bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship between microbiomes and selective regimes in the sponge genusIrcinia
Authors: Kelly Joseph B. , Carlson David , Low Jun Siong , Rice Tyler , Thacker Robert W.
Published: September 2020

Sponges are often densely populated by microbes that benefit their hosts through nutrition and bioactive secondary metabolites; however, sponges must simultaneously contend with the toxicity of microbes and thwart microbial overgrowth. Despite these fundamental tenets of sponge biology, the patterns of selection in the host sponges’ genomes that underlie tolerance and control of their microbiomes are still poorly understood. To elucidate these patterns of selection, we performed a population genetic analysis on multiple species ofIrciniafrom Belize, Florida, and Panama using anFST-outlier approach on transcriptome-annotated RADseq loci. As part of the analysis, we delimited species boundaries among seven growth forms ofIrcinia. Our analyses identified balancing selection in immunity genes that have implications for the hosts’ tolerance of high densities of microbes. Additionally, our results support the hypothesis that each of the seven growth forms constitutes a distinctIrciniaspecies that is characterized by a unique microbiome. These results illuminate the evolutionary pathways that promote stable associations between host sponges and their microbiomes, and that potentially facilitate ecological divergence amongIrciniaspecies.
Strategies of grain number determination differentiate barley row-types
Authors: Thirulogachandar Venkatasubbu , Koppolu Ravi , Schnurbusch Thorsten
Published: September 2020

Gaining knowledge on intrinsic interactions of various yield components is crucial to improve the yield potential in small grain cereals. It is well known in barley that increasing the grain number (GN) preponderantly improves their yield potential; however, the yield components determining GN and their association in barley row-types are less explored. In this study, we assessed different yield components like potential spikelet number (PSN), spikelet survival (SSL), spikelet number (SN), grain set (GS), and grain survival (GSL), as well as their interactions with GN by using a selected panel of two- and six-rowed barley types. Also, to analyze the stability of these interactions, we performed the study in two growth conditions, greenhouse and field. From this study, we found that in two-rowed, GN determination is strongly influenced by PSN rather than SSL and/or GS in both growth conditions. Conversely, in six-rowed, GN is associated with SSL instead of PSN and/or GS. Thus, our study exemplified that increasing GN might be possible by augmenting PSN in two-rowed genotypes, while for six-rowed genotypes, the ability of SSL needs to be improved. We speculate that this disparity of GN determination in barley row-types might be due to the fertility of lateral spikelets. Collectively, this study revealed that the GN of two-rowed largely depends on the developmental trait, PSN, while in six-rowed, it mainly follows the ability of SSL.

Highlight

In cereals, understanding the interactions of different yield components that influence the grain number is essential to increase their yield by modulating the components. We show in this study that the grain number of two-rowed barley is predominantly determined by the potential spikelet number while in six-rowed by spikelet survival.
Spontaneous rate of clonal mutations inDaphnia galeata
Authors: Pfenninger Markus , Doria Halina Binde , Nickel Jana , Thielsch Anne , Schwenk Klaus , Cordellier Mathilde
Published: September 2020

Mutations are the ultimate source of heritable variation and therefore the fuel for evolution, but direct estimates exist only for few species. We estimated the spontaneous nucleotide mutation rate among clonal generations in the waterfleaDaphnia galeatawith a short term mutation accumulation approach. Individuals from eighteen mutation accumulation lines over five generations were deep genome sequenced to count de novo mutations that were not present in a pool of F1 individuals, representing the parental genotype. We identified 12 new nucleotide mutations in 90 clonal generational passages. This resulted in an estimated haploid mutation rate of 0.745 x 10-9(95% c.f. 0.39 x 10-9− 1.26 x 10-9), which is slightly lower than recent estimates for otherDaphniaspecies. We discuss the implications for the population genetics of Cladocerans.
A gut-secreted peptide controls arousability through modulation of dopaminergic neurons in the brain
Authors: Titos Iris , Rogulja Dragana
Published: September 2020

Since sensory information is always present in the environment, animals need to internally regulate their responsiveness to fit the context. During sleep, the threshold for sensory arousal is increased so that only stimuli of sufficient magnitude can cross it. The mechanisms that make arousability flexible are largely mysterious, but they must integrate sensory information with information about physiology. We discovered a gut-to-brain signaling pathway that uses information about ingested nutrients to control arousability from sleep, without affecting sleep duration. Protein ingestion causes endocrine cells in theDrosophilagut to increase production of CCHa1, a peptide that decreases sensory responsiveness. CCHa1 is received by a small group of brain dopaminergic neurons whose activity gates behavioral responsiveness to mechanical stimulation. These dopaminergic neurons innervate the mushroom body, a brain structure involved in determining sleep duration. This work describes how the gut tunes arousability according to nutrient availability, allowing deeper sleep when dietary proteins are abundant. It also suggests that behavioral flexibility is increased through independent tuning of sleep depth and duration.
An Approach to Automatically Label & Order Brain Activity/Component Maps
Authors: Salman Mustafa S. , Wager Tor D. , Damaraju Eswar , Calhoun Vince D.
Published: September 2020

