bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of QuantiFERON SARS-CoV-2 interferon-γ release assay following SARS-CoV-2 infection and vaccination
Authors: Johnson Síle A , Phillips Eloise , Adele Sandra , Longet Stephanie , Malone Tom , Mason Chris , Stafford Lizzie , Jamsen Anni , Gardiner Siobhan , Deeks Alexandra , Neo Janice , Blurton Emily J , White Jemima , Ali Muhammed , Kronsteiner-Dobramysl Barbara , Skelly Dónal T , Jeffery Katie , Conlon Christopher P , Goulder Philip ,   PITCH Consortium, Carroll Miles , Barnes Eleanor , Klenerman Paul , Dunachie Susanna J 
Published: September 2022

AbstractBackgroundT cells are important in preventing severe disease from SARS-CoV-2, but scalable and field-adaptable alternatives to expert T cell assays are needed. The interferon-gamma release assay QuantiFERON platform was developed to detect T cell responses to SARS-CoV-2 from whole blood with relatively basic equipment and flexibility of processing timelines.Methods48 participants with different infection and vaccination backgrounds were recruited. Whole blood samples were analysed using the QuantiFERON SARS-CoV-2 assay in parallel with the well-established ‘Protective Immunity from T Cells in Healthcare workers’ (PITCH) ELISpot, which can evaluate spike-specific T cell responses.AimsThe primary aims of this cross-sectional observational cohort study were to establish if the QuantiFERON SARS-Co-V-2 assay could discern differences between specified groups and to assess the sensitivity of the assay compared to the PITCH ELISpot.FindingsThe QuantiFERON SARS-CoV-2 distinguished acutely infected individuals (12-21 days post positive PCR) from naïve individuals (p< 0.0001) with 100% sensitivity and specificity for SARS-CoV-2 T cells, whilst the PITCH ELISpot had reduced sensitivity (62.5%) for the acute infection group. Sensitivity with QuantiFERON for previous infection was 12.5% (172-444 days post positive test) and was inferior to the PITCH ELISpot (75%).Although the QuantiFERON assay could discern differences between unvaccinated and vaccinated individuals (55-166 days since second vaccination), the latter also had reduced sensitivity (55.5%) compared to the PITCH ELISpot (66.6%).ConclusionThe QuantiFERON SARS-CoV-2 assay showed potential as a T cell evaluation tool soon after SARS-CoV-2 infection but has lower sensitivity for use in reliable evaluation of vaccination or more distant infection.Graphical abstractWith the exception of acute infection group, the PITCH ELISpot S1+S2 had greater sensitivity for SARS-CoV-2 specific T cell responses compared with the QuantiFERON SARS-CoV-2 assay tube Ag3.
Evaluation of a microRNA-based Risk Classifier Predicting Cancer-Specific Survival in Renal Cell Carcinoma with Tumor Thrombus of the Inferior Vena Cava
Authors: Kotlyar Mischa J. , Krebs Markus , Burger Maximilian , Kübler Hubert , Bargou Ralf , Kneitz Susanne , Otto Wolfgang , Breyer Johannes , Vergho Daniel C. , Kneitz Burkhard , Kalogirou Charis 
Published: September 2022

Abstract(1)BackgroundClear cell renal cell carcinoma extending into the inferior vena cava (ccRCCIVC) represents a clinical high-risk setting. However, there is substantial heterogeneity within this patient subgroup regarding survival outcomes. Previously, members of our group developed a microRNA(miR)-based risk classifier – containing miR-21, miR-126 and miR-221 expression – which significantly predicted cancer-specific survival (CSS) of ccRCCIVCpatients.(2)MethodsExamining a single-center cohort of tumor tissue from n = 56 patients with ccRCCIVC, we measured expression levels of miR-21, miR-126 and miR-221 by qRT-PCR. Prognostic impact of clinicopathological parameters and miR expression were investigated via univariate and multivariate cox regression. Referring to the previously established risk classifier, we performed Kaplan Meier analyses for single miR expression levels and the combined risk classifier. Cut-off values and weights within the risk classifier were taken from the previous study.(3)ResultsmiR-21 and miR-126 expression were significantly associated with lymphonodal status at time of surgery, development of metastasis during follow-up, and cancer-related death. In Kaplan Meier analyses, miR-21 and miR-126 significantly impacted CSS in our cohort. Moreover, applying the miR-based risk classifier significantly stratified ccRCCIVCaccording to CSS.(4)ConclusionsIn our retrospective analysis, we successfully validated the miR-based risk classifier within an independent ccRCCIVCcohort.
Accuracy of the diagnostic tests for the detection of Chagas disease: a systematic review and meta-analysis
Authors: Candia-Puma Mayron Antonio , Luque Laura Yesenia Machaca , Pumahuanca Brychs Milagros Roque , Galdino Alexsandro Sobreira , Giunchetti Rodolfo Cordeiro , Coelho Eduardo Antonio Ferraz , Chávez-Fumagalli Miguel Angel 
Published: September 2022

