bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of Candida auris microsatellite typing and its application on a global collection of isolates
Authors: de Groot Theun , Puts Ynze , Berrio Indira , Chowdhary Anuradha , Meis Jacques F. 
Published: October 2019

AbstractCandida auris is a pathogenic yeast that causes invasive infections with high mortality. Infections most often occur in intensive care units of healthcare facilities. It is crucial to trace the source and prevent further spread of C. auris during an outbreak setting, therefore, genotyping of C. auris is required. To enable fast and cost-effective genotyping, we developed a microsatellite typing assay for C. auris.Short tandem repeats (STRs) in C. auris were identified, and a novel STR typing assay for C. auris was developed using 4 panels of three multiplex PCRs. Having shown that the microsatellite typing assay was highly reproducible and specific, a robust set of 444 C. auris isolates was investigated to identify genotypic diversity. In concordance with whole-genome sequencing (WGS) analysis we identified five major different C. auris clusters, namely, South-America, South-Asia, Africa, East-Asia and Iran. Overall, a total of 40 distinct genotypes were identified, with the largest variety in the East Asian clade. Comparison with WGS demonstrated that isolates with <20 SNPs are mostly not differentiated by STR analysis, while isolates with 30 or more SNPs usually have differences in one or more STR markers.Altogether, a highly reproducible and specific microsatellite typing assay for C. auris was developed, which distinguishes the five different C. auris clades in identical fashion to WGS, while most isolates differing >20 SNPs, as determined via WGS, are also separated. This new C. auris specific genotyping technique is a rapid, reliable, cost-effective alternative to WGS analysis to speedily investigate outbreaks.ImportanceCandida auris is an emerging fungal pathogen now recognized as a threat to public health. The pathogen has spread worldwide and mainly causes hospital associated outbreaks. To track and trace outbreaks and to relate them to new introductions from elsewhere, whole genome sequencing and amplified fragment length polymorphism (AFLP) have been used for molecular typing. While the former is costly and only available in few centers, AFLP is a complicated technique and standardization is not possible. We describe a novel simple microsatellite genotyping technique based on small tandem repeats in the C. auris genome. Further we show that this microsatellite based genotyping technique has been proven comparable to WGS. Overall, this work provides a novel, rapid, reliable and cost-effective method of molecular outbreaks investigations of C. auris.
Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry
Authors: Dvořák Zdeněk , Kopp Felix , Costello Cait M. , Kemp Jazmin S. , Li Hao , Vrzalová Aneta , Štěpánková Martina , Bartoňková Iveta , Jiskrová Eva , Poulíková Karolína , Vyhlídalová Barbora , Nordstroem Lars U. , Karunaratne Chamini , Ranhotra Harmit , Mun Kyu Shik , Naren Anjaparavanda P. , Murray Iain , Perdew Gary H. , Brtko Julius , Toporova Lucia , Schon Arne , Wallace William G. , Walton William G. , Redinbo Matthew R. , Sun Katherine , Beck Amanda , Kortagere Sandhya , Neary Michelle C. , Chandran Aneesh , Vishveshwara Saraswathi , Cavalluzzi Maria M. , Lentini Giovanni , Cui Julia Yue , Gu Haiwei , March John C. , Chaterjee Shirshendu , Matson Adam , Wright Dennis , Flannigan Kyle L. , Hirota Simon A. , Sartor R. Balfour , Mani Sridhar 
Published: October 2019

AbstractThe human pregnane X receptor (PXR), a master regulator of drug metabolism, has important roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows to exploit previously unexplored parts of chemical space. Here we report functionalized indole-derivatives as first-in-class non-cytotoxic PXR agonists, as a proof-of-concept for microbial metabolite mimicry. The lead compound, FKK6, binds directly to PXR protein in solution, induces PXR specific target gene expression in, cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to mine underexploited regions of chemical space.
TLR5 participates in the TLR4 receptor complex and biases towards MyD88-dependent signaling in environmental lung injury
Authors: Hussain Salik , Johnson Collin G , Sciurba Joseph , Meng Xianglin , Stober Vandy P , Liu Caini , Cyphert-Daly Jaime M , Bulek Katarzyna , Qian Wen , Solis Alma , Sakamachi Yosuke , Trempus Carol S , Aloor Jim J , Gowdy Kym M , Foster W. Michael , Hollingsworth John W , Tighe Robert M , Li Xiaoxia , Fessler Michael B , Garantziotis Stavros 
Published: October 2019

AbstractLung disease causes significant morbidity and mortality, and is exacerbated by environmental injury, e.g. through lipopolysaccharide (LPS) or ozone (O3). Toll-like receptors (TLRs) orchestrate immune responses to injury by recognizing pathogen- or danger-associated molecular patterns. TLR4, the prototypic receptor for LPS, also mediates inflammation after O3, triggered by endogenous hyaluronan. Regulation of TLR4 signaling is incompletely understood. TLR5, the flagellin receptor, is expressed in alveolar macrophages, and regulates immune responses to environmental injury. Usingin vivoanimal models of TLR4-mediated inflammations (LPS, O3, hyaluronan), we show that TLR5 impacts thein vivoresponse to LPS, hyaluronan and O3. We demonstrate that immune cells of human carriers of a dominant negative TLR5 allele have decreased inflammatory response to O3exposureex vivoand LPS exposurein vitro. Using primary murine macrophages, we find that TLR5 physically associates with TLR4 and biases TLR4 signaling towards the MyD88 pathway. Our results suggest an updated paradigm for TLR4/TLR5 signaling.
Defining epidermal basal cell states during skin homeostasis and wound healing using single-cell transcriptomics
Authors: Haensel Daniel , Jin Suoqin , Cinco Rachel , Sun Peng , Nguyen Quy , Cang Zixuan , Dragan Morgan , Gong Yanwen , MacLean Adam L , Kessenbrock Kai , Gratton Enrico , Nie Qing , Dai Xing 
Published: October 2019

SUMMARYOur knowledge of transcriptional heterogeneities in epithelial stem/progenitor cell compartments is limited. Epidermal basal cells sustain cutaneous tissue maintenance and drive wound healing. Previous studies have probed basal cell heterogeneity in stem/progenitor potential, but a non-biased dissection of basal cell dynamics during differentiation is lacking. Using single-cell RNA-sequencing coupled with RNAScope and fluorescence lifetime imaging, we identify three non-proliferative and one proliferative basal cell transcriptional states in homeostatic skin that differ in metabolic preference and become spatially partitioned during wound re-epithelialization. Pseudotemporal trajectory and RNA velocity analyses produce a quasi-linear differentiation hierarchy where basal cells progress fromCol17a1high/Trp63highstate to early response state, proliferate at the juncture of these two states, or become growth arrested before differentiating into spinous cells. Wound healing induces plasticity manifested by dynamic basal-spinous interconversions at multiple basal states. Our study provides a systematic view of epidermal cellular dynamics supporting a revised “hierarchical-lineage” model of homeostasis.
A Bayesian Non-parametric Mixed-Effects Model of Microbial Phenotypes
Authors: Tonner Peter D. , Darnell Cynthia L. , Bushell Francesca M.L. , Lund Peter A. , Schmid Amy K. , Schmidler Scott C. 
Published: October 2019

AbstractSubstantive changes in gene expression, metabolism, and the proteome are manifested in overall changes in microbial population growth. Quantifying how microbes grow is therefore fundamental to areas such as genetics, bioengineering, and food safety. Traditional parametric growth curve models capture the population growth behavior through a set of summarizing parameters. However, estimation of these parameters from data is confounded by random effects such as experimental variability, batch effects or differences in experimental material. A systematic statistical method to identify and correct for such confounding effects in population growth data is not currently available. Further, our previous work has demonstrated that parametric models are insufficient to explain and predict microbial response under non-standard growth conditions. Here we develop a hierarchical Bayesian non-parametric model of population growth that identifies the latent growth behavior and response to perturbation, while simultaneously correcting for random effects in the data. This model enables more accurate estimates of the biological effect of interest, while better accounting for the uncertainty due to technical variation. Additionally, modeling hierarchical variation provides estimates of the relative impact of various confounding effects on measured population growth.
Saak Transform-Based Machine Learning for Light-Sheet Imaging of Cardiac Trabeculation
Authors: Ding Yichen , Gudapati Varun , Lin Ruiyuan , Fei Yanan , Song Sibo , Chang Chih-Chiang , Baek Kyung In , Wang Zhaoqiang , Roustaei Mehrdad , Kuang Dengfeng , Jay Kuo C.-C. , Hsiai Tzung K. 
Published: October 2019

AbstractRecent advances in light-sheet fluorescence microscopy (LSFM) enable 3-dimensional (3-D) imaging of cardiac architecture and mechanics in toto. However, segmentation of the cardiac trabecular network to quantify cardiac injury remains a challenge. We hereby employed “subspace approximation with augmented kernels (Saak) transform” for accurate and efficient quantification of the light-sheet image stacks following chemotherapy-treatment. We established a machine learning framework with augmented kernels based on the Karhunen-Loeve Transform (KLT) to preserve linearity and reversibility of rectification. The Saak transform-based machine learning enhances computational efficiency and obviates iterative optimization of cost function needed for neural networks, minimizing the number of training data sets to three 2-D slices for segmentation in our scenario. The integration of forward and inverse Saak transforms serves as a light-weight module to filter adversarial perturbations and reconstruct estimated images, salvaging robustness of existing classification methods. The accuracy and robustness of the Saak transform are evident following the tests of dice similarity coefficients and various adversary perturbation algorithms, respectively. The addition of edge detection further allows for quantifying the surface area to volume ratio (SVR) of the myocardium in response to chemotherapy-induced cardiac remodeling. The combination of Saak transform, random forest, and edge detection augments segmentation efficiency by 20-fold as compared to manual processing; thus, establishing a robust framework for post light-sheet imaging processing, creating a data-driven machine learning for 3-D quantification of cardiac ultra-structure.
Further Exploration of the SAR of Imidazoquinolines; Identification of Potent C7 Substituted Imidazoquinolines
Authors: Hunt Jordan R. , Kleindl Peter A. , Moulder K. Ryan , Prisinzano Thomas E. , Forrest M. Laird 
Published: October 2019

ABSTRACTSmall molecule agonists of TLR7/8, such as imidazoquinolines, are validated agonists for the treatment of cancer and for use in vaccine adjuvants. Imidazoquinolines have been extensively modified to understand the structure-activity relationship (SAR) at the N1- and C2-positions resulting in the clinical drug imiquimod, resiquimod, and several other highly potent analogues. However, the SAR of the aryl ring has not been fully elucidated in the literature. This initial study examines the SAR of C7-substituted imidazoquinolines. These compounds not only demonstrated that TLR7/8 tolerate changes at the C7 position but can increase potency and change their cytokine profiles. The most notable TLR7/8 agonists developed from this study 5, 8, and 14 which are up to 4-fold and 2-fold more active than resiquimod for TLR8 and/or TLR7, respectively, and up to 100-fold more active than the FDA approved imiquimod for TLR7.
Live imaging-assisted domain-specific CRISPR genome editing at single cell resolution in plants
Authors: Li Ting , Yan An , Meyerowitz Elliot M. 
Published: October 2019

AbstractCRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology has been widely used for genome engineering in a wide range of organisms1, but much of the development of CRISPR-based genome editing has been aimed toward improving its efficiency and accuracy, so as to obtain genetic materials carrying known and stably heritable genome modifications. Precise spatiotemporal control over genome editing technology at cell type resolution is a key challenge for gene function studies. Some tissue-specific CRISPR genome editing methods relying on phenotypic characterization and fluorescent immune-staining techniques have been developed for biomedical research and gene therapy, they function by spatially controlling expression of Cas9 2. Recent work establishes the presence and location of mutational events at a single cell level in Arabidopsis roots and stomata3,4. Here we present an efficient domain-specific CRISPR-Cas9 system combined with a high resolution live-imaging based screening strategy, applied in the shoot apical meristem of Arabidopsis thaliana. Using the system we investigate PIN-FORMED1 (PIN1) protein functions in tissue morphogenesis and PIN1 mechanical stress response in a cell layer-specific fashion. We find that reported failure to generate new primordia in epidermal PIN1 knockout SAMs is due to a reduction in mechanical stress differences in the sub-epidermal layer. The methods described are applicable to spatial-temporal gene manipulation in plants.
Genome Elimination Mediated by Gene Expression from a Selfish Chromosome
Authors: Benetta Elena Dalla , Antoshechkin Igor , Yang Ting , Nguyen Hoa Quang My , Ferree Patrick M. , Akbari Omar S. 
Published: October 2019

AbstractNumerous plants and animals harbor selfish B chromosomes that “drive,” or transmit themselves at higher-than-Mendelian frequencies, despite long-term fitness costs to the organism. Currently it is unknown how B chromosome drive is mediated, and whether B-gene expression plays a role. We used modern sequencing technologies to analyze the fine-scale sequence composition and expression of Paternal Sex Ratio (PSR), a B chromosome in the jewel waspNasonia vitripennis. PSR causes female-to-male conversion by destroying the sperm’s hereditary material in young embryos in order to drive. Using RNA interference, we show that testis-specific expression of a PSR-linked gene, namedhaploidizer, facilitates this genome elimination-and-sex conversion effect.Haploidizershares homology with a gene inCandidatus cardinium, a bacterial symbiont that also induces genome elimination in its insect host.One Sentence Summaryhaploidizermediates B chromosome drive
The genetics of male pheromone preference difference betweenDrosophila melanogasterandD. simulans
Authors: Shahandeh Michael P. , Pischedda Alison , Rodriguez Jason M. , Turner Thomas L. 
Published: October 2019

AbstractSpecies of flies in the genusDrosophiladiffer dramatically in their preferences for mates, but little is known about the genetic or neurological underpinnings of this evolution. Recent advances have been made to our understanding of one case: pheromone preference evolution between the speciesD. melanogasterandD. simulans. Males of both species are very sensitive to the pheromone 7,11-HD that is present only on the cuticle of femaleD. melanogaster. In one species this cue activates courtship, and in the other it represses it. This change in valence was recently shown to result from the modification of central processing neurons, rather than changes in peripherally expressed receptors, but nothing is known about the genetic changes that are responsible. In the current study, we show that a 1.35 Mb locus on the X chromosome has a major effect on male 7,11-HD preference. Unfortunately, when this locus is divided, the effect is largely lost. We instead attempt to filter the 159 genes within this region using our newfound understanding of the neuronal underpinnings of this phenotype to identify and test candidate genes. We present the results of these tests, and discuss the difficulty of identifying the genetic architecture of behavioral traits and the potential of connecting these genetic changes to the neuronal modifications that elicit different behaviors.
Investigating the Influence of the Brain-Derived Neurotrophic Factor Val66Met Single Nucleotide Polymorphism on Familiarity and Recollection Event-Related Potentials
Authors: McKay Nicole S. , Moreau David , Corballis Paul M. , Kirk Ian J. 
Published: October 2019

AbstractThe Val66Met single nucleotide polymorphism (SNP) has previously been reported to impact performance on recognition memory tasks. Whether the two subprocesses of recognition—familiarity and recollection—are differentially impacted by the Val66Met SNP remains unknown. Using event-related potentials (ERPs) recorded during a source memory task, we attempted to dissociate these two subprocesses. Behaviourally, we used participants’ scores on an item-recognition subtask as a measure of familiarity, and participants’ scores on a source-recognition subtask as a measure of recollection. Our findings reveal that Val/Val individuals outperform Met allele carriers on the item-but not the source-recognition task. Electrophysiologically, we were interested in the N400, an early frontal component previously linked to familiarity, and the late positive complex (LPC), a posterior component linked to recollection. We found evidence for Val/Val individuals having larger amplitudes of the LPC compared to Met allele carriers, and evidence for no difference in the N400 amplitudes of these groups. Based on the lack of dissociation between familiarity- and recollection-specific ERPs at the LPC time window, we argue that our behavioural and ERP results might reflect better item-recognition for Val/Val individuals compared to Met allele carriers. We further suggest that both these results reflect differences related to familiarity, rather than recollection.
Human hepatic tryptophan 2,3-dioxygenase ubiquitin-dependent protein degradation: The critical role of its exosite as the molecular lynchpin of its substrate-mediated protein stabilization
Authors: Kim Sung-Mi , Liu Yi , Wang YongQiang , Karkashon Shay , Lewis-Ballester Ariel , Yeh Syun-Ru , Correia Maria Almira 
Published: October 2019

AbstractHepatic tryptophan 2,3-dioxygenase (TDO) is a cytoplasmic homotetrameric hemoprotein and the rate-limiting enzyme in the irreversible degradation of the essential amino acidL-tryptophan (L-Trp) to N-formylkynurenine, thus controlling the flux ofL-Trp into its serotonergic and kynureninic/NAD pathways. TDO has long been recognized to be substrate-inducible via protein stabilization, but the molecular mechanism of this stabilization has remained elusive. Recent elucidation of human TDO (hTDO) crystal structure has identified a high-affinity (Kd ≈ 0.5 μM) Trp-binding exosite in each of its 4 monomeric subunits. Mutation of the Glu105, Trp208and Arg211comprising this exosite not only abolished the high-affinityL-Trp binding, but also accelerated the ubiquitin-dependent proteasomal degradation of hTDO. We have further characterized this hTDO degradation by documenting that its ubiquitination by gp78/AMFR and CHIP E2/E3 ligase complexes occurs on external Lys-residues within or vicinal to acidic Asp/Glu and phosphorylated pSer/pThr (DEpSpT)-clusters. Furthermore, we have identified the unstructured hTDO N- and C-termini as imparting relatively high proteolytic instability, as their deletion (ΔNC) markedly prolonged hTDO t1/2. Additionally, although previous studies reported that upon hepatic heme-depletion, the heme-free apoTDO turns over with a t1/2≈ 2.2 h relative to the t1/2of 7.7 h of holoTDO, mutating the axial heme-ligating His328to Ala has the opposite effect of prolonging hTDO t1/2. Most importantly, introducing the exosite mutation into the ΔNC-deleted or H328A-mutant completely abolished their prolonged half-lives irrespective ofL-Trp presence or absence, thereby revealing that the exosite is the molecular lynchpin that definesL-Trp-mediated TDO induction via protein stabilization.
Theory of neural coding predicts an upper bound on estimates of memory variability
Authors: Taylor Robert , Bays Paul M 
Published: October 2019

AbstractObservers reproducing elementary visual features from memory after a short delay produce errors consistent with the encoding-decoding properties of neural populations. While inspired by electrophysiological observations of sensory neurons in cortex, the population coding account of these errors is based on a mathematical idealization of neural response functions that abstracts away most of the heterogeneity and complexity of real neuronal populations. Here we examine a more physiologically grounded model based on the tuning of a large set of neurons recorded in macaque V1, and show that key predictions of the idealized model are preserved. Both models predict long-tailed distributions of error when memory resources are taxed, as observed empirically in behavioral experiments and commonly approximated with a mixture of normal and uniform error components. Specifically, for an idealized homogeneous neural population, the width of the fitted normal distribution cannot exceed the average tuning width of the component neurons, and this also holds to a good approximation for more biologically realistic populations. Examining eight published studies of orientation recall, we find a consistent pattern of results suggestive of a median tuning width of approximately 20 degrees, which compares well with neurophysiological observations. The finding that estimates of variability obtained by the normal-plus-uniform mixture method are bounded from above leads us to reevaluate previous studies that interpreted a saturation in width of the normal component as evidence for fundamental limits on the precision of perception, working memory and long-term memory.