Functional magnetic resonance imaging (fMRI) is a brain imaging technique which provides detailed in-sights into brain function and its disruption in various brain disorders. fMRI data can be analyzed using data-driven or region-of-interest based methods. The data-driven analysis of brain activity maps involves several steps, the first of which is identifying whether the maps capture what might be interpreted as intrinsic connectivity networks (ICNs) or artifacts. This is followed by linking the ICNs to known anatomical and/or functional parcellations. Optionally, as in the study of functional network connectivity (FNC), rearranging the connectivity graph is also necessary for systematic interpretation. Here we present a toolbox that automates all these processes under minimal or no supervision with high accuracy. We provide a pretrained cross-validated elastic-net regularized general linear model for the noisecloud toolbox to separate the ICNs from artifacts. We include several well-known anatomical and functional parcellations from which researchers can choose to label the activity maps. Finally, we integrate a method for maximizing the within-domain modularity to generate a more systematically structured FNC matrix. We improve upon and integrate existing techniques and new methods to design this toolbox which can take care of all the above needs. Specifically, we show that our pretrained model achieves 89% accuracy and 100% precision at classifying ICNs from artifacts in a validation dataset. Researchers are generating brain imaging data and analyzing brain activity at an ever-increasing rate. The Autolabeller toolbox can help automate such analyses for faster and reproducible research.
Steady-state visually evoked potentials and feature-based attention: Pre-registered null results and a focused review of methodological considerations
Authors: Adam Kirsten C.S. , Chang Lillian , Rangan Nicole , Serences John T.
Published: September 2020

Feature-based attention is the ability to selectively attend to a particular feature (e.g., attend to red but not green items while looking for the ketchup bottle in your refrigerator), and steady-state visually evoked potentials (SSVEPs) measured from the human electroencephalogram (EEG) signal have been used to track the neural deployment of feature-based attention. Although many published studies suggest that we can use trial-by-trial cues to enhance relevant feature information (i.e., greater SSVEP response to the cued color), there is ongoing debate about whether participants may likewise use trial-by-trial cues to voluntarily ignore a particular feature. Here, we report the results of a pre-registered study in which participants either were cued to attend or to ignore a color. Counter to prior work, we found no attention-related modulation of the SSVEP response in either cue condition. However, positive control analyses revealed that participants paid some degree of attention to the cued color (i.e., we observed a greater P300 component to targets in the attended versus the unattended color). In light of these unexpected null results, we conducted a focused review of methodological considerations for studies of feature-based attention using SSVEPs. In the review, we quantify potentially important stimulus parameters that have been used in the past (e.g., stimulation frequency; trial counts) and we discuss the potential importance of these and other task factors (e.g., feature-based priming) for SSVEP studies.
A deeply conserved miR-1 dependent regulon supports muscle cell physiology
Authors: Gutiérrez-Pérez Paula , Santillán Emilio M. , Lendl Thomas , Schrempf Anna , Steinacker Thomas L. , Asparuhova Mila , Brandstetter Marlene , Haselbach David , Cochella Luisa
Published: September 2020

Muscles are not only essential for force generation but are also key regulators of systemic energy homeostasis1. Both these roles rely heavily on mitochondria and lysosome function as providers of energy and building blocks, but also as metabolic sensors2-4. Perturbations in these organelles or their crosstalk lead to a wide range of pathologies5. Here, we uncover a deeply conserved regulon of mitochondria and lysosome homeostasis under control of the muscle-specific microRNA miR-1. Animals lacking miR-1 display a diverse range of muscle cell defects that have been attributed to numerous different targets6. Guided by the striking conservation of miR-1 and some of its predicted targets, we identified a set of direct targets that can explain the pleiotropic function of miR-1. miR-1-mediated repression of multiple subunits of the vacuolar ATPase (V-ATPase) complex, a key player in the acidification of internal compartments and a hub for metabolic signaling7,8, and of DCT-1/BNIP3, a mitochondrial protein involved in mitophagy and apoptosis9,10, accounts for the function of this miRNA inC. elegans. Surprisingly, although multiple V-ATPase subunits are upregulated in the absence of miR-1, this causes a loss-of-function of V-ATPase due to altered levels or stoichiometry, which negatively impact complex assembly. Finally, we demonstrate the conservation of the functional relationship between miR-1 and the V-ATPase complex inDrosophila.
Chromatin-associated effectors of energy-sensing pathways mediate intergenerational effects
Authors: Robles Pedro , Turner Anisa , Zuco Giusy , Paganopolou Panagiota , Hill Beth , Kache Vikas , Bateson Christine , Pires-daSilva Andre
Published: September 2020

