Biology subjects

Reid, R.

Publications and source records attributed to Reid, R..

11 recordsLinked to original sources

bioRxiv2026

Simultaneous regeneration of skin and bone in full-thickness cranial composite defects

Traumatic cranial defects often involve concurrent loss of soft and hard tissues and can progress to chronic defects due to delayed healing associated with infection or other co-morbidities. Despite autologous reconstruction remaining the clinical standard, it requires staged procedures using heterogeneous tissues, increasing operative time, costs, and surgical risks. Moreover, current tissue engineering approaches focus on single tissues or acute tissue defect models, limiting their clinical applications. Herein, we describe an acellular, material-driven 3D-printed composite scaffold designed to regenerate both bone and skin within composite cranial defects. The scaffold integrates controlled copper ion release from both organic and inorganic components with 3D-printed citrate polymer and citrate polymer-ceramic composites. Integrated thermoresponsive citrate-based hydrogels further enable spatially defined dermoconductive and osteoconductive properties, supporting a one-step surgical approach. At 12 weeks post-implantation, our scaffold enhanced keratinocyte organization, collagen deposition, and defect coverage with mature bone, achieving histological outcomes comparable to autografts. Furthermore, the system suppressed bacterial burden. Thus, this acellular platform represents a clinically promising synchronized strategy to address the complex demands of traumatic craniofacial composite defects.

bioengineering↗

bioRxiv2025

Large scale prospective evaluation of co-folding across 557 Mac1-ligand complexes and three virtual screens

Accurate prediction of ligand-bound protein complexes and ranking them by affinity are central problems in drug discovery. While deep learning co-folding methods can help address these challenges, their evaluation has been hampered by the difficulties in assessing independence from training data and insufficiently large test sets. Here we test the ability of co-folding methods to predict the structures of 551 ligands, 489 of which are of sufficient quality for evaluation, bound to the SARS-CoV-2 NSP3 macrodomain (Mac1) that were determined after the training cut-off dates. AlphaFold3 (AF3), Boltz-2, and Chai-1 each reproduced >50% of the Mac1 ligand poses to better than 2 [A] RMSD of experiment. Despite the potential for co-folding to describe protein conformational changes that stabilize ligand binding, we did not find that common conformational rearrangements, including peptide flip and a large loop opening, were recapitulated by the co-folding prediction. For AF3 and Chai-1, ligand pose prediction confidence weakly, but significantly, tracked experimental potency, while DOCK3.7 energies were only weakly correlated. Boltz-2 affinity predictions showed the strongest correlation with measured potency and, after calibration, achieved lower mean absolute error than a baseline predictor. We next assessed whether co-folding scores could rescore docking hit-lists to distinguish true ligands from non-binders among hundreds of molecules prospectively experimentally tested against AmpC {beta}-lactamase, the dopamine D4 and the {sigma}2 receptors. AF3 ligand pose confidence values did not separate true ligands from high-scoring false-positives as effectively as docking scores or Boltz-2 affinity predictions did. Taken together, the modest, but independent correlations of docking score and co-folding confidence or affinity suggests that integrating physics-based and deep-learning approaches may help with hit prioritization and subsequent optimization in structure-based ligand discovery.

biophysics↗

bioRxiv2025

A Descriptive Analysis of Streptococcus suis-Associated Disease in Irish Pigs from 2010 to 2024: Serotypes, Pathology, and Antimicrobial Resistance

Streptococcus suis is a major cause of respiratory and systemic diseases in post-weaned pigs, leading to significant production losses and animal welfare concerns. This study provides the first long-term national level analysis of Streptococcus suis-associated disease (SSAD) in the Republic of Ireland. We examined the pig diagnostic submissions, characterised serotype distribution, antimicrobial susceptibility, and co-infection patterns from 2010 to 2024. The findings confirm that serotypes 9 and 2 or 1/2 were most frequently associated with disease. We observed a significant shift in recent years where serotype 9 has surpassed serotype 2 or 1/2 in number of occurrences. S. suis was frequently co-detected with viral pathogens including porcine reproductive and respiratory syndrome virus (PRRSV), porcine circovirus type 2, and swine influenza virus (SIV), as well as bacterial pathogens such as Actinobacillus pleuropneumonia and Pasteurella multocida, typically from pneumonic lungs. While resistance to tetracycline and erythromycin was high (44.4% to 65.8%), isolates remained susceptible to first-line beta-lactam antibiotics such as penicillin (7.9% resistance), ampicillin (5.5% resistance) and amoxycillin/clavulanate (0% resistance). The observed heterogeneity between and within herds challenges successful implementation of vaccination and highlights the need for ongoing disease monitoring. These findings provide the first in-depth assessment of SSAD in Irelands pig population which will offer valuable insights for future surveillance efforts, including genomic studies and supporting evidence-based strategies and vaccine selection for controlling S. suis in Irish pig sector.

