Biology subjects

Price, S.

Publications and source records attributed to Price, S..

13 recordsLinked to original sources

bioRxiv2026

Somatic cells non-autonomously control germline incomplete cytokinesis through FGF signaling

Across species, germ cells divide and differentiate as interconnected units, termed cysts. These cysts are generated through reiterative rounds of mitosis followed by incomplete cytokinesis to generate stable ring canals (RCs). Despite the ubiquity of germ cell incomplete cytokinesis, it is still unclear how this program is mechanistically regulated across multiple cell cycles to retain integrity of the cyst. Here, by leveraging longitudinal live imaging of the Drosophila testis we have identified a critical, non-autonomous role for somatic support cells in maintenance of germline RC stability. We find that F-actin at RCs is stable throughout interphase but is dynamically disassembled and reassembled at each reiterative mitotic entrance and exit. Importantly, we find that somatic cells regulate the stability of interphase RC F-actin through the secreted growth factor, FGF. Genetic or pharmacological inhibition of FGF signaling induces disassembly of RC F-actin during interphase. Persistent clearance of F-actin from the RC leads to failure of incomplete cytokinesis and cyst abscission, suggesting that stable F-actin at RCs is required for the robust maintenance of incomplete cytokinesis through multiple rounds of germ cell divisions. Finally, we mechanistically link FGF signaling to germline activity of the non-receptor tyrosine kinase, Src64, which is known to regulate RC F-actin through Arp2/3. Taken together, we find a previously unappreciated role for somatic support cells in controlling an essential aspect of germ cell biology in the mitotically dividing spermatogonial pool. Summary StatementSomatic cells of the gonad secrete FGF ligand, Pyramus, which is required for maintenance of F-actin at germline ring canals and integrity of germline incomplete cytokinesis.

cell biology↗

bioRxiv2026

vGPCR-mediated ANO1 Modulation of Apoptosis Regulates Lytic KSHV Infection

Kaposis Sarcoma herpesvirus (KSHV) is an oncogenic, enveloped double-stranded DNA virus that causes Kaposis Sarcoma (KS), an endothelial-derived tumor that primarily affects immunocompromised individuals. KSHV persists in a biphasic lifecycle of latency and lytic reactivation, with the lytic phase driving viral dissemination and disease progression through expression of viral proteins that reprogram host survival pathways. One such protein is the viral G protein-coupled receptor (vGPCR), a constitutively active lytic gene product that promotes angiogenic and pro-survival signaling, although the host mediators of these effects remain incompletely defined. Here, we identify Anoctamin-1 (ANO1), a calcium-activated chloride channel with ant-apoptotic functions, as a downstream target of vGPCR in endothelial cells. RNA sequencing and RT-qPCR in vGPCR-expressing HMEC-1 cells revealed broad transcriptional reprogramming, including strong ANO1 induction. Functional studies showed that ANO1 depletion had little effect on viability in full-serum conditions but selectively sensitized vGPCR-expressing cells to apoptosis during serum starvation. This loss of viability was rescued by the pan-caspase inhibitor Z-VADFMK, indicating caspase-dependent apoptosis. To examine relevance during infection, we analyzed iSLK.BAC16 cells undergoing lytic reactivation. ANO1 was similarly upregulated during reactivation. Genetic knockdown or pharmacological inhibition of ANO1 with DES or Ani9 increased late-stage apoptosis while minimally affecting early apoptosis. Notably, ANO1 loss enhanced early and late lytic gene expression and increased production of infectious virions. These findings identify ANO1 as a vGPCR-induced host survival factor that suppresses apoptosis while modulating KSHV lytic replication, revealing a host ion-channel-dependent checkpoint linking cell survival to viral replication and KSHV pathogenesis. IMPORTANCEKSHV drives tumorigenesis by manipulating host cell survival pathways, yet how apoptosis is regulated during infection remains incompletely understood. We identify ANO1 as a host factor induced by the vGPCR that suppresses caspase-dependent apoptosis in endothelial cells. ANO1 is upregulated in both vGPCR-expressing endothelial cells and during KSHV lytic reactivation in iSLK.BAC16 cells. Disruption of ANO1 increases apoptotic cell death and is accompanied by elevated lytic gene expression and greater production of infectious virions, suggesting that apoptosis can coincide with enhanced lytic replication. These findings implicate host ion-channel signaling in the control of apoptosis during KSHV infection and indicate that the balance between cell survival and apoptosis influences viral gene expression and replication. Understanding how KSHV manipulates host survival pathways provides insight into mechanisms governing viral replication and may inform approaches to limit KSHV-associated disease.

