Biology subjects

Robinson, E.

Publications and source records attributed to Robinson, E..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

A next-generation, histological atlas of the human brain and its application to automated brain MRI segmentation

Magnetic resonance imaging (MRI) is the standard tool to image the human brain in vivo. In this domain, digital brain atlases are essential for subject-specific segmentation of anatomical regions of interest (ROIs) and spatial comparison of neuroanatomy from different subjects in a common coordinate frame. High-resolution, digital atlases derived from histology (e.g., Allen atlas [7], BigBrain [13], Julich [15]), are currently the state of the art and provide exquisite 3D cytoarchitectural maps, but lack probabilistic labels throughout the whole brain. Here we present NextBrain, a next - generation probabilistic atlas of human brain anatomy built from serial 3D histology and corresponding highly granular delineations of five whole brain hemispheres. We developed AI techniques to align and reconstruct [~]10,000 histological sections into coherent 3D volumes with joint geometric constraints (no overlap or gaps between sections), as well as to semi-automatically trace the boundaries of 333 distinct anatomical ROIs on all these sections. Comprehensive delineation on multiple cases enabled us to build the first probabilistic histological atlas of the whole human brain. Further, we created a companion Bayesian tool for automated segmentation of the 333 ROIs in any in vivo or ex vivo brain MRI scan using the NextBrain atlas. We showcase two applications of the atlas: automated segmentation of ultra-high-resolution ex vivo MRI and volumetric analysis of Alzheimers disease and healthy brain ageing based on [~]4,000 publicly available in vivo MRI scans. We publicly release: the raw and aligned data (including an online visualisation tool); the probabilistic atlas; the segmentation tool; and ground truth delineations for a 100 m isotropic ex vivo hemisphere (that we use for quantitative evaluation of our segmentation method in this paper). By enabling researchers worldwide to analyse brain MRI scans at a superior level of granularity without manual effort or highly specific neuroanatomical knowledge, NextBrain holds promise to increase the specificity of MRI findings and ultimately accelerate our quest to understand the human brain in health and disease.

neuroscience↗

bioRxiv2023

Defining RNA oligonucleotides that reverse deleterious phase transitions of RNA-binding proteins with prion-like domains

RNA-binding proteins with prion-like domains, such as FUS and TDP-43, condense into functional liquids, which can transform into pathological fibrils that underpin fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD). Here, we define short RNAs (24-48 nucleotides) that prevent FUS fibrillization by promoting liquid phases, and distinct short RNAs that prevent and, remarkably, reverse FUS condensation and fibrillization. These activities require interactions with multiple RNA-binding domains of FUS and are encoded by RNA sequence, length, and structure. Importantly, we define a short RNA that dissolves aberrant cytoplasmic FUS condensates, restores nuclear FUS, and mitigates FUS proteotoxicity in optogenetic models and human motor neurons. Another short RNA dissolves aberrant cytoplasmic TDP-43 condensates, restores nuclear TDP-43, and mitigates TDP-43 proteotoxicity. Since short RNAs can be effectively delivered to the human brain, these oligonucleotides could have therapeutic utility for ALS/FTD and related disorders.

biochemistry↗

bioRxiv2023

Make Like a Tree and Leave: How Will Tree Species Loss and Climate Change Alter Future Temperate Broadleaved Forests?

Forest creation has the potential to reduce biodiversity loss and mitigate climate change but, tree disease emergence may counteract this. Further, given decadal timescales required for forest establishment, climate change is increasingly likely to act as a filter on plant community assembly. In the temperate lowlands succession takes 30 to 50 years for non-forest land to establish woodland plant assemblages, while the timescales required for new forest to sequester carbon suggest unassisted succession will be too slow for net zero 2050 targets. However, if plantations can establish faster than succession it would be beneficial to recommend planting native species as soon as possible. We explore scenarios of broadleaved woodland development across Wales, UK, as a case study area. We use a suite of empirical species niche models for British plants to estimate the potential species composition of forests with, and without, projected climate change. Additionally, we examine how tree canopy composition alters if Fraxinus excelsior is widely impacted by ash-dieback (Hymenoscyphus fraxineus). The results suggest soil total carbon and nitrogen could achieve baseline broadleaved forest values in less than 30 years. However only timber and woody flora species groups showed diversity surpassing baseline broadleaved forest diversity, with nectar plants and ancient woodland indicator species failing to reach baseline equivalents within 30 years; although complete congruence is unlikely given baseline forests could be hundreds of years old. Where Fraxinus excelsior was removed from the species pool we predicted that a scrub phase will persist or, if present, Acer pseudoplatanus will become the canopy dominant. The heavier shade cast this species is likely to result in differences in species composition of the understory and ground flora diversity is likely to decrease. Reliance on unassisted succession will also depend critically on (a) dispersal from local source populations and (b) on establishment filters that could be severe in landscapes with high management intensity history. These findings indicate that leaving the UKs fragmented habitats to relying on already degraded successional processes could lead to poor afforestation outcomes. HighlightsO_LIAfforestation can mitigate global change but tree disease makes outcomes uncertain C_LIO_LIAfforestation methods establishment timescales and time for benefits to occur C_LIO_LIWe model afforestation and predict how soils and plants change with climate C_LIO_LIAsh loss from die-back is replaced by low low-canopy woodland / scrub over 30 years C_LIO_LIAfforestation achieves baseline forest values for some variables within 30 years C_LI

