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Kaneko, K.

Publications and source records attributed to Kaneko, K..

At least 19 recordsLinked to original sources
bioRxiv2026

Adhesion and polarity-driven morphogenesis: Mechanismsand constraints in tissue formation

Embryonic development in multicellular organisms exhibits diverse morphogenetic patterns, which can generally be categorized into fundamental types such as monolayer and multilayer spheres, as well as cell masses. Furthermore, we identify two distinct processes for the formation of spherical structures. These basic patterns are thought to be governed by the microscopic properties of intercellular adhesion. However, the specific mechanisms linking the microscopic factors to the emergence of distinct macroscopic morphogenetic patterns remain poorly understood. In this study, we explore how different morphogenetic patterns arise by employing a computational model that incorporates intercellular adhesion and polarity. Our results demonstrate that all fundamental morphogenetic patterns can be generated through the interplay of two key parameters: the strength of cell polarity and the regulation of polarity via mechanical signals. Furthermore, analytical discussions reveal partial mechanisms underlying the formation of these patterns. These findings highlight the critical role of physical constraints in morphogenesis and suggest potential applications in the design principles for artificial tissues and organoids. Author summaryLiving organisms build their bodies through morphogenesis, during which cells autonomously arrange themselves into functional structures such as sheets, tubes, and spheres. From simple monolayered spheres to complex multilayered tissues organized by adhesion, it remains unclear how such diverse forms arise. Here, we mathematically modeled a population of proliferating cells governed only by two microscopic factors: the strength of polarity-dependent adhesion and the time scale at which polarity is regulated by cell-cell contact. Surprisingly, we found that this minimal model reproduces five basic morphological types observed in living embryos, including monolayer/multilayer structures and two distinct modes of cavity formation: by wrapping around or by inflating from the inside. Systematic simulations revealed that these macroscale outcomes are determined solely by two parameters controlling polarity strength and its regulation, suggesting that simple physical rules underlie diverse developmental architectures. Analysis of the model uncovers phase transitions between the five morphogenetic types and reveals how varying polarity and adhesion can recapitulate features of real embryogenesis. Our work proposes a unified framework that connects microscopic polarity mechanics to diverse developmental morphologies and provides a foundation for future applications in organoid design and tissue engineering.

biophysics↗
bioRxiv2026

Modeling Time to Visual Insight in Mooney Image Recognition with a Chaotic Recurrent Neural Network

Insight is often described as a sudden shift in or formation of a conceptual representation, enabling humans to restructure existing knowledge and solve problems beyond conventional analytical approaches. Although prior computational studies have modeled aspects of insight using deep neural networks (DNNs) or reinforcement learning, few have captured the dynamic emergence of insight through autonomous neural computation. Here, we present a neural network model that simulates the time required to reach visual insight in the Mooney image recognition task, a widely used paradigm for studying visual insight and perceptual reorganization. The model couples a DNN module for perceptual feature extraction with a recurrent neural network (RNN) that implements a chaotic search process for recognition. The RNN is formulated as a continuous-time dynamical system, autonomously explores internal states, and stabilizes when the missing visual features required for recognition are internally reconstructed. Using the same image set as in human psychophysical experiments, the model reproduces key statistical properties of human search times (STs), including (i) lognormal-like ST distributions across participants for each image, (ii) a proportional relationship between the log-scale mean and standard deviation estimated from lognormal fits across images, and (iii) discrete levels of the fitted log-scale mean across images (a proxy for image difficulty). Importantly, these properties emerge without assuming any lognormal distribution for participant-to-participant variability, whereas previous models reproduced similar signatures by positing lognormal-distributed individual differences. We further show that lognormal-like signatures can arise from exponential search dynamics when combined with both standard experimental preprocessing and finite observation windows, highlighting the need to distinguish generative mechanisms from measurement and analysis effects. Together, these results motivate a mechanistic link between chaotic neural dynamics and insight-related search and provide a computational framework for implementing insight in artificial systems.

