Biology subjects

Green, J.

Publications and source records attributed to Green, J..

At least 19 recordsLinked to original sources

bioRxiv2026

TRMT10A deficiency and tRNA fragmentation disrupt human pancreatic β-cell identity and insulin maturation

Mutations in the tRNA-modifying enzyme TRMT10A cause a rare monogenic syndrome characterized by early-onset diabetes and neurodevelopmental defects, yet the molecular mechanisms underlying TRMT10A diabetes remain unclear. Using human TRMT10A-deficient (knockout and mutant) induced pluripotent stem cells (iPSCs) differentiated into islet-like aggregates and TRMT10A-silenced EndoC-{beta}H1 human {beta}-cells, we show that TRMT10A deficiency impairs {beta}-cell differentiation, insulin content and glucose-stimulated insulin secretion while inducing widespread transcriptional alterations. These defects are accompanied by oxidative stress, diminished antioxidant capacity, and defective proinsulin processing driven by reduced PCSK1 expression. Mechanistically, the loss of TRMT10A promotes tRNA fragmentation and the generation of fragments derived from the 5 end of tRNAGln-CTG (tDRGln-CTG) that interact with hnRNPM. Our data support the existence of a previously unrecognized hnRNPM-PTBP1 interaction in human {beta}-cells and suggest that this complex may contribute to the regulation of PCSK1 mRNA stability and/or translation. Furthermore, through its interaction with hnRNPM, tDRGln-CTG may alter the function of the complex thereby contributing to reduced PCSK1 expression, defective proinsulin processing, and impaired insulin content. Our findings link tRNA fragmentation, RNA-binding protein networks and insulin maturation, positioning TRMT10A as a critical regulator of {beta}-cell identity and function and uncovering a novel mechanism of {beta}-cell failure in the pathogenesis of diabetes.

molecular biology↗

bioRxiv2026

FALCON: Closed-Loop Multi-Objective Optimization of Lipid Nanoparticles for Cell-Selective mRNA Delivery

Efficient, cell type-selective delivery of genetic payloads remains a central challenge in the development of gene and cell therapies. Lipid nanoparticles (LNPs) offer a versatile delivery platform, but their optimization is hindered by reliance on brute-force screening methods that are laborious, resource-intensive, and focus on single targets. Here, we present FALCON (Framework for Active Learning-driven Compositional Optimization of Nanoparticles), a closed-loop pipeline that leverages iterative screening, surrogate modeling, and multi-objective optimization to accelerate LNP compositional design. In B cell-targeted validation experiments, FALCON-optimized LNPs achieved a 1.8-fold increase in splenic B cell transfection in vivo compared with reference compositions. When optimized for selectivity, FALCON LNPs displayed an 84-fold improvement in selective transfection of splenic B cells over off-target liver populations and enabled spleen-tropic behavior across factorial panels of varying ionizable and helper lipid chemistries. In vaccine studies, these LNPs induced higher IgG2c antibody titers and a more Th1-biased immune profile. FALCON was also deployed to optimize LNPs for myeloid cell-selective delivery, achieving enhanced in vivo selectivity following systemic administration both across and within spleen and liver compartments. Our results establish FALCON as a useful tool for data-driven design of LNP compositions for precision gene delivery.

bioengineering↗

bioRxiv2026

p70 ribosomal protein S6 Kinase (p70S6K) as a potential peripheral biomarker for mental symptoms in 16p11.2 deletion and duplication syndromes

Neurodevelopmental disorders (NDDs) encompass heterogeneous cognitive, motor, and psychiatric manifestations that typically require extensive behavioural assessments for characterization. Individuals carrying 16p11.2 copy number variations (CNVs), including both deletions and duplications, represent a relatively common NDD subgroup marked by wide variability in psychiatric symptoms, as well as metabolic and peripheral abnormalities, complicating prediction of disease trajectory and treatment response. The identification of biomarkers in easily accessible tissues, such as peripheral blood mononuclear cells (PBMCs), could provide valuable tools for diagnosis and prognosis, yet remains an unmet clinical need. Converging evidence implicates dysregulation of ubiquitous signalling pathways, including ERK and mTOR cascades, in altered protein synthesis across both idiopathic and genetic NDDs. Here, using a hypothesis-driven screening approach, we examined candidate peripheral biomarkers in individuals with 16p11.2 deletions and duplications. We identified a significant reduction of ribosomal protein S6 kinase (p70S6K) levels in PBMCs across both genotypes. Notably, the magnitude of p70S6K reduction correlated with the severity of autistic symptoms independently of CNV genotype. In parallel, MAPK3/ERK1 protein levels mirrored gene dosage, showing increased expression in duplication carriers and reduced levels in deletion carriers, in accordance with the genotype. Collectively, these findings indicate that peripheral molecular alterations may support clinical stratification and suggest that p70S6K represents a promising biomarker for symptom severity and potentially treatment responsiveness in NDD patients carrying 16p11.2 CNVs.

