bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative genomic analysis of a novel heat-tolerant and euryhaline strain of unicellular marine cyanobacteriumCyanobacteriumsp. DS4 from a high-temperature lagoon
Authors: Chen Ching-Nen Nathan , Lin Keng-Min , Lin Yu-Chen , Chang Hsin-Ying , Yong Tze Ching , Chiu Yi-Fang , Kuo Chih-Horng , Chu Hsiu-An
Published: January 2025

Background

Cyanobacteria have diversified through their long evolutionary history and occupy a wide range of environments on Earth. To advance our understanding of their adaption mechanisms in extreme environments, we performed stress tolerance characterizations, whole genome sequencing, and comparative genomic analyses of a novel heat-tolerant and euryhaline strain of the unicellular cyanobacteriumCyanobacteriumsp. Dongsha4 (DS4). This strain was isolated from a lagoon on Dongsha Island in the South China Sea, a habitat with fluctuations in temperature, salinity, light intensity, and nutrient supply.

Results

DS4 cells can tolerate long-term high-temperature up to 50 ℃ and salinity from 0 to 6.6 %, which is similar to the results previously obtained forCyanobacterium aponinum. In contrast, most mesophilic cyanobacteria cannot survive under these extreme conditions. Based on the 16S rRNA gene phylogeny, DS4 is most closely related toCyanobacteriumsp. NBRC 102756 isolated from Iwojima Island, Japan, andCyanobacteriumsp. MCCB114 isolated from Vypeen Island, India. For comparison with strains that have genomic information available, DS4 is most similar toCyanobacterium aponinumstrain PCC 10605 (PCC10605), sharing 81.7% of the genomic segments and 92.9% average nucleotide identity (ANI). Gene content comparisons identified multiple distinct features of DS4. Unlike related strains, DS4 possesses the genes necessary for nitrogen fixation. Other notable genes include those involved in photosynthesis, central metabolisms, cyanobacterial starch metabolisms, stress tolerances, and biosynthesis of novel secondary metabolites.

Conclusions

These findings promote our understanding of the physiology, ecology, evolution, and stress tolerance mechanisms of cyanobacteria. The information is valuable for future functional studies and biotechnology applications of heat-tolerant and euryhaline marine cyanobacteria.
International Corneal and Ocular Surface Disease Dataset for Electronic Health Records
Authors: Ting Darren S. J. , Kaye Stephen B. , Rauz Saaeha ,   the International Corneal and Ocular Surface Disease (C&OSD) Dataset Development Working Group
Published: January 2025

Background/Aims

To provide a comprehensive and internationally standardised Cornea and Ocular Surface Disease (C&OSD) dataset for use in electronic health records (EHRs).

Methods

This was an international consensus study conducted through roundtable discussions involving 35 international experts specialising in the field of C&OSD. The Royal College of Ophthalmologists dataset guidelines were used to articulate initial C&OSD data elements template by curating data elements from validated published datasets obtained through scientific literature searches, and accessing existing international patient clinical and reported outcome recording instruments and registries. These included data elements recommended by the Dry Eye Workshop II, International Meibomian Gland Dysfunction Workshop, Ocular Surface Disease Activity and Damage Indices, the Cicatrising Conjunctivitis Assessment Tool, Limbal Stem Cell Deficiency Clinical and Confocal Grading, Chronic Ocular Manifestations in Patients with Stevens–Johnson Syndrome, and the UK Transplant Registry. Data elements pooled into an independent operational data model.

Results

A comprehensive generic dataset (common to all ophthalmology datasets) and C&OSD specific dataset was developed. Within the C&OSD dataset, several gateway disease datasets, such as atopic or allergic eye diseases, meibomian gland dysfunction, cicatrising conjunctivitis, chemical injury, dry eye, limbal stem cell deficiency, microbial or infectious keratitis, corneal erosion syndrome, and keratoconus, were established to streamline data entry for clinical audit and research purposes.

