Biology subjects

Murphy, D.

Publications and source records attributed to Murphy, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Complete mitochondrial genomes of Arizona West Nile virus vectors, Culex quinquefasciatus and Culex tarsalis

Here we report a newly developed method utilizing long-range PCR and long-read Pacific Biosciences HiFi sequencing that successfully obtained two full-length and annotated mitochondrial genomes from Culex quinquefasciatus Say, 1823 and Culex tarsalis Coquillett, 1896, both from Maricopa County, Arizona, USA. Given the substantial burden of West Nile virus in Maricopa County over the past decade, and that these vectors are primarily responsible for spillover to human populations in the county, it is critical to better understand their distribution over time and space. This study begins to approach this need by contributing a novel approach that has resulted in the first West Nile virus vector mitochondrial genomes from Arizona. Our circular Cx. quinquefasciatus mitogenome is 15,587 bp in length, making it the first USA-based mitogenome sequenced through the AT-rich control region. The Cx. tarsalis mitochondrial genome is 16,416 bp long, longer than recently published California-based CTarK1 and Texas-based PQ585801 mitogenomes. The increased length of the Cx. tarsalis mitogenome is a result of a 905 bp insertion in the AT-rich control region, not present in the species publicly available mitogenomes. A maximum likelihood-based phylogenetic reconstruction supports the species designation of these newly-sequenced mitogenomes. The newly developed methodology offers a unique approach to study medically-important vector species around the globe, providing a solution to study populations through pooled vector pathogen surveillance programs.

genomics↗

bioRxiv2026

Daily HIV pre-exposure prophylaxis enhances monocyte activation and effector function and reprogrammes cellular metabolism.

BackgroundPre-exposure prophylaxis (PrEP) with tenofovir/emtricitabine (TDF/FTC) is highly effective for HIV prevention. While antiretroviral therapy (ART) is linked to chronic inflammation in people living with HIV, its direct effects on immune phenotype, function, and metabolism in HIV-negative individuals remain unclear. MethodsGay, bisexual, and other men who have sex with men (gbMSM) on daily TDF/FTC PrEP underwent immunophenotyping and single-cell metabolic profiling using SCENITH. Cytokine and chemokine responses were measured ex vivo and after lipopolysaccharide or Mycobacterium tuberculosis stimulation. These were compared with a demographically similar PrEP-naive cohort, with five individuals followed 6-9 months after PrEP initiation. FindingsMonocytes from people taking PrEP (n=15; median 533 days) exhibited higher activation marker expression (HLA-DR, CD14) ex vivo and enhanced IL-1{beta} and TNF after bacterial challenge compared with PrEP-naive individuals (n=11). Longitudinal follow-up indicated that PrEP initiation increased monocyte activation markers (HLA-DR, CD14, CD40, TNFRI/II) and cytokine production (IL-1{beta}, TNF, GM-CSF, IFN-{gamma}, Granzyme B, MIP-1). Reduced glucose dependency was observed in monocytes, CD56dim NK cells and CD4+ T cells 6-9 months after PrEP initiation. InterpretationDaily TDF/FTC promotes monocyte activation, enhances pro-inflammatory responses, and reprogrammes immune cell metabolism, highlighting ARTs potential to modulate immune-mediated inflammatory pathways in HIV-negative individuals. FundingTrinity Translational Medicine Institute, Trinity College Dublin, Dublin, The Association of Physicians of Great Britain and Ireland, Health Research Board Ireland. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/698427v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@d48088org.highwire.dtl.DTLVardef@1428926org.highwire.dtl.DTLVardef@13a4facorg.highwire.dtl.DTLVardef@144d1f1_HPS_FORMAT_FIGEXP M_FIG C_FIG Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSDespite effective viral suppression with antiretroviral therapy (ART), people living with HIV (PLWHIV) experience persistent immune activation and chronic inflammation that increase their risk of age-associated comorbidities. The extent to which ART itself contributes to this dysregulated immune state remains unclear, as HIV infection confounds most studies. Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) offers a unique opportunity to examine the direct immunological effects of ART in HIV-negative individuals. However, few studies have explored how PrEP influences immune cell activation, effector function, or cellular metabolism in the absence of viral infection. Added value of this studyThis study is the first to characterise how daily PrEP with TDF/FTC modulates innate immune activation and cellular metabolism independently of HIV infection. We show that PrEP enhances monocyte activation and effector cytokine production while reprogramming metabolic pathways to reduce glucose dependency in monocytes, NK cells, and CD4 T cells. These findings reveal previously unrecognised immunometabolic effects of ART in HIV-negative individuals, providing mechanistic insight into how ART exposure can shape immune homeostasis in the absence of infection. Implications of all the available evidenceOur findings, together with existing data from PLWHIV, suggest that ART itself can remodel immune and metabolic pathways, potentially contributing to both beneficial and detrimental outcomes. ART-induced immunometabolic reprogramming may underlie persistent inflammation and the early onset of comorbidities observed in treated HIV infection, while also enhancing innate responsiveness to bacterial pathogens such as Mycobacterium tuberculosis. Understanding these mechanisms may inform future strategies to optimise ART regimens and mitigate inflammation-associated complications.

