bluuebunny/crossref_metadata_2025_split huggingface dataset:
Geographical Distance to the Epicenter of Covid-19 Predicts the Burnout of Working Population: Ripple effect or Typhoon Eye effect?
Authors: Zhang Stephen X , Huang Hao , Wei Feng 
Published: April 2020

ABSTRACTSCOVID-19 originated in Wuhan and rippled across China. We investigate how the geographical distance of working adults to the epicenter of Wuhan predicts their burnout. Preliminary results of a survey of 308 working adults in 53 cities showed working adults’ distance to the epicenter of Wuhan had an inverted U-shaped relationship with their burnout. Such results help to identify regions where people would need more psychiatric assistance, carrying direct implications to healthcare practitioners and policymakers.
Cryptic transmission of SARS-CoV-2 in Washington State
Authors: Bedford Trevor , Greninger Alexander L. , Roychoudhury Pavitra , Starita Lea M. , Famulare Michael , Huang Meei-Li , Nalla Arun , Pepper Gregory , Reinhardt Adam , Xie Hong , Shrestha Lasata , Nguyen Truong N , Adler Amanda , Brandstetter Elisabeth , Cho Shari , Giroux Danielle , Han Peter D. , Fay Kairsten , Frazar Chris D. , Ilcisin Misja , Lacombe Kirsten , Lee Jover , Kiavand Anahita , Richardson Matthew , Sibley Thomas R. , Truong Melissa , Wolf Caitlin R. , Nickerson Deborah A. , Rieder Mark J. , Englund Janet A. ,   the Seattle Flu Study Investigators, Hadfield James , Hodcroft Emma B. , Huddleston John , Moncla Louise H. , Müller Nicola F. , Neher Richard A. , Deng Xianding , Gu Wei , Federman Scot , Chiu Charles , Duchin Jeff , Gautom Romesh , Melly Geoff , Hiatt Brian , Dykema Philip , Lindquist Scott , Queen Krista , Tao Ying , Uehara Anna , Tong Suxiang , MacCannell Duncan , Armstrong Gregory L. , Baird Geoffrey S. , Chu Helen Y. , Shendure Jay , Jerome Keith R. 
Published: April 2020

AbstractFollowing its emergence in Wuhan, China, in late November or early December 2019, the SARS-CoV-2 virus has rapidly spread throughout the world. Genome sequencing of SARS-CoV-2 strains allows for the reconstruction of transmission history connecting these infections. Here, we analyze 346 SARS-CoV-2 genomes from samples collected between 20 February and 15 March 2020 from infected patients in Washington State, USA. We found that the large majority of SARS-CoV-2 infections sampled during this time frame appeared to have derived from a single introduction event into the state in late January or early February 2020 and subsequent local spread, indicating cryptic spread of COVID-19 before active community surveillance was implemented. We estimate a common ancestor of this outbreak clade as occurring between 18 January and 9 February 2020. From genomic data, we estimate an exponential doubling between 2.4 and 5.1 days. These results highlight the need for large-scale community surveillance for SARS-CoV-2 and the power of pathogen genomics to inform epidemiological understanding.
Coronavirus hemagglutinin-esterase and spike proteins co-evolve for functional balance and optimal virion avidity
Authors: Lang Yifei , Li Wentao , Li Zeshi , Koerhuis Danielle , van den Burg Arthur C.S. , Rozemuller Erik , Bosch Berend-Jan , van Kuppeveld Frank J.M. , Boons Geert-Jan P.H. , Huizinga Eric G. , van der Schaar Hilde M. , de Groot Raoul J. 
Published: April 2020

ABSTRACTHuman coronaviruses OC43 and HKU1 are respiratory pathogen of zoonotic origin that have gained worldwide distribution. OC43 apparently emerged from a bovine coronavirus (BCoV) spill-over. All three viruses attach to 9-O-acetylated sialoglycans via spike protein S with hemagglutinin-esterase HE acting as a receptor-destroying enzyme. In BCoV, an HE lectin domain promotes esterase activity towards clustered substrates. OC43 and HKU1, however, lost HE lectin function as an adaptation to humans. Replaying OC43 evolution, we knocked-out BCoV HE lectin function and performed forced evolution-population dynamics analysis. Loss of HE receptor-binding selected for second-site mutations in S, decreasing S binding affinity by orders of magnitude. Irreversible HE mutations selected for cooperativity in virus swarms with low-affinity S minority variants sustaining propagation of high-affinity majority phenotypes. Salvageable HE mutations induced successive second-site substitutions in both S and HE. Apparently, S and HE are functionally interdependent and co-evolve to optimize the balance between attachment and release. This mechanism of glycan-based receptor usage, entailing a concerted, fine-tuned activity of two envelope protein species, is unique among CoVs, but reminiscent of that of influenza A viruses (IAVs). Apparently, general principles fundamental to virion-sialoglycan interactions prompted convergent evolution of two important groups of human and animal pathogens.
In vitroscreening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication
Authors: Touret Franck , Gilles Magali , Barral Karine , Nougairède Antoine , Decroly Etienne , de Lamballerie Xavier , Coutard Bruno 
Published: April 2020

