bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling of hepatitis B virus infection spread in primary human hepatocytes
Authors: Shi Zhenzhen , Tsuge Masataka , Collier Nicholson , Takeuchi Yasue , Uchida Takuro , Rutter Carolyn , Teraoka Yuji , Uprichard Susan L , Ishida Yuji , Tateno Chise , Ozik Jonathan , Dahari Harel , Chayama Kazuaki
Published: February 2025

Chronic hepatitis B virus (HBV) infection poses a significant global health threat, causing severe liver diseases including cirrhosis and hepatocellular carcinoma. We characterized HBV DNA kinetics in primary human hepatocytes (PHH) over 32 days post-inoculation (pi) and used agent-based modeling (ABM) to gain insights into HBV lifecycle and spread. Parallel PHH cultures were mock-treated or HBV entry inhibitor Myr-preS1 (6.25 μg/mL) was initiated 24h pi. In untreated PHH, 3 viral DNA kinetic patterns were identified: (1) an initial decline, followed by (2) rapid amplification, and (3) slower amplification/accumulation. In the presence of Myr-preS1, viral DNA and infected cell numbers in phase 3 were effectively blocked, with minimal to no increase. This suggests that phase 2 represents viral amplification in initially infected cells, while phase 3 corresponds to viral spread to naïve cells. The ABM reproduced well the HBV kinetic patterns observed and predicted that the viral eclipse phase lasts between 18 and 38 hours. After the eclipse phase, the viral production rate increases over time, starting with a slow production cycle of 1 virion per day, which gradually accelerates to 1 virion per hour after 3 days. Approximately 4 days later, virion production reaches a steady state production rate of 4 virions/hour. The estimated median efficacy of Myr-preS1 in blocking HBV spread was 91% (range: 90-92%). The HBV kinetics and the predicted estimates of the HBV eclipse phase duration and HBV production cycles in PHH are similar of those predicted in uPA/SCID mice with human livers.
Harnessing Adaptive Chaos: Exploring the role of oxygen-ozone therapy in modulating complexity and repair in spine disorders via a bio-informatic model
Authors: Chirumbolo Salvatore , Franzini Marianno , Tirelli Umberto , Ricevuti Giovanni , Loprete Fortunato , Richelmi Tommaso , Vaiano Francesco , Galoforo Antonio Carlo , Chierchia Marianna , Valdenassi Luigi
Published: February 2025

Adaptive chaos represents a paradigm shift in understanding biological systems, where mild chaotic dynamics sustain homeostasis and resilience. This study delves into oxygen-ozone therapy’s ability to leverage adaptive chaos in treating spinal musculoskeletal disorders, particularly intervertebral disc degeneration (IVDD). Employing mathematical modelling and bioinformatic tools, the study evaluates chaos, complexity, and entropy across varying ozone doses to identify optimal therapeutic windows within a hormetic range. The results reveal that lower ozone doses (20–40 µg/ml O3) promote adaptive chaos, enhancing systemic complexity, reducing inflammatory cytokines, and fostering structural repair. Conversely, higher doses (60–80 µg/ml O3) induce excessive oxidative stress, exacerbating pathological chaos and impairing recovery. The integration of Shannon entropy, Lyapunov exponents, and fractal dimensions provides a novel framework for quantifying therapeutic outcomes. Findings highlight the role of controlled perturbations in stabilizing pathological systems, offering a dose-dependent roadmap for balancing flexibility and order. By correlating modelled insights with clinical evidence, the study underscores the significance of precision dosing, as the optimal range facilitates pain reduction and inflammatory control, correlating with improved complexity and reduced turbulence. This research pioneers the concept of adaptive chaos in medical interventions, emphasizing its translational potential for personalized and systemic medicine. Beyond IVDD, the findings establish a broader framework for adaptive chaos as a cornerstone of health restoration, advocating for therapies that optimize biological complexity. This work tries to bridge mathematical modelling and clinical evidence, offering a cutting-edge perspective on regenerative medicine and chaos-driven therapeutic strategies.
Pde5aDeficiency Prevents Diet-Induced Obesity via Adipose cAMP-PKA Activation Enhancing Fat Browning
Authors: Campolo F. , Giampaoli O. , Barbagallo F. , Palmisano B. , Di Maio A. , Sciarra F. , Rizzo F. , Monti S. , Cardarelli S. , Assenza M.R. , Poggiogalle E. , Patriarca A. , Sciubba F. , Filippini A. , Lenzi A. , Gianfrilli D. , Giorgi M. , Dolci S. , Naro F. , Sampaolesi M. , Riminucci M. , Mancini M. , Miccheli A. , Tessarollo L. , Venneri M.A , Isidori A.M
Published: February 2025

Cyclic nucleotides are critical regulators of adaptive thermogenesis and adipogenesis, with their intracellular levels finely tuned by phosphodiesterases. Phosphodiesterase type 5 (PDE5A) modulates cyclic guanosine monophosphate levels in adipocytes. While PDE5A inhibition has shown promise in patients with diabetes, its role in metabolism remains unclear. UsingPde5aknockout mouse models, we demonstrated that mice lackingPde5aexhibit enhanced browning of white adipose tissue and reduced hepatic fat content. Following high-fat diet,Pde5a−/−mice are resistant to obesity, displaying improved glucose metabolism and enhanced thermogenesis. These protective effects stem from an early developmental knockdown ofPde5a, leading to a metabolic reprogramming driven by cAMP-PKA pathway activation. The convergence of cGMP and cAMP signaling orchestrates thermogenic and systemic metabolic adaptations. Our findings establish PDE5A as a novel regulator of energy homeostasis, suggesting its inhibition as a valuable adjuvant therapy for metabolic disorders.
High-content morphological profiling by Cell Painting in 3D spheroids
Authors: Ringers Christa , Holmberg David , Flobak Åsmund , Georgieva Polina , Jarvius Malin , Johansson Martin , Larsson Anders , Rosén Dan , Seashore–Ludlow Brinton , Visnes Torkild , Carreras Puigvert Jordi , Spjuth Ola
Published: February 2025

