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Rapid autofluorescence flow cytometric analysis of agonist-induced neutrophil and eosinophil polarization reveals novel insights into 5-oxo-ETE-mediated granulocyte activation
Get PDFMinimizing unintended granulocyte activation while measuring functional responsiveness is essential, as the use of external probes, antibodies, or fluorescent dyes can potentially alter cellular responsiveness. To address this, we employed an antibody free flow cytometry approach that measures forward scatter (FSC) to detect variations in cell-size, morphology, and shape; some key indicators of neutrophil and eosinophil activation. Human peripheral blood neutrophils, containing contaminating eosinophils, were isolated using discontinuous Percoll gradients and pre-treated with receptor antagonists [e.g., cyclosporin-H (an FPR1 antagonist) and CP105696 (a BLT1 receptor antagonist)] prior to stimulation with agonists such as fMLF (an FPR1 agonist) and LTB4 (a BLT1 agonist). Furthermore, fMLF stimulation resulted in a loss CD62L and an increase in CD11b expression along with an increase in intracellular ROS production compared to control as analysed using flow cytometry. Imaging flow cytometry, together with FSC analysis, enabled assessment of cell polarization and associated morphological changes. Importantly, auto fluorescence-based gating allowed for the identification of contaminating eosinophils within the mixed granulocyte population, allowing parallel assessment of shape-change in both neutrophils and eosinophils in response to the same ligands. Stimulation of neutrophils with fMLF resulted in distinct FSC shifts compared to unstimulated controls across all flow cytometers tested, which were inhibited by cyclosporin-H, but not CP105696. Morphological analysis confirmed these changes corresponded with increased cell area and perimeter and decreased circularity, hallmarks of cell polarisation. Additionally, selective activation of eosinophils (but not neutrophils) by eotaxin, and dual activation of both cell types by the arachidonic acid metabolite 5-oxo-ETE, were confirmed through specific gating strategies. Taken together, these findings support the use of FSC-based flow cytometry as a rapid, scalable and effective method for evaluating granulocyte polarisation and screening candidate therapeutics targeting immune cell activation in disease contexts
Unlocking Antlers? An Evaluation of an Environmental Mediation Process in Scotland Based on Direct Observation
Get PDFEnvironmental conflicts are increasing as is interest in ways they can be managed. However, evaluations of Environmental Conflict Resolution (ECR) processes based on direct observation remain scarce, despite ECR existing for over half a century. Furthermore, there are few evaluations of ECR processes that have been conducted outside of the United States, which limits understanding about the different contextual applications of ECR. These significant shortcomings hamper the generation of practical and knowledge-based learning, as well as theory building in ECR. To address this, we use a subset of criteria from the ECR literature pertaining to (1) outcomes, (2) process, and (3) relationships to assess data generated through direct observation of an environmental mediation process, alongside interviews and surveys of participants, focused on ameliorating conflict over upland deer management in Scotland. Our results indicate that mediation fostered positive relationships, was generally procedurally effective but achieved limited tangible outcomes. We then provide some longer-term reflections on the mediation process, discuss the strengths and limitations of our criteria, and note lessons from our experience conducting an evaluation of an ECR process. We conclude by calling for more evaluations of ECR processes based on direct observation to be conducted to build understanding of effective practice
Hypertension in pregnancy and in midlife and the risk of dementia: prospective study of 1.3 million UK women
Get PDFCurrent strategies and future directions to enhance recovery following critical illness
Get PDFImprovements in critical care treatments have led to an increased number of survivors of critical illness and an enhanced recognition of the problems which these patients encounter. Despite this, the ideal strategies to both prevent and manage the problems which people face are yet to be fully elucidated.This review explores the current methods employed to help mitigate problems encountered by survivors of critical illnesses and current barriers that limit their implementation. We will explore the effect of these issues on under-represented communities and the feasibility of delivering these strategies globally, as well as recent advances in mechanistic research and methodological innovation as promising areas for further work. In doing so, it summarises the potential avenues for future research with a view to advancing clinical care and outcomes in survivors of critical illness.</p
Political scandals and vertical contagion in multilevel systems
Get PDFCan a scandal in one political sphere tarnish – or unexpectedly polish – the reputation of leaders in another? This study investigates the impact of political scandals in multilevel political systems and explores three possibilities: contagion, where trust erodes across all political levels; containment, where evaluations are limited to the specific institutions involved; and contrast, where actors at other levels appear more trustworthy in comparison. We present the first experimental test of vertical contagion, containment, and contrast effects following real-world scandals in UK and Scottish politics: Partygate and Campervangate. We find weak evidence of contagion in the Scottish-level ‘Campervangate’ scandal, although trust reductions were small and often not significant. However, the ‘Partygate’ scandal reveals a distinct contrast effect: trust decreased in UK political actors but increased at the Scottish level. These results suggest that scandals in multilevel polities can influence evaluations of ‘innocent’ political actors, with troubling consequences for democratic accountability mechanisms
Why are toilets not used? Using system effects modelling to understand stakeholder perceptions on the impacts and barriers to Taenia solium control in Eastern and Western Uganda
No full textTaenia solium taeniasis/cysticercosis in humans and pigs remains endemic to Uganda. Although, looking at the lifecycle of the parasite, the risk factors are well known, and many biomedical control options exist – no substantial progress has been made in the eradication of T. solium infections in Uganda to date. Contextual factors including socioeconomic, cultural and infrastructural factors, may influence the adoption of interventions. A community-based study using mixed methods and relying on system effects modelling approach was carried out between March and April 2021 in Kamuli district, Eastern Uganda, and Hoima district, Western Uganda. System effects modelling is a non-linear methodology that captures the varied nature of the unique, individually lived experiences and aggregates them to reflect what is experienced at a population level. The aim of the study was to capture individual stakeholder perceptions on the consequences of T. solium infections and barriers to practice known control options. Overall, 27 factors were identified by 192 participants as consequences of being infected with neurocysticercosis (NCC). For taeniasis, 35 factors were identified with 700 edges/connections made by the participants. Enlargement of stomach, weight loss, diarrhoea, weakness, and stunted growth were the most important consequences. Although porcine cysticercosis (PCC) seemed to be poorly understood by the participants, 14 factors were identified which included poor pig growth, loss of market for pig/pork, and poor pork quality. The study also identified important barriers hindering the adoption of control practices, including lack of knowledge on transmission, sociocultural factors, and resource constraints. For women, lack of knowledge on the mode of transmission and lack of a toilet in the compound ranked highly as important barriers with a weighted degree of 31 and 21, respectively, meaning they were identified by more participants unlike men who ranked lack of a toilet first with a weighted degree of 39, followed by lack of knowledge at 24. Different barriers are associated with the adoption of T. solium control practices among community members, stakeholders, and farmers. Despite efforts to address T. solium infections, misconceptions and limited understanding persist among stakeholders, particularly regarding NCC and its associated consequences. The system effects approach supports developing contextualized interventions to help in the control of the diseases associated with this parasite
Finding heterogeneous nucleating agents for ice using a data-driven approach
No full textWe present a high-throughput data-driven workflow to identify potential heterogeneous nucleating agents from structural databases for phase change materials, such as ice. Our model evaluates the fit between ice Ih and nucleator docked slabs, considering Miller index planes up to (333), thus addressing some of the structural complexities in nucleation by examining crystal morphology features. Bulk water immersion experiments on a set of ten known nucleators set a delineating temperature to distinguish between good and poor nucleation behaviour, which helped derive numerical tolerance limits to allow reliable differentiation on the basis of the number of predicted matching interface models. We then used our algorithm to screen 3500 simple metal oxides and halides taken from the inorganic chemistry structural database (ICSD), and show that just 7% of the former and 3% of the latter were predicted to nucleate ice on the basis of geometric slab matching alone. Subsequent experimental testing of 22 compounds suggested a 64% correct prediction rate, and identified four new ice nucleators (CeO2, WO3, Bi2O3, Ti2O3). Inspired by the ice-nucleating efficiency of copper oxides, we also tested copper tubing with local tap water, and observed sub-cooling suppression, most likely due to copper oxide buildup. Although based on a simple geometric interface matching model, this approach offers an efficient route as a first stage high throughput screen for potential heterogeneous nucleating agents.</p
Machine learning for air quality forecasting: Insights from five provinces of Rwanda
No full textAccurately predicting air quality is a crucial challenge for public health and environmental management. This study compares and contrasts machine learning approaches to benchmark best practices for the Rwandan context and to evaluate the added value of advanced statistical methods for air quality monitoring in data-scarce settings. We forecast fine particulate matter (PM2.5) concentrations across five provinces in Rwanda, using multi-year meteorological and air quality data to identify context-specific patterns. This work establishes a methodological foundation for context-optimized early warning systems and informs policy interventions to improve air quality management in Rwanda. By rigorously testing machine learning capabilities against regional constraints, we demonstrate how machine learning can reduce population exposure to pollution, quantify attribution gaps in under-monitored regions, and improve sustainable environmental governance in resource-limited settings. The results indicate significant seasonal variability, with higher PM2.5 levels during dry seasons than wet seasons. Our evaluation demonstrates that machine learning models can capture complex, non-linear relationships between environmental variables and pollution trends, although performance varies between algorithms. Limitations remain, including the integration of real-time data streams and localized variables such as industrial emissions, road traffic, and agricultural practices
TET knockout cells transit between pluripotent states and exhibit precocious germline entry
No full textTET1, TET2 and TET3 are DNA demethylases with critical roles in development and differentiation. To assess the contributions of TET proteins to cell function during early development, single and compound knockouts of Tet genes in mouse pluripotent embryonic stem cells (ESCs) were generated. Here we show that TET proteins are not required to transit between naïve, formative and primed pluripotency. Moreover, ESCs with double-knockouts of Tet1 and Tet2 or triple-knockouts of Tet1, Tet2 and Tet3 are phenotypically indistinguishable. These TET-deficient ESCs exhibit differentiation defects; they fail to activate somatic gene expression and retain expression of pluripotency transcription factors. Therefore, TET1 and TET2, but not TET3 act redundantly to facilitate somatic differentiation. Importantly however, TET-deficient ESCs can differentiate into primordial germ cell-like cells (PGCLCs), and do so at high efficiency in the presence or absence of PGC-promoting cytokines. Moreover, acquisition of a PGCLC transcriptional programme occurs more rapidly in TET-deficient cells. These results establish that TET proteins act at the juncture between somatic and germline fates: without TET proteins, epiblast cell differentiation defaults to the germline
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