Biology subjects

Tang, E.

Publications and source records attributed to Tang, E..

At least 19 recordsLinked to original sources

bioRxiv2026

Thille, a chromosome-level type B avocado genome, and the structural and allelic variation at candidate flowering-type loci

Avocado (Persea americana Mill.) is heterodichogamous: each flower opens first as female and then as male, and cultivars fall into two complementary flowering types, A and B, determined by the transcription factor SDMYB, whose dominant allele confers type A. Avocado genomes have so far come from type A cultivars. Here we report a chromosome-level genome of Thille, a type B cultivar used in breeding. From 72.2 Gb of PacBio HiFi reads (81x coverage) and Omni-C data, the assembly places 859.8 Mb, 96% of the expected 896 Mb genome, in 12 chromosomes with an NG50 of 84.5 Mb, a consensus quality of QV 69.95, and 97.3% complete BUSCO genes; repeats occupy 64.0% of the assembly, and 35,386 protein-coding genes were predicted. We compared Thille with the type A cultivars Hass and Puebla, a predominantly Guatemalan hybrid, and with a West Indian (WI) accession, a Lowland botanical group variety of unreported flowering type. The assemblies differ by large rearrangements, including an 18.8 Mb inversion on chromosome 12 specific to Hass. Using phased reads and haplotype assemblies, we reconstructed the alleles of candidate flowering genes from a type A versus type B Fst scan. Both WI haplotypes carry the recessive SDMYB allele found in Thille; based on this study and the previous study of SDMYB, we predict the WI accession to be type B. Six genes, including SDMYB, carry an allele shared by all three type A cultivars and absent from Thille and WI. The genome and HiFi reads are available under BioProject PRJNA1142556.

genomics↗

bioRxiv2026

Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features

Cancer arises from extensive genetic and epigenetic alterations that reshape chromatin, transcriptional regulation, and malignant cell states. To systematically chart cancer-intrinsic regulatory programs, we constructed a pan-cancer single-cell transcriptomic and epigenomic atlas encompassing 60 human cell lines representing 16 tissue origins and 20 cancer types, comprising 240,957 single-nucleus RNA-seq and 223,347 single-nucleus ATAC-seq profiles. Integrative analyses revealed extensive pan-cancer cell-state heterogeneity, core gene-regulatory networks, and a conserved epithelial-mesenchymal transition (EMT) axis that transcends tissue of origin. Copy-number variation analysis identified transcription factor amplification and downstream hyperactivation as key drivers of cancer cell-state reprogramming. To further examine how regulatory programs diverge within a cancer lineage and contribute to clinically divergent outcomes, we performed a focused comparison of cutaneous melanoma with acral melanoma, a rare, UV-independent subtype underrepresented in existing pan-cancer atlases. The comparison uncovered a universal inflammation-suppressive program in acral melanoma and an inflamed regulatory landscape in cutaneous melanoma, with the JAK-STAT pathway and downstream transcriptional responses as central discriminators. Integration of single-cell and bulk datasets across models and patient cohorts further linked in vitro tumor-intrinsic gene regulations with in vivo microenvironmental composition and immunotherapy responses. Together, by extending single-cell multi-omic profiling to rare alongside common cancer subtypes, this atlas offers a resource for mapping pan-cancer and subtype-specific gene-regulatory programs that shape cancer cell-state plasticity.

genomics↗

bioRxiv2026

The Urinary Tract Commensal Peptoniphilus spp. Encodes a Novel 17β-Hydroxysteroid Dehydrogenase

