Accounting for genetic effect heterogeneity in fine-mapping and improving power to detect gene-environment interactions with SharePro.

Classical gene-by-environment interaction (GxE) analysis can be used to characterize genetic effect heterogeneity but has a high multiple testing burden in the context of genome-wide association studies (GWAS). We adapt a colocalization method, SharePro, to account for effect heterogeneity in fine-mapping and identify candidates for GxE analysis with reduced multiple testing burden. SharePro demonstrates improved power for both fine-mapping and GxE analysis compared to existing methods as well as well-controlled false type I error in simulations.

C-H Activation of Pyridines by Boryl Pincer Complexes: Elucidation of Boryl-Directed C-H Oxidative Addition to Ir and Discovery of Transition Metal-Assisted Reductive Elimination from Boron at Rh.

Experimental and theoretical techniques were used to investigate the mechanism of pyridine C-H activation by diarylboryl/bis(phosphine) PBP pincer complexes of Ir. The critical intermediate (PBP)IrCO () contains a three-coordinate, Ir-bound boron that retains Lewis acidity in the perpendicular direction. Coordination of pyridine to this boron center in leads to fast insertion of Ir into the 2-CH bond of pyridine, providing a different topology of direction than the conventional directed C-H activation where both the directing group coordination and C-H activation happen at the same metal center.

Flash Communication: Rhodium Complexes of Acetamide-Derived PAlP Pincer.

The new alane/bis(phosphine) PAlP pincer-type ligands and have been prepared by protolysis reactions of -(diisopropylphoshino)acetamide with MeAl or EtAl in a 2:1 ratio. Upon reaction with a "RhCl" source and pyridine, gave rise to a (PAlP)RhMe(py) compound (), while led to the analogous hydride complex (PAlP)RhH(py) (), with a migration of the chloride from Rh to Al. and possess the shortest Rh-Al bonds to date.

Modular Ontologies for Genetically Modified People and their Bioethical Implications.

Participants in the long-running bioethical debate over human germline genetic modification (HGGM) tend to imagine future people abstractly and on the basis of conventionalized characteristics familiar from science fiction, such as intelligence, disease resistance and height. In order to distinguish these from scientifically meaningful terms like "phenotype" and "trait," this article proposes the term "persemes" to describe the units of difference for hypothetical people. In the HGGM debate, persemes are frequently conceptualized as similar, modular entities, like building blocks to be assembled into genetically modified people.

SharePro: an accurate and efficient genetic colocalization method accounting for multiple causal signals.

Motivation: Colocalization analysis is commonly used to assess whether two or more traits share the same genetic signals identified in genome-wide association studies (GWAS), and is important for prioritizing targets for functional follow-up of GWAS results. Existing colocalization methods can have suboptimal performance when there are multiple causal variants in one genomic locus.

Results: We propose SharePro to extend the COLOC framework for colocalization analysis.

Differential CpG methylation at Nnat in the early establishment of beta cell heterogeneity.

Aims/hypothesis: Beta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. These include a subpopulation of highly connected 'hub' cells, important for the propagation of intercellular Ca waves. Functional subpopulations have also been demonstrated in human beta cells, with an altered subtype distribution apparent in type 2 diabetes.

Silencing ANGPTL8 reduces mouse preadipocyte differentiation and insulin signaling.

ANGPTL8, expressed mainly in the liver and adipose tissue, regulates the activity of lipoprotein lipase (LPL) present in the extracellular space and triglyceride (TG) metabolism through its interaction with ANGPTL3 and ANGPTL4. Whether intracellular ANGPTL8 can also exert effects in tissues where it is expressed is uncertain. ANGPTL8 expression was low in preadipocytes and much increased during differentiation.

Heterogeneous effects on type 2 diabetes and cardiovascular outcomes of genetic variants and traits associated with fasting insulin.

Hyperinsulinemia is a complex and heterogeneous phenotype that characterizes molecular alterations that precede the development of type 2 diabetes (T2D). It results from a complex combination of molecular processes, including insulin secretion and insulin sensitivity, that differ between individuals. To better understand the physiology of hyperinsulinemia and ultimately T2D, we implemented a genetic approach grouping fasting insulin (FI)-associated genetic variants based on their molecular and phenotypic similarities.

