bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monitoring occurrence of SARS-CoV-2 in school populations: a wastewater-based approach
Authors: Gutierrez Victor Castro , Hassard Francis , Vu Milan , Leitao Rodrigo , Burczynska Beata , Wildeboer Dirk , Stanton Isobel , Rahimzadeh Shadi , Baio Gianluca , Garelick Hemda , Hofman Jan , Kasprzyk-Hordern Barbara , Kwiatkowska Rachel , Majeed Azeem , Priest Sally , Grimsley Jasmine , Lundy Lian , Singer Andrew C , Di Cesare Mariachiara 
Published: March 2021

AbstractClinical testing of children in schools is challenging, with economic implications limiting its frequent use as a monitoring tool of the risks assumed by children and staff during the COVID-19 pandemic. Here, a wastewater based epidemiology approach has been used to monitor 16 schools (10 primary, 5 secondary and 1 post-16 and further education for a total of 17 sites) in England. A total of 296 samples over 9 weeks have been analysed for N1 and E genes using qPCR methods. Of the samples returned, 47.3% were positive for one or both genes with a frequency of detection in line with the respective community. WBE offers a promising low cost, non-invasive approach for supplementing clinical testing and can offer longitudinal insights that are impractical with traditional clinical testing.
Implementation of the 2021 molecular ESGO/ESTRO/ESP risk groups in endometrial cancer
Authors: Imboden Sara , Nastic Denis , Ghaderi Mehran , Rydberg Filippa , Siegenthaler Franziska , Mueller Michael D , Rau Tilman T , Epstein Elisabeth , Carlson Joseph W. 
Published: March 2021

ABSTRACTIntroductionIn 2021, a joint ESGO/ESTRO/ESP committee updated their evidence-based guidelines for endometrial cancer, recommending a new risk grouping incorporating both clinicopathologic and molecular parameters. We applied the new risk grouping and compared the results to those of the prior 2016 clinicopathologic system.Materials and methodsWe classified molecularly a cohort of 604 women diagnosed with endometrial cancer using immunohistochemistry for TP53 and MMR proteins on a tissue microarray, as well as Sanger sequencing for POLE mutations. These results, combined with clinicopathologic data, allowed the patients to be risk grouped using both the new 2021 molecular/clinicopathologic parameters and the prior 2016 clinicopathologic system. In addition, clinical treatment and outcome data were collected from medical records.ResultsThe application of the 2021 molecular markers shows Kaplan-Meier curves with a significant difference between the groups for all survival. Molecular classification under the 2021 guidelines revealed a total of 39 patients (39/594, 7%) with a change in risk group in relation to the 2016 classification system: the shift was alone due to either P53abn or POLEmut molecular marker. In order to ensure correct 2021 molecular risk classification, not all patients with endometrial cancer need a molecular diagnostic: 386 (65.0%) cases would need to be analyzed by TP53 IHC, only 44 (7.4%) by MMR IHC and 109 (18.4%) POLE sequencing reactions.ConclusionApplication of the 2021 molecular risk groups is feasible and shows significant differences in survival. IHC for TP53 and MMR and applying POLE sequencing is only needed in selected cases and leads to shifting risk groups both upward and downward for a sizeable number of patients.
Combined prenatal Lactobacillus reuteri and ω-3 supplementation synergistically modulates DNA methylation in neonatal T helper cells
Authors: Huoman Johanna , Martínez-Enguita David , Olsson Elin , Ernerudh Jan , Nilsson Lennart , Duchén Karel , Gustafsson Mika , Jenmalm Maria C 
Published: March 2021