ecology↗

bioRxiv2023

3D analysis of dissection photographs with surface scanning and machine learning for quantitative neuropathology

We present open-source tools for 3D analysis of photographs of dissected slices of human brains, which are routinely acquired in brain banks but seldom used for quantitative analysis. Our tools can: (i) 3D reconstruct a volume from the photographs and, optionally, a surface scan; and (ii) produce a high-resolution 3D segmentation into 11 brain regions per hemisphere (22 in total), independently of the slice thickness. Our tools can be used as a substitute for ex vivo magnetic resonance imaging (MRI), which requires access to an MRI scanner, ex vivo scanning expertise, and considerable financial resources. We tested our tools on synthetic and real data from two NIH Alzheimers Disease Research Centers. The results show that our methodology yields accurate 3D reconstructions, segmentations, and volumetric measurements that are highly correlated to those from MRI. Our method also detects expected differences between post mortem confirmed Alzheimers disease cases and controls. The tools are available in our widespread neuroimaging suite "FreeSurfer" (https://surfer.nmr.mgh.harvard.edu/fswiki/PhotoTools).

neuroscience↗

bioRxiv2022

Toward Improving Immunotolerance for Stem Cell-Derived Islets

Transplanting human stem cell-derived islets (SC-islets) is a promising therapy for insulin-dependent diabetes. While functional SC-islets have been produced for clinical application, immune rejection by the host remains a challenge. Present attempts, including chronic immunosuppression and/or physical encapsulation, have some disadvantages. Here we explore a strategy to induce an immune-tolerant environment based on the immune privilege observed in the male gonad. Sperm appears after the maturation of the immune system and development of systemic self-tolerance and the testis protects these autoreactive germ cells by the physical structure of blood-testis-barrier (BTB) and active local immunosuppression. Human SC-islets transplanted into the mouse testis can be physically protected by the BTB and we find that the testis secretes cytokines that induce a population of regulatory T cells (Tregs) that express both CD4 and CD8. We identified cytokines secreted by testis and used a cocktail of IL-2, IL-10, and TGF-{beta} for in vitro co-culture and in vivo transplantation demonstrating improved survival of SC-islets and the induction of Tregs. One Sentence SummaryInducing local immunotolerance by suppressive cytokines for islet Transplantation.

developmental biology↗

bioRxiv2022

Evolutionary PTEN Gene Divergence Underpins the Remodeling of Plant Vacuolar Compartments

Membrane fusion and fission are fundamental processes in sustaining cellular compartmentalization. Fission of a lipid bilayer requires a furrow formation that brings membranes in close proximity prior to a contiguous membrane cleavage. Although plant ancestors abandoned cleavage furrow-mediated cytokinesis more than 500 million years ago, here we show that plants still employ this mechanical principle to divide embryonic vacuoles. The evolutionary divergence in PHOSPHATASE AND TENSIN HOMOLOG DELETED ON CHROMOSOME TEN (PTEN) enzymes was required to coordinate this process, as Arabidopsis loss-of-function pten2a pten2b mutants contain hyper compartmentalized embryonic vacuoles. In contrast, PTEN2 overexpression hinders lytic and secretion cellular pathways downstream of TGN in xylem cells. These processes are critical for the formation of secondary cell walls in xylem cells and depend on a poorly characterized and evolutionarily novel N-terminal domain in PTEN2s. The PTEN2 subfamily appeared with the emergence of the Phragmoplastophyta clade, when vacuolar compartments enlarged and cleavage furrow-mediated cytokinesis became extinct. Together, our work suggests that the evolutionary innovation of the PTEN family is conserved across terrestrial plants and central to vacuolar remodelling.

