Biology subjects

Mason, A.

Publications and source records attributed to Mason, A..

9 recordsLinked to original sources

bioRxiv2025

Explicit memory representations in decisions from experience

Reinforcement learning (RL) models explain how people adapt behavior through incremental value updates but assume that individual experiences are not explicitly stored or retrieved. Across two experiments (N = 282 and N = 1,818), we tested whether people rely on such explicit memory representations during experience-based choice. Participants sampled outcomes from two lotteries and, in an "ignore" condition, were instructed to disregard specific outcomes before deciding. Ignoring these outcomes substantially altered preferences, suggesting that choices were guided by explicit episodic representations rather than cumulative reinforcement. Frequency judgments revealed generally accurate memory for experienced outcomes, but reduced precision for continuous compared with discrete outcome distributions. These findings challenge purely incremental RL accounts and support theories proposing that human choice integrates flexible episodic memory with reinforcement mechanisms, bridging models of learning, memory, and decision-making. Statement of RelevanceHow people learn from experience shapes decisions in many everyday situations, from choosing a stock to invest in to selecting a restaurant or deciding which route to take home. Our experiments show that people do not rely solely on incremental value updates but instead exploit memory representations of past outcomes to guide choices. When asked to ignore certain outcomes, participants adjusted their preferences in line with these representations. These findings reveal that human decision-making also engages flexible use of memory for past experiences, highlighting the importance of memory-based mechanisms in adaptive, real-world choice behaviour.

neuroscience↗

bioRxiv2023

Dextrin conjugation to colistin inhibits its toxicity, cellular uptake and acute kidney injury in vivo.

The acute kidney injury (AKI) and dose-limiting nephrotoxicity, which occurs in 20-60% of patients following systemic administration of colistin, represents a challenge in the effective treatment of multi-drug resistant gram-negative infections. To reduce clinical toxicity of colistin and improve targeting to infected /inflamed tissues, we previously developed dextrin-colistin conjugates, whereby colistin is designed to be released by amylase-triggered degradation of dextrin in infected and inflamed tissues, after passive targeting by the enhanced permeability and retention effect. Whilst it was evident in vitro that polymer conjugation can reduce toxicity and prolong plasma half-life, without significant reduction in antimicrobial activity of colistin, it was unclear how dextrin conjugation would alter cellular uptake and localisation of colistin in renal tubular cells in vivo. We discovered that dextrin conjugation effectively reduced colistins toxicity towards human kidney proximal tubular epithelial cells (HK-2) in vitro, which was mirrored by significantly less cellular uptake of Oregon Green (OG)-labelled dextrin-colistin conjugate, when compared to colistin. Using live-cell confocal imaging, we revealed localisation of both, free and dextrin-bound colistin in endolysosome compartments of HK-2 and NRK-52E cells. Using a murine AKI model, we demonstrated dextrin-colistin conjugation dramatically diminishes both proximal tubular injury and renal accumulation of colistin. These findings reveal new insight into the mechanism by which dextrin conjugation can overcome colistins renal toxicity and show the potential of polymer conjugation to improve the side effect profile of nephrotoxic drugs. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/565265v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@1ec6ac8org.highwire.dtl.DTLVardef@56a2b1org.highwire.dtl.DTLVardef@1d347fborg.highwire.dtl.DTLVardef@1ab7da_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2023

Sex-specific Proximal Tubular Cell differentiation pathways identified by single-nucleus RNA

