Biology subjects

Edwards, M.

Publications and source records attributed to Edwards, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Knock-in = knock-out: differential fitness effects of cardinal mutations in Anopheles stephensi

The kynurenine pathway metabolizes tryptophan into 3-hydroxykynurenine (3-HK), a precursor for ommochrome eye pigments synthesized via the cardinal (cd) gene in mosquitoes. While cd disruption was presumed neutral, we observed fitness costs in Anopheles stephensi knock-in but not knock-out cd mutants. Here we investigated this anomaly further by assessing survival, fecundity, and midgut integrity across multiple cd mutant lines. Heterozygous knock-in lines, expressing a fluorescent marker and guide RNA for CRISPR/Cas9, exhibited reduced survival post-blood feeding, larva-to-adult survival deficits, and midgut barrier dysfunction, whereas knock-outs showed no such costs. Oral supplementation with xanthurenic acid partially rescued knock-in mortality, implicating oxidative stress linked to 3-HK metabolism. Expression analyses suggest transgene insertion effects, rather than cd disruption, underlie these fitness costs. These findings highlight the importance of evaluating insertional effects in gene drive target selection and support cd as a viable target for genetic control strategies in An. stephensi.

genetics↗

bioRxiv2025

Aging promotes escape from X chromosome inactivation in human tissues

Age-related diseases often show sex differences, yet their molecular bases remain unclear. Animal models suggest that age-related disruption of X-chromosome inactivation (XCI) occurs in female mice. We test whether this phenomenon extends to humans using bulk and single-cell datasets. We find that age-dependent escape from XCI also occurs in human females, particularly among genes at the distal ends of the X-chromosome and those involved in genome stability. These findings provide preliminary evidence that XCI erosion represents a human female-specific aging process.

bioinformatics↗

bioRxiv2025

Naegleria amoebae seek confinement and crawl persistently through narrow spaces

The "brain-eating amoeba" Naegleria fowleri dwells in ponds where it normally feeds on bacteria, but if it enters the brain it can cause a deadly infection. To establish infection, N. fowleri must migrate through different environments--along olfactory axons, through openings in the cribriform plate, and within brain tissue--yet how it does so remains unknown. As a model for N. fowleri migration within these environments, we examine how its non-pathogenic relative, Naegleria gruberi, navigates environments of distinct geometries. We show that Naegleria uses both actin-rich protrusions and membrane blebs to crawl across or between flat surfaces. We also explore how Naegleria interact with narrow channels and find that, unlike Dictyostelium amoebae that we show frequently disengage from channel interfaces, Naegleria amoebae probe channels until they enter. Once inside, Naegleria crawls quickly (>50 m/min) and unidirectionally over long distances (>1 mm) using only bleb-based motility. We also introduced Naegleria to granular hydrogel matrices that mimic pond sediments and found that cells readily enter and migrate through these three-dimensional matrices using both blebs and lamellar protrusions. Although cells in matrices showed lower persistence at short timescales, longer time scales correlate with increased persistence, suggesting Naegleria cells may retain memory of past orientation. We propose that pond life may select for three behaviors that prime Naegleria for pathogenesis: memory-guided motility that would facilitate exploration of sinus cavities, confinement-seeking ("claustrophilia") that would promote entry into narrow passages along olfactory axons, and persistent bleb-based migration that would allow rapid transit along axons to the brain.