SummaryA novel coronavirus, named SARS-CoV-2, emerged in 2019 from Hubei region in China and rapidly spread worldwide. As no approved therapeutics exists to treat Covid-19, the disease associated to SARS-Cov-2, there is an urgent need to propose molecules that could quickly enter into clinics. Repurposing of approved drugs is a strategy that can bypass the time consuming stages of drug development. In this study, we screened the Prestwick Chemical Library® composed of 1,520 approved drugs in an infected cell-based assay. 90 compounds were identified. The robustness of the screen was assessed by the identification of drugs, such as Chloroquine derivatives and protease inhibitors, already in clinical trials. The hits were sorted according to their chemical composition and their known therapeutic effect, then EC50 and CC50 were determined for a subset of compounds. Several drugs, such as Azithromycine, Opipramol, Quinidine or Omeprazol present antiviral potency with 2<EC50<20µM. By providing new information on molecules inhibiting SARS-CoV-2 replicationin vitro, this study could contribute to the short-term repurposing of drugs against Covid-19.
PresRAT: A server for identification of bacterial small-RNA sequences and their targets with probable binding region
Authors: Kumar Krishna , Chakraborty Abhijit , Chakrabarti Saikat 
Published: April 2020

AbstractBacterial small-RNA (sRNA) sequences are functional RNAs, which play an important role in regulating the expression of a diverse class of genes. It is thus critical to identify such sRNA sequences and their probable mRNA targets. Here, we discuss new procedures to identify and characterize sRNA and their targets via the introduction of an integrated online platform named PresRAT (Prediction of sRNA and their Targets). PresRAT uses the primary and secondary structural attributes of sRNA sequences to predict sRNA from a given sequence or bacterial genome. PresRAT also finds probable target mRNAs of sRNA sequences from a given bacterial chromosome and further concentrates on identification of the probable sRNA-mRNA binding regions. Using PresRAT we have identified a total of 60,518 potential sRNA sequences from 54 bacterial genomes and 2447 potential targets from 13 bacterial genomes. We have also implemented a protocol to build and refine 3D models of sRNA and sRNA-mRNA duplex regions and generated 3D models of 50 known sRNAs and 81 sRNA-mRNA duplexes using this platform. Along with the server part, PresRAT also contains a database section, which enlists the predicted sRNA sequences, sRNA targets and their corresponding 3D models with structural dynamics information.
A far-red fluorescent chemogenetic reporter for in vivo molecular imaging
Authors: Li Chenge , Tebo Alison G. , Thauvin Marion , Plamont Marie-Aude , Volovitch Michel , Morin Xavier , Vriz Sophie , Gautier Arnaud 
Published: April 2020

AbstractFar-red emitting fluorescent labels are highly desirable for spectral multiplexing and deep tissue imaging. Here, we describe the generation of frFAST (far-red Fluorescence Activating and absorption Shifting Tag), a 14-kDa monomeric protein that forms a bright far-red fluorescent assembly with (4-hydroxy-3-methoxy-phenyl)allylidene rhodanine (HPAR-3OM). As HPAR-3OM is essentially non-fluorescent in solution and in cells, frFAST can be imaged with high contrast in presence of free HPAR-3OM, which allowed the rapid and efficient imaging of frFAST fusions in live cells, zebrafish embryo/larvae and chicken embryo. Beyond enabling genetic encoding of far-red fluorescence, frFAST allowed the design of a far-red chemogenetic reporter of protein-protein interactions, demonstrating its great potential for the design of innovative far-red emitting biosensors.
A molecular filter for the cnidarian stinging response
Authors: Weir Keiko , Dupre Christophe , van Giesen Lena , Lee Amy S.Y. , Bellono Nicholas W. 
Published: April 2020

