Biology subjects

Smith, G.

Publications and source records attributed to Smith, G..

At least 19 recordsLinked to original sources

bioRxiv2026

BoltzMol-1: Towards Reliable Virtual Screening for Fast and Cost-Effective Hit Discovery

We present BoltzMol-1, a small-molecule hit discovery pipeline, centered on an optimized version of Boltz-2, explicitly adapted for prospective discovery. Reliable hit discovery that generalizes across target classes (rather than only the well-characterized families that dominate existing ligand data) would broaden the range of biology accessible to small-molecule intervention and reduce reliance on resource-intensive high-throughput screening. Towards this goal, the system prioritizes compounds for rapid experimental validation by coupling model-driven ranking with streamlined procurement from commercial catalogs. To improve developability at the point of selection, we introduce a suite of ADMET models for kinetic solubility (logS), lipophilicity (logD), and Caco-2 permeability. These models act as an early triage layer, systematically filtering out compounds with unfavorable physicochemical and absorption properties prior to synthesis or purchase. Across a panel of ten targets (most with no representation in the underlying affinity training data) we observe strong prospective performance on challenging systems. Functional actives or binders were identified for 6 of 10 targets, despite modest experimental budgets of 28-96 compounds per target. These results include successes on receptors and enzymes traditionally considered difficult for structure- or ligand-based approaches. Collectively, this work establishes a practical framework for low-throughput, cost-constrained discovery campaigns capable of delivering chemically tractable binders with favorable property profiles. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/736485v1_fig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@1d7ff06org.highwire.dtl.DTLVardef@1a7fc7aorg.highwire.dtl.DTLVardef@1b0dc98org.highwire.dtl.DTLVardef@62b978_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1:C_FLOATNO Overview of the prospective virtual-screening campaigns across all targets. For each target, the panel shows the predicted protein-ligand complex together with the number of compounds tested, the number of confirmed actives/binders, and the assays used for screening and follow-up. C_FIG

biochemistry↗

bioRxiv2026

The Effect of Depriving the Aedes aegypti Mosquito of Natural Levels of Radiation

Organisms have spent their life histories exposed to background levels of natural ionizing radiation. To document the role that radiation plays, the deprivation of these natural levels has been studied by incubating organisms in the shielded space of underground laboratories. We report here on two studies (Study I and Study II) using Aedes aegypti for the first time as a model organism incubated 655 meters underground at the Waste Isolation Pilot Plant (WIPP) outside of Carlsbad, New Mexico, U.S.A. Male mosquitos were incubated at the surface exposed to natural background radiation, and were compared to two underground treatments in which incubators were supplemented with radiation sources used to mimic background and these groups were compared to the underground, radiation-deprived treatment. In Study I, the mosquitos incubated underground in the absence of natural radiation had higher levels of mortality compared to those incubated at the surface and PCA plots of the two transcriptomes were clearly differentiated. Study II was conducted the following year and the experiment was narrowed to include only the surface control and underground, radiation-deprived treatment which allowed for four biological replicates. Again, there was a higher level of mortality in the mosquitos grown underground compared mosquitos grown at the surface. Transcriptomes were not as clearly differentiated by PCA analysis and fecundity data were similar between the two groups. Functional analysis of transcriptomic DEGs from two independent studies suggested there are stress responses in radiation deprived mosquitoes. The absence of a secondary stressor in Study II is discussed as an explanation for the transcriptome differences in the two experiments.

genetics↗

bioRxiv2026

H3K27M-driven hypertranscription leads to a new targetable dependency in diffuse midline gliomas

Diffuse midline gliomas (DMGs) are driven by the H3K27M oncohistone--a challenging therapeutic target. However, conventional therapeutic modalities are never curative. Against this backdrop, we address an important unresolved question--are there H3K27M-induced oncogenic vulnerabilities that can be exploited for therapeutic benefit. We show that H3K27M induces hypertranscription, thus identifying hypertranscription as a new molecular feature of H3K27M-driven DMGs. We demonstrate this finding in genetic mouse models, human DMG cells, and primary tumor specimens. We further demonstrate that H3K27M-induced hypertranscription perturbs replication, heightens basal replication stress, and enhances sensitivity to ATR inhibition. In exploring therapeutic implications of these findings, we document brain penetrance, target engagement, and therapeutic efficacy of a clinical-stage ATR inhibitor (alnodesertib) in vitro and in intracranial DMG xenografts. We further demonstrate synergistic activity of alnodesertib with radiotherapy--the current standard of care for DMGs. These findings provide the mechanistic underpinning and preclinical rationale for including alnodesertib as monotherapy and in combination with radiation in clinical trials for children with H3K27M DMGs. The broad implications of our studies highlight ATR inhibition as a therapy for aggressive human cancers displaying hypertranscription.

