bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell omics-based characterization of human basophils reveals two transcriptionally distinct populations
Authors: Papavasileiou Sofia , Mo Jiezhen , Boey Daryl , Wu Chenyan , Tronstad Magnus , Olsen Remi-André , Bachmann Jörg A. , Low Jing Hui , Ong Jocelyn , Blom Lars Heede , Andiappan Anand Kumar , Nilsson Gunnar , Dahlin Joakim S. 
Published: February 2025

AbstractBackgroundBasophils are implicated in various diseases including allergies, but a comprehensive characterization of human basophils has yet to be performed at the single-cell level.ObjectiveWe aimed to generate a single-cell omics-based resource of circulating human basophils, to be made accessible to the research community. We also sought to investigate basophil heterogeneity at the transcriptional and surface epitope levels.MethodsCirculating basophils were analyzed using short- and long-read single-cell RNA-sequencing in combination with large-scale immunoprofiling of more than 100 cell surface markers.ResultsWe used a cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) based cell barcoding system to accurately track side scatterlowlineage−CCR3+FcεRI+basophils through the single-cell omics analysis. The approach allowed for accurate transcriptional profiling of basophils among low-density peripheral blood leukocytes. The generation of an additional dataset with only basophils revealed two transcriptionally distinct populations. Single-cell transcriptomic analysis of samples from additional donors was performed and coupled with a large-scale immunoprofiling screen, producing a third CITE-seq dataset containing basophils. The analysis verified the existence of the two transcriptionally distinct populations and revealed that these populations have similar immunophenotypes with regard to the investigated surface markers. Long-read single-cell RNA-sequencing analysis provided further insights into the gene expression dynamics of the circulating basophils and confirmed the transcriptionally defined basophil states.ConclusionsThe single-cell omics analysis revealed two transcriptionally distinct basophil populations. Our single-cell omics resource constitutes a reference for charting human basophils at the cellular and molecular levels in health and disease.Capsule summaryShort- and long-read single-cell RNA-sequencing coupled with large-scale immunoprofiling characterize human basophils in peripheral blood and reveal two transcriptionally distinct populations.
Identification of novelcis-acting elements, E-box and ISRE, regulating IFNγ-IRF1 axis-mediated NLRC5 expression
Authors: Yoo Ji-Seung , Kasuga Yusuke , Vijayan Saptha , Yousuf Suhail , Kobayashi Koichi S. 
Published: February 2025

SUMMARYNLRC5 and CIITA are the primary transcriptional regulators of MHC class I and MHC class II, respectively, and play essential roles in adaptive immunity. While the regulatory mechanisms of CIITA have been extensively characterized, the transcriptional control of NLRC5 remains incompletely understood. In this study, we identified two novel conservedcis-regulatory elements within the NLRC5 promoter, an E-box and an ISRE. Furthermore, we revealed IRF1 as a novel transcriptional regulator of NLRC5, binding directly to the ISRE within the NLRC5 promoter. Using the newly identified NLRC5 ISRE, we established a screening platform to identify modulators of the IFNγ-IRF1-NLRC5 axis. This system corroborated the inhibitory effects of known viral antagonists and led to the identification of novel SARS-CoV-2 viral factors that suppress IFNγ- mediated IRF1 nuclear translocation, thereby inhibiting the MHC class I pathway. By elucidating the previously unproven molecular mechanism underlying IFNγ-mediated NLRC5 regulation, our study provides critical insights into viral immune evasion strategies and the modulation of antigen presentation. These findings may facilitate the development of MHC class I-targeted therapeutics by modulating the IRF1-NLRC5 axis.
Electrostatics facilitate mid-air host attachment in parasitic jumping nematodes
Authors: Ran Ranjiangshang , Burton Justin C. , Ortega-Jimenez Victor M. 
Published: February 2025

Jumping can be hazardous for entomopathogenic nematodes (EPNs) as those that fail to attach to an insect host face death by predation or starvation. Recently, it has been shown that electrostatic charges on large insects can prompt a close-range detachment of free-living nematodes, which are non-parasitic and unable to jump. However, it remains unclear if static electricity can influence aerial interactions between parasitic jumping worms and their insect hosts. Here we analyze and model the trajectories of jumping EPNs in still air as they approach fruit flies with varying electrostatic charge. We discover that the nematodes’ attachment to the host is facilitated by an electrical potential of a few hundred volts, a magnitude commonly found in flying insects. A model combining electrostatics, aerodynamics, and Bayesian inference indicates that the electrostatic charge on jumping nematodes is ~ 0.1 pC, which aligns with theoretical predictions for electrostatic induction. Drag coefficients based on host-nematode interactions in the presence of horizontal wind show differences at both low and high jumping velocities. Numerical simulations show that intermediate wind speeds (~ 0.2 m/s) can further increase the likelihood of host attachment, as wind-driven aerial drifting allows the worms to reach hosts at greater distances. Our results suggest that submillimeter parasites that become airborne may exploit the electric charge carried by their host to facilitate attachment and thus enhance survival. The use of quantitative physical models provides valuable insights into understanding complex airborne infectious diseases mediated by natural environmental forces.Significance StatementEntomopathogenic nematodes (EPNs) are submillimeter parasites renowned for their explosive aerial jumping, allowing them to reach distant insect hosts. They serve as important model organisms and natural biopesticides. Our work reveals that these tiny organisms can be electrostatically attracted to charged hosts, such as fruit flies, increasing the likelihood of infection. Experiments show that host attachment is significantly enhanced by electrostatic forces generated by naturally occurring electric fields from flying insect hosts. Our computational model confirms that the static charge of EPNs agrees with theoretical predictions from electrostatic induction. We propose that electrostatics play a crucial role in enhancing the survival of these jumping parasites and provide a framework for modeling environmental forces in aerial parasite-host interactions.
Phosphorylation Deficient Inducible cAMP Early Repressor (ICER) Modulates Tumorigenesis and Survival in a Transgenic Zebrafish (Danio rerio) Model of Melanoma
Authors: Wheelan Justin , Spigelman Melissa , Cirinelli Angelo , Reilly James , Molina Carlos A. 
Published: February 2025

AbstractMelanoma, the most lethal form of skin cancer, is commonly associated by mutations in the BRAF gene, particularly BRAFV600E, which drives tumor proliferation via ERK1/2 signaling cascade. While BRAF inhibitors initially demonstrate efficacy, therapeutic resistance remains a significant challenge. Emerging evidence implicates the cAMP signaling pathway, particularly the cAMP response element-binding protein (CREB) and its repressor, Inducible cAMP Early Repressor (ICER), in melanoma progression and drug resistance. ICER, a transcriptional repressor regulated via Ras/MAPK-mediated phosphorylation and ubiquitination, is degraded in melanoma, undermining its tumor-suppressive role. In abrafV600E;p53(loss of function) transgenic zebrafish (Danio rerio) model, we investigated the role of a ubiquitin-resistant ICER mutant (S35-41A-ICER) in tumor progression. Transgenic fish expressing S35-41A-ICER exhibited extended survival and reduced tumor invasiveness compared to wild-type ICER. RNA sequencing revealed dysregulation of CREB/CREM targets and compensatory pathways, including Rap1 and PI3K/AKT signaling, as well as candidate gene targets of ICER regulation, including the Protein Kinase A catalytic subunitprkacaa. Our findings suggest that a ubiquitin resistant ICER mitigates melanoma progression and represses oncogenic pathways in abrafV600Emelanoma context.Summary StatementThis study shows that ubiquitin-resistant ICER mutant suppresses melanoma progression, prolongs survival inbrafV600Ezebrafish, revealing its potential as a tumor suppressor and therapeutic target in melanoma resistance.
Risk of Alopecia Areata with Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss
Authors: Sodhi Mohit , Rezaeianzadeh Ramin , Kezouh Abbas , Frey Connor , Etminan Mahyar 
Published: February 2025