neuroscience↗
bioRxiv2025

CD133+ Vesicles Mediate Resistance to RAS-ERK Inhibition Regulated by YAP Activation in Liver Cancer Cells

CD133, a pentaspan plasma membrane protein, has been viewed as a biomarker of stem cells in normal and cancer tissues, although its function and mechanism are unclear. In previous studies, we identified a new type of CD133+ intracellular vesicles, named intercellsome, which is implicated in direct cell-cell communication under stress conditions. However, the regulatory mechanism and biological significance of these CD133+ vesicles are largely unknown, highlighting a gap in understanding of this cellular communication mechanism. We show here that CD133 acts as a stress response marker in cancer cells, with its expression and vesicle formation significantly induced under MEK inhibitor-mediated proliferative stress. The CD133+ vesicles are essential for maintaining cell proliferation under stress conditions in vitro. Mechanistically, the MEKi activates the Hippo-YAP signaling pathway, which promotes CD133 transcription, establishing a novel connection between YAP signaling and CD133+ vesicle biogenesis. Further, CD133 plays a critical role in YAP-driven liver cancer progression in mice. This study defines a critical role of CD133+ vesicles in stress response regulated by YAP, which advances the understanding of CD133 functions beyond its stem cell-associated roles and suggests new avenues for therapeutic intervention of liver cancer relapse.

cancer biology↗
bioRxiv2025

Compositional selection of phospholipid compartments in icy environments drives the inheritance of encapsulated genetic information

The lipid world hypothesis proposes that both intracellular components and the chemical composition of the membrane compartment carry heritable information that contributes to protocellular fitness. However, there are few experimental demonstrations of membrane compositional selection and no study has shown that phospholipids--the primary membrane components of modern cells--can support selection of this type. As lipid compartments generally grow in size before fission, faster-growing compartments should enjoy a selective advantage that favors both the membrane itself and the contents it hosts. When situated in icy environments undergoing cycles of freezing and thawing (F/T), we found that the growth of phospholipid vesicles depends on their phospholipid composition: Vesicles with more unsaturated bonds in the acyl chain showed higher growth efficiency. When vesicles composed of lipids with either one or two unsaturated bonds were mixed and subjected to F/T cycles, a selective enrichment of the lipid with two unsaturated bonds was observed. Moreover, selection acting on lipid composition was propagated to the encapsulated genetic material, which was also enriched while selectively neutral. We conclude that phospholipid composition can be a direct target of selection for grown vesicles under an icy environment leading to indirect but concurrent enrichment of compartmentalized genetic molecules.

synthetic biology↗
bioRxiv2025

Superior colliculus coordinates whole-brain dynamics for sudden unconscious visual insight

The human capacity for sudden insight, often marked by abrupt and illuminating "eureka" moments, has long intrigued neuroscientists seeking to understand its elusive neural basis1-6. Mooney image recognition offers a compelling behavioral paradigm of this phenomenon, in which ambiguous black-and-white patterns are abruptly perceived as coherent objects7-13. Whole-brain cortical involvement, which is mainly revealed by the contrast between recognition and nonrecognition, is well established8,14-27. However, the neural dynamics underlying the transition from nonrecognition to recognition, particularly the contributions of noncortical structures, have remained largely unknown. Here, we show that the transition in whole-brain dynamics can be effectively characterized by three large-scale activity patterns and that the superior colliculus (SC) emerges as a structure with a distinct temporal profile that is potentially critical for insight. Using functional clustering of functional magnetic resonance imaging data comprising 41,446 time points from 14 human participants performing this insight task, we identified three distinct functional clusters exhibiting stimulus-driven activation, suppression, and recognition-associated patterns. Notably, the SC in the third cluster displayed a distinct activation peak immediately before the recognition response. Furthermore, empirical dynamic modeling revealed that the SC was the only region in the whole brain that exhibited mutual positive directed interactions with all three clusters and was functionally embedded within higher-order cortical interactions mediating the transformation from stimulus input to motor output. Our findings provide compelling experimental evidence that the SC plays a critical role in orchestrating whole-brain dynamics for sudden insight, calling for a reappraisal of this evolutionarily conserved structure as a key player supporting unconscious but high-level cognitive processing.

