bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hippocampal efferents to retrosplenial cortex and lateral septum are required for memory acquisition
Authors: Opalka Ashley N , Wang Dong V 
Published: March 2020

AbstractLearning and memory involves a large neural network of many brain regions, including the notable hippocampus along with the retrosplenial cortex (RSC) and lateral septum (LS). Previous studies have established that the dorsal hippocampus (dHPC) plays a critical role during the acquisition and expression of episodic memories. However, the role of downstream circuitry from the dHPC, including the dHPC-to-RSC and dHPC-to-LS pathways, has come under scrutiny only recently. Here, we employed an optogenetic approach with contextual fear conditioning in mice to determine whether the above two pathways are involved in acquisition and expression of contextual fear memory. We found that a selective inhibition of the dHPC neuronal terminals in either the RSC or LS during acquisition impaired subsequent memory performance, suggesting that both the dHPC-to-RSC and dHPC-to-LS pathways play a critical role in memory acquisition. We also selectively inhibited the two dHPC efferent pathways during memory expression and found a differential effect on memory performance. These results indicate the intricacies of memory processing and that hippocampal efferents to cortical and subcortical regions may be differentially involved in aspects of physiological and cognitive memory processes.
Swine Promyelocytic Leukemia Isoform II Inhibits Pseudorabies Virus Infection by Suppressing Viral Gene Transcription in PML-NBs
Authors: Yu Cuilian , Xu Aotian , Lang Yue , Qin Chao , Yuan Xiufang , Feng Wenhai , Wang Mengdong , Gao Chao , Chen Jinwen , Zhang Rui , Tang Jun 
Published: March 2020

ABSTRACTPromyelocytic leukaemia nuclear bodies (PML-NBs) possess an important intrinsic antiviral activity against α-herpesvirus infection. PML is the structural backbone of NBs, comprising different isoforms. However, the contribution of each isoform to α-herpesvirus restriction is not well understood. Here, we report the role of PML-NBs and swine PML (sPML) isoforms in pseudorabies virus (PRV) infection in its natural host swine cells. We found that sPML-NBs exhibit an anti-PRV activity in the context of increasing the expression level of endogenous sPML. Of four sPML isoforms cloned and examined, only isoform sPML-II/IIa, not sPML-I and IVa, expressed in a sPML knockout cells inhibits PRV infection. Both the unique 7b region of sPML-II and sumoylation-dependent normal formation of PML-NBs are required. 7b possesses a transcriptional repression activity and suppresses viral gene transcription during PRV infection with the cysteine residue 589 and 599 being critically involved. We conclude that sPML-NBs inhibit PRV infection by repressing viral gene transcription through the 7b region of sPML-II.IMPORTANCEPML-NBs are nuclear sites that mediate the antiviral restriction of α-herpesvirus gene expression and replication. However, the contrition of each PML isoform to this activity of PML-NBs is not well characterized. Using PRV and its natural host swine cells as a system, we have discovered that the unique C-terminus of sPML isoform II is required for PML-NBs to inhibit PRV infection by directly engaging in repression of viral gene transcription. Our study not only confirms in swine cells that PML-NBs have an anti-viral function, but also presents a mechanism to suggest that PML-NBs inhibit viral infection in an isoform specific manner.
COP9 signalosome is an essential and druggable parasite target that regulates protein degradation
Authors: Ghosh Swagata , Farr Laura , Singh Aditya , Leaton Laura-Ann , Padalia Jay , Sullivan David , Moonah Shannon 
Published: March 2020

