21827 research outputs found
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RePol:A high‐throughput screen for optimizing membrane protein solubilization and purification using polymers
No full textExtraction and purification of membrane proteins has for a long time represented a significant challenge. Polymer‐based extraction methods, like those using styrene maleic acid co‐polymers have provided a fertile approach to generate samples that include the local lipid environment surrounding the protein. However, the wide variety of different polymers now available provides a challenge to identify the optimal solution. In this study we develop and demonstrate a novel high‐throughput screening approach for rapid optimization of polymer solubilization agents and chromatography resins for membrane protein purification. Using this approach, we explore whether there are standard conditions that perform well for a range of membrane protein morphologies, sources and functions. These data show that no such standard conditions exist for either polymer solubilization agent or chromatography resin and that some combinations are rarely suitable for membrane protein purifications under these conditions, such as the use of TALON resin at a pH of 7.5 or SMALP300 in the Synthetic Nanodisc Screening Kit MINI kit. Instead, the use of the screening approach developed in this work is the best route to an optimal membrane protein preparation protocol
Why HR Has Failed to Address Healthcare's Workforce Crisis: The Need for a Systems Partner Role
Get PDFAttempts to remedy sustained workforce challenges facing healthcare organizations globally have been largely ineffective, despite increased political attention. In this provocation piece we draw on contextually based human resource theory to explain why these challenges remain intractable. We demonstrate that professional healthcare workers' employment relationships are embedded within systems as well as organizations, and that system-level constraints limit organizational capacity to address workforce issues. Informed by UK and US examples of issue-oriented, place-based and system approaches to stakeholder convening we argue that progress requires both stakeholder coordination at the system level (premised on ‘deviant innovation’, Legge, 1978) and strategic HR innovation (‘conformist innovation’, Legge, 1978) within organizations. We develop a framework identifying three potential HR roles in system-level engagement: systems partner (actively convening stakeholders), participant (contributing to system-level initiatives), and bystander (remaining organizationally focused). While acknowledging barriers to HR adopting a systems partner role, we advocate for enhanced HR engagement as a systems participant, combined with strengthened within-organization ‘conformist innovation’ as a business partner to support health workforce recruitment, retention and reform. We identify corporate HR managers and OD specialists as particularly well-positioned to pioneer system-level engagement, whether as participants in existing initiatives, as collaborators through intermediaries or, where feasible, as systems partners driving stakeholder coordination
Cutting-edge synthetic strategies and interaction mechanisms in polymeric nanostructures: Bridging preformed polymers with polymerization-induced self-assembly
No full textRecent progress in nanosized drug delivery carrier design has immensely contributed to the development of next-generation smart healthcare facilities, offering enhanced solubility, prolonged circulation time, reduced toxicity to healthy cells and real-time monitoring. Among various materials, polymeric nanocarriers (PNCs) stand out due to the customizable properties of polymer molecules, which can further be tailored to fulfill specific requirements. This review provides a comprehensive evaluation of the different intermolecular interactions, such as hydrogen bonding, π-π stacking, electrostatic interactions, hydrophobic/hydrophilic interactions, and host-guest interactions, that influence the self-assembly processes during PNC design. It also explores a range of fabrication techniques for PNCs, including emulsion-evaporation, nanoprecipitation, dialysis, gelation, salting-out, supercritical fluid technology, coacervation, and molecularly imprinted polymerization. Additionally, the impact of experimental conditions on controlling the size of PNCs is analyzed in detail. The review further evaluates the process of polymerization-induced self-assembly (PISA) in conjunction with various polymerization methods, highlighting the potential for advanced PNC fabrication. Lastly, it discusses the prospects and challenges associated with PNC design, considering both preformed polymers and PISA methodologies
Factors associated with treatment-resistant hypertension:results of a prospective observational study