ABSTRACTGLP-1 (glucagon-like peptide-1) agonists including semaglutide and liraglutide are possibly the most prescribed medications in the world. Many recent studies have quantified their adverse events with a focus on gastrointestinal adverse events. However, no large epidemiologic study has investigated the risk of hair loss with these medications. We conducted a retrospective cohort study using a large health claims database to investigate this risk. Using a random sample of 16 million patients, we identified new users of semaglutide or liraglutide and an active comparator bupropion-naltrexone. We excluded those with a diagnosis of diabetes or use of antihyperglycemics prior to cohort entry. Cohort members were followed from the first date of a study drug prescription to the diagnosis of alopecia areata. We adjusted for age, sex, geographic location, depression, steroid use, hypothyroidism, polycystic ovary syndrome, and anemia. Our cohort included 926 semaglutide users, 17,898 liraglutide users, and 1,348 users of bupropion-naltrexone. We found that compared to bupropion-naltrexone, the crude hazard ratio and adjusted hazard ratio for alopecia areata for semaglutide or liraglutide use was 1.73 (95% confidence interval: 1.00-3.01) and 2.09 (95% confidence interval: 1.20-3.65) respectively. Our results demonstrate an increased risk of alopecia areata with GLP-1 agonists. Future studies are required to ascertain the association between GLP-1 agonists and alopecia areata.
Regulatory genomic circuitry of brain age by integrative functional genomic analyses
Authors: Zhao Xingzhong , Yang Anyi , Ding Jing , Yang Yucheng T. , Zhao Xing-Ming 
Published: February 2025

AbstractBrain age gap (BAG) is a valuable biomarker for evaluating brain healthy status and detecting age-associated cognitive degeneration. However, the genetic architecture of BAG and the underlying mechanisms are poorly understood. Here, we estimate brain age from magnetic resonance imaging with improved accuracy using our proposed adversarial convolution network (ACN), followed by applying the ACN model to an elder cohort from UK Biobank. The genetic heritability of BAG is significantly enriched in the regulatory regions and implicated in glial cells. We prioritize a set of BAG-associated genes, and further characterize their expression patterns across brain cell types and regions. Two BAG-associated genes,RUNX2andKLF3, are found as associated with epigenetic clock and diverse aging-related biological pathways. Finally, two BAG-associated hub transcription factors,KLF3andSOX10, are identified as regulators of pleiotropic risk genes from diverse brain disorders. Altogether, we improve the estimation of BAG, and identify BAG-associated genes and regulatory networks that are implicated in brain disorders.
RNA Transcripts Serve as a Template for Double-Strand Break Repair in Human Cells
Authors: Jalan Manisha , Brambati Alessandra , Shah Hina , McDermott Niamh , Patel Juber , Zhu Yingjie , Doymaz Ahmet , Wu Julius , Anderson Kyrie S , Gazzo Andrea , Pareja Fresia , Yamaguchi Takafumi N , Vougiouklakis Theodore , Ahmed-Seghir Sana , Steinberg Philippa , Neiman-Golden Anna , Azeroglu Benura , Gomez-Aguilar Joan , da Silva Edaise M , Hussain Suleman , Higginson Daniel , Boutros Paul C , Riaz Nadeem , Reis-Filho Jorge S , Powell Simon N , Sfeir Agnel 
Published: February 2025

ABSTRACTDouble-strand breaks (DSBs) are toxic lesions that lead to genome instability. While canonical DSB repair pathways typically operate independently of RNA, emerging evidence suggests that RNA:DNA hybrids and transcripts near damaged sites can influence repair outcomes. However, a direct role for transcript RNA as a template during DSB repair in human cells is yet to be established. In this study, we designed fluorescent- and sequencing-based assays, which demonstrated that RNA-containing oligonucleotides and messenger RNA serve as templates to promote DSB repair. We conducted a CRISPR/Cas9-based genetic screen to identify factors that promote RNA-templated DSB repair (RT-DSBR), and of the candidate polymerases, we identified DNA polymerase-zeta (Polζ) as the potential reverse transcriptase that facilitates RT-DSBR. Furthermore, by analyzing sequencing data from cancer genomes, we identified the presence of whole intron deletions, a unique genomic scar reflective of RT-DSBR activity generated when spliced mRNA serves as the repair template. These findings highlight RT-DSBR as an alternative pathway for repairing DSBs in transcribed genes, with potential mutagenic consequences.
Nonstandard coding of deceased-donor kidney out-of-sequence allocation leads to underrecognition of allocation deviations
Authors: Tucker Emma G. , Yu Miko E. , Adler Joel T. , Cron David C. , Sahni Prateek V. , Schold Jesse D. , Mohan Sumit , Husain Syed Ali 
Published: February 2025