Microbial steroid metabolism represents an underappreciated extension of the vertebrate endocrine system, with growing evidence that host-associated microbes contribute to the diversity and bioavailability of sex steroids within human tissues. Emerging studies have linked microbial androgen metabolism to urinary microbiome composition and to resistance to androgen deprivation therapy (ADT) in prostate cancer. While microbial pathways capable of converting steroid precursors such as cortisol to androgens, via the steroid-17,20-desmolase pathway, such as DesG-mediated interconversion of androstenedione to testosterone have been reported, the diversity of enzymes mediating downstream androgen interconversion remains incompletely defined. Here, we investigate the androgen-forming capabilities of anaerobic bacteria from the male genitourinary microbiome, focusing on NADPH-dependent 17{beta}-hydroxysteroid dehydrogenases (17{beta}-HSDHs) that catalyze interconversion of androstenedione and testosterone. We isolated androgen-forming bacterial strains from human male urine and identified a previously uncharacterized 17{beta}-HSDH encoded by Peptoniphilus obesi, demonstrated that this enzyme catalyzes the NADPH-dependent reduction of androstenedione to testosterone and the reverse oxidation reaction. Sequence similarity searches further identified a homologous 17{beta}-HSDH in Anaerococcus, which was synthesized and functionally validated, revealing conserved activity despite low sequence identity to the previously characterized urinary tract enzyme DesG. The enzymes were found to have broad substrate specificity for C19 and C18 17keto- and 17{beta}-hydroxysteroids. Together, these findings expand the known diversity of microbial 17{beta}-HSDHs and identify previously unrecognized androgen-forming activities within the genitourinary microbiome. ImportanceMicrobial steroid-transforming pathways may provide a mechanism by which commensal anaerobes contribute to androgen availability in the genitourinary tract. By identifying novel 17{beta}-hydroxysteroid dehydrogenases from Peptoniphilus and Anaerococcus, genera repeatedly associated with prostate cancer, this study provides mechanistic insight into how microbial steroid metabolism may influence hormone-driven disease.

microbiology↗

bioRxiv2026

IL-1β engages distinct peripheral sensory circuits to suppress feeding across time

Loss of appetite is a hallmark of acute and chronic inflammation, and sustained anorexia causes malnutrition and worsens disease outcomes. Interleukin-1{beta} (IL-1{beta}) is one of the most potently anorexigenic inflammatory cytokines, yet how it engages neural circuits that suppress feeding remains incompletely understood. Specifically, the role of peripheral sensory neurons in mediating IL-1{beta}-induced anorexia is unresolved. Here, using DREADD-mediated inhibition of discrete peripheral sensory neuron populations and fiber photometry, we show that IL-1{beta}-induced anorexia occurs in at least two temporally and mechanistically distinct phases. Shortly after IL-1{beta} administration, prostaglandin signaling through non-vagal sensory afferents rapidly inhibits hypothalamic AgRP neurons to suppress food intake. At later time points, anorexia becomes partially prostaglandin-independent and vagal afferent neuron-dependent. Our findings demonstrate that multiple molecular signals mediate IL-1{beta}-induced anorexia, and that diverse peripheral sensory pathways, including a previously unappreciated contribution from non-vagal afferents, are critical links between systemic inflammation and neural control of appetite.

neuroscience↗

bioRxiv2026

Polymer-lipid hybrid nanoparticle enhances mRNA delivery and T cell-mediated immunity

mRNA vaccines have transformed prophylactic immunization against infectious diseases as well as therapeutic interventions for cancer. However, their effectiveness against emerging viral variants and a range of malignancies continues to be hindered by suboptimal induction of T cell-mediated immunity. To overcome this limitation, here we developed a polymer-lipid hybrid nanoparticle (PLNP) platform engineered to improve mRNA delivery to antigen-presenting cells (APCs) and to potentiate T cell responses. Relative to conventional mRNA lipid nanoparticle (LNP) vaccines, mRNA PLNP vaccines demonstrated markedly improved lymph node targeting, APC activation, Th1-biased pro-inflammatory cytokine response, and antigen-specific T cell expansion while retaining robust humoral immunity. Remarkably, mRNA-PLNP vaccines generated approximately 50% more antigen-specific CD8+ T cells than mRNA-LNP vaccines across multiple antigens, including SARS-CoV-2 spike, influenza hemagglutinin, and ovalbumin. In prophylactic applications, mRNA PLNP vaccine provided complete protection against SARS-CoV-2 variants. As a therapeutic approach in a melanoma model, mRNA PLNP vaccination resulted in enhanced tumor control and significantly prolonged survival compared to LNP-based formulations. Collectively, these results establish PLNP as a versatile and broadly applicable platform for augmenting mRNA vaccine efficacy through improved mRNA delivery and T cell priming, offering promising implications for infection prevention and cancer immunotherapy.

