Biology subjects

Bates, S.

Publications and source records attributed to Bates, S..

13 recordsLinked to original sources

bioRxiv2026

Activity induced GEM-4/Copine expression inhibits gap junctions and promotes thermosensory plasticity

Activity induced gene expression promotes behavioral plasticity (including several forms of learning and memory) by altering synaptic connectivity and neuron excitability. While several transcriptional targets modify synapses, little is known about targets regulating excitability. Here, we identify a single MEF-2 and CRH-1/CREB transcriptional target, gem-4/Copine, whose expression increases the excitability of C. elegans body muscles. In muscles, gem-4 expression is repressed by MEF-2 and is induced by CRH-1. GEM-4 expression in muscles decreases the number of gap junctions, thereby increasing membrane resistance and excitability. These results identify activity induced copine expression as a mechanism to control gap junction coupling and excitability.

neuroscience↗

bioRxiv2026

Mitigating Bias in Spatial Transcriptomic Pipelines via Human Feedback

Biological discovery from experimental data, particularly large-scale assays, requires extensive preprocessing, during which raw outputs (e.g., images, sequences) are processed into structured forms that are more amenable to analysis. While statistical methods for such processed data are at the core of computational biology, the problem of coping with uncertainties introduced during preprocessing is a significant and underexplored issue. We address this issue in the context of differential expression analysis in spatial transcriptomics, which depends on a series of preprocessing steps, including demarcation of cell regions (segmentation), quantification of gene expression in cells, and cell-type annotation. We introduce Corrected Spatial Differential Expression (CSDE), a method that builds on Prediction-Powered Inference to leverage a small set of expert-validated data points (cells) to account for uncertainty due to preprocessing errors. Using two case studies, we demonstrate that CSDE produces more reliable and calibrated estimates of differential expression compared to the prevalent approach that neglects the impact of preprocessing. CSDE incorporates an efficient workflow to generate the required expert-annotated data, and is available as open-source at https://github.com/YosefLab/CSDE.

bioinformatics↗

bioRxiv2025

An enteric neuron-expressed variant ionotropic receptor detects ingested salts to regulate salt stress resistance

The detection of internal chemicals by interoceptive chemosensory pathways is critical for regulating metabolism and physiology. The molecular identities of interoceptors, and the functional consequences of chemosensation by specific interoceptive neurons remain to be fully described. The C. elegans pharyngeal neuronal network is anatomically and functionally homologous to the mammalian enteric nervous system. Here, we show that the I3 pharyngeal enteric neuron responds to cations via an I3-specific variant ionotropic receptor (IR) to regulate salt stress tolerance. The GLR-9 IR, located at the gut lumen-exposed sensory end of I3, is necessary and sufficient for salt sensation, establishing a chemosensory function for IRs beyond insects. Salt detection by I3 protects specifically against high salt stress, as glr-9 mutants show reduced tolerance of hypertonic salt but not sugar solutions, with or without prior acclimation. While cholinergic signaling from I3 promotes tolerance to acute high salt stress, peptidergic signaling from I3 during acclimation is essential for resistance to a subsequent high salt challenge. Transcriptomic analyses show that I3 regulates salt tolerance in part via regulating the expression of osmotic stress response genes in distal tissues. Our results describe the mechanisms by which chemosensation mediated by a defined enteric neuron regulates physiological homeostasis in response to a specific abiotic stress.

neuroscience↗

bioRxiv2025

Simultaneous immunomodulation and epithelial-to-mesenchymal transition drives lung adenocarcinoma progression

Lung cancer remains the deadliest cancer in the United States, with lung adenocarcinoma (LUAD) as its most prevalent subtype. While computed tomography (CT)-based screening has improved early detection and enabled curative surgeries, the molecular and cellular dynamics driving early-stage LUAD progression remain poorly understood, limiting non-surgical treatment options. To address this gap, we profiled 2.24 million cells from 122 early-stage LUAD patients using multiplexed imaging mass cytometry (IMC). This analysis revealed the molecular, spatial, and temporal dynamics of LUAD development. Our findings uncover a binary progression model. LUAD advances through either inflammation, driven by a balance of cytotoxic and regulatory immune activity, or fibrosis, characterized by stromal activation. Surprisingly, tumor cell populations did not increase significantly. Instead, they displayed a mixed phenotypic profile consistent with epithelial-to-mesenchymal transition (EMT), effectively masking the expansion of malignant cells. Furthermore, we addressed discrepancies between CT-based and histology-based subtyping. CT scans, while non-invasive, often mischaracterize invasive fibrotic tumors--which account for 20.5% of LUAD cases--as mild, non-solid ground glass opacities (GGOs). Using high-content IMC imaging, we demonstrate that these tumors harbor significant risks and advocate for improved diagnostic strategies. These strategies should integrate molecular profiling to refine patient stratification and therapeutic decision-making. Altogether, our study provides a high-resolution, systems-level view of the tumor microenvironment in early-stage LUAD. We characterize key transitions in oncogenesis and propose a precision-driven framework to enhance the detection and management of aggressive disease subtypes.

cancer biology↗

bioRxiv2025

Acquisition of discrete immune suppressive barriers contributes to the initiation and progression of preinvasive to invasive human lung cancer.

