Biology subjects

Sun, S.

Publications and source records attributed to Sun, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Transcranial Magnetic Stimulation Differentiates Egocentric vs. Allocentric Network Hubs for Memory-Guided Reach

Previous patient and imaging studies suggest that dorsal and ventral visual stream mechanisms contribute selectively to egocentric (eye-centred) and allocentric (landmark-centred) goal-directed behaviours, respectively. However, causal evidence for this ego-allocentric dissociation in healthy brains is lacking. Based on a recent neuroimaging study, we hypothesized that perturbations to dorsal stream network hubs would disrupt both egocentric and allocentric reaches, whereas perturbations to ventral hubs would affect only allocentric reaches. Sixteen participants viewed a briefly presented target in the presence of a landmark that later shifted after a memory interval. Participants were instructed to 1) ignore the landmark and reach toward / opposite the original target location (egocentric task) or 2) reach toward the targets location fixed relative to the shifted landmark (allocentric task). Transcranial magnetic stimulation (TMS) was applied during the memory period, spanning the landmark shift, at two occipital sites, based on the network hub coordinates from our previous study and individual brain anatomy. As predicted, superior occipital TMS impaired reaction time, accuracy, and precision in both tasks, whereas inferior occipital TMS only impaired allocentric performance. Further, spatial asymmetries in the resulting error patterns were influenced by TMS site and task: superior occipital TMS influenced asymmetries more strongly in the egocentric task, whereas inferior occipital TMS only influenced spatial asymmetries in the allocentric task. Finally, a functional network analysis revealed a widespread influence of TMS on network-behavior relations and another dissociation: greater influence of superior occipital TMS on the egocentric task and of inferior occipital TMS on the allocentric task. These results establish specific causal relationships between occipital hubs, widespread cortical networks, and reach behavior, confirming a default dorsal egocentric transformation for visually aimed reaches, and a role for the ventral stream for landmark-centred actions.

neuroscience↗

bioRxiv2026

Single-cell foundation modeling with species-nativeprotein tokens links regenerative competence across frog and mouse

Appendage regenerative capacity varies dramatically across species, developmental stages, and anatomical sites, yet comparing functional transitions across organisms remains difficult because gene vocabularies diverge. Cross-species single-cell analysis conventionally collapses divergent genomes to one-to-one orthologs--a reduction that is not neutral. Here, we construct a species-native input representation for allotetraploid Xenopus laevis that preserves duplicated L and S homeologs (96.39% feature coverage versus 53.14% under symbol collapse) within a frozen universal cell embedding (UCE). A causally validated tail-organizer contrast defines a portable vector competence ruler. While baseline representations (direct expression, SVD, Harmony) recover organizer identity, only species-native UCE preserves the stage-52-versus-stage-58 limb competence transition, which ortholog collapse reverses. Applied without refitting, the ruler distinguishes regenerative from fibrotic digit repair in adult mice and resolves an aligned component in state-balanced macrophages, an ordering reproduced by simpler representations. Preserving species-native gene vocabularies carries functional contrasts across evolutionary and genomic boundaries.

bioinformatics↗

bioRxiv2026

A Chairside Multimodal Platform for Temporomandibular Joint Biomechanical Assessment: Technical Evaluation and Illustrative Application

BackgroundTemporomandibular joint (TMJ) biomechanics can be characterized by mandibular motion, masticatory muscle activity, and bite force generation. When acquired synchronously, these functional variables can serve as model-ready inputs for subject-specific computational analyses of internal joint mechanics. However, existing tools typically measure these signals using separate hardware and software platforms, limiting synchronized acquisition within a clinically practical chairside workflow. MethodsWe developed and technically evaluated a compact multimodal platform for chairside acquisition of TMJ functional data and demonstrated its analytical utility in an illustrative orthognathic surgery application. The platform integrates motion, bite force, muscle activity, acoustic, and event-timing measurements with software for real-time preview, protocol guidance, and synchronized export. We assessed technical performance and chairside feasibility and analyzed representative pre- and postoperative data from an orthognathic surgery patient using kinematic, force-control, and computational modeling workflows. FindingsMotion capture demonstrated submillimeter accuracy, with static and dynamic errors of approximately 0.04 mm and 0.12 mm. Bite force sensors showed excellent linearity (R{superscript 2} = 0.998). Chairside deployment required approximately 15 minutes each for setup and data collection. The illustrative case demonstrated that synchronized chairside data can support preoperative and postoperative kinematic analysis, bite force control capacity assessment, and estimation of TMJ disc stress. InterpretationThe proposed platform enables time-efficient chairside acquisition of synchronized, model-ready multimodal datasets for quantitative TMJ biomechanical assessment. This platform and workflow could support subject-specific biomechanical analysis and future clinical studies of temporomandibular joint function.