microbiology↗

bioRxiv2026

Histology-Aware Graph for Modeling Intercellular Communication in Spatial Transcriptomics

Cell-cell communication (CCC) is essential to how life forms and functions. Recent tools achieve single-cell-resolved CCC inference utilizing spatial transcriptomics (ST). However, most ignore the modeling of tissue contexts surrounding cells, causing high false-positive/negative rates. Here, we propose HARMONIC, a CCC inference method integrating multimodal ST and hematoxylin and eosin (H&E)-stained images. HARMONIC causally modeling the transcriptomic-to-contextual relationships for CCC inference. The state-of-the-art performance was verified across ST platforms, species and healthy/diseased status, on both synthetic and biological samples. HARMONIC was applied in various real-world scenarios, especially on tissues with clear morphological boundaries, including cortical layers in mouse brain, medullary-cortex structures in mouse kidney, as well as tumor-stromal/immune interface. Significant refinement of false-positive/negative predictions was observed compared to ST-only CCC tools.

bioinformatics↗

bioRxiv2025

A Foundational Generative Model for Cross-platform Unified Enhancement of Spatial Transcriptomics

Spatial transcriptomics (ST) platforms are limited by spatial resolution, sensitivity to low expression levels, alignment with tissue structures, and the balance across tissue complexity. Computational enhancement typically targets a single challenge, e.g., super-resolution using hematoxylin and eosin (H&E) images or sensitivity enhancement with single-cell RNA sequencing (scRNA-seq). However, most ignore the interdependence across challenges, yielding biologically inconsistent enhancement. Here we introduce FOCUS, a foundational generative model for unified ST enhancement, conditioned on H&E images, scRNA-seq references, and spatial co-expression priors. With large-scale pretrained encoders, FOCUS uses a modular design for multimodal integration and a cross-challenge coordination strategy to target co-occurring challenges, enabling joint optimization. FOCUS was trained and comprehensively benchmarked on >1.7 million H&E-ST pairs and >5.8 million single-cell profiles, demonstrating state-of-the-art performance across ten ST platforms, on both individual and coupled challenges. The real-world utility and generalizability were validated on a rare suprasellar tumor, papillary craniopharyngioma, and an unseen ST platform (Open-ST) for primary and metastatic head and neck squamous cell carcinoma.

bioengineering↗

bioRxiv2024

Cell-specific delivery of GJB2 restores auditory function in mouse models of DFNB1 deafness and mediates appropriate expression in NHP cochlea

Mutations in the GJB2 gene cause the most common form of human hereditary hearing loss, known as DFNB1. GJB2 is expressed in two cell groups of the cochlea--epithelial cells of the organ of Corti and fibrocytes of the inner sulcus and lateral wall--but not by sensory hair cells or neurons. Attempts to treat mouse models of DFNB1 with AAV vectors mediating nonspecific Gjb2 expression have not substantially restored function, perhaps because inappropriate expression in hair cells and neurons could compromise their electrical activity. Here, we used genomic chromatin accessibility profiling to identify candidate gene regulatory elements (GREs) that could drive cell-type-specific expression of Gjb2 in the cochlea. HA-tagged GJB2, delivered to a conditional knockout model in an AAV vector with GRE control of expression, was localized to the appropriate cell types, prevented the cochlear degeneration observed in untreated knockout mice, and partially rescued hearing sensitivity. In a Gjb2 partial knockdown mouse model, such exogenous GJB2 prevented degeneration and completely restored hearing sensitivity. We tested control of expression by these GREs in nonhuman primate cochleas and found that vector-delivered human GJB2.HA was located in the appropriate cell types and caused little or no reduction in hearing sensitivity. Together, these findings suggest that GRE-mediated expression of GJB2 could prevent hearing loss in DFNB1 patients.

