Structure of mammalian AMPK and its regulation by ADP

The heterotrimeric AMP-activated protein kinase (AMPK) has a key role in regulating cellular energy metabolism; in response to a fall in intracellular ATP levels it activates energy-producing pathways and inhibits energy-consuming processes. AMPK has been implicated in a number of diseases related to energy metabolism including type 2 diabetes, obesity and, most recently, cancer. AMPK is converted from an inactive form to a catalytically competent form by phosphorylation of the activation loop within the kinase domain: AMP binding to the γ-regulatory domain promotes phosphorylation by the upstream kinase, protects the enzyme against dephosphorylation, as well as causing allosteric activation. Here we show that ADP binding to just one of the two exchangeable AXP (AMP/ADP/ATP) binding sites on the regulatory domain protects the enzyme from dephosphorylation, although it does not lead to allosteric activation. Our studies show that active mammalian AMPK displays significantly tighter binding to ADP than to Mg-ATP, explaining how the enzyme is regulated under physiological conditions where the concentration of Mg-ATP is higher than that of ADP and much higher than that of AMP. We have determined the crystal structure of an active AMPK complex. The structure shows how the activation loop of the kinase domain is stabilized by the regulatory domain and how the kinase linker region interacts with the regulatory nucleotide-binding site that mediates protection against dephosphorylation. From our biochemical and structural data we develop a model for how the energy status of a cell regulates AMPK activity.     

Using sampling and inverse distance weighted modeling for mapping invasive plants

Accurate time- and cost-efficient mapping is central to successful rangeland invasive plant management. In this study sampling together with Inverse Distance Weighted (IDW) interpolation modeling was tested as a mapping alternative to expensive full-coverage delineation survey mapping methods. Our objective was to examine accuracies of presence/absence maps generated from 18 sampling strategies (3 sampling methods × 6 sample densities) using IDW. Invasive plant field survey maps with known accuracies were used to generate samples and to test interpolation results at 2 sites. Site 1 was approximately 6.0 km 2 , dominated by Russian knapweed ( Acroptilon repens L.). Site 2, an upland area of approximately 13.5 km 2 , was dominated by spotted knapweed ( Centaurea maculosa Lam). Sampling method × sample density combinations were gathered from field survey infestation maps using repeated computer-based sampling methods. IDW modeling was applied to each of the sample data sets. Accuracies of the IDW interpolation results were calculated by re-referencing field survey maps. We determined that sampling at density of 0.25% (about 1 point per ha) using a systematic sampling method was the preferred sampling strategy for both sites. This combination of sampling density and method yielded 85% accurate presence/absence maps. We conclude that sampling combined with IDW interpolation modeling can generate accurate invasive plant maps and is a potential alternative to current delineation survey methods.     

Density, biomass, and diversity of grasshoppers (Orthoptera: Acrididae) in a California native grassland

A native California perennial grassland was sampled for grasshopper populations. The grassland is managed for the preservation of the native perennial bunchgrass, Nassella pulchra Hitch. Grasshopper density, biomass, diversity, and richness were measured from July 1993 to October 1994. Average density of all grasshoppers was 2.30 hoppers/m 2 (0.66 s ) for 1994 (June through August). Overall forage consumed for 1994 was 140 kg/ha, suggesting that grasshopper populations exist at economically damaging levels. Grasshoppers do not appear in the grasslands until late spring, after annual grasses have set seed. Biomass of grasshoppers peaks in July when adults are predominant. Both grasshopper density and biomass were higher in 1993 than in 1994, and a total of 5 species were found throughout the study. Melanoplus sanguinipes Fabricus dominated the acridid communities and accounted for more than 95% of the individuals.     

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P?相似文献   

碳纤维织物增强混凝土薄板的界面粘结性能试验

为了研究碳纤维织物增强混凝土薄板中织物和混凝土界面间粘结性能,首先介绍了德国斯图加特大学提出的测试织物在薄板的混凝土基体中界面粘结性能的拉拨试验方法,并通过初步试验,讨论了试验方法中试件养护条件和试验机夹具夹持试件的尺寸2个因素对试验结果的影响.然后,进一步研究了复合材料中的织物在其使用前的预浸胶和复合材料薄板制作过程中在织物上施加预拉力2项工艺对提高织物和混凝土基体间界面粘结性能的影响.采用Ohno ＆ Hannant理论,分析和探讨了该试验方法的机理.最后,得出该试验方法能较准确地反映织物增强混凝土薄板中织物和混凝土界面间粘结性能的结论,并提出织物浸胶和施加预拉力可以提高其界面间粘结性能的建议.     

Patterns and rates of exonic de novo mutations in autism spectrum disorders

Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.