全文获取类型
收费全文 | 514篇 |
免费 | 49篇 |
出版年
2023年 | 4篇 |
2022年 | 6篇 |
2021年 | 12篇 |
2020年 | 7篇 |
2019年 | 5篇 |
2018年 | 8篇 |
2017年 | 7篇 |
2016年 | 8篇 |
2015年 | 11篇 |
2014年 | 27篇 |
2013年 | 31篇 |
2012年 | 28篇 |
2011年 | 28篇 |
2010年 | 47篇 |
2009年 | 30篇 |
2008年 | 26篇 |
2007年 | 23篇 |
2006年 | 32篇 |
2005年 | 22篇 |
2004年 | 13篇 |
2003年 | 18篇 |
2002年 | 14篇 |
2001年 | 15篇 |
2000年 | 9篇 |
1999年 | 15篇 |
1998年 | 5篇 |
1997年 | 2篇 |
1996年 | 3篇 |
1995年 | 10篇 |
1994年 | 6篇 |
1993年 | 5篇 |
1992年 | 9篇 |
1991年 | 7篇 |
1990年 | 5篇 |
1989年 | 4篇 |
1988年 | 6篇 |
1987年 | 5篇 |
1986年 | 4篇 |
1985年 | 7篇 |
1984年 | 7篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 3篇 |
1978年 | 5篇 |
1977年 | 2篇 |
1975年 | 2篇 |
1974年 | 2篇 |
1970年 | 3篇 |
1940年 | 1篇 |
1916年 | 2篇 |
排序方式: 共有563条查询结果,搜索用时 593 毫秒
51.
Disruption of diacylglycerol kinase delta (DGKD) associated with seizures in humans and mice
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)
Leach NT Sun Y Michaud S Zheng Y Ligon KL Ligon AH Sander T Korf BR Lu W Harris DJ Gusella JF Maas RL Quade BJ Cole AJ Kelz MB Morton CC 《American journal of human genetics》2007,80(4):792-799
We report a female patient with a de novo balanced translocation, 46,X,t(X;2)(p11.2;q37)dn, who exhibits seizures, capillary abnormality, developmental delay, infantile hypotonia, and obesity. The 2q37 breakpoint observed in association with the seizure phenotype is of particular interest, because it lies near loci implicated in epilepsy in humans and mice. Fluorescence in situ hybridization mapping of the translocation breakpoints showed that no known genes are disrupted at Xp11.2, whereas diacylglycerol kinase delta (DGKD) is disrupted at 2q37. Expression studies in Drosophila and mouse suggest that DGKD is involved in central nervous system development and function. Electroencephalographic assessment of Dgkd mutant mice revealed abnormal epileptic discharges and electrographic seizures in three of six homozygotes. These findings implicate DGKD disruption by the t(X;2)(p11.2;q37)dn in the observed phenotype and support a more general role for DGKD in the etiology of seizures. 相似文献
52.
Proper regulation of cell morphogenesis and migration by adhesion and growth-factor receptors requires Abl-family tyrosine kinases [1-3]. Several substrates of Abl-family kinase have been identified, but they are unlikely to mediate all of the downstream actions of these kinases on cytoskeletal structure. We used a human protein microarray to identify the actin-regulatory protein cortactin as a novel substrate of the Abl and Abl-related gene (Arg) nonreceptor tyrosine kinases. Cortactin stimulates cell motility [4-6], and its upregulation in several cancers correlates with poor prognosis [7]. Even though cortactin can be tyrosine phosphorylated by Src-family kinases in vitro [8], we show that Abl and Arg are more adept at binding and phosphorylating cortactin. Importantly, we demonstrate that platelet-derived growth-factor (PDGF)-induced cortactin phosphorylation on three tyrosine residues requires Abl or Arg. Cortactin triggers F-actin-dependent dorsal waves in fibroblasts after PDGF treatment and thus results in actin reorganization and lamellipodial protrusion [9]. We provide evidence that Abl/Arg-mediated phosphorylation of cortactin is required for this PDGF-induced dorsal-wave response. Our results reveal that Abl-family kinases target cortactin as an effector of cytoskeletal rearrangements in response to PDGF. 相似文献
53.
