# ent

id: cord-018103-czjjnlkf
type: ORG
entity:
  the SARS Coronavirus Computational Identification of Putative Programmed Translational Frameshift Sites Bioinformatics


id: cord-024166-t3qxscbp
type: CHEMICAL
entity:
  Polygala vulgaris Centaurea jacea Pimpinella saxifraga Carum carvi Danthonia decumbens Lotus corniculatus


id: cord-007199-ol2du7ph
type: PROTEIN
entity:
  adam17 aggrecanase alpha secretase beta secretase caspase 6 cathepsin G arginine specific endoprotease C3 convertase chymosin collagenase dipeptidase dipeptidylpeptidase DPP4 easter elastase kallikrein


id: cord-007199-ol2du7ph
type: GGP
entity:
  endoprotease C3 convertase chymosin collagenase dipeptidase dipeptidylpeptidase DPP4 easter elastase kallikrein


id: cord-274409-4ugdxbmy
type: DNA
entity:
  SARS CoV 2 genomes D 9 A872T T882I Y925C E940D P971S G989V S1029I P1054L M1083I H1141Y A1268T S1534I T1543K T1567I M1588I V1629A S1733G T1761I G1861S T1822I T1854A T1854I N1871T K1973R S2103F K2029E G2035E P2144S


id: cord-274409-4ugdxbmy
type: GGP
entity:
  bioRxiv DOI 10 1101 2020 10 19 345066 sha 46487653521132ccf6dd19d286c2e538b8ce72fa doc_id 274409 cord_uid 4ugdxbmy


id: cord-009716-oxahu8nz
type: CHEMICAL
entity:
  Parthenium hysterophorus The small forbs Sida cordifolia Alternanthera bettzikiana Xanthium strumarium


id: cord-010307-sxh5mq1q
type: DNA
entity:
  Top End i Chalinolobus nigrogriseus Scotorepens greyii and Scotorepens sanborni ii Miniopterus schreibersii


id: cord-328681-jf2mj16z
type: GGP
entity:
  Refs 5 9 15 These methods involve the following steps counting synonymous S and nonsynonymous N sites


id: cord-034684-ehaiqye5
type: ORG
entity:
  the Central Bureau of Statistics the Department of Labor the Department of Nature and Environment the Aruba Tourism Authority


id: cord-034684-ehaiqye5
type: ORG
entity:
  Washington Inter American Development Bank Country Department Caribbean Inclusive Tourism Development Emotional


id: cord-009730-lc8712xm
type: CELL_LINE
entity:
  Lake Basin S reticulata S pulchm S rcticula fa S phlebophylla S lanata S alaxensls Dry Ridge Ice Scrape Dunes


id: cord-009730-lc8712xm
type: CHEMICAL
entity:
  S lanata S glauca S retimlata S alaxcnsis Lake Basin S reticulata S pulchm S rcticula fa S phlebophylla S lanata S


id: cord-260657-yf8fvx7k
type: WORK_OF_ART
entity:
  An Extended Signal Involved in Eukaryotic 1 Frameshifting Operates through Modification of the E Site tRNA date 2005 01 07


id: cord-322129-uyswj4ow
type: CARDINAL
entity:
  10 m of great apes ensuring that individuals needing to cough or sneeze ideally leave the area or at least cough sneeze into the crux of their elbows imposing a


id: cord-332855-u0amf1oh
type: FAC
entity:
  the Veterinary Pathologic Diagnostic Center Department of Pathobiology Faculty of Veterinary Medicine Utrecht University


id: cord-356264-q0yqnlyl
type: WORK_OF_ART
entity:
  The Effect of Species Representation on the Detection of Positive Selection in Primate Gene Data Sets UCSF Chimera


id: cord-332948-h297ukuu
type: ORG
entity:
  the Fusion Peptide Role of the Spike Glycoprotein of Human Middle East Respiratory Syndrome Coronavirus


id: cord-332948-h297ukuu
type: WORK_OF_ART
entity:
  Can We Rely on Computational Predictions To Correctly Identify Ligand Binding Sites on Novel Protein Drug Targets Assessment of Binding Site Prediction Methods and a Protocol for Validation of Predicted Binding Sites Identifying


id: cord-289443-46w52de3
type: PROTEIN
entity:
  ankyrin repeat domain 30A ANKRD30A CD4 microtubule associated protein 4 MAP4 nucleoporin 153 kDa NUP153


id: cord-289443-46w52de3
type: PROTEIN
entity:
  proteolytic fragments B2M β2 microglobulin BLMH bleomycin hydrolase CALR calreticulin CD40LG CD40 ligand


id: cord-289443-46w52de3
type: PROTEIN
entity:
  cellular proteases ACE2 angiotensin converting enzyme 2 DARC Duffy blood group atypical chemokine receptor MX1 myxovirus resistance 1 SSD sterol sensing domain TFRC transferrin receptor TLR4 Toll


