Biology subjects

Wall, M.

Publications and source records attributed to Wall, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Neurite Complexity and Plasticity Markers Track Synaptic Vesicle Density in the Living Human Brain: A Multimodal PET-MRI-EEG Study

Neuroplasticity, the brain's capacity to reorganise its structure and function, is a transdiagnostic feature across psychiatric and neurodegenerative diseases and a putative mechanism of action for pharmacological interventions. [11C]-UCBJ positron emission tomography (PET), which quantifies synaptic vesicle glycoprotein 2A (SV2A) density, offers the most direct in vivo measure of human synaptic density, but its relationship to complementary, more scalable neuroimaging measures of structural and functional plasticity remains uncharacterised. We combined [11C]-UCBJ PET, diffusion weighted imaging (DWI/NODDI), resting-state functional magnetic resonance imaging (rs-fMRI), and electroencephalography (EEG)-based sensory tasks (roving mismatch negativity, MMN; visual long-term potentiation, vLTP) in 18 healthy volunteers to test the relationship between synaptic terminal SV2A density and complementary structural and functional neuroplasticity measures, and whether these relationships were reproducible following pharmacological challenge with ketamine (n = 11) or N,N-dimethyltryptamine (DMT; n = 7). There were no statistically significant differences in PET-derived SV2A binding potential (BPND), DWI-derived neurite orientation dispersion (ODI) and structural weighted degree (SWD), EEG-derived MMN repetition suppression, and late-phase vLTP P2 potentiation, 1 to 8 days following DMT and ketamine exposure compared to baseline. BPND was coupled with ODI across cortical regions before and after pharmacological challenge, and this relationship was tighter within visual, attentional, and frontoparietal control brain networks. SWD showed a weaker, more spatially restricted association with BPND, primarily in regions belonging to the limbic and visual brain networks, but was not replicated post-drug. No consistent association was found between BPND and functional weighted degree (FWD), derived from rs-fMRI, at baseline or after pharmacological challenge. Frontotemporal BPND was positively associated with MMN repetition suppression (r = 0.61), and occipital BPND with late-phase vLTP P2 potentiation (r = 0.54), with the MMN-BPND association replicating after pharmacological challenge (r = 0.49). These findings link synaptic terminal SV2A density in the living human brain to neurite architecture and the capacity for short-term and Hebbian-like long-term synaptic plasticity, while dissociating these relationships from generic functional connectivity and magnitude of sensory-evoked responses. These data provide cross-modal validation for DWI- and EEG-derived measures as biological indices and surrogate measures of human synaptic plasticity.

neuroscience↗

bioRxiv2026

Structural and functional MRI signatures of Gambling Disorder: a case-control study

Gambling disorder (GD) is a behavioural addiction that may help identify addiction-related neural features without the direct neurobiological effects of a primary substance of dependence. We examined regional grey matter volume (GMV) and resting-state functional connectivity (rsFC) in the same well-characterised sample. Eighteen men with GD and 21 matched healthy controls underwent high-resolution structural and resting-state functional MRI. GMV was quantified across 214 cortical and subcortical regions, and seed-based rsFC analyses focused on striatal subdivisions and mesocorticolimbic regions. Group differences were evaluated using permutation testing and cluster-corrected mixed-effects modelling. GD was associated with lower GMV in the ventromedial prefrontal cortex, orbitofrontal regions and other cortical and subcortical areas, alongside higher GMV in a subset of limbic and default-mode regions. Participants with GD also showed lower connectivity between the limbic striatum and the hippocampus, thalamus and putamen. In exploratory analyses, somatomotor connectivity was positively associated with gambling severity (Problem Gambling Severity Index: Spearman's rho = 0.71, p = 0.003, false-discovery-rate-adjusted q = 0.016). Structural and functional findings overlapped spatially in regions associated with valuation, memory, reward and habit formation, but regional GMV did not mediate group differences in rsFC. These findings are broadly consistent with corticostriatal models of GD and identify candidate circuit-level differences for independent replication. Larger, more diverse and longitudinal samples are required to establish their reproducibility, temporal direction and clinical relevance.

