Mechanisms of Neuroprotection by Protein Disulphide Isomerase in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterised by the progressive loss of motor neurons, leading to paralysis and death within several years of onset. Although protein misfolding is a key feature of ALS, the upstream triggers of disease remain elusive. Recently, endoplasmic reticulum (ER) stress was identified as an early and central feature in ALS disease models as well as in human patient tissues, indicating that ER stress could be an important process in disease pathogenesis. One important chaperone induced by ER stress is protein disulphide isomerase (PDI), which is both upregulated and posttranslationally inhibited by S-nitrosylation in ALS. In this paper, we present evidence from studies of genetics, model organisms, and patient tissues which indicate an active role for PDI and ER stress in ALS disease processes

The Pathobiology of TDP-43 C-Terminal Fragments in ALS and FTLD

During neurodegenerative disease, the multifunctional RNA-binding protein TDP-43 undergoes a vast array of post-translational modifications, including phosphorylation, acetylation, and cleavage. Many of these alterations may directly contribute to the pathogenesis of TDP-43 proteinopathies, which include most forms of amyotrophic lateral sclerosis (ALS) and approximately half of all frontotemporal dementia, pathologically identified as frontotemporal lobar degeneration (FTLD) with TDP-43 pathology. However, the relative contributions of the various TDP-43 post-translational modifications to disease remain unclear, and indeed some may be secondary epiphenomena rather than disease-causative. It is therefore critical to determine the involvement of each modification in disease processes to allow the design of targeted treatments. In particular, TDP-43 C-terminal fragments (CTFs) accumulate in the brains of people with ALS and FTLD and are therefore described as a neuropathological signature of these diseases. Remarkably, these TDP-43 CTFs are rarely observed in the spinal cord, even in ALS which involves dramatic degeneration of spinal motor neurons. Therefore, TDP-43 CTFs are not produced non-specifically in the course of all forms of TDP-43-related neurodegeneration, but rather variably arise due to additional factors influenced by regional heterogeneity in the central nervous system. In this review, we summarize how TDP-43 CTFs are generated and degraded by cells, and critique evidence from studies of TDP-43 CTF pathology in human disease tissues, as well as cell and animal models, to analyze the pathophysiological relevance of TDP-43 CTFs to ALS and FTLD. Numerous studies now indicate that, although TDP-43 CTFs are prevalent in ALS and FTLD brains, disease-related pathology is only variably reproduced in TDP-43 CTF cell culture models. Furthermore, TDP-43 CTF expression in both transgenic and viral-mediated in vivo models largely fails to induce motor or behavioral dysfunction reminiscent of human disease. We therefore conclude that although TDP-43 CTFs are a hallmark of TDP-43-related neurodegeneration in the brain, they are not a primary cause of ALS or FTLD

Design optimization of a short-term duty electrical machine for extreme environment

This paper presents design optimisation of a short term duty electrical machine for extreme environments of high temperature and high altitudes. For such extreme environmental conditions of above 80⁰C and altitudes of 30km, thermal loading limits are a critical consideration in machines, especially if high power density and high efficiency are to be achieved. The influence of different material on the performance of such machines is investigated. Also the effect of different slot and pole combinations are studied for machines used for such extreme operating conditions but with short duty. In the research, A Non-dominated Sorting Genetic Algorithm (NSGAII) considering an analytical electromagnetic model, structural and thermal model together with Finite Element (FE) methods are used to optimise the design of the machine for such environments achieving high efficiencies and high power density with relatively minimal computational time. The adopted thermal model is then validated through experiments and then implemented within the Genetic Algorithm (GA). It is shown that, generally, the designs are thermally limited where the pole numbers are limited by volt-amps drawn from the converter. The design consisting of a high slot number allows for improving the current loading and thus, significant weight reduction can be achieved

VisualPDE: rapid interactive simulations of partial differential equations

Computing has revolutionised the study of complex nonlinear systems, both by allowing us to solve previously intractable models and through the ability to visualise solutions in different ways. Using ubiquitous computing infrastructure, we provide a means to go one step further in using computers to understand complex models through instantaneous and interactive exploration. This ubiquitous infrastructure has enormous potential in education, outreach and research. Here, we present VisualPDE, an online, interactive solver for a broad class of 1D and 2D partial differential equation (PDE) systems. Abstract dynamical systems concepts such as symmetry-breaking instabilities, subcritical bifurcations and the role of initial data in multistable nonlinear models become much more intuitive when you can play with these models yourself, and immediately answer questions about how the system responds to changes in parameters, initial conditions, boundary conditions or even spatiotemporal forcing. Importantly, VisualPDE is freely available, open source and highly customisable. We give several examples in teaching, research and knowledge exchange, providing high-level discussions of how it may be employed in different settings. This includes designing web-based course materials structured around interactive simulations, or easily crafting specific simulations that can be shared with students or collaborators via a simple URL. We envisage VisualPDE becoming an invaluable resource for teaching and research in mathematical biology and beyond. We also hope that it inspires other efforts to make mathematics more interactive and accessible.Comment: 19 pages, 7 figures. This is a companion paper to the website https://visualpde.com

Deaf academics' perceptions of 'trust' in relationships with signed language interpreters

The concept of 'trust' is frequently used when discussing the working relationship between deaf signers and signed language interpreters, with interpreters often claiming that trust is a prerequisite to a successful interaction. This paper presents original data from an in-depth research project which used collaborative autoethnography to gather the experiences of seven deaf academics who work regularly with British Sign Language (BSL) interpreters, who interpret between BSL and spoken English, to analyse the concept of 'trust' in our working relations with BSL interpreters. We found that 'trust' is not a useful or productive concept for our interpersonal and professional aims. Instead, we outline multiple ways in which deaf academics can assess and evaluate interpreters' values, competencies, and performance without relying on 'trust'. Our findings provide an important, powerful and under-explored perspective on the working relations between deaf academics and interpreters. We suggest these findings can be applied by deaf BSL signers and interpreters in contexts beyond academia, and constitute an important contribution to the literature on interpreting

