bluuebunny/crossref_metadata_2025_split huggingface dataset:
SpatialFormer: Universal Spatial Representation Learning from Subcellular Molecular to Multicellular Landscapes
Authors: Wang Jun , Huang Yuanhua , Winther Ole 
Published: January 2025

AbstractSpatial transcriptomics quantifies gene expression within its spatial context, significantly advancing biomedical research. Understanding gene spatial expression and the organization of multicellular systems is vital for disease diagnosis and studying biological processes. However, existing models often struggle to integrate gene expression data with cellular spatial information effectively. In this study, we introduce SpatialFormer, a hybrid framework combining convolutional networks and transformers to learn single-cell multimodal and multi-scale information in the niche context, including expression data and subcellular gene spatial distribution. Pre-trained on 300 million cell pairs from 12 million spatially resolved single cells across 62 Xenium slides, SpatialFormer merges gene spatial expression profiles with cell niche information via the pair-wise training strategy. Our findings demonstrate that SpatialFormer distills biological signals across various tasks, including single-cell batch correction, cell-type annotation, co-localization detection, and identifying gene pairs that are critical for the immune cell-cell interactions involved in the regulation of lung fibrosis. These advancements enhance our understanding of cellular dynamics and offer new pathways for applications in biomedical research.
Fate of a supergene in the shift from diploidy to polyploidy
Authors: Mora-Carrera Emiliano , Yousefi Narjes , Potente Giacomo , Stubbs Rebecca Lynn , Keller Barbara , Léveillé-Bourret Étienne , Stefan Grob , Celep Ferhat , Tedoradze Giorgi , Conti Elena 
Published: January 2025

ABSTRACTDespite the evolutionary importance of supergenes, their properties in polyploids remain unexplored. Polyploid genomes are expected to undergo chromosomal rearrangements and gene losses over time, potentially affecting supergene architecture. The iconic distyly supergene (S-locus), controlling a floral heteromorphism with two self-incompatible morphs, has been well-documented in diploids, but remains unknown in polyploids.Primula, the classic model for distyly since Darwin, is ancestrally diploid and distylous, yet polyploid, homostylous species with a single, self-compatible floral morph evolved repeatedly. The intraspecific loss of distyly is associated with small loss-of-function mutations in theS-locusCYPTgene controlling style length and female self-incompatibility. Over longer timescales, relaxed selection onCYPTshould generate greater accumulation of larger mutations, including exon and gene loss. By analyzing the first assembled genome of an allotetraploid, homostylous species (Primula grandis) in a comparative framework, we discovered two, nearly identicalS-locus alleles in the same subgenome, suggesting it originated via inter-specific hybridization between a homostylous and a distylous progenitor. Conformant to predictions from theory, the macroevolutionary loss of distyly coincided with considerable degeneration ofCYPT, while otherS-locus genes remained largely unaffected, suggesting the shift to homostyly preceded and facilitated polyploid establishment. At the whole-genome level, we found minimal subgenome dominance — as expected, given the inferred recent origin ofP. grandis— and highly reduced genetic diversity, congruently with its narrow distribution and self-compatibility. This study provides the first comparison of a supergene across ploidy levels and reproductive systems, contributing new knowledge on the previously unknown fate of supergenes in polyploids.SIGNIFICANCEThis study advances knowledge on genome evolution by elucidating how supergenes (clusters of tightly linked genes) evolve across species with different sets of chromosomes and reproductive systems. By analyzing the newly assembled genome of the polyploid, self-compatiblePrimulagrandis in a broad framework, we provide the first comparison of the distyly supergene between diploid outcrossers and polyploid self-fertilizers. We discovered one pair of identical supergene alleles in the same subgenome, rather than one pair per subgenome, revealing the species originated via a cross between a self-compatible and a self-incompatible progenitor. Conformant to theory, the gene controlling female self-incompatibility and style length (CYPT) was considerably degenerated, because of relaxed selection over time, with the rest of the supergene largely unaffected.
Inferring circadian rhythm disruptions in cancer using phase differences between clock genes
Authors: Zhang Ziang 
Published: January 2025