cell biology↗

bioRxiv2025

Integrating Genomics into Multimodal EHR Foundation Models

AO_SCPLOWBSTRACTC_SCPLOWThis paper introduces an innovative Electronic Health Record (EHR) foundation model that integrates Polygenic Risk Scores (PRS) as a foundational data modality, moving beyond traditional EHR-only approaches to build more holistic health profiles. Leveraging the extensive and diverse data from the All of Us (AoU) Research Program, this multimodal framework aims to learn complex relationships between clinical data and genetic predispositions. The methodology extends advancements in generative AI to the EHR foundation model space, enhancing predictive capabilities and interpretability. Evaluation on AoU data demonstrates the models predictive value for the onset of various conditions, particularly Type 2 Diabetes (T2D), and illustrates the interplay between PRS and EHR data. The work also explores transfer learning for custom classification tasks, showcasing the architectures versatility and efficiency. This approach is pivotal for unlocking new insights into disease prediction, proactive health management, risk stratification, and personalized treatment strategies, laying the groundwork for more personalized, equitable, and actionable real-world evidence generation in healthcare.

bioinformatics↗

bioRxiv2025

A comparative GWAS of eye colour in light and dark eye genetic backgrounds defined by HERC2 rs12913832 polymorphism

rs12913832, a polymorphism located in an enhancer within the HERC2 gene, which is known to regulate OCA2 transcription, is heavily relied upon as a predictor of light versus dark eyes. Individuals with the GG genotype are projected to have blue eyes, while individuals with the AA or AG genotypes are projected to have darker eye colours (primarily brown). However, eye colour is a polygenic trait, and previous studies have revealed that a significant proportion of individuals self-report an eye colour that is not concordant with their genotype at rs12913832. Herein, we address the question: What common markers are influencing eye colour in individuals whose self-reported phenotype does not correspond to the expected phenotype based on their rs12913832 genotype? Building upon our prior investigation of iris pigmentation genetics in individuals with an expected "blue eye" background (rs12913832:GG genotype) in a sample of the Canadian Partnership for Tomorrows Health (CanPath) cohort, this study extends the analysis to include individuals with an expected "brown eye" background (rs12913832:AA+AG). We identified variants in SLC45A2, TYRP1, TYR, SLC24A4 and TSPAN10, which may influence eye colour presentation in individuals with the rs12913832:GG genotype and variants in IRF4, TYRP1 and OCA2, which may influence eye colour presentation in individuals with the rs12913832:AA+AG genotype. These markers include well-known pigmentation-associated single nucleotide polymorphisms, such as rs16891982 (SLC45A2), rs1126809 (TYR), rs12203592 (IRF4), rs1800407 (OCA2) and rs6420484 (TSPAN10). Several of these loci were replicated using independent quantitative eye colour measures, including heterochromia and CIELAB colour dimensions. This research highlights the importance of gene-gene interactions and the polygenic nature of pigmentation traits, emphasizing modifying effects that can sometimes counteract the dominant influence of rs12913832, contributing to advancements in pigmentation genetics and forensic applications.

genetics↗

bioRxiv2025

Intracellular Mannanases Sustain Matrix Polysaccharide Biosynthesis

O_LIMannans with {beta}-1,4-linked backbones are common cell wall components of algae and land plants. Prior challenges to enhance {beta}-mannan content in plants point to unclear metabolic bottlenecks and the potential for hidden biosynthetic players. C_LIO_LIEndo-{beta}-MANNANASEs (MANs) are the main glycosyl hydrolases that mobilize extracellular {beta}-mannans during seed germination. However, we found that Arabidopsis man2 man5 seeds resemble {beta}-mannan biosynthetic mutants. C_LIO_LICELLULOSE SYNTHASE-LIKE A (CSLA) overexpression restored {beta}-mannan synthesis in the man double mutant and increased the distribution of crystalline polymers, but impaired the release of other mucilaginous polysaccharides. C_LIO_LIUsing yeast synthetic biology, we dissected the functional interplay of MAN enzymes with CSLAs. Intracellular MAN2 and MAN5 reduced the quantity of insoluble {beta}-mannan but elevated the content of water-soluble carbohydrates. C_LIO_LIWe propose that Arabidopsis MAN2/5, and orthologous crop enzymes with a transmembrane domain, sustain hemicellulose production in the Golgi apparatus by cleaving insoluble {beta}-mannan polymers into hydrophilic counterparts. C_LI

biochemistry↗

bioRxiv2024

A new class of penicillin-binding protein inhibitors to address drug-resistant Neisseria gonorrhoeae

