An analysis of interactions between fluorescently-tagged mutant and wild-type SOD1 in intracellular inclusions

By mechanisms yet to be discerned, the co-expression of high levels of wild-type human superoxide dismutase 1 (hSOD1) with variants of hSOD1 encoding mutations linked familial amyotrophic lateral sclerosis (fALS) hastens the onset of motor neuron degeneration in transgenic mice. Although it is known that spinal cords of paralyzed mice accumulate detergent insoluble forms of WT hSOD1 along with mutant hSOD1, it has been difficult to determine whether there is co-deposition of the proteins in inclusion structures.In the present study, we use cell culture models of mutant SOD1 aggregation, focusing on the A4V, G37R, and G85R variants, to examine interactions between WT-hSOD1 and misfolded mutant SOD1. In these studies, we fuse WT and mutant proteins to either yellow or red fluorescent protein so that the two proteins can be distinguished within inclusions structures.Although the interpretation of the data is not entirely straightforward because we have strong evidence that the nature of the fused fluorophores affects the organization of the inclusions that form, our data are most consistent with the idea that normal dimeric WT-hSOD1 does not readily interact with misfolded forms of mutant hSOD1. We also demonstrate the monomerization of WT-hSOD1 by experimental mutation does induce the protein to aggregate, although such monomerization may enable interactions with misfolded mutant SOD1. Our data suggest that WT-hSOD1 is not prone to become intimately associated with misfolded mutant hSOD1 within intracellular inclusions that can be generated in cultured cells

Margaret Wise Brown Correspondence

Entries include hand written letters from Brown and a humorous poodle chase publisher advertismen

Comparing indices of relative deprivation using behavioural evidence

What measure of relative deprivation best predicts health? While numerous indices of relative deprivation exist, few studies have compared how well different measures account for empirical data. Hounkpatin et al. (2016) demonstrated that the relative ranked position of an individual i's income within a comparison group (their relative rank) was a better predictor of i's health than i's relative deprivation as assessed by the widely-used Yitzhaki index. In their commentary, Stark and Jakubek (2020) argue that both relative rank and relative deprivation may matter, and they develop a composite index. Here we identify some issues with their composite index, develop an alternative based on behavioural evidence, and test the various indices against data. Although almost all existing indices assume that the significance of an income y to an individual with income y (y >y ) will be some increasing function of the difference between y and y , we find that the influence of j's income on i's health is actually a reducing function of (y -y ). This finding - that less significance is assigned to distant higher incomes than to near higher incomes - is consistent with the well-established idea that we compare ourselves primarily to similar others. [Abstract copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

MivacunaLA (MyshotLA): A Community-Partnered Mobile Phone Intervention to Improve COVID-19 Vaccination Behaviors among Low-Income, Spanish-Speaking, and Immigrant Latino Parents or Caregivers

We developed and tested MivacunaLA/MyshotLA, a community-informed mobile phone intervention, to increase COVID-19 vaccination among Latino parents/caretakers of minors in under-resourced areas of Los Angeles by addressing misinformation and building trust. We recruited Latino parents/caregivers with at least one unvaccinated child in East and South Los Angeles in the summer of 2021 and evaluated MivacunaLA as a randomized controlled trial with a wait-list control group. A difference-in-difference analysis showed Latino parents/caregivers that participated in MivacunaLA (n = 246), in comparison to the control group, were 15 percentage points more likely (p = 0.04) to report vaccination of minors aged 12-17 years, and 12 percentage points more likely (p = 0.03) to report a positive intention to vaccinate minors aged 2-11 years (when COVID-19 vaccines became available). Mobile phone-delivered digital interventions using videos and culturally tailored educational material to promote COVID-19 vaccine confidence can be an effective way to combat misinformation and deliver timely information to marginalized communities. Community-based participatory research approaches are crucial to advance health equity among minority communities, especially immigrant Spanish-speaking underserved communities

Otitis media in the Tgif knockout mouse implicates TGFβ signalling in chronic middle ear inflammatory disease

