bluuebunny/crossref_metadata_2025_split huggingface dataset:
TLR7 ligation augments haematopoiesis in Rps14 (uS11) deficiency via paradoxical suppression of inflammatory signalling and enhanced differentiation
Authors: Peña Oscar A , Lubin Alexandra , Rowell Jasmine , Hockings Catherine , Jung Youngrock , Hoade Yvette , Dace Phoebe , Valdivia Leonardo E , Tuschl Karin , Boiers Charlotta , Virgilio Maria C , Richardson Simon , Payne Elspeth M 
Published: July 2020

AbstractMyelodysplastic syndrome (MDS) is a haematological malignancy characterised by blood cytopenias and predisposition to acute myeloid leukaemia (AML). Therapies for MDS are lacking, particularly those that impact the early stages of disease. We developed a model of MDS using zebrafish using knockout of Rps14, the primary mediator of the anaemia associated with del (5q) MDS. These mutant animals display dose- and age-dependent abnormalities in haematopoiesis, culminating in bone marrow failure with dysplastic features. We utilized rps14 knockdown to undertake anin vivosmall molecule screen to identify compounds that ameliorate the MDS phenotype, identifying imiquimod, an agonist of TLR7 and TLR8. Imiquimod alleviates anaemia by promoting haematopoietic stem and progenitor cell expansion and erythroid differentiation, the mechanism of which is dependent on TLR7 ligation. TLR7 activation in this setting paradoxically promoted an anti-inflammatory gene signature suggesting crosstalk between pro-inflammatory pathways endogenous to Rps14 loss and TLR7 pathway activation. Finally, we show that in highly purified human bone marrow samples from anaemic patients, imiquimod leads to an increase in erythroid output from myelo-erythroid progenitors and common myeloid progenitors. Our findings have both specific implications for the development of targeted therapeutics for del (5q) MDS and wider significance identifying a potential role for TLR7 ligation in modifying anaemia.
MDA5 is an essential vita-PAMP sensor necessary for host resistance againstAspergillus fumigatus
Authors: Wang Xi , Caffrey-Carr Alayna K. , Liu Ko-wei , Espinosa Vanessa , Croteau Walburga , Dhingra Sourabh , Rivera Amariliz , Cramer Robert A. , Obar Joshua J. 
Published: July 2020

ABSTRACTRIG-I like receptors (RLR) are cytosolic RNA sensors that signal through the MAVS adaptor to activate interferon responses against viruses. Whether the RLR family has broader effects on host immunity against other pathogen families remains to be fully explored. Herein we demonstrate that MDA5/MAVS signaling was essential for host resistance against pulmonaryAspergillus fumigatuschallenge through the regulation of antifungal leukocyte responses in mice. Activation of MDA5/MAVS signaling was driven by dsRNA from liveA. fumigatusserving as a key vitality-sensing pattern-recognition receptor. Interestingly, induction of type I interferons afterA. fumigatuschallenge was only partially dependent on MDA5/MAVS signaling, whereas type III interferon expression was entirely dependent on MDA5/MAVS signaling. Ultimately, type I and III interferon signaling drove the expression of CXCL10. Furthermore, the MDA5/MAVS-dependent interferon response was critical for the induction of optimal antifungal neutrophil killing ofA. fumigatusspores. In conclusion, our data broaden the role of the RLR family to include a role in regulating antifungal immunity againstA. fumigatus.KEY POINTSMDA5 is essential for maintaining host resistance against Aspergillus fumigatusMDA5 serves as a critical vitality sensor after fungal challengeMDA5 is essential for IFNλ expression and anti-fungal neutrophil killing
Gene Expression Network Analysis Provides Potential Targets Against SARS-CoV-2
Authors: Hernández Cordero Ana I. , Li Xuan , Yang Chen Xi , Milne Stephen , Bossé Yohan , Joubert Philippe , Timens Wim , van den Berge Maarten , Nickle David , Hao Ke , Sin Don D. 
Published: July 2020

