An integrated functional genomic study of acute phenobarbital exposure in the rat.

BACKGROUND: Non-genotoxic carcinogens are notoriously difficult to identify as they do not damage DNA directly and have diverse modes of action, necessitating long term in vivo studies. The early effects of the classic rodent non-genotoxic hepatocarcinogen phenobarbital have been investigated in the Fisher rat using a combination of metabolomics and transcriptomics, to investige early stage mechanistic changes that are predictive of longer term pathology. RESULTS: Liver and blood plasma were profiled across 14 days, and multivariate statistics used to identify perturbed pathways. Both metabolomics and transcriptomics detected changes in the liver which were dose dependent, even after one day of exposure. Integration of the two datasets associated perturbations with specific pathways. Hepatic glycogen was decreased due to a decrease in synthesis, and plasma triglycerides were decreased due to an increase in fatty acid uptake by the liver. Hepatic succinate was increased and this was associated with increased heme biosynthesis. Glutathione synthesis was also increased, presumably in response to oxidative stress. Liquid Chromatography Mass Spectrometry demonstrated a remodeling of lipid species, possibly resulting from proliferation of the smooth endoplasmic reticulum. CONCLUSIONS: The data fusion of metabolomic and transcriptomic changes proved to be a highly sensitive approach for monitoring early stage changes in altered hepatic metabolism, oxidative stress and cytochrome P450 induction simultaneously. This approach is particularly useful in interpreting changes in metabolites such as succinate which are hubs of metabolism.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Dengue and climate change in Australia: predictions for the future should incorporate knowledge from the past

•Dengue transmission in Australia is currently restricted to Queensland, where the vector mosquito Aedes aegypti is established. Locally acquired infections have been reported only from urban areas in the north-east of the state, where the vector is most abundant. •Considerable attention has been drawn to the potential impact of climate change on dengue distribution within Australia, with projections for substantial rises in incidence and distribution associated with increasing temperatures. •However, historical data show that much of Australia has previously sustained both the vector mosquito and dengue viruses. Although current vector distribution is restricted to Queensland, the area inhabited by A. aegypti is larger than the disease-transmission areas, and is not restricted by temperature (or vector-control programs); thus, it is unlikely that rising temperatures alone will bring increased vector or virus distribution. •Factors likely to be important to dengue and vector distribution in the future include increased dengue activity in Asian and Pacific nations that would raise rates of virus importation by travellers, importation of vectors via international ports to regions without A. aegypti, higher rates of domestic collection and storage of water that would provide habitat in urban areas, and growing human populations in northern Australia. •Past and recent successful control initiatives in Australia lend support to the idea that well resourced and functioning surveillance programs, and effective public health intervention capabilities, are essential to counter threats from dengue and other mosquito-borne diseases. •Models projecting future activity of dengue (or other vector-borne disease) with climate change should carefully consider the local historical and contemporary data on the ecology and distribution of the vector and local virus transmission

Age-dependent loss of cohesion protection in human oocytes

Aneuploid human eggs (oocytes) are a major cause of infertility, miscarriage, and chromosomal disorders. Such aneuploidies increase greatly as women age, with defective linkages between sister chromatids (cohesion) in meiosis as a common cause. We found that loss of a specific pool of the cohesin protector protein, shugoshin 2 (SGO2), may contribute to this phenomenon. Our data indicate that SGO2 preserves sister chromatid cohesion in meiosis by protecting a ‘‘cohesin bridge’’ between sister chromatids. In human oocytes, SGO2 localizes to both sub-centromere cups and the pericentromeric bridge, which spans the sister chromatid junction. SGO2 normally colocalizes with cohesin; however, in meiosis II oocytes from older women, SGO2 is frequently lost from the pericentromeric bridge and sister chromatid cohesion is weakened. MPS1 and BUB1 kinase activities maintain SGO2 at sub-centromeres and the pericentromeric bridge. Removal of SGO2 throughout meiosis I by MPS1 inhibition reduces cohesion protection, increasing the incidence of single chromatids at meiosis II. Therefore, SGO2 deficiency in human oocytes can exacerbate the effects of maternal age by rendering residual cohesin at pericentromeres vulnerable to loss in anaphase I. Our data show that impaired SGO2 localization weakens cohesion integrity and may contribute to the increased incidence of aneuploidy observed in human oocytes with advanced maternal age

Comparative Cost-Effectiveness Analysis of Two MSF Surgical Trauma Centers

INTRODUCTION: There is a dearth of data on cost-effectiveness of surgical care in resource-poor countries. Doctors Without Borders (Médecins Sans Frontières; MSF) is a nongovernmental organization (NGO) involved in the many facets of health care for underserved populations, including surgical care. METHODS: A cost-effectiveness analysis (CEA) was attempted at two of their surgical trauma hospitals: Teme Hospital in Nigeria and La Trinité Hospital in Haiti. CONCLUSION: At $172 and$223 per Disability-Adjusted Life-Year (DALY) averted, respectively, they are in line with other reported CEAs for surgical and nonsurgical activities in similar contexts