neuroscience↗

bioRxiv2025

Decoding Lymphangioleiomyomatosis (LAM) Niche Environment via Integrative Analysis of Single Cell Multiomics and Spatial Transcriptomics

Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease characterized by cystic destruction and metastatic growth of smooth muscle-like cells. Despite advances in understanding its genetic basis, the cellular heterogeneity, regulatory mechanisms, and microenvironmental interactions driving LAM progression remain poorly defined. In this study, we employed an integrative multi-omics approach combining single-cell RNA sequencing (scRNA-seq), single-nucleus ATAC sequencing (snATAC-seq), and high-resolution spatial transcriptomics (Visium, Visium HD, and Xenium) to decode the LAM niche in its native environment. We identified two spatially and functionally distinct LAM subtypes: LAMCORE1 and LAMCORE2. LAMCORE1 cells exhibited a uterine smooth muscle-like phenotype, expressing associated markers (ACTA2, MYH11) and were enriched in MTORC1 signaling and myogenic pathways, supporting a uterine origin. In contrast, LAMCORE2 cells displayed fibroblast-like features, with upregulated extracellular matrix (ECM) remodeling genes (COL1A1, MMP11) and epithelial-to-mesenchymal transition (EMT) pathways, suggesting a role in niche formation. Pseudotime and regulon analyses revealed dynamic transitions between these subtypes, driven by distinct transcriptional networks (e.g., HOX/PBX in LAMCORE1, TWIST/ZEB in LAMCORE2). The presence of the two distinct LAM subtypes was further validated by RNAscope and immunofluorescence microscopy. We identified LAM-associated fibroblasts (LAFs) as activated stromal cells expressing canonical markers (FAP, S100A4, VIM, IGFBP7, SPARC) and localized within LAM lesions. Subpopulations of LAFs, LAF-seed (proximal to LAMCORE1) and LAF-niche (surrounding LAM niches), exhibited unique functional profiles, including ECM deposition, TGF-{beta} signaling, and myofibroblast activation. Regulatory network analysis pinpointed EGR1 as a central hub governing LAF phenotype. Our comprehensive spatial profiling revealed niche structures dominated by LAMCORE1 cells and surrounded by lymphatic endothelial cells (LECs), LAFs, scattered LAMCORE2 cells, macrophages, and reprogrammed alveolar epithelial cells (AT2). ECM remodeling and aberrant organization of cable-like structures (-smooth muscle actin+) of the LAM niches were further validated by second harmonic generation microscopy. These findings provide a high-resolution blueprint of LAM pathogenesis, highlighting the interplay between uterine-derived LAMCORE cells, activated fibroblasts, and the remodeled lung microenvironment. They significantly enhance our understanding of the LAM niche microenvironment and offer insights into potential therapeutic targets and strategies for managing this complex disease.

genomics↗

bioRxiv2025

Intrinsic higher potency of basal urothelial cells to intermediate and umbrella cells as the cell of origin for bladder cancer