AbstractThe present systematic review and meta-analysis about the accuracy of diagnostic tests aim to describe the findings of literature over the last thirty years for the diagnosis of Chagas disease (CD). This work aimed to determine the accuracy of diagnostic techniques for CD in the disease’s acute and chronic phases. The PubMed database was searched for studies published between 1990 and 2021 on CD diagnostic. Fifty-six published studies that met the criteria were analyzed and included in the meta-analysis, evaluating diagnostic accuracy through sensitivity and specificity. For Enzyme-Linked Immunosorbent Assay (ELISA), Fluorescent Antibody Technique (IFAT), Hemagglutination Test (HmT), Polymerase Chain Reaction (PCR) and (Real-Time Polymerase Chain Reaction qPCR diagnosis methods, the sensitivity had a median of 99.0%, 78.0%, 75.0%, 76.0% and 94.0%, respectively; while specificity presented a median of 99.0%, 99.0%, 99.0%, 98.0% and 98.0%, respectively. This meta-analysis showed that ELISA and qPCR techniques had a higher performance compared to other methods of diagnosing CD in the chronic and acute phases, respectively. It was concluded by means of the AUC restricted to the false positive rates, that the ELISA diagnostic test presents the highest performance in diagnosing acute and chronic CD, compared to serological and molecular tests. Future studies focusing on new CD diagnostics approaches should be targeted.
Novel subgroups of type 2 diabetes based on multi-Omics profiling: an IMI-RHAPSODY Study
Authors: Li Shiying , Dragan Iulian , Fung Chun Ho , Kuznetsov Dmitry , Hansen Michael K. , Beulens Joline W.J. , ’t Hart Leen M. , Slieker Roderick C. , Donnelly Louise A. , Gerl Mathias J. , Klose Christian , Mehl Florence , Simons Kai , Elders Petra JM , Pearson Ewan R. , Rutter Guy A. , Ibberson Mark 
Published: September 2022

AbstractType 2 diabetes is a complex, multifactorial disease with varying presentation and underlying pathophysiology. Recent studies using data-driven cluster analysis have led to a stratification of type 2 diabetes into novel subgroups based on six clinical measurements. Whether these subgroups truly correspond to the underlying phenotypic differences is nevertheless unclear. Here, we apply an unsupervised, data-driven clustering method (Similarity Network Fusion) to characterize type 2 diabetes in two independent cohorts involving 1,134 subjects in total based on integrated plasma lipidomics and peptidomics data without pre-selection. Logistic regression was then used to explore clustering based on ≥ 180 circulating lipids and 1,195 protein biomarkers, alongside clinical signatures. Two subgroups were identified, one of which associated with elevated C-peptide levels, diabetic complications and more severe insulin resistance compared to the other. GWAS analysis against 403 type 2 diabetes risk variants revealed associations of several SNPs with clusters and altered molecular profiles. We thus demonstrate that heterogeneity in type 2 diabetes can be captured by circulating omics alone using an unsupervised bottom-up approach. Such multiomics signatures could reflect pathological mechanisms underlying type 2 diabetes and thus may help inform on precision medicine approaches to disease management.
Clinical predictors of treatment outcome in Melanesian adults with Tuberculous Meningitis at the Kundiawa General Hospital in Papua New Guinea
Authors: Aiwara Stanley , Aglua Izzard 
Published: September 2022

