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Cells employ diverse strategies to repair double-strand breaks (DSBs), a dangerous form of DNA damage that threatens genome integrity. Eukaryotic nuclei consist of different chromatin environments, each displaying distinct molecular and biophysical properties that can significantly influence the DSB-repair process. DSBs arising in the compact and silenced heterochromatin domains have been found to move to the heterochromatin periphery in mouse and Drosophila to prevent aberrant recombination events. However, it is poorly understood how chromatin components, such as histone post-translational modifications, contribute to these DSB movements within heterochromatin. Using irradiation as well as locus-specific DSB induction in Drosophila tissues and cultured cells, we find enrichment of histone H3 lysine 9 acetylation (H3K9ac) at DSBs in heterochromatin but not euchromatin. We find this increase is mediated by the histone acetyltransferase dGcn5, which rapidly localizes to heterochromatic DSBs. Moreover, we demonstrate that in the absence of dGcn5, heterochromatic DSBs display impaired recruitment of the SUMO E3 ligase Nse2/Qjt and fail to relocate to the heterochromatin periphery to complete repair. In summary, our results reveal a previously unidentified role for dGcn5 and H3K9ac in heterochromatic DSB repair and underscore the importance of differential chromatin responses at heterochromatic and euchromatic DSBs to promote safe repair.

Health professions education (HPE) research in the General Practice domain (GP-HPE) is vital for high-quality healthcare. Collaboration among GP-HPE researchers is crucial but challenging. Formulating a research agenda, involving stakeholders, and fostering inter-institutional collaboration can address these challenges and connect educational research and practice. We used Q-methodology to explore perspectives on GP-HPE research of participants from all Dutch postgraduate GP training institutes. Participants individually sorted statements based on the relevance of future GP-HPE research for educational practice. Data analysis comprised inverted factor analysis, rotation, and qualitative interpretation of configurations of all statements. The National Meeting on Educational Research took a participatory approach. We included 73 participants with diverse involvement in GP-HPE research. We identified five distinct perspectives, each representing a research focus area for developing and innovating GP education: the clinician scientist, the socially engaged GP, the specific GP identity, the GP as an entrepreneur, and the GP engaged in lifelong learning. The resulting five perspectives align with General Practice hallmarks. Q-methodology and a participatory approach facilitated collaboration among stakeholders. Successful inter-institutional collaboration requires a common goal, neutral leadership, participant commitment, regular meetings, audit trail support, process transparency, and reflexivity. Future research should address evidence gaps within these perspectives. Using Q-methodology turned out to be valuable for compiling a national research agenda for GP-HPE research. The research process helped to cross boundaries between researchers in different institutions, thus putting inter-institutional collaborative advantage center stage. Our approach could provide a conceivable procedure for HPE researchers worldwide.

There has been little attention to personality in research on school refusal (SR). This study examined personality traits among 41 adolescents receiving cognitive-behavioral therapy (CBT) during participation in a School Refusal Program in the Netherlands. Traits were examined via clinical scales and 2-point code types derived from the Minnesota Multiphasic Personality Inventory--Adolescent. The influence of personality traits on treatment outcome was examined at post-treatment and 1-year follow-up. At pretreatment, eight of the 10 clinical scales were disproportionately skewed toward the "high to very high" range relative to a norm group. Social introversion and depressive symptomatology were significantly increased relative to the norm group, and nearly one-half of the adolescents were characterized by code type 2-3/3-2 (depression/hysteria) or 2-0/0-2 (depression/social introversion). Adolescents characterized by a 2-0/0-2 code type were almost twice as likely (odds ratio = 1.78) to be treatment responders at post-treatment. There was no relation between personality traits and treatment outcome at follow-up. The small sample size limits generalization of the study's findings. If the results are replicated, personality traits may provide useful indications for personalizing treatment when employing interventions recommended in CBT manuals for SR.

