Endoplasmic Reticulum Lumenal Indicators in Drosophila Reveal Effects of HSP-Related Mutations on Endoplasmic Reticulum Calcium Dynamics

Genes for endoplasmic reticulum (ER)-shaping proteins are among the most commonly mutated in hereditary spastic paraplegia (HSP). Mutation of these genes in model organisms can lead to disruption of the ER network. To investigate how the physiological roles of the ER might be affected by such disruption, we developed tools to interrogate its Ca2+ signaling function. We generated GAL4-driven Ca2+ sensors targeted to the ER lumen, to record ER Ca2+ fluxes in identified Drosophila neurons. Using GAL4 lines specific for Type Ib or Type Is larval motor neurons, we compared the responses of different lumenal indicators to electrical stimulation, in axons and presynaptic terminals. The most effective sensor, ER-GCaMP6-210, had a Ca2+ affinity close to the expected ER lumenal concentration. Repetitive nerve stimulation generally showed a transient increase of lumenal Ca2+ in both the axon and presynaptic terminals. Mutants lacking neuronal reticulon and REEP proteins, homologs of human HSP proteins, showed a larger ER lumenal evoked response compared to wild type; we propose mechanisms by which this phenotype could lead to neuronal dysfunction or degeneration. Our lines are useful additions to a Drosophila Ca2+ imaging toolkit, to explore the physiological roles of ER, and its pathophysiological roles in HSP and in axon degeneration more broadly

The storage capacity of Potts models for semantic memory retrieval

We introduce and analyze a minimal network model of semantic memory in the human brain. The model is a global associative memory structured as a collection of N local modules, each coding a feature, which can take S possible values, with a global sparseness a (the average fraction of features describing a concept). We show that, under optimal conditions, the number c of modules connected on average to a module can range widely between very sparse connectivity (c/N -> 0) and full connectivity (c = N), maintaining a global network storage capacity (the maximum number p of stored and retrievable concepts) that scales like c*S^2/a, with logarithmic corrections consistent with the constraint that each synapse may store up to a fraction of a bit.Comment: Accepted for publication in J-STAT, July 200

Convertible bond valuation in a jump diffusion setting with stochastic interest rates

This paper proposes an integrated pricing framework for convertible bonds, which comprises firm value evolving as an exponential jump diffusion, correlated stochastic interest rates movements and an efficient numerical pricing scheme. By construction, the proposed stochastic model fits in the framework of affine jump diffusion processes of Duffie et al. [Econometrica, 2000, 68, 1343–1376] with tractable behaviour. We define the firm’s optimal call policy and investigate its impact on the computed convertible bond prices. We illustrate the performance of the numerical scheme and highlight the effects originated by the inclusion of jumps, stochastic interest rates and a non-zero correlation structure between firm value and interest rates

Investigating the Uncanny Valley for prosthetic hands

Background: In 1970, Mori hypothesised the existence of an ‘uncanny valley’, whereby stimuli falling short of being fully human are found to be creepy or eerie. Objectives: To investigate how eerie people find different prosthetic hands and whether perceptions of eeriness can be accounted for by categorical ambiguity. Study Design: Students participated in computerised experiments during which photographic images of hands were presented. Methods: We compared photographs of prosthetic hands pre-selected as more (H+) or less human-like (H-), as well as mechanical and real hands. Participants rated the hands for eeriness and human-likeness, as well as performing a speeded classification (human/non-human) and location judgment (control) task. Results: The H- prosthetic hands were rated as more eerie than the H+ prosthetic, mechanical and real hands, and this was unaffected by hand orientation. Participants were significantly slower to categorise the H+ prosthetic hands compared to the H- prosthetic and real hands, which was not due to generally slower responses to the H+ prosthetic hands (control task). Conclusions: People find prosthetic hands to be eerie, most consistently for less human-like prosthetic hands. This effect is not driven by ambiguity about whether to categorise the prosthetic hand as human or artificial

Simvastatin is associated with superior lipid and glycaemic control to atorvastatin and reduced levels of incident Type 2 diabetes, in men and women, in the UK Biobank

INTRODUCTION: Cardiovascular disease (CVD) is the leading cause of mortality in people with Type 2 diabetes mellitus (T2DM). Statins reduce low‐density lipoproteins and positively affect CVD outcomes. Statin type and dose have differential effects on glycaemia and risk of incident T2DM; however, the impact of gender, and of individual drugs within the statin class, remains unclear. AIM: To compare effects of simvastatin and atorvastatin on lipid and glycaemic control in men and women with and without T2DM, and their association with incident T2DM. METHODS: The effect of simvastatin and atorvastatin on lipid and glycaemic control was assessed in the T2DM DiaStrat cohort. Prescribed medications, gender, age, BMI, diabetes duration, blood lipid profile and HbA1c were extracted from Electronic Care Record, and compared in men and women prescribed simvastatin and atorvastatin. Analyses were replicated in the UKBiobank in those with and without T2DM. The association of simvastatin and atorvastatin with incident T2DM was also investigated in the UKBiobank. Cohorts where matched for age, BMI and diabetes duration in men and women, in the UKBioBank analysis, where possible. RESULTS: Simvastatin was associated with better LDL (1.6 ± 0.6 vs 2.1 ± 0.9 mmol/L, p < .01) and total cholesterol (3.6 ± 0.7 vs 4.2 ± 1.0 mmol/L, p < .05), and glycaemic control (62 ± 17 vs 67 ± 19 mmol/mol, p < .059) than atorvastatin specifically in women in the DiaStrat cohort. In the UKBiobank, both men and women prescribed simvastatin had better LDL (Women: 2.6 ± 0.6 vs 2.6 ± 0.7 mmol/L, p < .05; Men: 2.4 ± 0.6 vs 2.4 ± 0.6, p < .01) and glycaemic control (Women:54 ± 14 vs 56 ± 15mmol/mol, p < .05; Men, 54 ± 14 vs 55 ± 15 mmol/mol, p < .01) than those prescribed atorvastatin. Simvastatin was also associated with reduced risk of incident T2DM in both men and women (p < .0001) in the UKBiobank. CONCLUSIONS: Simvastatin is associated with superior lipid and glycaemic control to atorvastatin in those with and without T2DM, and with fewer incident T2DM cases. Given the importance of lipid and glycaemic control in preventing secondary complications of T2DM, these findings may help inform prescribing practices

