bluuebunny/crossref_metadata_2025_split huggingface dataset:
Common and distinct roles of frontal midline theta and occipital alpha oscillations in coding temporal intervals and spatial distances
Authors: Liang Mingli , Zheng Jingyi , Isham Eve , Ekstrom Arne 
Published: August 2020

AbstractJudging how far something is and how long it takes to get there are critical to memory and navigation. Yet, the neural codes for spatial and temporal information remain unclear, particularly the involvement of neural oscillations in maintaining such codes. To address these issues, we designed an immersive virtual reality environment containing teleporters that displace participants to a different location after entry. Upon exiting the teleporters, participants made judgements from two given options regarding either the distance they had travelled (spatial distance condition) or the duration they had spent inside the teleporters (temporal duration condition). We wirelessly recorded scalp EEG while participants navigated in the virtual environment by physically walking on an omnidirectional treadmill and traveling through teleporters. An exploratory analysis revealed significantly higher alpha and beta power for short distance versus long distance traversals, while the contrast also revealed significantly higher frontal midline delta-theta-alpha power, and global beta power increases for short versus long temporal duration teleportation. Analyses of occipital alpha instantaneous frequencies revealed their sensitivity for both spatial distances and temporal durations, suggesting a novel and common mechanism for both spatial and temporal coding. We further examined the resolution of distance and temporal coding by classifying discretized distance bins and 250ms time bins based on multivariate patterns of 2-30 Hz power spectra, finding evidence that oscillations code fine-scale time and distance information. Together, these findings support partially independent coding schemes for spatial and temporal information, suggesting that low-frequency oscillations play important roles in coding both space and time.
Neurodegeneration and neuroinflammation are linked, but independent ofα-synuclein inclusions, in a seeding/spreading mouse model of Parkinson’s disease
Authors: Garcia Pierre , Jürgens-Wemheuer Wiebke , Uriarte Oihane , Schmit Kristopher J , Masuch Annette , Brioschi Simone , Weihofen Andreas , Koncina Eric , Coowar Djalil , Heurtaux Tony , Glaab Enrico , Balling Rudi , Sousa Carole , Michelucci Alessandro , Kaoma Tony , Nicot Nathalie , Pfander Tatjana , Schulz-Schaeffer Walter , Allouche Ahmad , Fischer Nicolas , Biber Knut , Mittelbronn Michel , Buttini Manuel 
Published: August 2020

AbstractA key process of neurodegeneration in Parkinson’s disease (PD) is the transneuronal spreading of α-synuclein. Alpha-synuclein is a presynaptic protein that is implicated in the pathogenesis of PD and other synucleinopathies, where it forms, upon intracellular aggregation, pathological inclusions. Other hallmarks of PD include neurodegeneration and microgliosis in susceptible brain regions. Whether it is primarily transneuronal spreading of α-synuclein particles, inclusion formation, or other mechanisms, such as inflammation, that cause neurodegeneration in PD is unclear. We used spreading/aggregation of α-synuclein induced by intracerebral injection of α-synuclein preformed fibrils into the mouse brain to address this question. We performed quantitative histological analysis for α-synuclein inclusions, neurodegeneration, and microgliosis in different brain regions, and a gene expression profiling of the ventral midbrain, at two different timepoints after disease induction. We observed significant neurodegeneration and microgliosis in brain regions not only with, but also without α-synuclein inclusions. We also observed prominent microgliosis in injured brain regions that did not correlate with neurodegeneration nor with inclusion load. In longitudinal gene expression profiling experiments, we observed early and unique alterations linked to microglial mediated inflammation that preceded neurodegeneration, indicating an active role of microglia in inducing neurodegeneration. Our observations indicate that α-synuclein inclusion formation is not the major driver in the early phases of PD-like neurodegeneration, but that diffusible, oligomeric α-synuclein species, which induce unusual microglial reactivity, play a key role in this process. Our findings uncover new features of α-synuclein induced pathologies, in particular microgliosis, and point to the necessity of a broader view of the process of “prion-like spreading” of that protein.
Osmolarity-independent electrical cues guide rapid response to injury in zebrafish epidermis
Authors: Kennard Andrew S. , Theriot Julie A. 
Published: August 2020

