ResearchPad - biophysics-and-computational-biology https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Understanding the computation of time using neural network models]]> https://www.researchpad.co/article/elastic_article_8305 To maximize future rewards in this ever-changing world, animals must be able to discover the temporal structure of stimuli and then anticipate or act correctly at the right time. How do animals perceive, maintain, and use time intervals ranging from hundreds of milliseconds to multiseconds in working memory? How is temporal information processed concurrently with spatial information and decision making? Why are there strong neuronal temporal signals in tasks in which temporal information is not required? A systematic understanding of the underlying neural mechanisms is still lacking. Here, we addressed these problems using supervised training of recurrent neural network models. We revealed that neural networks perceive elapsed time through state evolution along stereotypical trajectory, maintain time intervals in working memory in the monotonic increase or decrease of the firing rates of interval-tuned neurons, and compare or produce time intervals by scaling state evolution speed. Temporal and nontemporal information is coded in subspaces orthogonal with each other, and the state trajectories with time at different nontemporal information are quasiparallel and isomorphic. Such coding geometry facilitates the decoding generalizability of temporal and nontemporal information across each other. The network structure exhibits multiple feedforward sequences that mutually excite or inhibit depending on whether their preferences of nontemporal information are similar or not. We identified four factors that facilitate strong temporal signals in nontiming tasks, including the anticipation of coming events. Our work discloses fundamental computational principles of temporal processing, and it is supported by and gives predictions to a number of experimental phenomena.

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<![CDATA[Molecular dysregulation of ciliary polycystin-2 channels caused by variants in the TOP domain]]> https://www.researchpad.co/article/elastic_article_8269 Genetic variants in PKD2 which encodes for the polycystin-2 ion channel are responsible for many clinical cases of autosomal dominant polycystic kidney disease (ADPKD). Despite our strong understanding of the genetic basis of ADPKD, we do not know how most variants impact channel function. Polycystin-2 is found in organelle membranes, including the primary cilium—an antennae-like structure on the luminal side of the collecting duct. In this study, we focus on the structural and mechanistic regulation of polycystin-2 by its TOP domain—a site with unknown function that is commonly altered by missense variants. We use direct cilia electrophysiology, cryogenic electron microscopy, and superresolution imaging to determine that variants of the TOP domain finger 1 motif destabilizes the channel structure and impairs channel opening without altering cilia localization and channel assembly. Our findings support the channelopathy classification of PKD2 variants associated with ADPKD, where polycystin-2 channel dysregulation in the primary cilia may contribute to cystogenesis.

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<![CDATA[Quantitative analysis of amino acid metabolism in liver cancer links glutamate excretion to nucleotide synthesis]]> https://www.researchpad.co/article/elastic_article_8264 Many cancer cells consume glutamine at high rates; counterintuitively, they simultaneously excrete glutamate, the first intermediate in glutamine metabolism. Glutamine consumption has been linked to replenishment of tricarboxylic acid cycle (TCA) intermediates and synthesis of adenosine triphosphate (ATP), but the reason for glutamate excretion is unclear. Here, we dynamically profile the uptake and excretion fluxes of a liver cancer cell line (HepG2) and use genome-scale metabolic modeling for in-depth analysis. We find that up to 30% of the glutamine is metabolized in the cytosol, primarily for nucleotide synthesis, producing cytosolic glutamate. We hypothesize that excreting glutamate helps the cell to increase the nucleotide synthesis rate to sustain growth. Indeed, we show experimentally that partial inhibition of glutamate excretion reduces cell growth. Our integrative approach thus links glutamine addiction to glutamate excretion in cancer and points toward potential drug targets.