neuroscience↗
bioRxiv2024

INCOMPATIBILITY GROUPS OF PSEUDOMONAS PLASMIDS REVISITED: COMPREHENSIVE ANALYSIS OF R-FACTORS AND THEIR REPLICONS

Plasmids are the most influential engines of bacterial evolution and horizontal gene transfer, fueling the global spread of traits such as antimicrobial resistance. Their deep evolutionary relationships, however, remain difficult to resolve because current classification schemes are constrained by host range and nucleotide similarity. Replication initiation proteins (RIPs), which govern plasmid persistence and diversification, also remain poorly annotated across public databases. Here we establish PInc, a curated and experimentally grounded replicon classification framework anchored in historically defined incompatibility groups of Pseudomonas plasmids. Homology searches beyond PInc revealed that most replication initiators analyzed here share a conserved winged-helix (WH) domain, defining a broad WH RIP superfamily. Using the conserved WH region, we reconstructed a large-scale phylogeny that linked WH RIPs to over 100,000 plasmids, representing approximately half of those analyzed across public databases. This phylogeny resolved eight major clades and the deep split between the single- and double-winged-helix superclades, while revealing clade-specific host and environmental distributions and substantial RIP diversity not captured by current typing tools or annotation schemes. Together, these results overcome the historical host bias of plasmid typing and provide a replication-centered view of plasmid diversification across bacterial lineages and environments.

microbiology↗
bioRxiv2024

2-monopalmitin, but not 1-monopalmitin, enhances hypothalamic leptin responsiveness, energy balance, and glucose homeostasis under overnutrition

Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone for energy balance. Here, we found that 2-monopalmitin, but not 1-monopalmitin or palmitic acid, enhances hypothalamic leptin responsiveness in ex vivo brain slices. Centrally administered 2-monopalmitin markedly restored the leptin-induced suppression of food intake and reduction of body weight in diet-induced obese mice. Peripherally administered 2-monopalmitin also enhanced the anorectic effect of centrally administered leptin. Furthermore, daily 2-monopalmitin treatment protected against diet-induced body weight gain, and the energy expenditure of 2-monopalmitin-treated mice was significantly enhanced in a leptin-dependent manner. We also demonstrated that 2-monopalmitin lowered blood glucose levels, improved glucose and insulin tolerance, and protected mice against HFD-induced peripheral insulin resistance at the cellular and whole-body levels. Finally, treatment with 2-monopalmitin protected against LPS-induced leptin resistance, and decreased the hypothalamic levels of SOCS3, an inhibitor of leptin actions, and inflammatory cytokines. Altogether, our results showed that 2-monopalmitin in the brain, but not 1-monopalmitin or palmitic acid, is critical for linking overnutrition to the control of neural leptin actions.

physiology↗
bioRxiv2023

Developmental hourglass: Confirmation by numerical evolution and elucidation by dynamical-systems theory

