Biology subjects

Shapira, S.

Publications and source records attributed to Shapira, S..

8 recordsLinked to original sources

bioRxiv2026

Spine-neck electrical bottlenecks tune temporal precision and inhibitory gating in cortical pyramidal neurons: A connectomics-based biophysical study

Dendritic spines are nano-scale compartments that host the majority of excitatory synapses on cortical pyramidal neurons (PNs); hundreds of spines/PN also receive an inhibitory synapse (dually-innervated spines, DiSs). Using analytic theory and detailed biophysical models of [~]2,000 densely reconstructed spines, we show that recurrent spine-neck narrowing substantially increases spine-neck resistance (Rneck), and that elevated Rneck accelerates spine-head voltage dynamics, shortening spinous postsynaptic potentials by up to [~]3-fold. Rneck improves the tracking of high-frequency synaptic inputs and strongly modulates Ca2+ signaling and the potency and temporal precision of inhibitory gating in DiSs. This work identifies Rneck as a dynamic "knob", directly linking spine ultrastructure to information processing and plasticity in cortical PNs and circuits, yielding testable experimental predictions. Our "biophysics of connectomics" paradigm naturally raises computational-oriented questions, including how inhibitory "gates" in dendritic spines expand context-dependent computations, implement single-cell and network-level routing, and enable selective encoding of precise temporal patterns.

neuroscience↗

bioRxiv2026

CytoLight: A Rapid and Versatile Fluorescent-Based Labeling Method for Extracellular Vesicle Characterization and Tracking

Efficient, aggregation-free extracellular vesicles (EVs) labeling is essential for studying their dynamics in-vitro and in-vivo. However, traditional dyes introduce limitations including aggregation, membrane intercalation, fluorescence transfer and inconsistent performance across EV sources thus distorting quantification, altering surface properties and confounding uptake and biodistribution analyses. Here, we systematically evaluated CytoLight, a luminal dye traditionally used for live-cell imaging, as an alternative for EV quantification, characterization, uptake analysis and in-vivo tracking, benchmarking it against PKH26, CFSE and ExoBrite across multiple platforms. CytoLight generated stable, intravesicular fluorescence without aggregation or membrane alteration, eliminating artifacts characteristic of conventional dyes. Using fluorescence-NTA and single-EV flow cytometry, CytoLight showed more consistent labeling across EV types than CFSE or ExoBrite, while avoiding PKH-related micelle-driven artifacts and exhibited compatibility with CD81 dual-detection. In uptake assays, CytoLight produced EV-specific endocytosis-dependent internalization signals exceeding labeled-BPS/protein controls. In-vivo, CytoLight-labeled EVs enabled fluorescent biodistribution mapping showing conventional EV tropism patterns distinguishable from labeled-PBS controls. These findings establish CytoLight as an effective, aggregation-free EV-labeling strategy. Its stability, specificity, compatibility with single-EV platforms and reliable performance in both cellular uptake and biodistribution studies position CytoLight as a practical, scalable alternative to current dyes, providing a stronger foundation for standardized and reproducible EV research.

cell biology↗

bioRxiv2025

Olfactory Training Enhances Adult Neurogenesis of the Olfactory Epithelium Improving Odor Discriminability of the Olfactory Bulb

Olfaction enables us to detect chemicals in the environment, and its impairment affects one in four people worldwide. As the most common therapy, olfactory training involves repeated exposure to odorants restoring function in 30-50% of patients. However, the mechanisms underlying this therapy, and its partial efficacy, are unknown. By modelling olfactory training in mice, we found that odor exposure triggers quiescent neural stem cells of the olfactory epithelium to re-enter the cell cycle, enhancing neurogenesis and survival of olfactory sensory neurons. Coupling neuronal activity with stem cells proliferation, these effects scaled with odor concentration and were replicated without odorants upon chemogenetic activation of olfactory sensory neurons. Imaging mitral cells in the olfactory bulb revealed that increased neurogenesis in the olfactory epithelium enhanced odor sensitivity and discriminability. Our findings uncover activity-dependent cellular mechanisms linking peripheral nervous system regeneration to central olfactory processing, offering new avenues for treating olfactory dysfunction. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/692562v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@1a6a0b7org.highwire.dtl.DTLVardef@817a4forg.highwire.dtl.DTLVardef@84f063org.highwire.dtl.DTLVardef@1c20f8b_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTS- Olfactory training (OT) is a common clinical practice of unknown cellular mechanisms - OT in mice triggers stem cell activation and neurogenesis in the olfactory epithelium - Artificial stimulation of olfactory neurons is sufficient to trigger neural stem cell activity - Neurogenesis in the olfactory epithelium improves odor discrimination by mitral cells

cell biology↗

bioRxiv2024

A complete account of the behavioral repertoire uncovers principles of larval zebrafish hunting behavior

In goal-directed behavior animals select actions from a diverse repertoire of possible movements. Accurately quantifying the complete behavioral repertoire can uncover the underlying rules that guide such goal-directed behavior. However, these movements are usually complex, high-dimensional, and lead to various outcomes, posing a challenge to fully capture the complete repertoire. By tracking freely hunting zebrafish larvae using a highspeed camera and analyzing their movements, we developed a mathematical model that accurately reproduces the complete repertoire. Using the model, we show that fish position and change in heading angle following a movement are coupled, such that the choice of one of them limits the possibilities of the other. This repertoire structure uncovered fundamental principles of movements, showing that fish rotate around an identified rotation point and then move forward or backward along straight lines. From the uncovered movement principles, we identified a new guiding rule for prey interaction: in each movement, fish turn to face the prey and then move forward or backward. This enables decoupling between orientation and distance selections of the fish during the hunt. These results provide a comprehensive and continuous description of the repertoire of movements, reveal underlying algorithmic rules that govern the behavior, and offer insights into the potential neural implementation of the repertoire.