id: cord-289443-46w52de3
type: CL
entity:
  natural killer T iTCR invariant TCR LGMN legumain LNPEP leucyl cystinyl aminopeptidase NCF neutrophil cytosol


id: cord-289443-46w52de3
type: DISEASE
entity:
  HIV 1 replication HIV 1 capsid cyclophilin interactions determine nuclear import pathway integration targeting and replication efficiency This


id: cord-332165-31tbc31x
type: WORK_OF_ART
entity:
  Physical Principles in the Construction of Regular Viruses Characterization of the Adeno Associated Virus 1


id: cord-332165-31tbc31x
type: WORK_OF_ART
entity:
  Structure Based Inhibitors of Influenza Virus Sialidase A Benzoic Acid Lead with Novel Interaction Synthesis


id: cord-327069-vjlisnui
type: PROTEIN
entity:
  Orin S Baggett Henry C Brooks W Abdullah Feikin Daniel R Hammitt Laura L Howie Stephen R C Knoll Maria Deloria Kotloff Karen L Madhi


id: cord-341968-uc8i9h0m
type: PROTEIN
entity:
  unnatural amino acids 126 127 128 129 130 131 132 133 134 135 cyclic peptides 136 polyarginine 137 138 139


id: cord-304421-xpj6c0vx
type: CHEMICAL
entity:
  N terminal ORF 1a proteins of the coronavirus MHV A59 requires multiple proteolytic events Identification of polypeptides encoded in open reading frame 1b of the putative polymerase gene of the murine


id: cord-275307-d7htyfcl
type: GGP
entity:
  n 61 SOX n 178 B Frequency distribution histogram of log likelihood scores for the 20 nt surrounding


id: cord-103085-vf4qyvft
type: PROTEIN
entity:
  Human Influenza H3 Human Influenza A Virus Hemagglutinin Glycan Evolution Follows a Temporal Pattern


id: cord-103085-vf4qyvft
type: ORG
entity:
  the Innate Immune System Playing Hide and Seek How Glycosylation of the Influenza Virus Hemagglutinin


id: cord-103085-vf4qyvft
type: ORG
entity:
  Influenza Virus Using Computational Techniques To Extend Structural Data Molecular Simulations of Diffusion and Association


id: cord-103085-vf4qyvft
type: ORG
entity:
  Numerical Integration of the Cartesian Equations of Motion of a System with Constraints Molecular Dynamcis


id: cord-351115-dy81dtnk
type: GGP
entity:
  SCW z Score is 2 standard deviations above the randomized background suggesting that the alignments are informative and that the resulting ET rankings are meaningful Figure S1 Dataset S3 For the proteins


id: cord-351115-dy81dtnk
type: CHEBI
entity:
  protein drug complexes 7 8 51 52 53 and as shown in Figure 3 all ve drugs reside in protein surface pockets


id: cord-351115-dy81dtnk
type: GGP
entity:
  SARS CoV 2 helicase at 1 94 Angstrom resolution Structural basis and functional analysis of the SARS coronavirus nsp14 nsp10 complex


id: cord-351115-dy81dtnk
type: ORG
entity:
  SARS CoV 2 Remdesivir A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID 19


id: cord-338980-pygykil7
type: PROTEIN
entity:
  YP_009047202 1 polyprotein S protein YP_009047204 1 M protein YP_009047210 1 E protein YP_009047209 1


id: cord-338980-pygykil7
type: PROTEIN
entity:
  protein families NSP1 YP_009047202 1 1 193 NSP2 YP_009047202 1 194 853 NS3 YP_009047205 1 NS4A YP_009047206 1 NS4B YP_009047207 1 NS5 YP_009047208 1 ORF8b protein YP_009047212 1


id: cord-022955-vy0qgtll
type: PROTEIN
entity:
  brainspecific metalloprotease M Teufel Biochemistry Exploratory Research Sanofi Aventis Strasbourg France E


id: cord-022955-vy0qgtll
type: CELL_TYPE
entity:
  human B lymphocytes E Janas 1 R Priest 1 S Ratcliffe 2 and R Malhotra 1 1 Rheumatoid Arthritis Biology GlaxoSmithKline Stevenage UK 2 High Throughput Chemistry GlaxoSmithKline Stevenage UK E


id: cord-022955-vy0qgtll
type: PROTEIN
entity:
  zinc chelator Y Tamada 1 T Nakajima 1 T R Shearer 2 and M Azuma 1 2 1 Research Laboratories Senju Pharmaceutical Co Ltd


id: cord-022955-vy0qgtll
type: PROTEIN
entity:
  tissue type plasminogen activator t PA plasminogen activator inhibitor PAI 1 plasminogen a2 antiplasmin


