Biology subjects

Marshall, L.

Publications and source records attributed to Marshall, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Under-sampled KBAs, over-sampled roadsides: integrating historical and contemporary records of Malagasy bees

Madagascar hosts exceptional biodiversity and endemism, yet its native bee fauna remains poorly characterised. We assembled and cleaned the first comprehensive occurrence dataset for Malagasy bees, reducing 10,721 raw records to 4,071 validated occurrences covering 218 georeferenced species of the 224 checklist species across six families (89.3% endemic). Despite near-complete checklist coverage, the dataset remains critically sparse for Madagascar's size, with most species documented by only a few records. Sampling was highly uneven across taxa: most genera were underrepresented while a few were disproportionately sampled due to ecological prevalence, detectability, and collector specialisation. Spatial concentration within limited grid cells amplified these biases. Temporally, effort varied markedly, with historical peaks driven by individual collectors and a post-2010 shift toward Apidae-dominated records. Spatially, 79.9% of 25x25 km grid cells intersecting Madagascar held no bee records, and 77.1% of records fell within 2.5 km of roads, mirroring global sampling patterns. Sampling clustered near major cities, with common species consistently found near roads and rare species spread across wider distance ranges. Among 231 Key Biodiversity Areas (KBAs), 68.4% were entirely unsampled; sampled KBAs held only 26.7% of all records, and sampling remained uneven even there, leaving substantial undetected diversity across most sites. These results reveal pervasive temporal, spatial, taxonomic, and collector-driven biases, underscoring the need for targeted surveys within KBAs and beyond roadsides to improve coverage of data-deficient species and strengthen conservation assessments.

ecology↗

bioRxiv2026

Global Patterns and Drivers of Bee Diversity and Endemism on Islands

Islands harbor a disproportionate share of global biodiversity1, yet insects, even invaluable pollinators such as bees2, remain underrepresented in island biogeography research3. Here, we present the first global checklist of island bees, recording 4,140 species across 306 islands. Although islands comprise only [~]5% of Earths land area, they support [~]20% of global bee diversity, and 43% of insular species are endemic, making up [~]8% of all known bee species. Island bee species richness, mirroring continental trends4, peaks at mid-latitudes. Native richness increases with island area and declines with isolation, consistent with patterns in other taxa5. The strength of species-area relationships varies among biomes and is steepest in mediterranean-type systems, which also support disproportionately high bee richness relative to flowering plant diversity. Endemism is highest on large tropical islands, reflecting extensive in situ diversification. Major centers of bee endemism include Madagascar, Malesia (e.g. the Greater Sundas and New Guinea), and Hawaii, where a single large radiation of Hylaeus (Nesoprosopis) dominates6. Among islands capable of supporting endemic species, endemism scales strongly with total richness. These findings highlight the need to integrate island bee diversity into global conservation planning and position bees as a model for understanding insect evolution and conservation on islands.

ecology↗

bioRxiv2025

Closed-loop acoustic stimulation modified by cathodal tDCS is beneficial for retention