{beta}-Lactams are the most widely used antibiotics for the treatment of bacterial infections because of their proven track record of safety and efficacy. However, susceptibility to {beta}-lactam antibiotics is continually eroded by resistance mechanisms. Emerging multidrug-resistant (MDR) Neisseria gonorrhoeae strains possessing altered penA alleles (encoding PBP2) pose a global health emergency as they threaten the utility of ceftriaxone, the last remaining outpatient antibiotic. Here we disclose a novel benzoxaborinine-based penicillin-binding protein inhibitor series (boro-PBPi) that is envisioned to address penA-mediated resistance while offering protection against evolution and expansion of {beta}-lactamases. Optimization of boro-PBPi led to the identification of compound 21 (VNRX-14079) that exhibits potent antibacterial activity against MDR N. gonorrhoeae achieved by high affinity binding to the PBP2 target. Boro-PBPi/PBP2 complex structures confirmed covalent interaction of the boron atom with Ser310 and the importance of the {beta}3-{beta}4 loop for improved affinity. 21 elicits bactericidal activity, a low frequency of resistance, a good safety profile, suitable pharmacokinetic properties, and in vivo efficacy in a murine infection model against ceftriaxone-resistant N. gonorrhoeae. 21 is a promising anti-gonorrhea agent poised for further advancement.

microbiology↗

bioRxiv2024

Double crossed? Structural and computational studies of an unusual crosslinked heme in Methylococcus capsulatus cytochrome P460

Cytochromes P460 oxidise hydroxylamine within the nitrogen cycle and contain as their active site an unusual catalytic c-type heme where the porphyrin is cross-linked to the protein via a lysine residue in addition to the canonical cross links from cysteine residues. Understanding how enzymes containing P460 heme oxidise hydroxylamine into either nitrous oxide or nitric oxide has implications for climate change. Interestingly the P460 containing hydroxylamine oxidoreductase utilises a tyrosine cross link to heme and performs similar chemistry. Previous crystal structures of cytochrome P460 from Nitrosomonas europaea (NeP460) clearly show the existence of a single crosslink between the Nz atom of lysine and the heme porphyrin with mutagenesis studies indicating roles for the crosslink in positioning a proton transfer residue and/or influencing the distortion of the heme. Here we describe the evidence for a novel double cross link between lysine and heme in the cytochrome P460 from Methylococcus capsulatus (Bath). In order to understand the complexities of this enzyme system we applied high resolution structural biology approaches at synchrotron and XFEL sources paired with crystal spectroscopies. Linked to this we carried out QM/MM simulations that enabled the prediction of electronic absorption spectra providing a crucial validation to linking simulations and experimental structures. Our work demonstrates the feasibility of a double crosslink in McP460 and provides an opportunity to investigate how simulations can interact with experimental structures.

biochemistry↗

bioRxiv2024

ABHD2 activity is not required for the non-genomic action of progesterone on human sperm

