bluuebunny/crossref_metadata_2025_split huggingface dataset:
CircSMAD3 represses VSMC phenotype switching and neointima formation via promoting hnRNPA1 ubiquitination degradation
Authors: Mei Shuai , Zhou Li , Ma Xiaozhu , Wuyun Qidamugai , Chen Chen , Cai Ziyang , Yan Jiangtao , Ding Hu 
Published: September 2023

AbstractAimsCircular RNAs (circRNAs) are novel regulatory RNAs with high evolutionary conservation and stability, making them attractive therapeutic agents for various vascular diseases. SMAD family is a downstream mediator of the canonical TGFβ signalling pathway and has been considered a critical regulator in vascular injury. However, the role of circRNAs derived from the SMAD family members in vascular physiology remains unclear. Therefore, this study aimed to identify a functional circRNA derived from the SMAD family and elucidate its potential as an effective therapeutic agent for vascular proliferative diseases.Methods and ResultsWe initially identified potential functional circRNAs originating from the SMAD family using integrated transcriptome screening. circSMAD3, derived from the SMAD3 gene, was identified to be significantly downregulated in vascular injury and atherosclerosis. Transcriptome analysis was conducted to comprehensively illustrate the pathways modulated by circRNAs. Functionally, circSMAD3 repressed VSMC proliferation and phenotype switchingin vitroevidenced by morphological assays and ameliorated arterial injury-induced neointima formationin vivo. Mechanistically, circSMAD3 interacted with heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) within the nucleus, enhanced its interaction with E3 ligase WD repeat domain 76 (WDR76) to promote hnRNPA1 ubiquitination degradation, facilitated p53 pre-RNA splicing, activated p53γ signalling pathway, and finally suppressed VSMC proliferation and phenotype switching.ConclusionOur study identifies circSMAD3 as a novel epigenetic regulator that suppresses VSMC proliferation and phenotype switching, thereby attenuating vascular remodelling and providing a new circRNA-based therapeutic strategy for cardiovascular diseases.
The more symptoms the better? Covid-19 vaccine side effects and long-term neutralizing antibody response
Authors: Dutcher Ethan G. , Epel Elissa S. , Mason Ashley E. , Hecht Frederick M. , Robinson James E. , Drury Stacy S. , Prather Aric A. 
Published: September 2023

AbstractProtection against SARS-CoV-2 wanes over time, and booster uptake has been low, in part because of concern about side effects. We examined the relationships between local and systemic symptoms, biometric changes, and neutralizing antibodies (nAB) after mRNA vaccination. Data were collected from adults (n = 364) who received two doses of either BNT162b2 or mRNA-1273. Serum nAB concentration was measured at 1 and 6 months post-vaccination. Daily symptom surveys were completed for six days starting on the day of each dose. Concurrently, objective biometric measurements, including skin temperature, heart rate, heart rate variability, and respiratory rate, were collected. We found that certain symptoms (chills, tiredness, feeling unwell, and headache) after the second dose were associated with increases in nAB at 1 and 6 months post-vaccination, to roughly 140-160% the level of individuals without each symptom. Each additional symptom predicted a 1.1-fold nAB increase. Greater increases in skin temperature and heart rate after the second dose predicted higher nAB levels at both time points, but skin temperature change was more predictive of durable (6 month) nAB response than of short-term (1 month) nAB response. In the context of low ongoing vaccine uptake, our convergent symptom and biometric findings suggest that public health messaging could seek to reframe systemic symptoms after vaccination as desirable.
Integrated single-cell multiome analysis reveals muscle fiber-type gene regulatory circuitry modulated by endurance exercise
Authors: Rubenstein Aliza B. , Smith Gregory R. , Zhang Zidong , Chen Xi , Chambers Toby L. , Ruf-Zamojski Frederique , Mendelev Natalia , Cheng Wan Sze , Zamojski Michel , Amper Mary Anne S. , Nair Venugopalan D. , Marderstein Andrew R. , Montgomery Stephen B. , Troyanskaya Olga G. , Zaslavsky Elena , Trappe Todd , Trappe Scott , Sealfon Stuart C. 
Published: September 2023

