Nature of barriers determines first passage times in heterogeneous media.

Intuition suggests that passage times across a region increase with the number of barriers along the path. Can this fail depending on the nature of the barrier? To probe this fundamental question, we exactly solve for the first passage time in general -dimensions for diffusive transport through a spatially patterned array of obstacles - either entropic or energetic, depending on the nature of the obstacles. For energetic barriers, we show that first passage times vary non-monotonically with the number of barriers, while for entropic barriers it increases monotonically.

Theoretical analysis of cargo transport by catch bonded motors in optical trapping assays.

Dynein motors exhibit catch bonding, where the unbinding rate of the motors from microtubule filaments decreases with increasing opposing load. The implications of this catch bond on the transport properties of dynein-driven cargo are yet to be fully understood. In this context, optical trapping assays constitute an important means of accurately measuring the forces generated by molecular motor proteins.

Pan-cancer landscape of epigenetic factor expression predicts tumor outcome.

Oncogenic pathways that drive cancer progression reflect both genetic changes and epigenetic regulation. Here we stratified primary tumors from each of 24 TCGA adult cancer types based on the gene expression patterns of epigenetic factors (epifactors). The tumors for five cancer types (ACC, KIRC, LGG, LIHC, and LUAD) separated into two robust clusters that were better than grade or epithelial-to-mesenchymal transition in predicting clinical outcomes.

Anomalous diffusion of under microfluidic confinement and chemical gradient.

We report a two-layer microfluidic device to study the combined effect of confinement and chemical gradient on the motility of wild-type . We track individual in 50 μm and 10 μm wide microchannels, with a channel height of 2 μm, to generate quasi-2D conditions. We find that contrary to expectations, bacterial trajectories are superdiffusive even in the absence of a chemical (glucose) gradient.

Dynamic modelling predicts lactate and IL-1β as interventional targets in metabolic-inflammation-clock regulatory loop in glioma.

In an attempt to understand the role of dysregulated circadian rhythm in glioma, our recent findings highlighted the existence of a feed-forward loop between tumour metabolite lactate, pro-inflammatory cytokine IL-1β and circadian CLOCK. To further elucidate the implication of this complex interplay, we developed a mathematical model that quantitatively describes this lactate dehydrogenase A (LDHA)-IL-1β-CLOCK/BMAL1 circuit and predicts potential therapeutic targets. The model was calibrated on quantitative western blotting data in two glioma cell lines in response to either lactate inhibition or IL-1β stimulation.

Predicting scale-dependent chromatin polymer properties from systematic coarse-graining.

Simulating chromatin is crucial for predicting genome organization and dynamics. Although coarse-grained bead-spring polymer models are commonly used to describe chromatin, the relevant bead dimensions, elastic properties, and the nature of inter-bead potentials are unknown. Using nucleosome-resolution contact probability (Micro-C) data, we systematically coarse-grain chromatin and predict quantities essential for polymer representation of chromatin.

Screen time: an unbiased search for histone mutations that affect quiescence and chronological aging.

Quiescence, reversible cell cycle arrest, is essential for survival during nutrient limitations and the execution of precise developmental patterns. In yeast, entry into quiescence is associated with a loss of histone acetylation as the chromatin becomes tightly condensed. In this issue, Small and Osley performed an unbiased screen of mutations in histone H3 and H4 amino acids in budding yeast and identified histone residues that are critical for quiescence and chronological lifespan.

Multivalent binding proteins can drive collapse and reswelling of chromatin in confinement.

Collapsed conformations of chromatin have been long suspected of being mediated by interactions with multivalent binding proteins, which can bring together distant sections of the chromatin fiber. In this study, we use Langevin dynamics simulation of a coarse grained chromatin polymer to show that the role of binding proteins can be more nuanced than previously suspected. In particular, for chromatin polymer in confinement, entropic forces can drive reswelling of collapsed chromatin with increasing binder concentrations, and this reswelling transition happens at physiologically relevant binder concentrations.

Pseudocleavage furrows restrict plasma membrane-associated PH domain in syncytial Drosophila embryos.

Syncytial cells contain multiple nuclei and have local distribution and function of cellular components despite being synthesized in a common cytoplasm. The syncytial Drosophila blastoderm embryo shows reduced spread of organelle and plasma membrane-associated proteins between adjacent nucleo-cytoplasmic domains. Anchoring to the cytoarchitecture within a nucleo-cytoplasmic domain is likely to decrease the spread of molecules; however, its role in restricting this spread has not been assessed.

Is There a Histone Code for Cellular Quiescence?

Many of the cells in our bodies are quiescent, that is, temporarily not dividing. Under certain physiological conditions such as during tissue repair and maintenance, quiescent cells receive the appropriate stimulus and are induced to enter the cell cycle. The ability of cells to successfully transition into and out of a quiescent state is crucial for many biological processes including wound healing, stem cell maintenance, and immunological responses.

Novel mechanism for oscillations in catchbonded motor-filament complexes.

Generation of mechanical oscillations is ubiquitous to a wide variety of intracellular processes, ranging from activity of muscle fibers to oscillations of the mitotic spindle. The activity of motors plays a vital role in maintaining the integrity of the mitotic spindle structure and generating spontaneous oscillations. Although the structural features and properties of the individual motors are well characterized, their implications on the functional behavior of motor-filament complexes are more involved.

Intron retention is a robust marker of intertumoral heterogeneity in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate of <8%. Unsupervised clustering of 76 PDAC patients based on intron retention (IR) events resulted in two clusters of tumors (IR-1 and IR-2). While gene expression-based clusters are not predictive of patient outcome in this cohort, the clusters we developed based on intron retention were associated with differences in progression-free interval.

