bluuebunny/crossref_metadata_2025_split huggingface dataset:
The anti-HIV Drug Nelfinavir Mesylate (Viracept) is a Potent Inhibitor of Cell Fusion Caused by the SARS-CoV-2 Spike (S) Glycoprotein Warranting further Evaluation as an Antiviral against COVID-19 infections
Authors: Musarrat Farhana , Chouljenko Vladimir , Nabi Rafiq , Dahal Achyut , Jois Seetharama D. , Kousoulas Konstantin G. 
Published: April 2020

AbstractCoronaviruses belong to a group of enveloped, positive-single stranded RNA viruses that are known to cause severe respiratory distress in animals and humans. The current SARS coronavirus-2 (SARS CoV-2) pandemic has caused more than 2,000,000 infections globally and nearly 200,000 deaths. Coronaviruses enter susceptible cells via fusion of the viral envelope with the plasma membrane and/or via fusion of the viral envelope with endosomal membranes after endocytosis of the virus into endosomes. Previous results with SARS and MERS CoV have shown that the Spike (S) glycoprotein is a major determinant of virus infectivity and immunogenicity. Herein, we show that expression of SARS CoV-2 S (S-n) glycoprotein after transient transfection of African green monkey kidney (Vero) cells caused extensive cell fusion in comparison to limited cell fusion caused by the SARS S (S-o) glycoprotein. S-n expression was detected intracellularly and on transfected Vero cell surfaces and caused the formation of very large multinucleated cells (syncytia) by 48 hours post transfection. These results are in agreement with published pathology observations of extensive syncytial formation in lung tissues of COVID-19 patients. This differential S-n versus S-o-mediated cell fusion suggests that SARS-CoV-2 is able to spread from cell-to-cell much more efficiently than SARS effectively avoiding extracellular spaces and neutralizing antibodies. A systematic screening of several drugs for ability to inhibit S-n and S-o cell fusion revealed that the FDA approved HIV-protease inhibitor, nelfinavir mesylate (Viracept) drastically inhibited S-n and S-o-mediated cell fusion in a dose-dependent manner. Complete inhibition of cell fusion was observed at a 10 micromolar concentration. Computational modeling andin silicodocking experiments suggested the possibility that nelfinavir may bind inside the S trimer structure, proximal to the S2 amino terminus directly inhibiting S-n and S-o-mediated membrane fusion. Also, it is possible that nelfinavir mesylate acts on cellular processes to inhibit S proteolytic processing. These results warrant further investigations of the potential of nelfinavir mesylate as an antiviral drug, especially at early times after SARS-CoV-2 symptoms appear.
GlobalFungi: Global database of fungal records from high-throughput-sequencing metabarcoding studies
Authors: Větrovský Tomáš , Morais Daniel , Kohout Petr , Lepinay Clémentine , Gallardo Camelia Algora , Hollá Sandra Awokunle , Bahnmann Barbara Doreen , Bílohnědá Květa , Brabcová Vendula , D’Alò Federica , Human Zander Rainier , Jomura Mayuko , Kolařík Miroslav , Kvasničková Jana , Lladó Salvador , López-Mondéjar Rubén , Martinović Tijana , Mašínová Tereza , Meszárošová Lenka , Michalčíková Lenka , Michalová Tereza , Mundra Sunil , Navrátilová Diana , Odriozola Iñaki , Piché-Choquette Sarah , Štursová Martina , Švec Karel , Tláskal Vojtěch , Urbanová Michaela , Vlk Lukáš , Voříšková Jana , Žifčáková Lucia , Baldrian Petr 
Published: April 2020

AbstractFungi are key players in vital ecosystem services, spanning carbon cycling, decomposition, symbiotic associations with cultural and wild plants and pathogenicity. The high importance of fungi in the ecosystem processes contrasts with the incompleteness of understanding of the patterns of fungal biogeography and the environmental factors that drive it. To close this gap of knowledge, we have here collected and validated data published on the composition of soil fungal communities in terrestrial environments including soil and plant-associated habitats and made them publicly accessible through a user interface athttp://globalfungi.com. The GlobalFungi database contains over 650 million observations of fungal sequences across >20 000 samples with geographical locations and additional metadata contained in 207 original studies with millions of unique sequence variants of the fungal internal transcribed spacers (ITS) 1 and 2 representing fungal species and genera. As it is, the study represents the most comprehensive atlas of fungal distribution on the global scale open to further additions.
Integrative Omics for Informed Drug Repurposing: Targeting CNS Disorders
Authors: Shukla Rammohan , Henkel Nicholas D , Alganem Khaled , Hamoud Abdul-rizaq , Reigle James , Alnafisah Rawan S , Eby Hunter M , Imami Ali S , Creeden Justin , Miruzzi Scott A , Meller Jaroslaw , Mccullumsmith Robert E. 
Published: April 2020

