bluuebunny/crossref_metadata_2025 huggingface dataset:
Complexity of chess domination problems
Authors: Langlois-Rémillard Alexis , Müssig Mia , Roldán Érika
Published: February 2025

We study different domination problems of attacking and non-attacking rooks and queens on polyominoes and polycubes of all dimensions. Our main result proves that maximum independent domination is NP-complete for non-attacking queens and for non-attacking rooks on polycubes of dimension three and higher. We also analyze these problems for polyominoes and convex polyominoes, conjecture the complexity classes, and provide a computer tool for investigation. We have also computed new values for classical queen domination problems on chessboards (square polyominoes). For our computations, we have translated the problem into an integer linear programming instance. Finally, using this computational implementation and the game engine Godot, we have developed a video game of minimum domination of queens and rooks on randomly generated polyominoes.
Australian guidance documents informing nature playspaces for children: a scoping review
Authors: Dankiw Kylie A. , Miller Nicole C. , Kumar Saravana , Baldock Katherine L. , Tsiros Margarita D.
Published: February 2025

In Australia, the absence of standard practice guidelines for nature playspace development prompts reliance on guidance documents from government agencies and nature play advocacy groups, posing challenges for end-users. Therefore, the aims of this review were to map recommendations for nature playspace creation/planning, design, implementation, and management within the Australian context. Ten databases and grey literature sources were searched from inception to August 2023, with inclusion criteria focusing on children aged < 18 years, recommendations describing nature playspace creation/planning, design, implementation, and management within the context of Australian outdoor playspace settings. Data extraction was performed in duplicate to identify recommendations for the creation, planning, design, implementation, and management of nature play spaces, followed by a descriptive synthesis of these recommendations. Out of 7,123 articles, 10 met inclusion criteria. The types of documents included were reports, general guides and one regulatory guideline. Nature play was described diversely, with commonalities in elements like trees, water, and plants, but inconsistencies in development approaches led to recommendations lacking clarity and detail. There was a lack of explicit detail regarding development context, suggesting a need for context-specific guidelines. While the included guidance documents provide initial frameworks for guiding nature play, they lack comprehensive, evidence-based recommendations for diverse contexts. Future research should focus on creating standard practice recommendations to ensure safe, age-appropriate, inclusive nature playspaces promoting health and developmental outcomes.
Superreflexive tensor product spaces
Authors: Rueda Zoca Abraham
Published: February 2025

The aim of this note is to prove that, given two superreflexive Banach spaces X and Y, then

$$X\widehat{\otimes }_\pi Y$$

X

⊗
^

π

Y

is superreflexive if and only if either X or Y is finite-dimensional. In a similar way, we prove that

$$X\widehat{\otimes }_\varepsilon Y$$

X

⊗
^

ε

Y

is superreflexive if and only if either X or Y is finite-dimensional.
Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics
Authors: Ma Xiao , Huang Tengda , Chen Xiangzheng , Li Qian , Liao Mingheng , Fu Li , Huang Jiwei , Yuan Kefei , Wang Zhen , Zeng Yong
Published: February 2025

Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
USP4-mediated CENPF deubiquitylation regulated tumor metastasis in colorectal cancer
Authors: Xie Zhongdong , Lin Hanbin , Wu Yuecheng , Yu Yanan , Liu Xintong , Zheng Yating , Wang Xiaojie , Wu Jiashu , Xu Meifang , Han Yuting , Zhang Qiongying , Deng Yu , Lin Lin , Linzhu Yan , Qingyun Li , Lin Xinjian , Huang Ying , Chi Pan
Published: February 2025

Metastasis is a major challenge for colorectal cancer (CRC) treatment. In this study, we identified autophagy activation as a prognostic indicator in CRC and observed that the expression of key autophagy proteins is elevated in metastatic and recurrent cases. Our subsequent goal was to identify potential genes associated with the autophagy panel and assess their prognostic significance, biological roles, and mechanisms in CRC metastasis. Among the candidates, CENPF emerged as the top gene in our screening process. We found that CENPF expression was preferentially elevated in CRC tissues compared to adjacent normal tissues, with significantly higher levels in CRC patients with tumor recurrence. Furthermore, a multicenter cohort study demonstrated that upregulated CENPF expression was strongly associated with poorer disease-free survival in CRC. Functional experiments showed that CENPF knockdown inhibited CRC cell invasion and metastasis both in vitro and in vivo. Intriguingly, we found CENPF undergoes degradation in CRC via the ubiquitination-proteasome pathway. Mechanistically, we observed that USP4 interacted with and stabilized CENPF via deubiquitination. Furthermore, USP4-mediated CENPF upregulation was critical regulators of metastasis of CRC. Examination of clinical samples confirmed that USP4 expression positively correlates with CENPF protein expression, but not mRNA transcript levels. Taken together, this study describes a novel USP4-CENPF signaling axis which is crucial for CRC metastasis, potentially serving as a therapeutic target and a promising prognostic biomarker for CRC.
Inhibition of lanosterol synthase linking with MAPK/JNK signaling pathway suppresses endometrial cancer
Authors: Ma Liangjian , Huang Wunan , Liang Xiaolei , Li Hongli , Yu Wei , Liu Lexin , Guan Yuelin , Liu Chang , Chen Xiangjun , Hu Lidan
Published: February 2025

