bluuebunny/crossref_metadata_2025_split huggingface dataset:
Emergence of the Delta Variant and risk of SARS-CoV-2 infection in secondary school students and staff: prospective surveillance in 18 schools, England
Authors: Ladhani Shamez N. , Ireland Georgina , Baawuah Frances , Beckmann Joanne , Okike Ifeanyichukwu O , Ahmad Shazaad , Garstang Joanna , Brent Andrew J , Brent Bernadette , Aiano Felicity , Amin-Chowdhury Zahin , Kall Meaghan , Borrow Ray , Linley Ezra , Zambon Maria , Poh John , Warrener Lenesha , Lackenby Angie , Ellis Joanna , Amirthalingam Gayatri , Brown Kevin E , Ramsay Mary E 
Published: December 2021

ABSTRACTBackgroundThe role of educational settings on SARS-CoV-2 infection and transmission remains controversial. We investigated SARS-CoV-2 infection, seroprevalence and seroconversions rates in secondary schools during the 2020/21 academic year, which included the emergence of the more transmissible Alpha and Delta variants, in England.MethodsThe UK Health Security Agency (UKHSA) initiated prospective surveillance in 18 urban English secondary schools. Participants had nasal swabs for SARS-CoV-2 RT-PCR and blood sampling for SARS-CoV-2 Nucleoprotein and Spike protein antibodies at the start (Round 1: September-October 2020) and end (Round 2: December 2021) of the autumn term, when schools reopened after national lockdown was imposed in January 2021 (Round 3: March-April) and end of the academic year (Round 4: May-July).FindingsWe enrolled 2,314 participants (1277 students, 1037 staff). In-school testing identified 31 PCR-positive participants (20 students, 11 staff). Another 247 confirmed cases (112 students, 135 staff) were identified after linkage with national surveillance data, giving an overall positivity rate of 12.0% (278/2313; staff [14.1%, 146/1037] vs students [10.3%, 132/1276; p=0.006). Nucleoprotein-antibody seroprevalence increased for students and staff between Rounds 1-3 but changed little in Round 4, when the Delta variant was the dominant circulating strain. Overall, Nucleoprotein-antibody seroconversion was 18.4% (137/744) in staff and 18.8% (146/778) in students, while Spike-antibody seroconversion was higher in staff (72.8% (525/721) than students (21.3%, 163/764) because of vaccination.InterpretationSARS-CoV-2 infection and transmission in secondary schools remained low when community infection rates were low because of national lockdown, even after the emergence of the Delta variantFundingDHSC
Vitamin D Supplementation is Associated with Slower Epigenetic Aging
Authors: Vetter Valentin Max , Sommerer Yasmine , Kalies Christian Humberto , Spira Dominik , Bertram Lars , Demuth Ilja 
Published: December 2021

AbstractAdverse effects of low vitamin D level on mortality and morbidity are controversially discussed. Especially older people are at risk for vitamin D deficiency and therefore exposed to its potentially harmful influence on the aging process. A way of measuring differences in the biological age is through DNA methylation age (DNAm age) and its deviation from chronological age, DNAm age acceleration (DNAmAA). We previously reported on an association between vitamin D deficiency and higher 7-CpG DNAmAA in participants of the Berlin Aging Study II (BASE-II).In this study, we employ a quasi-interventional study design to assess the relationship between DNAmAA of five epigenetic clocks and vitamin D supplementation. Longitudinal data were available for 1,036 participants of BASE-II that were reexamined on average 7.4 years later in the GendAge study (mean age at follow-up: 75.6 years, SD = 3.8 years, age range: 64.9 – 94.1 years, 51.9 % female). DNAmAA was estimated with the 7-CpG clock, Horvath’s clock, Hannum’s clock, PhenoAge and GrimAge. Methylation data were obtained through methylation-sensitive single nucleotide primer extension (MS-SNuPE) or Illumina’s Infinium “MethylationEPIC” array.Vitamin D deficient participants who chose to start vitamin D supplementation after baseline examination showed a 2.6 year lower 7-CpG DNAmAA (p=0.011) and 1.3-year lower Horvath DNAmAA (p=0.042) compared to untreated and vitamin D deficient participants. DNAmAA did not statistically differ between participants with successfully treated vitamin D deficiency and healthy controls (p>0.16).Therefore, we conclude that intake of vitamin D supplement is associated with lower DNAmAA in participants with vitamin D deficiency. Additionally, our findings suggest that sufficient vitamin D supplementation can compensate and potentially reverse the increase in 7-CpG DNAmAA that we found in in vitamin D deficient participants.
Knockout of liver fluke granulin, Ov-grn-1, impedes malignant transformation during chronic infection with Opisthorchis viverrini
Authors: Chaiyadet Sujittra , Tangkawattana Sirikachorn , Smout Michael J. , Ittiprasert Wannaporn , Mann Victoria H. , Deenonpoe Raksawan , Arunsan Patpicha , Loukas Alex , Brindley Paul J. , Laha Thewarach 
Published: December 2021