Proteomic profiling of a parasitic wasp exposed to constant and fluctuating cold exposure 总被引:1,自引:0,他引:1
Colinet H Nguyen TT Cloutier C Michaud D Hance T 《Insect biochemistry and molecular biology》2007,37(11):1177-1188
When insects are exposed to fluctuating thermal regimes (FTRs) (i.e., cold exposure alternating with periodic short pulses to high temperature), in contrast to constant low temperature (CLT), mortality due to accumulation of chill injuries is markedly reduced. To investigate the physiological processes behind the positive impact of FTR, based on a holistic approach, two-dimensional electrophoresis (2-DE) analysis were performed with the parasitic wasp Aphidius colemani. Parasitoid proteomes revealed 369 well-distinguishable protein spots, where the overall response to cold exposure was clearly specific to treatments (CLT versus FTR). The reduced mortality under FTR was associated with up-regulation of several proteins playing key roles in energy metabolism (glycolysis, TCA cycle, synthesis and conversion of ATP), protein chaperoning (Hsp70/Hsp90), and protein degradation (proteasome). Our results also support the idea that cytoskeleton components, particularly actin arrangement, could play a role in the higher survival rates of insects under FTR. 相似文献
54.
MsCYS1, a developmentally-regulated cystatin from alfalfa. 总被引:1,自引:0,他引:1
Daniel Rivard Cécile Girard Rapha?l Anguenot Louis-P Vézina Sonia Trépanier Dominique Michaud 《Plant Physiology and Biochemistry》2007,45(6-7):508-514
Several roles have been attributed to cystatins in plants, ranging from the regulation of host [endogenous] cysteine proteases to the inhibition of herbivorous pest [exogenous] proteases. We report here the cloning, expression and functional characterization of a novel cystatin from alfalfa, Medicago sativa L. The new sequence, isolated from a cDNA expression library prepared from young leaves, encodes a protein, MsCYS1, with the typical inhibitory motifs of cystatins, namely the central signature motif QxVxG, a GG doublet in the N-terminal trunk, and a W residue in the C-terminal region, about 30 amino acids distant from the central inhibitory motif. As shown by a protein-based phylogenetic reconstruction, MsCYS1 is a close relative of other cystatins from Fabaceae presumably involved in the regulation of endogenous proteases. This cystatin is developmentally regulated in stems and leaves, and not induced by stress signals including methyl jasmonate, known to activate cystatins involved in plant defense. A recombinant form of MsCYS1 expressed in Escherichia coli was shown to strongly inhibit alfalfa leaf cysteine proteases while showing weak affinity for the digestive cysteine proteases of different herbivorous pests. Overall, these observations suggest an endogenous protease regulatory role for MsCYS1, possibly associated with the early development of stems and leaves. 相似文献
55.
P. B. Matheus Carnevali M. Rohrssen M. R. Williams A. B. Michaud H. Adams D. Berisford G. D. Love J. C. Priscu O. Rassuchine K. P. Hand A. E. Murray 《Geobiology》2015,13(2):181-197
The permafrost on the North Slope of Alaska is densely populated by shallow lakes that result from thermokarst erosion. These lakes release methane (CH4) derived from a combination of ancient thermogenic pools and contemporary biogenic production. Despite the potential importance of CH4 as a greenhouse gas, the contribution of biogenic CH4 production in arctic thermokarst lakes in Alaska is not currently well understood. To further advance our knowledge of CH4 dynamics in these lakes, we focused our study on (i) the potential for microbial CH4 production in lake sediments, (ii) the role of sediment geochemistry in controlling biogenic CH4 production, and (iii) the temperature dependence of this process. Sediment cores were collected from one site in Siqlukaq Lake and two sites in Sukok Lake in late October to early November. Analyses of pore water geochemistry, sedimentary organic matter and lipid biomarkers, stable carbon isotopes, results from CH4 production experiments, and copy number of a methanogenic pathway‐specific gene (mcrA) indicated the existence of different sources of CH4 in each of the lakes chosen for the study. Analysis of this integrated data set revealed that there is biological CH4 production in Siqlukaq at moderate levels, while the very low levels of CH4 detected in Sukok had a mixed origin, with little to no biological CH4 production. Furthermore, methanogenic archaea exhibited temperature‐dependent use of in situ substrates for methanogenesis, and the amount of CH4 produced was directly related to the amount of labile organic matter in the sediments. This study constitutes an important first step in better understanding the actual contribution of biogenic CH4 from thermokarst lakes on the coastal plain of Alaska to the current CH4 budgets. 相似文献
56.