neuroscience↗

bioRxiv2024

Cis-regulatory elements driving motor neuron-restricted viral payload expression within the mammalian spinal cord

Spinal motor neuron (MN) dysfunction is the cause of a number of clinically significant movement disorders. Despite the recent approval of gene therapeutics targeting these MN-related disorders, there are no viral delivery mechanisms that achieve MN-restricted transgene expression. In this study, chromatin accessibility profiling of genetically defined mouse MNs was used to identify candidate cis-regulatory elements (CREs) capable of driving MN-selective gene expression. Subsequent testing of these candidates identified two CREs that confer MN-selective gene expression in the spinal cord as well as reduced off-target expression in dorsal root ganglia. Within one of these candidate elements, we identified a compact core transcription factor (TF)-binding region that drives MN-selective gene expression. Finally, we demonstrate that selective spinal cord expression of this mouse CRE is preserved in non-human primates. These findings suggest that the generation of cell-type-selective viral reagents, in which cell-type-selective CREs drive restricted gene expression, will be valuable research tools in mice and other mammalian species, with potentially significant therapeutic value in humans. SIGNIFICANCE STATEMENTMotor neurons transduce the motor outputs of nervous system activity to muscle and are the vulnerable neurons in a number of clinically significant degenerative conditions, including spinal muscular atrophy and amyotrophic lateral sclerosis. A recent strategy for treating motor neuron degenerative diseases has been to use viruses to introduce genes into motor neurons to inhibit the degenerative process. However, we still lack viral reagents that promote gene expression in motor neurons without potentially toxic off-target expression in other cell types. Our study identifies cis-regulatory elements capable of conferring motor neuron-selective transgene expression in a viral context. These findings have important implications for future gene therapeutics for motor neuron-related disorders.

neuroscience↗

bioRxiv2024

Mitigating sTNF/TNFR1 activation on VGluT2+ spinal cord interneurons improves immune function after mid-thoracic spinal cord injury

Spinal cord injury (SCI) is a devastating condition with 250,000 to 500,000 new cases globally each year. Respiratory infections, e.g., pneumonia and influenza are the leading cause of death after SCI. Unfortunately, there is a poor understanding of how altered neuro-immune communication impacts an individuals outcome to infection. In humans and rodents, SCI leads to maladaptive changes in the spinal-sympathetic reflex (SSR) circuit which is crucial to sympathetic function. The cause of the impaired immune function may be related to harmful neuroinflammation which is detrimental to homeostatic neuronal function, aberrant plasticity, and hyperexcitable circuits. Soluble tumor necrosis factor (sTNF) is a pro-inflammatory cytokine that is elevated in the CNS after SCI and remains elevated for several months after injury. By pharmacologically attenuating sTNF in the CNS after SCI we were able to demonstrate improved immune function. Furthermore, when we investigated the specific cellular population which may be involved in altered neuro-immune communication we reported that excessive TNFR1 activity on excitatory INs promotes immune dysfunction. Furthermore, this observation is NF-kB dependent in VGluT2+ INs. Our data is the first report of a target within the CNS, TNFR1, that contributes to SCI-induced immune dysfunction after T9-SCI and is a potential avenue for future therapeutics.

neuroscience↗

bioRxiv2021

A suspension technique for efficient large-scale cancer organoid culturing and perturbation screens

