# ent

id: cord-001704-pdxm0iiw
type: ORG
entity:
  A Novel Chimeric Anti PA Neutralizing Antibody for Postexposure Prophylaxis and Treatment of Anthrax


id: cord-001823-v60vv99o
type: GGP
entity:
  RepoRts 5 15818 DOi 10 1038 srep15818 22 79 or 0 31 in Sierra Leone and 1 68 or 21 95 in Liberia respectively


id: cord-001823-v60vv99o
type: ORG
entity:
  NLODE Social Media Modeling of Information Transmission for Infectious Diseases Case Study Ebola Ebola Outbreak Response


id: cord-001823-v60vv99o
type: FAC
entity:
  Guinea Preliminary Report Modeling Post death Transmission of Ebola Challenges for Inference and Opportunities for Modeling surveillance


id: cord-002072-qbh728ec
type: CELL_LINE
entity:
  Beijing Ditan Hospital Capital Medical University The case was diagnosed as a laboratory confirmed case of influenza A H7N9


id: cord-001901-2s6hpakk
type: PROTEIN
entity:
  MAPKs 35 36 Src kinase 37 glycogen synthase kinase 3β GSK 3β 50 and cyclin dependent kinases CDKs 51


id: cord-002373-rueg4gsj
type: WORK_OF_ART
entity:
  Nanomaterials for Sensing and Destroying Pesticides Novel Optical Nanoprobes for Bioanalysis Development


id: cord-002373-rueg4gsj
type: ORG
entity:
  Interfacial Immobilization of Monoclonal Antibody and Detection of Human Prostate Specific Antigen Simultaneous Determination of Human Enterovirus 71


id: cord-002312-jyk7f8hz
type: PROTEIN
entity:
  E coli recombinant protein Neoclone Madison WI rabbit anti glial fibrillary acidic protein GFAP Dako Carpenteria CA


id: cord-002290-wvo22jx2
type: WORK_OF_ART
entity:
  Fitting Linear Mixed Effects Models Using lme4 A Language and Environment for Statistical Computing Identification


id: cord-002290-wvo22jx2
type: ORG
entity:
  Collaborative Innovation Center of Infectious Diseases PXM2014_014226_000011 and PXM2015_014226_000058


id: cord-002644-yzan95du
type: DNA
entity:
  rabbit anti mouse ASC sc 22514 R Santa Cruz CA USA mouse anti mouse caspase 1 AG 20B 0042 Adipogen San Diego CA USA rabbit


id: cord-002258-o9azey3m
type: DISEASE
entity:
  human bronchus or lung The introduction of compensatory human markers PB2 Q591K and D701N partly rescued the replication competence of the rgPB2 K627E virus in lung The mutant virus with rgPB2 K627E D701N


id: cord-002258-o9azey3m
type: DISEASE
entity:
  H1N1 viruses Tropism of and innate immune responses to the novel human betacoronavirus lineage C virus


id: cord-002177-yyfgl9x5
type: DNA
entity:
  FcRn 1286 5 ATGTGCCGTGGGTGTGGCCCTA 3 5 AACTTGCATCCCTGATAAGA 3 Co FcRn 1128 5 ATGGCTGTGGTATAGGCTGATA 3 5 CCTTTTTACAGCAATACATGCC 3


id: cord-002177-yyfgl9x5
type: PROTEIN
entity:
  chemokines cytokines proinflammatory enzymes adhesion molecules proinflammatory transcription factors


id: cord-002177-yyfgl9x5
type: DNA
entity:
  pFcRn primers 5 GGCGACGAGCACCACTACTG 3 and 5 AGCCGACCATGATTCCAACC 3 and GAPDH primers 5 ACATGGCCTCCAAGGAGTAAGA 3 and 5 GATCGAGTTGGGGCTGTGACT 3


id: cord-004181-exbs3tz7
type: PROTEIN
entity:
  bacteriocin transport accessory protein dihydrofolate reductase SSU ribosomal protein S8p transposase TnpA 1 4 alpha glucan cell wall surface anchor family protein


id: cord-004181-exbs3tz7
type: PROTEIN
entity:
  45F2 recombinant protein vaccine 2 42E2 recombinant protein vaccine 3 45F2 DNA vaccine 4 42E2 DNA vaccine 5 formalin killed FKC S agalactiae vaccine 58 and 6 pcDNA3 1 empty vector


id: cord-002932-5e7xrd1y
type: PERCENT
entity:
  6 7 8 1 Division of Virology Department of Microbiology and Immunology Institute of Medical Science University of Tokyo


id: cord-002874-9rxv6fy9
type: ORG
entity:
  a Diffusing Optical Fiber Using Radiochromic Film Radiation Technology for Polymers Angular Dependence


id: cord-003490-swlkjtyo
type: CHEBI
entity:
  molecular virus host interactions Foot and mouth disease Description of recent foot and mouth disease outbreaks


id: cord-002411-iiw878w8
type: PROTEIN
entity:
  macrophage inflammatory protein 2 MIP 2 macrophage chemoattractant protein 1 MCP 1 tumor necrosis factor alpha TNF


id: cord-002081-vi6rth9o
type: DISEASE
entity:
  carcinogenic human papillomavirus and herpesvirus 12 and the detection of Middle East Respiratory Syndrome Coronavirus


id: cord-003055-88q36g00
type: DNA
entity:
  primary antibodies rabbit monoclonal anti Olig2 antibody ab109186 1 100 Abcam Tokyo Japan or rabbit polyclonal anti GFAP antibody 23935 1 AP 1 100 Proteintech Chicago IL


id: cord-003055-88q36g00
type: GGP
entity:
  TNF α 5 GTAGCCCACGTCGTAGCAAAC 3 5 CTGGCACCACTAGTTGGTTGTC 3 IL 6 5 ACAACCACGGCCTTCCCTAC 3 5 TCCACGATTTCCCAGAGAACA 3 IL 1β 5 CATCCAGCTTCAAATCTCGCAG 3 5 CACACACCAGCAGGTTATCATC 3 β actin 5 CGTGGGCCGCCCTAGGCACCA 3 5 ACACGCAGCTCATTGTA 3 Table 1 List of primers


id: cord-002019-wtnf340p
type: PROTEIN
entity:
  DyLight 649 conjugated goat anti rabbit IgG antibody DyLight 488 conjugated goat anti rabbit IgG antibody DyLight 594 conjugated goat anti rabbit IgG antibody


id: cord-003623-n01rgqyv
type: PROTEIN
entity:
  marburgvirus antigen 5 3 Sudan virus antisera versus Marburg virus antigen 10 3 Sudan virus antisera versus Ravn virus antigen Fig 2 A


id: cord-003148-o7y3wygc
type: DNA
entity:
  rNDV rNDV S1 rNDV S1 IBV S TM CT rNDV S1 cs NDV F TM CT and rNDV S1 cs NDV F TM CT respectively A 130 kDa band


id: cord-003148-o7y3wygc
type: DNA
entity:
  rNDV rNDV S1 rNDV S1 IBV S TM CT rNDV S1 cs NDV F TM CT rNDV S1 cs NDV F TM CT respectively A 130 kD band


id: cord-003148-o7y3wygc
type: DNA
entity:
  rNDV S1 rNDV S1 IBV S TM CT rNDV S1 cs NDV F TM CT rNDV S1 cs NDV F TM CT rNDV S2 rNDV codon optimized S and rNDV non codon optimized S respectively


id: cord-003148-o7y3wygc
type: DNA
entity:
  N gene 296 forward primer 5 GACCAGCCGCTAACCTGAAT 3 and b N gene 445 reverse primer 5 GTCCTCCGTCTGAAAACCGT 3 amplifying 150 nt


id: cord-003148-o7y3wygc
type: CHEMICAL
entity:
  N gene 296 forward primer 5 GACCAGCCGCTAACCTGAAT 3 and b N gene 445 reverse primer 5 GTCCTCCGTCTGAAAACCGT 3 amplifying 150 nt of N gene of IBV strain Mass 41 PCRs


id: cord-002843-dvfmpm54
type: GGP
entity:
  DYZ3 0 23 Mbp alpha satellite array 16 that was simulated from the HuRef WGS reads library 6 Block II 100 15 Kbp and Block III 848 71 Kbp Fig 5 remained unclear about their assembling processes that


id: cord-002244-5h6monh3
type: CELL_TYPE
entity:
  Th17 and Tregs date 2016 10 06 journal Sci Rep DOI 10 1038 srep34617 sha 131e6a035170ed5bd2dba6bec02649e9508a0c55 doc_id 2244 cord_uid 5h6monh3 PTEN


id: cord-002013-rb9xdzro
type: ORG
entity:
  the Peking Union Medical College Center for New Drug Safety Evaluation Chinese Academy of Medical Sciences


id: cord-003166-k3jxvzfi
type: DNA
entity:
  bat paramyxovirus B16 40 10 5 75 TCID 50 mL and human parainfluenza virus 1 KBPV VR 44 10 5 75 TCID 50 mL


id: cord-003387-82573enr
type: WORK_OF_ART
entity:
  Osteocalcin Signaling in Myofibers Is Necessary and Sufficient for Optimum Adaptation to Exercise The


id: cord-002956-e5ihpe4i
type: ORG
entity:
  the Prediction of Prolonged Mechanical Ventilation in Patients Who Survive Sepsis Septic Shock with Respiratory Failure


id: cord-001868-utsvsja0
type: PROTEIN
entity:
  Phycoerythrin PE conjugated anti Ly 6G clone 1A8 PE conjugated anti SiglecH clone 551 biotin conjugated


id: cord-004062-yxx3xxio
type: PROTEIN
entity:
  interleukins IL 1 receptor antagonist Ra IL 2 IL 6 IL 8 IL 10 IL 12p40 granulocyte macrophage colony stimulating factor GM CSF monocyte chemotactic protein 1 MCP 1 macrophage inflammatory protein 1b MIP 1b vascular endothelial growth factor VEGF tumor necrosis factor TNF


id: cord-004060-nxw5k9y1
type: ORG
entity:
  Impacts of Road Traffic Network and Socioeconomic Factors on the Diffusion of 2009 Pandemic Influenza


id: cord-004060-nxw5k9y1
type: DISEASE
entity:
  influenza A H1N1 pdm09 latitude and longitude still remain statistically significant Holding all other covariates to zero and adjusting for spatiotemporal variation every one million increase in the number of influenza vaccines for sale approved by the China Food and Drug Administration


id: cord-004060-nxw5k9y1
type: DISEASE
entity:
  influenza A H1N1 pdm09 among the number of ILI specimens processed the percentage of influenza A H1N1 pdm09 among all the positive influenza specimens and protocol changes a spatially unstructured random effect term ν i a spatially structured conditional autoregression term υ i a first order random walk correlated time variable γ 1j


id: cord-004170-ri5qsarz
type: ORG
entity:
  Heparin Sensitivity and Resistance Management During Cardiopulmonary Bypass Aggregation Of Human Neutrophils


id: cord-002802-594mmlk8
type: DISEASE
entity:
  influenza A viruses H9N2 influenza virus in China a cause of concern Complete genome sequence of an H9N2 avian influenza virus


id: cord-002802-594mmlk8
type: DISEASE
entity:
  influenza A H3N2 virus affect HA thermal stability and fusion activity An improved reverse genetics system for influenza A virus generation


id: cord-003667-u1xa44nw
type: ORG
entity:
  Properties of Replication Competent Vesicular Stomatitis Virus Vectors Expressing Glycoproteins of Filoviruses and Arenaviruses Properties of Replication Competent Vesicular Stomatitis Virus Vectors Expressing Glycoproteins of Filoviruses


id: cord-003196-fdb6az0v
type: WORK_OF_ART
entity:
  The Lancet Effect of Home Noninvasive Ventilation With Oxygen Therapy vs Oxygen Therapy Alone on Hospital Readmission or Death


id: cord-004379-91a7sgir
type: ORG
entity:
  Older Influenza Centers for Disease Control and Prevention National Center for Immunization and Respiratory Diseases


id: cord-003444-dmpoy0b1
type: GGP
entity:
  neutrophil elastase cathepsin G and protease 3 12 18 We now show that inhibition of a single function of


id: cord-004310-hl7fa4af
type: WORK_OF_ART
entity:
  Down Syndrome Reduces the Sedative Effect of Midazolam in Pediatric Cardiovascular Surgical Patients


id: cord-004385-xna32qve
type: DISEASE
entity:
  influenza A H1N1 pandemic Clinical and prognostic features of patients with pandemic 2009 influenza a H1N1 virus in the intensive care unit Neuraminidase inhibitors superinfection


id: cord-004222-z4butywi
type: DNA
entity:
  human immunoglobulin Vλ light chain repertoire Immunoglobulin light chain gene rearrangements receptor


id: cord-010140-nl1j2s56
type: GGP
entity:
  basigin 5 24 44 However the data presented here is somewhat contradictory to those studies Specifically using the AVEXIS assay Galaway et


id: cord-010140-nl1j2s56
type: CHEMICAL
entity:
  K 377 3 K 378 N 557 4 M 558 K 719 5 C 720 D 934 6 G 935 N 1086 7 T 108 R 287 8 C 288 I 467 9 F 468 N 647 10 S 648 C 830


id: cord-003011-vclnb0eh
type: GGP
entity:
  mellitus OR 1 31 95 IC 0 38 4 46 and previous TB infection OR 2 66 95 CI 0 48 14 87 Conclusion Co morbid malignancy was associated with increased risk of in hospital death among pulmonary TB


id: cord-002842-4evbeijx
type: PROTEIN
entity:
  salivary protein precursor salivary galectin salivary lipase anti thrombin anopheline salivary protein SG3


id: cord-002842-4evbeijx
type: WORK_OF_ART
entity:
  Molecular Modeling and Virtual Screening Approach to Discover Potential Antileishmanial Inhibitors Against Ornithine Decarboxylase Protein


id: cord-005507-equnyib7
type: WORK_OF_ART
entity:
  Integrated Serologic Surveillance of Population Immunity and Disease Transmission Development of a Multiantigen Panel for Improved Detection of Borrelia burgdorferi Infection


id: cord-002791-tqchfdmy
type: DNA
entity:
  pACYCDuet 1 TM CoatDimer His vector Scientific RepoRts 7 17501 https doi org 10 1038 s41598 017 17951 5


id: cord-002791-tqchfdmy
type: PROTEIN
entity:
  His tag M marker spectra multicolor broad range protein ladder Fermentas the marker values are in kDa The figures


id: cord-004156-79peyzc9
type: WORK_OF_ART
entity:
  Using the BacMam Baculovirus System to Study Expression and Function of Recombinant Efflux Drug Transporters in Polarized Epithelial Cell Monolayers Drug


id: cord-010675-acdfvjm5
type: ORG
entity:
  Recommendations of the Advisory Committee on Immunization Practices ACIP The Molecular Virology of Enteric Viruses Uniformity


id: cord-011892-b9zlig0r
type: CELL_TYPE
entity:
  proliferative and quiescent stem cell marker genes A Adult proliferative neural progenitor cells PNPCs


id: cord-011892-b9zlig0r
type: CELL_TYPE
entity:
  normal stem cells GSE68270_PNPCbyQNSC GSE70696_TAPbyQNP GSE99777_ PSVZSCbyQSVZSC and GBM cell cultures GSE93991_PGBCbyQGBC GSE114574_PGBObyQGBO DEG SVA LM


id: cord-011892-b9zlig0r
type: DNA
entity:
  Grade_3 Grade_4 Grade_4 CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CON CONCON CON CON CON CON CON CON CON CON CON CON A


id: cord-011892-b9zlig0r
type: DNA
entity:
  c1_HuAgeGBsplit_38 528 111 c1_HuAgeGBsplit_156 196 191 c1_HuAgeGBsplit_1614 123 32 c1_HuAgeGBsplit_57 524 112 c1_HuAgeGBsplit_50 194 192 c1_HuAgeGBsplit_459 122 33 c1_HuAgeGBsplit_53 519 113 c1_HuAgeGBsplit_332 192 193 c1_HuAgeGBsplit_776 122 34 c1_HuAgeGBsplit_19 517 114 c1_HuAgeGBsplit_215 190 194 c1_HuAgeGBsplit_1129 121 35 c1_HuAgeGBsplit_188 500 115 c1_HuAgeGBsplit_2103 185 195 c1_HuAgeGBsplit_830 120 36 c1_HuAgeGBsplit_360 487 116 c1_HuAgeGBsplit_2024 184 196 c1_HuAgeGBsplit_107 119 37 c1_HuAgeGBsplit_71 487 117 c1_HuAgeGBsplit_106 183 197 c1_HuAgeGBsplit_164 119 38 c1_HuAgeGBsplit_528 484 118 c1_HuAgeGBsplit_51 182 198 c1_HuAgeGBsplit_1032 117 39 c1_HuAgeGBsplit_29 479 119 c1_HuAgeGBsplit_160 180 199 c1_HuAgeGBsplit_178 117 40 c1_HuAgeGBsplit_103 455 120 c1_HuAgeGBsplit_79 180 200 c1_HuAgeGBsplit_764 116 41 c1_HuAgeGBsplit_14 447 121 c1_HuAgeGBsplit_1106 179 201 c1_HuAgeGBsplit_515 115 42 c1_HuAgeGBsplit_12 443 122 c1_HuAgeGBsplit_291 177 202 c1_HuAgeGBsplit_832 115 43 c1_HuAgeGBsplit_94 423 123 c1_HuAgeGBsplit_75 176 203 c1_HuAgeGBsplit_2184 114 44 c1_HuAgeGBsplit_37 421 124 c1_HuAgeGBsplit_41 175 204 c1_HuAgeGBsplit_456 114 45 c1_HuAgeGBsplit_163 412 125 c1_HuAgeGBsplit_473 170 205 c1_HuAgeGBsplit_97 114 46 c1_HuAgeGBsplit_54 405 126 c1_HuAgeGBsplit_70 170 206 c1_HuAgeGBsplit_356 123 47 c1_HuAgeGBsplit_388 389 127 c1_HuAgeGBsplit_101 167 207 c1_HuAgeGBsplit_295 111 48 c1_HuAgeGBsplit_186 383 128 c1_HuAgeGBsplit_339 167 208 c1_HuAgeGBsplit_470 111 49 c1_HuAgeGBsplit_36 353 129 c1_HuAgeGBsplit_192 166 209 c1_HuAgeGBsplit_757 111 50 c1_HuAgeGBsplit_364 347 130 c1_HuAgeGBsplit_428 166 210 c1_HuAgeGBsplit_153 110 51 c1_HuAgeGBsplit_33 345 131 c1_HuAgeGBsplit_56 164 211 c1_HuAgeGBsplit_549 110


id: cord-011892-b9zlig0r
type: PROTEIN
entity:
  c1_HuAgeGBsplit_1293 303 143 c1_HuAgeGBsplit_151 155 223 c1_HuAgeGBsplit_125 105 64 c1_HuAgeGBsplit_32 302 144 c1_HuAgeGBsplit_622 155 224 c1_HuAgeGBsplit_228 105 65 c1_HuAgeGBsplit_73 298 145 c1_HuAgeGBsplit_1118 152 225 c1_HuAgeGBsplit_361 105


id: cord-004416-qw6tusd2
type: PROTEIN
entity:
  Angiotensin II Infused Apolipoprotein E Deficient Mouse Influence of Apolipoprotein E Age and Aortic Site


id: cord-004416-qw6tusd2
type: ORG
entity:
  the National Outcomes and Costs for Claudication and Limb Threatening Ischemia Angioplasty vs Bypass Graft


id: cord-004416-qw6tusd2
type: ORG
entity:
  The Australian National Workplace Health Project Design and Baseline Findings Muscle Fiber Characteristics in Patients With Peripheral Arterial Disease Evaluation


id: cord-004416-qw6tusd2
type: ORG
entity:
  the Mouse Physical Activity During Daily Life and Mortality in Patients With Peripheral Arterial Disease Skeletal Muscle Perfusion


id: cord-004416-qw6tusd2
type: ORG
entity:
  the Endothelium Oscillatory Shear Stress and Hydrostatic Pressure Modulate Cell Matrix Attachment Proteins


id: cord-009690-kbwz7xop
type: CELL_LINE
entity:
  Cyprus S5 10 11 A negative control containing only developing solution and a positive control containing 0 5


id: cord-009690-kbwz7xop
type: WORK_OF_ART
entity:
  Towards a Dual Lateral Flow Nanobiosensor for Simultaneous Detection of Virus Genotype Specific PCR Products A Nanostructured Microfluidic Immunoassay Platform for Highly Sensitive Infectious Pathogen Detection Development


id: cord-010328-uxpedpz8
type: CELL_LINE
entity:
  United States population Official CDC Health Advisory Distributed via the CDC Health Alert Network HAN Outbreak of Hepatitis A Virus HAV Infections among Persons Who Use Drugs and Persons Experiencing Homelessness Measles antibody


id: cord-012742-lpk6r54i
type: DNA
entity:
  nsP3 macro domain aminoacids 1 to 160 of Getah virus strain M1 GenBank ABK32031 1 amino acids 1 333 to 1 492


id: cord-007851-v6h1yro7
type: CHEBI
entity:
  amino acid binding motifs and sequence profiles including sequence weighting pseudo counts and two sided representation of amino acid


id: cord-007851-v6h1yro7
type: ORG
entity:
  Peptide Based Vaccination for Antibody Responses Against HIV Vaccines Basel Immunologic Response Elicited in Breast Cancer Patients Receiving a NeuGcGM3


id: cord-007851-v6h1yro7
type: WORK_OF_ART
entity:
  A Prognostic Model for Patients with Triple Negative Breast Cancer Importance of the Modified Nottingham Prognostic Index and Age Triple


id: cord-007851-v6h1yro7
type: WORK_OF_ART
entity:
  Assessment of Antigen Specific Cellular Immunogenicity Using Intracellular Cytokine Staining ELISpot and Culture Supernatants


id: cord-258678-0atfsivf
type: ORG
entity:
  Systematic Investigation of Optimal Aptamer Immobilization for Proteinâ Microarray Applications Minor


id: cord-263627-8ufjh70o
type: ORG
entity:
  Ministry of Science and Technology Research Center for Epidemic Prevention of National Yang Ming University


id: cord-254090-x8tnweih
type: DNA
entity:
  primer AMF sequence 5 GAGTCTTCTAACCGAGGTCGAAACGTA 3 primer flu AR sequence 5 CAAAGCGTCTACGCTGCAGTCC 3


id: cord-254090-x8tnweih
type: WORK_OF_ART
entity:
  Inactivation of Bacteriophage by Microwave Irradiation Inactivation of Lactobacillus Bacteriophage PL 1


id: cord-254090-x8tnweih
type: ORG
entity:
  Microwave Irradiation Influenza Virus Inactivation for Studies of Antigenicity and Phenotypic Neuraminidase Inhibitor Resistance


id: cord-259794-6qoksn00
type: PROTEIN
entity:
  chemokine CXCL16 10 translation elongation factor 1 alpha 11 cellular pyruvate kinase protein 12 and 14 3 3 13 Comparative


id: cord-259794-6qoksn00
type: GGP
entity:
  RepoRts 7 39700 DOI 10 1038 srep39700 has been reported to bind to the arginine rich basic region of the human T cell leukemia virus protein Rex


id: cord-259794-6qoksn00
type: WORK_OF_ART
entity:
  The Cellular Interactome of the Coronavirus Infectious Bronchitis Virus Nucleocapsid Protein and Functional Implications for Virus Biology Molecular Characterizations of Subcellular Localization Signals in the Nucleocapsid Protein of Porcine Epidemic Diarrhea Virus


id: cord-263088-zj14ro5j
type: WORK_OF_ART
entity:
  Proceedings of the Workshop on Trade and Conservation of Pangolins Native to South and Southeast Asia


id: cord-271602-f14wccj3
type: WORK_OF_ART
entity:
  Determine Compliance with Ambient Air Quality Standards for Suspended Particles Regional Contributions to


id: cord-259416-gvzp2h5g
type: DNA
entity:
  human IFITM3 date 2016 04 05 journal Sci Rep DOI 10 1038 srep24029 sha c798225c8b1b45e38fcd6163a711500c1f667b03 doc_id 259416 cord_uid


id: cord-280334-7b7rvr25
type: DNA
entity:
  16PLM1 NL2016 Canada2016 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 A single recombination breakpoint


id: cord-280334-7b7rvr25
type: CHEMICAL
entity:
  genome partitions nucleotide positions i 1 429 p16 supplementary information ii 430 5 295 p23 p37 p29 VPg protease and RdRp and iii 5 296 7 369 VP60 and VP10 Maximum likelihood phylogenetic


id: cord-269756-tid8a464
type: PROTEIN
entity:
  phospholipids 1 palmitoyl 2 hydroxy sn glycero 3 phosphocholine LPC 1 2 dipalmitoyl snglycero phosphatidylcholine DPPC 1 2 dipalmitoyl sn glycero 3 phospho 1


id: cord-269756-tid8a464
type: GGP
entity:
  POPA S 0 0 29 Those differences in the TMA orientation are likely due to distinct orienting forces that arise from the particular hydrogen bonding


id: cord-269756-tid8a464
type: ORG
entity:
  Membrane Surface Order An Electron Spin Resonance Study HIV gp41 Fusion Peptide Increases Membrane Ordering


id: cord-269756-tid8a464
type: ORG
entity:
  Pulsed Electron Paramagnetic Resonance of Spin Labels Investigation of Model Membrane Disruption Mechanism


id: cord-269756-tid8a464
type: ORG
entity:
  Kinetics and Activation Thermodynamics of Stalk and Pore Formation Differently Mechanistic Implications Conformation


id: cord-269756-tid8a464
type: CHEMICAL
entity:
  glycerol POPG 1 palmitoyl 2 oleoyl sn glycero 3 phospho L serine POPS 1 palmitoyl 2 oleoyl sn glycero 3 phosphate POPA


id: cord-269270-i2odcsx7
type: ORG
entity:
  Fractional Derivatives Fdifferential Equations to Methods of their Solution and Some of Their Applications Fractional


id: cord-271328-zdf5ji4k
type: ORG
entity:
  the Institutional Animal Care and Use Committee of Beijing Institute of Microbiology and Epidemiology ID SYXK2010 005


id: cord-281536-8y7yxcp4
type: CELL_LINE
entity:
  R426 Y53 T433 W226 N437 R162 Y440 D182 P470 D202 N479 D182 D480 R162 D480 S163 D480 N164 D480 R223 Y481 R223 Y484 Y102 T486 Y53 T487 Y53 T487 D99 G488 A33


id: cord-281536-8y7yxcp4
type: GGP
entity:
  RepoRtS 2020 10 16862 https doi org 10 1038 s41598 020 73820 8 www nature com scientificreports www nature com scientificreports correlation with site


id: cord-284374-sqxlnk9e
type: LOC
entity:
  Middle East Respiratory Syndrome Infection Control and Prevention Guideline for Healthcare Facilities Surveillance


id: cord-268414-7fcc5i7i
type: CELL_LINE
entity:
  MCF 7 MDA MB231 breast adenocarcinoma HepG2 hepatocellular cancer HT 29 colorectal adenocarcinoma and MCF 10A breast epithelial cell lines


id: cord-279598-xzionafe
type: DNA
entity:
  pcDNA3 1 PEDV S 1 435 V5 His pcDNA3 1 PEDV S 1 485 V5 His pcDNA3 1 PEDV S 1 501 V5 His pcDNA3 1 PEDV S 1 509 V5 His pcDNA3 1 PEDV S 1 575 V5 His pcDNA3 1 PEDV S 1 639 V5 His and pcDNA3 1 PEDV S V5 His


id: cord-279598-xzionafe
type: ORG
entity:
  Identification of Neutralizing Monoclonal Antibodies Targeting Novel Conformational Epitopes of the Porcine Epidemic Diarrhoea Virus Spike Protein


id: cord-276444-jidvkij5
type: WORK_OF_ART
entity:
  A Novel Protein Highly Expressed in Testis Is Overexpressed in Systemic Sclerosis Fibroblasts and Targeted by Autoantibodies A Mammalian Scaffold Complex


id: cord-286559-y8z0pwgn
type: DISEASE
entity:
  influenza A viruses HIV evolutionary dynamics within and among hosts Cross species virus transmission


id: cord-294220-ewp1m8jp
type: ORG
entity:
  The International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ICH


id: cord-288721-3bv3aak6
type: PROTEIN
entity:
  Cytochrome C oxidase COX IV Cytochrome C Cyt C Glyceraldehyde 3 phosphate dehydrogenase GAPDH Glucose regulated protein 78 GRP78 Histon 2B H2B


id: cord-288721-3bv3aak6
type: GGP
entity:
  Cytochrome C oxidase COX IV Cytochrome C Cyt C Glyceraldehyde 3 phosphate dehydrogenase GAPDH Glucose


id: cord-293747-ds8rhbkv
type: GGP
entity:
  herpes simplex virus HSV type 1 respiratory syncytial virus pseudorabies virus parainfluenza virus type 3


id: cord-289932-dsysiefx
type: DNA
entity:
  antisense probe antisense n 27 median 110 4 25 at 80 7 and 75 at 135 5 sense n 19 median 0 0 25 at 0 0 75 at 21 7 Mann Whitney Rank Sum Test P 0 001 DPP4 mRNA


id: cord-293505-1t3hg4wi
type: ORG
entity:
  Hospital Outbreak With Continued Circulation of Recombinant Virus Identified Transmission Dynamics of Middle East Respiratory Syndrome Coronavirus Infection


id: cord-293505-1t3hg4wi
type: LOC
entity:
  Middle East Respiratory Syndrome Infection Control and Prevention Guideline for Healthcare Facilities


id: cord-305473-w30hsr4m
type: DISEASE
entity:
  influenza A H1N1 pdm09 21 and a lack of association between days post onset and Ct values for adenovirus human metapneumovirus parainfluenza virus 1 3 22 PCR based assays may thus retain greater value


id: cord-305473-w30hsr4m
type: DISEASE
entity:
  influenza A H1N1 pdm09 based on epidemiological risk factors like travel and contact history Ethics approvals


id: cord-301016-9t7v7ipt
type: PROTEIN
entity:
  PoPMuSiC Δ Δ G values 0 kcal mol are mark of mutations increasing protein stability Therefore PoPMuSiC Δ Δ G


id: cord-296562-3h2oqb9k
type: PROTEIN
entity:
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  Diagnosis to Detect Porcine Transmissible Gastroenteritis Virus TGEV by Optical and Transmission Electron Microscopy Techniques Complete


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  524 pGL3 1000 1 nt 1000 to 1 pGL3 523 1 nt 523 to 1 pGL3 340 1 nt 340 to 1 and pGL3 119 1 nt 119 to 1


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  the Ethics of Committees of Union Hospital Tongji Medical College Huazhong University of Science and Technology


id: cord-312777-5925lvue
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  Ethics of Committees of Union Hospital Tongji Medical College Huazhong University of Science and Technology


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  Antisense GAC TGC GGC CGC CTA TCA AGC GTA ATC TGG AAC ATC GTA TGG GTA GTT TCC CTG ATT CTG GAG AA A3C Sense ACG CGA ATT CCA CCA TGA ATC CAC AGA TCA GAA ACC CGA TG Antisense GAC TGC GGC CGC CTA TCA AGC GTA ATC TGG AAC ATC GTA TGG GTA CTG GAG ACT CTC CCG TAG


id: cord-325405-cu4nx891
type: DISEASE
entity:
  Rotavirus norovirus enteric adenovirus astrovirus sapovirus mimiviruses aichivirus bocavirus parechovirus cytomegalovirus hepatitis A coronaviruses picornaviruses


id: cord-320709-2pnqpljt
type: DNA
entity:
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id: cord-315483-l6dm82pp
type: DNA
entity:
  SCIentIFIC REPORtS 2018 8 6794 DOI 10 1038 s41598 018 24905 y duck and human IFIT5 Fig 1C One of the structural hallmarks


id: cord-315483-l6dm82pp
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  42 Immortalized chicken fibroblasts DF 1 human embryonic kidney cells 293T HEK 293T and Madin Darby canine kidney MDCK cells


id: cord-324696-htx0ul4o
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  Comparative Intestinal Histomorphology of Five Species of Phyllostomid Bats Phyllostomidae Microchiroptera Ecomorphological Relations


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type: PROTEIN
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  lipoprotein hepatic panel albumin total protein alanine aminotransferase aspartate aminotransferase alkaline phosphatase


id: cord-331775-iaxkfszq
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  the Association for Assessment and Accreditation of Laboratory Animal Care International AAALAC Water


id: cord-331775-iaxkfszq
type: LAW
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  National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome ARDS Clinical Trials Network


id: cord-331775-iaxkfszq
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  the European Society of Hypertension International Protocol Revision 2010 Descriptive Investigation Noninvasive


id: cord-329766-9bwdb6o2
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  The Lancet Respiratory medicine Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease Association


id: cord-331475-mmcu18c8
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  ACAC alpha Acetyl coenzyme carboxylase alpha HMBS Hydroxymethylbilane synthase YWHAZ Tyrosine 3 monooxygenase activation protein zeta


id: cord-331475-mmcu18c8
type: GGP
entity:
  ACAC alpha Acetyl coenzyme carboxylase alpha HMBS Hydroxymethylbilane synthase YWHAZ Tyrosine 3 monooxygenase activation protein zeta polypeptide POLR2A Polymerase 32 II DNA


id: cord-333067-3zan82yf
type: PROTEIN
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  anti CD3 PerCPCy5 5 clone 145 2C11 anti CD4 Alexafluor 700 clone RM4 5 anti CD8a allophycocyanin APC Cy7 clone 53 6 7


id: cord-333067-3zan82yf
type: GGP
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  lipopolysaccharide and monophosphoryl lipid a differentially regulate effector and memory CD8 T Cell


id: cord-331148-40gvay7i
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  Report Prepared for the WHO Annual Consultation on the Composition of Influenza Vaccine for the Southern Hemisphere Influenza


id: cord-331148-40gvay7i
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  Report Prepared for the WHO Annual Consultation on the Composition of Influenza Vaccine for the Southern Hemisphere Risk Assessment of the


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  Seismic Noise Analysis System Power Spectral Density Probability Density Function Stand Alone Software Package United States Geological Survey Open File Report Seismic


id: cord-330562-dabjcvno
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  Seismic Network International Federation of Digital Seismograph Networks Regional Seismic Network of North Western Italy International Federation of Digital Seismograph


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  Improving the Accuracy of Demographic and Molecular Clock Model Comparison While Accommodating Phylogenetic Uncertainty Bayesian Coalescent Inference of Past Population Dynamics


id: cord-336493-ggo9wsrm
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  the Influenza Reagent Resource Influenza Division WHO Collaborating Center for Surveillance Epidemiology and Control of Influenza


id: cord-339973-kj56zi59
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  The MetaSUB International Consortium The Metagenomics and Metadesign of the Subways and Urban Biomes MetaSUB International Consortium


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  smooth muscle actin antibodies Dako mouse monoclonal anti human desmin antibodies Dako sheep polyclonal anti human fibronectin antibodies


id: cord-342289-zpstb7h9
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  Human Intestinal Enteroids a New Model To Study Human Rotavirus Infection Host Restriction and Pathophysiology Replication


id: cord-343302-g9vcchrh
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  Characterization and Demonstration of the Value of a Lethal Mouse Model of Middle East Respiratory Syndrome Coronavirus Infection


id: cord-344953-gtg12hiu
type: ORG
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  the Federation of Animal Science Societies Guide for the Care and Use of Agricultural Animals in Research and Teaching the USDA Animal Welfare Act and Animal Welfare Regulations


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  The Pharmacokinetics of Rafoxanide following Single Dose Intravenous and Oral Administration in Goats Extrapolation


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type: DNA
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  house rabbit anti core polyclonal sera 1 2000 commercial anti His monoclonal antibody 1 1000 Invitrogen and HRP labelled secondary antibodies


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type: CELL_LINE
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  Human Induced Pluripotent Stem Cell Derived Intestinal Epithelial Organoids A heterodimeric antibody fragment


id: cord-344344-q32b742a
type: WORK_OF_ART
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  A Refined Culture System for Human Induced Pluripotent Stem Cell Derived Intestinal Epithelial Organoids A heterodimeric


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entity:
  ethanol isopropanol citric acid monohydrate magnesium sulfate heptahydrate sodium hydrogen carbonate sodium carbonate


id: cord-350255-tthttyl3
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  Maimuna S Liu Dianbo Mandl Kenneth D Mooring Todd A Santillana Mauricio title The role of environmental factors


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  L1 protein L1 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 EATVYLPPVPVSKVV type16 L1 408 421 PPPGGTLEDTYRFV type16


id: cord-340781-z348xbn0
type: DNA
entity:
  L2 protein L2 22 23 24 25 26 27 28 29 30 31 32 33 34 35 KQSGTCPPDVVPKV type18 L2 100 113 PSDPSIVSLVEETS type16 L2 94 107


id: cord-340781-z348xbn0
type: RNA
entity:
  L1 12 13 14 15 16 17 18 19 20 21 YLPPVPVSKV type 16 and YLPPPSVARV type 18 L1 460 470 DQFPLGRKFLL type 16 L1 461 471 DQYPLGRKFLV type 18 L2 11 12 13 14 15 16 17 18 19 20 KRASATQLYK type 16


id: cord-340781-z348xbn0
type: PROTEIN
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  epitopes L1 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 EATVYLPPVPVSKVV type 16 L1 95 111 TQRLVWACVGVEVGRGQ type 16


id: cord-340781-z348xbn0
type: DNA
entity:
  L1 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 L1 408 421 L1 404 417 L2 22 35 L2 100 113 L2 94 107 and L2 57 70


id: cord-351659-ujbxsus4
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  Principles and Practice National Health and Family Planning Commission of China Report on China s mi grant population development


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entity:
  human coronaviruses HCoV metapneumovirus MPV parainfluenza virus type 1 to 4 PIV1 4 adenovirus ADV human bocavirus type 1 HBoV1 and human rhinovirus HRV subtypes A and


id: cord-352061-x6tt9kx5
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  ucOC p 0 05 p 0 01 NS not significant Dotted lines indicate baselines www nature com scientificreports BAP


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  AB330088_Gomen_1952_7p JN860679_JPN_Takeuchi_317_1958 AF065067_USA_55142_vaccine_1962_7a AY594256_USA_vaccine_1962


id: cord-348515-bqqyly23
type: GGP
entity:
  AF065067_USA_55142_vaccine_1962_7a AY594256_USA_vaccine_1962 AF515814_CHN_Beijing AY495969_CHN_vaccine JN860676_AR_87 922_1987_7h AF053086_JPN_383_1992_7d AF053087_JPN_bal_1995_7d2 AY769945_KR_95 81_1995_7d


# bib

id: cord-001116-2yvyiiuy
title: Inflammation and Immune System Activation in Aging: A Mathematical Approach
author: Nikas, Jason B.
date: 2013-11-19
txt: ./txt/cord-001116-2yvyiiuy.txt
cache: ./cache/cord-001116-2yvyiiuy.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3832874/
doi: 10.1038/srep03254
summary:
  Since those functions are associated with the hippocampus, I analyzed the global gene expression data from post-mortem hippocampal tissue of 25 old (age ≥ 60 yrs) and 15 young (age ≤ 45 yrs) cognitively intact human subjects. Having employed three different and independent methods of statistical significance, namely, ROC curve analysis, fold change, and P-value, I was able to identify 36 genes that were the most significant in terms of differential expression. The seven genes [C4A (C4B), ADORA3, MS4A7, BCL6, CD44, C3AR1, and HLA-DRB1], which are the constituent input variables of the model (F 1 super variable), and all of which are -in terms of function -inflammation or immune system activation genes (Table 1) , were all found to be over-expressed in the old subjects compared with the young subjects (Table 1) .

abstract:
  Memory and learning declines are consequences of normal aging. Since those functions are associated with the hippocampus, I analyzed the global gene expression data from post-mortem hippocampal tissue of 25 old (age ≥ 60 yrs) and 15 young (age ≤ 45 yrs) cognitively intact human subjects. By employing a rigorous, multi-method bioinformatic approach, I identified 36 genes that were the most significant in terms of differential expression; and by employing mathematical modeling, I demonstrated that 7 of the 36 genes were able to discriminate between the old and young subjects with high accuracy. Remarkably, 90% of the known genes from those 36 most significant genes are associated with either inflammation or immune system activation. This suggests that chronic inflammation and immune system over-activity may underlie the aging process of the human brain, and that potential anti-inflammatory treatments targeting those genes may slow down this process and alleviate its symptoms.


id: cord-001522-82plcxv9
title: Exploration of diarrhoea seasonality and its drivers in China
author: Xu, Zhiwei
date: 2015-02-04
txt: ./txt/cord-001522-82plcxv9.txt
cache: ./cache/cord-001522-82plcxv9.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4316158/
doi: 10.1038/srep08241
summary:
  In this study, we reviewed the data on ''''other infectious diarrhoea'''' in China from 2005-2012 obtained from CISDCP, aiming to characterize the seasonality of diarrhoea in China and identify its potential drivers, as well as explore potential opportunities for future diarrhoea control and prevention. In terms of the amplitude distribution by age and region (seasonal amplitude refers to the relative fluctuation of diarrhoea within a certain period of time, and it provides pivotal information on the possibility of diarrhoea outbreaks), we found that adults (.515 years) had much greater diarrhoea amplitudes than children (,15 years) (Figure 4 ), but the amplitude in persons .520 years declined progressively with increasing age, reaching its valley in elderly .585 years (Figure 4) , and this decreasing trend was remarkably consistent across years ( Figure S4 (supplementary material)). Demographic, economic, geographic and climate information in all 31 provinces from 2005 to 2012, including population, per capita gross regional product (PGRP), latitude, longitude, monthly average mean temperature, monthly average relative humidity, and monthly average rainfall, were collected from China Statistical Yearbook 27 to identify the putative drivers of diarrhoea seasonality.

abstract:
  This study investigated the diarrhoea seasonality and its potential drivers as well as potential opportunities for future diarrhoea control and prevention in China. Data on weekly infectious diarrhoea cases in 31 provinces of China from 2005 to 2012, and data on demographic and geographic characteristics, as well as climatic factors, were complied. A cosinor function combined with a Poisson regression was used to calculate the three seasonal parameters of diarrhoea in different provinces. Regression tree analysis was used to identify the predictors of diarrhoea seasonality. Diarrhoea cases in China showed a bimodal distribution. Diarrhoea in children <5 years was more likely to peak in fall-winter seasons, while diarrhoea in persons > = 5 years peaked in summer. Latitude was significantly associated with spatial pattern of diarrhoea seasonality, with peak and trough times occurring earlier at high latitudes (northern areas), and later at low latitudes (southern areas). The annual amplitudes of diarrhoea in persons > = 5 years increased with latitude (r = 0.62, P<0.001). Latitude 27.8° N and 38.65° N were the latitudinal thresholds for diarrhoea seasonality in China. Regional-specific diarrhoea control and prevention strategies may be optimal for China. More attention should be paid to diarrhoea in children <5 years during fall-winter seasons.


id: cord-001675-9717nzr7
title: The Tie2-agonist Vasculotide rescues mice from influenza virus infection
author: Sugiyama, Michael G.
date: 2015-06-05
txt: ./txt/cord-001675-9717nzr7.txt
cache: ./cache/cord-001675-9717nzr7.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4457136/
doi: 10.1038/srep11030
summary:
  Here we demonstrate that the Tie2-agonist tetrameric peptide Vasculotide improves survival in murine models of severe influenza, even if administered as late as 72 hours after infection; the benefit was observed using three strains of the virus and two strains of mice. While the drug had no effect on human lung endothelial proliferation (Supplemental Figure 8) , it significantly attenuated lung endothelial apoptosis in vitro in response to influenza virus, as assessed by cleavage of caspase-3 (Supplemental Figure 7c ); we observed a similar reduction in cleaved caspase-3 in lungs from infected mice who received Vasculotide (Supplemental Figure 7d ). First, these data strongly implicate failure of the lung endothelial barrier as the cause of death in murine models of severe influenza, as Vasculotide conferred a significant survival benefit against multiple strains of the virus in two strains of mice.