id: cord-022955-vy0qgtll
type: ORG
entity:
  F Sannier Laboratory of Biotechnology and Bioorganic Chemistry University of La Rochelle La Rochelle


id: cord-022955-vy0qgtll
type: ORG
entity:
  Group Hungarian Academy of Sciences Budapest Hungary 3 Department of Biochemistry University of Oxford Oxford


id: cord-022955-vy0qgtll
type: ORG
entity:
  K Troulinaki Institute of Molecular Biology and Biotechnology Foundation for Research and Technology


id: cord-022955-vy0qgtll
type: CHEMICAL
entity:
  auxins 2 4 Dichlorophenoxyacetic acid 2 4 D 4 amino 3 5 6 Trichloropiridin 2 carboxilic acid Picloram Indoleacetic acid IAA


id: cord-022955-vy0qgtll
type: CHEMICAL
entity:
  Chernova 1 K D Allen 2 E P Tennant 2 K D Wilkinson 1 and Y O Chernoff 2 1 Department of Biochemistry Emory


id: cord-001835-0s7ok4uw
type: PROTEIN
entity:
  villin headpiece miniprotein Stanislaw Oldziej 1 Wioletta _ Zmudzi nska 1 Anna Hałabis 1 1 The C terminal subdomain


id: cord-001835-0s7ok4uw
type: PROTEIN
entity:
  human glucose 6 phosphate dehydrogenase G6PD Nurriza Ab Latif 1 2 Paul Engel 1 1 Conway Institute Univerversity College Dublin 2 Faculty of Biosciences and Medical Engineering Universiti Teknologi Malaysia Human glucose 6 phosphate dehydrogenase G6PD


id: cord-001835-0s7ok4uw
type: PROTEIN
entity:
  coagulation factor VIIa Jais R Bjelke 1 Gorm Andersen 1 Henrik Østergaard 1 Laust B Johnsen 1 Anette A Pedersen 1 Tina H Glue 1 1


id: cord-001835-0s7ok4uw
type: PROTEIN
entity:
  enoyl CoA hydratase family Fernandes 1 Teresa Sorbo 2 Ivan Duka 2 Lia Christina Appold 3 Marianne Ilbert 4 Fabian Kiessling 3 CNRS UMR 7281 5 UCiBio REQUIMTE


id: cord-001835-0s7ok4uw
type: GGP
entity:
  Biryukova 1 Elizaveta Kostanova 1 Alexey Kononikhin 0 Anna Bugrova 1 Evgeny Nikolaev 0 Mark Rosenfeld 1 1 N M


id: cord-001835-0s7ok4uw
type: ORG
entity:
  School of Chemistry National University of Ireland Galway 2 School of Biochemistry and Immunology Trinity College


id: cord-001835-0s7ok4uw
type: WORK_OF_ART
entity:
  Destabilizing the Transient Helical Conformation of Islet Amyloid Polypeptide Hastens Peptide Self Assembly and Potentiates Cytotoxicity Carole Anne de Carufel 1


id: cord-001835-0s7ok4uw
type: EVENT
entity:
  Physical and Engineering Biology Yale University 3 Mechanical Engineering and Materials Science Yale University 4 Applied Physics Yale University


id: cord-001835-0s7ok4uw
type: ORG
entity:
  Department of Biology Stanford University 2 Department of Pediatrics Stanford University 3 Department of Pharmacology University of California San Diego 4 Department of Pediatrics Emory University 5 Institute for Biomedical Sciences


id: cord-001835-0s7ok4uw
type: ORG
entity:
  Graduate School of Science and Engineering Ibaraki University 3 Department of Life Science Graduate School of Life Science University of Hyogo 4


id: cord-001835-0s7ok4uw
type: ORG
entity:
  The New York Structural Biology Center 5 Department of Biochemistry Faculty of Medicine University of Montreal


id: cord-001835-0s7ok4uw
type: ORG
entity:
  University of Southern California Keck School of Medicine 2 Developing a Technique to Detect Deamidated Proteins


id: cord-001835-0s7ok4uw
type: ORG
entity:
  the Ethical Committee for Animal Experimentation from Center of Health and Science of the Federal University of Rio de Janeiro


id: cord-001835-0s7ok4uw
type: ORG
entity:
  1 National Autonomous University of Mexico Faculty of Medicine 2 National Autonomous University of Mexico Faculty of Chemistry 3


id: cord-001835-0s7ok4uw
type: WORK_OF_ART
entity:
  Deartment of Biology Wilfrid Laurier University 2 Department of Biology University of Waterloo Chloroplast


id: cord-001835-0s7ok4uw
type: ORG
entity:
  University of Greenwich Faculty of Engineering and Sciene 2 University of Greenwich Centre of Sports Science and Human Performance


id: cord-001835-0s7ok4uw
type: CHEMICAL
entity:
  N terminal recognition element In addition expressed protein ligation is being used to incorporate backbone modifications such as the thioamide


