Identification of novel genes associated with longevity in Drosophila melanogaster - a computational approach

Despite a growing number of studies on longevity in Drosophila, genetic factors influencing lifespan are still poorly understood. In this paper we propose a conceptually new approach for the identification of novel longevity-associated genes and potential target genes for SNPs in non-coding regions by utilizing the knowledge of co-location of various loci, governed by the three-dimensional architecture of the Drosophila genome. Firstly, we created networks between genes/genomic regions harboring SNPs deemed to be significant in two longevity GWAS summary statistics datasets using intra- and inter-chromosomal interaction frequencies (Hi-C data) as a measure of co-location. These networks were further extended to include regions strongly interacting with previously selected regions. Using various network measures, literature search and additional bioinformatics resources, we investigated the plausibility of genes found to have genuine association with longevity. Several of the newly identified genes were common between the two GWAS datasets and these possessed human orthologs. We also found that the proportion of non-coding SNPs in borders between topologically associated domains is significantly higher than expected by chance. Assuming co-location, we investigated potential target genes for non-coding SNPs. This approach therefore offers a stepping stone to identification of novel genes and SNP targets linked to human longevity

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5- HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5- HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in theGPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5- HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain

In re: ‘Experimental Music’

John Cage is universally associated with the phrase experimental music. But what did that phrase mean, for Cage and for Cage’s predecessors? I begin with Cage and Lejaren Hiller, both writing important texts on ‘experimental music’ in 1959. From there, I trace the phrase backwards, eventually reaching Emile Zola, Gertrude Stein, and William James. A final section traces the phrase forward to Cage and Hiller’s collaboration on HPSCHD (1969)

‘Capacity for what? Capacity for whom?’ A decolonial deconstruction of research capacity development practices in the Global South and a proposal for a value-centred approach

Whilst North to South knowledge transfer patterns have been extensively problematised by Southern and decolonial perspectives, there is very little reflection on the practice of research capacity development (RCD), still strongly focused on technoscientific solutionism, yet largely uncritical of its underlying normative directions and power asymmetries. Without making transparent these normative and epistemological dimensions, RCD practices will continue to perpetuate approaches that are likely to be narrow, technocratic and unreflexive of colonial legacies, thus failing to achieve the aims of RCD, namely, the equitable and development-oriented production of knowledge in low- and middle-income societies. Informed by the authors’ direct experience of RCD approaches and combining insights from decolonial works and other perspectives from the margins with Science and Technology Studies, the paper undertakes a normative and epistemological deconstruction of RCD mainstream practice. Highlighting asymmetries of power and material resources in knowledge production, the paper’s decolonial lens seeks to aid the planning, implementation and evaluation of RCD interventions. Principles of cognitive justice and epistemic pluralism, accessibility enabled by systems thinking and sustainability grounded on localisation are suggested as the building blocks for more reflexive and equitable policies that promote research capacity for the purpose of creating social value and not solely for the sake of perpetuating technoscience

Fertility Regulation

In the past two centuries the proportion of couples using some form of conscious pregnancy-prevention has risen from close to zero to about two-thirds. In European populations this radical change in behaviour occurred largely between 1870 and 1930 without the benefit of highly effective methods. In Asia, Africa and Latin America, the change took place after 1950 since when the global fertility rate has halved from 5.0 births to 2.5 births per woman. In this chapter we describe the controversies surrounding the idea of birth control and the role of early pioneers such as Margaret Sanger; the advances in contraceptive and abortion technologies; the ways in which family planning has been promoted by many governments, particularly in Asia; trends in use of specific methods; the problems of discontinuation of use; and the incidence of unintended pregnancies and abortions

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article