Biology subjects

Ross, J.

Publications and source records attributed to Ross, J..

At least 19 recordsLinked to original sources

bioRxiv2026

USP15 REGULATES NEUROINFLAMMATION AND DRIVES PATHOGENESIS IN SYNUCLEINOPATHIES

Neuroinflammation strongly contributes to the pathogenesis of neurological and neurodegenerative diseases, including Parkinson's disease. We show that ablation of Usp15 in astrocytes and in microglia protects against lethal neuroinflammation in vivo. In a mouse model of synucleinopathy, Usp15 deletion diminishes alpha-syn deposits in the brain, slows disease progression, and increases survival time. The neuroprotective effect of Usp15 is associated with differential expression of inflammatory pathways in situ including interferon stimulated genes. These USP15-dependent effects in vivo are recapitulated in vitro in primary human microglia and astrocytes. We detect high USP15 expression in microglia from Parkinson's patients with strong co-expression with LRRK2 and SNCA. In humans, we detect a strong cis-acting eQTL directing high USP15 expression in CD14+ myeloid cells. The allele driving this eQTL is itself associated with increased disease risk, linking myeloid USP15 expression, elevated USP15 plasma levels in Parkinson's patients, to genetic susceptibility.

neuroscience↗

bioRxiv2026

Transcriptomic Changes and Biomarkers in Barrett's Metaplasia, Dysplasia and Cancer

Esophageal adenocarcinoma (EAC) has a poor five-year survival rate and one of the fastest-rising incidences of any cancer. The presence of dysplasia in Barrett's esophagus (BE) is the main risk factor for EAC development and guides clinical management. Unfortunately, the current histopathological diagnosis of dysplasia is unreliable, with poor inter-observer agreement, highlighting the need for novel biomarkers that can improve diagnostic accuracy. Here, we performed transcriptome profiling across the full spectrum of BE-related neoplasia in 85 samples to delineate gene expression alterations in progressively worse disease stages and identify biomarkers that could complement histopathology to improve the detection of dysplasia and EAC in endoscopic biopsy specimens. Differential gene expression and pathway analyses revealed that the most extensive transcriptional changes occurred during the transition from normal squamous (NSq) to non-dysplastic BE (NDBE), consistent with metaplastic transformation. Compared to NDBE, dysplasia was characterized by enhanced cellular growth and proliferation; upregulation of immune processes and oncogenic signaling pathways were present in EAC. Using machine learning approaches, we identified a novel five-gene panel suitable for a potential RNAseq-based diagnostic test (SLC11A1, IL36A, LUCAT1, MIR215, RNU6-954P) and performed an initial validation of this signature in an additional 51 samples. We also identified several potential novel immunohistochemical markers that may warrant further evaluation, including TREM1, CXCL5, OSM, and motilin. In summary, by delineating transcriptional changes across the full disease spectrum, this study identifies several candidate biomarkers for improving current diagnostic methods for Barrett's dysplasia and EAC.

cancer biology↗

bioRxiv2026

A Stochastic Neural Mass Model for Cortical Beta Bursts in Parkinsons Disease

Beta-band (13-30 Hz) oscillations are increasingly understood to occur as transient "bursts" rather than sustained rhythms, with altered burst dynamics, specifically increased duration and power alongside reduced burst rates, in patients with Parkinsons disease (PD). In this study, we utilise resting state magnetoencephalography (MEG) data from healthy adults to quantify the temporal fluctuations in the beta-band, and examine the distributions of burst statistics. We then fit a stochastic next-generation neural mass model to these empirical statistics using a Genetic Algorithm. Systematic parameter sweeps reveal that reducing background drive to excitatory and inhibitory neuronal populations reproduces the altered burst statistics observed in PD. Crucially, we show that strengthening synaptic coupling can counteract these deficits and restore healthy bursting dynamics. Together, this work establishes a computational framework linking cellular-level mechanisms to macroscale burst statistics, and highlights potential targets for therapeutic neuromodulation in movement disorders. Author summaryBrain activity is comprised of rhythmic electrical patterns called "brain waves." Traditionally, these waves were viewed as smooth and continuous, but recent evidence reveals that they actually occur in brief, intense bursts. In conditions such as Parkinsons disease, these bursts become altered--lasting longer, growing stronger, and occurring less frequently. In this study, we developed a mathematical model of brain tissue to understand what drives these burst patterns. Using real brain scans from healthy human volunteers, we tuned our model with an optimisation algorithm until its simulated bursts closely matched real human brain activity. We then systematically varied the models settings to investigate how abnormal bursting arises in disease. We discovered that reducing the background signals to the brain cells reproduces the burst alterations seen in Parkinsons disease. Importantly, our simulations showed that strengthening the connections between brain cells can counteract this deficit, restoring healthy burst patterns. By connecting microscopic cell properties to whole-brain rhythms, our work offers new insights into how movement disorders disrupt brain networks and highlights potential cellular targets to guide future brain stimulation therapies or medications.

