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Axonal degeneration in hemorrhagic stroke: A systematic review
Get PDFHemorrhagic stroke occurs due to a rupture of a blood vessel in the brain. This leads to initial mechanical damage at the site of injury and secondary injuries including axonal degeneration (AxD). Since axons are critical for all brain functions, we systematically reviewed studies that focused on AxD in two major types of hemorrhagic stroke, intracerebral hemorrhage and subarachnoid hemorrhage, to understand how and to what extent AxD develops and to interrogate underlying mechanisms and potential therapeutic targets. After screening 817 publications published until September 18, 2024, we identified 68 records to be included. AxD was detected in patients as early as 24 h and in animal models as early as 6 h. Several outcomes were reported including the release of neurofilaments into the CSF and blood, increased serum or cerebral levels of tau protein, the accumulation of beta-amyloid precursor protein at the sites of axonal damage, degenerative changes in axonal density and shape observed with light and electron microscopy, or white matter disruption in diffusion magnetic resonance imaging. AxD is correlated with hematoma volume and worsening of clinical outcomes. It occurs in various locations, especially in the perihemorrhagic zone, and its extent increases over time. Targeting neuroinflammation, improving energy metabolism, inhibiting microtubule breakdown, and stimulating axonal growth and regeneration were assessed as therapeutic options. Further investigations are needed to understand whether any of these options could be developed into novel interventions for hemorrhagic stroke
Regional heterogeneity in left atrial stiffness impacts passive deformation in a cohort of patient-specific models
Get PDFIn atrial fibrillation (AF), atrial biomechanics are altered, reducing atrial movement. It remains unclear whether these changes are due to altered anatomy, myocardial stiffness, or constraints from surrounding structures. Understanding the causes of changed atrial deformation in AF could enhance tissue characterization and inform AF diagnosis, stratification, and treatment. We created patient-specific anatomical models of the left atrium (LA) from CT images. Passive LA biomechanics were simulated using finite deformation continuum mechanics equations. LA stiffness was represented by the Guccione material law, where α scaled the anisotropic stiffness parameters. Regional passive stiffness parameters were calibrated to peak regional deformation during the reservoir phase and validated against deformation transients derived from retrospective gated CT images during the reservoir and conduit phase. Physiological LA deformation varies regionally, with the roof deforming significantly less than other regions during the reservoir phase. The fitted model matched peak patient deformations globally and regionally with an average error of mm over our cohort. We compared deformation transients through the reservoir and conduit phases and found that the simulated deformation transients were within an average of mm per unit time of the CT-derived deformation transients. Regional stiffness varied across the atria with average α values of 1.8, 1.6, 2.2, 1.6 and 2.1 across the cohort in the anterior, posterior, septum, lateral and roof regions respectively. Using mixed effect models, we found no correlation between regional patient LA deformation and regional estimates of wall thickness or regional volumes of epicardial adipose tissue. We found a significant correlation between regionally calibrated stiffness and CT-derived LA biomechanics (p = 0.023). We have shown that regional heterogeneity in stiffness contributes to regional LA biomechanics, while anatomical features appeared less important. These findings provide insight into the underlying causes of altered LA biomechanics in AF
IR Spectroscopy: From Experimental Spectra to High-Resolution Structural Analysis by Integrating Simulations and Machine Learning
Get PDFUnderstanding biomolecular function at the atomic scale requires detailed insight into the structural changes underlying dynamic processes. Vibrational infrared (IR) spectroscopy─when paired with biomolecular simulations and quantum-chemical calculations─determines bond length variations on the order of 0.01 Å, providing insights into these structural changes. Here, we address the forward problem in IR spectroscopy: predicting high-accuracy vibrational spectra from known molecular structures identified by biomolecular simulations. Solving this problem lays the groundwork for the inverse problem: inferring structural ensembles directly from experimental IR spectra. We evaluate two computational approaches, normal-mode analysis and Fourier-transformed dipole autocorrelation, against experimental IR spectra of N-methylacetamide, a prototypical model for peptide bond vibrations. Spectra are derived from simulation models at multiple levels of theory, including hybrid quantum mechanics/molecular mechanics, machine-learned, and classical molecular mechanics approaches. Our results highlight the capabilities and limitations of current theoretical biophysical approaches to decode structural information from experimental vibrational spectroscopy data. These insights underscore the potential of future artificial intelligence (AI)-enhanced models to enable direct IR-based structure determination. For example, resolving the so-far experimentally inaccessible structures of toxic oligomers involved in neurodegenerative diseases, enabling improved disease diagnostics and targeted therapies
Accurate Prediction of Drug Resistance for Intrinsically Disordered Protein Regions
Get PDFRelative alchemical binding free energy calculations can be used to predict the effect of amino acid mutations on ligand binding affinities. However, these protocols are not well established for proteins containing intrinsically disordered regions (IDRs). In this work, we focus on the development of robust protein-free energy perturbation (FEP) protocols to reproduce experimental binding affinities that have been measured for a panel of mutants of the protein MDM2 against two ligands, AM-7209 and Nutlin-3a. We focus on mutations that occur in the N-terminal IDR lid of MDM2, which is known to undergo ligand-dependent folding upon binding. We systematically assess the effectiveness of both equilibrium and nonequilibrium alchemical protocols in reproducing these experimental binding affinities, in particular for mutations with slowly varying degrees of freedom. We show that the equilibrium protocol outperforms the nonequilibrium protocol in the precision of the free energy estimates obtained. In addition, we demonstrate the effect of the protein force field and the water model used to simulate the highly flexible IDR region. Overall, our findings demonstrate an accurate FEP protocol capable of reproducing these trends and further show the applicability of FEP protocols for elucidating the mutational effects on ligand binding affinity in highly dynamic intrinsically disordered protein regions
