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Multimodal bHLH-PAS DNA binding controls specificity and drives obesity
No full textPublished online 06 January 2026The basic-helix-loop-helix Per-Arnt-Sim (PAS) homology domain (bHLH-PAS) transcription factor (TF) family comprises critical sensors or actuators of physiological (hypoxia, tryptophan metabolites, neuronal activity, and appetite) and environmental (diet-derived metabolites and pollutants) stimuli regulating genes involved in signal adaptation and homeostasis. Despite the importance of this TF family, the mechanisms underlying specificity of DNA binding and target gene regulation by the bHLH-PAS subfamily remain unresolved. We systematically analysed cognate DNA binding hierarchies of prototypical bHLH-PAS family members (ARNT, ARNT2, HIF1α, HIF2α, AhR, NPAS4, SIM1), revealing large DNA binding footprints (12-15 bp) and unique mechanisms of DNA binding specificity involving preferential DNA sequences flanking the core motif. Flank-encoded DNA binding specificity discerns otherwise identical core sequence binding by SIM1 and the HIFs, mediated through N-terminal HIFα-DNA interactions. We also reveal an intimate relationship between DNA shape and core and flank TF binding that allows motif sequence flexibility and underpins multimodal mechanisms for achieving TF binding specificity. Furthermore, novel downstream SIM1 PAS-loop/DNA interactions are associated with AT-rich sequences contributing to DNA binding and transcriptional activity; these interactions are critical for TF biological function underpinning a monogenic cause of human hyperphagic obesity in a recapitulated SIM1.R171H knock-in mouse model.David C. Bersten, Daniel P. McDougal, Adrienne E. Sullivan, Alexis Gerassimou, James Breen, Rebecca L. Fitzsimmons, George EO Muscat, Stephen Pederson, John B. Bruning, Chen-Ming Fan, Paul Q. Thomas, Darryl L. Russell, Daniel J. Peet, Murray L. Whitela
Caspase-2 deficiency drives pathogenic liver polyploidy and increases age-associated hepatocellular carcinoma in mice
No full textPublished online 1 Jan 2026Hepatocyte polyploidization promotes liver homeostasis by enhancing resistance to cellular stress. Caspase-2, a proapoptotic protease, restricts polyploidization by deleting polyploid and aneuploid cells. While caspase-2 protects against diet-induced hepatic injury, it also acts as a tumor suppressor by controlling genomic instability and oxidative stress. To investigate these roles, we assessed hepatic ploidy dynamics, liver damage, and age-associated tumorigenesis in caspase-2-deficient and catalytically inactive mutant mice. We found that caspase-2 loss promotes early-onset hepatocyte hyperpolyploidy, accompanied by progressive liver inflammation, fibrosis, oxidative liver damage, ferroptosis, and higher incidence of spontaneous hepatocellular carcinoma in aged animals. Proteomic profiling revealed a pathogenic polyploidy-associated signature associated with caspase-2 deficiency and increased predisposition to liver disease and malignancy. These findings establish caspase-2 enzymatic activity as a critical regulator of hepatic genome stability and preventing age-related liver cancer that strongly argue against therapeutic caspase-2 inhibition as a strategy for managing liver injury or cancer risk.Loretta Dorstyn, Yoon Lim, Jack Scanlan, Emma McLennan, Dylan De Bellis, Michael Katschner, John Finnie, Samantha Emery-Corbin, Jumana Yousef, Laura F. Dagley, Chung H. Kok, Sonia S. Shah, Chiaki Takahashi, Mark A. Febbraio, Sharad Kuma
Effectiveness of play therapy versus non-play interventions in palliative care for children and adolescents with cancer: a systematic review protocol
No full textOnlinePublObjective: The objective of this review is to determine the effectiveness of play therapy versus non-play interventions in improving the quality of life, physical and psychosocial functioning, and activity participation of children and adolescents with cancer in palliative care settings. Introduction: Integrating play interventions early in pediatric palliative care for children and adolescents with cancer, especially in low- to middle-income countries where survival rates are low, is essential for addressing the holistic needs of children or adolescents and their families; however, it remains underutilized. Eligibility criteria: This review will include studies examining children and adolescents with cancer (≤18 years) receiving palliative care. Interventions of interest encompass play therapy, therapeutic play, or play-based activities. Studies will include a comparator group, which will consist of standard palliative care approaches that do not involve play therapy. The primary outcome is patient quality of life; the secondary outcomes encompass physical and psychosocial functions, and activity participation. Eligible study designs will include experimental and quasi-experimental designs, and analytical observational studies. Mixed methods studies that include quantitative data will also be considered. Methods: This review will follow the JBI methodology for systematic reviews of effectiveness. A comprehensive search will be conducted across MEDLINE, CINAHL, Embase, Web of Science, PEDro, ProQuest, World Health Organization, and Google Scholar. Eligible studies will be critically appraised for methodological quality using JBI appraisal instruments. Where possible, statistical meta-analysis will be conducted using a random-effects model. The certainty of evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, and a Summary of Findings will be created.Nikka Karla R. Santos, Jon Timothy M. Rivero, Valentin C. Dones III, Romy Menghao Jia, Sonia Jane Hine
