University of Dundee

This work presents a Bayesian classifier technique to categorize patients based on predictive biomarkers of time-to-event data utilizing the Accelerated Failure Time (AFT) model incorporating the frailty effect. Before classification, efficient and significant markers from a high-dimensional gene expression dataset need to be identified. Currently, it is an emerging area in oncology. A conventional three-step feature selection approach is introduced to select the most relevant markers from high-dimensional data. A threshold value for each selected marker is obtained using the proposed Bayesian classification procedure incorporating the AFT model with the frailty effect. The frailty effect is incorporated to account for unobserved heterogeneity in the expression values of subjects, allowing for a more accurate investigation of the risk of cancer-related outcomes. A simulation study is performed to validate the proposed classification approach, and the classification’s performance is evaluated using the Brier score, and the result indicates that it is relatively high. Application of the proposed classification technique is provided for two high-dimensional TCGA datasets of lung cancer patients. Our results provide evidence about the effect of classified gene expression values on the survival risk of lung cancer patients.

Cellular senescence and aging are two distinct but overlapping entities that are both characterized by the intracellular accumulation of lipofuscin, the “dark” matter of the cell. Tissues like liver composed of slow dividing cells are prone to lipofuscin accumulation, thus creating an interesting intersection between aging and senescence. In the current work, we propose two approaches for the discrimination of these entities. The first one regards the adjustment of an established in situ senescence detecting algorithm in human liver diseases. The second one is based on a novel senescence molecular signature that can be applied, solely or complementary, to the in situ algorithm, in RNA data from the above clinical settings for in silico identification of cellular senescence.

Lipofuscin, a yellow-brown complex mainly found in cellular waste, accumulates in cells as a byproduct of cellular degradation processes and is commonly associated with aging and oxidative stress. Lipofuscin’s molecular “signature” comprises a diverse repertoire of oxidized proteins, lipids, and metals, yet the detailed protein composition of this unique complex remains undetermined. Toward this end, high-throughput proteomic analyses of lipofuscin are pivotal for elucidating its global protein content, the protein interactome, as well as biological mechanisms related to senescence-associated lipofuscin accumulation. Existing proteomic profiling approaches of lipofuscin primarily rely on “in-gel” digestion methods, often leading to incomplete protein digestion, suboptimal peptide recovery, and other analytical pitfalls leading to “loss” of significant molecular information. In this chapter, we introduce a global proteomic profiling methodology for lipofuscin preparations derived from cell cultures, based on FASP (Filter-Aided Sample Preparation) method coupled with nano-liquid chromatography-tandem mass spectrometry (nano-LC/MS-MS). This methodology aims to deliver robust characterization of the lipofuscin proteome, elucidate its complex interactions, and introduce a superior alternative to traditional “in-gel” digestion technique.

Background Aspergillus fumigatus, the primary etiological agent of invasive aspergillosis, causes over 1.8 million deaths annually. Targeting cell wall biosynthetic pathways offers a promising antifungal strategy. Gfa1, a rate-limiting enzyme in UDP-GlcNAc synthesis, plays a pivotal role in the hexosamine biosynthetic pathway (HBP). Results Deletion of gfa1 (Δgfa1) results in auxotrophy for glucosamine (GlcN) or N-acetylglucosamine (GlcNAc). Under full recovery (FR) conditions, where minimal medium is supplemented with 5 mM GlcN as the sole carbon source, the Δgfa1 mutant shows growth comparable to the wild-type (WT). However, when supplemented with 5 mM GlcN and 55 mM glucose, growth is partially repressed, likely due to carbon catabolite repression, a condition termed partial repression (PR). Under PR conditions, Δgfa1 exhibits compromised growth, reduced conidiation, defective germination, impaired cell wall integrity, and increased sensitivity to endoplasmic reticulum (ER) stress and high temperatures. Additionally, Δgfa1 demonstrates disruptions in protein homeostasis and iron metabolism. Transcriptomic analysis of the mutant under PR conditions reveals significant alterations in carbohydrate and amino acid metabolism, unfolded protein response (UPR) processes, and iron assimilation. Importantly, Gfa1 is essential for A. fumigatus virulence, as demonstrated in Caenorhabditis elegans and Galleria mellonella infection models. Conclusions These findings underscore the critical role of Gfa1 in fungal pathogenicity and suggest its potential as a therapeutic target for combating A. fumigatus infections.

