bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Clinical Effectiveness of One-Dose HPV Vaccine: A meta-analysis of 902,368 vaccinated women
Authors: Setiawan Didik , Nurulita Nunuk Aries , Khoirunnisa Sudewi Mukaromah , Postma Maarten J 
Published: August 2023

AbstractIntroductionAlthough the effectiveness of the HPV vaccine has been comprehensively described, adherence to dosing and limited budget is one of the causes of delay in HPV vaccination implementation in a country. A one-dose HPV vaccine could possibly solve those issues since several studies show promising results.Areas coveredThis is a systematic review and meta-analysis focusing on the effectiveness of the one-dose HPV vaccine compared to two- and three doses of vaccination. We focused on clinical effectiveness, including prevention of HPV16, HPV18, and hrHPV infection, HSIL or ASC-H incidence, and CIN II/III incidence.Expert opinionOur review showed that a one-dose HPV vaccine could potentially be as effective as two-or three doses since it offers immunogenic protection up to 8 years follow up and also prevention on infection and pre-cancers incidence. However, more studies and an extended duration of existing studies are required in order to provide robust evidence of this recommendation.
Natural Language Processing for Adjudication of Heart Failure Hospitalizations in a Multi-Center Clinical Trial
Authors: Cunningham Jonathan W. , Singh Pulkit , Reeder Christopher , Claggett Brian , Marti-Castellote Pablo M. , Lau Emily S. , Khurshid Shaan , Batra Puneet , Lubitz Steven A. , Maddah Mahnaz , Philippakis Anthony , Desai Akshay S. , Ellinor Patrick T. , Vardeny Orly , Solomon Scott D. , Ho Jennifer E. 
Published: August 2023

AbstractBackgroundThe gold standard for outcome adjudication in clinical trials is chart review by a physician clinical events committee (CEC), which requires substantial time and expertise. Automated adjudication by natural language processing (NLP) may offer a more resource-efficient alternative. We previously showed that the Community Care Cohort Project (C3PO) NLP model adjudicates heart failure (HF) hospitalizations accurately within one healthcare system.MethodsThis study externally validated the C3PO NLP model against CEC adjudication in the INVESTED trial. INVESTED compared influenza vaccination formulations in 5260 patients with cardiovascular disease at 157 North American sites. A central CEC adjudicated the cause of hospitalizations from medical records. We applied the C3PO NLP model to medical records from 4060 INVESTED hospitalizations and evaluated agreement between the NLP and final consensus CEC HF adjudications. We then fine-tuned the C3PO NLP model (C3PO+INVESTED) and trained ade novomodel using half the INVESTED hospitalizations, and evaluated these models in the other half. NLP performance was benchmarked to CEC reviewer inter-rater reproducibility.Results1074 hospitalizations (26%) were adjudicated as HF by the CEC. There was high agreement between the C3PO NLP and CEC HF adjudications (agreement 87%, kappa statistic 0.69). C3PO NLP model sensitivity was 94% and specificity was 84%. The fine-tuned C3PO andde novoNLP models demonstrated agreement of 93% and kappa of 0.82 and 0.83, respectively. CEC reviewer inter-rater reproducibility was 94% (kappa 0.85).ConclusionOur NLP model developed within a single healthcare system accurately identified HF events relative to the gold-standard CEC in an external multi-center clinical trial. Fine-tuning the model improved agreement and approximated human reproducibility. NLP may improve the efficiency of future multi-center clinical trials by accurately identifying clinical events at scale.
Evaluating the Safety Profile of the CoronaVac in Adult and Elderly populations: A Phase IV Prospective Observational Study in Brazil
Authors:   Monica Akissue de Camargo Teixeira Cintra, Fernandes Eder Gatti , Infante Vanessa , Loch Ana Paula , Ragiotto Lucas , Braga Patrícia Emília , Salomão Maria da Graça , Lucchesi Maria Beatriz Bastos , de Oliveira Mayra Martho Moura , Gattás Vera Lúcia , da Silva Anderson Soares , Villas Boas Paulo José Fortes , Lopes Marta Heloisa , Moreira José , Boulos Fernanda Castro ,   CFV-01-IB study group
Published: August 2023

