bluuebunny/crossref_metadata_2025 huggingface dataset:
Isolation and identification of Streptococcus pneumoniae serotype 6B from a patient with bacterial meningitis infection in Jakarta, Indonesia
Authors: Purwanto Diana Shintawati , Loho Tonny , Tafroji Wisnu , Mangunatmadja Irawan , Immanuel Suzanna , Timan Ina Susianti , Yusra Yusra , Safari Dodi
Published: March 2020

CNS infection is a life-threatening condition in developing countries and

Streptococcus pneumoniae

has been reported as the most common cause of bacterial meningitis; however, there is limited data on pneumococcal meningitis in Indonesia. This cross-sectional study aimed to isolate and identity

S. pneumoniae

strains from cerebrospinal fluid (CSF) specimens collected as part of routine testing from patients with clinically diagnosed central nervous system infection at a national referral hospital in Jakarta, Indonesia in 2017.

S. pneumoniae

isolation and identification were performed using conventional culture and molecular tools. Antibiotic susceptibility patterns were monitored through minimum inhibitory concentration testing. From 147 CSF specimens, one

S. pneumoniae

strain was identified from a patient with bacterial meningitis symptoms. The isolate was serotype 6B (ST5661) and susceptible to 18 antimicrobial agents tested, including penicillin, tetracycline, and the macrolide group. Our data provide insights into the epidemiology of invasive pneumococcal disease in Indonesia.
Two cases of type-a Haemophilus influenzae meningitis within the same week in the same hospital are phylogenetically unrelated but recently exchanged capsule genes
Authors: Terrat Yves , Farnaes Lauge , Bradley John , Tromas Nicolas , Shapiro B. Jesse
Published: March 2020

Haemophilus influenzae

causes common and sometimes severe adult and pediatric disease including chronic obstructive respiratory disease, otitis media and infections of the central nervous system. Serotype b strains, with a b-type capsule, have been the historical cause of invasive disease, and the introduction of a serotype b-specific vaccine has led to their decline. However, unencapsulated or non-b-type

H. influenzae

infections are not prevented by the vaccine and appear to be increasing in frequency. Here we report two pediatric cases of severe central nervous system

H. influenzae

infection presenting to the same hospital in San Diego, California during the same week in January 2016. Due to good vaccine coverage in this part of the world,

H. influenzae

cases are normally rare and seeing two cases in the same week was unexpected. We thus suspected a recent transmission chain, and possible local outbreak. To test this hypothesis, we isolated and sequenced whole genomes from each patient and placed them in a phylogenetic tree spanning the known diversity of

H. influenzae

. Surprisingly, we found that the two isolates (SD2016_1 and SD2016_2) belonged to distantly related lineages, suggesting two independent transmission events and ruling out a local outbreak. Despite being distantly related, the two isolates belong to two different lineages that have exchanged capsule loci in the recent past. Therefore, as in other bacterial pathogens, capsule switching by horizontal gene transfer may be an important evolutionary mechanism of vaccine evasion in

H. influenzae

.
FKBP51 levels negatively correlate with Depressive symptoms in Chronic Hepatitis C
Authors: Pham Anh Duy , Wong Darren , Yeoh Sern Wei , Lewis Diana , Lee Ting Ting , Mostaid Md Shaki , Chana Gursharan , Bousman Chad , Holmes Alex , Saling Michael M , Liew Danny , Gorelik Alexandra , Everall Ian , Sood Siddharth , Nicoll Amanda J
Published: March 2020

Background and aims

Patients with chronic hepatitis C infection have high rates of major depressive disorder. The reasons for this are multifactorial, but social and demographic factors do not entirely explain the increased burden. Direct neuropathologic effect of the virus in the development of depression has been postulated but the mechanisms remain unclear. Single nucleotide polymorphisms (SNPs) in FKBP5 (protein product FKBP51), a co-chaperone of the glucocorticosteroid receptor, have been associated with greater severity of affective disorders. We examined the interaction between FKBP5 SNPs and chronic hepatitis C infection in patients with and without depressive symptoms.

Methods

forty-one subjects completed quality of life and psychiatric questionnaires. Thirteen patients were classified as depressed on the Hospital Anxiety and Depression Scale depression sub-score (HADS-D ≥11). FKBP51 protein expression, FKBP5 mRNA and FKBP5 SNP analysis was compared between those with and without depression.