bioengineering↗

bioRxiv2026

Multiscale Biomechanical and Electrophysiological Modeling of Nociceptive Activation in Musculoskeletal Joint Disorders: Insights from the Temporomandibular Joint

Background and objectiveMusculoskeletal joint disorders often show inconsistent relationships between structural degeneration and nociceptive pain. Temporomandibular joint (TMJ) disc displacement represents a clinically relevant model for investigating the structure-function-pain relationship. This study aimed to develop a multiscale computational framework integrating biomechanics, three-dimensional (3D) neural morphology, and electrophysiology to quantitatively link TMJ structural alterations, biomechanical loading, and peripheral nociceptive activation. MethodsStrain distributions in the TMJ disc and retrodiscal tissue during mouth opening and clenching were computed in ArtiSynth under varying degrees of displacement. Human TMJ 3D nerve architecture was reconstructed using porcine TMJ nerve mapping data as an anatomical reference, and ion channel dynamics were implemented in NEURON. Model coupling was achieved by mapping biomechanical strain fields onto nociceptor membranes to simulate mechanosensitive currents and action potential propagation to the trigeminal ganglion. ResultsAnterior DDwoR induced a severity dependent strain pattern in the TMJ disc and retrodiscal tissue, including posterior redistribution, increased strain magnitude, prolonged activation, and broader retrodiscal tissue involvement. Displacements of 4, 6, and 8 mm produced larger mechanosensitive currents, broader terminal depolarization, and higher trigeminal firing rates during mouth opening (6, 18, and 28 Hz) and clenching (8, 20, and 28 Hz), whereas 0- and 2-mm displacements produced negligible neural activation. ConclusionsThis study establishes a multiscale biomechanical-electrophysiological framework linking TMJ structural alterations to peripheral nociceptive activation. The framework quantitatively connects macroscale strain patterns with microscale neural activation, suggesting that anterior disc displacement may amplify peripheral nociceptive signaling by increasing the overlap between elevated strain and densely innervated retrodiscal tissue.

bioengineering↗

bioRxiv2026

Lipid Headgroup Hydration Regulates Distinct Remodeling of the Membrane Interface by Polyethylene Glycol and Dextran

Water-soluble polymers commonly interact with cell membranes, but their interactions are poorly understood. Here, we investigate polyethylene glycol (PEG) and dextran (DEX) interactions with different model lipid membranes. Using total internal reflection fluorescence microscopy, we observe that PEG and DEX trigger strikingly different membrane responses - DEX induces extensive membrane remodeling, including localized multilamellar domain formation, while PEG does not. Combining fluorescence spectroscopy, fluorescence anisotropy, and vibrational sum frequency spectroscopy, we show that DEX perturbs lipid headgroup hydration by displacing interfacial water with minimal effects on lipid packing, while PEG largely preserves this hydration layer. We find that membrane binding affinity alone does not determine the extent to which hydrophilic polymers perturb membrane structure and interfacial properties; and that lipid headgroup hydration, rather than lipid charge, is a general regulator of hydrophilic polymer-membrane interactions. This work gives mechanistic insights into how neutral polymers interact with cells and vesicles, with relevance to cell biology and drug delivery. O_FIG O_LINKSMALLFIG WIDTH=169 HEIGHT=200 SRC="FIGDIR/small/739366v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@16f7374org.highwire.dtl.DTLVardef@4e94forg.highwire.dtl.DTLVardef@7175dcorg.highwire.dtl.DTLVardef@f0e5b9_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2026

IL-21-producing peripheral helper T cells associate with autoimmune bile duct injury in biliary atresia