AbstractThe ability of epithelial tissues to heal after injury is essential for animal life, yet the mechanisms by which epithelial cells sense tissue damage are incompletely understood. In aquatic organisms such as zebrafish, osmotic shock following injury is believed to be an early and potent activator of a wound response. We find that, in addition to sensing osmolarity, basal skin cells in zebrafish larvae are also sensitive to changes in the particular ionic composition of their surroundings after wounding, specifically the concentration of sodium chloride in the immediate vicinity of the wound. This sodium chloride-specific wound detection mechanism is independent of cell swelling, and instead is suggestive of a mechanism by which cells sense changes in the transepithelial electrical potential generated by the transport of sodium and chloride ions across the skin. Consistent with this hypothesis, we show that electric fields directly applied within the skin are sufficient to initiate actin polarization and migration of basal cells in their native epithelial contextin vivo, even overriding endogenous wound signaling. This suggests that, in order to mount a robust wound response, skin cells respond to both osmotic and electrical perturbations arising from tissue injury.
Rapid GMP-compliant expansion of SARS-CoV-2-specific T cells from convalescent donors for use as an allogeneic cell therapy for COVID-19
Authors: Cooper Rachel S , Fraser Alasdair R , Smith Linda , Burgoyne Paul , Imlach Stuart N , Jarvis Lisa M , Zahra Sharon , Turner Marc L. , Campbell John DM 
Published: August 2020

AbstractCOVID-19 disease caused by the SARS-CoV-2 virus is characterized by dysregulation of effector T cells and accumulation of exhausted T cells. T cell responses to viruses can be corrected by adoptive cellular therapy using donor-derived virus-specific T cells. Here we show that SARS-CoV-2-exposed blood donations contain CD4 and CD8 memory T cells specific for SARS-CoV-2 spike, nucleocapsid and membrane antigens. These peptides can be used to isolate virus-specific T cells in a GMP-compliant process. These T cells can be rapidly expanded using GMP-compliant reagents for use as a therapeutic product. Memory and effector phenotypes are present in the selected virus-specific T cells, but our method rapidly expands the desirable central memory phenotype. A manufacturing yield ranging from 1010to 1011T cells can be obtained within 21 days culture. Thus, multiple therapeutic doses of virus-specific T cells can be rapidly generated from convalescent donors for treatment of COVID-19 patientsOne Sentence SummaryCD4+ and CD8+ T cells specific for SARS-CoV-2 can be isolated from convalescent donors and rapidly expanded to therapeutic doses at GMP standard, maintaining the desired central memory phenotype required for protective immune responses against severe COVID-19 infections.
Cortical silencing results in paradoxical fMRI overconnectivity
Authors: Canella Carola , Rocchi Federico , Noei Shahryar , Gutierrez-Barragan Daniel , Coletta Ludovico , Galbusera Alberto , Vassanelli Stefano , Pasqualetti Massimo , Iurilli Giuliano , Panzeri Stefano , Gozzi Alessandro 
Published: August 2020

ABSTRACTfMRI-based measurements of functional connectivity are commonly interpreted as an index of anatomical coupling and direct interareal communication. However, causal testing of this hypothesis has been lacking. Here we combine neural silencing, resting-state fMRI andin vivoelectrophysiology to causally probe how inactivation of a cortical region affects brain-wide functional coupling. We find that chronic silencing of the prefrontal cortex (PFC) via overexpression of a potassium channel paradoxically increases rsfMRI connectivity between the silenced area and its thalamo-cortical terminals. Acute chemogenetic silencing of the PFC reproduces analogous patterns of overconnectivity, an effect associated with over-synchronous fMRI coupling between polymodal thalamic regions and widespread cortical districts. Notably, multielectrode recordings revealed that chemogenetic inactivation of the PFC attenuates gamma activity and increases delta power in the silenced area, resulting in robustly increased delta band coherence between functionally overconnected regions. The observation of enhanced rsfMRI coupling between chemogenetically silenced areas challenges prevailing interpretations of functional connectivity as a monotonic index of direct axonal communication, and points at a critical contribution of slow rhythm generators to the establishment of brain-wide functional coupling.
Liquid-liquid phase separation of tau driven by hydrophobic interaction facilitates fibrillization of tau
Authors: Lin Yanxian , Fichou Yann , Longhini Andrew P. , Llanes Luana C. , Yin Yinson , Bazan Guillermo C. , Kosik Kenneth S. , Han Songi 
Published: August 2020

