Biology subjects

Coulter, A.

Publications and source records attributed to Coulter, A..

4 recordsLinked to original sources

bioRxiv2025

Generating 3D Models of Carbohydrates with GLYCAM-Web

The carbohydrate 3D structure-prediction tools (builders) at GLYCAM-Web (glycam.org) are widely used for generating experimentally-consistent 3D structures of oligosaccharides suitable for data interpretation, hypothesis generation, simple visualization, and subsequent molecular dynamics (MD) simulation. The graphical user interface (GUI) enables users to create carbohydrate sequences (e.g. DGalpb1-4DGlcpb1-OH) that are converted to 3D models of the carbohydrate structures in multiple formats, including PDB and OFF (AMBER software format). The resulting structures are energy minimized prior to download and online visualization. There are advanced options for selecting which shapes (rotamers) of the oligosaccharide to generate, and for creating explicitly solvated structures for subsequent MD simulation. The GLYCAM-Web builders integrate known conformational preferences of oligosaccharides, summarized here, and employ the GLYCAM forcefield for energy minimization with algorithms tailored for speed and scalability. Even for large oligosaccharides (100 residues, ~2100 atoms) a 3D structure is typically returned to the user in less than a minute.

biophysics↗

bioRxiv2025

distQTL: Distribution Quantitative Trait Loci Identification by Population-Scale Single-Cell Data

Mapping expression quantitative trait loci (eQTLs) is a powerful method to study how genetic variation influences gene expression. Traditional bulk eQTL methods rely on averaged gene expression across a possibly heterogeneous mixture of cells, which can obscure underlying regulatory heterogeneity. Single-cell eQTL methods circumvent the averaging artifacts, providing an immense opportunity to interrogate transcriptional regulation at a much finer resolution. Recent developments in metric space regression methods allow the use of full empirical distributions as response objects instead of simple summary statistics such as mean. Here, we leverage Frechet regression to identify distribution QTLs (distQTLs) using population-scale single-cell RNA sequencing data. We apply distQTL to the OneK1K cohort, consisting of scRNA-seq data of peripheral blood mononuclear cells from 982 donors, and compare results to various eQTL approaches based on summary statistics and mixed effects modeling. We demonstrate the superior performance of distQTL across different gene expression contexts compared to other methods and benchmark our results against findings from the Genotype-Tissue Expression Project. Finally, we orthogonally validate calls from distQTL using cell-type-specific epigenomic profiles.

genomics↗

bioRxiv2024

WHAMM functions in kidney reabsorption and polymerizes actin to promote autophagosomal membrane closure and cargo sequestration

The actin cytoskeleton is essential for many functions of eukaryotic cells, but the factors that nucleate actin assembly are not well understood at the organismal level or in the context of disease. To explore the function of the actin nucleation factor WHAMM in mice, we examined how Whamm inactivation impacts kidney physiology and cellular proteostasis. We show that male WHAMM knockout mice excrete elevated levels of albumin, glucose, phosphate, and amino acids, and display abnormalities of the kidney proximal tubule, suggesting that WHAMM activity is important for nutrient reabsorption. In kidney tissue, the loss of WHAMM results in the accumulation of the lipidated autophagosomal membrane protein LC3, indicating an alteration in autophagy. In mouse fibroblasts and human proximal tubule cells, WHAMM and its binding partner the Arp2/3 complex control autophagic membrane closure and cargo receptor recruitment. These results reveal a role for WHAMM-mediated actin assembly in maintaining kidney function and promoting proper autophagosome membrane remodeling.

cell biology↗

bioRxiv2020

Monocyte Subsets with High Osteoclastogenic Potential and Their Epigenetic Regulation Orchestrated by IRF8

Osteoclasts (OCs) are bone resorbing cells formed by the serial fusion of monocytes. In mice and humans, three distinct subsets of monocytes exist; however, it is unclear if all of them exhibit osteoclastogenic potential. Here we show that in wild-type mice, Ly6Chi and Ly6Cint monocytes are the primary source of OC formation when compared to Ly6C- monocytes. Their osteoclastogenic potential is dictated by increased expression of signaling receptors and activation of pre-established transcripts, as well as de novo gain in enhancer activity and promoter changes. In the absence of IRF8, a transcription factor important for myelopoiesis and osteoclastogenesis, all three monocyte subsets are programmed to display higher osteoclastogenic potential. Enhanced NFATc1 nuclear translocation and amplified transcriptomic and epigenetic changes initiated at early developmental stages direct the increased osteoclastogenesis in Irf8 deficient mice. Collectively, our study provides novel insights into the transcription factors and active cis-regulatory elements that regulate OC differentiation.

immunology↗