bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of campaign-style delivery of routine vaccines during Intensified Mission Indradhanush in India: a controlled interrupted time-series analysis
Authors: Clarke-Deelder Emma , Suharlim Christian , Chatterjee Susmita , Brenzel Logan , Ray Arindam , Cohen Jessica , McConnell Margaret , Resch Stephen C , Menzies Nicolas A 
Published: May 2020

AbstractIntroductionThe world is not on track to achieve the goals for immunization coverage and equity described by the World Health Organization’s Global Vaccine Action Plan. In India, only 62% of children had received a full course of basic vaccines in 2016. We evaluated the Intensified Mission Indradhanush (IMI), a campaign-style intervention to increase routine immunization coverage and equity in India, implemented in 2017-2018.MethodsWe conducted a comparative interrupted time-series analysis using monthly district-level data on vaccine doses delivered, comparing districts participating and not participating in IMI. We estimated the impact of IMI on coverage and under-coverage (defined as the proportion of children who were unvaccinated) during the four-month implementation period and in subsequent months.FindingsDuring implementation, IMI increased delivery of thirteen infant vaccines by between 1.6% (95% CI: −6.4, 10.2%) and 13.8% (3.0%, 25.7%). We did not find evidence of a sustained effect during the 8 months after implementation ended. Over the 12 months from the beginning of implementation, IMI reduced under-coverage of childhood vaccination by between 3.9% (−6.9%, 13.7%) and 35.7% (−7.5%, 77.4%). The largest estimated effects were for the first doses of vaccines against diptheria-tetanus-pertussis and polio.InterpretationIMI had a substantial impact on infant immunization delivery during implementation, but this effect waned after implementation ended. Our findings suggest that campaign-style interventions can increase routine infant immunization coverage and reach formerly unreached children in the shorter term, but other approaches may be needed for sustained coverage improvements.FundingBill & Melinda Gates Foundation.
The landscape of host genetic factors involved in immune response to common viral infections
Authors: Kachuri Linda , Francis Stephen S. , Morrison Maike , Wendt George A. , Bossé Yohan , Cavazos Taylor B. , Rashkin Sara R. , Ziv Elad , Witte John S. 
Published: May 2020

ABSTRACTIntroductionHumans and viruses have co-evolved for millennia resulting in a complex host genetic architecture. Understanding the genetic mechanisms of immune response to viral infection provides insight into disease etiology and therapeutic opportunities.MethodsWe conducted a comprehensive study including genome-wide and transcriptome-wide association analyses to identify genetic loci associated with immunoglobulin G antibody response to 28 antigens for 16 viruses using serological data from 7924 European ancestry participants in the UK Biobank cohort.ResultsSignals in human leukocyte antigen (HLA) class II region dominated the landscape of viral antibody response, with 40 independent loci and 14 independent classical alleles, 7 of which exhibited pleiotropic effects across viral families. We identified specific amino acid (AA) residues that are associated with seroreactivity, the strongest associations presented in a range of AA positions within DRβi at positions 11, 13, 71, and 74 for Epstein-Barr Virus (EBV), Varicella Zoster Virus (VZV), Human Herpes virus 7, (HHV7) and Merkel cell polyomavirus (MCV). Genome-wide association analyses discovered 7 novel genetic loci outside the HLA associated with viral antibody response (P<5.0×10-8), including FUT2 (19q13.33) for human polyomavirus BK (BKV), STING1 (5q31.2) for MCV, as well as CXCR5 (11q23.3) and TBKBP1 (17q21.32) for HHV7. Transcriptome-wide association analyses identified 114 genes associated with response to viral infection, 12 outside of the HLA region, including ECSCR: P=5.0*10-15 (MCV), NTN5: P=1.1×10-9 (BKV), and P2RY13: P=1.1×10-8 EBV nuclear antigen. We also demonstrated pleiotropy between viral response genes and complex diseases; from autoimmune disorders to cancer to neurodegenerative and psychiatric conditions.ConclusionsOur study confirms the importance of the HLA region in host response to viral infection and elucidates novel genetic determinants beyond the HLA that contribute to host-virus interaction.
Repeated seroprevalence of anti-SARS-CoV-2 IgG antibodies in a population-based sample
Authors: Stringhini Silvia , Wisniak Ania , Piumatti Giovanni , Azman Andrew S. , Lauer Stephen A. , Baysson Hélène , De Ridder David , Petrovic Dusan , Schrempft Stephanie , Marcus Kailing , Yerly Sabine , Vernez Isabelle Arm , Keiser Olivia , Hurst Samia , Posfay-Barbe Klara M. , Trono Didier , Pittet Didier , Gétaz Laurent , Chappuis François , Eckerle Isabella , Vuilleumier Nicolas , Meyer Benjamin , Flahault Antoine , Kaiser Laurent , Guessous Idris 
Published: May 2020

