Characterization of Highper, an ENU-induced mouse mutant with abnormal psychostimulant and stress responses

RationaleChemical mutagenesis in the mouse is a forward genetics approach that introduces random mutations into the genome, thereby providing an opportunity to annotate gene function and characterize phenotypes that have not been previously linked to a given gene.ObjectivesWe report on the behavioral characterization of Highper, an N-ethyl-N-nitrosourea (ENU)-induced mutant mouse line.MethodsHighper and B6 control mice were assessed for locomotor activity in the open field and home cage environments. Basal and acute restraint stress-induced corticosterone levels were measured. Mice were tested for locomotor response to cocaine (5, 20, 30, and 45mg/kg), methylphenidate (30mg/kg), and ethanol (0.75, 1.25, and 1.75g/kg). The rewarding and reinforcing effects of cocaine were assessed using conditioned place preference and self-administration paradigms.ResultsHighper mice are hyperactive during behavioral tests but show normal home cage locomotor behavior. Highper mice also exhibit a twofold increase in locomotor response to cocaine, methylphenidate, and ethanol and prolonged activation of the hypothalamic–pituitary–adrenal axis in response to acute stress. Highper mice are more sensitive to the rewarding and reinforcing effects of cocaine, although place preference in Highper mice appears to be significantly influenced by the environment in which the drug is administered.ConclusionsAltogether, our findings indicate that Highper mice may provide important insights into the genetic, molecular, and biological mechanisms underlying stress and the drug reward pathway.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-012-2827-5) contains supplementary material, which is available to authorized users

Genetic Factors Leading to Chronic Epstein–Barr Virus Infection and Nasopharyngeal Carcinoma in South East China: Study Design, Methods and Feasibility

Nasopharyngeal carcinoma (NPC) is a complex disease caused by a combination of Epstein-Barr virus chronic infection, the environment and host genes in a multi-step process of carcinogenesis. The identity of genetic factors involved in the development of chronic Epstein-Barr virus infection and NPC remains elusive, however. Here, we describe a two-phase, population-based, case-control study of Han Chinese from Guangxi province, where the NPC incidence rate rises to a high of 25-50 per 100,000 individuals. Phase I, powered to detect single gene associations, enrolled 984 subjects to determine feasibility, to develop infrastructure and logistics and to determine error rates in sample handling. A microsatellite screen of Phase I study participants, genotyped for 319 alleles from 34 microsatellites spanning an 18-megabase region of chromosome 4 (4p15.1-q12), previously implicated by a linkage analysis of familial NPC, found 14 alleles marginally associated with developing NPC or chronic immunoglobulin A production (p = 0.001-0.03). These associations lost significance after applying a correction for multiple tests. Although the present results await confirmation, the Phase II study population has tripled patient enrolment and has included environmental covariates, offering the potential to validate this and other genomic regions that influence the onset of NPC

The past and future roles of competition and habitat in the range-wide occupancy dynamics of Northern Spotted Owls

Slow ecological processes challenge conservation. Short-term variability can obscure the importance of slower processes that may ultimately determine the state of a system. Furthermore, management actions with slow responses can be hard to justify. One response to slow processes is to explicitly concentrate analysis on state dynamics. Here, we focus on identifying drivers of Northern Spotted Owl (Strix occidentalis caurina) territorial occupancy dynamics across 11 study areas spanning their geographic range and forecasting response to potential management actions. Competition with Barred Owls (Strix varia) has increased Spotted Owl territory extinction probabilities across all study areas and driven recent declines in Spotted Owl populations. Without management intervention, the Northern Spotted Owl subspecies will be extirpated from parts of its current range within decades. In the short term, Barred Owl removal can be effective. Over longer time spans, however, maintaining or improving habitat conditions can help promote the persistence of northern spotted owl populations. In most study areas, habitat effects on expected Northern Spotted Owl territorial occupancy are actually greater than the effects of competition from Barred Owls. This study suggests how intensive management actions (removal of a competitor) with rapid results can complement a slower management action (i.e., promoting forest succession)

The association between long-term DDT or DDE exposures and an altered sperm epigenome-a cross-sectional study of Greenlandic Inuit and South African VhaVenda men

Please read abstract in the article.The South African Medical Research Council, the Canadian Institutes of Health Research, the CIHR.https://ehp.niehs.nih.govhj2024School of Health Systems and Public Health (SHSPH)UP Centre for Sustainable Malaria Control (UP CSMC)SDG-03:Good heatlh and well-bein

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Parent and child physical activity and sedentary time: Do active parents foster active children?