Organoid cell culture methodologies are enabling the generation of cell models from healthy and diseased tissue. Patient-derived cancer organoids that recapitulate the genetic and histopathological diversity of patient tumours are being systematically generated, providing an opportunity to investigate novel cancer biology and therapeutic approaches. The use of organoid cultures for many applications, including genetic and chemical perturbation screens, is limited due to the technical demands and cost associated with their handling and propagation. Here we report and benchmark a suspension culture technique for cancer organoids which allows for the expansion of models to tens of millions of cells with increased efficiency in comparison to standard organoid culturing protocols. Using whole-genome DNA and RNA sequencing analyses, as well as medium-throughput drug sensitivity testing and genome-wide CRISPR-Cas9 screening, we demonstrate that cancer organoids grown as a suspension culture are genetically and phenotypically similar to their counterparts grown in standard conditions. This culture technique simplifies organoid cell culture and extends the range of organoid applications, including for routine use in large-scale perturbation screens.

cancer biology↗

bioRxiv2021

The secrets to domestic bliss - Partner fidelity and environmental filtering preserve stage-specific turtle ant gut symbioses for over 40 million years

BackgroundGut microbiomes can vary across development, a pattern often found for insects with complete metamorphosis. With varying nutritional need and distinct opportunities for microbial acquisition, questions arise as to how such holometabolous insects retain helpful microbes at larval and adult stages. Ants are an intriguing system for such study. In a number of lineages adults digest only liquid food sources, while larvae digest solid foods. Like some other social insects, workers and soldiers of some ant species engage in oral-anal trophallaxes, enabling microbial transfer among siblings. But do queens, the typical colony founding caste, obtain symbionts through such transfer? Does this enable transgenerational symbiont passage? And does the resulting partner fidelity promote the evolution of beneficial symbionts? Furthermore, how might such adult-centric biology shape larval microbiomes? To address these questions, we characterized symbiotic gut bacteria across 13 species of Cephalotes turtle ants, with up to 40-million years of divergence. Adding to the prior focus on workers we, here, study underexplored castes and stages including queens, soldiers, and larvae, by performing 16S rRNA qPCR, amplicon sequencing, and phylogenetic classification. ResultsWe show that adult microbiomes are conserved across species and largely across castes. Nearly 95% of the bacteria in adults have, thus far, been found only in Cephalotes ants. Furthermore, the microbiomes from most adults exhibit phylosymbiosis, a trend in which microbiome community similarity recapitulates patterns of host relatedness. Additionally, an abundant, adult-enriched symbiont cospeciates with some Cephalotes. Evidence here suggests that these partner fidelity patterns extend from transgenerational symbiont transfer through alate gyne dispersal and subsequent colony-founding by queens. Like adults, larvae of Cephalotes species exhibit strong microbiome conservation. Phylosymbiosis patterns are weaker, however, with further evidence elevating environmental filtering as a primary mechanism behind such conservation. Specifically, while adult-enriched symbionts are found in most larvae, symbionts of older larvae are highly related to free-living bacteria from the Enterobacteriaceae, Lactobacillales, and Actinobacteria. ConclusionsOur findings suggest that both partner fidelity and conserved environmental filtering drive stable, stage-specific, social insect symbioses. We discuss the implications for our broader understanding of insect microbiomes, and the means of sustaining a beneficial microbiome.

evolutionary biology↗

bioRxiv2020

Quantifying multivariate genotype-by-environment interactions, evolutionary potential and its context-dependence in natural populations of the water flea, Daphnia magna.

Genotype-by-environment interactions (G x E) underpin the evolution of plastic responses in natural populations. Theory assumes that G x E interactions exist but empirical evidence from natural populations is equivocal and difficult to interpret because G x E interactions are normally univariate plastic responses to a single environmental gradient. We compared multivariate plastic responses of 43 Daphnia magna clones from the same population in a factorial experiment that crossed temperature and food environments. Multivariate plastic responses explained more than 30% of the total phenotypic variation in each environment. G x E interactions were detected in most environment combinations irrespective of the methodology used. However, the nature of G x E interactions was context-dependent and led to environment-specific differences in additive genetic variation (G-matrices). Clones that deviated from the population average plastic response were not the same in each environmental context and there was no difference in whether clones varied in the nature (phenotypic integration) or magnitude of their plastic response in different environments. Plastic responses to food were aligned with additive genetic variation (gmax) at both temperatures, whereas plastic responses to temperature were not aligned with additive genetic variation (gmax) in either food environment. These results suggest that fundamental differences may exist in the potential for our population to evolve novel responses to food versus temperature changes, and challenges past interpretations of thermal adaptation based on univariate studies.

evolutionary biology↗

bioRxiv2020

Siderophore-mediated zinc acquisition enhances enterobacterial colonization of the inflamed gut.