AbstractObjectiveThis Phase IV prospective observational study aimed to evaluate the safety and monitor adverse events following immunization (AEFI) associated with CoronaVac, an inactivated SARS-CoV-2 vaccine, in Brazilian adult (18-59 years) and elderly (≥60 years) populations.MethodsParticipants (n=538; 487 adults and 51 elderly) were enrolled from three public health services in São Paulo, Brazil. A two-dose vaccination regimen, administered 14 days apart, was used. The study assessed Adverse Reactions (AR) necessitating medical attention within seven days post-vaccination dose and monitored AEFI for a period of 42 days. Safety was monitored through a review of participant diary cards, telephone contacts, and on-site study visits.ResultsAmong adults, the most frequently reported local AR after the first and second dose was pain (256[52.6%] and 129 [29.5], respectively), while the most common systemic reaction was a headache (158[34.5%] and 51 [11.6%], respectively). Most local and systemic solicited ARs were of Grade 1 or 2, with these reactions being more prevalent in adults after the first dose. One serious adverse event possibly related to the vaccine was reported among adults, but there were no fatalities. Nine adult participants experienced adverse events of special interest, which included five cases of Covid-19.ConclusionCoronaVac demonstrated safety and tolerability in the observed population. Ongoing post-marketing surveillance is crucial for the identification of rare adverse events and further affirmation of the vaccine’s safety profile.
Jumping between Turtles, Fishes, and a Frog: The Unexpected Horizontal Transfer of a DNA Transposon
Authors: Hassan Nozhat T. , Galbraith James D. , Adelson David L. 
Published: August 2023

AbstractHorizontal transfer of transposable elements (HTT) has been reported across many species and the impact of such events on genome structure and function has been well described. However, few studies have focused on reptilian genomes, especially HTT events in Testudines (turtles). Here, we investigated the repetitive content ofMalaclemys terrapin terrapin(Diamondback turtle) and found a high similarity hAT-6 DNA transposon shared between other turtle species, ray-finned fishes, and a frog. hAT-6 was notably absent in taxa closely related to turtles, such as crocodiles and birds. Successful invasion of DNA transposons into new genomes requires the conservation of specific residues in the encoded transposase, and through structural analysis, these residues were identified indicating retention of functional transposition activity. We document a rare and recent HTT event of a DNA transposon between turtles which are known to have a low genomic evolutionary rate and ancient repeats.
Serum metabolomics improve risk stratification for incident heart failure
Authors: Oexner Rafael R. , Ahn Hyunchan , Theofilatos Konstantinos , Shah Ravi A. , Schmitt Robin , Chowienczyk Philip , Zoccarato Anna , Shah Ajay M. 
Published: August 2023

AbstractBackground and AimsPrediction and early detection of heart failure (HF) is crucial to mitigate its impact on quality of life, survival, and healthcare expenditure. In this study, we explored the predictive value of serum metabolomics (168 metabolites detected by proton nuclear magnetic resonance (1H-NMR) spectroscopy) for incident HF.MethodsWe leveraged data of 68,311 individuals and > 0.8 million person-years of follow-up from the UK Biobank (UKB) cohort to assess individual metabolite associations and to train models to predict HF risk in individuals not previously considered at risk. Specifically, we (I) fitted per-metabolite COX proportional hazards (COX-PH) models to assess individual metabolite associations and (II) trained and internally validated elastic net (EN) models to predict incident HF using the serum metabolome. We benchmarked discriminative capacities against a comprehensive, well-validated clinical risk score (Pooled Cohort Equations to Prevent HF, PCP-HF1).ResultsDuring median follow-up of ≈ 12.3 years, several metabolites showed independent association with incident HF (90/168 adjusting for age and sex, 48/168 adjusting for PCP-HF; false discovery rate (FDR)-controlled P < 0.01). Performance-optimized risk models effectively retained key predictors representing highly correlated clusters (≈ 80 % feature reduction). The addition of metabolomics to PCP-HF improved predictive performance (Harrel’s C: 0.768 vs. 0.755.; continuous net reclassification improvement (NRI) = 0.287; relative integrated discrimination improvement (IDI): 17.47 %). Simplified models including age, sex and metabolomics performed almost as well as PCP-HF (Harrel’s C: 0.745 vs. 0.755, continuous NRI: 0.097, relative IDI: 13.445 %). Risk and survival stratification was improved by the integration of metabolomics.ConclusionsThe assessment of serum metabolomics improves incident HF risk prediction. Scores based simply on age, sex and metabolomics exhibit similar predictive power to clinically-based models, potentially offering a cost- and time-effective, standardizable, and scalable single-domain alternative to more complex clinical scores.
Antibody Neutralization of Emerging SARS-CoV-2: EG.5.1 and XBC.1.6
Authors: Wang Qian , Guo Yicheng , Zhang Richard M. , Ho Jerren , Mohri Hiroshi , Valdez Riccardo , Manthei David M. , Gordon Aubree , Liu Lihong , Ho David D. 
Published: August 2023