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<![CDATA[The microcircuits of striatum in silico]]> https://www.researchpad.co/article/Nb554bc96-b428-4c19-ba40-2736d903683b The basal ganglia play an important role in decision making and selection of action primarily based on input from cortex, thalamus, and the dopamine system. Their main input structure, striatum, is central to this process. It consists of two types of projection neurons, together representing 95% of the neurons, and 5% of interneurons, among which are the cholinergic, fast-spiking, and low threshold-spiking subtypes. The membrane properties, soma–dendritic shape, and intrastriatal and extrastriatal synaptic interactions of these neurons are quite well described in the mouse, and therefore they can be simulated in sufficient detail to capture their intrinsic properties, as well as the connectivity. We focus on simulation at the striatal cellular/microcircuit level, in which the molecular/subcellular and systems levels meet. We present a nearly full-scale model of the mouse striatum using available data on synaptic connectivity, cellular morphology, and electrophysiological properties to create a microcircuit mimicking the real network. A striatal volume is populated with reconstructed neuronal morphologies with appropriate cell densities, and then we connect neurons together based on appositions between neurites as possible synapses and constrain them further with available connectivity data. Moreover, we simulate a subset of the striatum involving 10,000 neurons, with input from cortex, thalamus, and the dopamine system, as a proof of principle. Simulation at this biological scale should serve as an invaluable tool to understand the mode of operation of this complex structure. This platform will be updated with new data and expanded to simulate the entire striatum.

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<![CDATA[Cavitation in soft matter]]> https://www.researchpad.co/article/Nd0a93384-098b-4855-abf9-29f74edc2c6d Cavitation is the sudden, unstable expansion of a void or bubble within a liquid or solid subjected to a negative hydrostatic stress. Cavitation rheology is a field emerging from the development of a suite of materials characterization, damage quantification, and therapeutic techniques that exploit the physical principles of cavitation. Cavitation rheology is inherently complex and broad in scope with wide-ranging applications in the biology, chemistry, materials, and mechanics communities. This perspective aims to drive collaboration among these communities and guide discussion by defining a common core of high-priority goals while highlighting emerging opportunities in the field of cavitation rheology. A brief overview of the mechanics and dynamics of cavitation in soft matter is presented. This overview is followed by a discussion of the overarching goals of cavitation rheology and an overview of common experimental techniques. The larger unmet needs and challenges of cavitation in soft matter are then presented alongside specific opportunities for researchers from different disciplines to contribute to the field.

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<![CDATA[Redefining the heterogeneity of peripheral nerve cells in health and autoimmunity]]> https://www.researchpad.co/article/Nf11306cd-b1fa-4dea-b8f8-c518a6d7fffd Peripheral nerves contain axons and their enwrapping glia cells named Schwann cells (SCs) that are either myelinating (mySCs) or nonmyelinating (nmSCs). Our understanding of other cells in the peripheral nervous system (PNS) remains limited. Here, we provide an unbiased single cell transcriptomic characterization of the nondiseased rodent PNS. We identified and independently confirmed markers of previously underappreciated nmSCs and nerve-associated fibroblasts. We also found and characterized two distinct populations of nerve-resident homeostatic myeloid cells that transcriptionally differed from central nervous system microglia. In a model of chronic autoimmune neuritis, homeostatic myeloid cells were outnumbered by infiltrating lymphocytes which modulated the local cell–cell interactome and induced a specific transcriptional response in glia cells. This response was partially shared between the peripheral and central nervous system glia, indicating common immunological features across different parts of the nervous system. Our study thus identifies subtypes and cell-type markers of PNS cells and a partially conserved autoimmunity module induced in glia cells.

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<![CDATA[Timing of fungal spore release dictates survival during atmospheric transport]]> https://www.researchpad.co/article/Na0cc59a5-8d25-472e-a2dc-3ff76238c271

Significance

Fungi move between habitats by dispersing small spores through the atmosphere. We ask what causes some species to release spores at a specific time every day versus irregularly. We find that timing of spore release dictates how long spores remain in the atmosphere before returning to the ground: Spores released at night are likely to travel for hours while spores released during the day may linger for days. Drivers are stronger in lower, warmer latitudes. Because spores in the open atmosphere are likely to die from prolonged exposure to light and air, the timing of spore release will impact survival. We have discovered a constraint likely to shape observed patterns of spore liberation.

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<![CDATA[The size of the immune repertoire of bacteria]]> https://www.researchpad.co/article/N0c3b499f-6252-4e1b-a5f5-d83ed90e6dc9

Significance

Some bacteria possess an adaptive immune system that maintains a memory of past viral infections in the CRISPR loci of their genomes. This memory is used to mount targeted responses against later threats but is remarkably shallow: it remembers only a few dozen to a few hundred viruses. We present a statistical theory of CRISPR-based immunity that quantitatively predicts the depth of bacterial immune memory in terms of a tradeoff with fundamental constraints of the cellular biochemical machinery.

