Quantitative trait loci for sensitivity to ethanol intoxication in a C57BL/6J × 129S1/SvImJ inbred mouse cross

Individual variation in sensitivity to acute ethanol (EtOH) challenge is associated with alcohol drinking and is a predictor of alcohol abuse. Previous studies have shown that the C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mouse strains differ in responses on certain measures of acute EtOH intoxication. To gain insight into genetic factors contributing to these differences, we performed quantitative trait locus (QTL) analysis of measures of EtOH-induced ataxia (accelerating rotarod), hypothermia, and loss of righting reflex (LORR) duration in a B6 × S1 F2 population. We confirmed that S1 showed greater EtOH-induced hypothermia (specifically at a high dose) and longer LORR compared to B6. QTL analysis revealed several additive and interacting loci for various phenotypes, as well as examples of genotype interactions with sex. QTLs for different EtOH phenotypes were largely non-overlapping, suggesting separable genetic influences on these behaviors. The most compelling main-effect QTLs were for hypothermia on chromosome 16 and for LORR on chromosomes 4 and 6. Several QTLs overlapped with loci repeatedly linked to EtOH drinking in previous mouse studies. The architecture of the traits we examined was complex but clearly amenable to dissection in future studies. Using integrative genomics strategies, plausible functional and positional candidates may be found. Uncovering candidate genes associated with variation in these phenotypes in this population could ultimately shed light on genetic factors underlying sensitivity to EtOH intoxication and risk for alcoholism in humans

Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control

DNA replication stress is a source of genomic instability. Here we identify ​changed mutation rate 1 (​Cmr1) as a factor involved in the response to DNA replication stress in Saccharomyces cerevisiae and show that ​Cmr1—together with ​Mrc1/​Claspin, ​Pph3, the chaperonin containing ​TCP1 (CCT) and 25 other proteins—define a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress. The diversity of proteins that localize to INQ indicates that other biological processes such as cell cycle progression, chromatin and mitotic spindle organization may also be regulated through INQ. Similar to ​Cmr1, its human orthologue ​WDR76 responds to proteasome inhibition and DNA damage by relocalizing to nuclear foci and physically associating with CCT, suggesting an evolutionarily conserved biological function. We propose that ​Cmr1/​WDR76 plays a role in the recovery from genotoxic stress through regulation of the turnover of sumoylated and phosphorylated proteins

Seasonal variations in carbon, nitrogen and phosphorus concentrations and C:N:P stoichiometry in different organs of a Larix principis-rupprechtii Mayr. plantation in the Qinling Mountains, China

Understanding how concentrations of elements and their stoichiometry change with plant growth and age is critical for predicting plant community responses to environmental change. Weusedlong-term field experiments to explore how the leaf, stem and root carbon (C), nitrogen (N) and phosphorous (P) concentrations and their stoichiometry changed with growth and stand age in a L.principis-rupprechtii Mayr. plantation from 2012–2015 in the Qinling Mountains, China. Our results showed that the C, N and P concentrations and stoichiometric ratios in different tissues of larch stands were affected by stand age, organ type andsampling month and displayed multiple correlations with increased stand age in different growing seasons. Generally, leaf C and N concentrations were greatest in the fast-growing season, but leaf P concentrations were greatest in the early growing season. However, no clear seasonal tendencies in the stem and root C, N and P concentrations were observed with growth. In contrast to N and P, few differences were found in organ-specific C concentrations. Leaf N:P was greatest in the fast-growing season, while C:N and C:P were greatest in the late-growing season. No clear variations were observed in stem and root C:N, C:P andN:Pthroughout the entire growing season, but leaf N:P was less than 14, suggesting that the growth of larch stands was limited by N in our study region. Compared to global plant element concentrations and stoichiometry, the leaves of larch stands had higher C, P, C:NandC:PbutlowerNandN:P,andtherootshadgreater PandC:NbutlowerN,C:Pand N:P. Our study provides baseline information for describing the changes in nutritional elements with plant growth, which will facilitates plantation forest management and restoration, and makes avaluable contribution to the global data pool on leaf nutrition and stoichiometry

Automated Home-Cage Behavioural Phenotyping of Mice

Neurobehavioral analysis of mouse phenotypes requires the monitoring of mouse behavior over long periods of time. Here, we describe a trainable computer vision system enabling the automated analysis of complex mouse behaviors. We provide software and an extensive manually annotated video database used for training and testing the system. Our system performs on par with human scoring, as measured from ground-truth manual annotations of thousands of clips of freely behaving mice. As a validation of the system, we characterized the home-cage behaviors of two standard inbred and two non-standard mouse strains. From this data we were able to predict in a blind test the strain identity of individual animals with high accuracy. Our video-based software will complement existing sensor based automated approaches and enable an adaptable, comprehensive, high-throughput, fine-grained, automated analysis of mouse behavior.McGovern Institute for Brain ResearchCalifornia Institute of Technology. Broad Fellows Program in Brain CircuitryNational Science Council (China) (TMS-094-1-A032