We investigated how combining transcranial direct current stimulation (tDCS) with closed-loop acoustic stimulation (CLAS) during slow-wave sleep (SWS) affects memory consolidation and sleep-related neural oscillations. Cathodal tDCS was used to slightly reduce cortical excitability, thereby simulating a shifted brain state during CLAS and allowing us to compare the effects of standard CLAS to CLAS delivered under altered cortical conditions (CmodCLAS). Twenty-three participants (mean age 21.3 {+/-} 2.6 years) completed two experimental nights: one with CLAS alone and one with CLAS combined with cathodal tDCS (CmodCLAS). Overnight retention on declarative memory tasks and morning learning performance were assessed. Memory outcomes revealed that CmodCLAS, but not CLAS alone, significantly improved overnight retention on the figural paired-associate task. In the EEG, CmodCLAS shifted the time-locked response to acoustic stimulation toward more negative potential values at the frontal region. CmodCLAS also prolonged slow oscillation (SO) duration at frontal sites while shortening SO duration at occipital sites, an effect not observed during standard CLAS. These findings demonstrate that the baseline level of cortical excitability during sleep modulates both the cognitive and electrophysiological effects of CLAS. They highlight the importance of brain state for non-invasive CLAS during sleep and suggest that CmodCLAS may serve as a useful approach for enhancing prefrontal cortical function during SWS. Significance statementNon-invasive brain stimulation (NIBS) is a promising approach to modulate brain activity and function. Unfortunately, NIBS studies are challenged by heterogenous findings. In addition to protocol differences, variability may depend strongly on the brains baseline activity (or brain state). Here, we used transcranial direct current stimulation (tDCS) to simulate a different brain state while applying closed-loop acoustic stimulation (CLAS) during slow-wave sleep (SWS). Sleep has been shown to enhance overnight memory retention. Results demonstrated significantly improved retention performance for cathodal tDCS modulated CLAS (CmodCLAS) as compared to CLAS alone. Furthermore, electrophysiological responses time-locked to the acoustic stimulus and spontaneous electrophysiological rhythms of SWS suggest that hippocampo-cortical function was specifically enhanced by CmodCLAS. Thus, underscoring the potential therapeutic relevance of CmodCLAS.

neuroscience↗

bioRxiv2025

Scarcity of flowering plants on Sedum roofs limits pollinator diversity

Green roofs can provide suitable habitats for pollinating insects in urban areas. Pollinators are a large and diverse group with high economic and ecological relevance to society. Yet their populations are in decline, highlighting the need for new habitats such as green roofs. An understanding of how local and landscape factors of green roofs shape pollinator communities is crucial to optimize the design and development of green roofs. This study aimed to identify how the surrounding landscape and green roof characteristics influence pollinator diversity and abundance. Pollinators - such as bees, wasps, hoverflies and butterflies - were sampled using pan traps and hand netting on 25 green roofs that were categorized into three types based on functionality and vegetation structure: sedum roofs, nature roofs, and roof gardens. To assess pollinator communities, we examined species richness, abundance, and functional diversity--defined here as the range of ecological roles or traits. Roof characteristics (e.g., flower diversity, microrelief, vegetation cover, roof height, size, and age) and landscape factors (e.g. percentage of surrounding green, distance to surrounding green) were analysed in relation to these diversity metrics. We show that a continuous supply of flowers throughout the year, flower abundance and the type of green roof significantly influence pollinator diversity and abundance. Sedum roofs supported lower pollinator diversity compared to the other roof types. Furthermore, our models indicated a decrease in pollinator diversity on higher green roofs, and when honeybee hives are present, while the presence of bee hotels increased pollinator abundance. The study highlights the value of nature roofs and roof gardens, compared to sedum roofs for supporting pollinator diversity. This is linked to the importance of constant forage availability, especially in early spring, which is absent on most sedum roofs. The results from this study offer guidelines to green roof designers on how to design pollinator friendly roofs in urban areas. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/676189v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@dfb4caorg.highwire.dtl.DTLVardef@d6478eorg.highwire.dtl.DTLVardef@1f3e725org.highwire.dtl.DTLVardef@1cc4ef0_HPS_FORMAT_FIGEXP M_FIG C_FIG Pollinator species: Macropis europea (Hymenoptera: Melittidae), Helophilus pendulus (Diptera: Syrhidae) and Polyommatus icarus (Lepidoptera: Lycaenidae). All three species were observed on green roofs during the authors fieldwork. Image created using biorender.com and personal drawings. HighlightsO_LIBiodiverse roofs and roof gardens support higher pollinator diversity compared to sedum roofs. C_LIO_LIA continuous supply of flowers throughout the year, along with a higher abundance of flowers, are key factors influencing pollinator diversity and abundance on green roofs. C_LIO_LIRoof height affects the diversity and abundance of different pollinator groups in distinct ways, a novel finding that needs further investigation. C_LIO_LIWe provide guidelines for green roof designers, emphasizing the importance of selecting roof types and designs that ensure constant flower availability. C_LI

ecology↗

bioRxiv2023

Human Endogenous Retrovirus Expression is Dynamically Regulated in Parkinson's Disease