abstract:
  Seasonal influenza virus infections cause hundreds of thousands of deaths annually while viral mutation raises the threat of a novel pandemic strain. Antiviral drugs exhibit limited efficacy unless administered early and may induce viral resistance. Thus, targeting the host response directly has been proposed as a novel therapeutic strategy with the added potential benefit of not eliciting viral resistance. Severe influenza virus infections are complicated by respiratory failure due to the development of lung microvascular leak and acute lung injury. We hypothesized that enhancing lung endothelial barrier integrity could improve the outcome. Here we demonstrate that the Tie2-agonist tetrameric peptide Vasculotide improves survival in murine models of severe influenza, even if administered as late as 72 hours after infection; the benefit was observed using three strains of the virus and two strains of mice. The effect required Tie2, was independent of viral replication and did not impair lung neutrophil recruitment. Administration of the drug decreased lung edema, arterial hypoxemia and lung endothelial apoptosis; importantly, Vasculotide is inexpensive to produce, is chemically stable and is unrelated to any Tie2 ligands. Thus, Vasculotide may represent a novel and practical therapy for severe infections with influenza.


id: cord-001704-pdxm0iiw
author: Xiong, Siping
date: 2015-07-02
txt: ./txt/cord-001704-pdxm0iiw.txt
cache: ./cache/cord-001704-pdxm0iiw.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488766/
doi: 10.1038/srep11776
summary:
  hmPA6 injection before or after LeTx administration protected all rats from developing anthrax (Fig. 6C) . In the present study, we developed four murine mAbs that could well neutralize LeTx in vitro, and one clone was selected to form a human/mouse chimeric antibody known as hmPA6. In the in vivo test in the present study, irrespective of whether LF was injected before or after hmPA6, the antibody protected the rats from death provided that it was administered before or simultaneously with PA. In summary, we reported a human/murine chimeric IgG, namely, hmPA6, which can specifically identify PA with high affinity, neutralize LeTx, and protect macrophages and F344 rats from anthrax-related death. In vitro and in vivo characterization of anthrax anti-protective antigen and anti-lethal factor monoclonal antibodies after passive transfer in a mouse lethal toxin challenge model to define correlates of immunity An anthrax lethal factor-neutralizing monoclonal antibody protects rats before and after challenge with anthrax toxin

title:
  A Novel Chimeric Anti-PA Neutralizing Antibody for Postexposure Prophylaxis and Treatment of Anthrax

abstract:
  Anthrax is a highly lethal infectious disease caused by the bacterium Bacillus anthracis, and the associated shock is closely related to the lethal toxin (LeTx) produced by the bacterium. The central role played by the 63 kDa protective antigen (PA63) region of LeTx in the pathophysiology of anthrax makes it an excellent therapeutic target. In the present study, a human/murine chimeric IgG mAb, hmPA6, was developed by inserting murine antibody variable regions into human constant regions using antibody engineering technology. hmPA6 expressed in 293F cells could neutralize LeTx both in vitro and in vivo. At a dose of 0.3 mg/kg, it could protect all tested rats from a lethal dose of LeTx. Even administration of 0.6 mg/kg hmPA6 48 h before LeTx challenge protected all tested rats. The results indicate that hmPA6 is a potential candidate for clinical application in anthrax treatment.


id: cord-001712-a1sbdhhn
author: Xiaokaiti, Yilixiati
date: 2015-07-16
txt: ./txt/cord-001712-a1sbdhhn.txt
cache: ./cache/cord-001712-a1sbdhhn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4503950/
doi: 10.1038/srep11494
summary:
  title: EGCG reverses human neutrophil elastase-induced migration in A549 cells by directly binding to HNE and by regulating α1-AT The mechanism underlying this effect may include two processes: EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity; EGCG enhances the expression of α1-antitrypsin by regulating the PI3K/AKT pathway. In this study, we demonstrated additional contributions of inflammation to the progression of lung cancer metastasis and a novel molecular target of EGCG, human neutrophil elastase, which induces lung cancer cell migration. 14 demonstrated that the natural polyphenol product curcumin inhibits tumor proliferation induced by neutrophil elastase via the upregulation of AAT in lung cancer. These results indicated that treatment with EGCG at a concentration between 10 and 20 μ M induces a substantial anti-migratory effect without affecting the proliferation of A549 cells exposed to neutrophil elastase. Our results showed that the neutrophil elastase-induced decrease in IRS-1 expression was significantly inhibited by EGCG in A549 cells.

title:
  EGCG reverses human neutrophil elastase-induced migration in A549 cells by directly binding to HNE and by regulating α1-AT

abstract:
  Lung carcinogenesis is a complex process that occurs in unregulated inflammatory environment. EGCG has been extensively investigated as a multi-targeting anti-tumor and anti-inflammatory compound. In this study, we demonstrated a novel mechanism by which EGCG reverses the neutrophil elastase-induced migration of A549 cells. We found that neutrophil elastase directly triggered human adenocarcinoma A549 cell migration and that EGCG suppressed the elevation of tumor cell migration induced by neutrophil elastase. We observed that EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity based on the CDOCKER algorithm, MD stimulation by GROMACS, SPR assay and elastase enzymatic activity assay. As the natural inhibitor of neutrophil elastase, α1-antitrypsin is synthesized in tumor cells. We further demonstrated that the expression of α1-antitrypsin was up-regulated after EGCG treatment in neutrophil elastase-treated A549 cells. We preliminarily discovered that the EGCG-mediated induction of α1-antitrypsin expression might be correlated with the regulatory effect of EGCG on the PI3K/Akt pathway. Overall, our results suggest that EGCG ameliorates the neutrophil elastase-induced migration of A549 cells. The mechanism underlying this effect may include two processes: EGCG directly binds to neutrophil elastase and inhibits its enzymatic activity; EGCG enhances the expression of α1-antitrypsin by regulating the PI3K/AKT pathway.


id: cord-001823-v60vv99o
title: Modeling the effect of comprehensive interventions on Ebola virus transmission
author: Shen, Mingwang
date: 2015-10-30
txt: ./txt/cord-001823-v60vv99o.txt
cache: ./cache/cord-001823-v60vv99o.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4626779/
doi: 10.1038/srep15818
summary:
  By fitting the model to reported cumulative cases and deaths in Guinea, Sierra Leone and Liberia until March 22, 2015, we estimate the basic reproduction number in these countries as 1.2552, 1.6093 and 1.7994, respectively. The objective of this paper is to assess the effect of all possible intervention strategies (isolation, media impact, safe burial, and vaccination) on controlling the spread of Ebola virus in Guinea, Sierra Leone, Liberia. Using the model, we evaluate the potential effect of increasing the fraction of latent individuals prior to symptoms onset, shortening the duration between symptoms onset and isolation, improving media coverage, following restrict burial procedures, and administrating timely vaccine on the epidemic of Ebola infection. If the effectiveness of isolation increases to 80%, i.e., the relative transmissibility  of isolated individuals decreases to 20% (magenta lines in Fig. 5 ), then about 35%, 65%, 60% of pre-symptomatic patients need to be detected in Guinea, Sierra Leone and Liberia to control the disease.

abstract:
  Since the re-emergence of Ebola in West Africa in 2014, comprehensive and stringent interventions have been implemented to decelerate the spread of the disease. The effectiveness of interventions still remains unclear. In this paper, we develop an epidemiological model that includes various controlling measures to systematically evaluate their effects on the disease transmission dynamics. By fitting the model to reported cumulative cases and deaths in Guinea, Sierra Leone and Liberia until March 22, 2015, we estimate the basic reproduction number in these countries as 1.2552, 1.6093 and 1.7994, respectively. Model analysis shows that there exists a threshold of the effectiveness of isolation, below which increasing the fraction of latent individuals diagnosed prior to symptoms onset or shortening the duration between symptoms onset and isolation may lead to more Ebola infection. This challenges an existing view. Media coverage plays a substantial role in reducing the final epidemic size. The response to reported cumulative infected cases and deaths may have a different effect on the epidemic spread in different countries. Among all the interventions, we find that shortening the duration between death and burial and improving the effectiveness of isolation are two effective interventions for controlling the outbreak of Ebola virus infection.


id: cord-001829-rwnbxmt4
author: Lu, Yi-Fan
date: 2015-11-04
txt: ./txt/cord-001829-rwnbxmt4.txt
cache: ./cache/cord-001829-rwnbxmt4.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631997/
doi: 10.1038/srep16037
summary:
  Genome-wide association studies performed on diverse patient populations have identified polymorphisms near the interferon-λ 3 (IFNL3; formerly IL28B) gene that predict the efficacy of interferon-based therapy for chronic infection. The differential effects on mRNA versus protein levels strongly suggest that the IFNL3 3′ UTR regulates gene expression by repressing the efficiency of mRNA translation rather than mRNA abundance in HeLa cells. We used polysome profiling to examine whether the variant IFNL3 reporter mRNAs were differentially associated with translating ribosomes in stable HeLa cell lines. Although rs4803217 is not independently associated with patient phenotypes in the cohort we analyzed, this SNP occurs in the 3′ UTR of IFNL3 and showed clear functional effects on reporter gene expression, suggesting a role for this variant in control of HCV infection.

title:
  IFNL3 mRNA structure is remodeled by a functional non-coding polymorphism associated with hepatitis C virus clearance

abstract:
  Polymorphisms near the interferon lambda 3 (IFNL3) gene strongly predict clearance of hepatitis C virus (HCV) infection. We analyzed a variant (rs4803217 G/T) located within the IFNL3 mRNA 3′ untranslated region (UTR); the G allele (protective allele) is associated with elevated therapeutic HCV clearance. We show that the IFNL3 3′ UTR represses mRNA translation and the rs4803217 allele modulates the extent of translational regulation. We analyzed the structures of IFNL3 variant mRNAs at nucleotide resolution by SHAPE-MaP. The rs4803217 G allele mRNA forms well-defined 3′ UTR structure while the T allele mRNA is more dynamic. The observed differences between alleles are among the largest possible RNA structural alterations that can be induced by a single nucleotide change and transform the UTR from a single well-defined conformation to one with multiple dynamic interconverting structures. These data illustrate that non-coding genetic variants can have significant functional effects by impacting RNA structure.


id: cord-001852-c79vwr6t
author: Xiao, Qiuyan
date: 2015-11-16
txt: ./txt/cord-001852-c79vwr6t.txt
cache: ./cache/cord-001852-c79vwr6t.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4644992/
doi: 10.1038/srep16639
summary:
  In conclusion, our results found that a history of recurrent wheezing may be a risk factor for the detection of EV-D68 and viral-induced asthma exacerbation may be a clinical feature of EV-D68 infection. In a previous hospital-based viral surveillance study of RTI cases in Chongqing, China, from 2009 to 2012, the detection rate of EV-D68 was 0.4% (7/1565) 11 . In our study, most children infected with EV-D68 had a history of recurrent wheezing or asthma and a diagnosis of acute asthma exacerbation. Our study found that a history of recurrent wheezing or asthma may be a risk factor for the detection of EV-D68 and viral-induced acute asthma exacerbation may be a clinical feature of EV-D68 infection in Chongqing area. A history of recurrent wheezing or asthma appeared to be a risk factor for the detection of EV-D68 and viral-induced acute asthma exacerbation might be a clinical feature of EV-D68 infection.

title:
  Prevalence and molecular characterizations of enterovirus D68 among children with acute respiratory infection in China between 2012 and 2014

abstract:
  EV-D68 is associated with respiratory tract infections (RTIs). Since its first isolation, EV-D68 has been detected sporadically. However, the US and Canada have experienced outbreaks of EV-D68 infections between August and December 2014. This study aimed to investigate the molecular epidemiology and clinical characteristics of EV-D68 in Chongqing, Southwestern China. From January 2012 to November 2014, 1876 nasopharyngeal aspirate specimens (NPAs) were collected from hospitalized children with RTIs. Among the 1876 NPAs, EV-D68 was detected in 19 samples (1.0%, 19/1876). Of these, 13 samples were detected in September and October 2014 (9.8%, 13/132). Phylogenetic analysis showed that all 13 strains detected in the 2014 Chongqing had high homology with the main strains of the 2014 US outbreak. Among the children with EV-D68 infection, 13 (68%) had a history of recurrent wheezing. A total of 13 children had a discharge diagnosis of asthma. Of these, 11 children were diagnosed with acute asthma exacerbation. EV-D68 was the predominant pathogen that evoked asthma exacerbation in September and October 2014. In conclusion, our results found that a history of recurrent wheezing may be a risk factor for the detection of EV-D68 and viral-induced asthma exacerbation may be a clinical feature of EV-D68 infection.


id: cord-001858-nmi39n6h
author: Petriccione, Milena
date: 2015-11-19
txt: ./txt/cord-001858-nmi39n6h.txt
cache: ./cache/cord-001858-nmi39n6h.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4652207/
doi: 10.1038/srep16961
summary:
  title: Reference gene selection for normalization of RT-qPCR gene expression data from Actinidia deliciosa leaves infected with Pseudomonas syringae pv. Primer sequence (5′-3′) BestKeeper and the deltaCt method) were used to evaluate the stability of expression of selected RGs. The analyses were performed for three comparison groups considering both low-and high-dose bacterial inocula in the leaves and their combined dataset. In kiwifruit leaves with a high dose of bacterial inoculum, BestKeeper revealed that only the expression of TUB overcame the stability threshold; CYP and GAPDH were considered to be the most stable genes, with SD values of 0.50 and 0.61, respectively (Table 3 ). The expression of three genes encoding the reactive oxygen species (ROS) scavenging enzymes ascorbate peroxidase (APX), superoxide dismutase (SOD) and catalase (CAT), induced during the systemic infection of kiwifruit leaves with PSA, were chosen to further validate the reliability of the selected RGs for the normalization of RT-qPCR data.

title:
  Reference gene selection for normalization of RT-qPCR gene expression data from Actinidia deliciosa leaves infected with Pseudomonas syringae pv. actinidiae

abstract:
  Normalization of data, by choosing the appropriate reference genes (RGs), is fundamental for obtaining reliable results in reverse transcription-quantitative PCR (RT-qPCR). In this study, we assessed Actinidia deliciosa leaves inoculated with two doses of Pseudomonas syringae pv. actinidiae during a period of 13 days for the expression profile of nine candidate RGs. Their expression stability was calculated using four algorithms: geNorm, NormFinder, BestKeeper and the deltaCt method. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and protein phosphatase 2A (PP2A) were the most stable genes, while β-tubulin and 7s-globulin were the less stable. Expression analysis of three target genes, chosen for RGs validation, encoding the reactive oxygen species scavenging enzymes ascorbate peroxidase (APX), superoxide dismutase (SOD) and catalase (CAT) indicated that a combination of stable RGs, such as GAPDH and PP2A, can lead to an accurate quantification of the expression levels of such target genes. The APX level varied during the experiment time course and according to the inoculum doses, whereas both SOD and CAT resulted down-regulated during the first four days, and up-regulated afterwards, irrespective of inoculum dose. These results can be useful for better elucidating the molecular interaction in the A. deliciosa/P. s. pv. actinidiae pathosystem and for RGs selection in bacteria-plant pathosystems.


id: cord-001862-a097byk5
author: Saisawang, Chonticha
date: 2015-11-24
txt: ./txt/cord-001862-a097byk5.txt
cache: ./cache/cord-001862-a097byk5.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657084/
doi: 10.1038/srep17125
summary:
  The proteolytic activity of nsP2 has been characterized in other alphaviruses, such as Sindbis virus (SINV), Semliki forest virus (SFV) and Venezuelan Equine Encephalitis virus (VEEV), as a papain-like cysteine protease with a cysteine-histidine catalytic dyad in the active site 11, 12, [16] [17] [18] [19] . Although the dyad residues have been identified previously in other alphavirus nsP2 proteins; in SINV, SFV and VEEV 11, 12, [16] [17] [18] , the CHIKV nsP2 protease active site has not been experimentally characterized. In performing this study a structural comparison showed that CHIKV nsP2 protease is not papain-like, and we have found what appears to be a unique feature of CHIKV nsP2 protease, in which the cysteine dyad residue can be catalytically replaced by a vicinal serine. In our study the protease inhibitors leupeptin and E-64 showed little to no effect on wild type, Cys478Ala and Ser482Ala enzyme activities for all 3 substrates (Table 2) .

title:
  Chikungunya nsP2 protease is not a papain-like cysteine protease and the catalytic dyad cysteine is interchangeable with a proximal serine

abstract:
  Chikungunya virus is the pathogenic alphavirus that causes chikungunya fever in humans. In the last decade millions of cases have been reported around the world from Africa to Asia to the Americas. The alphavirus nsP2 protein is multifunctional and is considered to be pivotal to viral replication, as the nsP2 protease activity is critical for proteolytic processing of the viral polyprotein during replication. Classically the alphavirus nsP2 protease is thought to be papain-like with the enzyme reaction proceeding through a cysteine/histidine catalytic dyad. We performed structure-function studies on the chikungunya nsP2 protease and show that the enzyme is not papain-like. Characterization of the catalytic dyad cysteine residue enabled us to identify a nearby serine that is catalytically interchangeable with the dyad cysteine residue. The enzyme retains activity upon alanine replacement of either residue but a replacement of both cysteine and serine residues results in no detectable activity. Protein dynamics appears to allow the use of either the cysteine or the serine residue in catalysis. This switchable dyad residue has not been previously reported for alphavirus nsP2 proteases and would have a major impact on the nsP2 protease as an anti-viral target.


id: cord-001868-utsvsja0
author: Uematsu, Takayuki
date: 2015-12-02
txt: ./txt/cord-001868-utsvsja0.txt
cache: ./cache/cord-001868-utsvsja0.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667252/
doi: 10.1038/srep17577
summary:
  In this study, we focused on CARD9, a signaling adaptor known to regulate innate immune activation through multiple innate sensor proteins, and investigated its role in anti-IFV defense and lung pathogenesis in a mouse model recapitulating severe influenza pneumonia with ARDS. Our results showed that the CARD9 pathway was involved in fatal influenza pneumonia mediated by inflammatory cytokine/chemokine production, whereas it was dispensable for type-I interferon production as well as the development of anti-viral acquired immunity. adapted IFV A/PR/8/34 strain (PR8) shows similar lung pathology to human ARDS 10-12 , we intratracheally infected wild-type (WT: C57BL/6) and Card9 -/mice with a lethal dose (10 4 PFU/mouse) of PR8 to determine whether CARD9-mediated innate immune responses contributed to severe influenza pneumonia. However, no reduction in cytokine/chemokine levels was evident on day 8, indicating that a CARD9-mediated innate response controls cytokine/chemokine production at an early time point after IFV infection and influences subsequent inflammatory cell recruitment and lung pathology at a later time point.

title:
  Loss of CARD9-mediated innate activation attenuates severe influenza pneumonia without compromising host viral immunity

abstract:
  Influenza virus (IFV) infection is a common cause of severe viral pneumonia associated with acute respiratory distress syndrome (ARDS), which is difficult to control with general immunosuppressive therapy including corticosteroids due to the unfavorable effect on viral replication. Studies have suggested that the excessive activation of the innate immunity by IFV is responsible for severe pathologies. In this study, we focused on CARD9, a signaling adaptor known to regulate innate immune activation through multiple innate sensor proteins, and investigated its role in anti-IFV defense and lung pathogenesis in a mouse model recapitulating severe influenza pneumonia with ARDS. We found that influenza pneumonia was dramatically attenuated in Card9-deficient mice, which showed improved mortality with reduced inflammatory cytokines and chemokines in the infected lungs. However, viral clearance, type-I interferon production, and the development of anti-viral B and T cell immunity were not compromised by CARD9 deficiency. Syk or CARD9-deficient DCs but not macrophages showed impaired cytokine but not type-I interferon production in response to IFV in vitro, indicating a possible role for the Syk-CARD9 pathway in DCs in excessive inflammation of IFV-infected lungs. Therefore, inhibition of this pathway is an ideal therapeutic target for severe influenza pneumonia without affecting viral clearance.


id: cord-001875-ulq1xqma
author: Li, Jing
date: 2015-12-11
txt: ./txt/cord-001875-ulq1xqma.txt
cache: ./cache/cord-001875-ulq1xqma.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676028/
doi: 10.1038/srep18094
summary:
  Our results represent the first step in determining the effects of climate factors on two different virus infections in China and provide warning guidelines for the future when provinces fall into the risky windows. Previously, data have indicated that environmental factors affect the prevalence of H5N1 and H7N9, with the infection and spread of the two viruses being closely correlated with bird habitats, migration, and local climate factors (e.g., temperature and relative humidity) 17 . We collected the H5N1 and H7N9 influenza data reported on the Chinese mainland from The climate dataset contained the air temperature, ground surface temperature, relative humidity, wind speed, and atmospheric pressure of all meteorological stations in the reported provinces at the reported dates for each record. Environmental factors influencing the spread of the highly pathogenic avian influenza H5N1 virus in wild birds in

title:
  Identification of climate factors related to human infection with avian influenza A H7N9 and H5N1 viruses in China

abstract:
  Human influenza infections display a strongly seasonal pattern. However, whether H7N9 and H5N1 infections correlate with climate factors has not been examined. Here, we analyzed 350 cases of H7N9 infection and 47 cases of H5N1 infection. The spatial characteristics of these cases revealed that H5N1 infections mainly occurred in the South, Middle, and Northwest of China, while the occurrence of H7N9 was concentrated in coastal areas of East and South of China. Aside from spatial-temporal characteristics, the most adaptive meteorological conditions for the occurrence of human infections by these two viral subtypes were different. We found that H7N9 infections correlate with climate factors, especially temperature (TEM) and relative humidity (RHU), while H5N1 infections correlate with TEM and atmospheric pressure (PRS). Hence, we propose a risky window (TEM 4–14 °C and RHU 65–95%) for H7N9 infection and (TEM 2–22 °C and PRS 980-1025 kPa) for H5N1 infection. Our results represent the first step in determining the effects of climate factors on two different virus infections in China and provide warning guidelines for the future when provinces fall into the risky windows. These findings revealed integrated predictive meteorological factors rooted in statistic data that enable the establishment of preventive actions and precautionary measures against future outbreaks.


id: cord-001901-2s6hpakk
author: Kwok, Hoi-Hin
date: 2016-01-06
txt: ./txt/cord-001901-2s6hpakk.txt
cache: ./cache/cord-001901-2s6hpakk.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702174/
doi: 10.1038/srep18941
summary:
  title: Anti-inflammatory effects of indirubin derivatives on influenza A virus-infected human pulmonary microvascular endothelial cells In this report, we examined the potential immunomodulatory effects of two indirubin derivatives, indirubin-3′-(2,3-dihydroxypropyl)-oximether (E804) and indirubin-3′-oxime (E231), on IAV (H9N2) infected-human pulmonary microvascular endothelial cells (HPMECs). Using specific inhibitors or small-interfering RNA, we confirmed that indirubin derivatives can suppress H9N2-induced cytokines production through MAPKs and STAT3 signaling pathways. To detect the activity of individual MAPKs after treatment with IAV and indirubin derivatives, the non-radioactive In vitro protein kinase assay kit from Cell Signaling Technology was used. In this study, we found that the infection of influenza A virus subtype A/Quali/Hong Kong/G1/97 (H9N2) on HPMECs induced excessive production of various pro-inflammatory cytokines and chemokines, including IP-10 ( In this report, we demonstrated that indirubin derivatives, particularly E804 is a potent immunomodulatory compound for IAV-infection in vitro by inhibiting intracellular signaling pathways in pulmonary endothelial cells.

title:
  Anti-inflammatory effects of indirubin derivatives on influenza A virus-infected human pulmonary microvascular endothelial cells

abstract:
  Influenza A virus (IAV) poses global threats to human health. Acute respiratory distress syndrome and multi-organ dysfunction are major complications in patients with severe influenza infection. This may be explained by the recent studies which highlighted the role of the pulmonary endothelium as the center of innate immune cells recruitment and excessive pro-inflammatory cytokines production. In this report, we examined the potential immunomodulatory effects of two indirubin derivatives, indirubin-3′-(2,3-dihydroxypropyl)-oximether (E804) and indirubin-3′-oxime (E231), on IAV (H9N2) infected-human pulmonary microvascular endothelial cells (HPMECs). Infection of H9N2 on HPMECs induced a high level of chemokines and cytokines production including IP-10, RANTES, IL-6, IFN-β and IFN-γ1. Post-treatment of E804 or E231 could significantly suppress the production of these cytokines. H9N2 infection rapidly triggered the activation of innate immunity through phosphorylation of signaling molecules including mitogen-activated protein kinases (MAPKs) and signal transducer and activator of transcription (STAT) proteins. Using specific inhibitors or small-interfering RNA, we confirmed that indirubin derivatives can suppress H9N2-induced cytokines production through MAPKs and STAT3 signaling pathways. These results underscore the immunomodulatory effects of indirubin derivatives on pulmonary endothelium and its therapeutic potential on IAV-infection.


id: cord-001915-b9dk07tk
author: Liang, Xun
date: 2016-01-18
txt: ./txt/cord-001915-b9dk07tk.txt
cache: ./cache/cord-001915-b9dk07tk.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726036/
doi: 10.1038/srep19176
summary:
  title: A CRISPR/Cas9 and Cre/Lox system-based express vaccine development strategy against re-emerging Pseudorabies virus Here we present an express vaccine development strategy based on CRISPR/Cas9 and Cre/Lox system against re-emerging Pseudorabies virus, which caused the recent devastating swine pseudorabies outbreak in China. To establish an express vaccine development strategy, two highly efficient gene edit systems, CRISPR/Cas9 and Cre/Lox system were employed. Eight hours post transfection, cells were then infected with PRV HNX with different MOI (multiplicity of infection) and incubated until recombinant virus expressing red and/or green fluorescence were observed (Fig. 3b) . As shown in Fig. 4a , the Cre recombinase gene transfected HEK293T cells were infected with PRV-HNX-TK − /gE − GFP + mCherry + recombinant PRV with various MOI (0.1, 1, and 10). Here, our animal experiments in mouse and piglets validated the protective effect of this gene editing technologies based new vaccine candidate, demonstrating its potential in controlling the current pseudorabies outbreak in the swine industry.

title:
  A CRISPR/Cas9 and Cre/Lox system-based express vaccine development strategy against re-emerging Pseudorabies virus

abstract:
  Virus evolves rapidly to escape vaccine-induced immunity, posing a desperate demand for efficient vaccine development biotechnologies. Here we present an express vaccine development strategy based on CRISPR/Cas9 and Cre/Lox system against re-emerging Pseudorabies virus, which caused the recent devastating swine pseudorabies outbreak in China. By CRISPR/Cas9 system, the virulent genes of the newly isolated strain were simultaneously substituted by marker genes, which were subsequently excised using Cre/Lox system for vaccine safety concern. Notably, single cell FACS technology was applied to further promote virus purification efficiency. The combination of these state-of-art technologies greatly accelerated vaccine development. Finally, vaccination and challenge experiments proved this vaccine candidate’s protective efficacy in pigs and the promise to control current pseudorabies outbreak. This is, to our knowledge, the first successful vaccine development based on gene edit technologies, demonstrating these technologies leap from laboratory to industry. It may pave the way for future express antiviral vaccine development.


id: cord-001963-4wjvykx7
author: Liu, Chia-Lin
date: 2016-02-26
txt: ./txt/cord-001963-4wjvykx7.txt
cache: ./cache/cord-001963-4wjvykx7.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768256/
doi: 10.1038/srep21662
summary:
  title: Using mutagenesis to explore conserved residues in the RNA-binding groove of influenza A virus nucleoprotein for antiviral drug development By interrupting the stacking interaction between Y148 and an RNA base, we identified an influenza virus NP inhibitor, (E, E)-1,7-bis(4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione; this inhibitor reduced the NP''s RNA-binding affinity and hindered viral replication. As shown in Fig. 7A , upon H7 treatment at 15μM, the M1 viral RNA synthesis in the influenza virus-infected cells was reduced by 75% at T2. NP is the most abundant RNA-binding viral protein in influenza virus-infected cells and is responsible for recognizing RNA and forming a filamentous nucleocapsid 24 . Using fluorescence titration and an SPR assay of the NPs, we identified one potential natural compound, curcumin (H7), that targets Y148 of influenza virus NP and potently interferes with its RNA-binding activity.

title:
  Using mutagenesis to explore conserved residues in the RNA-binding groove of influenza A virus nucleoprotein for antiviral drug development

abstract:
  Nucleoprotein (NP) is the most abundant type of RNA-binding viral protein in influenza A virus–infected cells and is necessary for viral RNA transcription and replication. Recent studies demonstrated that influenza NP is a valid target for antiviral drug development. The surface of the groove, covered with numerous conserved residues between the head and body domains of influenza A NP, plays a crucial role in RNA binding. To explore the mechanism by which NP binds RNA, we performed a series of site-directed mutagenesis in the RNA-binding groove, followed by surface plasmon resonance (SPR), to characterize the interactions between RNA and NP. Furthermore, a role of Y148 in NP stability and NP-RNA binding was evaluated. The aromatic residue of Y148 was found to stack with a nucleotide base. By interrupting the stacking interaction between Y148 and an RNA base, we identified an influenza virus NP inhibitor, (E, E)-1,7-bis(4-hydroxy-3-methoxyphenyl) -1,6-heptadiene-3,5-dione; this inhibitor reduced the NP’s RNA-binding affinity and hindered viral replication. Our findings will be useful for the development of new drugs that disrupt the interaction between RNA and viral NP in the influenza virus.


id: cord-002013-rb9xdzro
author: Zheng, Xuexing
date: 2016-04-12
txt: ./txt/cord-002013-rb9xdzro.txt
cache: ./cache/cord-002013-rb9xdzro.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4828711/
doi: 10.1038/srep24179
summary:
  To investigate whether EBOV infections can be controlled by virus neutralization alone, and to prevent the possible induction of serum sickness in humans that would be administered antisera, the post-exposure efficacy of F(ab′ ) 2 (immunoglobulin treated with pepsin to remove the Fc regions of the antibody) were also investigated side-by-side with equine antisera in all experiments as a potential alternate treatment. Three horses were immunized intramuscularly (IM) with 7 injections of eVLP over 11 weeks and the hyperimmune sera were collected from each animal at specified timepoints ( Fig. 1A) to determine the serum titers by neutralization assay against a recombinant HIV-1 virus pseudotyped with EBOV GP. The observation that administering F(ab′ ) 2 at 1 dpi is more efficacious than when the same treatment was given at 30 minutes post-exposure (Fig. 5A ) was also observed in past studies with therapeutic EBOV GP-specific monoclonal antibodies 25, 26 , and suggests that virus neutralization may play a bigger role in protection at a later timepoint after EBOV challenge.

title:
  Treatment with hyperimmune equine immunoglobulin or immunoglobulin fragments completely protects rodents from Ebola virus infection

abstract:
  Recent successes with monoclonal antibody cocktails ZMapp(TM) and MIL77 against Ebola virus (EBOV) infections have reignited interest in antibody-based therapeutics. Since the production process for monoclonal antibodies can be prolonged and costly, alternative treatments should be investigated. We produced purified equine antisera from horses hyperimmunized with EBOV virus-like particles, and tested the post-exposure efficacy of the antisera in a mouse model of infection. BALB/c mice were given up to 2 mg of purified equine antisera per animal, at 30 minutes, 1 or 2 days post-infection (dpi), in which all animals survived. To decrease the possibility of serum sickness, the equine antisera was digested with pepsin to generate F(ab′)(2) fragments, with in vitro neutralizing activity comparable to whole immunoglobulin. Full protection was achieved with when treatment was initiated at 1 dpi, but the suboptimal protection observed with the 30 minute and 2 dpi groups demonstrate that in addition to virus neutralization, other Fc-dependent antibody mechanisms may also contribute to survival. Guinea pigs given 20 mg of antisera or F(ab′)(2) at or starting at 1 or 2 dpi were also fully protected from EBOV infection. These results justify future efficacy studies for purified equine products in NHPs.


id: cord-002019-wtnf340p
author: Chen, Xiaojuan
date: 2016-04-15
txt: ./txt/cord-002019-wtnf340p.txt
cache: ./cache/cord-002019-wtnf340p.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832189/
doi: 10.1038/srep24152
summary:
  We demonstrated that elevated numbers of gut-homing CD8(+) T cells (which express α4β7 and CCR9 molecules) were presented in porcine inguinal lymph nodes and were recruited to the small intestine by RA. Taken together, the cell migration assay results revealed a strong chemotactic response in T cells when activated by RA-activated DCs. These data demonstrated that RA-pretreated BMDCs could activate T cells to express high functional levels of the gut-homing receptor CCR9, as well as to migrate towards the porcine chemokine CCL25. In agreement with the migration of gut-homing CD8 + cells, our observations showed that after RA plus TGEV s.c. treatment, many CD3 + T cells were recruited to the intestinal villi and lamina propria, and these data also showed that RA-assisted antigen s.c. can establish a stronger and faster cellular immune response to defend against foreign pathogens 40 .

title:
  Retinoic acid facilitates inactivated transmissible gastroenteritis virus induction of CD8(+) T-cell migration to the porcine gut

abstract:
  The digestive tract is the entry site for transmissible gastroenteritis virus (TGEV). TGEV transmission can be prevented if local immunity is established with increased lymphocytes. The current parenteral mode of vaccination stimulates systemic immunity well, but it does not induce sufficient mucosal immunity. Retinoic acid (RA) plays an important role in the induction of cells that imprint gut-homing molecules. We examined whether RA assist parenteral vaccination of pigs could improve mucosal immunity. We demonstrated that elevated numbers of gut-homing CD8(+) T cells (which express α4β7 and CCR9 molecules) were presented in porcine inguinal lymph nodes and were recruited to the small intestine by RA. Intestinal mucosal immunity (IgA titre) and systemic immunity (serum IgG titre) were enhanced by RA. Therefore, we hypothesized that RA could induce DCs to form an immature mucosal phenotype and could recruit them to the small intestinal submucosa. Porcine T-cells expressed β7 integrin and CCR9 receptors and migrated to CCL25 by a mechanism that was dependent of activation by RA-pretreated DCs, rather than direct activation by RA. Together, our results provide powerful evidence that RA can assist whole inactivated TGEV (WI-TGEV) via subcutaneous (s.c.) immunization to generate intestinal immunity, and offer new vaccination strategies against TGEV.


id: cord-002045-m44fic4g
author: Horie, Masayuki
date: 2016-05-13
txt: ./txt/cord-002045-m44fic4g.txt
cache: ./cache/cord-002045-m44fic4g.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865735/
doi: 10.1038/srep25873
summary:
  Endogenous bornavirus-like L (EBLL) elements are inheritable sequences derived from ancient bornavirus L genes that encode a viral RNA-dependent RNA polymerase (RdRp) in many eukaryotic genomes. Furthermore, we showed that the EBLLs evolved under purifying selection and still possess functional motifs conserved among the Mononegavirales RdRps. These results strongly suggest that the EBLL elements encode functional proteins that may be RdRps. ORF screening for these elements in several mammalian species and found an EBLL element in the bat species Eptesicus fuscus (designated efEBLL-1; accession number ALEH01013293). Notably, this element (eEBLL-1) contains a 1,718-amino acid ORF that was conserved for more than 11.8 MY and included almost all of the sequence motifs essential for the enzymatic activity of a RNA virus RdRp. To the best of our knowledge, eEBLL-1 is the first example of an RNA virus-derived RdRp encoded by the mammalian genome.

title:
  An RNA-dependent RNA polymerase gene in bat genomes derived from an ancient negative-strand RNA virus

abstract:
  Endogenous bornavirus-like L (EBLL) elements are inheritable sequences derived from ancient bornavirus L genes that encode a viral RNA-dependent RNA polymerase (RdRp) in many eukaryotic genomes. Here, we demonstrate that bats of the genus Eptesicus have preserved for more than 11.8 million years an EBLL element named eEBLL-1, which has an intact open reading frame of 1,718 codons. The eEBLL-1 coding sequence revealed that functional motifs essential for mononegaviral RdRp activity are well conserved in the EBLL-1 genes. Genetic analyses showed that natural selection operated on eEBLL-1 during the evolution of Eptesicus. Notably, we detected efficient transcription of eEBLL-1 in tissues from Eptesicus bats. To the best of our knowledge, this study is the first report showing that the eukaryotic genome has gained a riboviral polymerase gene from an ancient virus that has the potential to encode a functional RdRp.


id: cord-002072-qbh728ec
title: A new reassortment of influenza A (H7N9) virus causing human infection in Beijing, 2014
author: Bi, Yuhai
date: 2016-05-27
txt: ./txt/cord-002072-qbh728ec.txt
cache: ./cache/cord-002072-qbh728ec.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4882526/
doi: 10.1038/srep26624
summary:
  Genetic and phylogenetic analyses revealed that the virus belonged to a novel genotype, which probably emerged and further reassorted with other H9 or H7 viruses in poultry before transmitting to humans. The IFN-induced transmembrane protein-3 (IFITM3) C/C genotype was reported to be associated with severe clinical outcomes, as reflected by a higher viral load, more rapid progression to ARDS, higher cytokine/chemokine levels, and an increased mortality rate after H7N9 infection 22 . Although this was a severe H7N9-infected case with cytokine storm-like appearances and multiple organ failure, the patient was eventually cured after combination therapy with antivirals, mechanical ventilation, supportive nutrition and symptomatic treatment. Clinical, virological and immunological features from patients infected with re-emergent avian-origin human H7N9 influenza disease of varying severity in Guangdong province Cytokine and chemokine levels in patients infected with the novel avian influenza A (H7N9) virus in China

abstract:
  A 73-year-old man was confirmed to have an influenza A (H7N9) virus infection, and the causative agent A/Beijing/02/2014(H7N9) virus was isolated. Genetic and phylogenetic analyses revealed that the virus belonged to a novel genotype, which probably emerged and further reassorted with other H9 or H7 viruses in poultry before transmitting to humans. This virus caused a severe infection with high levels of cytokines and neutralizing antibodies. Eventually, the patient was cured after serially combined treatments. Taken together, our findings indicated that this novel genotype of the human H7N9 virus did not evolve directly from the first Beijing isolate A/Beijing/01/2013(H7N9), suggesting that the H7N9 virus has not obtained the ability for human-to-human transmissibility and the virus only evolves in poultry and then infects human by direct contact. Hence, the major measures to prevent human H7N9 virus infection are still to control and standardize the live poultry trade. Early antiviral treatment with combination therapies, including mechanical ventilation, nutrition support and symptomatic treatment, are effective for H7N9 infection.


id: cord-002081-vi6rth9o
author: Zhang, Chao
date: 2016-06-01
txt: ./txt/cord-002081-vi6rth9o.txt
cache: ./cache/cord-002081-vi6rth9o.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887897/
doi: 10.1038/srep26533
summary:
  In this work, a rapid one-step SNP detection method, real-time loop-mediated isothermal amplification (RT-LAMP), was first applied for CYP2C19 polymorphisms testing. The optimized method was established with specifically designed primers for target amplification by real-time detection in approximately 30 min under isothermal conditions. The successful establishment of an inexpensive, rapid and real-time LAMP protocol for CYP2C19*2 and CYP2C19*3 detection is significant for the extension of this technique for genotyping other SNPs. Our results suggest applications for this RT-LAMP assay system for both basic research and clinical diagnosis in pharmacogenomics. In this study, the successful establishment of an inexpensive, rapid and real-time LAMP protocol for CYP2C19 SNP genotyping expanded the scope of application of this technique to human gene mutation detection. In summary, as a rapid, feasible and cost-efficient point-of-care (POC) SNP detection method, we demonstrated that RT-LAMP could quantitatively detect human genomic DNA with high specificity and sensitivity in a single step.

title:
  Establishment and application of a real-time loop-mediated isothermal amplification system for the detection of CYP2C19 polymorphisms

abstract:
  Single-nucleotide polymorphisms (SNPs) represent the most widespread type of genetic variation (approximately 90%) in the human genome, and the demand to overcome such variation has received more attention now than ever before. The capacity to rapidly assess SNPs that correlate with disease predisposition, drug efficacy and drug toxicity is a key step for the development of personalized medicine. In this work, a rapid one-step SNP detection method, real-time loop-mediated isothermal amplification (RT-LAMP), was first applied for CYP2C19 polymorphisms testing. The optimized method was established with specifically designed primers for target amplification by real-time detection in approximately 30 min under isothermal conditions. RT-LAMP amplified few copies of template to produce significant amounts of product and quantitatively detected human DNA with compatible specificity and sensitivity. The success in the establishment of this RT-LAMP protocol for CYP2C19 polymorphism testing is significant for the extension of this technique for the detection of other SNPs, which will further facilitate the development of personalized medicine.


id: cord-002110-pbb247lp
author: Chen, Chin-Pei
date: 2016-06-29
txt: ./txt/cord-002110-pbb247lp.txt
cache: ./cache/cord-002110-pbb247lp.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4926278/
doi: 10.1038/srep28866
summary:
  title: Membrane protein assembly: two cytoplasmic phosphorylated serine sites of Vpu from HIV-1 affect oligomerization Coarse-grained molecular dynamic simulations with models of wild-type and mutant Vpu in a hydrated lipid bilayer supported the experimental data in demonstrating that, in addition to a previously known role in downregulation of host factors, the phosphorylation sites of Vpu also modulate oligomerization. Coarse grained molecular dynamics (CGMD) simulations of Vpu proteins embedded in a planar lipid bilayer model were chosen to evaluate the oligomeric assembly under likely in vivo conditions such as an abundance of Vpu proteins in a large lipid patch and simulated over a long time period. The dynamics data was plotted as area of the peak of the higher oligomer (A P1 ), divided by the total area of A P1 and the peak area of the dimer (A P2 ), A P1 /(A P1 + A P2 ), over time for Vpu-WT with a double logarithmic growth curve (Fig. 4b , black and Table 2 ). Three-dimensional structure of the channel-forming trans-membrane domain of virus protein "u" (Vpu) from HIV-1

title:
  Membrane protein assembly: two cytoplasmic phosphorylated serine sites of Vpu from HIV-1 affect oligomerization

abstract:
  Viral protein U (Vpu) encoded by human immunodeficiency virus type 1 (HIV-1) is a short integral membrane protein which is known to self-assemble within the lipid membrane and associate with host factors during the HIV-1 infectivity cycle. In this study, full-length Vpu (M group) from clone NL4-3 was over-expressed in human cells and purified in an oligomeric state. Various single and double mutations were constructed on its phosphorylation sites to mimic different degrees of phosphorylation. Size exclusion chromatography of wild-type Vpu and mutants indicated that the smallest assembly unit of Vpu was a dimer and over time Vpu formed higher oligomers. The rate of oligomerization increased when (i) the degree of phosphorylation at serines 52 and 56 was decreased and (ii) when the ionic strength was increased indicating that the cytoplasmic domain of Vpu affects oligomerization. Coarse-grained molecular dynamic simulations with models of wild-type and mutant Vpu in a hydrated lipid bilayer supported the experimental data in demonstrating that, in addition to a previously known role in downregulation of host factors, the phosphorylation sites of Vpu also modulate oligomerization.