Solar-to-chemical conversion in catalytic plastic transformation
No full textOnlinePublSolar-driven catalytic transformation of plastic waste into valuable products is an attractive strategy to mitigate adverse environmental impacts of waste accumulation and contribute to sustainable manufacturing. A crucial step in advancing this technology is to harness solar energy and boost “waste-to-value” conversion via appropriate reaction systems and high-performance catalysts. Despite continued efforts, catalytic system design and photo-induced reaction mechanisms for complex molecular conversion remain to be settled. This review analyzes reaction systems in state-of-the-art solar-driven plastic conversion, classified by catalyst-plastic interaction modes: solid-solid, liquid-solid, and liquid-liquid. It discusses relevant approaches, including photocatalysis, photoelectrocatalysis, and photothermal catalysis. Additionally, we evaluate the fundamental processes (i.e., photon absorption, charge carrier utilization, and surface/interface catalytic reactions) in different reaction systems and discuss the intrinsic solar-to-chemical conversion from a photophysical/chemical perspective. Finally, we present a range of design strategies for reaction systems and catalysts to raise reaction efficiency and the overall economics of solar-driven plastic conversion.Shuai Zhang, Xintong Gao, Meijun Guo, Jingrun Ran, Shi-Zhang Qia
When randomisation goes horribly wrong: examples of major failures of randomisation and strategies to avoid them
No full textBackground Randomisation forms the foundation of clinical trials, but its implementation can be prone to error. Often randomisation errors affect few participants and do not seriously compromise the integrity of the trial. However, in some cases randomisation errors can have widespread consequences and call into question the validity of trial conclusions. Published articles may be retracted as a result. Valuable insight can be gained from studying past errors to minimise the risk of similar errors and their disastrous consequences impacting future trials. The aims of this article are to (i) describe examples of major failures of randomisation, and (ii) provide guidance on how to avoid them in practice. Methods Major failures of randomisation were defined as inadvertent errors that affected many trial participants and occurred during the process of designing the randomisation scheme, generating the randomisation schedule, allocating participants to treatment groups, or providing the assigned treatment. Examples of major failures of randomisation were drawn from author experience and through a review of the published literature, which included a systematic search of the Retraction Watch Database for serious randomisation problems that led to the retraction of a published article. Practice points to avoid such errors were developed by consensus among the authors. Results Examples are provided of seven broad types of major failures of randomisation: randomisation schedule followed incorrectly, randomisation schedule sorted incorrectly, randomisation schedule too short, clusters handled incorrectly, incorrect or unknown treatment provided at randomisation, poorly designed randomisation scheme, and programming errors in adaptive randomisation schemes. Practice points for avoiding such errors are presented, including suggestions for written documentation, staff training, and thorough testing of the randomisation process prior to trial commencement. Conclusions Randomisation is of fundamental importance in clinical trials. Greater consideration should be given to the potential for major failures of randomisation and strategies to avoid them. When major failures of randomisation do occur, greater transparency in reporting is needed.Lisa N. Yelland, Kylie M. Lange, Sabine Braat, Kristy P. Robledo, Alana R. Cuthbert and Thomas R. Sulliva
Scalable and Stereoselective C-H Bond Hydroxylation of Steroids Using a Designer Heme-Thiolate Peroxygenase Biocatalyst
No full textA challenging yet critical reaction in chemical synthesis is the selective activation of unactivated carbon-hydrogen bonds in complex molecules. Here we demonstrate the biocatalytic regio- and stereoselective hydroxylation of steroids, including progesterone, testosterone, adrenosterone, androstenedione, and dehydroepiandrosterone (DHEA), using a variant of an engineered bacterial cytochrome P450 enzyme, CYP154C35 from Nocardia otitidiscaviarum. We replaced two amino acid residues within the oxygen-binding groove of the I-helix, and this modification of the acid-alcohol pair to a glutamine and a glutamate set of residues had the effect of converting the enzyme into an efficient peroxygenase (CYP154C35QE). This enzyme performed the biocatalytic oxidation of the steroids stereoselectively to form the 16α-hydroxylated metabolites. In the presence of a substrate, CYP154C35QE was stable to relatively high concentrations of H2O2 but could function catalytically using lower concentrations. The enzyme tolerated 20% DMSO and was not denatured upon being preheated for 1 h at 40 °C. The enzyme was capable of high turnover numbers (∼6500), resulting in complete conversion of the substrate, enabling the formation, purification, and characterization of the enantiopure 16α-hydroxylated steroids at up to 120 mg scale.Oghenesivwe Osiebe, Eva F. Hayball, Nikita Yevstigneyev, Annalise M. Abbott, and Stephen G. Bel
Selective singlet oxygen generation by microporous biochar for peracetic acid activation
No full textThis study shows that the pyrolysis temperature and atmosphere critically affect the physiochemical properties of biochar. NH3-assisted pyrolysis at 900 °C produces biochar (NH3-C-900) with superior activity for peracetic acid activation, selectively generating singlet oxygen for rapid phenol degradation. Micropores contribute positively to the catalytic performance, with C[double bond, length as m-dash]O groups serving as the key active sites, while C–O and COOH are unfavorable.Selusiwe Ncube, Zhihao Tian, Shuhui Liu, Shaobin Wang and Wenjie Tia
Autonomous UAV last-mile delivery in urban environments: A survey on deep learning and reinforcement learning solutions
No full textThis survey investigates the convergence of deep learning (DL) and reinforcement learning (RL) for unmanned aerial vehicle (UAV) applications, particularly in autonomous last-mile delivery. The ongoing growth of ecommerce heightens the need for advanced UAV technologies to overcome urban logistics challenges, including navigation and package delivery. DL and RL offer promising methods for object detection, path planning, and decision-making, enhancing delivery efficiency. However, significant challenges persist, particularly regarding scalability, computational constraints, and adaptation to volatile urban settings. Large UAV fleets and intricate city environments exacerbate scalability issues, while limited onboard processing capacity hinders the use of computationally intensive DL and RL models. Moreover, adapting to unpredictable conditions demands robust navigation strategies. This survey emphasizes hybrid approaches that integrate supervised and reinforcement learning or employ transfer learning to adapt pre-trained models. Techniques like model based RL and domain adaptation are highlighted as potential pathways to improve generalizability and bridge the gap between simulation and real-world deployment.Jingrui Guo, Yangyang Zhou, Laurent Burlion, Andrey V. Savkin, Chao Huan
RAFT Polymerization for Advanced Morphological Control: From Individual Polymer Chains to Bulk Materials
No full textControl of the morphology of polymer systems is achieved through reversible-deactivation radical polymerization techniques such as Reversible Addition-Fragmentation chain Transfer (RAFT). Advanced RAFT techniques offer much more than just “living” polymerization—the RAFT toolkit now enables morphological control of polymer systems across many decades of length-scale. Morphological control is explored at the molecular-level in the context of syntheses where individual monomer unit insertion provides sequence-defined polymers (single unit monomer insertion, SUMI). By being able to define polymer architectures, the synthesis of bespoke shapes and sizes of nanostructures becomes possible by leveraging self-assembly (polymerization induced self-assembly, PISA). Finally, it is seen that macroscopic materials can be produced with nanoscale detail, based on phaseseparated nanostructures (polymerization induced microphase separation, PIMS) and microscale detail based on 3D-printing technologies. RAFT control of morphology is seen to cross from molecular level to additive manufacturing length-scales, with complete morphological control over all length-scales.Karen Hakobyan, Fumi Ishizuka, Nathaniel Corrigan, Jiangtao Xu, Per B. Zetterlund, Stuart W. Prescott, and Cyrille Boye
Employing the interactive oral to mitigate threats to academic integrity from ChatGPT
No full textPublished September 2025ChatGPT is an artificial intelligence tool that generates human-like text, making it difficult to detect. Despite its potential as a pedagogical tool, educators must be aware of the risk of academic misconduct when students use ChatGPT to submit third-party material as their own work. To ensure authorship of assignments, ChatGPT is requiring
psychology educators to make the learning journey more visible. Interactive oral assessments require students to engage in conversation and demonstrate their knowledge of a topic in real time, making it challenging for students to rely solely on ChatGPT. To maximize the effectiveness of the interactive oral in preserving academic integrity, it is
important for psychology educators to carefully design and implement the assessment, establish clear guidelines, and provide training for markers and students. In addition, educators should hold honest discussions about ChatGPT and modeling to promote integrity among students. By implementing interactive oral assessments, educators can balance assessment security and academic integrity while providing students with opportunities to demonstrate their understanding of the material.Samantha J. Newel