Parkinsons disease (PD) is a progressive, debilitating neurodegenerative disease that afflicts approximately every 1000th individual. Recently, activation of genomic transposable elements (TE) has been suggested as a potential driver of PD onset. However, it is unclear where, when, and to what extent TEs are dysregulated in PD. Here, we performed a multi-tissue transcriptional analysis of multiple patient cohorts and identified TE transcriptional activation as a hallmark of PD. We find that PD patients exhibit up-regulation primarily of human endogenous retrovirus (HERV) transcripts in prefrontal cortex tissue, prefrontal neurons as well as in blood, and we demonstrate that TE activation in the blood is highest at the time of PD diagnosis. Supporting a potentially causal association between ERV dysregulation and PD heterogeneity, reduced gene dosage of the TE repressor Trim28 triggers transcriptional changes highly correlated to those measured in animal models of synucleinopathy (PFF-injection), and importantly, to those exhibited by patients themselves. These data identify ERV up-regulation as a common feature of central and peripheral PD etiology, and highlight potential roles for Trim28-dependent TEs in stratifying and monitoring PD and treatment compliance.

neuroscience↗

bioRxiv2023

A bioorthogonal antibody-based chemically-induced-dimerization switch for therapeutic application

We present the Indinavir Ligand Induced Transient Engagement switch (IDV LITE Switch), a fully synthetic Chemically Induced Dimerization (CID) system wherein two humanized antibody fragments are heterodimerized by the antiviral drug indinavir. The IDV LITE Switch represents the first CID system made from fully humanized protein components and dimerized by a clinically approved small molecule drug lacking a mammalian target, making it an ideal bioorthogonal molecular switch for application in small-molecule controlled therapeutics.

synthetic biology↗

bioRxiv2022

Chilean bee diversity: Contrasting patterns of species and phylogenetic turnover along a large-scale ecological gradient

Chiles isolation and varied climates have driven the evolution of a unique biodiversity with a high degree of endemism. The Mediterranean-type biome of Central Chile is one of 35 global biodiversity hotspots and has been highlighted as one of Chiles most endangered areas. It is threatened by anthropogenic land use change impacting the integrity of local biomes and associated species. This area holds the most extensive collections of the country with high endemicity regarding native bee species. Characterising habitat requirements of bees is a pressing priority to safeguard them and the ecosystem services they provide. We investigated broad-scale patterns of bee diversity using newly accessible expert-validated datasets comprising digitized specimen records from both Chilean and US collections and novel, expert-validated type specimen data for the bees of Chile. We used a generalised dissimilarity modelling (GDM) approach to explore both compositional and phylogenetic {beta}-diversity patterns across latitudinal, altitudinal, climate and habitat gradients in well-sampled bee assemblages in Central Chile. Using the GDM measures of increasing compositional and environmental dissimilarity we categorised and compared the most important drivers of these patterns and used them to classify wild bee ecoregions (WBE) representing unique assemblages. Turnover of bee assemblages was explained primarily by latitudinal variation (proxy for climate) along Chile. However, temperature variations, precipitation and the presence of bare soil also significantly explained the observed patterns. In comparison, we observed less turnover in phylogenetic biodiversity corresponding to spatial gradients. We were able to develop six de novo ecoregions (WBE) all with distinct taxa, endemic lineages, and representative species. The WBE represent distinct spatial classifications but have similarities to existing biogeographical classifications, ecosystems and bioclimatic zones. This approach establishes the baseline needed to prioritise bee species conservation efforts across this global biodiversity hotspot. We discuss the novelty of this classification considering previous biogeographical characterisations and its relevance for assessing conservation priorities for bee conservation. We argue that Chiles WBE show areas requiring funding for bee species exploration and description, distribution mapping and strengthening of conservation policies.