Results

There were no statistically significant differences between the groups in demographics, medical co-morbidities or substance use. A moderate negative correlation (Spearman rho -0.53, p<0.001) was found between HADS-D sub-score and FKBP51 protein levels in serum. Correspondingly, the average expression fold change in peripheral blood FKBP5 mRNA relative to a reference gene was lower in the depressed group at 0.76 compared to controls at 1.40. There was no differential expression of FKBP5 SNPs between the groups.

Conclusion

Levels of FKBP5 mRNA and FKBP51 are lower in hepatitis C patients with depression and further exploration of this interaction is required.
scRNA-seq reveals ACE2 and TMPRSS2 expression in TROP2+Liver Progenitor Cells: Implications in COVID-19 associated Liver Dysfunction
Authors: Wen Seow Justine Jia , Pai Rhea , Mishra Archita , Shepherdson Edwin , Hon Lim Tony Kiat , Goh Brian KP , Chan Jerry KY , Chow Pierce KH , Ginhoux Florent , DasGupta Ramanuj , Sharma Ankur
Published: March 2020

The recent pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 was first reported in China (December 2019) and now prevalent in ∼170 countries across the globe. Entry of SARS-CoV-2 into mammalian cells require the binding of viral Spike (S) proteins to the ACE2 (angiotensin converting enzyme 2) receptor. Once entered the S protein is primed by a specialised serine protease, TMPRSS2 (Transmembrane Serine Protease 2) in the host cell. Importantly, beside respiratory symptoms, consistent with other common respiratory virus infection when patients become viraemic, a significant number of COVID-19 patients also develop liver comorbidities. We explored if specific target cell-type in the mammalian liver, could be implicated in disease pathophysiology other than the general deleterious response to cytokine storms. Here we employed single-cell RNA-seq (scRNA-seq) to survey the human liver and identified potentially implicated liver cell-type for viral ingress. We report the co-expression of ACE2 and TMPRSS2 in a TROP2+liver progenitor population. Importantly, we fail to detect the expression of ACE2 in hepatocyte or any other liver (immune and stromal) cell types. These results indicated that in COVID-19 associated liver dysfunction and cell death, viral infection of TROP2+progenitors in liver may significantly impaired liver regeneration and could lead to pathology.

Highlights

- EPCAM+Liver progenitors co-express ACE2 and TMPRSS2

- ACE2 and TMPRSS2 expression is highest in TROP2highprogenitors

- ACE2 and TMPRSS2 cells express cholangiocyte biased fate markers

- ACE2 and TMPRSS2 positive cells are absent in human fetal liver
Genetic variation in the social environment affects behavioral phenotypes of oxytocin receptor mutants in zebrafish
Authors: Ribeiro D. , Nunes A.R. , Teles M.C. , Anbalagan S. , Blechman J. , Levkowitz G. , Oliveira R.F.
Published: March 2020

Oxytocin-like peptides have been implicated in the regulation of a wide range of social behaviors across taxa. On the other hand, the social environment, which is composed of conspecifics genotypes, is also known to influence the development of social behavior, creating the possibility for indirect genetic effects. Here we used a knockout line for the oxytocin receptor in zebrafish to investigate how the genotypic composition of the social environment (Es) interacts with the oxytocin genotype (G) of the focal individual in the regulation of its social behavior. For this purpose, we have raised wild-type or knock-out zebrafish in either wild-type or knock-out shoals and tested different components of social behavior in adults. GxEseffects were detected in some behaviors, highlighting the need to control for GxEseffects when interpreting results of experiments using genetically modified animals, since the social environment can either rescue or promote phenotypes associated with specific genes.
Neural Sensitivity to Natural Image Statistics Changes during Middle Childhood
Authors: Balas Benjamin , Saville Alyson
Published: March 2020

Natural images have lawful statistical properties that the adult visual system is sensitive to, both in terms of behavior and neural responses to natural images. The developmental trajectory of sensitivity to natural image statistics remains unclear, however. In behavioral tasks, children appear to slowly acquire adult-like sensitivity to natural image statistics during middle childhood (Ellemberg et al., 2012), but in other tasks, infants exhibit some sensitivity to deviations of natural image structure (Balas & Woods, 2014). Here, we used event-related potentials (ERPs) to examine how sensitivity to natural image statistics changes during childhood at distinct stages of visual processing (the P1 and N1 components). We asked children (5-10 years old) and adults to view natural texture images with either positive/negative contrast, and natural/synthetic texture appearance (Portilla & Simoncelli, 2000) to compare electrophysiological responses to images that did or did not violate natural statistics. We hypothesized that children may only acquire sensitivity to these deviations from natural texture appearance late in middle childhood. Counter to this hypothesis, we observed significant responses to unnatural contrast and texture statistics at the N1 in all age groups. At the P1, however, only young children exhibited sensitivity to contrast polarity. The latter effect suggests greater sensitivity earlier in development to some violations of natural image statistics. We discuss these results in terms of changing patterns of invariant texture processing during middle childhood and ongoing refinement of the representations supporting natural image perception.
Hippocampal efferents to retrosplenial cortex and lateral septum are required for memory acquisition
Authors: Opalka Ashley N , Wang Dong V
Published: March 2020

Learning 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

Promyelocytic 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.