immunology↗

bioRxiv2025

Differences in Brain Microtubule Electrical Activity of the Hippocampus and Neocortex from the Adult Rat

Microtubules (MTs) are essential cytoskeletal structures in neurons that generate electrical oscillations in the frequency range of mammalian brain waves. However, the role of these MT oscillations in brain function remains largely unknown. Here, we sought to gain insight into MT electrical oscillatory activity from different brain regions with specific functions, the hippocampus and the neocortex from the adult rat brain. We obtained local field potentials (LFP) from the frozen brain regions under non-depolarized (high external NaCl) and depolarized (high external KCl) saline solutions, observing spontaneous oscillations under both conditions. The electrical oscillations of the brain tissue had different amplitudes in the absence (0 mV) or presence (100 mV) of holding potential and were inhibited by the MT stabilizer paclitaxel. A frequency domain spectral analysis of the time records revealed the presence of two major peaks at approximately [~]38 Hz and [~]93 Hz in both preparations. However, the energy contribution of each peak was different in the hippocampus compared to neocortex. Coupled with our electron microscopy observations, these data suggest that rat brain MTs produce electrical oscillations with specific properties in the various regions of the mammalian brain, which could be partially related as their intra-axonal distributions. MT oscillations may be implicated in the wave coherence of brain activity, supporting their contribution to the concept of a brain central oscillator that drives its function.

biophysics↗

bioRxiv2025

Dehydration Adaptation of the Adult Rat Modifies Brain Microtubule Electrical Activity of the Osmosensitive Supraoptic Nucleus

Brain microtubules (MTs) are important cytoskeletal structures in neurons that generate electrical oscillations in the frequency range of mammalian brain waves. However, the functional role of MT oscillations in the physiology of brain function remains unknown. Acute dehydration (DH) induced by water restriction results in changes in osmolality that require the modification of osmosensitive neuronal activity in the regions of the CNS involved in osmoregulation, in particular magnocellular neurons from the hypothalamic supraoptic nucleus (SON), responsible for the release of vasopressin and implicate osmosensor channels, associated with an intricate mesh of MTs. In the present study, we evaluated the effect of 24 h water deprivation (DH, dehydrated group) on the MT-based cytoskeleton of adult Wistar rats, as compared to a control group with free access to water (Control, euhydrated group). We obtained local field potentials (LFP) from isolated SON and cortex (CTX) brain tissue, observing spontaneous oscillations under both conditions. The electrical oscillations of the brain tissue from DH animals had different amplitudes and frequency peaks as compared to controls. A frequency domain spectral analysis of the time records indicated specific, SON-associated MT energy contributions of the frequency peaks in the challenged group, most particularly a dramatic increase in the 10-20 Hz range, and a statistically significant reduction in the high frequency 83-100 Hz region, not observed in the CTX samples. The data indicate that brain MTs respond to dehydration to produce electrical oscillations with distinct properties in the areas of the mammalian brain that specifically contribute to the homeostatic response. The present study provides the first evidence for a novel physiological mechanism associated with the electrical activity of the neuronal cytoskeleton and points to its possible involvement in the brain osmoregulatory mechanism.

biophysics↗

bioRxiv2025

TX2P: A Proteogenomic Tool for Comprehensive Transcript Analysis

Long-read RNA sequencing has expanded our understanding of the transcriptome, revealing unannotated transcripts. However, interpreting their functional relevance remains challenging. To address this, we developed TX2P, a user-friendly tool that integrates transcriptomic and proteomic data to link RNA discoveries with protein function. Applied to epilepsy-associated genes, TX2P identified novel protein-coding transcripts, with peptide evidence supporting 17.2% transcripts and 18.0% of unique open reading frames. By seamlessly integrating transcriptomic and proteomic insights, TX2P facilitates transcriptome interpretation.