Zinc is an essential cofactor for bacterial metabolism, and many Enterobacteriaceae express the zinc transporters ZnuABC and ZupT to acquire this metal in the host. Unexpectedly, the probiotic bacterium Escherichia coli Nissle 1917 exhibited appreciable growth in zinc-limited media even when these transporters were deleted. By utilizing in vitro and in vivo studies, as well as native spray metal infusion mass spectrometry and ion identity molecular networking, we discovered that Nissle utilizes yersiniabactin as a zincophore. Indeed, yersiniabactin enables Nissle to scavenge zinc in zinc-limited media, to resist calprotectin-mediated zinc sequestration, and to thrive in the inflamed gut. Moreover, we discovered that yersiniabactins affinity for iron or zinc changes in a pH-dependent manner, with higher affinity for zinc as the pH increased. Altogether, we demonstrate that siderophore metal affinity can be influenced by the local environment and reveal a mechanism of zinc acquisition available to many commensal and pathogenic Enterobacteriaceae.

microbiology↗

bioRxiv2019

Genetic immunodeficiency and autoimmune disease reveal distinct roles of Hem1 in the WAVE2 and mTORC2 complexes

Immunodeficiency often coincides with immune hyperresponsiveness such as autoimmunity, lymphoproliferation, or atopy, but the molecular basis of this paradox is typically unknown. We describe four families with immunodeficiency coupled with atopy, lymphoproliferation, cytokine overproduction, hemophagocytic lymphohistocytosis, and autoimmunity. We discovered loss-of-function variants in the gene NCKAP1L, encoding the hematopoietic-specific Hem1 protein. Three mutations cause Hem1 protein and WAVE regulatory complex (WRC) loss, thereby disrupting actin polymerization, synapse formation, and immune cell migration. Another mutant, M371V encodes a stable Hem1 protein but abrogates binding of the Arf1 GTPase and identifies Arf1 as a critical Hem1 regulator. All mutations reduce the cortical actin barrier to cytokine release explaining immune hyperresponsiveness. Finally, Hem1 loss blocked mTORC2-dependent AKT phosphorylation, T cell proliferation, and effector cytokine production during T cell activation. Thus, our data show that Hem1 independently governs two key regulatory complexes, the WRC and mTORC2, and how Hem1 loss causes a combined immunodeficiency and immune hyperresponsiveness disease.\n\nOne sentence summaryHem1 loss of function mutations cause a congenital immunodysregulatory disease and reveal its role regulating WAVE2 and mTORC2 signaling.

immunology↗

bioRxiv2019

An Interscholastic Network to Generate LexA Enhancer Trap Lines in Drosophila

Binary expression systems like the LexA-LexAop system provide a powerful experimental tool kit to study gene and tissue function in developmental biology, neurobiology and physiology. However, the number of well-defined LexA enhancer trap insertions remains limited. In this study, we present the molecular characterization and initial tissue expression analysis of nearly 100 novel StanEx LexA enhancer traps, derived from the StonEx1 index line. This includes 76 insertions into novel, distinct gene loci not previously associated with enhancer traps or targeted LexA constructs. Additionally, our studies revealed evidence for selective transposase-dependent replacement of a previously-undetected KP element on chromosome III within the StanEx1 genetic background during hybrid dysgenesis, suggesting a molecular basis for the over-representation of LexA insertions at the NK7.1 locus in our screen. Production and characterization of novel fly lines were performed by students and teachers in experiment-based genetics classes within a geographically diverse network of public and independent high schools. Thus, unique partnerships between secondary schools and university-based programs have produced and characterized novel genetic and molecular resources in Drosophila for open-source distribution, and provide paradigms for development of science education through experience-based pedagogy.

genetics↗