AbstractBackgroundTuberculous meningitis is the most severe form of extrapulmonary TB and accounted for 5% of 10 million global TB cases in the WHO 2018 report, with mortality as high as 19% in children and 30% in adults. Clinicians in resource-poor settings are often challenged by limited diagnostic and therapeutic options for optimal patient care, and often rely on clinical parameters for diagnosis, treatment, monitoring and outcome.AimThis study was done to identify potential clinical predictors of i) 28-day mortality and ii) length of hospitalization, amongst Melanesian adults with TB meningitis at a provincial hospital in Papua New Guinea.MethodA retrospective observational study was conducted on 65 Melanesian adults with TB meningitis at a provincial hospital in Papua New Guinea between 2015 and 2019.ResultHigh case fatality (49%) and mortality rates (2.22 per 100 000 per year) for TB Meningitis were observed in this study. Even higher case fatality of 93% observed for HIV-TBM co-infection. 28-day mortality associated with HIV-TBM co-infection (p-value=0.007, 95% CI 2.49-289.19), positive fluid balance 24-hours after admission (p-value=0.019, 95% CI 1.23-10.19) and admission GCS ≤10 (p-value=0.049, 95% CI 1.01-16.58).ConclusionStudy showed high case fatality (49%) and mortality rates (2.22 per 100,000 per year) for TB Meningitis in Melanesian adults, with significantly high case fatality (93%) for HIV-TBM co-infection. HIV-TBM co-infection was strongly associated with 28-day mortality whilst a positive fluid balance 24-hours after admission and admission-GCS ≤10 were weakly associated with 28-day mortality.
The Impact of Variance in Carnitine Palmitoyltransferase-1 Expression on Breast Cancer Prognosis is Stratified by Clinical and Anthropometric Factors
Authors: Liu Ryan , Ospanova Shyryn , Perry Rachel J. 
Published: September 2022

1.AbstractCPT1A is a rate-limiting enzyme in fatty acid oxidation and is upregulated in high-risk breast cancer. Obesity and menopausal status’ relationship with breast cancer prognosis is well established, but its connection with fatty acid metabolism is not. We performed an observational study on anonymized RNA sequencing data in the Xena Functional Genomics Explorer, to explore CPT1A’s effect on breast cancer patients’ survival probability. Using [18F]-fluorothymidine positron emission tomography-computed tomography images from The Cancer Imaging Archive, we segmented these analyses by obesity and menopausal status. In 1214 patients, higher CPT1A expression is associated with lower breast cancer survivability. We confirmed a previously observed protective relationship between obesity and breast cancer in pre-menopausal patients and supported this data using two-sided Pearson correlations. Taken together, these analyses using open-access, deidentified databases bolster the potential role of CPT1A-dependent fatty acid metabolism as a pathogenic factor in breast cancer.
Higher level of Quinolones residue in poultry meat and eggs; an alarming public health issue in Nepal
Authors: Shrestha Nabaraj , Layalu Sundar , Amatya Serene , Shrestha Samrat , Basnet Shobha , Shrestha Manash , Shrestha Upendra Thapa 
Published: September 2022

ABSTRACTBackgroundWith extensive use of antimicrobial agents in poultry production to prevent and treat diseases and as growth promoters, there has been an increase in antibiotic residue in the poultry meat and eggs. Quinolones are one of the highly prioritized, critically important drugs, whose residue in poultry can cause transmission of resistant zoonotic pathogens to humans. This study was conducted to assess the qualitative and quantitative residue of the quinolone in meat and eggs supplied to Kathmandu Valley, Nepal.MethodsA standard questionnaire was used to identify the trend of antibiotic application in the poultry industry. Epicollect+ android application was used for the survey. A total of 120 meat samples and 120 egg samples were collected from the specified five sectors. Enzyme Linked Immuno Sorbant Assay was employed to screen antimicrobial residues in the samples. Only the samples with antimicrobial residues above maximum residual limit value were quantified with High Performance Liquid Chromatography.ResultAbout 88.33% of chicken meat and 80% egg samples were positive for Quinolone residue. Three meat samples from Kathmandu had residues above the maximum residue level (MRL). One sample each from commercial and education sector showed Enrofloxacin residues while 1 sample from the health sector showed residues of both Enrofloxacin and Ciprofloxacin. The egg samples of Kathmandu, Bhaktapur and Lalitpur district contained 83.9%, 76.9% and 65% Quinolone residues respectively. While the eggs collected from household sector had the highest (100%) Quinolone residues than eggs from any other sectors followed by the lowest (66.6%) in eggs from the education sector (p=0.005).ConclusionA high level of Quinolone residue in the chicken meat and egg samples in the study indicates the imprudent and haphazard use of antibiotics which is a cause of emergence of antimicrobial resistant poultry pathogens alarming the potential transmission of resistance to human pathogens.
Structural rearrangements of a caspase-like protease TPR-CHAT govern virus-host discrimination during type III-E CRISPR-Caspase immunity
Authors: Cui Ning , Zhang Jun-Tao , Li Zhuolin , Liu Xiao-Yu , Wang Chongyuan , Huang Hongda , Jia Ning 
Published: September 2022

