bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adaptation in cone photoreceptors contributes to an unexpected insensitivity of On parasol retinal ganglion cells to spatial structure in natural images
Authors: Yu Zhou , Turner Maxwell H. , Baudin Jacob , Rieke Fred 
Published: July 2021

AbstractNeural circuits are constructed from nonlinear building blocks, and not surprisingly overall circuit behavior is often strongly nonlinear. But neural circuits can also behave near linearly, and some circuits shift from linear to nonlinear behavior depending on stimulus conditions. Such control of the linearity or nonlinearity of circuit behavior is fundamental to neural computation. Here we study a surprising stimulus dependence of the responses of On (but not Off) parasol retinal ganglion cells: these cells respond nonlinearly to spatial structure in temporally-modulated grating stimuli but linearly to spatial structure in flashed gratings and natural visual inputs. We show that this unexpected response linearity can be explained by a shift in the balance of excitatory and inhibitory synaptic inputs that originates at least in part from adaptation in the cone photoreceptors. More generally, this highlights how subtle asymmetries in signaling - here in the cone signals - can qualitatively alter circuit computation.
Classifying COVID-19 variants based on genetic sequences using deep learning models
Authors: Basu Sayantani , Campbell Roy H. 
Published: July 2021

AbstractThe COrona VIrus Disease (COVID-19) pandemic led to the occurrence of several variants with time. This has led to an increased importance of understanding sequence data related to COVID-19. In this chapter, we propose an alignment-free k-mer based LSTM (Long Short-Term Memory) deep learning model that can classify 20 different variants of COVID-19. We handle the class imbalance problem by sampling a fixed number of sequences for each class label. We handle the vanishing gradient problem in LSTMs arising from long sequences by dividing the sequence into fixed lengths and obtaining results on individual runs. Our results show that one-vs-all classifiers have test accuracies as high as 92.5% with tuned hyperparameters compared to the multi-class classifier model. Our experiments show higher overall accuracies for B.1.1.214, B.1.177.21, B.1.1.7, B.1.526, and P.1 on the one-vs-all classifiers, suggesting the presence of distinct mutations in these variants. Our results show that embedding vector size and batch sizes have insignificant improvement in accuracies, but changing from 2-mers to 3-mers mostly improves accuracies. We also studied individual runs which show that most accuracies improved after the 20th run, indicating that these sequence positions may have more contributions to distinguishing among different COVID-19 variants.
A quantitative trait variant inGabra2underlies increased methamphetamine stimulant sensitivity
Authors: Goldberg Lisa R. , Yao Emily J. , Kelliher Julia C. , Reed Eric R. , Cox Jiayi Wu , Parks Cory , Kirkpatrick Stacey L. , Beierle Jacob A. , Chen Melanie M. , Johnson William E. , Homanics Gregg E. , Williams Robert W. , Bryant Camron D. , Mulligan Megan K. 
Published: July 2021

ABSTRACTPsychostimulant (methamphetamine, cocaine) use disorders have a genetic component that remains mostly unknown. Here, we conducted genome-wide quantitative trait locus (QTL) analysis of methamphetamine stimulant sensitivity. To facilitate gene identification, we employed a Reduced Complexity Cross between closely related C57BL/6 mouse substrains and examined maximum speed and distance traveled over 30 min following methamphetamine (2 mg/kg, i.p.). For maximum methamphetamine-induced speed following the second and third administration, we identified a single genome-wide significant QTL on chromosome 11 that peaked near theCyfip2locus [LOD = 3.5, 4.2; peak = 21 cM (36 Mb)]. For methamphetamine-induced distance traveled, we identified a single genome-wide significant QTL on chromosome 5 that peaked near a functional intronic indel inGabra2that codes for the alpha-2 subunit of the GABA-A receptor [LOD = 5.2; peak = 35 cM (67 Mb)]. Striatalcis-expression QTL mapping corroboratedGabra2as a functional candidate gene underlying methamphetamine-induced distance traveled. CRISPR/Cas9-mediated correction of the mutant intronic deletion on the C57BL/6J background to the wild-type C57BL/6NJ allele was sufficient to reduce methamphetamine-induced locomotor activity toward the wild-type C57BL/6NJ-like level, thus validating the quantitative trait variant (QTV). These studies demonstrate the power and efficiency of Reduced Complexity Crosses in identifying causal genes and variants underlying complex traits. Functionally restoringGabra2expression decreased methamphetamine stimulant sensitivity and supports preclinical and human genetic studies implicating the GABA-A receptor in psychostimulant addiction-relevant traits. Importantly, our findings have major implications for investigators studying psychostimulants in the C57BL/6J strain - the gold standard strain in biomedical research.
Temperature Evolution Following Joint Loading Promotes Chondrogenesis by Synergistic Cues via Calcium Signaling
Authors: Nasrollahzadeh Naser , Karami Peyman , Wang Jian , Bagheri Lida , Guo Yanheng , Abdel-Sayed Philippe , Applegate Lee Ann , Pioletti Dominique P. 
Published: July 2021

