全文获取类型
收费全文 | 855篇 |
免费 | 50篇 |
出版年
2022年 | 8篇 |
2021年 | 8篇 |
2020年 | 3篇 |
2019年 | 13篇 |
2018年 | 23篇 |
2017年 | 6篇 |
2016年 | 16篇 |
2015年 | 40篇 |
2014年 | 36篇 |
2013年 | 41篇 |
2012年 | 66篇 |
2011年 | 57篇 |
2010年 | 40篇 |
2009年 | 38篇 |
2008年 | 33篇 |
2007年 | 48篇 |
2006年 | 41篇 |
2005年 | 35篇 |
2004年 | 41篇 |
2003年 | 43篇 |
2002年 | 32篇 |
2001年 | 9篇 |
2000年 | 8篇 |
1999年 | 7篇 |
1998年 | 16篇 |
1997年 | 10篇 |
1996年 | 13篇 |
1995年 | 19篇 |
1994年 | 10篇 |
1993年 | 13篇 |
1992年 | 15篇 |
1991年 | 5篇 |
1990年 | 10篇 |
1989年 | 7篇 |
1988年 | 5篇 |
1987年 | 7篇 |
1985年 | 7篇 |
1984年 | 6篇 |
1983年 | 5篇 |
1982年 | 8篇 |
1981年 | 6篇 |
1980年 | 6篇 |
1979年 | 7篇 |
1977年 | 6篇 |
1976年 | 5篇 |
1975年 | 3篇 |
1974年 | 3篇 |
1973年 | 7篇 |
1972年 | 5篇 |
1970年 | 3篇 |
排序方式: 共有905条查询结果,搜索用时 531 毫秒
61.
LaMonte BH Wallace KE Holloway BA Shelly SS Ascaño J Tokito M Van Winkle T Howland DS Holzbaur EL 《Neuron》2002,34(5):715-727
To test the hypothesis that inhibition of axonal transport is sufficient to cause motor neuron degeneration such as that observed in amyotrophic lateral sclerosis (ALS), we engineered a targeted disruption of the dynein-dynactin complex in postnatal motor neurons of transgenic mice. Dynamitin overexpression was found to disassemble dynactin, a required activator of cytoplasmic dynein, resulting in an inhibition of retrograde axonal transport. Mice overexpressing dynamitin demonstrate a late-onset progressive motor neuron degenerative disease characterized by decreased strength and endurance, motor neuron degeneration and loss, and denervation of muscle. Previous transgenic mouse models of ALS have shown abnormalities in microtubule-based axonal transport. In this report, we describe a mouse model that confirms the critical role of disrupted axonal transport in the pathogenesis of motor neuron degenerative disease. 相似文献
62.
63.
Tetrahydrofolate (THF) is a central cofactor for one-carbon transfer reactions in all living organisms. In this study, we analyzed the expression of dihydropterin pyrophosphokinase-dihydropteroate synthase (HPPK-DHPS) in pea (Pisum sativum) organs during development, and so the capacity to synthesize dihydropteroate, an intermediate in the de novo THF biosynthetic pathway. During seedling development, all of the examined organs/tissues contain THF coenzymes, collectively termed folate, and express the HPPK-DHPS enzyme. This suggests that each organ/tissue is autonomous for the synthesis of THF. During germination, folate accumulates in cotyledons and embryos, but high amounts of HPPK-DHPS are only observed in embryos. During organ differentiation, folate is synthesized preferentially in highly dividing tissues and in photosynthetic leaves. This is associated with high levels of the HPPK-DHPS mRNA and protein, and a pool of folate 3- to 5-fold higher than in the rest of the plant. In germinating embryos and in meristematic tissues, the high capacity to synthesize and accumulate folate correlates with the general resumption of cell metabolism and the high requirement for nucleotide synthesis, major cellular processes involving folate coenzymes. The particular status of folate synthesis in leaves is related to light. Thus, when illuminated, etiolated leaves gradually accumulate the HPPK-DHPS enzyme and folate. This suggests that folate synthesis plays an important role in the transition from heterotrophic to photoautotrophic growth. Analysis of the intracellular distribution of folate in green and etiolated leaves indicates that the coenzymes accumulate mainly in the cytosol, where they can supply the high demand for methyl groups. 相似文献
64.
Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity 总被引:9,自引:0,他引:9
Hsieh JC Lee L Zhang L Wefer S Brown K DeRossi C Wines ME Rosenquist T Holdener BC 《Cell》2003,112(3):355-367
Specification of embryonic polarity and pattern formation in multicellular organisms requires inductive signals from neighboring cells. One approach toward understanding these interactions is to study mutations that disrupt development. Here, we demonstrate that mesd, a gene identified in the mesoderm development (mesd) deletion interval on mouse chromosome 7, is essential for specification of embryonic polarity and mesoderm induction. MESD functions in the endoplasmic reticulum as a specific chaperone for LRP5 and LRP6, which in conjunction with Frizzled, are coreceptors for canonical WNT signal transduction. Disruption of embryonic polarity and mesoderm differentiation in mesd-deficient embryos likely results from a primary defect in WNT signaling. However, phenotypic differences between mesd-deficient and wnt3(-)(/)(-) embryos suggest that MESD may function on related members of the low-density lipoprotein receptor (LDLR) family, whose members mediate diverse cellular processes ranging from cargo transport to signaling. 相似文献
65.
Boutin P Dina C Vasseur F Dubois S Corset L Séron K Bekris L Cabellon J Neve B Vasseur-Delannoy V Chikri M Charles MA Clement K Lernmark A Froguel P 《PLoS biology》2003,1(3):E68
The gene GAD2 encoding the glutamic acid decarboxylase enzyme (GAD65) is a positional candidate gene for obesity on Chromosome 10p11–12, a susceptibility locus for morbid obesity in four independent ethnic populations. GAD65 catalyzes the formation of γ-aminobutyric acid (GABA), which interacts with neuropeptide Y in the paraventricular nucleus to contribute to stimulate food intake. A case-control study (575 morbidly obese and 646 control subjects) analyzing GAD2 variants identified both a protective haplotype, including the most frequent alleles of single nucleotide polymorphisms (SNPs) +61450 C>A and +83897 T>A (OR = 0.81, 95% CI [0.681–0.972], p = 0.0049) and an at-risk SNP (−243 A>G) for morbid obesity (OR = 1.3, 95% CI [1.053–1.585], p = 0.014). Furthermore, familial-based analyses confirmed the association with the obesity of SNP +61450 C>A and +83897 T>A haplotype (χ2 = 7.637, p = 0.02). In the murine insulinoma cell line βTC3, the G at-risk allele of SNP −243 A>G increased six times GAD2 promoter activity (p < 0.0001) and induced a 6-fold higher affinity for nuclear extracts. The −243 A>G SNP was associated with higher hunger scores (p = 0.007) and disinhibition scores (p = 0.028), as assessed by the Stunkard Three-Factor Eating Questionnaire. As GAD2 is highly expressed in pancreatic β cells, we analyzed GAD65 antibody level as a marker of β-cell activity and of insulin secretion. In the control group, −243 A>G, +61450 C>A, and +83897 T>A SNPs were associated with lower GAD65 autoantibody levels (p values of 0.003, 0.047, and 0.006, respectively). SNP +83897 T>A was associated with lower fasting insulin and insulin secretion, as assessed by the HOMA-B% homeostasis model of β-cell function (p = 0.009 and 0.01, respectively). These data support the hypothesis of the orexigenic effect of GABA in humans and of a contribution of genes involved in GABA metabolism in the modulation of food intake and in the development of morbid obesity. 相似文献
66.
Polyclonal antibodies were produced for the development of competitive ELISA's and surface plasmon resonance (SPR)-based BIAcore inhibition assays for the detection of morphine-3-glucuronide (M3G, the main metabolite of heroin and morphine). A conjugate consisting of M3G and ovalbumin was produced and used for the generation of antibodies, for the coating of immunoplates and for immobilisation onto BIAcore chips. Competition ELISA's were developed in PBS and urine to characterise the antibodies ability to recognise free M3G. SPR-based inhibition immunoassays on BIAcore were developed. The regeneration of the surface of a chip immobilised with conjugate following antibody binding, essential for the development of inhibition assays was investigated. Regeneration of the conjugate-coated surface was optimised for both polyclonal antibodies resulting in binding-regeneration capacities of approximately 60 cycles for one antibody and 50 cycles for the second antibody. The inhibition assays developed in urine had ranges of detection of 762-24,400 (antibody 1) and 976-62,500 pg ml(-1) (antibody 2). The inter-day coefficients of variation for the assays ranged from 1.48 to 11.24%. 相似文献
67.
