Prolonged persistence of mutagenic DNA lesions in somatic cells.

DNA is subject to continual damage, leaving each cell with thousands of individual DNA lesions at any given moment1-3. The efficiency of DNA repair means that most known classes of lesion have a half-life of minutes to hours3,4, but the extent to which DNA damage can persist for longer durations remains unknown. Here, using high-resolution phylogenetic trees from 89 donors, we identified mutations arising from 818 DNA lesions that persisted across multiple cell cycles in normal human stem cells from blood, liver and bronchial epithelium5-12. Persistent DNA lesions occurred at increased rates, with distinctive mutational signatures, in donors exposed to tobacco or chemotherapy, suggesting that they can arise from exogenous mutagens. In haematopoietic stem cells, persistent DNA lesions, probably from endogenous sources, generated the characteristic mutational signature SBS1913; occurred steadily throughout life, including in utero; and endured for 2.2 years on average, with 15-25% of lesions lasting at least 3 years. We estimate that on average, a haematopoietic stem cell has approximately eight such lesions at any moment in time, half of which will generate a mutation with each cell cycle. Overall, 16% of mutations in blood cells are attributable to SBS19, and similar proportions of driver mutations in blood cancers exhibit this signature. These data indicate the existence of a family of DNA lesions that arise from endogenous and exogenous mutagens, are present in low numbers per genome, persist for months to years, and can generate a substantial fraction of the mutation burden of somatic cells

Exploring the policy implementation of a holistic approach to cancer investigation in non-specific symptom pathways in England: An ethnographic study.

OBJECTIVES: This study aimed to explore the policy implementation of non-specific symptom pathways within the English National Health Service. METHODS: A multi-site ethnographic project was conducted in four hospitals that contained non-specific symptom pathways between November 2021 and February 2023. The research involved observation (44 h), interviews (n = 54), patient shadowing, and document review. RESULTS: The study examined how the policy concept of 'holistic' care was understood and put into practice within four non-specific symptom pathways. Several challenges associated with providing holistic care were identified. One key challenge was the conflict between delivering holistic care and meeting timed targets, such as the Faster Diagnosis Standard, due to limited availability of imaging and diagnostic tools. The interpretation of a holistic approach varied among participants, with some acknowledging that the current model did not recognise holistic care beyond cancer exclusion. The findings also revealed a lack of clarity and differing opinions on the boundaries of holistic care, resulting in wide variation in NSS pathway implementation across health care providers. Additionally, holistic investigation of non-specific symptoms in younger patients were seen to pose difficulties due to younger patients' history of health anxiety or depression, as well as concerns over radiological risk exposure. CONCLUSIONS: The study highlights the complexity of implementing non-specific symptom pathways in light of standardised timed cancer targets and local cancer policies. There is a need for appropriately funded organisational models of care that prioritise holistic care in a timely manner over solely meeting cancer targets. Decision-makers should also consider the role of non-specific symptom pathways within the broader context of chronic disease management, with a particular emphasis on expanding diagnostic capacity

A giant specimen of Rhamphorhynchus muensteri and comments on the ontogeny of rhamphorhynchines.

Rhamphorhynchus is one of the best-known pterosaurs, with well over 100 specimens being held in public collections. Most of these represent juvenile animals, and the adults known are typically around 1 m in wingspan. Here we describe a near complete skeleton, preserved partially in 3D, of an animal with a wingspan of around 1.8 m, that is considerably larger than other known specimens, and is among the largest known non-pterodactyloid pterosaurs. This animal shows differences in the anatomy not seen in smaller specimens, revealing details of late-stage ontogeny in this genus. The specimen exhibits a disproportionate reduction in the size of the orbit and increase in the size of the lower temporal fenestra, a reduction in the proportional mandibular symphysis, and unusually laterally flattened teeth, which may point to a changing diet as these animals grew. These features show a transition from smaller to larger specimens of Rhamphorhynchus and also appear in other large specimens of rhamphorhyhchines and point to a consistent pattern in their development