id: cord-002111-mmpijsqb
author: Philp, Lisa K.
date: 2016-06-30
txt: ./txt/cord-002111-mmpijsqb.txt
cache: ./cache/cord-002111-mmpijsqb.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928056/
doi: 10.1038/srep28950
summary:
  title: Small Glutamine-Rich Tetratricopeptide Repeat-Containing Protein Alpha (SGTA) Ablation Limits Offspring Viability and Growth in Mice Small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA) has been implicated as a co-chaperone and regulator of androgen and growth hormone receptor (AR, GHR) signalling. As some, but not all, androgen-regulated organs displayed potential signs of hyperandrogenisation during development in Sgta +/− and Sgta −/− mutants, we measured Ar mRNA expression in androgen-regulated tissues, the brain, and the prostate and testis in males, and the mammary and ovary in females (Fig. 4C) . However, the relative weights of vital and sex organs, adipose tissue, muscle and bone were not affected by a genotype* age interaction, suggesting that Sgta-null mice are not any more vulnerable to age-related stress than WT. Small glutamine-rich tetratricopeptide repeat-containing protein (SGT) interacts with the ubiquitin-dependent endocytosis (UbE) motif of the growth hormone receptor

title:
  Small Glutamine-Rich Tetratricopeptide Repeat-Containing Protein Alpha (SGTA) Ablation Limits Offspring Viability and Growth in Mice

abstract:
  Small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA) has been implicated as a co-chaperone and regulator of androgen and growth hormone receptor (AR, GHR) signalling. We investigated the functional consequences of partial and full Sgta ablation in vivo using Cre-lox Sgta-null mice. Sgta(+/−) breeders generated viable Sgta(−/−) offspring, but at less than Mendelian expectancy. Sgta(−/−) breeders were subfertile with small litters and higher neonatal death (P < 0.02). Body size was significantly and proportionately smaller in male and female Sgta(−/−) (vs WT, Sgta(+/−) P < 0.001) from d19. Serum IGF-1 levels were genotype- and sex-dependent. Food intake, muscle and bone mass and adiposity were unchanged in Sgta(−/−). Vital and sex organs had normal relative weight, morphology and histology, although certain androgen-sensitive measures such as penis and preputial size, and testis descent, were greater in Sgta(−/−). Expression of AR and its targets remained largely unchanged, although AR localisation was genotype- and tissue-dependent. Generally expression of other TPR-containing proteins was unchanged. In conclusion, this thorough investigation of SGTA-null mutation reports a mild phenotype of reduced body size. The model’s full potential likely will be realised by genetic crosses with other models to interrogate the role of SGTA in the many diseases in which it has been implicated.


id: cord-002177-yyfgl9x5
title: TGEV infection up-regulates FcRn expression via activation of NF-κB signaling
author: Guo, Jinyue
date: 2016-08-24
txt: ./txt/cord-002177-yyfgl9x5.txt
cache: ./cache/cord-002177-yyfgl9x5.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995372/
doi: 10.1038/srep32154
summary:
  Furthermore, treatment of TGEV-infected IPEC-J2 cells with the NF-κB-specific inhibitor BAY 11-7082 resulted in down-regulation of pFcRn expression. We identified four NF-κB transcription factor binding sites in the promoter region of this gene using luciferase reporter system, chromatin immunoprecipitation, electromobility shift assay, and supershift analysis. In the present study, we investigated how TGEV infection activated the NF-κ B pathway in vitro and up-regulated pFcRn expression in IPEC-J2 cells. Furthermore, pFcRn expression induced by TGEV infection was strongly reduced by the NF-κ B-specific inhibitor BAY 11-7082 in IPEC-J2 cells (Fig. 3) . Transient transfection of the pFcRn promoter luciferase reporter plasmids revealed that pFcRn-luc-(1-3) plasmids resulted in increased promoter activity in the presence of TGEV infection (Fig. 4B) , further demonstrating that TGEV up-regulates pFcRn expression in IPEC-J2 cells. In summary, TGEV infection up-regulates pFcRn expression in IPEC-J2 cells, and activates the NF-κ B signaling pathway.

abstract:
  It has been well characterized that the neonatal Fc receptor (FcRn) transports maternal IgG to a fetus or newborn and protects IgG from degradation. We previously reported that FcRn is expressed in a model of normal porcine intestinal epithelial cells (IPEC-J2). Transmissible gastroenteritis is an acute enteric disease of swine that is caused by transmissible gastroenteritis virus (TGEV). How porcine FcRn (pFcRn) expression is regulated by pathogenic infection remains unknown. Our research shows that IPEC-J2 cells infected with TGEV had up-regulated pFcRn expression. In addition, the NF-κB signaling pathway was activated in IPEC-J2 cells by TGEV infection. Furthermore, treatment of TGEV-infected IPEC-J2 cells with the NF-κB-specific inhibitor BAY 11-7082 resulted in down-regulation of pFcRn expression. Transient transfection of pFcRn promoter luciferase report plasmids with overexpression of NF-κB p65 transcription factor enhanced the activation of the luciferase report plasmids. We identified four NF-κB transcription factor binding sites in the promoter region of this gene using luciferase reporter system, chromatin immunoprecipitation, electromobility shift assay, and supershift analysis. Together, the data provide the first evidence that TGEV infection up-regulates pFcRn expression via activation of NF-κB signaling.


id: cord-002244-5h6monh3
author: Lee, Seung Hoon
date: 2016-10-06
txt: ./txt/cord-002244-5h6monh3.txt
cache: ./cache/cord-002244-5h6monh3.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052580/
doi: 10.1038/srep34617
summary:
  Immunohistochemical analysis revealed that injection with PTEN overexpression vector significantly suppressed the expression of proinflammatory cytokines and osteoclastogenesis related factor such as RANKL and TRAP in joints compared to CIA mice treated with mock vector (Fig. 1D,E) . However, the differentiation of Treg cell was promoted in CIA induced mice injected with PTEN overexpression vector ( Fig. 2A) . However, the number of CD4 + p-Foxp3 + T cells in the spleen tissues of CIA induced mice was significantly upregulated compared to that in the spleen tissues of mice treated with mock vector based on immunofluorescence confocal microscopy ( Fig. 2C,D) . (A,B) Relative mRNA levels of PTEN and factors such as IL-17, RORγ t, and Foxp3 involved in the differentiation of Th17 and Treg in splenic CD4 + T cells, splenocytes, and draining lymph nodes from CIA induced WT or p53 −/− mice were assessed by real-time PCR.

title:
  PTEN ameliorates autoimmune arthritis through down-regulating STAT3 activation with reciprocal balance of Th17 and Tregs

abstract:
  PTEN is a tyrosine phosphatase with significant function in inhibiting STAT3 activation. Recently, inactivation of STAT3 has been demonstrated as a therapeutic candidate for autoimmune arthritis. The expression of PTEN controlled by p53 regulates autoimmune arthritis through modulating the balance between Th17 and Treg. We hypothesized that PTEN regulated by p53 might reduce CIA severity and inflammatory response via inhibiting STAT3 activation. Our results revealed that PTEN could ameliorate experimental autoimmune arthritis by reducing STAT3 activity and Th17 differentiation. Systemic infusion of PTEN overexpression downregulated CIA severity. In addition, PTEN overexpression decreased the activation of T cells and modulated reciprocal differentiation of Th17 and Treg cells. We observed that PTEN expression downregulated by p53 deficiency induced the activation of STAT3. Loss of p53 exacerbated autoimmune arthritis and dysregulated the population of Th17 and Treg. These data suggest that induction of STAT3-modulatory activity of PTEN may be a therapeutic target for rheumatoid arthritis therapy.


id: cord-002258-o9azey3m
author: Chan, Louisa L. Y.
date: 2016-10-14
txt: ./txt/cord-002258-o9azey3m.txt
cache: ./cache/cord-002258-o9azey3m.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064379/
doi: 10.1038/srep35401
summary:
  In this study, we evaluated the role of amino acid substitution PB2-627K or compensatory changes at PB2-591K and PB2-701N, on the tropism and replication competence of H7N9 viruses for human and swine respiratory tracts using ex vivo organ explant cultures. There were very limited influenza antigen positive cells in the rgPB2-K627E + Q591K and rgPB2-K627E + D701N inoculated ex vivo culture of human bronchus (Fig. 2C ) while more infected cells were shown in these mutant viruses infected lung tissues (Fig. 2D ). In this study, we evaluated the effects of PB2-E627K mutation as well as two mammalian adaptation markers, PB2-Q591K and D701N on H7N9 virus replication competence in ex vivo cultures of human and swine respiratory tracts and in vitro cultures of human primary ATI and PMφ . Tropism and innate host responses of a novel avian influenza A H7N9 virus: an analysis of ex-vivo and in-vitro cultures of the human respiratory tract

title:
  Evaluation of the human adaptation of influenza A/H7N9 virus in PB2 protein using human and swine respiratory tract explant cultures

abstract:
  Novel avian H7N9 virus emerged in China in 2013 resulting in a case fatality rate of around 39% and continues to pose zoonotic and pandemic risk. Amino acid substitutions in PB2 protein were shown to influence the pathogenicity and transmissibility of H7N9 following experimental infection of ferrets and mice. In this study, we evaluated the role of amino acid substitution PB2-627K or compensatory changes at PB2-591K and PB2-701N, on the tropism and replication competence of H7N9 viruses for human and swine respiratory tracts using ex vivo organ explant cultures. Recombinant viruses of A/Shanghai/2/2013 (rgH7N9) and its mutants with PB2-K627E, PB2-K627E + Q591K and PB2-K627E + D701N were generated by plasmid-based reverse genetics. PB2-E627K was essential for efficient replication of rgH7N9 in ex vivo cultures of human and swine respiratory tracts. Mutant rgPB2-K627E + D701N replicated better than rgPB2-K627E in human lung but not as well as rgH7N9 virus. The rgPB2-K627E mutant failed to replicate in human type I-like pneumocytes (ATI) and peripheral blood monocyte-derived macrophages (PMϕ) at 37 °C while the compensatory mutant rgPB2-K627E + Q591K and rgPB2-K627E + D701N had partly restored replication competence in PMϕ. Our results demonstrate that PB2-E627K was important for efficient replication of influenza H7N9 in both human and swine respiratory tracts.


id: cord-002290-wvo22jx2
title: Association of Mannose-binding Lectin Polymorphisms with Tuberculosis Susceptibility among Chinese
author: Liu, Cheng
date: 2016-11-04
txt: ./txt/cord-002290-wvo22jx2.txt
cache: ./cache/cord-002290-wvo22jx2.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095599/
doi: 10.1038/srep36488
summary:
  In this study four functional single-nucleotide polymorphisms (SNPs, H/L, X/Y, P/Q and A/B) across the MBL2 gene were genotyped by direct DNA sequencing of PCR products in a case-control population of Chinese Han origin, consisting of 1,020 patients with pulmonary TB and 1,020 controls. In 1,020 controls, this distribution was 723 (70.9%), 234 (22.9%) and 63 (6.2%), respectively (OR = 1.56, 95% CI 1.29-1.90, P = 1.4 × 10 −6 , with adjustment for age and gender; simulation number = 10,000,000; Table 2 ), implicating that the individuals bearing medium or low expression haplotype pairs had an increased risk of TB and that the MBL deficiency might play a potential role in susceptibility to TB. In this study, we investigated all of the four functional SNPs in the MBL2 gene, individually or in haplotype or haplotype pairs, in a large case-control population of Chinese Han origin, totally consisting of 1,020 patients with TB and 1,020 controls.

abstract:
  Tuberculosis (TB) is caused by infection of Mycobacterium tuberculosis. Host genetic variability is an important determinant of the risk of developing TB in humans. Although the association between MBL2 polymorphisms and TB has been studied in various populations, the results are controversial. In this study four functional single-nucleotide polymorphisms (SNPs, H/L, X/Y, P/Q and A/B) across the MBL2 gene were genotyped by direct DNA sequencing of PCR products in a case-control population of Chinese Han origin, consisting of 1,020 patients with pulmonary TB and 1,020 controls. We found that individuals carrying variant allele at A/B (namely BB or AB genotypes) was associated with increased susceptibility to TB (odds ratios [OR] = 1.57, 95% confidence interval [CI] 1.30–1.91, P = 1.3 × 10(−6)). Additionally, LYPB haplotype showed a significant association with increased risk of TB (OR = 1.54, 95% CI 1.27–1.87, P = 4.2 × 10(−6); global haplotype association P = 3.5 × 10(−5)). Furthermore, individuals bearing low- or medium- MBL expression haplotype pairs had an increased risk of TB (OR = 1.56, 95% CI 1.29–1.90, P = 1.4 × 10(−6)). Thus, the reduced expression of functional MBL secondary to having MBL2 variants may partially mediate the increased susceptibility to TB risk.


id: cord-002312-jyk7f8hz
title: Brain microbiota disruption within inflammatory demyelinating lesions in multiple sclerosis
author: Branton, W. G.
date: 2016-11-28
txt: ./txt/cord-002312-jyk7f8hz.txt
cache: ./cache/cord-002312-jyk7f8hz.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125007/
doi: 10.1038/srep37344
summary:
  Massively parallel (deep) sequencing (RNAseq) of total RNA permitted analysis of all RNA sequences in MS (n = 6) and nonMS (n = 6) white matter samples, revealing that bacterial RNA (ribosomal and non-ribosomal) sequences were detected in all nonMS and MS brain specimens, including MS patients with relapsing-remitting disease (receiving disease modifying therapy) (RR-MS, n = 3) and progressive (untreated) MS (P-MS; n = 3) ( Fig. 2A) . The current study shows the presence of bacterial RNA and DNA sequences and proteins in human brain which are disrupted in conjunction with inflammatory demyelination in patients with MS. The present studies revealed the ratio of bacterium-encoded 16s rDNA to rRNA in matched brain samples to be ~1:2 in both white matter (and cortex, data not shown) with bacterial numbers of 1200-1400 genomes/cm 3 suggesting both bacterial burden and replication were low compared to active pathogenic infections in other tissues.

abstract:
  Microbial communities reside in healthy tissues but are often disrupted during disease. Bacterial genomes and proteins are detected in brains from humans, nonhuman primates, rodents and other species in the absence of neurological disease. We investigated the composition and abundance of microbiota in frozen and fixed autopsied brain samples from patients with multiple sclerosis (MS) and age- and sex-matched nonMS patients as controls, using neuropathological, molecular and bioinformatics tools. 16s rRNA sequencing revealed Proteobacteria to be the dominant phylum with restricted diversity in cerebral white matter (WM) from MS compared to nonMS patients. Both clinical groups displayed 1,200–1,400 bacterial genomes/cm(3) and low bacterial rRNA:rDNA ratios in WM. RNAseq analyses showed a predominance of Proteobacteria in progressive MS patients’ WM, associated with increased inflammatory gene expression, relative to a broader range of bacterial phyla in relapsing-remitting MS patients’ WM. Although bacterial peptidoglycan (PGN) and RNA polymerase beta subunit immunoreactivities were observed in all patients, PGN immunodetection was correlated with demyelination and neuroinflammation in MS brains. Principal component analysis revealed that demyelination, PGN and inflammatory gene expression accounted for 86% of the observed variance. Thus, inflammatory demyelination is linked to an organ-specific dysbiosis in MS that could contribute to underlying disease mechanisms.


id: cord-002320-m99amd4y
author: Mathur, Kalika
date: 2016-11-30
txt: ./txt/cord-002320-m99amd4y.txt
cache: ./cache/cord-002320-m99amd4y.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5128919/
doi: 10.1038/srep38065
summary:
  Systematic analysis of all CHIKV proteins using a Sf21 RNAi sensor cell line based assay revealed that non-structural proteins nsP2 and nsP3 exhibited RNAi suppressor activity. Using cell lysate of the transfected cell expressing nsP2 and nsP3, we evaluated their ability to bind double stranded RNA by using [γ 32P] labeled shRNA of GFP and running the bound complex in a 6% polyacrylamide gel (Fig. 3e) . Having confirmed that both nsP2 and nsP3 exhibit RNAi suppressor activities, efforts were taken to characterise the proteins better and to identify those specific domains that were and NS4B (dengue virus) were taken as positive controls and empty vector was used as negative control. Taken together, the current study has identified CHIKV proteins nsP2 and nsP3 to exhibit RNAi suppressor activity in the in-vitro system that was further demonstrated in its natural hosts, namely, an Aedes and mammalian cell line.

title:
  Analysis of chikungunya virus proteins reveals that non-structural proteins nsP2 and nsP3 exhibit RNA interference (RNAi) suppressor activity

abstract:
  RNAi pathway is an antiviral defence mechanism employed by insects that result in degradation of viral RNA thereby curbing infection. Several viruses including flaviviruses encode viral suppressors of RNAi (VSRs) to counteract the antiviral RNAi pathway. Till date, no VSR has been reported in alphaviruses. The present study was undertaken to evaluate chikungunya virus (CHIKV) proteins for RNAi suppressor activity. We systematically analyzed all nine CHIKV proteins for RNAi suppressor activity using Sf21 RNAi sensor cell line based assay. Two non-structural proteins, namely, nsP2 and nsP3 were found to exhibit RNAi suppressor activity. We further validated the findings in natural hosts, namely in Aedes and in mammalian cell lines and further through EMSA and Agrobacterium infiltration in GFP silenced transgenic tobacco plants. Domains responsible for maximum RNAi suppressor activity were also identified within these proteins. RNA binding motifs in these domains were identified and their participation in RNAi suppression evaluated using site directed mutagenesis. Sequence alignment of these motifs across all species of known alphaviruses revealed conservation of these motifs emphasizing on a similar role of action in other species of alphaviruses as well. Further validation of RNAi suppressor activity of these proteins awaits establishment of specific virus infection models.


id: cord-002369-shk4n8f6
author: Fahmy, Ahmed M.
date: 2017-01-09
txt: ./txt/cord-002369-shk4n8f6.txt
cache: ./cache/cord-002369-shk4n8f6.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5220323/
doi: 10.1038/srep40351
summary:
  The expression of HCV proteins results in the induction of a major rearrangement of host cell membranes, thus leading to the formation of a complex membranous compartment termed the membranous web (MW), which favors viral RNA replication and assembly 3, 4 . To determine whether LC3 or the ATG5-12 conjugate modulates HCV RNA replication, we analyzed the effects of silencing these autophagy genes on viral RNA replication in Huh7 cells stably expressing the JFH1 subgenomic replicon (SGR). Because silencing of LC3 expression led to a clear inhibition of HCV RNA translation after electroporation of the viral RNA but did not significantly affect replication in JFH1-SGR cells, we sought to compare the effect of siRNA treatment before and after infection with HCVcc JFH1 (Fig. 3C) . The autophagy elongation complex proteins (ATG5-12 and ATG16L1) were also detected in the purified MW from NS4B HA replicon cells, but not in the control extract, thus indicating that the elongation complex is indeed present at the HCV replication site.

title:
  The autophagy elongation complex (ATG5-12/16L1) positively regulates HCV replication and is required for wild-type membranous web formation

abstract:
  Hepatitis C virus (HCV) infection induces intracellular membrane rearrangements, thus forming a membranous web (MW) in which HCV replication and assembly occur. The HCV-induced MW is primarily composed of double membrane vesicles (DMVs) transfused by multi-membrane vesicles. The autophagy machinery has been proposed to participate in the formation of such vesicles. However, no clear evidence has been found linking autophagy to the formation of these DMVs. In this study, we evaluated the role of the autophagy elongation complex (ATG5-12/16L1) in HCV replication and MW formation. Using a dominant negative form of ATG12 and an siRNA approach, we demonstrated that the ATG5-12 conjugate, but not LC3-II formation, is crucial for efficient viral replication. Furthermore, purification of HCV MW revealed the presence of ATG5-12 and ATG16L1 along with HCV nonstructural proteins. Interestingly, LC3 was not recruited along with the elongation complex to the site of viral replication. Finally, inhibition of the elongation complex, but not LC3, greatly impaired the formation of the wild-type MW phenotype. To our knowledge, this study provides the first evidence of the involvement of autophagy proteins in the formation of wild-type MWs.


id: cord-002373-rueg4gsj
author: Huang, Ao
date: 2017-01-13
txt: ./txt/cord-002373-rueg4gsj.txt
cache: ./cache/cord-002373-rueg4gsj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233999/
doi: 10.1038/srep40772
summary:
  Then, analyte IgG proteins in increasing concentrations were added to a set of buffer solutions containing antibody-conjugated GO. As the number density of the binding sites was limited on the modified GO, more adsorbed analyte IgG proteins resulted in a stronger fluorescence signal from free IgG-FITCs in the solutions. Therefore, there is a positive and quantitative correlation between the analyte IgG concentration and the fluorescence intensity of free IgG-FITCs. According to this principle, our assay relies on the effectiveness of GO as an energy acceptor to provide efficient fluorescence quenching. The experiment was repeated 4 times, and the average of the results was plotted in Fig. 4(a) , from which we can see the assay''s fluorescence signal increased readily with the increasing analyte IgG concentration. We established an immunosensor platform based on quantitative fluorescence quenching between fluorescein-labelled antigens and antibody-conjugated GO nanosheets, a process controlled quantitatively by the concentration of analyte proteins.

title:
  Quantitative Fluorescence Quenching on Antibody-conjugated Graphene Oxide as a Platform for Protein Sensing

abstract:
  We created an immunosensing platform for the detection of proteins in a buffer solution. Our sensing platform relies on graphene oxide (GO) nanosheets conjugated with antibodies to provide quantitative binding sites for analyte proteins. When analyte proteins and standard fluorescein-labelled proteins are competing for the binding sites, the assay exhibits quantitative fluorescence quenching by GO for the fluorescein-labelled proteins as determined by the analyte protein concentration. Because of this mechanism, measured fluorescence intensity from unquenched fluorescein-labelled protein was shown to increase with an increasing analyte protein concentration. As an alternative to the conventional enzyme-linked immunosorbent assay (ELISA), our method does not require an enzyme-linked second antibody for protein recognition and the enzyme for optical signal measurement. Thus, it is beneficial with its low cost and fewer systematic errors caused by the series of antigen-antibody recognition steps in ELISA. Immune globulin G (IgG) was introduced as a model protein to test our method and our results showed that the limit of detection for IgG was 4.67 pmol mL(−1) in the buffer solution. This sensing mechanism could be developed into a promising biosensor for the detection of proteins, which would broaden the spectrum of GO applications in both analytical biochemistry and clinical diagnosis.


id: cord-002389-k86hzbbx
author: Fan, Hanlu
date: 2017-01-24
txt: ./txt/cord-002389-k86hzbbx.txt
cache: ./cache/cord-002389-k86hzbbx.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259750/
doi: 10.1038/srep41226
summary:
  As all stages of Ebola entry (binding to and internalization from the cell surface, as well as trafficking to and fusion with the limiting membrane of endolysosome) are mediated by trimeric GP spikes arrayed around the Ebola particles 29, 30 , so the pseudovirion model with Ebola GP can simulate the stages of wild-type Ebola entry, and several groups have studied the Ebola entry mechanism and screened the anti-Ebola entry drugs with Ebola pseudovirion model 3, 6, 31, 32 . To determine whether endolysosomal calcium is involved in the mechanism of Ebola entry inhibition, we treated HepG2 cell line with a high-affinity Rhod-dextran to chelate intraluminal calcium, and infected the cells with Ebola, WSN, or VSV pseudovirions.

title:
  Selective inhibition of Ebola entry with selective estrogen receptor modulators by disrupting the endolysosomal calcium

abstract:
  The Ebola crisis occurred in West-Africa highlights the urgency for its clinical treatments. Currently, no Food and Drug Administration (FDA)-approved therapeutics are available. Several FDA-approved drugs, including selective estrogen receptor modulators (SERMs), possess selective anti-Ebola activities. However, the inhibitory mechanisms of these drugs remain elusive. By analyzing the structures of SERMs and their incidental biological activity (cholesterol accumulation), we hypothesized that this incidental biological activity induced by SERMs could be a plausible mechanism as to their inhibitory effects on Ebola infection. Herein, we demonstrated that the same dosages of SERMs which induced cholesterol accumulation also inhibited Ebola infection. SERMs reduced the cellular sphingosine and subsequently caused endolysosomal calcium accumulation, which in turn led to blocking the Ebola entry. Our study clarified the specific anti-Ebola mechanism of SERMs, even the cationic amphiphilic drugs (CADs), this mechanism led to the endolysosomal calcium as a critical target for development of anti-Ebola drugs.


id: cord-002408-bbtslrrt
title: Analysis of Influenza and RSV dynamics in the community using a ‘Local Transmission Zone’ approach
author: Almogy, Gal
date: 2017-02-09
txt: ./txt/cord-002408-bbtslrrt.txt
cache: ./cache/cord-002408-bbtslrrt.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5299452/
doi: 10.1038/srep42012
summary:
  We demonstrate that this urban area is not a single, perfectly mixed ecology, but is in fact comprised of a set of more basic, relatively independent pathogen transmission units, which we term here Local Transmission Zones, LTZs. By identifying these LTZs, and using the dynamic pathogen-content information contained within them, we are able to differentiate between disease-causes at the individual patient level often with near-perfect predictive accuracy. To investigate the possibility of LTZs in a large regional area, we analyze clinical data from a healthcare medical center in the city of Jerusalem, containing the clinical test results for Influenza virus and Respiratory Syncytial Virus (RSV) from patients presenting with ILI symptoms. Our analysis finds that while Influenza and RSV incidences tend to overlap and show more or less equal number of cases over the whole region, individual LTZs show a far more homogeneous disease content at most given times, with some being dominated by RSV while others by Influenza.

abstract:
  Understanding the dynamics of pathogen spread within urban areas is critical for the effective prevention and containment of communicable diseases. At these relatively small geographic scales, short-distance interactions and tightly knit sub-networks dominate the dynamics of pathogen transmission; yet, the effective boundaries of these micro-scale groups are generally not known and often ignored. Using clinical test results from hospital admitted patients we analyze the spatio-temporal distribution of Influenza Like Illness (ILI) in the city of Jerusalem over a period of three winter seasons. We demonstrate that this urban area is not a single, perfectly mixed ecology, but is in fact comprised of a set of more basic, relatively independent pathogen transmission units, which we term here Local Transmission Zones, LTZs. By identifying these LTZs, and using the dynamic pathogen-content information contained within them, we are able to differentiate between disease-causes at the individual patient level often with near-perfect predictive accuracy.


id: cord-002411-iiw878w8
title: TLR4 signaling induces TLR3 up-regulation in alveolar macrophages during acute lung injury
author: Ding, Xibing
date: 2017-02-15
txt: ./txt/cord-002411-iiw878w8.txt
cache: ./cache/cord-002411-iiw878w8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309825/
doi: 10.1038/srep34278
summary:
  The enhanced TLR3 up-regulation in AMΦ augmented the expression of cytokines and chemokines in response to sequential challenges with LPS and Poly I:C, a TLR3 ligand, which was physiologically associated with amplified AMΦ-induced PMN migration into lung alveoli. To address the effect of LPS/TLR4-mediated activation of TLR3 in AMΦ on inflammatory cytokines, we assessed TNF-α and IL-6 in the serum and BALF, as well as the chemokines MIP-2 and MCP-1 in the BALF, following sequential intratracheal challenges with LPS and Poly I:C. This cross talk between TLR4 and TLR3 in AMΦ resulted in the amplification of cytokine (IL-6, TNF-α ) and chemokine (MIP-2, MCP-1) expression in response to LPS and Poly I:C, which activate TLR4 and TLR3, respectively, and subsequently led to enhanced PMN sequestration into the lung, which was found to be correlated with ALI based on the assessment of alveolar-capillary permeability and histological sections of lung tissue.

abstract:
  Acute lung injury is a life-threatening inflammatory response caused by severe infection. Toll-like receptors in alveolar macrophages (AMΦ) recognize the molecular constituents of pathogens and activate the host’s innate immune responses. Numerous studies have documented the importance of TLR-TLR cross talk, but few studies have specifically addressed the relationship between TLR4 and TLR3. We explored a novel mechanism of TLR3 up-regulation that is induced by LPS-TLR4 signaling in a dose- and time-dependent manner in AMΦ from C57BL/6 mice, while the LPS-induced TLR3 expression was significantly reduced in TLR4(−/−) and Myd88(−/−) mice and following pretreatment with a NF-κB inhibitor. The enhanced TLR3 up-regulation in AMΦ augmented the expression of cytokines and chemokines in response to sequential challenges with LPS and Poly I:C, a TLR3 ligand, which was physiologically associated with amplified AMΦ-induced PMN migration into lung alveoli. Our study demonstrates that the synergistic effect between TLR4 and TLR3 in macrophages is an important determinant in acute lung injury and, more importantly, that TLR3 up-regulation is dependent on TLR4-MyD88-NF-κB signaling. These results raise the possibility that bacterial infections can induce sensitivity to viral infections, which may have important implications for the therapeutic manipulation of the innate immune system.


id: cord-002474-2l31d7ew
author: Lv, Yang
date: 2017-04-03
txt: ./txt/cord-002474-2l31d7ew.txt
cache: ./cache/cord-002474-2l31d7ew.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5377260/
doi: 10.1038/srep44190
summary:
  title: Actual measurement, hygrothermal response experiment and growth prediction analysis of microbial contamination of central air conditioning system in Dalian, China Based on the data of Cladosporium in hygrothermal response experiment, this paper used the logistic equation and the Gompertz equation to fit the growth predictive model of Cladosporium genera in different temperature and relative humidity conditions, and the square root model was fitted based on the two environmental factors. Besides, according to the tested microbial density and the identified genome sequence of collected microorganisms, the hygrothermal response experiment of dominant fungal was detected, and the fitting analysis was carried out based on the prediction model, followed by a series of statistical analysis. The unit A showed the obvious microbial contamination status, though all components and airborne microorganism meet the Hygienic specification of central air conditioning ventilation system in public buildings of China 22 .

title:
  Actual measurement, hygrothermal response experiment and growth prediction analysis of microbial contamination of central air conditioning system in Dalian, China

abstract:
  The microbial contamination of central air conditioning system is one of the important factors that affect the indoor air quality. Actual measurement and analysis were carried out on microbial contamination in central air conditioning system at a venue in Dalian, China. Illumina miseq method was used and three fungal samples of two units were analysed by high throughput sequencing. Results showed that the predominant fungus in air conditioning unit A and B were Candida spp. and Cladosporium spp., and two fungus were further used in the hygrothermal response experiment. Based on the data of Cladosporium in hygrothermal response experiment, this paper used the logistic equation and the Gompertz equation to fit the growth predictive model of Cladosporium genera in different temperature and relative humidity conditions, and the square root model was fitted based on the two environmental factors. In addition, the models were carried on the analysis to verify the accuracy and feasibility of the established model equation.


id: cord-002490-kw8psrmz
title: Structure of the Ebola virus glycoprotein spike within the virion envelope at 11 Å resolution
author: Beniac, Daniel R.
date: 2017-04-11
txt: ./txt/cord-002490-kw8psrmz.txt
cache: ./cache/cord-002490-kw8psrmz.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5387728/
doi: 10.1038/srep46374
summary:
  We present the structure of the surface Ebola virus (EBOV) trimeric glycoprotein (GP) spike at 11 Å resolution, in situ within the viral plasma membrane of purified virus particles. In addition, 29,976 images were selected for reference-free analysis of the half-diameter of EBOV to investigate the spatial distribution of the GP spikes, as well as the periodicity and symmetrical relationships between GP and the matrix protein VP40 in the envelope, and the underlying nucleocapsid layer (Figs 1c and S3) . The spike structure of Beniac et al imaged within the virus-like particles was somehow clipped, since this should have included the mucin-like domains: in addition, tomography was combined with single-particle analysis, which may have distorted the results 4 . The structure that we report here is based entirely on the well-accepted method of single-particle analysis using projection matching, and is broadly similar to that published of expressed GP in virus-like particles using tomography 28, 29 : there are noticeable differences in shape and size of the spike, as well as in resolution (Fig. 4) .

abstract:
  We present the structure of the surface Ebola virus (EBOV) trimeric glycoprotein (GP) spike at 11 Å resolution, in situ within the viral plasma membrane of purified virus particles. GP functions in cellular attachment, endosomal entry, and membrane fusion to initiate infection, and is a key therapeutic target. Nevertheless, only about half of the GP molecule has yet been solved to atomic resolution, excluding the mucin-like and transmembrane domains, and some of the glycans. Fitting of the atomic resolution X-ray data from expressed, truncated deletion constructs within our 11 Å structure of the entire molecule demonstrates the relationship between the GP1-GP2 domains, the mucin-like and transmembrane domains, and the bilaminar lipid envelope. We show that the mucin-like domain covers the glycan cap and partially occludes the receptor binding sites prior to proteolytic cleavage. Our structure is also consistent with key antibody neutralisation sites on GP being accessible prior to proteolysis. Based on the findings of us and others, GP-mediated binding may create an angle of 18 degrees between the planes of viral and endosomal membranes.


id: cord-002644-yzan95du
author: Ren, Rongrong
date: 2017-08-08
txt: ./txt/cord-002644-yzan95du.txt
cache: ./cache/cord-002644-yzan95du.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548739/
doi: 10.1038/s41598-017-07384-5
summary:
  Thus, our study reveals that the NLRP3 inflammasome is deleterious for the host during H7N9 infection in mice, which is due to an overwhelming inflammatory response via caspase-1 activation and associated IL-1 signal. To note, the production of above mentioned cytokines and chemokines from Nlrp3 −/− mice showed a similar pattern as that from Casp1/11 −/− mice (Fig. 5b) , indicating that deficiency of NLRP3 inflammasome genes reduced the secretion of several critical proinflammatory mediators in the lung of mice upon H7N9 IAV challenge. Pathology analysis showed that there were inflammatory responses in the infected lungs of all strains of mice, both at 3 d.p.i and at 7 d.p.i; and the pulmonary inflammations at 7 d.p.i. were more severe than that at 3 d.p.i.; moreover, the pulmonary inflammations of the WT mice were stronger than Casp1/11 −/− , Asc −/− and Nlrp3 −/− mice (Figs 3 and 7) .

title:
  The H7N9 influenza A virus infection results in lethal inflammation in the mammalian host via the NLRP3-caspase-1 inflammasome

abstract:
  The avian origin influenza A virus (IAV) H7N9 has caused a considerable number of human infections associated with high rates of death since its emergence in 2013. As a vital component of the host innate immune system, the nucleotide-binding domain leucine-rich repeat containing receptor, pyrin domain containing 3 (NLRP3) inflammasome plays a critical role against H1N1 viral infection. However, the function of NLRP3 inflammasome in host immunological responses to the lethal H7N9 virus is still obscure. Here, we demonstrated that mice deficient for NLRP3 inflammasome components, including NLRP3, caspase-1, and Apoptosis-associated speck-like protein containing a CARD (ASC), were less susceptible to H7N9 viral challenge than wild type (WT) controls. Inflammasome deficiency in these animals led to significantly milder mortality and less pulmonary inflammation compared with WT mice. Furthermore, IL-1 receptor deficient mice also exhibited a higher survival rate than WT controls. Thus, our study reveals that the NLRP3 inflammasome is deleterious for the host during H7N9 infection in mice, which is due to an overwhelming inflammatory response via caspase-1 activation and associated IL-1 signal. Therefore, fine-tuning the activity of NLRP3 inflammasome or IL-1 signaling may be beneficial for the host to control H7N9 associated lethal pathogenesis.


id: cord-002659-566uoozj
author: Fujimoto, Yousuke
date: 2017-08-22
txt: ./txt/cord-002659-566uoozj.txt
cache: ./cache/cord-002659-566uoozj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567326/
doi: 10.1038/s41598-017-08030-w
summary:
  Cytokine levels and virus titres in bronchoalveolar lavage fluid from mice with and without asthma after A(H1N1)pdm09 or seasonal H1N1 infection were examined. Virus titres in asthma/A(H1N1)pdm09 mice were highest at 3 days post-infection, and decreased by 7 days post-infection, although the levels at this time point were still higher than that in any other group. In the present study, we investigated the sequential changes in intra-tracheal cytokine production, viral loads, and pulmonary inflammation in a mouse model of bronchial asthma during the first 7 days after A(H1N1)pdm09 or seasonal H1N1 influenza infection. In contrast, the levels in control mice increased to 161.4 pg/mL by 3 days post-seasonal virus infection, which were similar to those in asthma/A(H1N1)pdm09 mice (p = 1.00), and these levels were maintained until 7 days post-infection. The notable findings in the present study were the early peak in both IL-6 and TNF-α levels, the high inflammatory cell infiltration in BAL fluids, and the severe pulmonary inflammation at 3 days post-infection in asthmatic/A(H1N1)pdm09 mice.

title:
  Pulmonary inflammation and cytokine dynamics of bronchoalveolar lavage fluid from a mouse model of bronchial asthma during A(H1N1)pdm09 influenza infection

abstract:
  Asthmatic patients present more rapid progression of respiratory distress after A(H1N1)pdm09 influenza infection than after seasonal infection. Here, we sought to clarify the pathophysiology of early deterioration in asthmatic patients after A(H1N1)pdm09 infection. Cytokine levels and virus titres in bronchoalveolar lavage fluid from mice with and without asthma after A(H1N1)pdm09 or seasonal H1N1 infection were examined. In asthma/A(H1N1)pdm09 mice, IL-6 and TNF-α levels peaked at 3 days post-infection and were higher than those in all other groups. IFN-γ levels in asthma/A(H1N1)pdm09 mice at 3 days post-infection were higher than in all other mice at any time point, whereas at 7 days post-infection, the levels were lowest in asthma/A(H1N1)pdm09 mice. Virus titres in asthma/A(H1N1)pdm09 mice were highest at 3 days post-infection, and decreased by 7 days post-infection, although the levels at this time point were still higher than that in any other group. Histopathological examination showed more inflammatory cell infiltration and lung tissue destruction in the asthma/A(H1N1)pdm09 group than in any other group. The distinct cytokine profiles in A(H1N1)pdm09-infected asthmatic mice indicated excessive inflammation and virus replication within a few days after infection. Thus, bronchial asthma could be a more exacerbating factor for pandemic influenza infection than for seasonal influenza infection.


id: cord-002673-5a1rfi6k
author: Knibb, Wayne
date: 2017-09-06
txt: ./txt/cord-002673-5a1rfi6k.txt
cache: ./cache/cord-002673-5a1rfi6k.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587679/
doi: 10.1038/s41598-017-11263-4
summary:
  This study uses statistical approaches and assessment of "characteristic attributes" (i.e. nucleotide positions that discriminate among strains) to assess whether published and new NNV RNA2 cds sequences show genetic differentiation over geography, host species and years. Within the red spotted grouper nervous necrosis virus (RGNNV) strain, to which all Asian grouper NNV belong, however, no one so far has reported evidence of genetic subgrouping by region, species or year in a formal statistical manner, especially when we restrict hosts just to Asian grouper. The goal of this report was to collate the most comprehensive data set to date on NNV RNA2 sequences for warm water Asian marine finfish, whether published and/or lodged in Genbank over the last 20 years, including some sequence data produced by our group for Vietnamese and Taiwanese grouper, to statistically test the data for evidence of NNV strain variation that associates with geography, host species and year and also to determine whether there are "characteristic attributes" that indicate regional (or host, year) specific differences among the strains.

title:
  Regional genetic diversity for NNV grouper viruses across the Indo-Asian region – implications for selecting virus resistance in farmed groupers

abstract:
  Grouper aquaculture around Asia is impacted by the nervous necrosis virus (NNV) and, in response, host resistance to this infection is being considered as a trait for selection. However efficient selection may be confounded if there are different genetic strains of NNV within and between regions and over years. This study uses statistical approaches and assessment of “characteristic attributes” (i.e. nucleotide positions that discriminate among strains) to assess whether published and new NNV RNA2 cds sequences show genetic differentiation over geography, host species and years. Rather clear evidence was found for regional strains of NNV. Interestingly, most of the geographic defining “characteristic attributes” were in codon position three, and not translated into differences for the protein capsid (i.e. they were synonymous variations), suggesting that while NNV strains were geographically isolated and had diverged in different regions for RNA sequences, selection had largely conserved the protein sequences among regions. The apparent selection constraint on the capsid protein may mitigate the risk that despite geographic subdivision, NNV strain variability will confound genetic selection for host resistance. The existence of regional Asian NNV strains may suggest that hatcheries are at risk from NNV not only from imported material but also from endemic reservoirs.


id: cord-002720-lrkscs71
author: Kurosaki, Yohei
date: 2017-10-18
txt: ./txt/cord-002720-lrkscs71.txt
cache: ./cache/cord-002720-lrkscs71.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5647432/
doi: 10.1038/s41598-017-13836-9
summary:
  title: Development and evaluation of a rapid molecular diagnostic test for Zika virus infection by reverse transcription loop-mediated isothermal amplification The assay detected viral RNA at 14.5 TCID(50)/mL in virus-spiked serum or urine samples within 15 min, although it was slightly less sensitive than reference real time RT-PCR assay. We then evaluated the utility of this assay as a molecular diagnostic test using 90 plasma or serum samples and 99 urine samples collected from 120 suspected cases of arbovirus infection in the states of Paraíba and Pernambuco, Brazil in 2016. Therefore, it is difficult to detect ZIKV in blood samples from patients after the acute phase of infection, even with sensitive molecular diagnostic methods, such as reverse transcription-polymerase chain reaction (RT-PCR) 14, 18, 19 . These results suggested that the RT-LAMP assay could be used as a rapid, sensitive diagnostic test for ZIKV, the Tp value (i.e., less than 15 min) can be used as an indicator of the number of RNA copies in each reaction.

title:
  Development and evaluation of a rapid molecular diagnostic test for Zika virus infection by reverse transcription loop-mediated isothermal amplification

abstract:
  The recent outbreak of Zika virus (ZIKV) disease caused an enormous number of infections in Central and South America, and the unusual increase in the number of infants born with microcephaly associated with ZIKV infection aroused global concern. Here, we developed a reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay using a portable device for the detection of ZIKV. The assay specifically detected ZIKV strains of both Asian and African genotypes without cross-reactivity with other arboviruses, including Dengue and Chikungunya viruses. The assay detected viral RNA at 14.5 TCID(50)/mL in virus-spiked serum or urine samples within 15 min, although it was slightly less sensitive than reference real time RT-PCR assay. We then evaluated the utility of this assay as a molecular diagnostic test using 90 plasma or serum samples and 99 urine samples collected from 120 suspected cases of arbovirus infection in the states of Paraíba and Pernambuco, Brazil in 2016. The results of this assay were consistent with those of the reference RT-PCR test. This portable RT-LAMP assay was highly specific for ZIKV, and enable rapid diagnosis of the virus infection. Our results provide new insights into ZIKV molecular diagnostics and may improve preparedness for future outbreaks.


id: cord-002758-d86hnox1
title: Computational design of fully overlapping coding schemes for protein pairs and triplets
author: Opuu, Vaitea
date: 2017-11-20
txt: ./txt/cord-002758-d86hnox1.txt
cache: ./cache/cord-002758-d86hnox1.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696523/
doi: 10.1038/s41598-017-16221-8
summary:
  We have examined the possibility to encode an arbitrary pair of protein domains as a dual gene, with the shorter coding sequence completely embedded in the longer one. An example of a designed overlapping gene was produced recently, where each DNA strand coded for a simplified but functional aminoacyl-tRNA synthetase "Urzyme" [13] [14] [15] [16] , with the two enzymes being homologous to the two modern synthetase classes. Considering all three reading frames, we found that over 16% of the (X, Y) pairs have homologous pairs (X′, Y′) that can be encoded in a fully overlapping manner, with a level of X/X′ and Y/Y′ homology corresponding to Blast E-values of 10 −10 or less and a match length of at least 85% of the total sequence length. Given the level of success and the generality of our algorithm, we also designed 200 triple genes, with three proteins encoded by the same DNA segment using both strands and three different reading frames.

abstract:
  Gene pairs that overlap in their coding regions are rare except in viruses. They may occur transiently in gene creation and are of biotechnological interest. We have examined the possibility to encode an arbitrary pair of protein domains as a dual gene, with the shorter coding sequence completely embedded in the longer one. For 500 × 500 domain pairs (X, Y), we computationally designed homologous pairs (X′, Y′) coded this way, using an algorithm that provably maximizes the sequence similarity between (X′, Y′) and (X, Y). Three schemes were considered, with X′ and Y′ coded on the same or complementary strands. For 16% of the pairs, an overlapping coding exists where the level of homology of X′, Y′ to the natural proteins represents an E-value of 10(−10) or better. Thus, for an arbitrary domain pair, it is surprisingly easy to design homologous sequences that can be encoded as a fully-overlapping gene pair. The algorithm is general and was used to design 200 triple genes, with three proteins encoded by the same DNA segment. The ease of design suggests overlapping genes may have occurred frequently in evolution and could be readily used to compress or constrain artificial genomes.