bioinformatics↗

bioRxiv2025

Diploid genome assembly of human fibroblast cell lines enables clone specific variant calling, improved read mapping and accurate phasing

Human cell lines are fundamental tools in biomedical research and are widely used in disease modeling, drug development, and many other domains. Here, we present chromosome-level, phased diploid genome assemblies of two popular human cell lines: the BJ foreskin fibroblast line and the IMR-90 fetal lung fibroblast line. Our high-quality assemblies, generated using long-read and Hi-C sequencing data, reveal substantial structural variation, including more than 50,000 insertions, deletions, duplications, and inversions compared to the recent T2T-CHM13v2.0 reference. Our assemblies provide detailed maps of genetic variation, enabling more accurate variant calling and the ability to phase reads when using newly generated or historical sequencing data on these cell lines or their derivatives. All assemblies and associated data have been made available as a resource for the research community. We envision that diploid genome assembly will become a cornerstone approach for personalized medicine in the near future.

genomics↗

bioRxiv2025

The impact of testosterone on paraventricular nucleus gene expression in male and female spontaneously hypertensive rats

BackgroundHypertension is a polygenic, complex disease that impacts men and women differently; whilst the incidence of high blood pressure (BP) is roughly equal over a lifetime, men typically are at higher risk of developing the disease earlier in life, before 50 years of age. There is adequate evidence that the brain is critical for the BP setpoint. The paraventricular nucleus (PVN) of the hypothalamus is an integrative structure that can influence not only neurohumoral responses to blood pressure changes, but also sympathetic drive. Here we manipulate the androgenic status of both male and female spontaneously hypertensive rats (SHRs) to determine how this changes gene expression within the PVN of these animals. MethodsSHR (8-weeks old) were either sham-operated or orchiectomized, whereas all females were oophorectomized, half of which received 10mg testosterone propionate subcutaneously. Mean arterial pressure (MAP) and testosterone (T) were measured by carotid cannulation and ELISA respectively. Sequencing was performed on hand-punched PVN sections and subjected to robust bioinformatic analysis. ResultsIn total, 6,571 differentially regulated genes (DRGs) are regulated in the PVN of male and female rats. High T (endogenous or replaced) correlates with higher MAP in both sexes. Orchidectomy-induced T depletion resulted in the significant regulation of 5,104 genes, involved in thousands of biological roles, including ones related to hormone and sex-hormone signalling. In the female SHR, testosterone replacement in oophorectomized animals induced the regulation of 1,727 genes, sharing many biological functions with those in the high T males. We validated key genes by qPCR to determine false discovery rate. ConclusionsT status in hypertensive rats correlates with MAP, and consistent changes in PVN transcriptome

neuroscience↗

bioRxiv2025

Zero-phase-delay connectivity increases the reliability, concordance with structure, and prognostic ability of functional connectivity metrics

Neural populations synchronise their activity with either zero-phase-delay (activity in interacting regions occurs simultaneously) or a phase-delay (activity in one region follows the other). In electroencephalography and magnetoencephalography functional connectivity analyses, artefactual connectivity can also occur with zero-phase-delay. To minimise artefact, contemporary analyses typically exclude all zero-phase-delay interactions. However, the extent to which true interactions are resultingly lost - and the impact this has on the performance of functional connectivity metrics as biomarkers - remains unknown. Here, we show that most cortico-cortical functional connectivity occurs with zero- or near-zero phase-delay, even where such connectivity is unlikely to be artefactual. Including, rather than excluding, zero-phase-delay connectivity increases the reliability, convergence with neurobiology (structure-function concordance, homotopic interhemispheric connectivity, and age-related connectivity changes), and prognostic ability of functional connectivity metrics. We find that excluding zero-phase-delay connections penalises functional connectivity strength between the strongest structurally connected regions: stronger structural connections lead to functional connections with phase-delays closer to zero, mediated by a shorter signal propagation time. Our findings challenge generally accepted assumptions that zero-phase-exclusive methods are superior to zero-phase-inclusive methods.

neuroscience↗

bioRxiv2025

Transcriptomic analysis of repeat expansion-ataxias uncovers distinct non-neuronal cell type-specific signatures of disease across the human brain

