Prior Binge Ethanol Exposure Potentiates the Microglial Response in a Model of Alcohol-Induced Neurodegeneration

Excessive alcohol consumption results in neurodegeneration which some hypothesize is caused by neuroinflammation. One characteristic of neuroinflammation is microglial activation, but it is now well accepted that microglial activation may be pro- or anti-inflammatory. Recent work indicates that the Majchrowicz model of alcohol-induced neurodegeneration results in anti-inflammatory microglia, while intermittent exposure models with lower doses and blood alcohol levels produce microglia with a pro-inflammatory phenotype. To determine the effect of a repeated binge alcohol exposure, rats received two cycles of the four-day Majchrowicz model. One hemisphere was then used to assess microglia via immunohistochemistry and while the other was used for ELISAs of cytokines and growth factors. A single binge ethanol exposure resulted in low-level of microglial activation; however, a second binge potentiated the microglial response. Specifically, double binge rats had greater OX-42 immunoreactivity, increased ionized calcium-binding adapter molecule 1 (Iba-1+) cells, and upregulated tumor necrosis factor-α (TNF-α) compared with the single binge ethanol group. These data indicate that prior ethanol exposure potentiates a subsequent microglia response, which suggests that the initial exposure to alcohol primes microglia. In summary, repeated ethanol exposure, independent of other immune modulatory events, potentiates microglial activity

Access to Justice software development, Participatory Action Research Methods and Researching the Lived Experiences of British Military Veterans

Participatory action research (PAR) methods aim to position the people who are most affected by the issue being studied as equal partners in the research process through a cyclical process of data gathering, data analysis, planning and implementing action and evaluation and reflection. In doing so, it ensures that the research better reflects participants’ ideas, priorities, and needs, thereby enhancing its validity and relevance and the support for the findings and proposed changes. Furthermore, it generates immediately applicable results. In this paper, we reflect on our experiences of developing the UK’s first access to justice platform for veterans and their families through an ongoing PAR project that brought together armed forces veterans, representatives from veterans' service providers, and the Veterans Legal Link team members comprising of legal academics, lawyers, sociologists, computer software designers and graphic designers to collect, interpret, and apply community information to address issues related to the delivery of access to justice. We present findings from Stages 1 and 2 of our three-stage iterative research process which includes the following steps: Understanding and cross-checking the lived experience of the veteran community (Stage 1), developing and testing a prototype of the access to justice platform (Stage 2) and creating the final product and giving real users an opportunity to use the platform (Stage 3). Data collection and analysis from Stage 1 of the study informed the themes that underpinned Stage 2. Specifically, data was collected through the following methods: co-facilitated focus group discussions, a web survey that was codesigned with veteran community stakeholders and remote and digitally enabled ethnographic research methods. We include several reflections that may help legal practitioners and researchers interested in applying PAR within the area of access to justice and the field of legal research

Rfam: annotating non-coding RNAs in complete genomes

Rfam is a comprehensive collection of non-coding RNA (ncRNA) families, represented by multiple sequence alignments and profile stochastic context-free grammars. Rfam aims to facilitate the identification and classification of new members of known sequence families, and distributes annotation of ncRNAs in over 200 complete genome sequences. The data provide the first glimpses of conservation of multiple ncRNA families across a wide taxonomic range. A small number of large families are essential in all three kingdoms of life, with large numbers of smaller families specific to certain taxa. Recent improvements in the database are discussed, together with challenges for the future. Rfam is available on the Web at http://www.sanger.ac.uk/Software/Rfam/ and http://rfam.wustl.edu/

X-ray Spectral Variability and Rapid Variability of the Soft X-ray Spectrum Seyfert 1 Galaxies Ark 564 and Ton S180

The bright, soft X-ray spectrum Seyfert 1 galaxies Ark 564 and Ton S180 were monitored for 35 days and 12 days with ASCA and RXTE (and EUVE for Ton S180). The short time scale (hours-days) variability patterns were very similar across energy bands, with no evidence of lags between any of the energy bands studied. The fractional variability amplitude was almost independent of energy band. It is difficult to simultaneously explain soft Seyferts stronger variability, softer spectra, and weaker energy-dependence of the variability relative to hard Seyferts. The soft and hard band light curves diverged on the longest time scales probed, consistent with the fluctuation power density spectra that showed relatively greater power on long time scales in the softest bands. The simplest explanation is that a relatively hard, rapidly-variable component dominates the total X-ray spectrum and a slowly-variable soft excess is present in the lowest energy channels of ASCA. Although it would be natural to identify the latter with an accretion disk and the former with a corona surrounding it, a standard thin disk could not get hot enough to radiate significantly in the ASCA band, and the observed variability time scales are much too short. The hard component may have a more complex shape than a pure power-law. The most rapid factor of 2 flares and dips occurred within ~1000 sec in Ark 564 and a bit more slowly in Ton S180. The speed of the luminosity changes rules out viscous or thermal processes and limits the size of the individual emission regions to <~15 Schwarzschild radii (and probably much less), that is, to either the inner disk or small regions in a corona

Neuroinflammation and Neurodegeneration in Adult Rat Brain from Binge Ethanol Exposure: Abrogation by Docosahexaenoic Acid

