Differentiation signals induce APOBEC3A expression via GRHL3 in squamous epithelia and squamous cell carcinoma.

Two APOBEC (apolipoprotein-B mRNA editing enzyme catalytic polypeptide-like) DNA cytosine deaminase enzymes (APOBEC3A and APOBEC3B) generate somatic mutations in cancer, driving tumour development and drug resistance. Here we used single cell RNA sequencing to study APOBEC3A and APOBEC3B expression in healthy and malignant mucosal epithelia, validating key observations with immunohistochemistry, spatial transcriptomics and functional experiments. Whereas APOBEC3B is expressed in keratinocytes entering mitosis, we show that APOBEC3A expression is confined largely to terminally differentiating cells and requires Grainyhead-like transcription factor 3 (GRHL3). Thus, in normal tissue, neither deaminase appears to be expressed at high levels during DNA replication, the cell cycle stage associated with APOBEC-mediated mutagenesis. In contrast, we show that in squamous cell carcinoma tissues, there is expansion of GRHL3 expression and activity to a subset of cells undergoing DNA replication and concomitant extension of APOBEC3A expression to proliferating cells. These findings indicate a mechanism for acquisition of APOBEC3A mutagenic activity in tumours.

An expert-novice comparison of lifeguard specific vigilance performance.

INTRODUCTION: Lifeguards must maintain alertness and monitor an aquatic space across extended periods. However, lifeguard research has yet to investigate a lifeguard's ability to maintain performance over time and whether this is influenced by years of certified experience or the detection difficulty of a drowning incident. The aim of this study was to examine whether lifeguard experience, drowning duration, bather number, and time on task influences drowning detection performance. METHOD: A total of 30 participants took part in nine 60-minute lifeguard specific tasks that included 11 drowning events occurring at five-minute intervals. Each task had manipulated conditions that acted as the independent variables, including bather number and drowning duration. RESULTS: The experienced group detected a greater number of drowning events per task, compared to novice and naïve groups. Findings further highlighted that time, bather number, and drowning duration has a substantial influence on lifeguard specific drowning detection performance. PRACTICAL APPLICATIONS: It is hoped that the outcome of the study will have applied application in highlighting the critical need for lifeguard organizations to be aware of a lifeguard's capacity to sustain attention, and for researchers to explore methods for minimizing any decrement in vigilance performance.

Self-regulation, stress appraisal, and esport action performance.

Electronic sport has seen substantial growth in market value and popularity in the last 10 years. With this growth has come the pursuit of elite esports performance, especially from a psychological perspective. This study aimed to investigate potential variations in self-regulation levels among athletes of different levels (national vs. student), compare the self-regulation profiles of CS:GO players in the current study to an international sample of e'athletes and to assess the predictive capacity of self-regulation on performance outcomes. A total of 53 esports athletes (student competitors, n = 27 and national-level CS:GO competitors, n = 26), participated in an experiment exploring self-regulation, DRES, and action performance. Furthermore, analysis comparing our collective findings against a larger global sample of e'athletes (n = 993) was conducted. Results demonstrated that CS:GO players who displayed higher levels of self-regulation tended to perceive stressful situations as challenges, consequently showcasing superior accuracy and time trial performance. In contrast, individuals with lower self-regulation tended to perceive such situations as threats, which correlated with less favorable performance outcomes. On a broader scale, the study observed that CS:GO competitors generally exhibited lower levels of self-regulation when compared to the larger global sample. Furthermore, self-regulation was identified as a mediating variable in the relationship between stress appraisal and performance, suggesting that improved self-regulation skills can lead to enhanced accuracy and quicker time trial performance. This may imply that competitors with greater self-regulatory abilities perceive themselves as having more personal resources, enabling them to effectively assess challenging situations and employ problem-focused coping strategies. Overall, this research underscores the significance of self-regulation in optimizing esports performance, while providing valuable insights for player development, action performance, and overall outcomes in the field.

The effects of simulated vision impairment on performance in football.