ABSTRACTBackgroundEnvironmental exposures may alter DNA methylation patterns of T helper cells. As T helper cells are instrumental for allergy development, changes in methylation patterns may constitute a mechanism of action for allergy preventive interventions. While epigenetic effects of separate perinatal probiotic or ω-3 fatty acid supplementation have been studied previously, the combined treatment has not been assessed. We aimed to investigate epigenome-wide DNA methylation patterns in cord blood samples from children in a randomised double-blind placebo-controlled allergy prevention trial using pre- and postnatal combined Lactobacillus reuteri and ω-3 fatty acid treatment. To this end, >866 000 CpG sites (MethylationEPIC 850K array) in cord blood CD4+ T cells were examined in samples from all four study arms (double-treatment: n=18, single treatments: probiotics n=16, ω-3 n=15, and double placebo: n=14). Statistical and bioinformatic analyses identified treatment-associated differentially methylated CpGs and genes, which were used to identify treatment-induced network modules. Pathway analyses inferred biological relevance, and comparisons were made to an independent allergy data set.ResultsComparing the active treatments to the double placebo group, most differentially methylated CpGs and genes were hypermethylated, suggesting induction of transcriptional inhibition. The double-treated group showed the largest number of differentially methylated CpGs, of which many were unique, suggesting synergy between interventions. Clusters within the double-treated network module consisted of immune-related pathways, including T cell receptor signalling, and antigen processing and presentation, with similar pathways revealed for the single-treatment modules. CpGs derived from differential methylation and network module analyses were enriched in an independent allergy data set, particularly in the double-treatment group, proposing treatment-induced DNA methylation changes as relevant for allergy development.ConclusionPrenatal L. reuteri and/or ω-3 fatty acid treatment results in hypermethylation and affects immune- and allergy-related pathways in neonatal T helper cells, with potentiallysynergistic effects between the interventions and relevance for allergic disease. Further studies need to address these findings on a transcriptional level, and whether the results associate to allergy development in the children. Understanding the role of DNA methylation in regulating effects of perinatal probiotic and ω-3 interventions may provide essential knowledge in the development of efficacious allergy preventive strategies.Trial registrationClinicalTrials.gov, ClinicalTrials.gov-ID: NCT01542970. Registered 27th of February 2012 – Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT01542970
Why ODE models for COVID-19 fail: Heterogeneity shapes epidemic dynamics
Authors: Großmann Gerrit , Backenköhler Michael , Wolf Verena 
Published: March 2021

AbstractIn the recent COVID-19 pandemic, mathematical modeling constitutes an important tool to evaluate the prospective effectiveness of non-pharmaceutical interventions (NPIs) and to guide policy-making. Most research is, however, centered around characterizing the epidemic based on point estimates like the average infectiousness or the average number of contacts.In this work, we use stochastic simulations to investigate the consequences of a population’s heterogeneity regarding connectivity and individual viral load levels.Therefore, we translate a COVID-19 ODE model to a stochastic multi-agent system. We use contact networks to model complex interaction structures and a probabilistic infection rate to model individual viral load variation.We observe a large dependency of the dispersion and dynamical evolution on the population’s heterogeneity that is not adequately captured by point estimates, for instance, used in ODE models. In particular, models that assume the same clinical and transmission parameters may lead to different conclusions, depending on different types of heterogeneity in the population. For instance, the existence of hubs in the contact network leads to an initial increase of dispersion and the effective reproduction number, but to a lower herd immunity threshold (HIT) compared to homogeneous populations or a population where the heterogeneity stems solely from individual infectivity variations.Author summaryComputational modeling can support decision-making in the face of pandemics like COVID-19. Models help to understand transmission data and predict important epidemiological properties (e.g.,When will herd immunity be reached?). They can also examine the effectiveness of certain measures, and—to a limited extent—extrapolate the dynamics under specific assumptions. In all these cases, the heterogeneity of the population plays an important role. For instance, it is known that connectivity differences in (and among) age groups influence the dynamics of epidemic propagation. Here we focus on two types of differences among individuals: their social interactions and on how infectious they are. We show that only considering population averages (e.g.,What is the average number of contacts of an individual?) may lead to misleading conclusions, because the individual differences (such as those related to the epidemic(over-)dispersion) play an important role in shaping the epidemic dynamics. Many commonly used model classes, such as SEIR-type ODE compartmental models, ignore differences within a population to a large extent. This omission bears the potential of misleading conclusions.
Characterizing the incidence of adverse events of special interest for COVID-19 vaccines across eight countries: a multinational network cohort study
Authors: Li Xintong , Ostropolets Anna , Makadia Rupa , Shaoibi Azza , Rao Gowtham , Sena Anthony G. , Martinez-Hernandez Eugenia , Delmestri Antonella , Verhamme Katia , Rijnbeek Peter R , Duarte-Salles Talita , Suchard Marc , Ryan Patrick , Hripcsak George , Prieto-Alhambra Daniel 
Published: March 2021