SummaryEndurance exercise is an important health modifier. We studied cell-type specific adaptations of human skeletal muscle to acute endurance exercise using single-nucleus (sn) multiome sequencing in human vastus lateralis samples collected before and 3.5 hours after 40 min exercise at 70% VO2max in four subjects, as well as in matched time of day samples from two supine resting circadian controls. High quality same-cell RNA-seq and ATAC-seq data were obtained from 37,154 nuclei comprising 14 cell types. Among muscle fiber types, both shared and fiber-type specific regulatory programs were identified. Single-cell circuit analysis identified distinct adaptations in fast, slow and intermediate fibers as well asLUM-expressing FAP cells, involving a total of 328 transcription factors (TFs) acting at altered accessibility sites regulating 2,025 genes. These data and circuit mapping provide single-cell insight into the processes underlying tissue and metabolic remodeling responses to exercise.
Biallelic non-productive enhancer-promoter interaction precedes imprinted expression ofKcnk9during mouse neural commitment
Authors: Rojas Cecilia Rengifo , Cercy Jil , Perillous Sophie , Gonthier-Guéret Céline , Montibus Bertille , Maupetit-Méhouas Stéphanie , Espinadel Astrid , Dupré Marylou , Hong Charles C. , Hata Kenichiro , Nakabayashi Kazuhiko , Plagge Antonius , Bouschet Tristan , Arnaud Philippe , Vaillant Isabelle , Court Franck 
Published: September 2023

AbstractHow constitutive allelic methylation at imprinting control regions (ICRs) interacts with other levels of regulation to drive timely parental allele-specific expression along large imprinted domains remains partially understood. To gain insight into the regulation of thePeg13-Kcnk9domain, an imprinted domain with important brain functions, during neural commitment, we performed an integrative analysis of the epigenetic, transcriptomic and cis-spatial organisation in an allele-specific manner in a mouse stem cell-based model of corticogenesis that recapitulates the control of imprinted gene expression during neurodevelopment. We evidence that despite an allelic higher-order chromatin structure associated with the paternally CTCF-boundPeg13ICR, the enhancer-Kcnk9promoter contacts can occur on both alleles, although they are only productive on the maternal allele. This observation challenges the canonical model in which CTCF binding isolates the enhancer and its target gene on either side, and suggests a more nuanced role for allelic CTCF binding at some ICRs.
Peds1 deficiency in zebrafish results in myeloid cell apoptosis and exacerbated inflammation
Authors: Arroyo Ana B. , Tyrkalska Sylwia D. , Bastida-Martínez Eva , Monera-Girona Antonio J. , Cantón-Sandoval Joaquín , Bernal-Carrión Martín , García-Moreno Diana , Elías-Arnanz Montserrat , Mulero Victoriano 
Published: September 2023

AbstractPlasmalogens are glycerophospholipids with a vinyl ether bond that confers unique properties. Recent identification of the gene encoding PEDS1, the desaturase generating the vinyl ether bond, enables evaluation of the role of plasmalogens in health and disease. Here, we report that Peds1-deficient zebrafish larvae display delayed development, increased basal inflammation, normal hematopoietic stem and progenitor cell emergence, and cell-autonomous myeloid cell apoptosis. In a sterile acute inflammation model, Peds1-deficient larvae exhibited impaired inflammation resolution and tissue regeneration, increased interleukin-1β and NF-κB activities, and elevated ROS levels at the wound site. Abnormal immune cell recruitment, neutrophil persistence, and fewer but predominantly pro-inflammatory macrophages was observed. Chronic skin inflammation worsened in Peds1-deficient larvae but was mitigated by exogenous plasmalogen, which also alleviated hyper-susceptibility to bacterial infection, as did pharmacological inhibition of caspase-3 and colony-stimulating factor 3-induced myelopoiesis. Overall, our results highlight an important role for plasmalogens in myeloid cell biology and inflammation.KeypointsPlasmalogens are crucial for cell autonomous survival, recruitment and activation of neutrophils and macrophages.Plasmalogen production aids inflammation resolution, while supplementation reduces inflammation and boosts bacterial clearance.
StableMate: a statistical method to select stable predictors in omics data
Authors: Deng Yidi , Mao Jiadong , Choi Jarny , Lê Cao Kim-Anh 
Published: September 2023