biophysics↗

bioRxiv2026

Functional Differentiation of GH172 Arabinofuranosidases Through Divergent Quaternary Structures

Mycobacteria synthesise the unusual glycan [x1D05]-arabinan as a major component of the cell wall glycoconjugates arabinogalactan (AG) and lipoarabinomannan (LAM). We previously identified Dysgonomonas gadei, a member of the Bacteroidota, as capable of complete [x1D05]-arabinan degradation through the concerted action of endo- and exo-acting enzymes. Among these are three glycoside hydrolase family 172 (GH172) enzymes with exo--[x1D05]-arabinofuranosidase activity against AG and LAM, although their linkage specificities were unknown. Here, using defined synthetic substrates, we show that the three enzymes possess distinct linkage preferences. We also develop -[x1D05]-arabinofuranosyl cyclophellitol aziridines as covalent inhibitors and activity-based probes for GH172 enzymes. X-ray crystallography and cryo-EM to reveal strikingly different quaternary assemblies across the three homologues, while a 1.5 [A] cryo-EM structure of dodecameric Dg67 covalently modified by an aziridine inhibitor identifies the catalytic nucleophile and provides direct structural support for a retaining mechanism. A BODIPY-tagged aziridine probe selectively labelled the three GH172 enzymes in D. gadei cell lysates. Together, these findings define functional and structural diversity within GH172 and establish chemical probes for profiling -[x1D05]-arabinofuranosidase activity in complex biological samples.

biochemistry↗

bioRxiv2026

Routine FFPE sections support clinically compatible single-nucleus transcriptomics across six human cancer types

Tumor cellular composition--including malignant cell states, immune populations, and stromal populations--is increasingly recognized as a determinant of therapeutic response and resistance to anti-cancer agents, yet comprehensive cellular profiling remains largely confined to research settings. Here, we present a clinically compatible sample-to-report workflow for tumor composition profiling from routine formalin-fixed paraffin-embedded (FFPE) clinical specimens. By combining low-input single-nucleus RNA sequencing with foundation model- based automated cell annotation, this workflow enables prospective sample-by-sample analysis without dedicated research material or cohort-based processing. Across 116 clinical specimens representing six cancer types, we generated reproducible measurements of cellular composition and cell-type-specific gene expression, demonstrated high technical reproducibility, and showed concordance with pathological assessment of immune infiltration. The workflow was similarly applicable to archival FFPE material and ultra-low-input biopsy specimens. Together, these findings establish a practical framework for routine single-cell profiling from standard pathology specimens and open the perspective of prospective evaluation of cellular composition as a clinical biomarker in precision oncology.

cancer biology↗

bioRxiv2026

Human Haematopoietic Stem Cells released into circulation following mobilization express multiple G0-associated quiescence markers

Haematopoietic stem cells (HSC), while usually quiescent, can rapidly divide following specific stimuli (mobilization). These HSC can seed additional niches, allowing for the swift generation of essential blood cells. However, studies in mice and humans have clearly demonstrated that cycling bone marrow (BM) HSC (cells in the G1/S/G2/M phases) engraft and reconstitute the haematopoietic system poorly compared with HSC in the G0 phase1. This raises the question why mobilized HSC, immediately following 3 or more cell divisions2, efficiently reconstitute the haematopoietic system. We studied this phenomenon in human HSC using scRNAseq analysis. We found that mobilized HSC rapidly start transcribing genes associated with quiescence, specific for the G0 phase of the cell cycle. We hypothesize that this rapid switch from actively dividing to quiescent cells combined with our extensive RNA expression data will allow us to better define pathways involved in this process.

