全文获取类型
收费全文 | 390篇 |
免费 | 22篇 |
国内免费 | 1篇 |
出版年
2022年 | 3篇 |
2021年 | 6篇 |
2017年 | 5篇 |
2016年 | 6篇 |
2015年 | 11篇 |
2014年 | 15篇 |
2013年 | 14篇 |
2012年 | 17篇 |
2011年 | 20篇 |
2010年 | 12篇 |
2009年 | 10篇 |
2008年 | 10篇 |
2007年 | 16篇 |
2006年 | 8篇 |
2005年 | 16篇 |
2004年 | 6篇 |
2003年 | 12篇 |
2002年 | 11篇 |
2001年 | 5篇 |
2000年 | 9篇 |
1999年 | 8篇 |
1998年 | 3篇 |
1997年 | 6篇 |
1994年 | 4篇 |
1993年 | 6篇 |
1991年 | 7篇 |
1990年 | 7篇 |
1989年 | 5篇 |
1988年 | 7篇 |
1987年 | 7篇 |
1986年 | 7篇 |
1985年 | 4篇 |
1984年 | 5篇 |
1983年 | 4篇 |
1982年 | 4篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 10篇 |
1978年 | 3篇 |
1977年 | 7篇 |
1976年 | 11篇 |
1975年 | 7篇 |
1974年 | 6篇 |
1973年 | 5篇 |
1971年 | 12篇 |
1970年 | 3篇 |
1969年 | 5篇 |
1968年 | 5篇 |
1967年 | 4篇 |
1966年 | 4篇 |
排序方式: 共有413条查询结果,搜索用时 15 毫秒
51.
Kim JS Coon SL Blackshaw S Cepko CL Møller M Mukda S Zhao WQ Charlton CG Klein DC 《The Journal of biological chemistry》2005,280(1):677-684
(S)-adenosylmethionine (SAM) is a critical element of melatonin synthesis as the methyl donor in the last step of the pathway, the O-methylation of N-acetyl 5-hydroxytryptamine by hydroxyindole-O-methyltransferase. The activity of the enzyme that synthesizes SAM, methionine adenosyltransferase (MAT), increases 2.5-fold at night in the pineal gland. In this study, we found that pineal MAT2A mRNA and the protein it encodes, MAT II, also increase at night, suggesting that the increase in MAT activity is caused by an increase in MAT II gene products. The night levels of MAT2A mRNA in the pineal gland were severalfold higher than in other neural and non-neural tissues examined, consistent with the requirement for SAM in melatonin synthesis. Related studies indicate that the nocturnal increase in MAT2A mRNA is caused by activation of a well described neural pathway that mediates photoneural-circadian regulation of the pineal gland. MAT2A mRNA and MAT II protein were increased in organ culture by treatment with norepinephrine (NE), the sympathetic neurotransmitter that stimulates the pineal gland at night. NE is known to markedly elevate pineal cAMP, and here it was found that cAMP agonists elevate MAT2A mRNA levels by increasing MAT2A mRNA synthesis and that drugs that block cAMP activation of cAMP dependent protein kinase block effects of NE. Therefore, the NE-cAMP dependent increase in pineal MAT activity seems to reflect an increase in MAT II protein, which occurs in response to cAMP-->protein kinase-dependent increased MAT2A expression. The existence of this MAT regulatory system underscores the importance that MAT plays in melatonin biogenesis. These studies also point to the possibility that SAM production in other tissues might be regulated through cAMP. 相似文献
52.
A fundamental aspect of cytochrome P450 function is the role of the strictly conserved axial cysteine ligand, replacement of which by histidine has invariably resulted in mammalian and bacterial preparations devoid of heme. Isolation of the His-436 variant of NH2-truncated P450 2B4 partly as the holoenzyme was achieved in the present study by mutagenesis of the I-helix Ala-298 residue to Glu and subsequent conversion of the axial Cys-436 to His. The expressed A298E/C436H double mutant, cloned with a hexahistidine tag, had a molecular mass equivalent to that of the primary structure of His-tagged truncated 2B4 and the sum of the two mutated residues, and contained a heme group which, when released on HPLC, showed a retention time and spectrum identical to those of iron protoporphyrin IX. The absolute spectra of A298E/C436H indicate a change in heme coordination structure from low- to high-spin, and, as expected for a His-ligated hemeprotein, the Soret maximum of the ferrous CO complex is at 422 nm. The double mutant has no oxygenase activity with representative substrates known to undergo transformation by the oxene [(FeO)3+] or peroxo activated oxygen species, but catalyzes significant H2O2 formation that is NADPH- and time-dependent, and directly proportional to the concentration of A298E/C436H in the presence of saturating reductase. Moreover, the catalytic efficiency of A298E/C436H in the H2O2-supported peroxidation of pyrogallol is more than two orders of magnitude greater than that of wild-type 2B4 or the A298E variant. The results unambiguously demonstrate that the proximal thiolate ligand is essential for substrate oxygenation by P450. 相似文献
53.
