全文获取类型
收费全文 | 179篇 |
免费 | 18篇 |
国内免费 | 1篇 |
出版年
2022年 | 1篇 |
2021年 | 3篇 |
2018年 | 3篇 |
2017年 | 1篇 |
2016年 | 5篇 |
2015年 | 7篇 |
2014年 | 6篇 |
2013年 | 5篇 |
2012年 | 16篇 |
2011年 | 9篇 |
2010年 | 8篇 |
2009年 | 14篇 |
2008年 | 9篇 |
2007年 | 6篇 |
2006年 | 16篇 |
2005年 | 11篇 |
2004年 | 9篇 |
2003年 | 6篇 |
2002年 | 5篇 |
2001年 | 7篇 |
2000年 | 4篇 |
1999年 | 3篇 |
1998年 | 4篇 |
1996年 | 1篇 |
1995年 | 1篇 |
1994年 | 1篇 |
1993年 | 3篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1989年 | 3篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1985年 | 2篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 3篇 |
1980年 | 1篇 |
1979年 | 3篇 |
1978年 | 2篇 |
1977年 | 1篇 |
1976年 | 4篇 |
1975年 | 2篇 |
1973年 | 1篇 |
1949年 | 1篇 |
1928年 | 1篇 |
1916年 | 1篇 |
排序方式: 共有198条查询结果,搜索用时 15 毫秒
81.
Bailey SM Robinson G Pinner A Chamlee L Ulasova E Pompilius M Page GP Chhieng D Jhala N Landar A Kharbanda KK Ballinger S Darley-Usmar V 《American journal of physiology. Gastrointestinal and liver physiology》2006,291(5):G857-G867
An early event that occurs in response to alcohol consumption is mitochondrial dysfunction, which is evident in changes to the mitochondrial proteome, respiration defects, and mitochondrial DNA (mtDNA) damage. S-adenosylmethionine (SAM) has emerged as a potential therapeutic for treating alcoholic liver disease through mechanisms that appear to involve decreases in oxidative stress and proinflammatory cytokine production as well as the alleviation of steatosis. Because mitochondria are a source of reactive oxygen/nitrogen species and a target for oxidative damage, we tested the hypothesis that SAM treatment during alcohol exposure preserves organelle function. Mitochondria were isolated from livers of rats fed control and ethanol diets with and without SAM for 5 wk. Alcohol feeding caused a significant decrease in state 3 respiration and the respiratory control ratio, whereas SAM administration prevented these alcohol-mediated defects and preserved hepatic SAM levels. SAM treatment prevented alcohol-associated increases in mitochondrial superoxide production, mtDNA damage, and inducible nitric oxide synthase induction, without a significant lessening of steatosis. Accompanying these indexes of oxidant damage, SAM prevented alcohol-mediated losses in cytochrome c oxidase subunits as shown using blue native PAGE proteomics and immunoblot analysis, which resulted in partial preservation of complex IV activity. SAM treatment attenuated the upregulation of the mitochondrial stress chaperone prohibitin. Although SAM supplementation did not alleviate steatosis by itself, SAM prevented several key alcohol-mediated defects to the mitochondria genome and proteome that contribute to the bioenergetic defect in the liver after alcohol consumption. These findings reveal new molecular targets through which SAM may work to alleviate one critical component of alcohol-induced liver injury: mitochondria dysfunction. 相似文献
82.
Richard A Notebaart Frank HJ van Enckevort Christof Francke Roland J Siezen Bas Teusink 《BMC bioinformatics》2006,7(1):296
Background
The genomic information of a species allows for the genome-scale reconstruction of its metabolic capacity. Such a metabolic reconstruction gives support to metabolic engineering, but also to integrative bioinformatics and visualization. Sequence-based automatic reconstructions require extensive manual curation, which can be very time-consuming. Therefore, we present a method to accelerate the time-consuming process of network reconstruction for a query species. The method exploits the availability of well-curated metabolic networks and uses high-resolution predictions of gene equivalency between species, allowing the transfer of gene-reaction associations from curated networks. 相似文献83.