microbiology↗

bioRxiv2024

Reinforcement learning enhances training and performance in skilled alpine skiers compared to traditional coaching instruction

Skilled athletes need powerful movement strategies to solve tasks effectively. Typically, athletes learn these strategies with instruction-based teaching methods where coaches offer athletes a correct solution. Inspired by recent evidence from decision neuroscience, we asked whether skilled athletes learn strategy choices better with an evaluation-based training strategy (reinforcement learning). To address this question, we conducted a three-day learning experiment with skilled alpine ski racers (n=98) designed to improve their performance on flat slopes on slalom with four strategies at their disposal to achieve this goal. We compared performance and strategy choices of three groups: a reinforcement learning group, that only received feedback about their race times after every run, a supervised (free choice) learning group, that received strategy instructions from their coach, and a supervised (target skill) learning group, being coached to use the theoretically optimal strategy for skiing well on flats. We found that despite making similar strategy choices, the skiers in the reinforcement learning group, showed greater improvements in their race times during the training sessions than their counterparts in the supervised (free choice) learning group and outperformed them during a subsequent retention test. Surprisingly, the skiers in the reinforcement learning group even showed descriptively (but not significantly) better performance than those in the supervised (target skill) learning group. Our findings show that reinforcement learning can be an effective training strategy for improving strategy choices and performance among skilled athletes, even among the best ones.

neuroscience↗

bioRxiv2024

Personalized composite scaffolds for accelerated cell- and growth factor-free craniofacial bone regeneration

Approaches to regenerating bone often rely on the integration of biomaterials and biological signals in the form of cells or cytokines. However, from a translational point of view, these approaches face challenges due to the sourcing and quality of the biologic, unpredictable immune responses, complex regulatory paths, and high costs. We describe a simple manufacturing process and a material-centric 3D-printed composite scaffold system (CSS) that offers distinct advantages for clinical translation. The CSS comprises a 3D-printed porous polydiolcitrate-hydroxyapatite composite elastomer infused with a polydiolcitrate-graphene oxide hydrogel composite. Using a continuous liquid interface production 3D printer, we fabricate a precise porous ceramic scaffold with 60% hydroxyapatite content resembling natural bone. The resulting scaffold integrates with a thermoresponsive hydrogel composite, customizable in situ to fit the defect. This hybrid phasic porous CSS mimics the bone microenvironment (inorganic and organic) while allowing independent control of each material phase (rigid and soft). The CSS stimulates osteogenic differentiation in vitro and in vivo. Moreover, it promotes M2 polarization and blood vessel ingrowth, which are crucial for supporting bone formation. Our comprehensive micro-CT analysis revealed that within 4 weeks in a critical-size defect model, the CSS accelerated ECM deposition (8-fold) and mineralized osteoid (69-fold) compared to the untreated. Our material-centric approach delivers impressive osteogenic properties and streamlined manufacturing advantages, potentially expediting clinical application for bone reconstruction surgeries.

bioengineering↗

bioRxiv2023

Cell-type-specific inhibitory circuitry from a connectomic census of mouse visual cortex