Transcriptome profiling of bladder cancer has revealed distinct basal-like and luminal-like molecular subtypes, which may be correlated with pathological subtypes of different patient outcomes. However, whether these molecular subtypes originate from the corresponding cell types in the normal urothelium and whether different cells of origin influence bladder cancer progression remain unclear. Here, we conducted cell-type-specific lineage tracing in CRISPR/Cas9-induced mouse bladder cancer models of Pten and Trp53 targeting. We show that although basal, intermediate, and superficial umbrella cells can all serve as the cell of origin for bladder cancer, transformed umbrella cells were gradually displaced by tumor cells from inner layers, particularly transformed basal cells, which had highest stemness. Histological and single cell RNA-sequencing data comparing basal- and intermediate-cell-induced bladder tumors revealed that basal-induced tumors displayed higher heterogeneity, and contained unique cell clusters including Krt14+Ki67+ highly proliferative basal cells, squamous cell carcinoma, and transitioning cells towards the Gata3+ luminal subtype. Trajectory analysis confirmed the cell lineage differentiation hierarchy uncovered in lineage tracing. Moreover, human bladder cancer molecular subtype signatures were highly enriched in mouse tumor cell clusters of the corresponding cell of origin, and a gene signature derived from the unique basal-induced clusters is predictive of worse patient outcome. Overall, our results support that the basal and luminal molecular subtypes of bladder cancer have the corresponding cells of origin as their basis, and that urothelial basal cells are intrinsically more competitive than intermediate and umbrella cells in generating aggressive bladder cancer subtypes.

cancer biology↗

bioRxiv2025

Investigating the repeatability and behavioral relationships of acuity, contrast sensitivity, form, and motion perception measurements using a novel tablet-based vision test tool

Visual function tests are important in basic and clinical vision research but are typically limited to very few aspects of human vision, coarse diagnostic resolution, and require an administrator. Recently, the generalizable, response-adaptive, self-administered Angular Indication Measurement (AIM) and Foraging Interactive D-prime (FInD) methods were developed to assess vision across different visual functions. The AIM and FInD paradigms show a range of visual stimuli per display (4x4 stimuli) spanning {+/-}2{sigma} around an adaptively estimated perceptual threshold across multiple displays. Here, we investigated the repeatability and behavioral relationships of the AIM and FInD paradigms for near visual acuity, contrast sensitivity function (CSF), form, and motion coherence threshold measurements using a novel tablet-based vision test tool. 31 healthy participants were recruited and completed two repetitions of each experiment in random order. Bland-Altman analyses were performed to calculate the Coefficient of Repeatability (precision) and Mean Bias (accuracy). Linear regressions and hierarchical cluster analysis were used to investigate the relationship between outcome parameters. Results show that AIM Form coherence and FInD Form horizontal coherence showed significant retest bias; all other tests were bias-free. Cluster analysis revealed overall clustering of CSF, form and motion outcomes. We further show significant correlations within CSF and between motion coherence outcomes but few significant correlations between form coherence outcomes. AIM and FInD near vision tests are generalizable across multiple visual functions and are precise and reliable. Most functions tested were bias-free. CSF, form, and motion outcomes clustered together, and CSF and motion outcomes correlated with one another. The combination of a generalizable, response-adaptive, and self-administered approach may be a suitable set of tests for basic science and clinical use cases.

neuroscience↗

bioRxiv2025

Diploid gametes in maize by mutation of A-Type cyclins: a step towards apomeiosis and synthetic apomixis.

Hybrid crops are agriculturally desirable due to heterosis but are costly or difficult to produce. Synthetic apomixis, clonal reproduction through seed, offers the ability to fix hybrid vigor. Two components are needed to achieve this goal: the formation of diploid gametes identical to the maternal parent through apomeiosis, and the induction of embryogenesis in the egg cell without fertilization, known as parthenogenesis. In maize, parthenogenesis was achieved by egg cell expression of the transcription factor ZmBABY BOOM 1 but a viable apomeiosis strategy has not been reported. In the MiMe (Mitosis instead of Meiosis) system, in addition to mutants that skip recombination and sister chromatid adhesion, mutation of genes involved in cell cycle control during meiosis is needed to skip the second division and ensure diploid gametes. In this report we describe the effect of mutation of maize A-type cyclin genes with similarity to Arabidopsis TARDY ASYNCHRONOUS MEIOSIS (TAM). In double mutant plants, we find that diploid gametes are formed with high efficiency and that the progeny are tetraploid. These genes provide a viable route towards creating synthetic apomixis in maize.

plant biology↗

bioRxiv2025

Fronto-parietal effective connectivity during working memory in Neurofibromatosis Type 1 adolescents and neurotypical controls