Silly Questions and Arguments for the Implicit, Cinematic Narrator

My chapter aims to advance the debate on a problem often raised by philosophers who are skeptical of implied narrators in movies. This is the concern that positing such elusive narrators gives rise to absurd imaginings (Gaut 2004: 242; Carroll 2006: 179-180). Friends of the implied cinematic narrator reply that the questions critics raise about the workings of the implied cinematic narrator are "silly ones" to ask. I examine how the "absurd imaginings" problem arises for all the central arguments for the elusive cinematic narrator and discuss why the questions critics pose about this narrator are legitimate ones to ask

Spiroindolines Identify the Vesicular Acetylcholine Transporter as a Novel Target for Insecticide Action

The efficacy of all major insecticide classes continues to be eroded by the development of resistance mediated, in part, by selection of alleles encoding insecticide insensitive target proteins. The discovery of new insecticide classes acting at novel protein binding sites is therefore important for the continued protection of the food supply from insect predators, and of human and animal health from insect borne disease. Here we describe a novel class of insecticides (Spiroindolines) encompassing molecules that combine excellent activity against major agricultural pest species with low mammalian toxicity. We confidently assign the vesicular acetylcholine transporter as the molecular target of Spiroindolines through the combination of molecular genetics in model organisms with a pharmacological approach in insect tissues. The vesicular acetylcholine transporter can now be added to the list of validated insecticide targets in the acetylcholine signalling pathway and we anticipate that this will lead to the discovery of novel molecules useful in sustaining agriculture. In addition to their potential as insecticides and nematocides, Spiroindolines represent the only other class of chemical ligands for the vesicular acetylcholine transporter since those based on the discovery of vesamicol over 40 years ago, and as such, have potential to provide more selective tools for PET imaging in the diagnosis of neurodegenerative disease. They also provide novel biochemical tools for studies of the function of this protein family

Melioidosis Vaccines: A Systematic Review and Appraisal of the Potential to Exploit Biodefense Vaccines for Public Health Purposes

The designation of Burkholderia pseudomallei as a category B select agent has resulted in considerable research funding to develop a protective vaccine. This bacterium also causes a naturally occurring disease (melioidosis), an important cause of death in many countries including Thailand and Australia. In this study, we explored whether a vaccine could be used to provide protection from melioidosis. An economic evaluation based on its use in Thailand indicated that a vaccine could be a cost-effective intervention if used in high-risk populations such as diabetics and those with chronic kidney or lung disease. A literature search of vaccine studies in animal models identified the current candidates, but noted that models failed to take account of the common routes of infection in natural melioidosis and major risk factors for infection, primarily diabetes. This review highlights important areas for future research if biodefence-driven vaccines are to play a role in reducing the global incidence of melioidosis

The MALATANG Survey : The L GAS-L IR Correlation on Sub-kiloparsec Scale in Six Nearby Star-forming Galaxies as Traced by HCN J = 4 → 3 and HCO + J = 4 → 3

This is an author-created, un-copyedited version of an article published in The Astrophysical Journal. The Version of Record is available online at https://doi.org/10.3847/1538-4357/aac512.We present HCN J = 4→3 and HCO+ J = 4→3 maps of six nearby star-forming galaxies, NGC 253, NGC 1068, IC 342, M82, M83, and NGC 6946, obtained with the James Clerk Maxwell Telescope as part of the MALATANG survey. All galaxies were mapped in the central 2×2 region at 14 (FWHM) resolution (corresponding to linear scales of ∼0.2-1.0 kpc). The LIR-Ldense relation, where the dense gas is traced by the HCN J = 4→3 and the HCO+ J = 4→3 emission, measured in our sample of spatially resolved galaxies is found to follow the linear correlation established globally in galaxies within the scatter. We find that the luminosity ratio, LIR/Ldense, shows systematic variations with LIR within individual spatially resolved galaxies, whereas the galaxy-integrated ratios vary little. A rising trend is also found between LIR/Ldense ratio and the warm-dust temperature gauged by the 70 μm/100 μm flux ratio. We find that the luminosity ratios of IR/HCN (4-3) and IR/HCO+ (4-3), which can be taken as a proxy for the star formation efficiency (SFE) in the dense molecular gas (SFE dense), appear to be nearly independent of the dense gas fraction ( f dense) for our sample of galaxies. The SFE of the total molecular gas (SFEmol) is found to increase substantially with f dense when combining our data with those on local (ultra)luminous infrared galaxies and high-z quasars. The mean LHCN(4-3) LHCO+(4-3) line ratio measured for the six targeted galaxies is 0.9±0.6. No significant correlation is found for the L'HCN(4-3) L'HCO+(4-3) ratio with the star formation rate as traced by L IR, nor with the warm-dust temperature, for the different populations of galaxies.Peer reviewe

A mathematical model for the burden of diabetes and its complications

BACKGROUND: The incidence and prevalence of diabetes are increasing all over the world. Complications of diabetes constitute a burden for the individuals and the whole society. METHODS: In the present paper, ordinary differential equations and numerical approximations are used to monitor the size of populations of diabetes with and without complications. RESULTS: Different scenarios are discussed according to a set of parameters and the dynamical evolution of the population from the stage of diabetes to the stage of diabetes with complications is clearly illustrated. CONCLUSIONS: The model shows how efficient and cost-effective strategies can be obtained by acting on diabetes incidence and/or controlling the evolution to the stage of complications