A large pseudoautosomal region on the sex chromosomes of the frog Silurana tropicalis

Sex chromosome divergence has been documented across phylogenetically diverse species, with amphibians typically having cytologically nondiverged (“homomorphic”) sex chromosomes. With an aim of further characterizing sex chromosome divergence of an amphibian, we used “RAD-tags” and Sanger sequencing to examine sex specificity and heterozygosity in theWestern clawed frog Silurana tropicalis (also known as Xenopus tropicalis). Our findings based on approximately 20 million genotype calls and approximately 200 polymerase chain reaction-amplified regions across multiple male and female genomes failed to identify a substantially sized genomic region with genotypic hallmarks of sex chromosome divergence, including in regions known to be tightly linked to the sex-determining region.Wealso foundthat expression andmolecular evolutionof genes linked to the sex-determining region did not differ substantially from genes in other parts of the genome. This suggests that the pseudoautosomal region, where recombination occurs, comprises a large portion of the sex chromosomes of S. tropicalis. These resultsmay in part explainwhy African clawed frogs have such a high incidence of polyploidization, shed light onwhy amphibians have a high rate of sex chromosome turnover, and raise questions about why homomorphic sex chromosomes are so prevalent in amphibians

Weight of evidence evaluation of the metabolism disrupting effects of triphenyl phosphate using an expert knowledge elicitation approach

Data availability: Data will be made available on request.Supplementary data are available online at: https://www.sciencedirect.com/science/article/pii/S0041008X24001935#s0160 .Identification of Endocrine-Disrupting Chemicals (EDCs) in a regulatory context requires a high level of evidence. However, lines of evidence (e.g. human, in vivo, in vitro or in silico) are heterogeneous and incomplete for quantifying evidence of the adverse effects and mechanisms involved. To date, for the regulatory appraisal of metabolism-disrupting chemicals (MDCs), no harmonised guidance to assess the weight of evidence has been developed at the EU or international level. To explore how to develop this, we applied a formal Expert Knowledge Elicitation (EKE) approach within the European GOLIATH project. EKE captures expert judgment in a quantitative manner and provides an estimate of uncertainty of the final opinion. As a proof of principle, we selected one suspected MDC -triphenyl phosphate (TPP) - based on its related adverse endpoints (obesity/adipogenicity) relevant to metabolic disruption and a putative Molecular Initiating Event (MIE): activation of peroxisome proliferator activated receptor gamma (PPARγ). We conducted a systematic literature review and assessed the quality of the lines of evidence with two independent groups of experts within GOLIATH, with the objective of categorising the metabolic disruption properties of TPP, by applying an EKE approach. Having followed the entire process separately, both groups arrived at the same conclusion, designating TPP as a “suspected MDC” with an overall quantitative agreement exceeding 85%, indicating robust reproducibility. The EKE method provides to be an important way to bring together scientists with diverse expertise and is recommended for future work in this area.European Union's Horizon 2020 research and innovation program under grant agreement No 825489 (“GOLIATH”)

Ingraft chimerism in lung transplantation - a study in a porcine model of obliterative bronchiolitis

<p>Abstract</p> <p>Background</p> <p>Bronchial epithelium is a target of the alloimmune response in lung transplantation, and intact epithelium may protect allografts from rejection and obliterative bronchiolitis (OB). Herein we study the influence of chimerism on bronchial epithelium and OB development in pigs.</p> <p>Methods</p> <p>A total of 54 immunosuppressed and unimmunosuppressed bronchial allografts were serially obtained 2-90 days after transplantation. Histology (H&E) was assessed and the fluorescence in situ hybridization (FISH) method for Y chromosomes using pig-specific DNA-label was used to detect recipient derived cells in graft epithelium and bronchial wall, and donor cell migration to recipient organs. Ingraft chimerism was studied by using male recipients with female donors, whereas donor cell migration to recipient organs was studied using female recipients with male donors.</p> <p>Results</p> <p>Early appearance of recipient-derived cells in the airway epithelium appeared predictive of epithelial destruction (<it>R </it>= 0.610 - 0.671 and <it>p </it>< 0.05) and of obliteration of the bronchial lumen (<it>R </it>= 0.698 and <it>p </it>< 0.01). All allografts with preserved epithelium showed epithelial chimerism throughout the follow-up. Antirejection medication did not prevent, but delayed the appearance of Y chromosome positive cells in the epithelium (<it>p </it>< 0.05), or bronchial wall (<it>p </it>< 0.05).</p> <p>Conclusions</p> <p>In this study we demonstrate that early appearance of Y chromosomes in the airway epithelium predicts features characteristic of OB. Chimerism occurred in all allografts, including those without features of OB. Therefore we suggest that ingraft chimerism may be a mechanism involved in the repair of alloimmune-mediated tissue injury after transplantation.</p

Impact of renal impairment on atrial fibrillation: ESC-EHRA EORP-AF Long-Term General Registry

Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p&nbsp;&lt;.001. Over 24&nbsp;months, impaired renal function was associated with significantly greater incidence of the primary composite outcome and all secondary outcomes. Multivariable Cox regression analysis demonstrated an inverse relationship between eGFR and the primary outcome (HR 1.07 [95% CI, 1.01–1.14] per 10&nbsp;ml/min/1.73&nbsp;m2 decrease), that was most notable in patients with eGFR &lt;30&nbsp;ml/min/1.73&nbsp;m2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90&nbsp;ml/min/1.73&nbsp;m2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF

Clinical complexity and impact of the ABC (Atrial fibrillation Better Care) pathway in patients with atrial fibrillation: a report from the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry

Background: Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The ‘Atrial fibrillation Better Care’ (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. Methods: From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. Results: Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58–0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52–0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58–0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56–0.98) and composite outcome (aHR: 0.76, 95%CI 0.60–0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. Conclusions: An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients

Intrusive memories of trauma: a clinical target

Background: Intrusive memories of traumatic events are distressing, vivid memories which come into the mind involuntarily, and comprise a core symptom of posttraumatic stress disorder (PTSD). Intrusive memories are a common consequence of frontline work among healthcare staff where exposure to traumatic events is unavoidable. There is a need to understand the functional implications of experiencing intrusive memories and to develop and evaluate effective treatments targeting intrusive memories to support the mental wellbeing of healthcare staff. Objectives: The objectives of this research thesis were twofold. First, to systematically review and synthesise the literature investigating the relationship between intrusive memories of trauma and functioning. Second, to investigate the effectiveness of a brief cognitive task intervention on the number of intrusive memories, general functioning, and mental health symptoms among healthcare staff. Feasibility and acceptability of the intervention was also assessed. Methods: To address the first objective, functioning was operationalised using domains of the WHO International Classification of Functioning, Disability and Health (ICF). Systematic searches of peer-reviewed journal articles were conducted using search terms related to PTSD and intrusive memories. To investigate the second objective, a case series using an AB single-case experimental design was employed. Results: From the seventeen studies reviewed, a relationship was found between intrusive memories and functioning impairments across multiple subcategories of the ICF, including sleep, concentration, rumination, and activities of daily living. The empirical study found an overall significant reduction in the number of intrusive memories from baseline to post-intervention. Improvements in functioning and mental health symptom reductions were reported. The intervention was generally feasible and acceptable to staff. Conclusions: Trauma-related intrusive memories are associated with impairments across several domains of functioning. Preliminary findings suggest that a brief cognitive task intervention could provide means to mitigate the impact of work-related traumatic events among healthcare staff. </p

Інновації та туристичні регіони: чи розглядають інновації як детермінанту розвитку в європейського туризму в регіонах?

У статті проаналізовано інноваційні аспекти розвитку туристичних регіонів у Європі. Основною метою статті є визначення ступеня сприйняття інновацій у туристичних регіонах як детермінанти їх розвитку. Авторами оцінено проблему розвитку туристичних регіонів у Європі у сфері інновацій, як можливого вихідного пункту для оптимізації змін у політиці місцевого та регіонального туризму. Вихідну базу дослідження сформовано на основі опитування 95 експертів у галузі регіонального туризму з 17 країн Європи. Для аналізу властивостей категоріальних даних та їх взаємозв'язків використано статистичні методи, такі як Gamma, Kendall's Tau-b, Somers' D C|R, коефіцієнт кореляції Спірмена, Коефіцієнт Фі, Коефіцієнт Контингентності, Коефіцієнт Крамера, а також алгоритм дерева рішень. Рівень інноваційного середовища у туристичних регіонах та їхня ступінь розвитку впливають на сприйняття інновацій. Регіони Південної Європи сприймають інновації як найбільш ефективний інструмент, що формує передумови їх розвитку. Туристичні регіони з вищим рівнем інноваційної активності мають встановлену систему управління якістю, а також комплексний і систематичний підхід до постачання продуктів як у сезонний, так і позасезонний періоди. Регіони, що віднесені до групи "Емерджентних інноваторів", виявляють більш інтенсивне сприйняття проблем у впровадженні інновацій. Це відображає недостатню координацію портфеля замовлень як за обсягом, так і за якістю, в країнах, де інноваційне середовище слабо розвинене. Головною рекомендацією для зменшення сприйняття інновацій як проблеми у розвитку туристичних регіонів Європи є акцент на впровадженні інструментів регіональної політики, які стимулюють участь туризму в синергетичних ефектах існуючого інноваційного середовища економіки.This article examines innovative aspects of the development of tourism regions in Europe. The article aims to determine the intensity of the perception of innovation in the tourism region as a problem in its development. The ambition of the article is to assess the problems in the development of tourism regions in Europe in the field of innovation as a possible starting point for optimizing changes in local and regional tourism policy. The research analyses the positions of 95 regional tourism experts from 17 European countries. The database was based on a databank of 150 representatives of academia and 275 representatives of regional tourism organizations. To analyse the properties of categorical data and the relationships between them, we used Gamma, Kendall's Tau-b, Somers' D C|R, Spearman correlation coefficient, Phi Coefficient, Contingency Coefficient, Cramer's V and the decision tree algorithm. The maturity of the innovation environment of tourism regions and their level of development influence the perception of innovations as a problem in their development. Southern European tourism regions perceive innovation as a problem in their development most intensively. Tourism regions with stronger innovation activity have a well-established quality management system and a comprehensive and systematically addressed supply of seasonal and offseason products. Tourism regions ranked in the emerging innovator group perceive the specified problems in the implementation of innovations more intensively. This reflects the lack of coordination of the product portfolio, both in terms of range and quality, in countries where the innovation environment is poorly developed. A key recommendation to mitigate the perception of innovations as a problem in the development of Europe's tourism regions is to focus attention on the implementation of regional policy instruments that stimulate the participation of tourism in the synergy effects of the existing innovation environment of the economy

Comparison of activation of aristolochic acid I and II with NADPH:quinone oxidoreductase, sulphotransferases and N-acetyltranferases

