Biology subjects

Sun, W.

Publications and source records attributed to Sun, W..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

Optimizing an avian influenza vaccine using a novel Bacterial Enzymatic Combinatorial Chemistry (BECC) TLR4 adjuvant

The development of broadly protective and dose-sparing influenza vaccines remains a critical challenge, particularly for zoonotic H5N1 strains with pandemic potential. This study evaluates BECC470s, a synthetic TLR4 adjuvant, for its ability to enhance the immunogenicity and protective efficacy of recombinant H5 hemagglutinin (rHA) vaccination in murine models. BECC470s-adjuvanted rHA elicited robust IgG1/IgG2a antibody responses and complete survival following homologous 2004 H5N1 challenge in a prime-boost model. Although BECC470s broadened antibody binding to both variable HA head and conserved stalk domains by ELISA, functional neutralizing antibody responses were restricted to the matched 2004 H5N1 isolate, with no detectable neutralization of H5N1 viruses isolated in 2022 or 2024. These data indicate that BECC470s enhances the magnitude and apparent breadth of binding antibody responses while maintaining strain-specific neutralizing activity, supporting its potential as an adjuvant for next-generation influenza vaccines while underscoring the need for further optimization to achieve true cross-neutralizing protection.

immunology↗

bioRxiv2026

Z-RNA-ZBP1 axis drives Tau-mediated neurodegeneration

Although the causes of Tau aggregates vary, once Tau aggregates are formed, their neurotoxicity significantly contributes to neuronal death and cognitive decline in tauopathies, with Alzheimers disease (AD) being the most well-known example. Despite its central pathogenic role, however, effective therapeutic strategies targeting neurotoxicity of Tau remain poor. Here we demonstrate the pathogenic role of neuronal cell death in Tau-related neurodegeneration. Tau-expressing neurons undergo cell death through Z-DNA-binding protein 1 (ZBP1) activation triggered by endogenous Z-RNAs. These Z-RNAs are derived from reactivated transposable elements (TEs) that are typically silenced within heterochromatin. Tau aggregates show a strong affinity for H3K9me3-modified chromatin, effectively sequestering these epigenetic marks from Heterochromatin Protein 1 (HP1), thereby disrupting the condensation of constitutive heterochromatin. Clinically, an inverse correlation between ZBP1 expression levels in excitatory neurons and cognitive performance in AD patients was observed. Importantly, Zbp1 haploinsufficiency significantly ameliorated cognitive deficits in aged Tau-transgenic mice (24-month-old), highlighting the therapeutic potential of ZBP1 inhibition to strive against neurodegeneration in tauopathies.

neuroscience↗

bioRxiv2026

Ataraxis: Bridging AI Coding Assistants and Scientific Hardware

AI coding assistants excel at software tasks but lack structured access to laboratory hardware, the physical instruments that define experimental science. We present AO_SCPLOWTARAXISC_SCPLOW, an open-source framework that provides hardware control capabilities spanning camera acquisition, microcontroller communication, precision timing, and inter-process coordination, while exposing these capabilities to AI agents through Model Context Protocol (MCP) servers and domain-specific skills. Critically, AO_SCPLOWTARAXISC_SCPLOW separates configuration-time AI assistance from runtime data acquisition, ensuring that experiments run deterministically regardless of AI service availability. We validate this architecture in a two-photon imaging and virtual reality rodent behavior platform, demonstrating up to order-of-magnitude reductions in hardware validation, integration, and personnel onboarding time. By bridging the gap between AI software capabilities and physical instrument control, AO_SCPLOWTARAXISC_SCPLOW offers a reusable blueprint for AI-assisted scientific instrumentation across experimental disciplines. All code is available at github.com/Sun-Lab-NBB/ataraxis.

neuroscience↗

bioRxiv2026

MATR3 is essential for oocyte growth and maturation quality through a dual molecular mechanism

