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A review of design protection in the UK with policy considerations
Get PDFThis report looks at how design protection in the UK is being used and makes suggestions for potential reform
PROTAC-mediated multi-target protein degradation in Alzheimer's disease: mechanistic insights, therapeutic applications, and translational challenges
Get PDFAlzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multiple interacting pathological mechanisms. Among these, the core driving factor is the accumulation of abnormally folded, neurotoxic proteins. Current therapeutic options, particularly immunotherapies, remain limited due to their reliance on immune-mediated clearance, the need for high-dose administration, and their inability to access intracellular targets, making them less patient-friendly and therapeutically efficient. This is precisely where proteolysis-targeting chimera (PROTAC) technology offers a transformative advantage. By harnessing the ubiquitin–proteasome system (UPS), PROTACs can selectively recruit degradation machinery to target proteins, thereby facilitating their ubiquitination and subsequent clearance. This mechanism allows PROTACs to efficiently eliminate pathogenic proteins while overcoming several inherent limitations of both traditional occupancy-based inhibitors and antibody-based therapies. In this review, we compare currently available AD therapies to highlight the advantages and mechanistic rationale underlying the promise of PROTAC technology in this field. We further discuss the molecular principles of PROTAC-mediated protein degradation and its emerging applications in tackling protein aggregation pathologies, focusing on both established and novel therapeutic targets. By drawing insights from existing PROTAC studies, we aim to inform future design strategies that reduce off-target effects, accelerate candidate optimization, and ultimately contribute to the development of a new generation of AD therapeutics
Reviewing the Psychological Sense of School Membership (PSSM) Scale: An Updated and Student-Centred Version
Get PDFThe concept of belonging within society is important to all human beings but this is enhanced in school settings, particularly amongst adolescents, who are negotiating their place in the community. School connectedness is linked to improved outcomes for young people. This research updates a measure of school connectedness with a participatory methodology involving adolescent co-production. Given our desire to develop a questionnaire that is easy to administer in schools and which reliably measures the level of school connectedness of students, it was important to include the voice of young people. The team tested a questionnaire, discussed the results, evaluated the question wording and structure, and developed a revised version of a belonging survey that is meaningful to young people. The resulting questionnaire was administered in two schools and the data shared with those schools. This paper discusses the validity of the questionnaire and uses statistical analysis to prove that the new version can be used to measure the level of school connectedness in individual schools and across schools. This will be a useful instrument for schools to use on a regular basis to measure the level of belonging within their schools, at whole school, year group, or class level
The key attributes and experience of the Falls Ambassador Programme
Get PDFBackground: Managing falls for care home residents is a key priority and a collaborative approach to learning about falls management may be helpful. The falls ambassador programme delivered by Lincolnshire Care Association aimed to provide this. This research explored the key attributes and learning experience of care home staff participating in the falls ambassador programme. Methods Non-participant observations, interviews and focus groups with care home staff participating in the programme were undertaken to explore the learning from the programme. Researcher field notes were maintained from the observations. Interview and focus groups were digital recorded and transcribed. The interviews and observation field notes were analysed thematically using the Consolidated Framework for Implementation Research (CFIR) theoretical framework. Results: Observations were completed over three workshops, and 8 care home staff took part in an interview or focus group. Themes within the CFIR domains of innovation, outer setting inner setting and process were identified. Key attributes included being delivered by a trusted source, having online and faceto- face opportunities and including a range of staff across care homes. Conclusions The programme increased learning across care homes in Lincolnshire providing a supportive forum to share challenges and experience. Further work to develop the programme to include the wider health and social care system would be beneficial
Multiplet structure of chromium(iii) dopants in wide band gap materials
Get PDFTransition metal doping is commonly used for altering the properties of solid-state materials to suit applications in science and technology. Partially filled d-shells of transition metal atoms lead to electronic states with diverse spatial and spin symmetries. Chromium(III) cations have shown great potential for designing laser materials and, more recently, for developing spin qubits in quantum applications. They also represent an intriguing class of chemical systems with strongly correlated multi-reference excited states, due to the d3 electron configuration. These states are difficult to describe accurately using single-reference quantum chemical methods such as density functional theory (DFT), the most commonly used method to study the electronic structures of solid-state systems. Recently, the periodic effective Hamiltonian of crystal field (pEHCF) method has been shown to overcome some limitations arising in the calculations of excited d-states. In this work, we assess the suitability of DFT and pEHCF to calculate the electronic structure and d–d excitations of chromium(III) dopants in wide band gap host materials. The results will aid computational development of novel transition metal-doped materials and provide a deeper understanding of the complex nature of transition metal dopants in solids
Explainable random forest predictions of polyester biodegradability using high-throughput biodegradation data
Get PDFThe development of new, biodegradable polyesters is becoming increasingly important as legislative and consumer drivers push society towards more sustainable polymers. One key bottleneck in the development of biodegradable polyesters is the slow nature of biodegradability testing, which can often take weeks to months. High-throughput screening assays serve as a rapid tool to determine the biodegradability of materials quickly, without the need for lengthy, expensive testing. When combined with machine learning, the data generated by high-throughput assays can be exploited to predict the properties of other similar materials. Here, we report the development of a high-throughput enzymatic biodegradation assay, which has been used to determine the biodegradability of 48 polyesters. Using data generated from the assay to train a predictive model, we can predict the biodegradability of polyesters using an explainable random forest model with 71% accuracy. Transfer learning and model chaining were investigated as routes to improve the model predictions by exploiting existing literature data. SHAP analysis gives insight into the beneficial structural features of biodegradable polyesters. This understanding can be applied in the development of future biodegradable polyesters
Acute measurement of flow‐mediated dilation following passive heating in adults: The confounding role of altered shear stress and baseline vasodilation
No full textChanges in flow-mediated dilation (FMD) following acute heating are not well understood, appear protocol-specific, and may be better understood by additional measures of acute vasoactivity. This study investigated FMD responses before and after three different 30-min hot-water immersion conditions (40°C-Shoulder, 42°C-Waist, and 40°C-Waist) in 22 adults. Brachial artery diameter was recorded at baseline (Dbase), during the final 30 s of occlusion (Docc), and at peak post-occlusion (Dpeak). Allometrically scaled FMD%, and changes in diameter during occlusion (OIV), and from end-occlusion to peak diameter (FMDDocc) were calculated. Pre-occlusion shear rate was greater post-immersion in 40-Shoulder (p < 0.001) and 42-Waist (p < 0.001), but not 40-Waist (p = 0.13), with the largest increase observed in 40-Shoulder. Alongside this, Dbase increased (Δ0.4 ± 0.2 mm, p < 0.001) and FMD% decreased (Δ−3.9 ± 3.8%, p = 0.04) following immersion in 40°C-Shoulder only. Across all conditions, ΔFMD% was negatively associated with ΔDbase (rrm = −0.47, p = 0.001). OIV% was the only vasoactivity metric to statistically differentiate between all conditions post-immersion (40°C-Shoulder: −8.1 ± 4.9%. 42°C-Waist: −3.0 ± 5.3%. 40°C-Waist: 1.1 ± 4.1%. p < 0.001). Post-heating FMD is confounded by heat-induced increases in baseline diameter, even after allometric scaling, while OIV% may provide complementary insight into acute vasoactivity following passive heating
Recent Advancements in Design and Energy Performance of Vapour Compression Systems for Air Conditioning in Buildings: A Review