AbstractAll animals detect and integrate diverse environmental signals to mediate behavior. Cnidarians, including jellyfish and sea anemones, both detect and capture prey using stinging cells called nematocytes which fire a venom-covered barb via an unknown triggering mechanism. Here, we show that nematocytes fromNematostella vectensisuse a specialized voltage-gated calcium channel (nCav) to distinguish salient sensory cues and control the explosive discharge response. Adaptations in nCavconfer unusually-sensitive, voltage-dependent inactivation to inhibit responses to non-prey signals, such as mechanical water turbulence. Prey-derived chemosensory signals are synaptically transmitted to acutely relieve nCavinactivation, enabling mechanosensitive-triggered predatory attack. These findings reveal a molecular basis for the cnidarian stinging response and highlight general principles by which single proteins integrate diverse signals to elicit discrete animal behaviors.
Cell-free synthesis of natural compounds from genomic DNA of biosynthetic gene clusters
Authors: Siebels Ilka , Nowak Sarah , Heil Christina S. , Tufar Peter , Cortina Niña S. , Bode Helge B. , Grininger Martin 
Published: April 2020

AbstractA variety of chemicals can be produced in a living host cell via optimized and engineered biosynthetic pathways. Despite the successes, pathway engineering remains demanding and partly impossible owing to the lack of specific functions or substrates in the host cell, its sensitivity in vital physiological processes to the heterologous components, or constrained mass transfer across the membrane. In this study, we demonstrate that cell-free systems can be useful in driving the characterization and engineering of biosynthetic pathways. We show that complex multidomain proteins involved in natural compound biosynthesis can be produced from encoding DNAin vitroin a minimal complex PURE system to directly run multistep reactions. We prove the concept of this approach on the direct synthesis of indigoidine and rhabdopeptides with thein vitroproduced multidomain megasynthases BpsA and KJ12ABC. Thein vitroproduced proteins are analyzed in detail, i.e., in yield, quality, post-translational modification and specific activity, and compared to recombinantly produced proteins. Our study highlights cell-free PURE systems as suitable setting for the rapid engineering of biosynthetic pathways.
Mycobacterium tuberculosisstimulates IL-1β production by macrophages in an ESAT-6 dependent manner with the involvement of serum amyloid A3
Authors: Jung Bock-Gie , Vankayalapati Ramakrishna , Samten Buka 
Published: April 2020

ABSTRACTTo explore interleukin (IL)-1β production in tuberculosis, we infected mouse bone marrow-derived macrophages (BMDM) withMycobacterium tuberculosis(Mtb)H37Rv, its early secreted antigenic target protein of 6 kDa (ESAT-6) gene deletion (H37Rv:Δ3875) or complemented strain (H37Rv:Δ3875C) and evaluated IL-1β production. H37Rv induced significantly increased IL-1β production by BMDMs compared to non-infected BMDMs. In contrast, H37Rv:Δ3875 induced significantly less mature IL-1β production despite eliciting comparable levels of pro-IL-1β and IL-8 from BMDMs compared to H37Rv and H37Rv:Δ3875C. Blocking either NLRP3 or K+efflux diminished H37Rv-induced IL-1β production by BMDMs. Infection of mice intranasally with H37Rv:Δ3875 induced less IL-1β production in the lungs compared with H37Rv.Intranasal delivery of ESAT-6 but not CFP10 induced production of IL-1β in mouse lungs and RNA-Seq analysis identified serum amyloid A (SAA) 3 as one of the highly expressed genes in mouse lungs. Infection of mice with H37Rv but not H37Rv:Δ3875 induced expression of lung SAA3 mRNA and protein, consistent with the effect of intranasal delivery of ESAT-6. Silencing SAA3 reducedMtb-induced IL-1β production by BMDMs. We conclude that the production of SAA3 is required forMtbstimulated IL-1β production by macrophages in tuberculosis infection.
Oncogene Regulated Release of Extracellular Vesicles
Authors: Kilinc Seda , Paisner Rebekka , Camarda Roman , Momcilovic Olga , Kohnz Rebecca A. , L’Etoile Noelle D. , Perera Rushika M. , Nomura Daniel K. , Goga Andrei 
Published: April 2020

AbstractOncogenes can alter cellular structure, function, development and metabolism including changing the balance between anabolic and catabolic processes. However, how oncogenes regulate tumor cell biomass remains poorly understood. Using isogenic mammary breast epithelial cells transformed with a panel of ten oncogenes found commonly mutated, amplified or overexpressed in multiple cancers, we show that specific oncogenes reduce the biomass of cancer cells by promoting extracellular vesicle release. While MYC and AURKB elicited the highest number of EVs, each oncogene tested selectively altered the protein composition of released EVs. Likewise, miRNAs were differentially sorted into EVs in an oncogene-specific manner. MYC overexpressing cells require ceramide, while AURKB require ESCRT to release high levels of EVs. Finally, lysosome-associated genes are broadly downregulated in the context of MYC and AURKB, suggesting that cellular contents instead of being degraded, were released via EVs. Thus, oncogene mediated biomass regulation via differential EV release is a new metabolic phenotype which may have implications for cellular signaling and homeostasis.
Annulohypoxylonsp. strainMUS1, an Endophyte isolated fromTaxus wallichianaZucc. produces Taxol and Other Bioactive Metabolites
Authors: Gauchan Dhurva Prasad , Vélëz Heriberto , Acharya Ashesh , Östman Johnny R. , Lundén Karl , Elfstrand Malin , García-Gil M Rosario 
Published: April 2020

AbstractEndophytes are microbial colonizers that reside in plants by symbiotic association produces several biological classes of natural products. The current study focuses on the isolation and characterization of bioactive compounds produced by endophytic fungi isolated from the Himalayan yew (Taxus wallichiana) collected from the Mustang district of Nepal. The plant materials were collected from the Lower-Mustang region in the month of October 2016 and the endophytic fungi were isolated on artificial media from inner tissues of bark and needles. Antimicrobial and antioxidant activity, along with total phenolic- and flavonoid-content assays, were used in the evaluation of bioactivity of the fermented crude extracts along with thein vitroability of the endophytes to produce the anticancer compound Taxol was analyzed. A total of 16 fungal morphotypes were obtained from asymptomatic inner tissues of the bark and needles ofT. wallichiana. Among the 16 isolates, the ethyl acetate (EA) fraction of isolateMUS1, showed antibacterial and antifungal activity against all test-pathogens used, with significant inhibition againstPseudomonas aeruginosaATCC 27853 (MIC: 250 µg/ml) and the pathogenic yeast,Candida albicans(MIC: 125 µg/ml). Antioxidant activity was also evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH). At a concentration of 100 µg/ml, the % radical scavenging activity was 83.15±0.40, 81.62±0.11, and 62.36±0.29, for ascorbic acid, butylated hydroxytoluene (BHT) and the EA fraction of MUS1, respectively. The DPPH-IC50value for the EA fraction was 81.52 µg/ml, compared to BHT (62.87 µg/ml) and ascorbic acid (56.15 µg/ml). The total phenolic and flavonoid content in the EA fraction were 16.90±0.075 µg gallic acid equivalent (GAE) and 11.59±0.148 µg rutin equivalent (RE), per mg of dry crude extract, respectively. IsolateMUS1, identified as anAnnulohypoxylonsp. by ITS sequencing, also produced Taxol (282.05 µg/L) as shown by TLC and HPLC analysis. Having the ability to produce antimicrobial and antioxidant compounds, as well as the anticancer compound Taxol, makesAnnulohypoxylonsp. strainMUS1, a promising candidate for further study given that naturally occurring bioactive compounds are of great interest to the pharmacological, food and cosmetic industries.
miRNAs and neural alternative polyadenylation specify the virgin behavioral state
Authors: Garaulet Daniel L. , Zhang Binglong , Wei Lu , Li Elena , Lai Eric C. 
Published: April 2020

SummaryHow are diverse regulatory strategies integrated to impose appropriately patterned gene expression that underliein vivophenotypes? Here, we reveal how coordinated miRNA regulation and neural-specific alternative polyadenylation (APA) of a single locus controls complex behaviors. Our entry was the unexpected observation that deletion of Bithorax-Complex (BX-C) miRNAs converts virgin female flies into a subjective post-mated behavioral state, normally induced by seminal proteins following copulation. Strikingly, this behavioral switch is directly attributable to misregulation ofhomothorax(hth). We localize specific CNS abdominal neurons where de-repressed Hth compromises virgin behavior in BX-C miRNA mutants. Moreover, we use genome engineering to demonstrate that precise mutation ofhth3’UTR sites for BX-C miRNAs, or deletion of its neural 3’ UTR extension containing most of these sites, both induce post-mated behaviors in virgins. Thus, facilitation of miRNA-mediated repression by neural APA is required for virgin females to execute behaviors appropriate to their internal state.
Dissecting individual pathogen-commensal interactions within a complex gut microbiota community
Authors: Hassall Jack , Unnikrishnan Meera 
Published: April 2020

