Hippocampal Regulation of Postsynaptic Density Homer1 by Associative Learning

Genes involved in synaptic plasticity, particularly genes encoding postsynaptic density proteins, have been recurrently linked to psychiatric disorders including schizophrenia and autism. Postsynaptic density Homer1 proteins contribute to synaptic plasticity through the competing actions of short and long isoforms. The activity-induced expression of shortHomer1isoforms,Homer1aandAnia-3, is thought to be related to processes of learning and memory. However, the precise regulation ofHomer1aandAnia-3with different components of learning has not been investigated. Here, we used in situ hybridization to quantify short and longHomer1expression in the hippocampus following consolidation, retrieval, and extinction of associative fear memory, using contextual fear conditioning in rats.Homer1aandAnia-3, but not longHomer1, were regulated by contextual fear learning or novelty detection, although their precise patterns of expression in hippocampal subregions were dependent on the isoform. We also show for the first time that the two short Homer1 isoforms are regulated after the retrieval and extinction of contextual fear memory, albeit with distinct temporal and spatial profiles. These findings support a role of activity-induced Homer1 isoforms in learning and memory processes in discrete hippocampal subregions and suggest that Homer1a and Ania-3 may play separable roles in synaptic plasticity.</jats:p

Biodiversity, Species Protection, and Animal Welfare Under International Law

The chapter explores the influence of the concept of animal welfare on international biodiversity law. A close examination of the recent evolution of this branch of international law shows that animal welfare has an ambivalent place in biodiversity-related agreements. Indeed, while welfare is only a faint consideration in the development of international regimes dealing with biodiversity as a whole, the concept has become an essential element for agreements dealing with the conservation of specific endangered species. Despite its role in these agreements, the place of animal welfare in international biodiversity law highlights that this corpus of rules is currently insufficient to be an effective tool for the protection of wildlife welfare. The last section of this study suggests that the adoption of international rules aiming at ensuring the protection of wild animals’ welfare could serve the double purpose of strengthening the conservation purpose of biodiversity regimes while also filling the welfare gap of international biodiversity law

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation

Comparative effectiveness of lifestyle interventions on cardiovascular risk factors among a Dutch overweight working population: A randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Overweight (Body Mass Index [BMI] ≥ 25 kg/m²) and obesity (BMI≥ 30 kg/m²) are associated with increased cardiovascular risk, posing a considerable burden to public health. The main aim of this study was to investigate lifestyle intervention effects on cardiovascular risk factors in healthy overweight employees.</p> <p>Methods</p> <p>Participants were 276 healthy overweight employees (69.2% male; mean age 44.0 years [SD 9.2]; mean BMI 29.7 kg/m²[SD 3.1]). They were randomized to one of two intervention groups receiving a six month lifestyle intervention with behavior counseling by phone (phone group) or e-mail (Internet group), or to a control group receiving usual care. Body weight, height, waist circumference, sum of skinfolds, blood pressure, total cholesterol level and predicted aerobic fitness were measured at baseline, at 6 and at 24 months. Regression analyses included the 141 participants with complete data.</p> <p>Results</p> <p>At 6 months a significant favorable effect on total cholesterol level (-0.2 mmol/l, 95%CI -0.5 to -0.0) was observed in the phone group and a trend for improved aerobic fitness (1.9 ml/kg/min, 95%CI -0.2 to 3.9) in the Internet group. At two years, favorable trends for body weight (-2.1 kg, 95%CI -4.4 to 0.2) and aerobic fitness (2.3 ml/kg/min, 95%CI -0.2 to 4.8) were observed in the Internet group.</p> <p>Conclusions</p> <p>The intervention effects were independent of the used communication mode. However short-term results were in favor of the phone group and long-term results in favor of the internet group. Thus, we found limited evidence for our lifestyle intervention to be effective in reducing cardiovascular risk in a group of apparently healthy overweight workers.</p> <p>Trial registration</p> <p><a href="http://www.controlled-trials.com/ISRCTN04265725">ISRCTN04265725</a></p

Inositol 1,4,5- Trisphosphate Receptor Function in Drosophila Insulin Producing Cells

The Inositol 1,4,5- trisphosphate receptor (InsP3R) is an intracellular ligand gated channel that releases calcium from intracellular stores in response to extracellular signals. To identify and understand physiological processes and behavior that depends on the InsP3 signaling pathway at a systemic level, we are studying Drosophila mutants for the InsP3R (itpr) gene. Here, we show that growth defects precede larval lethality and both are a consequence of the inability to feed normally. Moreover, restoring InsP3R function in insulin producing cells (IPCs) in the larval brain rescues the feeding deficit, growth and lethality in the itpr mutants to a significant extent. We have previously demonstrated a critical requirement for InsP3R activity in neuronal cells, specifically in aminergic interneurons, for larval viability. Processes from the IPCs and aminergic domain are closely apposed in the third instar larval brain with no visible cellular overlap. Ubiquitous depletion of itpr by dsRNA results in feeding deficits leading to larval lethality similar to the itpr mutant phenotype. However, when itpr is depleted specifically in IPCs or aminergic neurons, the larvae are viable. These data support a model where InsP3R activity in non-overlapping neuronal domains independently rescues larval itpr phenotypes by non-cell autonomous mechanisms

Population-based study of genetic variation in individuals with autism spectrum disorders from Croatia