The molecular mechanisms governing mRNA accumulation during oocyte growth, essential for developmental competence, remain poorly understood. This study investigates the role of Matrin-3 (MATR3), a highly expressed RNA-binding protein in growing oocytes (GOs), using oocyte-specific knockout mouse models and human oocyte maturation arrest (OMA) samples. The results showed that MATR3 was more abundant in GOs than fully-grown oocytes (FGOs), highly expressed in the nucleus of non-surrounded nucleolus (NSN) oocytes, and exited the nucleus during the NSN-to-surrounded nucleolus (SN) transition. In OMA patients, MATR3 nuclear localization was missed, with smaller oocytes than FGOs. Further, Matr3 deletion in mouse GOs caused restricted oocyte growth, global transcription disorders, follicle development failure, blocked GO-granulosa cell communication (via reduced Gdf9 and Radixin expression), and infertility. Mechanistically, MATR3 regulated transcription by recruiting H3K9me2-demethylating lysine-specific demethylase 3B or binding target gene promoters, like Radixin. These findings reveal a critical role of MATR3 in orchestrating transcription and paracrine signaling during oogenesis and suggest its potential as a diagnostic and therapeutic target for OMA.

physiology↗

bioRxiv2026

Elimination of intramuscular immunoglobulin accumulation alleviates Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a devastating neuromuscular disorder due to loss of dystrophin, a cytoskeletal protein critical for muscle integrity and functionality. Despite recent therapeutic advances, there remains a significant unmet need for more effective and accessible therapeutics. Here, we discovered an early accumulation of immunoglobulin G (IgG) in the sarcolemma, which exacerbates tissue inflammation and disease progression. The IgG accumulation primarily resulted from ectopic localization of Fc{gamma}R1, a high-affinity IgG Fc receptor, on dystrophin-deficient myofibers. In two independent murine models, eliminating IgG accumulation via B cell depletion provided sustained benefit to alleviate DMD progression. Our findings uncover a novel disease accelerator in DMD and demonstrate the potential to target this mechanism as therapeutics for broader population of patients with DMD.

immunology↗

bioRxiv2026

Lmna deficiency promotes EPHX2 nuclear translocation to ameliorate cardiac dysfunction in mice