AbstractOut-of-sequence (OOS) allocation, the process by which organ procurement organizations (OPOs) can deviate from standard rank lists of potential recipients to expeditiously allocate deceased-donor kidneys, is rising in the U.S. We aimed to determine whether current OPO reporting practices obscure the extent of OOS allocation. Using match-run data for all U.S. deceased-donor kidney transplants from 2021-2023, we defined “miscoded” OOS (mOOS) allocation transplants as those with use of the 799 or 898 OPO- initiated refusal codes (“other, specify”) with free text responses clearly indicating OOS allocation, and compared these to “explicit” OOS (eOOS) allocation, wherein OOS transplants are appropriately coded using refusal codes 861-863. We found that the prevalence of mOOS allocation increased from 2021 (122 transplants) to 2023 (430 transplants) and accounted for 12% of all OOS transplants by 2023. Organs allocated via mOOS had a lower median KDPI than those allocated via eOOS (51% vs 55%, p <0.01). While an increasing number of OPOs used mOOS throughout the study period, the practice remained concentrated overall, with 5 “outlier” OPOs performing 66% of mOOS allocations in 2023. These findings highlight the need for stricter oversight of organ allocation and underscore the responsibility of the OPTN to ensure proper data reporting.
Impact of Patient Positioning on Hemodynamic Assessment: A Comparison of Supine and Upright Right Heart Catheterization in Pulmonary Hypertension and HFpEF
Authors: Chowdhury Mohammed A. , Squires Johanna , Systrom David M. , Waxman Aaron B. 
Published: February 2025

AbstractBackgroundRight heart catheterization (RHC) is the gold standard for the objective diagnosis of heart failure with preserved ejection fraction (HFpEF) and pulmonary hypertension (PH). Typically performed in the supine position, RHC may not accurately reflect the hemodynamic changes that occur during upright activity. The effect of patient positioning on RHC measurements, especially in distinguishing between precapillary and postcapillary PH, has been underexplored. This study aims to compare hemodynamic measurements between supine and upright RHC and assess how patient positioning influences the diagnosis of PH.MethodsWe performed a retrospective observational study of patients who underwent both supine and upright RHC during invasive cardiopulmonary exercise testing (iCPET) at Brigham and Women’s Hospital between January 2015 and January 2024. Hemodynamic parameters were measured and compared between both positions.ResultsCompared to upright RHC, supine RHC showed consistently higher mean PAP (21 ± 8.5 mmHg vs. 16 ± 8 mmHg) and PCWP (12 ± 4.7 mmHg vs. 6.4 ± 4.9 mmHg). Supine RHC diagnosed significantly more cases of HFpEF (21.8% vs. 5.7%) and isolated postcapillary PH (10.9% vs. %), primarily due to overestimation of PCWP. Upright RHC had a higher specificity for detecting elevated PCWP (>15 mmHg) in patients with elevated NT-proBNP (92.8% vs. 74.3%), iCPET diagnosed exercise HFpEF (95.29% vs 80.92%), PCWP/CO>2 (98.27% vs 84.61%) and demonstrated stronger association with PCWP/CO>2 (OR 9.11, 95% CI 5-16) compared to supine RHC. The differences in mPAP and PCWP measurement between supine and upright RHC persisted regardless of sex, age, BMI, or severity of chronic lung disease.ConclusionsHemodynamic discrepancies between supine and upright RHC exist which can significantly affect the diagnosis of PH and HFpEF. Upright RHC provides more physiologically relevant data, potentially enhancing diagnostic accuracy and should be considered in the evaluation of patients with PH.Clinical PerspectiveWhat is new?This study highlights significant differences in hemodynamic measurements of mean pulmonary artery pressure and pulmonary capillary wedge pressure between supine and upright RHC.The difference in supine and upright hemodynamics persists despite age, sex, BMI, FEV1 or smoking.Compared to upright RHC, supine RHC results in overestimation of PCWP resulting in misclassification of PH.What are the clinical implications?Utilizing upright RHC may enhance the accuracy of diagnosing PH and HFpEF, leading to better-targeted therapies and management strategies for patients.Improved diagnostic precision could reduce unnecessary treatments and hospitalizations associated with misdiagnosed heart failure and pulmonary hypertension.
Shivering, but not adipose tissue thermogenesis, increases as a function of mean skin temperature in cold-exposed men and women
Authors: Dumont Lauralyne , Richard Gabriel , Espagnet Romain , Frisch Frédérique , Fortin Mélanie , Samson Arnaud , Bouchard Jonathan , Fontaine Réjean , Croteau Etienne , Phoenix Serge , Dubreuil Stéphanie , Guérin Brigitte , Turcotte Éric E. , Carpentier André C. , Blondin Denis P. 
Published: February 2025