Cell Painting is a popular assay for morphological profiling of multi-labeled 2D monolayer cell cultures used in a wide range of applications. Culturing cells in 3D has potential for higher physiological relevance, such as when studying effects of perturbations. Robust and scalable 3D models can be challenging to characterize through imaging – particularly because light has difficulty penetrating cell multilayers. We introduce a scalable method where the Cell Painting assay is combined with tissue-clearing and applied to 3D spheroids generated in a ULA microplate format. Multi-channel images are acquired using confocal microscopy, and cells can be segmented inside those spheroids allowing for relevant morphological features to be extracted. Our end-to-end analysis pipeline comprises cell segmentation, morphological feature extraction, and between-spheroids and within-spheroid normalization. We demonstrate the method using spheroids cultured from two colorectal cancer cell lines and successfully detect distinct phenotypic changes upon compound treatments, on both spheroid-level using maximum intensity projections and on single cell-level. We show that drugs group by mechanism of action, with biologically relevant clusters especially evident with single-cell data. Finally, we contrast our method to results from 2D Cell Painting and discover a different pattern in DNA damaging drugs in HCT116 colorectal cancer cells. This work lays the foundation for multi-channel image-based screening in 3D spheroids.
Investigating the dynamics of the aquatic community in Oslofjord through time series analysis of eDNA
Authors: Mahlangu Sibusiso , Ewers Isabelle , Carvalho Cintia Oliveira , Schrøder-Nielsen Audun , Dunthorn Micah , Karlsen Hans Erik , Sørnes Grete , Chavarie Louise , Endresen Dag , Ready Jonathan Stuart , de Boer Hugo J , Mauvisseau Quentin
Published: February 2025

Understanding temporal dynamics of marine communities is critical for assessing ecosystem health and guiding conservation efforts. Here, we conducted a survey using environmental DNA (eDNA) metabarcoding with two primer sets, MiFish and Elas02, to investigate seasonal and interannual changes in the fish community of Oslofjord (Norway) over two consecutive years. Using the MitoFish reference database through the GBIF querying tool, we identified 61 fish species and found significant changes in the dominant taxa between seasons and years.Clupea harengus(Atlantic herring) consistently peaked in early spring, whileScomber scombrus(Atlantic mackerel) dominated winter months in the second year. The MiFish primer set showed increased species richness in the second year, whereas the Elas02 primer set showed stable richness despite compositional turnover. Non-metric multidimensional scaling (NMDS) revealed distinct community separation between years in presence/absence data, driven by species turnover rather than abundance read changes. Our findings support the use of eDNA metabarcoding to capture fine-scale temporal dynamics and emphasise the importance of multi-year datasets for distinguishing ecological trends from stochastic changes. This strategy improves monitoring practices for marine ecosystems under anthropogenic stressors.
The G-protein coupled receptor OXER1 is a tissue redox sensor essential for intestinal epithelial barrier integrity
Authors: Lengyel Miklos , Ma Yanan , Gelashvili Zaza , Peng Siyang , Quraishi Meysoon , Niethammer Philipp
Published: February 2025

Generation of reactive oxygen species is an important part of the innate immune response. Generating microbicidal levels of reactive oxygen species (ROS) requires adaptation of mucosal barriers. High tolerance of ROS provides improved innate immune defenses against pathogens, whereas low tolerance renders host cells prone to chronic toxicity and mutagenesis, which can promote inflammation (e.g., in asthma and Crohn’s disease) and cancerogenesis. The mechanisms that sense and mediate host tolerance to ROS are little understood. In this study, we discover an unexpected role for the redox-sensitive, chemokine-like lipid 5-oxo-eicosatetraenoic acid (5-KETE) in redox adaptation. 5-KETE is known to attract leukocytes to damaged/infected mucosal barriers by signaling through its receptor, OXER1. Suggestive of a distinct non-immune function, we here report that the loss of the OXER1 ortholog Hcar1-4 causes barrier defects and baseline inflammation in the intestine of live zebrafish larvae. In zebrafish and cultured human cells, OXER1 signaling protects against oxidative nucleotide lesions by inducing DNA-protective Nudix hydrolases. Our data reveal the oxoeicosanoid pathway as a conserved ROS resilience mechanism that fortifies pathogen-exposed mucosal linings against increased oxidative stressin vivo.
scGPT-spatial: Continual Pretraining of Single-Cell Foundation Model for Spatial Transcriptomics
Authors: Wang Chloe , Cui Haotian , Zhang Andrew , Xie Ronald , Goodarzi Hani , Wang Bo
Published: February 2025

