Systems Chemistry and Parrondo’s Paradox: Computational Models of Thermal Cycling

A mathematical concept known as Parrondo’s paradox motivated the development of several novel computational models of chemical systems in which thermal cycling was explored. In these kinetics systems we compared the rates of formation of product under cycling temperature and steady-sate conditions. We found that a greater concentration of product was predicted under oscillating temperature conditions. Our computational models of thermal cycling suggest new applications in chemical and chemical engineering systems

The paradox of fiction revisited: a cognitive approach to understanding (cinematic) emotion

The following project is intended as a contribution to the inter-disciplinary enterprise of cognitive film theory. Employing a cognitive approach, the project examines our capacity to respond emotionally to audiovisual fictions in general and cinematic fictions in particular. In order to structure and focus the investigation, the project centres on the paradox of fiction: namely, the question of why and how we respond emotionally to fictional characters and events, especially when we are consciously aware of their fictional - i.e., non-existent - status. (It also considers the related paradoxes of representation and empathy.) The main strategy for solving the paradox is to challenge the proposition that (cinematic) emotions require 'existence beliefs'; in tum, this strategy can be divided into 'direct' and 'indirect approaches', as exemplified by the 'seeing' and 'thought theories' respectively. An additional strategy is to revise the Cartesian framework which underlies the paradox as a whole. The first three main chapters explicitly address the direct approach. The process of direct engagement can be divided roughly into a 'seeing stage' and a 'reacting stage'. In light of this, Chapter 2 outlines a modular and computational view of the mind/brain, considering some of the ways in which we 'see' the world and the cinema. In a corresponding fashion, Chapter 3 outlines a multi-level model of the emotion system from a neurobiological perspective, considering some of the ways in which we 'react' to what we see. The function of Chapter 4 is to develop the multi-level model in question by adopting a connectionist and cognitive perspective, thereby tracing both an associative network and a cognitive appraisal route to (cinematic) emotion. The final main chapter - Chapter 5 - explicitly addresses the indirect approach. Given that appeals to 'thought' and 'imagination' are potentially problematic, it re-traces the simulative route to (cinematic) emotion, demonstrating how the multi-level model acts as both a constraint on, and an alternative to, emotional simulation

Modeling Non-Force-Free and Deformed Flux Ropes in Titan’s Ionosphere

Previous work at Titan presented a set of 85 flux ropes detected during Cassini flybys of Titan from 2005 to 2017. In that study a force‐free model was used to determine the radii and axial magnetic field of the flux ropes. In this work we apply non‐force‐free models. The non‐force‐free model shows an improvement in the number of flux ropes that can be fitted with a model, along with improved uncertainties and χ2 values. A number of asymmetries and features in the magnetometer data cannot be reproduced by either model; therefore, we deform the force‐free model to show that small deformations can replicate these features. One such deformation is to use an elliptical cross section, which replicates a plateau in magnetic field strength along with asymmetries on either side of the center of the flux ropes. Additionally, we explore the properties of bending a flux rope, where we find that minimum variance analysis becomes increasingly degenerate with bending, along with a slight bend causing the switching of the axial field direction from intermediate to maximum variance direction. We conclude that the flux ropes at Titan show aspects of developing flux ropes, compared to other planetary bodies, which exhibit more agreement to the force‐free assumptions of mature flux ropes

Microbial liberation of N-methylserotonin from orange fiber in gnotobiotic mice and humans

Plant fibers in byproduct streams produced by non-harsh food processing methods represent biorepositories of diverse, naturally occurring, and physiologically active biomolecules. To demonstrate one approach for their characterization, mass spectrometry of intestinal contents from gnotobiotic mice, plus in vitro studies, revealed liberation of N-methylserotonin from orange fibers by human gut microbiota members including Bacteroides ovatus. Functional genomic analyses of B. ovatus strains grown under permissive and non-permissive N-methylserotonin mining conditions revealed polysaccharide utilization loci that target pectins whose expression correlate with strain-specific liberation of this compound. N-methylserotonin, orally administered to germ-free mice, reduced adiposity, altered liver glycogenesis, shortened gut transit time, and changed expression of genes that regulate circadian rhythm in the liver and colon. In human studies, dose-dependent, orange-fiber-specific fecal accumulation of N-methylserotonin positively correlated with levels of microbiome genes encoding enzymes that digest pectic glycans. Identifying this type of microbial mining activity has potential therapeutic implications

Segregation analysis identifies specific alpha-defensin (DEFA1A3) SNP–CNV haplotypes in predisposition to IgA nephropathy