SummaryBackgroundAs large-scale immunization programs against COVID-19 proceed around the world, safety signals will emerge that need rapid evaluation. We report population-based, age- and sex- specific background incidence rates of potential adverse events of special interest (AESI) in eight countries using thirteen databases.MethodsThis multi-national network cohort study included eight electronic medical record and five administrative claims databases from Australia, France, Germany, Japan, Netherlands, Spain, the United Kingdom, and the United States, mapped to a common data model. People observed for at least 365 days before 1 January 2017, 2018, or 2019 were included. We based study outcomes on lists published by regulators: acute myocardial infarction, anaphylaxis, appendicitis, Bell’s palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain-Barre syndrome, hemorrhagic and non-hemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, and transverse myelitis. We calculated incidence rates stratified by age, sex, and database. We pooled rates across databases using random effects meta-analyses. We classified meta-analytic estimates into Council of International Organizations of Medical Sciences categories: very common, common, uncommon, rare, or very rare.FindingsWe analysed 126,661,070 people. Rates varied greatly between databases and by age and sex. Some AESI (e.g., myocardial infarction, Guillain-Barre syndrome) increased with age, while others (e.g., anaphylaxis, appendicitis) were more common in young people. As a result, AESI were classified differently according to age. For example, myocardial infarction was very rare in children, rare in women aged 35-54 years, uncommon in men and women aged 55-84 years, and common in those aged ≥85 years.InterpretationWe report robust baseline rates of prioritised AESI across 13 databases. Age, sex, and variation between databases should be considered if background AESI rates are compared to event rates observed with COVID-19 vaccines.
Droplet Digital RT-PCR to detect SARS-CoV-2 variants of concern in wastewater
Authors: Heijnen Leo , Elsinga Goffe , de Graaf Miranda , Molenkamp Richard , Koopmans Marion P.G. , Medema Gertjan 
Published: March 2021

AbstractWastewater surveillance has shown to be a valuable and efficient tool to obtain information about the trends of COVID-19 in the community. Since the recent emergence of new variants, associated with increased transmissibility and/or antibody escape (variants of concern), there is an urgent need for methods that enable specific and timely detection and quantification of the occurrence of these variants in the community. In this study we demonstrate the use of RT-ddPCR on wastewater samples for specific detection of mutation N501Y. This assay enabled simultaneous enumeration of the concentration of variants with the 501Y mutation and Wild Type (WT, containing 501N) SARS-CoV-2 RNA. Detection of N501Y was possible in samples with mixtures of WT with low proportions of lineage B.1.351 (0.5%). The method could accurately determine the proportion of N501Y and WT in mixtures of SARS-CoV-2 RNA. The application to raw sewage samples from the cities of Amsterdam and Utrecht demonstrated that this method can be applied to determine the concentrations and the proportions of WT and N501Y containing SARS-CoV-2 RNA in wastewater samples. The emergence of N501Y in Amsterdam and Utrecht wastewater aligned with the emergence of B.1.1.7 as causative agent of COVID-19 in the Netherlands, indicating that RT-ddPCR of wastewater samples can be used to monitor the emergence of the N501Y mutation in the community. It also indicates that RT-ddPCR could be used for sensitive and accurate monitoring of current (like K417N, E484K) or future mutations present in SARS-CoV-2 variants of concern. Monitoring emergence of these mutations in the community via wastewater is rapid, efficient and valuable in supporting public health decision-making.
Aggresssion in School Children: Role of Gender, Family Factors and Exposure to Violence
Authors: Sehgal Mukul , Nayak Ajita 
Published: March 2021

