Neurocardiovascular deficits in the Q175 mouse model of Huntington's disease.

Cardiovascular dysautonomia as well as the deterioration of circadian rhythms are among the earliest detectable pathophysiological changes in individuals with Huntington's disease (HD). Preclinical research requires mouse models that recapitulate disease symptoms and the Q175 knock-in model offers a number of advantages but potential autonomic dysfunction has not been explored. In this study, we sought to test the dual hypotheses that cardiovascular dysautonomia can be detected early in disease progression in the Q175 model and that this dysfunction varies with the daily cycle. Using radiotelemetry implants, we observed a significant reduction in the diurnal and circadian activity rhythms in the Q175 mutants at the youngest ages. By middle age, the autonomically driven rhythms in core body temperature were highly compromised, and the Q175 mutants exhibited striking episodes of hypothermia that increased in frequency with mutant huntingtin gene dosage. In addition, Q175 mutants showed higher resting heart rate (HR) during sleep and greatly reduced correlation between activity and HR HR variability was reduced in the mutants in both time and frequency domains, providing more evidence of autonomic dysfunction. Measurement of the baroreceptor reflex revealed that the Q175 mutant could not appropriately increase HR in response to a pharmacologically induced decrease in blood pressure. Echocardiograms showed reduced ventricular mass and ejection fraction in mutant hearts. Finally, cardiac histopathology revealed localized points of fibrosis resembling those caused by myocardial infarction. Thus, the Q175 mouse model of HD exhibits cardiovascular dysautonomia similar to that seen in HD patients with prominent sympathetic dysfunction during the resting phase of the activity rhythm

Genome-Wide Identification of Expression Quantitative Trait Loci (eQTLs) in Human Heart.

In recent years genome-wide association studies (GWAS) have uncovered numerous chromosomal loci associated with various electrocardiographic traits and cardiac arrhythmia predisposition. A considerable fraction of these loci lie within inter-genic regions. The underlying trait-associated variants likely reside in regulatory regions and exert their effect by modulating gene expression. Hence, the key to unraveling the molecular mechanisms underlying these cardiac traits is to interrogate variants for association with differential transcript abundance by expression quantitative trait locus (eQTL) analysis. In this study we conducted an eQTL analysis of human heart. For a total of 129 left ventricular samples that were collected from non-diseased human donor hearts, genome-wide transcript abundance and genotyping was determined using microarrays. Each of the 18,402 transcripts and 897,683 SNP genotypes that remained after pre-processing and stringent quality control were tested for eQTL effects. We identified 771 eQTLs, regulating 429 unique transcripts. Overlaying these eQTLs with cardiac GWAS loci identified novel candidates for studies aimed at elucidating the functional and transcriptional impact of these loci. Thus, this work provides for the first time a comprehensive eQTL map of human heart: a powerful and unique resource that enables systems genetics approaches for the study of cardiac traits

A systematic review of vitamin D status in populations worldwide

Vitamin D deficiency is associated with osteoporosis and is thought to increase the risk of cancer and CVD. Despite these numerous potential health effects, data on vitamin D status at the population level and within key subgroups are limited. The aims of the present study were to examine patterns of 25-hydroxyvitamin D (25(OH)D) levels worldwide and to assess differences by age, sex and region. In a systematic literature review using the Medline and EMBASE databases, we identified 195 studies conducted in forty-four countries involving more than 168000 participants. Mean population-level 25(OH)D values varied considerably across the studies (range 4·9-136·2nmol/l), with 37·3% of the studies reporting mean values below 50nmol/l. The highest 25(OH)D values were observed in North America. Although age-related differences were observed in the Asia/Pacific and Middle East/Africa regions, they were not observed elsewhere and sex-related differences were not observed in any region. Substantial heterogeneity between the studies precluded drawing conclusions on overall vitamin D status at the population level. Exploratory analyses, however, suggested that newborns and institutionalised elderly from several regions worldwide appeared to be at a generally higher risk of exhibiting lower 25(OH)D values. Substantial details on worldwide patterns of vitamin D status at the population level and within key subgroups are needed to inform public health policy development to reduce risk for potential health consequences of an inadequate vitamin D statu

Developing welfare parameters for African elephants (Loxodonta africana) in fenced reserves in South Africa

South Africa has many fenced reserves harbouring small to medium sized populations of African elephant (Loxodonta africana), most of which have been translocated. Elephants on fenced reserves may be exposed to various management interventions and practices (translocation, hunting, darting, high tourism impact, contraception programs, disruption due to infrastructure maintenance, etc.). These factors may impact the welfare of elephants. Poor elephant welfare may have serious consequences such as increased inter- and intra-species aggression that could result in fatalities. This is the first study to attempt to define behavioural and physiological welfare parameters for free-ranging elephants on small to medium sized reserves. The eight study sites incorporated reserves with different social structure combinations, elephant life-histories, reserve sizes, habitat, management, and tourism intensity. Data collection consisted of behavioural observations (10-minute videos) as well as faecal samples. By incorporating both behavioural and physiological (faecal glucocorticoid metabolite (fGCM) concentration) parameters, we aimed to investigate whether the two parameters showed similar trends. Five behavioural categories were identified (Arousal, Assessing, Ambivalent, Ambivalent/ Body care, and Frustrated behaviour), with various detailed behaviours demonstrated by the elephants that may indicate the influence of anthropogenic disturbance and possibly impact on animal welfare. The study showed significant differences between the selected detailed behaviours, behavioural categories and fGCM concentrations of elephants across the eight reserves. History seemed to be a decisive factor, as reserves with predominantly ex-captive elephants showed higher frequencies of certain behaviours as well as higher fGCM concentrations. Age, sex, reserve size and season were also found to contribute to our defined welfare indices and fGCM concentrations. This indicates that behavioural parameters, indicative of certain behavioural states, are valuable indicators of welfare, as supported by the physiological response of the elephants. The results also highlight the importance of taking multiple specified behaviours from a category into consideration when evaluating the welfare of elephants, to account for individual variation.The EMS Foundation.http://www.plosone.orgdm2022Mammal Research Institut