plant biology↗

bioRxiv2021

Prefrontal cortical contributions to working memory loading, maintenance and recall are parsed by hippocampal-prefrontal oscillatory assembly dynamics

Working memory enables incorporation of recent experience into subsequent decision-making. This processing recruits both prefrontal cortex and hippocampus, where neurons encode task cues, rules and outcomes. However, precisely which information is carried when, and by which neurons, remains unclear. Using population decoding of activity in rat medial prefrontal cortex (mPFC) and dorsal hippocampal CA1, we confirm that mPFC populations lead in maintaining sample information across delays of an operant nonmatch to sample task, despite individual neurons firing only transiently. During sample encoding, distinct mPFC subpopulations joined distributed CA1-mPFC cell assemblies hallmarked by 4-5Hz rhythmic modulation; CA1-mPFC assemblies re-emerged during choice episodes, but were not 4-5Hz modulated. Delay-dependent errors arose when attenuated rhythmic assembly activity heralded collapse of sustained mPFC encoding; pharmacological disruption of CA1-mPFC assembly rhythmicity impaired task performance. Our results map component processes of memory-guided decisions onto heterogeneous CA1-mPFC subpopulations and the dynamics of physiologically distinct, distributed cell assemblies.

neuroscience↗

bioRxiv2021

Development of a novel rodent rapid serial visual presentation task reveals dissociable effects of stimulant vs non-stimulant treatments on attention

The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task a false-alarm image was included so performance could be assessed relative to two types of non-target distractors. The effects of acute administration of the stimulant and non-stimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus non-stimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.

animal behavior and cognition↗

bioRxiv2021

Spatial and temporal analysis of neutrophil trans-epithelial migration in response to RSV infection

The recruitment of neutrophils to the infected airway occurs early following respiratory syncytial virus (RSV) infection and high numbers of activated neutrophils in airway and blood is associated with the development of severe disease. Here, we investigated whether trans-epithelial migration across primary human airway epithelial cells (AECs) is sufficient and necessary for neutrophil activation during RSV infection. Using flow cytometry, we identified three populations of neutrophils in our in vitro model; those in suspension in basolateral and apical compartments and those that migrated and adhered to AECs. After 1h incubation, the number of adherent neutrophils was significantly greater following RSV infection compared to mock infected. We found that, when migration occurred, neutrophil expression of CD11b, CD62L, CD64, NE and MPO increased in all compartments. However, this did not occur when neutrophils were prevented from migrating. This suggests that the heightened neutrophil activation we detected in the basolateral compartment may be due to reverse migrating neutrophils, as has been suggested by clinical observations. Using live-cell fluorescent microscopy, we then profiled the early temporal and spatial movement and adherence of human neutrophils during migration. Our findings suggest three main phases of early neutrophil recruitment and behaviour in the airways during RSV infection, with neutrophil recruitment, activation and adherence to RSV infected AECs, with clustering, occurring within the first 20 minutes. This work and the model we developed could provide new insight into how neutrophil activation and a dysregulated neutrophil response to RSV mediates disease severity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/463016v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@16639c5org.highwire.dtl.DTLVardef@5aeeacorg.highwire.dtl.DTLVardef@1eb96ceorg.highwire.dtl.DTLVardef@1f9b899_HPS_FORMAT_FIGEXP M_FIG Building on previous work of neutrophil function we propose 3 main phases of early neutrophil recruitment and behaviour in the airways during RSV infection. Phase 1. Initial chemotaxis and adherence: Here unstimulated circulating neutrophils expressing baseline levels of CD11b migrate across infected AECs in response to chemotactic signals in the apical supernatant. Some neutrophils remain adherent to the infected AECs. Phase 2: Activation and reverse migration: once on the apical side of the epithelium, neutrophils increase expression of CD11b and other activation associated markers, and some activated neutrophils undergo reverse migration. Neutrophils with greater expression of CD11b are detected on the basolateral side Phase 3: Amplified chemotaxis and clustering: after 20 minutes, adherent neutrophils begin to rapidly cluster on RSV infected primary airway epithelial cells cultures, mediated by signalling from a dying neutrophil. Drawing created using BioRender.com. C_FIG

immunology↗

bioRxiv2021

The SARS-CoV-2 spike (S) and the orthoreovirus p15 cause neuronal and glial fusion