Cell Biology↗

bioRxiv2025

Cell type specific analysis of ALS associated proteins reveals immune-regulated targets

A substantial fraction of amyotrophic lateral sclerosis (ALS)-associated proteins remain poorly characterized, in part because of the limited availability of validated research antibodies. We established knockout (KO)-based antibody characterization workflows and demonstrated that widely used antibodies against the major ALS-associated protein C9orf72 lacked specificity (Laflamme et al., 2019). We subsequently scaled this framework to systematically benchmark research antibodies, revealing that up to 61% fail to perform as recommended by manufacturers (Ayoubi et al., 2023). Here, we extend this approach by establishing the ALS-Reproducible Antibody Platform (ALS-RAP), a comprehensive effort to generate a publicly available dataset of KO-validated antibodies targeting proteins encoded by ALS risk genes. In total, we characterized 303 antibodies against 33 ALS-associated proteins to identify high-quality reagents for use in western blot, immunoprecipitation, and immunofluorescence. Using these antibodies, we profiled protein levels across human induced pluripotent stem cell (iPSC)-derived and primary neurological cell types. These analyses revealed diverse cellular distributions and higher levels of several ALS-associated proteins in glial populations, consistent with emerging evidence for immune contributions to ALS. Together, ALS-RAP provides a validated antibody toolbox and protein expression resource to support the study of ALS-associated proteins.

neuroscience↗

bioRxiv2025

A Cell Type-Specific Role for Tubb6 in Ciliogenesis of Xenopus Epidermal Multiciliated Cells

Cilia are microtubule-based organelles found on the surface of most eukaryotic cells. These microtubules are composed of - and {beta}-tubulin heterodimers, and different tubulin isotypes can confer distinct properties to microtubules. Despite their importance, the contribution of individual tubulin isotype to cilia formation and function remains largely unexplored in vertebrates. Here, we identify a critical role for the {beta}-tubulin isotype Tubb6 in the formation of motile cilia in Xenopus epidermal multiciliated cells (MCCs). Tubb6 mRNA is selectively expressed in MCCs, and its protein product localizes to ciliary axonemes. Loss of Tubb6 leads to a marked reduction in cilia number and length, resulting in defective MCC function. In contrast, mono-motile cilia in the gastrocoel roof plate are unaffected by Tubb6 depletion, suggesting a selective requirement for ciliogenesis in MCCs. Together, our findings uncover a cell type-specific role for Tubb6 in motile cilia formation and highlight the functional specialization of tubulin isotypes in vertebrate cilia assembly.

developmental biology↗

bioRxiv2025

Beyond the Axoneme: Whole-Cell Proteomics Identifies Novel Regulators of Ciliogenesis in Xenopus Epidermal Multiciliated Cells

Motile cilia generate directional fluid flow critical for development and tissue homeostasis, and their dysfunction underlies a range of human diseases. Prior proteomic studies have focused on isolated axonemes, leaving the regulatory components of ciliogenesis located in other cellular compartments of multiciliated cells (MCCs) largely unidentified. To bridge this gap, we performed whole-cell proteomic profiling of MCCs in Xenopus using an inducible system that enables selective MCC-enrichment. Leveraging a single-vessel in-cell proteomics approach with ultra-high sample preservation, we identified over 9,000 proteins, including 832 upregulated in MCCs. These encompassed both established ciliary components and novel candidates localized to distinct ciliary structures. Functional validation confirmed the involvement of previously uncharacterized proteins in ciliogenesis. This study presents a high-resolution, whole-cell proteome of vertebrate MCCs, providing critical insights into the molecular networks that govern ciliogenesis and offering a valuable resource for understanding the mechanisms of cilia-related disorders.

developmental biology↗

bioRxiv2025

α7 nicotinic acetylcholine receptors regulate radial glia fate in the developing human cortex