Environmental stimuli experienced by the parental generation influence the phenotype of subsequent generations. The effects of these stimuli on the parental generation may be passed through the germline, but the mechanisms of this non-Mendelian type of inheritance are poorly known. Here we show that modulation of nutrient-sensing pathways in the parental generation of a nematode (Auanema freiburgensis) regulates phenotypic plasticity of its offspring. In response to pheromones, AMP-activated protein kinase (AMPK), mechanistic target of rapamycin complex 1 (mTORC1) and insulin signaling regulate stress resistance and sex determination across a generation. The effectors of these pathways are closely associated with the chromatin and their regulation affects the acetylation chromatin status in the germline. These results suggest that highly conserved metabolic sensors regulate phenotypic plasticity by changing the epigenetic status of the germline.
Reduced anterior cingulate cortex volume induced by chronic stress correlates with increased behavioral emotionality and decreased synaptic puncta density
Authors: Misquitta Keith A. , Miles Amy , Prevot Thomas D. , Knoch Jaime K. , Fee Corey , Newton Dwight F. , Ellegood Jacob , Lerch Jason P. , Sibille Etienne , Nikolova Yuliya S. , Banasr Mounira
Published: September 2020

Clinical and preclinical studies report that chronic stress induces behavioral deficits as well as volumetric and synaptic alterations in corticolimbic brain regions including the anterior cingulate cortex (ACC), amygdala (AMY), nucleus accumbens (NAc) and hippocampus (HPC). Here, we aimed to investigate the volumetric changes associated with chronic restraint stress (CRS) and link these changes to the CRS-induced behavioral and synaptic deficits. We first confirmed that CRS increases behavioral emotionality, defined as collective scoring of anxiety- and anhedonia-like behaviors. We then demonstrated that CRS induced a reduction of total brain volume which negatively correlated with behavioral emotionality. Region-specific analysis identified that only the ACC showed significant decrease in volume following CRS (p<0.05). Reduced ACC correlated with increased behavioral emotionality (r=-0.56; p=0.0003). Although not significantly altered by CRS, AMY and NAc (but not the HPC) volumes were negatively correlated with behavioral emotionality. Finally, using structural covariance network analysis to assess shared volumetric variances between the corticolimbic brain regions and associated structures, we found a progressive decreased ACC degree and increased AMY degree following CRS. At the cellular level, reduced ACC volume correlated with decreased PSD95 (but not VGLUT1) puncta density (r=0.35, p<0.05), which also correlated with increased behavioral emotionality (r=-0.44, p<0.01), suggesting that altered synaptic strength is an underlying substrate of CRS volumetric and behavioral effects. Our results demonstrate that CRS effects on ACC volume and synaptic density are linked to behavioral emotionality and highlight key ACC structural and morphological alterations relevant to stress-related illnesses including mood and anxiety disorders.

Highlights

Chronic restraint stress (CRS) decreases anterior cingulate cortex (ACC) volume

ACC and amygdala (AMY) volumes negatively correlate with behavioral emotionality

CRS decreased the strength and degree of the ACC structural covariance network

CRS increased the strength and degree of the AMY structural covariance network

PSD95 puncta density correlates with behavioral emotionality and ACC volume.
A systematic genetic interaction map of human solute carriers assigns a role to SLC25A51/MCART1 in mitochondrial NAD uptake
Authors: Girardi Enrico , Fiume Giuseppe , Goldmann Ulrich , Sin Celine , Müller Felix , Lindinger Sabrina , Sedlyarov Vitaly , Srndic Ismet , Agerer Benedikt , Kartnig Felix , Meixner Eva , Skucha Anna , Rebsamen Manuele , Bergthaler Andreas , Menche Jörg , Superti-Furga Giulio
Published: September 2020

Solute Carriers (SLCs) represent the largest family of human transporter proteins, consisting of more than 400 members1,2. Despite the importance of these proteins in determining metabolic states and adaptation to environmental changes, a large proportion of them is still orphan and lacks associated substrates1,3,4. Here we describe a systematic mapping of genetic interactions among SLCs in human cells. Network-based identification of correlated genetic interaction profile neighborhoods resulted in initial functional assignments to dozens of previously uncharacterized SLCs. Focused validation identified SLC25A51/MCART1 as the SLC enabling mitochondrial import of NAD(H). This functional interaction map of the human transportome offers a route for systematic integration of transporter function with metabolism and provides a blueprint for elucidation of the dark genome by biochemical and functional categories.
Evaluation of the effect of SiO2 and Fe3O4 nanoparticles onPisum sativumseeds in laboratory and field experiments
Authors: Galaktionova L.V. , Korotkova A.M. , Voskobulova N.I. , Lebedev S.V. , Terehova N.A. , Vershinina I.A.
Published: September 2020

The present study assessed the toxic effects and prospects of using nanoparticles of SiO2 and Fe3O4 by studying the influence of pre-sowing priming ofPisum sativum L. seeds with a suspension of nanoparticles of SiO2and Fe3O4in a concentration range of 10−2to 10−5mg/l. The results demonstrated the stimulating effect of the SiO2suspension (10−3mg/l and 10−4mg/l) and the mix of Fe3O4+SiO2at the corresponding concentrations of 10−3mg/l and 10−4mg/l on the length of roots and seedlings, and the increase in the viability of plant cells under the influence of a stress factor (based on Evans blue staining). Field experience has shown the ambiguous effect of nano-printing of seeds on plant productivity.
A genome-wide CRISPR-Cas9 screen identifies CENPJ as a host regulator of altered microtubule organization duringPlasmodiumliver infection
Authors: Vijayan Kamalakannan , Arang Nadia , Wei Ling , Morrison Robert , Geiger Rechel , Parks K. Rachael , Lewis Adam J , Mast Fred D , Douglass Alyse N , Kain Heather S , Aitchison John D , Johnson Jarrod S , Aderem Alan , Kaushansky Alexis
Published: September 2020

Prior to initiating symptomatic malaria, a singlePlasmodiumsporozoite infects a hepatocyte and develops into thousands of merozoites, in part by scavenging host resources. We show that host microtubules dynamically reorganize around the developing liver stage (LS) parasite. Using a genome-wide CRISPR-Cas9 screen, we identified host regulators of cytoskeleton organization, vesicle trafficking, ER/Golgi stress and lipid biogenesis that regulatePlasmodiumLS development. These novel regulators of infection, including Centromere Protein J (CENPJ), led us to interrogate how microtubule organizing centers (MTOCs) are regulated during infection. Foci of γ-tubulin localized to the parasite periphery; depletion of CENPJ exacerbated this re-localization and increased infection. Further, we show that the Golgi acts as a non-centrosomal MTOC by organizing γ-tubulin and stimulating microtubule nucleation at the parasite periphery. Collectively, we show that thePlasmodiumLS recruits the host Golgi to form MT mediated conduits along which host organelles are recruited to the PVM, to support liver stage development. Our findings suggest many host-targeted pharmacological inhibitors may inhibit LS infection.
Structural and functional insights into nitrosoglutathione reductase fromChlamydomonas reinhardtii
Authors: Tagliani Andrea , Rossi Jacopo , Marchand Christophe H. , De Mia Marcello , Tedesco Daniele , Libero Gurrieri , Meloni Maria , Falini Giuseppe , Trost Paolo , Lemaire Stéphane D. , Fermani Simona , Zaffagnini Mirko
Published: September 2020

Protein S-nitrosylation plays a fundamental role in cell signaling and nitrosoglutathione (GSNO) is considered as the main nitrosylating signaling molecule. Enzymatic systems controlling GSNO homeostasis are thus crucial to indirectly control the formation of protein S-nitrosothiols. GSNO reductase (GSNOR) is the key enzyme controlling GSNO levels by catalyzing its degradation in the presence of NADH. Here, we found that protein extracts from the microalgaChlamydomonas reinhardtiicatabolize GSNOviatwo enzymatic systems having specific reliance on NADPH or NADH and different biochemical features. Scoring the Chlamydomonas genome for orthologs of known plant GSNORs, we found two genes encoding for putative and almost identical GSNOR isoenzymes. One of the two, here named CrGSNOR1, was heterologously expressed and purified. The kinetic properties of CrGSNOR1 were determined and the high-resolution three-dimensional structures of the apo and NAD+-bound forms of the enzyme were solved. These analyses revealed that CrGSNOR1 has a strict specificity towards GSNO and NADH, and a conserved 3D-folding with respect to other plant GSNORs. The catalytic zinc ion, however, showed an unexpected variability of the coordination environment. Furthermore, we evaluated the catalytic response of CrGSNOR1 to thermal denaturation, thiol-modifying agents and oxidative modifications as well as the reactivity and position of accessible cysteines. Despite being a cysteine-rich protein, CrGSNOR1 contains only two solvent-exposed/reactive cysteines. Oxidizing and nitrosylating treatments have null or limited effects on CrGSNOR1 activity, highlighting a certain resistance of the algal enzyme to redox modifications. The molecular mechanisms and structural features underlying the response to thiol-based modifications are discussed.

One-sentence summary

GSNOR1 fromChlamydomonas reinhardtiidisplays an unusual variability of the catalytic zinc coordination environment and an unexpected resistance to thiol-based redox modifications
Resetting of the 24-nt siRNA landscape in rice zygotes
Authors: Li Chenxin , Gent Jonathan I. , Xu Hengping , Fu Hong , Russell Scott D. , Sundaresan Venkatesan
Published: September 2020

Background

The zygote, a totipotent stem cell, constitutes a critical stage of the life cycle of sexually reproducing organisms. It is produced by the fusion of two differentiated cells — the egg and sperm, which in plants have radically different siRNA transcriptomes from each other and from multicellular embryos. Due to technical challenges, the epigenetic changes that accompany the zygotic transition are poorly understood.

Results

Here, we characterized the small RNA transcriptome of rice zygotes. We found widespread redistribution of 24-nt siRNAs relative to gametes, including absence of sperm signature siRNAs, reduction at egg signature siRNA loci, and upregulation at seedling signature siRNA loci. Loci with reduced siRNAs in zygote relative to egg were gene-distal and heterochromatic, while loci with increased siRNAs relative to egg had a similar genomic distribution to canonical siRNA loci. Although both egg and zygote siRNA loci had higher mCHH level in wildtype than indrm2embryo, zygote but not egg siRNA loci were associated with hypermethylation in mature embryo. A small fraction of siRNA loci (~1%) called siren loci accounted for 60% of all siRNAs within zygote siRNA loci, that likely arose from maternal carryover as they had similarly abundant siRNAs in egg; these siren loci were not associated with embryo hypermethylation.

Conclusions

Taken together, our results indicate re-distribution of siRNAs in rice zygotes towards the canonical vegetative profile, that are consistent with the initiation of resetting of the gametic epigenome before the first embryonic division.
Serum proteomic profiling at diagnosis predicts clinical course, and need for intensification of treatment in inflammatory bowel disease
Authors: Kalla R , Adams AT , Bergemalm D , Vatn S , Kennedy NA , Ricanek P , Lindstrom J , Ocklind A , Hjelm F , Ventham NT , Ho GT , Petren C ,   IBD-Character Consortium, Repsilber D , Söderholm J , Pierik M , D’Amato M , Gomollón F , Olbjorn C , Jahnsen J , Vatn MH , Halfvarson J , Satsangi J
Published: September 2020

Background

Success in personalised medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay (PEA) to identify diagnostic and prognostic biomarkers in inflammatory bowel disease (IBD).

Methods

We conducted a prospective case-control study in an inception cohort of 552 patients (328 IBD, 224 non-IBD), profiling proteins recruited across 6 centres. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross validation was used to examine the performance of diagnostic and prognostic proteins.

Results

A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls including Matrix Metalloproteinase-12 (Holm adjusted p=4.1×10−23) and Oncostatin-M (OSM, p=3.7×10−16). Nine of these proteins associate withcis- germline variation (59 independent SNPs). Fifteen proteins, all members of TNF independent pathways including interleukin-1 and OSM predicted escalation, over a median follow-up of 518 (IQR 224-756) days. Nested cross-validation of the entire data set allows characterisation of 5-protein-models (96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7, and IL8) which define a high-risk subgroup in IBD (HR 3.90, 95% CI: 2.43-6.26), or allows distinct 2, and 3 protein models for UC and CD respectively.

Conclusion

We have characterised a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and predicts the evolution of disease over time. The technology could be suitable as a point of care testing in defining risk. Further prospective work is required to characterise the utility of the approach.
Micromanipulation of prophase I chromosomes from mouse spermatocytes reveals high stiffness and gel-like chromatin organization
Authors: Biggs Ronald , Liu Ning , Peng Yiheng , Marko John F. , Qiao Huanyu
Published: September 2020

Meiosis produces four haploid cells after two successive divisions in sexually reproducing organisms. A critical event during meiosis is construction of the synaptonemal complex (SC), a large, protein-based bridge that physically links homologous chromosomes. The SC facilitates meiotic recombination, chromosome compaction, and the eventual separation of homologous chromosomes at metaphase I. We present experiments directly measuring physical properties of captured mammalian meiotic prophase I chromosomes. Mouse meiotic chromosomes are about ten-fold stiffer than somatic mitotic chromosomes, even for genetic mutants lacking SYCP1, the central element of the SC. Meiotic chromosomes dissolve when treated with nucleases, but only weaken when treated with proteases, suggesting that the SC is not rigidly connected, and that meiotic prophase I chromosomes are a gel meshwork of chromatin, similar to mitotic chromosomes. These results are consistent with a liquid- or liquid-crystal SC, but with SC-chromatin stiff enough to mechanically drive crossover interference.
Antigen-specific competitive inhibition of CD4+T cell recruitment into the primary immune response
Authors: Spencer Alexandra J. , Smith Adrian L. , de St Groth Barbara Fazekas
Published: September 2020

Previous studies suggest that recruitment of naïve T cells into a program of cell division and differentiation is a highly synchronous process under tight regulation. However it is not known whether antigen availability is the major regulator of this process, or whether other factors such as ongoing responses to unrelated antigens can affect the size of the primary response. We have developed an adoptive transfer system to investigate the efficiency with which additional antigen specific cells are recruited into an ongoing primary immune response. Recruitment of additional cells is an inverse function of the size of the response and is progressively inhibited with time. Cells recruited late into the response proliferate less, and fewer secrete IL-2 and IFN-γ. Thus the size of the response changes very little as a result of late recruitment. The inhibition of recruitment, proliferation and differentiation affects only cells of the same specificity as the ongoing response, indicating that the size of an antigen specific response is independent of any shared factors such as access to APCs, costimulation or cytokines. Thus, during infection, the immune system retains the ability to respond as necessary to secondary infections or antigens not presented until later stages of the response.
The actin nucleator Spir-1 is a virus restriction factor that promotes IRF3 activation
Authors: Torres Alice Abreu , Macilwee Stephanie L. , Rashid Amir , Cox Sarah E. , Albarnaz Jonas D. , Bonjardim Claudio A. , Smith Geoffrey L.
Published: September 2020

