Biology subjects

Lewis, D.

Publications and source records attributed to Lewis, D..

25 records · Page 2Linked to original sources

bioRxiv2022

Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence

Acute Respiratory Distress Syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, has no cure. Hypoxemia is a defining feature, yet its impact on inflammation is often neglected. Patients with ARDS are monocytopenic early in the onset of the disease. Endotoxin or Streptococcus pneumoniae acute lung injury (ALI) in the context of hypoxia replicates this finding, through hypoxia-driven suppression of type I interferon signalling. This results in failed lung monocyte-derived interstitial macrophages (IM) niche expansion and unchecked neutrophilic inflammation. Administration of colony stimulating factor 1 (CSF1) rescues the monocytopenia, alters the circulating classical monocyte phenotype in hypoxic endotoxin-driven ALI and enables lung IM population expansion, thus limiting lung injury in endotoxin- and virally-induced hypoxic ALI. Hypoxia directly alters immune dynamics to the detriment of the host and manipulation of this aberrant response offers new therapeutic strategies for ARDS.

cell biology↗

bioRxiv2022

Frequency dependent growth of bacteria in living materials

The fusion of living bacteria and man-made materials represents a new frontier in medical and biosynthetic technology. However, the principles of bacterial signal processing inside three dimensional and fluctuating environments of synthetic materials remain elusive. Here, we study bacterial growth in a three-dimensional hydrogel. We find that bacteria expressing an antibiotic resistance module can take advantage of ambient kinetic disturbances to improve growth while encapsulated. We show that these changes in bacterial growth are specific to disturbance frequency and hydrogel density. This remarkable specificity is consistent with stochastic resonance theory, which we leverage to explain how bacteria can integrate spatial and temporal information to control growth. This research provides a quantitative foundation for the control of living materials and a systematic framework towards understanding bacterial information processing in three-dimensional environments.

biophysics↗

bioRxiv2021

Identification and correction of phase switches with Hi-C data in the Nanopore and HiFi chromosome-scale assemblies of the dikaryotic leaf rust fungus Puccinia triticina

BackgroundMost animals and plants have more than one set of chromosomes and package these haplotypes into a single nucleus within each cell. In contrast, many fungal species carry multiple haploid nuclei per cell. Rust fungi are such species with two nuclei (karyons) that contain a full set of haploid chromosomes each. The physical separation of haplotypes in dikaryons means that, unlike in diploids, Hi-C chromatin contacts between haplotypes are false positive signals. ResultsWe generate the first chromosome-scale, fully-phased assembly for the dikaryotic leaf rust fungus Puccinia triticina and compare Nanopore MinION and PacBio HiFi sequence-based assemblies. We show that false positive Hi-C contacts between haplotypes are predominantly caused by phase switches rather than by collapsed regions or Hi-C read mis-mappings. We introduce a method for phasing of dikaryotic genomes into the two haplotypes using Hi-C contact graphs, including a phase switch correction step. In the HiFi assembly, relatively few phase switches occur, and these are predominantly located at haplotig boundaries and can be readily corrected. In contrast, phase switches are widespread throughout the Nanopore assembly. We show that haploid genome read coverage of 30-40 times using HiFi sequencing is required for phasing of the leaf rust genome (~0.7% heterozygosity) and that HiFi sequencing resolves genomic regions with low heterozygosity that are otherwise collapsed in the Nanopore assembly. ConclusionsThis first Hi-C based phasing pipeline for dikaryons and comparison of long-read sequencing technologies will inform future genome assembly and haplotype phasing projects in other non-haploid organisms.

genomics↗

bioRxiv2020

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

BackgroundPrevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths. While opioid dependence has been extensively studied in preclinical models, an understanding of the biological alterations that occur in the brains of people who chronically use opioids and who are diagnosed with OUD remains limited. To address this limitation, RNA-sequencing (RNA-seq) was conducted on the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), regions heavily implicated in OUD, from postmortem brains in subjects with OUD. MethodsWe performed RNA-seq on the DLPFC and NAc from unaffected comparison subjects (n=20) and subjects diagnosed with OUD (n=20). Our transcriptomic analyses identified differentially expressed (DE) transcripts and investigated the transcriptional coherence between brain regions using rank-rank hypergeometric ordering (RRHO). Weighted gene co-expression analyses (WGCNA) also identified OUD-specific modules and gene networks. Integrative analyses between DE transcripts and GWAS datasets using linkage disequilibrium score (LDSC) assessed the genetic liability psychiatric-related phenotypes. ResultsRRHO analyses revealed extensive overlap in transcripts between DLPFC and NAc in OUD, primarily relating to synaptic remodeling and neuroinflammation. Identified transcripts were enriched for factors that control pro-inflammatory cytokine-mediated, chondroitin sulfate, and extracellular matrix signaling. Cell-type deconvolution implicated a role for microglia as a critical driver for opioid-induced neuroplasticity. Using LDSC, we discovered genetic liabilities for risky behavior, attention deficit hyperactivity disorder, and depression. ConclusionsOverall, our findings reveal new connections between the brains immune system and opioid dependence in the human brain.