AbstractThe treatment of CNS disorders, and in particular psychiatric illnesses, lacks disease-altering therapeutics for many conditions. This is likely due to regulatory challenges involving the high cost and slow-pace of drug development for CNS disorders as well as due to limited understanding of disease causality. Repurposing drugs for new indications have lower cost and shorter development timeline compared to that of de novo drug development. Historically, empirical drug-repurposing is a standard practice in psychiatry; however, recent advances in characterizing molecules with their structural and transcriptomic signatures along with ensemble of data analysis approaches, provides informed and cost-effective repurposing strategies that ameliorate the regulatory challenges. In addition, the potential to incorporate ontological approaches along with signature-based repurposing techniques addresses the various knowledge-based challenges associated with CNS drug development. In this review we primarily discuss signature-basedin silicoapproaches to drug repurposing, and its integration with data science platforms for evidence-based drug repurposing. We contrast variousin silicoand empirical approaches and discuss possible avenues to improve the clinical relevance. These concepts provide a promising new translational avenue for developing new therapies for difficult to treat disorders, and offer the possibility of connecting drug discovery platforms and big data analytics with personalized disease signatures.
Treating Influenza and SARS-CoV-2 via mRNA-encoded Cas13a
Authors: Blanchard Emmeline L. , Vanover Daryll , Bawage Swapnil Subhash , Tiwari Pooja Munnilal , Rotolo Laura , Beyersdorf Jared , Peck Hannah E. , Bruno Nicholas C , Hincapie Robert , Finn M.G. , Michel Frank , Lafontaine Eric R. , Hogan Robert J. , Zurla Chiara , Santangelo Philip J. 
Published: April 2020

ABSTRACTHere, Cas13a has been used to target and mitigate influenza virus A (IAV) and SARS-CoV-2 using a synthetic mRNA-based platform. CRISPR RNAs (crRNA) against PB1 and highly conserved regions of PB2 were screened in conjunction with mRNA-encoded Cas13a. Screens were designed such that only guides that decreased influenza RNA levels in a Cas13-mediated fashion, were valid. Cas13a mRNA and validated guides, delivered post-infection, simulating treatment, were tested in combination and across multiplicities of infection. Their function was also characterized over time. Similar screens were performed for guides against SARS-CoV-2, yielding multiple guides that significantly impacted cytopathic effect. Last, the approach was utilizedin vivo, demonstrating the ability to degrade influenza RNA in a mouse model of infection, using polymer-formulated, nebulizer-based mRNA delivery. Our findings demonstrate the applicability of Cas13a in mitigating respiratory infections bothin vitroand in a mouse model, paving the way for future therapeutic use.
Mu Transposition in the Absence of the Target-capture Protein MuB Reveals New Roles of MuB in Target Immunity and Target Selection, and Redraws the Boundaries of the Insular Ter Region ofE. coli
Authors: Walker David M. , Harshey Rasika M. 
Published: April 2020

AbstractThe target capture protein MuB is responsible for the high efficiency of phage Mu transposition within theE. coligenome. However, some targets are off-limits, such as regions immediately outside the Mu ends (cis-immunity) as well as the entire ∼37 kb genome of Mu (Mu genome immunity). Paradoxically, MuB is responsible forcis-immunity and is also implicated in Mu genome immunity, but via different mechanisms. In this study, we tracked Mu transposition from six different starting locations on theE. coligenome, in the presence and absence of MuB. The data reveal that Mu’s ability to sample the entire genome during a single hop in a clonal population is independent of MuB, and that MuB is responsible forcis-immunity, plays a lesser role in Mu genome immunity, and facilitates insertions into transcriptionally active regions. Unexpectedly, transposition patterns in the absence of MuB have helped extend the boundaries of the insular Ter segment of theE. coligenome.
Chronic environmental or genetic elevation of galanin in noradrenergic neurons confers stress resilience in mice
Authors: Tillage Rachel P. , Wilson Genevieve E. , Liles L. Cameron , Holmes Philip V. , Weinshenker David 
Published: April 2020