Prenatal nicotine exposure impairs fetal cortical grey matter volume, but the precise cellular mechanisms remain poorly understood. This study elucidates the role of nicotinic acetylcholine receptors (nAChRs) in progenitor cells and radial glia (RG) during human cortical development. We identify two nAChR subunits--CHRNA7 and the human-specific CHRFAM7A--expressed in SOX2+ progenitors and neurons, with CHRFAM7A particularly enriched along RG endfeet. nAChR activation in organotypic slices and dissociated cultures increases RG proliferation while decreasing neuronal differentiation, whereas nAChR knockdown reduces RG and increases neurons. Single-cell RNA sequencing reveals that nicotine exposure downregulates key genes in excitatory neurons (ENs), with CHRNA7 or CHRFAM7A selectively modulating these changes, suggesting an evolutionary divergence in regulatory pathways. Furthermore, we identify YAP1 as a critical downstream effector of nAChR signaling, and inhibiting YAP1 reverses nicotine-induced phenotypic alterations in oRG cells, highlighting its role in nicotine-induced neurodevelopmental pathophysiology.

neuroscience↗

bioRxiv2024

Local ionic conditions modulate the aggregation propensity and influence the structural polymorphism of alpha-synuclein

Parkinsons Disease (PD) is characterized by the aggregation of alpha-synuclein (aSyn), a presynaptic protein that transitions from a disordered monomer into beta-sheet rich amyloid fibrils. The precise triggers and mechanisms underlying aSyn misfolding and aggregation remain unclear, hindering the development of effective therapeutics. Monomeric aSyn is an intrinsically disordered protein (IDP) with high conformational flexibility. Local environmental factors, such as ion concentrations, can influence the conformational ensemble of aSyn, impacting its aggregation propensity and resulting in fibril polymorphism. In this study, we explore the impact of physiologically relevant ions, mainly Ca2+ and Na+, on the aggregation kinetics, monomer structural dynamics, and fibril polymorphism of aSyn. Using ThT fluorescence assays, we demonstrate that all ions accelerate aSyn aggregation, with Ca2+ having the most significant effect. Using Heteronuclear Single Quantum Correlation Nuclear Magnetic Resonance (1H-15NHSQC NMR) spectroscopy, we validate the specific binding of Ca2+ ions at the C-terminus, whereas Na+ ions display non-specific interactions along the sequence of aSyn. Small-angle neutron scattering (SANS) and hydrogen-deuterium exchange mass spectrometry (HDX-MS) further reveal that Na+ and Ca2+ induce distinct conformational changes in the aSyn monomer, with Na+ leading to more extended structures and Ca2+ promoting a moderate extension of the protein. Molecular dynamics simulations (MD) corroborate these findings, showing that Na+ ions increase the proteins extension, particularly between the non-amyloid beta component (NAC) region and the C-terminus, whereas Ca2+ ions bias the ensemble towards a more moderately elongated structure. Using MD, we further investigate the local environment and in particular the solvent effect and show the water persistence times in the hydration shell are also increased in the presence of Ca2+ ions, indicating that the aggregation propensity of the monomer is due to a combination of conformational bias of the monomer and solvent mobility. Atomic force microscopy (AFM) of aSyn fibrils formed under these different ionic conditions reveal distinct fibril polymorphs, suggesting that ion-induced conformational biases in the monomer contribute to the diversity of fibril structures. Collectively, these findings underscore the pivotal influence of the local ionic milieu in shaping the structure and aggregation propensity of aSyn, thus offering valuable insights into the molecular underpinnings of PD and potential therapeutic avenues aimed at manipulating aSyn conformational dynamics.

biophysics↗

bioRxiv2023

Transcranial ultrasound stimulation effect in the redundant and synergistic networks consistent across macaques

Low-intensity transcranial ultrasound stimulation (TUS) is a non-invasive technique that safely alters neural activity, reaching deep brain areas with good spatial accuracy. We investigated the effects of TUS at the level of macaque using a recent metric, the synergy minus redundancy rank gradient, that quantifies different kinds of causal neural information processing. We analyzed this high-order quantity on the fMRI data after TUS in two targets: the supplementary motor area (SMA-TUS) and the frontal polar cortex (FPC-TUS). The TUS produced specific changes at the limbic network at FPC-TUS and the motor network at SMA-TUS and altered, in both targets, the sensorimotor, temporal, and frontal networks, consistent across macaques. Moreover, there was a reduction in the structural and functional coupling after both stimulations. Finally, the TUS changed the intrinsic high-order network topology, decreasing the modular organization of the redundancy at SMA-TUS and increasing the synergistic integration at FPC-TUS.

