bluuebunny/crossref_metadata_2025_split huggingface dataset:
A dWDR45 knock-outDrosophilamodel to decipher the role of autophagy in BPAN
Authors: Celle Marion , Aniorte Sahra , Issa Abdoul Raouf , Jollivet Florence , Falabregue Marion , Jin Haixiu , Ding Shuze , Seugnet Laurent , Liao Lujian , Lesca Gaetan , Walter Ludivine , Mollereau Bertrand 
Published: February 2025

SummaryBeta-propeller protein-associated neurodegeneration (BPAN) is a rare neurological disease characterized by severe cognitive and motor impairments. BPAN is caused byde novopathogenic variants in theWDR45gene on the X chromosome.WDR45gene encodes the protein WDR45/WIPI4, a known regulator of autophagy. A defective autophagy has been observed in cellular models of BPAN disease and is associated with neurological dysfunctions inWDR45knockout (KO) mice. However, it remains unclear whether the autophagic defect directly contributes to all WDR45 loss-induced phenotypes or whether other WDR45-dependent cellular functions are involved. To investigate this, we generated a CRISPR/Cas9-mediated KO ofCG11975(dwdr45KO), theDrosophilahomolog ofWDR45. Our analysis revealed thatdwdr45KO flies display BPAN-like phenotypes, including impaired locomotor function, autophagy dysregulation and iron dyshomeostasis. Additionally,dwdr45KO flies exhibit shorten lifespan compared to control flies. These findings demonstrate thatdwdr45KO fly is a relevant model for investigating the key cellular and molecular mechanisms underlying BPAN-associated phenotypes. Notably, induction of autophagy indwdr45KO flies partially rescued the shortened lifespan, but did not restore locomotor function. This suggests that defective autophagy contributes to some, but not all, aspects of the phenotypes resulting from loss ofdwdr45function.
A truncation library for the soluble production of squalene synthase fromCandida albicansinEscherichia coli
Authors: Tolmie Carmien , Opperman Diederik J. 
Published: February 2025

AbstractThe rising global burden of infectious fungal disease and the steady increase of resistance by fungal pathogens to available treatments necessitate a concerted effort to develop new antifungal medicines. Squalene synthase is a critical enzyme in the synthesis of ergosterol, a fungal-specific sterol, and has not yet been exploited as an antifungal drug target for pathogenic yeast. In this study, we heterologously produce squalene synthase (SQS) from the opportunistic pathogenCandida albicansinEscherichia colito obtain high-quality pure protein for structural studies. A library of nine C- or N&C-terminally truncated SQS variants was successfully produced and purified with immobilised metal-affinity chromatography (IMAC). Two variants were upscaled and purified to near-homogeneity, but size-exclusion chromatography showed possible aggregation. Nevertheless, this study provides a starting point to further optimise buffer conditions to produce high-quality heterologous SQS fromC. albicansfor downstream crystallography experiments.
I helix Mediates the Allosteric Regulation in Cytochrome P450cam
Authors: Sahil Mohammad , Mondal Jagannath 
Published: February 2025

AbstractCytochrome P450cam, a key monooxygenase in the P450 superfamily, is pivotal in metabolic and industrial processes. Despite extensive studies, a unified mechanism governing its conformational heterogeneity, substrate-dependent allostery, and multi-substrate binding remains elusive. Here, integrating molecular dynamics simulations, NMR pseudocontact shift (PCS) analysis, and crystallographic data, we identify the I-helix (αI) as the central regulator of P450cam’s allostery. Its intrinsic flexibility, dictated by glycine residues (G248 and G249), orchestrates enzyme conformational dynamics. Specifically,αI transitions betweenstraightandkinkedconformations, modulating the opening and closing of substrate access channels (channel-1 and channel-2) and mediating allosteric communication between active and allosteric sites. Substrate binding stabilizes thestraightconformation, promoting channel closure and enhancing allosteric regulation. This I-helix-based mechanism reconciles 125 crystallographic poses, spanning straight-to-kinkedαI conformations. Notably, the kink-inducing glycine G249 is evolutionarily conserved across species, including humans, underscoringαI’s fundamental role in enzyme function and broader significance within the P450 superfamily. NMR PCS measurements align with the kinked and straight conformations in the substrate-free and substrate-bound states, with Q-scores of 0.108 and 0.061, respectively. Leveraging this mechanistic insight, we designed proof-of-concept P450cam mutants locked in either constitutively open or closed conformations for the first time. By shifting the focus from the traditional FG-helix-centric view to an I-helix-centric framework, this study provides a comprehensive blueprint for conformational and allosteric regulation, paving the way for engineering tailored P450 variants.
Applications of Artificial Intelligence in Neurosurgical Education: A Scoping Review
Authors: Piñera-Castro Hector Julio , Borges-García Christian 
Published: February 2025