Endometrial cancer (EC) is a significant health threat to women, with recurrence after treatment posing a major challenge. While abnormal cholesterol metabolism has been implicated in EC progression, the underlying mechanisms remain unclear. In this study, we identified lanosterol synthase (LSS) as a key mediator in cholesterol metabolism associated with EC. We found that LSS is significantly upregulated in EC tissues. Functional assays revealed that LSS promotes cell proliferation and migration, inhibits apoptosis, and drives tumor growth in vivo. Mechanistically, LSS exerts dual effects by accumulating cholesterol esters, thereby enhancing EC cell growth, and activating the MAPK/JNK signaling pathway. Importantly, inhibition of LSS with the specific inhibitor Ro 48-8071 not only reduced EC cell proliferation and suppressed xenograft tumor growth but also inhibited the growth of patient-derived tumor-like cell clusters (PTCs). These findings establish LSS as a novel oncogene in EC, promoting tumor progression through MAPK/JNK signaling activation and cholesterol ester accumulation, and highlight the therapeutic potential of targeting LSS in EC treatment.
Polarity-JaM: an image analysis toolbox for cell polarity, junction and morphology quantification
Authors: Giese Wolfgang , Albrecht Jan Philipp , Oppenheim Olya , Akmeriç Emir Bora , Kraxner Julia , Schmidt Deborah , Harrington Kyle , Gerhardt Holger
Published: February 2025

Cell polarity involves the asymmetric distribution of cellular components such as signalling molecules and organelles within a cell, alterations in cell morphology and cell-cell contacts. Advances in fluorescence microscopy and deep learning algorithms open up a wealth of unprecedented opportunities to characterise various aspects of cell polarity, but also create new challenges for comprehensible and interpretable image data analysis workflows to fully exploit these new opportunities. Here we present Polarity-JaM, an open source package for reproducible exploratory image analysis that provides versatile methods for single cell segmentation, feature extraction and statistical analysis. We demonstrate our analysis using fluorescence image data of endothelial cells and their collective behaviour, which has been shown to be essential for vascular development and disease. The general architecture of the software allows its application to other cell types and imaging modalities, as well as seamless integration into common image analysis workflows, see https://polarityjam.readthedocs.io. We also provide a web application for circular statistics and data visualisation, available at www.polarityjam.com, and a Napari plug-in, each with a graphical user interface to facilitate exploratory analysis. We propose a holistic image analysis workflow that is accessible to the end user in bench science, enabling comprehensive analysis of image data.
Unravelling single-cell DNA replication timing dynamics using machine learning reveals heterogeneity in cancer progression
Authors: Josephides Joseph M. , Chen Chun-Long
Published: February 2025

Genomic heterogeneity has largely been overlooked in single-cell replication timing (scRT) studies. Here, we develop MnM, an efficient machine learning-based tool that allows disentangling scRT profiles from heterogenous samples. We use single-cell copy number data to accurately perform missing value imputation, identify cell replication states, and detect genomic heterogeneity. This allows us to separate somatic copy number alterations from copy number changes resulting from DNA replication. Our methodology brings critical insights into chromosomal aberrations and highlights the ubiquitous aneuploidy process during tumorigenesis. The copy number and scRT profiles obtained by analysing >119,000 high-quality human single cells from different cell lines, patient tumours and patient-derived xenograft samples leads to a multi-sample heterogeneity-resolved scRT atlas. This atlas is an important resource for cancer research and demonstrates that scRT profiles can be used to study replication timing heterogeneity in cancer. Our findings also highlight the importance of studying cancer tissue samples to comprehensively grasp the complexities of DNA replication because cell lines, although convenient, lack dynamic environmental factors. These results facilitate future research at the interface of genomic instability and replication stress during cancer progression.
An ontology-based rare disease common data model harmonising international registries, FHIR, and Phenopackets
Authors: Graefe Adam S. L. , Hübner Miriam R. , Rehburg Filip , Sander Steffen , Klopfenstein Sophie A. I. , Alkarkoukly Samer , Grönke Ana , Weyersberg Annic , Danis Daniel , Zschüntzsch Jana , Nyoungui Elisabeth F. , Wiegand Susanna , Kühnen Peter , Robinson Peter N. , Beyan Oya , Thun Sylvia
Published: February 2025

Although rare diseases (RDs) affect over 260 million individuals worldwide, low data quality and scarcity challenge effective care and research. This work aims to harmonise the Common Data Set by European Rare Disease Registry Infrastructure, Health Level 7 Fast Healthcare Interoperability Base Resources, and the Global Alliance for Genomics and Health Phenopacket Schema into a novel rare disease common data model (RD-CDM), laying the foundation for developing international RD-CDMs aligned with these data standards. We developed a modular-based GitHub repository and documentation to account for flexibility, extensions and further development. Recommendations on the model’s cardinalities are given, inviting further refinement and international collaboration. An ontology-based approach was selected to find a common denominator between the semantic and syntactic data standards. Our RD-CDM version 2.0.0 comprises 78 data elements, extending the ERDRI-CDS by 62 elements with previous versions implemented in four German university hospitals capturing real world data for development and evaluation. We identified three categories for evaluation: Medical Data Granularity, Clinical Reasoning and Medical Relevance, and Interoperability and Harmonisation.
Neurocognitive dynamics and behavioral differences of symmetry and asymmetry processing in working memory: insights from fNIRS
Authors: Sztuka Izabela Maria , Kühn Simone
Published: February 2025