id: cord-001835-0s7ok4uw
type: CHEMICAL
entity:
  N terminal catalytic module 2 This module shows the capacity of recognize the GlcNAc MurNAc L Ala D isoGln muropeptide GMDP


id: cord-001835-0s7ok4uw
type: DISEASE
entity:
  acute myeloid leukemia mutations Daniela Marasco 1 Concetta Di Natale 1 Valentina Punzo 1 Domenico Riccardi 1 Pasqualina Scognamiglio 1 Roberta Cascella 2 Cristina Cecchi 2 Fabrizio Chiti 2 Marilisa Leone


id: cord-001835-0s7ok4uw
type: DISEASE
entity:
  human immunodeficiency virus type 1 subtype C based on Envelope V3 sequences Available http istree bioprotection org Signal processing based Bioinformatics methods


# bib

id: cord-000294-2g471tb4
title: A flexible loop in yeast ribosomal protein L11 coordinates P-site tRNA binding
author: Rhodin, Michael H. J.
date: 2010-08-12
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3001080/
doi: 10.1093/nar/gkq711
abstract:
  High-resolution structures reveal that yeast ribosomal protein L11 and its bacterial/archael homologs called L5 contain a highly conserved, basically charged internal loop that interacts with the peptidyl-transfer RNA (tRNA) T-loop. We call this the L11 ‘P-site loop’. Chemical protection of wild-type ribosome shows that that the P-site loop is inherently flexible, i.e. it is extended into the ribosomal P-site when this is unoccupied by tRNA, while it is retracted into the terminal loop of 25S rRNA Helix 84 when the P-site is occupied. To further analyze the function of this structure, a series of mutants within the P-site loop were created and analyzed. A mutant that favors interaction of the P-site loop with the terminal loop of Helix 84 promoted increased affinity for peptidyl-tRNA, while another that favors its extension into the ribosomal P-site had the opposite effect. The two mutants also had opposing effects on binding of aa-tRNA to the ribosomal A-site, and downstream functional effects were observed on translational fidelity, drug resistance/hypersensitivity, virus maintenance and overall cell growth. These analyses suggest that the L11 P-site loop normally helps to optimize ribosome function by monitoring the occupancy status of the ribosomal P-site.


id: cord-001835-0s7ok4uw
title: Abstracts of the 29th Annual Symposium of The Protein Society
author: nan
date: 2015-10-01
txt: ./txt/cord-001835-0s7ok4uw.txt
cache: ./cache/cord-001835-0s7ok4uw.txt
extension: .txt
mime: text/plain
url: https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/pro.2823
doi: 10.1002/pro.2823
abstract: nan
summary:
  Altogether, these results indicate that, although PHDs might be more selective for HIF as a substrate as it was initially thought, the enzymatic activity of the prolyl hydroxylases is possibly influenced by a number of other proteins that can directly bind to PHDs. Non-natural aminoacids via the MIO-enzyme toolkit Alina Filip 1 , Judith H Bartha-V ari 1 , Gergely B an oczy 2 , L aszl o Poppe 2 , Csaba Paizs 1 , Florin-Dan Irimie 1 1 Biocatalysis and Biotransformation Research Group, Department of Chemistry, UBB, 2 Department of Organic Chemistry and Technology An attractive enzymatic route to enantiomerically pure to the highly valuable a-or b-aromatic amino acids involves the use of aromatic ammonia lyases (ALs) and aminomutases (AMs). Continuing our studies of the effect of like-charged residues on protein-folding mechanisms, in this work, we investigated, by means of NMR spectroscopy and molecular-dynamics simulations, two short fragments of the human Pin1 WW domain [hPin1(14-24); hPin1(15-23)] and one single point mutation system derived from hPin1(14-24) in which the original charged residues were replaced with non-polar alanine residues.


id: cord-007199-ol2du7ph
title: Predicting proteolytic sites in extracellular proteins: only halfway there
author: Kliger, Yossef
date: 2008-04-15
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109841/
doi: 10.1093/bioinformatics/btn084
abstract:
  Motivation: Many secretory proteins are synthesized as inactive precursors that must undergo post-translational proteolysis in order to mature and become active. In the current study, we address the challenge of sequence-based discovery of proteolytic sites in secreted proteins using machine learning. Results: The results revealed that only half of the extracellular proteolytic sites are currently annotated, leaving over 3600 unannotated ones. Furthermore, we have found that only 6% of the unannotated sites are similar to known proteolytic sites, whereas the remaining 94% do not share significant similarity with any annotated proteolytic site. The computational challenges in these two cases are very different. While the precision in detecting the former group is close to perfect, only a mere 22% of the latter group were detected with a precision of 80%. The applicability of the classifier is demonstrated through members of the FGF family, in which we verified the conservation of physiologically-relevant proteolytic sites in homologous proteins. Contact: kliger@compugen.co.il; yossef.kliger@gmail.com Supplementary information: Supplementary data are available at Bioinformatics online.