Neurofibromatosis Type 1 (NF1) is a rare, single-gene neurodevelopmental disorder. Atypical brain activation patterns have been linked to working memory difficulties in individuals with NF1. The present work investigates if NF1 has increased inhibitory activity in the frontoparietal network during working memory tasks compared to neurotypical controls. Forty-three adolescents with NF1 and twenty-six age-matched neurotypical controls completed functional magnetic resonance imaging scans during a verbal working memory task. Dynamic causal models (DCMs) were estimated for bilateral frontoparietal network (dorsolateral and ventrolateral prefrontal cortices (dlPFC and vlPFC), superior and inferior parietal gyri (SPG and IPG)). The parametric empirical Bayes approach with Bayesian model reduction was used to test the hypothesis that NF1 diagnosis would be characterised by greater inhibitory self-connections (intrinsic connectivity). Leave-one-out cross-validation (LOO-CV) was performed to test the generalisability of group differences. NF1 participants demonstrated greater average intrinsic connectivity of left dlPFC, IPG, SPG and bilateral vlPFC. The DCM that best explained effects of working memory showed that NF1 group has increased intrinsic connectivity of left vlPFC, but weaker intrinsic connectivity of right vlPFC and left dlPFC. The parameters of these connections showed a modest but positive predictive correlation of r = 0.19 (p = 0.055) with diagnosis status, suggesting a trend toward predictive value. Overall, increased average intrinsic connectivity of left dlPFC, IPG, SPG and bilateral vlPFC in NF1, suggests reduced overall sensitivity of these regions to inputs. Working memory evoked different patterns of input processing in NF1, that cannot be characterised by increased inhibition alone. Instead, modulatory connectivity related to working memory showed less inhibitory self-connectivity of left dlPFC and left vlPFC, and more inhibitory intrinsic connectivity of right vlPFC in NF1. This discrepancy between average and modulatory connectivity suggests that overall NF1 participants are responsive to cognitive task-related inputs but may show atypical adaptation to the task demands of working memory.

neuroscience↗

bioRxiv2025

Methadone blockade of IK1 promotes both long QT and Brugada-like arrhythmias: Mechanistic insights from computational modeling

BackgroundMethadone is widely used for chronic pain relief and in the maintenance therapy of opioid use disorder, however, it also increases the risk of ventricular arrhythmias and sudden cardiac death. Methadone blocks several ionic currents with different half-maximal inhibitory concentrations (IC50), including the rapid component of the delayed rectifier potassium current (IKr), the inward rectifier potassium current (IK1), the L-type calcium current (ICa,L), and the late component of the sodium current (INaL). Despite the well-known proarrhythmic effect of IKr blockade, the effects of blocking other ionic currents on arrhythmogenesis remain less well understood. MethodsComputer simulations were used to explore the proarrhythmic effects of methadone by investigating how its blocking effects on ionic currents act alone or together in arrhythmogenesis. ResultsThe major findings are: 1) blocking IK1 potentiates QT prolongation-related arrhythmogenesis by enhancing a tissue-scale dynamical instability for the spontaneous genesis of ectopic excitations. Blocking IK1 and IKr together results in a synergistic effect, greatly increasing the arrhythmia propensity, much larger than that of blocking either one alone; 2) blocking IK1 in combination with lowering ICa,L potentiates phase-2 reentry caused by spike-and-dome action potential morphology, an arrhythmia mechanism of Brugada syndrome. Blocking IKr exhibits little effect for this mechanism of arrhythmias; and 3) hypoxia, often comorbid in methadone populations, can potentiate QT prolongation-related arrhythmias at high sympathetic activity and phase-2 reentry at low or basal sympathetic activity, mainly via its effect on ICa,L. ConclusionsThese simulation results provide mechanistic insights into the genesis of QT prolongation-related Torsades de Pointes and Brugada-like ECG related arrhythmias caused by methadone use.

pharmacology and toxicology↗

bioRxiv2025

Direct pathway bias and altered striatal neurogenesis in human iPSC models of 16p11.2 CNVs: Evidence from single-cell and functional analyses