BackgroundBiliary atresia (BA) is a severe neonatal liver disease characterized by progressive fibrosis and bile duct obliteration. ObjectiveAlthough immune dysregulation is implicated in the pathogenesis of BA, the specific mechanisms driving bile duct injury remain incompletely understood. This study aimed to characterize tertiary lymphoid structures (TLSs) within extrahepatic biliary remnants (EBRs), identify their cellular mediators, and evaluate the therapeutic potential of targeting IL-21 receptor signaling. DesignWe performed integrated bulk RNA sequencing, single-cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and flow cytometry on clinical samples from BA patients and non-BA cholestatic controls. TLS maturation was assessed by CD23 immunohistochemistry in EBRs from 148 BA patients and correlated with clinical parameters. Anti-IL-21R antibody treatment was evaluated in a rhesus rotavirus-induced BA mouse model, with treatment initiated on day 4 post-infection. ResultsTLSs were identified in BA EBRs with significantly higher prevalence than in matched liver tissues. Mature TLSs containing CD23 germinal centers were associated with elevated serum matrix metalloproteinase-7, more advanced hepatic fibrosis, and localized autoantibody deposition on injured bile ducts. Single-cell profiling revealed expanded CD4+ T peripheral helper (Tph) cells expressing IL-21 and CXCL13 within TLS-containing EBRs. Tph cells were enriched in peripheral blood of BA patients compared to non-BA cholestatic controls (P = 0.0025), and serum IL-21 was significantly elevated (P < 0.0001). Post-infection IL-21R blockade in the mouse model reduced jaundice incidence, improved weight gain, prevented extrahepatic biliary obstruction, and significantly improved long-term survival. ConclusionTLSs in BA extrahepatic biliary remnants harbor expanded Tph cells associated with IL-21-mediated B cell activation and bile duct injury. IL-21R blockade ameliorated disease in a murine BA model, identifying the IL-21/IL-21R axis as a potential therapeutic target warranting further investigation. Key MessagesO_ST_ABSWhat is already known on this topicC_ST_ABSImmune dysregulation contributes to biliary atresia (BA), with documented lymphocyte infiltration and defective B cell tolerance. However, the cellular mechanisms linking local immune activation to bile duct injury are unclear, and the roles of organized lymphoid structures and specific CD4 T cell subsets in orchestrating local humoral responses have not been characterized. What this study addsThis study demonstrates that mature tertiary lymphoid structures in extrahepatic biliary remnants are associated with disease severity markers and localized bile duct injury in BA. We identify T peripheral helper cells as an expanded IL-21-producing CD4 T cell population within these structures, and show that post-infection IL-21 receptor blockade prevents biliary obstruction and improves survival in a murine BA model. How this study might affect research, practice or policyThese findings identify the IL-21/IL-21R signaling axis as a candidate therapeutic target in BA warranting further preclinical and translational investigation. TLS maturation status in biliary remnants and serum autoantibody levels may serve as potential biomarkers of disease severity, meriting prospective evaluation in clinical cohorts.

immunology↗

bioRxiv2026

RD-OMICS: An Integrative Multi-Omics Data Inventory in Rare Diseases

Rare diseases (RD) impact over 30 million individuals in the United States, yet fewer than 5% of the identified conditions have FDA-approved treatments. Progress in RD research is hindered by small patient cohorts, biological heterogeneity, and the fragmented, inconsistently annotated publicly available omics data, which limits integrative analysis and translational discovery. Here, we present RD-OMICS, a data inventory with integrated and structured RD omics data from Gene Expression Omnibus (GEO), in the form of a knowledge graph. We developed a metadata harmonization pipeline that combines rule-based mapping and large language model (LLM)-assisted semantic categorization. The graph-based data model was defined to integrate different types of data including disease conditions, experiments, samples, platforms, projects, and publications into a centralized inventory graph. In this preliminary study, 11,049 GEO series for 126 rare diseases were processed and integrated into RD-OMICS, which includes 375,930 individual biospecimen samples, 1,578 sequencing and array platforms, 10,938 biological projects. Case studies demonstrate the use of RD-OMICS in supporting rare disease research, omics cohort construction, and transcriptome-based drug repurposing for amyotrophic lateral sclerosis (ALS). RD-OMICS provides a scalable foundation for transforming fragmented omics data into a structured, harmonized and interoperable resource, facilitating therapeutic development and other translational discoveries in rare diseases.