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<![CDATA[Reply to Desikan et al.: Micelle formation among various mechanisms of toxin pore formation]]> https://www.researchpad.co/article/N3e03ad40-3463-4c70-8536-2142982aec93 ]]> <![CDATA[High-resolution structural insights into the heliorhodopsin family]]> https://www.researchpad.co/article/N6e0e3258-548d-4b6e-961c-781cae623f6d

Significance

We present high-resolution crystal structures of the bacterial heliorhodopsin 48C12, a representative of the recently discovered family of microbial rhodopsins. In opposite to all other rhodopsins, heliorhodopsins face the cytoplasm of the cells with their N termini. The structures of two different states of 48C12 reveal specific features of heliorhodopsins, such as existence of a water-filled cavity in the cytoplasmic side near the retinal Schiff base able to accommodate anions of triangular geometry, such as nitrate, carbonate, or acetate, and completely hydrophobic organization of the inner extracellular part of the protein. Hence, the structure gives important insights into possible functions of 48C12.

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<![CDATA[Polymeric sheet actuators with programmable bioinstructivity]]> https://www.researchpad.co/article/Nd028f086-20f0-4495-a9be-657db02cdd5b

Significance

Stem cells can be conceptualized as computational processors capable of sensing, processing, and converting environmental information (input) to yield a specific differentiation pathway (output). In this study, we employ a temperature-controlled polymer sheet actuator to interpret and transfer information, controlled by the material’s programming, to mesenchymal stem cells. The cell’s interpretation of mechanical, thermal, and biochemical signaling is shown to be dependent on the actuator’s activity, utilized to accelerate differentiation toward bone cells, further elucidating the role of microenvironmental parameters on mammalian cells. Our method provides a unique approach to processing two discrete stimuli into one biochemical signal, calcium ions, providing a basis for the logical control of the flow of biological signals and the design of cellular functions.

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<![CDATA[Biophysical principles of choanoflagellate self-organization]]> https://www.researchpad.co/article/Ne6e23b9f-b81c-411d-b5f7-2f1e4f9b298f

Significance

Comparisons among animals and their closest living relatives, the choanoflagellates, have begun to shed light on the origin of animal multicellularity and development. Here, we complement previous genetic perspectives on this process by focusing on the biophysical principles underlying choanoflagellate colony morphology and morphogenesis. Our study reveals the crucial role of the extracellular matrix in shaping the colonies and leads to a phase diagram that delineates the range of morphologies as a function of the biophysical mechanisms at play.

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<![CDATA[A compartment size-dependent selective threshold limits mutation accumulation in hierarchical tissues]]> https://www.researchpad.co/article/N620fd9b5-3010-4245-8b60-9006c44685db

Significance

Renewed tissues of multicellular organism accumulate mutations that lead to aging and cancer. To mitigate these effects, self-renewing tissues produce cells along differentiation hierarchies, which have been shown to suppress somatic evolution both by limiting the number of cell divisions, and thus reducing mutational load, and by differentiation “washing out” mutations. Our analytical results reveal the existence of a third mechanism: a compartment size-dependent threshold in proliferative advantage, below which mutations cannot persist, but are rapidly expelled from the tissue by differentiation. In sufficiently small compartments, the resulting selective barrier can greatly slow down somatic evolution and reduce the risk of cancer by preventing the accumulation of mutations even if even they confer substantial proliferative advantage.

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<![CDATA[Intermediate states of molecular self-assembly from liquid-cell electron microscopy]]> https://www.researchpad.co/article/Nea75eb2e-c25a-4a0c-a62a-aea6e19545c8

Significance

Graphene liquid-cell electron microscopy reveals intermediate states of self-assembly—in this example, DNA when single strands form double helices. Molecules are observed for up to minutes at a time without apparent beam damage when electron energy and electron dose are low. Simultaneous in situ single-molecule imaging of conformational adaptations and motion gives more comprehensive understanding of self-assembly successes, failures, and error-producing mechanisms, confirming some earlier predictions and also presenting surprises. Loop intermediates were observed to facilitate error correction. Hybridization events accompany enhanced translational mobility and mechanistically specific persistent rotation. The information obtained goes beyond that from other single-molecule methods.