neuroscience↗

bioRxiv2026

WaterFlow: Prediction of Ordered Water Molecule Positions on Protein Structures

Ordered water molecules mediate many protein functions, including stability, ligand binding, and catalysis. Predicting their positions with sub-angstrom accuracy would support protein design, binding affinity prediction, and automated model building in X-ray crystallography and cryo-EM. However, water molecule prediction lags behind protein and other molecule structure predictions. Here, we introduce WaterFlow, a flow-matching-based generator model and confidence model for predicting the positions of ordered water molecules in protein structures. WaterFlow outperforms the existing state of the art at every precision level. We demonstrate that WaterFlow can accurately predict ground truth modeled water molecules, including those around protein-ligand interactions and on predicted structures. We also show that WaterFlow predictions fit well directly to experimental data, and therefore propose that it may be used for both prediction and modeling water molecules. This includes novel predictions that are often associated with positive electron difference density, meaning the model places water molecules at sites the original structure depositions omitted. We use this improved model to address the data constraint. By mapping the Pareto front of achievable accuracy of water molecule prediction, alongside analysis of different training data schemas, we quantified the trade-off between data quantity and data quality, demonstrating that the diversity of high-quality structures is limiting the possible results. Overall, WaterFlow predicts ordered water to serve as a solvent module for structure-based drug design and for water molecule placement during crystallographic refinement.

biophysics↗

bioRxiv2025

Restoration of ovarian endocrine function with encapsulated immune isolated human ovarian xenograft in ovariectomized mice

Anti-cancer treatments cause premature depletion of the non-renewable ovarian reserve of follicles, the source of key steroid hormones, leading to premature ovarian insufficiency (POI) in 50% of pediatric cancer survivors. Patients with POI, especially at the onset of pubertal development, experience significant endocrine complications, including delayed growth, elevated risks of obesity and diabetes, and accelerated cardiovascular, musculoskeletal and neurological disorders as adults. The only approved pharmacological treatment for POI is an off-label prescribed hormone replacement therapy, which does not replace physiologically functioning ovaries. To restore production of ovarian hormones and protect against immune-mediated injury, we developed a hydrogel-based capsule for implantation of donor ovarian tissue. We evaluated the restoration of ovarian endocrine function in ovariectomized immunodeficient (NOD scid gamma, NSG) mice implanted with encapsulated xenografts over 20 weeks through daily vaginal cytology, hormone measurements and histological analysis of explanted human xenografts. The encapsulated xenografts integrated into the murine hypothalamus-pituitary-gonad (HPG) axis responding to circulating murine gonadotropins and restoring ovarian endocrine function. As controls, we implanted non encapsulated human ovarian xenografts comparable in size. Without the need for exogeneous stimulation, the estrous cyclicity resumed in both groups of mice 12 weeks post implantation and all mice regularly cycled experiencing between 3 to 8 estrous cycles in 20 weeks. The levels of estradiol gradually increased reaching on average 50pg/mL 20 weeks post implantation. Morphological analysis of the encapsulated grafts revealed presence of large antral follicles, [~]3mm in diameter, consistent with regular cyclicity and measurable levels of circulating hormones. This work demonstrates that endocrine function of encapsulated human ovarian tissue was not affected by the encapsulation and integrated with the host physiology similarly to the non-encapsulated controls.

bioengineering↗

bioRxiv2024

Human brain changes after first psilocybin use

Psychedelics have robust effects on acute brain function and long-term behavior but whether they also cause enduring functional and anatomical brain changes is unknown. In a placebo-controlled, within-subjects, electroencephalography, and magnetic resonance imaging study in 28 healthy, entirely psychedelic-naive participants, anatomical and functional brain changes were detected from one-hour to one-month after a single high-dose (25 mg) of psilocybin. Increases in cognitive flexibility, psychological insight, and well-being were seen at one-month. Diffusion imaging done before and one-month after 25mg psilocybin revealed decreased axial diffusivity bilaterally in prefrontal-subcortical tracts that correlated with decreased brain network modularity over the same time period. Decreased modularity also correlated with improved well-being. Increased cortical signal entropy at 1- and 2-hours post-dosing predicted improved psychological well-being at one-month. Next-day psychological insight mediated the entropy to well-being relationship. All effects were exclusive to 25mg psilocybin; no effects occurred with a 1mg psilocybin placebo dose.

neuroscience↗

bioRxiv2024

MDRepo - an open environment for data warehousing and knowledge discovery from molecular dynamics simulations