Footballers with vision impairment (VI) are eligible to compete in the Para sport if they meet a minimum impairment criteria (MIC) based on measures of their visual acuity (VA) and/or visual field. Despite the requirements of the International Paralympic Committee Athlete Classification Code that each sport uses an evidence-based classification system, VI football continues to use a medical-based system that lacks evidence to demonstrate the relationship between impairment and performance in the sport. The aim of this study was to systematically simulate vision loss to establish the minimum level of impairment that would affect performance in futsal. Nineteen skilled sighted players completed tests of individual technical skill and anticipation performance under six levels of simulated blur that decreased both VA and contrast sensitivity (CS). VA needed to be reduced to a level of acuity that represents worse vision than that currently used for inclusion in VI football before meaningful decreases in performance were observed. CS did not have a clear effect on football performance. These findings produce the first evidence for the minimum impairment criteria in VI football and suggest a more severe degree of impairment may be required for the MIC.

The use of heart rate variability in esports: A systematic review.

Heart rate variability (HRV) is a psychophysiological measure of particular interest in esports due to its potential to monitor player self-regulation. This study aimed to systematically review the utilisation of HRV in esports. Consideration was given to the methodological and theoretical underpinnings of previous works to provide recommendations for future research. The protocol was made available on the Open Science Framework. Inclusion criteria were empirical studies, examining HRV in esports, using esports players, published in English. Exclusion criteria were non-peer-reviewed studies, populations with pre-existing clinical illness other than Internet Gaming Disorder (IGD), opinion pieces or review papers. In November 2022 a search of Web of Science, PubMed, and EBSCOHost identified seven studies using HRV in esports. Risk of bias was assessed using the Mixed Methods Appraisal Tool. Narrative review identified two primary uses of HRV in esports; stress response and IGD. A lack of theoretical and methodological underpinning was identified as a major limitation of current literature. Further investigation is necessary before making recommendations regarding the use of HRV in esports. Future research should employ sound theoretical underpinning such as the use of vagally mediated HRV and the robust application of supporting methodological guidelines when investigating HRV in esports.

Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts.

The chemotherapy resistance of esophageal adenocarcinomas (EACs) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that, by targeting the tumor-promoting functions of the predominant TME cell type, cancer-associated fibroblasts (CAFs) with phosphodiesterase type 5 inhibitors (PDE5i), we can enhance the efficacy of standard-of-care chemotherapy. In ex vivo conditions, PDE5i prevent the transdifferentiation of normal fibroblasts to CAF and abolish the tumor-promoting function of established EAC CAFs. Using shotgun proteomics and single-cell RNA-seq, we reveal PDE5i-specific regulation of pathways related to fibroblast activation and tumor promotion. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient and in vivo PDX-based model systems. These findings demonstrate that CAFs drive chemotherapy resistance in EACs and can be targeted by repurposing PDE5i, a safe and well-tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction.

Examining the Predictors of Mental Ill Health in Esport Competitors.

Few research studies have examined the predictors of mental ill health in esports. This study addresses that gap by investigating stressors, sleep, burnout, social phobia anxiety and mental ill health in esport athletes. An online survey was disseminated to competitive student esport athletes (n = 313) residing in the UK. The survey included measures of stressors resulting from competing in esports, sleep quality, burnout, and social phobia, as well as outcome measures of mental ill health. Hierarchical regression analyses examined these relationships. All the hypotheses were supported, with stressors significantly predicting sleep quality, burnout, and social phobia anxiety, and stressors, sleep quality, burnout, and social phobia anxiety were all significant positive predictors of mental ill health. The strength of these predictions varied, for example, the daytime dysfunction subscale of sleep was a strong predictor of all outcome variables; two subscales of burnout, reduced sense of accomplishment and exhaustion significantly predicted each of the three mental ill health outcome variables, and two subscales of social phobia anxiety, fear and avoidance, significantly predicted mental ill health. Our study has important implications for player health in esports, highlighting interventions that could target specific aspects of stress, sleep, burnout, and social phobia anxiety to improve the mental health of those who compete in esports.

Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma.

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20-37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n = 27) and non-responders classified as TRG4-5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

Music Student's Approach to the Forced Use of Remote Performance Assessments.

Music students at the University of Chichester Conservatoire completed questionnaires about their experience of the forced use of remote teaching and learning due to Lockdown, as imposed in the United Kingdom from March to June 2020, and how this impacted their self-beliefs, decision making processes, and methods of preparation for their performance assessments. Students had the choice to either have musical performance assessed in line with originally published deadlines (still in Lockdown) via self-recorded video or defer the assessment until the following academic year. Student's choice to defer or submit the assessment during Lockdown was influenced by a range of forced factors, such as adaptions required by online teaching, limitations of rehearsal in their home environment, and the challenges in facilitating and recording their own assessments. Students completed online questionnaires about their self-efficacy, resilience, wellbeing, and provided free text responses explaining the reasoning for their decision to record their performance or to defer the assessment were coded to reveal patterns impacting their decision and preparation processes. Those choosing to submit their assessments demonstrated more strategies in their preparation and reported higher perceived self-efficacy scores. The specific conditions for this assessment, as a result of Lockdown, revealed correlations between resilience and both self-efficacy and wellbeing. The impact on teaching and the student experience is discussed and suggestions to support students in future settings of blended delivery are presented. Theoretical and practical implications are discussed.

Goals and Self-Efficacy Beliefs During the Initial COVID-19 Lockdown: A Mixed Methods Analysis.

This study aimed to capture how the coronavirus disease 2019 (COVID-19) crisis disrupted and affected individuals' goal pursuits and self-efficacy beliefs early during the lockdown phase of COVID-19. Participants impacted by lockdown regulations accessed an online questionnaire during a 10-day window from the end of March to early April 2020 and reported a significant personal goal toward which they had been working, and then completed quantitative and qualitative survey items tapping self-efficacy beliefs for goal achievement, subjective caring about the goal during disrupted world events, and current pursuit or abandonment of the goal. The findings from both quantitative and qualitative measures demonstrated a significant drop in self-efficacy beliefs from before to during the pandemic with a large effect based on whether people thought they could still achieve their goal under current conditions. Over two-thirds of the sample was unsure or did not believe they could still carry out their goal, and over a quarter either abandoned or were uncertain they could pursue the goal. Despite this, people continued to care about their goals. Reasons for abandonment and strategies for coping with goals within the lockdown and beyond are discussed.

Predicting Airport Screening Officers' Visual Search Competency With a Rapid Assessment.

Objective The study's objective was to assess a new personnel selection and assessment tool for aviation security screeners. A mobile app was modified to create a tool, and the question was whether it could predict professional screeners' on-job performance. Background A variety of professions (airport security, radiology, the military, etc.) rely on visual search performance-being able to detect targets. Given the importance of such professions, it is necessary to maximize performance, and one means to do so is to select individuals who excel at visual search. A critical question is whether it is possible to predict search competency within a professional search environment. Method Professional searchers from the USA Transportation Security Administration (TSA) completed a rapid assessment on a tablet-based X-ray simulator (XRAY Screener, derived from the mobile technology app Airport Scanner; Kedlin Company). The assessment contained 72 trials that were simulated X-ray images of bags. Participants searched for prohibited items and tapped on them with their finger. Results Performance on the assessment significantly related to on-job performance measures for the TSA officers such that those who were better XRAY Screener performers were both more accurate and faster at the actual airport checkpoint. Conclusion XRAY Screener successfully predicted on-job performance for professional aviation security officers. While questions remain about the underlying cognitive mechanisms, this quick assessment was found to significantly predict on-job success for a task that relies on visual search performance. Application It may be possible to quickly assess an individual's visual search competency, which could help organizations select new hires and assess their current workforce.