neuroscience↗

bioRxiv2023

The inter-continental population dynamics of Neisseria gonorrhoeae

Neisseria gonorrhoeae is a globally distributed sexually transmitted bacterial pathogen. Recent studies have revealed that its evolution has been shaped by antibiotic use, while molecular surveillance efforts have demonstrated large changes in lineage composition over relatively short time-spans. However, the global population dynamics of N. gonorrhoeae remain unsatisfyingly characterized. To reconstruct recent large-scale population dynamics, we generated a dated phylogeny from 9,732 N. gonorrhoeae genomes and found the effective population size of the species to have expanded gradually over the past two centuries. While the effective population size of clades with reduced susceptibility to extended-spectrum cephalosporins started declining around 2010, a major clade containing a mosaic mtr operon associated with cephalosporin susceptibility and decreased azithromycin did not display any reduction in population size. Using ancestral trait reconstruction analyses, we delineated transmission lineages, defined as groups of sequences in which all the samples can be traced back to the same import event to a given location. Import, export and local transmission dynamics across two densely sampled locations (Norway and Victoria, Australia) were investigated in detail. Norway exhibited substantially higher rates of strain import and export compared to Victoria, where incidence was to a larger extent fuelled by locally transmitted lineages. Taken together, our work highlights the power of large-scale phylogenomic analyses to uncover the complex dynamics of lineage transmission in N. gonorrhoeae.

microbiology↗

bioRxiv2023

Characterization of extracellular vesicles isolated from Sorghum bicolor reveals a conservation between monocot and eudicot extracellular vesicle proteomes

Plant extracellular vesicles (EVs) are membrane bound organelles involved mainly in intercellular communications and defense responses against pathogens. Recent studies have demonstrated the presence of proteins, nucleic acids including small RNAs, and lipids along with other metabolites in plant EVs. In this paper, we described the isolation and characterization of extracellular vesicles from Sorghum bicolor. Nanoparticle tracking analysis, dynamic light scattering, and cryo-electron tomography showed the presence of a heterogeneous population of EVs isolated from the apoplastic wash of sorghum leaves. Cryo-electron microscopy revealed that EVs had a median size of 110 nm and distinct populations of vesicles with single or multiple lipid bilayers and low or high amounts of contents. The heterogeneity was further supported by data showing that only a subset of EVs that were stained with a membrane dye, Potomac Gold, were also stained with the membrane-permeant esterase-dependent dye, Calcein-acetoxymethyl ester. Proteomic analysis identified 437 proteins that were enriched in multiple EV isolations, with the majority of these also being found in the EV proteome of Arabidopsis. These data suggest a partial conservation of EV contents and function between the monocot, sorghum, and a distantly related eudicot, Arabidopsis.

plant biology↗

bioRxiv2023

Structure of the Commander endosomal trafficking complex linked to X-linked intellectual disability/Ritscher-Schinzel syndrome

The Commander complex is required for endosomal recycling of diverse transmembrane cargos and is mutated in Ritscher-Schinzel syndrome. It comprises two subassemblies; Retriever composed of VPS35L, VPS26C and VPS29, and the CCC complex which contains ten subunits COMMD1-COMMD10 and two coiled-coil domain-containing (CCDC) proteins CCDC22 and CCDC93. Combining X-ray crystallography, electron cryomicroscopy and in silico predictions we have assembled a complete structural model of Commander. Retriever is distantly related to the endosomal Retromer complex but has unique features preventing the shared VPS29 subunit from interacting with Retromer-associated factors. The COMMD proteins form a distinctive hetero-decameric ring stabilised by extensive interactions with CCDC22 and CCDC93. These adopt a coiled-coil structure that connects the CCC and Retriever assemblies and recruits a sixteenth subunit, DENND10, to form the complete Commander complex. The structure allows mapping of disease-causing mutations and reveals the molecular features required for the function of this evolutionarily conserved trafficking machinery.

biochemistry↗

bioRxiv2022

Mining the human gut microbiome identifies mycobacterial D-arabinan degrading enzymes

