bluuebunny/crossref_metadata_2025_split huggingface dataset:
“Trained Immunity” from BCG Vaccination andMycobacteriumspp. Exposure may be Linked to Reduced Early Childhood (<5-Year-olds) Brain and CNS Cancer Incidences
Authors: Singh Samer , Singh Rakesh K. 
Published: October 2024

ABSTRACTGlobally, with improvements in general hygiene, the incidence of early childhood (0-4Y-olds/<5Y-olds) brain and central nervous system (BCNS) cancers is increasing. Although immunological underpinning is suspected, the identification of protective variables in most BCNS cancer cases remains elusive. Extant hypotheses suggest a role for progressively diminishing exposure to common microbes/pathogens in the rise of childhood cancers in industrialized countries with improved hygiene. Natural exposure to common microbes/pathogens and childhood vaccinations help train the developing immune system of children to respond appropriately to future infections and maintain a healthy immune system. Considering the established role of childhood vaccinations in augmenting immunity, including “trained immunity,” their protective role in pediatric cancers can be surmised. However, a lack of definitive theoretical and practical frameworks to explain conflicting observations has impaired progress. When we analyzed the epidemiological data of European region countries with different childhood vaccination policies but more similar socioeconomic conditions, access to medical services, and genetic makeup as compared to other parts of the world, the coverage of seven major childhood (0-1Y-olds) vaccines was not significantly associated with BCNS cancer incidences in the same cohort of 0-4Y-olds (2020). However, interestingly, prevailing tuberculin immunoreactivity, a surrogate for the existence of heterologous cell-mediated immunity resulting from exposure toMycobacteriumspp., including Bacille Calmette-Guérin (BCG) vaccination, for these populations, is found consistently negatively correlated with the BCNS cancer incidence in 0-4Y-olds for countries mandating neonatal BCG vaccination [r(24): -0.7226, p-value:<0.0001]. Neonatal immune system priming by BCG and boosting by exposure to environmentalMycobacteriumspp. appear protective in 0-4Y-olds. Exploration of BCNS cancer incidence and prevailing immune correlates in matched cohorts, along with prospective randomized controlled trials, may be warranted to confirm the impact of childhood vaccinations and boosters (including natural exposure) on early childhood BCNS cancer incidence.STATEMENT OF SIGNIFICANCEThe discovery of preventive variables/interventions for early childhood (<5Y-old) brain and other CNS (BCNS) cancers is highly desirable. The early childhood BCNS cancer incidence rates in countries with differential childhood vaccination coverage and policies display a strong negative correlation withMycobacteriumspp. exposure chances/frequency in neonatal BCG-vaccinated children. A potentially protective cause- and-effect relationship with timelyMycobacteriumspp. exposures (BCGs and/or environmental) seems likely. An assessment of the biological and translational aspects of current observations is warranted.
A flexible multi-sensor device enabling handheld sensing of heart sounds by untrained users
Authors: McDonald Andrew , Nussbaumer Maximilian , Rathnayake Nirmani , Steeds Richard , Agarwal Anurag 
Published: October 2024

AbstractHeart valve disease has a large and growing burden, with a prognosis worse than many cancers. Screening with a traditional stethoscope is underutilised, often inaccurate even in skilled hands, and requires time-consuming, intimate examinations. Here, we present a handheld device to enable untrained users to record high-quality heart sounds without the need to undress. The device incorporates multiple high-sensitivity sensors embedded in a flexible substrate, placed at key chest locations by the user. To address challenges from localised heart sound vibrations and noise interference, we developed time-frequency signal quality algorithms that automatically select the best sensor in the device and reject recordings with insufficient diagnostic quality. A validation study demonstrates the device’s effectiveness across a diverse range of body types, with multiple sensors significantly increasing the likelihood of a successful recording. The device has the potential to enable accurate, accessible, low-cost heart disease screening.
Associations of PFASs and Pesticides with Lung Function Changes from Adolescence to Young Adulthood in the ESPINA study
Authors: Kornher Kayleigh , Gould Carlos F. , Manzano Jomel Meeko , Baines Katie , Kayser Georgia , Tu Xin , Suarez-Torres Jose , Martinez Danilo , Suarez-Lopez Jose R 
Published: October 2024

