bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fast recurrent processing via ventral prefrontal cortex is needed by the primate ventral stream for robust core visual object recognition
Authors: Kar Kohitij , DiCarlo James J 
Published: May 2020

SummaryDistributed neural population spiking patterns in macaque inferior temporal (IT) cortex that support core visual object recognition require additional time to develop for specific (“late-solved”) images suggesting the necessity of recurrent processing in these computations. Which brain circuit motifs are most responsible for computing and transmitting these putative recurrent signals to IT? To test whether the ventral prefrontal cortex (vPFC) is a critical recurrent circuit node in this system, here we pharmacologically inactivated parts of the vPFC and simultaneously measured IT population activity, while monkeys performed object discrimination tasks. Our results show that vPFC inactivation deteriorated the quality of the late-phase (>150 ms from image onset) IT population code, along with commensurate, specific behavioral deficits for “late-solved” images. Finally, silencing vPFC caused the monkeys’ IT activity patterns and behavior to become more like those produced by feedforward artificial neural network models of the ventral stream. Together with prior work, these results argue that fast recurrent processing through the vPFC is critical to the production of behaviorally-sufficient object representations in IT.
Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity
Authors: Shields Lauren Y. , Li Huihui , Nguyen Kevin , Kim Hwajin , Doric Zak , Gill T. Michael , Haddad Dominik , Vossel Keith , Calvert Meredith , Nakamura Ken 
Published: May 2020

ABSTRACTAlterations in mitochondrial fission may contribute to the pathophysiology of several neurodegenerative diseases, including Alzheimer’s disease (AD). However, we understand very little about the normal functions of fission, or how fission disruption may interact with AD-associated proteins to modulate pathogenesis. Here we show that loss of the central mitochondrial fission protein dynamin-related 1 (Drp1) in CA1 and other forebrain neurons markedly worsens the learning and memory of mice expressing mutant human amyloid-precursor protein (hAPP) in neurons. In cultured neurons, Drp1KO and hAPP converge to produce mitochondrial Ca2+(mitoCa2+) overload, despite decreasing mitochondria-associated ER membranes (MAMs) and cytosolic Ca2+. This mitoCa2+overload occurs independently of ATP levels. These findings reveal a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology.
ATP-driven Non-equilibrium Activation of Kinase Clients by the Molecular Chaperone Hsp90
Authors: Xu Huafeng 
Published: May 2020

AbstractThe molecular chaperone 90-kDa heat-shock protein (Hsp90) assists the late-stage folding and activation of diverse types of protein substrates (called clients), including many kinases. Previous studies have established that the Hsp90 homodimer undergoes an ATP-driven cycle through open and closed conformations. Here I propose a model of client activation by Hsp90, which predicts that this cycle enables Hsp90 to use ATP energy to drive a client out of thermodynamic equilibrium toward its active conformation. My model assumes that an Hsp90-bound client can transition between a deactivating conformation and an activating conformation. It suggests that the cochaperone Cdc37 aids Hsp90 to activate kinase clients by differentiating between these two intermediate conformations. My model makes experimentally testable predictions, including how modulating the stepwise kinetics of the Hsp90 cycle—for example, by various cochaperones—affects the activation of different clients. My model may inform client-specific and cell-type-specific therapeutic intervention of Hsp90-mediated protein activation.
An Atlas of Gene Regulatory Elements in Adult Mouse Cerebrum
Authors: Li Yang Eric , Preissl Sebastian , Hou Xiaomeng , Zhang Ziyang , Zhang Kai , Fang Rongxin , Qiu Yunjiang , Poirion Olivier , Li Bin , Liu Hanqing , Wang Xinxin , Han Jee Yun , Lucero Jacinta , Yan Yiming , Kuan Samantha , Gorkin David , Nunn Michael , Mukamel Eran A. , Behrens M. Margarita , Ecker Joseph , Ren Bing 
Published: May 2020

ABSTRACTThe mammalian cerebrum performs high level sensory, motor control and cognitive functions through highly specialized cortical networks and subcortical nuclei. Recent surveys of mouse and human brains with single cell transcriptomics1–3and high-throughput imaging technologies4,5have uncovered hundreds of neuronal cell types and a variety of non-neuronal cell types distributed in different brain regions, but the cell-type-specific transcriptional regulatory programs responsible for the unique identity and function of each brain cell type have yet to be elucidated. Here, we probe the accessible chromatin in >800,000 individual nuclei from 45 regions spanning the adult mouse isocortex, olfactory bulb, hippocampus and cerebral nuclei, and use the resulting data to define 491,818 candidatecisregulatory DNA elements in 160 distinct sub-types. We link a significant fraction of them to putative target genes expressed in diverse cerebral cell types and uncover transcriptional regulators involved in a broad spectrum of molecular and cellular pathways in different neuronal and glial cell populations. Our results provide a foundation for comprehensive analysis of gene regulatory programs of the mammalian brain and assist in the interpretation of non-coding risk variants associated with various neurological disease and traits in humans. To facilitate the dissemination of information, we have set up a web portal (http://catlas.org/mousebrain).
Phage infection and sub-lethal antibiotic exposure mediateEnterococcus faecalistype VII secretion system dependent inhibition of bystander bacteria
Authors: Chatterjee Anushila , Willett Julia L. E. , Dunny Gary M. , Duerkop Breck A. 
Published: May 2020

AbstractBacteriophages (phages) are being considered as alternative therapeutics for the treatment of multidrug resistant bacterial infections. Considering phages have narrow host-ranges, it is generally accepted that therapeutic phages will have a marginal impact on non-target bacteria. We have discovered that lytic phage infection induces transcription of type VIIb secretion system (T7SS) genes in the pathobiontEnterococcus faecalis. Membrane damage during phage infection induces T7SS gene expression resulting in cell contact dependent antagonism of different Gram positive bystander bacteria. Deletion ofessB, a T7SS structural component, abrogates phage-mediated killing of bystanders. A predicted immunity gene confers protection against T7SS mediated inhibition, and disruption of its upstream LXG toxin gene rescues growth ofE. faecalisandStaphylococcus aureusbystanders. Phage induction of T7SS gene expression and bystander inhibition requires IreK, a serine/threonine kinase, and OG1RF_11099, a predicted GntR-family transcription factor. Additionally, sub-lethal doses of membrane targeting and DNA damaging antibiotics activated T7SS expression independent of phage infection, triggering T7SS antibacterial activity against bystander bacteria. Our findings highlight how phage infection and antibiotic exposure of a target bacterium can affect non-target bystander bacteria and implies that therapies beyond antibiotics, such as phage therapy, could impose collateral damage to polymicrobial communities.Author SummaryRenewed interest in phages as alternative therapeutics to combat multi-drug resistant bacterial infections, highlights the importance of understanding the consequences of phage-bacteria interactions in the context of microbial communities. Although it is well established that phages are highly specific for their host bacterium, there is no clear consensus on whether or not phage infection (and thus phage therapy) would impose collateral damage to non-target bacteria in polymicrobial communities. Here we provide direct evidence of how phage infection of a clinically relevant pathogen triggers an intrinsic type VII secretion system (T7SS) antibacterial response that consequently restricts the growth of neighboring bacterial cells that are not susceptible to phage infection. Phage induction of T7SS activity is a stress response and in addition to phages, T7SS antagonism can be induced using sub-inhibitory concentrations of antibiotics that facilitate membrane or DNA damage. Together these data show that a bacterial pathogen responds to diverse stressors to induce T7SS activity which manifests through the antagonism of neighboring non-kin bystander bacterial cells.
Spike frequency adaptation supports network computations on temporally dispersed information
Authors: Salaj Darjan , Subramoney Anand , Kraišniković Ceca , Bellec Guillaume , Legenstein Robert , Maass Wolfgang 
Published: May 2020

AbstractFor solving tasks such as recognizing a song, answering a question, or inverting a sequence of symbols, cortical microcircuits need to integrate and manipulate information that was dispersed over time during the preceding seconds. Creating biologically realistic models for the underlying computations, especially with spiking neurons and for behaviorally relevant integration time spans, is notoriously difficult. We examine the role of spike frequency adaptation in such computations and find that it has a surprisingly large impact. The inclusion of this well known property of a substantial fraction of neurons in the neocortex — especially in higher areas of the human neocortex — moves the performance of spiking neural network models for computations on network inputs that are temporally dispersed from a fairly low level up to the performance level of the human brain.
Nance-Horan Syndrome-like 1 protein negatively regulates Scar/WAVE-Arp2/3 activity and inhibits lamellipodia stability and cell migration
Authors: Law Ah-Lai , Jalal Shamsinar , Pallett Tommy , Mosis Fuad , Guni Ahmad , Brayford Simon , Yolland Lawrence , Marcotti Stefania , Levitt James A. , Poland Simon P. , Rowe-Sampson Maia , Jandke Anett , Köchl Robert , Pula Giordano , Ameer-Beg Simon M. , Stramer Brian Marc , Krause Matthias 
Published: May 2020