Spatial transcriptomics has emerged as a pivotal technology for profiling gene expression of cells within their spatial context. The rapid growth of publicly available spatial data presents an opportunity to further our understanding of microenvironments that drive cell fate decisions and disease progression. However, existing foundation models, largely pretrained on single-cell RNA sequencing (scRNA-seq) data, fail to resolve the spatial relationships among samples or capture the unique distributions from various sequencing protocols. We introducescGPT-spatial, a specialized foundation model for spatial transcriptomics continually pretrained on our previously published scGPT scRNA-seq foundation model. We also curate SpatialHuman30M, a comprehensive spatial transcriptomics dataset comprising of 30 million spatial transcriptomic profiles, encompassing both imaging- and sequencing-based protocols. To facilitate integration, scGPT-spatial introduces a novel MoE (Mixture of Experts) decoder that adaptively routes samples for protocol-aware decoding of gene expression profiles. Moreover, scGPT-spatial employs a spatially-aware sampling strategy and a novel neighborhood-based training objective to better capture spatial co-localization patterns among cell states within tissue. Empirical evaluations demonstrate that scGPT-spatial robustly integrates spatial data in mulit-slide and multi-modal settings, and effectively supports cell-type deconvolution and contextualized missing gene expression imputation, outperforming many existing methods. The scGPT-spatial codebase is publicly available athttps://github.com/bowang-lab/scGPT-spatial.
Chromosome-level genome assembly ofProtandrena(Anthemurgus)passiflorae(Hymenoptera: Andrenidae), a host-plant specialist bee
Authors: Parys Katherine A. , Schweizer Rena M. , Benavides Ligia , Geib Scott , Sim Sheina , Evans Jay D. , Branstetter Michael G.
Published: February 2025

The passion flower bee,Protandrena(Anthemurgus)passiflorae(Robertson) is a monolectic, host-plant specialist of the passionflower plantPassiflora luteaL. Using a single adult male individual, we generated long-read PacBio HiFi, HiC, and short-read RNA sequencing data to build a well-annotated, chromosome-level genome assembly for this species. The final nuclear genome is 249 Mb with 150x coverage and with most of the genome scaffolding into 12 chromosomes. The scaffold N50 is 21.4 Mb and the genome has a Benchmarking Universal Single-Copy Ortholog (BUSCO) score of 97.2% for 5991 hymenopteran genes. BRAKER3 annotation of the genome identified 12,098 genes and 15,353 total transcripts and found that 20.27% of the genome is made up of repetitive elements. We resolved a mitochondrial genome of 12.7 kb. TheP. passifloraegenome represents one of only a few published andrenid bee genomes and one of the first monolectic bees. This new high-quality genome will serve as a valuable resource for investigating the genomic basis of specialization and for providing a useful resource for studying pollinator health and conservation.
DHRS7 Integrates NADP+/NADPH Redox Sensing with Inflammatory Lipid Signalling via the Oxoeicosanoid Pathway
Authors: Ma Yanan , Hui King Lam , Ambaw Yohannes A. , Walther Tobias C. , Farese Robert V. , Lengyel Miklos , Gelashvili Zaza , Lu Dajun , Niethammer Philipp
Published: February 2025

During the innate immune response at epithelial wound sites, oxidative stress acts microbicidal and—mechanistically less well understood—as an immune and resilience signal. The reversible sulfhydryl (SH) oxidation of kinases, phosphatases, and transcription factors constitute the perhaps best-known redox signalling paradigm, whereas mechanisms that transduce metabolic redox cues, such as redox cofactor balance, remain little explored.

Here, using mammalian cells, microsomes, and live zebrafish, we identify DHRS7, a short-chain fatty acid dehydrogenase/reductase (SDR), as conserved, 5-hydroxyeicosanoid dehydrogenase (5-HEDH). Under oxidative stress, DHRS7 consumes NADP+to convert arachidonic acid (AA)-derived 5(S)-HETE into the inflammatory lipid 5-KETE, which activates leukocyte chemotaxis via the OXER1 receptor. While Dhrs7 acts as a NADPH-dependent 5-KETE sink in unstressed, healthy tissue, it promotes rapid, 5-KETE dependent leukocytic inflammation in wounded zebrafish skin.

Thus, DHRS7 epitomizes an underappreciated mode of redox signalling—beyond classic SH oxidation—that leverages NADPH metabolism to generate or quench a paracrine lipid signal. Metabolic redox sensors like DHRS7 might be promising therapeutic targets in diseases characterized by disturbed redox balance.
Proteoform identification using multiplexed top-down mass spectra
Authors: Wang Zhige , Xiong Xingzhao , Liu Xiaowen
Published: February 2025

Top-down mass spectrometry (TDMS) is the method of choice for analyzing intact proteoforms, as well as their post-translational modifications and sequence variations. In TDMS experiments, multiple proteoforms are often co-fragmented in tandem mass spectrometry (MS/MS) analysis, resulting in multiplexed TD-MS/MS spectra. Since multiplexed TD-MS/MS spectra are more complex than common spectra generated from single proteoforms, these spectra pose a significant challenge for proteoform identification and quantification. Here we present TopMPI, a new computational tool specifically designed for the identification of multiplexed TD-MS/MS spectra. Experimental results demonstrate that TopMPI significantly increases proteoform identifications and reduces identification errors in multiplexed TD-MS/MS spectral analysis compared to existing tools.
Skin microbiomes of frogs vary among individuals and body regions, revealing differences that reflect known patterns of chytrid infection
Authors: Ghose Sonia L. , Eisen Jonathan A.
Published: February 2025