Comparative proximity biotinylation implicates the small GTPase RAB18 in sterol mobilization and biosynthesis.

Loss of functional RAB18 causes the autosomal recessive condition Warburg Micro syndrome. To better understand this disease, we used proximity biotinylation to generate an inventory of potential RAB18 effectors. A restricted set of 28 RAB18 interactions were dependent on the binary RAB3GAP1-RAB3GAP2 RAB18-guanine nucleotide exchange factor complex.

Molecular phenotyping of single pancreatic islet leader beta cells by "Flash-Seq".

Aims: Spatially-organized increases in cytosolic Ca within pancreatic beta cells in the pancreatic islet underlie the stimulation of insulin secretion by high glucose. Recent data have revealed the existence of subpopulations of beta cells including "leaders" which initiate Ca waves. Whether leader cells possess unique molecular features, or localisation, is unknown.

Hepatic glycerol shunt and glycerol-3-phosphate phosphatase control liver metabolism and glucodetoxification under hyperglycemia.

Objective: Glycerol-3-phosphate (Gro3P) phosphatase (G3PP) hydrolyzes Gro3P to glycerol that exits the cell, thereby operating a "glycerol shunt", a metabolic pathway that we identified recently in mammalian cells. We have investigated the role of G3PP and the glycerol shunt in the regulation of glucose metabolism and lipogenesis in mouse liver.

Methods: We generated hepatocyte-specific G3PP-KO mice (LKO), by injecting AAV8-TBG-iCre to male G3PP mice.

Single-Cell RNA Sequencing Reveals a Role for Reactive Oxygen Species and Peroxiredoxins in Fatty Acid-Induced Rat β-Cell Proliferation.

The functional mass of insulin-secreting pancreatic β-cells expands to maintain glucose homeostasis in the face of nutrient excess, in part via replication of existing β-cells. Type 2 diabetes appears when these compensatory mechanisms fail. Nutrients including glucose and fatty acids are important contributors to the β-cell compensatory response, but their underlying mechanisms of action remain poorly understood.

Discriminating protein tags on a dsDNA construct using a Dual Nanopore Device.

We report Brownian dynamics simulation results with the specific goal to identify key parameters controlling the experimentally measurable characteristics of protein tags on a dsDNA construct translocating through a double nanopore setup. First, we validate the simulation scheme in silico by reproducing and explaining the physical origin of the asymmetric experimental dwell time distributions of the oligonucleotide flap markers on a 48 kbp long dsDNA at the left and the right pore. We study the effect of the electric field inside and beyond the pores, critical to discriminate the protein tags based on their effective charges and masses revealed through a generic power-law dependence of the average dwell time at each pore.

Glycerol-3-phosphate phosphatase operates a glycerol shunt in pancreatic β-cells that controls insulin secretion and metabolic stress.

Objective: The recently identified glycerol-3-phosphate (Gro3P) phosphatase (G3PP) in mammalian cells, encoded by the PGP gene, was shown to regulate glucose, lipid and energy metabolism by hydrolyzing Gro3P and to control glucose-stimulated insulin secretion (GSIS) in β-cells, in vitro. However, whether G3PP regulates β-cell function and insulin secretion in vivo is not known.

Methods: We now examined the role of G3PP in the control of insulin secretion in vivo, β-cell function and glucotoxicity in inducible β-cell specific G3PP-KO (BKO) mice.

Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples.

The Genetic Discrimination Observatory: confronting novel issues in genetic discrimination.

Genetic discrimination (GD) is the differential or unfair profiling of an individual on the basis of genetic data. This article summarizes the actions of the Genetic Discrimination Observatory (GDO) in addressing GD and recent developments in GD since late 2020. It shows how GD can take many forms in today's rapidly evolving society.

Science fiction authors' perspectives on human genetic engineering.

Participants in the human gene editing debate often consider examples from science fiction but have rarely engaged directly with the science fiction community as stakeholders. To understand how science fiction authors develop and spread their views on gene editing, we created an online questionnaire that was answered by 78 authors, including 71 who had previously written about genetic engineering. When asked which ethical issues science fiction should explore, respondents most frequently mentioned affordability, new social divisions, consent and unforeseen safety risks.