BackgroundCardiovascular diseases are often associated with altered protein subcellular localization. As a major cause of inherited cardiomyopathy, LMNA deficiency could trigger nuclear envelope rupture and broadly impair the localization of nuclear and cytoplasmic proteins. Systemic approaches to identify, dissect and manipulate the localization of endogenous proteins are important for mechanistic and therapeutic investigation. MethodProximity proteomics of the nuclear lamina was performed specifically in cardiomyocytes in Lmna-deficient murine models. AAV-mediated Cas9-based gene silencing and subcellular gene upregulation were conducted via the nuclear localization signal (NLS) and nuclear export signal (NES). Cas9-based somatic mutagenesis was supplemented with the single-strand DNA templates of AAV to achieve robust homology-directed repair (HDR) and targeted NLS knock-in, which translocated cytoplasmic proteins into nuclei. ResultIn vivo proximity proteomics detected increased epoxide hydrolase 2 (EPHX2) in cardiomyocyte nuclei in mice carrying germline or cardiac-specific Lmna truncating variants. This phenotype was associated with ruptured nuclear envelope. Cas9-mediated Ephx2 knockout in cardiomyocytes ameliorated cardiac dysfunction in Lmna-deficient mice. Strikingly, overexpression of NLS-EPHX2, but not NES-EPHX2, also mitigated cardiac dysfunction. The cardiac protective EPHX2 substrates, epoxyeicosatrienoic acids (EETs), did not alter upon NLS-EPHX2 overexpression. By contrast, the Lmna-related DNA damage marker {gamma}-H2AX was reduced. The EPHX-D333A mutant lacking hydrolase activity recapitulated the effects of wildtype EPHX2 in nuclei. AAV-Cas9-based HDR achieved efficient NLS knock-in and EPHX2 nuclear translocation in more than 60% cardiomyocytes, which improved cardiac function. ConclusionLmna deficiency leads to the nuclear translocation of EPHX2, which ameliorated cardiac dysfunction in a hydrolase-independent manner. AAV-HDR-mediated somatic gene editing provides an efficient approach to manipulate the subcellular localization of endogenous proteins in cardiomyocytes in vivo. What is Known?O_LICardiovascular diseases are regulated by the changes in protein subcellular localization. In particular, LMNA-related cardiomyopathy is associated with nuclear rupture and impaired separation between nuclear and cytoplasmic proteins. C_LIO_LIEpoxide hydrolase 2 (EPHX2) is a cytoplasmic hydrolase that catalyzes the hydrolysis of cardioprotective epoxyeicosatrienoic acids (EETs) and aggravates an array of heart diseases including myocardial infarction and heart failure. C_LIO_LICRISPR/Cas9-mediated homology-directed repair (HDR) exhibits uniquely high gene editing efficiency in cardiomyocytes with an AAV-based DNA donor, which is suitable for somatic genetic knock-in of small DNA fragments in vivo. C_LI What New Information Does This Article Contribute?O_LILamin-targeted proximity proteomics specifically in cardiomyocytes uncovers novel proteins undergoing subcellular localization changes upon Lmna deficiency. C_LIO_LILmna deficiency leads to EPHX2 nuclear translocation that ameliorates cardiac dysfunction by both mechanisms of cytoplasmic reduction and nuclear induction. C_LIO_LIAAV-HDR-mediated knock-in provides a robust platform to manipulate subcellular localization of endogenous proteins specifically in cardiomyocytes in vivo. C_LI Cardiovascular diseases are often associated with altered protein subcellular localization, but systemic approaches to identify, study and manipulate subcellular localization remain incomplete. This study established an in vivo proximity proteomics approach to identify novel proteins undergoing localization changes relative to the nuclear lamina. In murine models of LMNA-related cardiomyopathy, this approach uncovered EPHX2, a classic cytoplasmic hydrolase that aggravates cardiovascular diseases, as a new protein that translocated into cell nucleus and exerted a cardiac protective effect. CRISPR/Cas9-based cardiomyocyte gene editing with an AAV-based DNA donor efficiently achieved NLS knock-in into the Ephx2 gene, promoted EPHX2 protein nuclear translocation and mitigated cardiac dysfunction with Lmna deficiency. These findings indicated a novel avenue to identify and manipulate the subcellular localization changes of endogenous proteins for basic and translational cardiology.

pathology↗

bioRxiv2026

The hippocampus as a small-world cognitive map

When a mouse perceives a hawks shadow, it may have only seconds to decide where to run, yet the safest refuge is often neither visible nor nearby. To survive, it must search its cognitive map quickly enough to choose among many possibilities, and accurately enough to avoid dead ends and hazards along the way, all while what counts as "safe" changes as paths, refuges, and threats shift with time. This scenario highlights a core design problem: cognitive maps must preserve fine local structure for reliable action, yet remain globally searchable so that distant, useful solutions can be found efficiently in both space and time. The hippocampus is thought to support such maps, with population activity representing world states and their transitions--yet how these maps are structured to solve this design problem is not well understood. Here, we used a novel geometry-aware autoencoder to model the structure of the cognitive map from longitudinal calcium imaging from thousands of hippocampal CA1 neurons in mice learning a memory-guided navigation task. We discovered that the hippocampal population code achieves both local fidelity and global searchability through small-world network structure in the space of neural representations that leverages two complementary mechanisms. At the population level, helical (rotation-plus-drift) dynamics of neural representations relative to past experience build new maps that preserve local information about nearby positions in space and time while remaining distinguishable from earlier representations. At the cellular level, neurons with coordinated multi-field activity create sparse, long-range shortcuts between distant representations. During synchronous population events in immobility, decoded activity often jumps to distant states in space, time, and task conditions, suggesting these shortcuts are engaged during offline processing. This functional organization, with implications for both neuroscience and artificial intelligence, sheds light on how hippocampal representations may be optimized for a fundamental challenge faced by intelligent systems: efficiently searching through accurate internal models of the world.