Numerous enveloped viruses use specialized surface molecules called fusogens to enter host cells1. During virus replication, these fusogens decorate the host cells membrane enabling them the ability to fuse with neighboring cells, forming syncytia that the viruses use to propagate while evading the immune system. Many of these viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), infect the brain and may cause serious neurological symptoms through mechanisms which remain poorly understood2-4. Here we show that expression of either the SARS-CoV-2 spike (S) protein or p15 protein from the baboon orthoreovirus is sufficient to induce fusion between interconnected neurons, as well as between neurons and glial cells. This phenomenon is observed across species, from nematodes to mammals, including human embryonic stem cells-derived neurons and brain organoids. We show that fusion events are progressive, can occur between distant neurites, and lead to the formation of multicellular syncytia. Finally, we reveal that in addition to intracellular molecules, fusion events allow diffusion and movement of large organelles such as mitochondria between fused neurons. Our results provide important mechanistic insights into how SARS-CoV-2 and other viruses could affect the nervous system circuitries causing neurological symptoms.

neuroscience↗

bioRxiv2020

Effects of pro-depressant and immunomodulatory drugs on biases in decision-making in the rat judgement bias task

Studies in human and non-human species suggest that decision-making behaviour can be biased by affective state, also termed an affective bias. To study these behaviours in non-human species, judgement bias tasks have been developed. Animals are trained to associate specific cues (tones) with a positive or negative/less positive outcome. Animals are then presented with intermediate ambiguous cues and affective biases quantified by observing whether animals make more optimistic or more pessimistic choices. Here we use a high versus low reward judgement bias task and test whether pharmacologically distinct compounds, which induce negative biases in learning and memory, have similar effects on decision-making: tetrabenazine (0.0-1.0mg/kg), retinoic acid (0.0-10.0mg/kg) and rimonabant (0.0-10.0mg/kg). We also tested immunomodulatory compounds: interferon- (0-100units/kg), lipopolysaccharide (0.0-10.0g/kg) and corticosterone (0.0-10.0mg/kg). We observed no specific effects in the judgement bias task with any acute treatment except corticosterone which induced a negative bias. We have previously observed a similar lack of effect with acute but not chronic psychosocial stress and so next tested decision-making behaviour following chronic interferon-alpha. Animals developed a negative bias which was sustained even after treatment was ended. These data suggest that decision-making behaviour in the task is sensitive to chronic but not acute effects of most pro-depressant drugs or immunomodulators, but exogenous administration of acute corticosterone induces pessimistic behaviour. This work supports our hypothesis that biases in decision-making develop over a different temporal scale to those seen with learning and memory which may be relevant in the development and perpetuation of mood disorders. Graphical abstract and textDecision-making bias in rats, measured using a judgement bias task, is not altered by acute treatments with pro-depressant or immunomodulatory drugs, but becomes more negative following chronic treatment. The time course of change in decision-making bias reflects the subjective reporting of changes in depression symptoms in humans treated with these drugs. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/358655v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@93dd2corg.highwire.dtl.DTLVardef@19d7e41org.highwire.dtl.DTLVardef@cc1ac1org.highwire.dtl.DTLVardef@1f0775c_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Dorsal raphe dopamine neurons signal motivational salience dependent on internal and external states

The ability to recognize motivationally salient events and respond to them adaptively is critical for survival. Here we tested whether dopamine (DA) neurons in the dorsal raphe nucleus (DRN) contribute to this process. Population recordings of DRNDA neurons during associative learning tasks showed that their activity dynamically tracks salience, developing excitation to both reward- and punishment-paired cues. The DRNDA response to reward-predicting cues was diminished after satiety, suggesting modulation by internal states. DRNDA activity was also greater for unexpected outcomes than for expected outcomes. Two-photon imaging of DRNDA neurons demonstrated that the majority of individual neurons developed activation to reward-predicting cues but not to punishment-predicting cues, which was surprising and qualitatively distinct from the population results. Head-fixation during fear learning abolished the neural response to aversive cues, indicating modulation by behavioral context. Overall, these results suggest that DRNDA neurons encode motivational salience, dependent on internal and external factors.

neuroscience↗

bioRxiv2020

Investigating the effects of incremental conditioning and supplemental dietary tryptophan on the voluntary activity and behaviour of mid-distance training sled dogs