AbstractINTRODUCTIONIncreasing instances of aggression in school children has become a cause of great concern for educationists, parents and mental health professionals. With increased globalization and information overload, today’s child is exposed to influences which probably adversely modify the child’s behavior. These aggressive tendencies could affect the child’s academic, social functioning and also may lead to psychiatric problems. Hence, this study was planned to find out the amount of aggression among school children and various potential contributing factors for the aggressive behavior. Identifying these risk factors could help design preventive strategies among school children.OBJECTIVETo evaluate the amount of aggression and its contributing factors among 10-12 year-old children.SUBJECTSThe subjects involved the school children and their teachers in various schools across Mumbai. The age group of study was 10-12 years i.e. class 5th to class 8thNo. of subjects:-102STUDY PROCEDUREA total of 102, 10-12 year-old school children (5th to 8th class) in the Mumbai metropolitan area were interviewed to assess the presence of aggression. A validated scale, Children’s Aggression Scale – Teacher version (CAS-T), was used to assess the presence of aggression. Children were assessed & scored on basis of this scale with questions answered by their teachers. Data was analyzed on the basis of each factor using unpaired t-test, ANOVA test and Kruskal-Wallis Test (Nonparametric ANOVA). Institutional ethics committee approval was taken for research at Seth GS Medical College, Mumbai, India.RESULTSA high level of aggression was present in 4% other children while moderate levels were present in 8%. Boys were found to be more aggressive than girls (p-value 0.003). Aggression scores were significantly higher in children from English medium and with poor academic performance. Children exposed to physical abuse and violence on Television showed significantly high aggression. Perceived parental conflict in boys was found to be significantly associated with lower aggression scores. Among the various factors studied, aggression scores showed highest correlation with exposure to violence on television for more than 2 hours/day (11.67 vs 3.19 p-value <0.001).CONCLUSIONAbout 12% of schoolchildren in the 10-12years group show aggressive behavior needing interventions. Boys from abusive families, with poor academic performance and exposed to excessive violence on TV seem particularly at risk for developing aggressive behavior.
The Hox transcription factor Ultrabithorax binds RNA and regulates co-transcriptional splicing through an interplay with RNA polymerase II
Authors: Carnesecchi Julie , Boumpas Panagiotis , van Nierop y Sanchez Patrick , Domsch Katrin , Pinto Hugo Daniel , Pinto Pedro Borges , Lohmann Ingrid 
Published: March 2021

ABSTRACTTranscription Factors (TFs) play a pivotal role in cell fate decision by coordinating distinct gene expression programs. Although most TFs act at the DNA regulatory layer, few TFs can bind RNA and modulate mRNA splicing. Yet, the mechanistic cues underlying TFs function in splicing remain elusive. Focusing on theDrosophilaHox TF Ultrabithorax (Ubx), our work shed light on a novel layer of Ubx function at the RNA level. Transcriptome and genome-wide binding profiles in embryonic mesoderm andDrosophilacells indicate that Ubx regulates mRNA expression and splicing to promote distinct functions in defined cellular contexts. Ubx modulates splicing via its DNA-binding domain, the Homeodomain (HD). Our results demonstrate a new RNA-binding ability of Ubx in cells andin vitro. Notably, the N51 amino acid of the HD, which mediates Ubx-DNA interaction, is non-essential for Ubx-RNA interactionin vitrobut is requiredin vivo. We find that the N51 amino acid is necessary to mediate interaction between Ubx and the active form of the RNA Polymerase II (Pol II S2Phos) inDrosophilacells. By combining molecular and imaging approaches, our results reveal that Ubx mediates elongation-coupled splicing via a dynamic interplay with active Pol II and chromatin binding. Overall, our work uncovered a novel role of the Hox TFs at the mRNA regulatory layer. This could be an essential function for other classes of TFs to control cell diversity.
Anti-cancer properties of cannabidiol and Δ9-tetrahydrocannabinol and potential synergistic effects with gemcitabine, cisplatin and other cannabinoids in bladder cancer
Authors: Tomko Andrea M. , Whynot Erin G. , Dupré Denis J. 
Published: March 2021