neuroscience↗

bioRxiv2026

Nanoscale Protonation Limits and Charge Density in Polymer Films Govern the Activity of Immobilized LacZ under Acid Stress

Under acidic conditions, polycationic polymer coatings function as protective immobilization supports through protonation-mediated local pH buffering. However, it remains unclear how polymer support design parameters, such as film thickness and charge density, govern that vital protonation process. Leveraging the precise control of film thickness and copolymer composition enabled by initiated chemical vapor deposition (iCVD), we systematically investigated how these parameters govern the protonation behavior of poly[glycidyl methacrylate-co-2-(dimethylamino)ethyl methacrylate] (pGD) thin films and, in turn, the activity of immobilized {beta}-galactosidase (LacZ). Infrared spectroscopy suggests that proton penetration was capped at a depth of [~]250 nm in pGD with 65% DMAEMA, limiting the polycationic thickness in pGD films thicker than this value. Consistent with this limit, immobilized LacZ activity under acidic stress (pH 4) increased with protonated thickness up to [~]250 nm and then plateaued. Raising the polycationic monomer content from 25 to 65 mol% increased LacZ activity at pH 4 by up to 83%, consistent with a higher positive charge density providing stronger local pH buffering. To test whether this behavior depends on immobilization sites, we evaluated two approaches: random immobilization (via amine-epoxy ring-opening reactions) and site-directed immobilization (via SpyCatcher/SpyTag binding). Directed immobilization preserved higher LacZ activity than random immobilization, but the protonation-dependent protection trend remained consistent for both strategies. These findings establish protonation depth and charge density as tunable design parameters for polycationic immobilization supports that stabilize enzymes under acidic conditions.

bioengineering↗

bioRxiv2026

Different modes of engagement with the nucleosome acidic patch yield distinct functional outcomes

The nucleosome acidic patch is a hub of coordinated engagement by proteins that regulate genomic function. Here we report that S. cerevisiae Dot5 contains an arginine-rich HMGN-like motif that mediates nucleosome acidic patch binding and is required for the cell growth, DNA repair and heterochromatin defects exhibited when the protein is overexpressed. The heterologous expression of camelid single chain antibodies to the nucleosome acidic patch confers a similar range of phenotypes, with the most severe observed when an arginine-anchor mode of binding analogous to many endogenous factors is employed. This highlights a delicate balance between nucleosome acidic patch interactors critical for normal cellular functions and dysregulated in disease.

molecular biology↗

bioRxiv2026

Dopamine Accumulation Dynamics Control Time Perception

Accurate timing is fundamental to perception and behavior, and the dopaminergic system plays a key role. According to the dopamine clock hypothesis, elevated dopamine accelerates the interval clock, while reduced levels slow it. However, optogenetic activation of substantia nigra pars compacta (SNc) dopaminergic neurons paradoxically disrupts this model, suggesting greater complexity. To resolve this paradox, we monitored ventral tegmental area (VTA) dopamine activity in mice performing a time perception task. We observed a ramping-to-threshold pattern, where slower ramping corresponded to longer durations. Optogenetic activation accelerated time estimation, whereas inhibition prolonged it. Systemic dopamine elevation had no effect, but reuptake inhibition accelerated timing. Strikingly, prolonged high dopamine levels slowed time estimation, correlating with slower accumulation due to increased reuptake. Our findings challenge the dopamine clock hypothesis, demonstrating that time perception depends not on absolute dopamine levels but on their temporal accumulation dynamics. This revised framework reconciles previous contradictions and highlights the role of dopamine accumulation rates in temporal cognition.

neuroscience↗

bioRxiv2025

CausalGRN: deciphering causal gene regulatory networks from single-cell CRISPR screens

Large-scale single-cell CRISPR screens with single-cell RNA-seq (scRNA-seq) readouts provide critical data to map causal gene regulatory networks (GRNs). However, translating the complex scRNA-seq outputs into reliable causal insights remains a major analytical challenge. Here we present CausalGRN, a scalable computational framework that infers causal GRNs and predicts cellular responses to unseen perturbations. CausalGRN first mitigates pervasive spurious partial correlations in sparse scRNA-seq data through a novel adaptive thresholding correction, enabling robust inference of an undirected graph. It then orients this graph using observed perturbation outcomes. The resulting directed GRN can be used to predict the downstream effects of novel perturbations via network propagation. Across both simulations and diverse experimental datasets, CausalGRN substantially outperforms existing approaches in network reconstruction accuracy and in predicting the effects of unseen perturbations, providing a principled bridge from perturbation data to causal gene regulation.

bioinformatics↗

bioRxiv2025

A stem cell knockout village reveals lineage rewiring and a non-canonical islet cell fate in monogenic diabetes

Genetics studies have identified a core set of regulators essential for pancreatic {beta} cell development, many of which are mutated in monogenic diabetes. However, how these mutations alter developmental trajectories to produce pathological cell states remains elusive. Here we introduce a knockout village framework that enables longitudinal scRNA-seq profiling of 79 human pluripotent stem cell mutant lines targeting 30 developmental regulators, including 15 diabetes genes, across five islet differentiation stages. We show that loss of lineage regulators impairs {beta} cell formation in a stage-specific manner and rewires developmental trajectories towards competing lineages. Notably, several monogenic diabetes gene mutations drive a shift from {beta} cells to enterochromaffin (EC)-like cells, a recently recognized non-canonical islet cell fate. These EC-like cells exhibit incomplete activation of hormone regulation programs, along with elevated neuron signatures. Leveraging the diversity of cell fate outcomes across mutants, we predicted and experimentally validated ISL1 as a key downstream effector of PDX1 and PAX6 that safeguards {beta} cell identity against an EC-like fate. Together, our findings reveal cell fate rewiring as a widespread, previously underappreciated pathological mechanism in monogenic diabetes and establish a scalable platform for uncovering developmental vulnerabilities in human genetic disorders.

developmental biology↗

bioRxiv2025

Evolutionarily Conserved T-tubule-Mitochondria Contacts in Striated Muscle

The intricate architecture of skeletal muscle is essential for its contractile function, with the spatial organization of organelles such as T-tubules and mitochondria playing a crucial role in maintaining muscle performance and health1,2. T-tubules propagate electrical signals deep into muscle fibers to ensure synchronous contraction, while mitochondria provide the necessary energy for muscle contraction3-5. Previous studies have extensively documented the interactions between T-tubules and the sarcoplasmic reticulum (SR), which are essential for excitation-contraction coupling6,7. However, the detailed spatial relationship between T-tubules and mitochondria has remained relatively unexplored. In this study, we utilized zebrafish and mice as model organisms to investigate the contacts between T-tubules and mitochondria. Using array tomography, deep learning-based analysis, and advanced microscopy techniques, we discovered extensive membrane contact sites, termed T-tubule-Mitochondria (TTM) contacts. These contacts are evolutionarily conserved across vertebrates, including skeletal and cardiac muscles. Our findings reveal a previously unrecognized, intimate spatial coupling between T-tubules and mitochondria, with significant implications for muscle physiology and pathology. Understanding these TTM contacts could provide new insights into the mechanisms underlying muscle function and the development of muscle-related diseases.