Genome scan for loci predisposing to anxiety disorders using a novel multivariate approach: strong evidence for a chromosome 4 risk locus
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)
Kaabi B Gelernter J Woods SW Goddard A Page GP Elston RC 《American journal of human genetics》2006,78(4):543-553
We conducted a 10-centimorgan linkage autosomal genome scan in a set of 19 extended American pedigrees (219 subjects) ascertained through probands with panic disorder. Several anxiety disorders--including social phobia, agoraphobia, and simple phobia--in addition to panic disorder segregate in these families. In previous studies of this sample, linkage analyses were based separately on each of the individual categorical affection diagnoses. Given the substantial comorbidity between anxiety disorders and their probable shared genetic liability, it is clear that this method discards a considerable amount of information. In this article, we propose a new approach that considers panic disorder, simple phobia, social phobia, and agoraphobia as expressions of the same multivariate, putatively genetically influenced trait. We applied the most powerful multipoint Haseman-Elston method, using the grade of membership score generated from a fuzzy clustering of these phenotypes as the dependent variable in Haseman-Elston regression. One region on chromosome 4q31-q34, at marker D4S413 (with multipoint and single-point nominal P values < .00001), showed strong evidence of linkage (genomewide significance at P<.05). The same region is known to be the site of a neuropeptide Y receptor gene, NPY1R (4q31-q32), that was recently connected to anxiolytic-like effects in rats. Several other regions on four chromosomes (4q21.21-22.3, 5q14.2-14.3, 8p23.1, and 14q22.3-23.3) met criteria for suggestive linkage (multipoint nominal P values < .01). Family-by-family analysis did not show any strong evidence of heterogeneity. Our findings support the notion that the major anxiety disorders, including phobias and panic disorder, are complex traits that share at least one susceptibility locus. This method could be applied to other complex traits for which shared genetic-liability factors are thought to be important, such as substance dependencies. 相似文献
84.
85.
A combined long-range phasing and long haplotype imputation method to impute phase for SNP genotypes 总被引:1,自引:0,他引:1
John M Hickey Brian P Kinghorn Bruce Tier James F Wilson Neil Dunstan Julius HJ van der Werf 《遗传、选种与进化》2011,43(1):12
Background
Knowing the phase of marker genotype data can be useful in genome-wide association studies, because it makes it possible to use analysis frameworks that account for identity by descent or parent of origin of alleles and it can lead to a large increase in data quantities via genotype or sequence imputation. Long-range phasing and haplotype library imputation constitute a fast and accurate method to impute phase for SNP data.Methods
A long-range phasing and haplotype library imputation algorithm was developed. It combines information from surrogate parents and long haplotypes to resolve phase in a manner that is not dependent on the family structure of a dataset or on the presence of pedigree information.Results
The algorithm performed well in both simulated and real livestock and human datasets in terms of both phasing accuracy and computation efficiency. The percentage of alleles that could be phased in both simulated and real datasets of varying size generally exceeded 98% while the percentage of alleles incorrectly phased in simulated data was generally less than 0.5%. The accuracy of phasing was affected by dataset size, with lower accuracy for dataset sizes less than 1000, but was not affected by effective population size, family data structure, presence or absence of pedigree information, and SNP density. The method was computationally fast. In comparison to a commonly used statistical method (fastPHASE), the current method made about 8% less phasing mistakes and ran about 26 times faster for a small dataset. For larger datasets, the differences in computational time are expected to be even greater. A computer program implementing these methods has been made available.Conclusions
The algorithm and software developed in this study make feasible the routine phasing of high-density SNP chips in large datasets. 相似文献86.
KLARA BJÖRG JAKOBSDÓTTIR þÓRA DÖGG JÖRUNDSDÓTTIR SIGURLAUG SKÍRNISDÓTTIR SIGRÍÐUR HJÖRLEIFSDÓTTIR GUÐMUNDUR Ó. HREGGVIÐSSON ANNA KRISTÍN DANÍELSDÓTTIR CHRISTOPHE PAMPOULIE 《Molecular ecology resources》2006,6(2):337-339
Nine out of 22 microsatellite primers tested were successfully amplified on three samples of cod Gadus morhua L. (two contemporary and one archived otolith samples). All loci were polymorphic (5–23 alleles/locus). The average observed heterozygosity across loci and samples was 0.625, ranging from 0.294 to 0.895 at each locus. All loci were under Hardy–Weinberg equilibrium, except PGmo56 that showed significant excess of heterozygotes in all studied samples. The isolated loci were suitable for degraded DNA and therefore useful for conducting a long‐term temporal study with DNA obtained from archived otoliths of cod. 相似文献
87.
88.
