Biology subjects

Elliott, J.

Publications and source records attributed to Elliott, J..

At least 19 recordsLinked to original sources

bioRxiv2026

An ex vivo gut mucosal explant assay to compare HIV tissue susceptibility shows increased HIV susceptibility with methamphetamine exposure

BackgroundExisting ex vivo mucosal explant models for HIV assess viral replication but do not fully capture the ability of tissue to support productive infection and transfer to target cells, an important indicator of tissue susceptibility. Additional tools to investigate relative mucosal susceptibility to HIV are necessary to better understand risk factors, such as substance use, or to evaluate therapeutics. ResultsWe developed an ex vivo gut mucosal explant assay incorporating a CCR5/CXCR4-expressing GFP-reporter cell co-culture to quantify both viral replication and transfer. Susceptibility was quantified using a composite metric based on time to infection endpoint across viral doses. Modulators of susceptibility, including anti-CD3 stimulation, tenofovir, and methamphetamine, were evaluated. The assay reliably detected differences in tissue susceptibility under various experimental conditions. We detected enhanced susceptibility following anti-CD3 stimulation, while tenofovir pretreatment reduced susceptibility in a dose-dependent manner. Methamphetamine exposure resulted in a modest but significant increase in gut tissue susceptibility to HIV. ConclusionsThis novel ex vivo explant susceptibility assay advances HIV mucosal transmission research by measuring both viral production and transfer. It can detect subtle changes in susceptibility, providing a versatile platform for evaluating prevention therapeutics, host and microbial factors, and substance use effects.

microbiology↗

bioRxiv2025

Is synuclein aggregation a derived or ancestral trait? Ancestral sequence reconstruction uncovers stepwise evolution of synuclein aggregation

Protein aggregation drives many neurodegenerative diseases, including Parkinsons disease, where misfolded -synuclein (Syn) forms fibrillar assemblies that accumulate as Lewy bodies. Although Syn aggregation has been extensively characterized, its evolutionary origins and sequence determinants remain unresolved. Here, we use ancestral sequence reconstruction (ASR) to trace the emergence of fibril-forming ability in the synuclein family. We inferred synuclein phylogeny and experimentally resurrected common ancestors, including ROOT synuclein, the last common ancestor of all synucleins, and key intermediates along the Syn lineage. Strikingly, ROOT synuclein is non-aggregating, demonstrating that fibril formation is an evolved, rather than ancestral property. Aggregation first emerges at the ancestral {beta} node, is retained in Syn, and suppressed in {beta}-synuclein. Biophysical analyses including mass spectrometry and NMR reveal that aggregation aligns with greater complexity and heterogeneity in the monomer conformational ensemble, suggesting that evolutionary sequence changes progressively remodel monomer landscapes to favor fibril formation. Complementing these insights, comparative sequence analysis reveals that the transition from ROOT to -WT is marked by the stepwise acquisition of residues critical for stabilizing the fibril core. Early mutations stabilized the {beta}-arch core, enabling the onset of fibril formation, followed by substitutions that reinforce protofilament-protofilament interactions. Together, ASR defines an evolutionary framework for synuclein aggregation linking progressive sequence evolution and conformational complexity to the molecular origins of Syn fibril formation.

biophysics↗

bioRxiv2025

Genomic Informational Field Theory (GIFT) to map complex traits in small sample sizes