Background The notion that debriefing quality is highly reliant on the skills and expertise of the facilitator is being increasingly challenged. There is therefore emerging interest in self-led debriefings (SLDs), whereby following a simulated learning event, individuals or groups of learners conduct a debriefing amongst themselves, without the immediate presence of a trained facilitator. The interest in this approach to debriefing is multifactorial but is, in part, driven by a desire to reduce costs associated with resource-intensive faculty presence. The debate regarding the role of SLDs in simulation-based education (SBE) therefore has important implications for the simulation community. Main body We comprehensively explore the role of SLDs by contextualising their application across the spectrum of SBE, both in terms of contrasting simulation factors, namely (i) simulation modality, (ii) debriefing forum, and (iii) debriefing adjuncts, as well as different learner characteristics, namely (i) learners’ previous simulation experience, (ii) learner numbers, and (iii) learners’ professional and cultural backgrounds. These factors inherently shape the conduct and format of SLDs, and thus impact their effectiveness in influencing learning. We have synthesised and critically analysed the available literature to illuminate this discussion. Conclusions The current evidence suggests that SLDs can, in the right circumstances, form part of an effective debriefing strategy and support learners to reach appropriate levels of critical self-reflection and learning. Careful consideration and due diligence must go into the design and implementation of SLDs to augment the advantages of this debriefing format, such as enhancing flexibility and learner autonomy, whilst mitigating potential risks, such as reinforcing errors and biases or causing psychological harm. In situations where resources for facilitator-led debriefings (FLDs) are limited, simulation educators should recognise SLDs as a potential avenue to explore in their local contexts. By leveraging the strengths of both formats, balancing learner autonomy and expert guidance, a combined SLD and FLD approach may yet prove to be the optimal debriefing strategy to maximise learning. Whilst more research is needed to deepen our understanding of the nuances of SLDs to assess their true applicability across the spectrum of SBE, the time may now have arrived to consider challenging the status quo.

Therapy with pegylated interferon alpha (pegIFNα) can induce a deep molecular response in a subset of patients with myeloproliferative neoplasms (MPN). Here we investigated the role of Socs2, a negative regulator of cytokine signaling, in modulating the response to pegIFNα in a JAK2-V617F mouse model of MPN. Deleting Socs2 in JAK2-V617F mice resulted in increased sensitivity to cytokines, without causing significant alterations in the MPN phenotype. When subjected to pegIFNα, the loss of Socs2 enhanced the depletion of JAK2-mutant hematopoietic stem cells (HSCs), evidenced by reduced chimerism in peripheral blood and bone marrow compared to vehicle controls. Additionally, pegIFNα-treated Socs2-deficient JAK2-mutant HSCs exhibited functional impairments in secondary transplantations, reflecting long-term detrimental decline of their stemness. These findings demonstrate that loss of Socs2 enhances the effectiveness of pegIFNα in depleting the JAK2-mutant HSC clone. In line with the genetic ablation of Socs2, the SOCS2 inhibitor MN714 combined with IFNα exhibited better efficacy than IFNα alone in reducing the output of CD34+ cells from PV patients in vitro. Targeting SOCS2 could therefore improve therapeutic responsiveness in MPN patients receiving interferon therapy.