<p>Abstract</p> <p>Background</p> <p>Physical activity has many positive effects on children's health while TV viewing has been associated with adverse health outcomes. Many children do not meet physical activity recommendations and exceed TV viewing guidelines. Parents are likely to be an important influence on their children's behaviour. There is an absence of information about the associations between parents' and children's physical activity and TV viewing.</p> <p>Methods</p> <p>Year 6 children and their parent were recruited from 40 primary schools. Results are presented for the 340 parent-child dyads with accelerometer data that met a ≥ 3 day inclusion criteria and the 431 parent-child dyads with complete self-reported TV viewing. Over 80% of the dyads with valid TV viewing data included mothers and their child. Mean minutes of moderate to vigorous physical activity (MVPA), minutes of sedentary time per day and counts per minute were assessed by accelerometer. Self-reported hours of TV viewing were coded into 3 groups (< 2 hours per day, 2-4 hours per day and >4 hours per day. Linear and multi-nominal regression models were run by child gender to examine parent-child associations.</p> <p>Results</p> <p>In linear regression models there was an association for the overall sedentary time of girls and their parents (t = 2.04. p = .020) but there was no association between girls' and parents' physical activity. There were no associations between parents' and boys' sedentary or physical activity time. For girls, the risk of watching more than 4 hours of TV per day, (reference = 2 hours of TV per day), was 3.67 times higher if the girl's parent watched 2-4 hours of TV per day (p = 0.037). For boys, the risk of watching more than 4 hours of TV per day, was 10.47 times higher if the boy's parent watched more than 4 hours of TV per day (p = 0.038).</p> <p>Conclusions</p> <p>There are associations in the sedentary time of parents and daughters. Higher parental TV viewing was associated with an increased risk of high levels of TV viewing for both boys and girls. There were no associations between the time that parents and children spend engaged in physical activity.</p

Are ribosomal DNA clusters rearrangement hotspots? A case study in the genus Mus (Rodentia, Muridae)

<p>Abstract</p> <p>Background</p> <p>Recent advances in comparative genomics have considerably improved our knowledge of the evolution of mammalian karyotype architecture. One of the breakthroughs was the preferential localization of evolutionary breakpoints in regions enriched in repetitive sequences (segmental duplications, telomeres and centromeres). In this context, we investigated the contribution of ribosomal genes to genome reshuffling since they are generally located in pericentromeric or subtelomeric regions, and form repeat clusters on different chromosomes. The target model was the genus <it>Mus </it>which exhibits a high rate of karyotypic change, a large fraction of which involves centromeres.</p> <p>Results</p> <p>The chromosomal distribution of rDNA clusters was determined by <it>in situ </it>hybridization of mouse probes in 19 species. Using a molecular-based reference tree, the phylogenetic distribution of clusters within the genus was reconstructed, and the temporal association between rDNA clusters, breakpoints and centromeres was tested by maximum likelihood analyses. Our results highlighted the following features of rDNA cluster dynamics in the genus <it>Mus</it>: i) rDNA clusters showed extensive diversity in number between species and an almost exclusive pericentromeric location, ii) a strong association between rDNA sites and centromeres was retrieved which may be related to their shared constraint of concerted evolution, iii) 24% of the observed breakpoints mapped near an rDNA cluster, and iv) a substantial rate of rDNA cluster change (insertion, deletion) also occurred in the absence of chromosomal rearrangements.</p> <p>Conclusions</p> <p>This study on the dynamics of rDNA clusters within the genus <it>Mus </it>has revealed a strong evolutionary relationship between rDNA clusters and centromeres. Both of these genomic structures coincide with breakpoints in the genus <it>Mus</it>, suggesting that the accumulation of a large number of repeats in the centromeric region may contribute to the high level of chromosome repatterning observed in this group. However, the elevated rate of rDNA change observed in the chromosomally invariant clade indicates that the presence of these sequences is insufficient to lead to genome instability. In agreement with recent studies, these results suggest that additional factors such as modifications of the epigenetic state of DNA may be required to trigger evolutionary plasticity.</p

Innovations in cryoconservation of animal genetic resources. Practical guide

Peer reviewe

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders