TDP43 proteinopathy is associated with aberrant DNA methylation in human amyotrophic lateral sclerosis

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neurone (MN) degeneration and death. ALS can be sporadic (sALS) or familial, with a number of associated gene mutations, including C9orf72 (C9ALS). DNA methylation is an epigenetic mechanism whereby a methyl group is attached to a cytosine (5mC), resulting in gene expression repression. 5mC can be further oxidized to 5‐hydroxymethylcytosine (5hmC). DNA methylation has been studied in other neurodegenerative diseases, but little work has been conducted in ALS. Aims To assess differences in DNA methylation in individuals with ALS and the relationship between DNA methylation and TDP43 pathology. Methods Post mortem tissue from controls, sALS cases and C9ALS cases were assessed by immunohistochemistry for 5mC and 5hmC in spinal cord, motor cortex and prefrontal cortex. LMNs were extracted from a subset of cases using laser capture microdissection. DNA from these underwent analysis using the MethylationEPIC array to determine which molecular processes were most affected. Results There were higher levels of 5mC and 5hmC in sALS and C9ALS in the residual lower motor neurones (LMNs) of the spinal cord. Importantly, in LMNs with TDP43 pathology there was less nuclear 5mC and 5hmC compared to the majority of residual LMNs that lacked TDP43 pathology. Enrichment analysis of the array data suggested RNA metabolism was particularly affected. Conclusions DNA methylation is a contributory factor in ALS LMN pathology. This is not so for glia or neocortical neurones

Psychological treatment of social anxiety disorder: a meta-analysis.

Abstract Background Older meta-analyses of the effects of psychological treatments of social anxiety disorder have found that these treatments have moderate to large effects. However, these earlier meta-analyses also included non-randomized studies, and there are many featured studies in this area which were published after the recent meta-analysis. Method We conducted a systematic literature search and identified 29 randomized studies examining the effects of psychological treatments, with a total of 1628 subjects. The quality of studies varied. For the analyses, we used the computer program comprehensive meta-analysis (version 2.2.021; Biostat, Englewood, NJ, USA). Results The mean effect size on social anxiety measures (47 contrast groups) was 0.70, 0.80 on cognitive measures (26 contrast groups) and 0.70 both on depression (19 contrast groups) and general anxiety measures (16 contrast groups). We found some heterogeneity, so we conducted a series of subgroup analyses for different variables of the studies. Studies with waiting-list control groups had significantly larger effect sizes than studies with placebo and treatment-as-usual control groups. Studies aimed at subjects who met Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for social anxiety disorder had smaller effect sizes than studies in which other inclusion criteria were used. Conclusions This study once more makes it clear that psychological treatments of social anxiety disorder are effective in adults, but that they may be less effective in more severe disorders and in studies in which care-as-usual and placebo control groups are use

Teaching Courses Online: A Review of the Research

This literature review summarizes research on online teaching and learning. It is organized into four topics: course environment, learners’ outcomes, learners’ characteristics, and institutional and administrative factors. The authors found little consistency of terminology, discovered some conclusive guidelines, and identified developing lines of inquiry. The conclusions overall suggest that most of the studies reviewed were descriptive and exploratory, that most online students are nontraditional and Anglo American, and that few universities have written policies, guidelines, or technical support for faculty members or students. Asynchronous communication seemed to facilitate in-depth communication (but not more than in traditional classes), students liked to move at their own pace, learning outcomes appeared to be the same as in traditional courses, and students with prior training in computers were more satisfied with online courses. Continued research is needed to inform learner outcomes, learner characteristics, course environment, and institutional factors related to delivery system variables in order to test learning theories and teaching models inherent in course design

The significance of seniority for women managers’ interpretations of organizational restructuring

This paper examines the impact of restructuring within the transport and logistics sector on women managers working at senior and less senior (middle/junior management) levels of the organization. The majority of women experienced increased performance pressures and heavier workloads as well as an increase in working hours. At the same time, there were pressures to work at home (i.e. week-ends and evenings) and reduced opportunities to work from home (i.e. during normal office hours). Management level emerged as an important factor in how these changes were interpreted. Senior managers perceived more positive outcomes in terms of increased motivation and loyalty. Despite a longer working week, they were less likely to report low morale as an outcome from long hours. In fact, irrespective of management level, women working shorter hours were more likely to report low morale as an outcome. Results are discussed in relation to literature on restructuring and careers, in terms of perceptual framing and in relation to different levels of investment in the organization

An Exploratory Study into the Factors Impeding Ethical Consumption

Although consumers are increasingly engaged with ethical factors when forming opinions about products and making purchase decisions, recent studies have highlighted significant differences between consumers’ intentions to consume ethically, and their actual purchase behaviour. This article contributes to an understanding of this “ethical purchasing gap” through a review of existing literature, and the inductive analysis of focus group discussions. A model is suggested which includes exogenous variables such as moral maturity and age which have been well covered in the literature, together with further impeding factors identified from the focus group discussions. For some consumers, inertia in purchasing behaviour was such that the decision-making process was devoid of ethical considerations. Several manifested their ethical views through post-purchase dissonance and retrospective feelings of guilt. Others displayed a reluctance to consume ethically due to personal constraints, a perceived negative impact on image or quality, or an outright negation of responsibility. Those who expressed a desire to consume ethically often seemed deterred by cynicism, which caused them to question the impact they, as an individual, could achieve. These findings enhance the understanding of ethical consumption decisions and provide a platform for future research in this area

Patterns and Predictors of Relapse Following Radical Chemoradiation Therapy Delivered Using Intensity Modulated Radiation Therapy With a Simultaneous Integrated Boost in Anal Squamous Cell Carcinoma

Purpose: To describe the patterns and predictors of treatment failure in patients receiving definitive chemoradiotherapy (CRT) for anal squamous cell carcinoma (ASCC), delivered using intensity modulated radiotherapy (IMRT). Materials and methods: A retrospective cohort analysis of consecutive patients treated with curative intent for ASCC using CRT delivered with a standardised IMRT technique in five UK cancer centres. Patients were included from the start of UK IMRT guidance in February 2013 to 31st October 2017. Collected data included baseline demographics, treatment details, tumour control, sites of relapse and overall survival. Statistical analysis to calculate outcomes and predictive factors for outcome measures were performed using SPSS and R. Results: The medical records of 385 consecutive patients were analysed. Median follow-up was 24.0 months. 86.7% of patients achieved a complete response (CR) within 6 months of completing chemoradiotherapy. 3yr disease free survival (DFS) and overall survival (OS) were 75.6% and 85.6% respectively. Of all relapses, 83.4% occurred at the site of primary disease. There were two isolated relapses in regional nodes not involved at outset. Predictive factors for cancer recurrence included male sex, high N-stage and failure to complete radiotherapy as planned. Conclusions: The treatment results compare favourably to published outcomes from similar cohorts using 3D conformal CRT. The observed patterns of failure support the current UK IMRT voluming guidelines and dose levels, highlighting our prophylactic nodal dose is sufficient to prevent isolated regional relapse in uninvolved nodes. Further investigation into strategies to optimise CR should remain a priority in ASCC, as the site of primary disease remains the overwhelming site of relapse

Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are relentlessly progressive neurodegenerative disorders with overlapping clinical, genetic and pathological features. Cytoplasmic inclusions of fused in sarcoma (FUS) are the hallmark of several forms of FTLD and ALS patients with mutations in the FUS gene. FUS is a multifunctional, predominantly nuclear, DNA and RNA binding protein. Here, we report that transgenic mice overexpressing wild-type human FUS develop an aggressive phenotype with an early onset tremor followed by progressive hind limb paralysis and death by 12 weeks in homozygous animals. Large motor neurons were lost from the spinal cord accompanied by neurophysiological evidence of denervation and focal muscle atrophy. Surviving motor neurons in the spinal cord had greatly increased cytoplasmic expression of FUS, with globular and skein-like FUS-positive and ubiquitin-negative inclusions associated with astroglial and microglial reactivity. Cytoplasmic FUS inclusions were also detected in the brain of transgenic mice without apparent neuronal loss and little astroglial or microglial activation. Hemizygous FUS overexpressing mice showed no evidence of a motor phenotype or pathology. These findings recapitulate several pathological features seen in human ALS and FTLD patients, and suggest that overexpression of wild-type FUS in vulnerable neurons may be one of the root causes of disease. Furthermore, these mice will provide a new model to study disease mechanism, and test therapies

The interplay between social and food environments on UK adolescents' food choices: implications for policy

Factors from social and food environments can influence the food choices of adolescents in ways not experienced during childhood. Evidence suggests these two environments influence adolescents' food choices independently, but there is limited knowledge of how the interplay between these environments influence adolescents' diets. An enhanced understanding of this interplay surrounding adolescent food choice could aid the development of more nuanced interventions and policies. This qualitative study involved 13 online focus groups with adolescents (n = 45) aged 11-18 years, attending secondary school or college in England, UK. Data were analysed using thematic analysis. Social experiences which accompanied eating were perceived as more important than the food itself, and fast-food outlets were described as uniquely suited to facilitating these interactions. Young people wanted to spend their money on foods they considered worthwhile, but this did not always relate to the most affordable foods. Adolescents wanted to put little effort into making food decisions and appreciated factors that helped them make quick decisions such as prominent placement and eye-catching promotions on foods they wanted to buy. Chain food outlets were valued as they offered familiar and frequently advertised foods, which minimized the effort needed for food decisions. Adolescents' sense of autonomy underpinned all themes. Participants described having limited opportunities to make their own food choices and they did not want to waste these buying unappealing 'healthy' foods. Interventions and government policies should align with adolescents' experiences and values relating to food choice to ensure that they are effective with this important age group