ABSTRACTThe neuropeptide galanin has been implicated in stress-related neuropsychiatric disorders in both humans and rodent models. While pharmacological treatments for these disorders are ineffective for many individuals, physical activity is beneficial for stress-related symptoms. Galanin is highly expressed in the noradrenergic system, particularly the locus coeruleus (LC), which is dysregulated in stress-related disorders and activated by exercise. Galanin expression is elevated in the LC by chronic exercise, and blockade of galanin transmission attenuates exercise-induced stress resilience. However, most research on this topic has been done in rats, so it is unclear whether the relationship between exercise and galanin is species-specific. Moreover, use of intracerebroventricular galanin receptor antagonists in prior studies precluded defining a causal role for LC-derived galanin specifically. Therefore, the goals of this study were twofold. First, we investigated whether physical activity (chronic voluntary wheel running) increases stress resilience and galanin expression in the LC of mice. Next, we used transgenic mice that overexpress galanin in noradrenergic neurons (Gal OX) to determine how chronically elevated noradrenergic-derived galanin, alone, alters anxiogenic-like responses to stress. We found that three weeks ofad libitumaccess to a running wheel in their home cage increased galanin mRNA in the LC of mice and conferred resilience to a stressor. The effects of exercise were phenocopied by galanin overexpression in noradrenergic neurons, and Gal OX mice were resistant to the anxiogenic effect of optogenetic LC activation. Together, these findings support a role for chronically increased noradrenergic galanin in mediating resilience to stress.Significance statementUnderstanding the neurobiological mechanisms underlying behavioral responses to stress is necessary to improve treatments for stress-related neuropsychiatric disorders. Increased physical activity is associated with stress resilience in humans, but the neurobiological mechanisms underlying this effect are not clear. Here we investigate the anxiolytic potential of the neuropeptide galanin from the main noradrenergic nucleus, the locus coeruleus (LC). We show that chronic voluntary wheel running in mice galanin expression in the LC and stress resilience. Furthermore, we show that genetic overexpression of galanin in noradrenergic neurons confers resilience to the anxiogenic effects of foot shock and optogenetic LC activation. These findings support a role for chronically increased noradrenergic galanin in mediating resilience to stress.
A Murine Model of Lyme Disease Demonstrates ThatBorrelia burgdorferiColonizes the Dura Mater and Induces Inflammation in the Central Nervous System
Authors: Casselli Timothy , Divan Ali , Tourand Yvonne , Pecoraro Heidi L. , Brissette Catherine A. 
Published: April 2020

ABSTRACTLyme disease, which is caused by infection withBorrelia burgdorferiand related species, can lead to inflammatory pathologies affecting the joints, heart, and nervous systems including the central nervous system (CNS). Inbred laboratory mice are effective models for characterizingB. burgdorferiinfection kinetics and host immune responses in joints and heart tissues; however, similar studies are lacking in the CNS of these animals. Here we characterize the kinetics ofB. burgdorfericolonization and associated immune responses in the CNS of infected C3H mice during early and subacute infection.B. burgdorfericolonized the dura mater following needle or tick challenge, and induced expression of inflammatory cytokines and a robust IFN response as well as histopathological changes. A sterile IFN response in the absence ofB. burgdorferior inflammatory cytokines was unique to the brain parenchyma, and could provide insights into the mechanism of inflammatory CNS pathology associated with this important pathogen.
Surface chemistry-mediated modulation of adsorbed albumin folding state specifies nanocarrier clearance by distinct macrophage subsets
Authors: Vincent Michael P. , Bobbala Sharan , Karabin Nicholas B. , Frey Molly , Liu Yugang , Navidzadeh Justin O. , Stack Trevor , Scott Evan A. 
Published: April 2020

AbstractControlling nanocarrier interactions with the immune system requires a thorough understanding of the surface properties that modulate protein adsorption in biological fluids, since the resulting protein corona redefines cellular interactions with nanocarrier surfaces. Albumin is initially the dominant protein to adsorb to nanobiomaterial surfaces, a process that is considered benign or beneficial by minimizing opsonization or inflammation. Here, we demonstrate the surface chemistry of a model self-assembled nanocarrier can be engineered to stabilize or denature the three-dimensional conformation of adsorbed albumin, which respectively promotes evasion or non-specific clearancein vivo. Interestingly, certain common chemistries that have long been considered to convey stealth properties were found to promote albumin recognition by macrophage class A1 scavenger receptors (SR-A1), providing a means for their eventual removal from systemic circulation. We establish that the surface chemistry of nanocarriers can be specified to modulate adsorbed albumin structure and thereby tune clearance by macrophage scavenger receptors.
The PhoPQ two-component system is the major regulator of cell surface properties, stress responses and plant-derived substrate utilisation during development ofPectobacterium versatile-host plant pathosystem
Authors: Kravchenko Uljana , Gogoleva Natalia , Kolubako Anastasia , Kruk Alla , Diubo Julia , Gogolev Yuri , Nikolaichik Yevgeny 
Published: April 2020