ABSTRACTPer- and polyfluoroalkyl substances (PFASs) and pesticides are ubiquitous environmental exposures with increasingly recognized adverse health outcomes; however, their impact on lung function, particularly in combination, remains poorly understood. We included 381 adolescent participants from a prospective cohort study in Ecuador who underwent measurements of serum PFAS (perfluorooctanoic acid [PFOA], perfluorooctanesulfonic acid [PFOS] and perfluorononanoic acid [PFNA]) and urinary herbicides (glyphosate, 2,4D) and fungicides (ethylene thiourea) and had spirometric measurements in either 2016 or 2022. We characterized the association between each PFAS or pesticide and each lung function measure in log-log models estimated via ordinary least squares regression. We used quantile g-computation to assess the association of the mixture of PFAS and pesticides with lung function outcomes. After accounting for multiple hypothesis testing, and in models adjusting for household income, parental education, and exposure to tobacco, we found that, individually, PFOA, glyphosate, and ETU were associated with slight increases in FEV1/FVC between 2016 and 2022. No other individual associations were significant. In mixtures analyses, a one quartile increase in all PFASs and pesticides simultaneously was also not associated with statistically significant changes in lung function outcomes after accounting for multiple hypothesis testing. In large part, we do not provide evidence for associations of PFAS and herbicide and fungicide pesticides with lung function among adolescents in moderate-to-high-altitude agricultural communities in Ecuador.
Distinct proteomic signatures in Ethiopians predict acute and long-term sequelae of COVID-19
Authors: Wolday Dawit , Gebrehiwot Abrha G. , Rameto Muhammed Ahmed , Abdella Saro , Gebreegziabxier Atsbeha , Amogne Wondwossen , de Wit Tobias F. Rinke , Hailu Messay , Tollera Getachew , Tasew Geremew , Tessema Masresha , Miller Matthew , Mukhreji Manali , Gillgrass Amy , Bowdish Dawn M.E. , Kaushic Charu , Verschoor Chris P. 
Published: October 2024

AbstractLittle is known about the acute and long-term sequelae of COVID-19 and its pathophysiology in African patients, who are known to have a distinct immunological profile compared to Caucasian populations. Here, we established proteomic signatures to define severe outcomes of acute COVID-19 and determined whether proteome signatures during the first week of acute illness predict the risk of post-acute sequelae of COVID-19 (Long COVID) in a low-income country (LIC) setting. Using the Olink inflammatory panel, we measured the expression of 92 proteins in the plasma of COVID-19 patients (n=55) and non-COVID-19 individuals (n=23). We identified distinct inflammatory proteomic signatures in acute severe COVID-19 individuals (n=22) compared to asymptomatic or mild/moderate COVID-19 cases (n=33), and non-COVID-19 controls. Levels of SLAMF1, CCL25, IL2RB, IL10RA, IL15RA, IL18 and CST5 were significantly upregulated in patients with critical COVID-19 illness compared to individuals negative for COVID-19. The cohort was followed for an average of 20 months, and 23 individuals developed Long COVID, based on the WHO’s case definition, while 32 COVID-19 patients recovered fully. Whereas upregulated levels of SLAMF1, TNF, TSLP, IL15RA, IL18, ADA, CXCL9, CXCL10, IL17C, and NT3 at the acute phase of the illness were associated with increased Long COVID risk, upregulated expression of TRANCE was associated with a reduced risk of developing Long COVID. Proteomic expression levels of SLAMF1, IL15RA, and IL18 associated with critical illness during the acute phase of COVID-19 also predicted Long COVID risk. Unravelling the pathophysiology of severe acute COVID-19 and Long COVID before its advent may contribute to designing novel interventions for diagnosing, treating, and monitoring of SARS-CoV-2 infection and its associated acute and long-term consequences.
Elucidation and functional characterization of natural sweetener biosynthesis in hortensia species
Authors: Padmakumar Sarala Goutham , Engel Frauke , Hartmann Anja , von Wirén Nicolaus , Hajirezaei Mohammad-Reza 
Published: October 2024