cancer biology↗

bioRxiv2026

Integrative Multi-omics Analysis of the Human Skeletal Muscle Response to Endurance or Resistance Exercise: Findings from the Molecular Transducers of Physical Activity Consortium (MoTrPAC)

The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to systematically characterize the molecular basis of the health benefits of exercise. Here, we present the integrative, multi-omics response of human skeletal muscle to acute endurance (EE) and resistance (RE) exercise. Distinct temporal responses were observed, with changes in ATAC-seq, phosphoproteome, and metabolome occurring before changes in the transcriptome and proteome. These distinct temporal multi-omic dynamics were used to identify transcriptional regulatory hubs converging around MEF2A and NFIC regulation of autophagy, angiogenesis and metabolism. Further, early RE-specific phosphoproteome signatures counteracted epigenetic modifications and downregulated transcripts involved in protein turnover. Additional findings include suppression of HIPK2/3 kinase signatures linked to the acute exercise regulation of sarcomeric proteins TTN, NEB, ANKRD2 and LMOD2. Our data demonstrate distinct temporal regulation across the multi-omic landscape of human skeletal muscle, with EE and RE eliciting common and unique molecular signatures.

systems biology↗

bioRxiv2026

Proteo-transcriptomics and morphometrics of teleost cardiac cells define regulatory networks and exercise-induced cardiomyocyte hypertrophy and hyperplasia

Zebrafish and medaka are powerful cardiovascular models, yet cellular and molecular investigations of adult heart cells have been constrained by suboptimal dissociation and characterization methods. To overcome these barriers, we developed a physiological-temperature workflow that generates high-yield, viable single-cell suspensions for FACS, imaging, and low-input molecular profiling. Using transgenic fluorescent reporters, we consistently isolate [~]6,000 cardiomyocytes per adult zebrafish ventricle and [~]12,000 from medaka, preserving cellular, structural, and molecular integrity. Single-cell morphometrics revealed cardiomyocyte heterogeneity and demonstrated that swimming exercise induces both hypertrophy and hyperplasia, while ventricular injury triggers expansion of regenerative gata4 cardiomyocytes. We integrated proteomics and RNA-seq from FACS-purified cells to construct cell-type-specific proteo-transcriptomic atlases. Functional enrichment, transcription factor, and network analyses identified protein hubs and regulatory circuits defining cardiomyocyte and endothelial cell identity. Our platform delivers cell-type-resolved molecular datasets of adult teleost cardiac cells, establishing a systems-level resource for heart regeneration research, cardiovascular disease modeling, and drug discovery. TeaserA robust workflow for isolation, FACS, imaging, and multi-omics profiling of cardiomyocytes and cardiac endothelial cells in fish. HIGHLIGHTSO_LITemperature-optimized dissociation and standardized FACS enable high-yield isolation of viable cardiac cells. C_LIO_LISingle-cell imaging uncovers morphological heterogeneity in adult ventricular cardiomyocytes. C_LIO_LISustained exercise induces both hypertrophy and hyperplasia of zebrafish cardiomyocytes. C_LIO_LIProteo-transcriptomics defines core molecular programs and interaction networks in cardiomyocytes and endothelial cells. C_LI

systems biology↗

bioRxiv2025

Virus community response rewires methane-suppressed peat microcosm carbon metabolism