Computerized chest tomography (CT)-guided screening in populations at risk for lung cancer has increased the detection of preinvasive subsolid nodules, which progress to solid invasive adenocarcinoma. Despite the clinical significance, there is a lack of effective therapies for intercepting the progression of preinvasive to invasive adenocarcinoma. To uncover determinants of early disease emergence and progression, we used integrated single-cell approaches, including scRNA-seq, multiplexed imaging mass cytometry and spatial transcriptomics, to construct the first high-resolution map of the composition, lineage/functional states, developmental trajectories and multicellular crosstalk networks from microdissected non-solid (preinvasive) and solid compartments (invasive) of individual part-solid nodules. We found that early disease initiation and subsequent progression are associated with the evolution of immune-suppressive cellular phenotypes characterized by decreased cytotoxic CD8 T and NK cells, increased T cell exhaustion and accumulation of immunosuppressive regulatory T cells (Tregs) and M2-like macrophages expressing TREM2. Within Tregs, we identified a unique population of 4-1BB+ Treg subset enriched for the IL2-STAT5 suppressive pathway with transcription profiles supporting discrete metabolic alterations. Spatial analysis showed increased density of suppressive immune cells around tumor cells, increased exhaustion phenotype of both CD4 and CD8 T cells expressing chemokine CXCL13, and spatial micro-complex of endothelial and lymphocyte interactions within tertiary lymphoid structures. The single-cell architecture identifies determinants of early disease emergence and progression, which may be developed not only as diagnostic/prognostic biomarkers but also as targets for disease interception. Additionally, our dataset constitutes a valuable resource for the preinvasive lung cancer research community.

cancer biology↗

bioRxiv2024

OMAnnotator: a novel approach to building an annotated consensus genome sequence

MotivationAdvances in sequencing technologies have enabled researchers to sequence whole genomes rapidly and cheaply. However, despite improvements in genome assembly, genome annotation (i.e. the identification of protein-coding genes) remains challenging, particularly for eukaryotic genomes: it requires combining several approaches (typically ab initio, transcriptomics, and homology search), each with its own pros and cons. Deciding which gene models to retain in a consensus is far from trivial, and automated approaches tend to lag behind laborious manual curation efforts in accuracy. ResultsHere, we present OMAnnotator, a novel approach to building a consensus annotation. OMAnnotator repurposes the OMA algorithm, originally designed to elucidate evolutionary relationships among genes across species, to integrate predictions from different annotation sources, using evolutionary information as a tie-breaker. We validated OMAnnotator by reannotating the Drosophila melanogaster reference genome and comparing it with the expert-curated reference and results from the automated pipelines BRAKER2 and EvidenceModeller. OMAnnotator produced a consensus annotation that outperformed each individual input and surpassed the existing pipelines. Finally, when applied to three recently published genomes, OMAnnotator gave substantial improvements in two cases, and mixed results in the third, which had already benefited from extensive expert curation. ConclusionWe introduce an original, flexible, and effective approach to annotating genomes by integrating multiple lines of evidence. The methods robustness is underlined by its successful implementation in re-annotating recently published genomes, opening up new avenues in eukaryotic genome annotation.

bioinformatics↗

bioRxiv2024

The thermotolerant Arabian killifish, Aphanius dispar, as a novel infection model for human fungal pathogens