IMPORTANCE

PML-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

Understanding 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 sentence

Parasite-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

Chikungunya 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.

Importance

The 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

Recent 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

Abstract

The 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

Plants 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 STATEMENT

Glutamate 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

The 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 Statement

Amphetamine 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

The 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

An 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

Background

Pathogenic 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.

Results

PathoFact 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.

Conclusion

PathoFact 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.
Filtering input fluctuations in intensity and in time underlies transcriptional pulses without feedback
Authors: Sassi Alberto Stefano , Garcia-Alcala Mayra , Cluzel Philippe , Tu Yuhai
Published: March 2020

Stochastic pulsatile dynamics have been observed in an increasing number of biological circuits with typical mechanism involving feedback control. Surprisingly, recent single-cell experiments showed that E. coli flagellar class-2&3 promoters are activated in stochastic pulses without the means of feedback, however, the underlying design principles of pulse generation have remained unclear. Here, by developing a system-level stochastic model constrained by a large set of E. coli flagellar synthesis data from different strains and mutants, we identify the underlying design principles for generating stochastic transcriptional pulses without feedback. Our model shows that YdiV, an inhibitor of the class-1 master regulator (FlhDC), creates an ultrasensitve switch that serves as a digital filter to eliminate small amplitude FlhDC fluctuations. Additionally, we demonstrate that fast temporal fluctuations of FlhDC are smoothed out and integrated over time before affecting class-2 downstream genes. Together, our results reveal the existence of a filter-and-integrate design that is necessary for generating stochastic pulses without feedback. This strategy suggests that E. coli may avoid premature activation of the expensive flagellar gene expression by filtering input fluctuations in intensity and in time.
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

The 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

The 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.
Agrammatism and paragrammatism: a cortical double dissociation revealed by lesion-symptom mapping
Authors: Matchin William , Basilakos Alexandra , Stark Brielle C. , Ouden Dirk-Bart den , Fridriksson Julius , Hickok Gregory
Published: March 2020

The fundamental distinction of grammatical deficits in aphasia, agrammatism and paragrammatism, was made over a century ago. However, the extent to which the agrammatism/paragrammatism distinction exists independently of differences in speech fluency has not clearly been investigated. Despite much research on agrammatism, the lesion correlates of paragrammatism are essentially unknown. Lesion-symptom mapping was used to investigate the degree to which the lesion correlates of agrammatism and paragrammatism overlap or dissociate. Four expert raters assessed videos of 53 right-handed patients with aphasia following chronic left hemisphere stroke retelling the Cinderella story. Consensus discussion determined each subject’s classification with respect to grammatical deficits as Agrammatic, Paragrammatic, Both, or No Grammatical Deficit. Each subject’s lesion was manually drawn on a high-resolution MRI and warped to standard space for group analyses. Lesion-symptom mapping analyses were performed in NiiStat including lesion volume as a covariate. Secondary analyses included speech rate (words per minute) as an additional covariate. Region of interest analyses identified a double dissociation between these syndromes: damage to Broca’s area was significantly associated with agrammatism, p = 0.001 (but not paragrammatism, p = 0.930), while damage to the left posterior superior and middle temporal gyri was significantly associated with paragrammatism, p < 0.001 (but not agrammatism, p = 0.873). The same results obtained when regressing out the effect of speech rate, and non-overlapping lesion distributions between the syndromes were confirmed by uncorrected whole brain analyses. Our results support a fundamental distinction between agrammatism and paragrammatism.
The mouse cortico-tectal projectome
Authors: Benavidez Nora L. , Bienkowski Michael S. , Khanjani Neda , Bowman Ian , Fayzullina Marina , Garcia Luis , Gao Lei , Korobkova Laura , Gou Lin , Cotter Kaelan , Becerra Marlene , Aquino Sarvia , Cao Chunru , Foster Nicholas N. , Song Monica Y. , Zhang Bin , Yamashita Seita , Zhu Muye , Lo Darrick , Boesen Tyler , Zingg Brian , Santarelli Anthony , Wickersham Ian R. , Ascoli Giorgio A. , Hintiryan Houri , Dong Hong-Wei
Published: March 2020