Symmetry is a ubiquitous property of the visual world. It facilitates cognitive processing and fosters aesthetic appeal. Despite its importance to aesthetic experience and perceptual prominence, the integration of symmetry in working memory remains underexplored. In our study, participants engaged in a novel working memory task involving both symmetrical and asymmetrical stimuli, while their brain activity was monitored using functional Near Infrared Spectroscopy (fNIRS). The study revealed that symmetry significantly enhances memory performance. Symmetry significantly improves task performance, with symmetrical stimuli leading to higher accuracy and faster recall than asymmetrical ones, especially under high cognitive load. This effect varies with the type of symmetry, with diagonal symmetry being the most effective. Neuroimaging data showed distinct brain activation patterns when participants processed symmetrical stimuli, particularly in the memory-straining condition. Significant differences in brain activity were observed in various brain regions, with lateral occipital, posterior parietal, medial and dorsolateral prefrontal cortices reacting to symmetry with decreased oxygenated hemoglobin (HbO), while in left orbitofrontal (HbO) and right ventrolateral prefrontal cortex (HbO and HbR) hemoglobin concentration increased. Overall, our findings highlight the complex, region-specific brain activation patterns in response to visual symmetry, emphasizing the nuanced role of symmetry in cognitive processing during memory tasks and their potential implication for creative thinking.
Looking outside the box with a pathology aware AI approach for analyzing OCT retinal images in Stargardt disease
Authors: Khateri Parisa , Koottungal Tiana , Wong Damon , Strauss Rupert W. , Janeschitz-Kriegl Lucas , Pfau Maximilian , Schmetterer Leopold , Scholl Hendrik P. N.
Published: February 2025

Stargardt disease type 1 (STGD1) is a genetic disorder that leads to progressive vision loss, with no approved treatments currently available. The development of effective therapies faces the challenge of identifying appropriate outcome measures that accurately reflect treatment benefits. Optical Coherence Tomography (OCT) provides high-resolution retinal images, serving as a valuable tool for deriving potential outcome measures, such as retinal thickness. However, automated segmentation of OCT images, particularly in regions disrupted by degeneration, remains complex. In this study, we propose a deep learning-based approach that incorporates a pathology-aware loss function to segment retinal sublayers in OCT images from patients with STGD1. This method targets relatively unaffected regions for sublayer segmentation, ensuring accurate boundary delineation in areas with minimal disruption. In severely affected regions, identified by a box detection model, the total retina is segmented as a single layer to avoid errors. Our model significantly outperforms standard models, achieving an average Dice coefficient of
$$99\%$$
for total retina and
$$93\%$$
for retinal sublayers. The most substantial improvement was in the segmentation of the photoreceptor inner segment, with Dice coefficient increasing by
$$25\%$$
. This approach provides a balance between granularity and reliability, making it suitable for clinical application in tracking disease progression and evaluating therapeutic efficacy.
Women are worse off in developing and recovering from temporomandibular disorder symptoms
Authors: Lövgren Anna , Vallin Simon , Häggman-Henrikson Birgitta , Kapos Flavia P. , Peck Christopher C. , Visscher Corine M. , Liv Per
Published: February 2025

Decision-making for temporomandibular disorders (TMDs) is reported being a clinical challenge, partly due to uncertainities in assessment of long-term prognosis. Therefore, our aim was to explore variations over time in TMD symptoms and possible sex or age differences. In this cohort study, data were prospectively collected 2010–2017 from the general population in Västerbotten, Northern Sweden. Adults were eligible if they had undergone at least two routine dental check-ups that included screening for TMDs (3Q/TMD) from which states were defined as absence or presence of TMD pain and/or jaw catching/locking. The rate of transitions was estimated between TMD states within a time span of one year. A total of 94,769 individuals were included (49.9% women) with 205,684 repeated visits and 9,006 state transitions recorded over the 8-year period. Compared to men, women had higher rates of transitions from no TMDs to any TMD symptoms. Furthermore, women had a lower rate of transition from TMD pain only to no TMDs. The finding of a poorer prognosis in women, as well as previously reported potential gender differences in pain perception and reporting, reinforces that gender differences should be accounted for in the treatment planning stage for patients with onset of TMDs.
Perceived coercion amongst healthcare workers during the COVID-19 pandemic
Authors: Stoltenberg Andrea S. , Ranieri Veronica , Dahlen Hege Kristine N. , Nastouli Eleni ,   SAFER Investigators, Byott Matt , Edwards Sarah J. L. , Frampton Daniel , Gilson Richard , Hayward Andrew , Heaney Jude , Houlihan Catherine , Lorencatto Fabiana , Manley Ed , Michie Susan , Spyer Moira , Vora Nina , Walker Naomi , Nastouli Eleni , Almvik Roger , Edwards Sarah J. L. , Kamboj Sunjeev K.
Published: February 2025