Genome-wide association studies (GWAS) are commonly used to investigate the genetic basis of complex traits. However, to be adequately powered they typically require large sample sizes to provide precise inferences. To address this challenge, this paper introduces GIFT, a novel data analytic method that enhances the power of genetic analyses, enabling the use of smaller datasets without compromising precision. In a small cohort of 157 ponies, GIFT was applied to examine the complex trait of "height at withers", comparing its performance to traditional GWAS. GIFT enabled the identification genetic loci linked to insulin physiology validating, in turn, a long-standing hypothesis that "height at withers" is associated with insulin physiology in equids, potentially promoting equine metabolic syndrome (EMS). By redefining correlations between single nucleotide polymorphisms (SNPs), GIFT provides new insights into linkage disequilibrium and reveals underlying gene network structures. This, in turn, enables the distinction between core and peripheral genes within these networks. By reducing the time and cost associated with large-scale genotype-phenotype mapping studies without sacrificing statistical robustness, GIFT broadens access to quantitative genetic research, allowing smaller-scale studies to investigate the genetic architecture of complex traits with greater resolution. NEW & NOTEWORTHYInferring genotype-phenotype associations typically require large sample sizes, limiting many genetic studies. GIFT, a novel data analytics tool, overcomes this by enabling accurate association mapping in small datasets. We further show how GIFTs extended framework infers linkage disequilibrium and gene networks, distinguishing core from peripheral genes involved in complex traits. This advancement enhances understanding of biological architecture and enables high-resolution genetic research in limited cohorts, offering a powerful, cost-effective alternative to traditional large-scale approaches.

genetics↗

bioRxiv2025

Comparison of oral and gut microbiome highlights role of oral bacteria in systemic inflammation in HIV

BackgroundChronic HIV-1 infection is associated with increased inflammation-related comorbidities, despite effective viral suppression with antiretroviral therapy. While the role of the gut microbiome in inflammation is well-studied, the contribution of the oral microbiome remains less clear. This study investigates the relationship between the oral and gut microbiomes in driving systemic inflammation in persons with HIV. MethodsThis cross-sectional study utilized archived samples from 198 participants (99 with HIV and 99 without HIV). Oral microbiome composition was analyzed via 16S rRNA sequencing and systemic inflammatory biomarkers were measured using multiplex assays. Gut microbiome data from previous studies were integrated for comparative analyses. Bacterial inflammatory potential was assessed through in vitro co-culture and epithelial barrier permeability assays. ResultsThe oral microbiome in HIV was characterized by increased Veillonella, Capnocytophaga, and Megasphaera, and several decreased genera including Fusobacterium. Using PERMANOVA, we found that the oral microbiome was a significant driver of cytokine variation in HIV compared to the gut microbiome, and identified specific associations with oral Veillonella and Megasphaera. We found no differences in anti-Veillonella parvula serum IgG by HIV status, but IgG titers did correlate with microbial translocation markers sCD14 and LBP in HIV. In vitro studies demonstrated that Veillonella parvula increased oral epithelial barrier permeability and induced monocyte activation. ConclusionsThe oral microbiome, particularly Veillonella parvula, may contributes to systemic inflammation in HIV through mechanisms involving epithelial barrier disruption, oral translocation, and monocyte activation.

microbiology↗

bioRxiv2024

Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson's disease

Alpha-synuclein (Syn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinsons disease and forms intraneuronal inclusions called Lewy Bodies. While the mechanism underlying the dysregulation of Syn in Parkinsons disease is unclear, it is thought that prionoid cell-to-cell propagation of Syn has an important role. Through a high throughput screen, we recently identified 38 genes whose knock down modulates Syn propagation. Follow up experiments were undertaken for two of those genes, TAX1BP1 and ADAMTS19, to study the mechanism with which they regulate Syn homeostasis. We used a recently developed M17D neuroblastoma cell line expressing triple mutant (E35K+E46K+E61K) "3K" Syn under doxycycline induction. 3K Syn spontaneously forms inclusions that show ultrastructural similarities to Lewy Bodies. Experiments using that cell line showed that TAX1BP1 and ADAMTS19 regulate how Syn interacts with lipids and phase separates into inclusions, respectively, adding to the growing body of evidence implicating those processes in Parkinsons disease. Through RNA sequencing, we identified several genes that are differentially expressed after knock-down of TAX1BP1 or ADAMTS19. Burden analysis revealed that those differentially expressed genes (DEGs) carry an increased frequency of rare risk variants in Parkinsons disease patients versus healthy controls, an effect that was independently replicated across two separate cohorts (GP2 and AMP-PD). Weighted gene co-expression network analysis (WGCNA) showed that the DEGs cluster within modules in regions of the brain that develop high degrees of Syn pathology (basal ganglia, cortex). We propose a novel model for the genetic architecture of sporadic Parkinsons disease: increased burden of risk variants across genetic networks dysregulates pathways underlying Syn homeostasis, thereby leading to pathology and neurodegeneration.