SummaryThe PhoPQ two-component system, originally described in pectobacteria as PehRS, was previously shown to regulate a single gene,pehA. Using an insertionalphoPmutant ofPectobacterium versatile, we demonstrate that PhoP controls a regulon of at least 116 genes with a large fraction of regulon members specific for pectobacteria. The functions performed by the PhoP controlled genes include transport and metabolism of plant-derived carbon sources (polygalacturonate, arabinose and citrate), modification of bacterial cell envelope and stress resistance. High concentrations of calcium and magnesium ions were found to abolish the PhoPQ-dependent transcription activation. Reduced PhoP expression and minimisation of PhoP dependence of regulon members’ expression in the cells isolated from rotten potato tuber tissues suggest that PhoPQ system may adjust expression levels of multiple virulence-related genes during the course ofP. versatile-host plant pathosystem development.
Specialized and shared functions of diguanylate cyclases and phosphodiesterases inStreptomycesdevelopment
Authors: Haist Julian , Neumann Sara Alina , Al-Bassam Mahmoud M , Lindenberg Sandra , Elliot Marie A , Tschowri Natalia 
Published: April 2020

AbstractLevels of the second messenger bis-3’-5’-cyclic di-guanosinemonophosphate (c-di-GMP) determine whenStreptomycesinitiate sporulation to survive under adverse conditions. c-di-GMP signals are integrated into the genetic differentiation network by the regulator BldD and the sigma factor σWhiG. However, functions of the development-specific c-di-GMP diguanylate cyclases (DGCs) CdgB and CdgC, and the phosphodiesterases (PDEs) RmdA and RmdB, are poorly understood. Here, we provide biochemical evidence that the GGDEF-EAL domain protein RmdB fromS. venezuelaeis a monofunctional PDE that hydrolyzes c-di-GMP to 5’pGpG. Despite having an equivalent GGDEF-EAL domain arrangement, RmdA cleaves c-di-GMP to GMP and exhibits residual DGC activity. We show that an intact EAL motif is crucial for thein vivofunction of both enzymes since strains expressing protein variants with an AAA motif instead of EAL are delayed in development, similar to null mutants. Global transcriptome analysis of ΔcdgB, ΔcdgC, ΔrmdAand ΔrmdBstrains revealed that the c-di-GMP specified by these enzymes has a global regulatory role, with about 20 % of allS. venezuelaegenes being differentially expressed in thecdgCmutant. Our data suggest that the major c-di-GMP-controlled targets determining the timing and mode of sporulation are genes involved cell division and the production of the hydrophobic sheath that coversStreptomycesaerial hyphae and spores. Altogether, this study provides a global view of the c-di-GMP-dependent genes that contribute to the hyphae-to-spores transition and sheds light on the shared and specific functions of the key enzymes involved in c-di-GMP metabolism inS. venezuelae.ImportanceStreptomycesare important producers of clinical antibiotics. The ability to synthesize these natural products is connected to their developmental biology, which includes a transition from filamentous cells to spores. The widespread bacterial second messenger c-di-GMP controls this complex switch and is a promising tool to improve antibiotic production. Here, we analyzed the enzymes that make and break c-di-GMP inS. venezuelaeby studying the genome-wide transcriptional effects of the DGCs CdgB and CdgC and the PDEs RmdA and RmdB. We found that the c-di-GMP specified by these enzymes has a global regulatory role. However, despite shared enzymatic activities, the four c-di-GMP enzymes have specialized inputs into differentiation. Altogether, we demonstrate that altering c-di-GMP levels through the action of selected enzymes yields characteristically distinct transcriptional profiles; this can be an important consideration when modulating c-di-GMP for the purposes of natural product synthesis inStreptomyces.
Sessile bacterium unlocks ability of surface motility through mutualistic interspecies interaction
Authors: Wang Miaoxiao , Geng Shuang , Hu Bing , Nie Yong , Wu Xiao-Lei 
Published: April 2020