AbstractAmyloid aggregation of tau protein is implicated in neurodegenerative diseases, yet its facilitating factors are poorly understood. Recently, tau has been shown to undergo liquid liquid phase separation (LLPS) bothin vivoandin vitro. LLPS was shown to facilitate tau amyloid aggregation in certain cases, while independent of aggregation in other cases. It is therefore important to understand the differentiating properties that resolve this apparent conflict. We report on a model system of hydrophobically driven LLPS induced by high salt concentration (LLPS-HS), and compare it to electrostatically driven LLPS represented by tau-RNA/heparin complex coacervation (LLPS-ED). We show that LLPS-HS promotes tau protein dehydration, undergoes maturation and directly leads to canonical tau fibrils, while LLPS-ED is reversible, remains hydrated and does not promote amyloid aggregation. We show that the nature of the interaction driving tau condensation is the differentiating factor between aggregation-prone and aggregation-independent LLPS.
A Facile Method for Simultaneous Visualization of Wet Cells and Nanostructured Biomaterials in SEM using Ionic Liquids
Authors: Lee Bryan E.J. , DiCecco Liza-Anastasia , Exir Hourieh , Weck Arnaud , Sask Kyla , Grandfield Kathryn 
Published: August 2020

AbstractThis work presents a successful methodology to image mammalian cells adhered to nanostructured biomaterials using scanning electron microscopy (SEM) operating in low-vacuum mode following ionic liquid treatment. Human osteoblast-like Saos-2 cells were treated with a room-temperature ionic liquid, 1-Ethyl-3-methylimidazolium tetrafluoroborate, and subsequently imaged on titanium utilizing SEM. Titanium substrates were modified to create laser-induced periodic surface structures (LIPSS) for visualizing at the sub-micron scale. Using a combination of fluorescence-based cell metabolism along with light microscopy and SEM image analysis, the shape and location of irradiated cells were confirmed to be unchanged after multiple irradiation sessions while the viability of minimally irradiated cells was unaltered. The wet imaging conditions combined with a rapid facile protocol using ionic liquid allows this technique to fulfill a niche in examining cellular behavior on biomaterials with sub-micron surface features. The demonstrated method to track observed cell adhesion to sub-micron surface features with SEM has great implications for the understanding of cell migration on nanostructured surfaces as well as on the exploration of simpler SEM preparation methods for cellular imaging.
The antimicrobial activity of the macrophage metabolite itaconate is synergistic with acidity
Authors: Duncan Dustin , Lupien Andréanne , Behr Marcel A. , Auclair Karine 
Published: August 2020