The metazoan tRNA ligase complex (tRNA-LC) has essential roles in tRNA biogenesis and unfolded protein response. Its catalytic subunit RTCB contains a conserved active-site cysteine that is susceptible to metal ion-induced oxidative inactivation. The flavin-containing oxidoreductase PYROXD1 preserves the activity of human tRNA-LC in a NAD(P)H-dependent manner, but its protective mechanism remains elusive. Here, we report a cryogenic electron microscopic structure of the human RTCB–PYROXD1 complex, revealing that PYROXD1 directly interacts with the catalytic center of RTCB through its carboxy-terminal tail. NAD(P)H binding and FAD reduction allosterically control PYROXD1 activity and RTCB recruitment, while reoxidation of PYROXD1 enables timed release of RTCB. PYROXD1 interaction is mutually exclusive with Archease-mediated RTCB guanylylation, and guanylylated RTCB is intrinsically protected from oxidative inactivation. Together, these findings provide a mechanistic framework for the protective function of PYROXD1 that maintains the activity of the tRNA-LC under aerobic conditions.

Overconsumption is a leading factor behind the rising incidence of obesity worldwide. As consumers struggle to understand the true caloric and nutritional value of the foods they consume in an increasingly cluttered marketplace, food manufacturers are being tasked with finding more effective ways of communicating nutritional facts. We thus examined the impact of sonic logos (sogos) on the perception of food satiability and purchase intention. Study 1 demonstrates that consumers perceive foods that are presented with high‐frequency (vs. low‐frequency) sogos as lighter (vs. heavier) and subsequently less (vs. more) filling (while ruling out the role of hunger and time since the last food intake). Study 2 reveals that when consumers regard health (vs. satiety) as important, high (vs. low) frequency sogos induce higher purchase intention due to the perceived congruency between the sogo frequency and consumption goal. Our findings add to the literature on food and multisensory marketing by demonstrating that low‐frequency sogos can connote food satiability through the underlying mechanism of the shared semantic meaning of heaviness between a low‐frequency sound and satiable foods. These insights can assist brands in strategically designing their sound signatures to promote food satiability.

Laws of criminal procedure and evidence have long been criticised by feminist scholars, particularly as they apply to rape and other sexual offences. Many countries have redefined rape and have enacted legislation to improve the experiences of rape complainers/the alleged victims at trial. It remains the case, however, that rape is a difficult crime to prove. Securing a conviction for rape is especially demanding in Scotland, where corroboration of the prosecution's case is a general requirement. The recent Scottish case of Lord Advocate's Reference (No. 1 of 2023) highlights many issues relating to rape—issues which have been raised by feminists in many jurisdictions—concerning law's gendered assumptions and biases. The article assess this case from a feminist perspective, and argues that it could be considered to be a ‘feminist judgment’.

Background To explore the views of dentists participating in the Selective Caries Removal in Permanent Teeth (SCRiPT) randomised controlled clinical trial on selective caries removal versus complete or near complete caries removal for the management of deep carious lesions. Methods Nineteen semi-structured one-to-one telephone or online video interviews were conducted with dentists involved in SCRiPT, using an interview guide informed by the Theoretical Domains Framework (TDF). Data were initially analysed deductively using a framework informed by the TDF, and subsequently using reflexive thematic analysis. Results Three themes and 25 sub-themes were generated. Themes were ‘comfort using selective caries removal’, ‘potential value of SCRiPT’ and ‘challenges of subjectivity’. Sub-themes included six enablers and five barriers to the use of selective caries removal, as well as five contextual factors potentially impacting dentists’ decision-making. The SCRiPT trial was found to have potential value in terms of ‘overcoming uncertainty’, although perceived limitations were noted. The potential value of SCRiPT may depend on other factors, including the willingness of dentists to follow evidence from the trial (reflecting personal attributes and comfort with selective caries removal). The interviews also highlighted how caries removal is perceived as subjective and involves the application of clinical judgement to individual cases. General dental practitioners who are less comfortable with selective caries removal may not start to use this approach as defined within SCRiPT, particularly if there is a lack of strong evidence from the trial. Conclusions Dentists’ level of comfort with selective caries removal is multi-faceted and informed by contextual factors. SCRiPT has the potential to increase acceptance of selective caries removal, but the findings may not be interpreted in this way. Future work should further explore the concept of comfort with selective caries removal, using the thematic framework outlined here to inform the design of interview topic guides. Trial registration Trial registry: ISRCTN. Trial registration number: ISRCTN76503940. Date of Registration: 30.10.2019.

This article contributes to our understanding of the use of counter accounting in social movements, through consideration of Bakhtinian dialogics as a theoretical framing. We explore counter and dialogic accounting in a significant socio‐political conflict in the city of Sheffield, UK. Our case covers a public–private partnership (PPP) highway maintenance scheme entailing conflict over a tree‐felling scheme in the city. The city‐based case had an organized and focused campaign, aligning a plurality of interests in opposition to the tree‐felling. This coordinated campaign opposed local authority actions that sought ostensibly to save money. Our study shows how local activist groups produced dialogic counter‐accounts of the symbolic and ecological importance of street trees, elevating the environment and community concerns above Sheffield City Council's monologic focus on money and contracts. The campaign's success in halting the tree‐felling scheme also helped foster conditions for broader grassroots‐led democratic reform in the city. Research on the city context vis‐à‐vis counter and dialogic accounting is rare.

The number of children experiencing poor emotional wellbeing, which can lead to clinically significant mental health conditions in the long term, is increasing rapidly, as are government initiatives outlining the ‘frontline role’ of the school in supporting children’s emotional wellbeing during critical periods such as primary-secondary school transitions. However, both concepts (‘primary-secondary school transitions’ and ‘emotional wellbeing’) are poorly and inconsistently conceptualised and/or theoretically defined. This has significant consequences for identifying and supporting children’s emotional wellbeing. The aim of this concept analysis is to report a synthesis of the extant literature and define emotional wellbeing in the context of primary-secondary school transitions as a concept of emerging importance. The Walker and Avant (2005) method was utilised as a framework. Attributes, antecedents, and empirical referents were identified through synthesis of methodological approaches (specifically an international systematic literature review, UK-wide survey and 10 focus groups) and the mapping of multiple stakeholder perspectives (specifically researchers, educational practitioners, policy influencers and/or makers, and children). Attributes of emotional wellbeing in the context of primary-secondary school transitions include children’s affective experience of navigating primary-secondary school transitions in the here-and-now (e.g. presence of both positive and negative emotions), and their evaluations of their emotional wellbeing both globally and in the context of specific domains. Antecedents include children’s perceptions of their internal and external resources to manage the demands of primary-secondary school transitions and maintain a stable affective state. Consequences (positive and negative) include academic attainment, social adjustment, and school belonging in the short-term, and mental health, life chances, and social inequalities in the long-term. Our novel conceptualisation overcomes limitations in existing understanding of both primary-secondary school transitions and emotional wellbeing, establishing a foundation for developing a more cohesive and theoretical body of work within the field. Our conceptualisation and operational definition will have notable positive implications in advancing future research, policy, and practice, which are outlined.

This study proposes a novel concept for the automated and computerised segmentation of ultrasound images of bone based on motion information. Force is applied on the heel region using the ultrasound probe and then removed while recording the video of the bone using ultrasound. The interface between the bone and surrounding tissues is the region that moves with maximum speed. This concept is utilised to determine a map of movement, where speed is the criterion used for the bone segmentation from the surrounding tissues. To achieve that, the image is subdivided into regions of uniform sizes, followed by tracking individual regions in the successive frames of the video using an optical flow algorithm. The average movement speed is calculated for the regions. Then, the regions with the higher speed are identified as bone surfaces. It is given as the initial contour for the Chan–Vese algorithm to achieve smoother bone surfaces. Then, the final output from the Chan–Vese is post-processed using a boundary tracing algorithm to get the last automated bone segmented output. The segmented outcomes are compared against the manually segmented images from the experts to determine the accuracy. Bhattacharyya distances are used to calculate the accuracy of the algorithmic and manual output. The quantitative results from Bhattacharyya distances indicated an excellent overlap between algorithmic and manual works (average ± STDEV Bhattacharyya distance: 0.06285 ± 0.002051). The bone-segmented output from the optical flow algorithm is compared with the model output and the texture-based segmentation method’s output. The work from the motion estimation methods has better segmentation accuracy than the model and texture segmentation methods. The results of this study suggest that this method is the first attempt to segment the heel bone from the ultrasound image using motion information.

