Intrinsically disordered regions (IDRs) represent at least one-third of the human proteome and defy the established structure-function paradigm. Because IDRs often have limited positional sequence conservation, the functional classification of IDRs using standard bioinformatics is generally not possible. Here, we show that evolutionarily conserved molecular features of IDRs enable clustering of the human disordered proteome (IDRome) into a map with strong functional enrichments. We quantify how conserved IDR features correlate with functional terms and, for a subset of terms, provide proteome-wide predictions of annotations for IDRs. Further, we show that conserved features of IDRs can predict protein localization to different biomolecular condensates and underlie elevated intracluster connectivity in condensate-associated IDRs, as well as enrich for short-linear motif-binding domains among interaction partners. We highlight patterns of conservation in disordered proteins with unknown function and in clusters enriched for proteins encoded by disease-risk genes. Our map of the human IDR-ome should be a valuable resource that aids in the discovery of new IDR biology.
Artificial intelligence (AI) has potential to revolutionize radiology, yet current solutions and guidelines are predominantly focused on adult populations, often overlooking the specific requirements of children. This is important because children differ significantly from adults in terms of physiology, developmental stages, and clinical needs, necessitating tailored approaches for the safe and effective integration of AI tools. This multi-society position statement systematically addresses four critical pillars of AI adoption: (1) regulation and purchasing, (2) implementation and integration, (3) interpretation and post-market surveillance, and (4) education. We propose pediatric-specific safety ratings, inclusion of datasets from diverse pediatric populations, quantifiable transparency metrics, and explainability of models to mitigate biases and ensure AI systems are appropriate for use in children. Risk assessment, dataset diversity, transparency, and cybersecurity are important steps in regulation and purchasing. For successful implementation, a phased strategy is recommended, involving early pilot testing, stakeholder engagement, and comprehensive post-market surveillance with continuous monitoring of defined performance benchmarks. Clear protocols for managing discrepancies and adverse incident reporting are essential to maintain trust and safety. Moreover, we emphasize the need for foundational AI literacy courses for all healthcare professionals which include pediatric safety considerations, alongside specialized training for those directly involved in pediatric imaging. Public and patient engagement is crucial to foster understanding and acceptance of AI in pediatric radiology. Ultimately, we advocate for a child-centered framework for AI integration, ensuring that the distinct needs of children are prioritized and that their safety, accuracy, and overall well-being are safeguarded.
Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold tremendous promise for in vitro modeling to assess native myocardial function and disease mechanisms as well as testing drug safety and efficacy. However, current iPSC- CMs are functionally immature, resembling in vivo CMs of fetal or neonatal developmental states. The use of targeted culture media and organoid formats have been identified as potential high-yield contributors to improve CM maturation. This study presents a novel iPSC-CM maturation medium formulation, designed using a differential evolutionary approach targeting metabolic functionality for iterative optimization. Relative to gold-standard reference formulations, our medium significantly matured morphology, Ca 2+ handling, electrophysiology, and metabolism, which was further validated by multiomic screening, for cells in either pure or co-cultured microtissue formats. Together, these findings not only provide a reliable workflow for highly functional iPSC-CMs for downstream use, but also demonstrate the power of high-dimensional optimization processes in evoking advanced biological function in vitro.
Genetic interaction (GI) networks in model organisms have revealed how combinations of genome variants can impact phenotypes. To advance efforts toward a reference human GI network, we developed the quantitative Genetic Interaction (qGI) score, a method for precise GI measurement from genome-wide CRISPR-Cas9 screens in different query mutants constructed in a single human cell line. We found surprising prevalent systematic variation unrelated to GIs in CRISPR screen data, including both genomically linked effects and functionally coherent covariation. Leveraging ~40 control screens in wild-type cells and half a billion differential fitness effect measurements, we developed a pipeline for CRISPR screen data processing and normalization to correct these artifacts and measure accurate, quantitative GIs. We also comprehensively characterized GI reproducibility by characterizing 4 - 5 biological replicates for ~125,000 unique gene pairs. The qGI framework enables systematic identification of human GIs and provides broadly applicable strategies for analyzing context-specific CRISPR screen data.
Anthracycline chemotherapy is commonly used to treat cancer in both adult and pediatric patients. While effective, anthracycline treatment is associated with a high risk of cardiotoxicity, often manifesting as a decline in left ventricular function, resulting in long term cardiovascular complications. Aerobic exercise has been studied extensively for its cardioprotective benefits in patients with anthracycline-induced cardiac dysfunction; however, the role of resistance training remains unexplored and controversial due to historical concerns regarding safety. This systematic review examined the existing literature on the effects and safety of resistance training in pediatric and adult cancer patients treated with anthracyclines. A two-part screening process was completed in Covidence (2025), starting with the screening of titles and abstracts, followed by the full-text screening. Eight studies, all incorporating AR-T were reviewed. The findings suggest that AR-T is safe and well-tolerated, with no evidence indicating that resistance training exacerbates cardiac dysfunction. No studies included exclusively pediatric or adolescent patients, limiting the generalizability of the findings to these populations. Randomized controlled trials focused solely on resistance training are needed to inform future clinical guidelines.