AbstractIdentifying statistical associations between biological variables is crucial to understand molecular mechanisms. Most association studies are based on correlation or linear regression analyses, but the identified associations often lack reproducibility and interpretability due to the complexity and variability of omics datasets, making it difficult to translate associations into meaningful biological hypotheses.We developed StableMate, a regression framework to address these challenges through a process of variable selection across heterogenous datasets. Given datasets from different environments, such as experimental batches, StableMate selects environment-agnostic (stable) and environment-specific predictors in predicting the response of interest. Stable predictors represent robust functional dependencies with the response, and can be used to build regression models that make generalizable prediction in unseen environments.We applied StableMate to 1) RNA-seq data of breast cancer to discover genes that consistently predict estrogen receptor expression across disease status, 2) metagenomics data to identify microbial signatures that show persistent association with colon cancer across study cohorts and 3) scRNA-seq data of glioblastoma to discern signature genes associated with development of pro-tumour microglia regardless of cell location.Our case studies demonstrate that StableMate is adaptable to regression and classification analyses and achieves comprehensive characterisation of biological systems for different omics data types.
A qualitative evaluation of treatment fidelity alongside a pilot trial of a novel therapy for pediatric IBD
Authors: Olson Jenny L. , Castillo Gisell , Palumbo Amelia , Harrison Megan , Singleton Ruth , Lalu Manoj M. , Fergusson Dean A. , Stintzi Alain , Mack David R. , Presseau Justin 
Published: September 2023

AbstractBackgroundProcess evaluations conducted alongside clinical trials can improve understanding of treatment fidelity and provide contextual knowledge to aide interpretations of trial outcomes. We adopted a multiple-goals perspective to investigate treatment fidelity in two related pilot clinical trials of an adjuvant treatment for pediatric-onset Inflammatory Bowel Disease. This included a focus on barriers and enablers of performing trial-specific activities and of integrating those activities into daily life.MethodsWe interviewed a sub-sample of participants of the Resistant Starch in Pediatric Inflammatory Bowel Disease (NCT04522271) and Optimized Resistant Starch in Inflammatory Bowel Disease pilot trials (NCT04520594) and their caregivers (N=42). The trials examined the effects of personalized food-derived resistant starches as an adjuvant therapy on intestinal microbiome functioning. Codes were identified inductively though conventional content analysis and then mapped to personal projects units of analysis, to explore how participants navigated between activities.ResultsThree themes were identified. The first described the potential impact of living with inflammatory bowel disease and taking prescribed medications. The second described characteristics of trial-specific activities that might impact on their enactment, including perceived difficulty, and challenges following procedures or using trial materials. The third described the integration of trial-specific activities with school, work, household demands, and social, and extracurricular activities.ConclusionsAdjusting to living with inflammatory bowel disease and managing its treatment can impact trial participation. Integrating trial-related activities into daily life can be challenging, which could heighten perceptions of goal conflict. Findings can inform interpretations of trial outcomes and development of strategies for trial optimization and implementation of the adjuvant therapy into clinical practice.
Exposure ofMycobacterium tuberculosisto human alveolar lining fluid shows temporal and strain-specific adaptation to the lung environment
Authors: Allué-Guardia Anna , Garcia-Vilanova Andreu , Schami Alyssa M. , Olmo-Fontánez Angélica M. , Hicks Amberlee , Peters Jay , Maselli Diego J. , Wewers Mark D. , Wang Yufeng , Torrelles Jordi B. 
Published: September 2023