SummaryAmong the various coumarins found in Hydrangea species, the bioactive dihydroisocoumarin known as phyllodulcin (PD) stands out as a non-caloric, high-intensity sweetener, which is up to 800 times sweeter than sucrose. Additionally, PD possesses notable medicinal properties, including antifungal, anti-ulcer, and anti-inflammatory effects. PD also plays several plant-specific roles, such as defending against phytopathogens, responding to abiotic and biotic stresses and regulating hormones. However, the biological function and biosynthetic pathway of PD in Hydrangea remain unexplored. This study employs targeted metabolomic and transcriptomic approaches to uncover the regulatory mechanisms and identify potential candidate genes involved in the biosynthesis of PD. 14 out of 182 different Hydrangea accessions, exhibiting varying levels of PD, were selected for detailed analysis. Accessions ofH. macrophyllawith high PD levels displayed distinct metabolite profiles compared to those with low PD concentrations. Specifically, pathways involving caffeic acid, ferulic acid, and their derivatives, such as scopolin, scopoletin, esculetin, and fraxetin, were predominant in accessions with low PD concentrations. Conversely, the metabolism of phenylalanine, umbelliferone, p-coumaric acid, naringenin, resveratrol, and Thn C was more active in accessions containing PD. Correlation analysis between PD and these metabolites offered valuable insights into their interrelationships. Transcriptome analysis revealed specific genes involved in phenylpropanoid biosynthesis, flavonoid biosynthesis, and stilbene biosynthesis pathways that are crucial for PD biosynthesis. Moreover, the identification of cyclase and ketoreductase genes, which were up regulated in accessions with high PD, provided further understanding of the biosynthetic pathway leading to PD. Finally, based on metabolite levels and gene expression data, a hypothetical pathway from resveratrol to Thn C was proposed, suggesting its potential involvement in PD biosynthesis.HighlightThe metabolic and transcriptomic analysis led to the identification of specific metabolites and genes that are involved in the biosynthesis of dihydrisocoumarin.
A phosphoramidate modification of FUDR, NUC-3373, causes DNA damage and DAMPs release from colorectal cancer cells, potentiating lymphocyte-induced cell death
Authors: Read Oliver J. , Bré Jennifer , Zhang Ying , Mullen Peter , Elshani Mustafa , Harrison David J. 
Published: October 2024

AbstractColorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide with 5-FU still the primary chemotherapeutic of choice. With the increasing use of immunotherapies, much research is focused on the ability to make tumours more immunogenic, thereby rationalising combination with immunotherapy. Here we investigate whether NUC-3373, a phosphoramidate transformation of FUDR, enhances immunogenicity in CRC cell lines and facilitates lymphocyte mediated cell deathin vitro. At sub IC50doses NUC-3373 upregulates damage associate molecular patterns (DAMPs) in both HCT116 and SW480 cells and increases surface expression of MHCII and PD-L1. Pre-treatment with NUC-3373 and subsequent coculture with NK-92 MI natural killer cells caused an increase in LAMP1 expression (degranulation), production of IFN-ψ, and NK-mediated cytotoxicity compared to vehicle controls. Cocultures with patient-derived PBMCs with heterologous CRC cells pre-treated with NUC-3373 demonstrated increased cell death compared to both vehicle controls and monocultures of CRC cells exposed to NUC-3373. Lastly, the PD-1 immune checkpoint inhibitor nivolumab showed synergistic activity when HCT116 cells were pre-treated with NUC-3373. To conclude, we show that NUC-3373 can modulate immune signaling and may therefore facilitate immune mediated tumour cell death.
Genomic and epigenomic maps of mouse centromeres and pericentromeres
Authors: Chaudhry Gitika , Chen Jinguye , Snipes Lucy , Bahl Smriti , Packiaraj Jenika , Lin Xuan , Thakur Jitendra 
Published: October 2024