The amphibian skin microbiome is an important line of defense against pathogens including the deadly chytrid fungus,Batrachochytrium dendrobatidis(Bd). Intra-species variation in disease susceptibility and intra-individual variation in infection distribution across the skin, therefore, may relate to differences in skin microbiomes. However, characterization of microbiome variation within and among amphibian individuals is needed. We utilized 16S rRNA gene amplicon sequencing to compare microbiomes of ten body regions from nine captiveR. sierraeindividuals and their tank environments. While frogs harbored distinct microbial communities compared to their tank environments, tank identity was associated with more variation in frog microbiomes than individual frog identity. Within individuals, we detected differences between microbiomes of body regions whereBdinfection would be expected compared to regions that infrequently experience infection. Notably, the bacterial families Burkholderiaceae (phylum Proteobacteria) and Rubritaleaceae (phylum Verrucomicrobia) were dominant on frog skin, and the relative abundances of undescribed members of these families were important to describing differences among and within individuals. Two undescribed Burkholderiaceae taxa were found to be putativelyBd-inhibitory, and both showed higher relative abundance on body regions whereBdinfection is often localized. These findings highlight the importance of considering intrapopulation and intraindividual heterogeneities, which could provide insights relevant to predicting localized interactions with pathogens.
Φ-Space ST: a platform-agnostic method to identify cell states in spatial transcriptomics studies
Authors: Mao Jiadong , Choi Jarny , Lê Cao Kim-Anh
Published: February 2025

We introduce Φ-Space ST, a platform-agnostic method to identify continuous cell states in spatial transcriptomics (ST) data using multiple scRNA-seq references. For ST with supercellular resolution, Φ-Space ST achieves interpretable cell type deconvolution with significantly faster computation. For subcellular resolution, Φ-Space ST annotates cell states without cell segmentation, leading to highly insightful spatial niche identification. Φ-Space ST harmonises annotations derived from multiple scRNA-seq references, and provides interpretable characterisations of disease cell states by leveraging healthy references. We validate Φ-Space ST in three case studies involving CosMx, Visium and Stereo-seq platforms for various cancer tissues. Our method revealed niche-specific enriched cell types and distinct cell type co-presence patterns that distinguish tumour from non-tumour tissue regions. These findings highlight the potential of Φ-Space ST as a robust and scalable tool for ST data analysis for understanding complex tissues and pathologies.
Draft Genome of the Endangered Visayan Spotted Deer (Rusa alfredi), a Philippine Endemic Species
Authors: Javier Ma. Carmel F. , Noblezada Albert C. , Sienes Persie Mark Q. , Guino-o Robert S. , Palomar-Abesamis Nadia , Malay Maria Celia D. , del Castillo Carmelo S. , Ferriols Victor Marco Emmanuel N.
Published: February 2025

The Visayan Spotted Deer (Rusa alfredi) is an endangered and endemic species in the Philippines facing significant threats from habitat loss and hunting. It is considered as the world’s most threatened deer species by the International Union for Conservation of Nature (IUCN) thus its conservation has been a top priority. Despite its status, there is a notable lack of genomic information available forR. alfrediand the genusRusain general. This study presents the first draft genome assembly of the Visayan Spotted Deer (VSD),Rusa alfredi, using Illumina short-read sequencing technology. The RusAlf_1.1 assembly has a 2.52 Gb total length with a contig N50 of 46 Kb and scaffold N50 size of 75 Mb. The assembly has a BUSCO complete score of 95.5%, demonstrating the genome’s completeness, and includes the annotation of 24,531 genes. Phylogenetic analysis based on single-copy orthologs reveals a close evolutionary relationship between theR. alfrediand the genusCervus. The availability of the RusAlf_1.1 genome assembly represents a significant advancement in our understanding of the VSD. It opens opportunities for further research in population genetics and evolutionary biology, which could contribute to more effective conservation and management strategies for this endangered species. This genomic resource can help in assuring the survival ofRusa alfrediin the country.
Phosphatidylinositol (4,5)-bisphosphate Impacts Ectosome Shedding fromC. elegansCiliated Sensory Neurons
Authors: Elsayyid Malek , Semmel Alexis E. , Prova Nahin Siara , Parekh Krisha D. , Tanis Jessica E.
Published: February 2025

Small secreted extracellular vesicles (EVs) mediate the intercellular transport of bioactive macromolecules during physiological processes and propagation of pathological conditions. The primary cilium, a sensory organelle protruding from most non-dividing cells, transmits signals by shedding EVs called ectosomes. Although the ciliary membrane is continuous with the plasma membrane, it exhibits unique phospholipid distribution, with levels of phosphatidylinositol 4,5-bisphosphate PI(4,5)P2high in the periciliary membrane compartment (PCMC), but low in the cilium proper and distal tip. The functional impact of PI(4,5)P2on ectosome biogenesis is not known. InC. eleganssensory neurons, different populations of ectosomes are shed from the PCMC and cilium distal tip. We used a genetic approach to increase PI(4,5)P2in the PCMC by overexpressing the type I phosphatidylinositol 4-phosphate 5-kinase (PIP5K1) PPK-1 or in the cilium proper through deletion of the phosphoinositide 5-phosphatase (INPP5E)inpp-1, then imaged released EVs that carried different fluorescently-tagged cargos. We discovered that high PI(4,5)P2differentially affected shedding of distinct ectosome populations from ciliary subcompartments, decreasing biogenesis of EVs from the PCMC, but increasing budding from the cilium distal tip. While manipulating PI(4,5)P2also impacted the trafficking, localization, and abundance of EV cargos in the cilium, localization of these proteins to distinct subsets of ectosome was unchanged, suggesting that PI(4,5)P2does not impact cargo sorting. Further, the PI(4,5)P2-dependent increase in ectosome shedding from the distal tip did not alter cilium length. Thus, altering PI(4,5)P2serves as a mechanism to specifically regulate biogenesis of ectosomes shed in response to physiological stimulus.