AbstractIn addition to their common planktonic lifestyle, bacteria frequently live in surface-associated habitats. Surface motility is essential for exploring these habitats for food sources. However, many bacteria are found on surfaces, even though they lack features required for migrating along surfaces. How these canonical non-motile bacteria adapt to the environmental fluctuations on surfaces remains unknown. Recently, several cases of interspecies interaction were reported that induce surface motility of non-motile bacteria either by using ‘hitchhiking’ strategies or through ‘social spreading’ mechanisms. Here, we report a previously unknown mechanism for interaction-dependent surface motility of the canonical non-motile bacterium,Dietziasp. DQ12-45-1b, which is induced by interaction with a dimorphic prosthecate bacterium,Glycocaulis alkaliphilus6B-8T.Dietziacells exhibits “sliding”-like motility in an area where the strainGlycocauliscells was pre-colonized with a sufficient density. Furthermore, we show that biosurfactants play a critical role in inducing the surface motility ofDietziacells. Our analysis also demonstrates thatDietziadegrade n-alkanes and provideGlycocauliswith the resulting metabolites for survival, which in turn enabled directional migration ofDietziatowards nutrients in the environment. Such interaction-dependent migration was also found betweenDietziaandGlycocaulisstrains isolated from other habitats, suggesting that this mutualistic relationship ubiquitously occurs in natural environments. In conclusion, we propose a novel model for such a ‘win-win’ strategy, whereby non-motile bacteria pay metabolites to dimorphic prosthecate bacteria in return for migrating to reach environments otherwise inaccessible. We propose that this mechanism represents a common strategy for canonically non-motile bacteria living on a surface.ImportanceCell motility provides a selective advantage for bacteria searching for nutrients. While a large body of evidence exists for how motile bacteria migrate on surface by virtue of different ways of motility, fewer studies concerned about how canonical non-motile bacteria adapted to those surface-associated habitats. Recent reports have proposed that interactions with other bacteria trigger the movement of those sessile bacteria. However, these interactions are limited to ‘hitchhiking’ or ‘social spreading’ modes. Here, we characterized a previously unknown interaction mode betweenDietziaandGlycocaulis.This interaction differs from previously described modes, thus advance our limited understanding of how sessile bacteria move on surfaces. We propose that this interaction mode represents a ‘win-win’ strategy for both strains, and this mode might be widely distributed across diverse environments. These novel insights should greatly assist in understanding the mechanisms responsible for the cellular interplay between microbes in complex microbiomes.
Geographic and subsequent biotic isolations led to a diversity anomaly ofHeterotropa(Aristolochiaceae) in insular versus continental regions of the Sino-Japanese Floristic Region
Authors: Takahashi Daiki , Feng Yu , Sakaguchi Shota , Isagi Yuji , Qiu Ying-Xiong , Li Pan , Lu Rui-Sen , Lu Chang-Tse , Chung Shih-Wen , Lin Yang-Shan , Chen Yun-Chao , Nagano Atsushi J. , Kawaguchi Lina , Setoguchi Hiroaki 
Published: April 2020

AbstractThe Sino-Japanese Floristic Region is highly diverse with respect to temperate plants. However, the reasons for this diversity are poorly understood because most studies have only considered geographic isolation caused by climatic oscillations.Heterotropa(genusAsarum; Aristolochiaceae) diverges here and shows high species diversity in insular systems (63 species) compared to continental areas (25 species).Heterotropashows low dispersal ability with small distribution ranges, implying diversification by geographic events, and high floral diversity, implying pollinator-mediated diversification. To reveal how abiotic and biotic factors have shaped the diversity anomaly ofHeterotropa, we conducted phylogenetic analysis using ddRAD-seq and chloroplast genome datasets including 79 species, estimation of floral trait evolution, and comparison of isolation factors within clades based on distribution range and floral trait analysis. Phylogenetic analysis indicates thatHeterotropaoriginated in mainland China and expanded to the Japanese Archipelago in the Miocene, and the major clades almost correspond to geographic distributions. Floral traits evolved repeatedly in the tip nodes within the clades. Although the major clades include a high proportion of species pairs showing isolation by floral traits, there are no conditional relationships between two isolation factors, indicating that most species pairs with floral trait isolation are distributed allopatrically. The repeated exposure and submergence of land-bridges caused by climatic oscillations would have led to significant population fragmentation in insular systems. Thus, the diversity anomaly ofHeterotropawould have resulted from geographic and climatic events during the Miocene, while subsequent repeated floral trait evolution would have followed geographic isolation during the Pleistocene.