immunology↗

bioRxiv2025

The urinary pathobiont Actinobaculum massiliense generates androgens via the dirAB pathway

While overlooked during the Human Microbiome Project, characterizing the urinary microbiota in health and disease is a new frontier in microbiome science. Recent studies have associated differential abundance of bacterial taxa including Propionimicrobium lymphophilum and Actinobaculum/Actinotignum spp. with prostate cancer. In this study, we collected urine from subjects prior to prostate biopsy and applied a novel Human Sterolbiome Discovery High-throughput (HSDH) assay to identify culturable urinary bacteria with the ability to generate androgens. Application of the HSDH assay to urine samples led to the isolation of eight P. lymphophilum strains positive for cortisol side-chain cleavage (steroid-17,20-desmolase), 17{beta}-HSDH activity, or both. In addition, we isolated three strains of Actinobaculum massiliense that encode DHEA isomerase reductase (dir) genes. The dirA gene encodes a novel 3{beta}/17{beta}-hydroxysteroid dehydrogenase/{Delta}4,5-isomerase and the dirB gene encodes a novel 17{beta}-hydroxysteroid dehydrogenase isoform. Structural prediction and molecular dynamics reveal probable catalytic mechanisms based on the shared catalytic triad but distinct binding pocket geometries of the DirA and DirB that describe their respective reactions. Phylogenetic analysis of DirA and DirB revealed homologs in urinary tract commensals as well as bacteria associated with steroid degradation found in aquatic and terrestrial environments. Taken together, the development of the HSDH assay and the identification of the dir pathway genes is a significant advance in microbial endocrinology, laying the methodological foundation and providing the molecular basis for understanding the role of urinary tract bacteria in host endocrine physiology.

microbiology↗

bioRxiv2025

MAIT cells induced by engineered Listeria exhibit antibacterial and antitumor activity

Mucosal-associated invariant T (MAIT) cells are among the most conserved and abundant innate-like T cells in humans that recognize microbial-derived riboflavin precursors and elicit potent antimicrobial responses. The foodborne pathogen Listeria monocytogenes is a broad host-range facultative intracellular pathogen that lacks the riboflavin biosynthetic pathway, leading us to hypothesize that this deficiency is pathoadaptive and allows the pathogen to evade MAIT cells. Here, we show that L. monocytogenes strains engineered to produce riboflavin (L. monocytogenes-ribDEAHT) are attenuated in wild-type mice but fully virulent in MAIT cell-deficient mice. Infection with L. monocytogenes-ribDEAHT prompted rapid and robust MAIT cell expansion in multiple tissues and required the cytolytic effector perforin to eliminate infected cells in vivo and in vitro. We also assessed the therapeutic potential of L. monocytogenes-ribDEAHT-stimulated MAIT cells in both infectious disease and cancer mouse models. Therapeutic administration of L. monocytogenes-ribDEAHT provided protection against Francisella tularensis in the lungs and inhibited tumor growth even in the absence of CD8+ T cells. These findings reveal the importance of MAIT cell evasion during L. monocytogenes infection and highlight the therapeutic potential of engineered L. monocytogenes to activate and harness MAIT cells for protection against infectious disease and cancer. Significance StatementListeria monocytogenes is a bacterial pathogen that grows freely in the environment but can become intracellular following ingestion of contaminated food. Although L. monocytogenes can synthesize most metabolites required for growth, it lacks the genes necessary to produce riboflavin (vitamin B2), an essential cofactor across all domains of life. We hypothesized that lacking riboflavin biosynthesis allows L. monocytogenes to evade mucosal-associated invariant T cells (MAIT cells), which generate potent antimicrobial responses against riboflavin-producing microbes. By engineering L. monocytogenes to produce riboflavin, we show that these strains robustly activate MAIT cells and are highly attenuated in wild-type mice, but not in MAIT cell-deficient mice. Furthermore, MAIT cells activated by engineered L. monocytogenes provided therapeutic protection against other riboflavin-producing bacteria and cancer.