Striatal medium spiny neurons (MSNs) control motor, cognitive, and social domains via direct (dMSNs) and indirect (iMSNs) basal ganglia pathways. Recent genomic analyses implicate striatal circuit dysfunction in neurodevelopmental disorders (NDDs) and highlight MSNs as a newly recognised cell type affected in schizophrenia, yet much NDD research still focuses on cortical interneurons and glutamatergic neurons, leaving MSN involvement understudied. Here, we use human iPSC-derived MSNs to demonstrate high-fidelity striatal development and explore 16p11.2 copy number variants (CNVs) - mutations predisposing carriers to autism spectrum disorder, schizophrenia, intellectual disability and other NDD conditions featuring basal ganglia deficits. By profiling both 16p11.2 duplication and deletion MSNs, we uncover reciprocal changes in MSN neurogenesis kinetics that converge on a dMSN fate bias. These shifts correspond to altered calcium signalling and enhanced firing upon direct-pathway activation. Our findings reveal a previously unappreciated role for MSN subtype imbalances in NDD pathogenesis and open new avenues for therapeutic intervention.

neuroscience↗

bioRxiv2024

Effects of non-invasive brain stimulation on effective connectivity during working memory task in Neurofibromatosis Type 1 patients

This study examined the effects of anodal transcranial direct current stimulation (atDCS) on effective connectivity during a working memory task. Eighteen adolescents with Neurofibromatosis Type 1 (NF1) completed a single{square}blind sham{square}controlled cross{square}over randomised atDCS trial. Dynamic causal modelling was used to estimate the effective connectivity between regions that showed working memory effects from the fMRI. Group-level inferences for between sessions (pre- and post-stimulation) and stimulation type (atDCS and sham) effects were carried out using the parametric empirical Bayes approach. A correlation analysis was performed to relate the estimated effective connectivity parameters of left dlPFC pre-atDCS and post-atDCS to the concentration of gamma-aminobutyric acid (GABA) measured via magnetic resonance spectroscopy (MRS-GABA). Next, correlation analysis was repeated using all working memory performance and all pre-atDCS and post-atDCS connectivity parameters. It was found that atDCS decreased average excitatory connectivity from left dorsolateral prefrontal cortex (dlPFC) to left superior frontal gyrus and increased average excitatory connectivity to left globus pallidus. Further, reduced average intrinsic (inhibitory) connectivity of left dlPFC was associated with lower MRS-GABA. However, none of the connectivity parameters of dlPFC showed any association with performance on a working memory task. These findings suggest that atDCS reorganised connectivity from frontal to fronto-striatal connectivity. As atDCS-related changes were not specific to the effect of working memory, they may have impacted general cognitive control processes. In addition, by reducing MRS-GABA, atDCS might make dlPFC more sensitive and responsive to external stimulation, such as performance of cognitive tasks. Highlights- atDCS was applied to left dlPFC in NF1 patients during working memory - After atDCS, no effect on modulatory connectivity - Evidence for increased N-back average connectivity from dlPFC to globus pallidus - Less dlPFC MRS-GABA was associated with less dlPFC inhibition

neuroscience↗

bioRxiv2024

Whole Genome 3D Blood Biopsy Profiling of Canine Cancers: Development and Validation of EpiSwitch Multi-Choice Array-Based Diagnostic Test.

Veterinary oncology has a critical need for an accurate, specific, and sensitive non-invasive (blood) biomarker assay to assess multiple canine oncological indications early to better inform therapeutic interventions. Extended from clinical applications in human oncology, here we report on a novel 3D genomics approach to identify systemic blood biomarkers for canine diffuse large B-cell lymphoma (DLBCL), T-zone lymphoma (TZL), hemangiosarcoma (HSA), histiocytic sarcoma, osteosarcoma, and canine malignant melanoma, in a single assay format that encompasses multiple classes and phenotypes of cancer. In the validation of the independent test cohort the 3D whole-genome profiling in peripheral blood demonstrated high sensitivity and specificity for lymphomas and sarcomas as a class, with accuracy >80%; and high sensitivity and specificity for individual indications, with accuracy >89%. This study demonstrates a 3D genomic approach can be used to develop a non-invasive, blood-based test for multiple choice diagnosis of canine oncological indications. The modular EpiSwitch(R) Specific Canine Blood (EpiSwitch SCB) test promises to help veterinary specialists to diagnose the disease, make more informed treatment decisions, better utilize alternative effective treatments, minimize or avoid unnecessarily toxicity, and efficiently manage costs and resources.

molecular biology↗

bioRxiv2024

Early-life exposures to specific commensal microbes prevent type 1 diabetes.