The Accidental Ally: Nucleosome Barriers Can Accelerate Cohesin-Mediated Loop Formation in Chromatin.

An important question in the context of the three-dimensional organization of chromosomes is the mechanism of formation of large loops between distant basepairs. Recent experiments suggest that the formation of loops might be mediated by loop extrusion factor proteins such as cohesin. Experiments on cohesin have shown that cohesins walk diffusively on the DNA and that nucleosomes act as obstacles to the diffusion, lowering the permeability and hence reducing the effective diffusion constant.

Cyto-architecture constrains the spread of photoactivated tubulin in the syncytial Drosophila embryo.

Drosophila embryogenesis begins with nuclear division in a common cytoplasm forming a syncytial cell. Morphogen gradient molecules spread across nucleo-cytoplasmic domains to pattern the body axis of the syncytial embryo. The diffusion of molecules across the syncytial nucleo-cytoplasmic domains is potentially constrained by association with the components of cellular architecture.

A Lamin-Associated Chromatin Model for Chromosome Organization.

We propose a simple model for chromatin organization based on the interaction of the chromatin fibers with lamin proteins along the nuclear membrane. Lamin proteins are known to be a major factor that influences chromatin organization and hence gene expression in the cells. We provide a quantitative understanding of lamin-associated chromatin organization in a crowded macromolecular environment by systematically varying the heteropolymer segment distribution and the strength of the lamin-chromatin attractive interaction.

Splicing Busts a Move: Isoform Switching Regulates Migration.

Cell migration is essential for normal development, neural patterning, pathogen eradication, and cancer metastasis. Pre-mRNA processing events such as alternative splicing and alternative polyadenylation result in greater transcript and protein diversity as well as function and activity. A critical role for alternative pre-mRNA processing in cell migration has emerged in axon outgrowth during neuronal development, immune cell migration, and cancer metastasis.

Alternative polyadenylation factors link cell cycle to migration.

Background: In response to a wound, fibroblasts are activated to migrate toward the wound, to proliferate and to contribute to the wound healing process. We hypothesize that changes in pre-mRNA processing occurring as fibroblasts enter the proliferative cell cycle are also important for promoting their migration.

Results: RNA sequencing of fibroblasts induced into quiescence by contact inhibition reveals downregulation of genes involved in mRNA processing, including splicing and cleavage and polyadenylation factors.

Integrative analysis of the inter-tumoral heterogeneity of triple-negative breast cancer.

Triple-negative breast cancers (TNBC) lack estrogen and progesterone receptors and HER2 amplification, and are resistant to therapies that target these receptors. Tumors from TNBC patients are heterogeneous based on genetic variations, tumor histology, and clinical outcomes. We used high throughput genomic data for TNBC patients (n = 137) from TCGA to characterize inter-tumor heterogeneity.

RECK isoforms have opposing effects on cell migration.

Cell migration is a highly conserved process involving cytoskeletal reorganization and restructuring of the surrounding extracellular matrix. Although there are many studies describing mechanisms underlying cell motility, little has been reported about the contribution of alternative isoform use toward cell migration. Here, we investigated whether alternative isoform use can affect cell migration focusing on reversion-inducing-cysteine-rich protein with Kazal motifs (RECK), an established inhibitor of cell migration.

Reprogramming, oscillations and transdifferentiation in epigenetic landscapes.

Waddington's epigenetic landscape provides a phenomenological understanding of the cell differentiation pathways from the pluripotent to mature lineage-committed cell lines. In light of recent successes in the reverse programming process there has been significant interest in quantifying the underlying landscape picture through the mathematics of gene regulatory networks. We investigate the role of time delays arising from multi-step chemical reactions and epigenetic rearrangement on the cell differentiation landscape for a realistic two-gene regulatory network, consisting of self-promoting and mutually inhibiting genes.

Diffusion dynamics and steady states of systems of hard rods on a square lattice.

It is known from grand canonical simulations of a system of hard rods on two-dimensional lattices that an orientationally ordered nematic phase exists only when the length of the rods is at least seven. However, a recent microcanonical simulation with diffusion kinetics, conserving both total density and zero nematic order, reported the existence of a nematically phase-segregated steady state with interfaces in the diagonal direction for rods of length six [Phys. Rev.

Determining Genome-wide Transcript Decay Rates in Proliferating and Quiescent Human Fibroblasts.

Quiescence is a temporary, reversible state in which cells have ceased cell division, but retain the capacity to proliferate. Multiple studies, including ours, have demonstrated that quiescence is associated with widespread changes in gene expression. Some of these changes occur through changes in the level or activity of proliferation-associated transcription factors, such as E2F and MYC.

An In Vitro Model of Cellular Quiescence in Primary Human Dermal Fibroblasts.

Cellular quiescence is a reversible mode of cell cycle exit that allows cells and organisms to withstand unfavorable stress conditions. The factors that underlie the entry, exit, and maintenance of the quiescent state are crucial for understanding normal tissue development and function as well as pathological conditions such as chronic wound healing and cancer. In vitro models of quiescence have been used to understand the factors that contribute to quiescence under well-controlled experimental conditions.

RNAs that make a heart beat.

An increase in stress-associated microRNAs has been observed in the heart after an induced myocardial infarction. Liu and colleagues now demonstrate that one of these stress-associated microRNAs, , can regulate a component of the voltage-gated channel that mediates rapid outward efflux of potassium during an action potential. Aberrations in the potassium current have been associated with ventricular arrhythmia and heart disease.