cell biology↗

bioRxiv2024

Biological sex and BMI influence the longitudinal evolution of adolescent and young adult MRI-visible perivascular spaces

Background and PurposeAn association recently emerged between magnetic resonance imaging (MRI)-visible perivascular spaces (MV-PVS) with intracerebral solute clearance and neuroinflammation, in adults. However, it is unknown how MV-PVS change throughout adolescence and what factors influence MV-PVS volume and morphology. This study assesses the temporal evolution of MV-PVS volume in adolescents and young adults, and secondarily evaluates the relationship between MV-PVS, age, sex, and body mass index (BMI). Materials and MethodsThis analysis included a 783 participant cohort from the longitudinal multicenter National Consortium on Alcohol and Neurodevelopment in Adolescence study that involved up to 6 imaging visits spanning 5 years. Healthy adolescents aged 12-21 years at study entry with at least two MRI scans were included. The primary outcome was mean MV-PVS volume (mm3/white matter cm3). ResultsOn average, males had greater MV-PVS volume at all ages compared to females. A linear mixed-effect model for MV-PVS volume was performed. Mean BMI and increases in a persons BMI were associated with increases in MV-PVS volume over time. In females only, changes in BMI correlated with MV-PVS volume. One unit increase in BMI above a persons average BMI was associated with a 0.021 mm3/cm3 increase in MV-PVS volume (p<0.001). ConclusionThis longitudinal study showed sex differences in MV-PVS features during adolescence and young adulthood. Importantly, we report that increases in BMI from a persons mean BMI are associated with increases in MV-PVS volume in females only. These findings suggest a potential link between MV-PVS, sex, and BMI that warrants future study.

neuroscience↗

bioRxiv2024

Direct quantification of condensate material properties in live cells reveals the regulation of synapsin condensates viscoelasticity by alpha-synuclein

Synapsin and -synuclein represent a growing list of condensate-forming proteins where the material states of condensates are directly linked to cellular functions (e.g., neurotransmission) and pathology (e.g., neurodegeneration). However, quantifying condensate material properties in living systems has been a significant challenge. To address this, we develop MAPAC (micropipette aspiration and whole-cell patch clamp), a platform that allows direct material quantification of condensates in live cells. We find 10,000-fold variations in the viscoelasticity of synapsin condensates, regulated by the partitioning of -synuclein, a marker for synucleinopathies. Through in vitro reconstitutions, we identify 4 molecular factors that distinctly regulate the viscosity and interfacial tension of synapsin condensates, verifying the cellular effects of -synuclein. Overall, our study provides unprecedented quantitative insights into the material properties of neuronal condensates and reveals a crucial role of -synuclein in regulating condensate viscoelasticity. Furthermore, we envision MAPAC applicable to study a broad range of condensates in vivo.

cell biology↗

bioRxiv2024

AHR activation accelerates the resolution of TGF-β1 induced fibroblast activation and promotes alveolar type 1 cell regeneration in alveolar organoids

Regeneration of the alveolar epithelium is necessary to restore tissue architecture and gas exchange capabilities in chronic pulmonary diseases such as fibrosing interstitial lung disease. While it is known alveolar type 2 (AT2) cells give rise to alveolar type 1 (AT1) cells to repair the alveolar epithelium after injury, methods to promote this process under pathological settings are poorly understood. Here, using a complex 3D organoid culture with TGF-{beta}1 dependent impaired AT1 spheroid formation, we performed a high-throughput screen (HTS) with [~]16,800 compounds to identify small molecules that increase number of AT1 spheroids. Longitudinal single cell RNA sequencing (scRNA-seq) revealed that DB-11-BE87 increased AT1 regeneration by reducing TGF-{beta}1 induced fibroblast activation, concurrently with AHR activation in those cells. These studies highlight a novel HTS system to identify factors that can promote AT1 differentiation and suggest AHR activation as a method to counteract pathological TGF-{beta}1 signaling in pulmonary disease.