ecology↗

bioRxiv2022

Single acoustic closed loop stimulation in mice to modulate hippocampo-thalamo-cortical activity and performance

Neural brain rhythms of sleep reflect neuronal activity underlying sleep-associated memory consolidation. The modulation of brain rhythms, for instance the sleep slow oscillation (SO) is used both to investigate neurophysiological mechanisms as well as to measure the impact on presumed functional correlates. In humans, auditory closed-loop stimulation targeted to the SO Up-state successfully enhanced the slow oscillation rhythm and phase-dependent spindle activity, although effects on memory retention have varied. Here, we aim to disclose relations between stimulation induced hippocampo-thalamo-cortical activity and retention performance on a hippocampus dependent task in mice. Closed-loop acoustic stimuli applied during four SO phases always acutely increased sharp wave ripple (SPWR) activity without disrupting non-rapid eye movement (NREM) sleep. Stimulation achieved an above chance preference index for stimuli delivered across a 3 h retention interval of sleep at the SO Up-state and at the Down-to-Up-state, but not at the Down-state nor late Up-state/Up-to Down-state. Results support the use of closed-loop acoustic stimulation in mice to investigate the inter-regional mechanisms underlying memory consolidation.

neuroscience↗

bioRxiv2021

Five years of citizen science and standardized field surveys reveal a threatened urban Eden for wild bees in Brussels, Belgium

O_LIUrbanisation is often put forward as an important driver of biodiversity loss, including for pollinators such as wild bees. However, recent evidence shows that the mosaics of urban green spaces, and in particular certain categories of informal urban green spaces (IGS), can play an important role to help native wild bees thrive in cities. C_LIO_LIHere, we describe the results of five years of citizen science and standardised field surveys of wild bees conducted at the Friche Josaphat, a 24-ha urban wasteland in the Brussels-Capital Region (Belgium). These field surveys were initiated following the planned restructuring and partial destruction of this site by the regional authorities. C_LIO_LIWe recorded a total of 2,507 specimens belonging to 127 species of wild bees, i.e. 60.5% of the 210 species recorded regionally, including nine that are threatened with extinction at national or European scales. The Friche Josaphat encompasses a significant share of the functional and phylogenetic diversity of wild bees known from the Brussels-Capital Region and is one of the most species-rich localities known to date for wild bees in Belgium. C_LIO_LICollectively, our results highlight the strong complementarity of citizen science and academic approaches in biodiversity surveys, and they reaffirm that wastelands are essential components of urban biodiversity. Our study stresses the need to provide biodiverse IGS with a formal status within the mosaic of urban green spaces, but also to acknowledge and safeguard their natural capital and the multiple ecosystem services they provide. C_LI

ecology↗

bioRxiv2021

Favourable antibody responses to human coronaviruses in children and adolescents with autoimmune rheumatic diseases

Differences in humoral immunity to coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), between children and adults remain unexplained and the impact of underlying immune dysfunction or suppression unknown. Here, we examined the antibody immune competence of children and adolescents with prevalent inflammatory rheumatic diseases, juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) and juvenile systemic lupus erythematosus (JSLE), against the seasonal human coronavirus (HCoV)-OC43 that frequently infects this age group. Despite immune dysfunction and immunosuppressive treatment, JIA, JDM and JSLE patients mounted comparable or stronger responses than healthier peers, dominated by IgG antibodies to HCoV-OC43 spike, and harboured IgG antibodies that cross-reacted with SARS-CoV-2 spike. In contrast, responses to HCoV-OC43 and SARS-CoV-2 nucleoproteins exhibited delayed age-dependent class-switching and were not elevated in JIA, JDM and JSLE patients, arguing against increased exposure. Consequently, autoimmune rheumatic diseases and their treatment were associated with a favourable ratio of spike to nucleoprotein antibodies.

immunology↗

bioRxiv2020

Drug screening linked to molecular profiling identifies novel dependencies in patient-derived primary cultures of paediatric high grade glioma and DIPG

