Biology subjects

Metcalf, J.

Publications and source records attributed to Metcalf, J..

7 recordsLinked to original sources

bioRxiv2024

A unified theory for predicting pathogen mutual invasibility and co-circulation

A key aim in the dynamics and control of infectious diseases is predicting competitive outcomes of pathogen interactions. Observed pathogen community structure indicates both considerable coexistence of related variants and spectacular instances of replacement, notably in seasonal influenza and SARS-CoV-2. However, an overall comparative quantitative framework for invasion and coexistence remains elusive. Inspired by modern ecological coexistence theory, we address this gap by developing pathogen invasion theory (PIT) and test the resulting framework against empirical systems. PIT predicts near-universal mutual invasibility across major pathogen systems, including seasonal influenza strains and SARS-CoV-2 variants. Predicting co-circulation from mutual invasibility further depends on the extent of overcompensatory susceptible depletion dynamics. Our analyses highlight the central role of immuno-epidemiological factors in determining pathogen coexistence and community structure.

ecology↗

bioRxiv2023

Integrated longitudinal multi-omics study identifies immune programs associated with COVID-19 severity and mortality in 1152 hospitalized participants

Hospitalized COVID-19 patients exhibit diverse clinical outcomes, with some individuals diverging over time even though their initial disease severity appears similar. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity. In this study, we carried out deep immunophenotyping and conducted longitudinal multi-omics modeling integrating ten distinct assays on a total of 1,152 IMPACC participants and identified several immune cascades that were significant drivers of differential clinical outcomes. Increasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, NETosis, and T-cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma immunoglobulins and B cells, as well as dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to the failure of viral clearance in patients with fatal illness. Our longitudinal multi-omics profiling study revealed novel temporal coordination across diverse omics that potentially explain disease progression, providing insights that inform the targeted development of therapies for hospitalized COVID-19 patients, especially those critically ill.

immunology↗

bioRxiv2023

Epigenome erosion in Alzheimer's disease brain cells and induced neurons

Late-onset Alzheimers disease (LOAD) is typically sporadic, correlated only to advanced age, and has no clear genetic risk factors. The sporadic nature of LOAD presents a challenge to understanding its pathogenesis and mechanisms. Here, we comprehensively investigated the epigenome of LOAD primary entorhinal cortex brain tissues via single-cell multi-omics technologies, simultaneously capturing DNA methylation and 3D chromatin conformation. We identified AD-specific DNA methylation signatures and found they interact with bivalent promoters of AD differentially expressed genes. In addition, we discovered global chromosomal epigenome erosion of 3D genome structure within and across brain cell types. Furthermore, to evaluate whether these age- and disease-dependent molecular signatures could be detected in the in vitro cellular models, we derived induced neurons (iNs) converted directly from AD patients fibroblasts and found a set of conserved methylation signatures and shared molecular processes. We developed a machine-learning algorithm to identify robust and consistent methylation signatures of LOAD in vivo primary brain tissues and in vitro fibroblast-derived iNs. The results recapitulate the age- and disease-related epigenetic features in iNs and highlight the power of epigenome and chromatin conformation for identifying molecular mechanisms of neuronal aging and generating biomarkers for LOAD. HIGHLIGHTO_LIAD-specific DNA methylation signatures are identified in entorhinal cortex brain cell types C_LIO_LIThe AD differentially expressed genes linked with differentially methylated regions via loop interactions are enriched in a bivalent chromatin state C_LIO_LIChromosomal epigenome erosion of 3D genome structures occurs in LOAD brain cell types. C_LIO_LIShared and reliable methylation signatures are observed in both in vitro cellular iN models and primary brain tissues. C_LIO_LIMachine learning models identify robust and reliable methylation loci as AD biomarkers across cell types. C_LI

genomics↗

bioRxiv2023

Reply to: Caution Regarding the Specificities of Pan-Cancer Microbial Structure

The cancer microbiome field tremendously accelerated following the release of our manuscript nearly three years ago1, including direct validation of our cancer type-specific conclusions in independent, international cohorts2,3 and the tumor microbiomes adoption into the hallmarks of cancer4. Disentangling contamination signals from biological signals is an important consideration for this research field. Therefore, despite numerous, high-impact, peer-reviewed research papers that either validated our conclusions or extended them using data we released2,5-13, we carefully considered criticism raised by Gihawi et al. about potential mishandling of contaminants, batch effects, and machine learning approaches--all of which were central topics in our manuscript. Nonetheless, a close examination of each concern alongside the original manuscript and re-analyses of our published data strongly demonstrates the robustness of the original findings. To remove all doubt, however, we have reproduced all key conclusions from the original manuscript using only overlapping bacterial genera identified in a highly decontaminated, multi-cancer, international cohort (Weizmann Institute of Science, WIS)2, with or without batch correction, and with multiclass machine learning analyses to mitigate class imbalances. Our published pan-cancer mycobiome manuscript3 also affirms these findings using updated, state-of-the-art methods. We also note that every analysis shown here was possible using public data and code that we had already provided.