AbstractCell migration is important for development and its aberrant regulation contributes to many diseases. The Scar/WAVE complex is essential for Arp2/3 mediated lamellipodia formation during mesenchymal cell migration and several coinciding signals activate it. However, so far, no direct negative regulators are known. We have identified Nance-Horan Syndrome-like 1 protein (NHSL1) as a novel, direct binding partner of the Scar/WAVE complex, which co-localise at protruding lamellipodia. This interaction is mediated by the Abi SH3 domain and two binding sites in NHSL1. Furthermore, active Rac binds to NHSL1 at two regions that mediate leading edge targeting of NHSL1. Surprisingly, NHSL1 inhibits cell migration through its interaction with the Scar/WAVE complex. Mechanistically, NHSL1 may reduce cell migration efficiency by impeding Arp2/3 activity, as measured in cells using a novel Arp2/3 FRET-FLIM biosensor, resulting in reduced F-actin density of lamellipodia, and consequently impairing the stability of lamellipodia protrusions.
The RNase J-based RNA degradosome is compartmentalized in the gastric pathogenHelicobacter pylori
Authors: Tejada-Arranz Alejandro , Galtier Eloïse , Mortaji Lamya El , Turlin Evelyne , Ershov Dmitry , De Reuse Hilde 
Published: May 2020

AbstractPost-transcriptional regulation is a major level of gene expression control in any cell. In bacteria, multiprotein machines called RNA degradosomes are central for RNA processing and degradation and some were reported to be compartmentalized inside these organelle-less cells. The minimal RNA degradosome of the important gastric pathogenHelicobacter pyloriis composed of the essential ribonuclease RNase J and RhpA, its sole DEAD-box RNA helicase, and plays a major role in the regulation of mRNA decay and adaptation to gastric colonization. Here, the subcellular localization of theH. pyloriRNA degradosome was investigated using cellular fractionation and both confocal and super-resolution microscopy. We established that RNase J and RhpA are peripheral inner membrane proteins and that this association was mediated neither by ribosomes, by RNA nor by the RNase Y membrane protein. In liveH. pyloricells, we observed that fluorescent RNase J and RhpA protein fusions assemble into non-polar foci. We identified factors that regulate the formation of these foci without affecting the degradosome membrane association. Flotillin, a bacterial membrane scaffolding protein, and free RNA promote foci formation inH. pylori. Finally, RNase J-GFP molecules and foci in cells were quantified by 3D-single-molecule fluorescence localization microscopy. The number and size of the RNase J foci were found to be scaled with growth phase and cell volume as was previously reported for eukaryotic ribonucleoprotein granules. In conclusion, we propose that membrane compartmentalization and the regulated clustering of RNase J-based degradosome hubs represent important levels of control of their activity and specificity.ImportanceHelicobacter pyloriis a bacterial pathogen that chronically colonizes the stomach of half of the human population worldwide. Infection byH. pylorican lead to the development of gastric pathologies such as ulcers and adenocarcinoma, that causes up to 800.000 deaths in the world each year. Persistent colonization byH. pylorirelies on regulation of the expression of adaptation-related genes. One major level of such control is post-transcriptional regulation that, inH. pylori, largely relies on a multi-protein molecular machine, an RNA-degradosome, that we previously discovered. In this study, we established that the two protein partners of this machine are associated to the membrane ofH. pylori. Using cutting-edge microscopy, we showed that these complexes assemble into hubs whose formation is regulated by free RNA and scaled with bacterial size and growth phase. Cellular compartmentalization of molecular machines into hubs emerges as an important regulatory level in the organelle-less bacteria.
Longitudinal profiles of dietary and microbial metabolites in formula- and breastfed infants
Authors: Sillner Nina , Walker Alesia , Lucio Marianna , Maier Tanja V , Bazanella Monika , Rychlik Michael , Haller Dirk , Schmitt-Kopplin Philippe 
Published: May 2020

ABSTRACTThe early-life metabolome of the intestinal tract is dynamically influenced by colonization of gut microbiota which in turn is affected by nutrition, i.e. breast milk or formula. A detailed examination of fecal metabolites was performed to investigate the effect of probiotics in formula compared to control formula and breast milk within the first months of life in healthy neonates. A broad metabolomics approach was conceptualized to describe fecal polar and semi-polar metabolites affected by diet within the first year of life. Fecal metabolomes were clearly distinct between formula- and breastfed infants, mainly originating from diet and microbial metabolism. Unsaturated fatty acids and human milk oligosaccharides were increased in breastfed, whereas Maillard products were found in feces of formula-fed children. Altered microbial metabolism was represented by bile acids and aromatic amino acid metabolites. Elevated levels of sulfated bile acids were detected in stool samples of breastfed infants, whereas secondary bile acids were increased in formula-fed infants. Co-microbial metabolism was supported by significant correlation between chenodeoxycholic or lithocholic acid and members of Clostridia. Fecal metabolites showed strong inter- and intra-individual behavior with features uniquely present in certain infants and at specific time points. Nevertheless, metabolite profiles converged at the end of the first year, coincided with solid food introduction.
Evidence for strong mutation bias towards, and selection against, T/U content in SARS-CoV2: implications for attenuated vaccine design
Authors: Rice Alan M. , Morales Atahualpa Castillo , Ho Alexander T. , Mordstein Christine , Mühlhausen Stefanie , Watson Samir , Cano Laura , Young Bethan , Kudla Grzegorz , Hurst Laurence D. 
Published: May 2020

ABSTRACTLarge-scale re-engineering of synonymous sites is a promising strategy to generate attenuated viruses for vaccines. Attenuation typically relies on de-optimisation of codon pairs and maximization of CpG dinculeotide frequencies. So as to formulate evolutionarily-informed attenuation strategies, that aim to force nucleotide usage against the estimated direction favoured by selection, here we examine available whole-genome sequences of SARS-CoV2 to infer patterns of mutation and selection on synonymous sites. Analysis of mutational profiles indicates a strong mutation bias towards T with concomitant selection against T. Accounting for dinucleotide effects reinforces this conclusion, observed TT content being a quarter of that expected under neutrality. A significantly different mutational profile at CDS sites that are not 4-fold degenerate is consistent with contemporaneous selection against T mutations more widely. Although selection against CpG dinucleotides is expected to drive synonymous site G+C content below mutational equilibrium, observed G+C content is slightly above equilibrium, possibly because of selection for higher expression. Consistent with gene-specific selection against CpG dinucleotides, we observe systematic differences of CpG content between SARS-CoV2 genes. We propose an evolutionarily informed gene-bespoke approach to attenuation that, unusually, seeks to increase usage of the already most common synonymous codons. Comparable analysis of H1N1 and Ebola finds that GC3 deviated from neutral equilibrium is not a universal feature, cautioning against generalization of results.
Development and optimization of a novel T7 polymerase-independent Marburg virus minigenome system
Authors: Vanmechelen Bert , Stroobants Joren , Vermeire Kurt , Maes Piet 
Published: May 2020

AbstractMarburg virus (MARV) is the only known pathogenic filovirus not belonging to the genusEbolavirus. Minigenomes have proven a useful tool to study MARV, but all existing MARV minigenomes are dependent on the addition of an exogenous T7 RNA polymerase to drive minigenome expression. However, exogenous expression of a T7 polymerase is not always feasible and acts as a confounding factor in compound screening assays. We have developed an alternative minigenome that is controlled by the natively expressed RNA polymerase II. We demonstrate here the characteristics of this new system and its applicability in a wide range of cell types. Our system shows a clear concentration-dependent activity and outperforms the existing T7 polymerase-based system at higher concentrations, especially in difficult-to-transfect cell lines. In addition, we show that our system can be used for high-throughput compound screening in a 96-well format, thereby providing an attractive alternative to previously developed MARV minigenomes.
HIV-1 and HIV-2 differentially regulate NF-κB activity during the late stages of the replication cycle through BST-2/tetherin antagonism
Authors: Dufrasne François E. , Dessilly Géraldine , Lucchetti Mara , Soumillion Kate , Ngyuvula Eléonore , Ruelle Jean , Tafforeau Lionel , Sanou Mahamoudou , Kabamba-Mukadi Benoit 
Published: May 2020

ABSTRACTHIV-2 is the second causative agent of AIDS and is commonly considered as an attenuated form of retroviral infection. Most of HIV-2-infected individuals display a slow-progressing disease, lower viral loads and a stronger immunological control of viral infection as compared with HIV-1-infected patients. The main hypothesis that could explain the difference of disease progression between HIV-1 and HIV-2 implies a more efficient T cell–mediated immunity in the control of HIV-2 infection. Herein, we investigate the effects of the HIV-2 envelope glycoprotein (Env) and its antitetherin function in the NF-κB signaling pathway during single-round infection of CD4+T cells. First, we report an essential role of the Env cytoplasmic tail (CT) in the activation of this signaling pathway and we also demonstrate that the HIV-2 Env CT activates NF-κB in a TRAF6-dependent but TAK1-independent manner. Further, we show that HIV-2 reference strains and clinical isolates are unable to completely inhibit NF-κB mainly via the Env-mediated BST-2/tetherin antagonism in the late stages of the viral replication cycle in CD4+T cells, in striking contrast to the HIV-1 Vpu-mediated counteraction of tetherin. We observe that this inability of HIV-2 to suppress NF-κB signaling pathway promotes stimulation of numerous genes involved in the antiviral immune response, such asil-6, il-21andifn-βgenes. Therefore, HIV-1 and HIV-2 differentially regulate the NF-κB-induced antiviral immune response mainly through the BST-2/tetherin antagonism. These new insights highlight molecular mechanisms determining, at least partly, the distinct immune control and disease outcomes of HIV-1 and HIV-2 infections.IMPORTANCEThis study explores how HIV-1 and HIV-2 diverge in their regulation of the NF-κB signaling pathway. We revealed that HIV-2 fails to completely inhibit NF-κB activity, thereby inducing a stronger antiviral response than HIV-1. We demonstrated that the ability to antagonize the cellular restriction factor BST-2/tetherin largely governs the regulation of the NF-κB pathway: at the late stages of the viral replication cycle, HIV-1 Vpu blocks this pathway whereas HIV-2 Env does not. We also demonstrated that several NF-κB-targeted genes are upregulated in CD4+T cells infected with HIV-2, but not with HIV-1. This stronger NF-κB-induced antiviral response may explain the better immune control of HIV-2 infection and the differences between HIV-1 and HIV-2 pathogenesis. Moreover, we observed in this study that non-pathogenic isolates of HIV-2 have an impaired NF-κB inhibitory capacity compared to pathogenic ones.
Evolution of resistance to fluoroquinolones by dengue virus serotype 4 provides insight into mechanism of action and consequences for viral fitness
Authors: Scroggs Stacey L. P. , Gass Jordan T. , Chinnasamy Ramesh , Widen Steven G. , Azar Sasha R. , Rossi Shannan L. , Arterburn Jeffrey B. , Vasilakis Nikos , Hanley Kathryn A. 
Published: May 2020

ABSTRACTDrugs against flaviviruses such as dengue (DENV) and Zika (ZIKV) virus are urgently needed. We previously demonstrated that three fluoroquinolones, ciprofloxacin, enoxacin, and difloxacin, suppress replication of six flaviviruses. To investigate the barrier to resistance and mechanism(s) of action of these drugs, DENV-4 was passaged in triplicate in HEK-293 cells in the presence or absence of each drug. Resistance to ciprofloxacin was detected by the seventh passage and to difloxacin by the tenth, whereas resistance to enoxacin did not occur within ten passages. Two putative resistance-conferring mutations were detected in the envelope gene of ciprofloxacin and difloxacin-resistant DENV-4. In the absence of ciprofloxacin, ciprofloxacin-resistant viruses sustained a significantly higher viral titer than control viruses in HEK-293 and HuH-7 cells and resistant viruses were more stable than control viruses at 37°C. These results suggest that the mechanism of action of ciprofloxacin and difloxacin involves interference with virus binding or entry.