Conclusion

A comprehensive C&OSD dataset is provided which can be used by both generalist and specialist ophthalmologists. Adoption of the full dataset by EHR providers will lead to better interoperability and patient care and facilitate international research collaboration.
Genetically Defined Organoid Models Reveal Mechanisms Driving Squamous Cell Neoplastic Evolution and Identify Potential Therapeutic Vulnerabilities
Authors: Zhao Hua , Park Young Min , Zheng Yueyuan , Mao Qiong , Collet Casey , Hu Boyan , Zhou Tianming , Lin Luda , Wong Stephanie , Pan Yuhao , Monreal Anette Vistoro , Sinha Uttam K. , Sedghizadeh Parish , Soragni Alice , Lin De-Chen
Published: January 2025

Upper aerodigestive squamous cell carcinoma (UASCC) is an aggressive and lethal neoplasm, with its early neoplastic transformation mechanisms remaining poorly understood. Here, we characterize over 25 genetically-defined organoid models derived from murine and human oral/esophageal tissues harboring key driver mutations. Double knockout ofTP53andCDKN2Ainduced morphological dysplasia, hyperproliferation, loss of squamous differentiation, and tumorigenicity, which were further exacerbated by additional driver mutations (e.g.,PIK3CA,NOTCH1,KMT2C). Single-cell analysis revealed an expansion of quiescent basal cells and proliferative squamous cells, alongside a loss of differentiated squamous cells during malignant transformation. A distinct senescence program, regulated by ANXA1, was markedly diminished during early neoplastic evolution. Mechanistically, the ANXA1-SMAD3-p27KIP1pathway was identified as a critical regulator of this senescence program, acting to suppress neoplastic features in organoid models. Lastly, our high-throughput, single-organoid-resolution drug screens unexpectedly revealedPIK3CA-driven organoids exhibited sensitivity to Mitomycin C and Onalespib. This study provides novel mechanistic insights into early neoplastic evolution and underscores the value of genetically-defined organoid models for investigating cancer biology and identifying targeted therapies.
RecAlign: A* recombination-aware sequence to graph mapping
Authors: Bonizzoni Paola , Monti Davide Cesare , Della Vedova Gianluca , Riccardi Brian , Rizzi Raffaella , Siren Jouni
Published: January 2025

Pangenomics and long reads bring the promise of integrating read mapping with variant calling, since a pangenome encodes a reference genome that incorporates evolutionary or population aspects, while even a single long read can provide a good evidence of different kinds of variants (not only the single nucleotide variants that can be easily observed by short reads). This promise needs to be fulfilled by the development of new read mapping approaches that are tailored for that purpose. This paper focuses on integrating recombination events, that are key in bacteria, into read mapping. A first approach in that direction [ACBC+24] provides an exact dynamic programming algorithm that is too slow to manage multiple recombinations or long reads. We present a novel A* algorithm for recombination-aware sequence-to-graph mapping that significantly reduces running time by incorporating haplotype information and an efficient heuristic function. Our tool,RecAlign, demonstrates up to a two-order magnitude improvement in time and space complexity over [ACBC+24] and efficiently handles multiple recombinations.
Draft genome sequences of four lactic acid bacteria from fermented chicken meat unveil biosynthetic gene clusters for antimicrobial compounds
Authors: Alam Mahabub , Hassan Tamanna , Nizami Tanvir Ahmad , Akter Lipi , Rakib Tofazzal Md
Published: January 2025

Lactic acid bacteria play a crucial role in fermented food production and serve as important sources of antimicrobial peptides. This study reports four lactic acid bacteria strains, isolated from fermented chicken meat, which harbor biosynthetic gene clusters encoding antimicrobial compounds. These strains are classified within the generaPediococcusandLactiplantibacillus.
Multifunctional bending magnet beamline with a capillary optic for X-ray fluorescence studies of metals in tissue sections
Authors: Roter Benjamin , Crawford Andrew M. , Jin Qiaoling , Glowacki Arthur T. , Lai Barry , Marin Fabricio S. , Maxey Evan , Shi Xianbo , Culotta Valeria C. , Wildeman Asia S. , Patel Naisargi K. , O’halloran Thomas V. , Jacobsen Chris
Published: January 2025