A subset of high Gleason grade prostate carcinomas contain a large burden of prostate cancer syndecan-1 positive stromal cells.

BACKGROUND: There is a pressing need to identify prognostic and predictive biomarkers for prostate cancer to aid treatment decisions in both early and advanced disease settings. Syndecan-1, a heparan sulfate proteoglycan, has been previously identified as a potential prognostic biomarker by multiple studies at the tissue and serum level. However, other studies have questioned its utility. METHODS: Anti-Syndecan-1 immunohistochemistry was carried out on 157 prostate tissue samples (including cancerous, adjacent normal tissue, and non-diseased prostate) from three independent cohorts of patients. A population of Syndecan-1 positive stromal cells was identified and the number and morphological parameters of these cells quantified. The identity of the Syndecan-1-positive stromal cells was assessed by multiplex immunofluorescence using a range of common cell lineage markers. Finally, the burden of Syndecan-1 positive stromal cells was tested for association with clinical parameters. RESULTS: We identified a previously unreported cell type which is marked by Syndecan-1 expression and is found in the stroma of prostate tumors and adjacent normal tissue but not in non-diseased prostate. We call these cells Prostate Cancer Syndecan-1 Positive (PCSP) cells. Immunofluorescence analysis revealed that the PCSP cell population did not co-stain with markers of common prostate epithelial, stromal, or immune cell populations. However, morphological analysis revealed that PCSP cells are often elongated and displayed prominent lamellipodia, suggesting they are an unidentified migratory cell population. Analysis of clinical parameters showed that PCSP cells were found with a frequency of 20-35% of all tumors evaluated, but were not present in non-diseased normal tissue. Interestingly, a subset of primary Gleason 5 prostate tumors had a high burden of PCSP cells. CONCLUSIONS: The current study identifies PCSP cells as a novel, potentially migratory cell type, which is marked by Syndecan-1 expression and is found in the stroma of prostate carcinomas, adjacent normal tissue, but not in non-diseased prostate. A subset of poor prognosis high Gleason grade 5 tumors had a particularly high PCSP cell burden, suggesting an association between this unidentified cell type and tumor aggressiveness.

Searching for prostate cancer stem cells: markers and methods.

The cancer stem cell hypothesis postulates that a single stem-like cancer cell is able to produce all cancer cell types found in a tumor. These cells are also thought to be the causative agents of relapse following therapy. In order to confirm the importance of cancer stem cells in tumor formation and patient prognosis, their role in prostate cancer must be comprehensively studied. This review describes current methods and markers for isolating and characterizing prostate cancer stem cells, including assays for self-renewal, multipotency and resistance to therapy. In particular the advantages and limitations of these approaches are analyzed. The review will also examine novel methods for studying the lineage of cancer stem cells in vivo using transgenic mouse models. These lineage tracing approaches have significant advantages and, if a number of challenges can be addressed, offer great potential for understanding the significance of cancer stem cells in human prostate cancer.

Accounting for time-dependent effects in biofuel life cycle greenhouse gas emissions calculations.

This paper proposes a time correction factor (TCF) to properly account for the timing of land use change-derived greenhouse gas emissions in the biofuels life cycle. Land use change emissions occur at the outset of biofuel feedstock production, and are typically amortized over an assumed time horizon to assign the burdens of land use change to multiple generations of feedstock crops. Greenhouse gas intensity calculations amortize emissions by dividing them equally over a time horizon, overlooking the fact that the effect of a greenhouse gas increases with the time it remains in the atmosphere. The TCF is calculated based on the relative climate change effect of an emission occurring at the outset of biofuel feedstock cultivation versus one amortized over a time horizon. For time horizons between 10 and 50 years, the TCF varies between 1.7 and 1.8 for carbon dioxide emissions, indicating that the actual climate change effect of an emission is 70-80% higher than the effect of its amortized values. The TCF has broad relevance for correcting the treatment of emissions timing in other life cycle assessment applications, such as emissions from capital investments for production systems or manufacturing emissions for renewable energy technologies.