Epigenetic Anti-Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue

5-Aza-2'-deoxycytidine (Decitabine, AzadC) is a nucleoside analogue, which is in clinical use to treat patients with myelodysplastic syndrome or acute myeloid leukemia. Its mode of action is unusual because the compound is one of the few drugs that act at the epigenetic level of the genetic code. AzadC is incorporated as an antimetabolite into the genome and creates covalent, inhibitory links to DNA methyltransferases (DNMTs) that methylate 2'-deoxycytidine (dC) to 5-methyl-dC (mdC). Consequently, AzadC treatment leads to a global loss of mdC, which presumably results in a reactivation of silenced genes, among them tumor suppressor and DNA damage response genes. Because AzadC suffers from severe instability, which limits its use in the clinic, a more sophisticated AzadC derivative would be highly valuable. Here, we report that a recently developed carbocyclic AzadC analogue (cAzadC) blocks DNMT1 in the AML cell line MOLM-13 as efficient as AzadC. Moreover, cAzadC has a surprisingly strong anti-proliferative effect and leads to a significantly higher number of double strand breaks compared to AzadC, while showing less off-target toxicity. These results show that cAzadC triggers more deleterious repair and apoptotic pathways in cancer cells than AzadC, which makes cAzadC a promising next generation epigenetic drug

Easing the transition: do Talent Lessons and Talent Talks support students’ self-regulated learning skills in the transition from primary to secondary education?

IntroductionThe transition from primary to secondary school is a period that can affect students negatively, with regular drops in academic achievement observed. Training students’ self-regulated learning skills might help prevent some of the negative outcomes associated with the transition. We investigate Talent Talk and Talent Lesson interventions, which aim to improve students’ metacognitive and affective self-regulation through enhancement of personal significance and strengthening of task-analysis skills.MethodThe present study researched whether Talents Talks and Talent Lessons can be used to improve students’ self-regulated learning skills, motivation, and self-efficacy. We employed a quasi-experimental 2 × 2 design comparing four groups (total N = 233), who received either Talent Talks or Talent Lessons, both, or neither. Students were tested at three separate moments on absolute monitoring accuracy and self-report measures of self-regulated learning, motivation, and self-efficacy, with the interventions being implemented between the first and second moment.ResultsThere were no significant differences between conditions at any of the test moments.DiscussionAs such, there is at present no evidence suggesting that Talent Talks and Talent Lessons positively influence self-regulation, self-efficacy, and motivation. Effectiveness of the intervention might be increased if Talent Talks and Talent Lessons are adapted, so that students’ reflections about talents are tailored to self-regulation of specific tasks

Predictors of Change Following Cognitive-Behavioral Treatment of Children with Anxiety Problems: A Preliminary Investigation on Negative Automatic Thoughts and Anxiety Control

The purpose of the present study was to evaluate negative automatic thoughts and anxiety control as predictors of change produced by cognitive-behavioral treatment of youths with anxiety disorders. Forty-five high-anxious children aged between 9 and 12 years who were selected from the primary school population, received a standardized CBT intervention that was provided in a group format. Before and after the intervention, children completed scales of negative automatic thoughts and perceived control over anxiety-related events as well as a questionnaire for measuring DSM-defined anxiety disorders symptoms, which was the outcome measure. Results indicated that CBT was effective in reducing children’s anxiety symptoms. Most importantly, the reduction of anxiety disorders symptoms was significantly associated with a decrease in negative automatic thoughts and an increase of anxiety control, which provides support for the notion that these variables are candidate mediators of CBT in anxious youths

Research and Innovation for and with Adolescent Young Carers to Influence Policy and Practice—The European Union Funded “ME-WE” Project

Young carers are children and adolescents who provide care to other family members or friends, taking over responsibilities that are usually associated with adulthood. There is emerging but still scarce knowledge worldwide about the phenomenon of young carers and the impact of a caring role on their health, social and personal development spheres. This paper provides an overview of the main results from the ME-WE project, which is the first European research and innovation project dedicated to adolescent young carers (AYCs) (15–17 years). The project methods relied on three main activities: (1) a systematization of knowledge (by means of a survey to AYCs, country case studies, Delphi study, literature review); (2) the co-design, implementation and evaluation of a primary prevention intervention addressing AYCs’ mental health (by means of Blended Learning Networks and a clinical trial in six European countries); (3) the implementation of knowledge translation actions for dissemination, awareness, advocacy and lobbying (by means of national and international stakeholder networks, as well as traditional and new media). Project results substantially contributed to a better understanding of AYCs’ conditions, needs and preferences, defined tailored support intervention (resilient to COVID-19 related restrictions), and significant improvements in national and European policies for AYCs

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements