The effect of APOE genotype on astrocytic phenotypes in sporadic Alzheimer’s disease

Alzheimer’s disease is the most common form of dementia worldwide accounting for between 60 and 70% of cases. For many years, Alzheimer’s disease has been considered a disease driven by beta-amyloid, however this has been increasingly questioned, largely due to the poor correlation between amyloid deposition and the cognitive deficits seen in the disease plus the failure of a multitude of anti-amyloid drugs. A better understanding of the pathogenesis of the disease, especially the first cellular events, is vital in the development of disease modifying treatments that could address this global health issue. The best neuropathological correlate of the cognitive deficits seen in Alzheimer’s disease is synaptic loss and the most significant genetic risk factor is variation of the Apoliprotein E (APOE) protein sequence, particularly the APOE3 and APOE4 alleles. The objective of this thesis was to use CRISPR-Cas9 technology to create isogenic APOE cell lines differing by only their APOE 3 and 4 genotypes. As ApoE is largely produced by astrocytes within the central nervous system, the effects of these genetic variations on astrocyte cell biology was investigated, in particular effects on ApoE expression, glutamate uptake, phagocytosis, cholesterol homeostasis and the expression profile of pro-inflammatory cytokines. All of these characteristics were changed in cells carrying the E4 genotype. I describe how these may be connected by a common pathway and outline future directions for further development of the cell model. Overall, this thesis describes a model system which has elucidated a number of astrocytic phenotypes associated with the APOE genotype highlighting areas of enquiry that are most likely to be fruitfu

Transforming growth factor‐beta induces skeletal muscle atrophy and fibrosis through the induction of atrogin‐1 and scleraxis

Introduction: Transforming growth factor‐beta (TGF‐β) is a well‐known regulator of fibrosis and inflammation in many tissues. During embryonic development, TGF‐β signaling induces expression of the transcription factor scleraxis, which promotes fibroblast proliferation and collagen synthesis in tendons. In skeletal muscle, TGF‐β has been shown to induce atrophy and fibrosis, but the effect of TGF‐β on muscle contractility and the expression of scleraxis and atrogin‐1, an important regulator of muscle atrophy, were not known. Methods: We treated muscles from mice with TGF‐β and measured force production, scleraxis, procollagen Iα2, and atrogin‐1 protein levels. Results: TGF‐β decreased muscle fiber size and dramatically reduced maximum isometric force production. TGF‐β also induced scleraxis expression in muscle fibroblasts, and increased procollagen Iα2 and atrogin‐1 levels in muscles. Conclusion: These results provide new insight into the effect of TGF‐β on muscle contractility and the molecular mechanisms behind TGF‐β–mediated muscle atrophy and fibrosis. Muscle Nerve 45: 55–59, 2012Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/89462/1/22232_ftp.pd

Effects of intrauterine exposure to synthetic glucocorticoids on fetal, newborn, and infant hypothalamic-pituitary-adrenal axis function in humans : a systematic review

BACKGROUND: Synthetic glucocorticoids are commonly used in reproductive medicine. Fetal organ systems are highly sensitive to changes in the intrauterine environment, including overexposure to glucocorticoids. Structural and functional alterations resulting from such changes may persist throughout life and have been associated with diverse diseases. One system that could be particularly sensitive to fetal glucocorticoid overexposure is the hypothalamic-pituitary-adrenal (hpa) axis. Many human studies have investigated this possibility, but a systematic review to identify consistent, emergent findings is lacking. METHODS: We systematically review 49 human studies, assessing the effects of intrauterine exposure to synthetic glucocorticoids on fetal, neonate, and infant hpa function. RESULTS: Study quality varied considerably, but the main findings held true after restricting the analyses to higher-quality studies: intrauterine exposure to synthetic glucocorticoids reduces offspring hpa activity under unstimulated conditions after pain but not pharmacological challenge. Although reduced unstimulated hpa function appears to recover within the first 2 wk postpartum, blunted hpa reactivity to pain is likely to persist throughout the first 4 months of life. There is some evidence that the magnitude of the effects is correlated with the total amount of glucocorticoids administered and varies with the time interval between glucocorticoid exposure and hpa assessment. CONCLUSIONS: This systematic review has allowed the demonstration of the way in which intrauterine exposure to various regimens of synthetic glucocorticoids affects various forms of hpa function. As such, it guides future studies in terms of which variables need to be focused on in order to further strengthen the understanding of such therapy, whilst continuing to profit from its clinical benefits

Lameness in dairy heifers; impacts of hoof lesions present around first calving on future lameness, milk yield and culling risk