ABSTRACTUpon infection,Mycobacterium tuberculosis(M.tb) reaches the alveolar space and comes in close contact with human alveolar lining fluid (ALF) for an uncertain period of time prior to its encounter with alveolar cells. We showed that homeostatic ALF hydrolytic enzymes modify theM.tbcell envelope, drivingM.tb-host cell interactions. Still, the contribution of ALF duringM.tbinfection is poorly understood. Here, we exposed 4M.tbstrains with different levels of virulence, transmissibility, and drug resistance (DR) to physiological concentrations of human ALF for 15-min and 12-h, and performed RNA sequencing. Gene expression analysis showed a temporal and strain-specific adaptation to human ALF. Differential expression (DE) of ALF-exposedvs.unexposedM.tbrevealed a total of 397 DE genes associated with lipid metabolism, cell envelope and processes, intermediary metabolism and respiration, and regulatory proteins, among others. Most DE genes were detected at 12-h post-ALF exposure, with DR-M.tbstrain W-7642 having the highest number of DE genes. Interestingly, genes from the KstR2 regulon, which controls the degradation of cholesterol C and D rings, were significantly upregulated in all strains post-ALF exposure. These results indicate thatM.tb-ALF contact drives initial metabolic and physiologic changes inM.tb, with potential implications in infection outcome.IMPORTANCETuberculosis, caused by airborne pathogenMycobacterium tuberculosis(M.tb), is one of the leading causes of mortality worldwide. Upon infection,M.tbreaches the alveoli and gets in contact with human alveolar lining fluid (ALF), where ALF hydrolases modify theM.tbcell envelope driving subsequentM.tb-host cell interactions. Still, the contributions of ALF during infection are poorly understood. We exposed 4M.tbstrains to ALF for 15-min and 12-h and performed RNA sequencing, demonstrating a temporal and strain-specific adaptation ofM.tbto ALF. Interestingly, genes associated with cholesterol degradation were highly upregulated in all strains. This study shows for the first time that ALF drives global metabolic changes inM.tbduring the initial stages of the infection, with potential implications in disease outcome. Biologically relevant networks and common and strain-specific bacterial determinants derived from this study could be further investigated as potential therapeutic candidates.
Femora Nutrient Foramina and Aerobic Capacity in Giant Extinct Xenarthrans
Authors: Varela Luciano , Tambusso P. Sebastián , Fariña Richard A. 
Published: September 2023

AbstractNutrient foramina are small openings in the periosteal surface of long bones that traverse the cortical layer and reach the medullary cavity. They are important for the delivery of nutrients and oxygen to bone tissue, and are crucial for the repair and remodeling of bones over time. The nutrient foramina in the femur’s diaphysis are related to the energetic needs of the femur, and have been shown to be related to the maximum metabolic rate (MMR) of taxa. Here, we investigate the relationship between nutrient foramen size and body mass as a proxy to the aerobic capacity of taxa in living and extinct xenarthrans, including living sloths, anteaters, and armadillos, as well as extinct xenarthrans such as glyptodonts, pampatheres, and ground sloths. Sixtynine femora were sampled, including 19 from extant taxa and 50 from extinct taxa. We obtained the blood flow index (Qi) based on foramina area and performed PGLS and phylogenetic ANCOVA in order to explore differences among mammalian groups. Our results show that among mammals, taxa commonly associated with lower metabolism like marsupials and living xenarthrans showed relatively smaller foramina, while the foramina of giant extinct xenarthrans like ground sloths and glyptodonts overlapped with non-xenarthran placentals. Consequently, Qiestimations indicated aerobic capacities comparable to other placental giant taxa like elephants or some ungulates. Furthermore, the estimation of the MMR for fossil giant taxa showed similar results, with almost all taxa showing high values except for those for which strong semi-arboreal or fossorial habits have been described. Moreover, the results are compatible with the diets predicted for extinct taxa, which indicate a strong consumption of grass similar to ungulates and in contrast to the folivorous or insectivorous diets of extant xenarthrans. The ancestral reconstruction of the MMR values indicated a lack of a common pattern for all xenarthrans, strongly supporting the occurrence of low metabolic rates in extant forms due to their particular dietary preferences and arboreal or fossorial habits. Our results highlight the importance of considering different evidence beyond the phylogenetic position of extinct taxa, especially when extinct forms are exceptionally different from their extant relatives. Future studies evaluating the energetic needs of giant extinct xenarthrans should not assume lower metabolic rates for these extinct animals based solely on their phylogenetic position and the observations on their extant relatives.
Comparative genomics reveals the diversity of CRISPR-Cas systems among neonatal sepsis causing group BStreptococcus agalactiae
Authors: Ghate Sudeep D , Rao R. Shyama Prasad , Shastry Rajesh P , Pinto Deepak , Shetty Praveenkumar 
Published: September 2023