Mammalian cortex features a vast diversity of neuronal cell types, each with characteristic anatomical, molecular and functional properties. Synaptic connectivity powerfully shapes how each cell type participates in the cortical circuit, but mapping connectivity rules at the resolution of distinct cell types remains difficult. Here, we used millimeter-scale volumetric electron microscopy1 to investigate the connectivity of all inhibitory neurons across a densely-segmented neuronal population of 1352 cells spanning all layers of mouse visual cortex, producing a wiring diagram of inhibitory connections with more than 70,000 synapses. Taking a data-driven approach inspired by classical neuroanatomy, we classified inhibitory neurons based on the relative targeting of dendritic compartments and other inhibitory cells and developed a novel classification of excitatory neurons based on the morphological and synaptic input properties. The synaptic connectivity between inhibitory cells revealed a novel class of disinhibitory specialist targeting basket cells, in addition to familiar subclasses. Analysis of the inhibitory connectivity onto excitatory neurons found widespread specificity, with many interneurons exhibiting differential targeting of certain subpopulations spatially intermingled with other potential targets. Inhibitory targeting was organized into "motif groups," diverse sets of cells that collectively target both perisomatic and dendritic compartments of the same excitatory targets. Collectively, our analysis identified new organizing principles for cortical inhibition and will serve as a foundation for linking modern multimodal neuronal atlases with the cortical wiring diagram.

neuroscience↗

bioRxiv2022

Bumblebees retrieve only the ordinal ranking of foraging options when comparing memories obtained in distinct settings

Are animals preferences determined by absolute memories for options (e.g., reward sizes) or by their remembered ranking (better/worse)? The only studies examining this question suggest humans and starlings utilize memories for both absolute and relative information. We show that bumblebees make decisions using only memories of ordinal comparisons. After learning to discriminate pairs of different flowers by sucrose concentration, bumblebees preferred flowers (in novel pairings) with 1) higher ranking over equal absolute reward, 2) higher ranking over higher absolute reward, and 3) identical qualitative ranking but different quantitative ranking equally. Despite these suboptimal choices, bumblebees found the optimal option in an ecologically relevant foraging task. Our results illuminate a divergent mechanism of learned preferences that may have arisen from adaptations to bumblebees natural environment.

animal behavior and cognition↗

bioRxiv2021

Regulation of skeletal muscle metabolism and contraction performance via teneurin-latrophilin action.

Skeletal muscle regulation is responsible for voluntary muscular movement in vertebrates. The genes of two essential proteins, teneurins and latrophilins (LPHN), evolving in ancestors of multicellular animals, form a ligand-receptor pair, and are now shown to be required for skeletal muscle function. Teneurins possess a bioactive peptide, termed the teneurin C-terminal associated peptide (TCAP) that interacts with the LPHNs to regulate skeletal muscle contractility strength and fatigue by an insulin-independent glucose importation mechanism. CRISPR-based knockouts and siRNA-associated knockdowns of LPHN-1 and-3 shows that TCAP stimulates an LPHN-mediated cytosolic Ca2+ signal transduction cascade to increase energy metabolism and enhance skeletal muscle function via increases in type-1 oxidative fiber formation and reduce the fatigue response. Thus, the teneurin/TCAP-LPHN system is presented as a novel mechanism likely to regulate the energy requirements and performance of skeletal muscle.

physiology↗

bioRxiv2021

Cellular resolution anatomical and molecular atlases for prenatal human brains

Increasing interest in studies of prenatal human brain development, particularly using new single-cell genomics and anatomical technologies to create cell atlases, creates a strong need for accurate and detailed anatomical reference atlases. In this study, we present two cellular-resolution digital anatomical atlases for prenatal human brain at post-conceptional weeks (PCW) 15 and 21. Both atlases were annotated on sequential Nissl-stained sections covering brain-wide structures on the basis of combined analysis of cytoarchitecture, acetylcholinesterase staining and an extensive marker gene expression dataset. This high information content dataset allowed reliable and accurate demarcation of developing cortical and subcortical structures and their subdivisions. Furthermore, using the anatomical atlases as a guide, spatial expression of 37 and 5 genes from the brains respectively at PCW 15 and 21 was annotated, illustrating reliable marker genes for many developing brain structures. Finally, the present study uncovered several novel developmental features, such as the lack of an outer subventricular zone in the hippocampal formation and entorhinal cortex, and the apparent extension of both cortical (excitatory) and subcortical (inhibitory) progenitors into the prenatal olfactory bulb. These comprehensive atlases provide useful tools for visualization, targeting, imaging and interpretation of brain structures of prenatal human brain, and for guiding and interpreting the next generation of cell census and connectome studies.

