bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigating sensitivity of nasal or throat (ISNOT): A combination of both swabs increases sensitivity of SARS-CoV-2 rapid antigen tests
Authors: Goodall Barbara L , LeBlanc Jason J , Hatchette Todd F , Barrett Lisa , Patriquin Glenn 
Published: January 2022

AbstractThe COVID-19 pandemic has been hallmarked by several waves of variants of concern (VoCs), each with novel challenges. Currently, the highly transmissible Omicron VOC is predominant worldwide, and sore throat is common among other cold-like symptoms. Anecdotes on social media suggested sampling one’s throat can increase sensitivity for Omicron detection by antigen-based rapid testing devices (Ag-RDTs). This work determines whether the sensitivity of Ag-RDTs designed for nasal sampling is altered with use of self-administered throat swabs in self-perceived asymptomatic individuals. This investigation compared results of a common Ag-RDT (i.e. Abbott Panbio COVID-19 Ag Rapid Test Device) using three sampling sites: nasal swab; throat swab and; combined nasal/throat. All Ag-RDT results were confirmed with molecular testing. Compared to RT-PCR, samples from nasal or throat swabs each detected 64.5% of SARS-CoV-2 cases; however, combining the contributions of each swab increased sensitivity to 88.7%. This trend was also evident with the Rapid Response Ag-RDT (BTNX), which uses a more flexible swabs than Panbio. When nasal swab collection was compared to paired sampling of the nasal/throat using a single swab with the Panbio Ag-RDT, the sensitivity of each was 68.4% and 81.6%, respectively. No false-positive results were observed with nasal, throat, or combined nasal/throat sampling. Self-administered throat and nasal/throat swabs both had >90% acceptability. These findings support the use of self-collected combined nasal/throat sampling for Ag-RDT based SARS-CoV-2 detection in self perceived asymptomatic individuals.
Seroprevalence of anti-SARS coronavirus 2 antibodies in Thai adults during the first three epidemic waves
Authors: Lerdsamran Hatairat , Mungaomklang Anek , Iamsirithaworn Sopon , Prasertsopon Jarunee , Wiriyarat Witthawat , Saritsiri Suthee , Anusorntanawat Ratikorn , Siriyakorn Nirada , Intalapaporn Poj , Sirikhetkon Somrak , Sangsiriwut Kantima , Dangsakul Worawat , Sawadpongpan Suteema , Thinpan Nattakan , Okada Pilailuk , Techasuwanna Ranida , Mongkalangoon Noparat , Prasert Kriengkrai , Puthavathana Pilaipan 
Published: January 2022

AbstractThis study sought to determine the anti-SARS-CoV-2 antibody status of 4111 Thai people from May 2020 to April 2021, a period which spanned the first two and part of the third epidemic wave of the COVID-19 in Thailand. Participants comprised 142 COVID-19 patients, 2113 individuals at risk due to their occupations [health personnel, airport officers, public transport drivers, and workers in entertainment venues (pubs, bars and massage parlors)], 1856 individuals at risk due to sharing workplaces or living communities with COVID-19 patients, and 553 Thai citizens returning after extended periods in countries with a high disease prevalence. All sera were tested in a microneutralization assay and a chemiluminescence immunoassay (CLIA) for IgG against the N protein. Furthermore, we performed an immunofluorescence assay to resolve discordant results between the two assays. Antibody responses developed in 88% (15 of 17) of COVID-19 patients at 8 days and in 94-100% between 15 and 60 days after disease onset. Neutralizing antibodies persisted for at least 8 months, longer than the IgG did, against the N protein. None of the health providers, airport officers, and public transport drivers were seropositive, while the antibodies were present in 0.44% of entertainment workers. This study showed the seropositivity of 1.9, 1.5, and 7.5% during the 3 epidemic waves, respectively, in Bangkok residents who were at risk due to sharing workplaces or communities with COVID-19 patients. Also, antibody prevalence was 1.3% in Chiang Mai people during the first epidemic wave, and varied between 6.5 and 47.0% in Thais returning from high-risk countries. This serosurveillance study found a low infection rate of SARS-CoV-2 in Thailand before the emergence of the Delta variant in late May 2021. The findings support the Ministry of Public Health’s data, which are based on numbers of patients and contact tracing.
Microenvironmental Sensing by Fibroblasts Controls Macrophage Population Size
Authors: Zhou Xu , Franklin Ruth A. , Adler Miri , Carter Trevor S. , Condiff Emily , Adams Taylor S. , Pope Scott D. , Philip Naomi H. , Meizlish Matthew L. , Kaminski Naftali , Medzhitov Ruslan 
Published: January 2022

AbstractAnimal tissues are comprised of diverse cell types. However, the mechanisms controlling the number of each cell type within tissue compartments remain poorly understood. Here, we report that different cell types utilize distinct strategies to control population numbers. Proliferation of fibroblasts, stromal cells important for tissue integrity, is limited by space availability. In contrast, proliferation of macrophages, innate immune cells involved in defense, repair, and homeostasis, is constrained by growth factor availability. Examination of density-dependent gene expression in fibroblasts revealed that Hippo and TGF-β target genes are both regulated by cell density. We found YAP1, the transcriptional co-activator of the Hippo signaling pathway, directly regulates expression of Csf1, the lineage-specific growth factor for macrophages, through an enhancer of Csf1 that is specifically active in fibroblasts. Activation of YAP1 in fibroblasts elevates Csf1 expression and is sufficient to increase the number of macrophages at steady state. Our data also suggest that expression programs in fibroblasts that change with density may result from sensing of mechanical force through actin-dependent mechanisms. Altogether, we demonstrate that two different modes of population control are connected and coordinated to regulate cell numbers of distinct cell types. Sensing of the tissue environment may serve as a general strategy to control tissue composition.Significance StatementCollections of distinct cell types constitute animal tissues. To perform their unique functions, each cell type must exist in the correct number and proportion in a given tissue compartment. However, many of the mechanisms regulating and coordinating cell population sizes remain enigmatic. Our study characterizes two different modes of population size control, utilized by two ubiquitous cell types, macrophages and fibroblasts. Macrophage populations are more sensitive to the presence of growth factors in the environment and fibroblasts are more sensitive to space limitations. Intriguingly, space-sensing mechanisms in fibroblasts directly control the production of growth factor for macrophages and thus macrophage numbers. This link suggests a mechanism by which macrophage compartment size is controlled by stromal cells according to the microenvironment.
Virtual Epileptic Patient (VEP): Data-driven probabilistic personalized brain modeling in drug-resistant epilepsy
Authors: Wang Huifang E , Woodman Marmaduke , Triebkorn Paul , Lemarechal Jean-Didier , Jha Jayant , Dollomaja Borana , Vattikonda Anirudh Nihalani , Sip Viktor , Villalon Samuel Medina , Hashemi Meysam , Guye Maxime , Scholly Julia , Bartolomei Fabrice , Jirsa Viktor 
Published: January 2022

AbstractOne-third of 50 million epilepsy patients worldwide suffer from drug resistant epilepsy and are candidates for surgery. Precise estimates of the epileptogenic zone networks (EZNs) are crucial for planning intervention strategies. Here, we present the Virtual Epileptic Patient (VEP), a multimodal probabilistic modeling framework for personalized end-to-end analysis of brain imaging data of drug resistant epilepsy patients. The VEP uses data-driven, personalized virtual brain models derived from patient-specific anatomical (such as T1-MRI, DW-MRI, and CT scan) and functional data (such as stereo-EEG). It employs Markov Chain Monte Carlo (MCMC) and optimization methods from Bayesian inference to estimate a patient’s EZN while considering robustness, convergence, sensor sensitivity, and identifiability diagnostics. We describe both high-resolution neural field simulations and a low-resolution neural mass model inversion. The VEP workflow was evaluated retrospectively with 53 epilepsy patients and is now being used in an ongoing clinical trial (EPINOV).
The quality of vital signs measurements in electronic medical records varies by hospital, specialty, and patient demographics
Authors: Jackson Niall , Woods Jessica , Watkinson Peter , Brent Andrew , Peto Tim EA , Walker A Sarah , Eyre David W 
Published: January 2022