Candida albicans: a fungal pathogen, can cause superficial and fatal infections in humans. An important virulence factor in C. albicans dissemination is the transformation from yeast to an invasive hyphal form, which is favoured at human body temperature. Zebrafish, a useful model for studying C. albicans infections, cannot survive at 37{degrees}C. Arabian killifish, Aphanius dispar, an emerging teleost model can tolerate temperatures up to 40 {degrees}C for up to 12 days (independent feeding time) allowing for longer analysis compared to zebrafish. This study introduces A. dispar as a thermo-relevant and a more accurate reporter of the virulence mechanisms relevant to C. albicans as a human pathogen. Using A. dispar, we tested virulence at human skin (30 {degrees}C), body temperature (37 {degrees}C) and a high fever condition (40{degrees}C). Infection by C. albicans at 37{degrees}C and 40{degrees}C significantly increased virulence, reduced survival of AKF embryos and formed invasive hyphal network compared to 30 {degrees}C. Two mutant strains of C. albicans. pmr1{Delta} (with aberrant cell surface glycans) exhibited reduced virulence at 37{degrees}C, whereas rsr1{Delta} (lacking a cell polarity marker) showed less virulence at 30 {degrees}C. Additionally, anti-fungal treatment rescued AKF survival in a dose-dependent manner, indicating AKFs potential for in vivo drug testing. Our data indicates the quantitative and qualitative importance of examining virulence traits at physiologically relevant temperatures and demonstrates an equivalence to findings for systemic infection derived in mouse models. The A. dispar embryo therefore provides an excellent in vivo model system for assessing virulence, drug-testing, and real-time imaging of host-pathogen interactions. Significance StatementThe virulence of many pathogens is dependent on host temperature. We demonstrate that the A. dispar embryo provides an excellent new thermo-relevant alternative to zebrafish and mouse models, which have limitations in terms of the range of temperatures that can be assessed in real-time. In this study, we have assessed C. albicans temperature-based virulence, focusing on human body and human skin temperatures (37, 40 and 30 {degrees}C, respectively) by examining different genetic backgrounds of C. albicans strains. The results indicate different C. albicans strains with genetic background show varied virulence depending on temperature indicating importance of examination of virulence mechanisms at physiological temperatures.

animal behavior and cognition↗

bioRxiv2023

Calibrated Identification of Feature Dependencies in Single-cell Multiomics

Data-driven identification of functional relationships between cellular properties is an exciting promise of single-cell genomics, especially given the increasing prevalence of assays for multiomic and spatial transcriptomic analysis. Major challenges include dealing with technical factors that might introduce or obscure dependencies between measurements, handling complex generative processes that require nonlinear modeling, and correctly assessing the statistical significance of discoveries. VI-VS (Variational Inference for Variable Selection) is a comprehensive framework designed to strike a balance between robustness and interpretability. VI-VS employs nonlinear generative models to identify conditionally dependent features, all while maintaining control over false discovery rates. These conditional dependencies are more stringent and more likely to represent genuine causal relationships. VI-VS is openly available at https://github.com/YosefLab/VIVS, offering a no-compromise solution for identifying relevant feature relationships in multiomic data, advancing our understanding of molecular biology.

bioinformatics↗

bioRxiv2023

Molecular encoding of stimulus features in a single sensory neuron type enables neuronal and behavioral plasticity

Neurons modify their transcriptomes in response to an animals experience. How specific experiences are transduced to modulate gene expression and precisely tune neuronal functions are not fully defined. Here, we describe the molecular profile of a thermosensory neuron pair in C. elegans experiencing different temperature stimuli. We find that distinct salient features of the temperature stimulus including its duration, magnitude of change, and absolute value are encoded in the gene expression program in this single neuron, and identify a novel transmembrane protein and a transcription factor whose specific transcriptional dynamics are essential to drive neuronal, behavioral, and developmental plasticity. Expression changes are driven by broadly expressed activity-dependent transcription factors and corresponding cis-regulatory elements that nevertheless direct neuron- and stimulus-specific gene expression programs. Our results indicate that coupling of defined stimulus characteristics to the gene regulatory logic in individual specialized neuron types can customize neuronal properties to drive precise behavioral adaptation.

neuroscience↗

bioRxiv2022

Meiotic drive does not impede success in sperm competition in the stalk-eyed fly, Teleopsis dalmanni