cell biology↗

bioRxiv2023

Extracellular modulation of TREK-2 activity with nanobodies provides insights into the mechanism of K2P channel regulation

Potassium channels of the Two-Pore Domain (K2P) subfamily, KCNK1-KCNK18, play crucial roles in controlling the electrical activity of many different cell types and represent attractive therapeutic targets. However, the identification of highly selective small molecule drugs against these channels has been challenging due to the high degree of structural and functional conservation that exists not only between K2P channels, but across the whole K+ channel superfamily. To address the issue of selectivity, we generated camelid antibody fragments (nanobodies) against the TREK-2 (KCNK10) K2P K+ channel and identified selective binders including several that directly modulate channel activity. X-ray crystallography and CryoEM data of these nanobodies in complex with TREK-2 also reveal insights into their mechanisms of activation and inhibition via binding to the extracellular loops and Cap domain, as well as their suitability for immunodetection. It also facilitated design of a biparatropic inhibitory nanobody with markedly improved affinity and efficacy. These new tools therefore provide important insights into TREK channel gating and suggest alternative, highly selective approach to modulation of K2P channel activity via their extracellular domains.

biophysics↗

bioRxiv2023

Eelgrass (Zostera spp.) associated phytomyxids are host-specific congeneric parasites and predominant eukaryotes in the eelgrass rhizosphere on a global scale

Together with increasing environmental and anthropogenic pressures, pathogenic diseases are one of important factors contributing to the ongoing decline of seagrass meadows worldwide; yet the diversity and ecology of the microorganisms acknowledged as seagrass parasites remain critically understudied. Here we investigate phytomyxid parasites (Rhizaria: Endomyxa: Phytomyxea) of three different eelgrass (Zostera spp.) species found in the Northern hemisphere. We present molecular evidence that Plasmodiophora bicaudata, a long-recognized parasite of dwarf eelgrass taxa, is closely related to the novel phytomyxid recently discovered in root hairs of Zostera marina, and together they form a distinct clade within the order Phagomyxida, proposed here as Feldmanniella gen. nov. A full life cycle is systematically described in a phagomyxid representative for the first time, proving its conformity with the generalized phytomyxid life history, despite previous uncertainties. The presence of primary infection stages in nearly all collected eelgrass specimens, and subsequent analysis of amplicon sequences from a global Z. marina dataset, reveal phytomyxids to be ubiquitous and one of the predominant microeukaryotes associated with eelgrass roots on a global scale. Our discoveries challenge the current view of Phytomyxea as rare entities in seagrass meadows and suggest their generally low pathogenicity in natural ecosystems. Originality-Significance StatementThis study addresses a group of microbial parasites critically understudied in the marine environment. It presents complex evidence that Phytomyxea - obligate intracellular biotrophs previously considered to be rare entities in the oceans, are in fact ubiquitous endobionts of seagrasses of the genus Zostera - foundation species and important primary producers in coastal areas worldwide. Our work represents a significant contribution to the fields of aquatic microbiology and seagrass ecology and is seminal to understanding the biology of Phytomyxea outside of terrestrial ecosystems.

microbiology↗

bioRxiv2023

Establishment of beta cell heterogeneity via differential CpG methylation at Nnat

