‘I didn’t want to face another day of failing’ The emotional wellbeing of young people with severe dyslexic difficulties in state mainstream education: social and discursive constructions

In this thesis I focus on the lived experience of young people with severe dyslexic difficulties in state, mainstream education in England. In considering school as a space where difference is constructed and stigma can be experienced, I draw on sociological theory to explore the kinds of emotional labour (Hochschild, 1979) that school demands from young people, when they have to explain their needs, as well as hide, downplay and negotiate their difficulties. Working with conceptual resources drawn from symbolic interactionism and the work of Foucault and Bourdieu, I explore how discursive and cultural practices form part of the institutional and relational contexts created by policy-makers, parents, teachers and peers and the implications of these for young people’s emotional wellbeing and identity. The study contributes to a very small body of existing literature about those whose dyslexic difficulties are most severe and broadens the conversation about young people’s experiences at school to consider the wider influences that shape their identities. The empirical basis of the research includes a mixed methods online survey with 474 parents and qualitative research with 15 young people aged 10-19 and their mothers. The findings of the study echo those within the existing literature, suggesting that access to early, evidence-based intervention in primary school makes it possible for young people to move on from a dyslexic identity and progress alongside their peers. However, my research presents a landscape of inconsistency in terms of the distribution and quality of provision, with parents holding government accountable for a lack of investment and varying levels of awareness and understanding of dyslexia among educators. Parents’ ability to negotiate access to support was also uneven, reflecting an unequal distribution of economic, cultural and social capital. Mothers emerge as central actors in the management of their children’s emotional states, playing a key role in scaffolding them away from notions of deficit towards ideas of difference. Drawing on Reay’s interpretation of emotional capital, I also consider classed cultures of parenting as having relevance to an understanding of young people’s emotional wellbeing. The role of teachers and trusted adults within the school is also examined, including the vital part they play in mediating institutional discourses through micro interactions with learners. On the basis of these findings, I argue that educators would benefit from opportunities to learn about the emotional impacts of living with severe dyslexic/literacy difficulties, challenging them about normative assumptions regarding difference and deficit. By amplifying positive stories about school, it becomes possible to understand the importance to young people of having their challenges recognised and their abilities and achievements acknowledged, as well as the importance of being able to express their agency, feeling cared for by staff, and a whole-school ethos supporting inclusivity and neurodiversity

Lipopolysaccharide-induced neuroinflammation induces presynaptic disruption through a direct action on brain tissue involving microglia-derived interleukin 1 beta.

BACKGROUND: Systemic inflammation has been linked to synapse loss and cognitive decline in human patients and animal models. A role for microglial release of pro-inflammatory cytokines has been proposed based on in vivo and primary culture studies. However, mechanisms are hard to study in vivo as specific microglial ablation is challenging and the extracellular fluid cannot be sampled without invasive methods. Primary cultures have different limitations as the intricate multicellular architecture in the brain is not fully reproduced. It is essential to confirm proposed brain-specific mechanisms of inflammatory synapse loss directly in brain tissue. Organotypic hippocampal slice cultures (OHSCs) retain much of the in vivo neuronal architecture, synaptic connections and diversity of cell types whilst providing convenient access to manipulate and sample the culture medium and observe cellular reactions. METHODS: OHSCs were generated from P6-P9 C57BL/6 mice. Inflammation was induced via addition of lipopolysaccharide (LPS), and cultures were analysed for changes in synaptic proteins, gene expression and protein secretion. Microglia were selectively depleted using clodronate, and the effect of IL1β was assessed using a specific neutralising monoclonal antibody. RESULTS: LPS treatment induced loss of the presynaptic protein synaptophysin without altering PSD95 or Aβ protein levels. Depletion of microglia prior to LPS application prevented the loss of synaptophysin, whilst microglia depletion after the inflammatory insult was partially effective, although less so than pre-emptive treatment, indicating a time-critical window in which microglia can induce synaptic damage. IL1β protein and mRNA were increased after LPS addition, with these effects also prevented by microglia depletion. Direct application of IL1β to OHSCs resulted in synaptophysin loss whilst pre-treatment with IL1β neutralising antibody prior to LPS addition prevented a significant loss of synaptophysin but may also impact basal synaptic levels. CONCLUSIONS: The loss of synaptophysin in this system confirms LPS can act directly within brain tissue to disrupt synapses, and we show that microglia are the relevant cellular target when all major CNS cell types are present. By overcoming limitations of primary culture and in vivo work, our study strengthens the evidence for a key role of microglia-derived IL1β in synaptic dysfunction after inflammatory insult.Alzheimer’s Research UK project grant ARUK-PG2015-24 and The John and Lucille Van Geest Foundation

Parent or community: Where do 20-month-olds exposed to two accents acquire their representation of words?

The recognition of familiar words was evaluated in 20-month-old children raised in a rhotic accent environment to parents that had either rhotic or non-rhotic accents. Using an Intermodal Preferential Looking task children were presented with familiar objects (e.g. 'bird') named in their rhotic or non-rhotic form. Children were only able to identify familiar words pronounced in a rhotic accent, irrespective of their parents' accent. This suggests that it is the local community rather than parental input that determines accent preference in the early stages of acquisition. Consequences for the architecture of the early lexicon and for models of word learning are discussed

Health stigma on Twitter:investigating the prevalence and type of stigma communication in tweets about different conditions and disorders