OBJECTIVES: Ingestion of aristolochic acid (AA) is associated with development of urothelial tumors linked with aristolochic acid nephropathy, and is implicated in the development of Balkan endemic nephropathy-associated urothelial tumors. Aristolochic acid I (AAI), the major toxic component of AA, is more toxic than its demethoxylated derivate AAII. A different enzymatic conversion of both carcinogens might be one of the reasons explaining this feature. Therefore, the present study has been designed to compare efficiency of human NAD(P)H:quinone oxidoreductase (NQO1) and phase II enzymes such as sulfotransferases (SULTs) and N,O-acetyltransferases (NATs) to activate AAI and AAII in vitro. In addition, to investigate the molecular mechanisms of AAI and AAII reduction by human NQO1, molecular modeling was used to compare interactions of AAI and AAII with the active site of this enzyme. METHODS: DNA adduct formation by AAI and AAII was investigated by the nuclease PI version of the P-32-postlabeling method. In silico docking, employing soft-soft (flexible) docking procedure, was used to study the interactions of AAI and AAII with the active site of human NQO1. RESULTS: Human NQO1 activated AAI and AAII, generating DNA adduct patterns reproducing those found in several species including human exposed to these compounds. These results demonstrate that NQO1 is capable of reducing both AAs to reactive species binding to DNA. However, concentrations required for half-maximum DNA binding mediated by NQO1 were higher for AAII (158 mu M) than for AAI (17 mu M). One of the reasons causing this phenomenon is a lower efficiency of NQO1 to reduce AAII than AAI we found in this work; although both AAI and AAII are bound with similar binding affinities to the NQO1 active site, the binding orientation of AAII in the active site of NQO1 does not favor the effective reduction of its nitro group. Because reduced nitro-aromatics are often further activated by SULTs or NATs, their roles in AAI and AAII activation were investigated. Our results indicate that phase II reactions do not stimulate the bioactivation of AAs; neither enzymes present in human hepatic cytosols nor human SULT1A1, 1A2, 1A3, 1E, or 2A nor NAT1 or NAT2 further enhanced DNA adduct formation by AAs. In contrast, human SULT1A1, 1A2 and 1A3 as well as NAT1 and NAT2 enzymes even inhibited NQO1-mediated bioactivation of AAII. Therefore, under the in vitro conditions used, DNA adducts arise by enzymatic reduction of AAs through the formation of N-hydroxyaristolactams that are spontaneously decomposed to the reactive species forming DNA adducts. CONCLUSION: The results found in this study emphasize the importance of NQO1 in the metabolic activation of AAI and AAII and provide the evidence that initial nitroreduction is the rate limiting step in their activation. This enzyme is more effective in activation of AAI relative to AAII, which might contribute to its lower binding to DNA found both in vitro and in vivo, Moreover, inhibition effects of conjugation reactions on AAII activation might further contribute to its decreased capability of forming DNA adducts and its lower toxicity comparing with AAI

Long-term efficacy update of crizotinib in patients with advanced, inoperable inflammatory myofibroblastic tumour from EORTC trial 90101 CREATE

Purpose: European Organisation for Research and Treatment of Cancer (EORTC) 90101 (CREATE) was a prospective, multicentric, non-randomised, open-label phase II bas-ket trial to assess the efficacy and safety of crizotinib in patients with different types of cancers, including advanced inflammatory myofibroblastic tumour (IMT) with or without anaplastic lymphoma kinase (ALK) rearrangements. Here, we report updated results with long-term follow-up. Patients/methods: After central reference pathology, eligible ALK-positive and ALK-negative patients with advanced/metastatic IMT deemed incurable with surgery, radiotherapy or sys-temic therapy received oral crizotinib 250 mg twice daily. The ALK status was assessed cen-trally using immunohistochemistry and fluorescence in situ hybridisation. The primary end-point was the proportion of patients who achieved an objective response (i.e. complete or par-tial response). If >6 ALK-positive patients achieved a confirmed response, the trial would be deemed successful. Results: At data cut-off on 28th January 2021, we performed the final analysis of this trial. Of the 20 eligible and treated patients (19 of whom were evaluable for efficacy), with a median follow-up of 50 months, five were still on crizotinib treatment (4/12 ALK-positive and 1/8 ALK-negative patients). The updated objective response rate (ORR) was 66.7% (95% confi-dence interval [CI] 34.9-90.1%) in ALK-positive patients and 14.3% (95% CI 0.0-57.9%) in ALK-negative patients. In the ALK-positive and ALK-negative patients, the median progression-free survival was 18.0 months (95% CI 4.0-NE) and 14.3 months (95% CI 1.2-31.1), respectively; 3-year overall survival rates were 83.3% (95% CI 48.2-95.6) and 34.3% (95% CI 4.8-68.5). Safety results were consistent with previously reported data. Conclusion: These updated results confirm previous findings that crizotinib is effective, with durable responses, in patients with locally advanced or metastatic ALK-positive IMT. With further follow-up after the original primary analysis, the ORR increased, as patients derived long-term benefit and some responses converted from stable disease to partial responses. Clinical trial number: EORTC 90101, NCT01524926. 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Experimentele farmacotherapi