AbstractSARS-CoV-2 variants EG.5.1 and XBC.1.6 have recently emerged, attracting increased attention due to their rapid expansion globally and in Australia, respectively. EG.5.1 evolved from Omicron subvariant XBB.1.9, harboring additional Q52H and F456L spike substitutions. The F456L mutation is located within the epitopes of many class-1 monoclonal antibodies (mAbs) directed to the receptor-binding domain (RBD), raising concerns about further antibody evasion. XBC.1.6, a descendant of a Delta-BA.2 recombinant, carries 15 additional spike mutations. The extent to which antibody evasion contributes to the growth advantage of XBC.1.6 in Australia remains to be determined. To assess the antibody evasion properties of the emergent variants, we conducted pseudovirus neutralization assays using sera from individuals who received three doses of COVID-19 mRNA monovalent vaccines plus one dose of a BA.5 bivalent vaccine, as well as from patients with BQ or XBB breakthrough infection. The assays were also performed using a panel of 14 mAbs that retained neutralizing activity against prior XBB subvariants. Our data suggested that EG.5.1 was slightly but significantly more resistant (< 2-fold) to neutralization by BQ and XBB breakthrough sera than XBB.1.16, which is known to be antigenically similar to XBB.1.5. Moreover, the F456L mutation in EG.5.1 conferred heightened resistance to certain RBD class-1 mAbs. In contrast, XBC.1.6 was more sensitive to neutralization by sera and mAbs than the XBB subvariants. Notably, XBB breakthrough sera retained only weak neutralization activity against XBB subvariants. In summary, EG.5.1 and XBC.1.6 exhibited distinct antibody evasion properties. The recent global expansion of EG.5.1 might be attributable, in part, to its enhanced neutralization resistance. That XBB breakthrough infections did not elicit a robust antibody neutralization response against XBB subvariants is indicative of immunological imprinting. The high prevalence of XBC.1.6 in Australia is not due to enhanced antibody evasion.
Enhancing t-SNE Performance for Biological Sequencing Data through Kernel Selection
Authors: Chourasia Prakash , Murad Taslim , Ali Sarwan , Patterson Murray 
Published: August 2023

AbstractThe genetic code for many different proteins can be found in biological sequencing data, which offers vital insight into the genetic evolution of viruses. While machine learning approaches are becoming increasingly popular for many “Big Data” situations, they have made little progress in comprehending the nature of such data. One such area is the t-distributed Stochastic Neighbour Embedding (t-SNE), a generalpurpose approach used to represent high dimensional data in low dimensional (LD) space while preserving similarity between data points. Traditionally, the Gaussian kernel is used with t-SNE. However, since the Gaussian kernel is not data-dependent, it determines each local bandwidth based on one local point only. This makes it computationally expensive, hence limited in scalability. Moreover, it can misrepresent some structures in the data. An alternative is to use the isolation kernel, which is a data-dependent method. However, it has a single parameter to tune in computing the kernel. Although the isolation kernel yields better performance in terms of scalability and preserving the similarity in LD space, it may still not perform optimally in some cases. This paper presents a perspective on improving the performance of t-SNE and argues that kernel selection could impact this performance. We use 9 different kernels to evaluate their impact on the performance of t-SNE, using SARS-CoV-2 “spike” protein sequences. With three different embedding methods, we show that the cosine similarity kernel gives the best results and enhances the performance of t-SNE.
Identifying LasR quorum sensors with improved signal specificity by mapping the sequence-function landscape
Authors: Zeng Min , Sarker Biprodev , Rondthaler Stephen N. , Vu Vanessa , Andrews Lauren B. 
Published: August 2023