AbstractThe RNA-targeting type III-E CRISPR-gRAMP effector forms a complex with a caspase-like protease TPR-CHAT, but the mechanistic details of their functional relationship remain unknown. Here, we report on cryo-EM structures of gRAMPcrRNA and gRAMPcrRNA-TPR-CHAT complexes, before and after either self or non-self RNA target binding, elucidating mechanisms underlying RNA-targeting and non-self RNA-induced protease activation. Noteworthy, the associated TPR-CHAT adopts a strikingly distinct conformation on self versus non-self RNA targets, with nucleotides at position −1 and −2 of crRNA serving as a sensor. Only binding of non-self RNA target activates TPR-CHAT protease, leading to the cleavage of Csx30 protein. Furthermore, given that TPR-CHAT structurally resembles eukaryotic separase, our results implicate an ancient mechanism for separase regulation. Our findings should not only facilitate the development of gRAMP-based RNA manipulation tools, but also lead to a mechanistic understanding of the virus-host discrimination process governed by a caspase-like protease during type III-E CRISPR-Caspase immunity.
Revisiting the burden borne by fumarase: enzymatic hydration of an olefin
Authors: Bellur Asutosh , Das Soumik , Jayaraman Vijay , Behera Sudarshan , Suryavanshi Arpitha , Balasubramanian Sundaram , Balaram Padmanabhan , Jindal Garima , Balaram Hemalatha 
Published: September 2022

ABSTRACTFumarate hydratase (FH) is a remarkable catalyst that decreases the free energy of the catalyzed reaction by 30 kcal mol−1, much larger than most exceptional enzymes with extraordinary catalytic rates. Two classes of FH are observed in nature: class-I and class-II, that have different folds, yet catalyze the same reversible hydration/dehydration reaction of the dicarboxylic acids fumarate/malate, with equal efficiencies. Using class-I FH from the hyperthermophilic archaeon Methanocaldococcus jannaschii (Mj) as a model along with comparative analysis with the only other available class-I FH structure from Leishmania major (Lm), we provide insights into the molecular mechanism of catalysis in this class of enzymes. The structure of MjFH apo-protein has been determined, revealing that large inter-subunit rearrangements occur across apo- and the holo-protein forms, with a largely preorganized active site for substrate binding. Site-directed mutagenesis of active site residues, kinetic analysis and computational studies including DFT and natural population analysis, together show that residues interacting with the carboxylate group of the substrate play a pivotal role in catalysis. Our study establishes that an electrostatic network at the active site of class-I FH, polarizes the substrate fumarate through interactions with its carboxylate groups, thereby permitting an easier addition of a water molecule across the olefinic bond. We propose a mechanism of catalysis in FH that occurs through transition state stabilization involving the distortion of the electronic structure of the substrate olefinic bond mediated by the charge polarization of the bound substrate at the enzyme active site.Abstract Figure
Structural basis of substrate recognition by human tRNA splicing endonuclease TSEN
Authors: Sekulovski Samoil , Sušac Lukas , Stelzl Lukas S. , Tampé Robert , Trowitzsch Simon 
Published: September 2022