Determining the general laws between evolution and development is a fundamental biological challenge. Developmental hourglasses have attracted increased attention as candidates for such laws, but the necessity of their emergence remains elusive. We conducted evolutionary simulations of developmental processes to confirm the emergence of the developmental hourglass and unveiled its establishment. We considered organisms consisting of cells containing identical gene networks that control morphogenesis and evolved them under selection pressure to induce more cell types. By computing the similarity between the spatial patterns of gene expression of two species that evolved from a common ancestor, a developmental hourglass was observed, that is, there was a correlation peak in the intermediate stage of development. The fraction of pleiotropic genes increased, whereas the variance in individuals decreased, consistent with previous experimental reports. Reduction of the unavoidable variance by initial or developmental noise, essential for survival, was achieved up to the hourglass bottleneck stage, followed by diversification in developmental processes, whose timing is controlled by the slow expression dynamics conserved among organisms sharing the hourglass. This study suggests why developmental hourglasses are observed within a certain phylogenetic range of species. Author SummaryUnderstanding the intriguing relationship between development and evolution in multicellular organisms has long been a challenge in biology. A recent hypothesis called the developmental hourglass proposes that there is a conserved middle stage during development across species of the same animal group. Despite growing evidence supporting this hypothesis, the underlying mechanisms and reasons for its emergence have remained elusive due to limited experimental data. To address this gap, we employed numerical evolution of gene regulation networks controlling pattern formation. Remarkably, our simulations revealed that species that diverged relatively recently in phylogeny displayed the highest similarity during the middle stage of development, which gradually diminished as they diverged further phylogenetically. Our findings satisfied not only the criteria of the developmental hourglass but also confirmed several essential characteristics of the developmental hourglass reported in recent experiments. Through theoretical analysis, we further demonstrated that the emergence of the developmental hourglass could be attributed to the acquisition of genes that change slowly and govern developmental processes, which also foster the robustness of development. By integrating computational simulations, theoretical insights, and previous experimental evidence, our study thus provides a comprehensive understanding of the developmental hourglass, which will unravel the intricate relationship between development and evolution.

systems biology↗
bioRxiv2022

Triggered Release from Thermosensitive Liposomes Improves Tumor Targeting of Vinorelbine

Triggered drug delivery strategies have been shown to enhance drug accumulation at target diseased sites in comparison to administration of free drug. In particular, many studies have demonstrated improved targetability of chemotherapeutics when delivered via thermosensitive liposomes. However, most studies continue to focus on encapsulating doxorubicin while many other drugs would benefit from this targeted and localized delivery approach. The proposed study explores the therapeutic potential of a thermosensitive liposome formulation of the commonly used chemotherapy drug vinorelbine in combination with mild hyperthermia (39-43 {degrees}C) in a murine model of rhabdomyosarcoma. Rhabdomyosarcoma, the most common soft tissue sarcoma in children, is largely treated using conventional chemotherapy which is associated with significant adverse long-term sequelae. In this study, mild hyperthermia was pursued as a non-invasive, non-toxic means to improve the efficacy and safety profiles of vinorelbine. Thorough assessment of the pharmacokinetics, biodistribution, efficacy and toxicity of vinorelbine administered in the thermosensitive liposome formulation was compared to administration in a traditional, non-thermosensitive liposome formulation. This study shows the potential of an advanced formulation technology in combination with mild hyperthermia as a means to target an untargeted therapeutic agent and result in a significant improvement in its therapeutic index. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/514937v1_ufig1.gif" ALT="Figure 1"> View larger version (78K): org.highwire.dtl.DTLVardef@3a5126org.highwire.dtl.DTLVardef@a5a130org.highwire.dtl.DTLVardef@1f97ea6org.highwire.dtl.DTLVardef@e9f376_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗
bioRxiv2022

Harnessing Immunotherapy to Enhance the Systemic Anti-Tumor Effects of Thermosensitive Liposomes