microbiology↗

bioRxiv2025

Metabolic and ribosomal dysregulation drive developmental arrest of Schistosoma japonicum in non-permissive rats

Parasitic flatworms of the genus Schistosoma infect a wide range of definitive hosts, which are categorized as permissive or non-permissive based on their capacity to support parasite development. Unlike permissive hosts such as mice, Schistosoma japonicum undergoes pronounced developmental arrest in non-permissive hosts like rats; however, the molecular mechanisms underlying this phenomenon remain largely unclear. In this study, we conducted a comprehensive morphological and transcriptomic comparison of S. japonicum derived from mouse and rat hosts at multiple time points post-infection, identifying the period between 12 and 24 days post-infection (dpi) as a critical window for developmental arrest in parasites from rats. Utilizing single-cell RNA sequencing, we constructed a high-resolution cellular atlas of S. japonicum at 14 and 24 dpi from both host species, revealing host-dependent alterations in cell composition and transcriptional programs during parasite development. Functional analyses further demonstrated that impairments in mitochondrial function and anaerobic glycolysis contribute to the developmental arrest observed in parasites from rats. Additionally, downregulation of ribosomal genes was associated with reduced protein synthesis and impaired cell proliferation. Together, these findings suggest that disruptions in energy metabolism and ribosomal function are key drivers of developmental arrest in non-permissive hosts. This study provides novel, parasite-centered insights into host permissiveness and identifies potential molecular targets for schistosomiasis control strategies.

developmental biology↗

bioRxiv2025

Low-Strength Type I Interferon Signaling Promotes CAR T-Cell Treatment Efficacy

CD19-directed chimeric antigen receptor (CAR) T-cell therapy has significantly advanced the treatment landscape for relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL). However, up to 60% of patients do not achieve a complete response. To uncover determinants of therapeutic efficacy, we analyzed the infusion products of eight r/r DLBCL patients with distinct clinical responses to axicabtagene ciloleucel using single-cell transcriptomics. Compared to patients who exhibited progressive disease, infusion products of complete responders demonstrated enriched signatures of type I interferon (IFN-I) signaling. Based on these findings, we developed a novel strategy to improve CD19-directed CAR T-cell treatment efficacy by incorporating IFN-I as an enhancer during the ex vivo manufacturing process, with IFN-I removal before CAR T-cell infusion to avoid in vivo toxicities. For both CD28- and 4-1BB-costimulated second-generation CARs, we found that low-strength IFN-I signaling enhanced CAR T-cell cytotoxicity and treatment efficacy against B-cell lymphoma and leukemia. Our low-strength IFN-I-enhanced CAR T-cell ex vivo manufacturing approach leverages an existing FDA-approved pharmacologic agent, circumvents in vivo interferon-associated toxicities, and remains fully compatible with current CAR constructs and manufacturing workflows. Together, our results establish IFN-I as a potent and costimulation-independent enhancer of CAR T-cell efficacy and provide a translationally feasible approach to enhance CAR T-cell therapies.

immunology↗

bioRxiv2025

Breaking the Link: Neural Dissociation of Attention and Working Memory through Inhibitory Control

Attention and working memory (WM) encoding have traditionally been considered inseparable processes with shared neural mechanisms. Here, using an innovative experimental design and a multimodal approach, we provide the first direct neural evidence that attention and WM encoding are dissociable. Functional MRI identifies the supramarginal gyrus (SMG) as the key region enabling this dissociation, while dynamic causal modeling reveals the neural circuitry through which the SMG exerts inhibitory control over attentional representations, regulating their integration into WM. Furthermore, neuromodulation via transcranial direct current stimulation (tDCS) demonstrates that enhancing SMG activity strengthens this inhibitory control, providing causal evidence for the dissociation mechanism. A second tDCS experiment with varied stimuli confirms the generalizability of this mechanism and reinforces the robustness of our results. These findings challenge the long-standing view that attention and WM encoding form a continuous process, demonstrating instead that they constitute two dissociable neural processes of information selection.