Scanning fluorescence X-ray microscopy lets one non-destructively and quantitatively map the distribution of most biologically-important metals in cells and tissues. For studies on large-scale tissues and organs, a spatial resolution of several micrometers is often sufficient; in this case, bending magnets at synchrotron light sources provide abundant X-ray flux. We describe here the use of bending magnet beamline 8-BM-B at the Advanced Photon Source (APS) with two distinct microscopy stations: a pre-existing one with Kirkpatrick-Baez (KB) mirror optics for slightly higher throughput and the ability to accommodate samples tens of centimeters across, and a new prototype station with an axially-symmetric, single-bounce, capillary optic with slightly less flux, but slightly higher fluence (which affects achievable resolution at low metal concentration) and higher spatial resolution. The KB station providesδres= 10.5 µm spatial resolution at a per-pixel exposure time oftdwell= 100 ms and a fluence per time of 5.8× 107photons /(µm2·s), while the prototype capillary station providesδres= 6.3 µm attdwell= 50 ms and a fluence per time of 6.1× 107photons (µm2·s). We used image power spectral density to estimate the achieved spatial resolutionδresfrom individually acquired images, withδresdepending-on the optic, the fluorescence signal strength of the sample being imaged, and the method used to process raw fluorescence spectral data.
SpatialFormer: Universal Spatial Representation Learning from Subcellular Molecular to Multicellular Landscapes
Authors: Wang Jun , Huang Yuanhua , Winther Ole
Published: January 2025

Spatial 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

Despite 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.

SIGNIFICANCE

This 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

Circadian 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

Marine 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

Mutations 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

Human 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

We 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

Triple-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

Vegetative 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

The 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

Rubisco 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.

Significance

Discovering 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

High-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.
Virus infection significantly decreases insect fitness: a meta-analysis
Authors: Cesar Cássia Siqueira , Miranda Vitória Horvath , Silveira Elielson Rodrigo , de Oliveira Thiago Assis , Cogni Rodrigo
Published: January 2025

Organisms are constantly at risk of being infected by pathogens such as viruses. Adaptations against viral infection include immune defenses encoded within the host genome and associations with defensive symbionts such asWolbachia. Wolbachiais widely spread among insects, and its success in nature may be due to its antiviral effects, which can benefit hosts if viruses significantly reduce host fitness. Here, we conducted a meta-analysis to assess the degree to which viral infection affects the fitness of insect hosts, and which factors may influence the impact of viral infection on hosts such as if the insect host is a vector or not of viruses that cause diseases in humans and plants, and if the insect is a new or a natural host of a specific virus. We gathered 1,040 effect sizes from 150 studies. Our results show that viruses significantly reduce host fitness, especially their survival. The decrease in host fitness is higher in non-vector than in vector insects, and we found no difference in fitness decrease caused by viral infection between new and natural hosts. Moreover, we found that fitness effects caused by viruses vary between host order and fitness components. In conclusion, our results show that viruses exert severe harmful effects on hosts by decreasing their fitness. In this context, harboring symbionts that confer antiviral protection, such asWolbachia, can be highly advantageous for hosts, enhancing their fitness. Conversely,Wolbachiacan benefit from the presence of viruses, facilitating its spread in insect populations by offering antiviral protection.
The metabolic enzyme GYS1 condenses with NONO/p54nrbin the nucleus to spatiotemporally regulate glycogenesis and myogenic differentiation
Authors: Peng Shujun , Li Canrong , Wang Yifan , Yi Yuguo , Chen Xinyu , Yin Yujing , Yang Fan , Chen Fengzhi , Ouyang Yingyi , Xu Haolun , Chen Baicheng , Shi Haowen , Li Qingrun , Zhao Yu , Feng Lin , Gan Zhenji , Xie Xiaoduo
Published: January 2025