BackgroundMolecular Dynamics (MD) simulation of biomolecules provides important insights into conformational changes and dynamic behavior, revealing critical information about folding and interactions with other molecules. This enables advances in drug discovery and the design of therapeutic interventions. The collection of simulations stored in computers across the world holds immense potential to serve as training data for future Machine Learning models that will transform the prediction of structure, dynamics, drug interactions, and more. A needIdeally, there should exist an open access repository that enables scientists to submit and store their MD simulations of proteins and protein-drug interactions, and to find, retrieve, analyze, and visualize simulations produced by others. However, despite the ubiquity of MD simulation in structural biology, no such repository exists; as a result, simulations are instead stored in scattered locations without uniform metadata or access protocols. A solutionHere, we introduce MDRepo, a robust infrastructure that supports a relatively simple process for standardized community contribution of simulations, activates common downstream analyses on stored data, and enables search, retrieval, and visualization of contributed data. MDRepo is built on top of the open-source CyVerse research cyberinfrastructure, and is capable of storing petabytes of simulations, while providing high bandwidth upload and download capabilities and laying a foundation for cloud-based access to its stored data.

biochemistry↗

bioRxiv2024

Drug resistant Mycobacterium tuberculosis strains have altered cell envelope hydrophobicity that influences infection outcomes in human macrophages

Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), is considered one of the top infectious killers in the world. In recent decades, drug resistant (DR) strains of M.tb have emerged that make TB even more difficult to treat and pose a threat to public health. M.tb has a complex cell envelope that provides protection to the bacterium from chemotherapeutic agents. Although M.tb cell envelope lipids have been studied for decades, very little is known about how their levels change in relation to drug resistance. In this study, we examined changes in the cell envelope lipids [namely, phthiocerol dimycocerosates (PDIMs)], glycolipids [phosphatidyl-myo-inositol mannosides (PIMs)], and the PIM associated lipoglycans [lipomannan (LM); mannose-capped lipoarabinomannan (ManLAM)] of 11 M.tb strains that range from drug susceptible (DS) to multi-drug resistant (MDR) to pre-extensively drug resistant (pre-XDR). We show that there was an increase in the PDIMs:PIMs ratio as drug resistance increases, and provide evidence of PDIM species only present in the DR-M.tb strains studied. Overall, the LM and ManLAM cell envelope levels did not differ between DS- and DR-M.tb strains, but ManLAM surface exposure proportionally increased with drug resistance. Evaluation of host-pathogen interactions revealed that DR-M.tb strains have decreased association with human macrophages compared to DS strains. The pre-XDR M.tb strain with the largest PDIMs:PIMs ratio had decreased uptake, but increased intracellular growth rate at early time points post-infection when compared to the DS-M.tb strain H37Rv. These findings suggest that PDIMs may play an important role in drug resistance and that this observed increase in hydrophobic cell envelope lipids on the DR-M.tb strains studied may influence M.tb-host interactions. AUTHOR SUMMARYTuberculosis (TB) is a leading cause of death due to an infectious organism and is caused by the bacteria Mycobacterium tuberculosis (M.tb). Drug resistant (DR) forms of TB have emerged over the past few decades which make the disease even more difficult to diagnose and treat. Currently, there is very little known about how the bacteria changes as it becomes more drug resistant. Here, we used biochemical techniques to study differences in the M.tb cell envelope across drug resistance categories. We examined 11 M.tb strains that range from drug-susceptible (DS) to multi-drug resistant (MDR) to pre-extensively drug resistant (pre-XDR) and observed that levels of hydrophobic phthiocerol dimycocerosates were increased and levels of hydrophilic higher-order phosphatidyl-myo-inositol mannosides were decreased in DR-M.tb strains compared to DS strains. We also found that DR-M.tb strains had decreased association with human macrophages, and that the pre-XDR-M.tb strain with the highest ratio of hydrophobic to hydrophilic lipids had decreased uptake but increased intracellular growth in macrophages at early timepoints after infection. Our study provides exciting insights into changes in the cell envelope composition of DR-M.tb strains and how these changes may influence infection outcomes in human macrophages.

microbiology↗

bioRxiv2024

Validation of Enhancer Regions in Primary Human Neural Progenitor Cells using Capture STARR-seq

