on the analysis of 100 cloned chromosome ends and in the context of the full-length Pot1 protein. Here, we describe several important differences between Pot1 and Pot1N with apparent consequences for chromosome end protection. Specifically, full-length Pot1.DNA complexes are more stable, and the minimal binding site for a Pot1 monomer is extended into two adjacent telomeric repeats. We provide evidence that Pot1 contains a second DNA binding motif that recognizes DNA with reduced sequence specificity compared with the domain present in Pot1N. The two DNA binding motifs cooperate, whereby the amino-terminal oligonucleotide/oligosaccharide binding fold determines the registry of binding, and the internal DNA binding motif stabilizes the complex and expands the protected region toward the 3' -end. Consistent with a role in chromosome end capping, Pot1 prevents access of telomerase to the 3'-end and protects against exonucleolytic degradation. 相似文献
92.
Phillips JD Whitby FG Warby CA Labbe P Yang C Pflugrath JW Ferrara JD Robinson H Kushner JP Hill CP 《The Journal of biological chemistry》2004,279(37):38960-38968
Coproporphyrinogen oxidase (CPO) is an essential enzyme that catalyzes the sixth step of the heme biosynthetic pathway. Unusually for heme biosynthetic enzymes, CPO exists in two evolutionarily and mechanistically distinct families, with eukaryotes and some prokaryotes employing members of the highly conserved oxygen-dependent CPO family. Here, we report the crystal structure of the oxygen-dependent CPO from Saccharomyces cerevisiae (Hem13p), which was determined by optimized sulfur anomalous scattering and refined to a resolution of 2.0 A. The protein adopts a novel structure that is quite different from predicted models and features a central flat seven-stranded anti-parallel sheet that is flanked by helices. The dimeric assembly, which is seen in different crystal forms, is formed by packing of helices and a short isolated strand that forms a beta-ladder with its counterpart in the partner subunit. The deep active-site cleft is lined by conserved residues and has been captured in open and closed conformations in two different crystal forms. A substratesized cavity is completely buried in the closed conformation by the approximately 8-A movement of a helix that forms a lid over the active site. The structure therefore suggests residues that likely play critical roles in catalysis and explains the deleterious effect of many of the mutations associated with the disease hereditary coproporphyria. 相似文献
93.
94.
Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4) 总被引:7,自引:0,他引:7
下载免费PDF全文
![点击此处可从《American journal of human genetics》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Donaudy F Snoeckx R Pfister M Zenner HP Blin N Di Stazio M Ferrara A Lanzara C Ficarella R Declau F Pusch CM Nürnberg P Melchionda S Zelante L Ballana E Estivill X Van Camp G Gasparini P Savoia A 《American journal of human genetics》2004,74(4):770-776
Myosins have been implicated in various motile processes, including organelle translocation, ion-channel gating, and cytoskeleton reorganization. Different members of the myosin superfamily are responsible for syndromic and nonsyndromic hearing impairment in both humans and mice. MYH14 encodes one of the heavy chains of the class II nonmuscle myosins, and it is localized within the autosomal dominant hearing impairment (DFNA4) critical region. After demonstrating that MYH14 is highly expressed in mouse cochlea, we performed a mutational screening in a large series of 300 hearing-impaired patients from Italy, Spain, and Belgium and in a German kindred linked to DFNA4. This study allowed us to identify a nonsense and two missense mutations in large pedigrees, linked to DFNA4, as well as a de novo allele in a sporadic case. Absence of these mutations in healthy individuals was tested in 200 control individuals. These findings clearly demonstrate the role of MYH14 in causing autosomal dominant hearing loss and further confirm the crucial role of the myosin superfamily in auditive functions. 相似文献
95.
Differential arrangements of conserved building blocks among homologs of the Rad50/Mre11 DNA repair protein complex 总被引:5,自引:0,他引:5
de Jager M Trujillo KM Sung P Hopfner KP Carney JP Tainer JA Connelly JC Leach DR Kanaar R Wyman C 《Journal of molecular biology》2004,339(4):937-949
Structural maintenance of chromosomes (SMC) proteins have diverse cellular functions including chromosome segregation, condensation and DNA repair. They are grouped based on a conserved set of distinct structural motifs. All SMC proteins are predicted to have a bipartite ATPase domain that is separated by a long region predicted to form a coiled coil. Recent structural data on a variety of SMC proteins shows them to be arranged as long intramolecular coiled coils with a globular ATPase at one end. SMC proteins function in pairs as heterodimers or as homodimers often in complexes with other proteins. We expect the arrangement of the SMC protein domains in complex assemblies to have important implications for their diverse functions. We used scanning force microscopy imaging to determine the architecture of human, Saccharomyces cerevisiae, and Pyrococcus furiosus Rad50/Mre11, Escherichia coli SbcCD, and S.cerevisiae SMC1/SMC3 cohesin SMC complexes. Two distinct architectural arrangements are described, based on the way their components were connected. The eukaryotic complexes were similar to each other and differed from their prokaryotic and archaeal homologs. These similarities and differences are discussed with respect to their diverse mechanistic roles in chromosome metabolism. 相似文献
96.
Glycosylation of immunodominant linear epitopes in the carboxy-terminal region of the caprine arthritis-encephalitis virus surface envelope enhances vaccine-induced type-specific and cross-reactive neutralizing antibody responses
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Trujillo JD Kumpula-McWhirter NM Hötzel KJ Gonzalez M Cheevers WP 《Journal of virology》2004,78(17):9190-9202
This study evaluated type-specific and cross-reactive neutralizing antibodies induced by immunization with modified surface glycoproteins (SU) of the 63 isolate of caprine arthritis-encephalitis lentivirus (CAEV-63). Epitope mapping of sera from CAEV-infected goats localized immunodominant linear epitopes in the carboxy terminus of SU. Two modified SU (SU-M and SU-T) and wild-type CAEV-63 SU (SU-W) were produced in vaccinia virus and utilized to evaluate the effects of glycosylation or the deletion of immunodominant linear epitopes on neutralizing antibody responses induced by immunization. SU-M contained two N-linked glycosylation sites inserted into the target epitopes by R539S and E542N mutations. SU-T was truncated at 518A, upstream from the target epitopes, by introduction of termination codons at 519Y and 521Y. Six yearling Saanen goats were immunized subcutaneously with 30 microg of SU-W, SU-M, or SU-T in Quil A adjuvant and boosted at 3, 7, and 16 weeks. SU antibody titers determined by indirect enzyme-linked immunosorbent assay demonstrated anamnestic responses after each boost. Wild-type and modified SU-induced type-specific CAEV-63 neutralizing antibodies and cross-reactive neutralizing antibodies against CAEV-Co, a virus isolate closely related to CAEV-63, and CAEV-1g5, an isolate geographically distinct from CAEV-63, were determined. Immunization with SU-T resulted in altered recognition of SU linear epitopes and a 2.8- to 4.6-fold decrease in neutralizing antibody titers against CAEV-63, CAEV-Co, and CAEV-1g5 compared to titers of SU-W-immunized goats. In contrast, immunization with SU-M resulted in reduced recognition of glycosylated epitopes and a 2.4- to 2.7-fold increase in neutralizing antibody titers compared to titers of SU-W-immunized goats. Thus, the glycosylation of linear immunodominant nonneutralization epitopes, but not epitope deletion, is an effective strategy to enhance neutralizing antibody responses by immunization. 相似文献
97.
98.
99.
Glaura Caroena Matsuyoshi Mori Marcos R.R. Gesualdi Edson A. Liberti Eduardo Ferrara Mikiya Muramatsu 《Journal of biomechanics》2010,43(4):680-686
The purpose of this work was the force–displacement response analysis of the masticatory process in a dried human skull by Double-Exposure Photorefractive Holographic Interferometry Technique (2E-PRHI). The load concentration and dissipation of the forces from dried human skull were analysed at applied loading stands as a Simulation of Isolated Contraction (SIC) of some mastication muscles. The 2EHI and Fringe Analysis Method were used to obtain the quantitative results of this force–displacement response. These results document quantitatively the real biomechanical response from dried human skull under applied loading and it can be used for complementary study by finite element model and others analysis type. 相似文献
100.
Ferrara GB Murgia B Parodi AM Valisano L Cerrano C Palmisano G Bavestrello G Sara M 《Cellular & molecular biology letters》2006,11(2):155-160
We developed a rapid, practical and non-toxic salting-out method for the extraction of DNA from marine organisms, and tested
it on two representative species of Porifera and Cnidaria, both living in association with symbiotic zooxanthellae. We tested
the efficiency of the protocol by comparing the output of the method for fresh tissue, frozen tissue and tissue stored in
ethanol. It proved to be effective for extracting DNA in the case of the methods of preservation considered here, and for
obtaining quantities of DNA comparable to those obtained via the traditional approach. The DNA from both species was of good
quality. The DNA obtained was amplified by PCR using specific primers for the large ribosomal subunit, allowing the identification
of the presence of both the host and symbiont genomes. 相似文献