Otitis media with effusion (OME) is the most common cause of hearing loss in children and tympanostomy to alleviate the condition remains the commonest surgical intervention in children in the developed world. Chronic and recurrent forms of OM are known to have a very significant genetic component, however, until recently little was known of the underlying genes involved. The identification of mouse models of chronic OM has indicated a role of transforming growth factor beta (TGFβ) signalling and its impact on responses to hypoxia in the inflamed middle ear. We have, therefore, investigated the role of TGFβ signalling and identified and characterized a new model of chronic OM carrying a mutation in the gene for transforming growth interacting factor 1 (Tgif1). Tgif1 homozygous mutant mice have significantly raised auditory thresholds due to a conductive deafness arising from a chronic effusion starting at around 3 weeks of age. The OM is accompanied by a significant thickening of the middle ear mucosa lining, expansion of mucin-secreting goblet cell populations and raised levels of vascular endothelial growth factor, TNF-α and IL-1β in ear fluids. We also identified downstream effects on TGFβ signalling in middle ear epithelia at the time of development of chronic OM. Both phosphorylated SMAD2 and p21 levels were lowered in the homozygous mutant, demonstrating a suppression of the TGFβ pathway. The identification and characterization of the Tgif mutant supports the role of TGFβ signalling in the development of chronic OM and provides an important candidate gene for genetic studies in the human population

‘Re-reading Raphael Samuel: Politics, Personality and Performance’

For British historian Raphael Samuel, history and politics were inextricable. Best known as the founder of the history workshop movement, the controversial historian took his stance on the democratisation of history-making, becoming an outspoken advocate for public history. Despite making a significant contribution to contemporary historiography, he remains a neglected, even disparaged, figure. This paper contends that the most significant aspect of Samuel’s historical work was not one or other theory of history or argument about the past but his entire way of being an historian. Samuel embodied as much as expressed his ideas, consciously using his personality as a powerful political tool. It is further argued that conventional approaches to intellectual history, focusing on textual outputs, do not fully recognise the significance of performative modes of thinking. Theoretical approaches to performance as identity offer important insight here but can be too schematic in their view of applied and enacted thought. A biographical approach, by contrast, provides the intimate perspective necessary to fully appreciate the fluidity and complexity of such a personality. The paper first situates Samuel in the context of his earlier life, focusing on how and why he created such a public persona and how he adapted it in response to changing circumstances. It then considers the implications and effectiveness of this persona by assessing how it was perceived and narrated by others, acknowledging, in the process, why different groups engaged with and interpreted it differently

Can the concept of Health Promoting Schools help to improve students' health knowledge and practices to combat the challenge of communicable diseases: Case study in Hong Kong?

<p>Abstract</p> <p>Background</p> <p>The growing epidemics of emerging infectious diseases has raised the importance of a setting approach and include the Health Promoting School (HPS) framework to promote better health and hygiene. Built on the concept of 'the' HPS framework, the Hong Kong Healthy Schools Award scheme includes "Personal Health Skills" as one of its key aspects to improve student hygiene knowledge and practices. This study examines the differences in student perceptions, knowledge and health behaviours between those schools that have adopted the HPS framework and those that have not adopted.</p> <p>Methods</p> <p>A cross-sectional study using multi-stage random sampling was conducted among schools with awards (HSA) and those schools not involved in the award scheme nor adopting the concept of HPS (non-HPS). For HSA group, 5 primary schools and 7 secondary schools entered the study with 510 students and 789 students sampled respectively. For the 'Non-HPS' group, 8 primary schools and 7 secondary schools entered the study with 676 students and 725 students sampled respectively. A self-administered questionnaire was used as the measuring instrument.</p> <p>Results</p> <p>Students in the HSA category were found to be better with statistical significance in personal hygiene practice, knowledge on health and hygiene, as well as access to health information. HSA schools were reported to have better school health policy, higher degrees of community participation, and better hygienic environment.</p> <p>Conclusion</p> <p>Students in schools that had adopted the HPS framework had a more positive health behaviour profile than those in non-HPS schools. Although a causal relationship is yet to be established, the HPS appears to be a viable approach for addressing communicable diseases.</p

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington\u27s Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington\u27s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington\u27s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression