Drosophila Histone Deacetylase-3 Controls Imaginal Disc Size through Suppression of Apoptosis

Histone deacetylases (HDACs) execute biological regulation through post-translational modification of chromatin and other cellular substrates. In humans, there are eleven HDACs, organized into three distinct subfamilies. This large number of HDACs raises questions about functional overlap and division of labor among paralogs. In vivo roles are simpler to address in Drosophila, where there are only five HDAC family members and only two are implicated in transcriptional control. Of these two, HDAC1 has been characterized genetically, but its most closely related paralog, HDAC3, has not. Here we describe the isolation and phenotypic characterization of hdac3 mutations. We find that both hdac3 and hdac1 mutations are dominant suppressors of position effect variegation, suggesting functional overlap in heterochromatin regulation. However, all five hdac3 loss-of-function alleles are recessive lethal during larval/pupal stages, indicating that HDAC3 is essential on its own for Drosophila development. The mutant larvae display small imaginal discs, which result from abnormally elevated levels of apoptosis. This cell death occurs as a cell-autonomous response to HDAC3 loss and is accompanied by increased expression of the pro-apoptotic gene, hid. In contrast, although HDAC1 mutants also display small imaginal discs, this appears to result from reduced proliferation rather than from elevated apoptosis. The connection between HDAC loss and apoptosis is important since HDAC inhibitors show anticancer activities in animal models through mechanisms involving apoptotic induction. However, the specific HDACs implicated in tumor cell killing have not been identified. Our results indicate that protein deacetylation by HDAC3 plays a key role in suppression of apoptosis in Drosophila imaginal tissue

Pleiotropy between neuroticism and physical and mental health:Findings from 108 038 men and women in UK Biobank

People with higher levels of neuroticism have an increased risk of several types of mental disorder. Higher neuroticism has also been associated, less consistently, with increased risk of various physical health outcomes. We hypothesised that these associations may, in part, be due to shared genetic influences. We tested for pleiotropy between neuroticism and 17 mental and physical diseases or health traits using linkage disequilibrium regression and polygenic profile scoring. Genetic correlations were derived between neuroticism scores in 108 038 people in UK Biobank and health-related measures from 14 large genome-wide association studies (GWAS). Summary information for the 17 GWAS was used to create polygenic risk scores for the health-related measures in the UK Biobank participants. Associations between the health-related polygenic scores and neuroticism were examined using regression, adjusting for age, sex, genotyping batch, genotyping array, assessment centre, and population stratification. Genetic correlations were identified between neuroticism and anorexia nervosa (rg = 0.17), major depressive disorder (rg = 0.66) and schizophrenia (rg = 0.21). Polygenic risk for several health-related measures were associated with neuroticism, in a positive direction in the case of bipolar disorder, borderline personality, major depressive disorder , negative affect , neuroticism (Genetics of Personality Consortium), schizophrenia , and coronary artery disease , and smoking (β between 0.009 – 0.043) and in a negative direction in the case of BMI (β = -0.0095). A high level of pleiotropy exists between neuroticism and some measures of mental and physical health, particularly major depressive disorder and schizophrenia

The Epistemic Goal of a Concept: Accounting for the Rationality of Semantic Change and Variation

The discussion presents a framework of concepts that is intended to account for the rationality of semantic change and variation, suggesting that each scientific concept consists of three components of content: 1) reference, 2) inferential role, and 3) the epistemic goal pursued with the concept’s use. I argue that in the course of history a concept can change in any of these components, and that change in the concept’s inferential role and reference can be accounted for as being rational relative to the third component, the concept’s epistemic goal. This framework is illustrated and defended by application to the history of the gene concept. It is explained how the molecular gene concept grew rationally out of the classical gene concept despite a change in reference, and why the use and reference of the contemporary molecular gene concept may legitimately vary from context to context