Disease- and age-related changes in histone acetylation at gene promoters in psychiatric disorders

Increasing evidence suggests that epigenetic factors have critical roles in gene regulation in neuropsychiatric disorders and in aging, both of which are typically associated with a wide range of gene expression abnormalities. Here, we have used chromatin immunoprecipitation-qPCR to measure levels of acetylated histone H3 at lysines 9/14 (ac-H3K9K14), two epigenetic marks associated with transcriptionally active chromatin, at the promoter regions of eight schizophrenia-related genes in n=82 postmortem prefrontal cortical samples from normal subjects and those with schizophrenia and bipolar disorder. We find that promoter-associated ac-H3K9K14 levels are correlated with gene expression levels, as measured by real-time qPCR for several genes, including, glutamic acid decarboxylase 1 (GAD1), 5-hydroxytryptamine receptor 2C (HTR2C), translocase of outer mitochondrial membrane 70 homolog A (TOMM70A) and protein phosphatase 1E (PPM1E). Ac-H3K9K14 levels of several of the genes tested were significantly negatively associated with age in normal subjects and those with bipolar disorder, but not in subjects with schizophrenia, whereby low levels of histone acetylation were observed in early age and throughout aging. Consistent with this observation, significant hypoacetylation of H3K9K14 was detected in young subjects with schizophrenia when compared with age-matched controls. Our results demonstrate that gene expression changes associated with psychiatric disease and aging result from epigenetic mechanisms involving histone acetylation. We further find that treatment with a histone deacetylase (HDAC) inhibitor alters the expression of several candidate genes for schizophrenia in mouse brain. These findings may have therapeutic implications for the clinical use of HDAC inhibitors in psychiatric disorders

Search for Extended Sources of Neutrino Emission in the Galactic Plane with IceCube

The Galactic plane, harboring a diffuse neutrino flux, is a particularly interesting target to study potential cosmic-ray acceleration sites. Recent gamma-ray observations by HAWC and LHAASO have presented evidence for multiple Galactic sources that exhibit a spatially extended morphology and have energy spectra continuing beyond 100 TeV. A fraction of such emission could be produced by interactions of accelerated hadronic cosmic rays, resulting in an excess of high-energy neutrinos clustered near these regions. Using 10 years of IceCube data comprising track-like events that originate from charged-current muon neutrino interactions, we perform a dedicated search for extended neutrino sources in the Galaxy. We find no evidence for time-integrated neutrino emission from the potential extended sources studied in the Galactic plane. The most significant location, at 2.6$\sigma$ post-trials, is a 1.7$^\circ$ sized region coincident with the unidentified TeV gamma-ray source 3HWC J1951+266. We provide strong constraints on hadronic emission from several regions in the Galaxy.Comment: 13 pages, 4 figures, 5 tables including an appendix. Accepted for publication in Astrophysical Journa

Exploring Predictors of Outcome in the Psychosis Prodrome: Implications for Early Identification and Intervention

Functional disability is a key component of many psychiatric illnesses, particularly schizophrenia. Impairments in social and role functioning are linked to cognitive deficits, a core feature of psychosis. Retrospective analyses demonstrate that substantial functional decline precedes the onset of psychosis. Recent investigations reveal that individuals at clinical-high-risk (CHR) for psychosis show impairments in social relationships, work/school functioning and daily living skills. CHR youth also demonstrate a pattern of impairment across a range of cognitive domains, including social cognition, which is qualitatively similar to that of individuals with schizophrenia. While many studies have sought to elucidate predictors of clinical deterioration, specifically the development of schizophrenia, in such CHR samples, few have investigated factors relevant to psychosocial outcome. This review integrates recent findings regarding cognitive and social-cognitive predictors of outcome in CHR individuals, and proposes potential directions for future research that will contribute to targeted interventions and improved outcome for at-risk youth

Burden of mortality and morbidity from dementia

The purpose of this study was to estimate severity-specific mortality and to quantify the global health burden of dementia by assessing the time spent disabled with dementia and the life years lost due to dementia. We used mortality data from the Rotterdam study, a population-based prospective study in the 55+-year age range to calculate overall and severity-specific excess mortality for the demented. Lost life years were calculated by decomposing the (mixed) Dutch life table of 1990-1992 in two populations, the demented and the healthy, using prevalence and excess (all cause) mortality. Healthy life loss was calculated by a modified Sullivan technique, weighting for disease severity. Our results indicated that mortality was increased in the demented, in all age, sex, and severity groups. Mortality rate ratios were 2.1 (men) and 2.3 (women), with ranges of 1.7-3.4 (men) and 2.0-3.1 (women), depending on severity. Fifty-five-year-old men lose 1.2 life years due to morbidity and mortality and 0.7 life years due to mortality resulting from dementia. Women lose 3.1 and 1.9 life years, respectively. This population-based study provides evidence that mortality is increased in the demented at all stages, including minimal dementia. The quantified health impact on the general population is in the same order as that of lung cancer or stroke