Biology subjects

Hunter, L.

Publications and source records attributed to Hunter, L..

12 recordsLinked to original sources

bioRxiv2026

The PMADS Project: A Longitudinal Multimodal Cohort Study to Understand Risk for Perinatal Mood and Anxiety Disorders

BackgroundPerinatal mood and anxiety disorders (PMADs) are among the most common and consequential complications of pregnancy. The perinatal period is also characterized by profound hormonal fluctuations and large-scale brain plasticity. However, the mechanisms linking these neurobiological changes to psychiatric risk are poorly understood. Prospective, clinically informed studies are needed to identify quantitative biomarkers and clarify pathways linking perinatal neurobiology to PMADs risk. MethodsThis report describes the design of a prospective, longitudinal cohort study integrating multimodal neuroimaging, biofluid sampling, and deep clinical phenotyping to enable precision characterization of neurobiological trajectories of PMADs risk. Twenty-five individuals at elevated risk for PMADs will be recruited prior to conception and followed across six in-person timepoints spanning the menstrual cycle, pregnancy, and early postpartum, with additional remote follow-ups through the first postpartum year. Data collection includes high-resolution structural MRI, functional brain mapping using multi-echo resting-state fMRI, diffusion MRI, arterial spin labeling, ultra-high field MR-based techniques for measuring glutamate (GluCEST and 1HMRS), biofluid sampling, and comprehensive clinical, behavioral, and cognitive assessments. Structured clinical interviews assess categorical diagnoses while dimensional symptom measures capture heterogeneity and transdiagnostic features of perinatal psychopathology. Longitudinal analyses will model nonlinear trajectories of brain and symptom change across the perinatal period as well as evaluate whether preconception network features and menstrual cycle-related brain changes are associated with subsequent perinatal symptom emergence. DiscussionThis cohort study establishes a longitudinal, multimodal framework for investigating neurobiological changes across the transition to pregnancy in individuals at elevated risk for PMADs. By anchoring pregnancy-related brain changes to preconception and menstrual cycle-related variability within the same individuals, this study is designed to evaluate associations between preconception hormone sensitivity, pregnancy-induced neuroplasticity, and PMADs risk. The resulting dataset will provide a deeply phenotyped longitudinal resource for investigating brain-behavior relationships across the perinatal period. Findings are expected to inform future larger-scale studies aimed at advancing mechanistic understanding of PMADs, improving individualized risk stratification, and supporting development of personalized preventive and neuromodulatory interventions.

neuroscience↗

bioRxiv2024

Density-Dependent Colour Scanning Electron Microscopy (DDC-SEM). Applications in the study of calcified tissues and visual impact.

Scanning Electron Microscopy (SEM) is widely used as a technique for materials characterization. It has also been successfully applied to the imaging of biological samples, providing invaluable insights into the topography, morphology and composition of biological structures. A particular method combining different SEM detectors, named Density-Dependent Coloured SEM (DDC-SEM), has proven to be most useful for the identification and visualization of minerals in soft tissues. The method consists of a manipulation of original greyscale SEM images to produce coloured images that provide both topography and density information for samples with components of different densities. Here we provide a discussion on how to use DDC-SEM to aid the visualization and intuitive understanding of pathological calcification. This method has become popular not only for its scientific improvement of conventional SEM greyscale images, but also for its aesthetical merits. Lay summaryScanning Electron Microscopes (SEM) are widely used tools for examining biological materials such as human tissue. Like other electron microscopes, it only produces images in greyscale. SEM has been useful, for instance, in improving our understanding of calcific diseases. These diseases involve the build-up of mineral in the bodys soft tissues, and frequently affect the heart, kidneys, or eyes. This work provides a discussion on using a SEM technique known as Density-Dependent Colour Scanning Electron Microscopy (DDC-SEM), which enhances SEM images through scanning the same area with different detectors, assigning a unique colour to each detectors output, and then overlaying these images.

scientific communication and education↗

bioRxiv2024

Highly Multiplexed Proteomic Analysis of HCMV-Infected Dendritic Cells Reveals Global Manipulation of Adaptive Immunity and Host Restriction of Viral Replication

Human cytomegalovirus (HCMV) is a clinically significant herpesvirus and a paradigm for pathogen-mediated immune-evasion. Its broad tropism includes antigen-presenting cells such as dendritic cells (DCs), which may partly explain a unique, dramatic imprint on host immunity that occurs following lifelong carriage. Despite this breadth of infection, most studies use fibroblasts as a model. We therefore developed systems to isolate pure populations of DCs infected with wild-type HCMV, before applying quantitative temporal proteomic technologies to systematically characterise the virus:DC interaction within cells and at the cell surface. This comprehensive dataset quantifying almost 9,000 proteins throughout the infection timecourse revealed multiple DC-specific viral:host effects, including key impacts on innate, intrinsic, and adaptive immunity. These effects included observations that APOBEC3A is downregulated in infected cells and restricts HCMV infection in ex vivo DCs, delaying the progression of lytic infection, and that cell surface ICOS-Ligand was downregulated by the viral genes US16 and US20, inhibiting the induction of adaptive immunity.

