Integrating DNA damage repair with the cell cycle

Abstract DNA is labile and constantly subject to damage. In addition to external mutagens, DNA is continuously damaged by the aqueous environment, cellular metabolites and is prone to strand breakage during replication. Cell duplication is orchestrated by the cell division cycle and specific DNA structures are processed differently depending on where in the cell cycle they are detected. This is often because a specific structure is physiological in one context, for example during DNA replication, while indicating a potentially pathological event in another, such as interphase or mitosis. Thus, contextualising the biochemical entity with respect to cell cycle progression provides information necessary to appropriately regulate DNA processing activities. We review the links between DNA repair and cell cycle context, drawing together recent advances

What's on your plate? Collecting multimodal data to understand commensal behavior

Eating is a fundamental part of human life and is, more than anything, a social activity. A new field, known as Computational Commensality has been created to computationally address various social aspects of food and eating. This paper illustrates a study on remote dining we conducted online in May 2021. To better understand this phenomenon, known as Digital Commensality, we recorded 11 pairs of friends sharing a meal online through a videoconferencing app. In the videos, participants consume a plate of pasta while chatting with a friend or a family member. After the remote dinner, participants were asked to fill in the Digital Commensality questionnaire, a validated questionnaire assessing the effects of remote commensal experiences, and provide their opinions on the shortcomings of currently available technologies. Besides presenting the study, the paper introduces the first Digital Commensality Data-set, containing videos, facial landmarks, quantitative and qualitative responses. After surveying multimodal data-sets and corpora that we could exploit to understand commensal behavior, we comment on the feasibility of using remote meals as a source to build data-sets to investigate commensal behavior. Finally, we explore possible future research directions emerging from our results

Timed inhibition of CDC7 increases CRISPR-Cas9 mediated templated repair.

Repair of double strand DNA breaks (DSBs) can result in gene disruption or gene modification via homology directed repair (HDR) from donor DNA. Altering cellular responses to DSBs may rebalance editing outcomes towards HDR and away from other repair outcomes. Here, we utilize a pooled CRISPR screen to define host cell involvement in HDR between a Cas9 DSB and a plasmid double stranded donor DNA (dsDonor). We find that the Fanconi Anemia (FA) pathway is required for dsDonor HDR and that other genes act to repress HDR. Small molecule inhibition of one of these repressors, CDC7, by XL413 and other inhibitors increases the efficiency of HDR by up to 3.5 fold in many contexts, including primary T cells. XL413 stimulates HDR during a reversible slowing of S-phase that is unexplored for Cas9-induced HDR. We anticipate that XL413 and other such rationally developed inhibitors will be useful tools for gene modification

Social Interaction Data-sets in the Age of Covid-19: a Case Study on Digital Commensality

Research focusing on social interaction often leverages data-sets, allowing annotation, analysis, and modeling of social behavior. When it comes to commensality, researchers have started working on computational models of food and eating-related activities recognition. The growing research area known as Digital Commensality, has focused on meals shared online, for instance, through videochat. However, to investigate this topic, traditional data-sets recorded in laboratory settings may not be the best option in terms of ecological validity. Covid-19 restrictions and lock-downs have increased in online gatherings, with many people becoming used to the idea of sharing meals online. Following this trend, we propose the concept of collecting data by recording online interactions and discuss the challenges related to this methodology. We illustrate our approach in creating the first Digital Commensality data-set, containing recordings of food-related social interactions collected online during the Covid-19 outbreak

The EarthCARE satellite: the next step forward in global measurements of clouds, aerosols, precipitation, and radiation

The collective representation within global models of aerosol, cloud, precipitation, and their radiative properties remains unsatisfactory. They constitute the largest source of uncertainty in predictions of climatic change and hamper the ability of numerical weather prediction models to forecast high-impact weather events. The joint European Space Agency (ESA)–Japan Aerospace Exploration Agency (JAXA) Earth Clouds, Aerosol and Radiation Explorer (EarthCARE) satellite mission, scheduled for launch in 2018, will help to resolve these weaknesses by providing global profiles of cloud, aerosol, precipitation, and associated radiative properties inferred from a combination of measurements made by its collocated active and passive sensors. EarthCARE will improve our understanding of cloud and aerosol processes by extending the invaluable dataset acquired by the A-Train satellites CloudSat, Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO), and Aqua. Specifically, EarthCARE’s cloud profiling radar, with 7 dB more sensitivity than CloudSat, will detect more thin clouds and its Doppler capability will provide novel information on convection, precipitating ice particle, and raindrop fall speeds. EarthCARE’s 355-nm high-spectral-resolution lidar will measure directly and accurately cloud and aerosol extinction and optical depth. Combining this with backscatter and polarization information should lead to an unprecedented ability to identify aerosol type. The multispectral imager will provide a context for, and the ability to construct, the cloud and aerosol distribution in 3D domains around the narrow 2D retrieved cross section. The consistency of the retrievals will be assessed to within a target of ±10 W m–2 on the (10 km)2 scale by comparing the multiview broadband radiometer observations to the top-of-atmosphere fluxes estimated by 3D radiative transfer models acting on retrieved 3D domains

AI in obstetrics: Evaluating residents' capabilities and interaction strategies with ChatGPT.

In line with the digital transformation trend in medical training, students may resort to artificial intelligence (AI) for learning. This study assessed the interaction between obstetrics residents and ChatGPT during clinically oriented summative evaluations related to acute hepatic steatosis of pregnancy, and their self-reported competencies in information technology (IT) and AI. The participants in this semi-qualitative observational study were 14 obstetrics residents from two university hospitals. Students' queries were categorized into three distinct types: third-party enquiries; search-engine-style queries; and GPT-centric prompts. Responses were compared against a standardized answer produced by ChatGPT with a Delphi-developed expert prompt. Data analysis employed descriptive statistics and correlation analysis to explore the relationship between AI/IT skills and response accuracy. The study participants showed moderate IT proficiency but low AI proficiency. Interaction with ChatGPT regarding clinical signs of acute hepatic steatosis gravidarum revealed a preference for third-party questioning, resulting in only 21% accurate responses due to misinterpretation of medical acronyms. No correlation was found between AI response accuracy and the residents' self-assessed IT or AI skills, with most expressing dissatisfaction with their AI training. This study underlines the discrepancy between perceived and actual AI proficiency, highlighted by clinically inaccurate yet plausible AI responses - a manifestation of the 'stochastic parrot' phenomenon. These findings advocate for the inclusion of structured AI literacy programmes in medical education, focusing on prompt engineering. These academic skills are essential to exploit AI's potential in obstetrics and gynaecology. The ultimate aim is to optimize patient care in AI-augmented health care, and prevent misleading and unsafe knowledge acquisition

Mouse SLX4 Is a Tumor Suppressor that Stimulates the Activity of the Nuclease XPF-ERCC1 in DNA Crosslink Repair

SLX4 binds to three nucleases (XPF-ERCC1, MUS81-EME1, and SLX1), and its deficiency leads to genomic instability, sensitivity to DNA crosslinking agents, and Fanconi anemia. However, it is not understood how SLX4 and its associated nucleases act in DNA crosslink repair. Here, we uncover consequences of mouse Slx4 deficiency and reveal its function in DNA crosslink repair. Slx4-deficient mice develop epithelial cancers and have a contracted hematopoietic stem cell pool. The N-terminal domain of SLX4 (mini-SLX4) that only binds to XPF-ERCC1 is sufficient to confer resistance to DNA crosslinking agents. Recombinant mini-SLX4 enhances XPF-ERCC1 nuclease activity up to 100-fold, directing specificity toward DNA forks. Mini-SLX4-XPF-ERCC1 also vigorously stimulates dual incisions around a DNA crosslink embedded in a synthetic replication fork, an essential step in the repair of this lesion. These observations define vertebrate SLX4 as a tumor suppressor, which activates XPF-ERCC1 nuclease specificity in DNA crosslink repairope

Заболевание тазобедренного сустава у детей с наследственной предрасположенностью: концептуальная модель

На основе принципов интегративной медицины, системного подхода с использованием концептуально−логического моделирования разработана единая система представлений о заболеваниях тазобедренного сустава у детей с наследственной предрасположенностью. Показано, что предлагаемый интегративный подход может служить основой для разработки диагностических и прогностических критериев развития суставов и проведения патогенетического хирургического лечения, направленного на ликвидацию или существенное снижение частоты формирования диспластического коксартроза.Based on the principles of integrative medicine, systemic approach with the use of concept of logical modelling, a uniform system of concepts about the diseases of the hip joint in children with hereditary susceptibility was worked out. It was shown that the suggested integrative approach can be used for working out diagnostic and prognostic criteria of joint development and performing pathogenetic surgery aimed at elimination or reduction in the frequency of forming dysplastic coxarthrosis