No full textIntroduction: Treatment-resistant hypertension (TRH) is defined as uncontrolled blood pressure despite the use of ≥3 antihypertensive medications at maximum tolerated doses. It is associated with increased risks of cardiovascular events, kidney disease, and mortality. White-coat hypertension, nonadherence, and inappropriate drug combinations overestimate its prevalence. The exact cause of TRH remains unclear, though obesity, obstructive sleep apnoea, and sympathetic overactivity may contribute. This study aimed to better understand the factors associated with true TRH. Methods: Adult patients with treated hypertension without confirmed secondary causes from the West Midlands Hypertension Centre, UK were recruited for comprehensive evaluation. Patients underwent thorough clinical assessment, including tests for endothelial function, body composition, arterial stiffness, sleep study, and inflammation and endothelial biomarkers; comparing true TRH with non-TRH patients. Results: Of 141 patients, 60 (43%) had true TRH after excluding whitecoat effect, secondary hypertension and medication nonadherence. The TRH patients were significantly older, had a longer duration of hypertension, and more frequently had diabetes. They had higher rates of left ventricular hypertrophy, higher extracellular water, lower eGFR, and higher urine albumin. They also had higher cardiac biomarkers, (serum NT-proBNP and hs-troponin), inflammatory markers (serum free light chains), aldosterone:renin ratio, and serum Endothelin-1. There was no difference between the groups in adjusted arterial stiffness, reactive hyperaemia or overnight pulse oximetry. Multivariate analysis identified only NT-proBNP as a significant factor associated with TRH ( P = 0.027). Conclusion: The FACT-RHY study provides valuable insights into the possible pathophysiological mechanisms of TRH. These results emphasize the need for further research into the mechanisms underlying TRH and potential management strategies
Glucocorticoids and Cell Fate in the Developing Brain: Neuroendocrine Mechanisms Shaping Developmental Trajectories
Get PDFEarly life stress (ELS) is a major risk factor for later psychiatric and neurological disorders. Glucocorticoids (GCs), the hormonal end-products of the neuroendocrine stress response, are central mediators of this risk, influencing how the developing brain grows and adapts. Research has shown that GCs affect processes such as cell proliferation, neuronal survival, and maturation, but much less attention has been given to whether they also shape cell fate—the developmental choices that determine whether stem and progenitor cells give rise to neurons, astrocytes, oligodendrocytes, or other specialised lineages. In this perspective, I argue that cell fate provides a valuable new lens for understanding how stress becomes embedded in brain architecture. Because GCs act directly on neural stem and progenitor populations, it is plausible that their influence extends beyond the quantity of cells produced, to the identities that emerge. I outline an initial framework for interpreting potential effects of GCs on fate, review emerging evidence from different model systems, and consider mechanisms by which stress hormones could alter developmental trajectories. By focusing on fate, this article highlights a novel dimension of neuroendocrine influence on brain development, with implications for how early experiences confer vulnerability, or resilience, to later mental health outcomes
Development of The COMBINED approach: Integrating a brief behaviour change intervention supported by a physiotherapist for people with rotator cuff disorders
Get PDFBackground: Modifiable lifestyle factors (smoking, inactivity, overweight) could contribute to the onset and persistence of rotator cuff disorders, yet physiotherapy practice rarely addresses them. Brief interventions (BIs) can support behaviour change but are not routinely embedded in musculoskeletal care. Objectives: To develop The COMBINED approach: a physiotherapist-supported intervention integrating BI's targeting modifiable health behaviours into routine consultations for people with rotator cuff disorders; and to explore how physiotherapists can be supported to deliver it. Materials and methods: A theory-, evidence-, and pragmatic-based development process incorporated stakeholder co-design, behavioural theory, and evidence across three workstreams: (1) narrative review of BIs targeting smoking, inactivity, and weight management; (2) four co-design workshops with 26 stakeholders (physiotherapists, patients, experts) to select and adapt a BI and identify key intervention features; (3) theoretical modelling using COM-B, TDF, and BCTTv1 to map barriers/facilitators, select behaviour change techniques, and develop prototype components. Findings: Fourteen BIs were identified; Moving Medicine had greatest utility. Barriers included time constraints, limited skills and confidence, and fear of offending patients, contrasting with patients' acceptability of lifestyle conversations. Recommendations included embedding the BI into routine care, scripts, infographics, patient resources, and training. Twelve TDF domains and 20 BCTs informed prototype development comprising: (1) patient-level intervention: a BI (adapted from Moving Medicine) embedded in routine consultations with tailored resources; (2) clinician-level implementation toolkit. Conclusions: The COMBINED approach is the first formally developed intervention supporting integration of BI's within routine consultations for people with rotator cuff disorders and is now ready for feasibility testing
Comparison of S-band doped fiber amplifier and Raman amplifiers in long-haul coherent transmission