bioinformatics↗

bioRxiv2026

SpaGRD deciphers signaling architectures in spatial transcriptomics using graph reaction-diffusion systems

The rapid emergence of spatial transcriptomics offers unprecedented opportunities to study cell-cell communication (CCC) by capturing gene expression alongside spatial context. However, existing CCC inference methods often rely on static, heuristic models that overlook the inherently spatiotemporal dynamics and mechanistic complexity of intercellular signaling, limiting both accuracy and biological interpretability. Here, we present SpaGRD, a first-principles-based method that explicitly models ligand-receptor interactions through partial differential equations derived from Ficks law of diffusion and the mass action law. Leveraging graph signal processing techniques, SpaGRD solves these equations on spatial graphs, providing a principled and generalizable approach to CCC inference. Through extensive simulations, SpaGRD demonstrates superior accuracy and robustness compared to existing methods. Applications to multiple datasets across diverse tissues and platforms reveal dynamic CCC patterns with spatially resolved signaling heterogeneity, providing biologically meaningful insights into cellular coordination and developmental processes. By bridging physical modeling with spatial transcriptomics, SpaGRD provides an accurate, interpretable, and mechanistically grounded framework for advancing quantitative studies of spatiotemporal cell-cell communication.

bioinformatics↗

bioRxiv2026

Generation of three induced pluripotent stem cell lines from an immune checkpoint inhibitor-induced myocarditis patient and controls

Immune checkpoint inhibitor-associated myocarditis (ICIM) is an uncommon but potentially fatal inflammatory heart disease triggered by cancer immunotherapy, with up to 40% mortality. The underlying mechanisms are still elusive, partly due to the lack of appropriate human disease models. Here, we report the generation of three induced pluripotent stem cell (iPSC) lines derived from an ICIM patient, an ICI-treated patient without myocarditis, and a healthy donor. These lines exhibit typical pluripotent stem cell morphology, express pluripotency markers, maintain normal karyotypes, and differentiate into derivatives of the three germ layers, providing a valuable platform for mechanistic studies and therapeutic discovery.

Developmental Biology↗

bioRxiv2026

Integrative Multi-Omics Analysis of Gut Microbiota Dysbiosis and Host-Microbiome Interaction Mechanisms in Hypertension

ObjectiveTo characterize gut microbiota dysbiosis in hypertension and investigate its multilevel interactions with the host immune system. MethodsIntegrated multi-cohort microbiome data were used to evaluate microbial diversity, differential abundance, and co-occurrence network features between individuals with hypertension and healthy controls. The scBPS framework was applied to analyze microbiome-cell associations, enabling the resolution of relationships between key microbial taxa and functional states of immune cells at single-cell resolution. ResultsSeveral potentially protective genera reduced in hypertension and occupied central topological positions in the co-occurrence networks. Single-cell analyses further demonstrated that multiple key genera were closely associated with the functional states of monocytes and T cells (p<0.05). Specifically, Bacteroides and Bifidobacterium were associated with the proliferation and repair of classical monocytes; Butyricimonas showed a negative association with antigen processing and presentation pathways in monocytes; and Oscillospira promoted the transition of dnT cells toward an immunoregulatory state, suggesting its potential role in immune homeostasis. ConclusionsIntegrated multi-omics analyses reveal that hypertension-associated gut microbes may contribute to disease development through immune regulation, providing insights into microbiome-immune interaction mechanisms and potential targets for precision interventions.

microbiology↗

bioRxiv2026

Xist expression in male Peromyscus leucopus is associated with restricted chromatin repression and incomplete X-to-autosome dosage compensation

