Quantifying cell cycle regulation by tissue crowding Monday, May 6, 2024 SIGNIFICANCE The correct regulation of cell proliferation is crucial for the emergence of collective cell behaviour during tissue morphogenesis, homeostasis and regeneration. Moreover, uncontrolled cell division often leads to tumour formation. Here, we propose a mathematical model of cell migration with cell cycle dynamics which accounts for density-dependent effects regulating cell cycle progression. Our model is capable of describing the spatiotemporal cell cycle dynamics observed during epithelial tissue expansion. By combining experimental data, Bayesian inference, and minimal modelling, we describe how each cell cycle phase depends on local cell density, and quantify the impact of tissue crowding on cell proliferation patterns. Read more
Spectral neural approximations for models of transcriptional dynamics Monday, May 6, 2024 The advent of high-throughput transcriptomics provides an opportunity to advance mechanistic understanding of transcriptional processes and their connections to cellular function at an unprecedented, genome-wide scale. These transcriptional systems, which involve discrete, stochastic events, are naturally modeled using Chemical Master Equations (CMEs), which can be solved for probability distributions to fit biophysical rates that govern system dynamics. While CME models have been used as standards in fluorescence transcriptomics for decades to analyze single species RNA distributions, there are often no closed-form solutions to CMEs that model multiple species, such as nascent and mature RNA transcript counts. Read more
Reconstruction of the real 3D shape of the SARS-CoV-2 virus Monday, May 6, 2024 The photographs of the SARS-CoV-2 virus taken by electron transmission microscopy and Cryo-electron microscopy provide only a 2D silhouette. The viruses appear to look like distorted circles. The present paper questions the real shape of the SARS-CoV-2 virus and makes an attempt to give an answer. Is this a general ellipsoid, a spheroid with rotational symmetry, a sphere, or something else? The answer requires the application of tools from three different disciplines, structural mechanics, microbiology, and statistics. Read more
A role for conformational changes in enzyme catalysis Friday, May 3, 2024 The role played by conformational changes in enzyme catalysis is controversial. In addition to examining specific enzymes, studying formal models can help identify the conditions under which conformational changes promote catalysis. Here, we present a model demonstrating how conformational changes can break a generic trade-off due to the conflicting requirements of successive steps in catalytic cycles, namely high specificity for the transition state to accelerate the chemical transformation and low affinity for the products to favor their release. Read more
OrganL: Dynamic Triangulation of Biomembranes using Curved Elements Friday, May 3, 2024 Our method provides a straightforward way to simulate any biomembrane geometry. It overcomes some of the limitations of previous dynamically triangulated surface (DTS) Monte Carlo schemes by providing a surface that contains an interpolant which allows to assign meaningful functions of curvature to almost every point of the discretization, yet keeps much of the simplicity of the common DTS schemes by not requiring any nonlocal information or iterations for its construction. Our tool is easily extensible and facilitates the simulation of complex lipid and protein compositions on membrane surfaces at any scale. Read more
Parkinson’s Disease-associated mutations in α-synuclein alters its lipid-bound state Thursday, May 2, 2024 Lipid binding properties of α-synuclein play a central role in protein aggregation and progression of Parkinson’s Disease (PD). α-Synuclein, an intrinsically disordered protein, binds to lipid membranes through the formation of two amphipathic helices that insert into the lipid bilayer. All disease-associated single point mutations have been identified to be within these helical regions of α-synuclein: V15A, A30P, E46K, H50Q, G51D, A53T, and A53V. However, the effects of these mutations on the bound states of the two α-helices of the protein have yet to be fully characterized. Read more
Fluorescence lifetime imaging microscopy of flexible and rigid dyes probes the biophysical properties of synthetic and biological membranes Thursday, May 2, 2024 Sensing of the biophysical properties of membranes using molecular reporters has recently regained wide-spread attention. This was elicited by the development of new probes of exquisite optical properties and increased performance, combined with developments in fluorescence detection. Here, we report on fluorescence lifetime imaging (FLIM) of various rigid and flexible fluorescent dyes to probe the biophysical properties of synthetic and biological membranes at steady state as well as upon the action of external membrane-modifying agents. Read more
Simulations predict preferred Mg2+ coordination in a nonenzymatic primer extension reaction center Wednesday, May 1, 2024 The mechanism by which genetic information was copied prior to the evolution of ribozymes is of great interest because of its importance to the origin of life. The most effective known process for the nonenzymatic copying of an RNA template is primer extension by a two-step pathway in which 2-aminoimidazole activated nucleotides first react with each other to form an imidazolium-bridged intermediate that subsequently reacts with the primer. Reaction kinetics, structure-activity relationships, and X-ray crystallography have provided insight into the overall reaction mechanism, but many puzzles remain. Read more
Protein Condensates in the Secretory Pathway: Deciphering Biophysical Interactions and Functional Significance Wednesday, May 1, 2024 The emergence of phase separation phenomena among macromolecules has identified biomolecular condensates as fundamental cellular organizers. These condensates concentrate specific components and accelerate biochemical reactions without relying on membrane boundaries. While extensive studies have revealed a large variety of nuclear and cytosolic membraneless organelles, we are witnessing a surge in the exploration of protein condensates associated with the membranes of the secretory pathway, such as the endoplasmic reticulum (ER) and the Golgi apparatus. Read more
Cryo-EM images of phase separated lipid bilayer vesicles analyzed with a machine learning approach Monday, April 29, 2024 Lateral lipid heterogeneity (i.e., raft formation) in biomembranes plays a functional role in living cells. Three-component mixtures of low- and high-melting lipids plus cholesterol offer a simplified experimental model for raft domains in which a liquid-disordered (Ld) phase coexists with a liquid-ordered (Lo) phase. Using such models, we recently showed that cryogenic electron microscopy (cryo-EM) can detect phase separation in lipid vesicles based on differences in bilayer thickness. However, the considerable noise within cryo-EM data poses a significant challenge for accurately determining the membrane phase state at high spatial resolution. Read more
Molecular simulations and NMR reveal how lipid fluctuations affect membrane mechanics Saturday, April 27, 2024 (Biophysical Journal 122, 984–1002; March 21, 2023) Read more
A bupropion modulatory site in Gloeobacter violaceus ligand-gated ion channel Friday, April 26, 2024 Bupropion is an atypical antidepressant and smoking cessation drug that causes adverse effects such as insomnia, irritability, and anxiety. Bupropion inhibits dopamine and norepinephrine reuptake transporters and eukaryotic cation-conducting pentameric ligand-gated ion channels (pLGICs), such as nicotinic acetylcholine (nACh) and serotonin type 3A (5-HT3A) receptors, at clinically relevant concentrations. Here, we demonstrate that bupropion also inhibits a prokaryotic homolog of pLGICs, the Gloeobacter violaceus ligand-gated ion channel (GLIC). Read more