Study questionIs the hydrolase ABHD2 required for progesterone-induced Ca2+ influx via CatSper and the resulting motility responses in human sperm? Summary answerProgesterone-induced Ca2+ influx via CatSper and the resulting motility responses in human sperm do not require ABHD2 activity. What is known alreadySperm motility is tightly regulated by signalling pathways that are activated as sperm ascend the female reproductive tract, including progesterone triggering Ca2+ influx via the CatSper channel and inducing hyperactivated motility needed for fertilization. This process is thought to involve ABHD2, which may hydrolyse the endogenous CatSper inhibitor 2-arachidonoylglycerol (2-AG), thereby relieving inhibition and enabling calcium entry into the flagellum. Study design, size, durationPotent small molecule inhibitors of ABHD2 activity were synthesized, characterized, and used as tools to scrutinize the role of ABHD2 in activation of CatSper and regulation of sperm motility. Participants/materials, setting, methodsDerivatives of published ABHD2 inhibitors were optimised for in vitro potency and cellular activity and subsequently tested in human sperm motility and Ca2+ influx assays. Main results and the role of chanceProgesterone does not activate ABHD2 in vitro. In addition, inhibition of ABHD2 in human sperm has no effect on progesterone-induced Ca2+ influx through CatSper nor on basal or progesterone-induced hyperactivated motility. This demonstrates that ABHD2 activity is, in fact, not required for the non-genomic action of progesterone on human sperm. Large scale datanone Limitations, reasons for cautionWe examined the effects of inhibition of the enzymatic activity of ABHD2. We cannot exclude that ABHD2 functions as a part of a larger multiprotein complex, in which it may play a structural role independent of its hydrolase activity. Wider implications of the findingsThis study presents conclusive evidence that ABHD2 does not bind progesterone and that its hydrolase activity is not required for progesterone activation of CatSper and resulting changes in motility of human sperm. These results highlight the need for further research to elucidate the mechanism underlying the non-genomic action of progesterone on human sperm. Study funding/competing interest(s)This publication is based on research funded by the Gates Foundation. The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Gates Foundation. LT, CB, and TS were supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - project numbers 329621271 (CRU326; CB, TS), and 404595355 (Research Training Group "Chemical biology of ion channels (Chembion); LT, TS). This work was funded by the German Federal Ministry of Education and Research (BMBF) within the framework of Contraception Research, grant number 01GR2501A and 01GR2502A. A.A., K.V., A.T., N.D., A.H., M.W. and R.L. are employees of Nuvisan ICB GMBH, Berlin, Germany. Nuvisan is recipient of a Gates Foundation grant. A.A is associate editor of Human Reproduction Open.

cell biology↗

bioRxiv2024

Testing for heavy metals in drinking water collected from Dog Aging Project participants

Heavy metals are commonly found in groundwater and can affect the quality of drinking water. In this pilot study, we analyzed the quality of drinking water for dogs participating in the Dog Aging Project (DAP) who lived in homes not served by a municipal water supply. In order to capture both diverse and localized environmental factors that may affect drinking water, 200 owners of DAP dogs located in one of 10 selected states were invited to participate. We tested for the presence of 28 metals in dogs drinking water, including eight (8) heavy metals that have maximum contaminant levels (MCLs) designated by the Environmental Protection Agency (EPA) and five (5) heavy metals that have EPA health guidance levels. The eight metals with MCLs are known to cause chronic health issues in humans after long-term ingestion. Our aim in this pilot was to determine whether such elements could be detected by at-home sampling of dogs drinking water. We found detectable levels of all metals tested. There were 126 instances when an analyte (arsenic, lead, copper, sodium, strontium, nickel, or vanadium) was above the EPA MCL or health guidance level. We further identified potential association between the presence of titanium and chromium, and occurrence of a known health condition in dogs. This prompts further investigation with a larger, stratified sample analyzing dogs drinking water composition and long-term health and wellness outcomes in dogs living in diverse geographies. These results may impact veterinary care decisions and husbandry, and underscore the validity and importance of utilizing dogs as sentinels of human health outcomes in the context of drinking water contamination.

ecology↗

bioRxiv2024

No enhancement of soil carbon persistence by sheep grazing in a long-term calcareous grassland experiment