The importance of lameness in primiparous dairy heifers is increasingly recognised. Although it is accepted that clinical lameness in any lactation increases the risk of future lameness, the impact of foot lesions during the first lactation on long-term lameness risk is less clear. This retrospective cohort study aimed to investigate the impacts of foot lesions occurring around the time of first calving in heifers on future lameness risk, daily milk yield and survival within a dairy herd. Records were obtained for 158 heifers from one UK dairy herd. Heifers were examined in 2 month blocks from 2 months pre-calving through to 4 months post-calving. Sole lesions and white line lesions were scored on a zero to 10 scale and digital dermatitis on a zero to 3 scale. Outcomes investigated were; lameness risk based on weekly locomotion scores, average daily milk yield and culling risk. Mixed effect models were used to investigate associations between maximum lesion scores and outcomes. Lesion scores in the highest score categories for claw horn lesions (sole lesions and white line lesions) in the 2 to 4 month post-calving period were associated with an increased risk of future lameness; heifers with white line lesion scores ≥3 compared with scores zero to 1 and heifers with sole lesion scores ≥4 compared with score 2, at this time point, had a predicted increased risk of future lameness of 1.6 and 2.6 respectively. Sole lesions ≥4 were also associated with a reduction in average daily milk yield of 2.68 kg. Managing heifers to reduce claw horn lesions during this time period post-calving may provide health, welfare and production benefits for the long-term future of those animals. A novel finding from the study was that mild lesion scores compared with scores zero to 1, were associated with a reduced risk of future lameness for white line lesions and sole lesions occurring in the pre-calving or 2 to 4 months post-calving periods respectively. Mild sole lesions in the pre-calving period were also associated with a reduced risk of premature culling. One hypothesis for this result is that a mild insult may result in adaptive changes to the foot leading to greater biomechanical resilience and so increased longevity

Open letter from UK based academic scientists to the secretaries of state for digital, culture, media and sport and for health and social care regarding the need for independent funding for the prevention and treatment of gambling harms

First paragraph: Dear secretaries of state, As leading academic scientists studying gambling behaviours and its harms, we are writing to express our concern about the continuing support shown for the voluntary system of funding treatment, prevention and research in Great Britain. We feel compelled to write to you following the Betting and Gaming Council’s (BGC) recent announcement (17 June 2020) that five of its operators will now allocate the long awaited increase in funding for prevention and treatment, first promised on 2 August 2019, to GambleAware rather than the charity Action Against Gambling Harms. Irrespective of which organisation funds are given to, the BGC’s announcement exemplifies the longstanding weakness of a funding system that allows the gambling industry to regulate the availability and distribution of vital funds to address gambling harms across our communities. As we outline below, the continuance of this arrangement produces several negative effects that undermine the collective effort to reduce harms from gambling. It is also our belief that funds for research into gambling harms and their reduction should primarily be distributed through recognised independent organisations, such as UK Research and Innovation. We hereby urge you, as the secretaries of state with responsibilities for addressing gambling harms, to implement a statutory levy to fund effective prevention and treatment of gambling harms that is free both from industry influence and the perception of industry influence...... [Read more in the article]Additional co-authors: Carolyn Downs, Simon Dymond, Emanuele Fino, Elizabeth Goyder, Cindy Gray, Mark Griffiths, Peter Grindrod, Lee Hogan, Alice Hoon, Richard James, Bev John, Jill Manthorpe, Jim McCambridge, David McDaid, Martin McKee, Sally McManus, Antony Moss, Caroline Norrie, David J Nutt, Jim Orford, Rob Pryce, Gerda Reith, Amanda Roberts, Emmett Roberts, Gareth Roderique-Davies, Jim Rogers, Robert D Rogers, Stephen Sharman, John Strang, Richard Tunney, John Turner, Robert West, David Zendl

COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases

Although most autoimmune diseases are considered to be CD4 T cell- or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of autoimmunity and COVID-19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS-CoV-2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority of SARS-CoV-2-infected, CD20-depleted people with autoimmunity have recovered. However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available

Welshness in British Wales: Negotiating national identity at the margins

Popular interpretations of national identity often focus on the unifying qualities of nationhood. However, societies frequently draw hierarchical distinctions between the people and places who are ‘most national’, and those who are ‘least national’. Little attention is paid to these marginal places within the nation and the experiences of their inhabitants. This article helps to address this by analysing the ‘less Welsh’ British Wales region of Wales, a country that has traditionally possessed a hierarchical, regionally constituted nationhood. The article studies the British Wales region both ‘from above’ – considering how some areas develop as ‘less national’ – and ‘from below’, introducing empirical ethnographic work into ‘everyday Welshness’ in this area. Whilst previous work on hierarchical nationhood focuses on how hierarchies are institutionalized by the state, this article demonstrates how people at the margins of the nation actively negotiate their place in the nation. Whilst people in this area expressed a strong Welshness, they also struggled to place themselves in the nation because they had internalized their lowly place within the national hierarchy. The article demonstrates the importance of place and social class for national identity construction and draws attention to the role of power in the discursive construction of hierarchical nationhood

Writing in Britain and Ireland, c. 400 to c. 800

No abstract available