AbstractSatellite DNA makes up ∼11% of the mouse genome, predominantly located in centromeric and pericentric regions, which are crucial for chromosome segregation. While comprehensive assemblies of these regions have been established in the human genome, they are still lacking in the mouse genome. In this study, we used PacBio long-read sequencing, CUT&RUN sequencing, DNA methylation analysis, and RNA sequencing to generate genomic and epigenomic maps of these regions. We find that centromeric regions are primarily occupied by 120-mer Minor satellites, with other Minor Satellite length variants, 112-mers and 112-64-dimers, localized at centromere-pericentric junctions. Pericentromeric regions are mainly composed of homogeneous Major satellites, while pericentric-chromosomal junctions contain a higher density of divergent satellites. Additionally, the density of non-satellite repeats increases progressively from centromeres to pericentromeres, and further toward chromosomal arm junctions. We found that 120-mer Minor satellites in the core centromere are highly enriched with CENP-A, while the 112-mers and 112-64-dimers show lower CENP-A levels. Homogeneous Major satellites are more enriched with H3K9me3 heterochromatin, whereas divergent Major satellites are preferentially associated with H3K27me3. Furthermore, DNA methylation levels are lower in centromeres compared to pericentric regions. We also observed that only a small subset of satellites is transcribed into RNA, particularly regions exhibiting lower DNA methylation density. Our comprehensive assembly and characterization of the genomic and epigenomic landscape of mouse centromeric and pericentric regions have major implications for satellite biology and ongoing mouse telomere-to-telomere (T2T) assembly efforts.
Rare-Event Sampling using a Reinforcement Learning-Based Weighted Ensemble Method
Authors: Yang Darian T. , Goldberg Alex M. , Chong Lillian T. 
Published: October 2024

AbstractDespite the power of path sampling strategies in enabling simulations of rare events, such strategies have not reached their full potential. A common challenge that remains is the identification of a progress coordinate that captures the slow relevant motions of a rare event. Here we have developed a weighted ensemble (WE) path sampling strategy that exploits reinforcement learning to automatically identify an effective progress coordinate among a set of potential coordinates during a simulation. We apply our WE strategy with reinforcement learning to three benchmark systems: (i) an egg carton-shaped toy potential, (ii) an S-shaped toy potential, and (iii) a dimer of the HIV-1 capsid protein (C-terminal domain). To enable rapid testing of the latter system at the atomic level, we employed discrete-state synthetic molecular dynamics trajectories using a generative, fine-grained Markov state model that was based on extensive conventional simulations. Our results demonstrate that using concepts from reinforcement learning with a weighted ensemble of trajectories automatically identifies relevant progress coordinates among multiple candidates at a given time during a simulation. Due to the rigorous weighting of trajectories, the simulations maintain rigorous kinetics.
Genome-wide studies define new genetic mechanisms of IgA vasculitis
Authors: Liu Lili , Zhu Li , Monteiro-Martins Sara , Griffin Aaron , Vlahos Lukas J. , Fujita Masashi , Berrouet Cecilia , Zanoni Francesca , Marasa Maddalena , Zhang Jun Y. , Zhou Xu-jie , Caliskan Yasar , Akchurin Oleh , Al-Akash Samhar , Jankauskiene Augustina , Bodria Monica , Chishti Aftab , Esposito Ciro , Esposito Vittoria , Claes Donna , Tesar Vladimir , Davis Thomas K. , Samsonov Dmitry , Kaminska Dorota , Hryszko Tomasz , Zaza Gianluigi , Flynn Joseph T. , Iorember Franca , Lugani Francesca , Rizk Dana , Julian Bruce A. , Hidalgo Guillermo , Kallash Mahmoud , Biancone Luigi , Amoroso Antonio , Bono Luisa , Mani Laila-Yasmin , Vogt Bruno , Lin Fangming , Sreedharan Raji , Weng Patricia , Ranch Daniel , Xiao Nianzhou , Quiroga Alejandro , Matar Raed Bou , Rheault Michelle N. , Wenderfer Scott , Selewski Dave , Lundberg Sigrid , Silva Cynthia , Mason Sherene , Mahan John D. , Vasylyeva Tetyana L. , Mucha Krzysztof , Foroncewicz Bartosz , Pączek Leszek , Florczak Michał , Olszewska Małgorzata , Gradzińska Agnieszka , Szczepańska Maria , Machura Edyta , Badeński Andrzej , Krakowczyk Helena , Sikora Przemysław , Kwella Norbert , Miklaszewska Monika , Drożdż Dorota , Zaniew Marcin , Pawlaczyk Krzysztof , Siniewicz-Luzeńczyk Katarzyna , Bomback Andrew S. , Appel Gerald B. , Izzi Claudia , Scolari Francesco , Materna-Kiryluk Anna , Mizerska-Wasiak Malgorzata , Berthelot Laureline , Pillebout Evangeline , Monteiro Renato C. , Novak Jan , Green Todd Jason , Smoyer William E. , Hastings M. Colleen , Wyatt Robert J. , Nelson Raoul , Martin Javier , González-Gay Miguel A. , De Jager Philip L. , Köttgen Anna , Califano Andrea , Gharavi Ali G. , Zhang Hong , Kiryluk Krzysztof 
Published: October 2024