Genome-wide association studies (GWAS) and expression analyses implicate noncoding regulatory regions as harboring risk factors for psychiatric disease, but functional characterization of these regions remains limited. We performed capture STARR-sequencing of over 78,000 candidate regions to identify active enhancers in primary human neural progenitor cells (phNPCs). We selected candidate regions by integrating data from NPCs, prefrontal cortex, developmental timepoints, and GWAS. Over 8,000 regions demonstrated enhancer activity in the phNPCs, and we linked these regions to over 2,200 predicted target genes. These genes are involved in neuronal and psychiatric disease-associated pathways, including dopaminergic synapse, axon guidance, and schizophrenia. We functionally validated a subset of these enhancers using mutation STARR-sequencing and CRISPR deletions, demonstrating the effects of genetic variation on enhancer activity and enhancer deletion on gene expression. Overall, we identified thousands of highly active enhancers and functionally validated a subset of these enhancers, improving our understanding of regulatory networks underlying brain function and disease.

neuroscience↗

bioRxiv2024

Short periods of decreased water flow may modulate long-term ocean acidification in reef-building corals

Ocean acidification (OA) poses a major threat to reef-building corals. Although water flow variability is common in coral reefs and modulates coral physiology, the interactive effects of flow and OA on corals remain poorly understood. Therefore, we performed a three-month OA experiment investigating the effect of changes in flow on coral physiology. We exposed the reef-building corals Acropora cytherea, Pocillopora verrucosa, and Porites cylindrica to control (pH 8.0) and OA (pH 7.8) conditions at moderate flow (6 cm s-1) and monitored OA effects on growth. Throughout the experiment, we intermittently exposed all corals to low flow (2 cm s-1) for 1.5 h and measured their photosynthesis:photosynthesis (P:R) ratio under low and moderate flow. On average, corals under OA calcified 18 % less and grew 23 % less in surface area than those at ambient pH. We observed species-specific interactive effects of OA and flow on coral physiology. P:R ratios decreased after 12 weeks of OA in A. cytherea (22 %) and P. cylindrica (28 %) under moderate flow, but were unaffected by OA under low flow. P:R ratios were stable in P. verrucosa. These results suggest that short periods of decreased water flow may modulate OA effects on some coral species, indicating that flow variability is a factor to consider when assessing long-term effects of climate change.

physiology↗

bioRxiv2024

Binding profiles for 954 Drosophila and C. elegans transcription factors revealtissue specific regulatory relationships

A catalog of transcription factor (TF) binding sites in the genome is critical for deciphering regulatory relationships. Here we present the culmination of the modERN (model organism Encyclopedia of Regulatory Networks) consortium that systematically assayed TF binding events in vivo in two major model organisms, Drosophila melanogaster (fly) and Caenorhabditis elegans (worm). We describe key features of these datasets, comprising 604 TFs identifying 3.6M sites in the fly and 350 TFs identifying 0.9 M sites in the worm. Applying a machine learning model to these data identifies sets of TFs with a prominent role in promoting target gene expression in specific cell types. TF binding data are available through the ENCODE Data Coordinating Center and at https://epic.gs.washington.edu/modERNresource, which provides access to processed and summary data, as well as widgets to probe cell type-specific TF-target relationships. These data are a rich resource that should fuel investigations into TF function during development.

genomics↗

bioRxiv2023

Trade-offs in a reef-building coral after six years of thermal acclimation

Evidence is growing that reef-building corals have the capacity to acclimate to new and challenging thermal conditions by increasing their thermal resistance. This raises hopes for their future persistence in a warming world. However, potential trade-offs that accompany such resistance gains, have remained largely unexplored. We provide the first report on the physiological trade-offs in a globally abundant and ecologically relevant coral species (Pocillopora acuta), after a long-term exposure to an elevated temperature of 31 {degrees}C in comparison to conspecifics cultivated under a cooler control thermal regime. At both temperatures, corals consistently appeared to be visually healthy throughout a six-year period. At 31 {degrees}C, corals had increased metabolic rates (both respiration and photosynthesis) that resulted in higher biomass accumulation and total energy reserves compared to the corals from the ambient regime. Further, the composition of coral host tissues shifted in favor of lipid build-up, suggesting an altered mechanism of energy storage. The increase in biomass growth came at the cost of declining skeletal growth rates and the formation of higher density skeletons. In the long-term, this trade-off will result in lower extension rates that can entail major ramifications for future reef building processes and reef community composition. Moreover, symbionts at 31 {degrees}C were physiologically more compromised with overall lower energy reserves, possibly indicating a stronger exploitation by the host and potentially a lower stress resilience. Our study provides first insights into a successful thermal acclimation mechanism that involved the prioritization of energy storage over skeletal growth, entailing higher demands on the symbionts. Our observation in this 6-year study does not align with observations of short-term studies, where elevated temperatures caused a depletion of tissue lipids in corals, which highlights the importance of studying acclimation of organisms over their relevant biological scales. Further investigations into trade-offs at biologically relevant scales and how they unfold under an acute heat stress will help to provide a more comprehensive picture of the future coral reef trajectory. Importantly, these insights will also help improve interventions aimed at increasing the thermal resilience of corals which anticipate to use thermal preconditioning treatments for stress-hardening. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=96 SRC="FIGDIR/small/549699v2_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@139b33corg.highwire.dtl.DTLVardef@1264477org.highwire.dtl.DTLVardef@158f7c9org.highwire.dtl.DTLVardef@1f3c35a_HPS_FORMAT_FIGEXP M_FIG C_FIG