Soils hold a globally important carbon pool that is generally more persistent than the carbon stored in plant biomass. However, this carbon is becoming increasingly vulnerable to disturbances such as soil warming, fire, and erosion. Managing land to increase soil carbon sequestration and persistence may therefore improve long-term soil carbon storage and contribute to climate change mitigation. It has been hypothesized that grazing by large herbivores may enhance the persistence of soil carbon by increasing the amount of soil organic matter forming more stable associations with mineral particles (mineral-associated organic matter). We compared sheep-grazed and ungrazed plots within the Gibson Grazing and Successional Experiment located in the Upper Seeds calcareous grassland in Wytham Woods, Oxfordshire, using organic matter fractionation to estimate the surface (0-5 cm) carbon stocks in the mineral-associated and particulate organic matter fractions. Counter to predictions, after 35 years sheep grazing had not increased mineral-associated organic matter carbon stocks relative to ungrazed plots. We hypothesize that this indicates the saturation of mineral surfaces in both grazed and ungrazed treatments and the inability of grazing to increase soil nitrogen stocks and decrease pH to levels conducive for mineral-associated carbon sequestration. Only one of twelve soil properties examined showed statistically detectable responses to grazing: spring-grazing increased the C:N ratio in the mineral-associated organic matter. While the number of tests performed (24) means this may be a false-positive result, if genuine it would be consistent with a more direct pathway from plant exudates to mineral-associated organic matter formation due to compensatory growth in response to spring-grazing. Overall, the results of this long-term experiment do not support the hypothesis that grazing can improve the persistence of the soil carbon pool.

ecology↗

bioRxiv2023

Deprivation-induced plasticity in the early central circuits of the rodent visual, auditory, and olfactory systems: a systematic review and meta-analysis of the literature

Activity-dependent neuronal plasticity is crucial for animals to adapt to dynamic sensory environments. Traditionally, research on activity dependent-plasticity has used sensory deprivation approaches in animal models, and it has focused on its effects in primary sensory cortices. However, emerging evidence emphasizes the importance of activity-dependent plasticity both in the sensory organs and in sub-cortical regions where cranial nerves relay information to the brain. Additionally, a critical question arises: do different sensory modalities share common cellular mechanisms for deprivation-induced plasticity at these central entry-points? Furthermore, does the duration of deprivation correlate with specific plasticity mechanisms? This study aims to systematically review and meta-analyse research papers that investigated visual, auditory, or olfactory deprivation in rodents. Specifically, it explores the consequences of sensory deprivation in homologous regions at the first central synapse after the cranial nerve: vision--lateral geniculate nucleus and superior colliculus; audition-- ventral and dorsal cochlear nucleus; olfaction--olfactory bulb. The systematic search yielded 91 research papers (39 vision, 22 audition, 30 olfaction), revealing significant heterogeneity in publication trends, experimental methods of inducing deprivation, measures of deprivation-induced plasticity, and reporting, across the three sensory modalities. Nevertheless, despite these methodological differences, commonalities emerged when correlating the plasticity mechanisms with the duration of the sensory deprivation. Following short-term deprivations (up to 1 day) all three systems showed reduced activity levels and increased disinhibition. Medium-term deprivation (1 day to a week) induced greater glial involvement and synaptic remodelling. Long-term deprivation (over a week) predominantly led to macroscopic structural changes including tissue shrinkage and apoptosis. These findings underscore the importance of standardizing methodologies and reporting practices. Additionally, they highlight the value of cross-modals synthesis for understanding how the nervous system, including peripheral, pre-cortical, and cortical areas, respond to and compensate for sensory inputs loss.

neuroscience↗

bioRxiv2023

ProteoMixture: A Cell Type Deconvolution Tool for Bulk Tissue Proteomics Data

Numerous multi-omic investigations of cancer tissue have documented varying and poor pairwise transcript:protein quantitative correlations and most deconvolution tools aiming to predict cell type proportions (cell admixture) have been developed and credentialed using transcript-level data alone. To estimate cell admixture using protein abundance data, we analyzed proteome and transcriptome data generated from contrived admixtures of tumor, stroma, and immune cell models or those selectively harvested from the tissue microenvironment by laser microdissection from high grade serous ovarian cancer (HGSOC) tumors. Co-quantified transcripts and proteins performed similarly to estimate stroma and immune cell admixture in two commonly used deconvolution algorithms, ESTIMATE and ConsensusTME (r [≥] 0.63). Here we have developed and optimized protein-based signatures to estimate cell admixture proportions and benchmarked these using bulk tumor proteomics data from over 150 HGSOC patients. The optimized protein signatures supporting cell type proportion estimates from bulk tissue proteomics data are available at (https://lmdomics.org/ProteoMixture/.