AbstractIgA vasculitis (IgAV) is a pediatric disease with skin and systemic manifestations. Here, we conducted genome, transcriptome, and proteome-wide association studies in 2,170 IgAV cases and 5,928 controls, generated IgAV-specific maps of gene expression and splicing from blood of 255 pediatric cases, and reconstructed myeloid-specific regulatory networks to define disease master regulators modulated by the newly identified disease driver genes. We observed significant association at theHLA-DRB1(OR=1.55, P=1.1×10−25) and fine-mapped specific amino-acid risk substitutions in DRβ1. We discovered two novel non-HLA loci:FCAR(OR=1.51, P=1.0×10−20) encoding a myeloid IgA receptor FcαR, andINPP5D(OR=1.34, P=2.2×10−09) encoding a known inhibitor of FcαR signaling. TheFCARrisk locus co-localized with a cis-eQTL increasingFCARexpression; the risk alleles disrupted aPRDM1binding motif within a myeloid enhancer ofFCAR. Another risk locus was associated with a higher genetically predicted levels of plasma IL6R. TheIL6Rrisk haplotype carried a missense variant contributing to accelerated cleavage of IL6R into a soluble form. Using systems biology approaches, we prioritized IgAV master regulators co-modulated byFCAR,INPP5DandIL6Rin myeloid cells. We additionally identified 21 shared loci in a cross-phenotype analysis of IgAV with IgA nephropathy, including novel lociPAID4, WLS, andANKRD55.
Genome-wide association study in chondrocalcinosis reveals ENPP1 as a candidate therapeutic target in calcium pyrophosphate deposition disease
Authors: Takei Riku , Rosenthal Ann , Pascart Tristan , Reynolds Richard J. , Tedeschi Sara K. , Merriman Tony R. 
Published: October 2024