BackgroundPostpartum kidney growth is substantial but proliferation and differentiation pathways underpinning nephron elongation are not well defined. Here we performed sequential characterization of mouse kidney transcriptomics at the single cell level to address this. MethodsSingle nuclear RNA sequencing (snRNA-seq) was performed on kidney tissue from male and female mice at 1, 2, 4 and 12 weeks of age using the 10x Chromium platform. ResultsUnbiased clustering was performed on 68,775 nuclei from 16 animals. 31 discrete cellular clusters were seen, which were identified through comparison of their gene expression profiles to canonical markers of kidney cell populations. High levels of proliferation were evident at early time points in some cell types, especially tubular cells, but not in other cell types, for example podocytes. Proliferation was especially evident in Proximal Tubular Cells (PTCs) which are the most abundant cell type in the adult kidney. Uniquely when compared to other kidney cell types, PTCs demonstrated sex-specific expression profiles at late, but not early, time points. Mapping of PTC differentiation pathways using techniques including trajectory and RNA Velocity analyses delineated increasing PTC specialization and sex-specific phenotype specification. ConclusionOur single-cell transcriptomics data characterise cellular states observed during kidney growth. We have identified PTC differentiation pathways that lead to sex-specific tubular cell phenotypes.

cell biology↗

bioRxiv2023

Mouse mammary tumor virus is implicated in severity of colitis and dysbiosis in the IL-10-/- mouse model of inflammatory bowel disease

BackgroundFollowing viral infection, genetically manipulated mice lacking immunoregulatory function may develop colitis and dysbiosis in a strain specific fashion that serves as a model for inflammatory bowel disease (IBD). We found that one such model of spontaneous colitis, the interleukin (IL)-10 knockout (IL-I0-/-) model derived from the SvEv mouse, had evidence of increased mouse mammary tumor virus (MMTV) viral RNA expression compared to the SvEv wildtype. MMTV is endemic in several mouse strains as an endogenously encoded betaretrovirus that is passaged as an exogenous agent in breast milk. As MMTV requires a viral superantigen to replicate in the gut associated lymphoid tissue prior to the development of systemic infection, we evaluated whether MMTV may contribute to the development of colitis in the IL-10-/- model. ResultsViral preparations extracted from IL-10-/- weanling stomachs revealed augmented MMTV load compared to the SvEv wildtype. Illumina sequencing of the viral genome revealed that the two largest contigs shared 96.4% - 97.3% identity with the mtv-1 endogenous loci and the MMTV(HeJ) exogenous virus from the C3H mouse. The MMTV sag gene cloned from IL-10-/- spleen encoded the MTV-9 superantigen that preferentially activates T cell receptor V{beta}-12 subsets, which were expanded in the IL-10-/- versus the SvEv colon. Evidence of MMTV cellular immune responses to MMTV Gag peptides was observed in the IL-10-/- splenocytes with amplified interferon-{gamma} production versus the SvEv wildtype. To address the hypothesis that MMTV may contribute to colitis, we used HIV reverse transcriptase inhibitors, tenofovir and emtricitabine, and the HIV protease inhibitor, lopinavir boosted with ritonavir, for 12 weeks treatment versus placebo. The combination anti-retroviral therapy with known activity against MMTV was associated with reduced colonic MMTV RNA and improved histological score in IL10-/- mice, as well as diminished secretion of pro-inflammatory cytokines and modulation of the microbiome associated with colitis. ConclusionsThis study suggests that immunogenetically manipulated mice with deletion of IL-10 may have reduced capacity to contain MMTV infection in a mouse-strain specific manner, and the antiviral inflammatory responses may contribute to the complexity of IBD with the development of colitis and dysbiosis.

microbiology↗

bioRxiv2022

Activation of ChvG-ChvI regulon by cell wall stress confers resistance to β-lactam antibiotics and initiates surface spreading in Agrobacterium tumefaciens