BACKGROUND: Immunoglobulin A (IgA) nephropathy is a disorder of the immune system affecting kidney function, and genome-wide association studies (GWAS) have defined numerous loci with associated variation, all implicating components of innate or adaptive immunity. Among these, single nucleotide polymorphisms (SNPs) in a region including the multiallelic copy number variation (CNV) of DEFA1A3 are associated with IgA nephropathy in both European and Asian populations. At present, the precise factors underlying the observed associations at DEFA1A3 have not been defined, although the key alleles differ between Asian and European populations, and multiple independent factors may be involved even within a single population. METHODS: In this study, we measured DEFA1A3 copy number in UK family trios with an offspring affected by IgA nephropathy, used the population distributions of joint SNP-CNV haplotypes to infer the likely segregation in trios, and applied transmission disequilibrium tests (TDT) to examine joint SNP-CNV haplotypes for over- or undertransmission into affected offspring from heterozygous parents. RESULTS AND CONCLUSIONS: We observed overtransmission of 3-copy class 2 haplotypes (raw p = 0.029) and some evidence for under-transmission of 3-copy class 1 haplotypes (raw p = 0.051), although these apparent effects were not statistically significant after correction for testing of multiple haplotypes

Long-Term Outcomes in IgA Nephropathy

BACKGROUND: IgA nephropathy can progress to kidney failure, and risk assessment soon after diagnosis has advantages both for clinical management and the development of new therapeutics. We present relationships among proteinuria, eGFR slope and lifetime risks for kidney failure. METHODS: The IgA nephropathy cohort (2,299 adults, 140 children) of the UK National Registry of Rare Kidney Diseases (RaDaR) was analyzed. Patients enrolled had a biopsy-proven diagnosis of IgA nephropathy, plus proteinuria >0.5 g/day or eGFR <60 mL/min/1.73m 2 . Incident and prevalent populations were studied as well as a population representative of a typical phase 3 clinical trial cohort. Analyses of kidney survival were conducted using Kaplan-Meier and Cox regression. eGFR slope was estimated using linear mixed models with random intercept and slope. RESULTS: Median (Q1, Q3) follow-up was 5.9 (3.0, 10.5) years; 50% of patients reached kidney failure or died in the study period. Median (95% CI) kidney survival was 11.4 (10.5, 12.5) years; mean age at kidney failure/death was 48 years, and most patients progressed to kidney failure within 10-15 years. Based on eGFR and age at diagnosis, almost all patients are at risk of progression to kidney failure within their expected lifetime unless a rate of eGFR loss ≤1 ml/min/1.73m 2 /year can be maintained. Time-averaged proteinuria was significantly associated with worse kidney survival and more rapid eGFR loss in incident, prevalent, and "clinical trial" populations. 30% of patients with time-averaged proteinuria of 0.44 to <0.88 g/g and approximately 20% of patients with time-averaged proteinuria <0.44 g/g developed kidney failure within 10 years. In the "clinical trial" population each 10% decrease in time-averaged proteinuria from baseline was associated with a hazard ratio (95% CI) for kidney failure/death of 0.89 (0.87-0.92). CONCLUSIONS: Outcomes in this large IgA nephropathy cohort are generally poor with few patients expected to avoid kidney failure in their lifetime. Significantly, patients traditionally regarded as being "low-risk", with proteinuria <0.88 g/g (<100 mg/mmol), have high rates of kidney failure within 10 years

A microbiota-directed food intervention for undernourished children

BACKGROUND: More than 30 million children worldwide have moderate acute malnutrition. Current treatments have limited effectiveness, and much remains unknown about the pathogenesis of this condition. Children with moderate acute malnutrition have perturbed development of their gut microbiota. METHODS: In this study, we provided a microbiota-directed complementary food prototype (MDCF-2) or a ready-to-use supplementary food (RUSF) to 123 slum-dwelling Bangladeshi children with moderate acute malnutrition between the ages of 12 months and 18 months. The supplementation was given twice daily for 3 months, followed by 1 month of monitoring. We obtained weight-for-length, weight-for-age, and length-for-age z scores and mid-upper-arm circumference values at baseline and every 2 weeks during the intervention period and at 4 months. We compared the rate of change of these related phenotypes between baseline and 3 months and between baseline and 4 months. We also measured levels of 4977 proteins in plasma and 209 bacterial taxa in fecal samples. RESULTS: A total of 118 children (59 in each study group) completed the intervention. The rates of change in the weight-for-length and weight-for-age z scores are consistent with a benefit of MDCF-2 on growth over the course of the study, including the 1-month follow-up. Receipt of MDCF-2 was linked to the magnitude of change in levels of 70 plasma proteins and of 21 associated bacterial taxa that were positively correlated with the weight-for-length z score (P\u3c0.001 for comparisons of both protein and bacterial taxa). These proteins included mediators of bone growth and neurodevelopment. CONCLUSIONS: These findings provide support for MDCF-2 as a dietary supplement for young children with moderate acute malnutrition and provide insight into mechanisms by which this targeted manipulation of microbiota components may be linked to growth. (Supported by the Bill and Melinda Gates Foundation and the National Institutes of Health; ClinicalTrials.gov number, NCT04015999.)

DeepReg: a deep learning toolkit for medical image registration

DeepReg (https://github.com/DeepRegNet/DeepReg) is a community-supported open-source toolkit for research and education in medical image registration using deep learning.Comment: Accepted in The Journal of Open Source Software (JOSS