id: cord-009716-oxahu8nz
author: Lawes, Roger A.
date: 2006-10-27
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163630/
doi: 10.1111/j.1472-4642.2006.00291.x
title:
  Comparing agglomerative clustering and three weed classification frameworks to assess the invasiveness of alien species across spatial scales

abstract:
  To prioritize weed management at the catchment scale, information is required on the species present, their relatively frequency, abundance, and likely spread and impact. The objective of this study was to classify the invasiveness of alien species that have invaded the Upper Burdekin Catchment in Queensland, Australia, at three spatial scales. A combination of three published weed classification frameworks and multivariate techniques were employed to classify species based on their frequency and cover at a range of spatial scales. We surveyed the Upper Burdekin Catchment for alien species, and for each species determined the following distribution indices — site frequency, total cover, transect frequency per site frequency and quadrat frequency per site frequency, cover per quadrat when present, cover per transect when present, and cover per site when present. These indices capture the effect of species abundance and frequency between sites (site frequency and total cover), within sites (transect frequency per site and cover per transect when present), and within transects (quadrat frequency per site frequency and cover per site). They were used to classify the species into seven groups using a hierarchical cluster analysis. The relationship between the indices was explored to determine how effective the small scale, site‐specific indices were at predicting the broader, landscape‐scale patterns. Strong correlations were observed between transect frequency per site and frequency (r (2) = 0.89) and cover per transect when present and total cover (r (2) = 0.62). This suggests that if a weed is abundant at the site level, it has the potential to occupy large areas of the catchment. The species groupings derived from the application of the three published weed classification frameworks were compared graphically to the groupings derived from the cluster analysis. One of the frameworks classified species into three groups. The other two frameworks classified species into four groups. There was a high degree of subjectivity in applying the frameworks to the survey data. Some of the data were of no relevance to the classification frameworks and were therefore ignored. We suggest that the weed classification frameworks should be used in conjunction with existing multivariate techniques to ensure that classifications capture important natural variations in observed data that may reflect invasion processes. The combined use of the frameworks and multivariate techniques enabled us to aggregate species into categories appropriate for management.


id: cord-009730-lc8712xm
author: HODKINSON, I. D.
date: 2008-03-14
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163764/
doi: 10.1111/j.1365-2311.1979.tb00568.x
title:
  The distribution, abundance and host plant relationships of Salix‐ feeding psyllids (Homoptera: Psylloidea) in arctic Alaska

abstract:
  Abstract. 1. Five species of psyllid occurred on seven species of Salix at Meade River, Alaska. Studies were made on the two common species Psylla pclmeni Löw and P.phlebophyllae Hodkinson. The former feeds on the phanerophy tes Salix pulchra, S.lanata, S.alaxensis and S.glauca, the latter on the chamaephytes S.phlebophylla and S.reticulata. 2. Both P.palmeni and P.phlebophyllae had a 1‐year life cycle and nymphal development took place on the female Salix catkin. The life cycle was generally closely synchronized with the period of catkin development. However, only a few eggs were laid on S.glauca 3. Seasonal perturbation of the host plant by flooding, ice movement and blown sand prevented psyllids breeding in certain areas colonized by the host plant. 4. In P.palmenidensities and ‘feeding pressure’, measured as biomass of psyllids per gram of catkin, on the different host plants followed the sequence S.pulchra>S.lanata> S.alaxensis > S.glauca. In P.phlebophyllae densities and feeding intensities were similar onS.phlebophyllaandS.reticulataand grazing intensity was comparable withP.palmenion S.pulchra. 5. A highly significant negative correlation was found between psyllid density and catkin dry weight in S.pulchra, S.phlebophylla and S.reticulata, suggesting that psyllid feeding is affecting catkin growth. 6. Predation of psyllid nymphs by syrphid larvae was heavy but there was no evidence of parasitism. 7. The life history strategies of the five psyllid species are discussed within the context of the constraints imposed by the arctic environment.


id: cord-010307-sxh5mq1q
author: MILNE, D. J.
date: 2005-11-23
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175956/
doi: 10.1111/j.1442-9993.2005.01535.x
title:
  Structure and environmental relationships of insectivorous bat assemblages in tropical Australian savannas

abstract:
  Abstract Patterns in the composition of assemblages of microbat species sampled during the late dry season (the ‘build‐up’) in north Australian savannas were assessed against a range of environmental factors as well as four a priori defined habitat types (riparian, escarpments, coastal and woodlands). Distinct species assemblages were most strongly associated with topographic and climatic variables. There were also limited associations with vegetation structure, fire and local roost potential but no associations with insects or water availability. Total species diversity at sample sites was associated with distance to rivers and rainfall. In general, species assemblages were not clearly defined and the number of significant environmental associations was relatively few. We compare these associations with those reported for bat assemblages elsewhere in Australia.