neuroscience↗

bioRxiv2025

Two-Stage CD8+ CAR T-Cell Differentiation in Patients with Large B-Cell Lymphoma

Chimeric antigen receptor (CAR) T-cell therapy has expanded therapeutic options for patients with diffuse large B-cell lymphoma (DLBCL). However, progress in improving clinical outcomes has been limited by an incomplete understanding of CAR T-cell differentiation in patients. To comprehensively investigate CAR T-cell differentiation in vivo, we performed single-cell, multi-modal, and longitudinal analyses of CD28-costimulated CAR T cells from infusion product and peripheral blood (day 8-28) of patients with DLBCL who were successfully treated with axicabtagene ciloleucel. Here, we show that CD8+ CAR T cells undergo two distinct waves of clonal expansion. The first wave is dominated by CAR T cells with an exhausted-like effector memory phenotype during the peak expansion period (day 8-14). The second wave is dominated by CAR T cells with a terminal effector phenotype during the post-peak persistence period (day 21-28). Importantly, the two waves have distinct ontogeny and are biologically uncoupled. Furthermore, lineage tracing analysis via each CAR T cells endogenous TCR clonotype demonstrates that the two waves originate from different effector precursors in the infusion product. Precursors of the first wave exhibit more effector-like signatures, whereas precursors of the second wave exhibit more stem-like signatures. These findings suggest that pre-infusion heterogeneity mediates the two waves of in vivo clonal expansion. Our findings provide evidence against the intuitive idea that the post-peak contraction in CAR abundance is solely apoptosis or extravasation of short-lived CAR T cells from peak expansion. Rather, our findings demonstrate that CAR T-cell expansion and persistence are mediated by clonally, phenotypically, and ontogenically distinct CAR T-cell populations that serve complementary clinical purposes.

immunology↗

bioRxiv2023

Recombination map tailored to Native Hawaiians reduces false positive findings in genomic scans of positive selection

Recombination events establish the patterns of haplotypic structure in a population and estimates of recombination rates are used in several downstream population and statistical genetic analyses. Using suboptimal maps from distantly related populations may reduce the efficacy of genomic analyses, particularly for underrepresented populations such as the Native Hawaiians. To overcome this challenge, we constructed recombination maps using genome-wide array data from two study samples of Native Hawaiians: one reflecting the current admixed state of Native Hawaiians (NH map), and one based on individuals of enriched Polynesian ancestries (PNS map) with the potential to be used for less admixed Polynesian populations such as the Samoans. We found the recombination landscape to be less correlated with those from other continental populations (e.g. Spearmans rho = 0.79 between PNS and CEU (Utah residents with Northern and Western European ancestry) compared to 0.92 between YRI (Yoruba in Ibadan, Nigeria) and CEU at 50 kb resolution), likely driven by the unique demographic history of the Native Hawaiians. PNS also shared the fewest recombination hotspots with other populations (e.g. 8% of hotspots shared between PNS and CEU compared to 27% of hotspots shared between YRI and CEU). We found that downstream analyses in the Native Hawaiian population, such as local ancestry inference, imputation, and IBD segment and relatedness detections, would achieve similar efficacy when using the NH map compared to an omnibus map. However, for genome scans of adaptive loci using integrated haplotype scores, we found several loci with apparent genome-wide significant signals (|Z-score| > 4) in Native Hawaiians that would not have been significant when analyzed using NH-specific maps. Population-specific recombination maps may therefore improve the robustness of haplotype-based statistics and help us better characterize the evolutionary history that may underlie Native Hawaiian-specific health conditions that persist today.