neuroscience↗

bioRxiv2020

Asbestos accelerates disease onset in a genetic model of Malignant Pleural Mesothelioma

HypothesisAsbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations. MethodsGenetically modified conditional allelic mice that were previously shown to develop mesothelioma in the absence of exposure to asbestos were induced with lentiviral vector expressing Cre recombinase with and without intrapleural injection of amosite asbestos and monitored until symptoms required euthanasia. Resulting tumours were examined histologically and by immunohistochemistry for expression of lineage markers and immune cell infiltration. ResultsInjection of asbestos dramatically accelerated disease onset and end-stage tumour burden. Tumours initiated in the presence of asbestos showed increased macrophage infiltration. Single-agent suppression of macrophages in mice with established tumours failed to extend survival. ConclusionAsbestos-driven inflammation contributes to the severity of mesothelioma beyond the acquisition of rate-limiting mutations, however, targeted suppression of macrophages alone in established disease showed no therapeutic benefit.

cancer biology↗

bioRxiv2020

Molecular Characterization of Depression Trait and State

Major Depressive disorder (MDD) is a chronic and recurrent brain disorder characterized by episode and remission phases, and poor therapeutic responses. The molecular correlates of MDD have been investigated in case-control settings, but the biological changes associated with trait (regardless of episode/remission) or state (illness phases) remains largely unknown, hence preventing therapeutic opportunities. To address this gap, we generated transcriptome profiles in the subgenual anterior cingulate cortex of MDD subjects who died during a single or recurrent episode or when in remission. We show that biological changes associated with MDD trait (inflammation, immune activation, reduced bioenergetics) are distinct from those associated with MDD phases or state (neuronal structure and function, neurotransmission). On the cell-type level, gene variability in subsets of GABAergic interneurons positive for corticotropin-releasing hormone, somatostatin or vasoactive-intestinal peptide was associated with MDD phases. Applying a probabilistic Bayesian network approach, we next show that gene modules enriched for immune system activation, cytokine response and oxidative stress, may exert causal roles across MDD phases. Finally, using a database of drug-induced transcriptome perturbations, we show that MDD-induced changes in putative causal pathways are antagonized by families of drugs associated with clinical response, including dopaminergic and monoaminergic ligands, and uncover potential novel therapeutic targets. Collectively, these integrative transcriptome analyses provide novel insight into cellular and molecular pathologies associated with trait and state MDD, and a method of drug discovery focused on disease-causing pathways. One Sentence SummaryIntegrating transcriptomic with various in-silico analyses identified cellular, molecular and putative biological causal pathways in trait and state depression

neuroscience↗

bioRxiv2018

Open Humans: A platform for participant-centered research and personal data exploration

BackgroundMany aspects of our lives are now digitized and connected to the internet. As a result, individuals are now creating and collecting more personal data than ever before. This offers an unprecedented chance for human-participant research ranging from the social sciences to precision medicine. With this potential wealth of data come practical problems (such as how to merge data streams from various sources), as well as ethical problems (such as how to best balance risks and benefits when enabling personal data sharing by individuals).\n\nResultsTo begin to address these problems in real time, we present Open Humans, a community-based platform that enables personal data collections across data streams, giving individuals more personal data access and control of sharing authorizations, and enabling academic research as well as patient-led projects. We showcase data streams that Open Humans combines (e.g. personal genetic data, wearable activity monitors, GPS location records and continuous glucose monitor data), along with use cases of how the data facilitates various projects.\n\nConclusionsOpen Humans highlights how a community-centric ecosystem can be used to aggregate personal data from various sources as well as how these data can be used by academic and citizen scientists through practical, iterative approaches to sharing that strive to balance considerations with participant autonomy, inclusion, and privacy.

bioinformatics↗