ABSTRACTBackgroundArtificial intelligence (AI) has revolutionized medical education due to its capacity to optimize instruction, assess competencies, and tailor learning. Given the interdisciplinary nature and transformative potential of AI, its integration into neurosurgical education merits thorough examination.ObjectiveTo evaluate systematically the applications of AI in neurosurgical education.MethodsA scoping review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. Original observational and experimental studies published in peer-reviewed journals that investigated the use of AI in neurosurgical education were included. The search was carried out in Scopus up to May 2024, and studies not written in English or Spanish were excluded. The selection process and data extraction were performed independently by two reviewers. A narrative synthesis approach was employed.ResultsTwenty-three studies were selected, identifying four main areas. In board examination performance, advanced models like ChatGPT-4 outperformed previous versions and residents in answering neurosurgical exam questions, achieving higher accuracy in complex theoretical and image-based inquiries. In simulation training and tutoring, neural networks analyzed surgical simulation data, classifying participants by expertise levels and providing individualized, metric-based feedback that improved technical skills and identified distinct learning patterns among trainees. In performance evaluation, machine learning techniques assessed surgical skills during simulations with high accuracy, identifying key behavioral metrics associated with expertise. Other innovative applications included AI for neuroanatomical segmentation in imaging studies, analysis of surgical instrument utilization patterns through computer vision, and generation of academic content. These studies highlighted AI’s multifaceted roles and ethical considerations, such as overreliance risks and the need for robust databases and realistic simulations.ConclusionsAI has enhanced neurosurgical education by improving knowledge assessment, simulation training, and performance evaluation. Despite its transformative potential, ethical and technical challenges persist. The continuous development of AI models and their responsible implementation are recommended to further optimize neurosurgical training and ensure safe integration into educational curricula.
Circulating causal protein networks linked to future risk of myocardial infarction
Authors: Bankier Sean , Gudmundsdottir Valborg , Jonmundsson Thorarinn , Bjarnadottir Heida , Loureiro Joseph , Wang Lingfei , Finkel Nancy , Orth Anthony P , Aspelund Thor , Launer Lenore J , Björkegren Johan LM , Jennings Lori L , Lamb John R , Gudnason Vilmundur , Michoel Tom , Emilsson Valur 
Published: February 2025

AbstractVariations in blood protein levels have been associated with a broad spectrum of complex diseases, including atherosclerotic cardiovascular disease (ACVD). These associations highlight the intricate interplay between local (e.g., cardiovascular) and systemic (non-cardiovascular) factors for the development of ACVD, emphasizing the need for a comprehensive, systems-level understanding of its etiology. To accomplish this, we developed a causal network inference framework by analyzing one of the largest serum proteomics studies to date, the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES), a prospective population-based study of 7,523 serum proteins measured in 5,376 older adults. To reconstruct a causal network of serum proteins, we usedcis-acting protein quantitative trait loci (pQTLs) as instrumental variables to infer causal relationships between protein pairs, while accounting for potential unobserved confounding factors. We identified 185 causal protein subnetworks (FDR = 1%, n ≥ 10 members), which collectively interacted with 5,611 target proteins, offering valuable biological insights and an overview of systemic homeostasis. Several subnetworks, many of which interact to establish a hierarchy of directional relationships, were significantly associated with future myocardial infarction and/or its long-term complications like heart failure, as well as with key cardiometabolic traits that contribute to the onset of ACVD.
The impact of deprivation and neighbourhood food environments on home food environments, parental feeding practices, and child eating behaviours, food preferences and BMI: The Family Food Experience Study-London
Authors: Smith Andrea , Kininmonth Alice , Tommerup Kristiane , Boniface David , Gericke Chiara , Denning Tiffany , Summerbell Carolyn , Vogel Christina , Llewellyn Clare 
Published: February 2025

