全文获取类型
收费全文 | 107篇 |
免费 | 20篇 |
出版年
2021年 | 4篇 |
2020年 | 2篇 |
2019年 | 1篇 |
2018年 | 4篇 |
2017年 | 1篇 |
2016年 | 8篇 |
2015年 | 6篇 |
2014年 | 8篇 |
2013年 | 8篇 |
2012年 | 6篇 |
2011年 | 8篇 |
2010年 | 6篇 |
2009年 | 6篇 |
2008年 | 9篇 |
2007年 | 7篇 |
2006年 | 3篇 |
2005年 | 5篇 |
2004年 | 4篇 |
2003年 | 2篇 |
2002年 | 4篇 |
2001年 | 1篇 |
2000年 | 1篇 |
1998年 | 3篇 |
1997年 | 1篇 |
1995年 | 1篇 |
1993年 | 2篇 |
1992年 | 3篇 |
1991年 | 2篇 |
1988年 | 2篇 |
1985年 | 1篇 |
1982年 | 2篇 |
1981年 | 2篇 |
1980年 | 1篇 |
1977年 | 3篇 |
排序方式: 共有127条查询结果,搜索用时 906 毫秒
51.
Laura J. White Carlos A. Sariol Melissa D. Mattocks Wahala Wahala M. P. B. Vorraphun Yingsiwaphat Martha L. Collier Jill Whitley Rochelle Mikkelsen Idia V. Rodriguez Melween I. Martinez Aravinda de Silva Robert E. Johnston 《Journal of virology》2013,87(6):3409-3424
Despite many years of research, a dengue vaccine is not available, and the more advanced live attenuated vaccine candidate in clinical trials requires multiple immunizations with long interdose periods and provides low protective efficacy. Here, we report important contributions to the development of a second-generation dengue vaccine. First, we demonstrate that a nonpropagating vaccine vector based on Venezuelan equine encephalitis virus replicon particles (VRP) expressing two configurations of dengue virus E antigen (subviral particles [prME] and soluble E dimers [E85]) successfully immunized and protected macaques against dengue virus, while antivector antibodies did not interfere with a booster immunization. Second, compared to prME-VRP, E85-VRP induced neutralizing antibodies faster, to higher titers, and with improved protective efficacy. Third, this study is the first to map antigenic domains and specificities targeted by vaccination versus natural infection, revealing that, unlike prME-VRP and live virus, E85-VRP induced only serotype-specific antibodies, which predominantly targeted EDIII, suggesting a protective mechanism different from that induced by live virus and possibly live attenuated vaccines. Fourth, a tetravalent E85-VRP dengue vaccine induced a simultaneous and protective response to all 4 serotypes after 2 doses given 6 weeks apart. Balanced responses and protection in macaques provided further support for exploring the immunogenicity and safety of this vaccine candidate in humans. 相似文献
52.
Benjamin I. Leach Aravinda Kuntimaddi Charles R. Schmidt Tomasz Cierpicki Stephanie A. Johnson John H. Bushweller 《Structure (London, England : 1993)》2013,21(1):176-183
- Download : Download high-res image (147KB)
- Download : Download full-size image
53.
Edward A. Wydysh Aravinda Vadlamudi Susan M. Medghalchi Craig A. Townsend 《Bioorganic & medicinal chemistry》2010,18(17):6470-6479
Glycerol 3-phosphate acyltransferase (GPAT) isozymes are central control points for fat synthesis in mammals. Development of inhibitors of these membrane-bound enzymes could lead to an effective treatment for obesity, but is thwarted by an absence of direct structural information. Based on a highly successful study involving conformationally constrained glycerol 3-phosphate analogs functioning as potent glycerol 3-phosphate dehydrogenase inhibitors, several series of cyclic bisubstrate and transition state analogs were designed, synthesized, and tested as GPAT inhibitors. The weaker in vitro inhibitory activity of these compounds compared to a previously described benzoic acid series was then examined in docking experiments with the soluble squash chloroplast GPAT crystal structure. These in silico experiments indicate that cyclopentyl and cyclohexyl scaffolds prepared in this study may be occluded from the enzyme active site by two protein loops that sterically guard the phosphate binding region. In view of these findings, future GPAT inhibitor design will be driven toward compounds based on planar frameworks able to slide between these loops and enter the active site, resulting in improved inhibitory activity. 相似文献
54.