ABSTRACTObjectiveThe genetic basis of calcium pyrophosphate deposition (CPPD) disease is largely unknown. This limits the development of therapeutic strategies. We aimed to analyze a genome-wide association study (GWAS) on a large administrative database to identify new candidate causal genes for CPPD disease.MethodsWe used publicly available GWAS summary statistics for chondrocalcinosis and for crystal arthropathy from the Veterans Affairs Million Veteran Program in people of African (AFR) and European (EUR) ancestry. Included were 3,004 (536 AFR and 2,468 EUR) cases for chondrocalcinosis and 3,766 (700 AFR and 3,066 EUR) cases for crystal arthropathy. Our primary analysis was in chondrocalcinosis with secondary analysis in crystal arthropathy. We tested for colocalization of chondrocalcinosis genetic association signals with genetic control of gene expression.ResultsThere were two genome-wide significant loci for chondrocalcinosis in both AFR and EUR, both on chromosome 6 (signals within theENPP1andRNF144Bgenes). Findings were supported by analysis of the crystal arthropathy cohort. Colocalization analysis of chondrocalcinosis genetic association signals with genetic control of gene expression and alternative splicing further supportedENPP1andRNF144Bas candidate casual genes. AtENPP1the allele that increases the risk for chondrocalcinosis associated with increasedENPP1expression.ConclusionENPP1encodes ectonucleotide pyrophosphatase / phosphodiesterase family member 1 that produces AMP and pyrophosphate, potentially contributing to the formation of calcium pyrophosphate crystals. Selective ENPP1 inhibitors developed for infectious disease and cancer could be repurposed for the treatment of chondrocalcinosis and CPPD disease.
Multiplex PCR detection of enteric pathogens in a community-based birth cohort in Ecuador: comparison of xTAG-GPP and TaqMan array card assays
Authors: Ayala Stuart Torres , Vivanco Lesly Simbaña , Walas Nikolina , Jesser Kelsey , Zhou Nicolette A. , Fagnant-Sperati Christine S. , Burroughs Hadley R. , Lee Gwenyth O. , Eisenberg Joseph N.S. , Trueba Gabriel , Levy Karen , Arnold Benjamin F. 
Published: October 2024

AbstractWe compared the performance of two multiplex platforms, Luminex xTAG Gastrointestinal Pathogen Panel®and TaqMan Array Card, against a panel of 14 enteric pathogen targets in a community-based birth cohort in Ecuador. We found high levels of agreement and similar prevalence estimates across most pathogens.
Medication use patterns among older patients in temporary stays in Denmark
Authors: Harbi Hanin , Lundby Carina , Jensen Peter Bjødstrup , Larsen Søren Post , Rørbæk Linda Grouleff , Ravn-Nielsen Lene Vestergaard , Ryg Jesper , Reilev Mette , Edwards Kasper , Pottegård Anton 
Published: October 2024

AbstractBackgroundPatients in temporary stays are typically older individuals with frailty and multimorbidity. However, limited knowledge exists about their medication use. This study aimed to describe prescription drug use among patients in temporary stays in Denmark.MethodsWe conducted a drug utilisation study on 11,424 patients in public healthcare-operated temporary stay units across 14 Danish municipalities between 2016 to 2023 (median age 81 years; 54% women). Prescription data were sourced from the Danish National Prescription Registry.ResultsPatients used a median of 6 drug classes (interquartile range [IQR] 4-10) in the four months before moving into a temporary stay facility; 68% used ≥ 5 drug classes, and 26% used ≥ 10. The most commonly used drug classes were paracetamol (49%), statins (30%), and proton pump inhibitors (29%). The monthly rate of new drug use increased from 23/100 patients six months before move-in to a peak of 262/100 patients in the first month after move-in, driven primarily by laxatives, analgesics, and antibiotics. High-risk drug use increased from 70% to 83% following move-in, with 49% of patients initiating at least one new high-risk drug, most commonly opioids (28%), potassium (17%), and anticoagulants (15%). General practitioners initiated 60%-70% of treatments and maintained 80%-90%. Hospital physician prescriptions increased around move-in, peaking at 55% for initiation and 25% for maintenance in the first month after move-in.ConclusionPatients in temporary stays in Denmark demonstrate high medication use, including high-risk drugs, with a notable increase in treatment initiations around the time of move-in.