bluuebunny/crossref_metadata_2025_split huggingface dataset:
EEG Correlates of Delirium in Children and Young Adults With CD19-Directed CAR T Cell Treatment-Related Neurotoxicity
Authors: Gust Juliane , Annesley Colleen E. , Gardner Rebecca A. , Bozarth Xiuhua 
Published: December 2019

Introduction:EEG patterns in chimeric antigen receptor T cell treatment-associated neurotoxicity (immune effector cell-associated neurotoxicity syndrome) have not yet been systematically studied. We tested the hypothesis that EEG background abnormalities in immune effector cell-associated neurotoxicity syndrome correlate with clinical signs of neurotoxicity. In addition, we describe ictal and interictal EEG patterns to better understand the natural history of immune effector cell-associated neurotoxicity syndrome-associated seizures.Methods:EEGs were obtained in 19 of 100 subjects in a prospective cohort study of children and young adults undergoing CD19-directed chimeric antigen receptor T cell therapy. We classified the EEG background on a severity scale of 0 to 5 during 30-minute epochs. EEG grades were compared with neurotoxicity scored by Common Terminology Criteria for Adverse Events and Cornell Assessment of Pediatric Delirium scores. Descriptive analysis was conducted for ictal and interictal EEG abnormalities.Results:EEG background abnormality scores correlated well with Common Terminology Criteria for Adverse Events neurotoxicity scores (P= 0.0022) and Cornell Assessment of Pediatric Delirium scores (P= 0.0085). EEG was better able to differentiate the severity of coma patterns compared with the clinical scores. The EEG captured electroclinical seizures in 4 of 19 subjects, 3 of whom had additional electrographic-only seizures. Seizures most often arose from posterior head regions. Interictal epileptiform discharges were focal, multifocal, or lateralized periodic discharges. No seizures or interictal epileptiform abnormalities were seen in subjects without previous clinical seizures.Conclusions:Continuous EEG monitoring is high yield for seizure detection in high-risk chimeric antigen receptor T cell patients, and electrographic-only seizures are common. Increasing severity of EEG background abnormalities correlates with increasing neurotoxicity grade.
Revisiting microbe-metabolite interactions: doing better than random
Authors: Morton James T. , McDonald Daniel , Aksenov Alexander A. , Nothias Louis Felix , Foulds James R. , Quinn Robert A. , Badri Michelle H. , Swenson Tami L. , Van Goethem Marc W. , Northen Trent R. , Vazquez-Baeza Yoshiki , Wang Mingxun , Bokulich Nicholas A. , Watters Aaron , Song Se Jin , Bonneau Richard , Dorrestein Pieter C. , Knight Rob 
Published: December 2019

I.ABSTRACTRecently, Quinn and Erb et al [1] made the case that when used correctly, correlation and proportionality can outperform MMvec when identifying microbe-metabolite interactions. We revisit this comparison and show that the proposed correlation and proportionality are outperformed by MMvec on real data due to their inability to deal with sparsity commonly observed in microbiome and metabolome datasets.
High-throughput screening of the ReFRAME library identifies potential drug repurposing candidates forTrypanosoma cruzi
Authors: Bernatchez Jean A. , Chen Emily , Hull Mitchell V. , McNamara Case W. , McKerrow James H. , Siqueira-Neto Jair L. 
Published: December 2019

AbstractChagas disease, caused by the kinetoplastid parasiteTrypanosoma cruzi, affects between 6 and 7 million people worldwide, with an estimated 300,000 to 1 million of these cases in the United States. In the chronic phase of infection,T. cruzican cause severe gastrointestinal and cardiac disease, which can be fatal. Currently, only benznidazole is clinically-approved by the FDA for pediatric use to treat this infection in the USA. Toxicity associated with this compound has driven the search for new anti-Chagas agents. Drug repurposing is a particularly attractive strategy for neglected diseases, as pharmacological parameters and toxicity are already known for these compounds, reducing costs and saving time in the drug development pipeline. Here, we screened ~ 12,000 compounds from the ReFRAME library, a collection of drugs or compounds with confirmed clinical safety, againstT. cruzi. We identified 7 compounds of interest with potentin vitroactivity against the parasite with a therapeutic index of 10 or greater, including the previously-unreported activity of the antiherpetic compound 348U87. These results provide the framework for further development of newT. cruzileads that can potentially move quickly to the clinic.
Is N-Hacking Ever OK? A simulation-based inquiry
Authors: Reinagel Pamela 
Published: December 2019

AbstractAfter an experiment has been completed, a trend may be observed that is “not quite significant”. Sometimes in this situation, researchers collect more data in an effort to achieve statistical significance. Such “N-hacking” is condemned because it can lead to an excess of false positive results. I use simulations to demonstrate how N-hacking causes false positives. However, in a parameter regime relevant for many experiments, the increase in false positives is quite modest. Moreover, results obtained this way have higher Positive Predictive Value than non-incremented experiments of the same sample size and statistical power. In other words, adding a few more observations to shore up a nearly-significant result canincreasethe reproducibility of results, counter to some current rhetoric. Many experiments are non-confirmatory, and unplanned sample augmentation with reasonable decision rules would not cause rampant irreproducibility in that context.
Microbiome Determinants and Physiological Effects of the Benzoate-Hippurate Microbial-Host Co-Metabolic Pathway
Authors: Brial François , Chilloux Julien , Nielsen Trine , Vieira-Silva Sara , Falony Gwen , Hoyles Lesley , Neves Ana L. , Rodriguez-Martinez Andrea , Mouawad Ghiwa Ishac , Pons Nicolas , Forslund Sofia , Chatelier Emmanuelle Le , Le Lay Aurélie M. , Nicholson Jeremy K , Hansen Torben ,   MetaHIT consortium, Clément Karine , Bork Peer , Ehrlich S. Dusko , Raes Jeroen , Pedersen Oluf , Gauguier Dominique , Dumas Marc-Emmanuel 
Published: December 2019

ABSTRACTObjectiveGut microbial products are involved in type 2 diabetes, obesity and insulin resistance. In particular, hippurate, a hepatic phase 2 conjugation product of microbial benzoate metabolism, has been associated with a healthy phenotype. This study aims to identify metagenomic determinants and test protective effects of hippurate.DesignWe profiled the urine metabolome by1H Nuclear Magnetic Resonance (NMR) spectroscopy to derive associations with metagenomic sequences in 271 middle-aged Danish individuals to identify dietary patterns in which urine hippurate levels were associated with health benefits. We follow up with benzoate and hippurate infusion in mice to demonstrate causality on clinical phenotypes.ResultsIn-depth analysis identifies that the urine hippurate concentration is associated with microbial gene richness, microbial functional redundancy as well as functional modules for microbial benzoate biosynthetic pathways across several enterotypes. Through dietary stratification, we identify a subset of study participants consuming a diet rich in saturated fat in which urine hippurate, independently of gene richness, accounts for links with metabolic health that we previously associated with gene richness. We then demonstrate causalityin vivothrough chronic subcutaneous infusions of hippurate or benzoate (20 nmol/day) resulting in improved glycemic control in mice fed a high-fat diet. Hippurate improved insulin secretion through increased β-cell mass and reduced liver inflammation and fibrosis, whereas benzoate treatment resulted in liver inflammation.ConclusionOur translational study shows that the benzoate-hippurate pathway brings a range of metabolic improvements in the context of high-fat diets, highlighting the potential of hippurate as a mediator of metabolic health.
An open-source multiple-bioreactor system for replicable gas-fermentation experiments: Nitrate feed results in stochastic inhibition events, but improves ethanol production ofClostridium ljungdahliiwith CO2and H2
Authors: Klask Christian-Marco , Kliem-Kuster Nicolai , Molitor Bastian , Angenent Largus T. 
Published: December 2019

AbstractThe pH-value in fermentation broth has a large impact on the metabolic flux and growth behavior of acetogens. A decreasing pH level throughout time due to undissociated acetic acid accumulation is anticipated under uncontrolled pH conditions such as in bottle experiment. As a result, the impact of changes in the metabolism (e.g., due to a genetic modification) might remain unclear or even unrevealed. In contrast, pH-controlled conditions can be easily achieved in commercially available bioreactors. However, their acquisition is costly and their operation is time consuming, and therefore the experiment is often limited to a single bioreactor run. Here, we present a self-built, relatively cheap, and easy to handle open-source multiple-bioreactor system (MBS) consisting of six pH-controlled bioreactors at a 1-L scale. The functionality of the MBS was tested in three experiments by cultivating the acetogenClostridium ljungdahliiwith CO2and H2at steady-state conditions (=chemostat). The experiments were addressing the questions: (1) does the MBS provide replicable data for gas-fermentation experiments?; (2) does feeding acetate alter the production rate of ethanol; and (3) does feeding nitrate influence the product spectrum under controlled pH conditions with CO2and H2? We applied four different periods in each experiment ranging from pH 6.0 to pH 4.5. Our data show high reproducibility for gas-fermentation experiments withC. ljungdahlii, using the MBS. We found that feeding acetate did not improve ethanol production, but rather impaired growth and reduced acetate production. Using nitrate as sole N-source, on the other hand, enhanced biomass production even at a low pH. However, we observed differences in growth, acetate, and ethanol production rates between triplicate bioreactors (n=3). We explained the different performances because of stochastic inhibition events, which we observed through the accumulation of nitrite, and which led to complete crashes at different operating times. One of these bioreactors recovered after the crash and showed enhanced ethanol production rates while simultaneously producing less acetate. The MBS offers a great opportunity to perform bench-scale bioreactor experiments at steady-state conditions with replicates, which is especially attractive for academia.
A genome-wide CRISPR screen identifies UFMylation and TRAMP-like complexes as host factors required for hepatitis A virus infection
Authors: Kulsuptrakul Jessie , Wang Ruofan , Meyers Nathan L. , Ott Melanie , Puschnik Andreas S. 
Published: December 2019

AbstractHepatitis A virus (HAV) is a positive-sense RNA virus causing acute inflammation of the liver. Here, using a genome-scale CRISPR screen in a human hepatocyte cell line, we provide a comprehensive picture of the cellular factors, which are exploited by HAV during replication. We identified genes involved in sialic acid biosynthesis and members of the eukaryotic translation initiation factor complex, corroborating their putative roles in HAV infection. Additionally, we uncovered all components of the cellular machinery for UFMylation, a ubiquitin-like protein modification. We showed that HAV translation specifically depends on UFM1 conjugation of the ribosomal protein RPL26. Furthermore, we found that components related to the yeast Trf4/5– Air1/2–Mtr4 polyadenylation (TRAMP) complex, are required for viral translation, independent of controlling HAV poly(A) tails. While the identified HAV host factors were largely distinct compared to other picornaviruses, we highlighted a surprising co-dependency of HAV and hepatitis B virus (HBV) on the TRAMP-like complex. Finally, we demonstrated that pharmacological inhibition of the TRAMP-like complex decreased HAV replication in hepatocyte cells and human liver organoids, thus providing a strategy for host-directed therapy of HAV infection.
Simple spectral transformations capture the contribution of peripheral processing to cortical responses to natural sounds
Authors: Rahman Monzilur , Willmore Ben D. B. , King Andrew J. , Harper Nicol S. 
Published: December 2019

AbstractProcessing in the sensory periphery involves various mechanisms that enable the detection and discrimination of sensory information. Despite their biological complexity, could these processing steps sub-serve a relatively simple transformation of sensory inputs, which are then transmitted to the CNS? Here we explored both biologically-detailed and very simple models of the auditory periphery to find the appropriate input to a phenomenological model of auditory cortical responses to natural sounds. We examined a range of cochlear models, from those involving detailed biophysical characteristics of the cochlea and auditory nerve to very pared-down spectrogram-like approximations of the information processing in these structures. We tested the capacity of these models to predict the time-course of single-unit neural responses recorded in the ferret primary auditory cortex, when combined with a linear non-linear encoding model. We show that a simple model based on a log-spaced, log-scaled power spectrogram with Hill-function compression performs as well as biophysically-detailed models of the cochlea and the auditory nerve. These findings emphasize the value of using appropriate simple models of the periphery when building encoding models of sensory processing in the brain, and imply that the complex properties of the auditory periphery may together result in a simpler than expected functional transformation of the inputs.
Deep Docking - a Deep Learning Approach for Virtual Screening of Big Chemical Datasets
Authors: Gentile Francesco , Agrawal Vibudh , Hsing Michael , Ban Fuqiang , Norinder Ulf , Gleave Martin E. , Cherkasov Artem 
Published: December 2019

ABSTRACTDrug discovery is an extensive and rigorous process that requires up to 2 billion dollars of investments and more than ten years of research and development to bring a molecule “from bench to a bedside”. While virtual screening can significantly enhance drug discovery workflow, it ultimately lags the current rate of expansion of chemical databases that already incorporate billions of purchasable compounds. This surge of available small molecules presents great opportunities for drug discovery but also demands for faster virtual screening methods and protocols. In order to address this challenge, we herein introduceDeep Docking(D2) - a novel deep learning-based approach which is suited for docking billions of molecular structures. The developedD2-platform utilizes quantitative structure-activity relationship (QSAR) based deep models trained on docking scores of subsets of a large chemical library (Big Base) to approximate the docking outcome for yet unprocessed molecular entries and to remove unfavorable structures in an iterative manner. We appliedD2to virtually screen 1.36 billion molecules form the ZINC15 library against 12 prominent target proteins, and demonstrated up to 100-fold chemical data reduction and 6,000-fold enrichment for top hits, without notable loss of well-docked entities. The developedD2protocol can readily be used in conjunction with any docking program and was made publicly available.
In vitro pancreatic islet cluster expansion facilitated by hormones and chemicals
Authors: Lin Jing-Yu , Cheng Jie , Du Ya-Qin , Pan Wei , Zhang Zhong , Wang Jin , An Jie , Yang Fan , Xu Yun-Fei , Lin Hui , An Wen-Tao , Wang Jia , Yang Zhao , Chai Ren-Jie , Sha Xue-Ying , Hu Hui-Li , Sun Jin-Peng , Yu Xiao 
Published: December 2019

AbstractTissue regeneration, such as pancreatic islet tissue propagation in vitro, could serve as a promising strategy for diabetes therapy and personalized drug testing. However, such a protocol has not been realized yet. Propagation could be divided by two steps, which are: (1) expansion in vitro and (2) repeat passaging. Even the in vitro expansion of the islet has not been achieved to date. Here, we describe a method to enable the expansion of islet clusters isolated from pregnant mice or wild-type rats by employing a combination of specific regeneration factors and chemical compounds in vitro. The expanded islet clusters expressed insulin, glucagon and somatostatin, which are markers corresponding to pancreatic β cells, α cells and δ cells, respectively. These different types of cells grouped together, were spatially organized and functioned similarly to primary islets. Further mechanistic analysis revealed that forskolin in our recipe contributed to renewal and regeneration, whereas exendin4 was essential for preserving islet cell identity. Our results provide a novel method for the in vitro expansion of islet clusters, which is an important step forward in developing future protocols and medium used for islet tissue propagation in vitro. Such method is important for future regenerative diabetes therapies and personalized medicine using large amounts of pancreatic islets derived from the same person.
Aberrant cocoons found on honey bee comb cells are found to beOsmia cornifrons(Radoszkowski) (Hymenoptera: Megachilidae)
Authors: Posada-Florez Francisco , Bloetscher Barbara , Lopez Dawn , Pava-Ripoll Monica , Rogers Curtis , Evans Jay D. 
Published: December 2019

AbstractPotential biological threats to honey bees must be addressed and validated quickly, before making disruptive and costly decisions. Here we describe numerousOsmia cornifrons(Hymenoptera: Megachilidae) cocoons in honey bee cells from one bee hive in Ohio. The developingOsmiacells presented themselves as a mystery at first, catching the attention of regulatory agencies. Along with identifying this species as a presumably benign resident in honey bee colonies, our observations suggestOsmiamay use stored honey bee resources to provision offspring. Conceivably, resident honey bees might even act as surrogates, by provisioningOsmiaoffspring with pollen. Since the cocoons were attached to one another with honey bee wax, it seems likely that honey bee hosts were present duringOsmiadevelopment.Osmiafemales have some plasticity when selecting nesting resources, and, upon discovering honey bee comb can use this resource for raising offspring. Along with resolving a potentially new biotic threat to honey bees, this diagnosis suggests a method for mass production ofOsmiapollinators using an array of single cell foundation.
Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche
Authors: Shinde Aparna , Paez Juan Sebastian , Libring Sarah , Hopkins Kelsey , Solorio Luis , Wendt Michael K. 
Published: December 2019

Abstract:The ability of breast cancer cells to interconvert between epithelial and mesenchymal states contributes to their metastatic potential. As opposed to cell autonomous effects, the impact of epithelial-mesenchymal plasticity (EMP) on primary and metastatic tumor microenvironments remains poorly characterized. Herein we utilize global gene expression analyses to characterize a metastatic model of EMP as compared to their non-metastatic counterparts. Using this approach we demonstrate that upregulation of the extracellular matrix crosslinking enzyme tissue transglutaminase-2 (TGM2) is part of novel gene signature that only emerges in metastatic cells that have undergone induction and reversion of epithelial-mesenchymal transition (EMT). Consistent with our model system patient survival is diminished when primary tumors demonstrate enhanced levels of TGM2 in conjunction with its substrate, fibronectin. Targeted depletion of TGM2 inhibits metastasis, while overexpression of TGM2 is sufficient to enhance this process. In addition to being present within cells, we demonstrate a robust increase in the amount of TGM2 and crosslinked fibronectin present within extracellular vesicle (EV) fractions derived from metastatic breast cancer cells. Confocal microscopy of these EVs suggests that FN becomes fibrillated on their surface via a TGM2 and Tesin1-dependent process. Uponin vivoadministration, the ability of tumor-derived EVs to induce metastatic niche formation and enhance subsequent pulmonary tumor growth requires the presence and activity of TGM2. Finally, we develop a novel 3D model of the metastatic niche to demonstrate that education of pulmonary fibroblasts via pretreatment with tumor-derived EVs promotes subsequent growth of breast cancer cells in a TGM2-dependent fashion. Overall, our studies illustrate a novel mechanism through which EMP contributes to metastatic niche development and distant metastasis via tumor-derived EVs containing abberent levels of TGM2 and fibular FN.
Tuba activates Cdc42 during neuronal polarization downstream of the small GTPase Rab8a
Authors: Urrutia Pamela J. , Bodaleo Felipe , Bórquez Daniel A. , Rozes-Salvador Victoria , Villablanca Cristopher , Conde Cecilia , Fukuda Mitsunori , González-Billault Christian 
Published: December 2019

ABSTRACTThe acquisition of neuronal polarity is a complex molecular process that involves several different cellular mechanisms that need to be finely coordinated to define the somatodendritic and axonal compartments. Amongst such mechanisms, cytoskeleton and membrane dynamics control both the morphological transitions that define neuronal polarity acquisition as well as provide molecular determinants to specific sites in neurons at a defined time point. Small GTPases from the Rab and Rho families are well known molecular determinants of neuronal differentiation. However, during axon specification, a molecular link that couples proteins from these two families has yet to be identified. In this paper, we describe the role of Tuba, a Cdc42-specific guanine nucleotide-exchange factor (GEF), in neuronal polarity through a Rab8a-dependent mechanism. Rab8a or Tuba gain-of-function generates neurons with supernumerary axons whereas Rab8a or Tuba loss-of-function abrogated axon specification, phenocopying the well-established effect of Cdc42 on neuronal polarity. Neuronal polarization associated to Rab8a is also evidencedin vivo, since a dominant negative version of Rab8a severely impaired neuronal migration.Remarkably, Rab8a activates Cdc42 in a Tuba-dependent manner, and dominant negative mutants of both GTPases reciprocally prevent the effect over polarity acquisition in the gain-of-function scenarios. Our results strongly suggest that a positive feedback loop linking Rab8a and Cdc42 activities via Tuba, is a primary event in neuronal polarization. In addition, we identified the GEF responsible for Cdc42 activation that is essential to specify axons in cultured neurons.