AbstractInteractions of commensal bacteria within the gut microbiota and with invading pathogens are critical in determining the outcome of an infection. While murine studies have been valuable, we lackin vitrotools to monitor community responses to pathogens at a single-species level. We have developed a multi-species community of nine representative gut species cultured together as a mixed biofilm and tracked numbers of individual species over time using a qPCR-based approach. Introduction of the major nosocomial gut pathogen,Clostridiodes difficile, to this community resulted in increased adhesion of commensals and inhibition ofC. difficilemultiplication. Interestingly, we observed an increase in individualBacteroidesspecies accompanying the inhibition ofC. difficile. Furthermore,Bacteroides doreireducedC. difficilegrowth within biofilms, suggesting a role forBacteroides sppin prevention ofC. difficilecolonisation. We report here anin vitrotool with excellent applications for investigating bacterial interactions within a complex community.
Rapamycin-PLGA microspheres induce autophagy and prevent senescence in chondrocytes and exhibit longin vivoresidence
Authors: Dhanabalan Kaamini M. , Gupta Vishal K. , Agarwal Rachit 
Published: April 2020

AbstractOsteoarthritis (OA) is a joint disease that results in progressive destruction of articular cartilage and the adjoining subchondral bone. The current treatment is focused on symptomatic relief due to the absence of disease-modifying drugs. The primary cells of the cartilage, chondrocytes, have limited regenerative capacity and when they undergo stress due to trauma or with aging, they senesce or become apoptotic. Autophagy, a cellular homeostasis mechanism has a protective role in OA during stress but gets downregulated in OA. Rapamycin, a potent immunomodulator, has shown promise in OA treatment by autophagy activation and is known to prevent senescence. However, its clinical translation for OA is hampered due to systemic toxicity as high and frequent doses are required. Hence, there is a need to develop suitable delivery carriers that can result in sustained and controlled release of the drug in the joint. In this study, we have fabricated rapamycin encapsulated poly (lactic-co-glycolic acid) (PLGA) based carriers that induced autophagy and prevented cellular senescence in human chondrocytes. The microparticle (MP) delivery system showed sustained release of drug for several weeks. Rapamycin-microparticles protectedin-vitrocartilage mimics from degradation, allowing sustained production of sGAG, and demonstrated a prolonged senescence preventive effectin vitrounder oxidative and genomic stress conditions. These microparticles also exhibited a long residence time of more than 19 days in the joint after intra-articular injections in murine knee joints. Such particulate systems are a promising candidate for intra-articular delivery of rapamycin for treatment of osteoarthritis.Statement of SignificanceCurrent OA treatment is symptomatic and does not change the disease progression. Many drugs have failed as they are rapidly cleared and are unable to maintain therapeutic concentration in the OA joint. Direct joint administration of drugs using sustained-release systems offer several advantages, which includes increased bioavailability, fewer off-target effects, and lower total drug cost. We have engineered a suitable drug carrier which provides a tunable drug release pattern. This study provides evidence that PLGA encapsulated rapamycin remained potent and prevented OA like changes in chondrocytes under genomic and oxidative stress. The particle formulation also had a longer residence time in the knee joint of mice which can be translated in clinics for intra-articular therapeutic injections for increased patient compliance.Graphical abstract
Inhibition of cell membrane ingression at the division site by cell wall in fission yeast
Authors: Chew Ting Gang , Lim Tzer Chyn , Osaki Yumi , Huang Junqi , Kamnev Anton , Osumi Masako , Balasubramanian Mohan K. 
Published: April 2020

AbstractEukaryotic cells assemble an actomyosin ring during cytokinesis to function as a force-generating machine to drive membrane invagination, and to counteract the intracellular pressure and the cell surface tension. It is unclear whether additional factors such as the extracellular matrix (cell wall in yeasts and fungi) affect the actomyosin ring contraction. While studying the fission yeast β-glucan synthase mutantcps1-191, which is defective in division septum synthesis and actomyosin ring contraction, we found that significantly weakening of the extracellular glycan matrix caused the spheroplasts to divide at the non-permissive condition. This division was dependent on a functional actomyosin ring and vesicular trafficking, but independent of normal septum synthesis.cps1-191 cells with weakened extracellular glycan matrix divide non-medially with a much slower ring contraction rate compared to wild type cells under similar conditions, which we term as cytofission. Interestingly, the high turgor pressure appears to play minimal roles in inhibiting ring contraction incps1-191 mutants as decreasing the turgor pressure alone does not enable cytofission. We propose that during cytokinesis, the extracellular glycan matrix restricts actomyosin ring contraction and membrane ingression, and remodeling of the extracellular components through division septum synthesis relieves the inhibition and facilitates actomyosin ring contraction.