Aims/hypothesisBeta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. These include a subpopulation of highly-connected hub cells, important for the propagation of intercellular Ca2+ waves. Functional subpopulations have also been demonstrated in human beta cells, with an altered subtype distribution apparent in type 2 diabetes. At present, the molecular mechanisms through which beta cell hierarchy is established are poorly understood. Changes at the level of the epigenome provide one such possibility which we explore here by focussing on the imprinted gene neuronatin (Nnat), which is required for normal insulin synthesis and secretion. MethodsSingle cell RNA-seq datasets were examined using Seurat 4.0 and ClusterProfiler running under R. Transgenic mice expressing eGFP under the control of the Nnat enhancer/promoter regions were generated for fluorescence-activated cell (FAC) sorting of beta cells and downstream analysis of CpG methylation by bisulphite and RNA sequencing, respectively. Animals deleted for the de novo methyltransferase, DNMT3A from the pancreatic progenitor stage were used to explore control of promoter methylation. Proteomics was performed using affinity purification mass spectrometry and Ca2+ dynamics explored by rapid confocal imaging of Cal-520 and Cal-590. Insulin secretion was measured using Homogeneous Time Resolved Fluorescence Imaging. ResultsNnat mRNA was differentially expressed in a discrete beta cell population in a developmental stage- and DNA methylation (DNMT3A)-dependent manner. Thus, pseudo-time analysis of embryonic data sets demonstrated the early establishment of Nnat-positive and negative subpopulations during embryogenesis. NNAT expression is also restricted to a subset of beta cells across the human islet that is maintained throughout adult life. NNAT+ beta cells also displayed a discrete transcriptome at adult stages, representing a sub-population specialised for insulin production, reminiscent of recently-described "{beta}HI" cells and were diminished in db/db mice. Hub cells were less abundant in the NNAT+ population, consistent with epigenetic control of this functional specialization. Conclusions/interpretationThese findings demonstrate that differential DNA methylation at Nnat represents a novel means through which beta cell heterogeneity is established during development. We therefore hypothesise that changes in methylation at this locus may thus contribute to a loss of beta cell hierarchy and connectivity, potentially contributing to defective insulin secretion in some forms of diabetes. Research in contextWhat is already known about this subject? - Neuronatin (Nnat/NNAT) is an imprinted gene in humans and mice and is required for glucose-stimulated insulin secretion in vivo - Pancreatic beta cells are functionally heterogeneous with specific highly-connected subpopulations known to coordinate islet wide Ca2+ dynamics - Functional subpopulations have been described in human beta cells and their distribution is altered in type 2 diabetes What is the key question? - Does NNAT mark a discrete subpopulation of functional beta cells and which epigenetic pathways coordinate its formation and maintenance? What are the new findings? - A subpopulation of NNAT+ beta cells is established prior to the first week of postnatal life in mice via de novo DNA methylation at the Nnat promoter - NNAT+ beta cells are transcriptionally highly differentiated and appear to be functionally specialised for insulin production, possibly corresponding to recently-described "{beta}HI" and "CD63hi" beta cells. NNAT is expressed in a subset of beta cells across the human islet, and its deficiency in human beta cells diminishes glucose-stimulated insulin secretion - NNAT+ cells are likelier to belong to the population of follower, rather than hub cells, consistent with a role in insulin production rather than glucose detection How might this impact on clinical practice in the foreseeable future? - Epigenome-modifying compounds may provide a way of enhancing beta cell function and the ensemble behaviour of the islet to stimulate insulin secretion

cell biology↗

bioRxiv2021

Slow-oscillatory tACS does not modulate human motor cortical response to repeated plasticity paradigms

Previous history of activity and learning modulates synaptic plasticity and can lead to saturation of synaptic connections. According to the synaptic homeostasis hypothesis, neural oscillations during slow-wave sleep play an important role in restoring plasticity within a functional range. However, it is not known whether slow-wave oscillations - without the concomitant requirement of sleep - play a causal role in human synaptic homeostasis. Here, slow-oscillatory transcranial alternating current stimulation (tACS, 1Hz, 1mA, 18 minutes) was interleaved between two plasticity-inducing interventions: motor learning, and a paradigm known to induce long-term-potentiation-like plasticity in human motor cortex (paired associative stimulation; PAS). The hypothesis tested was that slow-oscillatory tACS would abolish the expected interference between motor learning and PAS, and facilitate plasticity from successive interventions. Thirty-six participants received sham and active fronto-motor tACS in two separate sessions, along with electroencephalography (EEG) recordings. A further 38 participants received tACS through a control (posterior midline) montage. Using neuro-navigated transcranial magnetic stimulation (TMS) over the left motor cortex, motor evoked potentials (MEPs) were recorded throughout the session. Bayesian statistics were used to quantify evidence for or against the hypothesis of an effect of each intervention on MEP amplitude. As expected, there was converging evidence that motor training increased MEPs. Importantly, we found moderate evidence against an effect of active tACS in restoring PAS plasticity, and no evidence of lasting entrainment of slow-oscillations in the EEG. This suggests that, under the conditions tested here, slow-oscillatory tACS does not modulate synaptic homeostasis in the motor system of awake humans.