AbstractIntroductionWith the legalization of cannabis in multiple jurisdictions throughout the world, a larger proportion of the population consumes cannabis. Several studies have demonstrated anti-tumor effects of components present in cannabis in different models. Unfortunately, little is known about the potential anti-tumoral effects of cannabinoids in bladder cancer, and how cannabinoids could potentially synergize with chemotherapeutic agents. Our study aims to identify whether a combination of cannabinoids, like cannabidiol and Δ9-tetrahydrocannabinol with agents commonly used to treat bladder cancer, such as gemcitabine and cisplatin, is able to produce desirable synergistic effects. We also evaluated whether co-treatment of different cannabinoids also generated synergistic effects.Materials and MethodsWe generated concentration curves with different drugs to identify the range at which they could exert anti-tumor effects. We also evaluated the activation of the apoptotic cascade and whether cannabinoids have the ability to reduce invasion.ResultsCannabidiol, Δ9-tetrahydrocannabinol and other cannabinoids reduce cell viability of bladder cancer cell lines, and their combination with gemcitabine or cisplatin may induce differential responses: from antagonistic to additive and synergistic effects, depending on the concentrations used. Cannabidiol and Δ9-tetrahydrocannabinol were also shown to induce caspase 3 cleavage and reduce invasion in a Matrigel assay. Cannabidiol and Δ9-tetrahydrocannabinol also display synergistic properties with other cannabinoids like cannabichromene or cannabivarin.DiscussionOur results indicate that cannabinoids can reduce human bladder transitional cell carcinoma cell viability, and that they can potentially exert synergistic effects when combined with other agents. Ourin vitroresults will form the basis for future studiesin vivoand in clinical trials for the development of new therapies that could be beneficial for the treatment of bladder cancer in the future.
Antiviral Antibody Epitope Selection is a Heritable Trait
Authors: Venkataraman Thiagarajan , Valencia Cristian , Mangino Massimo , Morgenlander William , Clipman Steven J. , Liechti Thomas , Valencia Ana , Christofidou Paraskevi , Spector Tim , Roederer Mario , Duggal Priya , Larman H. Benjamin 
Published: March 2021

AbstractThere is enormous variability in human immune responses to viral infections. However, the genetic factors that underlie this variability are not well characterized. We used VirScan, a high-throughput viral epitope scanning technology, to analyze the antibody binding specificities of twins and SNP-genotyped individuals. These data were used to estimate the heritability and identify genomic loci associated with antibody epitope selection, response breadth, and the control of Epstein-Barr Virus (EBV) viral load. We identified 4 epitopes of EBV that were heritably targeted, and at least two EBNA-2 binding specificities that were associated with variants in the MHC class-II locus. We identified an EBV serosignature that predicted viral load in white blood cells and was associated with genetic variants in the MHC class-I locus. Our study provides a new framework for identifying genes important for pathogen immunity, with specific implications for the genetic architecture of EBV humoral responses and the control of viral load.Abstract Figure
Parasitic nematode fatty acid- and retinol-binding proteins compromise host immunity by interfering with host lipid signaling pathways
Authors: Parks Sophia C. , Nguyen Chau , Nasrolahi Shyon , Juncaj Damian , Lu Dihong , Ramaswamy Raghavendran , Dhillon Harpal , Buchman Anna , Akbari Omar S. , Yamanaka Naoki , Boulanger Martin J. , Dillman Adler R. 
Published: March 2021

AbstractParasitic nematodes cause significant morbidity and mortality globally. Excretory/secretory products (ESPs) such as fatty acid- and retinol- binding proteins (FARs) are hypothesized to suppress host immunity during infection, yet little is known about their interactions with host tissues. Leveraging the insect parasitic nematode,Steinernema carpocapsae, we provide the firstin vivostudy that shows FARs modulate animal immunity, causing an increase in susceptibility to bacterial infection. Next we determined that FARs dampen various aspects of the fly immune response including the phenoloxidase cascade and antimicrobial peptide (AMP) production. Finally, we found that FARs deplete lipid signaling precursorsin vivoas well as bind to these fatty acidsin vitro, suggesting that FARs elicit their immunomodulatory effects by altering the availability of lipid signaling molecules necessary for a functional immune response. Collectively, these data reveal a complex role for FARs in immunosuppression and provide detailed mechanistic insight into parasitism in phylum Nematoda.SignificanceA central aspect of parasitic nematode success is their ability to modify host biology, including evasion and/or subversion of host immunity. Modulation of host biology and the pathology caused by parasitic nematodes is largely effected through the release of proteins and small molecules. There are hundreds of proteins released by nematodes during an infection and few have been studied in detail. Fatty acid- and retinol-binding proteins (FARs) are a unique protein family released during infection. We report that nematode FARs fromS. carpocapsae,C. elegansandA. ceylanicumdampen fly immunity decreasing resistance to infection. Mechanistically, this is achieved through modulation of the phenoloxidase cascade and antimicrobial peptide production. Furthermore, FARs alter the availability of lipid immune signaling precursorsin vivoand show binding specificityin vitro.Graphical Abstract