Cellular proteins often have multiple and diverse functions. This is illustrated with protein Spir-1 that is an actin nucleator, but, as shown here, also functions to enhance IRF3 activation downstream of RNA sensing by RIG-I/MDA-5. In human and mouse cells lacking Spir-1, IRF3 activation is impaired, whereas Spir-1 overexpression enhanced IRF3 activation. Furthermore in Spir-1-/-cells, the infectious virus titres and sizes of plaques formed by two viruses that are sensed by RIG-I, vaccinia virus (VACV) and Zika virus, are increased. These observations demonstrate the biological importance of Spir-1 in the response to virus infection. Like cellular proteins, viral proteins also have multiple and diverse functions. Here, we also show that VACV virulence factor K7 binds directly to Spir-1 and that a diphenylalanine motif of Spir-1 is needed for this interaction and for Spir-1-mediated enhancement of IRF3 activation. Thus, Spir-1 is a new virus restriction factor and is targeted directly by an immunomodulatory viral protein that enhances virus virulence and diminishes IRF3 activation.

Author Summary

Infection of cells by viruses is sensed by host molecules called pattern recognition receptors (PRRs) that activate signalling pathways leading to an anti-viral response. In turn, viruses express proteins that negate these host responses to mediate escape from the anti-viral response. Here, we report that protein K7 from a large DNA virus called vaccinia virus (VACV), binds to a host cell protein called Spir-1. Spir-1 is known to regulate the assembly of actin filaments inside cells, but here we show that Spir-1 also functions to activate the host response to virus infection and to limit the replication and spread of both RNA and DNA viruses. Thus, this study has uncovered new functions of cellular protein Spir-1 as an activator of innate immunity and as a restriction factor for diverse viruses. Further, it shows that Spir-1 is targeted by a virus protein during infection.
Functional insights from KpfR, a new transcriptional regulator of fimbrial expression that is crucial forKlebsiella pneumoniaepathogenicity
Authors: Gomes Ana E. I. , Pacheco Thaisy , Santos Cristiane S. , Pereira José A. , Ribeiro Marcelo L. , Darrieux Michelle , Ferraz Lúcio F. C.
Published: September 2020

Although originally known as an opportunistic pathogen,Klebsiella pneumoniaehas been considered a worldwide health threat nowadays due to the emergence of hypervirulent and antibiotic-resistant strains capable of causing severe infections not only on immunocompromised patients but also on healthy individuals. Fimbriae is an essential virulence factor forK. pneumoniae, especially in urinary tract infections, because it allows the pathogen to adhere and invade urothelial cells and to form biofilms on biotic and abiotic surfaces. The importance of fimbriae forK. pneumoniaepathogenicity is highlighted by the large number of fimbrial gene clusters on the bacterium genome, which requires a coordinated and finely adjusted system to control the synthesis of these structures. In this work, we describe KpfR as a new transcriptional repressor of fimbrial expression inK. pneumoniaeand discuss its role in the bacterium pathogenicity.K. pneumoniaelacking thekpfRgene exhibited a hyperfimbriated phenotype with enhanced biofilm formation and greater adhesion to and replication within epithelial host cells. However, the mutant strain was attenuated for colonization of the bladder in a murine model of urinary tract infection. These results indicate that KpfR is an important transcriptional repressor that, by negatively controlling the expression of fimbriae, preventsK. pneumoniaefrom having a hyperfimbriated phenotype and from being recognized and eliminated by the host immune system.

IMPORTANCE

Fimbriae are crucial virulence factor for many pathogens because they allow the pathogen to adhere and invade host cells and to form biofilm on biotic and abiotic surfaces. However, the synthesis of fimbriae requires a precise and coordinated control to guarantees the production of these structures only when necessary, thus avoiding unnecessary energy expenditure and bacterial clearance by the host immune cells. Herein, we describe for the first time the role of the transcriptional repressor of fimbrial expression KpfR on the pathogenicity ofK. pneumoniae, a Gram-negative pathogen that has gained worldwide attention, notably for being the causative agent of severe and metastatic infections even on healthy individuals. By deleting thekpfRgene, we show that the mutant strain loses the control of fimbriae production, resulting in a hyperfimbriated phenotype that impairsK. pneumoniaeability to colonize a murine model of urinary tract infection.
Variation in the Gut Microbiota of Common Marmosets: Differences with Colony of Origin and Integration
Authors: Cooper Rachel E. , Mangus Lisa M. , Lynch Jessica , Schonvisky Kayla , Wright Justin R. , McLimans Christopher J. , Wong Hoi Tong , See Jeremy Chen , Lamendella Regina , Mankowski Joseph L.
Published: September 2020

Characterization of the gut microbiome may aid understanding and management of natural and experimental disease states in research animals, thereby promoting reproducibility. In this study, the rectal bacterial communities of three separate common marmoset (Callithrix jacchus) breeding colonies were defined using 16S rRNA sequencing of rectal swab samples. Study animals originated from two German colonies and a United States colony (JHU). The two German cohorts, previously fed the same diet, were imported into the JHU facility; they were then isolated, transitioned onto JHU diet, and then moved into rooms housing JHU animals. To dissect the contributions of diet and integration in shaping the rectal bacterial community, samples were collected from German origin marmosets upon JHU arrival (baseline), following diet transition (100 d), and following cohousing (390 d). Baseline and 390 d samples were collected from stably maintained JHU marmosets. Bacterial community composition was distinct between all three cohorts at baseline, suggesting that factors other than primary diet confer significant differences between captive populations. Beta-diversity of the animals from the two German colonies converged by 100 d but remained distinct from JHU sample beta-diversity throughout the 390-d study, indicating that diet had greater influence on bacterial community composition than did housing animals within the same room. Our results demonstrate substantial differences in gut bacteria between different captive marmoset colonies, with persistence of these differences following husbandry standardization and housing integration. Goals of rigor and reproducibility in research underscore the need to consider microbial differences between marmosets of diverse origin.

Importance

Characterizing gut microbial populations is expected to promote health and enhance research reproducibility in animal studies. As use of common marmosets as animal models of human diseases expands, evaluating the marmoset gut bacterial community will be critical for interpreting research findings, especially as marmosets are prone to gastrointestinal inflammation. In this study, using 16S rRNA sequencing of rectal swab samples, we compared bacterial community among three captive colonies of marmosets at baseline and following importation of cohorts from two of the colonies into the third colony. Diet history had sustained influence on bacterial community composition, while housing the animals within the same room over a period of eight months did not appear to be a major factor. These persistent differences in marmoset gut bacterial community highlight the need for careful consideration of animal origin as a variable in marmoset research studies.
Mental healthcare and service user impact of the COVID-19 pandemic: results of a UK survey of staff working with people with intellectual disability and developmental disorders
Authors: Sheehan Rory , Dalton-Locke Christian , Ali Afia , Totsika Vasiliki , Vera San Juan Norha , Hassiotis Angela
Published: September 2020

Background

Very little is known about the impact of previous epidemics on the care of people with intellectual and developmental disabilities, particularly in terms of mental health services. The COVID-19 pandemic has the potential to exacerbate existing health inequalities as well as expose gaps in service provision for this vulnerable population group.

Methods

We investigated the responses of 648 staff working in mental healthcare with people with intellectual disabilities and/or developmental disabilities. Participants contributed to a UK-wide online survey undertaken by the National Institute for Health Research Mental Health Policy Research Unit between 22nd April and 12th May 2020. Recruitment was via professional networks, social media and third sector organisations. Quantitative data describing staff experience over three domains (challenges at work, service user and carer problems, sources of help at work) were summarised and differences between groups explored using Chi square tests. Content analysis was used to organise qualitative data focusing on service changes in response to the pandemic.

Results

The majority of survey respondents worked in the NHS and in community mental health services. One third had managerial responsibility. Major concerns expressed by mental healthcare staff were: difficulties for service users due to lack of access to usual support networks and health and social care services during the pandemic; and difficulties maintaining adequate levels of support secondary to increased service user need. Staff reported having to quickly adopt new digital ways of working was challenging; nevertheless, free text responses identified remote working as the innovation that staff would most like to retain after the pandemic subsides.

Conclusions

Understanding the experiences of staff working across different settings in mental healthcare for people with intellectual and developmental disabilities during the COVID-19 pandemic is essential in guiding contingency planning and fostering service developments to ensure the health of this vulnerable group is protected in any future disease outbreaks.
Covid-19 SEIDRD Modelling for Pakistan with implementation of seasonality, healthcare capacity and behavioral risk reduction
Authors: Saadat Shoab , Mansoor Salman
Published: September 2020

INTRODUCTION

Introduction

December 2019 saw the origins of a new Pandemic which would soon spread to the farthest places of the planet. Several efforts of modelling of the geo-temporal transmissibility of the virus have been undertaken, but none describes the incorporation of effect of seasonality, contact density, primary care and ICU bed capacity and behavioral risk reduction measures such as lockdowns into the simulation modeling for Pakistan. We use above variables to create a close to real data curve function for the active cases of covid-19 in Pakistan.

Objective

The objective of this study was to create a new computational epidemiological model for Pakistan by implementing symptomatology, healthcare capacity and behavioral risk reduction mathematically to predict of Covid-19 case trends and effects of changes in community characteristics and policy measures.

Methods

We used a modified version of SEIR model called SEIDRD (Susceptible - Exposed Latent - Diagnosed as Mild or severe - Recovered - Deaths). This was developed using Vensim PLE software version 8.0. This model also incorporated the seasonal and capacity variables for Pakistan and was adjusted for behavioral risk reduction measures such as lockdowns.

Results

The SEIDRD model was able to closely replicate the active covid-19 cases curve function for Pakistan until now. It was able to show that given current trends, though the number of active cases are dropping, if the smart lockdown measures were to end, the cases are expected to show a rise from 28th August 2020 onwards reaching a second peak around 28th September 2020. It was also seen that increasing the ICU bed capacity in Pakistan from 4000 to 40000 will not make a significant difference in active case number. Another simulation for a vaccination schedule of 100000 vaccines per day was created which showed a decrease in covid cases in a slow manner over a period of months rather than days.

