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Targeting AhR suppresses hepatocyte ferroptosis in MASH by regulating the Pten/Akt/β catenin axis
Get PDFAryl hydrocarbon Receptor (AhR), an essential host regulator, has been observed to be significantly upregulated in patients with Metabolic dysfunction-associated steatohepatitis (MASH). However, the underlying mechanism remains unclear. The specific AhR antagonist CH223191 and siRNAs were employed to investigated the role of AhR and its potential as a therapeutic target for MASH in mice and hepatocytes model. Significant upregulation of hepatic AhR was found in our MASH model and across three public datasets. CH223191 (5 mg/kg) treatment effectively ameliorated lipid deposition, serum ALT/AST level, inflammatory cytokines and hepatocyte senescence. Moreover, inhibiting AhR reduced aberrant iron overload, MDA and ROS levels, and suppressed iron transporter DMT1 and iron storage protein ferritin. Furthermore, CH223191 treatment resulted in the restoration of β-catenin and Pten while reducing the phosphorylation of Akt. Suppression of Pten or β-catenin by specific antagonists significantly abolished the hepatoprotective effects of CH223191, leading to increased DMT1 and ferritin and subsequent hepatic ferroptosis in mice. In conclusions, these findings suggested a novel regulatory role of AhR plays in ferroptosis and iron overload through the Pten/Akt/βcatenin pathway, which makes AhR a promising therapeutic target for the treatment of MASH
Regulation and Governance Gaps in the Detection of Labour Exploitation Within State-Funded Domestic Services
Get PDFExamining the provision of domestic care, this article highlights governance gaps in the regional administration of labour rights protections within the direct state-funding of long-term care. Drawing upon data from secondary sources and semi-structured interviews with stakeholders in four European countries, municipal activities including whistleblowing procedures; care-worker professionalisation; the expansion of employee's roles and inter-agency data analysis have been identified and are described. My analysis suggests that initiatives to enhance individual agency are more commonly reported in traditionally familial welfare regimes while collective actions are more frequently described in countries which have had a more universalist approach to the provision of long-term care. Without further reform and greater theoretical diversification, particularly in relation to its gendered nature, our understanding of potential avenues to improve the detection of labour malpractices seems unlikely to adequately address the evidential threat. Implications for theory, policy, practice and future research are discussed
Synthesis and cell-induced luminescence of post-functionalisable ionisable polyesters from the Passerini 3-component polymerisation
Get PDFRecent developments in polymer synthesis methods allow the preparation of new materials across a wide chemical space and with high atom efficiency. In this work, we developed a strategic approach to the synthesis of a diverse array of novel ionisable polyesters via a modular and iterative synthetic approach. We initially designed a range of diacid monomers and subsequently used the Passerini 3-component reaction as a simple, one-pot step growth polymerisation to build a library of novel, highly functionalised polymers. This library was expanded further by the application of thiol/ene and copper-initiated azide/alkyne click chemistries to introduce further structural diversity into the materials. Selected polymers were found to internalise readily in a model cell line (HEK-293T), and for a subset of these polymers, bright luminescence was observed in the cells upon internalisation, even though neither the cells, nor the polymers, were luminescent on their own at these wavelengths. Our synthetic approach offers a versatile platform for the systematic development and modification of novel macromolecules and for cell-labelling components
A network outcome analysis of psychological factors and suicide risk in emergency department patients
Get PDFDifferent theories of suicide propose somewhat different psychological factors that lead to suicidal thoughts and behaviors. For example, Beck’s theory highlights hopelessness, while the interpersonal–psychological theory of suicide emphasizes burdensomeness, lack of belonging and fearlessness about death. Surprisingly, few studies have tested which theoretically proposed psychological factors are most predictive of suicidal thoughts and behaviors. We used network outcome analysis to disentangle the effects of these constructs in predicting suicidal ideation, suicide plans and attempts. Participants were 1,412 patients presenting to an emergency department with psychiatric complaints, with follow-up assessments one month and six months (n = 938) later. Here we showed that different psychological factors predicted different parts of the continuum of suicidal thoughts and behaviors. Lack of belongingness was most predictive of suicidal ideation (partial correlation (pcor) = 0.14), acquired capability for death (that is, fearlessness of death) was most predictive of suicide planning (pcor = 0.08), and hopelessness was most predictive of suicide attempts (pcor = 0.12). Individuals’ explicit associations with death (that is, death = me) prospectively predicted all three outcomes (pcor = 0.13–0.23). The occurrence of suicidal thoughts and behaviors is best predicted using constructs from several different theories of suicide. Future theoretical and empirical work should integrate components of existing theories