bioinformatics↗

bioRxiv2023

Loss of REP1 impacts choroidal melanogenesis in choroideremia

Choroideremia (CHM) is a rare X-linked chorioretinal dystrophy affecting the photoreceptors, retinal pigment epithelium (RPE) and choroid, however, the involvement of the choroid in disease progression is not fully understood. CHM is caused by mutations in the CHM gene, encoding the ubiquitously expressed Rab escort protein 1 (REP1). REP1 plays an important role in intracellular trafficking of vesicles, including melanosomes. In this study, we examined ultrastructure of the choroid in chmru848 fish and Chmnull/WT mouse models using transmission electron microscopy. Significant pigmentary disruptions were observed, with a lack of melanosomes in the choroid of chmru848fish from 4 days post fertilisation (4dpf). Total melanin and expression of melanogenesis genes tyr, tryp1a, mitf, dct and pmel were also reduced from 4dpf. In Chmnull/WT mice, choroidal melanosomes were significantly smaller at 1 month and at 1 year, eumelanin was reduced, and the choroid was thicker. The choroid in CHM patients was also examined using optical coherence tomography (OCT) and OCT- angiography (OCT-A) and the area of preserved choriocapillaris (CC) was found to be smaller than that of overlying photoreceptors, indicating that the choroid is degenerating at a faster rate. Histopathology of an enucleated eye from a 74-year-old CHM male patient revealed isolated areas of RPE but no associated underlying CC. Significant degenerative changes in the choroid of CHM patients and animal models are seen, highlighting the importance of administrative routes involving the choroid, such as suprachoroidal delivery. Pigmentary disruptions in CHM animal models reveal an important role for REP1 in melanogenesis, and drugs that improve melanin production represent a potential novel therapeutic avenue.

molecular biology↗

bioRxiv2023

H3.3-G34R Mutation-Mediated Epigenetic Reprogramming Leads to Enhanced Efficacy of Immune Stimulatory Gene Therapy in Pediatric High-Grade Gliomas

Diffuse hemispheric glioma (DHG), H3 G34-mutant, representing 9-15% of cases, are aggressive Central Nervous System (CNS) tumors with poor prognosis. This study examines the role of epigenetic reprogramming of the immune microenvironment and the response to immune-mediated therapies in G34-mutant DHG. To this end, we utilized human G34-mutant DHG biopsies, primary G34-mutant DHG cultures, and genetically engineered G34-mutant mouse models (GEMMs). Our findings show that the G34 mutation alters histone marks deposition at promoter and enhancer regions, leading to the activation of the JAK/STAT pathway, which in turn results in an immune-permissive tumor microenvironment. The implementation of Ad-TK/Ad-Flt3L immunostimulatory gene therapy significantly improved median survival, and lead to over 50% long term survivors. Upon tumor rechallenge in the contralateral hemisphere without any additional treatment, the long-term survivors exhibited robust anti-tumor immunity and immunological memory. These results indicate that immune-mediated therapies hold significant potential for clinical translation in treating patients harboring H3.3-G34 mutant DHGs, offering a promising strategy for improving outcomes in this challenging cancer subtype affecting adolescents and young adults (AYA). STATEMENT OF SIGNIFICANCEThis study uncovers the role of the H3.3-G34 mutation in reprogramming the tumor immune microenvironment in diffuse hemispheric gliomas. Our findings support the implementation of precision medicine informed immunotherapies, aiming at improving enhanced therapeutic outcomes in adolescents and young adults harboring H3.3-G34 mutant DHGs.