Significance

The membrane lipid phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P2) plays a critical role in many cellular processes including endocytosis, protein trafficking, cytoskeletal dynamics, ion channel activity, and cell polarity. Here we used a genetic approach to manipulate PI(4,5)P2levels in the primary cilium, a specialized sensory organelle that serves as a platform not only for organizing signal transduction, but also signal transmission via shedding of a class of extracellular vesicles, termed ectosomes. We discovered that high PI(4,5)P2differentially impacted shedding of two distinct EV subpopulations, decreasing biogenesis of ectosomes derived from the periciliary membrane compartment, but increasing budding from the cilium distal tip. This work defines a new role for PI(4,5)P2in the regulation of ectosome biogenesis and ciliary biology.
Checkerboard synergistic data analysis using a Hill function-based approach
Authors: Gutheil William G.
Published: February 2025

This study presents a checkerboard data analysis approach using a Hill function (y = 1/(1+(x/K)n) to fit each column and row of checkerboard assay data. Column fits give a K (MIC) value in units of row concentration for each column antibiotic concentration (MIC_row vs [Col]), and row fits give an MIC_col value for each row antibiotic (MIC_row vs [Row]). Since the corresponding row and column concentrations are themselves MICs, this provides two sets of MIC vs MIC data pairs which can be plotted together as an isobologram. These MIC_A vs MIC_B values can be subjected to a second round of Hill function fitting, separately in x-y and y-x directions. Finally, a fit based on overlapping Hill functions is developed that allows x-y and y-x dimension fits to be performed simultaneously. Formula for fractional inhibitory concentrations (FICIs) as a function of fit parameters, and other features of these curves, are derived. This analysis also provides “n” (steepness) values from column and row fits, which are themselves dependent on the other antibiotic concentration and can be exceptionally, as in the case of ceftobiprole alone (n>10). This synergistic checkerboard analysis approach is implemented in MATLAB, which performs the fits and provides statistics variable values and alternative models significance.
Dissecting dynamic gene regulatory network using transformer-based temporal causality analysis
Authors: Peng Rui , Qi Juntian , Lu Yuxing , Wu Wei , Sun Qichen , Zhang Chi , Chen Yihan , Wang Jinzhuo
Published: February 2025

Gene regulatory networks (GRNs) dynamically regulate gene activation and repression, driving cellular differentiation. Despite advancements in GRN inference, challenges remain in capturing differentiation dynamics and causal inference. To address these limitations, we developed TRIGON, a Transformer-based model that infers dynamic GRN through learning temporal causality among genes. TRIGON achieved state-of-the-art performance, improving accuracy by 204% over the latest methods across four developmental datasets. When applied to well-established paradigms, including mouse embryonic stem cell and hematopoietic stem cell differentiation, TRIGON identified key transcription factors (TFs) that were not detectable by differential expression analysis and revealed potential TFs associated with primitive endoderm differentiation. Furthermore, TRIGON constructed dynamic GRN across varying time resolutions, enabling the analysis of GRN dynamics from diverse time scales. Through in silico perturbation, TRIGON accurately recapitulated cell fate changes following Gata1 and Spi1 knockout and accurately predicted gene expression changes.
Prediction and Characterization of Genetically Regulated Expression of Target Tissues in Asthma
Authors: Slack Sarah D. , Esquinca Erika , Arehart Christopher H. , Boorgula Meher Preethi , Szczesny Brooke , Romero Alex , Campbell Monica , Chavan Sameer , Rafaels Nicholas , Watson Harold , Landis R. Clive , Hansel Nadia N. , Rotimi Charles N. , Olopade Christopher O. , Figueiredo Camila A. , Ober Carole , Liu Andrew H. , Kenny Eimear E. , Kammers Kai , Ruczinski Ingo , Taub Margaret A. , Daya Michelle , Gignoux Christopher R. , Kechris Katerina , Barnes Kathleen C. , Mathias Rasika A. , Johnson Randi K.
Published: February 2025

Background

Genetic control of gene expression in asthma-related tissues is not well-characterized, particularly for African-ancestry populations, limiting advancement in our understanding of the increased prevalence and severity of asthma in those populations.

Objective

To create novel transcriptome prediction models for asthma tissues (nasal epithelium and CD4+ T cells) and apply them in transcriptome-wide association study (TWAS) to discover candidate asthma genes.

Methods

We developed and validated gene expression prediction databases for unstimulated CD4+ T cells (CD4+T) and nasal epithelium using an elastic net framework. Combining these with existing prediction databases (N=51), we performed TWAS of 9,284 individuals of African-ancestry to identify tissue-specific and cross-tissue candidate genes for asthma. For detailed Methods, please see the Supplemental Methods.

Results

Novel databases for CD4+T and nasal epithelial gene expression prediction contain 8,351 and 10,296 genes, respectively, including four asthma loci (SCGB1A1, MUC5AC, ZNF366, LTC4S) not predictable with existing public databases. Prediction performance was comparable to existing databases and was most accurate for populations sharing ancestry with the training set (e.g. African ancestry). From TWAS, we identified 17 candidate causal asthma genes (adjustedP<0.1), including genes with tissue-specific (IL33in nasal epithelium) and cross-tissue (CCNCandFBXW7) effects.

Conclusions

Expression ofIL33, CCNC, andFBXW7may affect asthma risk in African ancestry populations by mediating inflammatory responses. The addition of CD4+T and nasal epithelium prediction databases to the public sphere will improve ancestry representation and power to detect novel gene-trait associations from TWAS.