id: cord-002782-mena480g
title: Long term outcomes in survivors of epidemic Influenza A (H7N9) virus infection
author: Chen, Jiajia
date: 2017-12-08
txt: ./txt/cord-002782-mena480g.txt
cache: ./cache/cord-002782-mena480g.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5722861/
doi: 10.1038/s41598-017-17497-6
summary:
  Our findings suggest that pulmonary function and imaging findings improved during the first 6 months especially for those with ARDS, however long-term lung disability and psychological impairment in H7N9 survivors persisted at 2 years after discharge from the hospital. In survivors of H5N1 virus infection, radiologic abnormalities including ground-glass opacities with a reticular pattern remained evident at the 12-month follow-up visit 10 . A study of the long-term outcomes of survivors with ARDS reported a mild restrictive pattern on lung-function testing, with a mild-to-moderate reduction in carbon monoxide diffusion capacity at 3 months; The median DLCO improved by 9% of the predicted value from 3 to 12 months 13 . A meta-analysis showed that recovery in the HRQoL of ARDS survivors occurred during the first 6 months after discharge 20 , but no significant improvement was evident at the 2-year follow-up in our study. Follow-up study on pulmonary function and lung radiographic changes in rehabilitating severe acute respiratory syndrome patients after discharge

abstract:
  Patients who survive influenza A (H7N9) virus infection are at risk of physical and psychological complications of lung injury and multi-organ dysfunction. However, there were no prospectively individualized assessments of physiological, functional and quality-of-life measures after hospital discharge. The current study aims to assess the main determinants of functional disability of these patients during the follow-up. Fifty-six influenza A (H7N9) survivors were investigated during the 2-year after discharge from the hospital. Results show interstitial change and fibrosis on pulmonary imaging remained 6 months after hospital discharge. Both ventilation and diffusion dysfunction improved, but restrictive and obstructive patterns on ventilation function test persisted throughout the follow-up period. For patients with acute respiratory distress syndrome lung functions improved faster during the first six months. Role-physical and Role-emotional domains in the 36-Item Short-Form Health Survey were worse than those of a sex- and age-matched general population group. The quality of life of survivors with ARDS was lower than those with no ARDS. Our findings suggest that pulmonary function and imaging findings improved during the first 6 months especially for those with ARDS, however long-term lung disability and psychological impairment in H7N9 survivors persisted at 2 years after discharge from the hospital.


id: cord-002791-tqchfdmy
author: Mikel, Pavel
date: 2017-12-13
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727534/
doi: 10.1038/s41598-017-17951-5
title:
  One-plasmid double-expression His-tag system for rapid production and easy purification of MS2 phage-like particles

abstract:
  MS2 phage-like particles (MS2 PLP) are artificially constructed pseudo-viral particles derived from bacteriophage MS2. They are able to carry a specific single stranded RNA (ssRNA) sequence of choice inside their capsid, thus protecting it against the effects of ubiquitous nucleases. Such particles are able to mimic ssRNA viruses and, thus, may serve as the process control for molecular detection and quantification of such agents in several kinds of matrices, vaccines and vaccine candidates, drug delivery systems, and systems for the display of immunologically active peptides or nanomachines. Currently, there are several different in vivo plasmid-driven packaging systems for production of MS2 PLP. In order to combine all the advantages of the available systems and to upgrade and simplify the production and purification of MS2 PLP, a one-plasmid double-expression His-tag system was designed. The described system utilizes a unique fusion insertional mutation enabling purification of particles using His-tag affinity. Using this new production system, highly pure MS2 PLP can be quickly produced and purified by a fast performance liquid chromatography (FPLC) approach. The system can be easily adapted to produce other MS2 PLP with different properties.


id: cord-002802-594mmlk8
author: Zhang, Yun
date: 2017-12-20
txt: ./txt/cord-002802-594mmlk8.txt
cache: ./cache/cord-002802-594mmlk8.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738434/
doi: 10.1038/s41598-017-18054-x
summary:
  Further, the recombinant TM-replaced H9N2-TM virus could provide better inter-clade protection in both mice and chickens against H9N2, suggesting that the H3-TM-replacement could be considered as a strategy to develop efficient subtype-specific H9N2 influenza vaccines. However, the biological characteristics, such as virus growth, ratio of trimer, thermal stability, acidic resistance and fusion activity were altered, suggesting an important role of the TM domain in viral replication and pathogenicity. Taken together, the increased thermal and acidic resistances of the recombinant H9N2-TM virus suggest that the substitution in the transmembrane (TM) domain can affect the stability of the HA, therefore alters viral biological characteristics. To explore whether the increased HA trimers and increased thermal and acidic resistances could result in better immune responses thus providing better protection in mice, we first vaccinated six-week-old mice with inactivated recombinant H9N2-WT and H9N2-TM viruses twice to check antibody responses.

title:
  Recombinant influenza H9N2 virus with a substitution of H3 hemagglutinin transmembrane domain showed enhanced immunogenicity in mice and chicken

abstract:
  In recent years, avian influenza virus H9N2 undergoing antigenic drift represents a threat to poultry farming as well as public health. Current vaccines are restricted to inactivated vaccine strains and their related variants. In this study, a recombinant H9N2 (H9N2-TM) strain with a replaced H3 hemagglutinin (HA) transmembrane (TM) domain was generated. Virus assembly and viral protein composition were not affected by the transmembrane domain replacement. Further, the recombinant TM-replaced H9N2-TM virus could provide better inter-clade protection in both mice and chickens against H9N2, suggesting that the H3-TM-replacement could be considered as a strategy to develop efficient subtype-specific H9N2 influenza vaccines.


id: cord-002842-4evbeijx
author: Pandey, Rajan Kumar
date: 2018-01-18
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773588/
doi: 10.1038/s41598-018-19456-1
title:
  Novel Immunoinformatics Approaches to Design Multi-epitope Subunit Vaccine for Malaria by Investigating Anopheles Salivary Protein

abstract:
  Malaria fever has been pervasive for quite a while in tropical developing regions causing high morbidity and mortality. The causal organism is a protozoan parasite of genus Plasmodium which spreads to the human host by the bite of hitherto infected female Anopheles mosquito. In the course of biting, a salivary protein of Anopheles helps in blood feeding behavior and having the ability to elicit the host immune response. This study represents a series of immunoinformatics approaches to design multi-epitope subunit vaccine using Anopheles mosquito salivary proteins. Designed subunit vaccine was evaluated for its immunogenicity, allergenicity and physiochemical parameters. To enhance the stability of vaccine protein, disulfide engineering was performed in a region of high mobility. Codon adaptation and in silico cloning was also performed to ensure the higher expression of designed subunit vaccine in E. coli K12 expression system. Finally, molecular docking and simulation study was performed for the vaccine protein and TLR-4 receptor, to determine the binding free energy and complex stability. Moreover, the designed subunit vaccine was found to induce anti-salivary immunity which may have the ability to prevent the entry of Plasmodium sporozoites into the human host.


id: cord-002843-dvfmpm54
title: GenomeLandscaper: Landscape analysis of genome-fingerprints maps assessing chromosome architecture
author: Ai, Hannan
date: 2018-01-18
txt: ./txt/cord-002843-dvfmpm54.txt
cache: ./cache/cord-002843-dvfmpm54.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773709/
doi: 10.1038/s41598-018-19366-2
summary:
  We create a geometric analysis method (called GenomeLandscaper) to conduct landscape analysis of genome-fingerprints maps (GFM), trace large-scale repetitive regions, and assess their impacts on the global architectures of assembled chromosomes. Specifically, we delete a 1.30-Mbp (from 9,999,936 bp to 11,299,986 bp) target segment (Supplementary Dataset 1) from the prior-cleaned GRCh38p1.chrY, as guided by the turning-changed long sharp straight line on the 2D-trajectory map (X-Length) of the GGFM (Fig. 4a ). We conclude that the 1.30-Mbp target segment (Supplementary Dataset 1) does locate in the centromeric and pericentromeric region of GRCh38p1.chrY (and throughout GRCh38p10.chrY) (Figs 3, 4 and 5), which encourages us to trace its sub-constituents that contributed to the observed turning-changed long sharp straight line on the GGFM (Figs 3 and 4 ).

abstract:
  Assessing correctness of an assembled chromosome architecture is a central challenge. We create a geometric analysis method (called GenomeLandscaper) to conduct landscape analysis of genome-fingerprints maps (GFM), trace large-scale repetitive regions, and assess their impacts on the global architectures of assembled chromosomes. We develop an alignment-free method for phylogenetics analysis. The human Y chromosomes (GRCh.chrY, HuRef.chrY and YH.chrY) are analysed as a proof-of-concept study. We construct a galaxy of genome-fingerprints maps (GGFM) for them, and a landscape compatibility among relatives is observed. But a long sharp straight line on the GGFM breaks such a landscape compatibility, distinguishing GRCh38p1.chrY (and throughout GRCh38p7.chrY) from GRCh37p13.chrY, HuRef.chrY and YH.chrY. We delete a 1.30-Mbp target segment to rescue the landscape compatibility, matching the antecedent GRCh37p13.chrY. We re-locate it into the modelled centromeric and pericentromeric region of GRCh38p10.chrY, matching a gap placeholder of GRCh37p13.chrY. We decompose it into sub-constituents (such as BACs, interspersed repeats, and tandem repeats) and trace their homologues by phylogenetics analysis. We elucidate that most examined tandem repeats are of reasonable quality, but the BAC-sized repeats, 173U1020C (176.46 Kbp) and 5U41068C (205.34 Kbp), are likely over-repeated. These results offer unique insights into the centromeric and pericentromeric regions of the human Y chromosomes.


id: cord-002844-jv42o789
author: Marcos-Villar, Laura
date: 2018-01-19
txt: ./txt/cord-002844-jv42o789.txt
cache: ./cache/cord-002844-jv42o789.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775356/
doi: 10.1038/s41598-018-19370-6
summary:
  These results indicate that epigenetic modifications induced by influenza virus infection mainly target the histone component of host cell chromatin, with H3K79 residue methylation the most frequently modified. Dot1L inhibition caused an increase in viral replication, higher in cells infected with the natural isolates, which suggests a general role of H3K79 methylation in control of the influenza virus life cycle. At 8 h, we found a weak increase on IFNβ, IFN-stimulated gene 56 (ISG56) and interferon-induced protein Mx1 (Mx1) RNA levels after IFNαβ addition or influenza virus infection, and Dot1L inhibitor treatment did not significantly decreased their accumulation (Fig. 6B,C) . Given the role of H3K79 methylation in the control of IFN signaling, we analyzed the effect of Dot1L inhibitor on influenza virus replication in cells with normal or deficient IFN responses. Since H3K79 methylation does not affect influenza virus replication in cells with impaired IFN signaling, we analyzed the effect of Dot1L inhibitor in subsequent stages of viral infection.

title:
  Epigenetic control of influenza virus: role of H3K79 methylation in interferon-induced antiviral response

abstract:
  Influenza virus stablishes a network of virus-host functional interactions, which depends on chromatin dynamic and therefore on epigenetic modifications. Using an unbiased search, we analyzed the epigenetic changes at DNA methylation and post-translational histone modification levels induced by the infection. DNA methylation was unaltered, while we found a general decrease on histone acetylation, which correlates with transcriptional inactivation and may cooperate with the impairment of cellular transcription that causes influenza virus infection. A particular increase in H3K79 methylation was observed and the use of an inhibitor of the specific H3K79 methylase, Dot1L enzyme, or its silencing, increased influenza virus replication. The antiviral response was reduced in conditions of Dot1L downregulation, since decreased nuclear translocation of NF-kB complex, and IFN-β, Mx1 and ISG56 expression was detected. The data suggested a control of antiviral signaling by methylation of H3K79 and consequently, influenza virus replication was unaffected in IFN pathway-compromised, Dot1L-inhibited cells. H3K79 methylation also controlled replication of another potent interferon-inducing virus such as vesicular stomatitis virus, but did not modify amplification of respiratory syncytial virus that poorly induces interferon signaling. Epigenetic methylation of H3K79 might have an important role in controlling interferon-induced signaling against viral pathogens.


id: cord-002874-9rxv6fy9
title: Far-UVC light: A new tool to control the spread of airborne-mediated microbial diseases
author: Welch, David
date: 2018-02-09
txt: ./txt/cord-002874-9rxv6fy9.txt
cache: ./cache/cord-002874-9rxv6fy9.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807439/
doi: 10.1038/s41598-018-21058-w
summary:
  Here we applied this approach to test the efficacy of the 222-nm far-UVC light to inactivate influenza A virus (H1N1) carried by aerosols in a benchtop aerosol UV irradiation chamber, which generated aerosol droplets of sizes similar to those generated by human coughing and breathing. If these results are confirmed in other scenarios, it follows that the use of overhead low-level far-UVC light in public locations may represent a safe and efficient methodology for limiting the transmission and spread of airborne-mediated microbial diseases such as influenza and tuberculosis. In conclusion, we have shown for the first time that very low doses of far-UVC light efficiently inactivate airborne viruses carried by aerosols. If these results are confirmed in other scenarios, it follows that the use of overhead very low level far-UVC light in public locations may represent a safe and efficient methodology for limiting the transmission and spread of airborne-mediated microbial diseases.

abstract:
  Airborne-mediated microbial diseases such as influenza and tuberculosis represent major public health challenges. A direct approach to prevent airborne transmission is inactivation of airborne pathogens, and the airborne antimicrobial potential of UVC ultraviolet light has long been established; however, its widespread use in public settings is limited because conventional UVC light sources are both carcinogenic and cataractogenic. By contrast, we have previously shown that far-UVC light (207–222 nm) efficiently inactivates bacteria without harm to exposed mammalian skin. This is because, due to its strong absorbance in biological materials, far-UVC light cannot penetrate even the outer (non living) layers of human skin or eye; however, because bacteria and viruses are of micrometer or smaller dimensions, far-UVC can penetrate and inactivate them. We show for the first time that far-UVC efficiently inactivates airborne aerosolized viruses, with a very low dose of 2 mJ/cm(2) of 222-nm light inactivating >95% of aerosolized H1N1 influenza virus. Continuous very low dose-rate far-UVC light in indoor public locations is a promising, safe and inexpensive tool to reduce the spread of airborne-mediated microbial diseases.


id: cord-002929-oqe3gjcs
title: Mapping road network communities for guiding disease surveillance and control strategies
author: Strano, Emanuele
date: 2018-03-16
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856805/
doi: 10.1038/s41598-018-22969-4
abstract:
  Human mobility is increasing in its volume, speed and reach, leading to the movement and introduction of pathogens through infected travelers. An understanding of how areas are connected, the strength of these connections and how this translates into disease spread is valuable for planning surveillance and designing control and elimination strategies. While analyses have been undertaken to identify and map connectivity in global air, shipping and migration networks, such analyses have yet to be undertaken on the road networks that carry the vast majority of travellers in low and middle income settings. Here we present methods for identifying road connectivity communities, as well as mapping bridge areas between communities and key linkage routes. We apply these to Africa, and show how many highly-connected communities straddle national borders and when integrating malaria prevalence and population data as an example, the communities change, highlighting regions most strongly connected to areas of high burden. The approaches and results presented provide a flexible tool for supporting the design of disease surveillance and control strategies through mapping areas of high connectivity that form coherent units of intervention and key link routes between communities for targeting surveillance.


id: cord-002932-5e7xrd1y
author: Watanabe, Tokiko
date: 2018-03-19
txt: ./txt/cord-002932-5e7xrd1y.txt
cache: ./cache/cord-002932-5e7xrd1y.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859186/
doi: 10.1038/s41598-018-23022-0
summary:
  In the ferret model, these studies demonstrated that the inoculation of animals with highly pathogenic avian influenza H5N1 virus via the aerosol route led to higher nasal wash virus titers, earlier onset of clinical signs, and/or a broader spectrum of disease compared with infection via intranasal inoculation despite no difference in lethality [9] [10] [11] . On day 3 post-infection, VN3040 virus was recovered from nasal swabs of two and three animals in the conventional and aerosol method groups, respectively, and the mean virus titers were comparable between the two groups. Cynomolgus macaques were inoculated with 4 ml of a 10 7 PFU/ml solution of the highly pathogenic H5N1 avian influenza virus A/Vietnam/ UT3040/2004 strain (VN3040) through the aerosol route by using the ultrasonic nebulizer NE-U17 (defined as "the aerosol method group"). In contrast, VN3040 replicated well in the right-and left-lower lung lobes of the infected animals in the conventional method group [the virus mean titers were 3.51 and 4.75 log 10 (PFU/g), respectively].

title:
  Experimental infection of Cynomolgus Macaques with highly pathogenic H5N1 influenza virus through the aerosol route

abstract:
  Several animal models are used to study influenza viruses. Intranasal inoculation of animals with a liquid inoculum is one of the main methods used to experimentally infect animals with influenza virus; however, this method does not reflect the natural infection with influenza virus by contact or aerosol route. Aerosol inhalation methods have been established with several influenza viruses for mouse and ferret models, but few studies have evaluated inoculation routes in a nonhuman primates (NHP) model. Here, we performed the experimental infection of NHPs with a highly pathogenic H5N1 influenza virus via the aerosol route and demonstrated that aerosol infection had no effect on clinical outcome, but caused broader infection throughout all of the lobes of the lung compared with a non-aerosolized approach. Aerosol infection therefore represents an option for inoculation of NHPs in future studies.


id: cord-002956-e5ihpe4i
author: Chang, Ya-Chun
date: 2018-04-04
txt: ./txt/cord-002956-e5ihpe4i.txt
cache: ./cache/cord-002956-e5ihpe4i.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884833/
doi: 10.1038/s41598-018-24028-4
summary:
  title: Ventilator Dependence Risk Score for the Prediction of Prolonged Mechanical Ventilation in Patients Who Survive Sepsis/Septic Shock with Respiratory Failure A total of 379 patients with sepsis or septic shock and acute respiratory failure requiring mechanical ventilation were admitted to the medical intensive care unit in the Kaohsiung Chang Gung Memorial Hospital from August 2013 to October 2015. We also tested and found that SOFA PaO 2 /FiO 2 subscore and GCS subscore on admission day 7 could help predict ventilator dependence on sepsis and septic shock patients with significant difference in univariate analysis ( Table 5 ). Ventilator dependence risk score, including a history of stroke and data from day 7 (thrombocytopenia, acidosis, and the higher fraction of inspired oxygen), can be applied to predict prolonged mechanical ventilation in patients who survive sepsis and septic shock.

title:
  Ventilator Dependence Risk Score for the Prediction of Prolonged Mechanical Ventilation in Patients Who Survive Sepsis/Septic Shock with Respiratory Failure

abstract:
  We intended to develop a scoring system to predict mechanical ventilator dependence in patients who survive sepsis/septic shock with respiratory failure. This study evaluated 251 adult patients in medical intensive care units (ICUs) between August 2013 to October 2015, who had survived for over 21 days and received aggressive treatment. The risk factors for ventilator dependence were determined. We then constructed a ventilator dependence (VD) risk score using the identified risk factors. The ventilator dependence risk score was calculated as the sum of the following four variables after being adjusted by proportion to the beta coefficient. We assigned a history of previous stroke, a score of one point, platelet count less than 150,000/μL a score of one point, pH value less than 7.35 a score of two points, and the fraction of inspired oxygen on admission day 7 over 39% as two points. The area under the curve in the derivation group was 0.725 (p < 0.001). We then applied the VD risk score for validation on 175 patients. The area under the curve in the validation group was 0.658 (p = 0.001). VD risk score could be applied to predict prolonged mechanical ventilation in patients who survive sepsis/septic shock.


id: cord-003004-iif2lnez
title: Clinical and Molecular Epidemiology of Human Parainfluenza Viruses 1–4 in Children from Viet Nam
author: Linster, Martin
date: 2018-05-01
txt: ./txt/cord-003004-iif2lnez.txt
cache: ./cache/cord-003004-iif2lnez.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5931535/
doi: 10.1038/s41598-018-24767-4
summary:
  The present study describes species-specific clinical presentation, the genetic variability and HPIV circulation in Viet Nam. The outcome of RSV infection in hospitalized children under 2 years of age presenting with acute lower respiratory infection (ALRI) in Ho Chi Minh City was described previously 17 . Samples were sourced from two previous acute respiratory infection (ARI) cohorts among in-and outpatients, that were conducted at Children''s Hospital 1 and 2 in Ho Chi Minh City, Viet Nam during years 2009 and 2010. For sequencing, HPIV-positive samples were further amplified in a hemi-nested PCR approach with newly designed species-specific primers targeting overlapping regions of the viral genome (Table S2) . In this study, the median age and gender distribution of infected children and frequency of clinical presentation (fever, cough, sore throat, runny nose and nasal congestion) as well as vital signs (pulse and respiratory rate) and duration of illness at presentation were similar between HPIV species (p > 0.05).

abstract:
  HPIVs are serologically and genetically grouped into four species that account for up to 10% of all hospitalizations due to acute respiratory infection in children under the age of five. Genetic and epidemiological data for the four HPIVs derived from two pediatric cohorts in Viet Nam are presented. Respiratory samples were screened for HPIV1–4 by real-time PCR. Demographic and clinical data of patients infected with different HPIV were compared. We used a hemi-nested PCR approach to generate viral genome sequences from HPIV-positive samples and conducted a comprehensive phylogenetic analysis. In total, 170 samples tested positive for HPIV. HPIV3 was most commonly detected in our cohort and 80 co-detections of HPIV with other respiratory viruses were found. Phylogenetic analyses suggest local endemic circulation as well as punctuated introductions of new HPIV lineages. Viral gene flow analysis revealed that Viet Nam is a net importer of viral genetic diversity. Epidemiological analyses imply similar disease severity for all HPIV species. HPIV sequences from Viet Nam formed local clusters and were interspersed with sequences from diverse geographic regions. Combined, this new knowledge will help to investigate global HPIV circulation patterns in more detail and ultimately define more suitable vaccine strains.


id: cord-003011-vclnb0eh
author: de Almeida, Carlos Podalirio Borges
date: 2018-05-08
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940698/
doi: 10.1038/s41598-018-25409-5
title:
  Predictors of In-Hospital Mortality among Patients with Pulmonary Tuberculosis: A Systematic Review and Meta-analysis

abstract:
  Background: There is uncertainty regarding which factors are associated with in-hospital mortality among patients with pulmonary TB (PTB). The aim of this systematic review and meta-analysis is to identify predictors of in-hospital mortality among patients with PTB. Methods: We searched MEDLINE, EMBASE, and Global Health, for cohort and case-control studies that reported risk factors for in-hospital mortality in PTB. We pooled all factors that were assessed for an association, and presented relative associations as pooled odds ratios (ORs). Results: We identified 2,969 records, of which we retrieved 51 in full text; 11 cohort studies that evaluated 5,468 patients proved eligible. Moderate quality evidence suggested an association with co-morbid malignancy and in-hospital mortality (OR 1.85; 95% CI 1.01–3.40). Low quality evidence showed no association with positive sputum smear (OR 0.99; 95% CI 0.40–2.48), or male sex (OR 1.09, 95% CI 0.84–1.41), and very low quality evidence showed no association with diabetes mellitus (OR 1.31, 95% IC 0.38–4.46), and previous TB infection (OR 2.66, 95% CI 0.48–14.87). Conclusion: Co-morbid malignancy was associated with increased risk of in-hospital death among pulmonary TB patients. There is insufficient evidence to confirm positive sputum smear, male sex, diabetes mellitus, and previous TB infection as predictors of in-hospital mortality in TB patients.


id: cord-003055-88q36g00
author: Imai, Kenji
date: 2018-06-15
txt: ./txt/cord-003055-88q36g00.txt
cache: ./cache/cord-003055-88q36g00.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003913/
doi: 10.1038/s41598-018-27626-4
summary:
  The aim of the present study was to investigate long-term outcomes of the offspring in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) model and the effect of maternal molecular hydrogen (H(2)) administration. We have previously demonstrated in the MIA mouse model that maternal administration of H(2) attenuates oxidative damage and neuroinflammation, including induced pro-inflammatory cytokines and microglial activation, in the fetal brain. Since MIA has been considered to be a cause of behavioral abnormalities in offspring, including ASD/ Schizophrenia-like behavior, we subsequently evaluated the effect of LPS and maternal administration of HW on short-term memory, sociability, social novelty, and sensorimotor gating. Based on those findings, we subsequently performed Nissl staining and evaluated the number of neurons in the amygdala, cerebral cortex, and hippocampus to investigate the brain regions related to the results of the behavioral deficits induced by LPS exposure.

title:
  Administration of molecular hydrogen during pregnancy improves behavioral abnormalities of offspring in a maternal immune activation model

abstract:
  The aim of the present study was to investigate long-term outcomes of the offspring in a lipopolysaccharide (LPS)-induced maternal immune activation (MIA) model and the effect of maternal molecular hydrogen (H(2)) administration. We have previously demonstrated in the MIA mouse model that maternal administration of H(2) attenuates oxidative damage and neuroinflammation, including induced pro-inflammatory cytokines and microglial activation, in the fetal brain. Short-term memory, sociability and social novelty, and sensorimotor gating were evaluated using the Y-maze, three-chamber, and prepulse inhibition (PPI) tests, respectively, at postnatal 3 or 4 weeks. The number of neurons and oligodendrocytes was also analyzed at postnatal 5 weeks by immunohistochemical analysis. Offspring of the LPS-exposed dams showed deficits in short-term memory and social interaction, following neuronal and oligodendrocytic loss in the amygdala and cortex. Maternal H(2) administration markedly attenuated these LPS-induced abnormalities. Moreover, we evaluated the effect of H(2) on LPS-induced astrocytic activation, both in vivo and in vitro. The number of activated astrocytes with hypertrophic morphology was increased in LPS-exposed offspring, but decreased in the offspring of H(2)-administered dams. In primary cultured astrocytes, LPS-induced pro-inflammatory cytokines were attenuated by H(2) administration. Overall, these findings indicate that maternal H(2) administration exerts neuroprotective effects and ameliorates MIA-induced neurodevelopmental deficits of offspring later in life.


id: cord-003148-o7y3wygc
author: Shirvani, Edris
date: 2018-08-10
txt: ./txt/cord-003148-o7y3wygc.txt
cache: ./cache/cord-003148-o7y3wygc.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086832/
doi: 10.1038/s41598-018-30356-2
summary:
  However, the results of the inoculation of the tracheal swab samples into 10-day-old embrynated chicken eggs showed that 14 out of 15 (93.3%) chickens vaccinated with rNDV expressing codon optimized S protein of IBV and 0 out of 5 (0%) of non-infected chickens were shedding virus in trachea, respectively, whereas 15 out of 15 (100%) of chickens of all other groups were shedding virus in the trachea (data not shown). To evaluate the effect of the route of inoculation of virulent IB challenge virus on the outcomes of the protective efficacy of rNDV expressing codon optimized S protein of IBV, SPF chicks were immunized at 1-day-old age. The protective efficacy of rNDV expressing codon optimized S gene of IBV was determined by challenging the immunized chickens with 10 4 EID 50 virulent IBV strain Mass-41 by the intraocular route at 3 week post-immunization.

title:
  A Recombinant Newcastle Disease Virus (NDV) Expressing S Protein of Infectious Bronchitis Virus (IBV) Protects Chickens against IBV and NDV

abstract:
  Infectious bronchitis virus (IBV) causes a highly contagious respiratory, reproductive and urogenital tract disease in chickens worldwide, resulting in substantial economic losses for the poultry industry. Currently, live-attenuated IBV vaccines are used to control the disease. However, safety, attenuation and immunization outcomes of current vaccines are not guaranteed. Several studies indicate that attenuated IBV vaccine strains contribute to the emergence of variant viruses in the field due to mutations and recombination. Therefore, there is a need to develop a stable and safe IBV vaccine that will not create variant viruses. In this study, we generated recombinant Newcastle disease viruses (rNDVs) expressing the S1, S2 and S proteins of IBV using reverse genetics technology. Our results showed that the rNDV expressing the S protein of IBV provided better protection than the rNDV expressing S1 or S2 protein of IBV, indicating that the S protein is the best protective antigen of IBV. Immunization of 4-week-old SPF chickens with the rNDV expressing S protein elicited IBV-specific neutralizing antibodies and provided complete protection against virulent IBV and virulent NDV challenges. These results suggest that the rNDV expressing the S protein of IBV is a safe and effective bivalent vaccine candidate for both IBV and NDV.


id: cord-003166-k3jxvzfi
author: Noh, Ji Yeong
date: 2018-08-22
txt: ./txt/cord-003166-k3jxvzfi.txt
cache: ./cache/cord-003166-k3jxvzfi.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105681/
doi: 10.1038/s41598-018-30319-7
summary:
  Even though the HN amino acids sequences were similar to those from viruses in the proposed genera Shaanvirus, it was also related to that of Sendai virus and human parainfluenza virus 1, which belong to a different genus, Respirovirus showing (Table 1) . In addition, among three pooled sera (two mouse sera each) against human parainfluenza virus 1 (KBPV-VR-44), one pooled serum was cross-reactive to the bat paramyxovirus B16-40 with 40 as the end-point titer for the fluorescent signal ( Table 2 , Fig. 4 ). Notably, even though the HN amino acids sequences were similar to those from viruses in the proposed genera Shaanvirus, it was also related to that of Sendai virus and human parainfluenza virus 1, which belong to a different genus, Respirovirus (Table 1) . In fact, in this study, when mouse antisera were made and tested against bat paramyxovirus B16-40 and human parainfluenza virus 1 (KBPV-VR-44), the two viruses were partially cross-reactive to each other in an indirect immunofluorescence assay.

title:
  Isolation and characterization of novel bat paramyxovirus B16-40 potentially belonging to the proposed genus Shaanvirus

abstract:
  The bat paramyxovirus B16-40 was first isolated in Korea in this study. Using the isolated virus, we could obtain not only genomic information, but also several biological characteristics of the virus. In the phylogenetic analysis, the virus was found to belong to the recently proposed genus Shaanvirus. Through sequence analyses and in vitro testing, the isolated virus was also found to have haemagglutinin-neuraminidase (HN) protein as one of the structural proteins. When mouse antiserum was generated against the isolated virus and tested, it was cross-reactive to human parainfluenza virus 1 in an indirect immunofluorescence assay but could not cross-neutralize human parainfluenza virus 1. In addition, the bat paramyxovirus B16-40 was not infectious in the mouse model. Collectively, this study provided basic information on further classification of the bat paramyxovirus B16-40 and related viruses in the proposed genus Shaanvirus.


id: cord-003196-fdb6az0v
author: Casalino-Matsuda, S. Marina
date: 2018-09-10
txt: ./txt/cord-003196-fdb6az0v.txt
cache: ./cache/cord-003196-fdb6az0v.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131151/
doi: 10.1038/s41598-018-32008-x
summary:
  title: Hypercapnia Alters Expression of Immune Response, Nucleosome Assembly and Lipid Metabolism Genes in Differentiated Human Bronchial Epithelial Cells These changes in gene expression indicate the potential for hypercapnia to impact bronchial epithelial cell function in ways that may contribute to poor clinical outcomes in patients with severe acute or advanced chronic lung diseases. Major clusters from hypercapnia-downregulated genes are linked to immune response, nucleosome assembly, cell differentiation, oxidation reduction, and ion and lipid transport (Fig. 2) . In addition, the suppressive effect of elevated CO 2 on immune gene expression in the airway epithelium, along with similar effects on immune cells, suggest a reason why severe COPD and other lung disease associated with hypercapnia all carry a high risk of pulmonary infection. Thus, CO 2 -induced alterations in airway epithelial gene expression may underlie the increase in mortality associated with hypercapnia in advanced COPD, as well as community-acquired pneumonia 9 , adenoviral lung infections 10 and cystic fibrosis 11 .

title:
  Hypercapnia Alters Expression of Immune Response, Nucleosome Assembly and Lipid Metabolism Genes in Differentiated Human Bronchial Epithelial Cells

abstract:
  Hypercapnia, the elevation of CO(2) in blood and tissues, commonly occurs in severe acute and chronic respiratory diseases, and is associated with increased risk of mortality. Recent studies have shown that hypercapnia adversely affects innate immunity, host defense, lung edema clearance and cell proliferation. Airway epithelial dysfunction is a feature of advanced lung disease, but the effect of hypercapnia on airway epithelium is unknown. Thus, in the current study we examined the effect of normoxic hypercapnia (20% CO(2) for 24 h) vs normocapnia (5% CO(2)), on global gene expression in differentiated normal human airway epithelial cells. Gene expression was assessed on Affymetrix microarrays, and subjected to gene ontology analysis for biological process and cluster-network representation. We found that hypercapnia downregulated the expression of 183 genes and upregulated 126. Among these, major gene clusters linked to immune responses and nucleosome assembly were largely downregulated, while lipid metabolism genes were largely upregulated. The overwhelming majority of these genes were not previously known to be regulated by CO(2). These changes in gene expression indicate the potential for hypercapnia to impact bronchial epithelial cell function in ways that may contribute to poor clinical outcomes in patients with severe acute or advanced chronic lung diseases.


id: cord-003387-82573enr
author: Nam, Gyu-Hwi
date: 2018-12-24
txt: ./txt/cord-003387-82573enr.txt
cache: ./cache/cord-003387-82573enr.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305387/
doi: 10.1038/s41598-018-36342-y
summary:
  title: Gene expression profiles alteration after infection of virus, bacteria, and parasite in the Olive flounder (Paralichthys olivaceus) In this study, we carried out transcriptome analysis using the olive flounder gill tissues after infection of three types of pathogens (Virus; Viral hemorrhagic septicemia virus, Bacteria; Streptococcus parauberis, and Parasite; Miamiensis avidus), respectively. Our goals are to provide plenty of genomic knowledge about olive flounder transcripts for further research and report genes, which were changed in their expression after specific pathogen infection. To profile gene expression after infection of three pathogens (VHSV, Streptococcus parauberis, and Miamiensis avidus), transcriptome analysis was conducted using gill tissues of olive flounders, respectively. In this study, we understood the relation between three types of pathogen infection and differential gene expression in the olive flounder genome through transcriptome analysis, respectively. cDNA microarray analysis of viral hemorrhagic septicemia infected olive flounder, Paralichthys olivaceus: immune gene expression at different water temperature

title:
  Gene expression profiles alteration after infection of virus, bacteria, and parasite in the Olive flounder (Paralichthys olivaceus)

abstract:
  Olive flounder (Paralichthys olivaceus) is one of economically valuable fish species in the East Asia. In comparison with its economic importance, available genomic information of the olive flounder is very limited. The mass mortality caused by variety of pathogens (virus, bacteria and parasites) is main problem in aquaculture industry, including in olive flounder culture. In this study, we carried out transcriptome analysis using the olive flounder gill tissues after infection of three types of pathogens (Virus; Viral hemorrhagic septicemia virus, Bacteria; Streptococcus parauberis, and Parasite; Miamiensis avidus), respectively. As a result, we identified total 12,415 differentially expressed genes (DEG) from viral infection, 1,754 from bacterial infection, and 795 from parasite infection, respectively. To investigate the effects of pathogenic infection on immune response, we analyzed Gene ontology (GO) enrichment analysis with DEGs and sorted immune-related GO terms per three pathogen groups. Especially, we verified various GO terms, and genes in these terms showed down-regulated expression pattern. In addition, we identified 67 common genes (10 up-regulated and 57 down-regulated) present in three pathogen infection groups. Our goals are to provide plenty of genomic knowledge about olive flounder transcripts for further research and report genes, which were changed in their expression after specific pathogen infection.


id: cord-003444-dmpoy0b1
title: A Novel Supplementation Approach to Enhance Host Response to Sublingual Vaccination
author: Rowe, John C.
date: 2019-01-24
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346055/
doi: 10.1038/s41598-018-36370-8
abstract:
  Sublingual immunization is emerging as an alternative to nasal immunization and induction of mucosal IgA responses. Using Bacillus anthracis edema toxin (EdTx) as an adjuvant, we previously showed that innate responses triggered after sublingual immunization could limit generation of IgA responses. We tested whether co-administration of a neutrophil elastase inhibitor (NEI) could rescue the ability of EdTx to induce broad antibody responses, including mucosal IgA. NEI supplementation of sublingual vaccines containing EdTx promoted antigen-specific serum IgA responses but also enhanced serum IgG1, and IgG2b responses. This enhancing effect of NEI did not extend to all antibody isotypes and IgG sublclasses, since NEI reduced serum IgE responses and did not affect IgG2a/c and IgG3 responses. NEI supplementation also promoted anti-Bacillus anthracis protective antigen (PA) neutralizing antibodies and enhanced high affinity IgG1 and IgA antibodies. In addition to serum IgA, NEI supplementation stimulated antigen-specific mucosal IgA responses in the GI tract, and enhanced antigen-specific IgG responses in vaginal washes. Analysis of CD4(+) T helper cell responses revealed that co-administration of NEI broadened the profile of cytokine responses, by stimulating Th1, Th2, Th17, and Tfh cytokines. We also noted that NEI had a higher stimulatory effect on IL-5, IL-10, IL-17 responses.


id: cord-003490-swlkjtyo
title: Quantitative impacts of incubation phase transmission of foot-and-mouth disease virus
author: Arzt, Jonathan
date: 2019-02-25
txt: ./txt/cord-003490-swlkjtyo.txt
cache: ./cache/cord-003490-swlkjtyo.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389902/
doi: 10.1038/s41598-019-39029-0
summary:
  The current investigation applied a Bayesian modeling approach to a unique experimental transmission study to estimate the occurrence of transmission of foot-and-mouth disease (FMD) during the incubation phase amongst group-housed pigs. This current study focused on investigating the concept of θ and ω for direct contact transmission of a virulent strain of foot-and-mouth disease virus (FMDV) amongst juvenile domestic pigs, and examining the impact of pre-clinical transmission on simulated outbreak size and severity within a US swine production system assuming either optimal or suboptimal response conditions. The most noteworthy findings from this approach were the substantial changes in the modeled estimates of the duration of latency and subclinical infectiousness (ω) when defining the onset of infectiousness by either the occurrence of clinical signs of FMD in donor pigs or by any detection of FMDV RNA in OPF.

abstract:
  The current investigation applied a Bayesian modeling approach to a unique experimental transmission study to estimate the occurrence of transmission of foot-and-mouth disease (FMD) during the incubation phase amongst group-housed pigs. The primary outcome was that transmission occurred approximately one day prior to development of visible signs of disease (posterior median 21 hours, 95% CI: 1.1–45.0). Updated disease state durations were incorporated into a simulation model to examine the importance of addressing preclinical transmission in the face of robust response measures. Simulation of FMD outbreaks in the US pig production sector demonstrated that including a preclinical infectious period of one day would result in a 40% increase in the median number of farms affected (166 additional farms and 664,912 pigs euthanized) compared to the scenario of no preclinical transmission, assuming suboptimal outbreak response. These findings emphasize the importance of considering transmission of FMD during the incubation phase in modeling and response planning.


id: cord-003504-wjab4y0g
author: Copland, Alastair
date: 2019-03-06
txt: ./txt/cord-003504-wjab4y0g.txt
cache: ./cache/cord-003504-wjab4y0g.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403281/
doi: 10.1038/s41598-019-40145-0
summary:
  Finally, an in vivo immunisation model showed that BCG vaccination under PD-L1 blockade could enhance antigen-specific memory CD4 T-cell responses. Here, we show for the first time that BCG can induce the up-regulation of PD-L1 on both macrophages and dendritic cells (DCs) via autocrine/paracrine secretion of STAT3-activating cytokines, chiefly IL-6 and IL-10. Upon infection with BCG, both APC types expressed high levels of PD-L1 compared to the unstimulated control at 24 h and 48 h (p < 0.0001), and a dose trend was observed for increasing MOI in macrophages at 48 h. To confirm that STAT3 was mediating the up-regulation of PD-L1 expression by BCG, cells were then pre-treated with Stattic or a vehicle control for 2 hours before infection with a low dose of bacteria (Fig. 5C) . BCG vaccine mediated reduction in the MHC-II expression of macrophages and dendritic cells is reversed by activation of Toll-like receptors 7 and 9

title:
  Bacillus Calmette-Guérin Induces PD-L1 Expression on Antigen-Presenting Cells via Autocrine and Paracrine Interleukin-STAT3 Circuits

abstract:
  Bacillus Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis (TB), and is also used as an immunotherapy for bladder cancer and other malignancies due to its immunostimulatory properties. Mycobacteria spp., however, are well known for their numerous immune evasion mechanisms that limit the true potential of their therapeutic use. One such major mechanism is the induction of programmed death ligand-1 (PD-L1), which mitigates adaptive immune responses. Here, we sought to unravel the molecular pathways behind PD-L1 up-regulation on antigen-presenting cells (APCs) by BCG. We found that infection of APCs with BCG induced PD-L1 up-regulation, but that this did not depend on direct infection, suggesting a soluble mediator for this effect. BCG induced potent quantities of IL-6 and IL-10, and the downstream transcription factor STAT3 was hyper-phosphorylated. Intracellular analyses revealed that levels of PD-L1 molecules were associated with the STAT3 phosphorylation state, suggesting a causal link. Neutralisation of the IL-6 or IL-10 cytokine receptors dampened STAT3 phosphorylation and BCG-mediated up-regulation of PD-L1 on APCs. Pharmacological inhibition of STAT3 achieved the same effect, confirming an autocrine-paracrine cytokine loop as a mechanism for BCG-mediated up-regulation of PD-L1. Finally, an in vivo immunisation model showed that BCG vaccination under PD-L1 blockade could enhance antigen-specific memory CD4 T-cell responses. These novel findings could lead to refinement of BCG as both a vaccine for infectious disease and as a cancer immunotherapy.


id: cord-003505-qr6ukfti
title: A colorimetric strategy based on dynamic chemistry for direct detection of Trypanosomatid species
author: Tabraue-Chávez, Mavys
date: 2019-03-06
txt: ./txt/cord-003505-qr6ukfti.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403333/
doi: 10.1038/s41598-019-39946-0
summary:
  In this work, we have developed a novel colorimetric molecular assay that integrates nucleic acid analysis by dynamic chemistry (ChemNAT) with reverse dot-blot hybridization in an array format for a rapid and easy discrimination of Leishmania major and Trypanosoma cruzi. Once the abasic PNA probes hybridize with target sequences, the SMART-C-Biotin dynamic incorporation takes place, enabling the unequivocal identification of the parasite present in the amplicon sample, because of the unique colorimetric pattern that each Trypanosomatid amplicon generates. DNA amplicon products were denatured and then together with the dynamic chemistry reaction reagents added directly into the internal column of the Spin-Tube that supports the nylon membrane for the color-development assay (Fig. 4) . 20 ng of human gDNA were used as PCR template for its amplification with the set of primers described in our study and neither colorimetric signals nor bands were detected using the Spin-Tube and capillary electrophoresis analysis respectively (Fig. 5 , column 2: 2A and 2B), hence probing the specificity when human gDNA is present.

abstract:
  Leishmaniasis and Chagas disease are endemic in many countries, and re-emerging in the developed countries. A rapid and accurate diagnosis is important for early treatment for reducing the duration of infection as well as for preventing further potential health complications. In this work, we have developed a novel colorimetric molecular assay that integrates nucleic acid analysis by dynamic chemistry (ChemNAT) with reverse dot-blot hybridization in an array format for a rapid and easy discrimination of Leishmania major and Trypanosoma cruzi. The assay consists of a singleplex PCR step that amplifies a highly homologous DNA sequence which encodes for the RNA component of the large ribosome subunit. The amplicons of the two different parasites differ between them by single nucleotide variations, known as “Single Nucleotide Fingerprint” (SNF) markers. The SNF markers can be easily identified by naked eye using a novel micro Spin-Tube device "Spin-Tube", as each of them creates a specific spot pattern. Moreover, the direct use of ribosomal RNA without requiring the PCR pre-amplification step is also feasible, further increasing the simplicity of the assay. The molecular assay delivers sensitivity capable of identifying up to 8.7 copies per µL with single mismatch specificity. The Spin-Tube thus represents an innovative solution providing benefits in terms of time, cost, and simplicity, all of which are crucial for the diagnosis of infectious disease in developing countries.