Human activities are accelerating permafrost thaw and subsequent methane emissions from increased microbial activity, prompting microbiome engineering efforts as an emissions mitigation strategy. We recently demonstrated that catechin amendment could drastically reduce methane emissions (>80%) in peat microcosms by enriching catechin-degrading prokaryotes that outcompeted methanogens for hydrogen. However, viral contributions to such microbiome-level responses remain unexplored and we hypothesized that viral dynamics could help shape the microbiome response as nutrient amendments may alter cellular physiology in ways that could induce lytic viral activity. Here, we performed virus ecogenomics analyses of the previously-studied time-resolved multi-omics data collected from catechin-amended peat microcosms. We conservatively identified 900 putatively lytic viral operational taxonomic units (vOTUs), with 41% predicted to infect active host genomes including the most transcriptionally active vOTUs predicted to infect key catechin-degrading genera (Clostridium and undescribed Bacillota JAGFXR01). Notably, a single JAGFXR01-targeting vOTU dominating the viral response (>40% of community viral transcription; 20-156-fold more abundant than its host), which we interpreted as induction resulting in intense lytic activity that could release catechin-degradation intermediates to other community members. Consistent with this, gene expression analysis revealed elevated catechin-intermediate degradation and hydrogenase signals in 34 additional polyphenol-degrading metagenome-assembled genomes. These findings support a model consistent with a viral shunt-like process that extends our previous prokaryote-centric model: viral lysis of fast-growing catechin degraders redistributes phenolic intermediates to diverse phenol-degrading taxa that sustain methane suppression via hydrogen consumption. Beyond carbon-cycling importance in this system, elucidating unintended virus-mediated responses to nutrient and prebiotic interventions will enable more predictable and effective microbiome engineering strategies across soil, ocean, and human ecosystems.

microbiology↗

bioRxiv2025

Oscillatory and elevated flow distinctly regulate gene expression in human coronary artery endothelial cells

BackgroundAtherosclerosis develops at arterial sites exposed to disturbed flow, while plaque rupture and plaque erosion predominantly occur in regions subjected to elevated flow. The impact of elevated flow on regulation of endothelial gene expression is less well studied; therefore, we undertook a comprehensive analysis of primary human coronary artery endothelial cell (HCAEC) gene expression under elevated flow, comparing it to gene expression induced by normal physiological and oscillatory flow. MethodsAnalysis of HCAEC mRNA, microRNA and protein expression cultured under oscillatory shear stress (OSS), physiological laminar shear stress (LSS), and elevated shear stress (ESS) for 72 hours. Identification of changes in RNA isoform expression and proximity of flow-responsive genes to established coronary artery disease (CAD) risk loci were also performed. Results2,175 shear-regulated genes were identified, with 665 uniquely responsive to ESS. Both ESS and OSS induced significant changes in RNA isoform selection, predicted to affect 848 and 580 genes respectively. Signalling pathways regulating CAD pathogenesis including HIPPO, TGF{beta}/BMP, and IRF, showed altered RNA isoform selection which may influence plaque development and plaque erosion. 65% of linkage disequilibrium (LD)-filtered CAD-associated genetic variants contained at least one OSS or ESS-regulated gene within 250Kb. Proteomic analysis identified 289 proteins differentially expressed under OSS and 171 under ESS, with notable discordance between mRNA and protein changes observed in 28.7% (OSS vs LSS) and 16.6% (ESS vs LSS) genes. Additionally, 40 shear-responsive microRNAs were identified. ConclusionElevated flow elicits a distinct gene expression programme in HCAECs, modulating pathways central to CAD pathogenesis. Research PerspectiveWhat New Question Does This Study Raise? O_LIPlaque erosion predominantly occurs on the upstream surface of the plaque, where the endothelium is exposed to elevated flow, which we show within this study to evoke a significant and largely unique regulation of the transcriptome, miRome and proteome within primary human coronary artery endothelial cells. C_LIO_LIIdentify shear stress as a significant regulator of alternative splicing, with elevated flow causing the greatest shift in alternative transcript selection. C_LIO_LIIdentify 135 oscillatory, and 101 elevated differentially expressed genes in proximity to CAD risk loci. C_LI What Question Should be Addressed Next? O_LIStudy of the response of the coronary endothelium directly in patients to understand how the risk factors involved in plaque erosion change endothelial function. C_LIO_LICreation of physiological 3D arterial models replicating in vivo observations to study the precipitating factors involved in plaque erosion. C_LI

cell biology↗

bioRxiv2025

Bioengineered human tonsil organoids as an immuno-engineering platform for evaluating immune functions