Chemotherapy plays an important role in debulking tumors in advance of surgery and/or radiotherapy, tackling residual disease, and treating metastatic disease. In recent years many promising advanced drug delivery strategies have emerged that offer more targeted delivery approaches to chemotherapy treatment. For example, thermosensitive liposome mediated drug delivery in combination with localized mild hyperthermia can increase local drug concentrations resulting in a reduction in systemic toxicity and an improvement in local disease control. However, the majority of solid tumor associated deaths are due to metastatic spread. A therapeutic approach focused on a localized target area harbors the risk of overlooking and undertreating potential metastatic spread. Previous studies reported systemic, albeit limited, anti-tumor effects following treatment with thermosensitive liposomal chemotherapy and localized mild hyperthermia. This work explores the systemic treatment capabilities of a thermosensitive liposome formulation of the vinca alkaloid vinorelbine in combination with mild hyperthermia in an immunocompetent murine model of rhabdomyosarcoma. This treatment approach was found to be highly effective at heated, primary tumor sites. However, it demonstrated limited anti-tumor effects in secondary, distant tumors. As a result, the addition of immune checkpoint inhibition therapy was pursued to further enhance the systemic anti-tumor effect of this treatment approach. Once combined with immune checkpoint inhibition therapy, a significant improvement in systemic treatment capability was achieved. We believe this is one of the first studies to demonstrate that a triple combination of thermosensitive liposomes, localized mild hyperthermia, and immune checkpoint inhibition therapy can enhance the systemic treatment capabilities of thermosensitive liposomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/505721v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1f5faa9org.highwire.dtl.DTLVardef@1b89f2org.highwire.dtl.DTLVardef@1fdab72org.highwire.dtl.DTLVardef@102ce7d_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗
bioRxiv2022

CD133+ Intercellsome Mediates Direct Cell-Cell Communication to Offset Intracellular Signaling Deficit

CD133 (prominin 1) is widely viewed as a cancer stem cell marker in association with drug resistance and cancer recurrence. Herein we report that with impaired RTK-Shp2 Ras-Erk signaling, heterogenous hepatocytes form clusters that manage to divide during liver regeneration. These hepatocytes are characterized by upregulated CD133 while negative for other progenitor cell markers. Pharmaceutical inhibition of proliferative signaling also induced CD133 expression in various cancer cell types, suggesting an inherent and common mechanism of stress response. Super-resolution and electron microscopy localize CD133 on intracellular vesicles that apparently migrate between cells, which we name "intercellsome". Isolated CD133+ intercellsomes are enriched with mRNAs rather than miRNAs. Single-cell RNA sequencing reveals lower intracellular diversity (entropy) of mitogenic mRNAs in Shp2-deficient cells, which may be remedied by intercellular mRNA exchanges between CD133+ cells. CD133-deficient cells are more sensitive to proliferative signal inhibition in livers and intestinal organoids. These data suggest a mechanism of intercellular communication to compensate intracellular signal deficit in various cell types.

cell biology↗
bioRxiv2022

Comprehensive analysis of gene regulatory dynamics, fitness landscape, and population evolution during sexual reproduction

The fitness landscape is a critical concept in evolutionary biology and genetics that depicts fitness in the genotype space and visualizes the relationship between genotype and fitness. However, the fitness landscape is challenging to characterize because the quantitative relationships between genotype and phenotype and their association to fitness has not been comprehensively well described. To address this challenge, we adopted gene regulatory networks to determine gene expression dynamics. We analyzed how phenotype and fitness are shaped by the genotype in two-gene networks. A two-by-two matrix provided the two-gene regulatory network in which a vector with two angle values ({Theta}) was introduced to characterize the genotype. Mapping from this angle vector to phenotypes allowed for the classification of steady-state expression patterns of genes into seven types. We then studied all possible fitness functions given by the Boolean output from the on/off expression of the two genes. The possible fitness landscapes were obtained as a function of the genetic parameters {Theta}. Finally, the evolution of the population distribution under sexual reproduction was investigated in the obtained landscape. We found that the distribution was restricted to a convex region within the landscape, resulting in the branching of population distribution, including the speciation process.