57.
The hypothalamus is a critical integrator of several homeostatic processes that are required for the survival of vertebrates. Disruption of the development of the hypothalamus thus has the potential of perturbing important physiological processes with lifelong consequences. We review current knowledge about how cell types are specified and circuits are formed within the developing hypothalamus. We emphasize the potential clinical impact of the perturbations of these pathways using the regulation of energy balance as a model. We predict that disruption of hypothalamic development is a common, previously unsuspected cause of disorders of homeostatic processes such as obesity and high blood pressure. 相似文献
58.
Sinorhizobium meliloti M5N1CS synthesizes a homopolymer of glucuronic acids beta-(1,4) linked and variably C2 and/or C3O-acetylated. To obtain beta-Delta-(4,5)-unsaturated oligoglucuronans, various acetylated forms of this bacterial polymer were cleaved by a Trichoderma sp. GL2 glucuronan lyase. Oligomers with polymerization degrees up to 8 were then produced, purified by liquid chromatography (size exclusion and anions exchange) and characterized using 1H NMR and ESI-Q/TOF-MS. Finally, the production (in gram quantity) of pure unsaturated oligoglucuronans non-acetylated (di- and trisaccharide) was investigated thanks to the complete depolymerization of deacetylated glucuronan. 相似文献
59.
Brunelle F Girard C Cloutier C Michaud D 《Archives of insect biochemistry and physiology》2005,60(1):20-31
Protein engineering approaches are currently being devised to improve the inhibitory properties of plant proteinase inhibitors against digestive proteinases of herbivorous insects. Here we engineered a potent hybrid inhibitor of aspartate and cysteine digestive proteinases found in the Colorado potato beetle, Leptinotarsa decemlineata Say. Three cathepsin D inhibitors (CDIs) from stressed potato and tomato were first compared in their potency to inhibit digestive cathepsin D-like activity of the insect. After showing the high inhibitory potency of tomato CDI (M(r) approximately 21 kDa), an approximately 33-kDa hybrid inhibitor was generated by fusing this inhibitor to the N terminus of corn cystatin II (CCII), a potent inhibitor of cysteine proteinases. Inhibitory assays with recombinant forms of CDI, CCII, and CDI-CCII expressed in Escherichia coli showed the CDI-CCII fusion to exhibit a dual inhibitory effect against cystatin-sensitive and cathepsin D-like enzymes of the potato beetle, resulting in detrimental effects against 3rd-instar larvae fed the hybrid inhibitor. The inhibitory potency of CDI and CCII was not altered after their fusion, as suggested by IC(50) values for the interaction of CDI-CCII with target proteinases similar to those measured for each inhibitor. These observations suggest the potential of plant CDIs and cystatins as functional inhibitory modules for the design of effective broad-spectrum, hybrid inhibitors of herbivorous insect cysteine and aspartate digestive proteinases. 相似文献
60.
Fuchs S Frenzel K Hubert C Lyng R Muller L Michaud A Xiao HD Adams JW Capecchi MR Corvol P Shur BD Bernstein KE 《Nature medicine》2005,11(11):1140-2; author reply 1142-3