PurposeChildhood obesity inequalities in England persist despite targeted interventions focused on promoting healthy diets and food environments. This study, part of the Family Food Experience Study-London, aimed to investigate the impact of deprivation and neighbourhood food environments on home food environments, parental feeding practices, child eating behaviours, food preferences, and child BMI.MethodsFamilies (n=728) with primary school-aged children were recruited from four socioeconomically diverse London boroughs in 2022. Data were collected through computer-assisted interviews (30.8% in-person, 69.2% telephone) on home food environment, parental feeding practices, and children’s eating behaviours and food preferences. Deprivation was characterised using a composite measure of family and neighbourhood indicators of socioeconomic position. Neighbourhood food environment exposures were derived from individualised activity spaces. Child BMI was measured objectively. Generalised linear models examined associations between deprivation and neighbourhood food environment with family food-related outcomes, adjusting for school-level clustering, child sex, age and ethnicity.ResultsGreater neighbourhood deprivation was significantly associated with more ‘obesogenic’ family food practices, child eating behaviours and child BMI. Deprivation was linked to higher food responsiveness (β=-0.12, p=0.002), emotional overeating (β=-0.11, p <0.001), and increased desire to drink (β=-0.26, p <0.001). Parents in deprived households used more emotional (β=-0.10, p<0.05), instrumental (β=-0.11, p=0.003) and pressuring feeding practices (β=-0.14, p<0.001). Greater deprivation was also associated with a more obesogenic home food environment (β=-0.19, p<0.001) and lower meal structure (β= 0.17, p<0.001). Exposure to less healthy neighbourhood food environments around and between home and school were associated with a more obesogenic home food environment (β=-0.07, p<0.01), but no significant associations were found with feeding practices or child eating behaviours or child BMI.ConclusionsFamily deprivation, rather than neighbourhood food environments, is more strongly linked to obesogenic feeding practices, child eating behaviours and child BMI. Policies focusing on improving neighbourhood food environments will likely be most effective if combined with those addressing systemic issues related to deprivation such as welfare policies (e.g. reforms to benefit caps) or targeted subsidies for healthy food. Future research should examine the independent and accumulative impact that environment and household interventions have on childhood obesity inequalities.
Exercise Crystal: simulations that drive National IHR Focal Point capacity strengthening
Authors: Goddard Laura , Khut Qiu Yi , Samaan Gina 
Published: February 2025

ABSTRACTThe International Health Regulations (IHR 2005) require States Parties to designate a National IHR Focal Point (NFP) for timely IHR communications with the World Health Organization (WHO) and, following recent amendments, to designate a National IHR Authority to coordinate IHR implementation within States Parties. Since 2008, the WHO Regional Office for the Western Pacific has been supporting the strengthening and testing of NFP functionality through an annual simulation exercise known as IHR Exercise Crystal. This study analyses NFP performance during IHR Exercise Crystal over a 16-year period to inform Member States’ planning for NFP capacity strengthening, in the context of the recent IHR amendments. Exercise monitoring data were analysed using descriptive statistics across six key NFP performance indicators. Findings show consistently high NFP accessibility via email (mean: 99%) but suboptimal NFP accessibility via telephone (mean: 64%). NFP participation in tele- and videoconferences improved over time (mean: 73%), as did the proportion of NFPs notifying WHO of simulated events (mean: 80%) and contributing information to Event Information Site postings (mean: 77%). Multisectoral communication remained variable with no clear trend (mean: 73%). This demonstrates that significant progress has been made and that opportunities remain to further enhance NFP functionality, particularly in the areas of NFP accessibility and multisectoral coordination. It is critical that States Parties continue strengthening and testing NFP functionality through simulation exercises and other capacity-building to ensure effective IHR implementation. Furthermore, States Parties should develop, test and maintain up-to-date SOPs to support the clear demarcation of roles and responsibilities between the NFP and the National IHR Authority.
Practice-level variation in the provision of subsidized dental services to adult Danes in 2019: A register-based study
Authors: Raittio Eero , Baelum Vibeke 
Published: February 2025