Evidence for variation in the effective population size of animal mitochondrial DNA

Background: It has recently been shown that levels of diversity in mitochondrial DNA are remarkably constant across animals of diverse census population sizes and ecologies, which has led to the suggestion that the effective population of mitochondrial DNA may be relatively constant. Results: Here we present several lines of evidence that suggest, to the contrary, that the effective population size of mtDNA does vary, and that the variation can be substantial. First, we show that levels of mitochondrial and nuclear diversity are correlated within all groups of animals we surveyed. Second, we show that the effectiveness of selection on non-synonymous mutations, as measured by the ratio of the numbers of non-synonymous and synonymous polymorphisms, is negatively correlated to levels of mitochondrial diversity. Finally, we estimate the effective population size of mitochondrial DNA in selected mammalian groups and show that it varies by at least an order of magnitude. Conclusions: We conclude that there is variation in the effective population size of mitochondria. Furthermore we suggest that the relative constancy of DNA diversity may be due to a negative correlation between the effective population size and the mutation rate per generation

The Emergence of Spanking Among a Representative Sample of Children Under 2 Years of Age in North Carolina

Spanking is common in the United States but less common in many European countries in which it has been outlawed. Being spanked has been associated with child abuse victimization, poor self-esteem, impaired parent–child relationships, and child and adult mental health, substance abuse, and behavioral consequences. Being spanked as a child has also been shown to increase the likelihood of abusing one's own children or spouse as an adult. Spanking of very young children less than two is almost never recommended even among experts that consider spanking as reasonable in some circumstances. Using a cross-sectional anonymous telephone survey, we describe spanking rates among a representative sample of North Carolina mothers of children less than 2 years old and the association of spanking with demographic characteristics. A substantial proportion of mothers admit to spanking their very young children. The rate of spanking in the last year among all maternal respondents was 30%. Over 5% of the mothers of 3-month olds reported spanking. Over 70% of the mothers of 23-month olds reported spanking. Increased spanking was associated with higher age of the child and lower maternal age. With every month of age, a child had 27% increased odds of being spanked. Early spanking has been shown to be associated with poor cognitive development in early childhood. Further, early trauma has been shown to have significant effects on the early developing brain. It is therefore critical that health and human services professionals address the risk of corporal punishment as a method of discipline early in the life of the child. The spanking of very young children may be an appropriate locus for policy and legislative debates regarding corporal punishment

Serum metabolomic profiles in dogs with chronic enteropathy

Background Metabolic profiles differ between healthy humans and those with inflammatory bowel disease. Few studies have examined metabolic profiles in dogs with chronic enteropathy (CE). Hypothesis Serum metabolic profiles of dogs with CE are significantly different from those of healthy dogs. Animals Fifty-five dogs with CE and 204 healthy controls. Methods A cross-sectional study. The serum concentrations of 99 metabolites measured using a canine-specific proton nuclear magnetic resonance spectroscopy platform were studied. A 2-sample unpaired t-test was used to compare the 2 study samples. The threshold for significance was set at P < .05 with a Bonferroni correction for each metabolite group. Results Nineteen metabolites and 18 indices of lipoprotein composition were significantly different between the CE and healthy dogs. Four metabolites were significantly higher in dogs with CE, including phenylalanine (mean and SD) (healthy: 0.0417 mmol/L; [SD] 0.0100; CE: 0.0480 mmol/L; SD: 0.0125; P value:Peer reviewe

Seasonal variation in serum metabolites of northern European dogs

Background Metabolic profiling identifies seasonal variance of serum metabolites in humans. Despite the presence of seasonal disease patterns, no studies have assessed whether serum metabolites vary seasonally in dogs. Hypothesis There is seasonal variation in the serum metabolite profiles of healthy dogs. Animals Eighteen healthy, client-owned dogs. Methods A prospective cohort study. Serum metabolomic profiles were assessed monthly in 18 healthy dogs over a 12-month period. Metabolic profiling was conducted using a canine-specific proton nuclear magnetic resonance spectroscopy platform, and the effects of seasonality were studied for 98 metabolites using a cosinor model. Seasonal component was calculated, which describes the seasonal variation of each metabolite. Results We found no evidence of seasonal variation in 93 of 98 metabolites. Six metabolites had statistically significant seasonal variance, including cholesterol (mean 249 mg/dL [6.47 mmol/L] with a seasonal component amplitude of 9 mg/dL [0.23 mmol/L]; 95% confidence interval [CI] 6-13 mg/dL [0.14-0.33 mmol/L], P < .008), with a peak concentration of 264 mg/dL (6.83 mmol/L) in June and trough concentration of 236 mg/dL (6.12 mmol/L) in December. In contrast, there was a significantly lower concentration of lactate (mean 20 mg/dL [2.27 mmol/L] with a seasonal component amplitude of 4 mg/dL [0.42 mmol/L]; 95% CI 2-6 mg/dL [0.22-0.62 mmol/L], P < .001) during the summer months compared to the winter months, with a peak concentration of 26 mg/dL (2.9 mmol/L) in February and trough concentration of 14 mg/dL (1.57 mmol/L) in July. Conclusions and Clinical Importance We found no clear evidence that seasonal reference ranges need to be established for serum metabolites of dogs.Peer reviewe