ABSTRACTBACKGROUNDCell entry of SARS-CoV-2, the novel coronavirus causing COVID-19, is facilitated by host cell angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). We aimed to identify and characterize genes that are co-expressed withACE2andTMPRSS2, and to further explore their biological functions and potential as druggable targets.METHODSUsing the gene expression profiles of 1,038 lung tissue samples, we performed a weighted gene correlation network analysis (WGCNA) to identify modules of co-expressed genes. We explored the biology of co-expressed genes using bioinformatics databases, and identified known drug-gene interactions.RESULTSACE2was in a module of 681 co-expressed genes; 12 genes with moderate-high correlation withACE2(r>0.3, FDR<0.05) had known interactions with existing drug compounds.TMPRSS2was in a module of 1,086 co-expressed genes; 15 of these genes were enriched in the gene ontology biologic process ‘Entry into host cell’, and 53TMPRSS2-correlated genes had known interactions with drug compounds.CONCLUSIONDozens of genes are co-expressed withACE2andTMPRSS2, many of which have plausible links to COVID-19 pathophysiology. Many of the co-expressed genes are potentially targetable with existing drugs, which may help to fast-track the development of COVID-19 therapeutics.
Structural and molecular basis of cross-seeding barriers in amyloids
Authors: Daskalov A. , Martinez D. , Coustou V. , El Mammeri N. , Berbon M. , Andreas L.B. , Bardiaux B. , Stanek J. , Noubhani A. , Kauffmann B. , Wall J.S. , Pintacuda G. , Saupe S.J. , Habenstein B. , Loquet A. 
Published: July 2020

AbstractNeurodegenerative disorders are frequently associated with β-sheet-rich amyloid deposits. Amyloid-forming proteins can aggregate under different structural conformations known as strains, which can exhibit a prion-like behaviour and distinct patho-phenotypes. Precise molecular determinants defining strain specificity and cross-strain interactions (cross-seeding) are currently unknown. The HET-s prion protein from the fungusPodospora anserinarepresents a model system to study the fundamental properties of prion amyloids. Here, we report the amyloid prion structure of HELLF, a distant homolog of the model prion HET-s. We find that these two amyloids, sharing only 17% sequence identity, have nearly identical β-solenoid folds but lack cross-seeding abilityin vivo, indicating that prion specificity can differ in extremely similar amyloid folds. We engineer the HELLF sequence to explore the limits of the sequence-to-fold conservation and to pinpoint determinants of cross-seeding and prion specificity. We find that amyloid fold conservation occurs even at an exceedingly low level of identity to HET-s (5%). Next, we derive a HELLF-based sequence, termed HEC, able to breach the cross-seeding barrierin vivobetween HELLF and HET-s, unveiling determinants controlling cross-seeding at residue level. These findings show that virtually identical amyloid backbone structures might not be sufficient for cross-seeding and that critical side-chain positions could determine the seeding specificity of an amyloid fold. Our work redefines the conceptual boundaries of prion strain and shed new light on key molecular features concerning an important class of pathogenic agents.
Bifurcation and sensitivity analysis reveal key drivers of multistability in a model of macrophage polarization
Authors: Josefine Frank Anna-Simone , Larripa Kamila , Ryu Hwayeon , Snodgrass Ryan , Röblitz Susanna 
Published: July 2020

AbstractIn this paper, we present and analyze a mathematical model for polarization of a single macrophage which, despite its simplicity, exhibits complex dynamics in terms of multistability. In particular, we demonstrate that an asymmetry in the regulatory mechanisms and parameter values is important for observing multiple phenotypes. Bifurcation and sensitivity analyses show that external signaling cues are necessary for macrophage commitment and emergence to a phenotype, but that the intrinsic macrophage metabolism is equally important. Based on our numerical results, we formulate hypotheses that could be further investigated byin vitroexperiments to deepen our understanding of macrophage polarization.2010 MSC93A30, 34C23, 49Q12, 92C42, 37N25
Prime editing efficiently generates W542L and S621I double mutations in two ALS genes in maize
Authors: Jiang Yuan-Yuan , Chai Yi-Ping , Lu Min-Hui , Han Xiu-Li , Lin Qiupeng , Zhang Yu , Zhang Qiang , Zhou Yun , Wang Xue-Chen , Gao Caixia , Chen Qi-Jun 
Published: July 2020

AbstractA novel and universal CRISPR/Cas-derived precision genome-editing technology named prime editing was developed. However, low efficiency of prime editing was shown in transgenic rice lines. We reasoned that enhancing pegRNA expression would improve prime-editing efficiency. In this report, we describe two strategies for enhancing pegRNA expression. We constructed a prime-editing vector harboring two pegRNA variants for W542L and S621I double mutations inZmALS1andZmALS2. Compared with previous reports in rice, we achieved much higher prime-editing efficiency in maize. Our results are inspiring and provide a direction for the optimization of plant prime editors.
Deletion ofTrpm4alters the function and expression of NaV1.5 channel in murine cardiac myocytes
Authors: Cherian Ozhathil Lijo , Rougier Jean-Sébastien , Arullampalam Prakash , Essers Maria C. , Abriel Hugues 
Published: July 2020

AbstractTransient receptor potential melastatin member 4 (TRPM4) encodes a Ca+-activated non-selective cation channel that is functionally expressed in several tissues including the heart. Pathogenic mutants inTRPM4have been reported in patients with inherited cardiac diseases including conduction block and Brugada syndrome. Heterologous expression of mutant channels in cell lines indicates that these mutations can lead to an increase or decrease in TRPM4 expression and function at the cell surface. While the expression and clinical variant studies further stress the importance of TRPM4 in cardiac function, the cardiac electrophysiological phenotypes inTrpm4knockdown mouse models remain incompletely characterized. To study the functional consequences ofTrpm4deletion on cardiac electrical activity in mice, we performed perforated-patch clamp and immunohistochemistry studies on isolated atrial and ventricular cardiac myocytes and surface, pseudo and intracardiac ECGs eitherin vivoor on Langendorff-perfused explanted mouse hearts. We observed that Trpm4 is expressed in atrial and ventricular cardiac myocytes and that deletion ofTrpm4unexpectedly reduces the peak Na+currents in the myocytes. Hearts fromTrpm4-/-mice presented increased sensitivity towards mexiletine, a Na+channel blocker, and slower intraventricular conduction, consistent with the reduction of peak Na+current observed in the isolated cardiac myocytes. This reduction in Na+current is explained by the observed decrease in protein expression of NaV1.5 inTrpm4-/-mice. This study suggests that Trpm4 expression impacts Na+current in murine cardiac myocytes and points towards a novel function of Trpm4 regulating the NaV1.5 expression in murine cardiac myocytes.
pH-dependent spontaneous hydrolysis rather than gut bacterial metabolism reduces levels of the ADHD treatment, Methylphenidate
Authors: Aresti-Sanz Julia , Maho Walid , Pereira Rob Rodrigues , Permentier Hjalmar , Aidy Sahar El 
Published: July 2020

AbstractMethylphenidate is absorbed in the small intestine. The drug is known to have low bioavailability and a high interindividual variability in terms of response to the treatment. Gut microbiota has been shown to reduce the bioavailability of a wide variety of orally administered drugs. Here, we tested the ability of small intestinal bacteria to metabolize methylphenidate.In silicoanalysis identified several small intestinal bacteria to harbor homologues of the human carboxylesterase 1 enzyme responsible for the hydrolysis of methylphenidate in the liver. Despite our initial results hinting towards possible bacterial hydrolysis of the drug, up to 60% of methylphenidate was spontaneously hydrolyzed in the absence of bacteria and this hydrolysis was pH-dependent. Overall, the study shows that pH-dependent spontaneous hydrolysis rather than gut bacterial metabolism reduces levels of methylphenidate and suggest a role of the luminal pH in the bioavailability of the drug.
Genome-wide analysis of the polyamine oxidase gene family in wheat (Triticum aestivumL.) reveals involvement in temperature stress response
Authors: Gholizadeh Fatemeh , Mirzaghaderi Ghader 
Published: July 2020

AbstractAmine oxidases (AOs) including copper containing amine oxidases (CuAOs) and FAD-dependent polyamine oxidases (PAOs) are associated with polyamine catabolism in the peroxisome, apoplast and cytoplasm and play an essential role in growth and developmental processes and response to biotic and abiotic stresses. Here, we identifiedPAOgenes in common wheat (Triticum aestivum),T. urartuandAegilops tauschiiand reported the genome organization, evolutionary features and expression profiles of the wheat PAO genes (TaPAO). Expression analysis using publicly available RNASeq data showed thatTaPAOgenes are expressed redundantly in various tissues and developmental stages. A large percentage ofTaPAOsrespond significantly to abiotic stresses, especially temperature (i.e. heat and cold stress). SomeTaPAOswere also involved in response to other stresses such as powdery mildew, stripe rust andFusariuminfection. Overall,TaPAOsmay have various functions in stress tolerances responses, and play vital roles in different tissues and developmental stages. Our results provided a reference for further functional investigation of TaPAO proteins.
Effects of exogenous β-glucanase on ileal digesta soluble β-glucan molecular weight, digestive tract characteristics, and performance of coccidiosis challenged broiler chickens fed hulless barley-based diets with and without medication
Authors: Karunaratne Namalika D. , Newkirk Rex W. , Ames Nancy P. , Van Kessel Andrew. G. , Bedford Michael R. , Classen Henry L. 
Published: July 2020

AbstractLimited use of medication in poultry feed led to the investigation of exogenous enzymes as antibiotic alternatives for controlling enteric disease. The objective of this study was to evaluate the effects of diet β-glucanase (BGase) and medication on β-glucan depolymerization, digestive tract characteristics, and performance of broilers. Broilers were fed hulless barley (HB) based diets with BGase (Econase GT 200P from AB Vista; 0 and 0.1%) and medication (Bacitracin and Salinomycin Na; with and without) arranged as a 2 × 2 factorial. In Experiment 1, 160 broilers were housed in cages from d 0 to 28. Each treatment was assigned to 10 cages. In Experiment 2, broilers (2376) were housed in floor pens and challenged with a coccidiosis vaccine on d 5. Each treatment was assigned to one floor pen in each of nine rooms. In Experiment 1, the soluble β-glucan weight average molecular weight (Mw) in the ileal digesta was lower with medication in the 0% BGase treatments. Peak molecular weight (Mp) and Mw were lower with BGase regardless of medication. The maximum molecular weight for the smallest 10% β-glucan (MW-10%) was lower with BGase. In Experiment 2, Mp was lower with medication in 0% BGase treatments. Beta-glucanase resulted in lower Mp regardless of medication, and the degree of response was lower with medication. The MW-10% was lower with BGase despite antibiotic addition. Body weight gain (BWG) and feed efficiency were higher with medication regardless of BGase use through-out the trial (except d 11-22 feed efficiency). Beta-glucanase resulted in higher BWG after d 11, and lower and higher feed efficiency before and after d 11, respectively, in unmedicated treatments. In conclusion, BGase and medication caused the depolymerization of soluble ileal β-glucan. Beta-glucanase appeared as a partial replacement for diet medication to increase coccidiosis challenged broiler performance.
The melissopalynological investigation in the Eastern Dry Zone of Karnataka, India
Authors: Shishira D. , Uthappa A. R. , Kumar Veeresh , Shringeshwara  , Kuberappa G. C. 
Published: July 2020

AbstractMelissopalynology, the analysis of pollen grains present in honey, indicates about the pollen and nectar sources in a region utilized by bees, which is used to determine the bee floral resources and botanical origin of the honey. This study investigated the melissopalynological analysis of the honey samples from the Eastern Dry zone of Karnataka. 24 honey samples were examined based on pollen analyses, among them 14 samples were unifloral, rest were multifloral. The unifloral honey had pollens ofCallistemon viminalis, Areca catechu, Citrussp.,Mallotus philippensis, Cocos nucifera, Eucalyptussp.,Ocimumsp.,Moringa oleiferaandPongamia pinnata. Samples collected in October, November, December, and January were rich in pollens ofEucalyptussp.. Similarly, samples collected in January, February and March had pollen of tree speciesviz.,Swietenia mahagoni, Canthium parviflorum, Simarouba glauca, Eucalyptussp.,Moringa oleifera, Syzygium cumini, Tabebuiasp.,Pongamia pinnata, Acanthaceae, Anacardium occidentale, Cocos nucifera, Areca catechu, Mallotus philippensis, Bauhinia variegata, Psidium guajava, Alangiaceae, Euphorbiaceae, Ulmaceae, Capparis zeylanica, Convolvulaceae. GKVK-11 followed by GKVK-12 sample recorded the highest Shannon diversity and GKVK-9 followed by GKVK-7 sample recorded the least diversity. Based on the similar floral composition samples were classified into four clusters. The PCA revealed that most of the samples grouped into a single cluster, except 7, 19, 20, 21, and 22 which were placed away from the origin. The presence of pollen in the honey of a particular plant species during different months is related to the blooming of that particular plant species from which the bees forage. The flora of honey changes with the season. The diversity of pollen grains in honey varied with location to location. The present study provides scientific knowledge to the beekeepers by indicating important plants for the development of the regional apiculture, through the identification of pollen types.
Compression of quantification uncertainty for scRNA-seq counts
Authors: Van Buren Scott , Sarkar Hirak , Srivastava Avi , Rashid Naim U. , Patro Rob , Love Michael I. 
Published: July 2020

AbstractMotivationQuantification estimates of gene expression from single-cell RNA-seq (scRNA-seq) data have inherent uncertainty due to reads that map to multiple genes. Many existing scRNA-seq quantification pipelines ignore multi-mapping reads and therefore underestimate expected read counts for many genes.alevinaccounts for multi-mapping reads and allows for the generation of “inferential replicates”, which reflect quantification uncertainty. Previous methods have shown improved performance when incorporating these replicates into statistical analyses, but storage and use of these replicates increases computation time and memory requirements.ResultsWe demonstrate that storing only the mean and variance from a set of inferential replicates (“compression”) is sufficient to capture gene-level quantification uncertainty. Using these values, we generate “pseudo-inferential” replicates from a negative binomial distribution and propose a general procedure for incorporating these replicates into a proposed statistical testing framework. We show reduced false positives when applying this procedure to trajectory-based differential expression analyses. We additionally extend theSwishmethod to incorporate pseudo-inferential replicates and demonstrate improvements in computation time and memory consumption without any loss in performance. Lastly, we show that the removal of multi-mapping reads can result in significant underestimation of counts for functionally important genes in a real dataset.Availability and implementationmakeInfRepsandsplitSwishare implemented in the development branch of the R/Bioconductorfishpondpackage available athttp://bioconductor.org/packages/devel/bioc/html/fishpond.html. Sample code to calculate the uncertainty-awarep-values can be found on GitHub athttps://github.com/skvanburen/scUncertaintyPaperCode.Contactmichaelisaiahlove@gmail.com
Clean Enzymatic depolymerization of highly crystalline polyethylene terephthalate in moist-solid reaction mixtures
Authors: Kaabel Sandra , Therien J. P. Daniel , Deschênes Catherine E. , Duncan Dustin , Friščić Tomislav , Auclair Karine 
Published: July 2020

AbstractLess than 9% of the plastic produced is recycled after use, contributing to the global plastic pollution problem. While polyethylene terephthalate (PET) is one of the most common plastics, its thermomechanical recycling generates a material of lesser quality. Enzymes are highly selective, renewable catalysts active at mild temperatures; however, the current consensus is that they lack activity towards the more crystalline forms of PET. We report here that when used in moist-solid reaction mixtures instead of the typical dilute aqueous solutions, enzymes can directly depolymerize high crystallinity PET in 13-fold higher space-time yield and a 15-fold higher enzyme efficiency than prior reports. Further, this process shows a 26-fold selectivity for terephthalic acid over other hydrolysis products, which allows the direct synthesis of UiO-66 metal-organic framework.
Numerical Model for Formation and Evolution of the Bleb
Authors: Feng J. , Tang L. , Liu Z. , Dong S. , Zhou L. , Liu Y. , Jiang Z. 
Published: July 2020

ABSTRACTThe bleb morphology and its changes are an important mechanism of cell’s amoeboid migration. By releasing bonds between the membrane and the cortex of a cell, the formation of bleb can be observed experimentally, but the mechanism that affects the size and shape of this kind of bleb is waiting for further study. In this paper, a two-dimensional fluid-solid coupling model is established to describe a cell with membrane, cortex and cytoplasm in a solution, and a numerical solving method for the fluid-solid coupling model is developed to simulate the behaviors of cell bleb. The effects of parameters, such as the number of broken bonds, the viscosity coefficient of the cortex, and the cell’s membrane modulus on the size and the shape of the bleb were investigated. Numerical results show that the model is effective to simulate the formation and evolution of cell’s bleb, and derive the contribution of several affecting factors to the bleb shape and size clearly.SIGNIFICANCETo understand the process of cell migration with bleb pseudopods in the amoeba cell migration, it is necessary to study the formation mechanism of cells protruding bleb. In this paper, we propose a reasonable and reliable cell numerical model. With this model we successfully simulate the bleb phenomenon consistent with the experimental phenomenon by changing the key impact factors. The method in this paper is applicable to the cell model of amoeba cell migration pattern, which helps to understand the important role of blebs in the process of cell migration.