全文获取类型
收费全文 | 404篇 |
免费 | 25篇 |
出版年
2022年 | 4篇 |
2021年 | 6篇 |
2020年 | 1篇 |
2019年 | 8篇 |
2018年 | 7篇 |
2017年 | 6篇 |
2016年 | 5篇 |
2015年 | 14篇 |
2014年 | 24篇 |
2013年 | 35篇 |
2012年 | 28篇 |
2011年 | 27篇 |
2010年 | 21篇 |
2009年 | 34篇 |
2008年 | 32篇 |
2007年 | 19篇 |
2006年 | 20篇 |
2005年 | 21篇 |
2004年 | 28篇 |
2003年 | 20篇 |
2002年 | 15篇 |
2001年 | 3篇 |
2000年 | 4篇 |
1999年 | 3篇 |
1998年 | 5篇 |
1997年 | 5篇 |
1996年 | 3篇 |
1994年 | 2篇 |
1993年 | 2篇 |
1992年 | 2篇 |
1991年 | 1篇 |
1990年 | 4篇 |
1989年 | 4篇 |
1988年 | 2篇 |
1987年 | 3篇 |
1985年 | 3篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1977年 | 1篇 |
1976年 | 3篇 |
1973年 | 1篇 |
1972年 | 1篇 |
排序方式: 共有429条查询结果,搜索用时 161 毫秒
31.
GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease 总被引:5,自引:0,他引:5
Leucine-rich repeat kinase 2 (LRRK2), a product of a causative gene for the autosomal-dominant form of familial Parkinson's disease (PARK8), harbors a Ras-like small GTP binding protein-like (ROC) domain besides the kinase domain, although the relationship between these two functional domains remains elusive. Here we show by thin-layer chromatographic analysis that LRRK2 stably binds GTP but lacks a GTPase activity in HEK293 and Neuro-2a cells. A ROC domain mutation that converts LRRK2 to a guanine nucleotide-free form (T1348N) abolishes the kinase activity of LRRK2 as well as its phosphate incorporation upon metabolic labeling. The phosphorylation of LRRK2 was inhibited by potential inhibitors for cyclic AMP-dependent protein kinase. These data suggest that binding of GTP to the ROC domain regulates the kinase activity of LRRK2 as well as its phosphorylation by other kinase(s). 相似文献
32.
33.
Using the transition matrix of inbreeding and coancestry coefficients, the inbreeding (N(eI)), variance (N(eV)), and asymptotic (N(e lambda)) effective sizes of mixed sexual and asexual populations are formulated in terms of asexuality rate (delta), variance of asexual (C) and sexual (K) reproductive contributions of individuals, correlation between asexual and sexual contributions (rho(ck)), selfing rate (beta), and census population size (N). The trajectory of N(eI) toward N(e lambda) changes crucially depending on delta, N, and beta, whereas that of N(eV) is rather consistent. With increasing asexuality, N(e lambda) either increases or decreases depending on C, K, and rho(ck). The parameter space in which a partially asexual population has a larger N(e lambda) than a fully sexual population is delineated. This structure is destroyed when N(1 - delta) < 1 or delta > 1 - 1/N. With such a high asexuality, tremendously many generations are required for the asymptotic size N(e lambda) to be established, and N(e lambda) is extremely large with any value of C, K, and rho(ck) because the population is dominated eventually by individuals of the same genotype and the allelic diversity within the individuals decays quite slowly. In reality, the asymptotic state would occur only occasionally, and instantaneous rather than asymptotic effective sizes should be practical when predicting evolutionary dynamics of highly asexual populations. 相似文献
34.