In male X-linked meiotic drive systems, the driver causes degeneration of Y-bearing sperm, leading to female-biased offspring sex ratios. This potentially leads to a two-fold transmission advantage to drive chromosomes. However, drive-bearing sperm often do poorly in sperm competition, limiting their ability to spread. We use the stalk-eyed fly, Teleopsis dalmanni, to investigate the success of the X-linked Sex Ratio (SR) meiotic drive system. In this species, polyandrous matings, where a female mates with multiple males, are common. Recent findings demonstrate SR males transfer the same numbers of viable sperm as wildtype (ST) males during mating, implying that they do not necessarily have reduced fertility under sperm competition. Reciprocal mating trials were performed to measure the success of SR and ST sperm in double mated females, with either a SR or ST male mated first followed by a male of the alternative genotype. There was no significant difference in the number of offspring sired by SR and ST males. This equivalence held regardless of whether the SR male mated first or second. We show these results are consistent with previous studies that suggested SR male sperm do poorly in sperm competition. Future experiments will determine whether the competitive ability of SR males is maintained under higher stress conditions likely to be experienced in nature, in which females mate repeatedly with multiple males. The results from the current study helps to explain the high meiotic drive frequency of around 20% in wild populations in this species. Impact SummaryMeiotic drive genes are selfish genetic elements that distort Mendelian patterns of inheritance to bias transmission in their favour. We use the stalk-eyed fly, Teleopsis dalmanni, to investigate the fitness effects associated with a meiotic drive gene called Sex Ratio (SR), which is linked to the X chromosome. In males, SR destroys Y-bearing sperm, meaning only X-bearing sperm are viable, and females who mate with drive males sire all-female broods. This confers a two-fold transmission advantage to the SR gene, as it is transmitted to all offspring. We recently discovered that drive males have evolved compensatory mechanisms to cope with the sperm destruction caused by meiotic drive. They have greatly enlarged testes, allowing them to produce more sperm. When drive males mate with females, they deliver as many sperm and sire as many offspring as wildtype males. Building on this finding, we measured how drive male sperm performs against sperm from a non-carrier male in sperm competition - where the sperm from different males compete to fertilise an egg. Double mating trials were performed, where a single female was mated once to a drive and once to a non-carrier male. By genotyping offspring, we show that the number of offspring sired by the drive male was not different from the number sired by the non-carrier competitor. These findings contrast with those in other species. Typically, drive males do poorly in sperm competition and their spread is severely restricted by sperm competition. In stalk-eyed flies, female multiple mating with many males is the norm, but this does not appear to inhibit the fertility of drive males. The success of drive under sperm competition helps to explain the high frequency of drive around 20% in natural populations of T. dalmanni.

evolutionary biology↗

bioRxiv2022

Case Study of Single-cell Protein Activity Based Drug Prediction for Precision Treatment of Cholangiocarcinoma

Cholangiocarcinoma is a rare, aggressive malignancy with limited treatment options, due to a paucity of actionable mutations and low response to immune checkpoint inhibitors. Furthermore, its extreme heterogeneity prevents identification of actionable dependencies from bulk-tissue profiles. To address these challenges, we introduce a highly generalizable, single-cell framework for the mechanism-based prioritization of drugs to treat rare, highly heterogeneous tumors. Analysis of transformed cells, accounting for only 10% of a cholangiocarcinoma patient biopsy revealed three molecularly-distinct subpopulations, predicted to be sensitive to four drugs by regulatory network-based analysis. Validation in a low-passage, patient-derived xenograft (PDX) from the same patient confirmed tumor growth rate control by two of these drugs (plicamycin and dacinostat) and further validated predicted subpopulation-specific effects, suggesting they may represent promising candidates for follow-up clinical trials, either alone or in combination with current standard-of-care chemotherapies. The proposed approach can be generalized to elucidate complementary dependencies of rare, heterogeneous tumors, at the single cell level.

cancer biology↗

bioRxiv2020

Controlling the false discovery rate in GWAS with population structure

We present a comprehensive statistical framework to analyze data from genome-wide association studies of polygenic traits, producing distinct and interpretable discoveries while controlling the false discovery rate. This approach leverages sophisticated multivariate models, correcting for linkage disequilibrium, and accounts for population structure and relatedness, adapting to the characteristics of the samples at hand. A key element is the recognition that the observed genotypes can be considered as a random sample from an appropriate model, encapsulating our knowledge of genetic inheritance and human populations. This allows us to generate imperfect copies (knockoffs) of these variables which serve as ideal negative controls; knockoffs are indistinguishable from the original genotypes in distribution, and independent from the phenotype. In sharp contrast with state-of-the-art methods, the validity of our inference in no way depends on assumptions about the unknown relation between genotypes and phenotype. We develop and leverage a model for the genotypes that accounts for arbitrary and unknown population structure, which may be due to diverse ancestries or familial relatedness. We build a pipeline that is robust to the most prominent possible confounders, facilitating the discovery of causal variants. Validity and effectiveness are demonstrated by extensive simulations with real data, as well as by the analysis of several phenotypes in the UK Biobank. Finally, fast software is made available for researchers to apply the proposed methodology to Biobank-scale data sets.

genomics↗

bioRxiv2019

Multi-resolution localization of causal variants across the genome

We present KnockoffZoom, a flexible method for the genetic mapping of complex traits at multiple resolutions. KnockoffZoom localizes causal variants by testing the conditional associations of genetic segments of decreasing width while provably controlling the false discovery rate using artificial genotypes as negative controls. Our method is equally valid for quantitative and binary phenotypes, making no assumptions about their genetic architectures. Instead, we rely on well-established genetic models of linkage disequilibrium. We demonstrate that our method can detect more associations than mixed effects models and achieve fine-mapping precision, at comparable computational cost. Lastly, we apply KnockoffZoom to data from 350k subjects in the UK Biobank and report many new findings.

genomics↗