AbstractInfection with the food-borne liver fluke Opisthorchis viverrini is the principal risk factor for cholangiocarcinoma (CCA) in the Mekong Basin countries of Thailand, Lao PDR, Vietnam, Myanmar and Cambodia. Using a novel model of CCA, involving infection with gene-edited liver flukes in the hamster during concurrent exposure to dietary nitrosamine, we explored the role of the fluke granulin-like growth factor Ov-GRN-1 in malignancy. We derived RNA-guided gene knockout flukes (ΔOv-grn-1) using CRISPR/Cas9/gRNA materials delivered by electroporation. Genome sequencing confirmed programmed Cas9-catalyzed mutations of the targeted genes, which was accompanied by rapid depletion of transcripts and the proteins they encode. Gene-edited parasites colonized the biliary tract of hamsters and developed into adult flukes, however less hepatobiliary tract disease manifested during chronic infection with ΔOv-grn-1 worms in comparison to hamsters infected with control gene-edited and non-edited parasites. Specifically, immuno- and colorimetric-histochemical analysis of livers revealed markedly less periductal fibrosis surrounding the flukes and less fibrosis globally within the hepatobiliary tract during infection with ΔOv-grn-1 genotype worms, minimal biliary epithelial cell proliferation, and significantly fewer mutations of TP53 in biliary epithelial cells. Moreover, fewer hamsters developed high-grade CCA compared to controls. The clinically relevant, pathophysiological phenotype of the hepatobiliary tract confirmed a role for this secreted growth factor in malignancy and morbidity during opisthorchiasis.Author summaryInfection with the human liver flukes, Opisthorchis viverrini, O. felineus and Clonorchis sinensis remains a public health concern in regions where these parasites are endemic. O. viverrini is endemic in the Mekong River drainage countries of including Thailand and the Lao People’s Democratic Republic. Infection follows the consumption of undercooked freshwater fish harboring the parasite. Liver fluke infection, opisthorchiasis, is associated with diseases of the liver and bile ducts including cancer of the biliary tract, cholangiocarcinoma, a cancer with a poor prognosis. This report characterizes for the first time experimental infection with gene-edited O. viverrini liver flukes during concurrent exposure to nitrosamine in a rodent model of liver fluke infection-associated cancer. Cancer development was slowed in hamsters infected with the parasite following CRISPR-based knock-out mutation and loss of a parasite gene known to stimulate growth of cells lining the bile ducts. These findings describe a new model for investigation of risk factors for infection-associated cholangiocarcinoma and to assess efficacy of anti-infection/anti-cancer vaccines.
SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-β signaling
Authors: Biering Scott B. , Sousa Francielle Tramontini Gomes de , Tjang Laurentia V. , Pahmeier Felix , Ruan Richard , Blanc Sophie F. , Patel Trishna S. , Worthington Caroline M. , Glasner Dustin R. , Castillo-Rojas Bryan , Servellita Venice , Lo Nicholas T.N. , Wong Marcus P. , Warnes Colin M. , Sandoval Daniel R. , Clausen Thomas Mandel , Santos Yale A. , Ortega Victoria , Aguilar Hector C. , Esko Jeffrey D. , Chui Charles Y. , Pak John E. , Beatty P. Robert , Harris Eva 
Published: December 2021

SummarySevere COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of this pathology are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to trigger barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-β signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-β signaling axis are required for S-mediated barrier dysfunction. Our findings suggest that S interactions with barrier cells are a contributing factor to COVID-19 disease severity and offer mechanistic insight into SARS-CoV-2 triggered vascular leak, providing a starting point for development of therapies targeting COVID-19 pathogenesis.
Mechanisms underlying melanoma invasion as a consequence of MLK3 loss
Authors: Balinda Henriette U. , Sedgwick Alanna , D’Souza-Schorey Crislyn 
Published: December 2021