AbstractBackgroundAssessing the burden of COVID-19 based on medically-attended case counts is suboptimal given its reliance on testing strategy, changing case definitions and the wide spectrum of disease presentation. Population-based serosurveys provide one avenue for estimating infection rates and monitoring the progression of the epidemic, overcoming many of these limitations.MethodsTaking advantage of a pool of adult participants from population-representative surveys conducted in Geneva, Switzerland, we implemented a study consisting of 8 weekly serosurveys among these participants and their household members older than 5 years. We tested each participant for anti-SARS-CoV-2-IgG antibodies using a commercially available enzyme-linked immunosorbent assay (Euroimmun AG, Lübeck, Germany). We estimated seroprevalence using a Bayesian regression model taking into account test performance and adjusting for the age and sex of Geneva’s population.ResultsIn the first three weeks, we enrolled 1335 participants coming from 633 households, with 16% <20 years of age and 53.6% female, a distribution similar to that of Geneva. In the first week, we estimated a seroprevalence of 3.1% (95% CI 0.2-5.99, n=343). This increased to 6.1% (95% CI 2.69.33, n=416) in the second, and to 9.7% (95% CI 6.1-13.11, n=576) in the third week. We found that 5-19 year-olds (6.0%, 95% CI 2.3-10.2%) had similar seroprevalence to 20-49 year olds (8.5%, 95%CI 4.99-11.7), while significantly lower seroprevalence was observed among those 50 and older (3.7%, 95% CI 0.99-6.0, p=0.0008).InterpretationAssuming that the presence of IgG antibodies is at least in the short-term associated with immunity, these results highlight that the epidemic is far from burning out simply due to herd immunity. Further, no differences in seroprevalence between children and middle age adults are observed. These results must be considered as Switzerland and the world look towards easing restrictions aimed at curbing transmission.
First Data-Set on SARS-CoV-2 Detection for Istanbul Wastewaters in Turkey
Authors: Kocamemi Bilge Alpaslan , Kurt Halil , Hacıoglu Sabri , Yaralı Cevdet , Saatci Ahmet Mete , Pakdemirli Bekir 
Published: May 2020

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in Wuhan, China, in December 2019 and became a global pandemic [1]. By 26 April 2020, more than 2.9 million people were infected by SARS-CoV-2 and over 203 thousand people lost their life globally. By 26 April 2020, 107773 confirmed cases were reported in Turkey with 2706 deaths. Majority of the cases in Turkey has been observed in Istanbul. In the world, the duration of availability of SARS-CoV-2 was found to be significantly longer in stool samples than in respiratory and serum samples [2]. SARS-CoV-2 was detected in wastewaters in Australia [3], Netherlands [4], USA [5], France [6], Spain [7] and USA [8] by using different virus concentration techniques. In this work, Istanbul metropole with 65 % of Covid-19 cases was chosen as the pilot city. On the 21st of April 2020, 24-hr composite samples were collected from the Ambarli, Pasakoy and Kadikoy wastewater treatment plants (WWTP). On the 25th of April 2020, more wastewater samples were taken from Terkos, Buyukcekmece, Baltalimani and Tuzla WWTPs. These wastewater treatment plants were selected among 81 plants in Istanbul in order to take representative samples from 4 different districts of Istanbul according to the severity of Covid-19 cases, like very serious, serious, moderate and mild. Grab samples were also collected from Bagcilar and Kartal manholes located nearby the pandemic hospitals on April 21st, 2020. Polyethylene glycol 8000 (PEG 8000) adsorption [5] SARS-Cov-2 concentration method was used for SARS-CoV-2 concentration after optimization. Real time RT-PCR diagnostic panel validated by US was used to quantify SARS-CoV-2 RNA in raw sewage taken from the inlets of treatment plants and manholes. Five samples out of seven from wastewater and all samples from manholes were tested positive. SARS-CoV-2 in raw sewage from Ambarli, Pasakoy, Kadikoy, Terkos, Buyukcekmece, Baltalimani and Tuzla WWTPs were found as 8.26×103, 1.80×104, ND, ND, 3.73×103, 4.95×103, 2.89×103, respectively. The Bagcilar and Kartal manholes nearby pandemic hospitals exhibited 4.49×104 and 9.33×104, respectively. SARS-CoV-2 virus titers of manhole were higher than those of inlet of WWTPs. The observed copy numbers were presented against the number of Covid-19 cases coming to the WWTP per treatment plant capacity. Quantitative measurements of SARS-CoV-2 in wastewater can be used as a tool in wastewater-based epidemiology (WBE) and it can provide information about SARS-CoV-2 distribution in wastewater of various districts of Istanbul which exhibit different scores of Covid-19 cases. The distribution of epidemy was followed not only with blood test but with wastewater monitoring. This may allow us to identify the districts not exhibiting many Covid-19 cases, but under high risk. Continuous monitoring of wastewater for SARS-Cov-2 may provide an early warning signs before an epidemy starts in case of infection resurge.
The oncometabolite L-2-hydroxyglutarate is a common product of Dipteran larval development
Authors: Mahmoudzadeh Nader H. , Fitt Alexander J. , Schwab Daniel B. , Martenis William E. , Nease Lauren M. , Owings Charity G. , Brinkley Garrett J. , Li Hongde , Karty Jonathan A. , Sudarshan Sunil , Hardy Richard W. , Moczek Armin P. , Picard Christine J. , Tennessen Jason M. 
Published: May 2020

ABSTRACTThe oncometabolite L-2-hydroxyglutarate (L-2HG) is considered an abnormal product of central carbon metabolism that is capable of disrupting chromatin architecture, mitochondrial metabolism, and cellular differentiation. Under most circumstances, mammalian tissues readily dispose of this compound, as aberrant L-2HG accumulation induces neurometabolic disorders and promotes renal cell carcinomas. Intriguingly,Drosophila melanogasterlarvae were recently found to accumulate high L-2HG levels under normal growth conditions, raising the possibility that L-2HG plays a unique role in insect metabolism. Here we explore this hypothesis by analyzing L-2HG levels in 18 insect species. While L-2HG was present at low-to-moderate levels in most of these species (<100 pmol/mg; comparable to mouse liver), Dipteran larvae exhibited a tendency to accumulate high L-2HG concentrations (>100 pmol/mg), with the mosquitoAedes aegypti,the blow flyPhormia regina,and three representativeDrosophilaspecies harboring concentrations that exceed 1 nmol/mg – levels comparable to those measured in mutant mice that are unable to degrade L-2HG. Overall, our findings suggest that one of the largest groups of animals on earth commonly generate high concentrations of an oncometabolite during juvenile growth, hint at a role for L-2HG in the evolution of Dipteran development, and raise the possibility that L-2HG metabolism could be targeted to restrict the growth of key disease vectors and agricultural pests.
Ubiquitin Substrates Dramatically Increase Ataxin3 Deubiquitinating Activity: Allosteric crosstalk connects three distinct sites
Authors: Rao Maya V. , Grasty Kimberly C. , Mehetre Prajakta D. , Loll Patrick J. 
Published: May 2020

AbstractAtaxin3 is the founding member of the MJD family of deubiquitinating enzymes, and plays important roles in maintaining protein homeostasis and promoting DNA repair. The enzyme also contains a polyglutamine tract of variable length, and in its expanded form the protein becomes the causative agent of a neurodegenerative disorder known as Machado-Joseph disease.In vitro,ataxin3 displays low catalytic activity, prompting questions about how the enzyme is regulated and what signals might lead to its activation. Recently, it has been demonstrated that ataxin3 activity can be stimulated by either mono-ubiquitination or high concentrations of free ubiquitin. Here, we show that ubiquitin conjugates with cleavable bonds can stimulate ataxin3 activity much more strongly than free ubiquitin, with physiological levels of these conjugates increasing activity up to 60-fold over basal levels. Our data are consistent with a model in which ubiquitin conjugates activate the enzyme allosterically by binding in a site adjacent to the catalytic center, known as Site 1. We further show that two additional ubiquitin-binding sites in the enzyme work in concert to modulate enzyme activation, and we propose a model in which ubiquitin conjugates bridge these two sites to drive the enzyme into a high-activity conformation.SignificanceUbiquitin signaling networks modulate almost all aspects of eukaryotic biology, and their outputs reflect the dynamic balance between ubiquitin attachment and removal. The latter process is catalyzed by deubiquitinating enzymes (DUBs), which must be carefully regulated to ensure that their activities are applied appropriately. Ataxin3 is a DUB that participates in quality-control pathways that support cellular health; however, the regulation of its activity has remained poorly understood. Here, we show that ataxin3 can be dramatically activated by naturally occurring ubiquitin species, and that this activation involves a previously uncharacterized interplay between three distinct sites on the enzyme. Our improved understanding of ataxin3 regulation provides insights into allosteric mechanisms that may prove applicable to other enzymes in the ubiquitin universe.
Comparison of drug inhibitory effects (IC50) in monolayer and spheroid cultures
Authors: Berrouet Catherine , Dorilas Naika , Rejniak Katarzyna A. , Tuncer Necibe 
Published: May 2020

AbstractTraditionally, the monolayer (two-dimensional) cell cultures are used for initial evaluation of the ef-fectiveness of anticancer drugs. In particular, these experiments provide the IC50curves that determine drug concentration that can inhibit growth of a tumor colony by half when compared to the cells grown with no exposure to the drug. Low IC50value means that the drug is effective at low concentrations, and thus will show lower systemic toxicity when administered to the patient. However, in these experiments cells are grown in a monolayer, all well exposed to the drug, whilein vivotumors expand as three-dimensional multicellular masses, where inner cells have a limited access to the drug. Therefore, we performed computational studies to compare the IC50curves for cells grown as a two-dimensional monolayer and a cross section through a three-dimensional spheroid. Our results identified conditions (drug diffusivity, drug action mechanisms and cell proliferation capabilities) under which these IC50curves differ significantly. This will help experimentalists to better determine drug dosage for futurein vivoexperiments and clinical trials.
Direct intracellular visualization of Ebola virus-receptor interaction byin situproximity ligation
Authors: Mittler Eva , Alkutkar Tanwee P , Jangra Rohit K , Chandran Kartik 
Published: May 2020

ABSTRACTEbola virus (EBOV) entry into host cells comprises stepwise and extensive interactions of the sole viral surface glycoprotein GP with multiple host factors. During the intricate process, following virus uptake and trafficking to late endosomal/lysosomal compartments, GP is proteolytically processed to GPCLby the endosomal proteases cathepsin B and L unmasking GP’s receptor-binding site. Engagement of GPCLwith the universal filoviral intracellular receptor Niemann-Pick C1 (NPC1) eventually culminates in fusion between viral and cellular membranes, cytoplasmic escape of the viral nucleocapsid and subsequent infection. Mechanistic delineation of the indispensable GPCL:NPC1 binding step has been severely hampered by the unavailability of a robust cell-based assay assessing interaction of GPCLwith full-length endosomal NPC1.Here, we describe a novelin situassay to monitor GPCL:NPC1 engagement in intact, infected cells. Visualization of the subcellular localization of binding complexes is based on the principle of DNA-assisted, antibody-mediated proximity ligation. Virus-receptor binding monitored by proximity ligation was contingent on GP’s proteolytic cleavage, and was sensitive to perturbations in the GPCL:NPC1 interface. Our assay also specifically decoupled detection of virus-receptor binding from steps post-receptor binding, such as membrane fusion and infection. Testing of multiple FDA-approved small molecule inhibitors revealed that drug treatments inhibited virus entry and GPCL:NPC1 recognition by distinctive mechanisms. Together, here we present a newly established proximity ligation assay, which will allow us to dissect cellular and viral requirements for filovirus-receptor binding, and to delineate the mechanisms of action of inhibitors on filovirus entry in a cell-based system.IMPORTANCEEbola virus causes episodic but increasingly frequent outbreaks of severe disease in Middle Africa, as shown by a currently ongoing outbreak in the Democratic Republic of Congo. Despite considerable effort, FDA-approved anti-filoviral therapeutics or targeted interventions are not available yet. Virus host-cell invasion represents an attractive target for antivirals; however our understanding of the inhibitory mechanisms of novel therapeutics is often hampered by fragmented knowledge of the filovirus-host molecular interactions required for viral infection. To help close this critical knowledge gap, here, we report anin situassay to monitor binding of the EBOV glycoprotein to its receptor NPC1 in intact, infected cells. We demonstrate that ourin situassay based on proximity ligation represents a powerful tool to delineate receptor-viral glycoprotein interactions. Similar assays can be utilized to examine receptor interactions of diverse viral surface proteins whose studies have been hampered until now by the lack of robustin situassays.
Myc-dependent cell competition and proliferative response requires induction of the ribosome biogenesis regulator Peter Pan
Authors: Zielke Norman , Vähärautio Anna , Liu Jianping , Taipale Jussi 
Published: May 2020

AbstractThe transcription factor Myc is activated in most major forms of human cancer. Myc regulates a large set of target genes, and drives cell growth across animal phyla. However, it has not been clear which target genes are required for Myc-induced growth, and whether the targets are individually necessary or act in an additive fashion. Here, we have used comparative functional genomics to identify a core set of Myc target genes whose regulation is conserved between humans andDrosophila melanogaster. Most of these targets are essential genes involved in ribosome biogenesis and ribonucleotide metabolism. To identifyDrosophilagenes whose upregulation is necessary for Myc induced growth, we deleted the Myc binding sites (E-boxes) in the promoter regions of four genes using CRISPR/Cas9. All mutant flies were homozygous viable, indicating that E-box sequences are not required for basal expression of the Myc target genes. E-Box deletions in RpS20, RpS24 and Nop56 did not cause strong growth phenotypes. However, deletion of the E-box in the rRNA processing factorPeter Pan(ppan) made the flies resistant to Myc-induced cell growth, without affecting Myc-induced apoptosis. Despite their failure to respond to Myc, theppanEbox−/−flies are healthy and display only a minor developmental delay, suggesting that it may be possible to treat or prevent tumorigenesis by targeting individual downstream targets of Myc.
Small protein 26 interacts and enhances glutamine synthetase activity inMethanosarcina mazei
Authors: Gutt Miriam , Jordan Britta , Weidenbach Katrin , Gudzuhn Mirja , Kiessling Claudia , Cassidy Liam , Helbig Andreas , Tholey Andreas , Pyper Dennis , Schwalbe Harald , Schmitz Ruth A. 
Published: May 2020

ABSTRACTSmall ORFs (sORF) encoded small proteins have been overlooked for a long time due to challenges in prediction and distinguishing between coding and non-coding predicted sORFs and in their biochemical detection and characterization. We report on the first biochemical and functional characterization of a small protein (sP26) in the archaeal model organismMethanosarcina mazei, comprising 23 amino acids. The corresponding encoding leaderless mRNA (spRNA26) is highly conserved within numerous Methanosarcina strains on the amino acid as well as on nucleotide level strongly arguing for a cellular function of the small protein. spRNA26 is significantly enhanced under nitrogen limitation, but also under oxygen and salt stress conditions. His-tagged sP26 was heterologously expressed and purified by fractionated ammonium sulfate precipitation, affinity chromatography and size exclusion centrifugation. Using independent biochemical approaches (pull-down by affinity chromatography followed by MS analysis, revers pull-down, microscale thermophoresis and size exclusion chromatography) we observed that sP26 interacts and forms complexes withM. mazeiglutamine synthetase (GlnA1) with high affinity (app. KD = 45 +/− 14 µM). Upon interaction with sP26, GlnA1activity was significantly stimulated independently and in addition to the known activation by the metabolite 2-oxoglutarate. Besides strong interaction of sP26 with the PII-like protein GlnK1was demonstrated (KD= 1.4 µM +/− 0.9 µM). On the basis of these findings, we hypothesize that in addition to 2-oxoglutarate, sP26 activates GlnA1activity under nitrogen limitation most likely by stabilizing the dodecameric structure of GlnA1.