Voltage imaging reveals the dynamic electrical signatures of human breast cancer cells.

Cancer cells feature a resting membrane potential (V) that is depolarized compared to normal cells, and express active ionic conductances, which factor directly in their pathophysiological behavior. Despite similarities to 'excitable' tissues, relatively little is known about cancer cell V dynamics. Here high-throughput, cellular-resolution V imaging reveals that V fluctuates dynamically in several breast cancer cell lines compared to non-cancerous MCF-10A cells.

Intrinsic bias estimation for improved analysis of bulk and single-cell chromatin accessibility profiles using SELMA.

Genome-wide profiling of chromatin accessibility by DNase-seq or ATAC-seq has been widely used to identify regulatory DNA elements and transcription factor binding sites. However, enzymatic DNA cleavage exhibits intrinsic sequence biases that confound chromatin accessibility profiling data analysis. Existing computational tools are limited in their ability to account for such intrinsic biases and not designed for analyzing single-cell data.

NETISCE: a network-based tool for cell fate reprogramming.

The search for effective therapeutic targets in fields like regenerative medicine and cancer research has generated interest in cell fate reprogramming. This cellular reprogramming paradigm can drive cells to a desired target state from any initial state. However, methods for identifying reprogramming targets remain limited for biological systems that lack large sets of experimental data or a dynamical characterization.

Metastatic Transition of Pancreatic Ductal Cell Adenocarcinoma Is Accompanied by the Emergence of Pro-Invasive Cancer-Associated Fibroblasts.

Cancer-associated fibroblasts (CAFs) are now appreciated as key regulators of cancer metastasis, particularly in cancers with high stromal content, e.g., pancreatic ductal cell carcinoma (PDAC).

Optogenetic manipulation of cardiac electrical dynamics using sub-threshold illumination: dissecting the role of cardiac alternans in terminating rapid rhythms.

Cardiac action potential (AP) shape and propagation are regulated by several key dynamic factors such as ion channel recovery and intracellular Ca cycling. Experimental methods for manipulating AP electrical dynamics commonly use ion channel inhibitors that lack spatial and temporal specificity. In this work, we propose an approach based on optogenetics to manipulate cardiac electrical activity employing a light-modulated depolarizing current with intensities that are too low to elicit APs (sub-threshold illumination), but are sufficient to fine-tune AP electrical dynamics.

Distinct MUNC lncRNA structural domains regulate transcription of different promyogenic factors.

Many lncRNAs have been discovered using transcriptomic data; however, it is unclear what fraction of lncRNAs is functional and what structural properties affect their phenotype. MUNC lncRNA (also known as eRNA) acts as an enhancer RNA for the Myod1 gene in cis and stimulates the expression of other promyogenic genes in trans by recruiting the cohesin complex. Here, experimental probing of the RNA structure revealed that MUNC contains multiple structural domains not detected by prediction algorithms in the absence of experimental information.

Tracing the cis-regulatory changes underlying the endometrial control of placental invasion.

Among eutherian (placental) mammals, placental embedding into the maternal endometrium exhibits great differences, from being deeply invasive (e.g., humans) to noninvasive (e.

A model of actin-driven endocytosis explains differences of endocytic motility in budding and fission yeast.

A comparative study (Sun , 2019) showed that the abundance of proteins at sites of endocytosis in fission and budding yeast is more similar in the two species than previously thought, yet membrane invaginations in fission yeast elongate twofold faster and are nearly twice as long as in budding yeast. Here we use a three-dimensional model of a motile endocytic invagination (Nickaeen , 2019) to investigate factors affecting elongation of the invaginations. We found that differences in turgor pressure in the two yeast species can largely explain the paradoxical differences observed experimentally in endocytic motility.

Understanding Lactobacillus paracasei and Streptococcus oralis Biofilm Interactions through Agent-Based Modeling.

As common commensals residing on mucosal tissues, species are known to promote health, while some Streptococcus species act to enhance the pathogenicity of other organisms in those environments. In this study, we used a combination of imaging of live biofilms and computational modeling to explore biofilm interactions between Streptococcus oralis, an accessory pathogen in oral candidiasis, and Lactobacillus paracasei, an organism with known probiotic properties. A computational agent-based model was created where the two species interact only by competing for space, oxygen and glucose.

Training a deep learning model for single-cell segmentation without manual annotation.

Advances in the artificial neural network have made machine learning techniques increasingly more important in image analysis tasks. Recently, convolutional neural networks (CNN) have been applied to the problem of cell segmentation from microscopy images. However, previous methods used a supervised training paradigm in order to create an accurate segmentation model.

dosage compensation is mediated by miRNA-transcription factor interactions in aneuploid cancer.