SUMMARYSkin cooling results in the activation of heat generating mechanisms to counteract heat lost to the environment. Here, we aim to understand the extent that variations in cold-stimulated heat production may be driven by differences in the contribution of shivering and non-shivering thermogenesis (NST) and the interaction with biological sex. Using a novel mean skin temperature clamping technique in healthy men and women, our data shows that cold-stimulated heat production rises with increasing shivering and myocardial oxidative metabolism in a skin temperature-dependent fashion. Shivering and myocardial thermogenesis were also moderately associated. In contrast, adipose tissue NST did not increase in a linear manner to reductions in skin temperature. Men and women displayed similar thermoregulatory responses, although women presented more pronounced shivering through a greater recruitment of lower-body muscles and greater number of motor units recruited. Thus, shivering contributes proportionally to cold-induced thermogenesis whereas adipose tissue thermogenesis displays an all-or-none response.
Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys
Authors: Pitts Jared , Zamora J. Lizbeth Reyes , Manhas Savrina , Aeschbacher Thomas , Chan Josolyn , Cutillas Vincent , Nair Varsha , Riola Nicolas C. , Vijjapurapu Arya , Vermillion Meghan S. , Eng Stacey , Richards Christopher , Han Dong , Perry Jason K. , Chaudhuri Subhra , Liu Iris , Martinez Clarissa , Peinovich Nadine , Sun Kai-Hui , Cai Arthur , Martin Ross , Moshiri Jasmine , Hedskog Charlotte , Babusis Darius , Siegel Dustin S. , Kalla Rao , Avadhanula Vasanthi , Piedra Pedro A. , Stobbelaar Kim , Delputte Peter L. , Marceau Caleb , Mateo Roberto , Svarovskaia Jenny , Mo Hongmei , Subramanian Raju , Mackman Richard L. , Cihlar Tomas , Fletcher Simon P. , Bilello John P. 
Published: February 2025

ABSTRACTRespiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20-0.66 μM). Resistance selection studies with ODV and GS-441524 against RSV identified a single amino acid substitution, I777L, in the L polymerase with reduced susceptibility (3.3-3.8-fold) to ODV and GS-441524, indicating a high barrier for resistance development. In an African green monkey RSV infection model, once-daily oral ODV doses of 30 or 90 mg/kg initiated ∼24 hours post-infection significantly reduced log10viral RNA copies/mL×day area under the curve by 69-92% in the upper and lower respiratory tracts. Together, these preclinical data support the clinical evaluation of ODV for the treatment of RSV infection.
Harnessing Mechanistic Simulators for Rapid Diagnostic Test Capture and Deep Learning Classification
Authors: Rogers Elliott , Turbé Valérian , Gareta Dickman , Herbst Carina , Herbst Kobus , Shahmanesh Maryam , McKendry Rachel A. 
Published: February 2025

AbstractRapid Diagnostic Tests (RDTs) are affordable tools for disease diagnosis and surveillance. There is growing evidence of the benefits of Machine Learning models to aid accurate decision making through classification of test results, improving sensitivity and specificity and reducing the risk of false positives/negatives. Yet to date these models have relied on large, clinically sensitive, costly, and time-intensive real-world image training libraries. Herein, we present SynSight – a classification pipeline for RDTs trained using mechanistically generated synthetic data. SynSight combines test region of interest segmentation using real-time object detection and result classification. We validate SynSight with HIV RDTs achieving 98.2% sensitivity and 99.2% specificity, and further with COVID-19 RDTs (two antigen, achieving 99% and 97% accuracy; one antibody, achieving 95% accuracy). This agile approach opens training opportunities for machine learning classifiers for RDTs with no available real-world image libraries, keeping pace with new RDT development and innovation.