Serotonin is a neurotransmitter synthesized by the amino acid tryptophan (Trp) that has the potential to impact the behaviour and activity of dogs. The objective of this study was to assess the effects of supplemental Trp and a 12-week incremental training regimen on the voluntary activity and behaviour of client-owned Siberian Huskies. Sixteen dogs were blocked for age, BW and sex and then randomly allocated to either the control or treatment group. Both groups were fed the same dry extruded diet; however, the treatment group were supplemented with Trp to achieve a Trp: large neutral amino acid ratio of 0.075:1. Once a week, a 5-minute video recording was taken immediately pre- and post- exercise to evaluate dogs behaviours. Activity monitors were used to record voluntary activity on both training and rest days. Linear regression analysis was used to assess the relationship between training week and time spent performing each behaviour. Additionally, a repeated measure mixed model was used to test differences between diet groups and training week for both behavioural and activity count data. The time spent performing agonistic behaviours prior to exercise was negatively associated with week for treatment dogs ({beta} = -0.32, 95% CI [-0.55, -0.10], P < 0.05) and no change was observed for control dogs ({beta} = -0.13, 95% CI [-0.41, 0.15], P > 0.10). Treatment did not have any effect on activity levels (P > 0.10). For all dogs, locomotive behaviours decreased prior to exercise as weeks progressed (P < 0.05), while run day voluntary activity depended on the distance run that day (P < 0.05). These data suggest that sled dogs experience an exercise-induced reduction in voluntary locomotion in response to both single bouts and repetitive bouts of exercise. Additionally, tryptophan supplementation may decrease agonistic behaviours, without having any effect on voluntary activity.

animal behavior and cognition↗

bioRxiv2020

DNA Thermo-Protection Facilitates Whole Genome Sequencing of Mycobacteria Direct from Clinical Samples by the Nanopore Platform

Mycobacterium tuberculosis (MTB) is the leading cause of death from bacterial infection. Improved rapid diagnosis and antimicrobial resistance determination, such as by whole genome sequencing, are required. Our aim was to develop a simple, low-cost method of preparing DNA for Oxford Nanopore Technologies (ONT) sequencing direct from MTB positive clinical samples (without culture). Simultaneous sputum liquefaction, bacteria heat-inactivation (99{degrees}C/30min) and enrichment for Mycobacteria DNA was achieved using an equal volume of thermo-protection buffer (4M KCl, 0.05M HEPES buffer pH7.5, 0.1% DTT). The buffer emulated intracellular conditions found in hyperthermophiles, thus protecting DNA from rapid thermo-degradation, which renders it a poor template for sequencing. Initial validation employed Mycobacteria DNA (extracted or intracellular). Next, mock clinical samples (infection-negative human sputum spiked 0-105 BCG cells/ml) underwent liquefaction in thermo-protection buffer and heat-inactivation. DNA was extracted and sequenced. Human DNA degraded faster than Mycobacteria DNA, resulting in target enrichment. Four replicate experiments each demonstrated detection at 101 BCG cells/ml, with 31-59 MTB complex reads. Maximal genome coverage (>97% at 5x-depth) was achieved at 104 BCG cells/ml; >91% coverage (1x depth) at 103 BCG cells/ml. Final validation employed MTB positive clinical samples (n=20), revealed initial sample volumes [≥]1ml typically yielded higher mean depth of MTB genome coverage, the overall range 0.55-81.02. A mean depth of 3 gave >96% one-fold TB genome coverage (in 15/20 clinical samples). A mean depth of 15 achieved >99% five-fold genome coverage (in 9/20 clinical samples). In summary, direct-from-sample sequencing of MTB genomes was facilitated by a low cost thermo-protection buffer.

microbiology↗

bioRxiv2020

A multimodal computational pipeline for 3D histology of the human brain

Ex vivo imaging enables analysis of the human brain at a level of detail that is not possible in vivo with MRI. In particular, histology can be used to study brain tissue at the microscopic level, using a wide array of different stains that highlight different microanatomical features. Complementing MRI with histology has important applications in ex vivo atlas building and in modeling the link between microstructure and macroscopic MR signal. However, histology requires sectioning tissue, hence distorting its 3D structure, particularly in larger human samples. Here, we present an open-source computational pipeline to produce 3D consistent histology reconstructions of the human brain. The pipeline relies on a volumetric MRI scan that serves as undistorted reference, and on an intermediate imaging modality (blockface photography) that bridges the gap between MRI and histology. We present results on 3D histology reconstruction of a whole human hemisphere.