Coon H Matsunami N Stevens J Miller J Pingree C Camp NJ Thomas A Krasny L Lainhart J Leppert MF McMahon W 《Human heredity》2005,60(4):220-226
Though autism shows strong evidence for genetic etiology, specific genes have not yet been found. We tested for linkage in a candidate region on chromosome 3q25-27 first identified in Finnish autism families [1]. The peak in this previous study was at D3S3037 (183.9 cM). We tested this region in seven affected family members and 24 of their relatives from a single large extended Utah pedigree of Northern European ancestry. A total of 70 single nucleotide polymorphisms (SNPs) were analyzed from 165 to 204 cM. The maximum NPL-all nonparametric score using SimWalk2snp was 3.53 (empirical p val ue = 0.0003) at 185.2 cM (SNP rs1402229), close to the Finnish peak. A secondary analysis using MCLINK supported this result, with a maximum of 3.92 at 184.6 cM (SNP rs1362645). We tested for alterations in a candidate gene in this region, the fragile X autosomal homolog, FXR1. No variants likely to contribute to autism were found in the coding sequence, exon-intron boundaries, or the promoter region of this gene. 相似文献
54.
Familial aggregation and genome-wide linkage analysis of carotid artery plaque: the NHLBI family heart study 总被引:3,自引:0,他引:3
Pankow JS Heiss G Evans GW Sholinsky P Province MA Coon H Ellison RC Miller MB Qaqish B 《Human heredity》2004,57(2):80-89
OBJECTIVE: To evaluate familial and genetic influences on carotid artery plaque, a qualitative marker of the systemic burden of atherosclerosis. METHODS: The design was a cross-sectional study of 2,223 members of 525 randomly-ascertained families and 2,514 members of 589 high coronary heart disease (CHD) risk families from 4 U.S. communities. RESULTS: The prevalence of plaque was 33, 36, and 47%, respectively, among probands with 0, 1, and 2 or more first-degree relatives with a history of CHD. There was evidence of sibling aggregation of plaque in random families (OR = 1.89; 95% CI: 1.44, 2.48), but associations were substantially attenuated when adjusted for major cardiovascular disease risk factors. A genome scan with 420 microsatellite markers revealed no regions of significant or suggestive linkage for plaque in 342 affected sibling pairs, although suggestive linkage (LOD score: 2.43) was found on chromosome 2p11.2 (D2S1790) in pairs aged 55 years or younger. Other markers with nominal evidence for linkage (p < 0.05) were found on chromosomes 2p25, 2q24-q32, 6q21-q23, 7p12-p21, 7q11-q21, 8q24, 12q12-q13, 18p11, 21q21 and Xp11, Xq12, and Xq24. CONCLUSIONS: There was modest familial aggregation of carotid artery plaque, but a genome-wide scan indicated no regions of significant or suggestive linkage. 相似文献
55.
A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration 总被引:1,自引:0,他引:1
Zebrafish possess a unique yet poorly understood capacity for cardiac regeneration. Here, we show that regeneration proceeds through two coordinated stages following resection of the ventricular apex. First a blastema is formed, comprised of progenitor cells that express precardiac markers, undergo differentiation, and proliferate. Second, epicardial tissue surrounding both cardiac chambers induces developmental markers and rapidly expands, creating a new epithelial cover for the exposed myocardium. A subpopulation of these epicardial cells undergoes epithelial-to-mesenchymal transition (EMT), invades the wound, and provides new vasculature to regenerating muscle. During regeneration, the ligand fgf17b is induced in myocardium, while receptors fgfr2 and fgfr4 are induced in adjacent epicardial-derived cells. When fibroblast growth factors (Fgf) signaling is experimentally blocked by expression of a dominant-negative Fgf receptor, epicardial EMT and coronary neovascularization fail, prematurely arresting regeneration. Our findings reveal injury responses by myocardial and epicardial tissues that collaborate in an Fgf-dependent manner to achieve cardiac regeneration. 相似文献
56.
57.
58.
59.
60.
Adi Tovin Shahar Alon Zohar Ben-Moshe Philipp Mracek Gad Vatine Nicholas S. Foulkes Jasmine Jacob-Hirsch Gideon Rechavi Reiko Toyama Steven L. Coon David C. Klein Eli Eisenberg Yoav Gothilf 《PLoS genetics》2012,8(12)
A wide variety of biochemical, physiological, and molecular processes are known to have daily rhythms driven by an endogenous circadian clock. While extensive research has greatly improved our understanding of the molecular mechanisms that constitute the circadian clock, the links between this clock and dependent processes have remained elusive. To address this gap in our knowledge, we have used RNA sequencing (RNA–seq) and DNA microarrays to systematically identify clock-controlled genes in the zebrafish pineal gland. In addition to a comprehensive view of the expression pattern of known clock components within this master clock tissue, this approach has revealed novel potential elements of the circadian timing system. We have implicated one rhythmically expressed gene, camk1gb, in connecting the clock with downstream physiology of the pineal gland. Remarkably, knockdown of camk1gb disrupts locomotor activity in the whole larva, even though it is predominantly expressed within the pineal gland. Therefore, it appears that camk1gb plays a role in linking the pineal master clock with the periphery. 相似文献