Key Messages

From the largest African-ancestry TWAS of asthma to date (N=9,284), we identified 17 candidate causal asthma genes, including: nasal epithelial expression ofIL33, and cross-tissue expression ofCCNCandFBXW7.

We provide gene expression prediction databases for CD4+ T cell and nasal epithelial tissues built in African-ancestry populations, improving ancestry representation and power to detect novel gene-trait associations from TWAS.

Capsule Summary

We developed novel gene expression prediction databases (CD4+ T cells, nasal airway epithelium) representing diverse populations across the African diaspora and identified 17 candidate causal asthma genes from TWAS.
Impacts of patient advisory councils on recovery for sepsis survivors: a case study
Authors: Sheehan Mia , Novakowski Stefanie K , Sheikh Fatima , Korstad Susan , MacDonald Kristin , Sacks Jordan , Russell Kristine , Bergeron Marie-Maxime , Vidler Marianne ,   Sepsis Canada
Published: February 2025

Background

Sepsis is a life-threatening condition with significant long-term impacts for survivors and their families. The known benefits of patient engagement have led to increased efforts globally to involve survivors in sepsis research. This study aimed to characterize the experiences of sepsis survivors and their families in patient advisory councils (PACs) for two Canadian sepsis research networks (Action on Sepsis and Sepsis Canada) and explore how PAC involvement supports long-term recovery.

Methods

This mixed-methods cross-sectional study consisted of a structured survey, ten interviews, and one focus group discussion. All current members of the Sepsis Canada and Action on Sepsis PACs (n=29) were invited to participate. The results of the survey were analyzed descriptively and used to inform the development of the semi-structured interview guide. Qualitative data were analyzed using a thematic approach.

Results

Overall, 15 PAC members participated. The majority of participants were women and over 40 years old. Survey scores showed that most participants felt meaningfully engaged, while the qualitative findings highlighted how PACs supported recovery and fostered community connections between survivors, families, and researchers. Major themes included sepsis experience, recovery journey, characteristics of PACs, characteristics of PAC participation, and impacts of PAC involvement.

Interpretation

Our findings demonstrate that PACs provide critical benefits that extend beyond feeling valued or appreciated for contributing to a specific project. These findings highlight the value of patient-oriented research in shaping evidence-based practices and policies and emphasize the need for trauma-informed approaches and improved post-sepsis care pathways to enhance recovery outcomes.
A tissue multiplexing approach to maximise spatial transcriptomics output from precious pathology specimens
Authors: Kao Yung-Ching , Lee Katie J. , Zhou Chenhao , Causer Andrew , Oey Harald , Khosrotehrani Kiarash , O’Brien Blake , Collins Angus , Nguyen Quan , Soyer H. Peter , Stark Mitchell S.
Published: February 2025

Since diagnostic specimens retrieved from pathology cannot be altered (except for sectioning) for ethicolegal reasons, we describe a method that combines multiple patient specimens, cut from individual blocks, allowing the measurement of several tissues in one capture array. This results in a cost-effective means to increase sample size to permit statistically robust data outputs and to fast-track clinical implementation. Importantly, our tissue multiplexing method is compatible with the standard 10X Genomics supported protocols. We have used skin biopsies in this instance as this is our primary area of research, but this method can be extended to any tissue of interest.
TELEHEALTH and digital health platforms in promoting access to sexual reproductive health self care among youth: A case of Rocket health services in Uganda
Authors: Ssenfuka Vincent , Bwanika John Mark , Kamulegeya Louis Henry , Kiracho Elizabeth Ekirapa , Akulume Martha , Atuyambe Lynn
Published: February 2025

Background

Sexual Reproductive Health (SRH) self-care offers a pathway for low income countries to advance towards Universal Health Coverage by empowering individuals, families, and communities to prioritize their SRH needs independently of healthcare providers. Facilitating access to SRH products is crucial for embracing self-care and digital health technologies hold promise for enhancing accessibility. This study explored the role played by rocket health digital platforms in enhancing accessibility to SRH self-care products among youth in Uganda.

Research methods

Employing a cross-sectional design with a mixed-method approach, the study involved key informant interviews with youth who had purchased SRH self-care products from Rocket Health in 2022, as well as key staff at Rocket Health.

Quantitative data were extracted from Rocket Health’s Electronic Medical Records covering the period from January 2022 to December 2022.

Results

More males (57%) utilized digital platforms for SRH compared to females (43%). The highest utilization was via the E-commerce platform (49%) while the least was via the voice call platforms (4%). A notable portion of youth (30%) still relied on visiting the pharmacy. Contraception products were predominantly consumed through digital platforms (44%), whereas self-testing were less frequently utilized (14%). The study also identified key resources such as the digital infrastructure that maximize the potential of digital health platforms in enhancing SRH self-care.