The Spanish Civil War as a spatial allegory for Japanese anti-fascism:Historical experience and political limitations of a liberal approach to Popular Front movements
Get PDFThis article investigates, for the first time, how Japanese anti-fascist intellectuals approached, in the mid-1930s, the sociopolitical and cultural reality of Spain as the world’s main stage of the anti-fascist struggle. As the article will show, modern Spanish society contained significant parallels with prewar Japan. That is partly why those intellectuals set their eyes on the Spanish Second Republic under fascist attack as a way to indirectly project an allegorical model that allowed implicit criticism of the problems of their own country in a context where freedom of expression was more and more repressed. In an atmosphere of increasingly advanced fascistisation, these intellectuals were arrested in 1937. Therefore, reporting from Japan on the fight against fascism in Spain meant, to some extent, attacking fascism as a global phenomenon and thus as both a Japanese and Spanish reality. Study of this empirical case opens the way for non-Eurocentric theoretical reflections on fascism and anti-fascism as universal phenomena with their national particularities, thus contributing to decentring comparative fascist studies from new perspectives
Effective Transcriptional Induction of the CARMN/miR-143/145 Complex Locus in Smooth Muscle Cells Using CRISPR Activation
Get PDFThe land of many laws:Brexit and the legacy of colonialism in Northern Ireland
Get PDFBrexit was a great revealer in many respects. In relation to Northern Ireland, it revealed the almost invisible role that joint EU membership had played in providing a scaffold for the peace process in the province and in resolving a postcolonial conflict with cross-border dimensions. In addition to EU political support and in facilitating good relations between Ireland and the UK, joint membership of the single market and customs union, along with the Common Travel Area between the two jurisdictions, reduced the practical and symbolic effect of the border between Ireland and Northern Ireland. It was thus the functional effects of single market law which provided the context within which a postcolonial conflict with cross-border dimensions could be managed. Brexit, particularly of the ‘hard’ variety, threatened to reintroduce this border, undermining a key element of the peace process. The Ireland/Northern Ireland Protocol or Windsor Framework is an imperfect substitute which results in an extremely complex legal landscape of multiple interacting sources of law: a form of legal pluralism or even legal entanglement
Leveraging deep learning models to increase the representation of nomadic pastoralists in health campaigns and demographic surveillance
Get PDFNomadic pastoralists are systematically underrepresented in the planning of health services and frequently missed by health campaigns due to their mobility. Previous studies have developed novel geospatial methods to address these challenges but rely on manual techniques that are too time and resource-intensive to scale on a national or regional level. To address this gap, we developed a computer vision-based approach to automatically locate active nomadic pastoralist settlements from satellite imagery. We curated labeled datasets of satellite images capturing approximately 1,000 historically active settlements in the Omo Valley of Ethiopia and the Samburu County of Kenya to train and evaluate deep learning models, studying their robustness to low spatial resolutions and limits in labeled training data. Using a novel training strategy that leveraged public road and water infrastructure data, we closed performance gaps introduced by shortages in labeled settlement data. We deployed our best model on a region spanning 5,400 square kilometers in the Omo Valley of Ethiopia, resulting in the identification of historical settlements with a 270-fold reduction in manual review volume. Our work serves as a promising framework for automating the localization of nomadic pastoralist settlements at a national scale for health campaigns and demographic surveillance.</p
NHS Staff's Experiences of Reflective Practice Groups in Prisons: A Reflexive Thematic Analysis
No full text## Access ## This dataset is held in the Edinburgh DataVault, directly accessible only to authorised University of Edinburgh staff. Requests for access will not necessarily be granted. University of Edinburgh users who wish to have direct access should consult the information about retrieving data from the DataVault at: https://www.ed.ac.uk/is/research-support/datavault.This is the archived dataset from Emer Heffernan's DClinPsychol research project (completed in May 2025), supervised by Dr Juliane Kloess. The dataset is comprised of nine interview transcripts and MS Word files recording the different stages of analysis. The data files are being archived for research integrity purposes, and are not available or accessible to anyone outside of the research team
The nature of sports coach development in China:What are we trying to achieve?
Get PDFCoach education and continuing career development have become a significant focus of global discussion within the sport domain. Current mainstream strategies for developing and assessing coaches in most countries, including China, are based on competency-based systems. However, there are many shortcomings of this system, especially when considering the varied practical challenges and needs of coaches and athletes; in short, such an approach does not facilitate enough adaptability. The purpose of this article is to critically review the literature, exploring both competence- and expertise-based coach development systems and their implications for coaching practice in China. Firstly, we introduce and discuss the competency-based approach, including its strengths and weaknesses and how this applies within the Chinese development system. Next, we introduce and evaluate an alternative, expertise-based development system characterised by adaptability and greater inclusiveness within the coaching domain, which is underpinned by a distinct set of cognitive decision making skills from the coach’s perspective. In addition, we expand this discussion by explaining the implications of this approach for coach assessment and offer some future suggestions for research in this area
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