genetics↗

bioRxiv2023

Imputation Efficacy Across Global Human Populations

Genotype imputation is now fundamental for genome-wide association studies but lacks fairness due to the underrepresentation of populations with non-European ancestries. The state-of-the-art imputation reference panel released by the Trans-Omics for Precision Medicine (TOPMed) initiative contains a substantial number of admixed African-ancestry and Hispanic/Latino samples to impute these populations with nearly the same accuracy as European-ancestry cohorts. However, imputation for populations primarily residing outside of North America may still fall short in performance due to persisting underrepresentation. To illustrate this point, we curated genome-wide array data from 23 publications published between 2008 to 2021. In total, we imputed over 43k individuals across 123 populations around the world. We identified a number of populations where imputation accuracy paled in comparison to that of European-ancestry populations. For instance, the mean imputation r-squared (Rsq) for 1-5% alleles in Saudi Arabians (N=1061), Vietnamese (N=1264), Thai (N=2435), and Papua New Guineans (N=776) were 0.79, 0.78, 0.76, and 0.62, respectively. In contrast, the mean Rsq ranged from 0.90 to 0.93 for comparable European populations matched in sample size and SNP content. Outside of Africa and Latin America, Rsq appeared to decrease as genetic distances to European reference increased, as predicted. Further analysis using sequencing data as ground truth suggested that imputation software may over-estimate imputation accuracy for non-European populations than European populations, suggesting further disparity between populations. Using 1496 whole genome sequenced individuals from Taiwan Biobank as a reference, we also assessed a strategy to improve imputation for non-European populations with meta-imputation, which can combine results from TOPMed with smaller population-specific reference panels. We found that meta-imputation in this design did not improve Rsq genome-wide. Taken together, our analysis suggests that with the current size of alternative reference panels, meta-imputation alone cannot improve imputation efficacy for underrepresented cohorts and we must ultimately strive to increase diversity and size to promote equity within genetics research.

genetics↗

bioRxiv2022

A single-cell atlas reveals shared and distinct immune responses and metabolism during SARS-CoV-2 and HIV-1 infections

SARS-CoV-2 and HIV-1 are RNA viruses that have killed millions of people worldwide. Understanding the similarities and differences between these two infections is critical for understanding disease progression and for developing effective vaccines and therapies, particularly for 38 million HIV-1+ individuals who are vulnerable to SARS-CoV-2 co-infection. Here, we utilized single-cell transcriptomics to perform a systematic comparison of 94,442 PBMCs from 7 COVID-19 and 9 HIV-1+ patients in an integrated immune atlas, in which 27 different cell types were identified using an accurate consensus single-cell annotation method. While immune cells in both cohorts show shared inflammation and disrupted mitochondrial function, COVID-19 patients exhibit stronger humoral immunity, broader IFN-I signaling, elevated Rho GTPase and mTOR pathway activities, and downregulated mitophagy. Our results elucidate transcriptional signatures associated with COVID-19 and HIV-1 that may reveal insights into fundamental disease biology and potential therapeutic targets to treat these viral infections. HighlightsO_LICOVID-19 and HIV-1+ patients show disease-specific inflammatory immune signatures C_LIO_LICOVID-19 patients show more productive humoral responses than HIV-1+ patients C_LIO_LISARS-CoV-2 elicits more enriched IFN-I signaling relative to HIV-I C_LIO_LIDivergent, impaired metabolic programs distinguish SARS-CoV-2 and HIV-1 infections C_LI

bioinformatics↗

bioRxiv2022

Genomic occupancy of the bromodomain protein Bdf3 is dynamic during differentiation of African trypanosomes from bloodstream to procyclic forms

Trypanosoma brucei, the causative agent of Human and Animal African trypanosomiasis, cycles between a mammalian host and a tsetse fly vector. The parasite undergoes huge changes in morphology and metabolism as it adapts to each host environment. These changes are reflected in the differing transcriptomes of parasites living in each host. While changes in the transcriptome have been well catalogued for parasites differentiating from the mammalian bloodstream to the insect stage, it remains unclear whether chromatin interacting proteins mediate transcriptomic changes during life cycle adaptation. We and others have shown that chromatin interacting bromodomain proteins localize to transcription start sites in bloodstream parasites, but whether the localization of bromodomain proteins changes as parasites differentiate from bloodstream to insect stage parasites remains unknown. To address this question, we performed Cleavage Under Target and Release Using Nuclease (CUT&RUN) timecourse experiments using a tagged version of Bromodomain Protein 3 (Bdf3) in parasites differentiating from bloodstream to insect stage forms. We found that Bdf3 occupancy at most loci increased at 3 hours following onset of differentiation and decreased thereafter. A number of sites with increased bromodomain protein occupancy lie proximal to genes known to have altered transcript levels during differentiation, such as procyclins, procyclin associated genes, and invariant surface glycoproteins. While most Bdf3 occupied sites are observed throughout differentiation, a very small number appear de novo as differentiation progresses. Notably, one such site lies proximal to the procyclin gene locus, which contains genes essential for remodeling surface proteins following transition to the insect stage. Overall, these studies indicate that occupancy of chromatin interacting proteins is dynamic during life cycle stage transitions, and provides the groundwork for future studies aimed at uncovering whether changes in bromodomain protein occupancy affect transcript levels of neighboring genes. Additionally, the optimization of CUT&RUN for use in Trypanosoma brucei may prove helpful for other researchers as an alternative to Chromatin Immunoprecipitation (ChIP).