id: cord-010628-71rkpco4
author: WISE, E. J.
date: 2006-05-29
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202231/
doi: 10.1111/j.1365-2427.1976.tb01621.x
title:
  Studies on the Ephemeroptera of a Northumbrian river system: I. Serial distribution and relative abundance

abstract:
  The River Coquet is a clean, fast flowing, moderately calcareous river. It is young to mature in development and supports a typical torrential fauna. Marked trends in successional replacement along the river course are confined to the scarce species of Ephemeroptera and the absence of longitudinal zonation in the distribution of some common species is related to the topographical characteristics of the system. A distinct successional trend by one species is attributed to its intolerance to the lower temperatures at high altitudes. Major discontinuities in distribution are found between the Ephemeroptera of the main river and certain tributaries. The paucity of certain otherwise abundant species in one region is related to silt deposition resulting from sand and gravel excavation.


id: cord-013443-x74uxdi4
author: Daniel, Dennis A.
date: 2020-06-25
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597756/
doi: 10.1097/pcc.0000000000002477
title:
  Pediatric Resident Engagement With an Online Critical Care Curriculum During the Intensive Care Rotation*

abstract:
  Residents are often assigned online learning materials as part of blended learning models, superimposed on other patient care and learning demands. Data that describe the time patterns of when residents interact with online learning materials during the ICU rotation are lacking. We describe resident engagement with assigned online curricula related to time of day and ICU clinical schedules, using website activity data. DESIGN: Prospective cohort study examining curriculum completion data and cross-referencing timestamps for pre- and posttest attempts with resident schedules to determine the hours that they accessed the curriculum and whether or not they were scheduled for clinical duty. Residents at each site were cohorted based on two differing clinical schedules—extended duration (>24 hr) versus shorter (maximum 16 hr) shifts. SETTING: Two large academic children’s hospitals. SUBJECTS: Pediatric residents rotating in the PICU from July 2013 to June 2017. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One-hundred and fifty-seven pediatric residents participated in the study. The majority of residents (106/157; 68%) completed the curriculum, with no statistically significant association between overall curriculum completion and schedule cohort at either site. Residents made more test attempts at nighttime between 6 pm and 6 am (1,824/2,828; 64%) regardless of whether they were scheduled for clinical duty. Approximately two thirds of test attempts (1,785/2,828; 63%) occurred when residents were not scheduled to work, regardless of time of day. Forty-two percent of all test attempts (1,199/2,828) occurred between 6 pm and 6 am while off-duty, with 12% (342/2,828) occurring between midnight and 6 am. CONCLUSIONS: Residents rotating in the ICU completed online learning materials mainly during nighttime and off-duty hours, including usage between midnight and 6 am while off-duty. Increasing nighttime and off-duty workload may have implications for educational design and trainee wellness, particularly during busy, acute clinical rotations, and warrants further examination.


id: cord-018103-czjjnlkf
title: Prediction of Ribosomal -1 Frameshifts in the Escherichia coli K12 Genome
author: Moon, Sanghoon
date: 2006
txt: ./txt/cord-018103-czjjnlkf.txt
cache: ./cache/cord-018103-czjjnlkf.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7122894/
doi: 10.1007/11816102_65
summary:
  We have developed a web-based application program called FSFinder2 for predicting frameshift sites of general type. In previous work we developed a program called FSFinder (Frameshift Signal Finder) for predicting -1 and +1 frameshift sites [5] . In previous experimental results of testing FSFinder2 on ~190 genomic and partial DNA sequences showed that it predicted frameshift sites efficiently and with greater sensitivity and specificity than other programs, because it focused on the overlapping regions of ORFs and prioritized candidate signals (For -1 frameshifts, sensitivity was 0.88 and specificity 0.97; for +1 frameshifts, sensitivity was 0.91 and specificity 0.94) [5] [6] [7] . coli K12 genome sequence, we found 18,401 frameshift sites after the X XXY YYZ motif. Among these sequences, 11,530 frameshift sites included secondary structure such as pseudoknots or stem-loops. Among these sites, 11 sites including 3 known frameshift sites were considered significant based on the gene length, shape and the length of overlapping region.

abstract:
  Ribosomal frameshifting at a particular site can yield two protein products from one coding sequence or one protein product from two overlapping open reading frames. Many organisms are known to utilize ribosomal frameshifting to express a minority of genes. However, finding ribosomal frameshift sites by a computational method is difficult because frameshift signals are diverse and dependent on the organisms and environments. There are few computer programs available for public use to identify frameshift sites from genomic sequences. We have developed a web-based application program called FSFinder2 for predicting frameshift sites of general type. We tested FSFinder2 on the Escherichia coli K12 genome to detect potential -1 frameshifting genes. From the genome sequence, we identified 18,401 frameshift sites following the X XXY YYZ motif. 11,530 frameshift sites out of the 18,401 sites include secondary structures. Comparison with the GenBank annotation produced 11 potential frameshift sites, including 3 known frameshift sites. The program is useful for analyzing frameshifts of various types and for discovering new genes expressed by frameshifts.