Direct and prolonged exposure to stress and uncertainty among healthcare workers (HCWs) during the COVID-19 pandemic likely had a significant negative impact on their mental health and general wellbeing. Although the contributors to such distress remain to be fully understood, the construct of perceived coercion appears to be relevant. Among HCWs, perceived coercion is conceptualised as appraisals about lack of control/‘freedom to choose’ and pressure to perform patient-care duties in the context of unprecedented threat of contagion from patients. To improve our understanding of perceived coercion amongst HCWs, we developed a 10-item scale—the Pandemic-specific Perceived Coercion Scale for Healthcare Workers (PPCS-HCW) scale—designed to be adaptable and applicable for use in future mass-contagion emergencies. A preliminary (exploratory) factor analysis (N = 546) showed that relevant items coalesced around three factors—‘internal pressure’, ‘external pressure’ and ‘perceived coercion’, that partly overlap with previous conceptualisations of perceived coercion. The exploratory conceptual and psychometric structure was confirmed in a separate sample of HCWs from the UK and Norway (N = 483). On average, across the three PPCS-HCW scale factors, HCWs showed low levels of perceived coercion (M = 0.22 (95% CI [0.11, 0.33] on a − 3 to + 3 scale). However, cluster analysis identified three groups: low (− 1.09 (95% CI [− 1.20, − 0.99]), moderate (0.17 (95% CI [0.08, 0.25]) and high scoring (1.57 (95% CI [1.47, 1.67]) PPCS-HCW clusters. High scoring participants showed higher levels of psychological distress, avoidance coping and compassion fatigue. In summary, our findings suggest that perceived coercion is a relevant construct in understanding the adverse psychological impact of large-scale contagion emergencies on HCWs.
Prediction of buckling damage of steel equal angle structural members using hybrid machine learning techniques
Authors: Ho Nang Xuan , Le Tien-Thinh , Dinh The-Hung , Nguyen Van-Hai
Published: February 2025

This article deals with prediction of buckling damage of steel equal angle structural members using a surrogate model combining machine learning and metaheuristic optimization technique. In particular, a hybrid Artificial Intelligence (AI)-based model involving Artificial Neural Network (ANN) and Particle Swarm Optimization (PSO) was developed and calibrated for the problem at hand. For this purpose, a database concerning compression tests of steel equal angle structural members was constructed from available resources with geometry variables such as length, width, thickness, mechanical properties of materials such as yield strength and initial imperfections (i.e. residual peak stress and initial geometric imperfections) and critical buckling load of columns. The hybrid PSOANN model was adopted because its prediction capability is higher than the traditional technique – i.e. scaled conjugate gradient (SCG). Indeed, ANN trained by PSO delivered better performance in terms of RMSE, MAE, ErrorStD, R2 and Slope in comparison to ANN trained by SCG, for instance. RMSE decreases from 0.141 to 0.055; MAE decreases from 0.108 to 0.042; R2 increases from 0.749 to 0.959, when switching from ANN alone to hybrid PSOANN, respectively. Moreover, a Partial Dependence (PD) investigation was performed to interpret the “black-box” PSOANN model.
Evaluating the reflux suppression properties of Gaviscon Infant powder with different milk formulations using an in vitro model of the infant stomach
Authors: McLaughlin Fiona , Fisher Jeanine , Atherton Mark , Coyle Cathal
Published: February 2025

Gastroesophageal reflux (GER) is common in babies and infants and is characterized by effortless regurgitation (with or without vomiting), which is a common symptom of other infant conditions, including cow’s milk protein allergy (CMPA). Various milk formulations are commercially available to help manage GER and CMPA symptoms (extensively hydrolyzed [eHF], partially hydrolyzed [pHF], and amino-acid formulas [AAF]). We aimed to understand if an alginate product (Gaviscon Infant powder) worked as intended in the presence of different milk formulations. A previously evaluated artificial infant stomach model simulated an internal pressure-inducing reflux event (five reflux events performed at 5 min intervals). Suppression activity of Gaviscon Infant combined with eHF, pHF, and AAF was assessed by measuring the height that the refluxate event traveled up a tube mimicking the infant esophagus, alongside a benchmark unhydrolyzed formulation (uHF) with Gaviscon Infant and a negative control without Gaviscon Infant. Each experiment was repeated six times per formulation in a random order. Gaviscon Infant combined with each milk formulation produced a lower height of refluxate versus the negative control. When formulations combined with Gaviscon Infant were grouped by category (eHF, pHF, AAF), two or more products from each category showed a lower refluxate height than the benchmark (uHF). There was a significant difference in median refluxate height (p = 0.0011 in Wilcoxon rank sum test) when comparing Gaviscon Infant combined with eHF against Gaviscon Infant combined with pHF, AAF, or uHF (benchmark). Refluxate height did not change significantly between events one and five for each milk formulation combined with Gaviscon Infant. In an artificial infant stomach model, Gaviscon Infant combined with different milk formulations (uHF, eHF, pHF, AAF) produced a lower refluxate height compared with a negative control (uHF without Gaviscon Infant), suggesting that Gaviscon Infant suppresses reflux as intended when used with different milk formulations.
Effect of Bio MTA plus & ProRoot MTA pulp capping materials on the regenerative properties of human dental pulp stem cells
Authors: Ayoub Khaled Mohamed , Nagy Mohamed Mokhtar , Aly Riham Mohamed , El Deen Ghada Nour , El-Batouty Karim
Published: February 2025