Division and degradation of bacterial cell walls requires coordinated action of a myriad of enzymes. This particularly applies to the elaborate cell walls of acid-fast organisms such as Mycobacterium tuberculosis, which consist of a multi-layered cell wall that contains an unusual glycan called arabinogalactan. Enzymes that cleave the O_SCPLOWDC_SCPLOW-arabinan core of this structure have not previously been identified in any organism. We have interrogated the diverse carbohydrate degrading enzymes expressed by the human gut microbiota and uncovered four families of glycoside hydrolases with the capability to degrade the O_SCPLOWDC_SCPLOW-arabinan or O_SCPLOWDC_SCPLOW-galactan components of arabinogalactan. Using novel exo-O_SCPLOWDC_SCPLOW-galactofuranosidases from gut bacteria we generated enriched O_SCPLOWDC_SCPLOW-arabinan and used it to identify D. gadei as a D-arabinan degrader. This enabled the discovery of endo- and exo-acting enzymes that cleave D-arabinan. We have identified new members of the DUF2961 family (GH172), and a novel family of glycoside hydrolases (DUF4185) that display endo-O_SCPLOWDC_SCPLOW-arabinofuranase activity. The DUF4185 enzymes are conserved in mycobacteria and found in many microbes, suggesting that the ability to degrade mycobacterial glycans plays an important role in the biology of diverse organisms. All mycobacteria encode two conserved endo-O_SCPLOWDC_SCPLOW-arabinanases that display different preferences for the O_SCPLOWDC_SCPLOW-arabinan-containing cell wall components arabinogalactan and lipoarabinomannan, suggesting they are important for cell wall modification and/or degradation. The discovery of these enzymes will support future studies into the structure and function of the mycobacterial cell wall.

biochemistry↗

bioRxiv2022

Latitudinal gradient in species diversity provides high niche opportunities for a range-expanding phytophagous insect

O_LIWhen species undergo poleward range expansions in response to anthropogenic change, they likely encounter less diverse communities in new locations. If low diversity communities provide weak biotic interactions, such as reduced competition for resources or predation, range-expanding species may experience high niche opportunities. C_LIO_LIHere, we uncover if oak gall wasp communities experience a latitudinal diversity gradient (LDG) and weaker interactions at the poles that might create high niche opportunities for a range-expanding community member. C_LIO_LIWe performed systematic surveys of oak gall wasps on a dominant oak, Quercus garryana, throughout most of its range, from northern California to Vancouver Island, British Columbia. On 540 trees at 18 sites, we identified 23 species in three guilds (leaf detachable, leaf integral, and stem galls). We performed regressions between oak gall wasp diversity, latitude, and other abiotic and habitat factors to reveal if cynipid communities follow an LDG. To uncover patterns in local interactions, we performed partial correlations on oak gall wasps co-occurring on trees within regions. Finally, we performed regressions between abundances of co-occurring gall wasps on trees to reveal potential interactions. C_LIO_LIQ. garryana-gall wasp communities followed an LDG, with lower diversity at higher latitudes, particularly with a loss of detachable leaf gall species. Detachable leaf gall wasps, including the range-expanding species, co-occurred most on trees and had weak interactions in the northern region. Abundances of the range-expander and detachable and integral leaf galls co-occurring on trees were negatively related, suggesting antagonistic interactions. Overall, we found that LDGs create communities with weaker antagonistic interactions at the poles that might facilitate ecological release in a range-expanding community member. C_LIO_LIHere, we uncover how regional and local scale patterns and processes create high niche opportunities for a range-expanding community member. This research provides insight into how biogeographical patterns in communities and species interactions influence the outcome of range expansions. Given the ubiquity of LDGs, these outcomes might be expected in other phytophagous insect communities. C_LI

ecology↗

bioRxiv2022

Lem2 is essential for cardiac development by maintaining nuclear integrity

Nuclear envelope integrity is essential for compartmentalisation of nucleus and cytoplasm. Importantly, mutations in nuclear envelope-encoding genes are the second-highest cause of familial dilated cardiomyopathy. One such nuclear envelope protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in mechanically active tissue such as heart remains poorly understood. We generated mice in which Lem2 was specifically ablated in cardiomyocytes and carried out detailed physiological, tissue and cellular analyses. Importantly, our data showed that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and conversely were exacerbated upon myosin activation. Our data suggest that Lem2 is critical for integrity at the nascent nuclear envelope in fetal hearts, and protects the nucleus from the mechanical forces of muscle contraction. Taken together, these data provide novel insight into mechanisms underlying striated muscle diseases caused by altered nuclear envelope integrity.

cell biology↗