id: cord-003558-7lvqpz21
author: Davies, Patrick
date: 2019-03-29
txt: ./txt/cord-003558-7lvqpz21.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441075/
doi: 10.1038/s41598-019-41774-1
summary:
  We present the clinical use of EIT in six conditions: Asthma, Ventilation weaning and expansion recoil, Sequential Lobar Collapse, Targeted Physiotherapy, Pleural Effusion assessment, and PEEP optimisation. Electrical Impedance Tomography (EIT) is a radiation-free functional modality that enables bedside imaging and monitoring of lung function and expansion. It has been used in various clinical settings including acute respiratory distress syndrome (ARDS), establishing the best positive end expiratory pressure (PEEP) [8] [9] [10] [11] [12] , the response of the lungs to recruitment manoeuvres [12] [13] [14] [15] [16] and trying to minimize areas of collapse and hyperinflation 6, 17 . Clinical interest in this method has been driven by the need for bedside monitoring of the dynamics of the lungs and the effects of ventilatory manoeuvres, including changes in ventilator settings, suctioning, chest drains, positioning and physiotherapy. Clinical interest in this method has been driven by the need for bedside monitoring of the dynamics of the lungs and the effects of ventilatory manoeuvres, including changes in ventilator settings, suctioning, chest drains, positioning and physiotherapy.

title:
  Clinical Scenarios of the Application of Electrical Impedance Tomography in Paediatric Intensive Care

abstract:
  EIT is a radiation-free functional modality that enables bedside imaging and monitoring of lung function and expansion. Clinical interest in this method has been driven by the need for bedside monitoring of the dynamics of the lungs and the effects of ventilatory manoeuvres, including changes in ventilator settings, suctioning, chest drains, positioning and physiotherapy. We aimed to describe the use of Electrical Impedance Tomography (EIT) as a clinical tool in a tertiary Paediatric Intensive Care unit. Children requiring intensive care with a variety of clinical conditions had an electrode belt with 16 electrodes wrapped around the chest, which sequentially applied a small alternating current from each electrode pair. The signal gives information on both real time, regional, global, and relative data. With the correct application, and understanding of the monitor, much clinical information can be gained, with potentially significant patient benefit. We present the clinical use of EIT in six conditions: Asthma, Ventilation weaning and expansion recoil, Sequential Lobar Collapse, Targeted Physiotherapy, Pleural Effusion assessment, and PEEP optimisation. Screenshots and analyses are offered displaying the pragmatic use of this technology. Electrical Impedance Tomography is a clinically useful tool on the Paediatric Intensive Care unit. It allows monitoring of a patient’s respiratory function in ways which are not possible through any other means. An understanding of respiratory physiology will allow use of this information to improve patient outcomes.


id: cord-003623-n01rgqyv
author: Schuh, Amy J.
date: 2019-04-30
txt: ./txt/cord-003623-n01rgqyv.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491471/
doi: 10.1038/s41598-019-43156-z
summary:
  To evaluate the ability of our system comprising seven filovirus-specific indirect ELISAs to predict the filovirus species most antigenically similar to the species responsible for past infection, we tested seven Marburg virus convalescent serum 35 or whole blood 36 samples collected from experimentally inoculated ERBs. Five of these samples www.nature.com/scientificreports www.nature.com/scientificreports/ were collected four weeks post primary Marburg virus inoculation 35, 36 , while two of the samples were collected at 23 and 27 weeks post primary inoculation following a "natural" boost (i.e., Marburg virus-specific antibody levels waned in these bats and then increased following contact with infectious cagemates) 36 . Although significant levels of serological IgG cross-reactivity were observed between the prime-boost filovirus-specific antisera and some of the filovirus antigens, when the overall covariance of the seven-individual indirect ELISAs in the system were considered, we were able to predict the filovirus species responsible for past infection 100% of the time using as little as 25 μL of sera (each serum was tested against each antigen in duplicate).

title:
  Comparative analysis of serologic cross-reactivity using convalescent sera from filovirus-experimentally infected fruit bats

abstract:
  With the exception of Reston and Bombali viruses, the marburgviruses and ebolaviruses (family Filoviridae) cause outbreaks of viral hemorrhagic fever in sub-Saharan Africa. The Egyptian rousette bat (ERB) is a natural reservoir host for the marburgviruses and evidence suggests that bats are also natural reservoirs for the ebolaviruses. Although the search for the natural reservoirs of the ebolaviruses has largely involved serosurveillance of the bat population, there are no validated serological assays to screen bat sera for ebolavirus-specific IgG antibodies. Here, we generate filovirus-specific antisera by prime-boost immunization of groups of captive ERBs with all seven known culturable filoviruses. After validating a system of filovirus-specific indirect ELISAs utilizing infectious-based virus antigens for detection of virus-specific IgG antibodies from bat sera, we assess the level of serological cross-reactivity between the virus-specific antisera and heterologous filovirus antigens. This data is then used to generate a filovirus antibody fingerprint that can predict which of the filovirus species in the system is most antigenically similar to the species responsible for past infection. Our filovirus IgG indirect ELISA system will be a critical tool for identifying bat species with high ebolavirus seroprevalence rates to target for longitudinal studies aimed at establishing natural reservoir host-ebolavirus relationships.


id: cord-003667-u1xa44nw
title: Vesicular Stomatitis Virus-Based Vaccine Protects Mice against Crimean-Congo Hemorrhagic Fever
author: Rodriguez, Sergio E.
date: 2019-05-23
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533279/
doi: 10.1038/s41598-019-44210-6
abstract:
  Crimean-Congo hemorrhagic fever virus (CCHFV), a tick-borne bunyavirus, can cause a life-threatening hemorrhagic syndrome in humans but not in its animal host. The virus is widely distributed throughout southeastern Europe, the Middle East, Africa, and Asia. Disease management has proven difficult and there are no broadly licensed vaccines or therapeutics. Recombinant vesicular stomatitis viruses (rVSV) expressing foreign glycoproteins (GP) have shown promise as experimental vaccines for several viral hemorrhagic fevers. Here, we developed and assessed a replication competent rVSV vector expressing the CCHFV glycoprotein precursor (GPC), which encodes CCHFV structural glycoproteins. This construct drives strong expression of CCHFV-GP, in vitro. Using these vectors, we vaccinated STAT-1 knock-out mice, an animal model for CCHFV. The vector was tolerated and 100% efficacious against challenge from a clinical strain of CCHFV. Anti-CCHFV-GP IgG and neutralizing antibody titers were observed in surviving animals. This study demonstrates that a rVSV expressing only the CCHFV-GP has the potential to serve as a replication competent vaccine platform against CCHF infections.


id: cord-004006-tfp2idq2
author: Hale, Alison C.
date: 2019-11-28
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6882870/
doi: 10.1038/s41598-019-53352-6
title:
  A real-time spatio-temporal syndromic surveillance system with application to small companion animals

abstract:
  Lack of disease surveillance in small companion animals worldwide has contributed to a deficit in our ability to detect and respond to outbreaks. In this paper we describe the first real-time syndromic surveillance system that conducts integrated spatio-temporal analysis of data from a national network of veterinary premises for the early detection of disease outbreaks in small animals. We illustrate the system’s performance using data relating to gastrointestinal disease in dogs and cats. The data consist of approximately one million electronic health records for dogs and cats, collected from 458 UK veterinary premises between March 2014 and 2016. For this illustration, the system predicts the relative reporting rate of gastrointestinal disease amongst all presentations, and updates its predictions as new data accrue. The system was able to detect simulated outbreaks of varying spatial geometry, extent and severity. The system is flexible: it generates outcomes that are easily interpretable; the user can set their own outbreak detection thresholds. The system provides the foundation for prompt detection and control of health threats in companion animals.


id: cord-004016-iaktm72a
author: Soto-Quintero, Albanelly
date: 2019-12-03
txt: ./txt/cord-004016-iaktm72a.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890765/
doi: 10.1038/s41598-019-54752-4
summary:
  The Ag@cur-P(MEO 2 MA) core-doped shell hybrid NPs were prepared by free radical precipitation polymerization (FRPP) of the stimuli-responsive MEO 2 MA monomer in the presence of TEGDMA (crosslinking agent), using curcumin-decorated Ag@cur NPs as seeds (Fig. 1) . However, the dual key-role of curcumin, as reducing agent and growth-polymerization promoter in this specific synthesis, required additional investigation to understand and optimize the chemical variables (solubility, concentration and reaction temperature) in order to achieve homogeneous, monodisperse and mononuclear Ag@cur-P(MEO 2 MA) core-shell nanohybrids. The presence of hydrophobic curcumin nearby the metallic surface led to precipitation-polymerization of P(MEO 2 MA) around the AgNPs previously formed (Fig. 1B,C) ; and the resulting Ag@cur-P(MEO 2 MA) nanoparticles were born negatively charged due to the persulfate groups from the APS initiator, which promotes their colloidal stability.

title:
  Curcumin to Promote the Synthesis of Silver NPs and their Self-Assembly with a Thermoresponsive Polymer in Core-Shell Nanohybrids

abstract:
  This work presents a simple one-pot protocol to achieve core-doped shell nanohybrids comprising silver nanoparticles, curcumin and thermoresponsive polymeric shell taking advantage of the reducing properties of phenolic curcumin substance and its ability to decorate metallic surfaces. Silver nanoparticles were synthesized, via sodium citrate and silver nitrate addition into a boiling aqueous solution of curcumin, monomers and surfactant. Curcumin and sodium citrate promoted silver nucleation, acting as reducing and stabilizing agents. These curcumin-capped AgNPs enabled, after adding the radical polymerization initiator, the assembling of the growing polymer chains around the hydrophobic AgNP surface. The resultant core-doped shell nanohybrids exhibit plasmonic, luminescent and volume thermoresponsive properties, with improved possibilities to be used as successful therapeutic platforms. In fact, the possibility to nanoconfine the synergistic antioxidant, antiviral, antibacterial features of silver and curcumin in one bioavailable hybrid paves the way to promising applications in the biomedical field.


id: cord-004060-nxw5k9y1
title: Spatiotemporal Analysis of Influenza in China, 2005–2018
author: Zhang, Yewu
date: 2019-12-23
txt: ./txt/cord-004060-nxw5k9y1.txt
cache: ./cache/cord-004060-nxw5k9y1.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928232/
doi: 10.1038/s41598-019-56104-8
summary:
  After adjusting for other covariates, a spatially unstructured random effect term (v i ), a spatially structured conditional autoregression term (υ i ), a first-order random walk-correlated time variable (γ 1j ), and an interaction term for time and place (δ ij ) in the multivariate adjusted spatiotemporal model, the flu vaccines (per million doses), flu surveillance protocols, rate of influenza A (H1N1)pdm09, latitude and longitude still remain statistically significant. Based on the incidence data of influenza gained from the Chinese Notifiable Infectious Disease Reporting System, we used the Bayesian spatiotemporal model in this study to assess the space-time patterns of the influenza epidemic at the prefecture level in mainland China from 2005 to 2018 and explored several factors that may be associated with the changing spatial and temporal patterns in the influenza incidence risk.

abstract:
  Influenza is a major cause of morbidity and mortality worldwide, as well as in China. Knowledge of the spatial and temporal characteristics of influenza is important in evaluating and developing disease control programs. This study aims to describe an accurate spatiotemporal pattern of influenza at the prefecture level and explore the risk factors associated with influenza incidence risk in mainland China from 2005 to 2018. The incidence data of influenza were obtained from the Chinese Notifiable Infectious Disease Reporting System (CNIDRS). The Besag York Mollié (BYM) model was extended to include temporal and space-time interaction terms. The parameters for this extended Bayesian spatiotemporal model were estimated through integrated nested Laplace approximations (INLA) using the package R-INLA in R. A total of 702,226 influenza cases were reported in mainland China in CNIDRS from 2005–2018. The yearly reported incidence rate of influenza increased 15.6 times over the study period, from 3.51 in 2005 to 55.09 in 2008 per 100,000 populations. The temporal term in the spatiotemporal model showed that much of the increase occurred during the last 3 years of the study period. The risk factor analysis showed that the decreased number of influenza vaccines for sale, the new update of the influenza surveillance protocol, the increase in the rate of influenza A (H1N1)pdm09 among all processed specimens from influenza-like illness (ILI) patients, and the increase in the latitude and longitude of geographic location were associated with an increase in the influenza incidence risk. After the adjusting for fixed covariate effects and time random effects, the map of the spatial structured term shows that high-risk areas clustered in the central part of China and the lowest-risk areas in the east and west. Large space-time variations in influenza have been found since 2009. In conclusion, an increasing trend of influenza was observed from 2005 to 2018. The insufficient flu vaccine supplements, the newly emerging influenza A (H1N1)pdm09 and expansion of influenza surveillance efforts might be the major causes of the dramatic changes in outbreak and spatio-temporal epidemic patterns. Clusters of prefectures with high relative risks of influenza were identified in the central part of China. Future research with more risk factors at both national and local levels is necessary to explain the changing spatiotemporal patterns of influenza in China.


id: cord-004062-yxx3xxio
author: Lee, Ing-Kit
date: 2019-12-24
txt: ./txt/cord-004062-yxx3xxio.txt
cache: ./cache/cord-004062-yxx3xxio.txt
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mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930266/
doi: 10.1038/s41598-019-56381-3
summary:
  We performed an in vitro study to evaluate the sequential immunological reactions and viral load in dengue virus type 2-infected mononuclear cells of patients with ESRD (n = 34) and in healthy controls (n = 30). The concentrations of interleukins (IL)-1 receptor antagonist (Ra), IL-2, IL-6, IL-8, IL-10, IL-12p40, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1b (MIP-1b), vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α and viral load cycle threshold (Ct) were measured in the dengue virus type 2-infected mononuclear cells at 6 h, 24 h, 48 h, and 72 h post-infection. In the present study, eleven immune mediators and viral load Ct values were measured in DENV2-infected mononuclear cells of adults with ESRD, and in healthy participants. Our results have been somewhat inconsistent with the reported overwhelming immune activation that is associated with dengue disease severity 5, 7 ; however, our findings clearly reflect the impairment of immune responses in vitro study of DENV2-infected mononuclear cells in ESRD patients.

title:
  Impaired production of immune mediators in dengue virus type 2-infected mononuclear cells of adults with end stage renal disease

abstract:
  Chronic kidney disease is an epidemiologically identified risk factor for development of severe dengue in dengue-affected patients. However, available data on the immune pathogenesis in end stage renal disease (ESRD) patients affected by dengue is insufficient. We performed an in vitro study to evaluate the sequential immunological reactions and viral load in dengue virus type 2-infected mononuclear cells of patients with ESRD (n = 34) and in healthy controls (n = 30). The concentrations of interleukins (IL)-1 receptor antagonist (Ra), IL-2, IL-6, IL-8, IL-10, IL-12p40, granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1b (MIP-1b), vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α and viral load cycle threshold (Ct) were measured in the dengue virus type 2-infected mononuclear cells at 6 h, 24 h, 48 h, and 72 h post-infection. We found in the ESRD group significantly higher GM-CSF and IL-2 levels at 6 h post-infection. However, IL-8, IL-10, IL-12p40, TNF-α, MCP-1, and MIP-1b levels were found significantly lower than in the control group. At 24 h, 48 h, and 72 h post-infection, significantly lower levels of IL-1Ra, IL-6, IL-8, IL-10, IL-12p40, TNF-α, MCP-1, and MIP-1b were detected in ESRD group. Concentration of VEGF at 24 h and 48 h, and of GM-CSF at 48 h and 72 h were also found to be lower in ESRD group than in control group. Compared with controls, the viral load Ct values were significantly lower in ESRD group at 6 h and 24 h post-infection No significant difference in viral load Ct values between two groups was found at 48 h and 72 h post-infection. Our study discloses that the expression of immune mediators of dengue-infected mononuclear cells is impaired in ESRD patients.


id: cord-004069-nuep8nim
title: In Vivo Activity of Amodiaquine against Ebola Virus Infection
author: DeWald, Lisa Evans
date: 2019-12-27
txt: ./txt/cord-004069-nuep8nim.txt
cache: ./cache/cord-004069-nuep8nim.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934550/
doi: 10.1038/s41598-019-56481-0
summary:
  A pharmacokinetic (PK) study in rhesus macaques (2 groups of 2 males and 2 females) was performed to monitor plasma concentrations of AQ (Fig. 1a ) and the active metabolite DEAQ (Fig. 1b) . samples from infected animals collected on days 0, 3, 5, and 7 postexposure and on day of necropsy (days 6, 7 or 8) were analyzed for determination of plasma levels of AQ and its metabolite DEAQ. Animals that were treated on days 0, 1 and 2 (Group 2, Fig. 7a ), had plasma DEAQ levels ranging from 0 to 205 ng/ml on days 3, 5, 7 and 8 postexposure. www.nature.com/scientificreports www.nature.com/scientificreports/ The goal of the study was to treat animals with AQ using a similar dosing strategy as for human patients, with a target blood concentration range of the parent compound AQ of 29.2 ± 10.9 ng/mL 12 .

abstract:
  During the Ebola virus disease (EVD) epidemic in Western Africa (2013‒2016), antimalarial treatment was administered to EVD patients due to the high coexisting malaria burden in accordance with World Health Organization guidelines. In an Ebola treatment center in Liberia, EVD patients receiving the combination antimalarial artesunate-amodiaquine had a lower risk of death compared to those treated with artemether-lumefantrine. As artemether and artesunate are derivatives of artemisinin, the beneficial anti-Ebola virus (EBOV) effect observed could possibly be attributed to the change from lumefantrine to amodiaquine. Amodiaquine is a widely used antimalarial in the countries that experience outbreaks of EVD and, therefore, holds promise as an approved drug that could be repurposed for treating EBOV infections. We investigated the potential anti-EBOV effect of amodiaquine in a well-characterized nonhuman primate model of EVD. Using a similar 3-day antimalarial dosing strategy as for human patients, plasma concentrations of amodiaquine in healthy animals were similar to those found in humans. However, the treatment regimen did not result in a survival benefit or decrease of disease signs in EBOV-infected animals. While amodiaquine on its own failed to demonstrate efficacy, we cannot exclude potential therapeutic value of amodiaquine when used in combination with artesunate or another antiviral.


id: cord-004140-ujzrqzv3
author: Lu, Xiaying
date: 2020-01-13
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957694/
doi: 10.1038/s41598-019-56899-6
title:
  Rolipram Protects Mice from Gram-negative Bacterium Escherichia coli-induced Inflammation and Septic Shock

abstract:
  Sepsis is typically triggered by an overwhelming systemic inflammatory response to pathogens, and may lead to severe organ dysfunction and/or death. Sepsis consequently has a high mortality rate and a high rate of complications for survivors, despite modern medical advances. Therefore, drug identification and validation for the treatment of sepsis is of the utmost importance. As a selective phosphodiesterase-4 inhibitor, rolipram also exhibits the abilities of inhibiting multiple pro-inflammatory cytokines production in macrophages and toxin-induced inflammation in mice. However, this drug has never been studied as a sepsis treatment method. We found that rolipram significantly improves survival in mice challenged with gram-negative bacterium E. coli, CLP, or E. coli derived lipopolysaccharide. We have also found that rolipram inhibits organ damage, pro-inflammatory cytokine production, and intracellular migration of early-stage inflammatory elements. Our results also show that rolipram increases anti-inflammatory cytokine production. The protective effects of rolipram on septic mice may result from inhibition of the MAP kinase and NF-κB signaling pathways. Rolipram may therefore be a potential novel sepsis treatment, one that would bypass the time-consuming and costly drug-discovery process.


id: cord-004150-ybikajhh
author: Nyarko, Prince B.
date: 2020-01-14
txt: ./txt/cord-004150-ybikajhh.txt
cache: ./cache/cord-004150-ybikajhh.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959351/
doi: 10.1038/s41598-019-56386-y
summary:
  The genes with most markedly increased expression included members of the erythrocyte binding antigens (EBA), reticulocyte binding homologues (RH), surface associated interspersed proteins (SURFIN), exported protein family 1 (EPF1) and Plasmodium Helical Interspersed Sub-Telomeric (PHIST) gene families. The data indicate changes in expression of a repertoire of genes not previously associated with erythrocyte invasion phenotypes, suggesting the possibility that moving suspension culture may also select for other traits. Additionally, a large number of virulence associated genes, including members of the surface-associated interspersed protein (SURFIN) family, exported protein family 1 (EPF1), ring exported protein 1 (REX1) and interspersed repeat antigen (FIRA); all of which are exported into host erythrocytes, were significantly expressed at higher levels in SP parasites relative to BL (Fig. 2) . A comparison of the levels of differential expression of the eba and rh gene between ST and SP parasites in the current RNA sequencing study and our previous RT-qPCR analysis shows a strong positive correlation of results from the two studies ( Supplementary Fig. 12 ).

title:
  Investigating a Plasmodium falciparum erythrocyte invasion phenotype switch at the whole transcriptome level

abstract:
  The central role that erythrocyte invasion plays in Plasmodium falciparum survival and reproduction makes this process an attractive target for therapeutic or vaccine development. However, multiple invasion-related genes with complementary and overlapping functions afford the parasite the plasticity to vary ligands used for invasion, leading to phenotypic variation and immune evasion. Overcoming the challenge posed by redundant ligands requires a deeper understanding of conditions that select for variant phenotypes and the molecular mediators. While host factors including receptor heterogeneity and acquired immune responses may drive parasite phenotypic variation, we have previously shown that host-independent changes in invasion phenotype can be achieved by continuous culturing of the W2mef and Dd2 P. falciparum strains in moving suspension as opposed to static conditions. Here, we have used a highly biologically replicated whole transcriptome sequencing approach to identify the molecular signatures of variation associated with the phenotype switch. The data show increased expression of particular invasion-related genes in switched parasites, as well as a large number of genes encoding proteins that are either exported or form part of the export machinery. The genes with most markedly increased expression included members of the erythrocyte binding antigens (EBA), reticulocyte binding homologues (RH), surface associated interspersed proteins (SURFIN), exported protein family 1 (EPF1) and Plasmodium Helical Interspersed Sub-Telomeric (PHIST) gene families. The data indicate changes in expression of a repertoire of genes not previously associated with erythrocyte invasion phenotypes, suggesting the possibility that moving suspension culture may also select for other traits.


id: cord-004156-79peyzc9
author: Lee, Shwu-Maan
date: 2020-01-15
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962329/
doi: 10.1038/s41598-019-57384-w
title:
  A C-terminal Pfs48/45 malaria transmission-blocking vaccine candidate produced in the baculovirus expression system

abstract:
  The Plasmodium falciparum gametocyte surface protein, Pfs48/45, is a potential target for malaria transmission-blocking vaccines. However, due to its size and complexity, expression of the full-length protein has been difficult, leading to focus on the C-terminal six cysteine domain (6C) with the use of fusion proteins to facilitate expression and folding. In this study, we utilized the baculovirus system to evaluate the expression of three Pfs48/45 proteins including the full-length protein, the 6C domain fragment and the 6C domain mutant to prevent glycosylation. Expression of the recombinant Pfs48/45 proteins was conducted in super Sf9 cells combined with the use of tunicamycin to prevent N-glycosylation. The proteins were then evaluated as immunogens in mice to demonstrate the induction of functionally active polyclonal antibody responses as measured in the standard membrane feeding assay (SMFA). Only the 6C protein was found to exhibit significant transmission-reducing activity. Further characterization of the biologically active 6C protein demonstrated it was homogeneous in terms of size, charge, conformation, absence of glycosylation, and containing proper disulfide bond pairings. This study presents an alternative expression system, without the need of a fusion protein partner, for the Pfs48/45 6C protein fragment including further evaluation as a potential transmission-blocking vaccine candidate.


id: cord-004170-ri5qsarz
author: Yashima, Nozomi
date: 2020-01-16
txt: ./txt/cord-004170-ri5qsarz.txt
cache: ./cache/cord-004170-ri5qsarz.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6965310/
doi: 10.1038/s41598-019-57173-5
summary:
  title: Leukocyte-derived extracellular DNA contributes to abnormal pressure elevation in the extracorporeal circulation circuit Abnormal in-circuit elevation in pressure was associated with deposition of extracellular DNA on the outlet surface of the filter. In-circuit pressure was elevated at the oxygenator if heparin was administered in whole blood that was stored for 7 days (Fig. S1B) . Then, we examined whether leukocyte stimulation results in elevation of in-circuit pressure since previous studies have suggested that stimulated leukocytes are prone to releasing DNA into the extracellular space 13 . Our study showed that leukocyte-derived extracellular DNA induced an elevation of in-circuit pressure. Our study suggested that extracellular DNA from disrupted leukocytes contributed to elevation of in-circuit pressure. In conclusion, our study shows that leukocyte-derived extracellular DNA contributes to abnormal in-circuit elevation of pressure in an ex vivo circuit.

title:
  Leukocyte-derived extracellular DNA contributes to abnormal pressure elevation in the extracorporeal circulation circuit

abstract:
  An abnormal elevation in pressure is a serious complication involving the extracorporeal circulation circuit. Clot formation might be associated with this complication, but the precise mechanism of an abnormal elevation in pressure has not been identified. We investigated sufficient conditions for in-circuit elevation in pressure using an ex vivo re-circulation circuit with porcine blood. Specifically, we investigated the effect of blood conditions, the type of anticoagulation, and pro-inflammatory stimulation on in-circuit pressure. We also examined the cause of an abnormal elevation of in-circuit pressure by specifically degrading DNA, RNA, or protein components of an obstructed filter and by using immunofluorescent techniques. Neither a change in temperature nor change in pH in the blood increased in-circuit pressure. In contrast, long-term storage of blood, pro-inflammatory stimulation by phorbol myristate acetate, and heparin administration significantly increased in-circuit pressure. Abnormal in-circuit elevation in pressure was associated with deposition of extracellular DNA on the outlet surface of the filter. Administration of DNase resulted in a rapid decline of in-circuit pressure. In an ex vivo re-circulation circuit system, extracellular DNA deposition on the filter is responsible for an abnormal in-circuit elevation in pressure. Senescent leukocytes, stimulated leukocytes, and heparin exposure are associated with extracellular DNA deposition.


id: cord-004181-exbs3tz7
author: Pumchan, Ansaya
date: 2020-01-17
txt: ./txt/cord-004181-exbs3tz7.txt
cache: ./cache/cord-004181-exbs3tz7.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6969146/
doi: 10.1038/s41598-019-57283-0
summary:
  The efficacy of the chimeric multiepitope construct as a recombinant protein vaccine and DNA vaccine was evaluated in Nile tilapia, followed by S. The epitopes of immunogenic proteins were predicted by the BCPREDS server based on B cell epitopes to be used in chimeric multiepitope vaccine construction. In this study, not only immunogenic proteins from the immunoproteomics analysis were used but also other subunit vaccine candidates were subjected to epitope prediction and combined to produce a chimeric multiepitope vaccine. The recombinant chimeric multiepitope protein vaccination showed that 45F2 and 42E2 produced cumulative mortality rates of 30.00 ± 10.00% and 26.67 ± 5.77%, respectively, which were significantly lower than those of the negative control group, at 70% (P < 0.05) (Fig. 6A) . agalactiae serotype Ia and III demonstrated that fish vaccinated with recombinant protein vaccine 42E2 and 45F2 showed cross-reactivity to whole cell lysate of S.

title:
  Novel Chimeric Multiepitope Vaccine for Streptococcosis Disease in Nile Tilapia (Oreochromis niloticus Linn.)

abstract:
  Streptococcus agalactiae is a causative agent of streptococcosis disease in various fish species, including Nile tilapia (Oreochromis niloticus Linn.). Vaccination is an effective disease prevention and control method, but limitations remain for protecting against catastrophic mortality of fish infected with different strains of streptococci. Immunoproteomics analysis of S. agalactiae was used to identify antigenic proteins and construct a chimeric multiepitope vaccine. Epitopes from five antigenic proteins were shuffled in five helices of a flavodoxin backbone, and in silico analysis predicted a suitable RNA and protein structure for protein expression. 45F2 and 42E2 were identified as the best candidates for a chimeric multiepitope vaccine. Recombinant plasmids were constructed to produce a recombinant protein vaccine and DNA vaccine system. Overexpressed proteins were determined to be 30 kDa and 25 kDa in the E. coli and TK1 systems, respectively. The efficacy of the chimeric multiepitope construct as a recombinant protein vaccine and DNA vaccine was evaluated in Nile tilapia, followed by S. agalactiae challenge at 1 × 10(7) CFU/mL. Relative percentage survival (RPS) and cumulative mortality were recorded at approximately 57–76% and 17–30%, respectively. These chimeric multiepitope vaccines should be applied in streptococcosis disease control and developed into a multivalent vaccine to control multiple diseases.


id: cord-004222-z4butywi
author: Joyce, Collin
date: 2020-01-24
txt: ./txt/cord-004222-z4butywi.txt
cache: ./cache/cord-004222-z4butywi.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981180/
doi: 10.1038/s41598-020-57764-7
summary:
  We characterized the heavy chain and kappa light chain antibody repertoires of a model animal, the OmniRat, by high throughput antibody sequencing and made use of two novel datasets for comparison to human repertoires. Multiple differences were found in both the heavy and kappa chain repertoires between OmniRats and humans including gene segment usage, CDR3 length distributions, class switch recombination, somatic hypermutation levels and in features of V(D)J recombination. We individually separated total RNA from spleens and lymph nodes of three unimmunized OmniRats and PCR amplified the heavy and kappa chain antibody V gene segments. We started by making intra-animal comparisons, intra-species comparisons and inter-species comparisons of the immunoglobulin gene segment usage frequencies for each antibody repertoire by performing hierarchical clustering ( Fig. 1 ) and linear regression analysis (Figs.

title:
  Comparisons of the antibody repertoires of a humanized rodent and humans by high throughput sequencing

abstract:
  The humanization of animal model immune systems by genetic engineering has shown great promise for antibody discovery, tolerance studies and for the evaluation of vaccines. Assessment of the baseline antibody repertoires of unimmunized model animals will be useful as a benchmark for future immunization experiments. We characterized the heavy chain and kappa light chain antibody repertoires of a model animal, the OmniRat, by high throughput antibody sequencing and made use of two novel datasets for comparison to human repertoires. Intra-animal and inter-animal repertoire comparisons reveal a high level of conservation in antibody diversity between the lymph node and spleen and between members of the species. Multiple differences were found in both the heavy and kappa chain repertoires between OmniRats and humans including gene segment usage, CDR3 length distributions, class switch recombination, somatic hypermutation levels and in features of V(D)J recombination. The Inference and Generation of Repertoires (IGoR) software tool was used to model recombination in VH regions which allowed for the quantification of some of these differences. Diversity estimates of the OmniRat heavy chain repertoires almost reached that of humans, around two orders of magnitude less. Despite variation between the species repertoires, a high frequency of OmniRat clonotypes were also found in the human repertoire. These data give insights into the development and selection of humanized animal antibodies and provide actionable information for use in vaccine studies.


id: cord-004280-c470nlie
title: Airborne Influenza A Virus Exposure in an Elementary School
author: Coleman, Kristen K.
date: 2020-02-05
txt: ./txt/cord-004280-c470nlie.txt
cache: ./cache/cord-004280-c470nlie.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002614/
doi: 10.1038/s41598-020-58588-1
summary:
  In this study, we evaluated the use of a bioaerosol sampling method to noninvasively detect and quantify airborne influenza A virus (IAV) densities in a public elementary school. Significantly different (p = 0.049) airborne IAV densities were detected between all three indoor locations (i.e., gymnasium, classroom, and corridor) and all positive samples were collected during the last two weeks of 66 , and a 20-30% relative humidity level; Descriptive of an average elementary school student in the USA weighing ~23-32 kg with an assumed tidal volume (V T ) of 7 mL per kg of body mass. Given the high airborne IAV densities detected in the school corridor, along with elevated student contact rates, it is plausible to conclude that the school corridor is a "hotspot" for influenza virus transmission.

abstract:
  Influenza contributes significantly to childhood morbidity and mortality. Given the magnitude of the school-aged child population, a sizeable proportion of influenza virus transmission events are expected to occur within school settings. However, influenza virus activity in schools is not well-understood, likely due to our limited ability to accurately monitor for respiratory viruses without disrupting the school environment. In this study, we evaluated the use of a bioaerosol sampling method to noninvasively detect and quantify airborne influenza A virus (IAV) densities in a public elementary school. Air samples were collected from multiple locations in the school, two days per week, throughout an eight-week sampling period during influenza season. Real-time RT-PCR targeting the IAV M gene revealed detectable IAV on five occasions in densities ranging from 2.0 × 10(−1) to 1.9 × 10(4). No significant differences in IAV densities were related to student presence/absence. The majority of IAV-associated particles were ≤4 μm in diameter, and theoretical calculations indicate infectious thresholds after minutes of exposure. Our study represents the first identification and quantification of airborne influenza virus in an elementary school, and the results suggest that airborne IAV has the potential to circulate in schools during influenza season, in large enough doses known to cause infection.


id: cord-004292-6lnxb0px
author: Lyu, Hongming
date: 2020-02-07
txt: ./txt/cord-004292-6lnxb0px.txt
cache: ./cache/cord-004292-6lnxb0px.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005712/
doi: 10.1038/s41598-020-59017-z
summary:
  With their flexible form factors, two pacemakers were implanted epicardially on the right and left ventricles of a porcine model and were inductively powered at 13.56 MHz and 40.68 MHz industrial, scientific, and medical (ISM) bands, respectively. The closed-chest pacing only requires the external source power of 0.3 W and 0.8 W at 13.56 MHz and 40.68 MHz, respectively, which leads to specific absorption rates (SARs) 2–3 orders of magnitude lower than the safety regulation limit. Not only is the need for intravascular leads eliminated, but synchronized and leadless pacing across different chambers becomes feasible, which offers the flexibility in customizing patient-specific CRTs. Prior studies have investigated wirelessly powered single-site cardiac pacing on rodent, rabbit and open-chest porcine models 4, 5, 21 . To demonstrate wireless CRT, two such pacemakers were epicardially implanted on the right ventricle (RV) and left ventricle (LV) in a porcine model for synchronized biventricular (BiV) pacing with controllable interventricular offsets.

title:
  Synchronized Biventricular Heart Pacing in a Closed-chest Porcine Model based on Wirelessly Powered Leadless Pacemakers

abstract:
  About 30% of patients with impaired cardiac function have ventricular dyssynchrony and seek cardiac resynchronization therapy (CRT). In this study, we demonstrate synchronized biventricular (BiV) pacing in a leadless fashion by implementing miniaturized and wirelessly powered pacemakers. With their flexible form factors, two pacemakers were implanted epicardially on the right and left ventricles of a porcine model and were inductively powered at 13.56 MHz and 40.68 MHz industrial, scientific, and medical (ISM) bands, respectively. The power consumption of these pacemakers is reduced to µW-level by a novel integrated circuit design, which considerably extends the maximum operating distance. Leadless BiV pacing is demonstrated for the first time in both open-chest and closed-chest porcine settings. The clinical outcomes associated with different interventricular delays are verified through electrophysiologic and hemodynamic responses. The closed-chest pacing only requires the external source power of 0.3 W and 0.8 W at 13.56 MHz and 40.68 MHz, respectively, which leads to specific absorption rates (SARs) 2–3 orders of magnitude lower than the safety regulation limit. This work serves as a basis for future wirelessly powered leadless pacemakers that address various cardiac resynchronization challenges.


id: cord-004310-hl7fa4af
author: Matsuishi, Yujiro
date: 2020-02-10
txt: ./txt/cord-004310-hl7fa4af.txt
cache: ./cache/cord-004310-hl7fa4af.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010829/
doi: 10.1038/s41598-020-58283-1
summary:
  We recorded patient information, including age, sex, surgical procedure, and daily severity data (including severity of organ dysfunction and sedative/muscle relaxant dosages) during PICU stays for five days after the end of muscle relaxant usage. We found that, overall, the amount of MDZ administered was increased in DS versus controls after ending muscle relaxants and observed the reduced sedative effect of MDZ for DS patients while DEX was not different as estimated by Bayesian inference modeling. To adjust these biases, we used multivariate www.nature.com/scientificreports www.nature.com/scientificreports/ analysis with respect to these factors but we also "double checked" our results by using the demographic data propensity score for DS patients as a covariate in Bayesian inference modeling. To conclude, we conducted a retrospective study based on validated evaluative tools that indicated a need for higher doses of MDZ with higher doses of compensating sedatives for the 5-day period immediately after muscle relaxant usage following pediatric heart surgery.

title:
  Down Syndrome Reduces the Sedative Effect of Midazolam in Pediatric Cardiovascular Surgical Patients

abstract:
  Down syndrome (DS) is frequently comorbid with congenital heart disease and has recently been shown to reduce the sedative effect of benzodiazepine (BDZ)-class anesthesia but this effect in a clinical setting has not been studied. Therefore, this study compared midazolam sedation after heart surgery in DS and normal children. We retrospectively reviewed patient records in our pediatric intensive care unit (PICU) of pediatric cardiovascular operations between March 2015 and March 2018. We selected five days of continuous post-operative data just after termination of muscle relaxants. Midazolam sedation was estimated by Bayesian inference for generalized linear mixed models. We enrolled 104 patients (average age 26 weeks) of which 16 (15%) had DS. DS patients had a high probability of receiving a higher midazolam dosage and dexmedetomidine dosage over the study period (probability = 0.99, probability = 0.97) while depth of sedation was not different in DS patients (probability = 0.35). Multi regression modeling included severity scores and demographic data showed DS decreases midazolam sedation compared with controls (posterior OR = 1.32, 95% CrI = 1.01–1.75). In conclusion, midazolam dosages should be carefully adjusted as DS significantly decreases midazolam sedative effect in pediatric heart surgery patients.


id: cord-004342-9uok77wb
author: Lin, Chun-Yu
date: 2020-02-14
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021775/
doi: 10.1038/s41598-020-59657-1
title:
  Elderly versus non-elderly patients undergoing surgery for left-sided native valve infective endocarditis: A 10-year institutional experience

abstract:
  This retrospective study aimed to clarify the short- and mid-term outcomes of elderly patients who underwent surgery to treat left-sided native valve infective endocarditis (LSNIE). Between July 2005 and September 2015, 179 patients underwent surgical treatment for active LSNIE at a single institution. Patients were classified into two groups: ≥65 years (elderly group) and <65 years (non-elderly group). Clinical features, surgical information, postoperative complications, and three-year survival rates were compared. The average ages were 74.2 ± 6.4 and 45.2 ± 12.6 years in the elderly and non-elderly groups, respectively. The elderly group had a higher predicted mortality rate and a lower incidence of preoperative septic emboli-related complications. Echocardiographic assessments of infected valves were generally homogenous between the groups. The elderly patients had a higher in-hospital mortality rate than the non-elderly patients (26.3% vs. 5.7%, P = 0.001). For patients who survived to discharge, the three-year cumulative survival rates were 75.0% ± 8.2% and 81.2% ± 3.4% in the elderly and non-elderly groups, respectively (P = 0.484). In conclusion, elderly patients are at a higher risk of in-hospital mortality after surgery for LSNIE. However, once elderly patients are stabilized by surgical treatment and survive to discharge, the mid-term outcomes are promising.


id: cord-004378-g1rxygef
author: Leinisch, Fabian
date: 2020-02-20
txt: ./txt/cord-004378-g1rxygef.txt
cache: ./cache/cord-004378-g1rxygef.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033146/
doi: 10.1038/s41598-020-59855-x
summary:
  In this study we show that exposure of isolated dimeric CRP-cAMP to UV modifies specific Met, Trp, Tyr, and Pro side-chains, induces inter-protein Tyr63-Tyr41 cross-links, and decreases DNA binding via oxidation of Met114/Pro110 residues in close proximity at the CRP dimer interface. The modifications at the CRP dimer interface, and the site-specific DNA strand cleavage are proposed to occur via oxidation of two species Met residues (Met114 and Met189, respectively) to reactive persulfoxides that damage neighbouring amino acids and DNA bases. Panel B: Material balance for Trp and Tyr residues determined by UPLC analysis with direct fluorescence detection on acid-hydrolysed UV-exposed CRP-cAMP complex. UPLC analysis of native and oxidized CRP showed that UV exposure of CRP resulted in significant modification (relative to controls) to Trp, Tyr, Ser, Met and Arg residues (Fig. 3A) . Q-TOF MS analysis of cAMP-CRP-DNA complexes exposed to UV light showed a similar pattern of damage, but higher extents of Met modification (7.6%; Fig. 3C ).

title:
  UV oxidation of cyclic AMP receptor protein, a global bacterial gene regulator, decreases DNA binding and cleaves DNA at specific sites

abstract:
  UV light is a widely-employed, and environmentally-sensitive bactericide but its mechanism of action is not fully defined. Proteins are major chromophores and targets for damage due to their abundance, but the role of proteins in inducing damage to bound DNA, and the effects on DNA-protein interactions is less well characterized. In E. coli (and other Gram-negative bacteria) the cyclic AMP receptor protein (CRP/CAP) regulates more than 500 genes. In this study we show that exposure of isolated dimeric CRP-cAMP to UV modifies specific Met, Trp, Tyr, and Pro side-chains, induces inter-protein Tyr63-Tyr41 cross-links, and decreases DNA binding via oxidation of Met114/Pro110 residues in close proximity at the CRP dimer interface. UV exposure also modifies DNA-bound cAMP-CRP, with this resulting in DNA cleavage at specific G/C residues within the sequence bound to CRP, but not at other G/C sites. Oxidation also increases CRP dissociation from DNA. The modifications at the CRP dimer interface, and the site-specific DNA strand cleavage are proposed to occur via oxidation of two species Met residues (Met114 and Met189, respectively) to reactive persulfoxides that damage neighbouring amino acids and DNA bases. These data suggest that modification to CRP, and bound DNA, contributes to UV sensitivity.


id: cord-004379-91a7sgir
author: Han, Nayoung
date: 2020-02-20
txt: ./txt/cord-004379-91a7sgir.txt
cache: ./cache/cord-004379-91a7sgir.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033147/
doi: 10.1038/s41598-020-60068-5
summary:
  The aim of this study was to evaluate age-related clinical manifestations of adverse events (AEs) related to NAIs. FAERS and WebMD data were downloaded. A disproportionality analysis showed that signals for vomiting and hallucinations were detected in younger patients given oseltamivir, while an abnormal hepatic function, cardiac failure, shock, and cardio-respiratory arrest were detected in older patients given peramivir. However, there is still concern regarding the adverse effects of NAIs. This study analyzed the age-related AEs associated with NAIs using data from FAERS and WebMD. Oseltamivir was the NAI most commonly showing AEs in the FAERS data, and the most common AEs for this drug were psychiatric and gastrointestinal disorders, similar to the findings of previous studies 8, [13] [14] [15] [16] . However, in the WebMD data, we could not detect signals by these disproportionality analyses due to the small number of AE cases, although psychiatric and gastrointestinal disorders were the most common AEs reported.

title:
  Assessment of adverse events related to anti-influenza neuraminidase inhibitors using the FDA adverse event reporting system and online patient reviews

abstract:
  The recommended antiviral drugs available for the treatment and prevention of influenza are neuraminidase inhibitors (NAIs). The aim of this study was to evaluate age-related clinical manifestations of adverse events (AEs) related to NAIs. FAERS and WebMD data were downloaded. The available NAIs selected for the analysis were oseltamivir, peramivir, zanamivir, and laninamivir. Disproportionality was analyzed using the proportional reporting ratio (PRR), the reporting odds ratio (ROR), and the information component (IC) methods. In total, 16729 AEs from 4598 patients and 575 AEs from 440 patients in the FAERS and WebMD, respectively, were included in the analysis. In the FAERS, AEs were more common among those who were younger (<19 years) for zanamivir, while for those who were older (>65 years) for peramivir. A disproportionality analysis showed that signals for vomiting and hallucinations were detected in younger patients given oseltamivir, while an abnormal hepatic function, cardiac failure, shock, and cardio-respiratory arrest were detected in older patients given peramivir. Psychiatric disorders were most common in younger and older patients, while gastrointestinal disorders were most common in adult given oseltamivir in the WebMD. Adverse symptoms related to NAIs varied and depended on the drugs used and the age of the patient.


