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Exploring the role of sortilin related receptor 1 in glioblastoma
Get PDFAn inverse comorbidity exists between neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease and various cancers. Likely due to occupying opposite ends of the same spectrum; neurodegeneration causing premature cell death and cancer driving uncontrolled cell proliferation. Alzheimer’s disease offers greatest protection against lung cancer but, surprisingly, the impact Alzheimer’s disease may have on brain cancers has not been fully investigated. This thesis will explore the role of the Alzheimer’s disease risk factor protein sortilin related receptor 1 (SorL1) in glioblastoma, the gravest and most common primary brain tumour. SorL1 binds to the amyloid precursor protein to regulate trafficking to the early and late endosomes for cleavage into amyloid beta (A) peptides. In Alzheimer’s disease, SorL1 expression is reduced, increasing A secretion and contributing to the characteristic extracellular amyloid plaques. SorL1 has previously been implicated in peripheral cancers including breast and leukaemia but has never been investigated in glioblastoma. This thesis explores the expression and function of SorL1 in glioblastoma and downstream effects on A40 (most abundant species of A) and A42 (the more aggregate prone species commonly found in Alzheimer’s disease).
Expression of SorL1 in immortalised cell lines (U87MG, 1321N1 and SVGp12) and primary cells (patient derived (PD) 301, PD304 and normal human astrocytes (NHA)), and subsequent expression of A40 and A42 was determined through combinations of immunofluorescence, western blot and ELISA. Secretion of SorL1 into spent medium of PD301, PD304 and NHA cells and in mouse serum from glioblastoma tumour bearing mice was investigated. The contribution SorL1 makes to cell function in glioblastoma was achieved by transiently transfecting PD301 and PD304 cells with siRNA vectors to knock down SorL1. Following confirmation of SorL1 knock down by western blot and immunofluorescence, cell proliferation, viability, migration and impact on amyloid processing was determined.
SorL1 was found to be more highly expressed in glioblastoma cells (U87MG, PD301 and PD304) than control cell counterparts (SVGp12 and NHA) with concomitant reduction in A42 expression in PD301 and PD304 cells compared to NHA cells. Expression of A40 was similar between PD301, PD304 and NHA cells. Furthermore, secretion of SorL1 from PD cells into medium was significantly reduced compared to NHA cells. SorL1 in mouse serum did not change during progression of tumour or between tumour bearing mice or mice following sham surgery. Successful transfection of siRNA against SorL1 in PD301 and PD304 cells knocked down SorL1 by approximately 50%. SorL1 siRNA transfected cells had increased A40 and A42 expression and SorL1 knock down reduced proliferation and migration of glioblastoma cells.
Findings here suggest SorL1 remains functional to drive APP processing away from A42 production in glioblastoma and reducing SorL1 activity may be a potential therapeutic strategy for glioblastoma in the future
Criminal Justice Bill 2023 - Written evidence - Committees - UK Parliament
Get PDFImposing a duty on to the College of Policing to introduce a code of practice about ethical policing, which must include a duty on chief officers to take actions to secure that their
officers act ethically and, in particular, “in an open a transparent way” (clause 73).
Question to answer: The Bill would require the College of Policing to introduce a code of practice on ethical policing, which must include a “duty of candour”. What impact would this have on the protection of human rights, particularly the investigative obligations under Article 2 ECHR (the right to life)
Supporting Mental Health and Well-Being of an Aging Prison Population Through Creative Nature-Based Interventions
Get PDFThis article focuses on an evaluation of a conservation and nature-based pilot project (BOOM) conduced in a UK local prison as part of the Greener on the Outside for Prisons therapeutic horticultural program. BOOM developed a tree and plant growing nursery where prisoners approaching the end of their sentences helped to restore endangered fauna and flora. They also engaged in tree-planting sessions within the prison grounds. Over 100 prisoners participated overall, with approximately a fifth of these going on to take part in an accredited course and engage in creative, arts-based activities related to nature as part of the project.