Takuro Furusawa Izumi Naka Taro Yamauchi Kazumi Natsuhara Ryosuke Kimura Minato Nakazawa Takafumi Ishida Tsukasa Inaoka Yasuhiro Matsumura Yuji Ataka Nao Nishida Naoyuki Tsuchiya Ryutaro Ohtsuka Jun Ohashi 《Human genetics》2010,127(3):287-294
Various Pacific Island populations have experienced a marked increase in the prevalence of obesity in past decades. This study examined the association of a promoter polymorphism of the leptin gene (LEP), G-2548A (rs7799039), and two non-synonymous single nucleotide polymorphisms of the leptin receptor gene (LEPR), K109R (rs1137100) and Q223R (rs1137101), with body weight, body mass index (BMI) and obesity (BMI ≥ 30) in Pacific Islanders. A total of 745 Austronesian (AN)-speaking participants were analyzed after adjusting for age, gender, and population differences. The results revealed that carriers of the 223Q alleles of LEPR had significantly higher body weight (P = 0.0009) and BMI (P = 0.0022) than non-carriers (i.e., 223R homozygotes); furthermore, the 223Q carriers also had a significantly higher risk of obesity in comparison to non-carriers (P = 0.0222). The other two polymorphisms, G-2548A and K109R, were associated with neither body weight, BMI, nor obesity. The 223Q allele was widely found among the AN-speaking study subjects, thus suggesting that the LEPR Q223R polymorphism is one of the factors contributing to the high prevalence of obesity in the Pacific Island populations. 相似文献
35.
Daisuke Shichi Takuro Arimura Taisuke Ishikawa Akinori Kimura 《The Journal of biological chemistry》2010,285(44):33680-33690
Phosphorylation of myosin regulatory light chain (MLC) plays a regulatory role in muscle contraction, and the level of MLC phosphorylation is balanced by MLC kinase and MLC phosphatase (MLCP). MLCP consists of a catalytic subunit, a large subunit (MYPT1 or MYPT2), and a small subunit. MLCP activity is regulated by phosphorylation of MYPTs, whereas the role of small subunit in the regulation remains unknown. We previously characterized a human heart-specific small subunit (hHS-M21) that increased the sensitivity to Ca2+ in muscle contraction. In this study, we investigated the role of hHS-M21 in the regulation of MLCP phosphorylation. Two isoforms of hHS-M21, hHS-M21A and hHS-M21B, preferentially bound the C-terminal one-third region of MYPT1 and MYPT2, respectively. Amino acid substitutions at a phosphorylation site of MYPT1, Ser-852, impaired the binding of MYPT1 and hHS-M21. The hHS-M21 increased the phosphorylation level of MYPT1 at Thr-696, which was attenuated by Rho-associated kinase (ROCK) inhibitors and small interfering RNAs for ROCK. In addition, hHS-M21 bound ROCK and enhanced the ROCK activity. These findings suggest that hHS-M21 is a heart-specific effector of ROCK and plays a regulatory role in the MYPT1 phosphorylation at Thr-696 by ROCK. 相似文献
36.
Transcriptomic analysis indicates putative metabolic changes caused by manipulation of phosphorus availability in rice leaves 总被引:10,自引:0,他引:10
37.
Quantification of mcrA by quantitative fluorescent PCR in sediments from methane seep of the Nankai Trough 总被引:1,自引:0,他引:1
A quantitative fluorogenic PCR method for group-specific methyl coenzyme M reductase subunit A genes (mcrA) from methanotrophic archaea was established and applied to the characterization of microbial communities in anoxic methane seep sediments at the accretionary prism of the Nankai Trough. All of the previously identified subgroups of anaerobic methanotroph (ANME) mcrA genes were detected in the cores up to 25 cm below the seafloor, but distributional patterns of mcrA genes were found to differ according to depth. These findings suggest a distinct distribution of phylogenetically and physiologically diverse methanotrophic archaea that mediate methane oxidation in the anoxic sediments. This quantification method will contribute to future investigations of methanotrophic microbial ecosystems in anoxic marine sediments. 相似文献
38.