id: cord-018865-melttpiq
author: Yu, Tian-fei
date: 2012
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7123857/
doi: 10.1007/978-3-642-27537-1_7
title:
  Express Transmissible Gastroenteritis Virus Spike Gene B and C Antigen Sites in Multiple Expression Systems

abstract:
  In order to illuminate the antigenicity of porcine transmissible gastroenteritis virus (TGEV) spike protein B and C antigen sites, the truncated spike gene including B and C antigen sites of Chinese isolate TH-98 was expressed respectively in E.coli, baculovirus and pichia pastoris expression systems. Dot enzyme-linked immunosorbent assays (Dot-ELISA) based on these three recombinant proteins were developed preliminarily. Ten sera obtained correspondingly from ten piglets two months old which showed up clinical symptom were used for examination. The study indicates that the assays are rapid, reliable and sensitive and it has the potential for use as serological methods for TGEV diagnosis.


id: cord-022955-vy0qgtll
title: Proteases
author: nan
date: 2005-06-20
txt: ./txt/cord-022955-vy0qgtll.txt
cache: ./cache/cord-022955-vy0qgtll.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164095/
doi: 10.1111/j.1742-4658.2005.4739_4.x
abstract: nan
summary:
  In order to understand the molecular basis of the enzyme-substrate binding mechanism, we employ the synthetic peptide and mass spectrometry-based approaches to investigate the significance of selected amino acid residues that are flanking both sides of the SARS-CoV 3CL pro cleavage site. To contribute to the assignment of a physiological role to genomic-derived peptidases and to make them more accessible for the drug discovery process, we have undertaken a program consisting of mRNA expression profiling, full-length recombinant expression in insect cells, purification and determination of the catalytic activity for the human proteolytic enzymes. This comprehensive analysis of the local backbone properties of SGTI in the free and in the complex form made possible to identify conformational similarities and differences responsible for its efficient binding to the enzyme, and provides a good basis for further studying the structural aspects of protease inhibitor specificity.


id: cord-024166-t3qxscbp
author: Losvik, Mary H.
date: 2008-06-28
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192332/
doi: 10.1111/j.1756-1051.1999.tb01231.x
title:
  Plant species diversity in an old, traditionally managed hay meadow compared to abandoned hay meadows in southwest Norway

abstract:
  A chronosequence, representing a successional series, was used for the comparison of a hay meadow site managed in an old traditional way for at least a hundred years, and hay meadow sites abandoned for about 10, 20 and 30 years, respectively. Old traditional management included grazing early and late in the growing season, mowing in August and light or no fertilizing. The tree cover was the most important factor deciding the composition of vegetation. Time since abandonment was not completely correlated to tree cover, as some plots had a dense canopy and others were situated in the open. The total species number decreased with number of years since abandonment in plots > 0.001 m(2)and <100 m(2). The highest species number in 1 m(2) plots was recorded in the managed site, with 38 species of phanerogams. Fourtyeight % of the indicators of traditional management present in the managed site was recorded in the site which had been abandoned for 30 years. Frequency — log area curves made it possible to group species according to persistence in the sward. As a result, a group of functional indicators of rare hay meadows in the region was distinguished.


id: cord-024619-0wihqs9i
author: Parvin, Farhana
date: 2020-05-11
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211563/
doi: 10.1007/s41324-020-00330-0
title:
  Accessibility and site suitability for healthcare services using GIS-based hybrid decision-making approach: a study in Murshidabad, India

abstract:
  Healthcare accessibility and site suitability analysis is an elongated and complex task that requires evaluation of different decision factors. The main objective of the present study was to develop a hybrid decision-making approach with geographic information systems to integrate spatial and non-spatial data to form a weighted result. This study involved three-tier analyses for assessing accessibility and selecting suitable sites for healthcare facilities, and analysing shortest-path network. The first tier of analysis stressed the spatial distance, density and proximity from existing healthcare to find more deprived and inaccessible areas in term of healthcare facilities. The result revealed that spatial discrepancy exists in the study area in term of access to healthcare facilities and for achieving equal healthcare access, it is essential to propose new plans. Thus, require finding suitable sites for put forward new healthcare service, which was highlighted in the second tier of analysis based on land use land cover, distancing to road and rail, proximity to residential areas, and weighted overlay of accessibility as decision factors. Finally, in the third tier of analysis, the most suitable site among the proposed healthcare was identified using the technique for order of preference by similarity to ideal solution. The road network analysis was also performed in this study to determine the shortest and fastest route from these healthcare facilities to connect with district medical hospital. The present study found some suitable sites throughout the district on inaccessible zones where people are deprived from better healthcare facilities. This attempt will highly helpful for preparing a spatial decision support system which assists the health authorities regarding the healthcare services in inaccessible, underprivileged, and rural areas. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s41324-020-00330-0) contains supplementary material, which is available to authorized users.