We hypothesize that dosage compensation of critical genes arises from systems-level properties for cancer cells to withstand the negative effects of aneuploidy. We identified several candidate genes in cancer multiomics data and developed a biocomputational platform to construct a mathematical model of their interaction network with micro-RNAs and transcription factors, where the property of dosage compensation emerged for and was dependent on the kinetic parameters of its feedback interactions with three micro-RNAs. These circuits were experimentally validated using a genetic tug-of-war technique to overexpress an exogenous , leading to overexpression of the three microRNAs involved and downregulation of endogenous In addition, overexpression or inhibition of its compensating miRNAs led to dosage-dependent cytotoxicity in -amplified colon cancer cells.

Novel Optics-Based Approaches for Cardiac Electrophysiology: A Review.

Optical techniques for recording and manipulating cellular electrophysiology have advanced rapidly in just a few decades. These developments allow for the analysis of cardiac cellular dynamics at multiple scales while largely overcoming the drawbacks associated with the use of electrodes. The recent advent of optogenetics opens up new possibilities for regional and tissue-level electrophysiological control and hold promise for future novel clinical applications.

UBR7 acts as a histone chaperone for post-nucleosomal histone H3.

Histone chaperones modulate the stability of histones beginning from histone synthesis, through incorporation into DNA, and during recycling during transcription and replication. Following histone removal from DNA, chaperones regulate histone storage and degradation. Here, we demonstrate that UBR7 is a histone H3.

Differential adhesion regulates neurite placement via a retrograde zippering mechanism.

During development, neurites and synapses segregate into specific neighborhoods or layers within nerve bundles. The developmental programs guiding placement of neurites in specific layers, and hence their incorporation into specific circuits, are not well understood. We implement novel imaging methods and quantitative models to document the embryonic development of the brain neuropil and discover that differential adhesion mechanisms control precise placement of single neurites onto specific layers.

Fast Optical Investigation of Cardiac Electrophysiology by Parallel Detection in Multiwell Plates.

Current techniques for fast characterization of cardiac electrophysiology employ optical technologies to control and monitor action potential features of single cells or cellular monolayers placed in multiwell plates. High-speed investigation capacities are commonly achieved by serially analyzing well after well employing fully automated fluorescence microscopes. Here, we describe an alternative cost-effective optical approach (MULTIPLE) that exploits high-power LED arrays to globally illuminate a culture plate and an sCMOS sensor for parallel detection of the fluorescence coming from multiple wells.

Hyperexcitable Phenotypes in Induced Pluripotent Stem Cell-Derived Neurons From Patients With 15q11-q13 Duplication Syndrome, a Genetic Form of Autism.

Background: Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurogenetic disorder caused by duplications of the maternal copy of this region. In addition to hypotonia, motor deficits, and language impairments, patients with Dup15q commonly meet the criteria for autism spectrum disorder and have a high prevalence of seizures. It is known from mouse models that synaptic impairments are a strong component of Dup15q pathophysiology; however, cellular phenotypes that relate to seizures are less clear.

Mechanism of actin filament nucleation.

We used computational methods to analyze the mechanism of actin filament nucleation. We assumed a pathway where monomers form dimers, trimers, and tetramers that then elongate to form filaments but also considered other pathways. We aimed to identify the rate constants for these reactions that best fit experimental measurements of polymerization time courses.

A Complete and Low-Cost Cardiac Optical Mapping System in Translational Animal Models.

Clinicians, biologists, physicists, engineers, and computer scientists are coming together to better understand heart disease, which is currently the leading cause of death globally. Optical mapping, a high-speed fluorescence imaging technique that visualizes and measures key cardiac parameters such as action potentials, cytosolic calcium transients, and fibrillation dynamics, is a core research tool that has arisen from such interdisciplinary collaborations. In an effort to broaden its use, especially among clinical scientists and students, we developed a complete and low-cost optical mapping system, including a constant-flow Langendorff perfusion system, which minimizes the economic threshold to widespread use of this powerful tool in cardiac electrophysiology research.

The solubility product extends the buffering concept to heterotypic biomolecular condensates.

Biomolecular condensates are formed by liquid-liquid phase separation (LLPS) of multivalent molecules. LLPS from a single ("homotypic") constituent is governed by buffering: above a threshold, free monomer concentration is clamped, with all added molecules entering the condensed phase. However, both experiment and theory demonstrate that buffering fails for the concentration dependence of multicomponent ("heterotypic") LLPS.

RunBioSimulations: an extensible web application that simulates a wide range of computational modeling frameworks, algorithms, and formats.

Comprehensive, predictive computational models have significant potential for science, bioengineering, and medicine. One promising way to achieve more predictive models is to combine submodels of multiple subsystems. To capture the multiple scales of biology, these submodels will likely require multiple modeling frameworks and simulation algorithms.

Ten steps to investigate a cellular system with mathematical modeling.

Cellular and intracellular processes are inherently complex due to the large number of components and interactions, which are often nonlinear and occur at different spatiotemporal scales. Because of this complexity, mathematical modeling is increasingly used to simulate such systems and perform experiments in silico, many orders of magnitude faster than real experiments and often at a higher spatiotemporal resolution. In this article, we will focus on the generic modeling process and illustrate it with an example model of membrane lipid turnover.