cell biology↗

bioRxiv2025

Increased Aperiodic Exponents Track Depression Symptom Severity

Roughly one-third of patients with major depressive disorder (MDD) fail to respond to standard treatments and develop treatment-resistant MDD. For these patients, alternative therapies ofer additional options but yield inconsistent outcomes. Progress has been limited by the absence of objective, brain-based biomarkers to guide target selection or track therapeutic response in real time. Instead, clinicians rely on behavioral assessments that evolve slowly over weeks to months, obscuring the underlying neural dynamics of symptom changes. Here, we test whether the aperiodic exponent of intracranial EEG (iEEG) local field potentials can serve as a neurophysiological marker of depression symptom severity. We leveraged a large iEEG cohort (N = 20) undergoing invasive monitoring for refractory epilepsy, yielding over 1,800 contacts spanning cortical and subcortical zones. For each contact, we estimated the aperiodic exponent (thought to reflect aspects of cortical excitability) of the power spectrum across 10-100 Hz within local brain regions and across distributed cortical association networks. Depressive symptoms were assessed with the Beck Depression Inventory-II (BDI-II) immediately before intracranial resting state recordings. With respect to the BDI-II scale, participants were identified as experiencing minimal (BDI-II [≤] 13) or elevated depression symptoms (BDI-II [≥] 14). Associations between symptom severity (BDI-II total score and Somatic-Afective, Cognitive, and Anhedonia subscales) and region- or network-level exponents were modeled with ordinary least squares (OLS) regression. The whole-brain, mean aperiodic exponent for each participant discriminated symptom status (AUC = 0.82). At the regional level, the orbitofrontal cortex, anterior cingulate cortex, insula, and amygdala showed higher exponents in the elevated depression symptom group (d = 1.18-1.71; p = 0.032-0.004). A post-hoc classification analysis across these four regions misclassified one participant per group (AUC = 0.86; 95% CI 0.64-1.00). In continuous analyses, BDI-II scores correlated positively with exponents in these same four regions (pFDR = 0.019-0.027; partial r=0.61-0.70) and at the network level in the Salience network (pFDR = 0.024; partial r = 0.63) and Default (pFDR = 0.046; partial r = 0.55) network. The Salience network significantly tracked Anhedonia symptoms (p = 0.004; partial r = 0.62). Here we report that intracranial aperiodic exponents within fronto-limbic and insular circuits, overlapping with networks implicated in contemporary accounts of depression pathophysiology, diferentiate depressive symptom status and scale with severity. These findings support the aperiodic exponent as a candidate neurophysiological marker of current depression symptom burden, with potential relevance for individualized neuromodulation in MDD.

neuroscience↗

bioRxiv2025

Verbal versus Nonverbal Processing Leads to Generalized Hemispheric Laterality Effects that Span Multiple Networks

Precision neuroimaging was used to explore specialization for verbal versus nonverbal processing. Consistent with prior findings, individuals exhibited a spatially left-lateralized association language network, with regions in both hemispheres robustly responding to processing of meaning-based sentences. We next examined differential responses to verbal (words) versus nonverbal (faces) materials within the same working memory task. The right hemisphere components of the language network responded more strongly to nonverbal than to verbal materials, splitting the networks functional profile between the hemispheres. Similar patterns were observed across multiple association networks including putative cognitive-control, action-mode, and attention networks. The hemispheric laterality effect was prospectively replicated in a second independent study. These findings highlight a generalized laterality phenomenon that transcends the specialization of individual networks that has been the recent focus of the human systems neuroscience field, and aligns with a broad mechanism that modulates processing between the hemispheres.

neuroscience↗

bioRxiv2025

Immunotherapy with Pro-regenerative Macrophages from Embryonic Stem Cells Ameliorate Osteoarthritis via TNFAIP3-Mediated Chondroprotection

