Genetic architecture of the APM1 gene and its influence on adiponectin plasma levels and parameters of the metabolic syndrome in 1,727 healthy Caucasians

Copyright: Copyright 2008 Elsevier B.V., All rights reserved.The associations of the adiponectin (APM1) gene with parameters of the metabolic syndrome are inconsistent. We performed a systematic investigation based on fine-mapped single nucleotide polymorphisms (SNPs) highlighting the genetic architecture and their role in modulating adiponectin plasma concentrations in a particularly healthy population of 1,727 Caucasians avoiding secondary effects from disease processes. Genotyping 53 SNPs (average spacing of 0.7 kb) in the APM1 gene region in 81 Caucasians revealed a two-block linkage disequilibrium (LD) structure and enabled comprehensive tag SNP selection. We found particularly strong associations with adiponectin concentrations for 11 of the 15 tag SNPs in the 1,727 subjects (five P values <0.0001). Haplotype analysis provided a thorough differentiation of adiponectin concentrations with 9 of 17 haplotypes showing significant associations (three P values <0.0001). No significant association was found for any SNP with the parameters of the metabolic syndrome. We observed a two-block LD structure of APM1 pointing toward at least two independent association signals, one including the promoter SNPs and a second spanning the relevant exons. Our data on a large number of healthy subjects suggest a clear modulation of adiponectin concentrations by variants of APM1, which are not merely a concomitant effect in the course of type 2 diabetes or coronary artery disease.publishersversionPeer reviewe

An agriculture and health inter-sectorial research process to reduce hazardous pesticide health impacts among smallholder farmers in the Andes

Authors are also recipients of the Teasdale-Corti grant (103460-068)Work with multiple actors is needed to shift agriculture away from pesticide use, and towards greater sustainability and human health, particularly for vulnerable smallholder farmers. This research in potato and vegetable farming communities in the Andean highlands worked with partners from various sectors over several projects. Increased involvement in organic agriculture was associated with greater household food security and food sovereignty. More diversified, moderately developed agricultural systems had lower pesticide use and better child nutrition. The Ecuadorian Ministry of Health has rolled out pesticide poisoning surveillance modeled on this research

Modelling Feedback Excitation, Pacemaker Properties and Sensory Switching of Electrically Coupled Brainstem Neurons Controlling Rhythmic Activity

What cellular and network properties allow reliable neuronal rhythm generation or firing that can be started and stopped by brief synaptic inputs? We investigate rhythmic activity in an electrically-coupled population of brainstem neurons driving swimming locomotion in young frog tadpoles, and how activity is switched on and off by brief sensory stimulation. We build a computational model of 30 electrically-coupled conditional pacemaker neurons on one side of the tadpole hindbrain and spinal cord. Based on experimental estimates for neuron properties, population sizes, synapse strengths and connections, we show that: long-lasting, mutual, glutamatergic excitation between the neurons allows the network to sustain rhythmic pacemaker firing at swimming frequencies following brief synaptic excitation; activity persists but rhythm breaks down without electrical coupling; NMDA voltage-dependency doubles the range of synaptic feedback strengths generating sustained rhythm. The network can be switched on and off at short latency by brief synaptic excitation and inhibition. We demonstrate that a population of generic Hodgkin-Huxley type neurons coupled by glutamatergic excitatory feedback can generate sustained asynchronous firing switched on and off synaptically. We conclude that networks of neurons with NMDAR mediated feedback excitation can generate self-sustained activity following brief synaptic excitation. The frequency of activity is limited by the kinetics of the neuron membrane channels and can be stopped by brief inhibitory input. Network activity can be rhythmic at lower frequencies if the neurons are electrically coupled. Our key finding is that excitatory synaptic feedback within a population of neurons can produce switchable, stable, sustained firing without synaptic inhibition

Extragenic Suppressors of Mar2(sir3) Mutations in Saccharomyces Cerevisiae

The silent mating-type genes (HML and HMR) of Saccharomyces cerevisiae are kept under negative transcriptional control by four trans-acting MAR (or SIR) loci. We have isolated extragenic suppressors of the mar2-1 mutation which, based on genetic complementation tests, define two additional loci involved in regulating the expression of HML and HMR. A strain with the genotype HMLa MATα HMRa mar2-1 is sterile due to the simultaneous expression of a and α information. Two mutants exhibiting an α phenotype (which may result from the restoration of MAR/SIR repression) were isolated and genetically characterized. The mutations in these strains: (1) are recessive, (2) are capable of suppressing a mar2-deletion mutation, (3) are unlinked to MAT, (4) complement one another as well as the previously identified sum1-1 mutation, and (5) are not new alleles of the known MAR/SIR loci. We designate these new regulatory loci SUM2 and SUM3 (supressor of mar). Unlike the sum1-1 mutation, suppression by sum2-1 and sum3-1 is mar2-locus specific. Both sum2-1 and sum3-1 affect the expression of a information at the HM loci. Transcript analysis shows a significant reduction in HMLa and HMRa gene transcription in mar2-1 sum2-1 and mar2-1 sum3-1 cells. Furthermore, we have found genetic evidence to suggest that mar2-1 sum2-1 cells exhibit only partial expression of silent α information. We conclude that the SUM2 and SUM3 gene products are required for expression of the HM loci and act downstream of the MAR2 (SIR3) gene function. Possible mechanisms for the action of the SUM gene products are discussed