id: cord-004385-xna32qve
author: Zhou, Yuqing
date: 2020-02-20
txt: ./txt/cord-004385-xna32qve.txt
cache: ./cache/cord-004385-xna32qve.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033254/
doi: 10.1038/s41598-020-59732-7
summary:
  title: Use of corticosteroids in influenza-associated acute respiratory distress syndrome and severe pneumonia: a systemic review and meta-analysis We obtained the following data: (a) characteristics of studies (design, setting, country, period, methodological details for quality assessment); (b) characteristics of participants (demographics, co-morbid illnesses, disease severity, numbers in each group, influenza virus type); (c) characteristics of interventions (type, dose, timing and duration of corticosteroid use); and (d) outcomes. Another study reporting the result of 62 patients with acute respiratory failure due to influenza showed no statistically significant difference between low dose and high dose corticosteroid therapy (8/19 versus 7/19, p > 0.05) 16 . The overall findings of this meta-analysis indicated that patients with pneumonia or acute respiratory distress syndrome who were administered corticosteroids had significantly higher mortality and incidence of nosocomial infection but the use of corticosteroids did not influence the length of hospital stay.

title:
  Use of corticosteroids in influenza-associated acute respiratory distress syndrome and severe pneumonia: a systemic review and meta-analysis

abstract:
  Influenza-related severe pneumonia and acute respiratory distress syndrome (ARDS) are severe threats to human health. The objective of this study was to assess the effects of systematic corticosteroid therapy in patients with pneumonia or ARDS. The PubMed, EMBASE, Web of Science and SCOPUS databases were searched up to July, 2019. Nineteen studies including 6637 individuals were identified, and fifteen studies (6427 patients) were included in the meta-analysis of mortality. Eighteen were observational studies and one was a randomized controlled trial (RCT). The meta-analysis results showed that corticosteroid therapy was associated with significantly higher mortality (OR 1.53, 95% CI [1.16, 2.01]) and incidence of nosocomial infection (OR 3.15, 95% CI [1.54, 6.45]). Subgroup analysis showed that among patients with unadjusted estimates, the odds of mortality were higher in patients receiving corticosteroid treatment (OR 1.98, 95% CI [1.23, 3.17]), however, among patients with adjusted estimates, the result showed no statistically significant difference between corticosteroid group and control group (OR 1.31, 95% CI [0.95, 1.80]). Current data do not support the routine use of corticosteroids in patients with influenza severe pneumonia or ARDS. RCTs are needed to provide more robust evidence.


id: cord-004416-qw6tusd2
title: Development of a two-stage limb ischemia model to better simulate human peripheral artery disease
author: Krishna, Smriti M.
date: 2020-02-26
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044206/
doi: 10.1038/s41598-020-60352-4
abstract:
  Peripheral arterial disease (PAD) develops due to the narrowing or blockage of arteries supplying blood to the lower limbs. Surgical and endovascular interventions are the main treatments for advanced PAD but alternative and adjunctive medical therapies are needed. Currently the main preclinical experimental model employed in PAD research is based on induction of acute hind limb ischemia (HLI) by a 1-stage procedure. Since there are concerns regarding the ability to translate findings from this animal model to patients, we aimed to develop a novel clinically relevant animal model of PAD. HLI was induced in male Apolipoprotein E (ApoE(−/−)) deficient mice by a 2-stage procedure of initial gradual femoral artery occlusion by ameroid constrictors for 14 days and subsequent excision of the femoral artery. This 2-stage HLI model was compared to the classical 1-stage HLI model and sham controls. Ischemia severity was assessed using Laser Doppler Perfusion Imaging (LDPI). Ambulatory ability was assessed using an open field test, a treadmill test and using established scoring scales. Molecular markers of angiogenesis and shear stress were assessed within gastrocnemius muscle tissue samples using quantitative polymerase chain reaction. HLI was more severe in mice receiving the 2-stage compared to the 1-stage ischemia induction procedure as assessed by LDPI (p = 0.014), and reflected in a higher ischemic score (p = 0.004) and lower average distance travelled on a treadmill test (p = 0.045). Mice undergoing the 2-stage HLI also had lower expression of angiogenesis markers (vascular endothelial growth factor, p = 0.004; vascular endothelial growth factor- receptor 2, p = 0.008) and shear stress response mechano-transducer transient receptor potential vanilloid 4 (p = 0.041) within gastrocnemius muscle samples, compared to animals having the 1-stage HLI procedure. Mice subjected to the 2-stage HLI receiving an exercise program showed significantly greater improvement in their ambulatory ability on a treadmill test than a sedentary control group. This study describes a novel model of HLI which leads to more severe and sustained ischemia than the conventionally used model. Exercise therapy, which has established efficacy in PAD patients, was also effective in this new model. This new model maybe useful in the evaluation of potential novel PAD therapies.


id: cord-004418-08dljap3
author: Young, Ginger
date: 2020-02-26
txt: ./txt/cord-004418-08dljap3.txt
cache: ./cache/cord-004418-08dljap3.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044319/
doi: 10.1038/s41598-020-60415-6
summary:
  In this study we evaluated the antibody responses and efficacy of an aluminum hydroxide adjuvanted purified inactivated Zika vaccine (PIZV) against challenge with Zika virus (ZIKV) strain PRVABC59. As with neutralizing antibodies, all PIZV doses were immunogenic and no anti-Zika IgG was detected in the control group prior to ZIKV challenge. PIZV elicited a dose dependent neutralizing antibody immune response and an anti-Zika IgG response which correlated with a reduction in ZIKV vRNA post-challenge (Table 2 ). Vaccinating with a broad range of PIZV dose levels enabled us to correlate both neutralizing and anti-Zika IgG antibody titers to protection against ZIKV infection. A Zika RVP assay (Sonnberg et al., manuscript in preparation) was used to determine neutralizing antibody titers in serum following the administration of PIZV (study days 1, 29, 57, and 71), and 30 days post-ZIKV challenge (day 101).

title:
  Complete Protection in Macaques Conferred by Purified Inactivated Zika Vaccine: Defining a Correlate of Protection

abstract:
  A critical global health need exists for a Zika vaccine capable of mitigating the effects of future Zika epidemics. In this study we evaluated the antibody responses and efficacy of an aluminum hydroxide adjuvanted purified inactivated Zika vaccine (PIZV) against challenge with Zika virus (ZIKV) strain PRVABC59. Indian rhesus macaques received two doses of PIZV at varying concentrations ranging from 0.016 µg − 10 µg and were subsequently challenged with ZIKV six weeks or one year following the second immunization. PIZV induced a dose-dependent immune response that was boosted by a second immunization. Complete protection against ZIKV infection was achieved with the higher PIZV doses of 0.4 µg, 2 µg, and 10 µg at 6 weeks and with 10 ug PIZV at 1 year following vaccination. Partial protection was achieved with the lower PIZV doses of 0.016 µg and 0.08 µg. Based on these data, a neutralizing antibody response above 3.02 log(10) EC50 was determined as a correlate of protection in macaques. PIZV elicited a dose-dependent neutralizing antibody response which is protective for at least 1 year following vaccination.


id: cord-004419-81w7apdk
author: Course, Christopher
date: 2020-02-26
txt: ./txt/cord-004419-81w7apdk.txt
cache: ./cache/cord-004419-81w7apdk.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044423/
doi: 10.1038/s41598-020-60091-6
summary:
  Little variation was seen between level two and three units, although gestational age was a significant independent variable for several practices, including delayed cord clamping, stabilisation with intubation, early enteral feeding and caffeine administration. Prospective, anonymised audits of the management of RDS in all preterm infants born at <34 weeks gestational age and cared for in a participating neonatal unit in Wales were undertaken. This represented the best-practice document for the management of RDS in infants born at <34 weeks gestational age, concentrating on areas which were supported by Grade A evidence (http://www.gradeworkinggroup.org/). The audit proforma was based upon the recommendations in the European Consensus Guideline on the Management of RDS in Preterm Infants 2013, and concentrated on management areas which were supported by Grade A evidence 9 . The 2013 edition of the European consensus guideline recommended a change in practice towards stabilising preterm infants on non-invasive respiratory support at delivery rather than elective intubation 9 .

title:
  Management of Respiratory Distress Syndrome in Preterm Infants In Wales: A Full Audit Cycle of a Quality Improvement Project

abstract:
  Respiratory Distress Syndrome (RDS) is the commonest diagnosis after premature birth. We aimed to audit clinical practices before and after introduction of a national guideline in Wales on RDS management. Anonymised, prospective data on all infants born at <34 weeks of gestation and cared for at one of the participating neonatal units in Wales were collected in two six-month time periods in 2015 and 2018. A national guideline was introduced in 2016 by the Wales Neonatal Network. Data collection included areas of antenatal management, delivery room stabilisation, invasive and non-invasive respiratory support, surfactant treatment and elements of supportive care. Univariate and multivariate methods were used to compare data between the two epochs. Comparing care before and after introduction of the national guideline, areas of significant improvement include use of targeted tidal volume ventilation, use of caffeine therapy, oxygen therapy post-surfactant and increasing early use of parenteral nutrition. Areas of poorer management included levels of positive end expiratory pressures and timing of introduction of enteral feeds. Little variation was seen between level two and three units, although gestational age was a significant independent variable for several practices, including delayed cord clamping, stabilisation with intubation, early enteral feeding and caffeine administration. A national guideline for management of RDS in Wales has significantly improved practice in several areas. However, despite a large volume of high-quality evidence and robust guidance, there remains a significant variation in some elements of best practice for RDS management. Further work should focus on education and training, especially for elements requiring cross-departmental work.


id: cord-005507-equnyib7
title: Antibody epitope repertoire analysis enables rapid antigen discovery and multiplex serology
author: Kamath, Kathy
date: 2020-03-24
txt: ./txt/cord-005507-equnyib7.txt
cache: ./cache/cord-005507-equnyib7.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093460/
doi: 10.1038/s41598-020-62256-9
summary:
  Given this, we developed serum epitope repertoire analysis (SERA), a method to rapidly discover conserved, pathogen-specific antigens and their epitopes, and applied it to develop an assay for Chagas disease caused by the protozoan parasite Trypanosoma cruzi. We applied serum epitope repertoire analysis (SERA) to discover shared, but highly specific immunogenic epitope motifs associated with Chagas disease caused by the protozoan parasite Trypanosoma cruzi, and thereby develop a serological assay. To identify antibody epitope motifs specific to Chagas disease, we applied the IMUNE motif discovery algorithm 15 (see Methods for parameters) to epitope repertoires from 28 Chagas specimens and 30 non-Chagas sera, yielding 331 candidate motifs (Supplementary Table S2 ). Using Chagas disease seropositive specimens, a panel of 31 peptide motifs was identified that exhibited 100% sensitivity (60/60) and 100% specificity (120/120) in independent validation sets.

abstract:
  The detection of pathogen-specific antibodies remains a cornerstone of clinical diagnostics. Yet, many test exhibit undesirable performance or are completely lacking. Given this, we developed serum epitope repertoire analysis (SERA), a method to rapidly discover conserved, pathogen-specific antigens and their epitopes, and applied it to develop an assay for Chagas disease caused by the protozoan parasite Trypanosoma cruzi. Antibody binding peptide motifs were identified from 28 Chagas repertoires using a bacterial display random 12-mer peptide library and next-generation sequencing (NGS). Thirty-three motifs were selected and mapped to candidate Chagas antigens. In a blinded validation set (n = 72), 30/30 Chagas were positive, 30/30 non-Chagas were negative, and 1/12 Leishmania sp. was positive. After unblinding, a Leishmania cross-reactive epitope was identified and removed from the panel. The Chagas assay exhibited 100% sensitivity (30/30) and specificity (90/90) in a second blinded validation set including individuals with other parasitic infections. Amongst additional epitope repertoires with unknown Chagas serostatus, assay specificity was 99.8% (998/1000). Thus, the Chagas assay achieved a combined sensitivity and specificity equivalent or superior to diagnostic algorithms that rely on three separate tests to achieve high specificity. NGS-based serology via SERA provides an effective approach to discover antigenic epitopes and develop high performance multiplex serological assays.


id: cord-007851-v6h1yro7
author: Han, Ki-Cheol
date: 2020-04-03
txt: ./txt/cord-007851-v6h1yro7.txt
cache: ./cache/cord-007851-v6h1yro7.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125174/
doi: 10.1038/s41598-020-62244-z
summary:
  We used a combined application of this method involving immune-specific signature analysis and HLA-associated peptidomics using samples from six patients with triple-negative breast cancer (TNBC) in order to select immunogenic HLA epitopes for in vitro testing. Integrated WTS data revealed a higher priority to select promising HLA-peptides via high-resolution bioinformatics analysis, showing immune-cell-specific signatures and TCR-repertoire diversity in tumors. We then found a positive correlation between TCR diversity, reflecting clonal composition, and the expression of MHC-class І molecules, suggesting that active tumor-antigen presentation promotes the generation of antigen-specific TILs. Additionally, immune-specific signature analysis can discriminate specific immune-cell types in each patient and thus enhance the efficiency of selective HLA-peptidomic approaches. In this study, the HLA-peptidomics approach combined with comprehensive analysis of immune-specific signatures and TCR repertories showed high selectivity to determine the immunogenic T-cell epitopes. Identification of potential vaccine epitopes coupled with immune-specific signature analysis, HLA-peptidomics, and single-cell-based immunogenicity testing offers a discriminative and powerful tool for cancer-vaccine development.

title:
  Streamlined selection of cancer antigens for vaccine development through integrative multi-omics and high-content cell imaging

abstract:
  Identification of tumor antigens that induce cytotoxic T lymphocytes (CTLs) is crucial for cancer-vaccine development. Despite their predictive ability, current algorithmic approaches and human leukocyte antigen (HLA)-peptidomic analysis allow limited selectivity. Here, we optimized a method to rapidly screen and identify highly immunogenic epitopes that trigger CTL responses. We used a combined application of this method involving immune-specific signature analysis and HLA-associated peptidomics using samples from six patients with triple-negative breast cancer (TNBC) in order to select immunogenic HLA epitopes for in vitro testing. Additionally, we applied high-throughput imaging at the single-cell level in order to confirm the immunoreactivity of the selected peptides. The results indicated that this method enabled identification of promising CTL peptides capable of inducing antitumor immunity. This platform combining high-resolution computational analysis, HLA-peptidomics, and high-throughput immunogenicity testing allowed rapid and robust identification of highly immunogenic epitopes and represents a powerful technique for cancer-vaccine development.


id: cord-009690-kbwz7xop
author: Toubanaki, Dimitra K.
date: 2020-04-16
txt: ./txt/cord-009690-kbwz7xop.txt
cache: ./cache/cord-009690-kbwz7xop.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162894/
doi: 10.1038/s41598-020-63553-z
summary:
  title: Development of a Nanoparticle-based Lateral Flow Strip Biosensor for Visual Detection of Whole Nervous Necrosis Virus Particles The principle of viral particles detection based on lateral flow biosensor with functionalized nanoparticles is presented in Fig. 1 . Nodavirus intact particles (virions), obtained either from SSN-1 cell culture supernatants or homogenized tissue samples, are directly applied on the LFB. The sample contains the nodavirus particles (virions) and is applied on the conjugation pad next to functionalized gold nanoparticles (Au) with polyclonal anti-nodavirus antibody. Application of that conjugate on the LFB resulted in a strong signal in the control zone, confirming the successful conjugation of anti-nodavirus antibody to Au nanoparticles (Fig. 2e) . To enable on site analysis of nodavirus, we developed and optimized a paper LFB based on gold nanoparticles for easy, specific and sensitive visual detection of nodavirus viral particles (virions) in biological samples.

title:
  Development of a Nanoparticle-based Lateral Flow Strip Biosensor for Visual Detection of Whole Nervous Necrosis Virus Particles

abstract:
  Effective analysis of pathogens causing human and veterinary diseases demands rapid, specific and sensitive detection methods which can be applied in research laboratory setups and in field for routine diagnosis. Paper lateral flow biosensors (LFBs) have been established as attractive tools for such analytical applications. In the present study a prototype LFB was designed for whole particles (virions) detection of nodavirus or fish nervous necrosis virus. Nodavirus is an important threat in the aquaculture industry, causing severe economic losses and environmental problems. The LFB was based on polyclonal antibodies conjugated on gold nanoparticles for signal visualization. Brain and retinas from fish samples were homogenized, centrifuged and the supernatant was directly applied on the LFB. Formation of a red test line was indicative of nodavirus virions presence. Nodavirus visual detection was completed in short time (30 min). Key factors of the LFB development influencing the assays’ detection limit were characterized and the optimum parameters were determined, enabling increased efficiency, excluding non-specific interactions. Therefore, the proposed LFB assay consists a robust, simple, low cost and accurate method for detection of nodavirus virions in fish samples. The proposed biosensor is ideal for development of a commercial kit to be used on aquaculture facilities by fish farmers. It is anticipated that disease monitoring and environmental safety will benefit from the simplification of time consuming and costly procedures.


id: cord-009691-gkynxdz3
author: Rizzato, Cosmeri
date: 2020-04-16
txt: ./txt/cord-009691-gkynxdz3.txt
cache: ./cache/cord-009691-gkynxdz3.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162905/
doi: 10.1038/s41598-020-63463-0
summary:
  The present study revealed that several cagPAI genes from Latin American Western HP strains contains a number of non-synonymous variants in relatively high frequencies which could influence on the clinical outcome. When comparing the frequency of the 520 selected alleles between the isolates from subjects with gastritis and isolates from subjects with IM or GC we found statistically significant differences in allele distribution for three polymorphisms in cagA gene (Q/K427R, N467G and V1041T), three in cagC gene (V22I, V37I, I45V), one in the cagE gene (K981E), one in cagL gene (S10F), one in cagX gene (G11N), one in cagS (G146D), one in cagζ (S35A), three in cagδ (V353I, P406L, N407E) and one in cagβ (N125A) ( Table 2) . In a previous study conducted with amplicon sequencing by 454 for 84 Mexican and 11 Venezuelan samples we reported 10 non-synonymous SNPs with differential allelic distribution between gastritis and gastric cancer at conventional P-values between 0.01-0.05 28 .

title:
  Variations in cag pathogenicity island genes of Helicobacter pylori from Latin American groups may influence neoplastic progression to gastric cancer

abstract:
  Helicobacter pylori (HP) colonizes the human stomach and induces acute gastritis, peptic ulcer disease, atrophic gastritis, and gastric adenocarcinoma. Increased virulence in HP isolates derives from harboring the cag (cytotoxin-associated genes) pathogenicity island (cagPAI). We analyzed the microvariants in cagPAI genes with the hypothesis that they may play an important role in determining HP virulence. We tested DNAs from cagA positive patients HP isolates; a total of 74 patients with chronic gastritis (CG, N = 37), intestinal metaplasia (IM, N = 21) or gastric cancer (GC, N = 16) from Mexico and Colombia. We selected 520 non-synonymous variants with at least 7.5% frequency in the original sequence outputs or with a minimum of 5 isolates with minor allele. After adjustment for multiple comparisons, no variants were statistically significantly associated with IM or GC. However, 19 non-synonymous showed conventional P-values < 0.05 comparing the frequency of the alleles between the isolates from subjects with gastritis and isolates from subjects with IM or GC; 12 of these showed a significant correlation with the severity of the disease. The present study revealed that several cagPAI genes from Latin American Western HP strains contains a number of non-synonymous variants in relatively high frequencies which could influence on the clinical outcome. However, none of the associations remained statistically significant after adjustment for multiple comparison.


id: cord-010140-nl1j2s56
author: Nagaoka, Hikaru
date: 2020-04-20
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171142/
doi: 10.1038/s41598-020-63611-6
title:
  Antibodies against a short region of PfRipr inhibit Plasmodium falciparum merozoite invasion and PfRipr interaction with Rh5 and SEMA7A

abstract:
  Plasmodium falciparum merozoite invasion into erythrocytes is an essential step of the blood-stage cycle, survival of parasites, and malaria pathogenesis. P. falciparum merozoite Rh5 interacting protein (PfRipr) forms a complex with Rh5 and CyRPA in sequential molecular events leading to erythrocyte invasion. Recently we described PfRipr as a conserved protein that induces strain-transcending growth inhibitory antibodies in in vitro assays. However, being a large and complex protein of 1086 amino acids (aa) with 87 cysteine residues, PfRipr is difficult to express in conventional expression systems towards vaccine development. In this study we sought to identify the most potent region of PfRipr that could be developed to overcome difficulties related to protein expression, as well as to elucidate the invasion inhibitory mechanism of anti-PfRipr antibodies. Using the wheat germ cell-free system, Ecto- PfRipr and truncates of approximately 200 aa were expressed as soluble proteins. We demonstrate that antibodies against PfRipr truncate 5 (PfRipr_5: C(720)-D(934)), a region within the PfRipr C-terminal EGF-like domains, potently inhibit merozoite invasion. Furthermore, the antibodies strongly block PfRipr/Rh5 interaction, as well as that between PfRipr and its erythrocyte-surface receptor, SEMA7A. Taken together, PfRipr_5 is a potential candidate for further development as a blood-stage malaria vaccine.


id: cord-010328-uxpedpz8
author: Ciencewicki, Jonathan M.
date: 2020-04-22
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176631/
doi: 10.1038/s41598-020-63794-y
title:
  Plasma Donors in the Southwestern United States Positively Contribute to the Diverse Therapeutic Antibody Profile of Immune Globulin Products

abstract:
  Human-plasma-derived immune globulin (IG) is used in augmentation therapy to provide protective levels of antibodies to patients with primary immune deficiency diseases (PIDD) and for prophylaxis against infectious diseases. To maintain the breadth of antibodies necessary for clinical protection, it is important to understand regional patterns of antibody seroprevalence in source plasma from which IG products are manufactured. In this study, source plasma from donation centers in various locations of the Southwestern quarter of the United States was surveyed for antibody titers to hepatitis A virus (HAV), measles virus (MeV), and cytomegalovirus (CMV). A broad range of anti-HAV Ig plasma titers was observed among these centers, with some centers exhibiting 3–5 times the titers of the others. Minor to no differences were observed for levels of anti-MeV and anti-CMV, respectively. Importantly, elevated anti-HAV Ig titers were broadly observed across plasma units obtained from the centers exhibiting high titers, indicative of a potential regional phenomenon among donors as opposed to few donors with singularly high titers. Plasma from these high-titer centers conferred significantly greater neutralization against HAV in vitro. The outcomes of this study give a glimpse of the antibody diversity inherent in human plasma used to manufacture IG products..


id: cord-010640-s1oqphvn
author: Baral, Prabin
date: 2020-05-06
txt: ./txt/cord-010640-s1oqphvn.txt
cache: ./cache/cord-010640-s1oqphvn.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203123/
doi: 10.1038/s41598-020-63640-1
summary:
  In an effort to discover new LASV vaccines, we employ several sequence-based computational prediction tools to identify LASV GP major histocompatibility complex (MHC) class I and II T-cell epitopes. In this study, we have identified and characterized T and B-cell epitopes for the LASV GP using different sequence and structure-based computational epitope prediction methods. MHC-I T-cell epitope prediction with the LASV GP sequence was performed using three different methods separately: ProPred-1, CTLPred, and NetCTL1.2, and the results are shown in Supplementary Table S1. MHC-II T-cell epitope prediction with the LASV GP sequence was performed using three different methods separately: ProPred, NetMHCII 2.3, and EpiTOP 3.0, and the results are shown in Supplementary Table S2 . Docking of the four consensus MHC-I epitopes (Table 1 ) was performed using Autodock Vina, which enabled the docking of epitopes obtained from the sequence-based MHC-1 T-cell prediction into the promising allele structures.

title:
  In-silico identification of the vaccine candidate epitopes against the Lassa virus hemorrhagic fever

abstract:
  Lassa virus (LASV), a member of the Arenaviridae, is an ambisense RNA virus that causes severe hemorrhagic fever with a high fatality rate in humans in West and Central Africa. Currently, no FDA approved drugs or vaccines are available for the treatment of LASV fever. The LASV glycoprotein complex (GP) is a promising target for vaccine or drug development. It is situated on the virion envelope and plays key roles in LASV growth, cell tropism, host range, and pathogenicity. In an effort to discover new LASV vaccines, we employ several sequence-based computational prediction tools to identify LASV GP major histocompatibility complex (MHC) class I and II T-cell epitopes. In addition, many sequence- and structure-based computational prediction tools were used to identify LASV GP B-cell epitopes. The predicted T- and B-cell epitopes were further filtered based on the consensus approach that resulted in the identification of thirty new epitopes that have not been previously tested experimentally. Epitope-allele complexes were obtained for selected strongly binding alleles to the MHC-I T-cell epitopes using molecular docking and the complexes were relaxed with molecular dynamics simulations to investigate the interaction and dynamics of the epitope-allele complexes. These predictions provide guidance to the experimental investigations and validation of the epitopes with the potential for stimulating T-cell responses and B-cell antibodies against LASV and allow the design and development of LASV vaccines.


id: cord-010675-acdfvjm5
author: Vila-Vicent, Susana
date: 2020-05-08
txt: ./txt/cord-010675-acdfvjm5.txt
cache: ./cache/cord-010675-acdfvjm5.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210269/
doi: 10.1038/s41598-020-64767-x
summary:
  The aims of the present work were to determine the prevalence and titer of serum antibodies against several rotavirus VP8* proteins from different P genotypes in children and adults in Valencia, Spain; and to determine the role of the secretor status (FUT2(G428A) polymorphism) in the antibody response. Significant differences in the antibody titers between secretors and non-secretors were found when the whole viral particles from the Wa rotavirus strain (G1P[8]) were used as the antigen. Sero-epidemiological studies are of importance to elucidate the different viral agents and genotypes that are circulating in a particular area, for this reason the main aim of this work was to determine the serum antibody prevalence and titer to a panel of VP8* proteins from different rotavirus genotypes (P [4] , P [6] , P [8] , P [9] , P [11] , P [14] and P [25] ) in children and adults.

title:
  Sero-epidemiological study of the rotavirus VP8* protein from different P genotypes in Valencia, Spain

abstract:
  The aims of the present work were to determine the prevalence and titer of serum antibodies against several rotavirus VP8* proteins from different P genotypes in children and adults in Valencia, Spain; and to determine the role of the secretor status (FUT2(G428A) polymorphism) in the antibody response. The VP8* protein from the P[4], P[6], P[8], P[9], P[11], P[14] and P[25] genotypes were produced in E. coli. These proteins were tested with 88 serum samples from children (n = 41, 3.5 years old in average) and from adults (n = 47, 58 years old in average) by ELISA. A subset of 55 samples were genotyped for the FUT2(G428A) polymorphism and the antibody titers compared. The same subset of samples was also analysed by ELISA using whole rotavirus Wa particles (G1P[8]) as antigen. Ninety-three per cent of the samples were positive for at least one of the VP8* antigens. Differences in the IgG seroprevalence were found between children and adults for the P[4], P[8] and P[11] genotypes. Similarly, significant differences were found between adults and children in their antibody titers against the P[4], P[8], and P[11] VP8* genotypes, having the children higher antibody titers than adults. Interestingly, positive samples against rare genotypes such as P[11] (only in children), P[14] and P[25] were found. While no statistical differences in the antibody titers between secretors and non-secretors were found for any of the tested P genotypes studied, a higher statistic significant prevalence for the P[25] genotype was found in secretors compared to non-secretors. Significant differences in the antibody titers between secretors and non-secretors were found when the whole viral particles from the Wa rotavirus strain (G1P[8]) were used as the antigen.


id: cord-011892-b9zlig0r
author: Mukherjee, Shradha
date: 2020-07-02
txt: ./txt/cord-011892-b9zlig0r.txt
cache: ./cache/cord-011892-b9zlig0r.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363816/
doi: 10.1038/s41598-020-67753-5
summary:
  In this work, two different network construction algorithms, Weighted correlation network analysis (WGCNA) and Multiscale Clustering of Geometric Network (MEGENA), were applied on publicly available glioma, control brain and stem cell gene expression RNA-seq datasets, to identify gene network regulatory modules associated with GBM. Characterization of HuAgeGBsplit_18 (WGCNA) and c1_HuAgeGBsplit_32/193 (MEGENA) modules showed significant enrichment of rodent quiescent stem cell marker genes (GSE70696_QNPbyTAP). Enrichment of proliferative and quiescent stem cell marker genes identified by differential gene expression analysis above, in WGCNA and MEGENA modules was determined using useListEnrichment R function 22, 23, 46 . showed that HuAgeGBsplit_18 WGCNA GBM module and its equivalent c1_HuAgeGBsplit_193/32 MEGENA GBM modules, were the only GBM modules significantly enriched with proliferative and quiescent stem cell marker genes (Fig. 4A,B) . A meta-analysis was performed on publicly available high-throughput gene expression datasets from human glioma samples, control human brains, normal stem cells and GBM cells in quiescent and proliferative states 18, [26] [27] [28] [29] [30] [31] [32] [33] [34] .

title:
  Quiescent stem cell marker genes in glioma gene networks are sufficient to distinguish between normal and glioblastoma (GBM) samples

abstract:
  Grade 4 glioma or GBM has poor prognosis and is the most aggressive grade of glioma. Accurate diagnosis and classification of tumor grade is a critical determinant for development of treatment pathway. Extensive genomic sequencing of gliomas, different cell types, brain tissue regions and advances in bioinformatics algorithms, have presented an opportunity to identify molecular markers that can complement existing histology and imaging methods used to diagnose and classify gliomas. ‘Cancer stem cell theory’ purports that a minor population of stem cells among the heterogeneous population of different cell types in the tumor, drive tumor growth and resistance to therapies. However, characterization of stem cell states in GBM and ability of stem cell state signature genes to serve as diagnostic or prognostic molecular markers are unknown. In this work, two different network construction algorithms, Weighted correlation network analysis (WGCNA) and Multiscale Clustering of Geometric Network (MEGENA), were applied on publicly available glioma, control brain and stem cell gene expression RNA-seq datasets, to identify gene network regulatory modules associated with GBM. Both gene network algorithms identified consensus or equivalent modules, HuAgeGBsplit_18 (WGCNA) and c1_HuAgeGBsplit_32/193 (MEGENA), significantly associated with GBM. Characterization of HuAgeGBsplit_18 (WGCNA) and c1_HuAgeGBsplit_32/193 (MEGENA) modules showed significant enrichment of rodent quiescent stem cell marker genes (GSE70696_QNPbyTAP). A logistic regression model built with eight of these quiescent stem cell marker genes (GSE70696_QNPbyTAP) was sufficient to distinguish between control and GBM samples. This study demonstrates that GBM associated gene regulatory modules are characterized by diagnostic quiescent stem cell marker genes, which may potentially be used clinically as diagnostic markers and therapeutic targets in GBM.


id: cord-012742-lpk6r54i
title: Snapshots of ADP-ribose bound to Getah virus macro domain reveal an intriguing choreography
author: Ferreira-Ramos, Ana Sofia
date: 2020-09-02
txt: ./txt/cord-012742-lpk6r54i.txt
cache: ./cache/cord-012742-lpk6r54i.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468284/
doi: 10.1038/s41598-020-70870-w
summary:
  Soaking experi-Scientific RepoRtS | (2020) 10:14422 | https://doi.org/10.1038/s41598-020-70870-w www.nature.com/scientificreports/ ments were performed with crystals of GETV macro domain co-crystallized with ADP-ribose by adding mother liquor supplemented with aspartic acid to the crystallization droplet followed by 2-3 h or overnight incubation at 20 °C. Finally, we obtained a last GETV macro domain/ADP-ribose complex by co-crystallizing the protein with 3 mM ADP-ribose and 3 mM aspartic acid and diffraction data were collected to 1.45 Å resolution. Lastly, co-crystallization of GETV macro domain with low concentrations of ADP-ribose and aspartic acid (3 mM each) led to a structure where the distal ribose is covalently attached to Cys34. In addition to the pose of ADP-ribose found in other structures of alphavirus macro domain, this work reveals original features such as the opening of the distal Scientific RepoRtS | (2020) 10:14422 | https://doi.org/10.1038/s41598-020-70870-w www.nature.com/scientificreports/ ribose, and its stabilization by Ser30, representing a peculiar GETV specific substitution in the catalytic loop.

abstract:
  Alphaviruses are (re-)emerging arboviruses of public health concern. The nsP3 gene product is one of the key players during viral replication. NsP3 comprises three domains: a macro domain, a zinc-binding domain and a hypervariable region. The macro domain is essential at both early and late stages of the replication cycle through ADP-ribose (ADPr) binding and de-ADP-ribosylation of host proteins. However, both its specific role and the precise molecular mechanism of de-ADP-ribosylation across specific viral families remains to be elucidated. Here we investigate by X-ray crystallography the mechanism of ADPr reactivity in the active site of Getah virus macro domain, which displays a peculiar substitution of one of the conserved residues in the catalytic loop. ADPr adopts distinct poses including a covalent bond between the C′′1 of the ADPr and a conserved Togaviridae-specific cysteine. These different poses observed for ADPr may represent snapshots of the de-ADP-ribosylation mechanism, highlighting residues to be further characterised.


id: cord-013977-xb0r2axf
author: Heng, Kevin
date: 2020-11-09
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653910/
doi: 10.1038/s41598-020-76563-8
title:
  The approximately universal shapes of epidemic curves in the Susceptible-Exposed-Infectious-Recovered (SEIR) model

abstract:
  Compartmental transmission models have become an invaluable tool to study the dynamics of infectious diseases. The Susceptible-Infectious-Recovered (SIR) model is known to have an exact semi-analytical solution. In the current study, the approach of Harko et al. (Appl. Math. Comput. 236:184–194, 2014) is generalised to obtain an approximate semi-analytical solution of the Susceptible-Exposed-Infectious-Recovered (SEIR) model. The SEIR model curves have nearly the same shapes as the SIR ones, but with a stretch factor applied to them across time that is related to the ratio of the incubation to infectious periods. This finding implies an approximate characteristic timescale, scaled by this stretch factor, that is universal to all SEIR models, which only depends on the basic reproduction number and initial fraction of the population that is infectious.


id: cord-030295-jlhht2l9
author: Cruz-Flores, Roberto
date: 2020-08-10
txt: ./txt/cord-030295-jlhht2l9.txt
cache: ./cache/cord-030295-jlhht2l9.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417530/
doi: 10.1038/s41598-020-70435-x
summary:
  title: Genome reconstruction of white spot syndrome virus (WSSV) from archival Davidson''s-fixed paraffin embedded shrimp (Penaeus vannamei) tissue In this study, the complete genome of white spot syndrome virus (WSSV) was reconstructed from ~ 2-year-old archived Davidson''s-fixed paraffin-embedded (DFPE) shrimp tissue using Next Generation Sequencing (NGS). Archived Davidson''s-fixed paraffin-embedded (DFPE) tissues in the Aquaculture Pathology Laboratory of The University of Arizona are an untapped invaluable resource for pathogen discovery, metagenomic and evolutionary studies to understand the origin, evolution and spread of shrimp pathogens worldwide. Our results confirm that NGS from DNA extracted from DFPE tissue is also a viable approach to detect know viral sequences. The ability to reconstruct DNA viral genomes as large as 300 kbp size from DFPE tissues shows the feasibility to generate baseline genetic data from archived tissue and determine how pathogens have evolved over time.

title:
  Genome reconstruction of white spot syndrome virus (WSSV) from archival Davidson’s-fixed paraffin embedded shrimp (Penaeus vannamei) tissue

abstract:
  Formalin-fixed paraffin-embedded (FFPE) tissues are a priceless resource for diagnostic laboratories worldwide. However, DNA extracted from these tissues is often not optimal for most downstream molecular analysis due to fragmentation and chemical modification. In this study, the complete genome of white spot syndrome virus (WSSV) was reconstructed from ~ 2-year-old archived Davidson’s-fixed paraffin-embedded (DFPE) shrimp tissue using Next Generation Sequencing (NGS). A histological analysis was performed on archived DFPE shrimp tissue and a sample showing a high level of WSSV infection was selected for molecular analysis. The viral infection was further confirmed by molecular methods. DNA isolated from DFPE and fresh frozen (FF) tissues were sequenced by NGS. The complete genome reconstruction of WSSV (~ 305 kbp) was achieved from both DFPE and FF tissue. Single nucleotide polymorphisms, insertion and deletions were compared between the genomes. Thirty-eight mutations were identified in the WSSV genomes from the DFPE and FF that differed from the reference genome. This is the first study that has successfully sequenced the complete genome of a virus of over 300 kbp from archival DFPE tissue. These findings demonstrate that DFPE shrimp tissue represents an invaluable resource for prospective and retrospective studies, evolutionary studies and opens avenues for pathogen discovery.


id: cord-031937-qhlatg84
author: Verma, Anukriti
date: 2020-09-15
txt: ./txt/cord-031937-qhlatg84.txt
cache: ./cache/cord-031937-qhlatg84.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492238/
doi: 10.1038/s41598-020-71674-8
summary:
  In-silico analysis involving text mining, metabolic network reconstruction, simulation, filtering, host-microbe interaction, docking and molecular mimicry studies results in robust drug target/s and biomarker/s for co-evolved IBD and ReA. The contributions of the microorganisms in the co-evolved IBD and ReA as part of the disease network was created through the interactive maps of the essential host interaction proteins (verified using literature survey) and the information processed through gene expression data analysis 64 . The pathways of the above host interacting proteins were found out using KEGG database that provides ontologies for proteins related to biological processes 67 www.nature.com/scientificreports/ Subsequently, the role of drugs or inhibitors used to suppress the effect of IBD and ReA such as indomethacin, prednisone, ciprofloxacin, sulfasalazine, azathioprine, methotrexate and hydroxychloroquine was scored in the disease network through their docking studies against the potential targets (both host as well microbial targets) as per published methodologies 68, 69 .

title:
  Elucidating potential molecular signatures through host-microbe interactions for reactive arthritis and inflammatory bowel disease using combinatorial approach

abstract:
  Reactive Arthritis (ReA), a rare seronegative inflammatory arthritis, lacks exquisite classification under rheumatic autoimmunity. ReA is solely established using differential clinical diagnosis of the patient cohorts, where pathogenic triggers linked to enteric and urogenital microorganisms e.g. Salmonella, Shigella, Yersinia, Campylobacter, Chlamydia have been reported. Inflammatory Bowel Disease (IBD), an idiopathic enteric disorder co-evolved and attuned to present gut microbiome dysbiosis, can be correlated to the genesis of enteropathic arthropathies like ReA. Gut microbes symbolically modulate immune system homeostasis and are elementary for varied disease patterns in autoimmune disorders. The gut-microbiota axis structured on the core host-microbe interactions execute an imperative role in discerning the etiopathogenesis of ReA and IBD. This study predicts the molecular signatures for ReA with co-evolved IBD through the enveloped host-microbe interactions and microbe-microbe ‘interspecies communication’, using synonymous gene expression data for selective microbes. We have utilized a combinatorial approach that have concomitant in-silico work-pipeline and experimental validation to corroborate the findings. In-silico analysis involving text mining, metabolic network reconstruction, simulation, filtering, host-microbe interaction, docking and molecular mimicry studies results in robust drug target/s and biomarker/s for co-evolved IBD and ReA. Cross validation of the target/s or biomarker/s was done by targeted gene expression analysis following a non-probabilistic convenience sampling. Studies were performed to substantiate the host-microbe disease network consisting of protein-marker-symptom/disease-pathway-drug associations resulting in possible identification of vital drug targets, biomarkers, pathways and inhibitors for IBD and ReA. Our study identified Na((+))/H((+)) anti-porter (NHAA) and Kynureninase (KYNU) to be robust early and essential host-microbe interacting targets for IBD co-evolved ReA. Other vital host-microbe interacting genes, proteins, pathways and drugs include Adenosine Deaminase (ADA), Superoxide Dismutase 2 (SOD2), Catalase (CAT), Angiotensin I Converting Enzyme (ACE), carbon metabolism (folate biosynthesis) and methotrexate. These can serve as potential prognostic/theranostic biomarkers and signatures that can be extrapolated to stratify ReA and related autoimmunity patient cohorts for further pilot studies.


id: cord-034746-uxhpufnv
author: Nusshag, Christian
date: 2020-11-05
txt: ./txt/cord-034746-uxhpufnv.txt
cache: ./cache/cord-034746-uxhpufnv.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644703/
doi: 10.1038/s41598-020-76050-0
summary:
  We therefore analyzed standard markers of glomerular proteinuria (e.g. immunoglobulin G [IgG]), urinary nephrin excretion (podocyte injury) and serum levels of the soluble urokinase plasminogen activator receptor (suPAR), a proposed pathomechanically involved molecule in INS, in PUUV-infected patients. On admission, patients suffering from hantavirus infection showed significantly increased urinary nephrin, IgG, α1-MG and serum suPAR levels compared to healthy controls (Fig. 3A ). Though, urinary biomarker levels decreased in both groups over time, patients with severe PCR showed significantly higher levels of nephrin, IgG, ACR and PCR during the first 48 h after admission ( Table 2 ). Our data show a strong association between urinary nephrin levels and the extent of (non-selective) glomerular proteinuria, suggesting that hantavirus infection causes a pronounced podocyte damage and subsequent impairment of the GFB. To date, one other study showed significantly elevated blood suPAR levels and their association with hantavirus disease severity but did not include nephrinuria and the extent of proteinuria in their analysis 19 .

title:
  Glomerular filtration barrier dysfunction in a self-limiting, RNA virus-induced glomerulopathy resembles findings in idiopathic nephrotic syndromes

abstract:
  Podocyte injury has recently been described as unifying feature in idiopathic nephrotic syndromes (INS). Puumala hantavirus (PUUV) infection represents a unique RNA virus-induced renal disease with significant proteinuria. The underlying pathomechanism is unclear. We hypothesized that PUUV infection results in podocyte injury, similar to findings in INS. We therefore analyzed standard markers of glomerular proteinuria (e.g. immunoglobulin G [IgG]), urinary nephrin excretion (podocyte injury) and serum levels of the soluble urokinase plasminogen activator receptor (suPAR), a proposed pathomechanically involved molecule in INS, in PUUV-infected patients. Hantavirus patients showed significantly increased urinary nephrin, IgG and serum suPAR concentrations compared to healthy controls. Nephrin and IgG levels were significantly higher in patients with severe proteinuria than with mild proteinuria, and nephrin correlated strongly with biomarkers of glomerular proteinuria over time. Congruently, electron microcopy analyses showed a focal podocyte foot process effacement. suPAR correlated significantly with urinary nephrin, IgG and albumin levels, suggesting suPAR as a pathophysiological mediator in podocyte dysfunction. In contrast to INS, proteinuria recovered autonomously in hantavirus patients. This study reveals podocyte injury as main cause of proteinuria in hantavirus patients. A better understanding of the regenerative nature of hantavirus-induced glomerulopathy may generate new therapeutic approaches for INS.


id: cord-254090-x8tnweih
author: Yang, Szu-Chi
date: 2015-12-09
txt: ./txt/cord-254090-x8tnweih.txt
cache: ./cache/cord-254090-x8tnweih.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/26647655/
doi: 10.1038/srep18030
summary:
  It is interesting to notice that the required threshold electric field magnitudes at the resonant frequency (86.9 V/m) to fracture H3N2 viruses as shown in Fig. 3 (c) are within the IEEE Microwave Safety Standard (106 V/m), indicating high SRET efficiency, even though the quality factor of the H3N2 virus is low. To further investigate the efficiency of this SRET effect from microwave to virus and the threshold effect, we further measured the inactivation ratio of H3N2 virus with different power densities at the resonant frequency ~8 GHz of the confined acoustic dipolar mode. Second, at the resonant frequency, we do observe H3N2 virus inactivation by illuminating 82 W/m 2 (lower than the IEEE safety standard in public space) 8 GHz microwaves on our viral solution, corresponding to an average 87 V/m electric field intensity inside the solution, confirming that our proposed simple model to estimate the field threshold (86.9 V/m) to structurally fracture the virus is quantitatively correct, especially combining the observed threshold effect as discussed above.

title:
  Efficient Structure Resonance Energy Transfer from Microwaves to Confined Acoustic Vibrations in Viruses

abstract:
  Virus is known to resonate in the confined-acoustic dipolar mode with microwave of the same frequency. However this effect was not considered in previous virus-microwave interaction studies and microwave-based virus epidemic prevention. Here we show that this structure-resonant energy transfer effect from microwaves to virus can be efficient enough so that airborne virus was inactivated with reasonable microwave power density safe for the open public. We demonstrate this effect by measuring the residual viral infectivity of influenza A virus after illuminating microwaves with different frequencies and powers. We also established a theoretical model to estimate the microwaves power threshold for virus inactivation and good agreement with experiments was obtained. Such structure-resonant energy transfer induced inactivation is mainly through physically fracturing the virus structure, which was confirmed by real-time reverse transcription polymerase chain reaction. These results provide a pathway toward establishing a new epidemic prevention strategy in open public for airborne virus.


id: cord-254653-4ffuivil
title: The COVID-19 social media infodemic
author: Cinelli, Matteo
date: 2020-10-06
txt: ./txt/cord-254653-4ffuivil.txt
cache: ./cache/cord-254653-4ffuivil.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33024152/
doi: 10.1038/s41598-020-73510-5
summary:
  We address the diffusion of information about the COVID-19 with a massive data analysis on Twitter, Instagram, YouTube, Reddit and Gab. We analyze engagement and interest in the COVID-19 topic and provide a differential assessment on the evolution of the discourse on a global scale for each platform and their users. We fit information spreading with epidemic models characterizing the basic reproduction number [Formula: see text] for each social media platform. Unlike previous works, we do not only focus on models that imply specific growth mechanisms, but also on phenomenological models that emphasize the reproducibility of empirical data 41 www.nature.com/scientificreports/ Most of the epidemiological models focus on the basic reproduction number R 0 , representing the expected number of new infectors directly generated by an infected individual for a given time period 42 . Furthermore, we model the spread of information using epidemic models and provide basic growth parameters for each social media platform.

abstract:
  We address the diffusion of information about the COVID-19 with a massive data analysis on Twitter, Instagram, YouTube, Reddit and Gab. We analyze engagement and interest in the COVID-19 topic and provide a differential assessment on the evolution of the discourse on a global scale for each platform and their users. We fit information spreading with epidemic models characterizing the basic reproduction number [Formula: see text] for each social media platform. Moreover, we identify information spreading from questionable sources, finding different volumes of misinformation in each platform. However, information from both reliable and questionable sources do not present different spreading patterns. Finally, we provide platform-dependent numerical estimates of rumors’ amplification.


id: cord-255511-nk3iyg07
title: Spatial super-spreaders and super-susceptibles in human movement networks
author: Chin, Wei Chien Benny
date: 2020-10-29
txt: ./txt/cord-255511-nk3iyg07.txt
cache: ./cache/cord-255511-nk3iyg07.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-75697-z
doi: 10.1038/s41598-020-75697-z
summary:
  Here, we propose a quantitative and systematic framework to identify spatial super-spreaders and the novel concept of super-susceptibles, i.e. respectively, places most likely to contribute to disease spread or to people contracting it. We applied this analysis framework to the Singapore public transport flow network, and identified the SSP and SSS using the SUI and SPI indexes. This study uses a community detection method (MapEquation algorithm 60 ) to identify the zones from the flow network, instead of using the administrative spatial boundaries (i.e. the boundaries of planning areas and regions as defined by the Singapore Government in its Master Plan 2014 59 ) that were designed and selected for governance and political purposes. Figure 7 shows the local out-and in-degree (left column), the outgoing and incoming neighborhood zone-entropy (central column) and coreness-entropy (right column) of the weekday (first two rows) and weekend (bottom two rows) flow networks.

abstract:
  As lockdowns and stay-at-home orders start to be lifted across the globe, governments are struggling to establish effective and practical guidelines to reopen their economies. In dense urban environments with people returning to work and public transportation resuming full capacity, enforcing strict social distancing measures will be extremely challenging, if not practically impossible. Governments are thus paying close attention to particular locations that may become the next cluster of disease spreading. Indeed, certain places, like some people, can be “super-spreaders”. Is a bustling train station in a central business district more or less susceptible and vulnerable as compared to teeming bus interchanges in the suburbs? Here, we propose a quantitative and systematic framework to identify spatial super-spreaders and the novel concept of super-susceptibles, i.e. respectively, places most likely to contribute to disease spread or to people contracting it. Our proposed data-analytic framework is based on the daily-aggregated ridership data of public transport in Singapore. By constructing the directed and weighted human movement networks and integrating human flow intensity with two neighborhood diversity metrics, we are able to pinpoint super-spreader and super-susceptible locations. Our results reveal that most super-spreaders are also super-susceptibles and that counterintuitively, busy peripheral bus interchanges are riskier places than crowded central train stations. Our analysis is based on data from Singapore, but can be readily adapted and extended for any other major urban center. It therefore serves as a useful framework for devising targeted and cost-effective preventive measures for urban planning and epidemiological preparedness.


id: cord-255586-wshvvgxg
title: Clinical characteristics of “re-positive” discharged COVID-19 pneumonia patients in Wuhan, China
author: He, Shengyang
date: 2020-10-15
txt: ./txt/cord-255586-wshvvgxg.txt
cache: ./cache/cord-255586-wshvvgxg.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-74284-6
doi: 10.1038/s41598-020-74284-6
summary:
  The demographic features, clinical symptoms, laboratory results, comorbidities, co-infections, treatments, illness severities and chest CT scan results of 267 patients were collected from 1st January to 15th February 2020. | (2020) 10:17365 | https://doi.org/10.1038/s41598-020-74284-6 www.nature.com/scientificreports/ disease progression, no differences were found, suggesting this group of COVID-19 patients could be difficult to detect by using standard clinical data. All raw clinical and laboratory results were collected from electronic medical records system of the Central Hospital of Wuhan, followed by a follow up visit up to 14 days (also known as the discharge quarantine) to test for a re-positive nucleic acid assay. Definition of "re-positive": when a confirmed COVID-19 patient is detected SARS-CoV-2 RNA positive during the 14 days post-discharge quarantine (random test timing). Since understanding of the mechanisms of SARS-CoV-2 infection is still lacking, a careful discharge protocol should be applied (e.g. negative results of the nucleic acid tests of respiratory pathogens for 3 consecutive times), and post-discharge quarantine should be strictly observed, especially for severe and critical COVID-19 patients.

abstract:
  To analyze the clinical characteristics of re-positive discharged COVID-19 patients and find distinguishing markers. The demographic features, clinical symptoms, laboratory results, comorbidities, co-infections, treatments, illness severities and chest CT scan results of 267 patients were collected from 1st January to 15th February 2020. COVID-19 was diagnosed by RT-PCR. Clinical symptoms and nucleic acid test results were collected during the 14 days post-hospitalization quarantine. 30 out of 267 COVID-19 patients were detected re-positive during the post-hospitalization quarantine. Re-positive patients could not be distinguished by demographic features, clinical symptoms, laboratory results, comorbidities, co-infections, treatments, chest CT scan results or subsequent clinical symptoms. However, re-positive rate was found to be correlated to illness severity, according the Acute Physiology and Chronic Health Evaluation II (APACHE II) severity-of-disease classification system, and the confusion, urea, respiratory rate and blood pressure (CURB-65) score. Common clinical characteristics were not able to distinguish re-positive patients. However, severe and critical cases classified high according APACHE II and CURB-65 scores, were more likely to become re-positive after discharge.


id: cord-258678-0atfsivf
title: A Universal Protein Tag for Delivery of SiRNA-Aptamer Chimeras
author: Liu, Hong Yan
date: 2013-11-07
txt: ./txt/cord-258678-0atfsivf.txt
cache: ./cache/cord-258678-0atfsivf.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/24196104/
doi: 10.1038/srep03129
summary:
  Here, we report the development of a small and simple protein tag that complements the therapeutic and targeting functionalities of chimera with two functional domains: a dsRNA binding domain (dsRBD) for siRNA docking and a pH-dependent polyhistidine to disrupt endosomal membrane. Therefore, it is of critical importance to design a delivery system that is simple for potential regulatory approval and mass production, universal for all siRNAaptamer chimera, neutral and siRNA-binding specific to ensure aptamer targeting, and small to avoid major alteration of chimera''s biodistribution profile. To assess their dsRNA binding activity, siRNA-aptamer chimera labeled with fluorophore FAM were incubated with the protein tags and probed with gel electrophoresis (1% agarose). To evaluate the targeting specificity of the aptamer block, PSMA-positive LNCaP cells and PSMA-negative PC3 cells were treated with complex of chimera and dsRBD-His 18 (chimera/protein tag molar ratio at 152, 100 nM chimera) in serum free medium for 2 hours, followed by incubation in complete medium for another 12 h.

abstract:
  siRNA-aptamer chimeras have emerged as one of the most promising approaches for targeted delivery of siRNA due to the modularity of their diblock RNA structure, relatively lower cost over other targeted delivery approaches, and, most importantly, the outstanding potential for clinical translation. However, additional challenges must be addressed for efficient RNA interference (RNAi), in particular, endosomal escape. Currently, vast majority of siRNA delivery vehicles are based on cationic materials, which form complexes with negatively charged siRNA. Unfortunately, these approaches complicate the formulations again by forming large complexes with heterogeneous sizes, unfavorable surface charges, colloidal instability, and poor targeting ligand orientation. Here, we report the development of a small and simple protein tag that complements the therapeutic and targeting functionalities of chimera with two functional domains: a dsRNA binding domain (dsRBD) for siRNA docking and a pH-dependent polyhistidine to disrupt endosomal membrane. The protein selectively tags along the siRNA block of individual chimera, rendering the overall size of the complex small, desirable for deep tissue penetration, and the aptamer block accessible for target recognition. More interestingly, we found that extending the c-terminal polyhistidine segment in the protein tag to 18 amino acids completely abolishes the RNA binding function of dsRBD.


id: cord-259378-5g2y68i2
title: Small-volume point-of-care analytical methods
author: Cheng, Chao-Min
date: 2020-08-27
txt: ./txt/cord-259378-5g2y68i2.txt
cache: ./cache/cord-259378-5g2y68i2.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-70903-4
doi: 10.1038/s41598-020-70903-4
summary:
  With recent technological advances in multiple research fields-such as materials science, micro-/nano-technology, cellular and molecular biology, and bioengineering-attention is shifting toward the development of new diagnostic tools that not only address needs for high sensitivity and specificity, but that fulfill economic, environmental, and rapid point-of-care (POC) needs, for groups and individuals with constrained resources and, possibly, limited training. This pump accepted commonly available silicone rubber tubing in a range of sizes, from 1.5 to 3 mm, and was capable of producing flow rates up to 1.6 mL/min 6 www.nature.com/scientificreports/ microfluidic technologies may be used for a variety of POC diagnostic applications (e.g., infectious diseases, COVID-19 diagnosis) because they are disposable, inexpensive, portable, and easy to use, especially when they are manufactured using low-cost materials such as paper (and other materials such as cotton or bamboo 7, 8 ).

abstract:
  Detecting clinically relevant diagnostic biomarkers, suitable for point-of-care detection, may facilitate rapid treatment and prevention of disease. However, medical diagnosis for which there are limited quantities of testable tissue or fluid, require point-of-care technologies with superior sensitivity and specificity. The purpose of this Editorial is to provide an overview of the Collection’s content, comprising original research into fluidics-based diagnostic platforms—specifically those made of paper or other low-cost materials, that can suitably operate with tiny sample volumes from mL to nL. In particular, we will focus on the clinical applications of such research, with potential uses in a number of fields including combating the COVID-19 pandemic for instance.


id: cord-259416-gvzp2h5g
title: Combined approaches of EPR and NMR illustrate only one transmembrane helix in the human IFITM3
author: Ling, Shenglong
date: 2016-04-05
txt: ./txt/cord-259416-gvzp2h5g.txt
cache: ./cache/cord-259416-gvzp2h5g.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/27046158/
doi: 10.1038/srep24029
summary:
  Systematic site-directed spin labeling (SDSL) and electron paramagnetic resonance (EPR) studies of IFITM3 in detergent micelles identified a single, long transmembrane helix in the C-terminus and an intramembrane segment in the N-terminal hydrophobic region. Systematic site scanning of spin labeling, EPR dynamic and accessibility analysis identified a C-terminal transmembrane α -helix and an N-terminal IFITM3 segment (composed of two short α -helices) lying on the surface of micelles. Collectively, the analysis of the accessibility parameter (Π O2 and Π NiEDDA ) and the immersion depth parameter (Φ ) derived from the power saturation experiments demonstrated that the IFITM3 protein contains a long transmembrane α -helix covering the residue sequence from A96 to A131 in the putative hydrophobic region. Therefore, the combined EPR and solution NMR studies clearly supported the type II transmembrane protein topology model for IFITM3, which is consistent with the previously proposed mechanism of its antiviral function.

abstract:
  Interferon-inducible transmembrane protein IFITM3 was known to restrict the entry of a wide spectrum of viruses to the cytosol of the host. The mechanism used by the protein to restrict viral entry is unclear given the unavailability of the membrane topology and structures of the IFITM family proteins. Systematic site-directed spin labeling (SDSL) and electron paramagnetic resonance (EPR) studies of IFITM3 in detergent micelles identified a single, long transmembrane helix in the C-terminus and an intramembrane segment in the N-terminal hydrophobic region. Solution NMR studies of the same sample verified the secondary structure distribution and demonstrated two rigid regions interacting with the micellar surface. The resulting membrane topology of IFITM3 supports the mechanism of an enhanced restricted membrane hemi-fusion.


id: cord-259794-6qoksn00
author: Shi, Da
date: 2017-01-03
txt: ./txt/cord-259794-6qoksn00.txt
cache: ./cache/cord-259794-6qoksn00.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/28045037/
doi: 10.1038/srep39700
summary:
  Porcine epidemic diarrhea virus (PEDV) replicates in the cytoplasm of infected cells, but its nucleocapsid (N) protein localizes specifically to the nucleolus. The results suggest potential linkages among viral strategies for the regulation of cell survival activities, possibly through an interaction of N protein with NPM1 which prevents its proteolytic cleavage and enhances cell survival, thus ultimately promoting the replication of PEDV. In this study, to determine the intracellular distribution of N protein at the protein level, PEDV-infected Vero E6 cells were lysed, separated into nuclear and cytoplasmic fractions, and analyzed by western blotting. This study was based on different lines of evidence, reflecting both in vivo and in vitro situations, and demonstrated that PEDV N protein is able to associate with the major nucleolar protein NPM1 of Vero E6 cells (Fig. 2) ; we failed to detect an interaction with the fibrillarin or nucleolin (See Supplementary Fig. S2 ).

title:
  Nucleocapsid Interacts with NPM1 and Protects it from Proteolytic Cleavage, Enhancing Cell Survival, and is Involved in PEDV Growth

abstract:
  Porcine epidemic diarrhea virus (PEDV) replicates in the cytoplasm of infected cells, but its nucleocapsid (N) protein localizes specifically to the nucleolus. The mechanism of nuclear translocation, and whether N protein associates with particular nucleolar components, is unknown. In this study, we confirm that a nucleolar phosphoprotein nucleophosmin (NPM1) interacts and co-localizes with the N protein in the nucleolus. In vitro binding studies indicated that aa 148–294 of N and aa 118–188 of NPM1 were required for binding. Interestingly, N protein importation into the nucleolus is independent of the ability of NPM1 to shuttle between the nucleus and the cytoplasm. Furthermore, overexpression of NPM1 promoted PEDV growth, while knockdown of NPM1 suppressed PEDV growth. In addition, binding of N protein to NPM1 protects it from proteolytic degradation by caspase-3, leading to increased cell survival. Taken together, our studies demonstrate a specific interaction of the N protein with the host cell protein NPM1 in the nucleolus. The results suggest potential linkages among viral strategies for the regulation of cell survival activities, possibly through an interaction of N protein with NPM1 which prevents its proteolytic cleavage and enhances cell survival, thus ultimately promoting the replication of PEDV.


id: cord-260834-v254de8k
author: Lim, Chia Chiu
date: 2019-04-15
txt: ./txt/cord-260834-v254de8k.txt
cache: ./cache/cord-260834-v254de8k.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/30988390/
doi: 10.1038/s41598-019-42628-6
summary:
  The phage ELISA was conducted to measure the performances and effects of different blocking agents on the binding of αUbi phages against crude rUbi. Out of the four samples, the combination of PTM buffer and lysate showed the highest signal (1.226) detected with anti-c-myc-HRP as shown in Fig. 4c . Lysate preblocking and phage preincubation effects towards αUbi and M13KO7 phages against rUbi. To further optimize the biopanning conditions against crude antigens, the ''Yin-Yang'' (capture and eliminate) approach was designed to reduce non-specific binding by background phages. coli proteins in the crude fraction of rUbi with the actual concentration of rUbi being expected to be lower than the purified rUbi, the binding capability of αUbi is still unaffected as shown in phage ELISA assay upon affinity selection against crude rUbi. The blocking effect of PTM and E.

title:
  Development of a Phage Display Panning Strategy Utilizing Crude Antigens: Isolation of MERS-CoV Nucleoprotein human antibodies

abstract:
  Antibody phage display has been pivotal in the quest to generate human monoclonal antibodies for biomedical and research applications. Target antigen preparation is a main bottleneck associated with the panning process. This includes production complexity, downstream purification, quality and yield. In many instances, purified antigens are preferred for panning but this may not be possible for certain difficult target antigens. Here, we describe an improved procedure of affinity selection against crude or non-purified antigen by saturation of non-binders with blocking agents to promote positive binder enrichment termed as Yin-Yang panning. A naïve human scFv library with kappa light chain repertoire with a library size of 10(9) was developed. The improved Yin-Yang biopanning process was able to enrich monoclonal antibodies specific to the MERS-CoV nucleoprotein. Three unique monoclonal antibodies were isolated in the process. The Yin-Yang biopanning method highlights the possibility of utilizing crude antigens for the isolation of monoclonal antibodies by phage display.


id: cord-263088-zj14ro5j
author: DiPaola, Joshua D.
date: 2020-06-17
txt: ./txt/cord-263088-zj14ro5j.txt
cache: ./cache/cord-263088-zj14ro5j.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-65898-x
doi: 10.1038/s41598-020-65898-x
summary:
  All trials across the ''olfactory'' , ''visual'' , and ''acoustic'' conditions of phase I were pseudo-randomised within a session so that each session consisted of an equal number of trials of left and right correct choices (based on the side of the chamber in which a container was placed), no one side was baited with food more than three consecutive times in a row, and the first three trials for each session across all conditions were always tests rather than controls to avoid a frustration effect. Phase I control containers (i.e., opaque with solid lids) were used as the stimulus containers in the test trials for this condition as we wanted the subject to make olfactory decisions based on the trail scent without being influenced by the odor of the food inside the container.

title:
  Investigating the use of sensory information to detect and track prey by the Sunda pangolin (Manis javanica) with conservation in mind

abstract:
  Pangolins are of conservation concern as one of the most heavily poached, yet least understood mammals. The Sunda pangolin (Manis javanica) in particular is a critically endangered species. Here, we investigate the behaviour of these pangolins, for the first time, using a battery of cognitive tasks based on a manipulation of available sensory information. In an object-choice task in which only one of two containers was baited with food, the pangolins were able to find the food with olfactory information alone (N = 2), but not with visual or acoustic information alone (N = 1). The single subject tested on all three domains was further tested on how he used smell to find food by providing him with an opportunity to find it from a controlled distance or by using scent trails as a guide. The results suggest that our subject may have the capacity to exploit scent trails left by prey which can be tracked to a final source, though we found no evidence to suggest that he had the ability to initiate hunts based on distant prey odors. Despite the small sample size, this is the first controlled experiment to investigate pangolin foraging behaviour and cognition, which may have implications for the future protection of pangolin habitat based on the location of prey species.


id: cord-263627-8ufjh70o
title: Covid-19 mortality is negatively associated with test number and government effectiveness
author: Liang, Li-Lin
date: 2020-07-24
txt: ./txt/cord-263627-8ufjh70o.txt
cache: ./cache/cord-263627-8ufjh70o.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/32709854/
doi: 10.1038/s41598-020-68862-x
summary:
  Covid-19 mortality rate was negatively associated with Covid-19 test number per 100 people (RR = 0.92, P = 0.001), government effectiveness score (RR = 0.96, P = 0.017), and number of hospital beds (RR = 0.85, P < 0.001). Furthermore, the negative association between Covid-19 mortality and test number was stronger among low-income countries and countries with lower government effectiveness scores, younger populations and fewer hospital beds. In the multiple regression analysis, Covid-19 mortality rate was regressed on Covid-19 test number, case number, critical case rate, government effectiveness score, proportion of population aged 65 or older, number of beds, deaths attributable to communicable diseases, and transport infrastructure quality score. Figure 1e and 1f exhibits that the negative correlation between Covid-19 mortality rate and test number was significant for countries with moderate (r = -0.33, P = 0.021) and low (r = − 0.42, P = 0.002) government effectiveness scores, respectively.

abstract:
  A question central to the Covid-19 pandemic is why the Covid-19 mortality rate varies so greatly across countries. This study aims to investigate factors associated with cross-country variation in Covid-19 mortality. Covid-19 mortality rate was calculated as number of deaths per 100 Covid-19 cases. To identify factors associated with Covid-19 mortality rate, linear regressions were applied to a cross-sectional dataset comprising 169 countries. We retrieved data from the Worldometer website, the Worldwide Governance Indicators, World Development Indicators, and Logistics Performance Indicators databases. Covid-19 mortality rate was negatively associated with Covid-19 test number per 100 people (RR = 0.92, P = 0.001), government effectiveness score (RR = 0.96, P = 0.017), and number of hospital beds (RR = 0.85, P < 0.001). Covid-19 mortality rate was positively associated with proportion of population aged 65 or older (RR = 1.12, P < 0.001) and transport infrastructure quality score (RR = 1.08, P = 0.002). Furthermore, the negative association between Covid-19 mortality and test number was stronger among low-income countries and countries with lower government effectiveness scores, younger populations and fewer hospital beds. Predicted mortality rates were highly associated with observed mortality rates (r = 0.77; P < 0.001). Increasing Covid-19 testing, improving government effectiveness and increasing hospital beds may have the potential to attenuate Covid-19 mortality.


id: cord-265211-a7whyds8
author: Hussein, Hosni A. M.
date: 2017-12-21
txt: ./txt/cord-265211-a7whyds8.txt
cache: ./cache/cord-265211-a7whyds8.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-017-18225-w
doi: 10.1038/s41598-017-18225-w
summary:
  title: miRNA-36 inhibits KSHV, EBV, HSV-2 infection of cells via stifling expression of interferon induced transmembrane protein 1 (IFITM1) In this study, we show the ability of host cell novel miR-36 to specifically inhibit KSHV-induced expression of interferon induced transmembrane protein 1 (IFITM1) to limit virus infection of cells. Transfecting cells with miR-36 mimic specifically lowered IFITM1 expression and thereby significantly dampening KSHV infection. The doses of the mimic In panels ''C and D'' , Student t test was performed to study the effect of HS and compare infection of cells with KSHV versus UV.KSHV on miR-36 expression at 5, 10, 15, and 30 min PI. Transfection of BJAB (Fig. 2C ) and HMVEC-d (Fig. 2D ) cells with miR-36 mimic significantly reduced KSHV infection of cells as monitored by the expression of ORF50 gene as early as 30 min PI. Interestingly, the effect of miR-36 mimic on KSHV infection of BJAB and HMVEC-d cells could be significantly reversed by co-transfecting cells with 10 nM of miR-36 inhibitor (Fig. 2E ).

title:
  miRNA-36 inhibits KSHV, EBV, HSV-2 infection of cells via stifling expression of interferon induced transmembrane protein 1 (IFITM1)

abstract:
  Kaposi’s sarcoma-associated herpesvirus (KSHV) is etiologically associated with all forms of Kaposi’s sarcoma worldwide. Little is currently known about the role of microRNAs (miRNAs) in KSHV entry. We recently demonstrated that KSHV induces a plethora of host cell miRNAs during the early stages of infection. In this study, we show the ability of host cell novel miR-36 to specifically inhibit KSHV-induced expression of interferon induced transmembrane protein 1 (IFITM1) to limit virus infection of cells. Transfecting cells with miR-36 mimic specifically lowered IFITM1 expression and thereby significantly dampening KSHV infection. In contrast, inhibition of miR-36 using miR-36 inhibitor had the direct opposite effect on KSHV infection of cells, allowing enhanced viral infection of cells. The effect of miR-36 on KSHV infection of cells was at a post-binding stage of virus entry. The highlight of this work was in deciphering a common theme in the ability of miR-36 to regulate infection of closely related DNA viruses: KSHV, Epstein-Barr virus (EBV), and herpes simplexvirus-2 (HSV-2). Taken together, we report for the first time the ability of host cell miRNA to regulate internalization of KSHV, EBV, and HSV-2 in hematopoietic and endothelial cells.


id: cord-265891-jmpterrj
title: Cost–benefit of limited isolation and testing in COVID-19 mitigation
author: Eilersen, Andreas
date: 2020-10-29
txt: ./txt/cord-265891-jmpterrj.txt
cache: ./cache/cord-265891-jmpterrj.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33122753/
doi: 10.1038/s41598-020-75640-2
summary:
  Therefore, we will here implement a crude form of contact tracing where we (1) close the workplaces of people who are tested positive for the disease, (2) isolate their regular social contacts for a limited period, and (3) keep symptomatic individuals in quarantine until they recover. If 10% efficiency is possible, corresponding to detecting about a third of infectious cases, then peak height could be reduced by a factor of almost three with to a 60% drop, if the probability of infected people being tested is only 10% per day of illness. In Fig. 4 , we show two possible scenarios where testing and contact tracing is implemented after a 30-day lockdown with a 75% reduction of the work and social spheres. Using reasonable COVID-19 infection parameters we find that the 1STQ strategy can contribute to epidemic mitigation, in the sense that it can reduce the peak number of infected individuals by about a factor of two even with a realistic testing rate of 10% per day of illness.

abstract:
  The international community has been put in an unprecedented situation by the COVID-19 pandemic. Creating models to describe and quantify alternative mitigation strategies becomes increasingly urgent. In this study, we propose an agent-based model of disease transmission in a society divided into closely connected families, workplaces, and social groups. This allows us to discuss mitigation strategies, including targeted quarantine measures. We find that workplace and more diffuse social contacts are roughly equally important to disease spread, and that an effective lockdown must target both. We examine the cost–benefit of replacing a lockdown with tracing and quarantining contacts of the infected. Quarantine can contribute substantially to mitigation, even if it has short duration and is done within households. When reopening society, testing and quarantining is a strategy that is much cheaper in terms of lost workdays than a long lockdown. A targeted quarantine strategy is quite efficient with only 5 days of quarantine, and its effect increases when testing is more widespread.


id: cord-268414-7fcc5i7i
author: Hassani, Abdelkader
date: 2020-10-20
txt: ./txt/cord-268414-7fcc5i7i.txt
cache: ./cache/cord-268414-7fcc5i7i.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33082415/
doi: 10.1038/s41598-020-71175-8
summary:
  The formulated nanoparticles (GANPs) were characterized for physicochemical properties and size and were then evaluated for antioxidant and antihypertensive effects using various established in vitro assays, including 1,1-diphenyl-2-picrylhydrazyl (DPPH), nitric oxide scavenging (NO), β-carotene bleaching and angiotensin-converting enzyme (ACE) inhibitory assays. This study is the first to confirm the synergistic effects of gum arabic in the encapsulation of gallic acid by increasing the selectivity towards cancer cells and enhancing the antioxidant properties. According to the results, significant cytotoxicity was elicited among the HepG2, MCF7, MDA-MB231, and HT29 cell lines after treatment with IC 50 concentrations of free and nano encapsulated gallic acid as shown in Fig. 12 . The MDA-MB231 and HT29 cells had a lower fluorescence intensity of PI attributed to the lower toxicity of GA/C6NPs. www.nature.com/scientificreports/ The migration assay was carried out to assess the effect of GANPS and free GA with the IC 50 value of concentrations on MCF7, MDA-MB-231, HepG2, and HT29.

title:
  Preparation, characterization and therapeutic properties of gum arabic-stabilized gallic acid nanoparticles

abstract:
  Gallic acid (GA) is a natural phenolic compound with therapeutic effects that are often challenged by its rapid metabolism and clearance. Therefore, GA was encapsulated using gum arabic into nanoparticles to increase its bioavailability. The formulated nanoparticles (GANPs) were characterized for physicochemical properties and size and were then evaluated for antioxidant and antihypertensive effects using various established in vitro assays, including 1,1-diphenyl-2-picrylhydrazyl (DPPH), nitric oxide scavenging (NO), β-carotene bleaching and angiotensin-converting enzyme (ACE) inhibitory assays. The GANPs were further evaluated for the in vitro cytotoxicity, cell uptake and cell migration in four types of human cancer cell lines including (MCF-7, MDA-MB231) breast adenocarcinoma, HepG2 hepatocellular cancer, HT-29 colorectal adenocarcinoma, and MCF-10A breast epithelial cell lines. The GANPs demonstrated potent antioxidant effects and have shown promising anti-cancer properties in a dose-dependent manner with a predilection toward HepG2 and MCF7 cancer cells. The uptake of GANPs was successful in the majority of cancer cells with a propensity to accumulate in the nuclear region of the cells. The HepG2 and MCF7 cancer cells also had a significantly higher percentage of apoptosis and were more sensitive to gallic acid nanoparticle treatment in the cell migration assay. This study is the first to confirm the synergistic effects of gum arabic in the encapsulation of gallic acid by increasing the selectivity towards cancer cells and enhancing the antioxidant properties. The formulated nanoparticles also had remarkably low toxicity in normal cells. Based on these findings, GANPs may have promising therapeutic applications towards the development of more effective treatments with a probable targeting precision in cancer cells.


id: cord-269270-i2odcsx7
title: COVID-19 image classification using deep features and fractional-order marine predators algorithm
author: Sahlol, Ahmed T.
date: 2020-09-21
url: https://doi.org/10.1038/s41598-020-71294-2
doi: 10.1038/s41598-020-71294-2
abstract:
  Currently, we witness the severe spread of the pandemic of the new Corona virus, COVID-19, which causes dangerous symptoms to humans and animals, its complications may lead to death. Although convolutional neural networks (CNNs) is considered the current state-of-the-art image classification technique, it needs massive computational cost for deployment and training. In this paper, we propose an improved hybrid classification approach for COVID-19 images by combining the strengths of CNNs (using a powerful architecture called Inception) to extract features and a swarm-based feature selection algorithm (Marine Predators Algorithm) to select the most relevant features. A combination of fractional-order and marine predators algorithm (FO-MPA) is considered an integration among a robust tool in mathematics named fractional-order calculus (FO). The proposed approach was evaluated on two public COVID-19 X-ray datasets which achieves both high performance and reduction of computational complexity. The two datasets consist of X-ray COVID-19 images by international Cardiothoracic radiologist, researchers and others published on Kaggle. The proposed approach selected successfully 130 and 86 out of 51 K features extracted by inception from dataset 1 and dataset 2, while improving classification accuracy at the same time. The results are the best achieved on these datasets when compared to a set of recent feature selection algorithms. By achieving 98.7%, 98.2% and 99.6%, 99% of classification accuracy and F-Score for dataset 1 and dataset 2, respectively, the proposed approach outperforms several CNNs and all recent works on COVID-19 images.


id: cord-269756-tid8a464
title: SARS-CoV fusion peptides induce membrane surface ordering and curvature
author: Basso, Luis G. M.
date: 2016-11-28
txt: ./txt/cord-269756-tid8a464.txt
cache: ./cache/cord-269756-tid8a464.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/srep37131
doi: 10.1038/srep37131
summary:
  Although membrane fusion promoted by class I viral glycoproteins, such as SARS-CoV Spike, human immunodeficiency virus (HIV) gp160 or influenza virus hemagglutinin (HA), has been broadly studied in recent years [16] [17] [18] [19] , many aspects of the molecular mechanism behind the virus-host cell membrane fusion remain unknown, including conformational changes of the lipid bilayers during peptide-membrane interactions. In the present study, we investigated the effects of two putative fusion peptides from SARS-CoV S glycoprotein, corresponding to residues 770-788 (SARS FP ) and 873-888 (SARS IFP ) 13, 15, 22, 23 , on the structural dynamics, physicochemical properties, and thermotropic phase behavior of lipid model membranes by differential scanning calorimetry (DSC), continuous wave (CW) and pulsed electron spin resonance (ESR) along with nonlinear least-squares (NLLS) spectral fitting 24 .

abstract:
  Viral membrane fusion is an orchestrated process triggered by membrane-anchored viral fusion glycoproteins. The S2 subunit of the spike glycoprotein from severe acute respiratory syndrome (SARS) coronavirus (CoV) contains internal domains called fusion peptides (FP) that play essential roles in virus entry. Although membrane fusion has been broadly studied, there are still major gaps in the molecular details of lipid rearrangements in the bilayer during fusion peptide-membrane interactions. Here we employed differential scanning calorimetry (DSC) and electron spin resonance (ESR) to gather information on the membrane fusion mechanism promoted by two putative SARS FPs. DSC data showed the peptides strongly perturb the structural integrity of anionic vesicles and support the hypothesis that the peptides generate opposing curvature stresses on phosphatidylethanolamine membranes. ESR showed that both FPs increase lipid packing and head group ordering as well as reduce the intramembrane water content for anionic membranes. Therefore, bending moment in the bilayer could be generated, promoting negative curvature. The significance of the ordering effect, membrane dehydration, changes in the curvature properties and the possible role of negatively charged phospholipids in helping to overcome the high kinetic barrier involved in the different stages of the SARS-CoV-mediated membrane fusion are discussed.


id: cord-271328-zdf5ji4k
title: Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus
author: Gu, Hongjing
date: 2016-01-27
txt: ./txt/cord-271328-zdf5ji4k.txt
cache: ./cache/cord-271328-zdf5ji4k.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/26813885/
doi: 10.1038/srep19840
summary:
  In this paper, we report that angiotensin-converting enzyme-2 (ACE2) protected against severe lung injury induced by RSV infection in an experimental mouse model and in pediatric patients. To determine the role of ACE2 in RSV-induced lung injury, we first measured the levels of Ang II in the plasma of RSV-infected patients. Importantly, ACE2 protein levels were dramatically decreased in lung homogenates from mice infected with RSV BJ016 virus at 3 days post-infection (p < 0.01; Fig. 1d ). Our data suggest that RSV infection causes severe lung injury in an experimental mouse model and in patients, at least in part by modulating the RAS system via down-regulation of the ACE2-AT1R axis. Importantly, the levels of Ang II were elevated following down-regulation of ACE2, causing severe lung injury via AT1R during the process of RSV infection (Fig. 5d) .

abstract:
  Respiratory syncytial virus (RSV) infection is a major cause of severe lower respiratory illness in infants and young children, but the underlying mechanisms responsible for viral pathogenesis have not been fully elucidated. To date, no drugs or vaccines have been employed to improve clinical outcomes for RSV-infected patients. In this paper, we report that angiotensin-converting enzyme-2 (ACE2) protected against severe lung injury induced by RSV infection in an experimental mouse model and in pediatric patients. Moreover, ACE2 deficiency aggravated RSV-associated disease pathogenesis, mainly by its action on the angiotensin II type 1 receptor (AT1R). Furthermore, administration of a recombinant ACE2 protein alleviated the severity of RSV-induced lung injury. These findings demonstrate that ACE2 plays a critical role in preventing RSV-induced lung injury, and suggest that ACE2 is a promising potential therapeutic target in the management of RSV-induced lung disease.


id: cord-271602-f14wccj3
title: Recent increase of surface particulate matter concentrations in the Seoul Metropolitan Area, Korea
author: Kim, Hyun Cheol
date: 2017-07-05
txt: ./txt/cord-271602-f14wccj3.txt
cache: ./cache/cord-271602-f14wccj3.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-017-05092-8
doi: 10.1038/s41598-017-05092-8
summary:
  A 12-year (2004–2015) regional air quality simulation was conducted over East Asia (27-km) and over South Korea (9-km) to assess the impact of meteorology under constant anthropogenic emissions. Simulated PM concentrations show a strong negative correlation (i.e. R = −0.86) with regional wind speed, implying that reduced regional ventilation is likely associated with more stagnant conditions that cause severe pollutant episodes in South Korea. We conclude that the current PM concentration trend in South Korea is a combination of long-term decline by emission control efforts and short-term fluctuation of regional wind speed interannual variability. Three factors, long-term trend by emission control, short-term variation by meteorology, and sporadic offsets by unexpected social or economic episodes, seem to be affecting PM concentrations in South Korea. In order to investigate the interannual variation of surface PM concentration in the SMA, we conducted a 12-year simulation using a regional air quality modeling system.

abstract:
  Recent changes of surface particulate matter (PM) concentration in the Seoul Metropolitan Area (SMA), South Korea, are puzzling. The long-term trend of surface PM concentration in the SMA declined in the 2000s, but since 2012 its concentrations have tended to incline, which is coincident with frequent severe hazes in South Korea. This increase puts the Korean government’s emission reduction efforts in jeopardy. This study reports that interannual variation of surface PM concentration in South Korea is closely linked with the interannual variations of wind speed. A 12-year (2004–2015) regional air quality simulation was conducted over East Asia (27-km) and over South Korea (9-km) to assess the impact of meteorology under constant anthropogenic emissions. Simulated PM concentrations show a strong negative correlation (i.e. R = −0.86) with regional wind speed, implying that reduced regional ventilation is likely associated with more stagnant conditions that cause severe pollutant episodes in South Korea. We conclude that the current PM concentration trend in South Korea is a combination of long-term decline by emission control efforts and short-term fluctuation of regional wind speed interannual variability. When the meteorology-driven variations are removed, PM concentrations in South Korea have declined continuously even after 2012.


id: cord-272092-ko9y5m2s
author: Scalabrin, Matteo
date: 2017-03-24
txt: ./txt/cord-272092-ko9y5m2s.txt
cache: ./cache/cord-272092-ko9y5m2s.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/28338097/
doi: 10.1038/srep45244
summary:
  title: The cellular protein hnRNP A2/B1 enhances HIV-1 transcription by unfolding LTR promoter G-quadruplexes Surface plasmon resonance confirmed G-quadruplex specificity over linear sequences and fluorescence resonance energy transfer analysis indicated that hnRNP A2/B1 is able to efficiently unfold the LTR G-quadruplexes. Our data highlight a tightly regulated control of transcription based on G-quadruplex folding/unfolding, which depends on interacting cellular proteins. Silencing of the LTR G4 folding/stabilizing protein nucleolin significantly increased promoter activity, indicating the inhibitory effect of nucleolin on LTR-driven transcription 22 . Our results showing decreased transcriptional activity upon depletion of hnRNP A2/B1 indicate a possible additional mechanism of inhibition of virus production mediated by increased G4 folding in the HIV-1 LTR promoter in the absence of hnRNP A2/B1. Nucleolin stabilizes G-quadruplex structures folded by the LTR promoter and silences HIV-1 viral transcription Protein hnRNP A1 and its derivative Up1 unfold quadruplex DNA in the human KRAS promoter: implications for transcription

title:
  The cellular protein hnRNP A2/B1 enhances HIV-1 transcription by unfolding LTR promoter G-quadruplexes

abstract:
  G-quadruplexes are four-stranded conformations of nucleic acids that act as cellular epigenetic regulators. A dynamic G-quadruplex forming region in the HIV-1 LTR promoter represses HIV-1 transcription when in the folded conformation. This activity is enhanced by nucleolin, which induces and stabilizes the HIV-1 LTR G-quadruplexes. In this work by a combined pull-down/mass spectrometry approach, we consistently found hnRNP A2/B1 as an additional LTR-G-quadruplex interacting protein. Surface plasmon resonance confirmed G-quadruplex specificity over linear sequences and fluorescence resonance energy transfer analysis indicated that hnRNP A2/B1 is able to efficiently unfold the LTR G-quadruplexes. Evaluation of the thermal stability of the LTR G-quadruplexes in different-length oligonucleotides showed that the protein is fit to be most active in the LTR full-length environment. When hnRNP A2/B1 was silenced in cells, LTR activity decreased, indicating that the protein acts as a HIV-1 transcription activator. Our data highlight a tightly regulated control of transcription based on G-quadruplex folding/unfolding, which depends on interacting cellular proteins. These findings provide a deeper understanding of the viral transcription mechanism and may pave the way to the development of drugs effective against the integrated HIV-1, present both in actively and latently infected cells.


id: cord-272576-ez731lif
author: Wada, Yoshiko
date: 2016-11-03
url: https://www.ncbi.nlm.nih.gov/pubmed/27808119/
doi: 10.1038/srep36197
title:
  Directional and reoccurring sequence change in zoonotic RNA virus genomes visualized by time-series word count

abstract:
  Ebolavirus, MERS coronavirus and influenza virus are zoonotic RNA viruses, which mutate very rapidly. Viral growth depends on many host factors, but human cells may not provide the ideal growth conditions for viruses invading from nonhuman hosts. The present time-series analyses of short and long oligonucleotide compositions in these genomes showed directional changes in their composition after invasion from a nonhuman host, which are thought to recur after future invasions. In the recent West Africa Ebola outbreak, directional time-series changes in a wide range of oligonucleotides were observed in common for three geographic areas, and the directional changes were observed also for the recent MERS coronavirus epidemics starting in the Middle East. In addition, common directional changes in human influenza A viruses were observed for three subtypes, whose epidemics started independently. Long oligonucleotides that showed an evident directional change observed in common for the three subtypes corresponded to some of influenza A siRNAs, whose activities have been experimentally proven. Predicting directional and reoccurring changes in oligonucleotide composition should become important for designing diagnostic RT-PCR primers and therapeutic oligonucleotides with long effectiveness.


id: cord-272623-j5gpww9q
title: The pathogenesis of multifocal osteonecrosis
author: Sun, Wei
date: 2016-07-11
url: https://www.ncbi.nlm.nih.gov/pubmed/27404962/
doi: 10.1038/srep29576
abstract:
  Our objective was to study the incidence, etiology, and diagnosis of multifocal osteonecrosis (MFON) and its treatment options to facilitate an earlier diagnosis and to optimize treatment. A radiological investigation was performed in osteonecrosis patients with a high risk of MFON for a more accurate diagnosis between January 2010 and June 2015. For patients with osteonecrosis of both the hip and knee joints or for patients with a history of corticosteroid use or alcohol abuse who had osteonecrosis of one or more joints in the shoulder, ankle, wrist or elbow, magnetic resonance imaging (MRI) was also performed on other joints, regardless of whether these joints were symptomatic. Furthermore, we performed a radiological screening of 102 patients who had a negative diagnosis of MFON but were at a high risk; among them, another 31 MFON cases were successfully identified (30.4%). Thus, the incidence of MFON during the study period increased from 3.1% to 5.2%. Patients diagnosed with osteonecrosis and who are at a high risk of MFON should have their other joints radiologically examined when necessary. This will reduce missed diagnosis of MFON and facilitate an earlier diagnosis and treatment to achieve an optimal outcome.


id: cord-273283-gb0m6fue
title: A novel severity score to predict inpatient mortality in COVID-19 patients
author: Altschul, David J.
date: 2020-10-07
url: https://www.ncbi.nlm.nih.gov/pubmed/33028914/
doi: 10.1038/s41598-020-73962-9
abstract:
  COVID-19 is commonly mild and self-limiting, but in a considerable portion of patients the disease is severe and fatal. Determining which patients are at high risk of severe illness or mortality is essential for appropriate clinical decision making. We propose a novel severity score specifically for COVID-19 to help predict disease severity and mortality. 4711 patients with confirmed SARS-CoV-2 infection were included. We derived a risk model using the first half of the cohort (n = 2355 patients) by logistic regression and bootstrapping methods. The discriminative power of the risk model was assessed by calculating the area under the receiver operating characteristic curves (AUC). The severity score was validated in a second half of 2356 patients. Mortality incidence was 26.4% in the derivation cohort and 22.4% in the validation cohort. A COVID-19 severity score ranging from 0 to 10, consisting of age, oxygen saturation, mean arterial pressure, blood urea nitrogen, C-Reactive protein, and the international normalized ratio was developed. A ROC curve analysis was performed in the derivation cohort achieved an AUC of 0.824 (95% CI 0.814–0.851) and an AUC of 0.798 (95% CI 0.789–0.818) in the validation cohort. Furthermore, based on the risk categorization the probability of mortality was 11.8%, 39% and 78% for patient with low (0–3), moderate (4–6) and high (7–10) COVID-19 severity score. This developed and validated novel COVID-19 severity score will aid physicians in predicting mortality during surge periods.