ABSTRACTProgrammable intercellular signaling using components of naturally-occurring quorum sensing can allow for coordinated functions to be engineered in microbial consortia. LuxR-type transcriptional regulators are widely used for this purpose and are activated by homoserine lactone (HSL) signals. However, they often suffer from imperfect molecular discrimination of structurally similar HSLs, causing misregulation within engineered consortia containing multiple HSL signals. Here, we studied one such example, the regulator LasR fromPseudomonas aeruginosa. We elucidated its sequence-function relationship for ligand specificity using targeted protein engineering and multiplexed high-throughput biosensor screening. A pooled combinatorial saturation mutagenesis library (9,486 LasR DNA sequences) was created by mutating six residues in LasR’s β5 sheet with single, double, or triple amino acid substitutions. Sort-seq assays were performed in parallel using cognate and non-cognate HSLs to quantify each corresponding sensor’s response to each HSL signal, which identified hundreds of highly specific variants. Sensor variants identified were individually assayed and exhibited up to 60.6-fold (p= 0.0013) improved relative activation by the cognate signal compared to the wildtype. Interestingly, we uncovered prevalent mutational epistasis and previously unidentified residues contributing to signal specificity. The resulting sensors with negligible signal crosstalk could be broadly applied to engineer bacteria consortia.
Engineering of a graphene oxide-based two-dimensional platform for immune activation and modulation
Authors: Despotopoulou Despoina , Stylianou Maria , Arellano Luis Miguel , Kisby Thomas , Lozano Neus , Kostarelos Kostas 
Published: August 2023

AbstractNanoscale-based tools for immunomodulation are expected to offer a rich battery of options for more targeted and safer approaches to achieve clinically effective manipulation of the local and systemic immune environment. In this study, we aimed to design nanoscale constructs based on graphene oxide (GO) nanosheets as platform carriers for the TLR7/8 agonist Resiquimod (R848). The non-covalent complexation of R848 molecules on the GO surface resulted in stable complexes by preserving their biological activity. The physicochemical properties, molecular quantification, as well as the overall performance of the complex were systematically investigated. We hypothesized the formation of GO:drug nano-constructs with strong colloidal stability over time, due to the strong π-π interactions between the R848 molecules and the GO surface, and identified that R848 loading efficiency consistently ranged around 75% (of starting molecules), quantified by HPLC and UV-Vis. The 2D morphology of the thin nanosheets was retained after complexation, determined by various (AFM and SEM) microscopic techniques. Based on the surface physicochemical characterization of the complexes by Raman, FTIR, XPS, and XRD, the formation of non-covalent interactions among the GO surface and the R848 molecules was confirmed. Most importantly, GO:R848 complexes did not compromise the biological activity of R848, and effectively activated macrophagesin vitro. Collectively, this study demonstrates that thin GO sheets can act as platforms for the non-covalent association with small TLR7/8 agonist molecules, forming stable and highly reproducible complexes, that could be exploited as effective immunomodulatory agents.
Making Proteomics Accessible: RokaiXplorer for interactive analysis of phospho-proteomic data
Authors: Yılmaz Serhan , Lopes Filipa Blasco Tavares Pereira , Schlatzer Daniela , Ayati Marzieh , Chance Mark R. , Koyutürk Mehmet 
Published: August 2023