Paediatric high grade glioma and diffuse midline glioma (including DIPG) are comprised of multiple biological and clinical subgroups, the majority of which urgently require novel therapies. Patient-derived in vitro primary cell cultures represent potentially useful tools for mechanistic and preclinical investigation based upon their retention of key features of tumour subgroups under experimental conditions amenable to high-throughput approaches. We present 17 novel primary cultures derived from patients in London, Dublin and Belfast, and together with cultures established or shared from Barcelona, Brisbane, Rome and Stanford, assembled a panel of 52 models under 2D (laminin matrix) and/or 3D (neurospheres) conditions, fully credentialed by phenotypic and molecular comparison to the original tumour sample (methylation BeadArray, panel/exome sequencing, RNAseq). In screening a subset of these against a panel of ~400 approved chemotherapeutics and small molecules, we identified specific dependencies associated with tumour subgroups and/or specific molecular markers. These included MYCN-amplified cells and ATM/DNA-PK inhibitors, and DIPGs with PPM1D activating truncating mutations and inhibitors of MDM2 or PARP1. Specific mutations in PDGFRA were found to confer sensitivity to a range of RTK inhibitors, though not all such mutations conferred sensitivity to targeted agents. Notably, dual PDGFRA/FGFR and downstream pathway MEK inhibitors showed profound effects against both PDGFRA-sensitising mutant and FGFR1-dependent non-brainstem pHGG and DIPG. In total, 85% cells were found to have at least one drug screening hit in short term assays linked to the underlying biology of the patients tumour, providing a rational approach for individualised clinical translation.

cancer biology↗

bioRxiv2020

Detection And Purification Of Lewy Pathology From Formalin Fixed Primary Human Tissue Using Biotinylation By Antigen Recognition

The intracellular misfolding and accumulation of alpha-synuclein into structures collectively called Lewy pathology is a central phenomenon for the pathogenesis of Parkinsons disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy. Understanding the molecular architecture of Lewy pathology is crucial for understanding disease origins and progression. Here we developed a method to label, extract, and purify molecules from Lewy pathology of formalin fixed PD and DLB brain for blotting and mass spectrometry analysis. Using the biotinylation antibody recognition (BAR) technique, we labeled phosphoserine 129 alpha-synuclein positive pathology and associated molecules with biotin. Formalin crosslinks were then reversed, protein extracted, and pathology associated molecules isolated with streptavidin beads. Results showed superior immunohistochemical staining of Lewy pathology following the BAR protocol when compared to standard avidin biotin complex (ABC) based detection. The enhanced staining was particularly apparent for fibers of the medial forebrain bundle and punctate pathology within the striatum and cortex, which otherwise were weakly labeled or not detected. Subsequent immunoblotting BAR-labeled Lewy pathology extracts revealed the presence of high molecular weight alpha-synuclein, ubiquitin protein conjugates, and phosphoserine 129 alpha-synuclein. Mass spectrometry analysis of BAR-labeled Lewy pathology extracts from PD and DLB patients identified 815 proteins with significant enrichment for many pathways. Notably the most significant KEGG pathway was Parkinsons disease (FDR = 2.48 x 10-26) and GO Cellular compartment was extracellular exosomes (GO Cellular Compartment; FDR = 2.66x 10-34). We used enrichment data to create a functional map of Lewy Pathology from primary disease tissues, which implicated Vesicle Trafficking as the primary disease associated pathway in DLB and PD. In summary, this protocol can be used to enrich for Lewy pathology from formalin fixed human primary tissues, which allows the determination of molecular signatures of Lewy pathology. This technique has broad potential to help understand the phenomenon of Lewy pathology in primary human tissue and animal models.

neuroscience↗

bioRxiv2019

Epigenetic contributions to hemisphere asymmetry in healthy brain, aging, and Parkinson’s disease