evolutionary biology↗
bioRxiv2022

The Statistical Trends of Protein Evolution: A Lesson from AlphaFold Database

The recent development of artificial intelligence provides us with new and powerful tools for studying the mysterious relationship between organism evolution and protein evolution. In this work, based on the AlphaFold Protein Structure Database (AlphaFold DB), we perform comparative analyses of the proteins of different organisms. The statistics of AlphaFold-predicted structures show that, for organisms with higher complexity, their constituent proteins will have larger radii of gyration, higher coil fractions, and slower vibrations, statistically. By conducting normal mode analysis and scaling analyses, we demonstrate that higher organismal complexity correlates with lower fractal dimensions in both the structure and dynamics of the constituent proteins, suggesting that higher functional specialization is associated with higher organismal complexity. We also uncover the topology and sequence bases of these correlations. As the organismal complexity increases, the residue contact networks of the constituent proteins will be more assortative, and these proteins will have a higher degree of hydrophilic-hydrophobic segregation in the sequences. Furthermore, by comparing the statistical structural proximity across the proteomes with the phylogenetic tree of homologous proteins, we show that, statistical structural proximity across the proteomes may indirectly reflect the phylogenetic proximity, indicating a statistical trend of protein evolution in parallel with organism evolution. This study provides new insights into how the diversity in the functionality of proteins increases and how the dimensionality of the manifold of protein dynamics reduces during evolution, contributing to the understanding of the origin and evolution of lives.

biophysics↗
bioRxiv2021

Heterosis Related to Fitness and Phenotypic Variance in the Evolution of Diploid Gene Regulatory Network

Heterosis describes the phenomenon whereby a hybrid population has higher fitness than an inbred population, and has previously been explained by either Mendelian dominance or overdominance, where it is generally assumed that one gene controls one trait. How-ever, recent studies have demonstrated that genes interact through a complex gene regulatory network (GRN). Furthermore, phenotypic variance due to noise is reportedly lower for heterozygotes, whereas the origin of such variance-related heterosis remains elusive. There-fore, a theoretical analysis linking heterosis to GRN evolution and stochastic gene expression dynamics is required. Here, we investigate heterosis related to fitness and phenotypic variance in a system with interacting genes, by numerically evolving diploid GRNs. According to the results, the heterozygote population exhibited higher fitness than the homozygote population, that is, fitness-related heterosis resulting from evolution. In addition, the heterozygote population expressed lower noise-related phenotypic variance in expression levels than the homozygous population, implying that the heterozygote population is more robust to noise. Furthermore, the distribution of the ratio of heterozygote phenotypic variance to homozygote phenotypic variance exhibited quantitative agreement with previous experimental results. By applying dominance and over-dominance to the gene expression pattern rather than only a single gene expression, we confirmed the correlation between heterosis and overdominance. We explain our results by proposing that the convex high-fitness region is evolutionarily shaped in the genetic space to gain noise robustness under genetic mixing through sexual reproduction. Significance StatementHeterosis, that is higher fitness in hybrid populations than inbred populations, is a long-standing problem in genetics, evolution, and breeding studies. Heterosis is not necessarily the result of a trait uniquely determined by a single gene, but likely involves stochasticity and interactions among genes. Through numerical evolution of the gene regulatory network, we demonstrate that heterosis is shaped by evolution to achieve robustness against noise and genetic mixing by sexual recombination in gene expression dynamics. That is, a mixed population is more robust to noise than inbred populations, as revealed experimentally by reduced phenotypic variance. The observed link between heterosis and phenotypic robustness, Mendelian dominance, and the convex single-humped fitness landscape represents a novel avenue in evolution and genetics research.

evolutionary biology↗
bioRxiv2021

Intensive Single Cell Analysis Reveals Immune Cell Diversity among Healthy Individuals

It is believed that immune responses are different between individuals and at different times. In addition, personal health histories and unique environmental conditions should collectively determine the present state of immune cells. However, the cellular and molecular system mechanisms underlying such heterogeneity remain largely elusive. In this study, we conducted a systematic time-lapse single-cell analysis, using 171 single-cell libraries and 30 mass cytometry datasets intensively for seven healthy individuals. We found substantial diversity in immune cell populations and their gene expression patterns between different individuals. These patterns showed daily fluctuations even within the same individual spending a usual life. Similar diversities were also observed for the T cell receptor and B cell receptor repertoires. Detailed immune cell profiles at healthy statuses should give an essential background information to understand their immune responses, when the individual is exposed to various environmental conditions. To demonstrate this idea, we conducted the similar analysis for the same individuals on the vaccination of Influenza and SARS-CoV-2, since the date and the dose of the antigens are well-defined in these cases. In fact, we found that the distinct responses to vaccines between individuals, althougth key responses are common. Single cell immune cell profile data should make fundamental data resource to understand variable immune responses, which are unique to each individual.