ABSTRACTUnderstanding how the protozoan protein degradation pathway is regulated could uncover new parasite biology for drug discovery. We found the COP9 signalosome (CSN) conserved in multiple pathogens such asLeishmania, Trypanosoma, Toxoplasma, and used the severe diarrhea-causingEntamoeba histolyticato study its function in medically significant protozoa. We show that CSN is an essential upstream regulator of parasite protein degradation. Genetic disruption ofE. histolyticaCSN by two distinct approaches inhibited cell proliferation and viability. Both CSN5 knockdown and dominant negative mutation trapped cullin in a neddylated state, disrupting UPS activity and protein degradation. In addition, zinc ditiocarb (ZnDTC), a main metabolite of the inexpensive FDA-approved alcohol-abuse drug disulfiram, was active against parasites acting in a COP9-dependent manner. ZnDTC, given as disulfiram-zinc, had oral efficacy in clearing parasites in vivo. Our findings provide insights into the regulation of parasite protein degradation, and supports the significant therapeutic potential of COP9 inhibition.Summary sentenceParasite-encoded COP9 signalosome is an essential upstream regulator of ubiquitin-proteasome mediated protein degradation, and shows significant potential as a therapeutic target.
Serotonergic drugs inhibit CHIKV infection at different stages of the cell entry pathway
Authors: Bouma Ellen M. , van de Pol Denise P.I. , Sanders Ilson D. , Rodenhuis-Zybert Izabela A. , Smit Jolanda M. 
Published: March 2020

AbstractChikungunya virus (CHIKV) is an important re-emerging human pathogen transmitted by mosquitoes. The virus causes an acute febrile illness, chikungunya fever, which is characterized by headache, rash and debilitating (poly)arthralgia that can reside for months to years after infection. Currently, effective antiviral therapies and vaccines are lacking. Due to the high morbidity and economic burden in the countries affected by CHIKV, there is a strong need for new strategies to inhibit CHIKV replication. The serotonergic drug, 5-nonyloxytryptamine (5-NT), was previously identified as a potential host-directed inhibitor for CHIKV infection. In this study, we determined the mechanism of action by which the serotonin receptor agonist 5-NT controls CHIKV infection. Using time-of-addition and entry bypass assays we found that 5-NT predominantly inhibits CHIKV in the early phases of the replication cycle; at a step prior to RNA translation and genome replication. Intriguingly, however, no effect was seen during virus-cell binding, internalization, membrane fusion and gRNA release into the cell cytosol. Additionally, we show that the serotonin receptor antagonist MM also has antiviral properties towards CHIKV and specifically interferes with the cell entry process and/or membrane fusion. Taken together, pharmacological targeting of 5-HT receptors may represent a potent way to limit viral spread and disease severity.ImportanceThe rapid spread of mosquito-borne viral diseases in humans puts a huge economic burden on developing countries. For many of these infections, including Chikungunya virus (CHIKV), there are no specific treatment possibilities to alleviate disease symptoms. Understanding the virus:host interactions that are involved in the viral replication cycle is imperative for the rational design of therapeutic strategies. In this study, we discovered an antiviral compound and elucidated the mechanism of action and propose serotonergic drugs as potential host-directed antivirals for CHIKV.
Linking flexibility of brain networks to cognitive development in preschool children
Authors: Chamakura Lily , Daimi Syed Naser , Watanabe Katsumi , Bhattacharya Joydeep , Saha Goutam 
Published: March 2020

AbstractRecent studies of functional connectivity networks (FCNs) suggest that the reconfiguration of brain network across time, both at rest and during task, is linked with cognition in human adults. In this study, we tested this prediction, i.e. cognitive ability is associated with a flexible brain network in preschool children of 3-4 years - a critical age, representing a ‘blossoming period’ for brain development. We recorded magnetoen-cephalogram (MEG) data from 88 preschoolers, and assessed their cognitive ability by a battery of cognitive tests. We estimated FCNs obtained from the source reconstructed MEG recordings, and characterized the temporal variability at each node using a novel path-based measure of temporal variability; the latter captures reconfiguration of the node’s interactions to the rest of the network across time. Using connectome predictive modeling, we demonstrated that the temporal variability of fronto-temporal nodes in the dynamic FCN can reliably predict out-of-scanner performance of short-term memory and attention distractability in novel participants. Further, we observed that the network-level temporal variability increased with age, while individual nodes exhibited an inverse relationship between temporal variability and node centrality. These results demonstrate that functional brain networks, and especially their reconfiguration ability, are important to cognition at an early but a critical stage of human brain development.
A Self-Supervised Deep Neural Network for Image Completion Resembles Early Visual Cortex fMRI Activity Patterns for Occluded Scenes
Authors: Svanera Michele , Morgan Andrew T. , Petro Lucy S. , Muckli Lars 
Published: March 2020