Accumulating evidence indicates that metabolic enzymes can directly couple metabolic signals to transcriptional adaptation and cell differentiation. Glycogen synthase 1 (GYS1), the key metabolic enzyme for glycogenesis, is a nucleocytoplasmic shuttling protein compartmentalized in the cytosol and nucleus. However, the spatiotemporal regulation and biological function of nuclear GYS1 (nGYS1) microcompartments remain unclear. Here, we show that GYS1 dynamically reorganizes into nuclear condensates under conditions of glycogen depletion or transcription inhibition. nGYS1 complexes with the transcription factor NONO/p54nrband undergoes liquid-liquid phase separation to form biomolecular condensates, leading to its nuclear retention and inhibition of glycogen biosynthesis. Compared to their wild-type littermates, Nono-deficient mice exhibit exercise intolerance, higher muscle glycogen content, and smaller myofibers. Additionally, Gys1 or Nono deficiency prevents C2C12 differentiation and cardiotoxin-induced muscle regeneration in mice. Mechanistically, nGYS1 and NONO co-condense with the myogenic transcription factor MyoD and preinitiation complex (PIC) proteins to form transcriptional condensates, driving myogenic gene expression during myoblast differentiation. These results reveal the spatiotemporal regulation and subcellular function of nuclear GYS1 condensates in glycogenesis and myogenesis, providing mechanistic insights into glycogenoses and muscular dystrophy.
Regulation of cell cycle by the novel GATA1/TAL1/Sphingomyelin Synthase 1 (SGMS1) transcriptional axis. Implications for anti-leukemic strategies
Authors: Raza Yasharah , Moorthi Sitapriya , Yu Gui-Qin , Chiappone Sam , Vacchi-Suzzi Caterina , Luberto Chiara
Published: January 2025

Sphingomyelin Synthase 1 (gene name:SGMS1) participates in regulation of sphingolipid levels by synthesizing sphingomyelin from ceramide and phosphatidylcholine. Evidence have supported SGMS1’s functions in regulating proliferation, cell cycle, cell death and migration. While its functions have begun to be explored, very little is known about upstream regulators. Here, we demonstrate thatSGMS1is a direct gene target of the GATA1-TAL1 transcriptional complex in K562 erythroleukemic cells. A predicted GATA1 consensus DNA binding sequence was identified with in a newly characterized alternativeSGMS1promoter (TSS-7 promoter) and ChIP analysis confirmed GATA1 occupancy on the promoter. Down-regulation of GATA1 in K562 cells significantly decreased SGMS1 expression and enzymatic activity, and ChIP-Seq analysis from ENCODE showed colocalized peaks for GATA1 and TAL1(a well-established GATA1 DNA binding partner) on theSGMS1gene. Analysis of publicly available datasets shows that elevatedGATA1, TAL1andSGMS1expression not only clusters GATA1 positive chronic myelogenous leukemia cells (like K562), but also selectively identifies acute erythrocytic and megakaryocytic leukemias (M6 and M7 AML, respectively). Microarray gene expression analysis after down-regulation ofSGMS1in M6 AML Hel cells revealed alteration of genes regulating G2/M check point and mitotic spindle formation. This phenotype was functionally confirmed by the significant delay in G2/M cell cycle progression of cells withSGMS1downregulation and sensitization to the clinically relevant anti-mitotic agent, Taxol. Altogether, these results identifySGMS1as a novel target of GATA1/TAL1 transcriptional complex and they support a role for the GATA1/TAL1/SGMS1 axis in regulating transit through G2/M. Importantly, results also point to combination of anti-mitotic agents and inhibition of SGMS1 as a potential novel therapeutic approach against the aggressive and resilient M6 AMLs.

KEY POINTS

The Sphingomyelin Synthase 1 gene (SGMS1) is a novel direct target of GATA1 and TAL1.

HighSGMS1levels are associated with highGATA1/TAL1expression and regulate cell cycle progression through the G2/M checkpoint in GATA1+erythroleukemic Acute Myeloid Leukemia Hel cells.