neuroscience↗

bioRxiv2020

Prepronociceptin expressing neurons in the extended amygdala encode and promote rapid arousal responses to motivationally salient stimuli

Motivational states are complex and consist of cognitive, emotional, and physiological components controlled by a network across multiple brain regions. An integral component of this neural circuitry is the bed nucleus of the stria terminalis (BNST). Here, we identified a subpopulation of neurons within BNST expressing the gene prepronociceptin (PnocBNST), that can modulate the rapid changes in physiological arousal that occur upon exposure to stimuli with motivational salience. Using in vivo two-photon calcium imaging we found that excitatory responses from individual PnocBNST neurons directly corresponded with rapid increases in pupillary size and occurred upon exposure to both aversive and rewarding odors. Furthermore, optogenetic activation of these neurons increased pupillary size, but did not alter approach/avoidance or locomotor behaviors. These findings suggest that excitatory responses in PnocBNST neurons encode rapid arousal responses irrespective of tested behaviors. Further histological, electrophysiological, and single-cell RNA sequencing data revealed that PnocBNST neurons are composed of genetically and anatomically identifiable subpopulations that can be further investigated. Taken together, our findings demonstrate a key role for a PnocBNST neuronal ensemble in encoding the rapid arousal responses that are triggered by motivational stimuli.

neuroscience↗

bioRxiv2019

Neutrophil: Airway Epithelial Interactions Result in Increased Epithelial Damage and Viral Clearance during RSV Infection

Respiratory syncytial virus (RSV) is a major cause of paediatric respiratory disease. Large numbers of neutrophils are recruited into the airways of children with severe RSV disease. It is not clear whether or how neutrophils enhance recovery from disease or contribute to its pathology. Using an in vitro model of the differentiated airway epithelium, we found that addition of physiological concentrations of neutrophils to RSV infected nasal cultures was associated with greater epithelial damage with lower ciliary activity, cilia loss, less tight junction expression (ZO-1) and more detachment of epithelial cells than seen with RSV infection alone. This was also associated with a decrease in infectious virus and fewer RSV positive cells in cultures after neutrophil exposure compared to pre-exposure. Epithelial damage in response to RSV infection was associated with neutrophil activation (within 1h), and neutrophil degranulation with significantly greater cellular expression of CD11b, MPO and higher neutrophil elastase and myeloperoxidase activity in apical surface medias compared to that from mock-infected AECs. We also recovered more apoptotic neutrophils from RSV infected cultures (>40%), compared to <5% in mock infected cultures after 4h. The results of this study could provide important insights into the role of neutrophils in host response in the airway.

immunology↗

bioRxiv2019

Genetic and clinical analyses of psychosis spectrum symptoms in a large multi-ethnic youth cohort reveal significant link with ADHD.

ObjectivePsychotic symptoms are an important feature of severe neuropsychiatric disorders, but are also common in the general population, especially in youth. The genetic etiology of psychosis symptoms in youth remains poorly understood. To characterize genetic risk for psychosis spectrum symptoms (PS), we leverage a community-based multi-ethnic sample of children and adolescents aged 8-22 years, the Philadelphia Neurodevelopmental Cohort (n = 7,225, 20% PS).\n\nMethodsUsing an elastic net regression model, we aim to classify PS status using polygenic scores (PGS) based on a range of heritable psychiatric and brain-related traits in a multi-PGS model. We also perform univariate PGS associations and evaluate age-specific effects.\n\nResultsThe multi-PGS analyses do not improve prediction of PS status over univariate models, but reveal that the attention deficit hyperactivity disorder (ADHD) PGS is robustly and uniquely associated with PS (OR 1.12 (1.05, 1.18) P = 0.0003). This association is: i) driven by subjects of European ancestry (OR=1.23 (1.14, 1.34), P=4.15x10-7) but is not observed in African American subjects (P=0.65) and ii) independent of phenotypic overlap. We also find a significant interaction with age (P=0.01), with a stronger association in younger children. In an independent sample, we replicate an increased ADHD PGS in 328 youth at clinical high risk for psychosis, compared to 216 unaffected controls (OR 1.06, CI(1.01, 1.11), P= 0.02).\n\nConclusionsOur findings suggest that PS in youth may reflect a different genetic etiology than psychotic symptoms in adulthood, one more akin to ADHD, and shed light on how genetic risk can be investigated across early disease trajectories.

genetics↗