Lettre G Palmer CD Young T Ejebe KG Allayee H Benjamin EJ Bennett F Bowden DW Chakravarti A Dreisbach A Farlow DN Folsom AR Fornage M Forrester T Fox E Haiman CA Hartiala J Harris TB Hazen SL Heckbert SR Henderson BE Hirschhorn JN Keating BJ Kritchevsky SB Larkin E Li M Rudock ME McKenzie CA Meigs JB Meng YA Mosley TH Newman AB Newton-Cheh CH Paltoo DN Papanicolaou GJ Patterson N Post WS Psaty BM Qasim AN Qu L Rader DJ Redline S Reilly MP Reiner AP Rich SS Rotter JI Liu Y Shrader P Siscovick DS 《PLoS genetics》2011,7(2):e1001300
Coronary heart disease (CHD) is the leading cause of mortality in African Americans. To identify common genetic polymorphisms associated with CHD and its risk factors (LDL- and HDL-cholesterol (LDL-C and HDL-C), hypertension, smoking, and type-2 diabetes) in individuals of African ancestry, we performed a genome-wide association study (GWAS) in 8,090 African Americans from five population-based cohorts. We replicated 17 loci previously associated with CHD or its risk factors in Caucasians. For five of these regions (CHD: CDKN2A/CDKN2B; HDL-C: FADS1-3, PLTP, LPL, and ABCA1), we could leverage the distinct linkage disequilibrium (LD) patterns in African Americans to identify DNA polymorphisms more strongly associated with the phenotypes than the previously reported index SNPs found in Caucasian populations. We also developed a new approach for association testing in admixed populations that uses allelic and local ancestry variation. Using this method, we discovered several loci that would have been missed using the basic allelic and global ancestry information only. Our conclusions suggest that no major loci uniquely explain the high prevalence of CHD in African Americans. Our project has developed resources and methods that address both admixture- and SNP-association to maximize power for genetic discovery in even larger African-American consortia. 相似文献
55.
56.
57.
A novel mechanism of complement inhibition unmasked by a tick salivary protein that binds to properdin 总被引:1,自引:0,他引:1
Ixodes scapularis salivary protein 20 (Salp20) is a member of the Ixodes scapularis anti-complement protein-like family of tick salivary proteins that inhibit the alternative complement pathway. In this study, we demonstrate that the target of Salp20 is properdin. Properdin is a natural, positive regulator of the alternative pathway that binds to the C3 convertase, stabilizing the molecule. Salp20 directly bound to and displaced properdin from the C3 convertase. Displacement of properdin accelerated the decay of the C3 convertase, leading to inhibition of the alternative pathway. S20NS is distinct from known decay accelerating factors, such as decay accelerating factor, complement receptor 1, and factor H, which directly interact with either C3b or cleaved factor B. 相似文献
58.
The alpha-aminoisobutyric (Aib) residue has generally been considered to be a strongly helicogenic residue as evidenced by its ability to promote helical folding in synthetic and natural sequences. Crystal structures of several peptide natural products, peptaibols, have revealed predominantly helical conformations, despite the presence of multiple helix-breaking Pro or Hyp residues. Survey of synthetic Aib-containing peptides shows a preponderance of 3(10)-, alpha-, and mixed 3(10)/alpha-helical structures. This review highlights the examples of Aib residues observed in nonhelical conformations, which fall 'primarily' into the polyproline II (P(II)) and fully extended regions of conformational space. The achiral Aib residue can adopt both left (alpha(L))- and right (alpha(R))-handed helical conformations. In sequences containing chiral amino acids, helix termination can occur by means of chiral reversal at an Aib residue, resulting in formation of a Schellman motif. Examples of Aib residues in unusual conformations are illustrated by surveying a database of Aib-containing crystal structures. 相似文献
59.
60.
Aja S Landree LE Kleman AM Medghalchi SM Vadlamudi A McFadden JM Aplasca A Hyun J Plummer E Daniels K Kemm M Townsend CA Thupari JN Kuhajda FP Moran TH Ronnett GV 《American journal of physiology. Regulatory, integrative and comparative physiology》2008,294(2):R352-R361
Inhibition of brain carnitine palmitoyl-transferase-1 (CPT-1) is reported to decrease food intake and body weight in rats. Yet, the fatty acid synthase (FAS) inhibitor and CPT-1 stimulator C75 produces hypophagia and weight loss when given to rodents intracerebroventricularly (icv). Thus roles and relative contributions of altered brain CPT-1 activity and fatty acid oxidation in these phenomena remain unclarified. We administered compounds that target FAS or CPT-1 to mice by single icv bolus and examined acute and prolonged effects on feeding and body weight. C75 decreased food intake rapidly and potently at all doses (1-56 nmol) and dose dependently inhibited intake on day 1. Dose-dependent weight loss on day 1 persisted through 4 days of postinjection monitoring. The FAS inhibitor cerulenin produced dose-dependent (560 nmol) hypophagia for 1 day, weight loss for 2 days, and weight regain to vehicle control by day 3. The CPT-1 inhibitor etomoxir (32, 320 nmol) did not alter overall day 1 feeding. However, etomoxir attenuated the hypophagia produced by C75, indicating that CPT-1 stimulation is important for C75's effect. A novel compound, C89b, was characterized in vitro as a selective stimulator of CPT-1 that does not affect fatty acid synthesis. C89b (100, 320 nmol) decreased feeding in mice for 3 days and produced persistent weight loss for 6 days without producing conditioned taste aversion. Similarly, intraperitoneal administration decreased feeding and body weight without producing conditioned taste aversion. These results suggest a role for brain CPT-1 in the regulation of energy balance and implicate CPT-1 stimulation as a pharmacological approach to weight loss. 相似文献