The aim of the present study was to investigate the effects of the biological properties of hDPSCs exposed to Bio MTA+ & ProRoot MTA pulp capping materials on the proliferation and odontogenic differentiation of hDPSCs. Human dental pulp stem cells (hDPSCs) were isolated from impacted third molars. Extracts of Bio MTA + and ProRoot MTA were prepared at a 1:1 ratio. The effects of the extracts on hDPSCs cytotoxicity and proliferation were assessed via a CCK-8 assay. Annexin V expression was investigated to assess the effects of both materials on the induction of apoptosis. The effects of ProRoot MTA and Bio MTA + extraction media on the stemness properties of hDPSCs were assessed via real-time quantitative PCR, and the expression of odontogenic markers (RUNX2, DMP1 & DSSP) was analyzed via RT‒PCR Alizarin Red staining. Cells exposed to Bio MTA + had the greatest degree of proliferation. The results of Annexin V staining indicated that Bio MTA + caused the least amount of apoptosis. RUNX2, DMP1 and DSSP were highly expressed by Bio MTA + and indicated successful odontogenic differentiation. Compared with ProRoot MTA, Bio MTA + exhibited an exceptional level of cytocompatibility, as well as advantageous bioactivities, including the preservation of stemness and an increase in the proliferation capacity of hDPSCs. In addition, it demonstrated favorable bioactive properties by stimulating odontogenic differentiation. Bio MTA + offers significant advantages in terms of biocompatibility, bioactivity, and regenerative potential, making it an excellent choice for procedures aimed at preserving or regenerating dental pulp tissue. However, additional research is required to address the lack of in vivo validation, as replicating physiological conditions is crucial for accurately assessing clinical outcomes and comparing them with results obtained from in vitro experiments.
Structured reporting of neuroendocrine tumors in PET/CT using [18F]SiTATE - impact on interdisciplinary communication
Authors: Hinterberger Anna , Trupka Lukas , Kortbein Sophia , Ebner Ricarda , Fink Nicola , Froelich Matthias F. , Nörenberg Dominik , Wängler Carmen , Wängler Björn , Schirrmacher Ralf , Holzgreve Adrien , Brendel Matthias , Corradini Stefanie , Auernhammer Christoph , Rübenthaler Johannes , Grawe Freba
Published: February 2025

Our retrospective single-center study aims to evaluate the impact of structured reporting (SR) using a self-developed template on report quality compared to free-text reporting (FTR) in [18F]SiTATE Positron Emission Tomography/Computer Tomography (PET/CT) for the primary staging and therapy monitoring of patients diagnosed with neuroendocrine tumors (NET). In total 50 patients were included. FTRs and SRs were generated post-examination. All reports were evaluated by a radiologist and a surgeon through a questionnaire to determine their contribution to facilitating clinical decision-making and to assess their completeness, linguistic quality, and overall quality. SR significantly increased the capacity of facilitating therapy decision-making from 32% in FTR to 55% in SR (p < 0.001). Trust in the report was significantly higher in SR with a mean of 5.0 (SD = 0.5) vs. 4.7 (SD = 0.5) for FTR (p < 0.001). SR received significantly higher mean ratings regarding linguistic quality with 4.7 for SR vs. 4.4 for FTR (p = 0.004) and overall report quality with a mean of 4.9 for SR vs. 4.6 for FTR (p < 0.001). Concluding that SR enhances the overall quality of reports in [18F]SiTATE-PET/CTs for NET staging, serving as a tool to streamline clinical decision-making and enhance interdisciplinary communication in the future.
Characterization of the genomic landscape of canine diffuse large B-cell lymphoma reveals recurrent H3K27M mutations linked to progression-free survival
Authors: van der Heiden Anna Darlene , Pensch Raphaela , Agger Sophie , Gardner Heather L. , Hendricks William , Zismann Victoria , Wong Shukmei , Briones Natalia , Turner Bryce , Forsberg-Nilsson Karin , London Cheryl , Lindblad-Toh Kerstin , Arendt Maja Louise
Published: February 2025

Diffuse large B-cell lymphoma (DLBCL) is an aggressive hematopoietic neoplasm that affects humans as well as dogs. While previous studies on canine DLBCL (cDLBCL) have significantly advanced our understanding of the disease, the majority of this research has relied on whole-exome sequencing, which is limited in its ability to detect copy number aberrations and other genomic changes beyond coding regions. Furthermore, many of these studies lack sufficient clinical follow-up data, making it difficult to draw meaningful associations between genetic variants and patient outcomes. Our study aimed to characterize the mutational landscape of cDLBCL using whole-genome sequencing of matched tumor-normal samples obtained from a cohort of 43 dogs previously enrolled in a clinical trial for which longitudinal follow-up was available. We focused on identifying genes that were significantly or recurrently mutated with coding point mutations, copy number aberrations, and their associations with patient outcomes. We identified 26 recurrently mutated genes, 18 copy number gains, and 8 copy number losses. Consistent with prior studies, the most commonly mutated genes included TRAF3, FBXW7, POT1, TP53, SETD2, DDX3X and TBL1XR1. The most prominent copy number gain occurred on chromosome 13, overlapping key oncogenes such as MYC and KIT, while the most frequent deletion was a focal loss on chromosome 26, encompassing IGL, PRAME, GNAZ, RAB36, RSPH14, and ZNF280B. Notably, our set of recurrently mutated genes was significantly enriched with genes involved in epigenetic regulation. In particular, we identified hotspot mutations in two histone genes, H3C8, and LOC119877878, resulting in H3K27M alterations predicted to dysregulate gene expression. Finally, a survival analysis revealed that H3K27M mutations in H3C8 were associated with increased hazard ratios for progression-free survival. No copy number aberrations were associated with survival. These findings underscore the critical role of epigenetic dysregulation in cDLBCL and affirm the dog as a relevant large animal model for interrogating the biological activity of novel histone-modifying treatment strategies.
Bioelectric stimulation outperforms brain derived neurotrophic factor in promoting neuronal maturation
Authors: Diego-Santiago María del Pilar , González María Ujué , Zamora Sánchez Esther María , Cortes-Carrillo Nuria , Dotti Carlos , Guix Francesc Xavier , Mobini Sahba
Published: February 2025

Neuronal differentiation and maturation are crucial for developing research models and therapeutic applications. Brain-derived neurotrophic factor (BDNF) is a widely used biochemical stimulus for promoting neuronal maturation. However, the broad effects of biochemical stimuli on multiple cellular functions limit their applicability in both in vitro models and clinical settings. Electrical stimulation (ES) offers a promising physical method to control cell fate and function, but it is hampered by lack of standard and optimised protocols. In this study, we demonstrate that ES outperforms BDNF in promoting neuronal maturation in human neuroblastoma SH-SY5Y. Additionally, we address the question regarding which ES parameters regulate biological responses. The neuronal differentiation and maturation of SH-SY5Y cells were tested under several pulsed ES regimes. We identified accumulated charge and effective electric field time as novel criteria for determining optimal ES regimes. ES parameters were obtained using electrochemical characterisation and equivalent circuit modelling. Our findings show that neuronal maturation in SH-SY5Y cells correlates with the amount of accumulated charge during ES. Higher charge accumulation (~ 50 mC/h) significantly promotes extensive neurite outgrowth and ramification, and enhances the expression of synaptophysin, yielding effects exceeding those of BDNF. In contrast, fewer charge injection to the culture (~ 0.1 mC/h) minimally induces maturation but significantly increases cell proliferation. Moreover, ES altered the concentration and protein cargo of secreted extracellular vesicles (EV). ES with large enough accumulated charge significantly enriched EV proteome associated with neural development and function. These results demonstrate that each ES regime induces distinct cellular responses. Increased accumulated charge facilitates the development of complex neuronal morphologies and axonal ramification, outperforming exogenous neurotrophic factors. Controlled ES methods are immediately applicable in creating mature neuronal cultures in vitro with minimal chemical intervention.
U-shaped association between TC/HDL-C ratio and osteoporosis risk in older adults
Authors: Zhao Chuanwei , Zhang Xiaochun , Zhang Xu , Zhao Bo , Yang Yane , Lin Mu , Qiao Wenli , Hu Zeyao , Yang Haijie
Published: February 2025

This study aimed to evaluate the association between the total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio and the risk of osteoporosis in older adults. A cross-sectional analysis was conducted using data from 7,465 individuals aged 60 and above from the 2005–2020 National Health and Nutrition Examination Survey (NHANES). The TC/HDL-C ratio was calculated and divided into quartiles. Osteoporosis was defined by self-reported physician diagnosis or dual-energy x-ray absorptiometry (DXA) measurements. Multivariable logistic regression models assessed the association between the TC/HDL-C ratio and osteoporosis prevalence. Restricted cubic splines were used to explore non-linear associations and threshold effects. Among the participants, 1,608 had osteoporosis. A higher TC/HDL-C ratio was inversely associated with osteoporosis (OR: 0.92, 95% CI: 0.86–0.99, p = 0.02). The analysis revealed a U-shaped association (p for nonlinearity = 0.005) with a threshold at 4.66. Below this threshold, the TC/HDL-C ratio was negatively associated with osteoporosis (OR: 0.83, 95% CI: 0.72–0.94, p = 0.010), while no significant association was observed above the threshold. In sex-specific analyses, a U-shaped relationship was found in women, with a threshold at 4.35 (p for nonlinearity = 0.0016), but no significant association was found in men. The TC/HDL-C ratio demonstrates a U-shaped association with osteoporosis risk in older adults, particularly in women. Further longitudinal studies are required to validate these findings and determine optimal lipid management strategies for osteoporosis prevention.
Comparison of CRISPR-Cas13b RNA base editing approaches for USH2A-associated inherited retinal degeneration
Authors: Fry Lewis E. , Major Lauren , Salman Ahmed , McDermott Lucy A. , Yang Jun , King Andrew J. , McClements Michelle E. , MacLaren Robert E.
Published: February 2025