Hereditary ataxias are a heterogeneous group of neurogenetic conditions characterised by the clinical syndrome of progressive loss of coordination from neurodegeneration of the cerebellum. A commonality across the most prevalent ataxias is the underlying disease mechanism secondary to expansions of short tandem DNA repeats. There is currently an incomplete understanding of the pathogenic mechanisms of these repeat expansion disorders, a core feature of which revolves around RNA-dysregulation. In this study, we used both bulk and single nuclear RNA-sequencing to study post-mortem brain tissue of human donors with a range of repeat-expansion ataxias to reveal further mechanistic insights. We compared post-mortem paired cerebellar and frontal cortex tissue bulk RNA-sequencing data from 23 ataxia patients and 22 sex-, age-matched controls from two brain banks (spinocerebellar ataxia (SCA)1, SCA2, SCA6, SCA7, SCA17, Friedreichs ataxia (FRDA), and 7 cases with unknown molecular diagnoses). We analysed bulk RNA-sequencing data for transcript usage, differential and cell-type-specific expression to transcriptomically profile these diseases. We also generated single nuclear RNA-sequencing data of the cerebellum from donors with SCA1, SCA2, SCA6 and FRDA to decipher changes in cell type proportions in the disease state. Using this approach, we found that: (i) despite the commonalities in the genetics of ataxia, there were components of their transcriptional signatures which were distinct; (ii) there were extensive transcriptional changes evident not only in the cerebellum but also the frontal cortex in ataxia cases; (iii) activation of immune and inflammatory pathways, as well as involvement of non-neuronal cell types was a feature of all ataxias to a lesser or greater extent. This study provides a novel resource to understand the mechanisms of disease in ataxia. Furthermore, taken together, these results highlight immune pathways and the role of non-neuronal cell types as early and potentially important therapeutic targets. These findings provide a map of transcriptomic changes in ataxia to further understanding of the underlying pathogenesis.

neuroscience↗

bioRxiv2024

Vgamma1+ gammadelta T cell-derived IL-4 initiates CD8 T cell immunity

Dendritic cells (DC) are pivotal for initiating adaptive immunity, a process triggered by the activation of DC via pathogen products or damage. Here, we describe an additional layer to this process, essential when pathogen-derived signals alone cannot directly achieve full DC activation. Immunisation with sporozoites from Plasmodium leads to CD8 T cell priming in a complex response that is initiated by a collaboration between conventional type 1 DC (cDC1) and {gamma}{delta} T cells. We unveil a pivotal initiating role for V{gamma}1+ {gamma}{delta} T cells, as they directly supply IL-4 to DC and CD8 T cells. IL-4 synergises with a CD4 T cell-derived CD40L signal to induce IL-12 production by cDC1. Both IL-12 and IL-4 then directly signal CD8 T cells, with synergy between these cytokines driving enhanced IL-12 receptor expression and expansion of responding CD8 T cells. This study reveals a key role for V{gamma}l+ {gamma}{delta} T cells in initiating CD8 T cell immunity to Plasmodium. More broadly, it shows that responses to some pathogens require help from innate-like T cells to pass an initiation threshold and further amplify the response in a process underscored by IL-4 production.

immunology↗

bioRxiv2024

A histomorphological atlas of resected mesothelioma from 3446 whole-slide images discovered by self-supervised learning

1Mesothelioma is a highly lethal and poorly biologically understood disease which presents diagnostic challenges due to its morphological complexity. This study uses self-supervised AI (Artificial Intelligence) to map the histomorphological landscape of the disease. The resulting atlas consists of recurrent patterns identified from 3446 Hematoxylin and Eosin (H&E) stained images scanned from resected tumour slides. These patterns generate highly interpretable predictions, achieving state-of-the-art performance with 0.65 concordance index (c-index) for outcomes and 88% AUC in subtyping. Their clinical relevance is endorsed by comprehensive human pathological assessment. Furthermore, we characterise the molecular underpinnings of these diverse, meaningful, predictive patterns. Our approach both improves diagnosis and deepens our understanding of mesothelioma biology, highlighting the power of this self-learning method in clinical applications and scientific discovery.

pathology↗

bioRxiv2024

Qualitative EEG abnormalities signal a shift towards inhibition-dominated brain networks. Results from the EU-AIMS LEAP studies

Qualitative EEG abnormalities are common in Autism Spectrum Disorder (ASD) and hypothesized to reflect disrupted excitation/inhibition balance. To test this, we recently introduced a functional measure of network-level E/I ratio (fE/I). Here, we applied fE/I and other EEG measures to alpha oscillations from source-reconstructed data in the EU-AIMS dataset (267 ASD, 209 controls). We analyzed these measures alongside qualitative EEG abnormalities ranging from slowing of activity to epileptiform patterns, aiming to replicate the findings from the SPACE-BAMBI study. EEG abnormalities were rare in adults and could not be statistically assessed. ASD children-adolescents with EEG abnormalities exhibited lower relative alpha power and fE/I compared to those without. However, EEG-abnormality scoring did not stratify the behavioral heterogeneity of ASD using clinical measures. Surprisingly, several controls also exhibited qualitative EEG abnormalities with a strikingly similar anatomical distribution of reduced fE/I, suggesting a shift towards inhibition-dominated network dynamics in sensory processing regions. The robustness of this association between EEG abnormalities and reduced fE/I was further supported by re-analysis of the SPACE-BAMBI study in source space. Stratification by the presence of EEG abnormalities and their effects on network activity may help understand neurodevelopmental physiological heterogeneity and the difficulties in implementing E/I targeting treatments in unselected cohorts.

neuroscience↗

bioRxiv2024

Melanocortin system activates carotid body arterial chemoreceptors in hypertension

BackgroundThe bodys internal milieu is controlled by a system of interoceptors coupled to motor outflows that drive compensatory adaptive responses. These include the arterial chemoreceptors, best known for sensing arterial oxygen. In cardiometabolic diseases, such as essential hypertension, the carotid bodies (CB) exhibit heightened reflex sensitivity and tonic activity without an apparent stimulus. The mechanisms behind CB sensitization in these conditions are not well understood. MethodsGuided by functional genomics, a range of functional assays is used to interrogate downstream intracellular and interorgan signalling pathways involved in arterial chemosensory function. ResultsHere, we report the presence of the Melanocortin 4 receptor (MC4R) in the mammalian CB and show its elevated expression in experimental hypertension. We demonstrate that melanocortin agonists activate arterial chemosensory cells, modulating CB chemosensory afferent drive to influence both resting and chemoreflex-evoked sympathetic and ventilatory activity. Transcriptional analysis of hypertensive CB implicates the activation of the Mash1 (Ascl1) regulatory network in driving elevated Mc4r expression. ConclusionsCollectively, our data indicate a primarily pathophysiological role of melanocortin signalling in arterial chemosensation, contributing to excess sympathetic activity in cardiometabolic disease.

neuroscience↗

bioRxiv2024

The diversity of SNCA transcripts in neurons, and its impact on antisense oligonucleotide therapeutics

The role of the SNCA gene locus in driving Parkinsons disease (PD) through rare and common genetic variation is well-recognized, but the transcriptional diversity of SNCA in vulnerable cell types remains unclear. We performed SNCA long-read RNA sequencing in human dopaminergic neurons and show that annotated SNCA transcripts account for only 5% of expression. Rather, the majority of expression (75%) at the SNCA locus originates from transcripts with alternative 5 and 3 untranslated regions. Importantly, 10% originates from transcripts encoding open reading frames not previously annotated, which are translated and detectable in human postmortem brain. Defining the 3 untranslated regions enabled the rational design of antisense oligonucleotides targeting the majority of SNCA transcripts, leading to the effective reversal of PD pathology, including protein aggregation, mitochondrial dysfunction, and toxicity. Resolving the complexity of the SNCA transcriptional landscape impacts RNA therapies and highlights differences in protein isoforms and their contribution to disease.

neuroscience↗

bioRxiv2024

CRISPR Screening Uncovers a Long-Range Enhancer for ONECUT1 in Pancreatic Differentiation and Links a Diabetes Risk Variant

Functional enhancer annotation is a valuable first step for understanding tissue-specific transcriptional regulation and prioritizing disease-associated non-coding variants for investigation. However, unbiased enhancer discovery in physiologically relevant contexts remains a major challenge. To discover regulatory elements pertinent to diabetes, we conducted a CRISPR interference screen in the human pluripotent stem cell (hPSC) pancreatic differentiation system. Among the enhancers uncovered, we focused on a long-range enhancer [~]664 kb from the ONECUT1 promoter, since coding mutations in ONECUT1 cause pancreatic hypoplasia and neonatal diabetes. Homozygous enhancer deletion in hPSCs was associated with a near-complete loss of ONECUT1 gene expression and compromised pancreatic differentiation. This enhancer contains a confidently fine-mapped type 2 diabetes associated variant (rs528350911) which disrupts a GATA motif. Introduction of the risk variant into hPSCs revealed substantially reduced binding of key pancreatic transcription factors (GATA4, GATA6 and FOXA2) on the edited allele, accompanied by a slight reduction of ONECUT1 transcription, supporting a causal role for this risk variant in metabolic disease. This work expands our knowledge about transcriptional regulation in pancreatic development through the characterization of a long-range enhancer and highlights the utility of enhancer discovery in disease-relevant settings for understanding monogenic and complex disease.

developmental biology↗

bioRxiv2024

Same data, different results? Evaluating machine learning approaches for individual identification in animal vocalisations

Automated acoustic analysis is increasingly used in behavioural ecology, and determining caller identity is a key element for many investigations. However, variability in feature extraction and classification methods limits the comparability of results across species and studies, constraining conclusions we can draw about the ecology and evolution of the groups under study. We investigated the impact of using different feature extraction (spectro-temporal measurements, linear and Mel-frequency cepstral coefficients, as well as highly comparative time-series analysis) and classification methods (discriminant function analysis, neural networks, random forests, and support vector machines) on the consistency of caller identity classification accuracy across 16 mammalian datasets. We found that Mel-frequency cepstral coefficients and random forests yield consistently reliable results across datasets, facilitating a standardised approach across species that generates directly comparable data. These findings remained consistent across vocalisation sample sizes and number of individuals considered. We offer guidelines for processing and analysing mammalian vocalisations, fostering greater comparability, and advancing our understanding of the evolutionary significance of acoustic communication in diverse mammalian species.

animal behavior and cognition↗

bioRxiv2024

Unique functional neuroimaging signatures of genetic versus clinical high risk for psychosis

Background22q11.2 Deletion Syndrome (22qDel) is a copy number variant (CNV) associated with psychosis and other neurodevelopmental disorders. Adolescents at clinical high risk for psychosis (CHR) have subthreshold psychosis symptoms without known genetic risk factors. Whether common neural substrates underlie these distinct high-risk populations is unknown. We compared functional brain measures in 22qDel and CHR cohorts and mapped results to biological pathways. MethodsWe analyzed two large multi-site cohorts with resting-state functional MRI (rs-fMRI): 1) 22qDel (n=164, 47% female) and typically developing (TD) controls (n=134, 56% female); 2) CHR individuals (n=244, 41% female) and TD controls (n=151, 46% female) from the North American Prodrome Longitudinal Study-2. We computed global brain connectivity (GBC), local connectivity (LC), and brain signal variability (BSV) across cortical regions, testing case-control differences for 22qDel and CHR separately. Group difference maps were related to published brain maps using autocorrelation-preserving permutation. ResultsBSV, LC, and GBC are significantly disrupted in 22qDel compared with TD controls (False Discovery Rate q<0.05). Spatial maps of BSV and LC differences are highly correlated with each other, unlike GBC. In CHR, only LC is significantly altered versus controls, with a different spatial pattern compared to 22qDel. Group differences map onto biological gradients, with 22qDel effects strongest in regions with high predicted blood flow and metabolism. Conclusion22qDel and CHR exhibit divergent effects on fMRI temporal variability and multi-scale functional connectivity. In 22qDel, strong and convergent disruptions in BSV and LC not seen in CHR individuals suggest distinct functional brain alterations.

neuroscience↗

bioRxiv2024

Distinct Type 1 Immune Networks Underlie the Severity of Restrictive Lung Disease after COVID-19

The variable etiology of persistent breathlessness after COVID-19 have confounded efforts to decipher the immunopathology of lung sequelae. Here, we analyzed hundreds of cellular and molecular features in the context of discrete pulmonary phenotypes to define the systemic immune landscape of post-COVID lung disease. Cluster analysis of lung physiology measures highlighted two phenotypes of restrictive lung disease that differed by their impaired diffusion and severity of fibrosis. Machine learning revealed marked CCR5+CD95+ CD8+ T-cell perturbations in mild-to-moderate lung disease, but attenuated T-cell responses hallmarked by elevated CXCL13 in more severe disease. Distinct sets of cells, mediators, and autoantibodies distinguished each restrictive phenotype, and differed from those of patients without significant lung involvement. These differences were reflected in divergent T-cell-based type 1 networks according to severity of lung disease. Our findings, which provide an immunological basis for active lung injury versus advanced disease after COVID-19, might offer new targets for treatment.

immunology↗