bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneous evolution of SARS-CoV-2 seroprevalence in school-age children: Results from the school-based cohort study Ciao Corona in November-December 2021 in the canton of Zurich
Authors: Haile Sarah R , Raineri Alessia , Rueegg Sonja , Radtke Thomas , Ulyte Agne , Puhan Milo A , Kriemler Susi 
Published: June 2022

AbstractBackgroundMuch remains unknown regarding the evolution of SARS-CoV-2 seroprevalence and variability in seropositive children in districts, schools, and classes as only a few school-based co-hort studies exist. Vaccination of children, initiated at different times for different age groups, adds additional complexity to understand how seroprevalence developed in the school aged population.AimWe investigated the evolution of SARS-CoV-2 seroprevalence in children and its variability in districts, schools, and classes in Switzerland from June/July 2020 to November/December 2021.MethodsIn this school-based cohort study, SARS-CoV-2 antibodies were measured in primary and secondary school children from randomly selected schools in the canton of Zurich in October/November 2020, March/April 2021, and November/December 2021. Seroprevalence was estimated using Bayesian logistic regression to adjust for test sensitivity and specificity. Variability of seroprevalence between school classes was expressed as maximum minus minimum sero-prevalence in a class and summarized as median (interquartile range).Results1875 children from 287 classes in 43 schools were tested, with median age 12 (range 6-17), 51% 12+ vaccinated. Seroprevalence increased from 5.6% (95% CrI: 3.5-7.6%) to 31.1% (27.0-36.1%) in unvaccinated children, and 46.4% (42.6-50.9%) in all children (including vaccinated). Earlier in the pandemic, seropositivity rates in primary schools were similar to or slightly higher (<5%) than those in secondary schools, but by late 2021, primary schools had 12.3% (44.3%) lower seroprevalence for unvaccinated (all) subjects. Variability in seroprevalence among districts and schools increased more than twofold over time, and in classes from 11% (7-17%) to 40% (22-49%).ConclusionSeroprevalence in children increased greatly, especially in 2021 following introduction of vaccines. Variability in seroprevalence was high and increased substantially over time, suggesting complex transmission chains.Trial Registration:ClinicalTrials.govNCT04448717
Descriptive Epidemiology of SARS-CoV-2 Gamma (P.1/501Y.V3) variant cases in England, August 2021
Authors: Aziz Nurin Abdul , Twohig Katherine A , Sinnathamby Mary , Zaidi Asad , Aliabadi Shirin , Groves Natalie , Nash Sophie , Thelwall Simon , Dabrera Gavin 
Published: June 2022

AbstractPurposeThe Gamma variant of SARS-CoV-2, first detected in travellers from Brazil, was found to have high transmissibility and virulence; following this finding, this paper aims to describe the epidemiology of Gamma cases in England from its first detection on 12 February 2021 to 31 August 2021.MethodsThe demographic analysis of Gamma cases was stratified by travel exposure. Travel-associated cases were further analysed by countries travelled from, stratified by categories set in place by the Red (highest risk countries), Amber, Green (lowest risk countries) travel policy, which was implemented from May to October 2021.ResultsThere were 251 confirmed Gamma cases detected in England in the study period. 35.1% were imported, 5.6% were secondary, and 29.5% were not travel associated. Early cases were predominantly travel-associated, with later cases likely obtained through community transmission. 51.0% of travel-related cases were travellers from Amber countries, and 40.2% had at least one Red country in their journey.ConclusionThe Gamma variant has not seen the same expansion as other variants such as Delta, most likely due to Delta out-competing community transmission of Gamma. Findings indicate the travel policy requiring quarantine for Red and Amber list travellers may have also contributed to preventing onward transmission of Gamma.
GDNF-RET signaling and EGR1 form a positive feedback loop that promotes tamoxifen resistance via cyclin D1
Authors: Marks Brooke A. , Pipia Ilissa M. , Mukai Chinatsu , Horibata Sachi , Rice Edward J. , Danko Charles G. , Coonrod Scott A. 
Published: June 2022

AbstractBackgroundRearranged during transfection (RET) tyrosine kinase signaling has been previously implicated in endocrine resistant breast cancer, however the mechanism by which this signaling cascade promotes resistance is currently not well described. We recently reported that glial-cell derived neurotrophic factor (GDNF)-RET signaling appears to promote a positive feedback loop with the transcription factor early growth response 1 (EGR1). Here we investigate the mechanism behind this feedback loop and test the hypothesis that GDNF-RET signaling forms a regulatory loop with EGR1 to upregulate cyclin D1 (CCND1) transcription, leading to cell cycle progression and tamoxifen resistance.MethodsTo gain a better understanding of the GDNF-RET-EGR1 resistance mechanism, we studied the GDNF-EGR1 positive feedback loop and the role of GDNF and EGR1 in endocrine resistance by modulating their transcription levels using CRISPR-dCAS9 in tamoxifen sensitive (TamS) and tamoxifen resistant (TamR) MCF-7 cells. Additionally, we performed kinetic studies using recombinant GDNF (rGDNF) treatment of TamS cells. Statistical significance for qPCR and chromatin immunoprecipitation (ChIP)-qPCR was determined using a student’s t-test.ResultsGDNF-RET signaling formed a positive feedback loop with EGR1 and also downregulated estrogen receptor 1 (ESR1) transcription. Upregulation of GDNF and EGR1 promoted tamoxifen resistance in TamS cells and downregulation of GDNF promoted tamoxifen sensitivity in TamR cells. Additionally, we show that rGDNF treatment activated GDNF-RET signaling in TamS cells, leading to recruitment of p-ELK-1 to the EGR1 promoter, upregulation of EGR1 mRNA and protein, binding of EGR1 to the GDNF and CCND1 promoters, increased GDNF protein expression, and subsequent upregulation of CCND1 mRNA levels.ConclusionOutcomes from these studies support the hypotheses that GDNF-RET signaling forms a positive feedback loop with the transcription factor EGR1, and that GDNF-RET-EGR1 signaling promotes endocrine resistance via signaling to cyclin D1. Inhibition of components of this signaling pathway could lead to therapeutic insights into the treatment of endocrine resistant breast cancer.
Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer’s Disease related proteins
Authors: Oatman Stephanie R. , Reddy Joseph S. , Quicksall Zachary , Carrasquillo Minerva M. , Wang Xue , Liu Chia-Chen , Yamazaki Yu , Nguyen Thuy T. , Malphrus Kimberly , Heckman Michael , Biswas Kristi , Baker Matthew , Martens Yuka A. , Zhao Na , Rademakers Rosa , DeTure Michael , Murray Melissa E. , Kanekiyo Takahisa , Dickson Dennis W. , Bu Guojun , Allen Mariet , Ertekin-Taner Nilüfer 
Published: June 2022

AbstractAlzheimer’s disease (AD) is neuropathologically characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Main protein components of these hallmarks include Aβ40, Aβ42, tau, phospho-tau and APOE. With the exception of the APOE-ε4 variant, genetic risk factors associated with brain biochemical measures of these proteins have yet to be characterized. We performed a genome-wide association study in brains of 441 AD patients for quantitative levels of these proteins collected from three distinct fractions reflecting soluble, membrane-bound and insoluble biochemical states. We identified 123 genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD- related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.
Best organic farming expansion scenarios for pest control: a modeling approach
Authors: Delattre Thomas , Memah Mohamed-Mahmoud , Franck Pierre , Valsesia Pierre , Lavigne Claire 
Published: June 2022