AbstractCircadian rhythms exist across various levels of biological activities, from molecular processes to behaviors. Circadian clock genes are closely linked to the onset and progression of cancer; however, systematic analysis of their rhythmic expression in human tumors is still lacking due to difficulties in time-series sampling. In this study, we examined and improved the method for inferring phase differences through clock gene co-expression to investigate circadian rhythms in timestamp-free samples. We found that the co-expression levels of rhythmic genes are primarily determined by phase differences and are influenced by the strength and tissue specificity of rhythmic expression. Thus, we identified evolutionarily conserved rhythmic genes across multiple tissues to construct tissue-specific phase difference matrices. On this basis, we developed a method for inferring phase difference variations and extended it to the single-sample level as ssDistance to evaluate circadian rhythm disruptions in tumors. The results showed that significant changes in phase differences between clock genes in tumors exhibit cancer-type specificity and have complex effects on patient survival. Results revealed that the significant alterations in phase differences between clock genes in tumors are cancer-type-specific and have complex effects on patient survival. This method provides an effective tool for studying circadian rhythms in large-scale public datasets lacking temporal information.
Isolation and Bioassay of Linear Veraguamides from a Marine Cyanobacterium (Okeania sp.)
Authors: Parker Stacy-Ann J. , Hough Andrea , Wright Thomas , Lax Neil , Faruk Asef , Fofie Christian K. , Simcik Rebekah , Cavanaugh Jane E. , Kolber Benedict J. , Tidgewell Kevin J. 
Published: January 2025

AbstractMarine cyanobacteria have gained momentum in recent years as a source of novel bioactive small molecules. This paper describes the structure elucidation and pharmacological evaluation of two new, veraguamide O (1) and veraguamide P (2), and one known, veraguamide C(3), analogs isolated from a cyanobacterial collection made in the Las Perlas Archipelago of Panama. We hypothesized that these compounds would be cytotoxic in cancer cell lines. The compounds were screened against HEK-293, estrogen receptor positive (MCF-7), and triple-negative breast cancer (MDA-MB-231) cells as well as against a broad panel of membrane bound receptors. The planar structures were determined based on NMR and MS data along with comparison to previously isolated veraguamide analogs. Phylogenetic analysis of the collection suggests it to be anOkeaniasp., a similar species to the cyanobacterium reported to produce other veraguamides. Veraguamide O shows no cytotoxicity (greater than 100 M) against ER positive cells (MCF-7) with 13 M IC50against MDA-MB-231 TNBC cells. Interestingly, these compounds show affinity for the sigma2/TMEM-97 receptor making them potential leads for development of non-toxic sigma 2 targeting ligands.
Tobacco smoke carcinogens exacerbate APOBEC mutagenesis and carcinogenesis
Authors: Durfee Cameron , Bergstrom Erik N. , Díaz-Gay Marcos , Zhou Yufan , Temiz Nuri Alpay , Ibrahim Mahmoud A. , Nandi Shuvro P. , Wang Yaxi , Liu Xingyu , Steele Christopher D. , Proehl Joshua , Vogel Rachel I. , Argyris Prokopios P. , Alexandrov Ludmil B. , Harris Reuben S. 
Published: January 2025

ABSTRACTMutations in somatic cells are inflicted by both extrinsic and intrinsic sources and contribute over time to cancer. Tobacco smoke contains chemical carcinogens that have been causatively implicated with cancers of the lung and head & neck1,2. APOBEC family DNA cytosine deaminases have emerged as endogenous sources of mutation in cancer, with hallmark mutational signatures (SBS2/SBS13) that often co-occur in tumors of tobacco smokers with an equally diagnostic mutational signature (SBS4)3,4. Here we challenge the dogma that mutational processes are thought to occur independently and with additive impact by showing that 4-nitroquinoline 1-oxide (NQO), a model carcinogen for tobacco exposure, sensitizes cells to APOBEC3B (A3B) mutagenesis and leads to synergistic increases in both SBS2 mutation loads and oral carcinomasin vivo. NQO-exposed/A3B-expressing animals exhibit twice as many head & neck lesions as carcinogen-exposed wildtype animals. This increase in carcinogenesis is accompanied by a synergistic increase in mutations from APOBEC signature SBS2, but not from NQO signature SBS4. Interestingly, a large proportion of A3B-catalyzed SBS2 mutations occurs as strand-coordinated pairs within 32 nucleotides of each other in transcribed regions, suggesting a mechanism in which removal of NQO-DNA adducts by nucleotide excision repair exposes short single-stranded DNA tracts to enzymatic deamination. These highly enriched pairs of APOBEC signature mutations are termeddidyma(Greek for twins) and are mechanistically distinct from other types of clustered mutation (omikliandkataegis). Computational analyses of lung and head & neck tumor genomes show that both APOBEC mutagenesis anddidymaare elevated in cancers from smokers compared to non-smokers. APOBEC signature mutations anddidymaare also elevated in normal lung tissues in smokers prior to cancer initiation. Collectively, these results indicate that DNA adducting mutagens in tobacco smoke can amplify DNA damage and mutagenesis by endogenous APOBEC enzymes and, more broadly, suggest that mutational mechanisms can interact synergistically in both cancer initiation and promotion.
Unlocking Antiviral Potentials of Traditional Plants: A Multi-Method Computational Study against Human Metapneumovirus (HMPV)
Authors: Dubey Amit , Kumar Manish , Tufail Aisha , Dwivedi Vivek Dhar 
Published: January 2025