Conclusions

By gaining insights into the digital infrastructure, preferences, barriers, and financial considerations associated with accessing SRH self-care services through digital platforms, targeted interventions can be developed to promote positive SRH outcomes among youth
3D-Mapping of QRS Loops: Visualizing the Ventricular Electrical Activities
Authors: Ghosal Tania , Kumar Subhankar , Ahmed Imran , Goswami Damodar Prasad , Bandyopadhyay Anupam , Sengupta Arnab
Published: February 2025

This paper presents innovative visualization tools for the analysis and interpretation of three-dimensional vectorcardiogram (VCG), focusing on the QRS complex of the cardiac cycle. Traditional electrocardiography (ECG) lacks the spatial detail necessary for comprehensive cardiac evaluations; however, VCG provides a three-dimensional representation of electrical activity in the heart, allowing for a nuanced understanding of cardiac dynamics. We propose five distinct methodologies for representing spatial QRS VCG loops: (1) unmodified spatial VCG loops that track the progression of ventricular depolarization, (2) fixed-scale VCG loops that facilitate direct comparisons across individuals and conditions, (3) orientation of QRS loop with respect to three orthogonal planes in the 3D space. (4) octant-specific plots that offer insights into spatial distributions, and (5) unit vector and unit sphere representations that emphasize directional movement while normalizing magnitude. Each method has unique strengths in elucidating ventricular electrodynamics in normal and in cardiac conditions such as anterior wall myocardial infarction and inferior wall myocardial infarction, highlighting differences in loop size, directionality of propagation, orientation, and morphology. Together, these methodologies provide a robust framework for advancing VCG research and enhancing clinical assessments of cardiac function. Preliminary findings highlight the potential of these innovative tools.
Pitfalls in understanding how multiple long-term conditions cluster: whole population and age-stratified associations in 7,490,874 people in England
Authors: Romero Moreno Guillermo , Restocchi Valerio , Lone Nazir , Fleuriot Jacques D. , Palmer Jake , De Ferrari Luna , Guthrie Bruce
Published: February 2025

Studies of how multiple long-term conditions (MLTC) cluster together in individuals vary in the populations studied, and whether they age and/or sex stratify, which limits comparison between studies and reproducibility. This study uses a large, UK primary-care dataset to examine how pairwise strength of association between 74 conditions varies by age in both men and women aged 30-99 years, and to explore implications for MLT cluster analyses. Joint prevalence of conditions was lowest in younger age-groups and progressively increased with age, whereas Association Beyond Chance (ABC) was highest in younger age-groups and progressively decreased with age. Condition clustering based on ABC identified different clusters in all men and all women aged 30-99 years, and these clusters differed from those identified in each age-group. Researchers examining how MLTC cluster should consider whether age and sex stratification is appropriate given their study aims and/or would improve comparability and reproducibility, and explicitly justify their choices.
Mathematically modeling worried-well behavior during infectious disease outbreaks
Authors: Singh Bismark , Gromov Dmitry
Published: February 2025

Mitigation and control of novel infectious disease outbreaks requires a strategic response from public health officials. Such a response requires curtailment of both the underlying pathogen as well as public concern. There is an extensive amount of literature on the former, however empirical models catered to the latter are lacking. We seek to fill this gap by presenting a mathematical model that governs spread of “worried-well” behavior within an infectious disease outbreak. Such behavioral concerns, that are marked by an absence of the underlying pathogen infection, manifest themselves in varied degrees ranging from protesting behavior against public health measures to overly isolating behavior leading to mental anxiety. Our work shows different strategies are required for different degrees of worried-well behavior. We provide a framework to mathematically formulate such behavior and provide guidance on controlling surges of such population groups under varied proportions. Since compliance to public health measures is strongly influenced by effective public health messaging, estimates of such population groups are imperative to public health officials.
Harms of short-course systemic corticosteroids among children and adolescents: a systematic review and meta-analysis of randomized controlled trials
Authors: Lima João Pedro , Chowdhury Saifur R. , Tangamornsuksan Wimonchat , Zhai Chunjuan , Chu Xiiajing , Matos Silva Jessyca , Rahman Chowdhury Mahmudur , Kabir Humayun , Couban Rachel , Eltorki Mohamed , Guyatt Gordon H , Chu Derek
Published: February 2025

Introduction

Short courses of systemic corticosteroids are used in the clinical management of a number of acute clinical conditions. In this systematic review and meta-analysis of randomized controlled trials we document the harms of the short-term use (≤ 14 days) of systemic corticosteroids in children and adolescents (1-18 years old) across different clinical conditions.

Methods

We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to January 2024 for randomized controlled trials evaluating the harms of short-course systemic corticosteroids We performed pairwise meta-analyses using the Mantel-Haenszel methods with risk difference. We assessed the certainty of evidence using the GRADE approach and subgroup analysis credibility with the ICEMAN instrument. PROSPERO registration (CRD42023400934).

Results

We identified 45 trials that included 6,470 children. Corticosteroids probably cause few if any serious adverse events (RD 1 fewer per 1000 [95% CI 9 fewer to 7 more]; moderate certainty), but probably do result in adverse events leading to discontinuation (RD 4 more per 1000 [95%CI 3 fewer to 11 more]; moderate certainty) compared to usual care. Corticosteroids probably increase the risk of hyperglycemia (RD 38 more per 1000 [95%CI 11 to 64 more]; moderate certainty), sleep problems (RD 15 more [95% CI 1 to 28 more]; moderate certainty), change in behavior (RD 8 more [95% CI 5 fewer to 21 more]; moderate certainty) and gastrointestinal bleeding (RD 13 more per 1000 [95% CI 3 to 23 more]; moderate certainty).

Conclusion

Corticosteroids likely increase the risk of hyperglycemia, sleep problems, change in behavior and gastrointestinal bleeding, but these adverse events are very seldom if ever serious.
Characterizing Stroke Clots Using Single-Cell Sequencing
Authors: Renedo Daniela , Barak Tanyeri , DeLong Jonathan , Acosta Julian N. , Sujijantarat Nanthiya , Koo Andrew , Antonios Joseph , Rivier Cyprien , Clocchiatti-Tuozzo Santiago , Huo Shufan , Giles James , Falcone Guido J , Sheth Kevin N , Hebert Ryan , Gunel Murat , Sansing Lauren H , Navaratnam Dhasakumar S , Matouk Charles
Published: February 2025

Background

Ischemic stroke result in significant morbidity and mortality. By examining gene expression of cells comprising stroke clots, we aim to gain valuable insights into the underlying mechanisms of this disease and identify potential biomarkers of stroke etiology.