Hemispheric asymmetry in neuronal processes is a fundamental feature of the human brain and drives symptom lateralization in Parkinsons disease (PD), but its molecular determinants are unknown. Here, we determine epigenetic differences involved in hemispheric asymmetry in the healthy and the PD brain. Neurons of the healthy brain exhibit numerous hemispheric differences in DNA methylation, which affect genes implicated in neurodegenerative diseases. In PD patients, hemispheric asymmetry in DNA methylation is even greater and involves many PD risk genes. The lateralization of clinical PD symptoms involves epigenetic, transcriptional, and proteomic differences across hemispheres that affect neurodevelopment, immune activation, and synaptic transmission. During aging, healthy neurons show a progressive loss of hemispheric asymmetry in the epigenome, which is amplified in PD. For PD patients, a long disease course is associated with greater hemispheric asymmetry in neuronal epigenomes than a short disease course. Hemispheric differences in epigenetic gene regulation are prevalent in neurons and may affect the progression and symptoms of PD.

neuroscience↗

bioRxiv2019

Epigenomic analysis of Parkinson’s disease neurons identifies Tet2 loss as neuroprotective

PD pathogenesis may involve the epigenetic control of enhancers that modify neuronal functions. Here, we comprehensively profile DNA methylation at enhancers, genome-wide, in neurons of 57 PD patients and 48 control individuals. We found a widespread increase in cytosine modifications at enhancers in PD neurons, which is partly explained by elevated hydroxymethylation levels. Epigenetic dysregulation of enhancers in PD converge on transcriptional abnormalities affecting neuronal signaling and immune activation pathways. In particular, PD patients exhibit an epigenetic and transcriptional upregulation of TET2, a master-regulator of cytosine modification status. TET2 inactivation in a neuronal cell line results in cytosine modification changes that are reciprocal to those observed in PD neurons. Furthermore, Tet2 inactivation in mice fully prevents dopaminergic neuronal loss in the substantia nigra induced by prior inflammation. Tet2 loss in mice also attenuates transcriptional immune responses to an inflammatory trigger. Thus, widespread epigenetic dysregulation of enhancers in PD neurons may, in part, be mediated by increased TET2 expression. Decreased Tet2 activity is neuroprotective, in vivo, and may be a novel therapeutic target for PD.

neuroscience↗

bioRxiv2019

Genetic analysis of seed and pod traits in a set of Recombinant Inbred Lines (RILs) in peanut (Arachis hypogaea L.)

Although seed and pod traits are important for peanut breeding, little is known about the inheritance of these traits. A recombinant inbred line (RIL) population of 156 lines from a cross of Tifrunner x NC 3033 was genotyped with the Axiom_Arachis1 SNP array and SSRs to generate a genetic map composed of 1524 markers in 29 linkage groups (LG). The genetic positions of markers were compared with their physical positions on the peanut genome to confirm the validity of the linkage map and explorethe distribution of recombination and potential chromosomal rearrangements. These traits were phenotyped over three consecutive years for the purpose of developing trait-associated markers for breeding. Forty-nine QTL were identified in 14 LG for seed size index, kernel percentage, seed weight, pod weight, single-kernel, double-kernel, pod area and pod density. Twenty QTL demonstrated phenotypic variance explained (PVE) greater than 10% and eight more than 20%. Of note, seven of the eight major QTL for pod area, pod weight and seed weight (PVE >20% variance) were attributed to NC 3033 and located in a single linkage group, LG B06_1. In contrast, the most consistent QTL for kernel percentage were located on A07/B07 and derived from Tifrunner.

plant biology↗

bioRxiv2019

Stimulation augments spike sequence replay and memory consolidation during slow-wave sleep