ecology↗

bioRxiv2023

CyVerse: Cyberinfrastructure for Open Science

CyVerse, the largest publicly-funded open-source research cyberinfrastructure for life sciences, has played a crucial role in advancing data-driven research since the 2010s. As the technology landscape evolved with the emergence of cloud computing platforms, machine learning and artificial intelligence (AI) applications, CyVerse has enabled access by providing interfaces, Software as a Service (SaaS), and cloud-native Infrastructure as Code (IaC) to leverage new technologies. CyVerse services enable researchers to integrate institutional and private computational resources, custom software, perform analyses, and publish data in accordance with open science principles. Over the past 13 years, CyVerse has registered more than 110,000 verified accounts from 160 countries and was used for over 1,600 peer-reviewed publications. Since 2011, 45,000 students and researchers have been trained to use CyVerse. The platform has been replicated and deployed in two countries outside the US, with additional private deployments on commercial clouds for US government agencies and multinational corporations. In this manuscript, we present a strategic blueprint for creating and managing SaaS cyberinfrastructure and IaC as free and open-source software.

scientific communication and education↗

bioRxiv2023

Natural thermal stress-hardening of corals through cold temperature pulses in the Thai Andaman Sea

Thermal variability can render corals stress resistant through a phenomenon coined as "stress-hardening induced by environmental priming". Fluctuations that involve high temperature peaks have been commonly investigated, however, the effects of a stress-hardening stimulus generated by cold-water pulses has rarely been studied. Offshore island reefs in the Andaman Sea offer an ideal natural setting to study these effects, as cooling water of internal waves induce strong variability with peak intensity in January to June and absence in August to November. While western island shores are exposed to this stimulus, eastern shores remain sheltered. This study examined (1) whether corals from exposed reefs were more heat stress resistant compared to stimulus-sheltered conspecifics and (2) whether this trait can last in the absence of the stimulus. We quantified the thermal stress resistance in two ecologically important coral species, Pocillopora sp. and Porites sp., from the two island shores, during the two seasons. Coral bleaching intensity and photosynthetic efficiency of algal symbionts were measured as response variables after a short-term heat stress assay (24-48 h, 34 {degrees}C) to assess thermal stress resistance. Stress responses of all stimulus-exposed corals were either undetectable (during the season of stimulus presence) or very weak (during stimulus absence), while corals from the stimulus-sheltered shore responded strongly to heat stress irrespective of the season. Hence, thermal resistance was overall greater in corals originating from the stimulus-exposed shore, but it was slightly diminished during the season of stimulus absence, emphasizing the relevance of stimulus recurrence in maintaining the resistance trait. We exemplify that the stimulus of fluctuating low temperature pulses successfully induced stress-hardening in corals. This suggests that priming stimuli do not necessarily need to transgress certain upper thermal thresholds, but can also touch on lower thresholds to be effective. Even more, we argue that cooling pulses might represent a safer stress-hardening regime, since warming-stress accumulation can be avoided. More research is required to obtain a better understanding of environmental priming, but current findings should encourage the development of artificial stress-hardening approaches to enhance coral resistance in reef restoration efforts.

ecology↗

bioRxiv2023

Dysregulated expression of Hoxa1 isoforms in hematopoietic stem and progenitor cells causes myelodysplastic syndromes.