AbstractThe promise of artificial intelligence in understanding biological vision relies on the comparison of computational models with brain data with the goal of capturing functional principles of visual information processing. Convolutional neural networks (CNN) have successfully matched the transformations in hierarchical processing occurring along the brain’s feedforward visual pathway extending into ventral temporal cortex. However, we are still to learn if CNNs can successfully describe feedback processes in early visual cortex. Here, we investigated similarities between human early visual cortex and a CNN with encoder/decoder architecture, trained with self-supervised learning to fill occlusions and reconstruct an unseen image. Using Representational Similarity Analysis (RSA), we compared 3T fMRI data from a non-stimulated patch of early visual cortex in human participants viewing partially occluded images, with the different CNN layer activations from the same images. Results show that our self-supervised image-completion network outperforms a classical object-recognition supervised network (VGG16) in terms of similarity to fMRI data. This provides additional evidence that optimal models of the visual system might come from less feedforward architectures trained with less supervision. We also find that CNN decoder pathway activations are more similar to brain processing compared to encoder activations, suggesting an integration of mid- and low/middle-level features in early visual cortex. Challenging an AI model and the human brain to solve the same task offers a valuable way to compare CNNs with brain data and helps to constrain our understanding of information processing such as neuronal predictive coding.
Sponging of glutamate at the outer plasma membrane surface reveals roles for glutamate in development
Authors: Castro-Rodríguez Vanessa , Kleist Thomas J. , Gappel Nicoline M. , Atanjaoui Fatiha , Okumoto Sakiko , Machado Mackenzie , Denyer Tom , Timmermans Marja C. P. , Frommer Wolf B. , Wudick Michael M. 
Published: March 2020

SUMMARYPlants use electrical and chemical signals for systemic communication. Herbivory, for instance, appears to trigger local apoplasmic glutamate accumulation, systemic electrical signals and calcium waves that travel to report insect damage to neighboring leaves and initiate defense. To monitor extra- and intracellular glutamate concentrations in plants, we generated Arabidopsis lines expressing genetically encoded fluorescent glutamate sensors. In contrast to cytosolically localized sensors, extracellularly displayed variants inhibited plant growth and proper development. Phenotypic analyses of high-affinity display sensor lines revealed that root meristem development, particularly the quiescent center (QC), number of lateral roots, vegetative growth and floral architecture were impacted. Notably, the severity of the phenotypes was positively correlated with the affinity of the display sensors, intimating that their ability to sequester glutamate at the surface of the plasma membrane was responsible for the defects. Root growth defects were suppressed by supplementing culture media with low levels of glutamate. Together, the data indicate that sequestration of glutamate at the cell surface either disrupts the supply of glutamate to meristematic cells and/or impairs localized glutamatergic signaling important for developmental processes.SIGNIFICANCE STATEMENTGlutamate is an important signaling molecule in animals and plants. The affinity-dependent effects of surface-displayed glutamate sensors on plant development intimate that glutamate levels in the vicinity of the plasma membrane play important roles in signaling in plants.
Amphetamine reduces utility encoding and stabilizes neural dynamics in rat anterior cingulate cortex
Authors: Hashemnia Saeedeh , Euston David R. , Gruber Aaron J. 
Published: March 2020

AbstractThe anterior cingulate cortex (ACC) appears to support decisions by encoding the effort-reward utility of choice options. We show here that d-amphetamine (AMPH) has dose-dependent effects on this encoding and on neural dynamics in rat ACC that are concordant with its behavioral effects. Low-dose AMPH increased task engagement and had mild effects on neural encoding, whereas high doses disrupted utility signaling and decreased task engagement. The disruption involved reduced reward signaling and compressed effort-reward encoding of utility cells, which corresponded with reduced reward consumption behaviors. Furthermore, low-dose AMPH stabilized and accelerated trajectories of neural activity in state-space, whereas high-dose AMPH destabilized trajectories. We propose that low-dose AMPH increases both excitability and stability, which preserves information and accelerates evolution of a neural ‘script’ for task execution. Excessive excitability at high doses overcomes stability enhancement to suppress weakly encoded features (e.g. reward) and cause deviation from the script, which interrupts task performance.Significance StatementAmphetamine reduced reward signaling by individual neurons in rat prefrontal cortex, but increased the stability of ensemble dynamics. These effects account for animals’ increased task engagement, despite reduced reward intake.
Multiple loci linked to inversions are associated with eye size variation in species of theDrosophila virilisphylad
Authors: Reis Micael , Wiegleb Gordon , Claude Julien , Lata Rodrigo , Horchler Britta , Ha Ngoc-Thuy , Reimer Christian , Vieira Cristina P. , Vieira Jorge , Posnien Nico 
Published: March 2020