neuroscience↗

bioRxiv2023

Natural and age-related variation in circulating human hematopoietic stem cells

Hematopoietic stem and progenitor cells (HSPCs) deliver life-long multi-lineage output. However, with aging, we exhibit certain characteristic blood count changes and accumulation of clonal disorders. Better understanding of inter-individual variation in HSPC behavior is needed to understand these age-related phenomena and the transition from health to chronic and acute hematological malignancies. Here we study 627K single circulating CD34+ HSPCs (cHSPCs) from 148 healthy individuals, along with their clinical information and clonal hematopoiesis (CH) profiles, to characterize population-wide and age-related hematopoietic variability. Individuals with CH were linked with reduced frequencies of lymphocyte progenitors and higher RDW. An age-related decrease in lymphoid progenitors was observed, predominantly in males. Inter-individual transcriptional variation in expression of a Lamin-A signature and stemness gene programs were linked with aging and presence of macrocytic anemia. Based on our model for healthy cHSPC variation we construct the normal reference for cHSPC subtype frequencies. We show how compositional and expression deviations from this normal reference can robustly identify myeloid malignancies and pre-malignant states. Together, our data and methodologies present a novel resource, shedding light on various age-related hematopoietic processes, and a comprehensive normal cHSPC reference, which can serve as a tool for diagnosing and characterizing hematological disorders.

molecular biology↗

bioRxiv2022

Accelerated signal propagation speed in human neocortical microcircuits

Human-specific cognitive abilities depend on information processing in the cerebral cortex, where the neurons are significantly larger and their processes longer and sparser compared to rodents. We found that, in synaptically connected layer 2/3 pyramidal cells (L2/3 PCs), the delay in signal propagation from soma to soma is similar in humans and rodents. To compensate for the longer processes of neurons, membrane potential changes in human axons and/or dendrites must propagate faster. Dual somato-dendritic and somato-axonal patch recordings show that the propagation speed of action potentials (APs) is similar in human and rat axons, but the forward propagation of excitatory postsynaptic potentials (EPSPs) and the backward propagation of APs are 26 and 47% faster in human dendrites, respectively. Accurate biophysical models of human and rat L2/3 PCs, combined with pharmacological manipulations of membrane properties, have shown that various factors enhance EPSP propagation in humans; the key factor is the large conductance load imposed by the large basal dendritic tree in humans, the key factor responsible for the accelerated signal propagation in human cortical dendrites. Larger dendritic diameter in humans as well as differences in cable and ion channel properties, also contribute to the enhancement of signal propagation in human L2/3 dendrites.

neuroscience↗

bioRxiv2021

Systemic Tissue and Cellular Disruption from SARS-CoV-2 Infection revealed in COVID-19 Autopsies and Spatial Omics Tissue Maps

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus has infected over 115 million people and caused over 2.5 million deaths worldwide. Yet, the molecular mechanisms underlying the clinical manifestations of COVID-19, as well as what distinguishes them from common seasonal influenza virus and other lung injury states such as Acute Respiratory Distress Syndrome (ARDS), remains poorly understood. To address these challenges, we combined transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues, matched with spatial protein and expression profiling (GeoMx) across 357 tissue sections. These results define both body-wide and tissue-specific (heart, liver, lung, kidney, and lymph nodes) damage wrought by the SARS-CoV-2 infection, evident as a function of varying viral load (high vs. low) during the course of infection and specific, transcriptional dysregulation in splicing isoforms, T cell receptor expression, and cellular expression states. In particular, cardiac and lung tissues revealed the largest degree of splicing isoform switching and cell expression state loss. Overall, these findings reveal a systemic disruption of cellular and transcriptional pathways from COVID-19 across all tissues, which can inform subsequent studies to combat the mortality of COVID-19, as well to better understand the molecular dynamics of lethal SARS-CoV-2 infection and other viruses.

microbiology↗

bioRxiv2020

A sweep of earth's virome reveals host-guided viral protein structural mimicry; with implications for human disease

Viruses deploy an array of genetically encoded strategies to coopt host machinery and support viral replicative cycles. Molecular mimicry, manifested by structural similarity between viral and endogenous host proteins, allow viruses to harness or disrupt cellular functions including nucleic acid metabolism and modulation of immune responses. Here, we use protein structure similarity to scan for virally encoded structure mimics across thousands of catalogued viruses and hosts spanning broad ecological niches and taxonomic range, including bacteria, plants and fungi, invertebrates and vertebrates. Our survey identified over 6,000,000 instances of structural mimicry, the vast majority of which (>70%) cannot be discerned through protein sequence. The results point to molecular mimicry as a pervasive strategy employed by viruses and indicate that the protein structure space used by a given virus is dictated by the host proteome. Interrogation of proteins mimicked by human-infecting viruses points to broad diversification of cellular pathways targeted via structural mimicry, identifies biological processes that may underly autoimmune disorders, and reveals virally encoded mimics that may be leveraged to engineer synthetic metabolic circuits or may serve as targets for therapeutics. Moreover, the manner and degree to which viruses exploit molecular mimicry varies by genome size and nucleic acid type, with ssRNA viruses circumventing limitations of their small genomes by mimicking human proteins to a greater extent than their large dsDNA counterparts. Finally, we identified over 140 cellular proteins that are mimicked by CoV, providing clues about cellular processes driving the pathogenesis of the ongoing COVID-19 pandemic.

microbiology↗