The homeobox gene, Hoxa1, has two different isoforms generated by alternative splicing: a full-length homeodomain-containing Hoxa1 (Hoxa1-FL), and a truncated Hoxa1 (Hoxa1-T), that lacks the homeodomain. The effects of the distinct Hoxa1 isoforms in hematopoiesis have not been investigated. Oncoretroviral studies revealed that Hoxa1-T acts in a dominant negative manner, regulating transcriptionally active Hoxa1. Oncoretroviral overexpression of wildtype Hoxa1 (WT-Hoxa1), which generates both Hoxa1 isoforms, in murine hematopoietic stem and progenitor cells (HSPCs) perturbed hematopoiesis, resulting in transplantable myelodysplastic syndromes (MDS) in mice. Overexpression of a mutated Hoxa1 cDNA (MUT-Hoxa1) that generates Hoxa1-FL, but not Hoxa1-T, led to a more severe MDS that transformed to secondary acute myeloid leukemia (sAML). DNA damage repair pathways were downregulated in Hoxa1-overexpressing hematopoietic progenitor cells, accompanied by increased {gamma}H2AX foci. In silico analyses revealed that CD34+ cells from approximately 50% of patients with MDS had elevated HOXA1-FL expression. Conditional knock-in WT-Hoxa1 and MUT-Hoxa1 mice were generated and had features of pre-MDS, developing altered hematopoiesis within 4 months of Hoxa1 isoform overexpression in HSPCs. HSPCs were significantly reduced in all knock-in mice, accompanied by significantly increased apoptosis in WT-Hoxa1 HSPCs. Healthy wildtype recipients transplanted with bone marrow cells from Hoxa1 knock-in mice developed trilineage MDS, with Hoxa1 isoform and gene dosage dependent phenotypes. Collectively our data identify a role for HOXA1 in the pathogenesis of MDS. Our Hoxa1 mouse models capture different stages of progression of disease from pre-MDS to MDS to sAML and provide novel, clinically relevant tools to study MDS. Key pointsHOXA1 is upregulated in approximately 50% of MDS patient CD34+ BM cells, highlighting a potential role for HOXA1 in the pathogenesis of MDS. Dysregulated expression of Hoxa1 isoforms in murine hematopoietic stem and progenitor cells predisposes mice to pre-MDS and MDS.

cancer biology↗

bioRxiv2022

Species-dependent actions of the Gαob selective adenosine A1 receptor agonist BnOCPA

We have previously reported that in rat hippocampal area CA1, the A1R-selective agonist, BnOCPA, potently inhibited excitatory synaptic transmission but did not cause membrane hyperpolarisation in CA1 pyramidal neurons, as would be expected of A1R agonists. This functional discrimination by BnOCPA may arise from its ability, in cAMP inhibition assays, to selectively activate only Gob out of the six Gi/o subtypes. This may explain why BnOCPA is a potent analgesic that does not cause sedation or cardiorespiratory depression in the rat. Since many preclinical studies are performed using mice, we have here investigated whether BnOCPAs functional discrimination extends to the mouse. While the potency of BnOCPA against the inhibition of hippocampal synaptic transmission was comparable between rats and mice, we discovered that low concentrations of BnOCPA hyperpolarised mouse CA1 neurons and reduced both their input resistance and firing rate in an A1R-dependent manner. In interleaved experiments we confirmed our previous observations in the rat that concentrations of BnOCPA equivalent to those tested in the mouse had little or no effect on membrane potential or input resistance. Using NanoBRET binding we established that BnOCPA had similar affinity at the mouse and rat A1Rs, and displayed little difference in G protein coupling, as determined using the TRUPATH assay. Thus, although the mechanism for the loss of BnOCPA functional selectivity between pre- and postsynaptic receptors in the mouse hippocampus is currently unclear, it may stem from differences in expression of the individual G proteins subunits or the coupling to murine K+ channels. Short summaryWe describe the differential actions of the selective A1R agonist BnOCPA in mouse vs rat hippocampus. In mice, BnOCPA does not show a selectivity between pre and postsynaptic A1Rs, unlike in rats. This may stem from differences in the G protein coupling to K+ channels.

neuroscience↗

bioRxiv2022

Srsf2P95H/+ co-operates with loss of TET2 to promote myeloid bias and initiate a chronic myelomonocytic leukemia like disease in mice.