AbstractInvasive melanoma is an aggressive form of skin cancer with high incidence of mortality. The process of invasion is a crucial primary step in the metastatic cascade, yet the mechanisms involved are still under investigation. Here we document a critical role for MLK3 (MAP3K11) in the regulation of melanoma cell invasion. We report that cellular loss of MLK3 in melanoma cells promotes cell invasion. Knock down of MLK3 expression results in the hyperactivation of ERK, which is linked to the formation of a BRAF/Hsp90/Cdc37 protein complex. ERK hyperactivation leads to enhanced phosphorylation and inactivation of GSK3β and the stabilization of c-Jun and JNK activity. Blocking of ERK and JNK signaling as well as Hsp90 activity downstream of MLK3-silencing significantly reduces melanoma invasion. Furthermore, our studies show that ERK activation in the aforementioned context is coupled to MT1-MMP transcription as well as the TOM1L1-dependent localization of the membrane protease to invadopodia at the invasive front. These studies provide critical insight into the mechanisms that couple MLK3 loss with BRAF hyperactivation and its consequence on melanoma invasion.
Multiple ETS Factors Participate in the Transcriptional Control of TERT Mutant Promoter in Thyroid Cancers
Authors: Thornton Caitlin E.M. , Hao Jingzhu , Tamarapu Prasanna P. , Landa Iñigo 
Published: December 2021

AbstractHotspot mutations in the TERT (telomerase reverse transcriptase) gene are key determinants of thyroid cancer progression. TERT promoter mutations (TPM) create de novo consensus binding sites for the ETS (“E26 transforming sequence”) family of transcription factors. In this study, we systematically knocked down each of the 20 ETS factors expressed in thyroid tumors and screened their effects on TERT expression in seven thyroid cancer cell lines with defined TPM status. We observed that, unlike in other TPM-carrying cancers such as glioblastomas, ETS factor GABPA does not unambiguously regulate transcription from the TERT mutant promoter in thyroid specimens. In fact, multiple members of the ETS family impact TERT expression, and they typically do so in a mutation-independent manner. In addition, we observe that partial inhibition of MAPK, a central pathway in thyroid cancer transformation, is more effective at suppressing TERT transcription in the absence of TPMs. Taken together, our results show a more complex scenario of TERT regulation in thyroid cancers compared to other lineages, suggest that compensatory mechanisms by ETS and other regulators likely exist and advocate for the need of a more comprehensive understanding of the mechanisms of TERT deregulation in thyroid tumors before eventually exploring TPM-specific therapeutic strategies.Graphical Abstract
EraSOR: Erase Sample Overlap in polygenic score analyses
Authors: Choi Shing Wan , Mak Timothy Shin Heng , Hoggart Clive J. , O’Reilly Paul F. 
Published: December 2021

AbstractBackgroundPolygenic risk score (PRS) analyses are now routinely applied in biomedical research, with great hope that they will aid in our understanding of disease aetiology and contribute to personalized medicine. The continued growth of multi-cohort genome-wide association studies (GWASs) and large-scale biobank projects has provided researchers with a wealth of GWAS summary statistics and individual-level data suitable for performing PRS analyses. However, as the size of these studies increase, the risk of inter-cohort sample overlap and close relatedness increases. Ideally sample overlap would be identified and removed directly, but this is typically not possible due to privacy laws or consent agreements. This sample overlap, whether known or not, is a major problem in PRS analyses because it can lead to inflation of type 1 error and, thus, erroneous conclusions in published work.ResultsHere, for the first time, we report the scale of the sample overlap problem for PRS analyses by generating known sample overlap across sub-samples of the UK Biobank data, which we then use to produce GWAS and target data to mimic the effects of inter-cohort sample overlap. We demonstrate that inter-cohort overlap results in a significant and often substantial inflation in the observed PRS-trait association, coefficient of determination (R2) and false-positive rate. This inflation can be high even when the absolute number of overlapping individuals is small if this makes up a notable fraction of the target sample. We develop and introduce EraSOR (Erase Sample Overlap and Relatedness), a software for adjusting inflation in PRS prediction and association statistics in the presence of sample overlap or close relatedness between the GWAS and target samples. A key component of the EraSOR approach is inference of the degree of sample overlap from the intercept of a bivariate LD score regression applied to the GWAS and target data, making it powered in settings where both have sample sizes over 1,000 individuals. Through extensive benchmarking using UK Biobank and HapGen2 simulated genotype-phenotype data, we demonstrate that PRSs calculated using EraSOR-adjusted GWAS summary statistics are robust to inter-cohort overlap in a wide range of realistic scenarios and are even robust to high levels of residual genetic and environmental stratification.ConclusionThe results of all PRS analyses for which sample overlap cannot be definitively ruled out should be considered with caution given high type 1 error observed in the presence of even low overlap between base and target cohorts. Given the strong performance of EraSOR in eliminating inflation caused by sample overlap in PRS studies with large (>5k) target samples, we recommend that EraSOR be used in all future such PRS studies to mitigate the potential effects of inter-cohort overlap and close relatedness.
Synthesis and Evaluation of Acridone and Xanthone Epoxides with Anti-MRSA and Anti-MSSA Activity
Authors: Chittepu Padmaja , Yang Junshu , Benoit Adam , Salomon Christine E. , Ji Yinduo , Ferguson David M. 
Published: December 2021