A dynamical view of Tijdeman's solution of the chairman assignment problem

In 1980, R. Tijdeman provided an online algorithm that generates sequences over a finite alphabet with minimal discrepancy, that is, such that the occurrence of each letter optimally tracks its frequency. We define discrete dynamical systems generating these sequences. The dynamical systems are defined as exchanges of polytopal pieces, yielding cut and project schemes, and they code tilings of the line whose sets of vertices form model sets. We prove that these sequences of low discrepancy are natural codings of toral translations with respect to polytopal atoms, and that they generate a minimal and uniquely ergodic subshift with purely discrete spectrum. Finally, we show that the factor complexity of these sequences is of polynomial growth order n d − 1 , where d is the cardinality of the alphabet

Understanding and Improving User-controlled Content Moderation Systems on Social Media

This thesis presents a comprehensive exploration of the design and execution of user-controlled content moderation systems that prioritize both fairness and efficiency. These systems range from decentralised blocklists on Twitter to Web3 content moderation (referred to as ''mute'') on memo.cash. memo.cash is a microblogging platform built on the Bitcoin Cash (BCH) blockchain and stands out as the only Web3 platform that enables user-to-user moderation. In contrast, other Web3 platforms like Steemit and Noise.cash employ a less decentralized approach, involving community moderators and administrators. Through extensive data mining, encompassing social interactions and moderation actions from 2.8 million Twitter users and 24 thousand memo.cash users, a thorough analysis of user behaviour among moderated users and moderators, and in-depth machine learning classification and moderation recommendation, this research offers insights into the perspectives and practices of various stakeholders. These stakeholders include users who invest time or financial resources in moderation and individuals whose timelines are affected by content hiding. This study not only furnishes theoretical insights but also offers practical guidance. It prompts the challenges of individual users engaging in moderation while upholding the principles of free speech. It also delves into designing solutions that cater to the diverse needs of user groups and the integration of automated moderation tools

The role of cardiovascular multimodality imaging in the evaluation of Anderson-Fabry disease: from early diagnosis to therapy monitoring A clinical consensus statement of the ESC Working Group on Myocardial & Pericardial Diseases and the European Association of Cardiovascular Imaging of the ESC.

Anderson-Fabry disease (AFD) is a rare genetic disease with X-linked transmission characterized by a defect in the enzyme alpha-galactosidase A (alpha-GAL), which impairs glycosphingolipid metabolism and leads to an excessive storage of globotriaosylceramide (Gb3) within lysosomes. AFD involves renal, cardiac, vascular, and nervous systems and is mainly observed in male patients with onset in childhood, although cardiac manifestation is often shown in adults. AFD cardiomyopathy is caused by the accumulation of Gb3 within myocytes first showed by left ventricular (LV) hypertrophy and diastolic dysfunction, leading to restrictive cardiomyopathy and systolic heart failure with biventricular involvement. The diagnosis of AFD cardiomyopathy may be insidious in the first stages and requires accurate differential diagnosis with other cardiomyopathies with hypertrophic phenotype. However, it is fundamental to promptly initiate specific therapies that have shown promising results, particularly for early treatment. A careful integration between clinical evaluation, genetic tests, and cardiac imaging is required to diagnose AFD with cardiac involvement. Basic and advanced echocardiography, cardiac magnetic resonance, and nuclear imaging may offer pivotal information for early diagnosis (Central illustration) and the management of these patients is often limited to centres with high expertise in the field. This clinical consensus statement, developed by experts from the European Society of Cardiology (ESC) Working Group on Myocardial & Pericardial Diseases and the European Association of Cardiovascular Imaging of the ESC, aims to provide practical advice for all clinicians regarding the use of multimodality imaging to simplify the diagnostic evaluation, prognostic stratification, and management of cardiac involvement in AFD