ABSTRACTThe pathogenStreptococcus agalactiae, or Group BStreptococcus(GBS) infection is the leading cause of neonatal sepsis and meningitis in neonates. In this study, we aimed to investigate the occurrence and diversity of the CRISPR-Cas system inS. agalactiaegenomes using computational biology approaches. A total of 51 out of 52 complete genomes (98.07%) ofS. agalactiaepossess CRISPR arrays (75 CRISPR arrays) with 17 strains possessing multiple CRISPR arrays. There were only two CRISPR-Cas systems – type II-A system and type I-C system inS. agalactiaestrains. RNA secondary structure analysis through direct repeat analysis showed that the analyzed strains could form stable secondary structures. The 16S rRNA phylogeny exhibited clustering of the strains into three major clades grouped on the type of CRISPR-Cas system. The anti-CRISPRs that contribute to CRISPR-Cas system diversity and prevent genome editing were also detected. These results provide valuable insights into elucidating the evolution, diversity, and function of CRISPR/Cas elements in this pathogen.
Mechanical imbalance between normal and transformed cells drives epithelial homeostasis through cell competition
Authors: Gupta Praver , Kayal Sayantani , Tanimura Nobuyuki , Pothapragada Shilpa P. , Senapati Harish K. , Devendran Padmashree , Fujita Yasuyuki , Bi Dapeng , Das Tamal 
Published: September 2023

AbstractCell competition in epithelial tissue eliminates transformed cells expressing activated oncoproteins to maintain epithelial homeostasis. Although the process is now understood to be of mechanochemical origin, direct mechanical characterization and associated biochemical underpinnings are lacking. Here, we employ tissue-scale stress and compressibility measurements and theoretical modeling to unveil a mechanical imbalance between normal and transformed cells, which drives cell competition. In the mouse intestinal epithelium and epithelial monolayer, transformed cells get compacted during competition. Stress microscopy reveals an emergent compressive stress at the transformed loci leading to this compaction. A cell-based self-propelled Voronoi model predicts that this compressive stress originates from a difference in the collective compressibility of the competing populations. A new collective compressibility measurement technique named gel compression microscopy then elucidates a two-fold higher compressibility of the transformed population than the normal population. Mechanistically, weakened cell-cell adhesions due to reduced junctional abundance of E-cadherin in the transformed cells render them collectively more compressible than normal cells. Taken together, our findings unveil a mechanical basis for epithelial homeostasis against oncogenic transformations with implications in epithelial defense against cancer.
Structural basis of Cfr-mediated antimicrobial resistance and mechanisms for its evasion
Authors: Aleksandrova Elena V. , Wu Kelvin J. Y. , Tresco Ben I. C. , Syroegin Egor A. , Killeavy Erin E. , Balasanyants Samson M. , Svetlov Maxim S. , Gregory Steven T. , Atkinson Gemma C. , Myers Andrew G. , Polikanov Yury S. 
Published: September 2023

ABSTRACTThe ribosome is an essential drug target as many classes of clinically important antibiotics bind and inhibit its functional centers. The catalytic peptidyl transferase center (PTC) is targeted by the broadest array of inhibitors belonging to several chemical classes. One of the most abundant and clinically prevalent mechanisms of resistance to PTC-acting drugs is C8-methylation of the universally conserved adenine residue 2503 (A2503) of the 23S rRNA by the methyltransferase Cfr. Despite its clinical significance, a sufficient understanding of the molecular mechanisms underlying Cfr-mediated resistance is currently lacking. In this work, we developed a method to express a functionally-active Cfr-methyltransferase in the thermophilic bacteriumThermus thermophilusand report a set of high-resolution structures of the Cfr-modified 70S ribosome containing aminoacyl- and peptidyl-tRNAs. Our structures reveal that an allosteric rearrangement of nucleotide A2062 upon Cfr-methylation of A2503 is likely responsible for the inability of some PTC inhibitors to bind to the ribosome, providing additional insights into the Cfr resistance mechanism. Lastly, by determining the structures of the Cfr-methylated ribosome in complex with the antibiotics iboxamycin and tylosin, we provide the structural bases behind two distinct mechanisms of evading Cfr-mediated resistance.