Researchers carried out a series of focus groups with prisoners and staff who had taken part in prison-based BOOM activities during 2022–2023. In addition to BOOM staff, 18 prisoners were interviewed in four narrative-based focus groups, which gave participants a forum to discuss their experience of the project. A thematic analysis of this data has drawn out key themes in relation to health and well-being benefits of the project for an aging prison group and opportunities and challenges that arise from partnership working in this context. These health and well-being themes incorporate trust, connecting with nature, raising environmental consciousness, the value of creativity, and thinking beyond the gate. These findings have implications for future prison-based prisons project involving older prisoners, who are the fastest growing group in the prison population, and whose particular health and well-being needs are not currently entirely understood or met within the UK prison system
The SAInT study: a protocol for a randomized controlled trial of steroid injection for subacromial pain syndrome using the anterolateral versus posterior approach
Get PDFAims
Steroid injections are used for subacromial pain syndrome and can be administered via the anterolateral or posterior approach to the subacromial space. It is not currently known which approach is superior in terms of improving clinical symptoms and function. This is the protocol for a randomized controlled trial (RCT) to compare the clinical effectiveness of a steroid injection given via the anterolateral or the posterior approach to the subacromial space.
Methods
The Subacromial Approach Injection Trial (SAInT) study is a single-centre, parallel, two-arm RCT. Participants will be allocated on a 1:1 basis to a subacromial steroid injection via either the anterolateral or the posterior approach to the subacromial space. Participants in both trial arms will then receive physiotherapy as standard of care for subacromial pain syndrome. The primary analysis will compare the change in Oxford Shoulder Score (OSS) at three months after injection. Secondary outcomes include the change in OSS at six and 12 months, as well as the Pain Numeric Rating Scale (0 = no pain, 10 = worst pain), Disabilities of Arm, Shoulder and Hand questionnaire (DASH), and 36-Item Short-Form Health Survey (SF-36) (RAND) at three months, six months, and one year after injection. Assessment of pain experienced during the injection will also be determined. A minimum of 86 patients will be recruited to obtain an 80% power to detect a minimally important difference of six points on the OSS change between the groups at three months after injection.
Conclusion
The results of this trial will demonstrate if there is a difference in shoulder pain and function after a subacromial space steroid injection between the anterolateral versus posterior approach in patients with subacromial pain syndrome. This will help to guide treatment for patients with subacromial pain syndrome
Hip contact force pathways in total hip replacement differ between patients and activities of daily living
Get PDFOne of the main causes of implant failure and revision surgery in total hip replacement (THR) is aseptic loosening often caused by the accumulation of wear debris arising between the contact surfaces of the acetabular cup and femoral head during activities of daily living (ADL’s). However, limited information is available regarding the contact force pathways between these two surfaces during specific ADL’s. In this study, through musculoskeletal modelling, we aimed to estimate the orientation of the hip contact force pathway on the acetabular cup. One hundred and thirty-two THR patients underwent motion capture analysis whilst undertaking locomotor and non-locomotor ADL’s. Musculoskeletal simulations were performed to calculate contact force pathways using inverse dynamics analysis. We then qualitatively compared differences in the contact force pathways between patients and between ADL’s. Walking resulted in a typical figure-of-eight pattern, with the peak contact forces occurring in the superior-anterior area of the cup. The non-locomotive activities such as stand up, sit down and squat had a more linear shape, spanning across the superior-posterior quarter of the cup. Our results showed a large inter-patient variability in the shape and location of the contact force pathway.