AbstractThe production of itaconate by macrophages was only discovered in 2011. A rapidly increasing number of studies have since revealed essential biological roles for itaconate, ranging from antimicrobial to immunomodulator. Itaconate has been estimated to reach low-millimolar concentrations in activated macrophages, including those within infected lungs and brains, whereas itaconate’s MIC towards several bacterial strains were measured to be in the low-to-mid-millimolar range, casting some doubts on the antibacterial role of itaconatein vivo. Several of these investigations, in particular those measuring MIC values of itaconate or itaconic acid, have however tended to ignore the high acidity of this small diacid (pKas 3.85 and 5.45), thereby potentially biasing the MIC measurements. We report herein that: 1) at high concentration, itaconic acid can significantly reduce the pH of growth media; 2) the antibacterial activity of itaconate increases in a synergistic manner with acidity; 3) this synergistic effect is not simply due to increased permeability of monoanionic itaconate; 4) considering that the MIC of itaconate is many fold lower under acidic conditions for all strains tested, itaconate may serve an antimicrobial role, particularly in acidic vesicles such as the phagolysosome; and 5) differential growth behavior in the presence of disodium itaconate versus itaconic acid may serve to rapidly screen bacterial strains for their ability to metabolize itaconate. Our results further support the hypothesis that inhibitors of itaconate degradation in bacteria may provide a new strategy to treat infections.
IFN-γand TNF-αdrive aCXCL10+CCL2+ macrophage phenotype expanded in severe COVID-19 and other diseases with tissue inflammation
Authors: Zhang Fan , Mears Joseph R. , Shakib Lorien , Beynor Jessica I. , Shanaj Sara , Korsunsky Ilya , Nathan Aparna ,   Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Consortium, Donlin Laura T. , Raychaudhuri Soumya 
Published: August 2020

AbstractImmunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. Using an integrative strategy, we built a reference by meta-analyzing > 300,000 immune cells from COVID-19 and 5 inflammatory diseases including rheumatoid arthritis (RA), Crohn’s disease (CD), ulcerative colitis (UC), lupus, and interstitial lung disease. Our cross-disease analysis revealed that anFCN1+ inflammatory macrophage state is common to COVID-19 bronchoalveolar lavage samples, RA synovium, CD ileum, and UC colon. We also observed that aCXCL10+CCL2+ inflammatory macrophage state is abundant in severe COVID-19, inflamed CD and RA, and expresses inflammatory genes such asGBP1, STAT1, andIL1B. We found that theCXCL10+CCL2+ macrophages are transcriptionally similar to blood-derived macrophages stimulated with TNF-αand IFN-γ ex vivo. Our findings suggest that IFN-γ, alongside TNF-α, might be a key driver of this abundant inflammatory macrophage phenotype in severe COVID-19 and other inflammatory diseases, which may be targeted by existing immunomodulatory therapies.
The DHODH Inhibitor PTC299 Arrests SARS-CoV-2 Replication and Suppresses Induction of Inflammatory Cytokines
Authors: Luban Jeremy , Sattler Rachel , Mühlberger Elke , Graci Jason D. , Cao Liangxian , Weetall Marla , Trotta Christopher , Colacino Joseph M. , Bavari Sina , Strambio-De-Castillia Caterina , Suder Ellen L. , Wang Yetao , Soloveva Veronica , Cintron-Lue Katherine , Naryshkin Nikolai A. , Pykett Mark , Welch Ellen M. , O’Keefe Kylie , Kong Ronald , Goodwin Elizabeth , Jacobson Allan , Paessler Slobodan , Peltz Stuart 
Published: August 2020

SUMMARYThe coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-CoV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally available compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS CoV-2 replication (EC50range, 2.0 to 31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.
Analysis of the potential impact of genomic variants in SARS-CoV-2 genomes from India on molecular diagnostic assays
Authors: Jain Abhinav , Rophina Mercy , Mahajan Saurabh , Krishnan Bhavya Balaji , Sharma Manasa , Mandal Sreya , Fernandez Teresa , Sultanji Sumayra , Mathew Samatha , Sivasubbu Sridhar , Scaria Vinod 
Published: August 2020