AbstractObjectivesThe aim was to investigate practice-level variation in common dental diagnostic, preventive, and care services provided for Danish adults who underwent a dental examination.MethodsThis was a nationwide register-based study. Subsidized dental services delivered during the 13-week-period subsequent to the provision of one of three eligible dental examinations (extended, basic, or recall examination) during the first nine months of 2019 were investigated. Bayesian multilevel regression models were used to estimate the practice-level average predicted probability of supragingival care, subgingival care, individual prevention, bitewing radiographs, and endodontic treatment, and the average predicted count of extractions and direct restorations while adjusting for individual sociodemographics and dental treatments received during the previous 10 years.ResultsThe final sample included 445,516 examinations conducted in 1,593 dental practices. Supragingival care after basic or recall examinations showed the lowest practice-level variation, with around two-fold difference between top and bottom 2.5%. Individual preventive services after recall examinations showed the highest variation with over 30-fold difference between top and bottom 2.5%. All other outcomes showed around 3- to 8-fold differences between practices at top and bottom 2.5% across all examination types. The differences across practices were smaller—1.2- to 3.0-fold—when the top 25% and bottom 25% were compared instead.ConclusionsThis study found considerable variation in diagnostic, preventive, and treatment services provided for Danish adults who underwent a dental examination. The findings highlight the need for research that can inform evidence-based practice through the development of quality clinical practice guidelines, continuing education programs, and closer surveillance of care delivery.
Nim1-related kinases regulate septin organization and cytokinesis by modulating Hof1 at the cell division site
Authors: Bhojappa Bindu , Dhar Anubhav , VT Bagyashree , Kumari Jayanti , Cardozo Freya , Rizvi Vaseef , Palani Saravanan 
Published: February 2025

ABSTRACTThe septin scaffold recruits and organizes the actomyosin ring (AMR) components, thus ensuring faithful cytokinesis. The septin-associated kinases - Elm1, Gin4, Hsl1, and Kcc4 are believed to stabilize the septins at the bud neck, but the underlying mechanisms are largely unknown. Here, we present a comprehensive, quantitative analysis of these four septin regulatory kinases and reveal major roles for Elm1 and Gin4 in septin stability. We find that Elm1 and Gin4 play an overlooked role in actomyosin ring organization and constriction. We report that Gin4 kinase directly interacts with F-BAR protein Hof1 via its C-terminal membrane-binding domain and may be involved in proper organization and anchoring of AMR component Hof1 at the bud neck, representing an unappreciated mode of regulation of cytokinesis by the septin kinase network. We also show that Gin4 controls septin organisation and AMR constriction in a kinase-independent manner similar to Elm1. We have also performed an extensive GFP-GBP-based tethering screen in Δelm1and Δgin4cells and found an important role for Hsl1 in maintaining septin organisation and cell shape in coordination with Elm1, Gin4, and Kcc4. Furthermore, our data indicate that Hsl1 acts downstream of Elm1, with its membrane-binding KA1 domain being critical for its function. Together, these findings reveal new insights into modes of cytokinesis regulation by kinases Gin4 and Elm1 and highlight a redundant role for Hsl1 in controlling septin organization and cytokinesis, revealing the in-built adaptability of the septin kinase network inS. cerevisiae.
stDyer-image improves clustering analysis of spatially resolved transcriptomics and proteomics with morphological images
Authors: Xu Ke , Zhou Xin Maizie , Zhang Lu 
Published: February 2025

