Bound States and the Special Composition Question

The Special Composition Question asks under what conditions a plurality of objects form another, composite object. We propose a condition grounded in our scientific knowledge of physical reality, the essence of which is that objects form a composite object when and only when they are in a bound state – whence our Bound State Proposal. We provide a variety of reasons in favour of a mereological theory that accommodates our Proposal. We consider but reject another proposal, which is quantum-physical in nature: the Entanglement Proposal. We close by responding to Teller’s ‘Suit Objection’

Gene Regulation in the Pi Calculus: Simulating Cooperativity at the Lambda Switch

Part of the Lecture Notes in Computer Science book series (LNCS, volume 4230).Also part of the Lecture Notes in Bioinformatics book sub series (volume 4230).International audienceWe propose to model the dynamics of gene regulatory networks as concurrent processes in the stochastic pi calculus. As a first case study, we show how to express the control of transcription initiation at the lambda switch, a prototypical example where cooperative enhancement is crucial. This requires concurrent programming techniques that are new to systems biology, and necessitates stochastic parameters that we derive from the literature. We test all components of our model by exhaustive stochastic simulations. A comparison with previous results reported in the literature, experimental and simulation based, confirms the appropriateness of our modeling approach

Multi-ancestry transcriptome-wide association analyses yield insights into tobacco use biology and drug repurposing

Most transcriptome-wide association studies (TWASs) so far focus on European ancestry and lack diversity. To overcome this limitation, we aggregated genome-wide association study (GWAS) summary statistics, whole-genome sequences and expression quantitative trait locus (eQTL) data from diverse ancestries. We developed a new approach, TESLA (multi-ancestry integrative study using an optimal linear combination of association statistics), to integrate an eQTL dataset with a multi-ancestry GWAS. By exploiting shared phenotypic effects between ancestries and accommodating potential effect heterogeneities, TESLA improves power over other TWAS methods. When applied to tobacco use phenotypes, TESLA identified 273 new genes, up to 55% more compared with alternative TWAS methods. These hits and subsequent fine mapping using TESLA point to target genes with biological relevance. In silico drug-repurposing analyses highlight several drugs with known efficacy, including dextromethorphan and galantamine, and new drugs such as muscle relaxants that may be repurposed for treating nicotine addiction

Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD