bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prediction of pyrazinamide resistance inMycobacterium tuberculosisusing structure-based machine learning approaches
Authors: Carter Joshua J , Walker Timothy M , Walker A Sarah , Whitfield Michael G. , Morlock Glenn P. , Lynch Charlotte I. , Adlard Dylan , Peto Timothy EA , Posey James E. , Crook Derrick W , Fowler Philip W 
Published: January 2019

SynopsisBackgroundPyrazinamide is one of four first-line antibiotics used to treat tuberculosis, however antibiotic susceptibility testing for pyrazinamide is challenging. Resistance to pyrazinamide is primarily driven by genetic variation inpncA,an enzyme that converts pyrazinamide into its active form.MethodsWe curated a dataset of 664 non-redundant, missense amino acid mutations inpncAwith associated high-confidence phenotypes from published studies and then trained three different machine learning models to predict pyrazinamide resistance. All models had access to a range of protein structural-, chemical- and sequence-based features.ResultsThe best model, a gradient-boosted decision tree, achieved a sensitivity of 80.2% and a specificity of 76.9% on the hold-out Test dataset. The clinical performance of the models was then estimated by predicting the binary pyrazinamide resistance phenotype of 4,027 samples harboring 367 unique missense mutations inpncAderived from 24,231 clinical isolates.ConclusionsThis work demonstrates how machine learning can enhance the sensitivity/specificity of pyrazinamide resistance prediction in genetics-based clinical microbiology workflows, highlights novel mutations for future biochemical investigation, and is a proof of concept for using this approach in other drugs.
SGI-4 in monophasic Salmonella Typhimurium ST34 is a novel ICE that enhances resistance to copper
Authors: Branchu Priscilla , Charity Oliver J. , Bawn Matt , Thilliez Gaetan , Dallman Timothy J , Petrovska Liljana , Kingsley Robert A. 
Published: January 2019

AbstractA multi drug resistant (MDR) Salmonella enterica 4,[5],12:i-of sequence type 34 (monophasic S. Typhimurium ST34) is a current pandemic clone associated with livestock and numerous outbreaks in the human population. A large genomic island, termed SGI-4, is present in the monophasic Typhimurium ST34 clade and absent from other S. Typhimurium strains. SGI-4 consists of 78 open reading frames including sil and pco genes previously implicated in resistance to copper and silver, and multiple genes predicted to be involved in mobilisation and transfer by conjugation. SGI-4 was excised from the chromosome, circularised and transferred to recipient strains of S. Typhimurium at a frequency influenced by stress and induced by mitomycin C and oxygen tension. The presence of SGI-4 was associated with increased resistance to copper, particularly but not exclusively under anaerobic conditions. The presence of silCBA genes, predicted to encode an RND family efflux pump that transports copper from the periplasm to the external milieu, was sufficient to impart the observed enhanced resistance to copper. The presence of silCBA genes resulted in the absence of copper-dependent induction of a multicopper oxidase system encoded by pco genes, also present on SGI-4, suggesting that the system effectively limits the copper availability in the periplasm. The presence of silCBA genes did not affect SodCI-dependent macrophage survival.
Loss of a glutaredoxin gene underlies parallel evolution of trichome pattern inAntirrhinum
Authors: Tan Ying , Barnbrook Matthew , Wilson Yvette , Molnár Attila , Hudson Andrew 
Published: January 2019

ABSTRACTMost angiosperms produce trichomes--epidermal hairs that have protective or more specialised roles. In almost all species trichomes are multicellular and, in the majority, secretory. Despite the importance of multicellular trichomes for plant protection and as a source of high-value products, little is known about the mechanisms that control their development. Here we use natural variation betweenAntirrhinum(snapdragon) species to examine how trichome distribution is regulated and has evolved. We show that a single gene,Hairy(H), which is needed to repress trichome fate, underlies variation in trichome distribution patterns between allAntirrhinumspecies except one.Hencodes an epidermis-specific glutaredoxin and trichome distribution within individual plants reflects the location ofHexpression. Gene phylogenies and functional tests suggest thatHgained its trichome-repressing role late in eudicot evolution and thatAntirrhinumspecies with widespread trichomes evolved multiple times from a largely bald ancestor though independent losses of H activity. We also find evidence for an evolutionary reversal involving a suppressor mutation, and for a pleiotropic effect ofHthat might constrain the evolution of trichome patterns.
Cleaning genotype data from Diversity Outbred mice
Authors: Broman Karl W. , Gatti Daniel M. , Svenson Karen L. , Sen Śaunak , Churchill Gary A. 
Published: January 2019

AbstractData cleaning is an important first step in most statistical analyses, including efforts to map the genetic loci that contribute to variation in quantitative traits. Here we illustrate approaches to quality control and cleaning of array-based genotyping data for multiparent populations (experimental crosses derived from more than two founder strains), using MegaMUGA array data from a set of 291 from Diversity Outbred (DO) mice. Our approach employs data visualizations that can reveal problems at the level of individual mice or with individual SNP markers. We find that the proportion of missing genotypes for each mouse is an effective indicator of sample quality. We use microarray probe intensities for SNPs on the X and Y chromosomes to confirm the sex of each mouse, and we use the proportion of matching SNP genotypes between pairs of mice to detect sample duplicates. We use a hidden Markov model (HMM) reconstruction of the founder haplotype mosaic across each mouse genome to estimate the number of crossovers and to identify potential genotyping errors. To evaluate marker quality, we find that missing data and genotyping error rates are the most effective diagnostics. We also examine the SNP genotype frequencies with markers grouped according to their minor allele frequency in the founder strains. For markers with high apparent error rates, a scatterplot of the allele-specific probe intensities can reveal the underlying cause of incorrect genotype calls. The decision to include or exclude low-quality samples can have a significant impact on the mapping results for a given study. We find that the impact of low-quality markers on a given study is often minimal, but reporting problematic markers can improve the utility of the genotyping array across many studies.
The Ptr1 locus of Solanum lycopersicoides confers resistance to race 1 strains of Pseudomonas syringae pv. tomato and to Ralstonia pseudosolanacearum by recognizing the type III effectors AvrRpt2/RipBN
Authors: Mazo-Molina Carolina , Mainiero Samantha , Hind Sara R. , Kraus Christine M. , Vachev Mishi , Maviane-Macia Felicia , Lindeberg Magdalen , Saha Surya , Strickler Susan R. , Feder Ari , Giovannoni James J. , Smart Christine D. , Peeters Nemo , Martin Gregory B. 
Published: January 2019

AbstractRace 1 strains of Pseudomonas syringae pv. tomato, which causes bacterial speck disease of tomato, are becoming increasingly common and no simply-inherited genetic resistance to such strains is known. We discovered that a locus in Solanum lycopersicoides, termed Pseudomonas tomato race 1 (Ptr1), confers resistance to race 1 Pst strains by recognizing the type III effector AvrRpt2. In Arabidopsis, AvrRpt2 degrades the RIN4 protein thereby activating RPS2-mediated immunity. Ptr1 also recognized homologs of AvrRpt2 from diverse bacteria including one in Ralstonia pseudosolanacearum and this correlated with the ability of AvrRpt2 to degrade RIN4. Using site-directed mutagenesis of AvrRpt2 we found that Ptr1 and RPS2 recognize identical features of AvrRpt2. However, the genome sequence of S. lycopersicoides revealed no RPS2 homolog in the Ptr1 region. Ptr1 could play an important role in controlling bacterial speck disease and its future cloning may shed light on an example of convergent evolution for recognition of a widespread type III effector.
Computational Drug Recommendation Approaches toward Safe Polypharmacy
Authors: Chiang Wen-Hao , Ning Xia 
Published: January 2019

AbstractAdverse drug reactions (ADRs) induced from high-order drug-drug interactions (DDIs) due to polypharmacy - simultaneous use of multiple drugs - represent a significant public health problem. Unfortunately, computational efforts to facilitate decision making for safe polypharmacy, particularly to assist safe multi-drug prescribing, are lacking. We formally formulate the to-avoid and safe drug recommendation problems for multi-drug prescriptions. We investigate preliminary computational approaches to tackling these problems, utilizing a minimum set of available prescription data from a large population, and demonstrate their potentials in assisting safe-polypharmacy decision making once richer data (e.g., electronic medical records, omics data and pathology data) are available. We develop a joint model with a recommendation component and an ADR label prediction component to conduct to-avoid and safe drug recommendation. We also develop real drug-drug interaction datasets and corresponding evaluation protocols to facilitate future computational research on safe polypharmacy.
Species dynamics and interactions via metabolically informed consumer-resource models
Authors: Muscarella Mario E. , O’Dwyer James P. 
Published: January 2019

AbstractQuantifying the strength, sign, and origin of species interactions, along with their dependence on environmental context, is at the heart of prediction and understanding in ecological communities. Pairwise interaction models like Lotka-Volterra provide an important and flexible foundation, but notably absent is an explicit mechanism mediating interactions. Consumer-resource models incorporate mechanism, but describing competitive and mutualistic interactions is more ambiguous. Here, we bridge this gap by modeling a coarse-grained version of a species’ true, cellular metabolism to describe resource consumption via uptake and conversion into biomass, energy, and byproducts. This approach does not require detailed chemical reaction information, but it provides a more explicit description of underlying mechanisms than pairwise interaction or consumer-resource models. Using a model system, we find that when metabolic reactions require two distinct resources we recover Liebig’s Law and multiplicative co-limitation in particular limits of the intracellular reaction rates. In between these limits, we derive a more general phenomenological form for consumer growth rate, and we find corresponding rates of secondary metabolite production, allowing us to model competitive and non-competitive interactions (e.g., facilitation). Using the more general form, we show how secondary metabolite production can support coexistence even when two species compete for a shared resource, and we show how differences in metabolic rates change species’ abundances in equilibrium. Building on these findings, we make the case for incorporating coarse-grained metabolism to update the phenomenology we use to model species interactions.
iPSC-derived Cancer Organoids Recapitulate Genomic and Phenotypic Alterations of c-met-mutated Hereditary Kidney Cancer
Authors: Hwang Jin Wook , Desterke Christophe , Féraud Olivier , Richard Stephane , Ferlicot Sophie , Verkarre Virginie , Patard Jean Jacques , Loisel-Duwattez Julien , Foudi Adlen , Griscelli Frank , Bennaceur-Griscelli Annelise , Turhan Ali G 
Published: January 2019

SUMMARYHereditary cancers with cancer-predisposing mutations represent unique models of human oncogenesis as a driving oncogenic event is present in germline, exposing the healthy member of a family to the occurrence of cancer. The study of the secondary events in a tissue-specific manner is now possible by the induced pluripotent stem cell (iPSC) technology offering the possibility to generate an unlimited source of cells that can be induced to differentiate towards a tissue at risk of malignant transformation. We report here for the first time, the generation of a c-met-mutated iPSC lines from the somatic cells of a patient with type 1 papillary renal cell carcinoma (PRCC). We demonstrate the feasibility of kidney differentiation with iPSC-derived organoids expressing markers of kidney progenitors with presence of tight junctions and brush borders in tubular structures at transmission electron microscopy. Importantly, c-met-mutated kidney organoids expressed PRCC markers both in vitro and in vivo in NSG mice. Gene expression profiling of c-met-mutated iPSC-derived organoid structures showed striking molecular similarities with signatures found in a large cohort of PRCC patient samples and identified 11 common genes. Among these, BHLHE40 and KDM4C, well-known factors involved in PRCC pathogenesis, were expressed in c-met-mutated kidney organoids. This analysis applied to primary cancers with and without c-met mutation showed overexpression of the BHLHE40 and KDM4C only in the c-met-mutated PRCC tumors, as predicted by c-met-mutated organoid transcriptome. These data represent therefore the first proof of concept of the generation of “renal carcinoma in a dish” model using c-met-mutated iPSC-derived organoids, opening new perspectives for discovery of novel potentially predictive disease markers and novel drugs for future precision medicine strategies.
IFITM3 protects the heart during influenza virus infection
Authors: Kenney Adam D. , McMichael Temet M. , Imas Alexander , Chesarino Nicholas M. , Zhang Lizhi , Dorn Lisa E. , Wu Qian , Alfaour Omar , Amari Foued , Chen Min , Zani Ashley , Chemudupati Mahesh , Accornero Federica , Coppola Vincenzo , Rajaram Murugesan V.S. , Yount Jacob S. 
Published: January 2019

AbstractInfluenza virus primarily targets the lungs, but dissemination and damage to heart tissue is also known to occur in severe infections. Despite this knowledge, influenza virus-induced cardiac pathogenesis and its underlying mechanisms have been difficult to study due to a lack of small animal models. In humans, polymorphisms in the gene encoding interferon-induced transmembrane protein 3 (IFITM3), an antiviral restriction factor, are associated with susceptibility to severe influenza, but whether IFITM3 deficiencies contribute to other aspects of pathogenesis, including cardiac dysfunction, is unknown. We now show that IFITM3 deficiency in a newly generated knockout (KO) mouse model exacerbates illness and mortality following influenza A virus infection. Enhanced pathogenesis correlated with increased replication of virus in the lungs, spleens, and hearts of KO mice relative to wildtype (WT) mice. IFITM3 KO mice exhibited normal cardiac function at baseline, but developed severely aberrant electrical activity upon infection, including decreased heart rate and irregular, arrhythmic RR (interbeat) intervals. In contrast, WT mice exhibited a mild decrease in heart rate without irregularity of RR intervals. Heightened cardiac virus titers and electrical dysfunction in KO animals was accompanied by increased activation of fibrotic pathways and fibrotic lesions in the heart. Our findings reveal an essential role for IFITM3 in controlling influenza virus replication and pathogenesis in heart tissue and establish IFITM3 KO mice as a powerful model to study virus-induced cardiac dysfunction.
Syntrophic co-culture amplification of production phenotype for high-throughput screening of microbial strain libraries
Authors: Saleski Tatyana E. , Kerner Alissa R. , Chung Meng Ting , Jackman Corine M. , Khasbaatar Azzaya , Kurabayashi Katsuo , Lin Xiaoxia Nina 
Published: January 2019

AbstractMicrobes can be engineered to synthesize a wide array of bioproducts, yet production phenotype evaluation remains a frequent bottleneck in the design-build-test cycle where strain development requires iterative rounds of library construction and testing. Here, we presentSyntrophicCo-cultureAmplification ofProduction phenotype (SnoCAP). Through a metabolic cross-feeding circuit, the production level of a target molecule is translated into highly distinguishable co-culture growth characteristics, which amplifies differences in production into highly distinguishable growth phenotypes. We demonstrate SnoCAP with the screening ofEscherichia colistrains for production of two target molecules: 2-ketoisovalerate, a precursor of the drop-in biofuel isobutanol, and L-tryptophan. The dynamic range of the screening can be tuned by employing an inhibitory analog of the target molecule. Screening based on this framework requires compartmentalization of individual producers with the sensor strain. We explore three formats of implementation with increasing throughput capability: confinement in microtiter plates (102-104assays/experiment), spatial separation on agar plates (104-105assays/experiment), and encapsulation in microdroplets (105-107assays/experiment). Using SnoCAP, we identified an efficient isobutanol production strain from a random mutagenesis library, reaching a final titer that is 5-fold higher than that of the parent strain. The framework can also be extended to screening for secondary metabolite production using a push-pull strategy. We expect that SnoCAP can be readily adapted to the screening of various microbial species, to improve production of a wide range of target molecules.HighlightsA high-throughput screening platform based on cross-feeding auxotrophs was developed.Compartmentalization was implemented in three formats: microplates, agar plates, and microdroplets.Utility of the screening was demonstrated for two proof-of-concept target molecules: 2-ketoisovalerate and L-tryptophan.The assay dynamic range was tuned by addition of an inhibitory analog.The screening was applied to identify a strain from a chemically mutagenized library that produces 5-fold higher isobutanol titer than the parent strain.
Evolution of asymmetric gamete signaling and suppressed recombination at the mating type locus
Authors: Hadjivasiliou Zena , Pomiankowski Andrew 
Published: January 2019

AbstractThe two partners required for sexual reproduction are rarely the same. This pattern extends to species which lack sexual dimorphism yet possess self-incompatible gametes determined at mating-type regions of suppressed recombination, likely precursors of sex chromosomes. Here we investigate the role of cellular signaling in the evolution of mating-types. We develop a model of ligand-receptor dynamics within cells, and identify factors that determine the capacity of cells to send and receive signals. The model specifies conditions favoring the evolution of gametes producing ligand and receptor asymmetrically and shows how these are affected by recombination. When the recombination rate can evolve, the conditions favoring asymmetric signaling also favor tight linkage of ligand and receptor loci in distinct linkage groups. These results suggest that selection for asymmetric signaling between gametes was the first step in the evolution of non-recombinant mating-type loci, paving the road for the evolution of anisogamy and sexes.
BDNF/TrkB.T1 signaling is a novel mechanism for astrocyte morphological maturation
Authors: Holt Leanne M. , Pacheco Natasha L. , Hernandez Raymundo , Hossain Muhannah , Olsen Michelle L. 
Published: January 2019

AbstractBrain derived neurotrophic factor (BDNF) is a critical growth factor involved in the maturation of neurons, including neuronal morphology and synapse refinement. Herein, we demonstrate astrocytes express high levels of BDNF’s receptor, TrkB (in the top 20 of protein-coding transcripts), with nearly exclusive expression of the truncated isoform, TrkB.T1 which peaks in expression during astrocyte morphological maturation. Using a novel culture paradigm, we show that astrocyte morphological complexity is increased in the presence of BDNF and is dependent upon BDNF/TrkB.T1 signaling. Deletion of TrkB.T1 in vivo revealed morphologically immature astrocytes with significantly reduced volume and branching, as well as dysregulated expression of perisynaptic genes associated with mature astrocyte functions, including synaptogenic genes. Indicating a role for functional astrocyte maturation via BDNF/TrkB.T1 signaling, TrkB.T1 KO astrocytes do not support normal excitatory synaptogenesis. These data suggest a significant role for BDNF/TrkB.T1 signaling in astrocyte morphological maturation, a critical process for CNS development.
A novel self-organizing embryonic stem cell system reveals signaling logic underlying the patterning of human ectoderm
Authors: Britton George , Heemskerk Idse , Hodge Rachel , Qutub Amina A , Warmflash Aryeh 
Published: January 2019

SummaryDuring development, the ectoderm is patterned by a combination of BMP and WNT signaling. Research in model organisms has provided substantial insight, however, there are currently no systems to study this patterning in humans. Further, the complexity of neural plate border specification has made it difficult to transition from discovering the genes involved to deeper mechanistic understanding. Here, we develop anin vitromodel of human ectodermal patterning, in which hESCs self-organize to form robust and quantitatively reproducible patterns corresponding to the dorsal-ventral axis of the embryo. Using this platform, we show that the duration of endogenous WNT signaling is a crucial control parameter, and that cells sense relative levels of BMP and WNT signaling in making fate decisions. These insights allowed us to develop an improved protocol for placodal differentiation. Thus, our platform is a powerful tool for studying human ectoderm patterning and for improving directed differentiation protocols.
Kin-dependent dispersal influences relatedness and genetic structuring in a lek system
Authors: Cayuela Hugo , Boualit Laurent , Laporte Martin , Prunier Jérôme G. , Preiss Françoise , Laurent Alain , Foletti Francesco , Clobert Jean , Jacob Gwenaël 
Published: January 2019

AbstractKin selection and dispersal play a critical role in the evolution of cooperative breeding systems. Limited dispersal dramatically increases relatedness in spatially structured populations (population viscosity), with the result that neighbours tend to be genealogical relatives. Yet the increase in neighbours’ performance through altruistic interaction may also result in habitat saturation and thus exacerbate local competition between kin. Our goal was to detect the footprint of kin selection and competition by examining the spatial structure of relatedness and by comparing non-effective and effective dispersal in a population of a lekking bird,Tetrao urogallus. For this purpose, we analysed capture–recapture and genetic data collected over a 6-year period on a spatially structured population ofT. urogallusin France. Our findings revealed a strong spatial structure of relatedness in males. They also indicated that the population viscosity allowed male cooperation through two non-exclusive mechanisms. First, at their first lek attendance, males aggregate in a lek composed of relatives. Second, the distance corresponding to non-effective dispersal dramatically outweighed effective dispersal distance, which suggests that dispersers incur high post-settlement costs. These two mechanisms result in strong population genetic structuring in males. In females, our findings revealed a lower level of spatial structure of relatedness and genetic structure in respect to males. Additionally, non-effective dispersal and effective dispersal distances in females were highly similar, which suggests limited post-settlement costs. These results indicate that kin-dependent dispersal decisions and costs are factors driving the evolution of cooperative courtship and have a genetic footprint in wild populations.