68.
Jeffrey A. Pogany Ephraim J. Simon Rebecca B. Katzman Bernadette M. De Guzman Lita Po Yu Amy E. Trotochaud Steven E. Clark 《Journal of plant research》1998,111(2):307-313
New organs are initiated throughout the life span of higher plants. This process occurs at the shoot meristem, which is initiated
during embryogenesis and is later responsible for generating the above-ground portion of the plant. The shoot meristem can
be thought of as having two zones, a central zone containing meristematic cells in an undifferentiated state, and a surrounding
peripheral zone where cells enter a specific developmental pathway toward a differentiated state. Recent advances have revealed
several genes that specifically regulate meristem development inArabidopsis. However, extensive mutagenesis by several labs have identified only a handful, of loci that appear to specifically regulate
shoot meristem development. We have undertaken an enhancer/suppressor mutagenesis of an existing meristem mutant (clv1) and have identified novel regulators of meristem development.
The extended abstract of a paper presented at the 13th International Symposium in Conjugation with Award of the International
Prize for Biology “Frontier of Plant Biology” 相似文献
69.
Tom?Ashmore Lee?D.?Roberts Andrea?J.?Morash Aleksandra?O.?Kotwica John?Finnerty James?A.?West Steven?A.?Murfitt Bernadette?O.?Fernandez Cristina?Branco Andrew?S.?Cowburn Kieran?Clarke Randall?S.?Johnson Martin?Feelisch Julian?L.?Griffin Andrew?J.?MurrayEmail author 《BMC biology》2015,13(1):110
Background
Insulin sensitivity in skeletal muscle is associated with metabolic flexibility, including a high capacity to increase fatty acid (FA) oxidation in response to increased lipid supply. Lipid overload, however, can result in incomplete FA oxidation and accumulation of potentially harmful intermediates where mitochondrial tricarboxylic acid cycle capacity cannot keep pace with rates of β-oxidation. Enhancement of muscle FA oxidation in combination with mitochondrial biogenesis is therefore emerging as a strategy to treat metabolic disease. Dietary inorganic nitrate was recently shown to reverse aspects of the metabolic syndrome in rodents by as yet incompletely defined mechanisms.Results
Herein, we report that nitrate enhances skeletal muscle FA oxidation in rodents in a dose-dependent manner. We show that nitrate induces FA oxidation through a soluble guanylate cyclase (sGC)/cGMP-mediated PPARβ/δ- and PPARα-dependent mechanism. Enhanced PPARβ/δ and PPARα expression and DNA binding induces expression of FA oxidation enzymes, increasing muscle carnitine and lowering tissue malonyl-CoA concentrations, thereby supporting intra-mitochondrial pathways of FA oxidation and enhancing mitochondrial respiration. At higher doses, nitrate induces mitochondrial biogenesis, further increasing FA oxidation and lowering long-chain FA concentrations. Meanwhile, nitrate did not affect mitochondrial FA oxidation in PPARα?/? mice. In C2C12 myotubes, nitrate increased expression of the PPARα targets Cpt1b, Acadl, Hadh and Ucp3, and enhanced oxidative phosphorylation rates with palmitoyl-carnitine; however, these changes in gene expression and respiration were prevented by inhibition of either sGC or protein kinase G. Elevation of cGMP, via the inhibition of phosphodiesterase 5 by sildenafil, also increased expression of Cpt1b, Acadl and Ucp3, as well as CPT1B protein levels, and further enhanced the effect of nitrate supplementation.Conclusions
Nitrate may therefore be effective in the treatment of metabolic disease by inducing FA oxidation in muscle.70.
Esperanza Diaz Beatriz Poblador-Pou Luis-Andrés Gimeno-Feliu Amaia Calderón-Larra?aga Bernadette N. Kumar Alexandra Prados-Torres 《PloS one》2015,10(12)