Early-life disruptions of the gut microbiome have long-lasting impacts on the risk of developing autoimmune diseases. How the composition of the early-life microbiota contributes to autoimmunity and whether manipulating it can prove therapeutically beneficial remains largely unexplored. Here we demonstrate that a simple consortium of nine early-life commensal bacteria (PedsCom) prevents type 1 diabetes (T1D) in diabetes-susceptible NOD mice. Remarkably, we find that this protection is completely dependent upon early-life colonization. During this critical time window of early-life colonization and immune development, specific microbes unexpectedly translocate from the gut to peripheral tissues and induce the tolerogenic responses required for T1D protection. These findings highlight how the timing and localization of microbial interactions during a pivotal stage of immune development contribute to protection from T1D. Altogether, these findings suggest an opportunity to develop microbial therapies for human infants to prevent autoimmune diseases. One sentence summaryA defined consortium of early-life microbes shapes immune development and prevents type 1 diabetes.

immunology↗

bioRxiv2024

A tale of too many trees: a conundrum for phylogenetic regression

AO_SCPLOWBSTRACTC_SCPLOWJust exactly which tree(s) should we assume when testing evolutionary hypotheses? This question has plagued comparative biologists for decades. Given a perfectly estimated tree (if this is even possible in practice), we seldom know with certainty whether such a tree is truly best (or even adequate) to represent the evolutionary history of our studied traits. Regardless of our certainty, choosing a tree is required for all phylogenetic comparative methods. Yet, phylogenetic conflict and error are ubiquitous in modern comparative biology, and we are still learning about their dangers when testing evolutionary hypotheses. Here we investigated the consequences of gene tree-species tree mismatch for phylogenetic regression in the presence of incomplete lineage sorting. Our simulation experiments reveal excessively high false positive rates for mismatched phylogenetic regression with both small and large trees, simple and complex traits, and known and estimated phylogenies. In some cases, we find evidence of a directionality of error: incorrectly assuming a species tree for traits that evolved according to a gene tree sometimes fares worse than the opposite. To explore difficult yet realistic regression scenarios, we also used estimated rather than known trees to conduct case studies, as well as an expansive gene expression dataset to investigate an arguably best-case scenario in which one may have a better chance to match tree with trait. Though never meant to be a panacea for all that may ail phylogenetic comparative methods, we found promise in the application of a robust estimator as a potential, albeit imperfect, solution to some issues raised by tree mismatch, perhaps offering a path forward. Collectively, our results emphasize the importance of careful study design for comparative methods, highlighting the need to fully appreciate the role of adequate phylogenetic modeling for testing evolutionary hypotheses.

evolutionary biology↗

bioRxiv2023

PfAP2-MRP DNA-binding protein is a master regulator of parasite pathogenesis during malaria parasite blood stages

Malaria pathogenicity results from the parasites ability to invade, multiply within and then egress from the host red blood cell (RBC). Infected RBCs are remodeled, expressing antigenic variant proteins (such as PfEMP1, coded by the var gene family) for immune evasion and survival. These processes require the concerted actions of many proteins, but the molecular regulation is poorly understood. We have characterized an essential Plasmodium specific Apicomplexan AP2 (ApiAP2) transcription factor in Plasmodium falciparum (PfAP2-MRP; Master Regulator of Pathogenesis) during the intraerythrocytic developmental cycle (IDC). An inducible gene knockout approach showed that PfAP2-MRP is essential for development during the trophozoite stage, and critical for var gene regulation, merozoite development and parasite egress. ChIP-seq experiments performed at 16 hour post invasion (h.p.i.) and 40 h.p.i. matching the two peaks of PfAP2-MRP expression, demonstrate binding of PfAP2-MRP to the promoters of genes controlling trophozoite development and host cell remodeling at 16 h.p.i. and antigenic variation and pathogenicity at 40 h.p.i. Using single-cell RNA-seq and fluorescence-activated cell sorting, we show de-repression of most var genes in{Delta} pfap2-mrp parasites that express multiple PfEMP1 proteins on the surface of infected RBCs. In addition, the{Delta} pfap2-mrp parasites overexpress several early gametocyte marker genes at both 16 and 40 h.p.i., indicating a regulatory role in the sexual stage conversion. Using the Chromosomes Conformation Capture experiment (Hi-C), we demonstrate that deletion of PfAP2-MRP results in significant reduction of both intra-chromosomal and inter-chromosomal interactions in heterochromatin clusters. We conclude that PfAP2-MRP is a vital upstream transcriptional regulator controlling essential processes in two distinct developmental stages during the IDC that include parasite growth, chromatin structure and var gene expression.