Although animal models remain the preclinical gold standard, they are constrained by interspecies differences in adaptive immunity, including antibody class-switching, affinity maturation, and multicellular interactions. To address this gap, we established a more physiologically relevant platform, a bioengineered tonsil organoid (BTO) system that combines autologous tonsil-derived stromal cells with immune cells to generate highly uniform organoids, preserving multicellular complexity and sustained stromal-immune interactions. BTO cultures mounted robust, antigen-specific recall responses to influenza, tetanus, and COVID-19 antigens. Notably, stimulation with ovalbumin and SARS-CoV-1 spike protein expanded antigen-recognizing B cells, indicating capacity for naive responses. Digital spatial transcriptomics and proteomics analysis confirmed immune-stromal crosstalk underpinning both humoral and cellular responses of BTO after challenge. These data highlight stromal cells as active scaffolds that not only maintain 3D architecture but also facilitate immune activation, memory recall, and recognition of naive antigens. Together, BTO offers a human-relevant model for mechanistic immunology and for pre-clinical evaluation on immunotherapies and vaccines not achievable with 2D cultures or animal models.

bioengineering↗

bioRxiv2025

Both terminal misfolding and polymerisation contribute to disease-relevant phenotypic changes in cell models of α1-antitrypsin deficiency-associated liver disease

Polymerisation of 1-antitrypsin within hepatocytes is considered central to the pathogenesis of 1-antitrypsin deficiency-associated liver fibrosis, most commonly in homozygotes for the Z (p.Glu342Lys) allele. Polymerisation proceeds via self-association of monomeric intermediate states. In parallel, >50% of synthesised Z 1-antitrypsin is instead recognized as terminally-misfolded and degraded. It is unclear whether this contributes to Z 1-antitrypsin deficiency-associated liver disease. We characterised the relationships between polymer formation, terminal misfolding and their cellular consequences, using label-free proteomics mass spectrometry (MS), light and electron microscopy, and cellular assays. Proteomic analyses of well-established CHO cell models of hepatocyte handling of 1-antitrypsin variants indicated that cellular responses to the Z mutation were surprisingly similar to those seen with the NullHongKong variant (NHK), which can only misfold terminally and cannot polymerise. A minor set of proteins showed increases associated with Z and not NHK 1-antitrypsin expression, consistent with a polymer-specific response, characterized by association with increased organellar organization and vesicle-mediated transport. Conversely, proteostatic and pro-fibrotic integrin-associated pathways increased with the degree of terminal misfolding of the expressed 1-antitrypsin variant. Bioenergetic pathway changes indicated concomitant switching from oxidative to glycolytic metabolism. Cell studies further correlated fibrosis-associated behaviours with terminal misfolding rather than polymerisation. Terminal misfolding, as well as polymerisation behaviour, may therefore be important for pro-fibrotic responses including metabolic reprogramming and senescence in Z 1-antitrypsin deficiency. Molecular therapies may prove most efficacious for associated liver disease if they address terminal misfolding as well as polymerisation.

cell biology↗

bioRxiv2025

New iPSC resource with long-read whole genome sequencing characterizations for enhanced in vitro modeling

Here we present a new iPSC resource of apparently healthy subject biospecimens available to the research community through the National Institute of General Medical Sciences Human Genetic Cell Repository (NIGMS Repository). This resource includes five iPSCs and matched parental cell lines with accompanying publicly available, HiFi whole-genome sequencing data. Structural variant (SV) and single nucleotide variant (SNV) concordance between iPSC and parental lines was generally high; however, we found a notable reduction in concordance between the iPSC reprogrammed with retroviral reprogramming and its parental line consistent with previous work showing newer Sendai approaches to be more robust in preserving genomic integrity. This iPSC resource additionally includes pharmacogenomic and human leukocyte antigen (HLA) gene annotations as well as a set of user-friendly, web-based search tools to visualize and explore SVs and SNVs. This new resource is designed to offer a highly characterized set of in vitro models for research into cell-type specific functional characterization of genetic, genomic and pharmacogenomic variation. More generally, these renewable biospecimens and genomic data search tools are available to the scientific community to support high-quality and reproducible biomedical research.