A core component of nearly all bacteria, the cell wall is an ideal target for broad spectrum antibiotics. Many bacteria have evolved strategies to sense and respond to antibiotics targeting cell wall synthesis, especially in the soil where antibiotic-producing bacteria compete with one another. Here we show that cell wall stress caused by both chemical and genetic inhibition of the essential, bifunctional penicillin-binding protein PBP1a prevents microcolony formation and activates the canonical host-invasion two-component system ChvG-ChvI in Agrobacterium tumefaciens. Using RNA-seq, we show that depletion of PBP1a for 6 hours results in a downregulation in transcription of flagellum-dependent motility genes and an upregulation in transcription of type VI secretion and succinoglycan biosynthesis genes, a hallmark of the ChvG-ChvI regulon. Depletion of PBP1a for 16 hours, results in differential expression of many additional genes and may promote a general stress response. Remarkably, the overproduction of succinoglycan causes cell spreading and deletion of the succinoglycan biosynthesis gene exoA restores microcolony formation. Treatment with cefsulodin phenocopies depletion of PBP1a and we correspondingly find that chvG and chvI mutants are hypersensitive to cefsulodin. This hypersensitivity only occurs in response to treatment with {beta}-lactam antibiotics and moenomycin, suggesting that the ChvG-ChvI pathway may play a key role in resistance to antibiotics targeting cell wall synthesis. Finally, we provide evidence that ChvG-ChvI likely has a conserved role in conferring resistance to cell wall stress within the Alphaproteobacteria. AUTHOR SUMMARYSoil dwelling bacteria reside in changing environments requiring them to frequently adapt to stressful conditions to ensure survival. The bacterial envelope provides structural integrity and protection against osmotic stress and turgor pressure imposed by the environment. While the mechanisms of cell membrane and cell wall biogenesis have been extensively studied, our understanding of how diverse microbes respond to cell envelope and cell wall stress to increase their fitness remains limited. In this work, we identify ChvG-ChvI regulon as an envelope stress response system that confers protection under cell wall stress conditions in the bacterial plant pathogen Agrobacterium tumefaciens. This is a new function for the well-characterized ChvG-ChvI pathway which is also acid induced and promotes plant host invasion. Our results suggest that the ChvG-ChvI pathway has a broadly conserved role in protecting Alphaproteobacterial cells from extracellular stress and a more specific role in response to acid stress and promoting plant-microbe interactions.

microbiology↗

bioRxiv2021

Reconstruction of sound driven, actively amplified and spontaneous motions within the tree cricket auditory organ

AO_SCPLOWBSTRACTC_SCPLOWHearing consists of a delicate chain of events. Sound is first captured by an eardrum or similar organ which is set into vibrations, these vibrations must then be transmitted to sensory cells in a manner that opens mechanosensory channels generating an electrical signal. Studying this process is challenging. Auditory vibrations are in the nano- to picometer-scale and occur at fast temporal scales of milli to microseconds. Finally, most of this process occurs within the body of the animal where it is inaccessible to conventional measurement techniques. For instance, even in crickets, a century-old auditory model system, it is unclear how sound evoked vibrations are transmitted to sensory neurons. Here, we use optical coherence tomography (OCT) to measure how vibrations travel within the auditory organ of the western tree cricket (Oecanthus californicus). We also measure the reversal of this process as mechanosensory cells generate spontaneous oscillations and amplify sound-evoked vibrations. Most importantly, we found that while the mechanosensory neurons were not attached to the peripheral sound collecting structures, they were mechanically well-coupled through acoustic trachea. Thus, the acoustic trachea are not merely conduits for sound but also perform a mechanical function. Our results generate several insights into the similarities between insect and vertebrate hearing, and into the evolutionary history of auditory amplification.

biophysics↗

bioRxiv2020

The Role of Oxygen Intake and Liver Enzyme on The Dynamics of Damaged Hepatocytes}: \\ Implications to Ischaemic Liver Injury via A Mathematical Model.