AbstractOrganic Farming (OF) has been expanding recently in response to growing consumer demand and as a response to environmental concerns. The area under OF is expected to further increase in the future. The effect of OF expansion on pest densities in organic and conventional crops remains difficult to predict because OF expansion impacts Conservation Biological Control (CBC), which depends on the surrounding landscape (i.e. both the crop mosaic and semi-natural habitats). In order to understand and forecast how pests and their biological control may vary during OF expansion, we modeled the effect of spatial changes in farming practices on population dynamics of a pest and its natural enemy. We investigated the impact on pest density and on predator to pest ratio of three contrasted scenarios aiming at 50% organic fields through the progressive conversion of conventional fields. Scenarios were 1) conversion of Isolated conventional fields first (IP), 2) conversion of conventional fields within Groups of conventional fields first (GP), and 3) Random conversion of conventional field (RD). We coupled a neutral spatially explicit landscape model to a predator-prey model to simulate pest dynamics in interaction with natural enemy predators. The three OF expansion scenarios were applied to nine landscape contexts differing in their proportion and fragmentation of semi-natural habitat. We further investigated if the ranking of scenarios was robust to pest control methods in OF fields and pest and predator dispersal abilities.We found that organic farming expansion affected more predator densities than pest densities for most combinations of landscape contexts and OF expansion scenarios. The impact of OF expansion on final pest and predator densities was also stronger in organic than conventional fields and in landscapes with large proportions of highly fragmented semi-natural habitats. Based on pest densities and the predator to pest ratio, our results suggest that a progressive organic conversion with a focus on isolated conventional fields (scenario IP) could help promote CBC. Careful landscape planning of OF expansion appeared most necessary when pest management was substantially less efficient in organic than in conventional crops, and in landscapes with low proportion of semi-natural habitats.
Predicting higher-order mutational effects in an RNA enzyme by machine learning of high-throughput experimental data
Authors: Beck James D. , Roberts Jessica M. , Kitzhaber Joey , Trapp Ashlyn , Serra Edoardo , Spezzano Francesca , Hayden Eric J. 
Published: June 2022

AbstractRibozymes are RNA molecules that catalyze biochemical reactions. Self-cleaving ribozymes are a common naturally occurring class of ribozymes that catalyze site-specific cleavage of their own phosphodiester backbone. In addition to their natural functions, self-cleaving ribozymes have been used to engineer control of gene expression because they can be designed to alter RNA processing and stability. However, the rational design of ribozyme activity remains challenging, and many ribozyme-based systems are engineered or improved by random mutagenesis and selection (in vitro evolution). Improving a ribozyme-based system often requires several mutations to achieve the desired function, but extensive pairwise and higher-order epistasis prevent a simple prediction of the effect of multiple mutations that is needed for rational design. Recently, high-throughput sequencing-based approaches have produced data sets on the effects of numerous mutations in different ribozymes (RNA fitness landscapes). Here we used such high-throughput experimental data from variants of the CPEB3 self-cleaving ribozyme to train a predictive model through machine learning approaches. We trained models using either a random forest or long short-term memory (LSTM) recurrent neural network approach. We found that models trained on a comprehensive set of pairwise mutant data could predict active sequences at higher mutational distances, but the correlation between predicted and experimentally observed self-cleavage activity decreased with increasing mutational distance. Adding sequences with increasingly higher numbers of mutations to the training data improved the correlation at increasing mutational distances. Systematically reducing the size of the training data set suggests that a wide distribution of ribozyme activity may be the key to accurate predictions. Because the model predictions are based only on sequence and activity data, the results demonstrate that this machine learning approach allows readily obtainable experimental data to be used for RNA design efforts even for RNA molecules with unknown structures. The accurate prediction of RNA functions will enable a more comprehensive understanding of RNA fitness landscapes for studying evolution and for guiding RNA-based engineering efforts.
Plasma amyloid-β homeostasis is associated with Body Mass Index and weight loss in people with overweight and obesity
Authors: Brook Emily S. , D’Alonzo Zachary J. , Lam Virginie , Chan Dick , Dhaliwal Satvinder Singh , Watts Gerald F. , Mamo John C. L , Takechi Ryusuke 
Published: June 2022