Get PDFWe compare the long-haul coherent transmission performance of 30 GBaud DP-16-QAM WDM signals using five different S-band optical amplifiers: a thulium doped fiber amplifier (TDFA), a distributed Raman amplifier (DRA) and three different lumped Raman amplifiers (LRAs) using 10 km inverse dispersion fiber (IDF), 10 km, and 5 km Raman optical fibers (ROFs). Over 1050 km standard single-mode fiber (SSMF), the DRA performed the best with an SNR of 14.2 dB at the optimum launch power of -2.3 dBm, followed by the TDFA with an SNR of 13.0 dB and the LRA using 10 km IDF with 11.6 dB of SNR
Risk of Self-Harm and the Use of Leukotriene Receptor Antagonists and Inhaled Corticosteroids: a Population-Based Study
Get PDFBackground: Whether leukotriene receptor antagonist (LTRA) or inhaled corticosteroid (ICS) use can increase the risk of self-harm remains unclear. Objective: To evaluate the association between self-harm and use of LTRAs and ICSs among patients with asthma. Methods: This self-controlled case series study used data from the UK Clinical Practice Research Datalink linked to hospital and mortality records. We included patients with asthma aged 10 years or more who had at least 1 prescription of LTRA, 1 prescription of ICS, and an incident self-harm during the period 2005 to 2020. Incidence rate ratios (IRRs) of self-harm during periods of (presented in order of precedence if they overlapped) pre-LTRA, pre-ICS, LTRA-alone, ICS-alone, and combination use of LTRA and ICS, versus nonuse, were calculated using conditional Poisson regression model. Additional analyses using self-controlled case series extension, case-case-time-control, and cohort study designs were used to examine robustness of results. Results: Among 313,943 individuals prescribed LTRAs and ICSs, 2900 had incident self-harm. IRRs were 0.77 (95% CI, 0.58-1.01) during pre-LTRA, 0.68 (95% CI, 0.57-0.82) during LTRA-alone, and 0.70 (95% CI, 0.56-0.86) during combination use. Further analysis suggested that the self-harm incidence was lower during the first 90 days of LTRA use (IRR, 0.74; 95% CI, 0.58-0.95), before returning to nonuse level (IRR, 0.93; 95% CI, 0.74-1.17). Comparable incidence to nonuse was observed during pre-ICS (IRR, 0.99; 95% CI, 0.71-1.39) and ICS-alone (IRR, 0.88; 95% CI, 0.75-1.04). The results were robust across sensitivity analyses and study designs, which did not suggest increased risk of self-harm with LTRA/ICS use. Conclusions: Using the self-controlled case series design, which was based on comparisons within a population with both the outcome and exposure of interest, our study does not support an association between self-harm and LTRA or ICS use in patients with asthma
A Game-Theoretic Framework for Intelligent EV Charging Network Optimisation in Smart Cities
No full textThe transition to Electric Vehicles (EVs) demands intelligent, congestion-aware infrastructure planning to balance user convenience, economic viability, and traffic efficiency. We present a joint optimisation framework for EV Charging Station (CS) placement and pricing, explicitly capturing strategic driver behaviour through coupled non-atomic congestion games over road networks and charging facilities. From a Public Authority (PA) perspective, the model minimises social cost, travel times, queuing delays and charging expenses, while ensuring infrastructure profitability. To solve the resulting Mixed-Integer Nonlinear Programme, we propose a scalable two-level approximation method, Joint Placement and Pricing Optimisation under Driver Equilibrium (JPPO-DE), combining driver behaviour decomposition with integer relaxation. Experiments on the benchmark Sioux Falls Transportation Network (TN) demonstrate that our method consistently outperforms single-parameter baselines, effectively adapting to varying budgets, EV penetration levels, and station capacities. It achieves performance improvements of at least 16% over state-of-the-art approaches. A generalisation procedure further extends scalability to larger networks. By accurately modelling traffic equilibria and enabling adaptive, efficient infrastructure design, our framework advances key intelligent transportation system goals for sustainable urban mobility
Accounting education and neocolonialism in Pakistan: A Gramscian perspective
Get PDFResearch has shown how accounting is an important tool in the weaponry of colonial and neocolonial powers. However, less is known on how accounting education can be a means to ensure the silent reproduction of Western values and priorities. This study explores the relationship between current arrangements in university accounting education in Pakistan and neocolonialism. The paper is based on interviews with the three main categories of actors who have an impact on higher education, namely accounting policymakers, educators and students, and adopts Gramsci's understanding of hegemony and the role of intellectuals in society. Policymakers, who enjoy strong ties with large multinational corporations, through accreditation mechanisms influence the meanings and content of accounting education, which educators then transmit to students, thereby altering their ‘common sense’. Consistently, many students are influenced by beliefs such as the primacy of the West and its ‘neutral’ practices and the need to embrace internationalisation. Nevertheless, others refuse such taken for granted assumptions and act as potential ‘organic intellectuals’, who may fuel the creation of new understandings around the role and content of accounting education in developing countries
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