AbstractA series of acridone and xanthone-based compounds bearing 1,2-epoxypropyl or 1,2-propanediol substituents were synthesized and evaluated for activity against MRSA and MSSA bacterial strains. The results indicate a correlation exists between the number of epoxide groups and activity, with peak MIC values observed for bis-epoxy derivatives. Both activity and heathy cell toxicity was shown to decrease with the addition of a third epoxy group. The corresponding ring-opened diol analogs were devoid of activity, demonstrating the critical function of the epoxide in mediating antimicrobial activity. The most active compounds were also screened using a regulated antisense RNA expression library. The results show no increase in activity against cells sensitized by down-regulation of the most common drug targets, including DNA gyrase, DNA topoisomerase, tRNA synthetase, and the fatty acid biosynthesis pathway. The compounds are postulated to function as membrane disrupting agents, similar to the xanthone natural product α-mangostin.
Candidatus Nitrosopolaris, a genus of putative ammonia-oxidizing archaea with a polar/alpine distribution
Authors: Pessi Igor S. , Rutanen Aino , Hultman Jenni 
Published: December 2021

AbstractAmmonia-oxidizing archaea (AOA) are key players in the nitrogen cycle of polar soils. Here, we analysed metagenomic data from tundra soils in Rásttigáisá, Norway, and recovered four metagenome-assembled genomes (MAGs) assigned to the genus “UBA10452”, an uncultured lineage of putative AOA in the order Nitrososphaerales (“terrestrial group I.1b”), phylum Thaumarchaeota. Analysis of other eight previously reported MAGs and publicly available amplicon sequencing data revealed that the UBA10452 lineage is predominantly found in acidic polar and alpine soils. In particular, UBA10452 MAGs were more abundant in highly oligotrophic environments such as mineral permafrost than in more nutrient-rich, vegetated tundra soils. UBA10452 MAGs harbour multiple copies of genes related to cold tolerance, particularly genes involved in DNA replication and repair. Based on the phylogenetic, biogeographical, and ecological characteristics of 12 UBA10452 MAGs, which include a high-quality MAG (90.8% complete, 3.9% redundant) with a nearly complete 16S rRNA gene, we propose a novel Candidatus genus, Ca. Nitrosopolaris, with four species representing clear biogeographical/habitat clusters.
Brassica napus genes Rlm4 and Rlm7, conferring resistance to Leptosphaeria maculans, are alleles of the Rlm9 wall-associated kinase-like resistance locus
Authors: Haddadi Parham , Larkan Nicholas J. , Van de Wouw Angela , Zhang Yueqi , Neik Ting Xiang , Beynon Elena , Bayer Philipp , Edwards Dave , Batley Jacqueline , Borhan M. Hossein 
Published: December 2021

AbstractBrassica napus (canola/rapeseed) race specific resistance genes against blackleg disease, caused by the ascomycete fungus Leptosphaeria maculans, have been commonly used in canola breeding. To date; LepR3, Rlm2 and Rlm9 R genes against L. maculans have been cloned from B. napus. LepR3 and Rlm2 are Receptor Like Proteins (RLP) and the recently reported Rlm9 is a Wall Associated Kinase-Like (WAKL) protein. Rlm9 located on chromosome A07 is closely linked with Rlm3, Rlm4, RLm7 genes. Recognition of AvrLm5-9 and AvrLm3 by their corresponding Rlm9 and Rlm3 proteins is masked in the presence of AvrLm4-7. Here we report cloning of Rlm4 and Rlm7 by generating genome sequence of the doubled haploid (DH) B. napus cv Topas DH16516 introgression lines Topas-Rlm4 and Topas-Rlm7. Candidate Rlm4 and Rlm7 genes were identified form the genome sequence and gene structures were determined by mapping RNA-sequence reads, generated from infected cotyledon tissues, to the genome of Topas-Rlm4 and Topas-Rlm7. Rlm4 and Rlm7 genomic constructs with their native promoters were transferred into the blackleg susceptible B. napus cv Westar N-o-1. Complementation of resistance response in the transgenic Westar:Rlm4 and Westar:Rlm7 that were inoculated with L. maculans transgenic isolates 2367:AvrRlm4-7 or 2367:AvrLm7 confirmed the function of Rlm4 and Rlm7 genes. Wild type L. maculans isolate 2367 that does not contain AvrLm4-7 or AvrLm7, and transgenic 2367:AvrLm3 and 2367:AvrLm5-9 did not induce resistance proving the specificity of Rlm4 and Rlm7 response. Rlm4 and Rlm7 alleles are also allelic to Rlm9. Rlm4 and Rlm7 genes encode WAKL proteins. Comparison of highly homologous sequences of Rlm4 and Rlm7 with each other and with the sequence of additional alleles, using whole genome sequencing of additional 128 lines, identified a limited number of point mutation located within the predicted extracellular receptor domains.
There and Back to the Present: An Evolutionary Tale on Biological Diversity
Authors: Duarte Leandro , Nakamura Gabriel , Debastiani Vanderlei , Maestri Renan , Pereira Maria João Ramos , Cianciaruso Marcus , Diniz-Filho José Alexandre F. 
Published: December 2021