ABSTRACTAn isolated epidemic of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causing Coronavirus Diseases (COVID-19) originating in Wuhan, China has now rapidly emerged into a global pandemic affecting millions of people worldwide. Molecular detection of SARS-CoV-2 using reverse transcription polymerase chain reaction (RT-PCR) forms the mainstay in screening, diagnosis and epidemiology of disease. The virus has been evolving through base substitutions. The recent availability of genomes of SARS-CoV-2 isolates from different countries including India motivated us to assess the presence and potential impact of variations in target sites for the oligonucleotide primers and probes used in molecular diagnosis. We catalogued a total of 132 primers or probes sequences from the literature and the public domain. Our analysis revealed a total of 125 unique genetic variants in 80 either primers or probes binding sites. A total of 13 unique variants had allele frequency of ≥ 1% in Indian SARS-CoV-2 genomes mapped to the primers or probes binding sites. A total of 15 primers or probes binding sites had cumulative variant frequency of ≥ 1% in the SARS-CoV-2 genomes. These included primers or probes sites which are widely used in India and across the world for molecular diagnosis as well as approved by national and international agencies. This highlights the need for sequencing genomes of emerging pathogens to make evidence based policies for development and approval of diagnostics. To the best of our knowledge, ours is the most comprehensive analysis of genomic variants in genomes of SARS-CoV-2 isolates from India and their potential impact on efficacy of molecular diagnostics.
Dynamic patterns of correlated activity in the prefrontal cortex encode information about social behavior
Authors: Frost Nicholas A. , Haggart Anna , Sohal Vikaas S. 
Published: August 2020

ABSTRACTNew technologies have made it possible to measure activity from many neurons simultaneously. Nevertheless, most studies still analyze the activity of simultaneously recorded neurons one-at-a-time, then group together neurons which increase their activity during similar behaviors into an ‘ensemble.’ This notion of an ensemble ignores the ability of neurons to act collectively, and encode and transmit information in ways that are not reflected by their individual activity levels. We used microendoscopic GCaMP imaging to measure prefrontal activity while mice were either alone or engaged in social interaction. We developed new approaches, using neural network classifiers and surrogate (shuffled) datasets, to characterize how neurons synergistically transmit information about social behavior. Surrogate datasets which preserve behaviorally-specific patterns of coactivity (correlations) outperform those which preserve behaviorally-driven changes in activity levels but not correlated activity. This shows that prefrontal neurons act collectively to transmit information about socialization, because social behavior elicits increases in correlated activity that are not explained simply by the activity levels of the underlying neurons. Notably, this ability of correlated activity to enhance the information transmitted by neuronal ensembles is lost in mice lacking the autism-associated gene Shank3. These results show that synergy is an important concept for the coding of social behavior which can be disrupted in disease states, reveal a specific mechanism underlying this synergy (social behavior increases correlated activity within specific ensembles), and outlines methods for studying how neurons within an ensemble can work together to encode information.
Disruption of innate defense responses by endoglycosidase HPSE promotes cell survival
Authors: Agelidis Alex , Turturice Benjamin A. , Suryawanshi Rahul K. , Yadavalli Tejabhiram , Jaishankar Dinesh , Ames Joshua , Hopkins James , Koujah Lulia , Patil Chandrashekhar D. , Hadigal Satvik R. , Kyzar Evan J. , Campeau Anaamika , Wozniak Jacob M. , Gonzalez David J. , Vlodavsky Israel , Li Jin-ping , Perkins David L. , Finn Patricia W. , Shukla Deepak 
Published: August 2020

AbstractThe drive to withstand environmental stresses and defend against invasion is a universal trait extant in all forms of life. While numerous canonical signaling cascades have been characterized in detail, it remains unclear how these pathways interface to generate coordinated responses to diverse stimuli. To dissect these connections, we follow heparanase (HPSE), a protein best known for its endoglycosidic activity at the extracellular matrix but recently recognized to drive various forms of late stage disease through unknown mechanisms. Using herpes simplex virus-1 (HSV-1) infection as a model cellular perturbation, we demonstrate that HPSE acts beyond its established enzymatic role to restrict multiple forms of cell-intrinsic defense and facilitate host cell reprogramming by the invading pathogen. We reveal that cells devoid of HPSE are innately resistant to infection and counteract viral takeover through multiple amplified defense mechanisms. With a unique grasp of the fundamental processes of transcriptional regulation and cell death, HPSE represents a potent cellular intersection with broad therapeutic potential.