AbstractDuring loading of viscoelastic tissues, part of the mechanical energy is transformed into heat that can locally increase the tissue temperature, a phenomenon known as self-heating. In the framework of mechanobiology, it has been accepted that cells react and adapt to mechanical stimuli. However, the cellular effect of temperature increase as a by-product of loading has been widely neglected. In this work, we focused on cartilage self-heating to present a “thermo-mechanobiological” paradigm, and demonstrate how the synergy of a biomimetic temperature evolution and mechanical loading could influence cell behavior. We thereby developed a customized in vitro system allowing to recapitulate pertinent in vivo physical cues and determined the cells chondrogenic response to thermal and/or mechanical stimuli. Cellular mechanisms of action and potential signaling pathways of thermo-mechanotransduction process were also investigated. We found that co-existence of thermo-mechanical cues had a superior effect on chondrogenic gene expression compared to either signal alone. Specifically, a synergetic effect was observed for upregulation of Sox9 by application of the physiological thermo-mechanical stimulus. Multimodal TRPV4 channels were identified as key mediators of thermo-mechanotransduction process, which becomes ineffective without external calcium sources. We also observed that the isolated temperature evolution, as a by-product of loading, is a contributing factor to the cells response and this could be considered as important as the conventional mechanical loading. Providing an optimal thermo-mechanical environment by synergy of heat and loading portrays new opportunity for development of novel treatments for cartilage regeneration and can furthermore signal key elements for emerging cell-based therapies.
Efficient linear dsDNA tagging using deoxyuridine excision
Authors: Strobel Eric J. 
Published: July 2021

AbstractSite-specific strategies for exchanging segments of dsDNA are important for DNA library construction and molecular tagging. Deoxyuridine (dU) excision is an approach for generating 3’ ssDNA overhangs in gene assembly and molecular cloning procedures. Unlike approaches that use a multi-base pair motif to specify a DNA cut site, dU excision requires only a dT→dU substitution. Consequently, excision sites can be embedded in biologically active DNA sequences by placing dU substitutions at non-perturbative positions. In this work, I describe a molecular tagging method that uses dU excision to exchange a segment of a dsDNA strand with a long synthetic oligonucleotide. The core workflow of this method, called deoxyUridine eXcision-tagging (dUX-tagging), is an efficient one-pot reaction: strategically positioned dU nucleotides are excised from dsDNA to generate a 3’ overhang so that additional sequence can be appended by annealing and ligating a tagging oligonucleotide. The tagged DNA is then processed by one of two procedures to fill the 5’ overhang and remove excess tagging oligo. To facilitate its widespread use, all dUX-tagging procedures exclusively use commercially available reagents. As a result, dUX-tagging is a concise and easily implemented approach for high-efficiency linear dsDNA tagging.
A genetic toolkit for studying transposon control in the Drosophila melanogaster ovary
Authors: ElMaghraby Mostafa F. , Tirian Laszlo , Senti Kirsten-André , Meixner Katharina , Brennecke Julius 
Published: July 2021