ABSTRACTEcologists often agree on the importance of macroevolution for niche-mediated distribution of biological diversity along environmental gradients. Yet, macroevolutionary diversification and dispersal in time and space generate uneven geographic distribution of phylogenetic pools, which affects the imprint let by macroevolution on local species pools. In this article we introduce an individual-based simulation approach coupled to Approximate Bayesian Computation (ABC) that allows to parameterize the adaptation rate of species’ niche positions along the evolution of a monophyletic lineage, and the intensity of dispersal limitation, associated with the distribution of biological diversity between assemblages potentially connected by dispersal (metacommunity). The analytical tool was implemented in an R package calledmcfly. We evaluated the statistical performance of the analytical framework using simulated datasets, which confirmed the suitability of the analysis to estimate adaptation rate and dispersal limitation parameters. Further, we evaluated the role played by niche evolution and dispersal limitation on species diversity distribution of Phyllostomidae bats across the Neotropics. The framework proposed here shed light on the links between niche evolution, dispersal limitation and the distribution of biological diversity, and thereby improved our understanding of evolutionary imprints on ecological patterns. Perhaps more importantly, it offers new possibilities for solving the eco-evolutionary puzzle.
High temporal resolution systems profiling reveals distinct patterns of interferon response after Covid-19 mRNA vaccination and SARS-CoV2 infection
Authors: Rinchai Darawan , Deola Sara , Zoppoli Gabriele , Ahamed Kabeer Basirudeen Syed , Taleb Sara , Pavlovski Igor , Maacha Selma , Gentilcore Giusy , Toufiq Mohammed , Mathew Lisa , Liu Li , Vempalli Fazulur Rehaman , Mubarak Ghada , Lorenz Stephan , Sivieri Irene , Cirmena Gabriella , Dentone Chiara , Cuccarolo Paola , Giacobbe Daniele Roberto , Baldi Federico , Garbarino Alberto , Cigolini Benedetta , Cremonesi Paolo , Bedognetti Michele , Ballestrero Alberto , Bassetti Matteo , Hejblum Boris P. , Augustine Tracy , Panhuys Nicholas Van , Thiebaut Rodolphe , Branco Ricardo , Chew Tracey , Shojaei Maryam , Short Kirsty , Feng Carl ,   PREDICT-19 consortium, Zughaier Susu M. , Maria Andrea De , Tang Benjamin , Hssain Ali Ait , Bedognetti Davide , Grivel Jean-Charles , Chaussabel Damien 
Published: December 2021

ABSTRACTKnowledge of the mechanisms underpinning the development of protective immunity conferred by mRNA vaccines is fragmentary. Here we investigated responses to COVID-19 mRNA vaccination via ultra-low-volume sampling and high-temporal-resolution transcriptome profiling (23 subjects across 22 timepoints, and with 117 COVID-19 patients used as comparators). There were marked differences in the timing and amplitude of the responses to the priming and booster doses. Notably, we identified two distinct interferon signatures. The first signature (A28/S1) was robustly induced both post-prime and post-boost and in both cases correlated with the subsequent development of antibody responses. In contrast, the second interferon signature (A28/S2) was robustly induced only post-boost, where it coincided with a transient inflammation peak. In COVID19 patients, a distinct phenotype dominated by A28/S2 was associated with longer duration of intensive care. In summary, high-temporal-resolution transcriptomic permitted the identification of post- vaccination phenotypes that are determinants of the course of COVID-19 disease.