Місто як екзистенційна пастка (на матеріалі сучасної поезії)

Осмислюється специфіка екзистенційно зумовленого сприймання урбаністичного простору в творчості сучасних українських поетів. Окреслюється своєрідне осмислення символів дороги, лабіринту, човна, мосту, що є елементами просторової символіки художнього світу. Стверджується, що урбаністичний простір сприймається сучасними митцями як екзистенцій на пастка, духовно мертвий простір “недоіснування”, вихід з якого потребує духовного зусилля. Ключові слова: хронотоп, топос, екзистенційний, ліричний герой, постмодернізм, символ.Осмысливается специфика экзистенциально преопределенного восприятия урбанистического пространства в творчестве современных украинских поэтов. Анализируется своеобразное осмысление символов дороги, лабиринта, лодки, моста, который является элементами пространственной символики художественного мира. Утверждается, что урбанистическое пространство воспринимается современными художниками как экзистенциальная ловушка, духовно мертвое пространство “недосуществования”, выход из которого требует в духовном усилии. Ключевые слова: хронотоп, топос, экзистенциальный, лирический герой, постмодернизм, символ.A specific is comprehended ekzistenciаl the predefined perception of urbanism space in creation of the modern Ukrainian poets. The original comprehension of symbols of road, labyrinth, boat, bridge which is the elements of spatial symbolism of the artistic world is outlined. It becomes firmly established that urbanism space is perceived modern artists as ekzistencial on trap, spiritually dead ground, an exit from which needs spiritual effort. Keywords: khronotop, topos, ekzistencial, lyric hero, postmodernizm, symbol

Shaping the BRCAness mutational landscape by alternative double-strand break repair, replication stress and mitotic aberrancies

Tumours with mutations in the BRCA1/BRCA2 genes have impaired double-stranded DNA break repair, compromised replication fork protection and increased sensitivity to replication blocking agents, a phenotype collectively known as 'BRCAness'. Tumours with a BRCAness phenotype become dependent on alternative repair pathways that are error-prone and introduce specific patterns of somatic mutations across the genome. The increasing availability of next-generation sequencing data of tumour samples has enabled identification of distinct mutational signatures associated with BRCAness. These signatures reveal that alternative repair pathways, including Polymerase θ-mediated alternative end-joining and RAD52-mediated single strand annealing are active in BRCA1/2-deficient tumours, pointing towards potential therapeutic targets in these tumours. Additionally, insight into the mutations and consequences of unrepaired DNA lesions may also aid in the identification of BRCA-like tumours lacking BRCA1/BRCA2 gene inactivation. This is clinically relevant, as these tumours respond favourably to treatment with DNA-damaging agents, including PARP inhibitors or cisplatin, which have been successfully used to treat patients with BRCA1/2-defective tumours. In this review, we aim to provide insight in the origins of the mutational landscape associated with BRCAness by exploring the molecular biology of alternative DNA repair pathways, which may represent actionable therapeutic targets in in these cells

Personalized surveillance and aftercare for non-metastasized breast cancer:the NABOR study protocol of a multiple interrupted time series design

Background: Follow-up of curatively treated primary breast cancer patients consists of surveillance and aftercare and is currently mostly the same for all patients. A more personalized approach, based on patients’ individual risk of recurrence and personal needs and preferences, may reduce patient burden and reduce (healthcare) costs. The NABOR study will examine the (cost-)effectiveness of personalized surveillance (PSP) and personalized aftercare plans (PAP) on patient-reported cancer worry, self-rated and overall quality of life and (cost-)effectiveness.Methods: A prospective multicenter multiple interrupted time series (MITs) design is being used. In this design, 10 participating hospitals will be observed for a period of eighteen months, while they -stepwise- will transit from care as usual to PSPs and PAPs. The PSP contains decisions on the surveillance trajectory based on individual risks and needs, assessed with the ‘Breast Cancer Surveillance Decision Aid’ including the INFLUENCE prediction tool. The PAP contains decisions on the aftercare trajectory based on individual needs and preferences and available care resources, which decision-making is supported by a patient decision aid. Patients are non-metastasized female primary breast cancer patients (N = 1040) who are curatively treated and start follow-up care. Patient reported outcomes will be measured at five points in time during two years of follow-up care (starting about one year after treatment and every six months thereafter). In addition, data on diagnostics and hospital visits from patients’ Electronical Health Records (EHR) will be gathered. Primary outcomes are patient-reported cancer worry (Cancer Worry Scale) and overall quality of life (as assessed with EQ-VAS score). Secondary outcomes include health care costs and resource use, health-related quality of life (as measured with EQ5D-5L/SF-12/EORTC-QLQ-C30), risk perception, shared decision-making, patient satisfaction, societal participation, and cost-effectiveness. Next, the uptake and appreciation of personalized plans and patients’ experiences of their decision-making process will be evaluated. Discussion: This study will contribute to insight in the (cost-)effectiveness of personalized follow-up care and contributes to development of uniform evidence-based guidelines, stimulating sustainable implementation of personalized surveillance and aftercare plans. Trial registration: Study sponsor: ZonMw. Retrospectively registered at ClinicalTrials.gov (2023), ID: NCT05975437.</p