The superior colliculus (SC) is a midbrain structure that receives diverse and robust cortical inputs to drive a range of cognitive and sensorimotor behaviors. However, it remains unclear how descending cortical inputs arising from higher-order associative areas coordinate with SC sensorimotor networks to influence its outputs. In this study, we constructed a comprehensive map of all cortico-tectal projections and identified four collicular zones with differential cortical inputs: medial (SC.m), centromedial (SC.cm), centrolateral (SC.cl) and lateral (SC.l). Computational analyses revealed that cortico-tectal projections are organized as multiple subnetworks that are consistent with previously identified cortico-cortical and cortico-striatal subnetworks. Furthermore, we delineated the brain-wide input/output organization of each collicular zone and described a subset of their constituent neuronal cell types based on distinct connectional and morphological features. Altogether, this work provides a novel structural foundation for the integrative role of the SC in controlling cognition, orientation, and other sensorimotor behaviors.
Draft Genome Sequence of pyschrotolerantClostridiumsp. M14 Isolated from Spoiled Uncooked Venison
Authors: Palevich Nikola , Palevich Faith P. , Maclean Paul H. , Jauregui Ruy , Altermann Eric , Mills John , Brightwell Gale
Published: March 2020

The non-proteolytic, non-toxigenic and pyschrotolerantClostridiumsp. M14 was isolated from vacuum-packaged refrigerated spoiled venison. This report describes the generation and annotation of the 3.9 Mb draft genome sequence ofClostridiumsp. M14.
Severe and multifaceted systemic immunosuppression caused by experimental cancers of the central nervous system requires release of non-steroid soluble mediators
Authors: Ayasoufi K , Pfaller CK , Evgin L , Khadka RH , Tritz ZP , Goddery EN , Fain CE , Yokanovich LT , Himes BT , Jin F , Zheng J , Schuelke MR , Hansen MJ , Tung W , Pease LR , Vile RG , Johnson AJ
Published: March 2020

Immunosuppression of unknown etiology is a hallmark feature of glioblastoma (GBM) and is characterized by decreased CD4 T cell counts and down regulation of MHC class II expression on peripheral blood monocytes in patients. This immunosuppression is a critical barrier to the successful development of immunotherapies for GBM. We recapitulated the immunosuppression observed in GBM patients in the C57BL/6 mouse and investigated the etiology of low CD4 T cell counts. We determined that thymic involution was a hallmark feature of immunosuppression in three distinct models of CNS cancer, including mice harboring GL261 glioma, B16 melanoma, and in a spontaneous model of Diffuse Intrinsic Pontine Glioma (DIPG). In addition to thymic involution, we determined that tumor growth in the brain induced significant splenic involution, reductions in peripheral T cells, reduced MHC class II expression on hematopoietic cells, and a modest increase in bone marrow resident CD4 T cells with a naïve phenotype. Using parabiosis we report that thymic involution, declines in peripheral T cell counts, and reduced MHC class II expression levels were mediated through circulating blood-derived factors. Conversely, T cell sequestration in the bone marrow was not governed through circulating factors. Serum isolated from glioma-bearing mice potently inhibited proliferation and functions of T cells bothin vitroandin vivo. Interestingly, the factor responsible for immunosuppression in serum is nonsteroidal and of high molecular weight. Through further analysis of neurological disease models, we determined that the aforementioned immunosuppression was not unique to cancer itself, but rather occurs in response to CNS injury. Noncancerous acute neurological insults also induced significant thymic involution and rendered serum immunosuppressive. Both thymic involution and serum-derived immunosuppression were reversible upon clearance of brain insults. These findings demonstrate that CNS cancers cause multifaceted immunosuppression and pinpoint circulating factors as a target of intervention to restore immunity.

Short Summary

CNS cancers and other brain-injuries suppress immunity through release of non-steroid soluble factors that disrupt immune homeostasis and dampen responses of the peripheral immune system.

Graphical Abstract
Access to PCNA by Srs2 and Elg1 controls the choice between alternative repair pathways in yeast
Authors: Arbel Matan , Bronstein Alex , Sau Soumitra , Liefshitz Batia , Kupiec Martin
Published: March 2020

During DNA replication stalling can occur when the replicative DNA polymerases encounter lesions or hard-to replicate regions. Under these circumstances the processivity factor PCNA gets ubiquitylated at lysine 164, inducing the DNA damage tolerance (DDT) mechanisms that can bypass lesions encountered during DNA replication. PCNA can also be SUMOylated at the same residue or at lysine 127. Surprisingly,pol30-K164Rmutants display a higher degree of sensitivity to DNA damaging agents thanpol30-KK127,164RRstrains, unable to modify any of the lysines. Here we show that in addition to trans-lesion synthesis and strand-transfer DTT mechanisms, an alternative repair mechanism (“salvage recombination”) that copies information from the sister chromatid, is repressed by the recruitment of Srs2 to SUMOylated PCNA. Overexpression of Elg1, the PCNA unloader, or of the recombination protein Rad52 allows its activation. We dissect the genetic requirements for this pathway, as well as the interactions between Srs2 and Elg1.
Metabolic disturbances and inflammatory dysfunction predict severity of coronavirus disease 2019 (COVID-19): a retrospective study
Authors: Nie Shuke , Zhao Xueqing , Zhao Kang , Zhang Zhaohui , Zhang Zhentao , Zhang Zhan
Published: March 2020

Background

The coronavirus disease 2019 (COVID-19) is spreading worldwide with 16,558 deaths till date. Serum albumin, high-density lipoprotein (HDL-C), and C-reactive protein have been known to be associated with the severity and mortality of community-acquired pneumonia. However, the characteristics and role of metabolic and inflammatory indicators in COVID-19 is unclear.

Methods

We included 97 hospitalized patients with laboratory-confirmed COVID-19. Epidemiological, clinical, and laboratory indices; radiological features; and treatment were analysed. The differences in the clinical and laboratory parameters between mild and severe COVID-19 patients and the role of these indicators in severity prediction of COVID-19 were investigated.

Results

All were Wuhan residents with contact with confirmed COVID-19 cases. The median age was 39 years (IQR: 30–59). The most common presenting symptoms were fever (58.8%), cough (55.7%), and fatigue (33%). Other features were lymphopenia, impaired fasting glucose, hypoproteinaemia, hypoalbuminemia, low high-density lipoproteinemia. Decrease in lymphocyte count, serum total protein, serum albumin, high-density lipoprotein cholesterol (HDL-C), ApoA1, CD3+T%, and CD8+T% were found to be valuable in predicting the transition of COVID-19 from mild to severe illness. Chest computed tomography (CT) images showed that the absorption of bilateral lung lesions synchronized with the recovery of metabolic and inflammatory indicators.

Conclusions

Hypoproteinaemia, hypoalbuminemia, low high-density lipoproteinemia, and decreased ApoA1, CD3+T%, and CD8+T% could predict severity of COVID-19. Lymphocyte count, total serum protein, and HDL-C may be potentially useful for the evaluation of COVID-19.
Home collection of nasal swabs for detection of influenza in the Household Influenza Vaccine Evaluation Study
Authors: Malosh Ryan E. , Petrie Joshua G. , Callear Amy P. , Monto Arnold S. , Martin Emily T.
Published: March 2020

Background

Community based studies of influenza and other respiratory viruses (e.g. SARS-COV-2) require laboratory confirmation of infection. During the current COVID-19 pandemic, social distancing guidelines require alternative data collection in order protect both research staff and participants.

Home-collected respiratory specimens are less resource intensive, can be collected earlier after symptom onset, and provide a low-contact means of data collection. A prospective, multi-year, community-based cohort study is an ideal setting to examine the utility of home-collected specimens for identification of influenza.

Methods

We describe the feasibility and reliability of home-collected specimens for the detection of influenza. We collected data and specimens between October 2014 and June 2017 from the Household Influenza Vaccine Evaluation (HIVE) Study. Cohort participants were asked to collect a nasal swab at home upon onset of acute respiratory illness. Research staff also collected nose and throat swab specimens in the study clinic within 7 days of onset. We estimated agreement using Cohen’s kappa and calculated sensitivity and specificity of home-collected compared to staff-collected specimens.

Results

We tested 336 paired staff- and home-collected respiratory specimens for influenza by RT-PCR; 150 staff-collected specimens were positive for influenza A/H3N2, 23 for influenza A/H1N1, 14 for influenza B/Victoria, and 31 for influenza B/Yamagata. We found moderate agreement between collection methods for influenza A/H3N2 (0.70) and B/Yamagata (0.69) and high agreement for influenza A/H1N1 (0.87) and B/Victoria (0.86). Sensitivity ranged from 78-86% for all influenza types and subtypes. Specificity was high for influenza A/H1N1 and both influenza B lineages with a range from 96-100%, and slightly lower for A/H3N2 infections (88%).

Conclusions

Collection of nasal swab specimens at home is both feasible and reliable for identification of influenza virus infections.