Conclusion

This study attempts to successfully model the active covid-19 cases curve function of Pakistan and mathematically models the effect of seasonality, contact density, ICU bed availability and Lockdown measures. We were able to show the effectiveness of smart lockdowns and were also to predict that in case of no smart lockdowns, Pakistan can see a rise in active case number starting from 28th of August 2020.
Trust and Transparency in times of Crisis: Results from an Online Survey During the First Wave (April 2020) of the COVID-19 Epidemic in the UK
Authors: Enria Luisa , Waterlow Naomi , Rogers Nina T , Brindle Hannah , Lal Sham , Eggo Rosalind M , Lees Shelley , Roberts Chrissy h
Published: September 2020

Background

The success of a government’s COVID-19 control strategy relies on public trust and broad acceptance of response measures. We investigated public perceptions of the UK government’s COVID-19 response, focusing on the relationship between trust and transparency, during the first wave (April 2020) of the COVID-19 pandemic in the United Kingdom.

Methods

Anonymous survey data were collected (2020-04-06 to 2020-04-22) from 9,322 respondents, aged 20+ using an online questionnaire. We took a mixed methods approach to data analysis, combining statistical analyses, structural topic modelling (STM) and qualitative thematic coding of a sub-set of responses. Missing data were imputed via multiple imputation.

Results

Most respondents (95.1%) supported government enforcement of behaviour change. While 52.1% of respondents thought the government was making good decisions, differences were apparent across demographic groups, for example respondents from Scotland had lower odds of responding positively than respondents in London. Higher educational levels saw decreasing odds of having a positive opinion of the government response and decreasing household income associated with decreasing positive opinion. Of respondents who thought the government was not making good decisions 60% believed the economy was being prioritised over people and their health. Positive views on government decision-making were associated with positive views on government transparency about the COVID-19 response. Qualitative analysis about government transparency highlighted five key themes: (1) the justification of opacity due to the condition of crisis, (2) generalised mistrust of politics, (3) concerns about the role of scientific evidence, (4) quality of government communication and (5) questions about political decision-making processes.

Conclusion

We recommend targeted community engagement tailored to different groups’ experiences and a focus on accountability and openness around how decisions are made in the response to the UK COVID-19 pandemic.
Enhanced synaptic transmission in the extended amygdala and altered excitability in an extended amygdala to brainstem circuit in a Dravet syndrome mouse model
Authors: Yan Wen Wei , Xia Maya , Levitt Alyssa , Hawkins Nicole , Kearney Jennifer , Swanson Geoffrey T. , Chetkovich Dane , Nobis William P.
Published: September 2020

Objective

Dravet syndrome (DS) is a severe, early-onset epilepsy with an increased incidence of sudden death. Evidence of interictal breathing deficits in DS suggest that alterations in subcortical projections to brainstem nuclei may exist, which might be driving comorbidities in DS. The aim of this study was to determine if a subcortical structure, the bed nucleus of the stria terminalis (BNST) in the extended amygdala, is activated by seizures, exhibits changes in excitability, and expresses any alterations in neurons projecting to a brainstem nucleus associated with respiration, stress response and homeostasis.

Methods

Experiments were conducted using F1 mice generated by breeding 129.Scn1a+/-mice with wildtype C57BL/6J mice. Immunohistochemistry was performed to quantify neuronal c-fos activation in DS mice after observed spontaneous seizures. Whole cell patch clamp and current clamp electrophysiology recordings were conducted to evaluate changes in intrinsic and synaptic excitability in the BNST.

Results

Spontaneous seizures in DS mice significantly enhanced neuronal c-fos expression in the BNST. Further, the BNST had altered AMPA/NMDA postsynaptic receptor composition and showed changes in spontaneous neurotransmission, with greater excitation and decreased inhibition. BNST to parabrachial nucleus (PBN) projection neurons exhibited intrinsic excitability in wildtype mice, while these projection neurons were hypoexcitable in DS mice.

Significance

The findings suggest that there is altered excitability in neurons of the BNST, including BNST to PBN projection neurons, in DS mice. These alterations could potentially be driving comorbid aspects of DS outside of seizures, including respiratory dysfunction and sudden death.

SIGNIFICANCE STATEMENT

Dravet syndrome (DS) is an early-onset epilepsy with an increased risk of sudden death. We determined that there are alterations in a subcortical nucleus, the bed nucleus of the stria terminalis (BNST) of the extended amygdala, in a murine DS model. The BNST is involved in stress, anxiety, feeding, and respiratory function. We found enhanced activation in the BNST after seizures and alterations in basal synaptic neurotransmission–with enhanced spontaneous excitatory and decreased spontaneous inhibitory postsynaptic events. Evaluating those neurons that project to the parabrachial nucleus (PBN), a nucleus with multiple homeostatic roles, we found them to be hypoexcitable in DS. Alterations in BNST to brainstem projections could be implicated in comorbid aspects of DS, including respiratory dysfunction and sudden death.