HighSGMS1is associated with lower probability of survival of patients with Acute Myeloid Leukemia and down-regulation of SGMS1 co-operates with microtubule targeting agents to induce cytotoxicity in GATA1 positive AML Hel cells.
Primate-specific microRNA-1202 regulates dopaminergic neurogenesis by targeting APC2 and modulates WNT/β-catenin signaling pathway in midbrain organoid
Authors: Long Xiaohang , Cao Dandan , Chan See-Wing , Hao Suyu , Liu Lingxiao , Chan Wai-Yee , Cheung Hoi-Hung
Published: January 2025

MicroRNAs (miRNAs) are generally evolutionarily conserved, but a small number of them are found exclusively in primates. MiR-1202 is a primate-specific miRNA that was previously revealed as being involved in major depression disorder (MDD). Moreover, the genomic locus where miR-1202 locates (6q25.3) is strongly associated with recurrent early-onset MDD and neurodevelopmental disorder. We hypothesize that miR-1202 plays a unique role in the brain in fine-tuning the transcriptional network that governs neurogenesis. Here, we reported that microdeletion of miR-1202 resulted in retarded organoid growth but enhanced dopaminergic (DA) neuron differentiation in midbrain organoids. Integrated analysis of miRNA-interacting targets and transcriptional changes in miR-1202 knockout cells revealed that APC2, a negative regulator of canonical WNT/β-catenin pathway, was a downstream target of miR-1202. Knockdown of APC2 resulted in attenuated DA neurogenesis, in contrast to the enhanced DA neurogenesis in miR-1202 knockout cells. Treatments of the brain organoids with antidepressants increased miR-1202 expression and simultaneously inhibited APC2 expression. Consistently, APC2 expression was found to increase in MDD patients. Our results suggest that miR-1202 regulates dopamine neurogenesis by inhibiting the APC2/WNT signaling pathway, which plays a distinct role in the midbrain-hindbrain regional patterning during the early development of the central nervous system.
Exome Sequencing for Head and Neck Cancer Predisposition Genes
Authors: Yu Yao , Feng Bingjian , Chang Chun-Pin , Bell Russell , Wood Austin , Sturgis Erich , Li Guojun , Olshan Andrew , Chen Chien-Jen , Lou Pen-Jen , Hsu Wan-Lun , Cessna Melissa , Witt Benjamin , Neklason Deb , Hashibe Mia , Huff Chad , Tavtigian Sean
Published: January 2025

Introduction

While common variants have been studied for head and neck cancer (HNC) risk and exome sequencing has been conducted for head and neck tumor tissue samples, large-scale studies of exome sequencing on head and neck cancer risk have not been conducted. Our study aimed to identify head and neck cancer predisposition genes with exome sequencing and to assess interactions between the head and neck cancer susceptibility genes and tobacco use.

Methods

We conducted a case-control analysis to identify germline susceptibility genes for HNC risk. We used whole-exome sequencing data in Phase 1, targeted gene sequencing data in Phase 2 (2,134 HNC cases and 2,072 controls), and publicly available whole-exome sequencing data from the UK Biobank database. We conducted a gene-based association analysis and estimated the effect size of known and novel HNC susceptibility genes and pathways.

Results

Six known cancer predisposition genes reached nominal significance (p < 0.05), includingBRCA1,BRCA2,RAD51B,BAP1,APC, andMUTYH. Additionally, we identified 21 novel HNC risk genes with meta p-value < 0.05. LoF variants inBRCA1(OR=5.0, 95% CI: 1.72-14.57),BRCA2(OR=2.56, 95% CI: 1.22-5.41), andMUTYH(OR=4.84, 95% CI: 1.01-13.86) exhibited significantly elevated effect sizes.APC, BRCA2, and the DNA repair gene set exhibited borderline interactions with smoking, with synergy indices and 95% confidence intervals of 1.92 [0.98, 3.75], 1.77 [0.91, 3.46], and 1.57 [0.97, 2.54], respectively.