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<![CDATA[Cooperation mitigates diversity loss in a spatially expanding microbial population]]> https://www.researchpad.co/article/Nfc3a672d-391a-47c7-9b6a-6f35b84c6977

Significance

Spatially expanding populations lose genetic diversity rapidly because of repeated bottlenecks formed at the colonization front. However, the rate of diversity loss depends on the specifics of the expanding population, such as its growth and dispersal dynamics. We have previously demonstrated that changing the amount of within-species cooperation leads to a qualitative transition in the nature of expansion from pulled (driven by growth at the low-density tip) to pushed (driven by migration from the high-density region at the front, but behind the tip). Here we demonstrate experimentally that pushed waves result in strongly reduced genetic drift during range expansions, thus preserving genetic diversity in the newly colonized region.

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<![CDATA[Markovian approaches to modeling intracellular reaction processes with molecular memory]]> https://www.researchpad.co/article/N5bc9cb86-31db-495a-95d5-6a5749800496

Significance

Modeling intracellular processes has long relied on the markovian assumption. However, as soon as a reactant interacts with its environment, molecular memory definitely exists and its effects cannot be neglected. Since the Markov theory cannot translate directly to modeling and analysis of nonmarkovian processes, this leads to many significant challenges. We develop a formulation, namely the stationary generalized chemical-master equation, to model intracellular processes with molecular memory. This formulation converts a nonmarkovian question to a markovian one while keeping the stationary probabilistic behavior unchanged. Both a stationary generalized Fokker–Planck equation and a generalized linear noise approximation are further developed for the fast evaluation of fluctuations. These formulations can have broad applications and may help us discover new biological knowledge.

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<![CDATA[SNARE machinery is optimized for ultrafast fusion]]> https://www.researchpad.co/article/5c8015bdd5eed0c484a9fa66

Significance

We propose a mechanistic description of fusion of a synaptic vesicle with a target membrane executed by a team of zippering SNARE complexes (SNAREpins). In the context of neurotransmitters release, this process naturally decomposes in two steps with rates that depend on the number of SNAREpins N. The first step is synchronized escape from the metastable half-zippered state, which gets exponentially more sluggish as N increases. The second step is fusion of two closely tethered membranes, which is accelerated exponentially by an increase of N. The tradeoff between these two antagonist trends results in a sharply optimal number of SNAREpins N=36, which ensures fusion at the physiological submillisecond timescale.

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<![CDATA[Differential growth and shape formation in plant organs]]> https://www.researchpad.co/article/5c26b51ad5eed0c484764b2d

Significance

Plant leaves and flower petals in nature exhibit a wide variety of complex 3D shapes. Formation of these shapes has largely been studied from genetic and biomolecular viewpoints, overlooking contributions from biophysical factors such as mechanical stress and deformation. By means of computational simulations and quantitative analyses of the growth strains in live plant organs, we develop fundamental mechanistic insights into how nature invokes mechanics in the evolution of four commonly found shapes in plant organs by differential growth. We also demonstrate how these common shapes can be synthetically reproduced in hydrogel using this mechanistic understanding. Our study provides a broad scientific framework for rationalizing plant organ morphogenesis, but also provides pathways for generating bioinspired 3D architectures in soft materials.

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<![CDATA[Bottom–up modeling of chromatin segregation due to epigenetic modifications]]> https://www.researchpad.co/article/5c26b3d5d5eed0c4847613fa

Significance

Predicting how epigenetic marks control the 3D organization of the genome is key to understanding how these marks regulate gene expression. We show that a physical model of a chromosome with experimentally measured local interactions segregates into euchromatin- and heterochromatin-like phases. The model reproduces many of the features of the large-scale organization of the chromosome as measured by Hi-C. Our work provides an estimate of the amount of epigenetic marking needed to segregate a gene into heterochromatin.

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<![CDATA[Structure and architecture of immature and mature murine leukemia virus capsids]]> https://www.researchpad.co/article/5c26b3d2d5eed0c484761377

Significance

Immature retroviruses are built by the Gag polyprotein; Gag is then cut into domains, and the resulting CA capsid proteins form the mature capsid, which can mediate infection of a new cell. Murine leukemia virus (MLV) is a model retrovirus and the basis for gene-delivery vectors. We determined the capsid structures and architectures for immature and mature MLV. The mature MLV core does not enclose the genome in a closed capsid by using only part of the available proteins, as is the case for HIV-1. Instead, it wraps the genome in curved sheets incorporating most CA proteins. Retroviruses therefore have fundamentally different modes of core assembly and genome protection, which may relate to differences in their early replication.

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