ABSTRACTArgonaute proteins of the PIWI class complexed with PIWI-interacting RNAs (piRNAs) protect the animal germline genome by silencing transposable elements. One of the leading experimental systems for studying piRNA biology is the Drosophila melanogaster ovary. In addition to classical mutagenesis, transgenic RNA interference (RNAi), which enables tissue-specific silencing of gene expression, plays a central role in piRNA research. Here, we establish a versatile toolkit focused on piRNA biology that combines germline transgenic RNAi, GFP marker lines for key proteins of the piRNA pathway, and reporter transgenes to establish genetic hierarchies. We compare constitutive, pan-germline RNAi with an equally potent transgenic RNAi system that is activated only after germ cell cyst formation. Stage-specific RNAi allows us to investigate the role of genes essential for germline cell survival, for example nuclear RNA export or the SUMOylation pathway, in piRNA-dependent and independent transposon silencing. Our work forms the basis for an expandable genetic toolkit provided by the Vienna Drosophila Resource Center.
Varenicline Prevents SARS-CoV-2 Infection In Vitro and in Rhesus Macaques
Authors: Nau Jeffrey , Luthra Priya , Lanzer Kathleen , Szaba Frank , Cookenham Tres , Carlson Eric 
Published: July 2021

ABSTRACTBackgroundSARS-CoV-2 infections have resulted in a global pandemic, but an antiviral therapy for this novel strain of coronavirus does not currently exist. The objective of our study was to investigate the antiviral potential of the nicotinic acetylcholine receptor (nACHR) agonist varenicline tartrate against SARS-CoV-2.MethodsWe assessed antiviral activity usingin vitrohuman cell assays and we assessedin vivoefficacy in a rhesus macaque model.ResultsIn vitrostudies found that varenicline tartrate, over a range of concentrations, reduced the infectivity of SARS-CoV-2 wildtype, alpha, and beta variants in Calu-3 cells and Caco-2 cells, with maintenance of cell viability.In vivostudies found that varenicline tartrate, administered as a nasal spray to rhesus macaques, reduced SARS-CoV-2 wildtype viral load and inhibited viral replication in the nasal mucosa and upper airway.ConclusionAlthough the study reported here was exploratory, we have confirmed that the nAChR agonist varenicline has the potential to interact with and inhibit SARS-CoV-2 infection and replication.
Predicting trait phenotypes from knowledge of the topology of gene networks
Authors: Beatty Andy , Winkler Christopher R. , Hagen Thomas , Cooper Mark 
Published: July 2021

ABSTRACTIn many fields there is interest in manipulating genes and gene networks to realize improved trait phenotypes. The practicality of doing so, however, requires accepted theory on the properties of gene networks that is well-tested by empirical results. The extension of quantitative genetics to include models that incorporate properties of gene networks expands the long tradition of studying epistasis resulting from gene-gene interactions. Here we consider NK models of gene networks by applying concepts from graph theory and Boolean logic theory, motivated by a desire to model the parameters that influence predictive skill for trait phenotypes under the control of gene networks; N defines the number of graph nodes, the number of genes in the network, and K defines the number of edges per node in the graph, representing the gene-gene interactions. We define and consider the attractor period of an NK network as an emergent trait phenotype for our purposes. A long-standing theoretical treatment of the dynamical properties of random Boolean networks suggests a transition from long to short attractor periods as a function of the average node degree K and the bias probability P in the applied Boolean rules. In this paper we investigate the appropriateness of this theory for predicting trait phenotypes on random and real microorganism networks through numerical simulation. We show that: (i) the transition zone between long and short attractor periods depends on the number of network nodes for random networks; (ii) networks derived from metabolic reaction data on microorganisms also show a transition from long to short attractor periods, but at higher values of the bias probability than in random networks with similar numbers of network nodes and average node degree; (iii) the distribution of phenotypes measured on microorganism networks shows more variation than random networks when the bias probability in the Boolean rules is above 0.75; and (iv) the topological structure of networks built from metabolic reaction data is not random, being best approximated, in a statistical sense, by a lognormal distribution. The implications of these results for predicting trait phenotypes where the genetic architecture of a trait is a gene network are discussed.
Toxicological profile of Umbilical Cord Blood-derived small Extracellular Vesicles
Authors: Rodrigues S.C. , Cardoso R.M.S. , Gomes C.F. , Duarte F.V. , Freire P. C. , Neves R. , Simões-Correia J. 
Published: July 2021

AbstractThe development and adoption of cell therapies has been largely limited by difficulties associated with their safety, handling and storage. Extracellular vesicles (EV) have recently emerged as a likely mediator for the therapeutic effect of cells, offering several advantages over cell therapies. Due to their small size and inability to expand and metastasize, EV are generally considered safer than cell transplantation. Nevertheless, few studies have scrutinized the toxicity profile of EV, particularly after repeated high dose administration. The present study aimed to evaluate a preparation of small EV obtained from umbilical cord blood mononuclear cells (UCB-MNC-sEV) for its cytotoxicity in different cell lines, as well as its differential accumulation, distribution and toxicity following repeated intravenous (IV) administrations in a rodent model. In vitro, repeated sEV exposure in concentrations up to 1×1011 particles/ml had no deleterious impact on the viability or metabolic activity of peripheral blood mononuclear cells, THP-1 monocytes, THP-1-derived macrophages, normal dermal human fibroblasts or human umbilical vein endothelial cells. DiR-labeled sEV, injected IV for four weeks in healthy rats, were detected in clearance organs, particularly kidneys, spleen and liver, similarly to control dye. Moreover, repeated administrations during six and twelve weeks of up to 1×1010 total particles of sEV-dye were well tolerated, with no changes in general hematological cell counts, or kidney and liver toxicity markers. Importantly, unlabeled sEV likewise did not induce significant alterations in cellular and biochemical blood parameters, nor any morphological changes in heart, kidney, lung, spleen, or liver tissue. In sum, our data shows that UCB-MNC-sEV have no significant toxicity in vitro or in vivo, even when administered repeatedly at high concentrations, therefore confirming their safety profile and potential suitability for future clinical use.
Early neuroadaptations to an obesogenic diet identify the schizophrenia-related ErbB4 receptor in obesity-induced hippocampal abnormalities
Authors: Vega-Torres Julio David , Ontiveros-Angel Perla , Terrones Esmeralda , Stuffle Erwin C. , Solak Sara , Tyner Emma , Oropeza Marie , Peña Ike Dela , Obenaus Andre , Ford Byron D. , Figueroa Johnny D. 
Published: July 2021

AbstractChildhood obesity leads to hippocampal atrophy and altered cognition. However, the molecular mechanisms underlying these impairments are poorly understood. The neurotrophic factor neuregulin-1 (NRG1) and its cognate ErbB4 receptor play critical roles in hippocampal maturation and function. This study aimed to determine whether altered NRG1-ErbB4 activities may partly explain hippocampal abnormalities in rats exposed to an obesogenic Western-like diet (WD). Lewis rats were randomly divided into four groups (12 rats/group): 1) control diet+vehicle (CDV); 2) CD+NRG1 (CDN) (daily intraperitoneal injections: 5 μg/kg/day; between postnatal day, PND 21-PND 41); 3) WD+VEH (WDV); 4) WD+NRG1 (WDN). Neurobehavioral assessments were performed at PND 43-49. Brains were harvested for MRI and molecular analyses at PND 49. We found that NRG1 administration reduced hippocampal volume (7%) and attenuated hippocampal-dependent cued fear conditioning in CD rats (56%). NRG1 administration reduced PSD-95 protein expression (30%) and selectively reduced hippocampal cytokine levels (IL-33, GM-CSF, CCL-2, IFN-γ) while significantly impacting microglia morphology (increased span ratio and reduced circularity). WD rats exhibited reduced right hippocampal volume (7%), altered microglia morphology (reduced density and increased lacunarity), and increased levels of cytokines implicated in neuroinflammation (IL-1α, TNF-α, IL-6). Notably, NRG1 synergized with the WD to increase hippocampal ErbB4 phosphorylation and the tumor necrosis alpha converting enzyme (TACE/ADAM17) protein levels. Together, these data suggest a novel interaction between obesogenic diet exposure and TACE/ADAM17-NRG1-ErbB4 signaling during hippocampal maturation. Our results indicate that supraoptimal ErbB4 activities may contribute to the abnormal hippocampal structure and cognitive vulnerabilities observed in obese individuals.HighlightsObesogenic diet consumption during adolescence induces anxiety-like behaviors before the onset of obesity-related changes in metabolism.Obesogenic diet-driven abnormal behaviors co-occurred with alterations in hippocampal pro-inflammatory cytokine profiles.Obesogenic diet consumption attenuates exogenous NRG1 effects on hippocampal-related behaviors and structure.Exogenous NRG1 administration during adolescence resulted in reduced hippocampal volumes and domain-specific cognitive impairments.Exogenous NRG1 administration has potent immunomodulatory actions and alters hippocampal microglia morphology.
Rewiring the Three-Carbon Metabolism Abrogates Multiple MAPK-Induced Cellular Dysfunctions During Metabolic Disorder
Authors: Dubé Alexandre K. , Malenfant Nicolas , Ladonne Florence , Piano Amanda , Mohammad Karamat , Bélanger Marc , Bégin Frédéric , LeBel-Guay Florence , Titorenko Vladimir I. , Bourbonnais Yves 
Published: July 2021