Get PDFRapid urbanisation and rising thermal comfort expectations are propelling global energy demand for space cooling and heating in buildings, cementing vapour compression air conditioning as the dominant technology due to its proven simplicity and efficiency. However, conventional mechanical configurations remain constrained by intrinsic ther-modynamic irreversibilities and by international protocols mandating the phase-out of high global warming potential refrigerants. While a growing body of research proposes performance-enhancement measures, these advances remain fragmented across technolo-gies and application contexts. This paper critically reviews recent vapour compression cy-cle developments, structuring the literature around five interrelated thematic pathways: refrigerant-centric strategies, thermodynamic cycle modifications, hybrid system integra-tion, heat exchanger innovations, and control-centric optimisations. The analysis reveals that no single technology can universally optimise vapour compression cycle perfor-mance; instead, effective system improvements emerge from context-specific combinations of refrigerant innovation, heat-transfer enhancement, cycle modification, and hybridisa-tion, with the most successful strategies closely aligned to required temperature lifts and regional climatic conditions. This review introduces a simplified constraint–strategy–technology framework in which dominant system constraints (regulatory and proprietary, thermodynamic and climatic conditions, and demand-related) are first identified. Then corresponding technological improvement strategies (cycle modification, hybridisation, material selection, and control optimisation) are mapped out while enabling technologies are evaluated for suitability, scalability, and maturity. Therefore, this framework provides a system-level synthesis that links performance gains to context-specific operating con-straints
Bronchial epithelial cell-derived extracellular vesicle analysis using conventional, imaging, and nanoscale flow cytometry technologies
Get PDFBronchial epithelial cell-derived extracellular vesicles (EVs) are central to airway immune responses to inhaled particulate stimuli, as well as regulating respiratory diseases. Through a complex bioactive cargo, EVs can influence inflammatory signalling in the epithelium. Typically, a variety of technologies are used to analyse EVs derived from biofluids, such as nanoparticle tracking analysis, western blotting, and transmission electron microscopy. But recent advances in flow cytometers (FCs) potentially provide a single technology that can rapidly enumerate, size and phenotype epithelial cell-derived EVs, without the absolute need for purification. With multiple FCs available, this study aimed to describe methods and discuss considerations for analysing epithelial cell-derived EV on different FCs. Thus, supernatants containing EVs from primary human bronchial epithelial cells were stained with calcein-AM, in combination with anti-fluorescently conjugated tetraspanin antibodies, before analysing on a CytoFLEX S, ImageStream X MKII, and CytoFLEX nano. NIST traceable polystyrene particle size standards or synthetic EV size standards were used for EV size calibration, and antibody capture microspheres were used to measure the limit of detection for tetraspanin antibodies. We demonstrated that epithelial cell-derived EVs can be sized, enumerated, and phenotyped using all tested FC technologies, with varying sizing sensitivities and considerations for each FC. These findings provide a guidance for selecting suitable FC technologies for EV characterisation and highlight their potential to dissect epithelial EV heterogeneity in the context of airway immune responses and inflammation
Factors influencing UK arthroplasty surgeons' decision-making between total and medial unicompartmental knee surgery: A vignette-based behavioural experiment
Get PDFPurpose: Surgical options for end-stage knee osteoarthritis (OA) include total and medial unicompartmental knee replacement (TKR and UKR). Deciding which surgery to perform is complex and ill-defined, yet it has important implications for patients and the health service. The study aimed to identify clinical and surgeon factors predicting surgeons' preferences. Methods: Based on a preliminary survey of 162 UK surgeons, we identified clinical features frequently considered when deciding between TKR and UKR. By systematically varying patient age, obesity, site of pain, anaesthetic risk and anterior cruciate ligament (ACL) integrity, we constructed 32 clinical vignettes. We used these in a new survey, where surgeons indicated which surgery they would recommend on an 11-point rating scale with end points anchored at ‘definitely TKR’ and ‘definitely medial UKR’. Data were analysed with mixed-effects linear regressions. Results: Eighty-three UK arthroplasty surgeons completed the vignettes. Preference for UKR over TKR was significantly lower for patients over 50 years (b = −0.57 [−0.82 to −0.33], p < 0.001) with abnormal ACL (b = −1.93 [−2.17 to −1.68], p < 0.001) and severe systemic disease (b = −0.46 [−0.70 to −0.21], p < 0.001). Obesity was a weak and unreliable predictor, and we did not detect any influence of site of pain. The surgeons' habitual practice (proportion of UKRs over all knee replacements performed in a typical year) was the second strongest predictor after ACL (b = 1.26 [0.54–1.99], p = 0.001). Conclusions: ACL integrity was the most important determinant of surgeons' preferences between TKR and UKR. Their habitual practice was also a strong predictor, outweighing most clinical factors in the vignettes. Level of Evidence: Level II, prospective cohort study
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