AbstractHuman metapneumovirus (HMPV) remains a critical challenge in respiratory healthcare, particularly due to the lack of targeted antiviral therapies and vaccines. This study employs an integrative computational framework to identify and evaluate the antiviral potential of nature-based compounds derived from traditional medicinal plants. A suite of advanced methodologies, including virtual screening, molecular docking, molecular dynamics (MD) simulations, density functional theory (DFT) calculations, pharmacophore modeling, and ADMET profiling, was utilized to comprehensively analyze candidate compounds.Among the tested compounds, Glycyrrhizin exhibited exceptional properties, with a binding energy of −65.4 kcal/mol, eight stabilizing hydrogen bonds, and remarkable dynamic stability (RMSD 1.3 Å). Similarly, Withaferin A demonstrated a binding energy of −63.7 kcal/mol and high pharmacokinetic potential. Quantum-level analyses revealed favorable electronic properties, while ADMET profiling confirmed the compounds’ safety and drug-like characteristics. These findings underscore the potential of traditional phytochemicals to serve as lead candidates in antiviral drug development. This research bridges the gap between traditional medicine and modern computational techniques, paving the way for innovative and efficient therapeutic strategies against HMPV.
Nonlinear locomotion patterns in the Egyptian Locust (Anacridium aegyptium) during walking: a detailed case study
Authors: Tozzi Arturo 
Published: January 2025

ABSTRACTWe explored the nonlinear movement patterns ofAnacridium aegyptiumduring terrestrial locomotion, providing insights into the walking dynamics of this large grasshopper species. Using video recordings, we analysed the trajectory of an insect and quantified key metrics, including curvature, tortuosity and fractal dimension. Curvature analysis revealed irregular turning behaviors with sharp directional changes, suggesting that locomotion was not random but deliberate. Compared with simulated linear trajectories, the curvature exhibited distinct peaks, highlighting the presence of statistically significant nonlinear features in the movement patterns. Phase space reconstruction revealed repetitive patterns indicating the potential presence of a limit cycle attractor. The trajectory remained confined within a specific region of the phase space, highlighting structured dynamics rather than unbounded behaviour. Fractal dimension analysis and Lyapunov exponent were consistent with a stable and predictable system over time, rather than one governed by chaos. These findings align with the behavioral ecology ofA. aegyptium, suggesting that its walking dynamics are governed by efficient spatial exploration and obstacle negotiation rather than erratic or chaotic motion. Our study underscores the value of advanced mathematical and computational methods in boosting behavioural studies of locomotion. The insights derived from our analysis enhance our understanding of insect locomotion strategies and hold potential applications in the field of biomimetic robotics, where adaptive and efficient movement is mandatory. Future research could explore the impact of environmental factors, such as substrate type and food availability, on the observed nonlinear patterns, providing deeper context to the intricate locomotion behaviour ofAnacridium aegyptium.
Enhanced AkaLuc Bioluminescence Imaging for Longitudinal Intravital Monitoring of Minimal Residual Disease in a Murine Model of Triple-negative Breast Cancer
Authors: Steinbauer Silvia , Cowles Jamie D. , Sabbaghi Mohammad Ali , Poppelaars Marle , Hussain Azaz , Wagesreither Marina , Laimer-Gruber Daniela , Tovari Jozsef , Szakacs Gergely , Csiszar Agnes 
Published: January 2025