cancer biology↗

bioRxiv2023

A conserved pressure-driven mechanism for regulating cytosolic osmolarity

Controlling intracellular osmolarity is essential to all cellular life. Cells that live in hypo-osmotic environments like freshwater must constantly battle water influx to avoid swelling until they burst. Many eukaryotic cells use contractile vacuoles to collect excess water from the cytosol and pump it out of the cell. Although contractile vacuoles are essential to many species, including important pathogens, the mechanisms that control their dynamics remain unclear. To identify basic principles governing contractile vacuole function, we here investigate the molecular mechanisms of two species with distinct vacuolar morphologies from different eukaryotic lineages--the discoban Naegleria gruberi, and the amoebozoan slime mold Dictyostelium discoideum. Using quantitative cell biology we find that, although these species respond differently to osmotic challenges, they both use actin for osmoregulation, as well as vacuolar-type proton pumps for filling contractile vacuoles. We also use analytical modeling to show that cytoplasmic pressure is sufficient to drive water out of contractile vacuoles in these species, similar to findings from the alveolate Paramecium multimicronucleatum. Because these three lineages diverged well over a billion years ago, we propose that this represents an ancient eukaryotic mechanism of osmoregulation.

cell biology↗

bioRxiv2023

Single-strand mismatch and damage patterns revealed by single-molecule DNA sequencing

Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other genetic diseases1-4. Almost all of these mosaic mutations begin as nucleotide mismatches or damage in only one of the two strands of the DNA prior to becoming double-strand mutations if unrepaired or misrepaired5. However, current DNA sequencing technologies cannot resolve these initial single-strand events. Here, we developed a single-molecule, long-read sequencing method that achieves single-molecule fidelity for single-base substitutions when present in either one or both strands of the DNA. It also detects single-strand cytosine deamination events, a common type of DNA damage. We profiled 110 samples from diverse tissues, including from individuals with cancer-predisposition syndromes, and define the first single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumors deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples deficient in only polymerase proofreading. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. Since the double-strand DNA mutations interrogated by prior studies are only the endpoint of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable new studies of how mutations arise in a variety of contexts, especially in cancer and aging.

genomics↗

bioRxiv2022

Crowdsourcing Temporal Transcriptomic Coronavirus Host Infection Data: resources, guide, and novel insights.

The emergence of SARS-CoV-2 reawakened the need to rapidly understand the molecular etiologies, pandemic potential, and prospective treatments of infectious agents. The lack of existing data on SARS-CoV-2 hampered early attempts to treat severe forms of COVID-19 during the pandemic. This study coupled existing transcriptomic data from SARS-CoV-1 lung infection animal studies with crowdsourcing statistical approaches to derive temporal meta-signatures of host responses during early viral accumulation and subsequent clearance stages. Unsupervised and supervised machine learning approaches identified top dysregulated genes and potential biomarkers (e.g., CXCL10, BEX2, and ADM). Temporal meta-signatures revealed distinct gene expression programs with biological implications to a series of host responses underlying sustained Cxcl10 expression and Stat signaling. Cell cycle switched from G1/G0 phase genes, early in infection, to a G2/M gene signature during late infection that correlated with the enrichment of DNA Damage Response and Repair genes. The SARS-CoV-1 meta-signatures were shown to closely emulate human SARS-CoV-2 host responses from emerging RNAseq, single cell and proteomics data with early monocyte-macrophage activation followed by lymphocyte proliferation. The circulatory hormone adrenomedullin was observed as maximally elevated in elderly patients that died from COVID-19. Stage-specific correlations to compounds with potential to treat COVID-19 and future coronavirus infections were in part validated by a subset of twenty-four that are in clinical trials to treat COVID-19. This study represents a roadmap to leverage existing data in the public domain to derive novel molecular and biological insights and potential treatments to emerging human pathogens. The data from this study is available in an interactive portal (http://18.222.95.219:8047).

bioinformatics↗