Ischaemic Hepatitis (IH) or Hypoxic Hepatitis (HH) also known as centrilobular liver cell necrosis is an acute liver injury characterized by a rapid increase in serum aminotransferase. The liver injury typically results from another underlying medical conditions like cardiac failure, respiratory failure and septic shock in which the liver becomes damaged due to deprivation of either blood or oxygen. IH is a potentially lethal condition which is often preventable if diagnosed properly. Unfortunately, mechanism that causes IH are often not well understood, making it difficult to diagnose or accurately quantify the patterns of related biomakers. In most cases, currently the only way to determine a case of IH (i.e., to diagnose it) is to rule out all other possible conditions for other liver injuries. A better understanding of the livers response to IH is necessary to aid in its diagnosis, measurement and improve outcomes. The goal of this study, is to identify mechanisms that can alter a few associated biomarkers for reducing density of damaged hepatocytes, and thus reduce chances of IH. To this end, we develop a mathematical model capturing dynamics of hepatocytes in the liver through the rise and fall of associated liver enzymes aspartate transaminase (AST), alanine transaminase (ALT) and lactate dehydrogenase (LDH) related to condition of IH. The model analysis provides a novel approach to predict the level of biomarkers given variations in the systemic oxygen in the body. Using IH patient data in US, novel model parameters are described and then estimated for the first time to capture real time dynamics of hepatocytes in the presence and absence of IH condition. Different scenarios of patient conditions were also analyzed and validated using empirical information. This study and its results may allow physicians to estimate the extent of liver damage in a IH patient based on their enzyme levels and receive faster treatment on real time basis.

cell biology↗

bioRxiv2020

Body size and composition and site-specific cancers in UK Biobank: a Mendelian randomisation study

ObjectivesTo investigate the casual role of body mass index, body fat composition and height in cancer. DesignTwo stage mendelian randomisation study SettingPrevious genome wide association studies and the UK Biobank ParticipantsGenetic instrumental variables for body mass index (BMI), fat mass index (FMI), fat free mass index (FFMI) and height from previous genome wide association studies and UK Biobank. Cancer outcomes from 367 586 participants of European descent from the UK Biobank. Main outcome measuresOverall cancer risk and 22 site-specific cancers risk for genetic instrumental variables for BMI, FMI, FFMI and height. ResultsGenetically predicted BMI (per 1 kg/m2) was not associated with overall cancer risk (OR 0.99; 95% confidence interval (CI) 0-98-1.00, p=0.105). Elevated BMI was associated with increased risk of stomach cancer (OR 1.15, 95% (CI) 1.05-1.26; p=0.003) and melanoma (OR 0.96, 95% CI 0.92-1.00; p=0.044). For sex-specific cancers, BMI was positively associated with uterine cancer (OR 1.08, 95% CI 1.01-1.14; p=0.015) but inversely associated with breast (OR 0.95, 95% CI 0.92-0.98; p=0.001), prostate (OR 0.95, 95% CI 0.92-0.99; p=0.007) and testicular cancer (OR 0.89, 95% CI 0.81-0.98; p=0.017). Elevated FMI (per 1 kg/m2) was associated with gastrointestinal cancer (stomach cancer OR 4.23, 95% CI 1.18-15.13, p=0.027; colorectal cancer OR 1.94, 95% CI 1.23-3.07; p=0.004). Increased height (per 1 standard deviation, approximately 6.5cm) was associated with increased risk of overall cancer (OR 1.06; 95% 1.04-1.09; p = 2.97x10-8) and most site-specific cancers with the strongest estimates for kidney, non-Hodgkin lymphoma, colorectal, lung, melanoma and breast cancer. ConclusionsThere is little evidence for BMI as a casual risk factor for cancer. BMI may have a causal role for sex-specific cancers, although with inconsistent directions of effect, and FMI for gastrointestinal malignancies. Elevated height is a risk factor for overall cancer and multiple site cancers.

genetics↗

bioRxiv2017

Trends in Escherichia coli bloodstream infection, urinary tract infections and antibiotic susceptibilities in Oxfordshire, 1998-2016: an observational study