molecular biology↗

bioRxiv2021

A curated collection of human vaccination response signatures

Recent advances in high-throughput experiments and systems biology approaches have resulted in hundreds of publications identifying "immune signatures". Unfortunately, these are often described within text, figures, or tables in a format not amenable to computational processing, thus severely hampering our ability to fully exploit this information. Here we present a data model to represent immune signatures, along with the Human Immunology Project Consortium (HIPC) Dashboard (www.hipc-dashboard.org), a web-enabled application to facilitate signature access and querying. The data model captures the biological response components (e.g., genes, proteins, cell types or metabolites) and metadata describing the context under which the signature was identified using standardized terms from established resources (e.g., HGNC, Protein Ontology, Cell Ontology). We have manually curated a collection of >600 immune signatures from >60 published studies profiling human vaccination responses for the current release. The system will aid in building a broader understanding of the human immune response to stimuli by enabling researchers to easily access and interrogate published immune signatures.

bioinformatics↗

bioRxiv2019

Reactive oxygen species rescue lysosome coalescence during PIKfyve inhibition

Lysosomes are terminal, degradative organelles of the endosomal pathway that undergo repeated fusion-fission cycles with themselves, endosomes, phagosomes, and autophagosomes. Lysosome number and size depends on balanced fusion and fission rates. Thus, conditions that favour fusion over fission can reduce lysosome numbers while enlarging their size. Conversely, favouring fission over fusion may cause lysosome fragmentation and increase their numbers. PIKfyve is a phosphoinositide kinase that generates phosphatidylinositol-3,5-bisphosphate to modulate lysosomal functions. PIKfyve inhibition causes an increase in lysosome size and reduction in lysosome number, consistent with lysosome coalescence. This is thought to proceed through reduced lysosome reformation and/or fission after fusion with endosomes or other lysosomes. Previously, we observed that photo-damage during live-cell imaging prevented lysosome coalescence during PIKfyve inhibition. Thus, we postulated that lysosome fusion and/or fission dynamics are affected by reactive oxygen species (ROS). Here, we show that ROS generated by various independent mechanisms all impaired lysosome coalescence during PIKfyve inhibition and accelerated lysosome fragmentation during re-activation. However, depending on the ROS species or mode of production, lysosome dynamics were affected distinctly. H2O2 impaired lysosome motility and reduced lysosome fusion with phagosomes, suggesting that H2O2 reduces lysosome fusogenecity. In comparison, inhibitors of oxidative phosphorylation, glutathione, and thioredoxin that produce superoxide, did not impair lysosome motility but instead promoted clearance of actin puncta on lysosomes formed during PIKfyve inhibition. Additionally, actin depolymerizing agents prevented lysosome coalescence during PIKfyve inhibition. Thus, we discovered that ROS can generally prevent lysosome coalescence during PIKfyve inhibition using distinct mechanisms depending on the type of ROS.

cell biology↗

bioRxiv2019

Immune gene expression profiling reveals heterogeneity in luminal breast tumors

Disease heterogeneity of immune gene expression patterns of luminal breast cancer (BC) has not been well studied. We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 Asian luminal BC patients and identified three distinct immune subtypes. Tumors in one subtype exhibited signs of T-cell activation, lower ESR1/ESR2 expression ratio and higher expression of immune checkpoint genes, nonsynonymous mutation burden, APOBEC-signature mutations, and increasing body mass index compared to other luminal tumors. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in cases drawn from The Cancer Genome Atlas and a Korean breast cancer study. Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification.

genomics↗