Yabuuchi H Yamada Y Uchida T Sunathvanichkul T Nakagawa T Masukata H 《The EMBO journal》2006,25(19):4663-4674
Initiation of chromosome DNA replication in eukaryotes is tightly regulated through assembly of replication factors at replication origins. Here, we investigated dependence of the assembly of the initiation complex on particular factors using temperature-sensitive fission yeast mutants. The psf3-1 mutant, a GINS component mutant, arrested with unreplicated DNA at the restrictive temperature and the DNA content gradually increased, suggesting a defect in DNA replication. The mutation impaired GINS complex formation, as shown by pull-down experiments. Chromatin immunoprecipitation assays indicated that GINS integrity was required for origin loading of Psf2, Cut5 and Cdc45, but not Sld3. In contrast, loading of Psf2 onto origins depended on Sld3 and Cut5 but not on Cdc45. These results suggest that Sld3 functions furthest upstream in initiation complex assembly, followed by GINS and Cut5, then Cdc45. Consistent with this conclusion, Cdc7-Dbf4 kinase (DDK) but not cyclin-dependent kinase (CDK) was required for Sld3 loading, whereas recruitment of the other factors depended on both kinases. These results suggest that DDK and CDK regulate distinct steps in activation of replication origins in fission yeast. 相似文献
39.
Yoshida-Takashima Y Nunoura T Kazama H Noguchi T Inoue K Akashi H Yamanaka T Toki T Yamamoto M Furushima Y Ueno Y Yamamoto H Takai K 《Applied and environmental microbiology》2012,78(5):1311-1320
Viruses play important roles in marine surface ecosystems, but little is known about viral ecology and virus-mediated processes in deep-sea hydrothermal microbial communities. In this study, we examined virus-like particle (VLP) abundances in planktonic and attached microbial communities, which occur in physical and chemical gradients in both deep and shallow submarine hydrothermal environments (mixing waters between hydrothermal fluids and ambient seawater and dense microbial communities attached to chimney surface areas or macrofaunal bodies and colonies). We found that viruses were widely distributed in a variety of hydrothermal microbial habitats, with the exception of the interior parts of hydrothermal chimney structures. The VLP abundance and VLP-to-prokaryote ratio (VPR) in the planktonic habitats increased as the ratio of hydrothermal fluid to mixing water increased. On the other hand, the VLP abundance in attached microbial communities was significantly and positively correlated with the whole prokaryotic abundance; however, the VPRs were always much lower than those for the surrounding hydrothermal waters. This is the first report to show VLP abundance in the attached microbial communities of submarine hydrothermal environments, which presented VPR values significantly lower than those in planktonic microbial communities reported before. These results suggested that viral lifestyles (e.g., lysogenic prevalence) and virus interactions with prokaryotes are significantly different among the planktonic and attached microbial communities that are developing in the submarine hydrothermal environments. 相似文献
40.
Sazaki G Van Driessche AE Dai G Okada M Matsui T Otálora F Tsukamoto K Nakajima K 《Protein and peptide letters》2012,19(7):743-760
To start systematically investigating the quality improvement of protein crystals, the elementary growth processes of protein crystals must be first clarified comprehensively. Atomic force microscopy (AFM) has made a tremendous contribution toward elucidating the elementary growth processes of protein crystals and has confirmed that protein crystals grow layer by layer utilizing kinks on steps, as in the case of inorganic and low-molecular-weight compound crystals. However, the scanning of the AFM cantilever greatly disturbs the concentration distribution and solution flow in the vicinity of growing protein crystals. AFM also cannot visualize the dynamic behavior of mobile solute and impurity molecules on protein crystal surfaces. To compensate for these disadvantages of AFM, in situ observation by two types of advanced optical microscopy has been recently performed. To observe the elementary steps of protein crystals noninvasively, laser confocal microscopy combined with differential interference contrast microscopy (LCM-DIM) was developed. To visualize individual mobile protein molecules, total internal reflection fluorescent (TIRF) microscopy, which is widely used in the field of biological physics, was applied to the visualization of protein crystal surfaces. In this review, recent progress in the noninvasive in situ observation of elementary steps and individual mobile protein molecules on protein crystal surfaces is outlined. 相似文献