neuroscience↗

bioRxiv2019

Active Notch Signaling is Required for Arm Regeneration in a Brittle Star

Cell signaling pathways play vital roles in coordinating cellular events in development. For example, the Notch signaling pathway is highly conserved across all multicellular animals and is known to coordinate a multitude of diverse cellular events, including proliferation, differentiation, fate specification, and cell death. Specific functions of the pathway are, however, highly context-dependent and are not well characterized in post-traumatic regeneration. Here, we use a small-molecule inhibitor of the pathway (DAPT) to demonstrate that Notch signaling is required for proper arm regeneration in the brittle star Ophioderma brevispina, a highly regenerative member of the phylum Echinodermata. We also employ a transcriptome-wide gene expression analysis to characterize the downstream genes controlled by the Notch pathway in the brittle star regeneration. We demonstrate that arm regeneration involves an extensive crosstalk between the Notch pathway and other cell signaling pathways. In the regrowing arm, Notch regulates the composition of the extracellular matrix, cell migration, proliferation, and apoptosis, as well as components of the innate immune response. We also show for the first time that Notch signaling regulates the activity of several transposable elements. Our data also suggests that one of the possible mechanisms through which Notch sustains its activity in the regenerating tissues is via suppression of Neuralized1.

developmental biology↗

bioRxiv2018

Global emergence and population dynamics of divergent serotype 3 CC180 pneumococci

Streptococcus pneumoniae serotype 3 remains a significant cause of morbidity and mortality worldwide, despite inclusion in the 13-valent pneumococcal conjugate vaccine (PCV13). Serotype 3 increased in carriage since the implementation of PCV13 in the United States, while invasive disease rates remain unchanged. We investigated the persistence of serotype 3 in carriage and disease, through genomic analyses of a global sample of 301 serotype 3 isolates of the Netherlands3-31 (PMEN31) clone CC180, combined with associated patient data and PCV utilization among countries of isolate collection. We assessed phenotypic variation between dominant clades in capsule charge (zeta potential), capsular polysaccharide shedding, and susceptibility to opsonophagocytic killing, which have previously been associated with carriage duration, invasiveness, and vaccine escape. We identify a recent shift in the CC180 population attributed to a lineage termed Clade II, which was estimated by Bayesian coalescent analysis to have first appeared in 1968 [95% HPD: 1939-1989] and increased in prevalence and effective population size thereafter. Clade II isolates are divergent from the pre-PCV13 serotype 3 population in non-capsular antigenic composition, competence, and antibiotic susceptibility, the last resulting from the acquisition of a Tn916-like conjugative transposon. Differences in recombination rates among clades correlated with variations in the ATP-binding subunit of Clp protease as well as amino acid substitutions in the comCDE operon. Opsonophagocytic killing assays elucidated the low observed efficacy of PCV13 against serotype 3. Variation in PCV13 use among sampled countries was not independently correlated with the CC180 population shift; therefore, genotypic and phenotypic differences in protein antigens and, in particular, antibiotic resistance may have contributed to the increase of Clade II. Our analysis emphasizes the need for routine, representative sampling of isolates from disperse geographic regions, including historically under-sampled areas. We also highlight the value of genomics in resolving antigenic and epidemiological variations within a serotype, which may have implications for future vaccine development.\n\nAuthor SummaryStreptococcus pneumoniae is a leading cause of bacterial pneumoniae, meningitis, and otitis media. Despite inclusion in the most recent pneumococcal conjugate vaccine, PCV13, serotype 3 remains epidemiologically important globally. We investigated the persistence of serotype 3 using whole-genome sequencing data form 301 isolates collected among 24 countries from 1993-2014. Through phylogenetic analysis, we identified three distinct lineages within a single clonal complex, CC180, and found one has recently emerged and grown in prevalence. We then compared genomic difference among lineages as well as variations in pneumococcal vaccine use among sampled countries. We found that the recently emerged lineage, termed Clade II, has a higher prevalence of antibiotic resistance compared to other lineages, diverse surface protein antigens, and a higher rate of recombination, a process by which bacteria can uptake and incorporate genetic material from its surroundings. Differences in vaccine use among sampled countries did not appear to be associated with the emergence of Clade II. We highlight the need to routine, representative sampling of bacterial isolates from diverse geographic areas and show the utility of genomic data in resolving epidemiological differences within a pathogen population.

evolutionary biology↗