Methods

We employed single-cell RNA sequencing to analyze 10 clot samples from patients diagnosed with large vessel occlusion stroke. We aimed to identify and compare the immune cell compositions and gene expression profiles between stroke clots (atrial fibrillation vs carotid atherosclerosis). We also used MAGMA and GWAS summary statistics from the GIGASTROKE consortium to assess associations association between genetic variants and cell type-specific gene expression within the stroke subtypes.

Results

Our analysis revealed distinct immune cell populations, including monocytes, macrophages, dendritic cells, neutrophils, and T-cells in both clot types. Notably, we observed significant differences in gene expression within the mononuclear phagocytic system cells between clots from atrial fibrillation and carotid atherosclerosis patients.We identified specific genes associated with atherosclerosis and stroke-related processes, such asCD74, HLA- DRB1*01, HTRA1, C1Q, CD81, andCR1clots from carotid atherosclerosis patients. In atrial fibrillation clots, CD8 T-cells and NK-cells show upregulated expression of genes such as GZMH, GZMB, S100A4, FCGBP2, HLA-A, TIMP1, CLIC1, and IFITM2, indicating their involvement in cytotoxic activities and potential tissue damage. The MAGMA approach highlighted significant genetic associations within leukocytes, particularly in atrial fibrillation and carotid clots, underscoring the potential roles of B-cells, T-cells, and macrophages in clot pathogenesis.

Conclusions

This study illuminates the immune and transcriptomic landscape within clots, offering potential biomarkers and lays the foundation for future research.
Germline sequence variation within the ribosomal DNA is associated with human complex traits
Authors: Rodriguez-Algarra Francisco , Cooper Maia , Mardakheh Faraz K , Evans David M , Rakyan Vardhman K
Published: February 2025

The ribosome is one of the core macromolecules in the cell. The ribosomal RNAs (rRNA), which are essential components of the ribosome, are coded by the multi-copy ribosomal DNA (rDNA). Despite its highly conserved function, the rDNA displays substantial variation within all species analysed to date. This variation comprises both inter-individual differences in total copy number (CN) as well as inter- and intragenomic sequence variation in the form of single nucleotide variants (SNV) and insertions/deletions (INDELs) across rDNA copies. Whether germline variation of rDNA sequence associates with phenotypic traits in humans is, to date, unknown. Here, using the UK Biobank whole genome sequencing data, we first derive a high confidence list of rDNA-associated SNVs and INDELs that we validate in multiple ways. Using this list, we show that specific rDNA variants associate with several human traits. In particular, traits associated with body size appear enriched in variants within the Expansion Segment 15L region in the 28S rRNA. The strength of these associations does not diminish when accounting for the total rDNA CN of each individual. Our work represents the first large-scale association analysis of human traits with germline sequence variation in the rDNA, a source of human complex trait-relevant genetic variation that has thus far been largely ignored.
Ribbit: Accurate identification and annotation of complex tandem repeat sequences in genomes
Authors: Avvaru Akshay Kumar , Sharma Anukrati , Sowpati Divya Tej
Published: February 2025

DNA tandem repeats (TRs) are crucial for genomic functions like protein binding, chromatin modulation, splicing, and gene regulation. Abnormal length variations in TRs, especially expansions, are associated with over 60 neurodegenerative diseases. The function and stability of a TR locus is dependent on its sequencing composition and purity. Recent studies report the disease-causing propensity of non-canonical motif expansions in TR loci, and highlight the intricate polymorphism dynamics in complex loci encompassing adjacent, overlapping, and nested TRs. These reports emphasize the need for precise definition and motif decomposition of TR loci. To address this, we present Ribbit, a tool that accurately and efficiently identifies and annotates TR loci in a genome. Ribbit uses 2-bit representation of DNA sequences for rapid identification of TRs of 2–100 bp motif size and resolves complex TR structures. Ribbit efficiently handles imperfections such as indels and substitutions, providing insights into nested and compound TR relationships through detailed motif decomposition. Comparative analyses using simulated data show Ribbit outperforms existing tools like Dot2dot and TRF in terms of runtime and accuracy. Ribbit reports TR loci in the human genome with lower redundancy than TRF and provides resolved TR regions comparable to variation clusters reported in recent catalogues. Therefore, Ribbit can be leveraged to understand the evolution and biology of complex TR regions in large genomes.
Psilocybin alters visual contextual computations
Authors: Aqil Marco , de Hollander Gilles , Vreugdenhil Nina , Knapen Tomas , Dumoulin Serge O.
Published: February 2025

Psilocybin alters perception and brain dynamics. Contextual computations are ubiquitous in the brain. Here, we investigate the effects of psilocybin using psychophysics, ultra-high field functional MRI, and computational modeling. We find that 1) psilocybin alters contextual perception in the Ebbinghaus illusion, 2) psilocybin alters contextual modulation in cortical responses to visual stimuli, and 3) we propose a computational model capable of capturing and linking these changes. Leveraging vision as a beachhead, our findings highlight the alteration of contextual computations as a potential general mechanism underlying psychedelic action.

Teaser

Psilocybin alters visual-contextual computations, a potential general computational mechanism for psychedelic effects in the human brain.