X-chromosome inactivation (XCI) equalizes X-linked gene dosage between XX females and XY males in eutherian mammals and is canonically initiated by the long noncoding RNA Xist, which coats one X chromosome and recruits Polycomb-mediated chromatin silencing. Xist expression has therefore been considered female-specific and central to balancing gene dosage between two X chromosomes in females and a single X chromosome in males. However, emerging evidence suggests that Xist can also be expressed in male cells in both healthy and pathogenic contexts, raising fundamental questions about the scope and constraints of Xist function. Here, we identify robust Xist expression in somatic cells of male white-footed deermice (Peromyscus leucopus), a placental mammal with a conventional XY karyotype. Unlike the chromosome-wide Xist RNA coating observed in females, male Xist RNA localizes as discrete nuclear puncta and is detected across multiple tissues by RNA-seq, RT-qPCR, and RNA fluorescence in situ hybridization. Integrative transcriptomic and chromatin profiling using CUT&Tag and single-nucleus Paired-Tag reveals that male Xist expression is not merely incidental but has measurable regulatory consequences. In females, Xist expression is associated with chromosome-wide enrichment of the repressive histone mark H3K27me3 and transcriptional silencing of X-linked genes. In males, although Xist transcription is also associated with H3K27me3, this interaction does not induce global X-chromosome inactivation. Instead, Xist selectively represses a subset of dosage-sensitive neural and mitochondrial X-linked genes, while the majority of X-linked genes remain largely active. Notably, with persistent Xist activity, neither males nor females achieve complete X-to-autosome dosage compensation in P. leucopus. These findings establish P. leucopus as a mammalian system in which male Xist operates outside the canonical female-specific XCI pathway, revealing a gene-selective model of X-chromosome regulation. Our results challenge the universality of prevailing XCI models and suggest that partial, context-dependent Xist activity represents a viable and evolutionarily stable dosage compensation strategy in mammals. Author SummaryIn mammals, females and males differ in their sex chromosome: females have two X chromosomes, while males have one. This difference creates a potential imbalance in gene dosage, which can disrupt development if not properly controlled. Typically, females compensate by turning off one chromosome through a process called X-chromosome inactivation (XCI), which is triggered by the long noncoding RNA Xist. In parallel, a process known as X-to-autosome dosage compensation balances X-linked gene expression relative to the rest of the genome. Because XCI occurs in females, Xist has long been considered to function only in female cells and be inactive in males. Here, we show that Xist is persistently expressed in male white-footed deermice (Peromyscus leucopus), a cricetid rodent with a conventional XY sex chromosome system. Unlike the large Xist RNA "cloud" that covers the inactive X chromosome in females, Xist RNA in males appears as small, discrete spots in the nucleus. By combining gene expression and chromatin profiling, we find that male Xist associates with the repressive histone mark H3K27me3 but does not switch off the entire X chromosome. Instead, Xist in males selectively reduces the activity of a limited set of X-linked genes, while most X-linked genes remain active. Surprisingly, we also find that neither male nor female P. leucopus achieves complete balance between X-linked and autosomal gene expression, despite the long-held view that such balance is essential for mammalian viability. By uncovering functional Xist activity in males of a non-model species and demonstrating incomplete dosage compensation in both sexes, this work challenges the traditional view of XCI as a strictly female-specific strategy and reveals an unexpected flexibility in how mammals regulate the X chromosome.

genetics↗

bioRxiv2026

The HUSH Complex Dictates EBV-transformed B cell Sensitivity to NK Cell Surveillance Through Repression of NKG2A Ligand γ-Proto-cadherin

Natural Killer (NK) cells control Epstein-Barr virus (EBV), though how EBV+ B-cells escape NK surveillance to form tumors remains unknown. To gain insights, we performed a human genome-wide CRISPR-Cas9 screen in EBV-transformed lymphoblastoid cell lines (LCL). This revealed that the HUSH complex maintains LCL sensitivity to NK. HUSH knockout (KO) de-repressed LCL protocadherin gamma (PCDHG), typically expressed by neurons. PCDHG expression protected LCLs from NK and was necessary for HUSH KO-driven NK resistance. CRISPR analyses revealed NKG2A/CD94 as the PCDHG NK inhibitory counter-receptor, and NKG2A KO restored NK lysis of HUSH KO LCLs. HUSH perturbation impaired NK control of murine LCL xenografts in vivo. A subset of follicular lymphoma (FL) upregulate PCDHG, and PCDHG KO enhanced FL lysis by NK. Therefore, HUSH plays dual roles in foreign DNA surveillance and in support of NK, potentially as a neuronal dont kill me signal that can be exploited by transformed cells.

immunology↗

bioRxiv2026

β-Catenin Drives Apical-Basal Polarization to facilitate TE lineage commitment In Vitro and In Vivo