genomics↗

bioRxiv2025

Hexavalent Chromium Inhibits Nitrate-Dependent Anaerobic Methane Oxidation While Enriching Denitrifiers: Insights into Microbial Interactions for Simultaneous Methane, Nitrate and Chromate Removal

Chromate (Cr(VI)) is a widely distributed heavy metal known for its toxicity and adverse effects on human health. Due to its extensive industrial use, Cr(VI) is commonly detected in municipal and industrial wastewater, often co-occurring with other contaminants such as nitrate (NO3-). Nitrate-dependent anaerobic methane oxidation (N-DAMO) is a promising microbially driven process that enables the simultaneous removal of methane (CH4) and NO3-, potentially lowering the carbon footprint of wastewater treatment plants (WWTPs). Given that Cr(VI) can act as an alternative electron acceptor, its presence may influence the N-DAMO process either by supporting CH4 oxidation or, conversely, by exerting toxic effects that inhibit microbial activity. In this study, we investigated the impact of Cr(VI) on an N-DAMO enrichment culture composed of Candidatus Methanoperedens and Candidatus Methylomirabilis, using NO3- as the electron acceptor and 13C-CH4 as the sole electron donor. Cultures were exposed to varying concentrations of Cr(VI), and microbial activity was assessed through GC-MS, 16S rRNA gene sequencing and qPCR. Here we found that while Cr(VI) was reduced within the culture, this process was not coupled to CH4 oxidation. In fact, CH4 oxidation was significantly inhibited, and the relative abundances of Ca. Methanoperedens and Ca. Methylomirabilis declined under increasing Cr(VI) concentrations. Cr(VI) reduction was likely mediated by the flanking microbial community via two possible pathways: (i) enzymatically, through nitrate reductase activity in denitrifying bacteria, and (ii) abiotically, through chemical reaction with nitrite (NO2-), an intermediate of denitrification. These findings highlight the potential of N-DAMO microbes to confer functional resilience in contaminated environments. However, the sensitivity of methanotrophic organisms to Cr(VI) underscores a limitation in applying this process to wastewater treatment systems containing heavy metals.

microbiology↗

bioRxiv2025

Novel Adomaviruses Associated with Blotchy Bass Syndrome in Black Basses (Micropterus spp.)

Black bass (Micropterus spp.) are the most important warmwater game fishes in the United States. They have high socioeconomic and recreational value and support an important aquaculture industry. Since 2008, fisheries managers have been reporting the observation of hyperpigmented melanistic lesions (HPMLs) on smallmouth bass (M. dolomieu) in different ecoregions of the United States. Similar HPMLs have been observed in largemouth bass (M. nigricans) since the 1980s. Here, we report a close association between novel adomaviruses and the hallmark blotchy clinical presentation of hyperpigmented lesions on the skin smallmouth and largemouth black bass and provide evidence that satisfies Rivers postulates. The two adomaviruses are structurally and phylogenetically similar but share only 68.0% identity at aligned nucleotide sites and each has been found in only one host species to date. The manifestation of this skin disease appears to be seasonal in both species, primarily affects adults and is of unknown health consequence. Although the significance of infection to fish health remains unclear, understanding the disease ecology of these can inform biosecurity and the interjurisdictional movement of individuals. Moreover, as hyperpigmentation in other fish species is often idiopathic, our findings reframe perspectives for future investigations into this clinical presentation in other species.