Molecular mechanisms of homologous and heterologous desensitization mediated by vasopressin in smooth muscle cells 总被引:2,自引:0,他引:2
Arginine vasopressin (AVP) has been shown previously to enhance phosphatidylinositol (PI) turnover and mobilize calcium in the rat aortic smooth muscle cell-line (A10; ATCC CRL 1476) via the V1 receptor (Aiyar, N., Nambi, P., Stassen, F. L., and Crooke, S. T. (1986) Life Sci. 39, 37-45). Exposure of A10 cells to AVP for periods ranging from 5 min to 2 h resulted in 30-40% loss in AVP-binding sites and an inhibition of the production of inositol di- and trisphosphates and the mobilization of calcium when the cells were rechallenged by addition of AVP. We now report that during the same time course AVP induces a dose- and time-dependent decrease in labeled PI, phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate reaching a minimum after 30 min of incubation. After 2 h of exposure to AVP, the levels of labeled PI, phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate increased to a new basal level approximately 30% less than the untreated cultures. The decrease in inositol lipid labeling mediated by AVP was inhibited when the V1 antagonist SK&F 100273 was included in the incubations with AVP. No decrease was observed when the V2 agonist 1-deamino, [8-D-arginine]vasopressin was used for pretreatment of the cells. Furthermore, when PI kinase activity was measured in cell extracts from untreated and AVP-treated (2 h) cells a significant decrease (p less than 0.05) was observed in the absence, but not in the presence, of added PI in the AVP-treated cells as compared with the control cells. Thrombin also stimulates PI metabolism and calcium mobilization in these cells and brought about both a prolonged decrease in inositol lipids and inhibition of PI kinase activity. AVP pretreatment affected the release of intracellular Ca2+ induced by AVP, thrombin, and ATP, differently. The time of AVP pretreatment required to induce half-maximal inhibition of intracellular Ca2+ release in response to AVP, thrombin, and ATP was approximately 8, 24, and 30 min, respectively. Consequently, we suggest that the reduction in response to AVP with short term preincubation is due to homologous desensitization as reflected by 30-40% decrease in V1 receptors. Subsequently, a decrease in inositol lipid pools and PI kinase activity results in heterologous desensitization in response to AVP, thrombin, and ATP. 相似文献
89.
Serreze DV Choisy-Rossi CM Grier AE Holl TM Chapman HD Gahagan JR Osborne MA Zhang W King BL Brown A Roopenian D Marron MP 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(5):3250-3259
When expressed in NOD, but not C57BL/6 (B6) genetic background mice, the common class I variants encoded by the H2g7 MHC haplotype aberrantly lose the ability to mediate the thymic deletion of autoreactive CD8+ T cells contributing to type 1 diabetes (T1D). This indicated some subset of the T1D susceptibility (Idd) genes located outside the MHC of NOD mice interactively impair the negative selection of diabetogenic CD8+ T cells. In this study, using both linkage and congenic strain analyses, we demonstrate contributions from a polymorphic gene(s) in the previously described Idd7 locus on the proximal portion of Chromosome 7 predominantly, but not exclusively, determines the extent to which H2g7 class I molecules can mediate the thymic deletion of diabetogenic CD8+ T cells as illustrated using the AI4 TCR transgenic system. The polymorphic Idd7 region gene(s) appears to control events that respectively result in high vs low expression of the AI4 clonotypic TCR alpha-chain on developing thymocytes in B6.H2g7 and NOD background mice. This expression difference likely lowers levels of the clonotypic AI4 TCR in NOD, but not B6.H2g7 thymocytes, below the threshold presumably necessary to induce a signaling response sufficient to trigger negative selection upon Ag engagement. These findings provide further insight to how susceptibility genes, both within and outside the MHC, may interact to elicit autoreactive T cell responses mediating T1D development in both NOD mice and human patients. 相似文献
90.
Yuzeng Liang Ashoke Sharon Jason P. Grier Kimberly L. Rapp Raymond F. Schinazi Chung K. Chu 《Bioorganic & medicinal chemistry》2009,17(3):1404-1409
A series of (?)-β-d-(2R,4R)-dioxolane-thymine-5′-O-aliphatic acid esters as well as amino acid esters were synthesized as prodrugs of (?)-β-d-(2R,4R)-dioxolane-thymine (DOT). The compounds were evaluated for anti-HIV activity against HIV-1LAI in human peripheral blood mononuclear (PBM) cells as well as for their cytotoxicity in PBM, CEM and Vero cells. Improved anti-HIV potency in vitro was observed for the compound 2–4 (5′-O-aliphatic acid esters) without increase in cytotoxicity in comparison to the parent drug. Chemical and enzymatic hydrolysis of the prodrugs was also studied, in which the prodrugs exhibited good chemical stability with the half-lives from 3 h to 54 h at pH 2.0 and 7.4 phosphate buffer. However, the prodrugs were relatively labile to porcine esterase with the half-lives from 12.3 to 48.0 min. 相似文献