AbstractTriple-negative breast cancer (TNBC) is an aggressive form of cancer with poor prognosis. Beyond the absence of targeted therapies, a major challenge is its high recurrence rate, driven by the outgrowth of residual tumor cells that survive chemotherapy and persist during minimal residual disease (MRD). To monitor the therapy response of TNBC by enhanced intravital imaging, we established a clinically relevant combination chemotherapy protocol for the treatment of mouse mammary tumors engrafted from K14cre;Brca1F/F;Trp53F/F(KB1P) organoids engineered to express an mCherry-AkaLuc dual reporter (mCA-KB1P). Reproducible MRD and relapse response patterns with significantly extended relapse-free survivals were achieved with the TAC protocol, consisting of docetaxel, doxorubicin and cyclophosphamide. AkaLuc bioluminescence imaging (AkaBLI) of mCA-KB1P organoids verified the single-cell sensitivity of the systemin vitro,and showed a detection limit of approximately 1000 cells in the mammary gland of living mice. Unexpectedly, mCA-KB1P organoids elicited an immune response, which necessitated the use of immunodeficient hosts for the longitudinal intravital monitoring of MRD. AkaBLI and an adapted TAC protocol enabled, for the first time, the non-invasive intravital tracking and an estimation of the number of surviving tumor cells in the MRD state following intensive chemotherapy. Engineering KB1P organoids for Histon2B-mCherry reporter expression (HmC-KB1P) enabled the estimation of tumor cell survival also in syngeneic immunocompetent hosts. Flow cytometry and histological analysis revealed that immunocompetent hosts harbored only a few residual cells at MRD, which exhibited a transient loss of epithelial characteristics, whereas immunodeficient hosts had a greater number of surviving cells with a maintained epithelial phenotype. These findings are consistent with the immune system’s role in shaping phenotypic changes influencing survival following chemotherapy Together, the results demonstrate the utility of the AkaBLI system for rare tumor cell tracking and highlight the immune system’s role in triggering adaptive responses to chemotherapy.
Estimating fruit tree growth curves in breeding field using fragmented longitudinal data: An application to citrus hybrid seedlings
Authors: Kimura Soh , Minamikawa Mai F. , Nonaka Keisuke , Shimizu Tokurou , Iwata Hiroyoshi 
Published: January 2025

AbstractVegetative and reproductive growth in fruit trees is interconnected, and analyzing this relationship can provide valuable insights into fruit quality. However, characterizing vegetative growth through growth models is challenging because of the difficulty in obtaining longitudinal data, given the slow growth rate. In breeding fields, in contrast, seedlings of different ages are planted, allowing for simultaneous measurements that yield a dataset resembling longitudinal data with missing values --termed “fragmented longitudinal data.” Because longitudinal data are obtained from a single measurement, they can potentially shorten the period required for growth curve estimation. Bayesian nonlinear models offer advantages in estimating curves from incomplete data. In this study, we generated fragmented longitudinal data using genome data with 45,929 markers from 624 citrus hybrid seedlings and applied a Bayesian nonlinear model to explore its potential. We also incorporated genomic information into the model to assess the impact of the estimation accuracy. Our simulations indicated that the Bayesian nonlinear model’s ability to interpolate missing values significantly improved the estimation performance. At best, the mean square error of the parameter characterizing the later growth stage was reduced by 84.3 mm2. Although the improvement from incorporating genomic information was modest, it still surpassed models that lacked genomic data. We also predicted the curves of untested individuals using the estimated parameters. Although the prediction accuracy of each parameter measured by the correlation coefficient was lower than 0.5, one parameter consistently showed a better accuracy. Further research is required to reveal the advantages of integrating genomic data for better predictions.
A method for inducing a senescence trend in mesenchymal stem cells using D-galactose1
Authors: Ji Xiaoming , Zhou Xiaoyu , Chen Tingting , Duan Chunchun , Tian Wenjing , Zhu Liyang , Ma Yan , Gao Liyang 
Published: January 2025