Intermittent applied mechanical loading induces subchondral bone thickening that may be intensified locally by contiguous articular cartilage lesions

Objectives: Changes in subchondral bone (SCB) and cross-talk with articular cartilage (AC) have been linked to osteoarthritis (OA). Using micro-computed tomography (micro-CT) this study: (1) examines changes in SCB architecture in a non-invasive loading mouse model in which focal AC lesions are induced selectively in the lateral femur, and (2) determines any modifications in the contralateral knee, linked to changes in gait, which might complicate use of this limb as an internal control. Methods: Right knee joints of CBA mice were loaded: once with 2weeks of habitual use (n=7), for 2weeks (n=8) or for 5weeks (n=5). Both left (contralateral) and right (loaded) knees were micro-CT scanned and the SCB and trabecular bone analysed. Gait analysis was also performed. Results: These analyses showed a significant increase in SCB thickness in the lateral compartments in joints loaded for 5weeks, which was most marked in the lateral femur; the contralateral non-loaded knee also showed transient SCB thickening (loaded once and repetitively). Epiphyseal trabecular bone BV/TV and trabecular thickness were also increased in the lateral compartments after 5 weeks of loading, and in all joint compartments in the contralateral knee. Gait analysis showed that applied loading only affected gait in the contralateral himd-limb in all groups of mice from the second week after the first loading episode. Conclusions: These data indicate a spatial link between SCB thickening and AC lesions following mechanical trauma, and the clear limitations associated with the use of contralateral joints as controls in such OA models, and perhaps in OA diagnosis

Selective hydroxylation of 1,8- and 1,4-cineole using bacterial P450 variants

This study has evaluated the use of the P450 metalloenzymes CYP176A1, CYP101A1 and CYP102A1, together with engineered protein variants of CYP101A1 and CYP102A1, to alter the regioselectivity of 1,8- and 1,4-cineole hydroxylation. CYP176A1 was less selective for 1,4-cineole oxidation when compared to its preferred substrate, 1,8-cineole. The CYP102A1 variants significantly improved the activity over the WT enzyme for oxidation of 1,4- and 1,8-cineole. The CYP102A1 R47L/Y51F/A74G/F87V/L188Q mutant generated predominantly (1S)-6α-hydroxy-1,8-cineole (78% e.e.) from 1,8-cineole. Oxidation of 1,4-cineole by the CYP102A1 R47L/Y51F/F87A/I401P variant generated the 3α product in >90% yield. WT CYP101A1 formed a mixture metabolites with 1,8-cineole and very little product was generated with 1,4-cineole. In contrast the F87W/Y96F/L244A/V247L and F87W/Y96F/L244A variants of CYP101A1 favoured formation of 5α-hydroxy-1,8-cineole (>88%, 1S 86% e.e.) while the F87V/Y96F/L244A variant generated (1S)-6α-hydroxy-1,8-cineole in excess (90% regioselective, >99% e.e.). The CYP101A1 F87W/Y96F/L244A/V247L and F87W/Y96F/L244A mutants improved the oxidation of 1,4-cineole generating an excess of the 3α metabolite (1S > 99% e.e. with the latter). The CYP101A1 F87L/Y96F variant also improved the oxidation of this substrate but shifted the site of oxidation to the isopropyl group, (8-hydroxy-1,4-cineole). When this 8-hydroxy metabolite was generated in significant quantities desaturation of C8C9 to the corresponding alkene was also detected

The climate change skepticism questionnaire: Validation of a measure to assess doubts regarding climate change

Climate change skepticism (CCS) is a significant impediment to sustainable behavior. An in-depth understanding of CCS is therefore essential. However, existing measures vary considerably. In this paper, we address the differences and limitations of existing measures of CCS and present a new measure. In three studies (n = 534; n = 352; n = 252), we examined the factor structure, test-retest reliability, and associations with intentions for sustainable behaviors, psychological resistance to change, and dispositional tendencies for motivated reasoning. The resulting climate change skepticism questionnaire (CCS-Q) is a 12-item scale that assesses four dimensions of CCS: trend, attribution, impact, and response skepticism. The CCS-Q combines expressions of doubt or uncertainty with denial. The studies we conducted support our four-dimensional structure and test-retest reliability was good. Furthermore, CCS-Q scores were negatively related to intentions for sustainable behavior and positively related to resistance to change. We did not find any association with motivated reasoning. Overall, the new CCS-Q offers a reliable and valid measure for CCS