<p>Abstract</p> <p>Background</p> <p>Genome-wide studies on autism spectrum disorders (ASDs) have mostly focused on large-scale population samples, but examination of rare variations in isolated populations may provide additional insights into the disease pathogenesis.</p> <p>Methods</p> <p>As a first step in the genetic analysis of ASD in Croatia, we characterized genetic variation in a sample of 103 subjects with ASD and 203 control individuals, who were genotyped using the Illumina HumanHap550 BeadChip. We analyzed the genetic diversity of the Croatian population and its relationship to other populations, the degree of relatedness via Runs of Homozygosity (ROHs), and the distribution of large (>500 Kb) copy number variations.</p> <p>Results</p> <p>Combining the Croatian cohort with several previously published populations in the FastME analysis (an alternative to Neighbor Joining) revealed that Croatian subjects cluster, as expected, with Southern Europeans; in addition, individuals from the same geographic region within Europe cluster together. Whereas Croatian subjects could be separated from a sample of healthy control subjects of European origin from North America, Croatian ASD cases and controls are well mixed. A comparison of runs of homozygosity indicated that the number and the median length of regions of homozygosity are higher for ASD subjects than for controls (p = 6 × 10^-3). Furthermore, analysis of copy number variants found a higher frequency of large chromosomal rearrangements (>2 Mb) in ASD cases (5/103) than in ethnically matched control subjects (1/197, p = 0.019).</p> <p>Conclusions</p> <p>Our findings illustrate the remarkable utility of high-density genotype data for subjects from a limited geographic area in dissecting genetic heterogeneity with respect to population and disease related variation.</p

Developmental malformation of the corpus callosum: a review of typical callosal development and examples of developmental disorders with callosal involvement

This review provides an overview of the involvement of the corpus callosum (CC) in a variety of developmental disorders that are currently defined exclusively by genetics, developmental insult, and/or behavior. I begin with a general review of CC development, connectivity, and function, followed by discussion of the research methods typically utilized to study the callosum. The bulk of the review concentrates on specific developmental disorders, beginning with agenesis of the corpus callosum (AgCC)—the only condition diagnosed exclusively by callosal anatomy. This is followed by a review of several genetic disorders that commonly result in social impairments and/or psychopathology similar to AgCC (neurofibromatosis-1, Turner syndrome, 22q11.2 deletion syndrome, Williams yndrome, and fragile X) and two forms of prenatal injury (premature birth, fetal alcohol syndrome) known to impact callosal development. Finally, I examine callosal involvement in several common developmental disorders defined exclusively by behavioral patterns (developmental language delay, dyslexia, attention-deficit hyperactive disorder, autism spectrum disorders, and Tourette syndrome)

Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015:a systematic analysis for the Global Burden of Disease Study 2015

Background Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015.Methods We estimated incidence and prevalence by age, sex, cause, year, and geography with a wide range of updated and standardised analytical procedures. Improvements from GBD 2013 included the addition of new data sources, updates to literature reviews for 85 causes, and the identification and inclusion of additional studies published up to November, 2015, to expand the database used for estimation of non-fatal outcomes to 60 900 unique data sources. Prevalence and incidence by cause and sequelae were determined with DisMod-MR 2.1, an improved version of the DisMod-MR Bayesian meta-regression tool first developed for GBD 2010 and GBD 2013. For some causes, we used alternative modelling strategies where the complexity of the disease was not suited to DisMod-MR 2.1 or where incidence and prevalence needed to be determined from other data. For GBD 2015 we created a summary indicator that combines measures of income per capita, educational attainment, and fertility (the Socio-demographic Index [SDI]) and used it to compare observed patterns of health loss to the expected pattern for countries or locations with similar SDI scores.Findings We generated 9.3 billion estimates from the various combinations of prevalence, incidence, and YLDs for causes, sequelae, and impairments by age, sex, geography, and year. In 2015, two causes had acute incidences in excess of 1 billion: upper respiratory infections (17.2 billion, 95% uncertainty interval [UI] 15.4-19.2 billion) and diarrhoeal diseases (2.39 billion, 2.30-2.50 billion). Eight causes of chronic disease and injury each affected more than 10% of the world's population in 2015: permanent caries, tension-type headache, iron-deficiency anaemia, age-related and other hearing loss, migraine, genital herpes, refraction and accommodation disorders, and ascariasis. The impairment that affected the greatest number of people in 2015 was anaemia, with 2.36 billion (2.35-2.37 billion) individuals affected. The second and third leading impairments by number of individuals affected were hearing loss and vision loss, respectively. Between 2005 and 2015, there was little change in the leading causes of years lived with disability (YLDs) on a global basis. NCDs accounted for 18 of the leading 20 causes of age-standardised YLDs on a global scale. Where rates were decreasing, the rate of decrease for YLDs was slower than that of years of life lost (YLLs) for nearly every cause included in our analysis. For low SDI geographies, Group 1 causes typically accounted for 20-30% of total disability, largely attributable to nutritional deficiencies, malaria, neglected tropical diseases, HIV/AIDS, and tuberculosis. Lower back and neck pain was the leading global cause of disability in 2015 in most countries. The leading cause was sense organ disorders in 22 countries in Asia and Africa and one in central Latin America; diabetes in four countries in Oceania; HIV/AIDS in three southern sub-Saharan African countries; collective violence and legal intervention in two north African and Middle Eastern countries; iron-deficiency anaemia in Somalia and Venezuela; depression in Uganda; onchoceriasis in Liberia; and other neglected tropical diseases in the Democratic Republic of the Congo.Interpretation Ageing of the world's population is increasing the number of people living with sequelae of diseases and injuries. Shifts in the epidemiological profile driven by socioeconomic change also contribute to the continued increase in years lived with disability (YLDs) as well as the rate of increase in YLDs. Despite limitations imposed by gaps in data availability and the variable quality of the data available, the standardised and comprehensive approach of the GBD study provides opportunities to examine broad trends, compare those trends between countries or subnational geographies, benchmark against locations at similar stages of development, and gauge the strength or weakness of the estimates available. Copyright (C) The Author(s). Published by Elsevier Ltd.</p