Conclusions

We observed associations with HNC risk for DNA repair pathway genes associated with breast cancer and polyposis colorectal cancer predisposition genes. Potential interactions between these genes and tobacco smoking were also identified. Our study utilized targeted gene sequencing and whole-exome sequencing approaches to identify cancer susceptibility genes, while further studies are needed to confirm the associations observed with HNC risk.
Optimal control and cost-effectiveness analysis of mitigation strategies for monkeypox virus infection in the presence of routine interventions
Authors: Naandam Samuel M. , Chataa Paul , Nikingbong Christopher , Adom-Konadu Agnes
Published: January 2025

Empirical evidence substantiates the pivotal role of vaccination in eradicating monkeypox virus (Mpox) infections. Mathematical modeling serves as a crucial tool for identifying strategies to curtail the disease’s proliferation. This study introduces a comprehensive mathematical framework for analyzing the dynamics of monkeypox transmission, incorporating imperfect vaccination and immunity degradation post-recovery. The theoretical constructs of positivity and boundedness are employed to confirm the model’s well-posedness. The next-generation matrix approach is utilized to calculate the control reproduction number (ℛc), and the equilibrium points of the model are identified. The investigation demonstrates that the disease-free equilibrium is both locally and globally asymptotically stable, while the endemic equilibrium is proven to exhibit global asymptotic stability as well. Sensitivity analyses of parameters influencing ℛcare performed using Latin Hypercube Sampling (LHS) and Partial Rank Correlation Coefficients (PRCC). Furthermore, the model is extended to incorporate time-dependent interventions, including the administration of high-efficacy vaccines, the quarantine of exposed individuals, and the treatment of infected individuals. The model’s qualitative findings are reinforced through numerical simulations, which validate the effectiveness of various control strategies in suppressing monkeypox spread among susceptible, exposed, and infected populations. Simulations without vaccination controls reveal an initial surge in exposed and infected cases, followed by gradual containment over time. The findings highlight the critical importance of vaccination as a pharmaceutical intervention, though its effectiveness is hindered by challenges such as viral mutations, the diminishing efficacy of vaccines, and limited vaccination resources. These constraints underscore the necessity of adopting integrated intervention measures, especially as instances of reinfection post-vaccination and treatment of infected cases have been documented in several studies. Policymakers are thus encouraged to employ a balanced and pragmatic approach when easing other preventive measures for monkeypox. Additionally, a cost-effectiveness analysis was performed to determine the most economical strategy for controlling monkeypox transmission. The results indicate that the optimal control strategy involves combining high-efficacy vaccination with the quarantine of exposed individuals, demonstrating superior cost-effectiveness among the examined interventions.
Online General Exercise Management (GEM) Program for patients with Breast Cancer-Related Lymphedema: A Protocol for a Pilot Randomized Controlled Trial
Authors: Arinaga Yoko , Sato Fumiko , Miyata Satoshi , Piller Neil , Ohtake Tohru
Published: January 2025

Background

Breast cancer-related lymphedema (BCRL) requires a lifetime commitment to self-care.

Aims

This is a study protocol for a pilot parallel-group randomized controlled trial which will assess the effectiveness of an online version of the General Exercise Management (GEM) program for patients with BCRL.

Methods

Sixty patients will be recruited through online advertisements and randomly allocated to either an intervention or control group. The intervention group will be provided with an educational program on standard self-care for BCRL as well as the GEM program, while the control group will receive only the self-care education program. Both groups will participate in a six-month online program, perform daily self-checks and participate in monthly small-group sessions. All participants, session facilitators and a statistical analyst will be blinded to group allocation.

Anticipated Results

The primary expected outcome is a reduction of BCRL symptoms, and the secondary outcomes are health-related quality of life and self- care adherence improvements.

Conclusions

The findings will inform further investigation in a Phase III trial.

Declaration of Interest

All authors declare that they have no competing financial interests.

This study was approved by the Institutional Review Board of Fukushima Medical University Hospital (REC2024-068) and registered with UMIN-CTR (UMIN000055357).