CRISPR-Cas13 systems have therapeutic promise for the precise correction of point mutations in RNA. Using adenosine deaminase acting on RNA (ADAR) effectors, A-I base conversions can be targeted using guide RNAs (gRNAs). We compare the Cas13 effectors PspCas13b and Cas13bt3 for the repair of the gene USH2A, a common cause of inherited retinal disease and Usher syndrome. In cultured cells, we demonstrate up to 80% efficiency for the repair of the common c.11864 G > A and its murine equivalent c.11840 G > A, across different gRNAs and promoters. We develop and characterize a mouse model of Usher syndrome carrying the c.11840 G > A mutation designed for the evaluation of base editors for inherited retinal disease. Finally, we compare Cas13 effectors delivered via AAV for the repair of Ush2a in photoreceptors. Mean RNA editing rates in photoreceptors across different constructs ranged from 0.32% to 2.04%, with greater efficiency in those injected with PspCas13b compared to Cas13bt3 constructs. In mice injected with PspCas13b constructs, usherin protein was successfully restored and correctly localized to the connecting cilium following RNA editing. These results support the development of transcriptome targeting gene editing therapies for retinal disease.
Molecular optimization using a conditional transformer for reaction-aware compound exploration with reinforcement learning
Authors: Nakamura Shogo , Yasuo Nobuaki , Sekijima Masakazu
Published: February 2025

Designing molecules with desirable properties is a critical endeavor in drug discovery. Because of recent advances in deep learning, molecular generative models have been developed. However, the existing compound exploration models often disregard the important issue of ensuring the feasibility of organic synthesis. To address this issue, we propose TRACER, which is a framework that integrates the optimization of molecular property optimization with synthetic pathway generation. The model can predict the product derived from a given reactant via a conditional transformer under the constraints of a reaction type. The molecular optimization results of an activity prediction model targeting DRD2, AKT1, and CXCR4 revealed that TRACER effectively generated compounds with high scores. The transformer model, which recognizes the entire structures, captures the complexity of the organic synthesis and enables its navigation in a vast chemical space while considering real-world reactivity constraints.
Mackinawite partial oxidation to green rust produces a large, abiotic uranium isotope fractionation
Authors: Guilbaud Romain , Andersen Morten B. , Freeman Helen M. , Perez Jeffrey Paulo H. , Uhlig David , Benning Liane G.
Published: February 2025

Low-oxygen settings and transition zones between strictly anoxic and oxic conditions may have characterised large expanses of Precambrian continental margins, where oxygen-breathing, complex life emerged and diversified. Accurate reconstructions of oxygen levels in such conditions are therefore required, but current geochemical proxies fail in identifying transitional redox conditions. Uranium isotopes are an emerging palaeoredox proxy, as large isotope fractionations are recorded during the reduction of uranium into anoxic sediments. Their potential application to transitional conditions is, however, unclear, because the redox regulating mineralogy of such environments and the associated isotope fractionations are poorly constrained. Here, we explore the mineralogical transformations occurring during the partial oxidation of mackinawite. We show that green rust, a key mineral of Precambrian oceans, forms as a by-product of mackinawite oxidation, along with uraninite and polysulphide. We also demonstrate that this mechanism records a large abiotic uranium isotope fractionation during its reaction with aqueous iron sulphide.
Omega-3 PUFAs improve cognitive function in heat-stressed mice by enhancing autophagy via inhibition of the phosphorylation of the PI3K–Akt–mTOR pathway
Authors: Ren Zifu , Cai Mengyu , Liu Xinyao , Li Xin , Shi Wenjing , Lu Hongtao , Shen Hui , Miao Gen , Zhou Qicheng , Li Hongxia
Published: February 2025

The adverse effects of elevated temperatures on human health are becoming progressively severe.
Megamerger of porphyrin (phthalocyanine) with azulene-based graphene nanosheets for high-performance nonlinear optical materials
Authors: Zhang Ya Qing , Yang Cui-Cui , Li Li , Tian Wei Quan
Published: February 2025

The merger of appropriate functional groups provides a novel strategy for designing high-performance second and third order nonlinear optical materials.
Recent advances on electrocyclic reactions in complex natural product synthesis: an update
Authors: Chen Ruyi , Liu Yanlin , Ding Hanfeng
Published: February 2025

The recent advances on the application of electrocyclic reactions in the total synthesis of notable natural products are summarized.
Structural aspects of dimeric prodrug-based carrier-free nanomedicines for tumor chemotherapy
Authors: Yang Chen , Liu Peng
Published: February 2025

The effect of the flexible linker length in the dimeric prodrugs was explained by their aggregation structures and revealed through molecular dynamics simulation.
Highly efficient orange luminescence in Sn2+-doped Cs2AgInCl6 double perovskite with a large Stokes shift
Authors: Guo Jingrui , Guo Jing , Peng Yuchen , Wang Jiajia , Ma Weidan , Zhang Na , Zhang Yan , Liu Yufeng , Fang Yongzheng
Published: February 2025

Cs2AgInCl6:xSn2+ with orange luminescence exhibits a large Stokes shift (360 nm) and enhanced PLQY in the visible range. The fabricated WLED shows an appropriate CCT and high Ra, indicating its potential application in optoelectronic devices.
Impact of radiative accelerations on the stellar characterization of FGK-type stars using spectroscopic and seismic constraints
Authors: Moedas Nuno , Deal Morgan , Bossini Diego
Published: February 2025

Context. Chemical transport mechanisms are fundamental processes in stellar evolution models. They are responsible for the chemical distribution, and their impact determines how accurately we can characterize stars. Radiative accelerations are one of these processes. They allow the accumulation of elements at different depths in the star.