Newly acquired memory traces are spontaneously reactivated during slow-wave sleep (SWS), leading to the consolidation of recent memories. Empirical studies found that sensory stimulation during SWS selectively enhances memory consolidation and the effect depends on the phase of stimulation. In this new study, we aimed to understand the mechanisms behind the role of sensory stimulation on memory consolidation using computational models implementing effects of neuromodulators to simulate transitions between awake and SWS sleep, and synaptic plasticity to allow the change of synaptic connections due to the training in awake or replay during sleep. We found that when closed-loop stimulation was applied during the Down states (900-2700) of sleep slow oscillation, particularly right before transition from Down to Up state, it significantly affected the spatio-temporal pattern of the slow-waves and maximized memory replay. In contrast, when the stimulation was presented during the Up states (2700-3600 and 00-900), it did not have a significant impact on the slow-waves or memory performance after sleep. For multiple memories trained in awake, presenting stimulation cues associated with specific memory trace could selectively augment replay and enhance consolidation of that memory and interfere with consolidation of the others (particularly weak) memories. Our study proposes a synaptic level mechanism of how memory consolidation is affected by sensory stimulation during sleep.\n\nSignificance statementStimulation, such as training-associated cues or auditory stimulation, during sleep can augment consolidation of the newly encoded memories. In this study, we used a computational model of the thalamocortical system to describe the mechanisms behind the role of stimulation in memory consolidation during slow-wave sleep. Our study suggested that stimulation preferentially strengthens the memory traces when delivered at specific phase of slow oscillations just before Down to Up state transition when it makes the largest impact on the spatio-temporal pattern of sleep slow waves. In the presence of multiple memories, presenting sensory cues during sleep could selectively strengthen selected memories. Our study proposes a synaptic level mechanism of how memory consolidation is affected by sensory stimulation during sleep.

neuroscience↗

bioRxiv2018

A novel innate lymphoid cell delineates childhood autoimmune arthritis

Inflammation in autoimmune disease is mediated by a complex network of interacting cells. Their identity and cross-talk are encoded in messenger RNA (mRNA). Juvenile idiopathic arthritis (JIA), a chronic autoimmune arthritis of childhood, is characterised by synovial inflammation with infiltration of both innate and adaptive immune cells1. Activated T cells play a role in disease2 but the cell types that drive the recruitment and activation of immune cells within the synovium are not known. Here, we utilised droplet-based and full length single cell mRNA sequencing to obtain a quantitative map of the cellular landscape of JIA. We studied 45,715 cells from the synovial fluid of inflamed knee joints and peripheral blood. We identified a population of synovial innate lymphoid cells (ILCs), shared across patients, that exhibited a unique transcriptional profile in comparison to canonical ILC subtypes. Validation at protein-level across a spectrum of autoimmune arthritides revealed that these ILCs are pathologically expanded in a particular type of JIA. Using statistical tools to assess cellular interactions in synovial fluid, ILCs emerged as a central node of communication, expressing the full repertoire of genes required to orchestrate and maintain the inflammatory milieu. Several ILC-mediated signalling pathways may lend themselves as novel therapeutic targets. Together our findings demonstrate a distinct ILC subtype associated with a tissue-specific childhood autoimmune disease.

immunology↗

bioRxiv2018

Craniofacial traits determined by neural crest cells-restricted expression of Dlx5/6: probing the origin of matching functional jaws

Gnathostome jaws derive from the first pharyngeal arch (PA1), a complex structure constituted by Neural Crest Cells (NCCs), mesodermal, ectodermal and endodermal cells. Here, to determine the regionalized morphogenetic impact of Dlx5/6 expression, we specifically target their inactivation or overexpression to NCCs. NCC-specific Dlx5/6 inactivation (NCC{Delta}Dlx5/6) generates severely hypomorphic lower jaws that present typical maxillary traits. Therefore, differently from the symmetric jaws obtained after constitutive Dlx5/6 inactivation, NCC{Delta}Dlx5/6 embryos present a strikingly asymmetric mouth. Reciprocally, forced Dlx5 expression in maxillary NCCs provokes the appearance of distinct mandibular characters in the upper jaw. We conclude that: 1) Dlx5/6 activation in NCCs invariably determines lower jaw identity; 2) the morphogenetic processes that generate functional matching jaws depend on the harmonization of Dlx5/6 expression in NCCs and in distinct ectodermal territories. The co-evolution of synergistic opposing jaws requires the coordination of distinct regulatory pathways involving the same transcription factors in distant embryonic territories.

developmental biology↗