AbstractThe size and shape of organs is tightly controlled to achieve optimal function. Natural morphological variations often represent functional adaptations to an ever-changing environment. For instance, variation in head morphology is pervasive in insects and the underlying molecular basis is starting to be revealed in theDrosophilagenus for species of themelanogastergroup. However, it remains unclear whether similar diversifications are governed by similar or different molecular mechanisms over longer timescales. To address this issue, we used species of thevirilisphylad because they have been diverging fromD. melanogasterfor at least 40 million years. Our comprehensive morphological survey revealed remarkable differences in eye size and head shape among these species withD. novamexicanahaving the smallest eyes and southernD. americanapopulations having the largest eyes. We show that the genetic architecture underlying eye size variation is complex with multiple associated genetic variants located on most chromosomes. Our genome wide association study (GWAS) strongly suggests that some of the putative causative variants are associated with the presence of inversions. Indeed, northern populations ofD. americanashare derived inversions withD. novamexicanaand they show smaller eyes compared to southern ones. Intriguingly, we observed a significant enrichment of genes involved in eye development on the4thchromosome after intersecting chromosomal regions associated with phenotypic differences with those showing high differentiation amongD. americanapopulations. We propose that variants associated with chromosomal inversions contribute to both intra- and inter-specific variation in eye size among species of thevirilisphylad.
Multiple known and a novel parvovirus associated with an outbreak of feline diarrhea and vomiting
Authors: Li Yanpeng , Gordon Emilia , Idle Amanda , Altan Eda , Seguin M. Alexis , Estrada Marko , Deng Xutao , Delwart Eric 
Published: March 2020

AbstractAn unexplained outbreak of feline diarrhea and vomiting, negative for common enteric viral and bacterial pathogens, was subjected to viral metagenomics and PCR. We characterized from fecal samples the genome of a novel chapparvovirus we named fechavirus that was shed by 8/17 affected cats and different feline bocaviruses shed by 9/17 cats. Also detected were nucleic acids from attenuated vaccine viruses, members of the normal feline virome, viruses found in only one or two cases, and viruses likely derived from ingested food products. Epidemiological investigation of disease signs, time of onset, and transfers of affected cats between three facilities support a possible role for this new chapparvovirus in a highly contagious feline diarrhea and vomiting disease.
PathoFact: A pipeline for the prediction of virulence factors and antimicrobial resistance genes in metagenomic data
Authors: de Nies Laura , Lopes Sara , Heintz-Buschart Anna , Laczny Cedric Christian , May Patrick , Wilmes Paul 
Published: March 2020