neuroscience↗

bioRxiv2020

Towards establishing no observed adverse effect levels (NOAEL) for different sources 1 of dietary phosphorus in feline adult diets: results from a 7 month feeding study

High dietary phosphorus (P), particularly soluble salts, may contribute to chronic kidney disease development in cats. The aim of this study was to assess the safety of P supplied at 1g/1000kcal from a highly soluble P salt in P-rich dry format feline diets. Seventy-five healthy adult cats (n=25/group) were fed either a low P control (1.4g/1000 kcal; calcium:phosphorus ratio, Ca:P 0.97) or one of two test diets with 4g/1000 kcal (4184kJ); Ca:P 1.04 or 5g/1000kcal; Ca:P 1.27, both incorporating 1g/1000kcal (4184kJ) sodium tripolyphosphate (STPP) - for a period of 30 weeks in a randomised parallel-group study. Health markers in blood and urine, glomerular filtration rate, renal ultrasound and bone density were assessed at baseline and at regular time points. At the end of the test period, responses following transition to a commercial diet (total P - 2.34g/1000kcal, Ca:P 1.3) for a 4-week washout period were also assessed. No adverse effects on general, kidney or bone (skeletal) function and health were observed. P and Ca balance, some serum biochemistry parameters and regulatory hormones were increased in cats fed test diets from week 2 onwards (p[≤]0.05). Data from the washout period suggest that increased serum creatinine and urea values observed in the two test diet groups were influenced by dietary differences during the test period, and not indicative of changes in renal function. The present data suggest NOAELs for feline diets containing 1g P/1000kcal (4184kJ) from STPP and total phosphorus level of up to 5g/1000kcal (4184kJ) when fed for 30 weeks.

pharmacology and toxicology↗

bioRxiv2020

A systematic review of European farmer and non-farmer attitudes towards landscapes, ecosystem services, and agricultural management practices: Implications for permanent grassland management.

Permanent grassland (PG) is an important agricultural land use for the delivery of multiple ecosystem services (ES), including carbon sequestration, water quality protection, food production, habitat provision, and cultural activities. However, PG environments are threatened by sub-optimal management, cultivation, and abandonment that are influenced by context, land managers attitudes and societal demand for ES. Therefore, the perceptions and attitudes of key decision-makers (farmers) and other stakeholders (non-farmers, including citizens and consumers of the products of permanent grasslands, and ES) need to be understood to ensure the sustainability of PGs and the ES they provide. A systematic review of the literature identified 135 scholarly articles. Application of thematic analysis, allowed the organization, and synthesis of current research related to (different) stakeholder attitudes, and how these influence PG management and the delivery of ES. The results suggest that different stakeholders hold different views towards permanent grassland, with farmers in particular having to balance economic with other (potentially conflicting) drivers. The types of knowledge held by different groups of stakeholders, access to sources of information, as well as the influence of knowledge on behaviour; and environmental values (for example in relation to aesthetics or conservation of biodiversity) explained why certain motivations for attitudes and behaviours are held. A major gap, however, was identified in relation to PG as opposed to other types of landscape.