genomics↗

bioRxiv2022

New high-resolution maps show that rubber causes significant deforestation

Understanding the impacts of cash crop expansion on natural forest is of fundamental importance. However, for most crops there are no remotely-sensed global maps1, and global deforestation impacts are estimated using models and extrapolations. Natural rubber is an example of a major commodity for which deforestation impacts have been highly uncertain, with estimates differing more than five-fold1-4. Here we harnessed earth observation satellite data and cloud computing5 to produce the first high-resolution maps of rubber and associated deforestation covering all Southeast Asia. Our maps indicate that rubber-related forest loss has been significantly underestimated in policy, by the public and in recent reports6-8. Our direct remotely-sensed observations show that deforestation for rubber is two to threefold higher than suggested by figures currently widely used for setting policy4. With over 3.76 million hectares of forest loss for rubber since 1993 (2.77 [2.5-3 95% CI] million hectares since 2000), and over 1 million hectares of rubber plantations established in Key Biodiversity Areas, the impacts of rubber on biodiversity and ecosystem services in Southeast Asia are extensive. Thus, rubber deserves more attention in domestic policy, within trade agreements and in incoming due diligence regulations.

ecology↗

bioRxiv2022

Modulation of adaptive immune responses by Akkermansia muciniphila is restricted to an early life window in NOD mice

Early life microbiota drive immune system development and influence risk for immune dysfunction later in life, including the development of type 1 diabetes (T1D). Which specific early-life microbes modulate diabetes risk and the timing of these critical interactions are not well understood. To address this gap in knowledge, we screened for microbes that induce systemic IgG1 responses in young NOD mice. We isolated a strain of Akkermansia muciniphila that potently induces systemic IgG1 antibodies and peripheral regulatory T cells (pTregs). Since this mucus-degrading commensal protects NOD mice from T1D and is associated with lower risk of developing T1D in children, we investigated how A. muciniphila impacts early-life host-commensal interactions using gnotobiotic NOD mice colonized with a defined 9-member bacterial consortium that models the early life microbiome. We find that A. muciniphila potently induces pTregs and enhances antibody responses to other commensal microbes. Remarkably, these effects only occur when A. muciniphila colonizes NOD mice prior to weaning, establishing that the specific window of exposure to A. muciniphila shapes adaptive immune system development in diabetes-susceptible NOD mice. This time dependence provides important evidence that early-life exposure may enhance microbiota-based therapies to prevent T1D. One Sentence SummaryAkkermansia muciniphila induces peripheral Tregs and enhances antibody responses to itself and other commensals during an early life window.

immunology↗

bioRxiv2022

Craniofacial dysmorphology in Down Syndrome is caused by increased dosage of Dyrk1a and at least three other genes

Down syndrome (DS), trisomy of human chromosome 21 (Hsa21), occurs in 1 in 800 live births and is the most common human aneuploidy. DS results in multiple phenotypes, including craniofacial dysmorphology, characterised by midfacial hypoplasia, brachycephaly and micrognathia. The genetic and developmental causes of this are poorly understood. Using morphometric analysis of the Dp1Tyb mouse model of DS and an associated genetic mouse genetic mapping panel, we demonstrate that four Hsa21-orthologous regions of mouse chromosome 16 contain dosage-sensitive genes that cause the DS craniofacial phenotype, and identify one of these causative genes as Dyrk1a. We show that the earliest and most severe defects in Dp1Tyb skulls are in bones of neural crest (NC) origin, and that mineralisation of the Dp1Tyb skull base synchondroses is aberrant. Furthermore, we show that increased dosage of Dyrk1a results in decreased NC cell proliferation and a decrease in size and cellularity of the NC-derived frontal bone primordia. Thus, DS craniofacial dysmorphology is caused by increased dosage of Dyrk1a and at least three other genes. Summary statementCraniofacial dysmorphology in mouse models of Down syndrome is caused by increased dosage of at least four genes including Dyrk1a, resulting in reduced proliferation of neural crest-derived cranial bone progenitors.

developmental biology↗