Objectives: Overweight and obesity among school-aged children pose a threat to both their academic performance and public health. The Healthy Primary School of the Future (HPSF) initiative was established to address this issue. Our objective was to explore the conditions that make HPSF sustainable based on the perspectives of relevant stakeholders. Design: The study utilised Group Concept Mapping, a structured methodology for conducting mixed-methods participative research, combining qualitative data collection with quantitative data analysis measures. Method: Participants included parents, teachers, school directors, politicians, labour unions, educational, nutrition and health scientists and policymakers. They were asked to respond to the prompt, 'A necessary condition to make the HPSF sustainable is . . .'. The statements generated were then assessed for their importance and feasibility. Using multidimensional scaling and hierarchical cluster analyses, we identified the shared vision among the stakeholders. Results: A total of 106 unique statements were generated and grouped statistically into 10 clusters. The most significant clusters were identified as Financing; Accessibility for everyone; and Content/Lifestyle/School Programme. The clusters that were deemed most feasible included Content/Lifestyle/School Programme; Accessibility for everyone; and Evaluation. Conclusion: Achieving sustainability for the HPSF requires a comprehensive approach that addresses the conditions outlined in all 10 clusters. Based on the ratings of feasibility and importance, our recommendation is to prioritise implementation of Content/Lifestyle/School Programme and Accessibility for everyone. Subsequently, efforts should be directed towards realising the less feasible but crucial conditions, such as Financing and Evaluation, followed by the remaining six clusters of conditions as identified.

A student's middle school science experience strongly impacts their future science, technology, engineering, and mathematics interest. The Japanese lesson study (JLS) model strengthens the student's experience through a research-based, collaborative, multistep, teaching-centered process focused on transforming local instructional practices. The JLS model has seen very limited application to middle school life science classrooms. The six-year-long implementation of JLS to core standards in the seventh-grade life science curriculum at a Los Angeles area school serving a historically underrepresented population found large, gender-independent increases in student mastery of key science standards, increased teacher collaboration in the areas of lesson development and data analysis, and school-site reform yielding district and statewide recognition.

Impaired control of the G1/S checkpoint allows initiation of DNA replication under non-permissive conditions. Unscheduled S-phase entry is associated with DNA replication stress, demanding for other checkpoints or cellular pathways to maintain proliferation. Here, we uncovered a requirement for ADARp150 to sustain proliferation of G1/S-checkpoint-defective cells under growth-restricting conditions. Besides its well-established mRNA editing function in inversely oriented short interspersed nuclear elements (SINEs), we found ADARp150 to exert a critical function in mitosis. ADARp150 depletion resulted in tetraploidization, impeding cell proliferation in mitogen-deprived conditions. Mechanistically we show that ADAR1 depletion induced aberrant expression of Cyclin B3, which was causative for mitotic failure and whole-genome duplication. Finally, we find that also in vivo ADAR1-depletion-provoked tetraploidization hampers tumor outgrowth.

AIMS: The concept of atrial cardiomyopathy (AtCM) had been percolating through the literature since its first mention in 1972. Since then, publications using the term were sporadic until the decision was made to convene an expert working group with representation from four multinational arrhythmia organizations to prepare a consensus document on atrial cardiomyopathy in 2016 (EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication). Subsequently, publications on AtCM have increased progressively. METHODS AND RESULTS: The present consensus document elaborates the 2016 AtCM document further to implement a simple AtCM staging system (AtCM stages 1-3) by integrating biomarkers, atrial geometry, and electrophysiological changes. However, the proposed AtCM staging needs clinical validation. Importantly, it is clearly stated that the presence of AtCM might serve as a substrate for the development of atrial fibrillation (AF) and AF may accelerates AtCM substantially, but AtCM per se needs to be viewed as a separate entity. CONCLUSION: Thus, the present document serves as a clinical consensus statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asian Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS) to contribute to the evolution of the AtCM concept.

In drug discovery, the in silico prediction of binding affinity is one of the major means to prioritize compounds for synthesis. Alchemical relative binding free energy (RBFE) calculations based on molecular dynamics (MD) simulations are nowadays a popular approach for the accurate affinity ranking of compounds. MD simulations rely on empirical force field parameters, which strongly influence the accuracy of the predicted affinities. Here, we evaluate the ability of six different small-molecule force fields to predict experimental protein-ligand binding affinities in RBFE calculations on a set of 598 ligands and 22 protein targets. The public force fields OpenFF Parsley and Sage, GAFF, and CGenFF show comparable accuracy, while OPLS3e is significantly more accurate. However, a consensus approach using Sage, GAFF, and CGenFF leads to accuracy comparable to OPLS3e. While Parsley and Sage are performing comparably based on aggregated statistics across the whole dataset, there are differences in terms of outliers. Analysis of the force field reveals that improved parameters lead to significant improvement in the accuracy of affinity predictions on subsets of the dataset involving those parameters. Lower accuracy can not only be attributed to the force field parameters but is also dependent on input preparation and sampling convergence of the calculations. Especially large perturbations and nonconverged simulations lead to less accurate predictions. The input structures, Gromacs force field files, as well as the analysis Python notebooks are available on GitHub.

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant "ultrahypermutation". The median age at diagnosis was 50 years (range 27-78), compared with 63 years for the other 450 patients with conventional glioblastoma (p

Despite ample anecdotal evidence, there are limited meaningful studies speaking to the important role of the human-animal bond (HAB) in reducing suicidality. However, research is increasingly showing the viability of service dogs (SDs) as a complementary approach for military Veterans suffering from post-traumatic stress disorder (PTSD) and substance use harms – two of the strongest indicators of suicidality across any population. An original, exploratory study completed in 2020 focused on how SDs supported Canadian Veterans living with PTSD and substance use concerns. From this work, a secondary analysis was then undertaken: 28 transcripts were examined through thematic analysis to explore the experiences of the Veterans who were identified as being at high risk for suicide to better understand how SDs may assist with their suicidality. Our methodological approach for the secondary analysis employed affective coding to discover how the social support system enabled by the SDs reduced experiences of loneliness and hopelessness, as well as symptoms of PTSD, depression, and substance use concerns that are commonly associated with suicidality. The SDs were reported by the Veterans as being a catalyst in reducing self-harm and suicidality, as the HAB provided a unique and necessary form of social support for Veterans that was distinct from what other human-human interactions could provide. While acknowledgement of how context specificity and the lived experience of each individual remains crucial for making sense of suicidality, the significant finding from this research has been the identification of the critical impact that SDs have in the lives of Veterans when it comes to preventing suicide. The SD has been explained as a bridge to improve Veterans’ overall quality of life and reduce markers commonly recognized as precursors to suicide – a finding that may be critical in helping reduce future suicide risk among military Veterans, and warrants further investigation.

PURPOSE OF REVIEW: Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed. RECENT FINDINGS: We discuss how the blood-brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody-drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood-brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.

This comprehensive Review delves into the chemical principles governing RNA-mediated crowding events, commonly referred to as granules or biological condensates. We explore the pivotal role played by RNA sequence, structure, and chemical modifications in these processes, uncovering their correlation with crowding phenomena under physiological conditions. Additionally, we investigate instances where crowding deviates from its intended function, leading to pathological consequences. By deepening our understanding of the delicate balance that governs molecular crowding driven by RNA and its implications for cellular homeostasis, we aim to shed light on this intriguing area of research. Our exploration extends to the methodologies employed to decipher the composition and structural intricacies of RNA granules, offering a comprehensive overview of the techniques used to characterize them, including relevant computational approaches. Through two detailed examples highlighting the significance of noncoding RNAs, NEAT1 and XIST, in the formation of phase-separated assemblies and their influence on the cellular landscape, we emphasize their crucial role in cellular organization and function. By elucidating the chemical underpinnings of RNA-mediated molecular crowding, investigating the role of modifications, structures, and composition of RNA granules, and exploring both physiological and aberrant phase separation phenomena, this Review provides a multifaceted understanding of the intriguing world of RNA-mediated biological condensates.