AbstractSpatially resolved transcriptomics (SRT) and spatially resolved proteomics (SRP) data enable the study of gene expression and protein abundances within their precise spatial and cellular contexts in tissues. Certain SRT and SRP tech-nologies also capture corresponding morphology images, adding another layer of valuable information. However, few existing methods developed for SRT data effectively leverage these supplementary images to enhance clustering performance. Here, we introduce stDyer-image, an end-to-end deep learning framework designed for clustering for SRT and SRP datasets with images. Unlike existing methods that utilize images to complement gene expression data, stDyer-image directly links image features to cluster labels. This approach draws inspiration from pathologists, who can visually identify specific cell types or tumor regions from morphological images without relying on gene expression or protein abundances. Benchmarks against state-of-the-art tools demonstrate that stDyer-image achieves superior performance in clustering. Moreover, it is capable of handling large-scale datasets across diverse technologies, making it a versatile and powerful tool for spatial omics analysis.
Topological conditions of gene regulatory networks enabling robust binary cell-fate decision-making
Authors: Shyam Sai , Nandan Nikhil , Jolly Mohit Kumar , Hari Kishore 
Published: February 2025

AbstractEmbryonic development entails multi-layer branching of cell-fate decision processes; often, each branch corresponding to a binary cell-fate decision. The two phenotypes at such branching points usually have mutually exclusive gene expression patterns, driven by two master regulators that mutually inhibit each other and can activate themselves, forming a toggle switch. The dynamics of a toggle switch have been extensively studied, however, the regulatory networks underlying cell-fate decision often involve many transcription factors. We recently showed that these networks can be organized as two mutually inhibiting “teams of nodes”, such that the nodes of the same team predominantly activate themselves, while those of the opposite teams primarily inhibit each other. While the ideal cases of fully connected and consistent networks of two “teams of nodes” have been well-understood, a detailed understanding of the effect of varying levels of connectivity and inconsistency in the edges with respect to the configuration of teams is lacking. Here, we simulate networks of two-teams (TTN) under varying degrees of edge density, edge impurity and external influence to identify the conditions under which these networks can give rise to a robust binary cell-fate decision system. We find that the emergent cell-fate decision landscape is much more sensitive to inconsistent edges than to low connectivity, and that TTN generally lead to a more robust landscape than a toggle switch in the context of buffering external perturbations. Our results offer insights into the design principles of gene regulatory networks engaged in binary cell-fate decisions and can be extended to evaluate strategies for cellular reprogramming.
Elucidation andde novoReconstitution of Glyceollin Biosynthesis
Authors: Sun Yunlong , Chen Cong , Lin Chao , Zhang Hao , Lian Jiazhang , Hong Benke 
Published: February 2025

AbstractGlyceollins are phytoalexins produced by soybeans in response to stressors such as pathogen invasion, injury, and environmental challenges. In addition to their antibacterial and antifungal activities, these compounds have attracted significant attention for their potential anticancer, anti-inflammatory, and antioxidant properties. However, their limited accessibility-due to the challenges and high costs associated with organic synthesis or purification from treated soybean seedlings-has hindered further physiological and biochemical studies. Moreover, the incomplete understanding of glyceollin biosynthesis, particularly the final cyclization steps, remains a major barrier to elucidating their physiological functions and achieving sustainable production through synthetic biology. In this study, we identified previously uncharacterized genes encoding two reductases for 7,2’,4’-trihydroxy-isoflavanol (THI) synthesis and five P450 enzymes responsible for the final oxidative cyclization in glyceollins I, II, and III biosynthesis, thereby completing the entire biosynthetic pathway. By reconstructing the pathwayde novothrough synthetic biology, we achieved the successful production of glyceollins from simple carbon sources in Baker’s yeast. This work advances understanding of glyceollin biosynthesis, facilitates sustainable production in microbial hosts and offers new opportunities for their applications in agriculture and biology.