How neurons maintain their axons long-term: an integrated view of axon biology and pathology

Axons are processes of neurons, up to a metre long, that form the essential biological cables wiring nervous systems. They must survive, often far away from their cell bodies and up to a century in humans. This requires self-sufficient cell biology including structural proteins, organelles, and membrane trafficking, metabolic, signalling, translational, chaperone, and degradation machinery—all maintaining the homeostasis of energy, lipids, proteins, and signalling networks including reactive oxygen species and calcium. Axon maintenance also involves specialised cytoskeleton including the cortical actin-spectrin corset, and bundles of microtubules that provide the highways for motor-driven transport of components and organelles for virtually all the above-mentioned processes. Here, we aim to provide a conceptual overview of key aspects of axon biology and physiology, and the homeostatic networks they form. This homeostasis can be derailed, causing axonopathies through processes of ageing, trauma, poisoning, inflammation or genetic mutations. To illustrate which malfunctions of organelles or cell biological processes can lead to axonopathies, we focus on axonopathy-linked subcellular defects caused by genetic mutations. Based on these descriptions and backed up by our comprehensive data mining of genes linked to neural disorders, we describe the ‘dependency cycle of local axon homeostasis’ as an integrative model to explain why very different causes can trigger very similar axonopathies, providing new ideas that can drive the quest for strategies able to battle these devastating diseases

Review of parameterisation and a novel database (LiionDB) for continuum Li-ion battery models

The Doyle–Fuller–Newman (DFN) framework is the most popular physics-based continuum-level description of the chemical and dynamical internal processes within operating lithium-ion-battery cells. With sufficient flexibility to model a wide range of battery designs and chemistries, the framework provides an effective balance between detail, needed to capture key microscopic mechanisms, and simplicity, needed to solve the governing equations at a relatively modest computational expense. Nevertheless, implementation requires values of numerous model parameters, whose ranges of applicability, estimation, and validation pose challenges. This article provides a critical review of the methods to measure or infer parameters for use within the isothermal DFN framework, discusses their advantages or disadvantages, and clarifies limitations attached to their practical application. Accompanying this discussion we provide a searchable database, available at www.liiondb.com, which aggregates many parameters and state functions for the standard DFN model that have been reported in the literature

Physically fit or physically literate? Children with special educational needs understanding of physical education

The role of physical literacy within physical education (PE) has become a widely debated topic in recent years. Its role in educating children about physicality through embodiment, skill acquisition and reading the environment is argued to be of great benefit to children. However, whether children understand the role of PE in the development of these competencies is not clear, and this is even truer for children who have special educational needs (SEN). Drawing on qualitative phenomenological data from 30 children in key stages 2 and three (7 to 14 years of age) who have SEN, this paper explores notions of physical fitness and physical literacy as understood by children in PE lessons. It aims to gain insight into the ways that children understand the purpose of PE, and places these perceptions within a physical literacy framework, using the National Curriculum for PE (NCPE) as a foundation. Findings demonstrate that children with SEN perceive PE as a means for improving physical fitness, whereas concepts surrounding physical literacy appear to be lost. The paper concludes by making recommendations for factoring physical literacy components more forcibly into the PE curriculum, and through initial teacher training and continued professional development

Prebiotic Driven Increases in IL-17A Do Not Prevent Campylobacter jejuni Colonization of Chickens

© Copyright © 2020 Flaujac Lafontaine, Richards, Connerton, O’Kane, Ghaffar, Cummings, Fish and Connerton. Worldwide Campylobacter jejuni is a leading cause of foodborne disease. Contamination of chicken meat with digesta from C. jejuni-positive birds during slaughter and processing is a key route of transmission to humans through the food chain. Colonization of chickens with C. jejuni elicits host innate immune responses that may be modulated by dietary additives to provide a reduction in the number of campylobacters colonizing the gastrointestinal tract and thereby reduce the likelihood of human exposure to an infectious dose. Here we report the effects of prebiotic galacto-oligosaccharide (GOS) on broiler chickens colonized with C. jejuni when challenged at either an early stage in development at 6 days of age or 20 days old when campylobacters are frequently detected in commercial flocks. GOS-fed birds had increased growth performance, but the levels of C. jejuni colonizing the cecal pouches were unchanged irrespective of the age of challenge. Dietary GOS modulated the immune response to C. jejuni by increasing cytokine IL-17A expression at colonization. Correspondingly, reduced diversity of the cecal microbiota was associated with Campylobacter colonization in GOS-fed birds. In birds challenged at 6 days-old the reduction in microbial diversity was accompanied by an increase in the relative abundance of Escherichia spp. Whilst immuno-modulation of the Th17 pro-inflammatory response did not prevent C. jejuni colonization of the intestinal tract of broiler chickens, the study highlights the potential for combinations of prebiotics, and specific competitors (synbiotics) to engage with the host innate immunity to reduce pathogen burdens