ABSTRACTBACKGROUNDObesity is linked to a higher incidence of Alzheimer’s disease (AD). Studies show that plasma amyloid-β (Aβ) dyshomeostasis, particularly low 42/40 ratio indicates a heightened risk for developing AD. However, the relationship between body mass index (BMI) and circulating plasma Aβ has not been extensively studied.OBJECTIVEWe hypothesised that people with a high BMI have altered plasma Aβ homeostasis compared with people with a lower BMI. We also tested whether reducing BMI by calorie-restriction could normalise plasma concentrations of Aβ.METHODSPlasma concentrations of Aβ40, Aβ42and Aβ42/40ratio were measured in 106 participants with BMIs classified as lean, overweight, or obese. From this cohort, twelve participants with overweight or obese BMIs entered a 12-week calorie-restriction weight loss program. We then tested whether decreasing BMI affected plasma Aβ concentrations.RESULTSPlasma Aβ42/40ratio was 17.54% lower in participants with an obese BMI compared to lean participants (p<0.0001), and 11.76% lower compared to participants with an overweight BMI (p<0.0001). The weight loss regimen decreased BMI by an average of 4.02% (p=0.0005) and was associated with a 6.5% decrease in plasma Aβ40(p=0.0425). However, weight loss showed negligible correlations with plasma Aβ40, Aβ42and Aβ42/40ratio.CONCLUSIONObesity is associated with aberrant plasma Aβ homeostasis which may be associated with an increased risk for AD. Weight loss appears to lower Aβ40, but large-scale longitudinal studies in addition to molecular studies are required to elucidate the underlying mechanisms of how obesity and weight loss influence plasma Aβ homeostasis.
Synergistic activation of RARb and RARg nuclear receptors restores cell specialization during stem cell differentiation by hijacking RARa-controlled programs
Authors: Koshy Aysis , Mathieux Elodie , Stüder François , Bramoulle Aude , Lieb Michele , Colombo Bruno Maria , Gronemeyer Hinrich , Mendoza-Parra Marco Antonio 
Published: June 2022

AbstractHow cells respond to different external cues to develop along defined cell lineages to form complex tissues is a major question in systems biology. Here, we investigated the potential of retinoic acid receptor (RARs)-selective synthetic agonists to activate the gene-regulatory programs driving cell specialization during nervous tissue formation from P19 stem cells. Specifically, we found that the synergistic activation of the RARβ and RARγ by selective ligands (BMS641 or BMS961) induces cell maturation to specialized neuronal subtypes, as well as to astrocytes and oligodendrocyte precursors.Using RAR istoype knockout lines exposed to RAR-specific agonists, interrogated by global transcriptome landscaping and in silico modeling of transcription regulatory signal propagation, revealed major RARα−driven gene programs essential for optimal neuronal cell specialization, and hijacked by the synergistic activation of the RARβ and RARγ receptors.Overall, this study provides a systems biology view of the gene programs accounting for the previously observed redundancy between RAR receptors, paving the way towards their potential use for directing cell specialization during nervous tissue formation.
High and low permeability of human pluripotent stem cell-derived Blood Brain barrier models depend on epithelial or endothelial features
Authors: Girard Stéphane D. , Julien-Gau Ingrid , Molino Yves , Combes Benjamin F. , Greetham Louise , Khrestchatisky Michel , Nivet Emmanuel 
Published: June 2022

SUMMARYThe search for reliable human blood-brain barrier (BBB) models represents a challenge for the development/testing of strategies aiming to enhance brain delivery of drugs. Human induced pluripotent stem cells (hiPSCs) have raised hopes in the development of predictive BBB models. Differentiating strategies are thus required to generate endothelial cells (ECs), a major component of the BBB. Several hiPSC-based protocols have reported the generation ofin vitromodels with significant differences in barrier properties. We studied in depth the properties of iPSCs byproducts from two protocols that have been established to yield thesein vitrobarrier models. Our analysis/study reveals that iPSCs endowed with EC features yield high permeability models, while the cells that exhibit outstanding barrier properties show principally epithelial cell-like (EpC) features. Our study demonstrates that hiPSC-based BBB models need extensive characterization beforehand and that a reliable human BBB model is still needed.
Plasma glycoproteomics delivers high-specificity disease biomarkers by detecting site-specific glycosylation abnormalities
Authors: Wessels Hans JCT , Kulkarni Purva , van Dael Maurice , Suppers Anouk , Willems Esther , Zijlstra Fokje , Kragt Else , Gloerich Jolein , Schmit Pierre-Olivier , Pengelley Stuart , Marx Kristina , van Gool Alain J , Lefeber Dirk J 
Published: June 2022