Introduction Paracetamol, the most used analgesic medicine in the world, is considered a safe treatment, but when overdosed, it can be fatal. Evidence suggests that despite sales legislations, paracetamol overdose still accounts for around 100 000 accident and emergency visits and 50 000 hospital admissions per year in the UK. This systematic review aims to describe the possible factors linked to paracetamol overdoses (intentional and/or accidental) in the adult and child populations in the UK and the subgroups of the population that are at higher risk and identify any preventative interventions. Methods and analysis This review will be carried out in accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) guidance. Literature searches will be performed using six bibliographic databases: MEDLINE via PubMed, EMBASE, SCOPUS, PsycINFO, the Cochrane Library and PROSPERO register. Grey literature and social media will also be searched, and article reference lists are reviewed. Studies included will be in English with populations in the UK from 1998 onwards, experiencing paracetamol overdose (intentional or accidental), with no age restriction. Title and abstract screening and full-text review of included articles will be performed by two independent reviewers (with a third member to resolve disagreement). The risk of bias will be assessed using the JBI critical appraisal checklist. The quality of any systematic reviews included will be assessed using the AMSTAR 2 tool or the Mixed Methods Appraisal Tool (MMAT), as appropriate. It is anticipated to adopt a narrative synthesis of the findings via a thematic analysis. Meta-analysis and subgroup analysis will be considered if data are available. Ethics and dissemination Ethics approval is not required for this work since no data will be collected. Results will be disseminated through a peer-reviewed publication and local as well as national conference presentations; and a range of creative and inclusive methods and formats to inform and educate patients and the community. PROSPERO registration number CRD42024555406.

Bifunctional targeted protein degraders, also known as Proteolysis Targeting Chimeras (PROTACs), are an emerging drug modality that may offer a new approach to understand and treat neurodegenerative diseases. These molecules have a non-occupancy based, sub-stoichiometric mechanism of action which results in removal of target proteins from cells, presenting new opportunities to interrogate and intervene in pathogenic signalling. Identifying chemical starting points for PROTACs remains a largely empirical process and the design rules for identifying in vivo quality tools to interrogate new therapeutic hypotheses in the Central Nervous System (CNS) have yet to be established. We demonstrate a concept of using orthogonally reactive linker reagents, that allowed us to construct screening libraries varying the E3 ligase recruiting ligand, the target protein recruiting ligand and the linker simultaneously and test compounds directly in cells. This led us identify a molecule directly from our screen that upon further profiling demonstrated rapid and selective Glycogen Synthase Kinase 3 (GSK3) degradation in cells, as well as CNS in vivo activity in mouse. Our findings provide new opportunities to investigate the role of GSK3 paralogs in cellular and in vivo disease models and demonstrate a successful Direct-to-Biology approach, with broad potential for identifying in vivo quality bifunctional chemical probes for CNS disease concepts.

A large number of drugs and compounds produced by the chemical and agrochemical industry, often referred to as ‘non-genotoxic carcinogens’ (NGC), score as tumour promotors in rodent models. It is unclear whether these compounds act similarly in humans. The most extensively investigated compounds have been the anti-convulsive drugs, phenobarbital (PB), and phenytoin. Liver tumours induced by PB are dependent upon the activation of the constitutive androstane receptor (CAR). However, marked species differences in CAR activation by exogenous chemicals exist with some being much more potent activators of human CAR, e.g., 6-(4-chlorophenyl)imidazo[2,1-β][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime (CITCO). We have compared CITCO-induced tumour formation in the livers of mice in which murine CAR has been replaced with its human counterpart. Our findings reveal that CITCO-dependent liver tumours are only formed in mice-expressing human CAR and not in wild-type animals. In addition, contrary to one of the proposed mechanisms of NGC carcinogenicity, we show that CITCO did not induce a hyperplastic response in the liver of the humanised mice. These data raise some key questions about the mechanism of action of NGCs and identify the limitations of current rodent carcinogenicity test systems in relation to risk assessment.