Withdrawal noticeThe authors have withdrawn their manuscript. The lipidomic data presented in the manuscript were based on an excel summary sheet provided by VIT, whose group (AP and KM) conducted the analysis using an Orbitrap mass spectrometer. However, after submitting to BioRxiv, the VIT group could not recover the RAW (primary source) files from the lipidomic platform because these files were deleted due to the maintenance protocol used for the Orbitrap mass spectrometer. It was agreed to reconduct the lipidomic analysis. As the Orbitrap mass spectrometer was out of service at that time, the lipidomic analysis was conducted with the help of a QToF mass spectrometer. Important differences were noted for the relative abundance and species of many lipids across the strains compared to the previously reported data hence casting some doubt on their interpretation. Therefore, until further analysis can be carried out the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
spiralize: an R Package for Visualizing Data on Spirals
Authors: Gu Zuguang , Hübschmann Daniel 
Published: July 2021

AbstractSummarySpiral layout has two major advantages for data visualization. First, it is able to visualize data with long axes, which greatly improves the resolution of visualization. Second, it is efficient for time series data to reveal periodic patterns. Here we present the R package spiralize that provides a general solution for visualizing data on spirals. spiralize implements numerous graphics functions so that self-defined high-level graphics can be easily implemented by users. The flexibility and power of spiralize are demonstrated by five examples from real-world datasets.Availability and implementationThe spiralize package and documentations are freely available at the Comprehensive R Archive Network (CRAN) https://CRAN.R-project.org/package=spiralize.Contactz.gu@dkfz.de or d.huebschmann@dkfz.deSupplementary informationSupplementary data are available at Bioinformatics online.
Shortening of 3’ UTRs in most cell types composing tumor tissues implicates alternative polyadenylation in protein metabolism
Authors: Burri Dominik , Zavolan Mihaela 
Published: July 2021

AbstractDuring pre-mRNA maturation 3’ end processing can occur at different polyadenylation sites in the 3’ untranslated region (3’ UTR) to give rise to transcript isoforms that differ in the length of their 3’UTRs. Longer 3’ UTRs contain additional cis-regulatory elements that impact the fate of the transcript and/or of the resulting protein.Extensive alternative polyadenylation (APA) has been observed in cancers, but the mechanisms and roles remain elusive. In particular, it is unclear whether the APA occurs in the malignant cells or in other cell types that infiltrate the tumor. To resolve this, we developed a computational method, called SCUREL, that quantifies changes in 3’UTR length between groups of cells, including cells of the same type originating from tumor and control tissue. We used this method to study APA in human lung adenocarcinoma (LUAD).SCUREL relies solely on annotated 3’UTRs and on control systems, such as T cell activation and spermatogenesis gives qualitatively similar results at much greater sensitivity compared to the previously published scAPA method.In the LUAD samples, we find a general trend towards 3’UTR shortening not only in cancer cells compared to the cell type of origin, but also when comparing other cell types from the tumor vs. the control tissue environment. However, we also find high variability in the individual targets between patients. The findings help to understand the extent and impact of APA in LUAD, which may support improvements in diagnosis and treatment.