microbiology↗

bioRxiv2025

Spatiotemporal Dynamics of Invariant Face Representations in the Human Brain

The human brain can effortlessly extract a familiar faces age, gender, and identity despite dramatic changes in appearance, such as head orientation, lighting, or expression. Yet, the spatiotemporal dynamics underlying this ability, and how they depend on task demands, remain unclear. Here, we used multivariate decoding of magnetoencephalography (MEG) responses and source localization to characterize the emergence of invariant face representations. Human participants viewed natural images of highly familiar celebrities that systematically varied in viewpoint, gender, and age, while performing a one-back task on the identity or the image. Time-resolved decoding revealed that identity information emerged rapidly and became increasingly invariant to viewpoint over time. We observed a temporal hierarchy: view-specific identity information appeared at 64 ms, followed by mirror-invariant representations at 75 ms and fully view-invariant identity at 89 ms. Identity-invariant age and gender information emerged around the same time as view-invariant identity. Task demands modulated only late-stage identity and gender representations, suggesting that early face processing is predominantly feedforward. Source localization at peak decoding times showed consistent involvement of the occipital face area (OFA) and fusiform face area (FFA), with stronger identity and age signals than gender. Our findings reveal the spatiotemporal dynamics by which the brain extracts view-invariant identity from familiar faces, suggest that age and gender are processed in parallel, and show that task demands modulate later processing stages. Together, these results offer new constraints on computational models of face perception.

neuroscience↗

bioRxiv2025

DNA Divers: volunteer-based eDNA capture for local and global marine biodiversity monitoring

Volunteer-based biodiversity recording is a powerful source of scalable data yet to be used to its full potential by the scientific community. Coastal ecosystems are varied and diverse, making it difficult for managers to identify flexible methods for monitoring biological components. Emerging technologies such as environmental DNA (eDNA) analysis are promising for measuring aquatic biodiversity, yet most management organizations lack personnel and capacity to collect molecular data. Here we investigate, together as professional and non-professional scientists, the efficacy of a quasi-passive eDNA capture technique. Volunteer SCUBA divers and snorkelers used low-cost materials, namely cotton medical gauze, to capture eDNA via swimming. We compared this method to conventional eDNA capture techniques in an aquarium and nature, collectively iterating the field and laboratory procedures to improve feasibility. With a small (< 30) network of volunteers, we detected 275 unique teleost and elasmobranch species from varied marine habitats spanning 90 degrees of latitude. The swimming motion of divers was more effective than stationary soaking and the fish communities sampled by divers were comparable to that of conventional eDNA samples. The ease of this technique matched by the eagerness and generosity of volunteers presents an untapped, viable approach for scaling multi-species marine eDNA monitoring as well as an avenue for improving science literacy. Data availabilityhttps://zenodo.org/records/14853820?token=eyJhbGciOiJIUzUxMiJ9.eyJpZCI6ImYxMTlhODFiLTI3NGYtNDQ2Ni05MDYyLTIyOTlkNWVhY2FkNiIsImRhdGEiOnt9LCJyYW5kb20iOiIwYmZlMzJhMWU0YWZkM2ZhMWEwYTE0NmY0ZWM5YWZkNSJ9.0R7GJjVJLEuq-UJVKA1CcMT8LCTamv3GEvPl-5ItzP10pFRd-cAzAr_Q5ggjEewZUtByHjBu-eSegWWlLAx_Rw

ecology↗

bioRxiv2025

Unbiased Population-Based Statistics to Obtain Pathologic Burden of Injury after Experimental TBI

Reproducibility of scientific data is a current concern throughout the neuroscience field. There are multiple on-going efforts to help resolve this problem. Within the preclinical neuroimaging field, the continued use of a region-of interest (ROI) type approaches combined with the well-known spatial heterogeneity of traumatic brain injury pathology is a barrier to the replicability and repeatability of data. Here we propose the conjoint use of an unbiased analysis of the whole brain after injury together with a population-based statistical analysis of sham-control brains as one approach that has been used in clinical research to help resolve this issue. The approach produces two volumes of pathology that are outside the normal range of sham brains, and can be interpreted as whole brain burden of injury. Using diffusion weighted imaging derived scalars from a tensor analysis of data acquired from adult, male rats at 2, 9 days, 1 and 5 months after lateral fluid percussion injury (LFPI) and in shams (n=73 and 12, respectively), we compared a data-driven, z-score mapping method to a whole brain and white matter-specific analysis, as well as an ROI-based analysis with brain regions preselected by virtue of their large group effect sizes. We show that the data-driven approach is statistically robust, providing the advantage of a large group effect size typical of a ROI analysis of mean scalar values derived from the tensor in regions of gross injury, but without the large multi-region statistical correction required for interrogating multiple brain areas, and without the potential bias inherent with using preselected ROIs. We show that the technique correctly captures the expected longitudinal time-course of the diffusion scalar volumes based on the spatial extent of the pathology and the known temporal changes in scalar values in the LFPI model.

