Mutational Effects of Human Dopamine Transporter at Tyrosine88, Lysine92, and Histidine547 on Basal and HIV-1 Tat-Inhibited Dopamine Transport

Dysregulation of dopaminergic system induced by HIV-1 Tat protein-mediated direct inhibition of the dopamine transporter (DAT) has been implicated as a mediating factor of HIV-1 associated neurocognitive disorders. We have reported that single point mutations on human DAT (hDAT) at tyrosine88 (Y88F), lysine92 (K92M), and histidine547 (H547A) differentially regulate basal dopamine uptake but diminish Tat-induced inhibition of dopamine uptake by changing dopamine transport process. This study evaluated the effects of double (Y88F/H547A) and triple (Y88F/K92M/H547A) mutations on basal dopamine uptake, Tat-induced inhibition of DAT function, and dynamic transport process. Compared to wild-type hDAT, the Vmax values of [3H]Dopamine uptake were increased by 96% in Y88F/H547A but decreased by 97% in Y88F/K92M/H547A. [3H]WIN35,428 binding sites were not altered in Y88F/H547A but decreased in Y88F/K92M/H547A. Y88F/H547A mutant attenuated Tat-induced inhibition of dopamine uptake observed in wild-type hDAT. Y88F/H547A displayed an attenuation of zinc-augmented [3H]WIN35,428 binding, increased basal dopamine efflux, and reduced amphetamine-induced dopamine efflux, indicating this mutant alters transporter conformational transitions. These findings further demonstrate that both tyrosine88 and histidine547 on hDAT play a key role in stabilizing basal dopamine transport and Tat-DAT integration. This study provides mechanistic insights into developing small molecules to block multiple sites in DAT for Tat binding

Effect of distance from the Cagayan de Oro, Philippines, dumpsite on the groundwater quality of shallow dug wells

Abstract: Leachate from dumpsites is generated as a result of the contact of water, during precipitation, with solid wastes. In this study, selected physical and chemical parameters of water were compared in the areas near and far from the dumpsite. Findings showed that the proportion of sampled wells that yielded poor in color was not significantly different in both near and far from the dumpsite areas; but, the levels of turbidity were observed to be significantly poor in the areas far from the dumpsite. On the chemical parameters of water, the proportion of sampled wells that yielded poor in TDS was significantly higher in the areas far from the dumpsite compared to the areas near the dumpsite. The chemical parameters pH, sulfate, chloride, and nitrate of the groundwater in wells were within the permissible limits of Philippine National Standards for Drinking Water (PNSDW). With these assessments of groundwater quality understudied, it is recommended that further study, with an appropriate plan and design, on the hydrogeological formation of the dumpsite be conducted and trace the flow of leachate

Genetic network identifies novel pathways contributing to atherosclerosis susceptibility in the innominate artery

Abstract Background Atherosclerosis, the underlying cause of cardiovascular disease, results from both genetic and environmental factors. Methods In the current study we take a systems-based approach using weighted gene co-expression analysis to identify a candidate pathway of genes related to atherosclerosis. Bioinformatic analyses are performed to identify candidate genes and interactions and several novel genes are characterized using in-vitro studies. Results We identify 1 coexpression module associated with innominate artery atherosclerosis that is also enriched for inflammatory and macrophage gene signatures. Using a series of bioinformatics analysis, we further prioritize the genes in this pathway and identify Cd44 as a critical mediator of the atherosclerosis. We validate our predictions generated by the network analysis using Cd44 knockout mice. Conclusion These results indicate that alterations in Cd44 expression mediate inflammation through a complex transcriptional network involving a number of previously uncharacterized genes

Responsiveness of cardiometabolic-related microbiota to diet is influenced by host genetics

Intestinal microbial community structure is driven by host genetics in addition to environmental factors such as diet. In comparison with environmental influences, the effect of host genetics on intestinal microbiota, and how host-driven differences alter host metabolism is unclear. Additionally, the interaction between host genetics and diet, and the impact on the intestinal microbiome and possible down-stream effect on host metabolism is not fully understood, but represents another aspects of inter-individual variation in disease risk. The objectives of this study were to investigate how diet and genetic background shape microbial communities, and how these diet- and genetic-driven microbial differences relate to cardiometabolic phenotypes. To determine these effects, we used the 8 progenitor strains of the collaborative cross/diversity outbred mapping panels (C57BL/6J, A/J, NOD/ShiLtJ, NZO/HILtJ, WSB/EiJ, CAST/EiJ, PWK/PhJ, and 129S1/SvImJ). 16s rRNA profiling of enteric microbial communities in addition to the assessment of phenotypes central to cardiometabolic health was conducted under baseline nutritional conditions and in response to diets varying in atherogenic nutrient (fat, cholesterol, cholic acid) composition. These studies revealed strain-driven differences in enteric microbial communities which were retained with dietary intervention. Diet–strain interactions were seen for a core group of cardiometabolic-related microbial taxa. In conclusion, these studies highlight diet and genetically regulated cardiometabolic-related microbial taxa. Furthermore, we demonstrate the progenitor model is useful for nutrigenomic-based studies and screens seeking to investigate the interaction between genetic background and the phenotypic and microbial response to diet.Electronic supplementary materialThe online version of this article (doi:10.1007/s00335-014-9540-0) contains supplementary material, which is available to authorized users

Genetic network identifies novel pathways contributing to atherosclerosis susceptibility in the innominate artery

Abstract Background Atherosclerosis, the underlying cause of cardiovascular disease, results from both genetic and environmental factors. Methods In the current study we take a systems-based approach using weighted gene co-expression analysis to identify a candidate pathway of genes related to atherosclerosis. Bioinformatic analyses are performed to identify candidate genes and interactions and several novel genes are characterized using in-vitro studies. Results We identify 1 coexpression module associated with innominate artery atherosclerosis that is also enriched for inflammatory and macrophage gene signatures. Using a series of bioinformatics analysis, we further prioritize the genes in this pathway and identify Cd44 as a critical mediator of the atherosclerosis. We validate our predictions generated by the network analysis using Cd44 knockout mice. Conclusion These results indicate that alterations in Cd44 expression mediate inflammation through a complex transcriptional network involving a number of previously uncharacterized genes

"Investing in Farmers--The Impacts of Farmer Field Schools in Relation to Integrated Pest Management"--A Comment

Summary In a recent article in World Development, van den Berg and Jiggins [van den Berg, H. & Jiggins, J. (2007). Investing in farmers: The impacts of farmer field schools in relation to integrated pest management. World Development, 35(4), 663-686] (to be referred to in the discussion below as the "BJ paper") challenge the validity of results in two papers written by us, [Feder, G., Murgai, R., & Quizon, J. (2004a). Sending farmers back to school: the impact of farmer field schools in Indonesia, Review of Agricultural Economics 26(1), 45-62, Feder, G., Murgai, R. & Quizon, J. (2004b). The acquisition and diffusion of knowledge: the case of pest management training in farmer field schools, Indonesia. Journal of Agricultural Economics 55(2), 217-239] focusing their criticism on a number of points, and concluding that our studies "appear to be less authoritative than they purport to be." In the following, we will discuss the various points raised in the BJ paper, and show that they do not amount to a significant challenge to the validity of our results.