Aims. We aim to assess the impact of radiative accelerations on the modeling of FGK-type stars and their impact on the prediction of surface abundances.

Methods. To reduce the cost of the computation of radiative accelerations, we implemented the single-valued parameters (SVP) method in the stellar evolution code MESA. The SVP method is more efficient in calculating radiative accelerations, which enables computations of large enough grids of models for stellar characterization.

Results. Compared to models that include atomic diffusion (with only gravitational settling), the inclusion of radiative accelerations has a small effect on the inference of fundamental properties, with an impact of 2%, 0.7%, and 5% for mass, radius, and age. However, the treatment of radiative accelerations is necessary to predict the chemical composition of and accurately characterize stars.
Determinanten der Inanspruchnahme des Gesundheits-Check-ups von
älteren Erwachsenen in Sachsen-Anhalt: Welchen Einfluss hat der Zugang zur
Gesundheitsversorgung auf die Inanspruchnahme?
Authors: Kubat Denise , Epping Jelena , Stallmann Christoph , March Stefanie , Swart Enno
Published: February 2025

Aufgrund der demografischen Entwicklung besteht ein steigender Bedarf an
Präventionsmaßnahmen. In Deutschland haben gesetzlich krankenversicherte
Personen einen Anspruch auf Gesundheitsuntersuchungen zur Früherkennung von
bevölkerungsmedizinisch bedeutsamen Erkrankungen. Insbesondere die ältere
Bevölkerung nutzt diese Leistung bislang jedoch unzureichend, wodurch
bedeutende Präventionspotenziale verloren gehen. Ziel des Beitrages ist es,
den Einfluss des objektiven und subjektiv empfundenen Zugangs zur
Gesundheitsversorgung auf die Inanspruchnahme des Gesundheits-Check-ups bei
Einwohner*innen ab 55 Jahren in Sachsen-Anhalt zu untersuchen.

Als Datengrundlage dienen Daten einer schriftlichen Querschnittsbefragung von
Einwohner*innen aus vier groß- und kleinstädtischen Regionen
Sachsen-Anhalts. Zur Analyse der Daten wird nach deskriptiven Auswertungen
eine mehrstufige binär-logistische Regression verwendet, um den
statistischen Zusammenhang zwischen vier Zugangsparametern und der
Inanspruchnahme zu evaluieren.

In die Analysen wurden 953 Fragebögen eingeschlossen. 59,7% der Befragten
nahmen den Gesundheits-Check-up im empfohlenen Zeitintervall in Anspruch. Im
Rahmen der multivariaten Analysen konnte für die subjektive Zufriedenheit
mit dem Zugang und für die selbsteingeschätzten Reisezeiten zu
Hausärzt*innen kein signifikanter Einfluss auf die Inanspruchnahme
nachgewiesen werden. Die Zugehörigkeit zur gesetzlichen Krankenversicherung
und die Nutzung des eigenen Autos erhöhten hingegen die Chance einer
Inanspruchnahme. Als einflussreich erwiesen sich zudem das Einkommen und die
Pflegebedürftigkeit.

Die Untersuchung zeigt Steigerungspotenziale in der Inanspruchnahme des
Gesundheits-Check-ups bei älteren Menschen auf. Die Ergebnisse deuten jedoch
darauf hin, dass die aus Public Health-Perspektive notwendige Steigerung der
Teilnahmequote derzeit nicht über die Verbesserung der Zugänglichkeit
erfolgen kann, sondern an anderen Faktoren, wie der Einstellung gegenüber
den Check-ups, angesetzt werden muss, welches allerdings weiterer Analysen
bedarf.
Imaging of the postoperative spine
Authors: Kaur Simranjeet , Lalam Radhesh , Trivedi Rishi
Published: February 2025

There has been a significant increase in the number of spinal surgical procedures performed over the last few decades, resulting in a proportionate increase in the number of postoperative imaging studies.

An exhaustive literature search was performed along with consideration of various guidelines and expert opinions regarding postoperative spine imaging. Complications are divided into early (in the first few weeks) and delayed, depending on the time of onset. Some complications occurring in the early postoperative period are common for both the instrumented and non-instrumented spine. Delayed complications are specific to the type of surgery performed and have been described as such. This review discusses the normal postoperative appearance and the various early and delayed complications.

An understanding of the normal postoperative appearance is pertinent to distinguish normal from abnormal. A plain radiograph is the primary imaging modality for immediate postoperative assessment and long-term follow-up after spinal instrumentation. MRI with or without contrast is the imaging modality of choice for the evaluation of the postoperative spine. CT is the best modality for the assessment of the instrumented spine and status of bony fusion. Imaging assessment of the postoperative spine is complex and requires knowledge of key factors for interpretation like indications for the initial surgical procedure, type and approach of the surgical procedure, instrumentation used, time elapsed since surgery, and clinical complaints.