AbstractThe aging of the body is accompanied by a decline in tissue function, and this decline mainly stems from the aging of tissue stem cells. Therefore, they play a crucial role in the aging of the body.This study explores the biological characteristics of senescent hUCMSCs by establishing a replicative senescence model of hUCMSCs and a rapid senescence model induced by D - galactose (D-Gal), and analyzing the proliferative capacity, cell viability, cell cycle, pluripotency, and reactive oxygen species (ROS) levels of senescent hUCMSCs.
Rubisco is slow across the tree of life
Authors: de Pins Benoit , Malbranke Cyril , Jabłońska Jagoda , Shmuel Assaf , Sharon Itai , Bitbol Anne-Florence , Mueller-Cajar Oliver , Noor Elad , Milo Ron 
Published: January 2025

AbstractRubisco is the main gateway through which inorganic carbon enters the biosphere, catalyzing the vast majority of carbon fixation on Earth. This pivotal enzyme has long been observed to be kinetically constrained. Yet, this impression is based on kinetic measurements heavily focused on eukaryotic rubiscos, a rather conserved group of low genetic diversity. Moreover, the fastest rubiscos that we know of so far were found among the sparsely sampled prokaryotes. Could there be yet faster rubiscos among the uncharted regions of rubisco’s phylogenetic diversity? Here, we perform a characterization of more than 250 rubiscos from a wide range of bacteria and archaea, thereby doubling the coverage of the diversity of this key enzyme. We assess the distribution of the carboxylation rates at saturating levels of CO2, and establish that rubisco is a relatively slow enzyme across the tree of life, never exceeding ≈20 reactions per second. We show that relatively faster subclades share similar evolutionary contexts, involving micro-oxygenic environments or a CO2concentrating mechanism. Leveraging a simple machine learning model trained on this dataset, we predict the carboxylation rate for all ≈68,000 sequenced rubisco variants found in nature to date. This study provides the largest and most diverse dataset of natural variants for an enzyme and their associated rates, establishing a solid benchmark for future efforts to predict catalytic rates from sequence data.SignificanceDiscovering a fast carboxylating rubisco has been a long-standing challenge in the scientific community, given its potential impact on sustainable food and fuel production. Yet, only a small fraction of rubisco’s natural diversity has been kinetically characterized. Here, we present a large-scale kinetic survey covering the entire spectrum of rubisco’s diversity found in nature. Focusing on genetic clusters with above-average rates, we show that rubisco’s catalytic rate does not exceed ≈20 reactions per second. Supported by a machine-learning predictive model, we extend this finding to all sequenced natural variants. Our study provides the most comprehensive kinetic dataset for a single enzyme to date.
Free acid β-hydroxybutyrate supplementation does not ameliorate dextran sodium sulfate-induced colitis similar to ketogenic diet in male mice
Authors: Toivio Lotta , Toivio Jyri , Lindén Jere , Lee Keehoon , Lehto Markku , Salmenkari Hanne , Korpela Riitta 
Published: January 2025

AbstractHigh-fat, low-carbohydrate ketogenic diets have been found to alleviate experimental colitis in rodents. These diets lead to increased endogenous production and utilization of ketone bodies, such as β-hydroxybutyrate (BHB), and supplementation with exogenous ketones has arisen as a potential alternative to ketogenic diets. This study aimed to investigate how continuous high-dose feeding with free acid BHB influences experimental colitis compared to a ketogenic diet with the hypothesis that BHB would also alleviate the inflammation. We fed nine-week-old C57BL/6J male mice for four weeks with one of three diets: a low-fat control diet, a ketogenic diet, or a low-fat diet supplemented with free acid R-BHB and then induced colonic inflammation with dextran sodium sulfate (DSS). We assessed macroscopic and histological changes in the colon, intestinal permeability to fluorescein isothiocyanate dextran, colonic mRNA expression of tight junction proteins and inflammatory markers, fecal calprotectin, and microbiota composition. While the ketogenic diet alleviated DSS-induced weight loss, macroscopic changes, and histological lesions, the BHB-supplemented diet did not have the same effect. The pre-DSS composition of the microbiota was drastically different between the diet groups which may partly explain the different outcomes. In conclusion, high-dose supplementation with free acid BHB may not produce the same benefits as ketogenic diet in the context of colonic inflammation.