ecology↗

bioRxiv2019

Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis

A large number of HIV-1 integrase (IN) alterations, referred to as class II substitutions, exhibit pleotropic effects during virus replication. However, the underlying mechanism for the class II phenotype is not known. Here we demonstrate that all tested class II IN substitutions compromised IN-RNA binding in virions by one of three distinct mechanisms: i) markedly reducing IN levels thus precluding formation of IN complexes with viral RNA; ii) adversely affecting functional IN multimerization and consequently impairing IN binding to viral RNA; iii) directly compromising IN-RNA interactions without substantially affecting IN levels or functional IN multimerization. Inhibition of IN-RNA interactions resulted in mislocalization of the viral ribonucleoprotein complexes outside the capsid lattice, which led to premature degradation of the viral genome and IN in target cells. Collectively, our studies uncover causal mechanisms for the class II phenotype and highlight an essential role of IN-RNA interactions for accurate virion maturation.

microbiology↗

bioRxiv2019

Systematic identification of factors bound to isolated metaphase ESC chromosomes reveals a role for chromatin repressors in compaction

Epigenetic information is transmitted from mother to daughter cells through mitosis. To identify trans-acting factors and cis-acting elements that might be important for conveying epigenetic memory through cell division, we isolated native (unfixed) chromosomes from metaphase-arrested cells using flow cytometry and performed LC-MS/MS to determine the repertoire of chromosome-bound proteins. Quantitative proteomic comparisons between metaphase-arrested cell lysates and chromosome-sorted samples revealed a cohort of proteins that were significantly enriched on mitotic ESC chromosomes. These include pluripotency-associated transcription factors, repressive chromatin-modifiers (such as PRC2 and DNA methyl-transferases) and proteins governing chromosome architecture. We showed that deletion of PRC2, DNMT1/3a/3b or Mecp2 provoked an increase in the size of individual mitotic chromosomes consistent with de-condensation, as did experimental cleavage of cohesin complexes. These data provide a comprehensive inventory of chromosome-bound factors in pluripotent stem cells at mitosis and reveal an unexpected role for chromatin repressor complexes in preserving mitotic chromosome compaction.

cell biology↗

bioRxiv2018

Genome-wide association and functional studies identify 46 novel loci for alcohol consumption and suggest common genetic mechanisms with neuropsychiatric disorders

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. We conducted a genome-wide association study (GWAS) of alcohol use in ~480,000 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 novel, common loci, and investigated their potential functional significance using magnetic resonance imaging data, gene expression and behavioral studies in Drosophila. Our results identify new genetic pathways associated with alcohol consumption and suggest common genetic mechanisms with several neuropsychiatric disorders including schizophrenia.

genetics↗

bioRxiv2018

Diagnosing Bacterial Vaginosis with a Novel, Clinically-Actionable 1 Molecular Diagnostic Tool

Abstract/SummaryBacterial vaginosis is a common condition among women of reproductive age and is associated with potentially serious side-effects, including an increased risk of preterm birth. Recent advancements in microbiome sequencing technologies have produced novel insights into the complicated mechanisms underlying bacterial vaginosis and have given rise to new methods of diagnosis. Here we report on the validation of a quantitative, molecular diagnostic algorithm based on the relative abundances of ten potentially pathogenic bacteria and four commensal Lactobacillus species in research subjects (n = 172) classified as symptomatic (n = 149) or asymptomatic (n = 23). We observe a clear and reinforcing pattern among patients diagnosed by the algorithm that is consistent with the current understanding of biological dynamics and dysregulation of the vaginal microbiome during infection. Using this enhanced assessment of the underlying biology of infection, we demonstrate improved diagnostic sensitivity (93%) and specificity (90%) relative to current diagnostic tools. Our algorithm also appears to provide enhanced diagnostic capabilities in ambiguous classes of patients for whom diagnosis and medical decision-making is complicated, including asymptomatic patients and those deemed \"intermediate\" by Nugent scoring. Ultimately, we establish CLS2.0q as a quantitative, sensitive, specific, accurate, robust, and flexible algorithm for the clinical diagnosis of bacterial vaginosis - importantly, one that is also ideal for the differential diagnosis of non-BV infections with clinically similar presentations.

microbiology↗