AbstractThe heterotetrameric human transfer RNA (tRNA) splicing endonuclease (TSEN) catalyzes the excision of intronic sequences from precursor tRNAs (pre-tRNAs)1. Mutations in TSEN and its associated RNA kinase CLP1 are linked to the neurodegenerative disease pontocerebellar hypoplasia (PCH)2–8. The three-dimensional (3D) assembly of TSEN/CLP1, the mechanism of substrate recognition, and the molecular details of PCH-associated mutations are not fully understood. Here, we present cryo-electron microscopy structures of human TSEN with intron-containing pre-tRNATyrgta and pre-tRNAArgtct. TSEN exhibits broad structural homology to archaeal endonucleases9 but has evolved additional regulatory elements that are involved in handling and positioning substrate RNA. Essential catalytic residues of subunit TSEN34 are organized for the 3’ splice site which emerges from a bulge-helix configuration. The triple-nucleotide bulge at the intron/3’-exon boundary is stabilized by an arginine tweezer motif of TSEN2 and an interaction with the proximal minor groove of the helix. TSEN34 and TSEN54 define the 3’ splice site by holding the tRNA body in place. TSEN54 adapts a bipartite fold with a flexible central region required for CLP1 binding. PCH-associated mutations are located far from pre-tRNA binding interfaces explaining their negative impact on structural integrity of TSEN without abrogating its catalytic activity in vitro10. Our work defines the molecular framework of pre-tRNA recognition and cleavage by TSEN and provides a structural basis to better understand PCH in the future.
WITHDRAWN:In vivoCRISPR screen definesSlc25a37as an organ-specific regulator of antioxidant metabolism in metastasis
Authors: Cuadros Alejandro M. , Fernández-Garcia Juan , Planque Mélanie , Altea-Manzano Patricia , Schalley Tessa , Vermeire Ines , Broekaert Dorien , Wu Qi , Van Brussel Thomas , Leduc Sophia , Maetens Marion , Nguyen Ha-Linh , Van Baelen Karen , Darzi Naama , Floris Giuseppe , Wildiers Hans , Desmedt Christine , Lambrechts Diether , Fendt Sarah-Maria 
Published: September 2022

Withdrawal StatementThe authors have withdrawn their manuscript owing to the detection of inaccurate data analysis in some figure panels that leads in some but not all cases to a different interpretation of the data after corrected analysis. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
The Role of the Posterior Medial Network in Language Comprehension: Dissociating Construction of Episodic versus Semantic Representations
Authors: Branzi Francesca M. , Lambon Ralph Matthew A. 
Published: September 2022

AbstractLanguage comprehension involves the construction of complex mental representations, i.e., “event representations”, reflecting current events or situation models. The construction of these representations requires manipulation of both semantic and episodic content and has been widely associated with the functioning of the posterior medial network, a subsystem of the default network. However, it is still unknown the extent to which activity in posterior medial network reflects construction of the variable episodic versus semantic content of event representations. In this fMRI study, we establish the unique neural correlates of (1) episodic richness and (2) semantic coherence measured during a narrative reading task. Interestingly, we observed a functional fractionation within the posterior medial network in terms of brain regions whose activity was modulated by semantic or episodic content. Specifically, the number of episodic details in the narratives modulated the activity in the left angular gyrus and the retrosplenial cortex/ventral posterior cingulate cortex. Semantic coherence, in contrast, modulated neural responses in the right anterior temporal lobe/middle temporal gyrus, but also in brain regions within the posterior medial network, such as the dorsal posterior cingulate cortex. These results provide the first demonstration of functional dissociations within the posterior medial network in terms of brain regions involved in the construction of semantic versus episodic representational content during a language comprehension task.Significance StatementThe construction of “event representations”, which is crucial to understand the world around us, predict the future and make plans, requires manipulation of both semantic and episodic information. The functioning of the posterior medial network has been tightly linked to formation of event representations. However, it is unclear the extent to which activity in this network reflects construction of the variable episodic versus semantic content of event representations. The present study provides the first demonstration of functional dissociations within posterior medial network in terms of brain regions involved in construction of semantic versus episodic representational content during language comprehension. These findings represent a first step towards understanding how episodic and semantic memory systems operate during the construction of event representations.
Structural insights into the formation of repulsive Netrin guidance complexes
Authors: Priest Jessica M. , Nichols Ev L. , Mendoza Juan L. , Shen Kang , Özkan Engin 
Published: September 2022

ABSTRACTNetrins can dictate attractive and repulsive responses during axon growth and cell migration, where presence of the receptor UNC-5 on target cells results in Netrin-mediated repulsion. Molecular details of Netrin–UNC-5 interactions and how they signal remain elusive. Here, we show that nematode UNC-5 is a heparin-binding protein, and the UNC-5–heparin affinity can be modulated using directed evolution or via rational design using our novel structure of UNC-5 with a heparin fragment. Furthermore, UNC-5 and nematode UNC-6/Netrin form a large, stable and rigid oligomeric complex in the presence of heparin, which can incorporate the attractive UNC-40/DCC receptor, demonstrating binary and ternary ectodomain complexes at preparative scale.C. eleganswith a heparin-binding deficient UNC-5 fail to establish proper gonad morphology due to abrogated distal tip cell migration, which relies on repulsive UNC-5 signaling in response to UNC-6. Our findings establish Netrin responses to be mediated through glycosaminoglycan-regulated large macromolecular complexes.