Impact of central adjudication of the score on the modified Rankin Scale in an international, randomized, acute stroke trial
Get PDFIntroduction:The modified Rankin Scale (mRS) is the most frequently used primary outcome measure in acute stroke research despite significant interobserver variability in assigning grades. We assessed the use of central blinded adjudication of the mRS based on a video recording of an interview in the PRECIOUS trial.Patients and methods:PRECIOUS was an international, randomized, open-label, clinical trial with blinded outcome assessment of preventive treatment with metoclopramide, paracetamol, and ceftriaxone in elderly patients with acute stroke. Trained local investigators interviewed patients or their representatives and graded functional outcome at 90 days after stroke with the mRS. In each participating country, a video recording of the interview was assessed by three blinded, independent adjudicators. The primary outcome of the present substudy was interobserver agreement between the local mRS score and the median score of the three central adjudicators for patients alive at 90 days, assessed with Cohen’s kappa and quadratic weighted kappa statistics. The difference between treatment effect estimates based on local and central adjudication was a secondary outcome.Results:Of 1493 patients enrolled in PRECIOUS, 1471 were included in this analysis. At 90 days, 1117 patients (75.9%) were alive and had both a central and local assessment; 28 participants did not have a central mRS score. Interobserver agreement was seen in 829 (74.2%) patients and was substantial (kappa of 0.68; 95% CI 0.65–0.71). Disagreement occurred more often in patients with a central mRS score of 0–2 (OR 2.24; 95% CI 1.14–4.24). Treatment effects were neutral for all three study drugs and did not differ between central and local adjudication.Discussion and conclusion:Central adjudication of the mRS based on a video recording is feasible in a large international, randomized stroke trial. This ensures blinding of the outcome assessment. In this neutral trial, the impact of central adjudication on the precision of effect size estimates could not be assessed
High fat diet induces differential age- and gender-dependent changes in neuronal function in Drosophila linked to redox stress
Get PDFThe prevalence of neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, is steadily increasing, thus posing significant challenges to global healthcare systems. Emerging evidence suggests that dietary habits, particularly consumption of high-fat diets, may play a pivotal role in the development and progression of neurodegenerative disorders. Moreover, several studies have shed light on the intricate communication between the gut and the brain, linking gut health with neuroinflammation and its involvement in neurodegenerative processes. This study aims to assess the effects of a high-fat dietary intake on various aspects of neuronal function during aging in a gender specific manner to help understand the potential contributions of diet to neuronal function. To investigate the effects of a high-fat diet, Drosophila melanogaster was used and exposed to a standard normal food diet (NF) and a high-fat diet (HF). Adults were grouped at 10 and 45 days of age in male and female flies reared under the same conditions starting the HF diet at 5 days of age with data showing differential gender- and HF diet-induced phenotypes. Malondialdehyde (MDA) levels were higher in males at 10 and 45 days (p < 0.05), caspase-3 expression increased at 45 days (p < 0.01) implicating apoptosis induction and a reduced climbing activity at 10 and 45 days was apparent in females only (p < 0.01). Adult lifespan under both dietary conditions was unchanged when reared at 18°C but odour-associated learning ability was reduced in larvae reared in a HF diet throughout their development (p < 0.05). This is the first study to characterise effects of a HF diet on neuronal phenotypes in an age- and gender-specific manner in a Drosophila model. Our findings suggest a HF diet induces differential effects of neuronal dysfunction with age and sex-specific outcomes, characterised by enhanced oxidative stress and cell death impacting on behaviour
A Psychometric Analysis of the Stress Management Competency Indicator Tool
Get PDFBackground: Work-related stress is a growing concern in the United Kingdom, negatively impacting both employee well-being and organisational effectiveness. Addressing work-related stress through effective managerial practices is essential, however, existing tools are often lengthy and impractical for routine use.Aims: The study aimed to develop and validate a shortened version of the 36-item stress management competency indicator tool (SMCIT) to enhance its practicality and relevance to changing working practices, while maintaining reliability and validity in assessing stress management competences. Methods: A secondary data analysis was undertaken using data from 224 line managers across 12 organisations. Principle component analysis was applied to reduce the SMCIT from 36 to 19 items. Psychometric analysis, including Cronbach’s alpha, factor loadings and total variance explained, were used to ensure the shortened tool retained