Embryo polarization is critical for the first cell fate segregation. While mechanisms underlying its initiation have been described, the intrinsic signaling pathways that regulate this process remain poorly understood. Here, we show that mouse embryonic stem cells, when aggregated under defined conditions, recapitulate the first lineage segregation to generate trophectoderm (TE)-like cell populations and undergo self-organized morphogenesis into blastocyst-like structures. In the blastoid-forming medium, we identify CHIR99021 is essential for the generation of blastoids from both ESCs and totipotent-like cells. CHIR99021 promotes cell polarization and TE differentiation by activating the WNT/{beta}-catenin pathway and upregulating associated genes. Consistent with this, genetic ablation of {beta}-catenin abolished the cell polarization and disrupted blastoid formation from ESCs, a defect that was restored by {beta}-catenin overexpression. Moreover, {beta}-catenin depletion compromised cell polarization in natural embryos. Collectively, this study establishes the Wnt/{beta}-catenin as a critical regulator initiating polarization in vitro and in mouse early embryo development.

developmental biology↗

bioRxiv2026

Directional bone matrix mineralization in the CAM assay is governed by vascular integration and matrix remodeling

Bone matrix mineralization plays an important role in maintaining bone health but is a highly dynamic process for which few physiologically relevant model systems exist. The chorioallantoic membrane (CAM) assay is one such assay and has been used to study biomineralization; however, the mechanisms controlling mineral deposition in the CAM assay remain poorly understood. Here, we implanted decellularized, organic bone matrices onto the CAM and investigated their mineralization using a combination of micro-computed tomography, Raman spectroscopy, scanning electron microscopy, and histochemistry. These studies revealed increased mineralization and microvessel density on the shell-facing interface of the implanted matrices, while their embryo-facing counterpart lacked mineralization but was densely infiltrated by cells. Seeding organic bone matrices with mesenchymal stromal cells (MSCs) prior to CAM-implantation prevented mineralization by altering matrix micro- and nanostructure and limiting vessel integration. Collectively, our results suggest that mineral precursors from the eggshell and vasculature combine to mineralize organic bone matrix in the CAM assay, while proteolytic remodeling by invaded or implanted stromal cells inhibits that process. Our findings provide critical new insights into the interplay between acellular and cellular drivers of bone matrix mineralization, and will inform future studies of biomineralization using the CAM assay.

bioengineering↗

bioRxiv2026

Elamipretide reverses female fertility decline during reproductive aging via regulating VEGF in oocytes

Aging is one of the primary drivers for the decline of female fertility, and oocyte quality is the main cause for ovary aging, which is related with infertility. Although some effective anti-aging natural components have been reported, highly efficient strategies for reversing ovary aging remain lacking. In this study, we reported that peptide elamipretide reserved ovary function for female fertility during maternal aging. Our findings demonstrated that elamipretide improved aged human oocyte maturation and fertilization. Elamipretide injection increased the litter size of aged mice, and improved oocyte quality with the reverse of follicle and embryo development defect. Metabolomic and transcriptomic analyses demonstrated that multiple biological processes in oocytes were significantly reserved. Both nuclear maturation and cytoplasmic maturation of aged oocytes were improved, showing with enhancing cytoskeletal dynamics, mitochondrial metabolism and organelle rearrangement. In vitro supplementation during culture also restored oocyte developmental competence in both mouse and porcine oocytes. Mechanistic analysis suggested that elamipretide reversed age-related ovarian damage via synergistic activation of the Vitamin B6-VEGF axis. Therefore, our study proposed a new peptide therapy for aging-induced infertility, showing that elamipretide reverses aged oocyte quality for fertility by promoting both nuclear and cytoplasmic maturation through the coordination with VEGF signaling pathway.

developmental biology↗

bioRxiv2026

Genomic hallmarks of parasexual reproduction in three hybrid groups of the human pathogen Cryptococcus neoformans