neuroscience↗

bioRxiv2025

Evidence Aggregator: AI reasoning applied to rare disease diagnostics

Variant assessment of rare disease diagnostics depends on using domain knowledge in the time- consuming process of retrieving, reviewing, and synthesizing clinical and technical information. To address these challenges, we developed the Evidence Aggregator (EvAgg), an open-source, generative-AI-based tool designed for rare disease diagnosis that systematically extracts relevant information from the scientific literature for any human gene. EvAgg provides a thorough and current summary of observed genetic variants and their associated clinical features, enabling rapid synthesis of evidence concerning gene-disease relationships. We constructed an expert-curated dataset and evaluated EvAggs performance. EvAgg achieves 92% recall in identifying relevant papers, 96% recall in detecting instances of genetic variation within those papers, and [~]80% accuracy in extracting individual case and variant-level content (e.g. zygosity, inheritance, variant type, and phenotype). Further, EvAgg complemented the process of manual literature review by identifying substantial additional relevant information. When tested with analysts in rare disease case analysis, EvAgg reduced review time by 34% (p-value < 0.002) and increased the number of papers, variants, and cases evaluated per unit time. These savings have the potential to reduce diagnostic latency and increase solve rates for challenging rare disease cases.

genomics↗

bioRxiv2025

Planetary-scale marine community modeling predicts metabolic synergy and viral impacts

The oceans buffer against climate change via biogeochemical cycles underpinned by microbial metabolic activities. While planetary-scale surveys provide baseline microbiome data, inferring metabolic and biogeochemical impacts remains challenging. Genome-scale modeling has addressed analogous issues at the cellular level, highlighting key metabolic reactions contingent upon specific environmental conditions. Here we adapt this mechanistic modeling framework towards analyzing global ocean microbial communities to reveal metabolic processes predicted to maintain ecosystem functioning. To achieve this, we developed a genome-scale superorganism metabolic model for each TARA Ocean metagenome or metatranscriptome (i.e., limited to reactions known from heterotrophic prokaryotes and viruses), and evaluated these models to establish a community-wide metabolic phenotype for each sample. To validate, we showed that even with reaction-mappable genes only ([~]1/4 of the total genes), model composition revealed metabolism-inferred ecological zones that matched taxonomy-inferred zones. Model inferred metabolic phenotypes revealed reaction cooperation associated with microbial metabolism and organism diversity. These phenotypes also suggest elevated ecological roles for viruses as model predictions suggest they genomically target community-critical metabolic reactions that underpin metabolic phenotype stability, and also demonstrate that, as metabolites are better understood, immediate estimates could be made for where viruses remineralize versus sink carbon. While this new constraints-based, agile, and mechanistic modeling framework is highly upgradable, it already begins to convert molecular-scale environmental omics data to ecological and even planetary-scale biogeochemical features that will better bring microbes and their viruses into Earth system and climate models.

systems biology↗

bioRxiv2025

Mobile genetic elements that shape microbial diversity and functions inthawing permafrost soils

The worlds ecosystems are shaped by microbiota. Their niches and their impacts depend on functional profiles influenced by gene gains and losses. While culture-based experiments demonstrate that mobile genetic elements (MGEs) can mediate gene flux, quantitative field data on the rates and impacts of MGE activity remains scarce. Here we leverage large-scale soil meta-omic data to develop and apply analytics for studying MGEs in complex natural systems. In our model permafrost-thaw ecosystem, Stordalen Mire, we identify [~]2.1 million MGE recombinases across 89 microbial phyla to assess ecological distributions, affected functions, past mobility, and current activity. This revealed MGEs shaping natural genetic diversity via differential impacts on major phyla; affecting a wide range of functions, including diverse regulatory and metabolic genes affecting carbon flux and nutrient cycling; and moving at rates that should significantly influence the realized functional profiles of natural microbiomes. These findings and this systematic meta-omic framework open new avenues to better investigate MGE diversity, activity, mobility, and impacts in nature.

microbiology↗