AbstractBackgroundPathogenic microorganisms cause disease by invading, colonizing and damaging their host. Virulence factors including bacterial toxins contribute to their pathogenicity. Additionally, antimicrobial resistance genes allow pathogens to evade otherwise curative treatments. To understand causal relationships between microbiome compositions, functioning, and disease, it is therefore essential to identify virulence factors and antimicrobial resistance genes in metagenomic datasets. At present, there is a clear lack of computational approaches to simultaneously identifying these factors. Here we present PathoFact, a tool for the contextualized prediction of virulence factors and antimicrobial resistance genes in metagenomic data.ResultsPathoFact predicts virulence factors, bacterial toxins and antimicrobial resistance genes with high accuracy (0.92, 0.83 and 0.99) and specificity (0.96, 0.99 and 0.98), respectively. The performance of PathoFact was furthermore demonstrated on three publicly available case-control metagenomic datasets representing an actual infection as well as chronic diseases in which either pathogenic potential or bacterial toxins were predicted to play a role. With PathoFact, we identified virulence factors (including toxins) and antimicrobial resistance genes, and identified signature genes which differentiated between the disease and control groups.ConclusionPathoFact is an easy-to-use, modular, and reproducible pipeline for the identification of virulence factors, toxins and antimicrobial resistance genes in metagenomic data. Additionally, PathoFact combines the prediction of these pathogenicity factors with the identification of mobile genetic elements. This provides further depth to the analysis by considering the genomic context of the pertinent genes. Furthermore, each module (virulence factors, toxin and antimicrobial resistance genes) of PathoFact is also a standalone component, making it a flexible and versatile tool. PathoFact is freely available online athttps://git-r3lab.uni.lu/laura.denies/PathoFact.
Analysis of Serologic Cross-Reactivity Between Common Human Coronaviruses and SARS-CoV-2 Using Coronavirus Antigen Microarray
Authors: Khan Saahir , Nakajima Rie , Jain Aarti , de Assis Rafael Ramiro , Jasinskas Al , Obiero Joshua M. , Adenaiye Oluwasanmi , Tai Sheldon , Hong Filbert , Milton Donald K. , Davies Huw , Felgner Philip L. ,   Prometheus Study Group
Published: March 2020

AbstractThe current practice for diagnosis of SARS-CoV-2 infection relies on PCR testing of nasopharyngeal or respiratory specimens in a symptomatic patient at high epidemiologic risk. This testing strategy likely underestimates the true prevalence of infection, creating the need for serologic methods to detect infections missed by the limited testing to date. Here, we describe the development of a coronavirus antigen microarray containing immunologically significant antigens from SARS-CoV-2, in addition to SARS-CoV, MERS-CoV, common human coronavirus strains, and other common respiratory viruses. A preliminary study of human sera collected prior to the SARS-CoV-2 pandemic demonstrates overall high IgG reactivity to common human coronaviruses and low IgG reactivity to epidemic coronaviruses including SARS-CoV-2, with some cross-reactivity of conserved antigenic domains including S2 domain of spike protein and nucleocapsid protein. This array can be used to answer outstanding questions regarding SARS-CoV-2 infection, including whether baseline serology for other coronaviruses impacts disease course, how the antibody response to infection develops over time, and what antigens would be optimal for vaccine development.
Increased power from bacterial genome-wide association conditional on known effects identifiesNeisseria gonorrhoeaemacrolide resistance mutations in the 50S ribosomal protein L4
Authors: Ma Kevin C , Mortimer Tatum D , Duckett Marissa A , Hicks Allison L , Wheeler Nicole E , Sánchez-Busó Leonor , Grad Yonatan H 
Published: March 2020

AbstractThe emergence of resistance to azithromycin complicates treatment ofN. gonorrhoeae, the etiologic agent of gonorrhea. Population genomic analyses of clinical isolates have demonstrated that some azithromycin resistance remains unexplained after accounting for the contributions of known resistance mutations in the 23S rRNA and the MtrCDE efflux pump. Bacterial genome-wide association studies (GWAS) offer a promising approach for identifying novel resistance genes but must adequately address the challenge of controlling for genetic confounders while maintaining power to detect variants with lower effect sizes. Compared to a standard univariate GWAS, conducting GWAS conditioned on known resistance mutations with high effect sizes substantially reduced the number of variants that reached genome-wide significance and identified a G70D mutation in the 50S ribosomal protein L4 (encoded by the generplD) as significantly associated with increased azithromycin minimum inhibitory concentrations (β = 1.03, 95% CI [0.76, 1.30]). The role and prevalence of theserplDmutations in conferring macrolide resistance inN. gonorrhoeaehad been unclear. Here, we experimentally confirmed our GWAS results, identified other resistance-associated mutations in RplD, and showed that in total these RplD binding site mutations are prevalent (present in 5.42% of 4850 isolates) and geographically and temporally widespread (identified in 21/65 countries across two decades). Overall, our findings demonstrate the utility of conditional associations for improving the performance of microbial GWAS and advance our understanding of the genetic basis of macrolide resistance in a prevalent multidrug-resistant pathogen.