AbstractObjectiveTo assess the frequency of digit preference in recording of vital signs in electronic healthcare records (EHRs) and associated patient and hospital factors.Study Design and SettingWe used EHR data from Oxford University Hospitals, UK, between 01-January-2016 and 30-June-2019 and multivariable logistic regression to investigate associations between temperature readings of 36.0°C or systolic and diastolic blood pressure (SBP/DBP) readings both ending in zero and patient age, sex, ethnicity, deprivation, comorbidities, calendar time, hour of day, days into admission, hospital, day of week and speciality.ResultsIn 4,305,914 records from 143,352 patients, there was an excess of temperature readings of 36.0°C (15.1%, 649,976/4,305,914), compared to an expected 4.9% from the underlying distribution. 2.2% (95,215) BP readings had a SBP and DBP both ending in zero vs. 1% expected by chance. Digit preference was more common in older and male patients, as length of stay increased, following a previous normal set of vital signs and typically more common in medical vs. surgical specialities. Differences were seen between hospitals, however, digit preference reduced over calendar time.ConclusionVital signs may not always be accurately documented. Allowances and adjustments may be needed in observational analyses using these factors as outcomes or exposures.What’s New?Key findings▪Digit preference in the recording of vital signs in electronic healthcare records is common, affecting approximately 10% of temperature measurements and 1% of blood pressure recordings in a large UK teaching hospital group▪These findings were obtained in hospitals using a semi-automated data capture system that required manual re-entry of vital signs into a tablet computer prior to automated upload to electronic patient records▪Digit preference was associated with patient characteristics and was more common in older and male patients, as length of stay increased and following previously normal vital signs▪Digit preference varied between hospitals, but decreased over time▪Digit preference was generally more common in medical compared to surgical specialtiesWhat this adds to what is known▪Most previous studies of data quality in electronic patient records have focused on the accuracy of coding▪This study focuses on the accuracy of numeric values in patient records, and also adds new data on patient and hospital factors associated with the accuracy of values in electronic patient recordsImplications▪Clinicians and researchers need to be aware that vital signs may not always be accurately documented▪Appropriate allowances and adjustments for digit preference should be considered in observational analyses using these factors as outcomes or exposures.▪Further work is required to understand the mechanisms behind values preference on a systems, patient and clinician level
1-deoxysphingolipid biosynthesis compromises anchorage-independent growth and plasma membrane endocytosis in cancer cells
Authors: Cordes Thekla , Kuna Ramya S. , McGregor Grace H. , Khare Sanika V. , Gengatharan Jivani , Muthusamy Thangaselvam , Metallo Christian M. 
Published: January 2022

ABSTRACTSerine palmitoyltransferase (SPT) predominantly incorporates serine and fatty acyl-CoAs into diverse sphingolipids that serve as structural components of membranes and signaling molecules within or amongst cells. However, SPT also uses alanine as a substrate in the contexts of low serine availability, alanine accumulation, or disease-causing mutations in hereditary sensory neuropathy type I (HSAN1), resulting in the synthesis and accumulation of 1-deoxysphingolipids. These species promote cytotoxicity in neurons and impact diverse cellular phenotypes, including suppression of anchorage-independent cancer cell growth. While altered serine and alanine can promote 1-deoxysphingolipid synthesis, they impact numerous other metabolic pathways important for cancer cells. Here we combined isotope tracing, quantitative metabolomics, and functional studies to better understand the mechanistic drivers of 1-deoxysphingolipid toxicity in cancer cells. Both alanine treatment andSPTLC1C133Wexpression induce 1-deoxy(dihydro)ceramide synthesis and accumulation but fail to broadly impact intermediary metabolism, abundances of other lipids, or growth of adherent cells. However, spheroid culture and soft agar colony formation were compromised when endogenous 1-deoxysphingolipid synthesis was induced viaSPTLC1C133Wexpression. Consistent with these impacts on anchorage-independent cell growth, we observed that 1-deoxysphingolipid synthesis reduced plasma membrane endocytosis. These results highlight a potential role for SPT promiscuity in linking altered amino acid metabolism to plasma membrane endocytosis.
Development of Actionable Targets of Multi-kinase Inhibitors (AToMI) screening platform to dissect kinase targets of staurosporines in glioblastoma cells
Authors: Denisova Oxana V. , Merisaari Joni , Kaur Amanpreet , Yetukuri Laxman , Jumppanen Mikael , von Schantz-Fant Сarina , Ohlmeyer Michael , Wennerberg Krister , Aittokallio Tero , Taipale Mikko , Westermarck Jukka 
Published: January 2022

ABSTRACTTherapeutic resistance to kinase inhibitors constitutes a major unresolved clinical challenge in cancer and especially in glioblastoma. Multi-kinase inhibitors may be used for simultaneous targeting of multiple target kinase and thereby potentially overcome kinase inhibitor resistance. However, in most cases identification of the target kinases mediating therapeutic effects of multi-kinase inhibitors has been challenging. To tackle this important problem, we developed an Actionable Targets of Multi-kinase Inhibitors (AToMI) strategy and used it for characterization of glioblastoma target kinases of staurosporine derivatives displaying synergy with protein phosphatase 2A (PP2A) reactivation. AToMI consists of interchangeable modules combining drug-kinase interaction assay, siRNA high-throughput screening, bioinformatics analysis and validation screening with more selective target kinase inhibitors. As a result, AToMI analysis revealed AKT and mitochondrial pyruvate dehydrogenase kinase PDK1 and PDK4 as kinase targets of staurosporine derivatives UCN-01, CEP-701, and K252a that synergized with PP2A activation across heterogeneous glioblastoma cells. Based on these proof-of-principle results we propose that application and further development of AToMI for clinically applicable multi-kinase inhibitors could provide significant benefits in overcoming the challenge of lack of knowledge of target specificity of multi-kinase inhibitors.
PROTAC-mediated selective degradation of cytosolic soluble epoxide hydrolase enhances ER-stress reduction
Authors: Wang Yuxin , Morisseau Christophe , Takamura Akihiro , Wan Debin , Li Dongyang , Sidoli Simone , Yang Jun , Wolan Dennis W. , Hammock Bruce D. , Kitamura Seiya 
Published: January 2022

SummarySoluble epoxide hydrolase (sEH) is a bifunctional enzyme responsible for lipid metabolism and is a promising drug target. Here, we report the first-in-class PROTACs small molecule degraders of sEH. Our optimized PROTAC selectively targets the degradation of cytosolic but not peroxisomal sEH, resulting in exquisite spatiotemporal control. Remarkably, our sEH PROTAC molecule has higher potency in cellular assays compared to the parent sEH inhibitor as measured by significantly reduced ER stress. Interestingly, our mechanistic data indicate that our PROTAC directs degradation of cytosolic sEH via the lysosome, not through the proteasome. The molecules presented here are useful chemical probes to study the biology of sEH with the potential for therapeutic development. Broadly, our results represent a proof-of-concept for the superior cellular potency of sEH degradation over sEH enzymatic inhibition, as well as subcellular compartment-selective modulation of a protein by PROTACs.HighlightsFirst-in-class soluble epoxide hydrolase (sEH) small-molecule degraders.Selective degradation of cytosolic but not peroxisomal sEH.Significant and stable reduction in sEH protein levels, leading to enhanced cellular efficacy in ER stress reduction relative to the parent inhibitor.
A novel, NADH-dependent acrylate reductase in Vibrio harveyi
Authors: Bertsova Yulia V. , Serebryakova Marina V. , Baykov Alexander A. , Bogachev Alexander V. 
Published: January 2022

AbstractBacteria coping with oxygen deficiency use alternative terminal electron acceptors for NADH regeneration, particularly fumarate. Fumarate is reduced by the FAD_binding_2 domain of cytoplasmic fumarate reductase in many bacteria. The variability of the primary structure of this domain in homologous proteins suggests the existence of reducing activities with different specificities. Here we produced and characterized one such protein, Vibrio harveyi ARD, and found it to be a specific NADH:acrylate oxidoreductase. This previously unknown enzyme contains covalently bound FMN and non-covalently bound FAD and FMN in a ratio of 1:1:1. The covalently bound FMN is absolutely required for activity and is attached by the specific flavin transferase, ApbE, to a threonine residue in the auxiliary FMN_bind domain. RT-qPCR and activity measurements indicated dramatic stimulation of ARD biosynthesis by acrylate in the V. harveyi cells grown aerobically. In contrast, the ard gene expression in the cells grown anaerobically was high without acrylate and increased only twofold in its presence. These findings suggest that the principal role of ARD in Vibrio is energy-saving detoxification of acrylate coming from the environment.ImportanceThe benefits of the massive genomic information accumulated in recent years for biological sciences have been limited by the lack of data on the function of most gene products. Approximately half of the known prokaryotic genes are annotated as “proteins with unknown functions,” and many other genes are annotated incorrectly. Thus, the functional and structural characterization of the products of such genes, including identification of all existing enzymatic activities, is a pressing issue in modern biochemistry. In this work, we have shown that the ard gene product of V. harveyi (GenBank ID: AIV07243) exhibits a yet undescribed NADH:acrylate oxidoreductase activity. This activity may allow acrylate detoxification and its use as a terminal electron acceptor in anaerobic or substrate in aerobic respiration of marine and other bacteria.
Aerosol measurement identifies SARS-CoV 2 PCR positive adults compared with healthy controls
Authors: Gutmann Desireé , Scheuch Gerhard , Lehmkühler Timon , Herrlich Laura-Sabine , Hutter Martin , Stephan Christoph , Vehreschild Maria , Khodamoradi Yascha , Gossmann Ann-Kathrin , King Florian , Weis Frederik , Weiss Maximilian , Rabenau Holger F , Graf Juergen , Donath Helena , Schubert Ralf , Zielen Stefan 
Published: January 2022