Immune cell-based therapies for osteoarthritis (OA) remains underexplored. Macrophages coordinate tissue repair, yet their functional heterogeneity and therapeutic applicability, particularly for designed stem cell-derived populations with tailored reparative properties are not fully delineated. Inspired by embryonic skeletal development as a paradigm of scarless regeneration, we identified a pro-regenerative macrophage population through a single-cell RNA atlas of developing skeletal tissues. We subsequently established a mechanically dynamic induction approach to efficiently generate pro-regenerative macrophages from human embryonic stem cells (hESCs), mimicking this developmental phenotype. In vitro, these macrophages mitigate cartilage degradation in OA explants and suppress pro-inflammatory, catabolic signaling in chondrocytes. Injection into murine OA joints robustly attenuates disease progression, reduces extracellular matrix breakdown, and resolves synovial inflammation, representing the first demonstration of immune cell-based therapy for OA. Mechanistically, these macrophages orchestrate chondroprotection not through broad immunosuppression, but by activating a TNFAIP3-dependent signaling hub that restrains inflammatory and catabolic responses in chondrocytes. This TNFAIP3 activation precisely reversed the OA-associated gene signature, suppressing catabolic mediators while enhancing reparative factors, thereby restoring the anabolic-catabolic balance. Our findings uncover a developmental blueprint for engineering pro-regenerative macrophages from stem cells and establish a pioneering targeted immune cell therapy that engages an intrinsic chondroprotective program, offering a transformative and translationally relevant strategy for OA treatment.

immunology↗

bioRxiv2025

Genomic architecture of species-specific sex pheromone variation and mate choice

Speciation often begins with subtle changes in sexual communication and mate choice, yet the genetic basis of these early reproductive barriers remains largely unresolved. Here, we dissect the chemical and genomic architecture underlying species-specific female cuticular sex pheromones and their role in mate choice in two closely related parasitoid wasp species. Using high-resolution quantitative trait locus (QTL) mapping, fine-scale chemical profiling, and behavioral assays on hybrid populations, we identify three methyl-branched alkanes as key pheromonal compounds that strongly predict male mating preferences. QTL explaining their species-specific variation partially co-localize with genomic regions enriched for candidate genes involved in cuticular hydrocarbon biosynthesis, including cytochrome P450 enzymes and fatty acid synthases. These findings suggest a potential mechanistic link between the variation in these gene clusters and species-specific chemical signaling. Further comparative analyses reveal hitherto unrecognized sex-specific regulatory effects, cytoplasmic influences, and complex genomic interactions shaping the variation in these pheromonal profiles. This study is among the first to connect individual pheromone compounds with mate choice and their underlying genomic basis in a haplodiploid system, offering a rare glimpse into how chemical divergence can reinforce behavioral isolation and potentially drive early speciation.

evolutionary biology↗

bioRxiv2025

Role of Myc family proteins in transcriptional regulation of growth and oncogenic transformation in fusion-positive rhabdomyosarcoma

Fusion-positive rhabdomyosarcoma (FP-RMS) is driven by a PAX3::FOXO1 (P3F) or PAX7::FOXO1 fusion gene. After finding that MYCN is required for P3F-induced oncogenic transformation in a human myoblast model of FP-RMS, we further investigated the role of Myc family proteins in FP-RMS. Expression studies revealed that myoblast models and a subset of FP-RMS lines have predominant MYCN or MYC expression whereas other FP-RMS lines have both high MYCN and MYC expression. In myoblast models, MYCN was required for optimal P3F binding to and high-level activation of FGF8, a P3F target that is necessary and sufficient for oncogenic transformation. MYCN or MYC knockdown suppressed transformation in myoblast and FP-RMS lines with dominant MYCN or MYC expression, respectively. In FP-RMS lines with high MYCN and MYC expression, there was partial loss of transformation when one gene was targeted and complete loss when both genes were targeted. Despite the loss of oncogenic activity in lines with knockdown of a dominant Myc family member, FGF8 expression was not decreased. Transcriptomic analyses revealed that P3F target genes were not affected by MYCN or MYC knockdown, and instead a group of Myc-specific targets was down-regulated. Collectively, these results indicate that MYCN or MYC is functionally dominant in myoblast models and FP-RMS lines with dominant expression of one Myc family protein whereas MYCN and MYC are functionally redundant in FP-RMS cell lines with high expression of both. These Myc family proteins contribute to oncogenic properties by facilitating P3F activation of FGF8 and increasing expression of Myc-specific targets.

cancer biology↗