Recurrent mutations in two pathways - the RNA spliceosome (eg. SRSF2, SF3B1, U2AF1) and epigenetic regulators (eg. DNMT3, TET2) - contribute to the development of myelodysplastic syndrome (MDS) and related myeloid neoplasms. In chronic myelomonocytic leukemia (CMML), SRSF2 mutations occur in [~]50% of patients and TET2 mutations in [~]60%, representing two of the most frequent mutations in these cancers. Clonal analysis has indicated that either mutation can arise as the founder lesion, however, our understanding of the basis for the co-operativity of these mutations in the evolution of CMML is limited. Based on human cancer genetics we crossed an inducible Srsf2P95H/+ mutant model with Tet2fl/fl mice to mutate both concomitantly (or individually) in hematopoietic stem cells. At 20-24 weeks post gene mutation, we observed subtle differences in the Srsf2/Tet2 mutants compared to either single mutant. Under conditions of native hematopoiesis with aging, we see a distinct myeloid bias and monocytosis in the Srsf2/Tet2 mutants. A subset of the compound Srsf2/Tet2 mutants display an increased granulocytic and distinctive monocytic proliferation (myelo-monocytic hyperplasia), with increased immature promonocytes and monoblasts ([~]10-15% total nucleated cells), and evidence of binucleate promonocytes. Exome analysis of progressed disease demonstrates mutations in genes and pathways similar to those reported in human CMML. Upon transplantation, recipients developed leukocytosis, monocytosis and splenomegaly. This demonstrates we can reproduce Srsf2/Tet2 co-operativity in vivo, yielding a disease with core characteristics of CMML, unlike single Srsf2 or Tet2 mutation. This model represents a significant step toward building high fidelity and genetically tractable models of CMML. Key pointsO_LISrsf2P95H/+ co-operates with Tet2-/- to initiate CMML in a murine model C_LIO_LISrsf2P95H and Tet2 null mutations synergize in the development of monocytosis C_LI

cancer biology↗

bioRxiv2021

The Open Perimetry Initiative: a framework for cross-platform development for the new generation of portable perimeters

The Open Perimetry Initiative is fully open source and consists of the Open Perimetry Interface (OPI) and an accompanying package (visualFields) with analytical tools. The OPI package contains an ever-growing number of drivers for commercially available perimeters, head-mounted devices, and virtual reality headsets. The visualFields package contains tools for the analysis and visualization of visual field data, including methods to compute deviation values and probability maps. The use of the OPI and visualFields is shown through a custom static automated perimetry test for the full visual field (up to 50{degrees} nasally and 80{degrees} temporally) developed with the OPI driver for the Octopus 900 and using visualFields for statistical analysis. Its potential for the development of cross-platform apps for driving and testing portable devices is demonstrated with an OPI driver for an Android-based headset. With more than 55 citations in clinical and translational science as listed in Scopus, this initiative has contributed significantly to expanding the knowledge base in perimetry and clinical vision research at large, and with clinical translation. The continued support of researchers, clinicians, industry, and public institutions are key in transforming perimetry research from closed to open science. The Open Perimetry Initiative provides framework to achieve this.

bioinformatics↗

bioRxiv2021

Synergy between vesicular and non-vesicular gliotransmission regulates synaptic plasticity and working memory

Astrocytes are an active element of brain signalling, capable of release of small molecule gliotransmitters by vesicular and channel-mediated mechanisms. However, specific physiological roles of astroglial exocytosis of glutamate and D-Serine remain controversial. Our data demonstrate that cortical astrocytes can release glutamate and D-Serine by combination of SNARE-dependent exocytosis and non-vesicular mechanisms dependent on TREK-1 and Best1 channels. Astrocyte-derived glutamate and D-serine elicited complex multicomponent phasic response in neocortical pyramidal neurons, which is mediated by extra-synaptic GluN2B receptors. Impairment of either pathway of gliotransmission (in the TREK1 KO, Best-1 KO or dnSNARE mice) strongly affected the NMDAR-dependent long-term synaptic plasticity in the hippocampus and neocortex. Moreover, impairment of astroglial exocytosis in dnSNARE mice led to the deficit in the spatial working memory which was rescued by environmental enrichment. We conclude that synergism between vesicular and non-vesicular gliotransmission is crucial for astrocyte-neuron communication and astroglia-driven regulation of synaptic plasticity and memory. HighlightsO_LIAstrocytes in situ release glutamate via exocytosis and channel-mediated release. C_LIO_LIAstroglia-derived glutamate and D-Serine activate phasic NMDAR currents in neurons C_LIO_LIBoth vesicular and non-vesicular gliotransmission are required for synaptic plasticity C_LIO_LIImpaired exocytosis of gliotransmitters causes deficit in working memory C_LI

neuroscience↗