Background: Health-related stigma can act as a barrier to seeking treatment and can negatively impact wellbeing. Comparing stigma communication across different conditions may generate insights previously lacking from condition-specific approaches and help to broaden our understanding of health stigma as a whole.Method: A sequential explanatory mixed-methods approach was used to investigate the prevalence and type of health-related stigma on Twitter by extracting 1.8 million tweets referring to five potentially stigmatized health conditions and disorders (PSHCDs): Human Immunodeficiency Virus (HIV)/Acquired Immunodeficiency Syndrome (AIDS), Diabetes, Eating Disorders, Alcoholism, and Substance Use Disorders (SUD). Firstly, 1,500 tweets were manually coded by stigma communication type, followed by a larger sentiment analysis (n = 250,000). Finally, the most prevalent category of tweets, “Anti-Stigma and Advice” (n = 273), was thematically analyzed to contextualize and explain its prevalence.Results: We found differences in stigma communication between PSHCDs. Tweets referring to substance use disorders were frequently accompanied by messages of societal peril. Whereas, HIV/AIDS related tweets were most associated with potential labels of stigma communication. We found consistencies between automatic tools for sentiment analysis and manual coding of stigma communication. Finally, the themes identified by our thematic analysis of anti-stigma and advice were Social Understanding, Need for Change, Encouragement and Support, and Information and Advice.Conclusions: Despite one third of health-related tweets being manually coded as potentially stigmatizing, the notable presence of anti-stigma suggests that efforts are being made by users to counter online health stigma. The negative sentiment and societal peril associated with substance use disorders reflects recent suggestions that, though attitudes have improved toward physical diseases in recent years, stigma around addiction has seen little decline. Finally, consistencies between our manual coding and automatic tools for identifying language features of harmful content, suggest that machine learning approaches may be a reasonable next step for identifying general health-related stigma online

Interaction between a MAPT variant causing frontotemporal dementia and mutant APP affects axonal transport.

In Alzheimer's disease, many indicators point to a central role for poor axonal transport, but the potential for stimulating axonal transport to alleviate the disease remains largely untested. Previously, we reported enhanced anterograde axonal transport of mitochondria in 8- to 11-month-old MAPTP301L knockin mice, a genetic model of frontotemporal dementia with parkinsonism-17T. In this study, we further characterized the axonal transport of mitochondria in younger MAPTP301L mice crossed with the familial Alzheimer's disease model, TgCRND8, aiming to test whether boosting axonal transport in young TgCRND8 mice can alleviate axonal swelling. We successfully replicated the enhancement of anterograde axonal transport in young MAPTP301L/P301L knockin animals. Surprisingly, we found that in the presence of the amyloid precursor protein mutations, MAPTP301L/P3101L impaired anterograde axonal transport. The numbers of plaque-associated axonal swellings or amyloid plaques in TgCRND8 brains were unaltered. These findings suggest that amyloid-β promotes an action of mutant tau that impairs axonal transport. As amyloid-β levels increase with age even without amyloid precursor protein mutation, we suggest that this rise could contribute to age-related decline in frontotemporal dementia.This work was supported by Alzheimer’s Research UK (ART/PG2009/2 to R.A.), MRC project grant (MR/L003813/1 to R.A., S.G.), Medical Research Council studentship (S.M.), Alzheimer’s Research UK studentship (ARUKPhD2013-13 to C.D.), Biotechnology and Biological Sciences Research Council Institute Strategic Programme Grant (M.P.C.), the Foundation for Alzheimer Research (FRA/SAO) (JPB) and the Belgian F.N.R.S. (K.A and JPB)

Beta secretase 1-dependent amyloid precursor protein processing promotes excessive vascular sprouting through NOTCH3 signalling

Funder: Alzheimer's Research UK (ARUK)Funder: John and Lucille Van Geest FoundationAbstract: Amyloid beta peptides (Aβ) proteins play a key role in vascular pathology in Alzheimer’s Disease (AD) including impairment of the blood–brain barrier and aberrant angiogenesis. Although previous work has demonstrated a pro-angiogenic role of Aβ, the exact mechanisms by which amyloid precursor protein (APP) processing and endothelial angiogenic signalling cascades interact in AD remain a largely unsolved problem. Here, we report that increased endothelial sprouting in human-APP transgenic mouse (TgCRND8) tissue is dependent on β-secretase (BACE1) processing of APP. Higher levels of Aβ processing in TgCRND8 tissue coincides with decreased NOTCH3/JAG1 signalling, overproduction of endothelial filopodia and increased numbers of vascular pericytes. Using a novel in vitro approach to study sprouting angiogenesis in TgCRND8 organotypic brain slice cultures (OBSCs), we find that BACE1 inhibition normalises excessive endothelial filopodia formation and restores NOTCH3 signalling. These data present the first evidence for the potential of BACE1 inhibition as an effective therapeutic target for aberrant angiogenesis in AD

Protein retention in the endoplasmic reticulum rescues Aβ toxicity in Drosophila

Amyloid β (Aβ) accumulation is a hallmark of Alzheimer's disease. In adult Drosophila brains, human Aβ overexpression harms climbing and lifespan. It's uncertain whether Aβ is intrinsically toxic or activates downstream neurodegeneration pathways. Our study uncovers a novel protective role against Aβ toxicity: intra-endoplasmic reticulum (ER) protein accumulation with a focus on laminin and collagen subunits. Despite high Aβ, laminin B1 (LanB1) overexpression robustly counters toxicity, suggesting a potential Aβ resistance mechanism. Other laminin subunits and collagen IV also alleviate Aβ toxicity; combining them with LanB1 augments the effect. Imaging reveals ER retention of LanB1 without altering Aβ secretion. LanB1's rescue function operates independently of the IRE1α/XBP1 ER stress response. ER-targeted GFP overexpression also mitigates Aβ toxicity, highlighting broader ER protein retention advantages. Proof-of-principle tests in murine hippocampal slices using mouse Lamb1 demonstrate ER retention in transduced cells, indicating a conserved mechanism. Though ER protein retention generally harms, it could paradoxically counter neuronal Aβ toxicity, offering a new therapeutic avenue for Alzheimer's disease