microbiology↗

bioRxiv2023

Hypothesizing mechanistic links between microbes and disease using knowledge graphs

Knowledge graphs have found broad biomedical applications, providing useful representations of complex knowledge. Although plentiful evidence exists linking the gut microbiome to disease, mechanistic understanding of those relationships remains generally elusive. Here we demonstrate the potential of knowledge graphs to hypothesize plausible mechanistic accounts of host-microbe interactions in disease. To do so, we constructed a knowledge graph of linked microbes, genes and metabolites called MGMLink. Using a semantically constrained shortest path search through the graph and a novel path prioritization methodology based on cosine similarity, we show that this knowledge supports inference of mechanistic hypotheses that explain observed relationships between microbes and disease phenotypes. We discuss specific applications of this methodology in inflammatory bowel disease and Parkinsons disease. This approach enables mechanistic hypotheses surrounding the complex interactions between gut microbes and disease to be generated in a scalable and comprehensive manner.

bioinformatics↗

bioRxiv2023

Characterization of methods for mechanistic inference of the gut microbiome in disease

MotivationKnowledge graphs have found broad biomedical applications, providing useful representations of complex knowledge. Although plentiful evidence exists linking the gut microbiome to disease, mechanistic understanding of those relationships remains generally elusive. A structured analysis of existing resources is necessary to characterize the resources and methodologies needed to facilitate mechanistic inference. ResultsHere we demonstrate the potential of knowledge graphs to hypothesize plausible mechanistic accounts of host-microbe interactions in disease and define the need for semantic constraint in doing so. We constructed a knowledge graph of linked microbes, genes and metabolites called MGMLink, and one of microbial traits, environments, and human pheno-types called KG-microbe-phenio. Using a shortest path search and a pattern based semantically constrained path search through the graphs, we highlight the need for a microbiome-disease resource and semantically informed search methods to enable mechanistic inference. AvailabilityThe software to create MGMLink is openly available at https://github.com/bsantan/MGMLink, and KG-microbe is available at https://github.com/Knowledge-Graph-Hub/kg-microbe and KG-phenio is available at https://github.com/Knowledge-Graph-Hub/kg-phenio. Contactbrook.santangelo@cuanschutz.edu

bioinformatics↗

bioRxiv2023

Evidence for deliberate burial of the dead by Homo naledi

In this study we describe new results of excavations in the Dinaledi Subsystem of the Rising Star cave system, South Africa. In two areas within the Hill Antechamber and the Dinaledi Chamber this work uncovered concentrations of abundant Homo naledi fossils including articulated, matrix-supported skeletal regions consistent with rapid covering by sediment prior to the decomposition of soft tissue. We additionally re-examine the spatial positioning of skeletal material and associated sediments within the Puzzle Box area, from which abundant H. naledi remains representing a minimum of six individuals were recovered in 2013 and 2014. Multiple lines of evidence exclude the hypothesis that skeletal remains from these three areas come from bodies that decomposed on the floor of the chamber or within a shallow depression prior to burial by sediments. The spatial positioning of skeletal material, the topography of the subsystem, and observations on sediments within and surrounding features exclude the hypothesis that rapid burial by sediment was a result of gravity-driven slumping or spontaneous movement of sediments. We present a minimal hypothesis of hominin cultural burial and test the evidence from all three areas, finding that this hypothesis is most compatible with the pattern of evidence. These results suggest that mortuary behavior including cultural burial was part of the repertoire of Homo naledi.

paleontology↗

bioRxiv2021

Human cytomegalovirus protein RL1 degrades the antiviral factor SLFN11 via recruitment of the CRL4 E3 ubiquitin ligase complex