id: cord-276185-ysspkbj7
title: APOBEC3-mediated restriction of RNA virus replication
author: Milewska, Aleksandra
date: 2018-04-13
txt: ./txt/cord-276185-ysspkbj7.txt
cache: ./cache/cord-276185-ysspkbj7.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/29654310/
doi: 10.1038/s41598-018-24448-2
summary:
  In experiments in vitro, three human APOBEC3 proteins (A3C, A3F and A3H) inhibited HCoV-NL63 infection and limited production of progeny virus, but did not cause hypermutation of the coronaviral genome. Although the precise molecular mechanism of deaminase-dependent inhibition of coronavirus replication remains elusive, our results further our understanding of APOBEC-mediated restriction of RNA virus infections. HCoV-NL63 infection resulted in upregulation of expression of A3A, A3C, A3D and A3F and A3C, A3F and A3H all inhibited HCoV-NL63 replication, we tested whether this inhibition was the result of the catalytic activity of the APOBECs. Plasmids encoding variants of A3C, A3F and A3H with Glu → Gln substitutions in the catalytic site were prepared 31 and mRNAs encoding active or inactive proteins were transfected into LLC-Mk2 cells, which were infected with HCoV-NL63 and cultured prior to visualisation of viral proteins with specific antibodies.

abstract:
  APOBEC3 family members are cytidine deaminases with roles in intrinsic responses to infection by retroviruses and retrotransposons, and in the control of other DNA viruses, such as herpesviruses, parvoviruses and hepatitis B virus. Although effects of APOBEC3 members on viral DNA have been demonstrated, it is not known whether they edit RNA genomes through cytidine deamination. Here, we investigated APOBEC3-mediated restriction of Coronaviridae. In experiments in vitro, three human APOBEC3 proteins (A3C, A3F and A3H) inhibited HCoV-NL63 infection and limited production of progeny virus, but did not cause hypermutation of the coronaviral genome. APOBEC3-mediated restriction was partially dependent on enzyme activity, and was reduced by the use of enzymatically inactive APOBEC3. Moreover, APOBEC3 proteins bound to the coronaviral nucleoprotein, and this interaction also affected viral replication. Although the precise molecular mechanism of deaminase-dependent inhibition of coronavirus replication remains elusive, our results further our understanding of APOBEC-mediated restriction of RNA virus infections.


id: cord-276444-jidvkij5
author: Robitaille, Alexa C.
date: 2017-12-12
url: https://www.ncbi.nlm.nih.gov/pubmed/29234123/
doi: 10.1038/s41598-017-17689-0
title:
  DUSP1 regulates apoptosis and cell migration, but not the JIP1-protected cytokine response, during Respiratory Syncytial Virus and Sendai Virus infection

abstract:
  The host antiviral response involves the induction of interferons and proinflammatory cytokines, but also the activation of cell death pathways, including apoptosis, to limit viral replication and spreading. This host defense is strictly regulated to eliminate the infection while limiting tissue damage that is associated with virus pathogenesis. Post-translational modifications, most notably phosphorylation, are key regulators of the antiviral defense implying an important role of protein phosphatases. Here, we investigated the role of the dual-specificity phosphatase 1 (DUSP1) in the host defense against human respiratory syncytial virus (RSV), a pathogenic virus of the Pneumoviridae family, and Sendai virus (SeV), a model virus being developed as a vector for anti-RSV vaccine. We found that DUSP1 is upregulated before being subjected to proteasomal degradation. DUSP1 does not inhibit the antiviral response, but negatively regulates virus-induced JNK/p38 MAPK phosphorylation. Interaction with the JNK-interacting protein 1 scaffold protein prevents dephosphorylation of JNK by DUSP1, likely explaining that AP-1 activation and downstream cytokine production are protected from DUSP1 inhibition. Importantly, DUSP1 promotes SeV-induced apoptosis and suppresses cell migration in RSV-infected cells. Collectively, our data unveils a previously unrecognized selective role of DUSP1 in the regulation of tissue damage and repair during infections by RSV and SeV.


id: cord-276997-hbovh7s9
title: Aerosolization and recovery of viable murine norovirus in an experimental setup
author: Alsved, Malin
date: 2020-09-29
txt: ./txt/cord-276997-hbovh7s9.txt
cache: ./cache/cord-276997-hbovh7s9.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-72932-5
doi: 10.1038/s41598-020-72932-5
summary:
  However, the infectivity of airborne human noroviruses has not been possible to assess in real-world environments, nor in laboratory experiments, since there is no well-established cell culturing system for these viruses working at the low concentrations obtained in air samples 6 . SLAG: Sparging liquid aerosol generator; HEPA filter: high efficiency particulate air filter; nsRNA: negative sense RNA; psRNA: positive sense RNA; MNV: murine norovirus; qRT-PCR: quantitative reverse transcriptase polymerase chain reaction. Taken together, as compared to the atomizer, a smaller amount of SLAG aerosol is collected by the BioSampler (i.e., higher physical dilution), but these particles contain more MNV psRNA copies (lower viral dilution relative the physical dilution). The experimental setup described here highlights some difficulties in studies on aerosolized viruses: (1) the lack of standards in how to generate bioaerosol that results in significant differences in aerosol particle size and concentration, (2) the necessity to determine both physical and viral dilution factors, and (3) www.nature.com/scientificreports/ during airborne transport due to the low-solute solution and dilution in the setup.

abstract:
  Noroviruses are the major cause for viral acute gastroenteritis in the world. Despite the existing infection prevention strategies in hospitals, the disease continues to spread and causes extensive and numerous outbreaks. Hence, there is a need to investigate the possibility of airborne transmission of norovirus. In this study, we developed an experimental setup for studies on the infectivity of aerosolized murine norovirus (MNV), a model for the human norovirus. Two aerosol generation principles were evaluated: bubble bursting, a common natural aerosolization mechanism, and nebulization, a common aerosolization technique in laboratory studies. The aerosolization setup was characterized by physical and viral dilution factors, generated aerosol particle size distributions, and the viral infectivity after aerosolization. We found a lower physical dilution factor when using the nebulization generator than with the bubble bursting generator. The viral dilution factor of the system was higher than the physical dilution; however, when comparing the physical and viral dilution factors, bubble bursting generation was more efficient. The infectivity per virus was similar using either generation principle, suggesting that the generation itself had a minor impact on MNV infectivity and that instead, the effect of drying in air could be a major reason for infectivity losses.


id: cord-277816-ncdy9qgb
author: Wang, Ji-gan
date: 2020-10-20
txt: ./txt/cord-277816-ncdy9qgb.txt
cache: ./cache/cord-277816-ncdy9qgb.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33082472/
doi: 10.1038/s41598-020-74913-0
summary:
  title: Gastrointestinal symptoms and fecal nucleic acid testing of children with 2019 coronavirus disease: a systematic review and meta-analysis In order to understand the clinical manifestations and incidence of gastrointestinal symptoms of coronavirus disease (COVID-19) in children and discuss the importance of fecal nucleic acid testing.We retrospectively analyzed studies on gastrointestinal symptoms and fecal nucleic acid detection in pediatric COVID-19 patients from January 1, 2020 to August 10, 2020, including prospective clinical studies and case reports. Stata12.0 software was used for meta-analysis.The results showed that the most common gastrointestinal symptoms in children with COVID-19 were vomiting and diarrhea, with a total incidence of 17.7% (95% Cl 13.9–21.5%). At present, there is no relevant study on whether there is a difference in the positive rate of fecal nucleic acid testing in COVID-19 children with and without diarrhea. Clinical features of 33 cases in children infected with SARS-CoV-2 in Anhui Province, China: a multi-center retrospective cohort study.

title:
  Gastrointestinal symptoms and fecal nucleic acid testing of children with 2019 coronavirus disease: a systematic review and meta-analysis

abstract:
  In order to understand the clinical manifestations and incidence of gastrointestinal symptoms of coronavirus disease (COVID-19) in children and discuss the importance of fecal nucleic acid testing.We retrospectively analyzed studies on gastrointestinal symptoms and fecal nucleic acid detection in pediatric COVID-19 patients from January 1, 2020 to August 10, 2020, including prospective clinical studies and case reports. The results of fecal nucleic acid detection were analyzed systematically. Stata12.0 software was used for meta-analysis.The results showed that the most common gastrointestinal symptoms in children with COVID-19 were vomiting and diarrhea, with a total incidence of 17.7% (95% Cl 13.9–21.5%). However, the prevalence of gastrointestinal symptoms in other countries (21.1%, 95% CI 16.5–25.7%) was higher compared to China (12.9%, 95% CI 8–17.7%). In Wuhan, the pooled prevalence was much higher (41.3%, 95% CI 3.2–79.4%) compared to areas outside Wuhan in China (7.1%, 95% CI 4.0–10.3%). The positive rate of fecal nucleic acid testing in COVID-19 children was relatively high at 85.8% (91/106). Additionally, 71.2% (52/73) were still positive for fecal nucleic acid after respiratory tract specimens turned negative. One and two weeks after the respiratory tract specimens turned nucleic acid-negative, 45.2% (33/73) and 34.2% (25/73) patients, respectively, remained fecal nucleic acid-positive. The longest interval between the respiratory tract specimens turning negative and fecal specimens turning negative exceeded 70 days. Conclusions and relevance: gastrointestinal symptoms in pediatric COVID-19 are relatively common. Attention should be paid to the detection of fecal nucleic acids in children. Fecal nucleic acid-negative status should be considered as one of the desegregation standards.


id: cord-279598-xzionafe
author: Chang, Chia-Yu
date: 2019-02-21
url: https://doi.org/10.1038/s41598-019-39844-5
doi: 10.1038/s41598-019-39844-5
title:
  Identification of Neutralizing Monoclonal Antibodies Targeting Novel Conformational Epitopes of the Porcine Epidemic Diarrhoea Virus Spike Protein

abstract:
  Since 2010, newly identified variants of porcine epidemic diarrhoea virus (PEDV) have caused high mortality in neonatal piglets which has devastated the swine industry. The spike (S) glycoprotein of PEDV contains multiple neutralizing epitopes and is a major target for PEDV neutralization and vaccine development. To understand the antigenicity of the new PEDV variant, we characterized the neutralizing epitopes of a new genotype 2b PEDV isolate from Taiwan, PEDV Pintung 52 (PEDV-PT), by the generation of neutralizing monoclonal antibodies (NmAbs). Two NmAbs, P4B-1, and E10E-1–10 that recognized the ectodomain of the full-length recombinant PEDV S protein and exhibited neutralizing ability against the PEDV-PT virus were selected. Recombinant truncated S proteins were used to identify the target sequences for the NmAbs and P4B-1 was shown to recognize the C-terminus of CO-26K equivalent epitope (COE) at amino acids (a.a.) 575–639 of the PEDV S. Interestingly, E10E-1–10 could recognize a novel neutralizing epitope at a.a. 435–485 within the S1(A) domain of the PEDV S protein, whose importance and function are yet to be determined. Moreover, both NmAbs could not bind to linearized S proteins, indicating that only conformational epitopes are recognized. This data could improve our understanding of the antigenic structures of the PEDV S protein and facilitate future development of novel epitope-based vaccines.


id: cord-280334-7b7rvr25
author: Abrantes, Joana
date: 2020-09-02
url: https://www.ncbi.nlm.nih.gov/pubmed/32879332/
doi: 10.1038/s41598-020-71303-4
title:
  Recombination at the emergence of the pathogenic rabbit haemorrhagic disease virus Lagovirus europaeus/GI.2

abstract:
  Rabbit haemorrhagic disease is a viral disease that emerged in the 1980s and causes high mortality and morbidity in the European rabbit (Oryctolagus cuniculus). In 2010, a new genotype of the rabbit haemorrhagic disease virus emerged and replaced the former circulating Lagovirus europaeus/GI.1 strains. Several recombination events have been reported for the new genotype Lagovirus europaeus/GI.2, with pathogenic (variants GI.1a and GI.1b) and benign (genotype GI.4) strains that served as donors for the non-structural part while GI.2 composed the structural part; another recombination event has also been described at the p16/p23 junction involving GI.4 strains. In this study, we analysed new complete coding sequences of four benign GI.3 strains and four GI.2 strains. Phylogenetic and recombination detection analyses revealed that the first GI.2 strains, considered as non-recombinant, resulted from a recombination event between GI.3 and GI.2, with GI.3 as the major donor for the non-structural part and GI.2 for the structural part. Our results indicate that recombination contributed to the emergence, persistence and dissemination of GI.2 as a pathogenic form and that all described GI.2 strains so far are the product of recombination. This highlights the need to study full-genomic sequences of lagoviruses to understand their emergence and evolution.


id: cord-281536-8y7yxcp4
author: Lim, Hocheol
date: 2020-10-08
txt: ./txt/cord-281536-8y7yxcp4.txt
cache: ./cache/cord-281536-8y7yxcp4.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/33033344/
doi: 10.1038/s41598-020-73820-8
summary:
  title: Hot spot profiles of SARS-CoV-2 and human ACE2 receptor protein protein interaction obtained by density functional tight binding fragment molecular orbital method In this work, to find common hot spot amino acids on the interfaces between the RBD domain and hACE2 of the three complexes, RBD-SARS-CoV-2/hACE2 (twelve experimental structural data), RBD-SARS-CoV-1/ hACE2 (four experimental structural data), and RBD-HCoV-NL63/hACE2 (one experimental structural data), we performed FMO-DFTB3/D/PCM calculations. Consequently, we summarized the FMO-DFTB3/D/PCM/3D-SPIEs results as interaction maps and found the hot spot regions in RBD-SARS-CoV-2 and hACE2 at a QM level. In order to narrow down the hot spot regions between hACE2 and RBD-SARS-CoV-1, we performed FMO calculations on four RBD-SARS-CoV-1/antibody complexes (Supplementary Table S14-S19). In order to find common hot spot amino acids in RBD-SARS-CoV-1 against hACE2 and SARS-CoV-1 antibodies, we illustrated the FMO results with a 3D-SPIEs-based map.

title:
  Hot spot profiles of SARS-CoV-2 and human ACE2 receptor protein protein interaction obtained by density functional tight binding fragment molecular orbital method

abstract:
  The prevalence of a novel β-coronavirus (SARS-CoV-2) was declared as a public health emergency of international concern on 30 January 2020 and a global pandemic on 11 March 2020 by WHO. The spike glycoprotein of SARS-CoV-2 is regarded as a key target for the development of vaccines and therapeutic antibodies. In order to develop anti-viral therapeutics for SARS-CoV-2, it is crucial to find amino acid pairs that strongly attract each other at the interface of the spike glycoprotein and the human angiotensin-converting enzyme 2 (hACE2) complex. In order to find hot spot residues, the strongly attracting amino acid pairs at the protein–protein interaction (PPI) interface, we introduce a reliable inter-residue interaction energy calculation method, FMO-DFTB3/D/PCM/3D-SPIEs. In addition to the SARS-CoV-2 spike glycoprotein/hACE2 complex, the hot spot residues of SARS-CoV-1 spike glycoprotein/hACE2 complex, SARS-CoV-1 spike glycoprotein/antibody complex, and HCoV-NL63 spike glycoprotein/hACE2 complex were obtained using the same FMO method. Following this, a 3D-SPIEs-based interaction map was constructed with hot spot residues for the hACE2/SARS-CoV-1 spike glycoprotein, hACE2/HCoV-NL63 spike glycoprotein, and hACE2/SARS-CoV-2 spike glycoprotein complexes. Finally, the three 3D-SPIEs-based interaction maps were combined and analyzed to find the consensus hot spots among the three complexes. As a result of the analysis, two hot spots were identified between hACE2 and the three spike proteins. In particular, E37, K353, G354, and D355 of the hACE2 receptor strongly interact with the spike proteins of coronaviruses. The 3D-SPIEs-based map would provide valuable information to develop anti-viral therapeutics that inhibit PPIs between the spike protein of SARS-CoV-2 and hACE2.


id: cord-283583-pwlbrxn3
title: Prevalence and genetic characteristics of Saffold cardiovirus in China from 2009 to 2012
author: Zhang, Xiao-Ai
date: 2015-01-09
txt: ./txt/cord-283583-pwlbrxn3.txt
cache: ./cache/cord-283583-pwlbrxn3.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/25572936/
doi: 10.1038/srep07704
summary:
  A higher frequency of severe clinical outcome and nervous system manifestation were also observed in the SAFV-positive HFMD patients. A patient was considered to be infected with SAFV when positive detection was obtained in any type of the samples. Genetic characterization of SAFVs. A phylogenetic tree was constructed based on the VP1 nucleotide sequences of Saffold cardiovirus detected in clinical samples of 82 patients in the current study, and sequences downloaded from GenBank by maximum likelihood method using MEGA 6.0 (Figure 1) . Detection of SAFV in sera and CSFs. Additional 171 CSFs were collected from patients with HFMD-associated encephalitis, and six (3.5%) were found to be SAFV-positive using real-time RT-PCR, and five were further confirmed by nested RT-PCR targeting the 59-UTR. In our study, SAFVs were co-detected with other viruses in 14 (82.4%), 9 (75.0%), and 28 (32.6) specimens in ARTI, diarrhea and HFMD patients respectively.

abstract:
  The epidemiology and clinical features of the Saffold cardiovirus (SAFV) remain ambiguous. The present study was designed to systematically and intensively investigate the epidemiological features of SAFV in pediatric patients in China. Three cohorts of pediatric patients were recruited from 2009 to 2012. Cohort 1 comprised patients with acute respiratory tract infections. Cohort 2 comprised patients with diarrhea. Cohort 3 comprised hand, foot, and mouth disease (HFMD) patients. A total of 115 patients (1.6%) among 6052 (17/1647, 12/2013, and 86/2392 in cohorts 1, 2, and 3, respectively) were SAFV-positive. The samples from 82 SAFV-positive patients were successfully sequenced, and four genotypes were identified: 8 SAFV-1, 41 SAFV-2, 29 SAFV-3, and 4 SAFV-6. A significantly higher detection rate was found in the HFMD patients than in other two cohorts (both P <0.001). A higher frequency of severe clinical outcome and nervous system manifestation were also observed in the SAFV-positive HFMD patients. Additionally, 6 (3.5%) cerebrospinal fluid and 7 (2.2%) serum samples from the HFMD-associated encephalitis patients were SAFV-positive. Based on the VP1 sequences, all four genotypes displayed distinct geographical clustering. SAFV infection might be associated with a wide clinical spectrum and contribute to HFMD.


id: cord-284374-sqxlnk9e
author: Park, Jiyeon
date: 2020-01-15
txt: ./txt/cord-284374-sqxlnk9e.txt
cache: ./cache/cord-284374-sqxlnk9e.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-019-57216-x
doi: 10.1038/s41598-019-57216-x
summary:
  title: Infection Prevention Measures for Surgical Procedures during a Middle East Respiratory Syndrome Outbreak in a Tertiary Care Hospital in South Korea Our experience with setting up a temporary negative-pressure operation room and our conservative approach for managing MERS-related patients can be referred in cases of future unexpected MERS outbreaks in non-endemic countries. Anesthesiologists were recommended to apply enhanced PPE (including PAPR from the middle of the outbreak) when managing all MERS-related patients because they were most directly exposed to the aerosol-producing high-risk procedures, such as endotracheal intubation and extubation. Almost all hospitals generally have positive-pressure operating rooms and they may experience an outbreak without facilities that are prepared for perioperative management of MERS patients, as our hospital did in 2015. First, although the previous guidelines recommended that asymptomatic MERS-exposed patients be managed as general patients undergoing surgery, we applied standard PPE to HCWs and we performed MERS-CoV PCR screening twice.

title:
  Infection Prevention Measures for Surgical Procedures during a Middle East Respiratory Syndrome Outbreak in a Tertiary Care Hospital in South Korea

abstract:
  In 2015, we experienced the largest in-hospital Middle East respiratory syndrome (MERS) outbreak outside the Arabian Peninsula. We share the infection prevention measures for surgical procedures during the unexpected outbreak at our hospital. We reviewed all forms of related documents and collected information through interviews with healthcare workers of our hospital. After the onset of outbreak, a multidisciplinary team devised institutional MERS-control guidelines. Two standard operating rooms were converted to temporary negative-pressure rooms by physically decreasing the inflow air volume (−4.7 Pa in the main room and −1.2 Pa in the anteroom). Healthcare workers were equipped with standard or enhanced personal protective equipment according to the MERS-related patient’s profile and symptoms. Six MERS-related patients underwent emergency surgery, including four MERS-exposed and two MERS-confirmed patients. Negative conversion of MERS-CoV polymerase chain reaction tests was noticed for MERS-confirmed patients before surgery. MERS-exposed patients were also tested twice preoperatively, all of which were negative. All operative procedures in MERS-related patients were performed without specific adverse events or perioperative MERS transmission. Our experience with setting up a temporary negative-pressure operation room and our conservative approach for managing MERS-related patients can be referred in cases of future unexpected MERS outbreaks in non-endemic countries.


id: cord-284429-d7qxfo6d
author: Trezza, Alfonso
date: 2020-08-17
url: https://doi.org/10.1038/s41598-020-70863-9
doi: 10.1038/s41598-020-70863-9
title:
  An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors

abstract:
  The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein – ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.


id: cord-284582-xwedgllw
title: Cell-free DNA in plasma as an essential immune system regulator
author: Korabecna, M.
date: 2020-10-15
txt: ./txt/cord-284582-xwedgllw.txt
cache: ./cache/cord-284582-xwedgllw.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-74288-2
doi: 10.1038/s41598-020-74288-2
summary:
  These expression profiles provide evidence that the presence of cfDNA and its clearance in plasma of healthy individuals regulate fundamental mechanisms of the inflammation process and tissue homeostasis. We used native human plasma samples obtained from healthy volunteers with no animal serum addition to the cultivation medium in order to avoid the presence of uncharacterized animal cfDNA and DNases in the experiments. We used the validation phase results to perform a direct comparison of signaling pathways activated in cells as a consequence of their treatment with NP or TP samples (Table 1a , b) using the database Reactome. The changes in expression profiles of selected validated genes were detectable after the decrease of cfDNA levels to 69.10% of its original native concentration as the result of endogenous DNAse I activity ( Supplementary Fig. 1 ). However, the cells treated with identical plasma samples with degraded cfDNA directly activate IIR with elevated production of mRNA for interleukin 8 at the transcriptomic level.

abstract:
  The cell-free DNA (cfDNA) is always present in plasma, and it is biomarker of growing interest in prenatal diagnostics as well as in oncology and transplantology for therapy efficiency monitoring. But does this cfDNA have a physiological role? Here we show that cfDNA presence and clearance in plasma of healthy individuals plays an indispensable role in immune system regulation. We exposed THP1 cells to healthy individuals’ plasma with (NP) and without (TP) cfDNA. In cells treated with NP, we found elevated expression of genes whose products maintain immune system homeostasis. Exposure of cells to TP triggered an innate immune response (IIR), documented particularly by elevated expression of pro-inflammatory interleukin 8. The results of mass spectrometry showed a higher abundance of proteins associated with IIR activation due to the regulation of complement cascade in cells cultivated with TP. These expression profiles provide evidence that the presence of cfDNA and its clearance in plasma of healthy individuals regulate fundamental mechanisms of the inflammation process and tissue homeostasis. The detailed understanding how neutrophil extracellular traps and their naturally occurring degradation products affect the performance of immune system is of crucial interest for future medical applications.


id: cord-286413-a7wue2e3
author: Cohen, Isaac V.
date: 2020-11-05
txt: ./txt/cord-286413-a7wue2e3.txt
cache: ./cache/cord-286413-a7wue2e3.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1038/s41598-020-76258-0
doi: 10.1038/s41598-020-76258-0
summary:
  title: Cardiac adverse events associated with chloroquine and hydroxychloroquine exposure in 20 years of drug safety surveillance reports The cardiac AEs of these therapeutics are of increased concern since a subset of patients infected with COVID-19 present with cardiac injury, suggesting a relevant cardiovascular involvement in the pathophysiology of the disease 22 . The goal of this study is to reanalyze the extensive clinical data of CQ and HCQ cardiac AEs collected during the last 20 years to derive the strength of the associations and, more importantly, contributing risk factors. In our study we analyzed 702,274 FDA adverse event reports divided into CQ, HCQ and control cohorts to determine their association with cardiac AEs when taking into account other factors. The regression model was instrumental to exclude this aspirin association from the quantification of the direct cardiac side effects of CQ and HCQ, which remained significant after adjustment ( Generalizability of results to COVID-19 treatment with CQ and HCQ.

title:
  Cardiac adverse events associated with chloroquine and hydroxychloroquine exposure in 20 years of drug safety surveillance reports

abstract:
  Chloroquine (CQ) and hydroxychloroquine (HCQ) are on the World Health Organization’s List of Essential Medications for treating non-resistant malaria, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In addition, both drugs are currently used off-label in hospitals worldwide and in numerous clinical trials for the treatment of SARS-CoV-2 infection. However, CQ and HCQ use has been associated with cardiac side effects, which is of concern due to the higher risk of COVID-19 complications in patients with heart related disorders, and increased mortality associated with COVID-19 cardiac complications. In this study we analyzed over thirteen million adverse event reports form the United States Food and Drug Administration Adverse Event Reporting System to confirm and quantify the association of cardiac side effects of CQ and HCQ. Additionally, we identified several confounding factors, including male sex, NSAID coadministration, advanced age, and prior diagnoses contributing to drug related cardiotoxicity. These findings may help guide therapeutic decision making and ethical trial design for COVID-19 treatment.


id: cord-286559-y8z0pwgn
title: A permanent host shift of rabies virus from Chiroptera to Carnivora associated with recombination
author: Ding, Nai-Zheng
date: 2017-03-21
url: https://doi.org/10.1038/s41598-017-00395-2
doi: 10.1038/s41598-017-00395-2
abstract:
  Bat virus host shifts can result in the spread of diseases with significant effects. The rabies virus (RABV) is able to infect almost all mammals and is therefore a useful model for the study of host shift mechanisms. Carnivore RABVs originated from two historical host shifts from bat viruses. To reveal the genetic pathways by which bat RABVs changed their host tropism from bats to carnivores, we investigated the second permanent bat-to-carnivore shift resulting in two carnivore variants, known as raccoon RABV (RRV) and south-central skunk RABV (SCSKV). We found that their glycoprotein (G) genes are the result of recombination between an American bat virus and a carnivore virus. This recombination allowed the bat RABV to acquire the head of the G-protein ectodomain of the carnivore virus. This region is involved in receptor recognition and binding, response to changes in the pH microenvironment, trimerization of G proteins, and cell-to-cell transmission during the viral infection. Therefore, this recombination event may have significantly improved the variant’s adaptability to carnivores, altering its host tropism and thus leading to large-scale epidemics in striped skunk and raccoon.


id: cord-287708-0qvwjejv
author: Gera, Tamás
date: 2020-09-25
url: https://doi.org/10.1038/s41598-020-72865-z
doi: 10.1038/s41598-020-72865-z
title:
  Application of pulsed laser ablation (PLA) for the size reduction of non-steroidal anti-inflammatory drugs (NSAIDs)

abstract:
  We studied the application of pulsed laser ablation (PLA) for particle size reduction in non-steroidal anti-inflammatory drugs (NSAIDs). Grinding of the poorly water-soluble NSAID crystallites can considerably increase their solubility and bioavailability, thereby the necessary doses can be reduced significantly. We used tablets of ibuprofen, niflumic acid and meloxicam as targets. Nanosecond laser pulses were applied at various wavelengths (KrF excimer laser, λ = 248 nm, FWHM = 18 ns and Nd:YAG laser, λ(1) = 532 nm/λ(2) = 1064 nm, FWHM = 6 ns) and at various fluences. FTIR and Raman spectra showed that the chemical compositions of the drugs had not changed during ablation at 532 nm and 1064 nm laser wavelengths. The size distribution of the ablated products was established using two types of particle size analyzers (SMPS and OPC) having complementary measuring ranges. The mean size of the drug crystallites decreased from the initial 30–80 µm to the submicron to nanometer range. For a better understanding of the ablation mechanism we made several investigations (SEM, Ellipsometry, Fast photography) and some model calculations. We have established that PLA offers a chemical-free and simple method for the size reduction of poorly water-soluble drugs and a possible new way for pharmaceutical drug preformulation for nasal administration.


id: cord-288451-npefpo3t
title: Novel highly divergent reassortant bat rotaviruses in Cameroon, without evidence of zoonosis
author: Yinda, Claude Kwe
date: 2016-09-26
url: https://www.ncbi.nlm.nih.gov/pubmed/27666390/
doi: 10.1038/srep34209
abstract:
  Bats are an important reservoir for zoonotic viruses. To date, only three RVA strains have been reported in bats in Kenya and China. In the current study we investigated the genetic diversity of RVAs in fecal samples from 87 straw-colored fruit bats living in close contact with humans in Cameroon using viral metagenomics. Five (near) complete RVA genomes were obtained. A single RVA strain showed a partial relationship with the Kenyan bat RVA strain, whereas the other strains were completely novel. Only the VP7 and VP4 genes showed significant variability, indicating the occurrence of frequent reassortment events. Comparing these bat RVA strains with currently used human RVA screening primers indicated that most of the novel VP7 and VP4 segments would not be detected in routine epidemiological screening studies. Therefore, novel consensus screening primers were developed and used to screen samples from infants with gastroenteritis living in close proximity with the studied bat population. Although RVA infections were identified in 36% of the infants, there was no evidence of zoonosis. This study identified multiple novel bat RVA strains, but further epidemiological studies in humans will have to assess if these viruses have the potential to cause gastroenteritis in humans.


id: cord-288721-3bv3aak6
author: Schneider, Annika
date: 2019-06-11
txt: ./txt/cord-288721-3bv3aak6.txt
cache: ./cache/cord-288721-3bv3aak6.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/31186476/
doi: 10.1038/s41598-019-44922-9
summary:
  Thus, single-organelle and multi-parameter resolution allows to explore altered energy metabolism and antiviral defence by tagged mitochondria selectively in virus-infected cells and will be instrumental to identify viral immune escape and to develop and monitor novel mitochondrial-targeted therapies. When challenged with high concentrations of calcium (100 µM), mitochondria isolated from virus-infected livers are much more fragile shown by time-dependent loss of membrane potential and change of their morphology indicated by decrease in side-scatter (Fig. 2F ). Number of viable mitochondria detected per second by flow-cytometry declined after calcium challenge, consistent with loss of mitochondrial integrity, and did so much faster in samples from virus-infected livers (Fig. 2F ). In order to further evaluate mitochondrial functionality, we challenged mitochondria with Ca 2+ as stress test and performed time kinetic measurements of DilC 1 (5) fluorescence and side-scatter of mito-DsRed + and mito-DsRed − mitochondria isolated from Ad-CMV-mitoRL infected livers.

title:
  Single organelle analysis to characterize mitochondrial function and crosstalk during viral infection

abstract:
  Mitochondria are key for cellular metabolism and signalling processes during viral infection. We report a methodology to analyse mitochondrial properties at the single-organelle level during viral infection using a recombinant adenovirus coding for a mitochondrial tracer protein for tagging and detection by multispectral flow cytometry. Resolution at the level of tagged individual mitochondria revealed changes in mitochondrial size, membrane potential and displayed a fragile phenotype during viral infection of cells. Thus, single-organelle and multi-parameter resolution allows to explore altered energy metabolism and antiviral defence by tagged mitochondria selectively in virus-infected cells and will be instrumental to identify viral immune escape and to develop and monitor novel mitochondrial-targeted therapies.


id: cord-288731-x2cwyvb7
author: Puenpa, Jiratchaya
date: 2020-10-06
url: https://www.ncbi.nlm.nih.gov/pubmed/33024144/
doi: 10.1038/s41598-020-73554-7
title:
  Molecular epidemiology of the first wave of severe acute respiratory syndrome coronavirus 2 infection in Thailand in 2020

abstract:
  The coronavirus disease 2019 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major global concern. Several SARS-CoV-2 gene mutations have been reported. In the current study associations between SARS-CoV-2 gene variation and exposure history during the first wave of the outbreak in Thailand between January and May 2020 were investigated. Forty samples were collected at different time points during the outbreak, and parts of the SARS-CoV-2 genome sequence were used to assess genomic variation patterns. The phylogenetics of the 40 samples were clustered into L, GH, GR, O and T types. T types were predominant in Bangkok during the first local outbreak centered at a boxing stadium and entertainment venues in March 2020. Imported cases were infected with various types, including L, GH, GR and O. In southern Thailand introductions of different genotypes were identified at different times. No clinical parameters were significantly associated with differences in genotype. The results indicated local transmission (type T, Spike protein (A829T)) and imported cases (types L, GH, GR and O) during the first wave in Thailand. Genetic and epidemiological data may contribute to national policy formulation, transmission tracking and the implementation of measures to control viral spread.


id: cord-288761-fyvr0tc1
title: Allosteric inhibition of aminopeptidase N functions related to tumor growth and virus infection
author: Santiago, César
date: 2017-04-10
txt: ./txt/cord-288761-fyvr0tc1.txt
cache: ./cache/cord-288761-fyvr0tc1.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/28393915/
doi: 10.1038/srep46045
summary:
  These structures identified three distinct APN conformations, based on active site accessibility, which we termed closed, intermediate and open forms (Fig. 1a) . The phenylalanine was located in the loop that connects α 26 and α 27 in the single domain IV ARM repeat of human and pig APN (Fig. 2a) ; it penetrated the active site groove in the closed conformation and locked the peptide, ready for hydrolysis. CoV binding to APN would lock the protein in its open conformation (Fig. 2b) , preventing the ectodomain movement probably necessary for peptide hydrolysis (Fig. 2a) . In flow cytometry, we determined the binding of an RBD-Fc fusion protein to cells that expressed pAPN or an active site mutant (pAPN-HH/AA), alone or with various drugs (Fig. 4a,b) . Disulfide bonds that lock the APN closed conformation or drugs that prevent opening of the ectodomain inhibited CoV protein binding and cell infection, whereas porcine CoV S proteins probably hinder APN transition to the closed form and peptide hydrolysis.

abstract:
  Cell surface aminopeptidase N (APN) is a membrane-bound ectoenzyme that hydrolyzes proteins and peptides and regulates numerous cell functions. APN participates in tumor cell expansion and motility, and is a target for cancer therapies. Small drugs that bind to the APN active site inhibit catalysis and suppress tumor growth. APN is also a major cell entry receptor for coronavirus, which binds to a region distant from the active site. Three crystal structures that we determined of human and pig APN ectodomains defined the dynamic conformation of the protein. These structures offered snapshots of closed, intermediate and open APN, which represent distinct functional states. Coronavirus envelope proteins specifically recognized the open APN form, prevented ectodomain progression to the closed form and substrate hydrolysis. In addition, drugs that bind the active site inhibited both coronavirus binding to cell surface APN and infection; the drugs probably hindered APN transition to the virus-specific open form. We conclude that allosteric inhibition of APN functions occurs by ligand suppression of ectodomain motions necessary for catalysis and virus cell entry, as validated by locking APN with disulfides. Blocking APN dynamics can thus be a valuable approach to development of drugs that target this ectoenzyme.


id: cord-289932-dsysiefx
author: Király, Kornél
date: 2018-02-22
url: https://doi.org/10.1038/s41598-018-21799-8
doi: 10.1038/s41598-018-21799-8
title:
  Glial cell type-specific changes in spinal dipeptidyl peptidase 4 expression and effects of its inhibitors in inflammatory and neuropatic pain

abstract:
  Altered pain sensations such as hyperalgesia and allodynia are characteristic features of various pain states, and remain difficult to treat. We have shown previously that spinal application of dipeptidyl peptidase 4 (DPP4) inhibitors induces strong antihyperalgesic effect during inflammatory pain. In this study we observed low level of DPP4 mRNA in the rat spinal dorsal horn in physiological conditions, which did not change significantly either in carrageenan-induced inflammatory or partial nerve ligation-generated neuropathic states. In naïve animals, microglia and astrocytes expressed DPP4 protein with one and two orders of magnitude higher than neurons, respectively. DPP4 significantly increased in astrocytes during inflammation and in microglia in neuropathy. Intrathecal application of two DPP4 inhibitors tripeptide isoleucin-prolin-isoleucin (IPI) and the antidiabetic drug vildagliptin resulted in robust opioid-dependent antihyperalgesic effect during inflammation, and milder but significant opioid-independent antihyperalgesic action in the neuropathic model. The opioid-mediated antihyperalgesic effect of IPI was exclusively related to mu-opioid receptors, while vildagliptin affected mainly delta-receptor activity, although mu- and kappa-receptors were also involved. None of the inhibitors influenced allodynia. Our results suggest pathology and glia-type specific changes of DPP4 activity in the spinal cord, which contribute to the development and maintenance of hyperalgesia and interact with endogenous opioid systems.


id: cord-293372-saqoft9p
author: Heffner, Kelley
date: 2020-09-28
txt: ./txt/cord-293372-saqoft9p.txt
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url: https://www.ncbi.nlm.nih.gov/pubmed/32985598/
doi: 10.1038/s41598-020-72959-8
summary:
  Quantitative proteomics data were obtained from two CHO cell lines (CHO-S and CHO DG44) and compared with seven Chinese hamster (Cricetulus griseus) tissues (brain, heart, kidney, liver, lung, ovary and spleen) by tandem mass tag (TMT) labeling followed by mass spectrometry, providing a comprehensive hamster tissue and cell line proteomics atlas. This study was undertaken to compare protein expression of various CHO cell lines and hamster tissues, resulting in the most comprehensive multi-tissue analysis of the Cricetulus griseus proteome (Fig. 1A) . Similar to the ovary and lung comparison, there are a greater number of proteins with higher expression in the heart tissue when compared to cell lines. These differences highlight the role of tissues in executing key organ functions which require a specific metabolic processes, such as transport and communication, in comparison to CHO cells, which are focused on replication and gene expression, characteristics useful for rapid growth and the production of biologics.

title:
  Expanded Chinese hamster organ and cell line proteomics profiling reveals tissue-specific functionalities

abstract:
  Chinese hamster ovary (CHO) cells are the predominant production vehicle for biotherapeutics. Quantitative proteomics data were obtained from two CHO cell lines (CHO-S and CHO DG44) and compared with seven Chinese hamster (Cricetulus griseus) tissues (brain, heart, kidney, liver, lung, ovary and spleen) by tandem mass tag (TMT) labeling followed by mass spectrometry, providing a comprehensive hamster tissue and cell line proteomics atlas. Of the 8470 unique proteins identified, high similarity was observed between CHO-S and CHO DG44 and included increases in proteins involved in DNA replication, cell cycle, RNA processing, and chromosome processing. Alternatively, gene ontology and pathway analysis in tissues indicated increased protein intensities related to important tissue functionalities. Proteins enriched in the brain included those involved in acidic amino acid metabolism, Golgi apparatus, and ion and phospholipid transport. The lung showed enrichment in proteins involved in BCAA catabolism, ROS metabolism, vesicle trafficking, and lipid synthesis while the ovary exhibited enrichments in extracellular matrix and adhesion proteins. The heart proteome included vasoconstriction, complement activation, and lipoprotein metabolism enrichments. These detailed comparisons of CHO cell lines and hamster tissues will enhance understanding of the relationship between proteins and tissue function and pinpoint potential pathways of biotechnological relevance for future cell engineering.


id: cord-293505-1t3hg4wi
author: Bernard-Stoecklin, Sibylle
date: 2019-05-14
url: https://www.ncbi.nlm.nih.gov/pubmed/31089148/
doi: 10.1038/s41598-019-43586-9
title:
  Comparative Analysis of Eleven Healthcare-Associated Outbreaks of Middle East Respiratory Syndrome Coronavirus (Mers-Cov) from 2015 to 2017

abstract:
  Since its emergence in 2012, 2,260 cases and 803 deaths due to Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported to the World Health Organization. Most cases were due to transmission in healthcare settings, sometimes causing large outbreaks. We analyzed epidemiologic and clinical data of laboratory-confirmed MERS-CoV cases from eleven healthcare-associated outbreaks in the Kingdom of Saudi Arabia and the Republic of Korea between 2015–2017. We quantified key epidemiological differences between outbreaks. Twenty-five percent (n = 105/422) of MERS cases who acquired infection in a hospital setting were healthcare personnel. In multivariate analyses, age ≥65 (OR 4.8, 95%CI: 2.6–8.7) and the presence of underlying comorbidities (OR: 2.7, 95% CI: 1.3–5.7) were associated with increased mortality whereas working as healthcare personnel was protective (OR 0.07, 95% CI: 0.01–0.34). At the start of these outbreaks, the reproduction number ranged from 1.0 to 5.7; it dropped below 1 within 2 to 6 weeks. This study provides a comprehensive characterization of MERS HCA-outbreaks. Our results highlight heterogeneities in the epidemiological profile of healthcare-associated outbreaks. The limitations of our study stress the urgent need for standardized data collection for high-threat respiratory pathogens, such as MERS-CoV.


id: cord-293747-ds8rhbkv
title: Antiviral activity of silymarin against chikungunya virus
author: Lani, Rafidah
date: 2015-06-16
url: https://doi.org/10.1038/srep11421
doi: 10.1038/srep11421
abstract:
  The mosquito-borne chikungunya virus (CHIKV) causes chikungunya fever, with clinical presentations such as severe back and small joint pain, and debilitating arthritis associated with crippling pains that persist for weeks and even years. Although there are several studies to evaluate the efficacy of drugs against CHIKV, the treatment for chikungunya fever is mainly symptom-based and no effective licensed vaccine or antiviral are available. Here, we investigated the antiviral activity of three types of flavonoids against CHIKV in vitro replication. Three compounds: silymarin, quercetin and kaempferol were evaluated for their in vitro antiviral activities against CHIKV using a CHIKV replicon cell line and clinical isolate of CHIKV of Central/East African genotype. A cytopathic effect inhibition assay was used to determine their activities on CHIKV viral replication and quantitative reverse transcription PCR was used to calculate virus yield. Antiviral activity of effective compound was further investigated by evaluation of CHIKV protein expression using western blotting for CHIKV nsP1, nsP3, and E2E1 proteins. Briefly, silymarin exhibited significant antiviral activity against CHIKV, reducing both CHIKV replication efficiency and down-regulating production of viral proteins involved in replication. This study may have important consequence for broaden the chance of getting the effective antiviral for CHIKV infection.


id: cord-294220-ewp1m8jp
title: Monocaprin eye drop formulation to combat antibiotic resistant gonococcal blindness
author: Churchward, Colin P.
date: 2020-07-21
url: https://doi.org/10.1038/s41598-020-68722-8
doi: 10.1038/s41598-020-68722-8
abstract:
  Neisseria gonorrhoeae bacteria are acknowledged as an urgent threat to human health because this species has developed resistances to all of the antibiotics used clinically to treat its infections. N. gonorrhoeae causes the sexually transmitted disease gonorrhoea, but also causes blindness when the bacteria infect the eyes. Infants are particularly susceptible, acquiring the infection from their mothers at birth. We have shown that the monoglyceride monocaprin rapidly kills N. gonorrhoeae and other bacterial species and is non-irritating in ocular assays. Here we show that the physical and chemical properties of monocaprin make it ideal for use in a thickened eye drop formulation to combat eye infections. Monocaprin-containing formulations were assessed using analytical techniques and for antimicrobial activity in vitro and in ex vivo infections. Monocaprin-containing formulations retained activity after three years and are non-irritating, unlike preparations of povidone iodine in our assays. A recommended formulation for further development and investigation is 0.25% monocaprin in 1% HPMC with 1% polysorbate 20.