There is a distinct difference in the location and shape of the pathway between locomotor and non-locomotor activities and this could result in different wear accumulations. These results could enhance our understanding why revision rates vary across the population and could inform the development of personalised implant design
Experimental and computational assessment of an energy-saving innovation in a customised testing cabin
Get PDFThe aim of this paper is to assess the performance of an energy saving device, called ‘Thermocill’ in a customised test cabin, located in a controlled environment. With the UK domestic energy sector responsible for nearly 27 % of the total energy mix in 2022, and massive increases in the cost of energy on homeowners and tenants, simple and low-cost retrofit measures could potentially be of great value, if they prove to be effective at saving energy. The paper describes the experimental and computational methods in detail with the goal of setting an important example/standard for assessment of similar energy-saving innovations under the UK Standard Assessment Procedure (SAP). This, in turn, would enable the performance of such innovations to be captured in the Energy Performance Certificates (EPCs) for Building Regulation compliance. On that basis, a test cabin was constructed at Salford Energy house 2.0 to investigate Thermocill’s impacts on energy consumption and loss within the cabin. The experimental procedure is subsequently compared against a series of Computational Fluid Dynamics (CFD) simulations conducted for a larger number of scenarios. The performance of Thermocill was explored at different room temperature setpoints (16, 21, and 24 °C), window types (air and argon-filled double-glazed), and with/without blinds. The results were presented for four main scenarios including ‘cabin without Thermocill/blind’, ‘cabin with blind’, ‘cabin with Thermocill’, and ‘cabin with blind/Thermocill’. The results were presented in the form of U-values and heat losses for the windows, while additional results were provided from CFD simulations. A good correlation between the experiments and the CFD is found, showing confidence in both methods. Findings demonstrated that, when Thermocill is in operation, it reduces the average U-value by around 3–4 %, which is considered a significant payback for a passive and economical measure. The methodology presented in this paper is expected to set an important example/standard for assessment of similar energy saving innovations under UK SAP. This, in turn, would enable the performance of such innovations to be captured in the EPCs for Building Regulation compliance
‘There for me’: Learning from young people about challenges and enablers to continuing education
Get PDFYoung people’s perspectives are not always central to policy and practice in widening participation contexts. This article explores enablers and barriers to educational progression by considering factors that young people suggest influence how they envisage and act on their futures. The underpinning study asked students aged 12–23 in disadvantaged areas of northern England to think about their possible selves using creative methods to encourage dialogue, including an animation and board game co-designed with university students. The findings suggested that students’ perceptions of their own futures are influenced by their experiences of being categorised or labelled, both in and out of school, as well as the quality of their relationships with adults and peers. The authors discuss how these factors tended to shape the young people’s experiences of being at school, with a view to rethinking labelling and enabling participatory spaces that cultivate the intersecting relationships, influences, structures and self-belief that make a difference
Stopover by migrant Montagu's Harriers in the Thar Desert is determined by vegetation greenness and grasshopper abundance but not locust outbreaks
No full textFood availability is an important criterion for migrant birds' decision to stay or leave a stopover site. This can vary depending on the conditions at the site. The Thar Desert of the Indian subcontinent is a major stopover area for birds wintering further south in the region. The desert is also prone to stochastic outbreaks of desert locusts that often coincide with the stopover time of migrating birds. Between 2017 and 2022, we tracked nine tagged Montagu's Harriers (Circus pygargus) using PTT and GPS-GSM transmitters to determine if the stopover duration at stopover sites in the desert is influenced by the availability of migratory locusts or resident grasshoppers and the strategies the birds employ, such as, foraging over a wide area or multiple sites to ensure refuelling during stopover. The mean stopover duration during the 2019 peak locust outbreak was 12 days compared to 18 days in other years. Birds did not track locust occurrence deliberately and preferred to stopover at the same sites each year, irrespective of locust outbreaks. The stopover duration at stopover sites appears to be linked to arrival date, vegetation greenness (NDVI) and marginally to grasshopper abundance. We conclude that the stochastic availability of locusts at stopover sites may provide only an opportunistic source of abundant food for migrant harriers and does not seem to affect their stopover duration. Instead, they choose a more stable strategy of relying on resident grasshoppers, less prone to strong fluctuations in abundance and distribution at the stopover sites
Down-regulation of wheat Rubisco activase isoforms expression by virus-induced gene silencing
Get PDFRubisco activase (Rca) is an essential photosynthetic enzyme that removes inhibitors from the catalytic sites of the carboxylating enzyme Rubisco. In wheat, Rca is composed of one longer 46 kDa α-isoform and two shorter 42 kDa β-isoforms encoded by the genes TaRca1 and TaRca2. TaRca1 produces a single transcript from which a short 1β-isoform is expressed, whereas two alternative transcripts are generated from TaRca2 directing expression of either a long 2α-isoform or a short 2β-isoform. The 2β isoform is similar but not identical to 1β. Here, virus-induced gene silencing (VIGS) was used to silence the different TaRca transcripts. Abundance of the transcripts and the respective protein isoforms was then evaluated in the VIGS-treated and control plants. Remarkably, treatment with the construct specifically targeting TaRca1 efficiently decreased expression not only of TaRca1 but also of the two alternative TaRca2 transcripts. Similarly, specific targeting of the TaRca2 transcript encoding a long isoform TaRca2α resulted in silencing of both TaRca2 alternative transcripts. The corresponding protein isoforms decreased in abundance. These findings indicate concomitant down-regulation of TaRca1 and TaRca2 at both transcript and protein levels and may impact the feasibility of altering the relative abundance of Rca isoforms in wheat