its measurement rigour. Results: The 19 item SMCIT retained four latent constructs: respectful/ responsible, managing the individual within the team, conflict/problem management, and organisational resources. The revised tool explained 46% of the variance, compared to 37% for the original, and showed factor loadings ranging from point .43 to .86. Reliability scores ranged from .65 to .69, indicating moderate internal consistency. We conclude that the shortened tool enhances measurement efficiency by removing redundant items, while maintaining key competencies. Conclusions: The shortened SMCIT is a reliable and practical tool for evaluating line management competencies, reducing response burden while improving data quality and relevance to hybrid working. We recommend further validation through confirmatory factor analysis and expert review to enhance its application in occupational settings
Waterborne debris impact forces on wall structures: Elastic analytical model integrating the effects of the structural mass
Get PDFTo evaluate the structural safety against waterborne debris impacts, the impact loads are usually computed with analytical models such as those proposed by ASCE/SEI 7–22. These models often assume a massless structure to simplify the analytical formulations, which can be an oversimplifying and inaccurate assumption in cases where the structure is heavier and more flexible than the debris. To address this problem, we aim to define the domain in which the existing models are inaccurate and to propose a new analytical model to accurately compute the debris impact forces through comprehensive finite element simulations and analytical modelling. We defined such a domain in the design space of structure-to-debris mass and stiffness ratios and assessed which are the most accurate analytical models to compute debris impact forces across this space. Our proposed model significantly improves upon the overestimating results of the ASCE/SEI 7–22 model when both stiffness and mass are important in determining the impact forces
Measuring the Intracluster Light Fraction with Machine Learning
Get PDFThe intracluster light (ICL) is an important tracer of a galaxy cluster’s history and past interactions. However, only small samples have been studied to date due to its very low surface brightness and the heavy manual involvement required for the majority of measurement algorithms. Upcoming large imaging surveys such as the Vera C. Rubin Observatory’s Legacy Survey of Space and Time (LSST) are expected to vastly expand available samples of deep cluster images. However, to process this increased amount of data, we need faster, fully automated methods to streamline the measurement process. This paper presents a machine learning model designed to automatically measure the ICL fraction in large samples of images, with no manual preprocessing required. We train the fully supervised model on a training data set of 50,000 images with injected artificial ICL profiles. We then transfer its learning onto real data by fine-tuning with a sample of 101 real clusters with their ICL fraction measured manually using the surface brightness threshold method. With this process, the model is able to effectively learn the task and then adapt its learning to real cluster images. Our model can be directly applied to Hyper Suprime-Cam images, processing up to 500 images in a matter of seconds on a single GPU, or fine-tuned for other imaging surveys such as LSST, with the fine-tuning process taking just 3 minutes. The model could also be retrained to match other ICL measurement methods. Our model and the code for training it are made available on GitHub
The impact of binders on magnetic framework composite pellets for CO2 capture
Get PDFMagnetic framework composites (MFCs), comprising magnetic nanoparticles (MNPs) embedded in metal–organic frameworks (MOFs), have emerged as an exciting novel class of advanced functional materials. MFCs show particular promise for CO2 capture, where they overcome the low thermal conductivity barriers of MOFs by facilitating the use of magnetic induction heating for thermal regeneration. Current research in the field has focussed on dry powder MFCs. However, for scale up towards use in industry, these powders require formulating into larger structures such as pellets. Herein we present the first study of pelletisation routes for MFCs.MFCs were first produced via an innovative continuous flow synthesis with multiple concentrations of magnetic nanoparticles, then formulated into pellets with various polymer binders. Surface area and CO2 capacity losses caused by pelletisation were minimised using a low-pressure extruder, with some binders showing zero pore blocking effects. Pellet mechanical strength was increased by 107% (crushing load) and 87% (elastic modulus) from formulating with just 4% polyvinyl alcohol binder. We also present the first investigation into the thermal properties of MFCs, essential for modelling the materials’ behaviours in packed bed adsorbers. Notably, thermal conductivity increased by 47% with 7.8% MNPs in the MFCs, compared to the pristine MOF, highly beneficial for applications requiring thermal cycling. The formulation and pelletisation methods explored are applicable to a range of MOFs and MFCs, facilitating the shaping of these exciting materials for positive impact across CO2 capture and other applications
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