Hybridization is a major driver of fungal evolution, yet knowledge of the molecular mechanisms underpinning hybridization and its genomic impact remain limited. Here, we analyse 197 Cryptococcus neoformans genomic sequences, including 13 newly sequenced strains, identifying three genetically clustered and distinct hybrid groups (H1, H2 and H3) each with unique parental origins and ecological associations. Using phylogenomics, population structure analyses, and long-read genome assemblies, we identified hybrid genomes with chromosome-wide loss of heterozygosity (LOH), inheritance of large intact parental haplotype blocks and widespread aneuploidy within and across genomes. These patterns are also observed when progeny were generated with spo11{Delta} parents, indicating these features are a result of a meiotic-independent process such as parasex. This is further underscored by discovery of haploid and near-haploid recombinants in both spo11{Delta} mutant progeny and reanalysed wild-type hybrid progeny. We hypothesise these haploid and near-haploid recombinants are generated through ploidy reduction via independent chromosome assortment because of concerted chromosomal loss, which is a key feature of the parasexual cycle. Phenotypic assays demonstrated that several hybrid isolates have diverse growth and virulence patterns, underscoring functional consequences of genome plasticity. Together, our work suggests a non-meiotic reproductive process contributes to shape the genotypic and phenotypic diversity of Cryptococcus neoformans.

genomics↗

bioRxiv2026

Active and unusually expanded PIF/Harbinger transposable elements in the Caenorhabditis inopinata genome

BackgroundTransposable elements (TEs) serve as powerful drivers of genome innovation but also threaten genome integrity. The PIF/Harbinger superfamily is distinctive among DNA transposons because mobilisation typically requires proteins, a DDE transposase and a MADF DNA-binding protein. Caenorhabditis inopinata, the closest known relative of C. elegans, has a TE-rich genome and lacks multiple components of the ERGO-1-class endogenous small-RNA pathway, making it a useful system for examining TE dynamics in a distinct host context. We identified a spontaneous dumpy mutant of C. inopinata caused by insertion of a PIF/Harbinger-family element into the coding region of Cin-dpy-11. The inserted element, designated Harbinger-1M_cIno, belongs to the Turmoil2 lineage originally defined in C. elegans and retains a MADF domain but lacks a recognisable DDE transposase ORF. Genome-wide curation recovered 258 related copies, revealing a strongly asymmetric family structure. Short noncoding derivatives were predominant, MADF-bearing derivatives were expanded and only one DDE-bearing locus retained an apparently intact transposase gene, suggesting that DDE and MADF functions are partitioned across distinct elements and may be supplied in trans during mobilisation. We also identified a second PIF/Harbinger-derived family, Harbinger-2M_cIno, associated with the Turmoil1 lineage. This family comprises 1,376 copies and therefore records substantial past amplification, but it lacks a detectable DDE source, shows greater sequence divergence and more degraded terminal structures than Harbinger-1M_cIno. Together, these data indicate that the two PIF/Harbinger lineages in C. inopinata differ not in whether amplification occurred, but in when it occurred and whether present-day mobilisation competence has been retained.

genetics↗

bioRxiv2026

The in vivo inhibitory function of the MHC-I alpha3 domain/CD8alpha interaction

The interaction between the Major Histocompatibility Complex Class I (MHC-I) 3 domain and CD8 has classically been viewed as a positive coreceptor interaction that stabilizes TCR signaling during antigen recognition. However, its physiological function in mature peripheral CD8+ T cells in vivo remains incompletely understood. Here, we identify the MHC-I 3 domain-CD8 interaction as a previously unrecognized inhibitory pathway that tonically restrains peripheral CD8+ T-cell activation and maintains T-cell tolerance in vivo. Antibody-mediated disruption of the MHC-I 3 domain-CD8 interaction induced spontaneous activation of peripheral CD8+ T cells without impairing their survival, lowered the threshold for antigen-induced activation, and enhanced responsiveness to cognate peptide stimulation. In peptide-induced OT-I T-cell anergy models, blockade of either H-2Db or H-2Kb 3 domain interactions with CD8 prevented the induction of anergy and restored responsiveness of previously anergic T cells. Notably, blockade of the H-2Kb 3 domain enhanced OT-I responses despite simultaneously disrupting the classical positive coreceptor interaction within the TCR-peptide-MHC complex, indicating that tonic inhibitory signaling mediated by the MHC-I 3 domain predominates under these conditions. Together, these findings redefine the classical MHC-I-CD8 interaction as a bidirectional pathway that not only supports antigen recognition but also imposes tonic inhibitory control over peripheral CD8+ T cells. These results identify the MHC-I 3 domain-CD8 axis as a potential target for reversing T-cell tolerance and enhancing antitumor or antiviral immunity.

immunology↗