BackgroundThe incidence of Escherichia coli bloodstream infections (EC-BSIs), particularly those caused by antibiotic-resistant strains, is increasing in the UK and internationally. This is a major public health concern but the evidence base to guide interventions is limited.\n\nMethodsIncidence of EC-BSIs and E. coli urinary tract infections (EC-UTIs) in one UK region (Oxfordshire) were estimated from anonymised linked microbiological and hospital electronic health records, and modelled using negative binomial regression based on microbiological, clinical and healthcare exposure risk factors. Infection severity, 30-day allcause mortality, and community and hospital co-amoxiclav use were also investigated.\n\nFindingsFrom 1998-2016, 5706 EC-BSIs occurred in 5215 patients, and 228376 EC-UTIs in 137075 patients. 1365(24%) EC-BSIs were nosocomial (onset >48h post-admission), 1863(33%) were community (>365 days post-discharge), 1346(24%) were quasi-community (31-365 days post-discharge), and 1132(20%) were quasi-nosocomial ([≤]30 days postdischarge). 1413(20%) EC-BSIs and 36270(13%) EC-UTIs were co-amoxiclav-resistant (41% and 30%, respectively, in 2016). Increases in EC-BSIs were driven by increases in community (10%/year (95% CI:7%-13%)) and quasi-community (8%/year (95% CI:7%-10%)) cases. Changes in EC-BSI-associated 30-day mortality were at most modest (p>0{middle dot}03), and mortality was substantial (14-25% across groups). By contrast, co-amoxiclav-resistant EC-BSIs increased in all groups (by 11%-19%/year, significantly faster than susceptible EC-BSIs, pheterogeneity<0{middle dot}001), as did co-amoxiclav-resistant EC-UTIs (by 13%-29%/year, pheterogeneity*0{middle dot}001). Co-amoxiclav use in primary-care facilities was associated with subsequent co-amoxiclav-resistant EC-UTIs (p=0{middle dot}03) and all EC-UTIs (p=0{middle dot}002).\n\nInterpretationCurrent increases in EC-BSIs in Oxfordshire are primarily community-associated, with high rates of co-amoxiclav resistance, nevertheless not impacting mortality. Interventions should target primary-care facilities with high co-amoxiclav usage.\n\nFundingNational Institute for Health Research.\n\nResearch in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed for publications from inception up until October 26, 2017, with the terms \"Escherichia coli\", \"E. coli\", \"bacteraemia\", \"bloodstream infection\", restricting the search to English language articles, and also reviewed references from retrieved articles. Escherichia coli (E. coli) is the most common cause of bloodstream infection, and the incidence of E. coli bloodstream infection, and particularly antibiotic-resistant infections, is increasing in the UK and internationally. Although the UK government aims to reduce healthcare-associated E. coli bloodstream infection, there is only limited evidence to inform appropriate interventions.\n\nAdded value of this studyWe investigated potential drivers for these increases in incidence by exploiting available linked electronic health records over 19 years for ~5200 patients with E. coli bloodstream infection and ~140000 with E. coli urinary tract infection, together with community antimicrobial prescribing data for the most recent six years. Our study identified several findings with significant implications for health policy and patient care: O_LIIncreases in the incidence of E. coli bloodstream infections were driven mainly by non-hospital-associated cases; however, neither patients with previous urinary tract infections nor having previously had urine specimens sent from catheters appeared to be driving the increases\nC_LIO_LICo-amoxiclav-resistant bloodstream infections rose significantly faster than co-amoxiclav-susceptible bloodstream infections, with the greatest number of co-amoxiclav-resistant bloodstream infections in 2016 being in patients discharged more than a month previously (i.e. community-associated)\nC_LIO_LIHigher co-amoxiclav use in primary care was associated with higher rates of both co-amoxiclav-resistant E. coli urinary tract infections and E. coli urinary tract infections overall, supporting drives to reduce broad-spectrum and inappropriate antibiotic use in primary care\nC_LIO_LIDespite substantial increases in co-amoxiclav-resistant bloodstream infections there was no evidence that mortality was increasing in these cases; this does not support moving to broader empiric antibiotic prescribing in hospitals (i.e. carbapenems, piperacillin-tazobactam)\nC_LI\n\nImplications of all available adviceThis suggests that government strategies to effectively reduce E. coli bloodstream infections should target community settings, as well as healthcare-associated settings. The absence of an increased mortality signal suggests that co-amoxiclav resistant E. coli infections are either being successfully treated by dual empiric therapy in severe cases (e.g. with concomitant gentamicin), can be \"rescued\" once isolate susceptibilities become available, or currently deployed phenotypic susceptibility testing breakpoints do not adequately correlate with clinical outcome.

epidemiology↗