genomics↗
bioRxiv2021

Chemophoresis Engine: Universal Principle of ATPase-driven Cargo Transport

Cell polarity regulates the orientation of the cytoskeleton members that directs intracellular transport for cargo-like organelles, using chemical gradients sustained by ATP or GTP hydrolysis. However, how cargo transports are directly mediated by chemical gradients remains unknown. We previously proposed a physical mechanism that enables directed movement of cargos, referred to as chemophoresis. According to the mechanism, a cargo with reaction sites is subjected to a chemophoresis force in the direction of the increased concentration. Based on this, we introduce an extended model, the chemophoresis engine, as a general mechanism of cargo motion, which transforms chemical free energy into directed motion through the catalytic ATP hydrolysis. We applied the engine to plasmid motion in a parABS system to demonstrate the the self-organization system for directed plasmid movement and pattern dynamics of ParA-ATP concentration, thereby explaining plasmid equi-positioning and pole-to-pole oscillation observed in bacterial cells and in vitro experiments. We mathematically show the existence and stability of the plasmid-surfing pattern, which allows the cargo-directed motion through the symmetry-breaking transition of the ParA-ATP spatiotemporal pattern. Finally, based on its generality, we discuss the chemophoresis engine as a universal principle of hydrolysis-driven intracellular transport. SIGNIFICANCEThe formation of organelle/macromolecule patterns depending on chemical concentration under non-equilibrium conditions, first observed during macroscopic morphogenesis (1), has recently been observed at the intracellular level as well, and its relevance as intracellular morphogen has been demonstrated in the case of bacterial cell division. These studies have discussed how cargos maintain positional information provided by chemical concentration gradients/localization. However, how cargo transports are directly mediated by chemical gradients remains unknown. Based on the previously proposed mechanism of chemotaxis-like behavior of cargos (referred to as chemophoresis, (2, 3)), we introduce a chemophoresis engine as a physicochemical mechanism of cargo motion, which transforms chemical free energy to directed motion. The engine is based on the chemophoresis force to make cargoes move in the direction of the increasing ATPase(-ATP) concentration and an enhanced catalytic ATPase hydrolysis at the positions of the cargoes. Applying the engine to ATPase-driven movement of plasmid-DNAs in bacterial cells, we constructed a mathematical model to demonstrate the self-organization for directed plasmid motion and pattern dynamics of ATPase concentration, as is consistent with in vitro and in vivo experiments. We propose that this chemophoresis engine works as a universal principle of hydrolysis-driven intracellular transport.

biophysics↗
bioRxiv2021

Developmentally-regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome

Dravet syndrome (DS) is a neurodevelopmental disorder defined by epilepsy, intellectual disability, and sudden death, due to heterozygous variants in SCN1A with loss of function of the sodium channel subunit Nav1.1. Nav1.1-expressing parvalbumin GABAergic interneurons (PV-INs) from pre-weanling Scn1a+/- mice show impaired action potential generation. A novel approach assessing PV-IN function in the same mice at two developmental time points showed that, at post-natal day (P) 16-21, spike generation was impaired all mice, deceased prior or surviving to P35. However, synaptic transmission was selectively dysfunctional in pre-weanling mice that did not survive. Spike generation in surviving mice normalized by P35, yet we again identified abnormalities in synaptic transmission. We conclude that combined dysfunction of PV-IN spike generation and synaptic transmission drives disease severity, while ongoing dysfunction of synaptic transmission contributes to chronic pathology. Modeling revealed that PV-IN axonal propagation is more sensitive to decreases in sodium conductance than spike generation.

neuroscience↗