bioinformatics↗

bioRxiv2022

Cas12a2 elicits abortive infection via RNA-triggered destruction of double-stranded DNA

Bacterial abortive infection systems limit the spread of foreign invaders by shutting down or killing infected cells before the invaders can replicate1, 2. Several RNA-targeting CRISPR-Cas systems (e.g., types III and VI) cause Abi phenotypes by activating indiscriminate RNases3-5. However, a CRISPR-mediated abortive mechanism that relies on indiscriminate DNase activity has yet to be observed. Here we report that RNA targeting by the type V Cas12a2 nuclease drives abortive infection through non-specific cleavage of double-stranded (ds)DNA. Upon recognition of an RNA target with an activating protospacer-flanking sequence, Cas12a2 efficiently degrades single-stranded (ss)RNA, ssDNA, and dsDNA. Within cells, the dsDNase activity induces an SOS response and impairs growth, stemming the infection. Finally, we harnessed the collateral activity of Cas12a2 for direct RNA detection, demonstrating that Cas12a2 can be repurposed as an RNA-guided, RNA-targeting tool. These findings expand the known defensive capabilities of CRISPR-Cas systems and create additional opportunities for CRISPR technologies.

microbiology↗

bioRxiv2019

Population Health Genetic Screening for Tier 1 Inherited Diseases in Northern Nevada: 90% of At-Risk Carriers are Missed

In an unselected population of 23,713 participants who underwent clinical exome sequencing as a part of the Healthy Nevada Project (HNP) in Northern Nevada (Renown Health, Reno, Nevada) from March 15, 2018, to Sept 30, 2018 (Table S1) we find a 1.26% carrier rate for expected pathogenic and likely pathogenic genetic variants in (FH: LDLR, PCSK9, APOB), Hereditary Breast and Ovarian Cancer (HBOC: BRCA1, BRCA2) and Lynch Syndrome (LS: MLH1, MSH2, MSH6, PSM2) with over 90% of carriers undetected under current medical practice. 26% of carriers were found to have advanced disease with 70% first diagnosed before the age of 65. Less than 20% of all carriers had any documented suspicion for inherited genetic disease in the medical record and upon direct follow-up survey under 40% of carriers had family history of relevant disease. A population preventative genetic screening approach for patients under 45 may improve outcomes.\n\nO_TBL View this table:\norg.highwire.dtl.DTLVardef@1eb1896org.highwire.dtl.DTLVardef@19b2a11org.highwire.dtl.DTLVardef@1e6da81org.highwire.dtl.DTLVardef@1138699org.highwire.dtl.DTLVardef@e9c415_HPS_FORMAT_FIGEXP M_TBL O_FLOATNOTable S1:C_FLOATNO O_TABLECAPTIONDemographic Profile of Healthy Nevada Project Participants.\n\nC_TABLECAPTION C_TBL

genetics↗

bioRxiv2018

The Healthy Nevada Project: rapid recruitment for population health study

BackgroundNevada ranks in the bottom half of overall health rankings in the United States. The majority of residents of Northern Nevada live in Washoe County, which is confounded with high age-adjusted death rates for heart disease, cancer and chronic lower respiratory disease.\n\nMethodsSaliva as a source of DNA was collected from adults in Northern Nevada as the first phase of a much larger (100,000 participants) effort to contribute to comprehensive population health studies in Nevada. The personal genetics company 23andMe was used to genotype the first 10,250 participants and deliver their custom ancestry, traits, wellness, and carrier status reports.\n\nResultsThe study was announced by Governor Brian Sandoval on September 15, 2016 and within two days the registration of 9,700 volunteers for an appointment was complete. Processing of 9,344 participants was achieved in 3 months, with a no-show rate of just over 11%. The participant population was skewed to female and was less racially diverse than the population.\n\nConclusionDNA genotyping was administered free-of-charge and the patient population was representative of the socio-economic diversity in northern Nevada - indicating that free genetic testing is of interest to a broad swath of the population and a powerful motivator for comprehensive population health study research.

scientific communication and education↗