Evidence that brain edema and aquaporin-4 (AQP4) water channels have roles in experimental binge ethanol-induced neurodegeneration has stimulated interest in swelling/edema-linked neuroinflammatory pathways leading to oxidative stress. We report here that neurotoxic binge ethanol exposure produces comparable significant effects in vivo and in vitro on adult rat brain levels of AQP4 as well as neuroinflammation-linked enzymes: key phospholipase A2 (PLA2) family members and poly (ADP-ribose) polymerase-1 (PARP-1). In adult male rats, repetitive ethanol intoxication (3 gavages/d for 4 d, ∼ 9 g/kg/d, achieving blood ethanol levels ∼ 375 mg/dl; Majchrowicz model) significantly increased AQP4, Ca+2-dependent PLA2 GIVA (cPLA2), phospho-cPLA2 GIVA (p-cPLA2), secretory PLA2 GIIA (sPLA2) and PARP-1 in regions incurring extensive neurodegeneration in this model--hippocampus, entorhinal cortex, and olfactory bulb--but not in two regions typically lacking neurodamage, frontal cortex and cerebellum. Also, ethanol reduced hippocampal Ca+2-independent PLA2 GVIA (iPLA2) levels and increased brain oxidative stress footprints (4-hydroxynonenal-adducted proteins). For in vitro studies, organotypic cultures of rat hippocampal-entorhinocortical slices of adult age (∼ 60 d) were ethanol-binged (100 mM or ∼ 450 mg/dl) for 4 d, which augments AQP4 and causes neurodegeneration (Collins et al. 2013). Reproducing the in vivo results, cPLA2, p-cPLA2, sPLA2 and PARP-1 were significantly elevated while iPLA2 was decreased. Furthermore, supplementation with docosahexaenoic acid (DHA; 22:6n-3), known to quell AQP4 and neurodegeneration in ethanol-treated slices, blocked PARP-1 and PLA2 changes while counteracting endogenous DHA reduction and increases in oxidative stress footprints (3-nitrotyrosinated proteins). Notably, the PARP-1 inhibitor PJ-34 suppressed binge ethanol-dependent neurodegeneration, indicating PARP upstream involvement. The results with corresponding models support involvement of AQP4- and PLA2-associated neuroinflammatory pro-oxidative pathways in the neurodamage, with potential regulation by PARP-1 as well. Furthermore, DHA emerges as an effective inhibitor of these binge ethanol-dependent neuroinflammatory pathways as well as associated neurodegeneration in adult-age brain

The “problem” of teacher quality: exploring challenges and opportunities in developing teacher quality during the Covid-19 global pandemic in England

Teachers and teacher education are often presented as “problems” to be solved, with policy solutions that focus on ways to make teachers “better” and improve teacher “quality” by introducing prescriptive strategies. We investigate the ways Covid-19-related changes to university and school-based facets of Initial Teacher Education (ITE) in England influence teacher quality in relation to both student teachers and early career teachers, working in secondary schools. Drawing on 34 interviews with school leaders, school mentors and ITE tutors, we critically explore the ways in which teacher quality was developed through key aspects of teachers’ pedagogy and practice during the pandemic crisis when schools were closed and teaching moved online. Our findings show that the pandemic crisis has highlighted the different facets of teacher quality which arguably disrupt narrow and prescriptive understandings of what constitutes “quality” in policy terms. Although there were many instances of challenge in the development of new and student teachers, our data also shows how ITE tutors, school mentors and leaders responded creatively to the crisis. Participants highlighted the opportunities afforded by the pandemic to develop diverse and innovative pedagogies and practice, enhance students’ subject knowledge, as well as overcome some of the challenges in other areas of pedagogy and practice. Furthermore, the study shows that teacher quality was not substantially reduced despite the challenges arising from the pandemic and concerns that pre-service teachers would not be ready and prepared for a career in the classroom

Collaborative identity development during a global pandemic: exploring teacher identity through the experiences of pre-service high school teachers in England

Since early 2020, COVID-19 has had a substantial impact on teacher education. We consider novel aspects of how pre-service teachers have collaboratively developed their professional identities during the pandemic. Drawing on findings from forty-five interviews with pre-service high school teachers working in England during September 2020 – June 2021, we share how collaborative identity development was central and occurred in a variety of spaces, communities and modes. Collaborative identity development featured in how pre-service teachers saw themselves making a positive contribution to society through education and, in strong subject connections. Reflection that is collaborative, personalised, iterative, and separate from notions of formal progression enables positive identity work. Notions of identity are absent from international policy initiatives in ITE (Initial Teacher Education). This case study provides insights for policy makers in and beyond England who aim to support teachers at the beginning of their career so that they are retained

Pfam: clans, web tools and services

Pfam is a database of protein families that currently contains 7973 entries (release 18.0). A recent development in Pfam has enabled the grouping of related families into clans. Pfam clans are described in detail, together with the new associated web pages. Improvements to the range of Pfam web tools and the first set of Pfam web services that allow programmatic access to the database and associated tools are also presented. Pfam is available on the web in the UK (http://www.sanger.ac.uk/Software/Pfam/), the USA (http://pfam.wustl.edu/), France (http://pfam.jouy.inra.fr/) and Sweden (http://pfam.cgb.ki.se/)