Human cytomegalovirus (HCMV) is an important human pathogen and a paradigm of viral immune evasion, targeting intrinsic, innate and adaptive immunity. We have employed two novel, orthogonal multiplexed tandem mass tag-based proteomic screens to identify host proteins downregulated by viral factors expressed during the latest phases of viral infection. This approach revealed that the HIV-1 restriction factor Schlafen-11 (SLFN11) was degraded by the poorly characterised, late-expressed HCMV protein RL1, via recruitment of the Cullin4-RING E3 Ubiquitin Ligase (CRL4) complex. SLFN11 potently restricted HCMV infection, inhibiting the formation and spread of viral plaques. Overall, we show that a restriction factor previously thought only to inhibit RNA viruses additionally restricts HCMV. We define the mechanism of viral antagonism and also describe an important resource for revealing additional molecules of importance in antiviral innate immunity and viral immune evasion. Significance StatementPrevious proteomic analyses of host factors targeted for downregulation by HCMV have focused on early or intermediate stages of infection. Using multiplexed proteomics, we have systematically identified viral factors that target each host protein downregulated during the latest stage of infection, after the onset of viral DNA replication. Schlafen-11 (SLFN11), an interferon-stimulated gene and restriction factor for retroviruses and certain RNA viruses, potently restricted HCMV infection. Our discovery that the late-expressed HCMV protein RL1 targets SLFN11 for proteasomal degradation provides the first evidence for a viral antagonist of this critical cellular protein. We therefore redefine SLFN11 as an important factor that targets DNA viruses as well as RNA viruses, offering novel therapeutic potential via molecules that inhibit RL1-mediated SLFN11 degradation.

microbiology↗

bioRxiv2020

Immunological and pathological outcomes of SARS-CoV-2 challenge after formalin-inactivated vaccine immunisation of ferrets and rhesus macaques

There is an urgent requirement for safe and effective vaccines to prevent novel coronavirus disease (COVID-19) caused by SARS-CoV-2. A concern for the development of new viral vaccines is the potential to induce vaccine-enhanced disease (VED). This was reported in several preclinical studies with both SARS-CoV-1 and MERS vaccines but has not been reported with SARS-CoV-2 vaccines. We have used ferret and rhesus macaques challenged with SARS-CoV-2 to assess the potential for VED in animals vaccinated with formaldehyde-inactivated SARS-CoV-2 (FIV) formulated with Alhydrogel, compared to a negative control vaccine in ferrets or unvaccinated macaques. We showed no evidence of enhanced disease in ferrets or rhesus macaques given FIV except for mild transient enhanced disease seen at seven days post infection in ferrets. This increased lung pathology was observed early in the infection (day 7) but was resolved by day 15. We also demonstrate that formaldehyde treatment of SARS-CoV-2 reduces exposure of the spike receptor binding domain providing a mechanistic explanation for suboptimal immunity.

pathology↗

bioRxiv2020

Comparison of Rhesus and Cynomolgus macaques as an authentic model for COVID-19.

A novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques, resembling the mild clinical cases of COVID-19 in humans. Immune responses against SARS-CoV-2 were also similar in both species and equivalent to those reported in milder infections and convalescent human patients. Importantly, we have devised a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the optimal study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of novel and repurposed interventions against SARS-CoV-2. Accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks.

microbiology↗

bioRxiv2020

A burning question: Can natural climate solutions and carbon financing save the lion from extinction?

Lions (Panthera leo) in Africa have lost nearly half their population in just the last two decades, and effective management of the protected areas (PAs) where lions live will cost an estimated USD >$1 B/year in new funding. We explore the potential for launching a fire management and habitat restoration carbon-financing program to help fill this PA management funding gap. We demonstrate how introducing early dry season fire management programs could produce potential carbon revenues (PCR) from either a single carbon-financing method (avoided emissions) or from multiple sequestration methods of USD $59.6-$655.9 M/year (at USD $5/ton) or USD $155.0 M-$1.7 B/year (at USD $13/ton). We highlight variable but significant PCR for PAs with the greatest potential for restoring lion numbers between USD $1.5-$44.4 M per PA. We suggest investing in lion-centric fire management programs to jump-start the United Nations Decade of Ecological Restoration and help preserve African lions across their range. SCIENCE FOR SOCIETYThe United Nations recently launched the Decade of Ecological Restoration in response to planet-wide land degradation. This study analyses the potential for savanna fire management programs to restore fire regimes that can generate new sources of revenue from carbon financing for chronically under-funded protected areas in Africa with lions, as lions are a key indicator of savanna ecosystem health. We estimated the amount of carbon saved by shifting fires that normally burn in the late dry season (and emit more carbon) to the early dry season (that accrue more carbon in the soil and woody vegetation). Based on current carbon market values we found substantial potential to eliminate or significantly reduce the $>1B annual funding gap needed to save the lion from extinction. Given additional benefits for nature and people from new savanna fire programs, we recommend integrated conservation and development projects direct more funding to some of the least developed countries with high biodiversity and support fire management programs in Africa.

ecology↗

bioRxiv2020

Dose-dependent response to infection with SARS-CoV-2 in the ferret model: evidence of protection to re-challenge

In December 2019 an outbreak of coronavirus disease (COVID-19) emerged in Wuhan, China. The causative agent was subsequently identified and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which rapidly spread worldwide causing a pandemic. Currently there are no licensed vaccines or therapeutics available against SARS-CoV-2 but numerous candidate vaccines are in development and repurposed drugs are being tested in the clinic. There is a vital need for authentic COVID-19 animal models to further our understanding of pathogenesis and viral spread in addition to pre-clinical evaluation of candidate interventions. Here we report a dose titration study of SARS-CoV-2 to determine the most suitable infectious dose to use in the ferret model. We show that a high (5x106 pfu) and medium (5x104 pfu) dose of SARS-CoV-2 induces consistent upper respiratory tract (URT) viral RNA shedding in both groups of six challenged animals, whilst a low dose (5x102 pfu) resulted in only one of six displaying signs of URT viral RNA replication. The URT shedding lasted up to 21 days in the high dose animals with intermittent positive signal from day 14. Sequential culls revealed distinct pathological signs of mild multifocal bronchopneumonia in approximately 5-15% of the lung, observed on day 3 in high and medium dosed animals, with presence of mild broncho-interstitial pneumonia on day 7 onwards. No obvious elevated temperature or signs of coughing or dyspnoea were observed although animals did present with a consistent post-viral fatigue lasting from day 9-14 in the medium and high dose groups. After virus shedding ceased, re-challenged ferrets were shown to be fully protected from acute lung pathology. The endpoints of URT viral RNA replication in addition to distinct lung pathology and post viral fatigue were observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease (as displayed by 80% of patients infected with SARS-CoV-2). In addition, intermittent viral shedding on days 14-21 parallel observations reported in a minority of clinical cases.

microbiology↗

bioRxiv2019

Constitutive TRIM22 expression within the respiratory tract identifies tissue-specific and cell-type dependent intrinsic immune barriers to influenza A virus infection

We hypothesized that increased expression of antiviral host factors at portals of viral entry may protect exposed tissues from the constant threat of invading pathogens. Comparative transcriptomic analysis identified the broad-acting restriction factor TRIM22 (TRIpartite Motif 22) to be among the most abundantly expressed antiviral host factors in the lung, a major portal of entry for many respiratory pathogens. This was surprising, as TRIM22 is currently considered to be an interferon stimulated gene (ISG) product that confers protection following the activation of pathogen-induced cytokine-mediated innate immune defences. Using human respiratory cell lines and the airways of rhesus macaques, we experimentally confirmed high levels of constitutive TRIM22 expression in the lung. In contrast, TRIM22 expression in many widely used transformed cell lines could only be observed following immune stimulation. Endogenous levels of TRIM22 in non-transformed cells were sufficient to restrict human and avian influenza A virus (IAV) infection by inhibiting the onset of viral transcription independently of cytokine-mediated innate immune defences. Thus, TRIM22 confers a pre-existing (intrinsic) tissue-specific immune barrier to IAV infection in the respiratory tract. We investigated whether the constitutive expression of TRIM22 was a characteristic shared by other ISGs in human lung tissue. Transcriptomic analysis identified a large group of ISGs and IAV immuno-regulatory host factors that were similarly enriched in the lung relative to other mucosal tissues, but whose expression was downregulated in transformed cell-lines. We identify common networks of immune gene downregulation which correlated with enhanced permissivity of transformed cells to initiate IAV replication. Our data highlight the importance of tissue-specific and cell-type dependent patterns of pre-existing immune gene expression in the intrinsic intracellular restriction of IAV; findings highly relevant to the immune regulation of many clinically important respiratory pathogens.\n\nAuthor SummaryThe respiratory tract is a major portal of virus entry for many clinically important viruses, including seasonal and pandemic influenza A virus (IAV). We reasoned that cells within the respiratory tract might differentially express antiviral host factors to protect against the constant challenge of viral infection. We found the broad-acting antiviral protein TRIM22, conventionally regarded as an interferon stimulated gene (ISG) product upregulated in response to virus infection, to be constitutively expressed to high levels in the lung. We found that constitutive expression of TRIM22 restricted the initiation of human and avian IAV infection independently of cytokine-mediated innate immune defences. We identified pre-existing tissue-specific and cell-type dependent patterns of constitutive immune gene expression that strongly correlated with enhanced resistance to IAV replication from the outset of infection. Importantly, we show that these constitutive patterns of immune gene expression are lost or downregulated in many transformed cell lines widely used for respiratory virus research. Our data highlight the importance of pre-existing tissue-specific and cell-type dependent patterns of constitutive antiviral gene expression in the intracellular restriction of respiratory viral pathogens not captured in conventional cell culture model systems of infection.

immunology↗