AbstractBackgroundSARS-CoV-2 is spread primarily through droplets and aerosols. Exhaled aerosols are generated in the lung periphery by ‘reopening of collapsed airways’. Aerosol measuring may detect highly contagious individuals (“super spreaders or super-emitters”) and discriminate between SARS-CoV-2 infected and non-infected individuals. This is the first study comparing exhaled aerosols in SARS-CoV-2 infected individuals and healthy controls.DesignA prospective observational cohort study in 288 adults, comprising 64 patients testing positive by SARS CoV-2 PCR before enrollment, and 224 healthy adults testing negative (matched control sample) at the University Hospital Frankfurt, Germany, from February to June 2021. Study objective was to evaluate the concentration of exhaled aerosols during physiologic breathing in SARS-CoV-2 PCR-positive and -negative subjects. Secondary outcome measures included correlation of aerosol concentration to SARS-CoV-2 PCR results, change in aerosol concentration due to confounders, and correlation between clinical symptoms and aerosol.ResultsThere was a highly significant difference in respiratory aerosol concentrations between SARS-CoV-2 PCR-positive (median 1490.5/L) and -negative subjects (median 252.0/L; p<0.0001). There were no significant differences due to age, sex, smoking status, or body mass index. ROC analysis showed an AUC of 0.8918.ConclusionsMeasurements of respiratory aerosols were significantly elevated in SARS-CoV-2 positive individuals and may become a helpful tool in detecting highly infectious individuals via a noninvasive breath test.Clinical Trial NumberClinicalTrials.gov Identifier: NCT04739020.Summary of the main pointIn this prospective, comparative cohort study, higher numbers of exhaled respiratory aerosols correlate with a positive PCR test for SARS-CoV-2. Measurement of exhaled aerosols may become a helpful tool in detecting contagious individuals via a readily available breath test.
IL-21 has a critical role in establishing germinal centers by amplifying early B cell proliferation
Authors: Dvorscek Alexandra R. , McKenzie Craig I. , Robinson Marcus J. , Ding Zhoujie , Pitt Catherine , O’Donnell Kristy , Zotos Dimitra , Brink Robert , Tarlinton David M. , Quast Isaak 
Published: January 2022

AbstractThe proliferation and differentiation of antigen-specific B cells, including the generation of germinal centers (GC), are prerequisites for long-lasting, high-affinity antibody-mediated immune protection. Affinity for antigen determines B cell recruitment, proliferation, differentiation and competitiveness in the response, largely through determining access to T cell help. However, how T cell derived signals contribute to these outcomes is incompletely understood. Here we report how the signature cytokine of follicular helper T cells, IL-21, acts as a key regulator of the initial B cell response. By activating AKT and S6, IL-21 accelerates cell cycle progression and the rate of cycle entry of B cells, increasing their contribution to the ensuing GC. This effect occurs over a wide range of initial B cell receptor affinities and the resultant increased proliferation can explain the IL-21-mediated promotion of plasma cell differentiation. Collectively, our data establish that IL-21 acts from the outset of a T cell dependent immune response to increase cell cycle progression and fuel cyclic re-entry of B cells thereby regulating the initial GC size and early plasma cell output.SummaryThe cytokine IL-21 is a regulator of B cell responses, increasing antibody quantity and quality. Here, we report that during germinal center initiation, IL-21 acts to increase the response magnitude by accelerating cell cycle speed and rate of entry.