Knockout mice: Is it just genetics? Effect of enriched housing on fibulin-4+/- mice

Background. Fibulin-4 is an extracellular matrix protein expressed by vascular smooth muscle cells that is essential for maintaining arterial integrity. Fibulin-4-/- mice die just before birth due to arterial hemorrhage, but fibulin-4+/- mice appear to be outwardly normal. Experiments were therefore performed to determine whether fibulin-4+/- mice display arterial pathologies on a microscopic scale. After preliminary experiments were performed, a second purpose developed, which was to test the hypothesis that any observed pathologies would be ameliorated by housing the animals in enriched cages. Methodology. Fibulin-4+/- and wild-type mice were housed either four/cage in standard cages or two per cage in larger cages, each cage containing a tunnel and a wheel. After three weeks the mice were sacrificed, and the aortas perfusion-fixed and excised for light and electron microscopy. Principle Findings. When the mice were in standard cages, localized regions of disorganized extracellular matrix and collagen fibers consistently appeared between some of the medial smooth muscle cells in the fibulin-4+/- mice. In the wild-type mice, the smooth muscle cells were closely connected to each other and the media was more compact. The number of disorganized regions per square mm was significantly greater for fibulin-4+/- mice (172±43 (SEM)) than for wild-type mice (15±8) (p<0.01, n = 8). When the mice were in enriched cages, the fibulin-4+/- mice showed significantly fewer disorganized regions than those in standard cages (35±12) (p<0.05, n = 8). The wild type mice also showed fewer disorganized regions (3±2), but this difference was not significant. Conclusions. These results indicate that arterial pathologies manifested in fibulin-4+/- mice can be reduced by enriching the housing conditions, and imply that appropriate environments may counteract the effects of some genetic deficiencies

A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol

Sonification and Music as Support to the Communication of Alcohol-Related Health Risks to Young People : Study design and results

Excessive consumption of alcohol has been recognised as a significant risk factor impacting the health of young people. Effective communication of such risk is considered to be one key step to improve behaviour. We evaluated an innovative multimedia intervention that utilised audio (sonification—using sound to display data—and music) and interactivity to support the visual communication of alcohol health risk data. A 3-arm pilot experiment was undertaken. The trial measures included health knowledge, alcohol risk perception and user experience of the intervention. Ninety-six subjects participated in the experiment. At 1 month follow-up, alcohol knowledge and alcohol risk perception improved significantly in the whole sample. However, there was no difference between the intervention groups that experienced (1) visual presentation with interactivity (VI-Exp group) and, (2) visual presentation with audio (sonification and music) and interactivity (VAI-Exp group), when compared to the control group which experienced a (3) visual only presentation (V-Cont group). Participants reported enjoying the presentations and found them educational. The majority of participants indicated that the audio, music and sonification helped to convey the information well, and, although a larger sample size is needed to fully establish the effectiveness of the different interventions, this study provides a useful model for future similar studies

Advancing global health through environmental and public health tracking

Challenges such as climate change, resource depletion (with its huge implications for human health and wellbeing), and persistent social inequalities in health have been identified as global public health issues with implications for both communicable and noncommunicable diseases. This contributes to pressure on healthcare systems, as well as societal systems that affect health. A novel strategy to tackle these multiple, interacting and interdependent drivers of change is required to protect the population’s health. Public health professionals have found that building strong, enduring interdisciplinary partnerships across disciplines can address environment and health complexities, and that developing Environmental and Public Health Tracking (EPHT) systems has been an effective tool. EPHT aims to merge, integrate, analyse and interpret environmental hazards, exposure and health data. In this article, we explain that public health decision-makers can use EPHT insights to drive public health actions, reduce exposure and prevent the occurrence of disease more precisely in efficient and cost-effective ways. An international network exists for practitioners and researchers to monitor and use environmental health intelligence, and to support countries and local areas toward sustainable and healthy development. A global network of EPHT programs and professionals has the potential to advance global health by implementing and sharing experience, to magnify the impact of local efforts and to pursue data knowledge improvement strategies, aiming to recognise and support best practices. EPHT can help increase the understanding of environmental public health and global health, improve comparability of risks between different areas of the world including Low and Middle-Income Countries (LMICs), enable transparency and trust among citizens, institutions and the private sector, and inform preventive decision making consistent with sustainable and healthy development. This shows how EPHT advances global health efforts by sharing recent global EPHT activities and resources with those working in this field. Experiences from the US, Europe, Asia and Australasia are outlined for operating successful tracking systems to advance global health