AbstractThe human plasma glycoproteome holds enormous potential to identify personalized biomarkers to diagnose and understand disease. Recent advances in mass spectrometry and software development are opening novel avenues to mine the glycoproteome for protein- and site-specific glycosylation changes. Here, we describe a novel plasma N-glycoproteomics method for disease diagnosis and evaluated its clinical applicability by performing comparative glycoproteomics in blood plasma of 40 controls and a cohort of 74 patients with 13 different genetic diseases that directly impact the protein N-glycosylation pathway. The plasma glycoproteome yielded high-specificity biomarker signatures for each of the individual genetic defects. Bioinformatic analyses revealed site-specific glycosylation differences that could be explained by underlying glycobiology and in specific diseases by protein-intrinsic factors. Our work illustrates the strong potential of plasma glycoproteomics to significantly increase specificity of glycoprotein biomarkers with direct insights in site-specific glycosylation changes to better understand the mechanisms underlying human disease.
Intracellular level of S. cerevisiae Rad51 is regulated via proteolysis in a SUMO- and ubiquitin-dependent manner
Authors: Antoniuk-Majchrzak Justyna , Długajczyk Anna , Enkhbaatar Tuguldur , Kaminska Joanna , Skoneczny Marek , Klionsky Daniel J. , Skoneczna Adrianna 
Published: June 2022

AbstractAmong various DNA lesions, the DNA double-strand breaks are particularly deleterious; especially, when an error-free repair pathway is unavailable, and the cell takes the risk of using the error-prone recombination pathways to repair the DNA breaks, resume the cell cycle, and continue growth. The latter comes at the expense of decreased well-being of the cells due to genome rearrangements. One of the major players involved in recombinational repair of DNA damage is Rad51 recombinase, a protein responsible for presynaptic complex formation. We previously noticed that the level of this protein is strongly increased when illegitimate recombination is engaged in repair. The regulation of Rad51 protein turnover is not known; therefore, we decided to look closer at this issue because we expect that an excessively high level of Rad51 may lead to genome instability. Here we show that the level of Rad51 is regulated via the ubiquitin-dependent proteolytic pathway. The ubiquitination of Rad51 depends on multiple E3 enzymes, including SUMO-targeted ubiquitin ligases. We also demonstrate that Rad51 can be modified by both ubiquitin and SUMO. Moreover, these modifications may lead to opposite effects. Ubiquitin-dependent degradation depends on Rad6, Rad18, Slx8, Dia2 and the anaphase-promoting complex. Rsp5-dependent ubiquitination leads to Rad51 stabilization.
Fatty acid synthesis knockdown promotes biofilm wrinkling and inhibits sporulation in Bacillus subtilis
Authors: Arjes Heidi A. , Gui Haiwen , Porter Rachel , Atolia Esha , Peters Jason , Gross Carol , Kearns Daniel B. , Huang Kerwyn Casey 
Published: June 2022

AbstractMany bacterial species typically live in complex three-dimensional biofilms, yet little is known about systematic changes to gene function between non-biofilm and biofilm lifestyles. Here, we created a CRISPRi library of knockdown strains covering all known essential genes in the biofilm-forming Bacillus subtilis strain 3610. We show that gene essentiality is largely conserved between liquid and surface growth and between two media. We developed an image analysis algorithm to quantify biofilm colony wrinkling, which identified strains with high or low levels of wrinkling that were uncorrelated with extracellular matrix gene expression. We also designed a high-throughput screen for sensitive quantification of sporulation efficiency and performed the first screens of sporulation during essential gene knockdown. We found that all basal knockdowns of essential genes were competent for sporulation in a sporulation-inducing medium, but certain strains exhibited reduced sporulation efficiency in LB, a medium with generally lower levels of sporulation. Knockdown of fatty acid synthesis increased wrinkling and inhibited sporulation. These results highlight the importance of essential genes in biofilm structure and sporulation/germination and suggest a previously unappreciated and multifaceted role for fatty acid synthesis in bacterial lifestyles and developmental processes.Abstract ImportanceFor many bacteria, life typically involves growth in dense, three-dimensional communities called biofilms that contain cells with differentiated roles and are held together by extracellular matrix. To examine how gene function varies between non-biofilm and biofilm growth, we created a comprehensive library of strains using CRISPRi to knockdown expression of each essential gene in the model species Bacillus subtilis 3610, which can develop into a wrinkled biofilm structure or a spore capable of surviving harsh environments. This library enabled us to determine when gene essentiality depends on growth conditions. We also developed high-throughput assays and computational algorithms to identify essential genes involved in biofilm wrinkling and sporulation. Knockdown of fatty acid synthesis increased the density of wrinkles, and also inhibited sporulation in a medium with generally lower sporulation levels. These findings indicate that essential processes such as fatty acid synthesis can play important and multifaceted roles in bacterial development.