AbstractIn this work, we present RokaiXplorer, an intuitive web tool designed to address the scarcity of user-friendly solutions for proteomics and phospho-proteomics data analysis and visualization. RokaiXplorer streamlines data processing, analysis, and visualization through an interactive online interface, making it accessible to researchers without specialized training in proteomics or data science. With its comprehensive suite of modules, RokaiXplorer facilitates the analysis of phosphosites, proteins, kinases, and gene ontology terms. The tool offers functionalities such as data normalization, statistical testing, enrichment analysis, subgroup analysis, report generator, and multiple visualizations, including volcano plots, bar plots, heatmaps, tables, and interactive networks. Additionally, RokaiXplorer allows researchers to effortlessly deploy their own data browsers, fostering the sharing of research data and findings interactively. By providing simplicity, efficiency, and multi-level data analysis within a single application, it is poised to become a valuable resource for the scientific community working with phospho-proteomic data. Access RokaiXplorer at:http://explorer.rokai.io
Guanidine Production by Plant Homoarginine-6-hydroxylases
Authors: Funck Dietmar , Sinn Malte , Forlani Giuseppe , Hartig Jörg S. 
Published: August 2023

AbstractMetabolism and biological functions of the nitrogen-rich compound guanidine have long been neglected. The discovery of four classes of guanidine-sensing riboswitches and two pathways for guanidine degradation in bacteria hint at widespread sources of unconjugated guanidine in nature. So far, only three enzymes from a narrow range of bacteria and fungi have been shown to produce guanidine, with the ethylene-forming enzyme (EFE) as the most prominent example. Here, we show that a related class of Fe2+- and 2-oxoglutarate-dependent dioxygenases (2-ODD-C23) highly conserved among plants and algae catalyze the hydroxylation of homoarginine at the C6-position. Spontaneous decay of 6-hydroxyhomoarginine yields guanidine and 2-aminoadipate-6-semialdehyde. The latter can be reduced to pipecolate by pyrroline-5-carboxylate reductase but more likely is oxidized to aminoadipate by aldehyde dehydrogenase ALDH7Bin vivo. Arabidopsis has three 2-ODD-C23 isoforms, among which Din11 is unusual because it also accepted arginine as substrate, which was not the case for the other 2-ODD-C23 isoforms from Arabidopsis or other plants. In contrast to EFE, none of the three Arabidopsis enzymes produced ethylene. Guanidine contents were typically between 10 and 20 nmol*(g fresh weight)-1in Arabidopsis but increased to 100 or 300 nmol*(g fresh weight)-1after homoarginine feeding or treatment with Din11-inducing methyljasmonate, respectively. In 2-ODD-C23 triple mutants, the guanidine content was strongly reduced, whereas it increased in overexpression plants. We discuss the implications of the finding of widespread guanidine-producing enzymes in photosynthetic eukaryotes as a so far underestimated branch of the bio-geochemical nitrogen cycle and propose possible functions of natural guanidine production.
Impairment of the SKN-1A/NRF1 proteasome surveillance pathway triggers tissue-specific protective immune responses against distinct natural pathogens inC. elegans
Authors: Grover Manish , Gang Spencer S. , Troemel Emily R. , Barkoulas Michalis 
Published: August 2023

ABSTRACTProtein quality control pathways play important roles in resistance against pathogen infection. For example, the conserved transcription factor SKN-1/NRF upregulates proteostasis capacity after blockade of the proteasome, and also promotes resistance against bacterial infection in the nematodeC. elegans. SKN-1/NRF has three isoforms, and the SKN-1A/NRF1 isoform in particular regulates proteasomal gene expression upon proteasome dysfunction as part of a conserved bounce-back response. We report here that, in contrast to the previously reported role of SKN-1 in promoting resistance against bacterial infection, loss-of-function mutants inskn-1aand its activating enzymesddi-1andpng-1,show constitutive expression of immune response programmes against natural eukaryotic pathogens ofC. elegans. These programmes are the Oomycete Recognition Response (ORR), which promotes resistance against oomycetes that infect through the epidermis, and the Intracellular Pathogen Response (IPR), which promotes resistance against intestine-infecting microsporidia. Consequently,skn-1amutants show increased resistance to both oomycete and microsporidia infections. We also report that almost all ORR/IPR genes induced in common between these programmes are regulated by the proteasome and interestingly, specific ORR/IPR genes can be induced in distinct tissues depending on the exact trigger. Furthermore, we show that increasing proteasome function significantly reduces oomycete-mediated induction of multiple ORR markers. Altogether, our findings demonstrate that proteasome regulation keeps innate immune responses in check in a tissue-specific manner, against natural eukaryotic pathogens of theC. elegansepidermis and intestine.