id: cord-028681-e2zh6092
title: It Never Rains but It Pours: Analyzing and Detecting Fake Removal Information Advertisement Sites
author: Koide, Takashi
date: 2020-06-11
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338187/
doi: 10.1007/978-3-030-52683-2_9
abstract:
  Fake antivirus (AV) software is a serious threat on the Internet to make users install malware and expose their personal information. Fake removal information advertisement (FRAD) sites, which introduce fake removal information for cyber threats, have emerged as platforms for distributing fake AV software. Although FRAD sites seriously threaten users who have been suffering from cyber threats and need information for removing them, little attention has been given to revealing these sites. In this paper, we propose a system to automatically crawl the web and identify FRAD sites. To shed light on the pervasiveness of this type of attack, we performed a comprehensive analysis of both passively and actively collected data. Our system collected 2,913 FRAD sites in 31 languages, which have 73.5 million visits per month in total. We show that FRAD sites occupy search results when users search for cyber threats, thus preventing the users from obtaining the correct information.


id: cord-034684-ehaiqye5
title: Over the Caribbean Top: Community Well-Being and Over-Tourism in Small Island Tourism Economies
author: Peterson, Ryan R.
date: 2020-11-05
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643527/
doi: 10.1007/s42413-020-00094-3
abstract:
  The Caribbean is one of the most tourism-intense regions of the world with rising levels of over-tourism, especially in dependent small island tourism economies (SITE). More critically, mounting socio-ecological pressures are compounded by increasing climate change and enduring social vulnerabilities, thereby challenging traditional policies and paradigms of growth and sustainability. Drawing on previous studies of inclusive development and community well-being, this research paper frames and extends the phenomenon of over-tourism from a political economic perspective. Based on a historical account of small island tourism development, an in-depth case study of Aruba is presented. Recognized internationally as the ‘One Happy Island’ and one of the most tourism-dependent small island economies, the findings yield a contextualized understanding of the complex and dynamic nature of over-tourism, and identify the main antecedents and effects of over-tourism. The study discusses the evolving economic disconnectedness, environmental decay, social inequality, and institutional failures. The findings describe the role of institutional capture and policy drift which stem primarily from political as well as market forces, and have resulted in a gradual marginalization of community well-being and agency. The paper proposes an extended conceptualization of over-tourism in small island tourism economies by explicitly recognizing that the crux of the over-tourism conundrum in SITE is political in nature and institutional by nurture. Recommendations are provided for transitioning towards community-driven development by building capabilities and pathways for innovation, internalization, and institutionalization in order to strengthen the resilience of small island tourism development.


id: cord-048327-xgwbl8em
title: Antisense-induced ribosomal frameshifting
author: Henderson, Clark M.
date: 2006-08-18
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1616946/
doi: 10.1093/nar/gkl531
abstract:
  Programmed ribosomal frameshifting provides a mechanism to decode information located in two overlapping reading frames by diverting a proportion of translating ribosomes into a second open reading frame (ORF). The result is the production of two proteins: the product of standard translation from ORF1 and an ORF1–ORF2 fusion protein. Such programmed frameshifting is commonly utilized as a gene expression mechanism in viruses that infect eukaryotic cells and in a subset of cellular genes. RNA secondary structures, consisting of pseudoknots or stem–loops, located downstream of the shift site often act as cis-stimulators of frameshifting. Here, we demonstrate for the first time that antisense oligonucleotides can functionally mimic these RNA structures to induce +1 ribosomal frameshifting when annealed downstream of the frameshift site, UCC UGA. Antisense-induced shifting of the ribosome into the +1 reading frame is highly efficient in both rabbit reticulocyte lysate translation reactions and in cultured mammalian cells. The efficiency of antisense-induced frameshifting at this site is responsive to the sequence context 5′ of the shift site and to polyamine levels.


id: cord-103085-vf4qyvft
title: Multiscale simulations examining glycan shield effects on drug binding to influenza neuraminidase
author: Seitz, Christian
date: 2020-11-02
txt: ./txt/cord-103085-vf4qyvft.txt
cache: ./cache/cord-103085-vf4qyvft.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.08.12.248690
doi: 10.1101/2020.08.12.248690
summary:
  Using Brownian dynamics simulations, we observe a twoto eight-fold decrease in the rate of ligand binding to the primary binding site of neuraminidase due to the presence of glycans. We have utilized BD to estimate the rates of binding of small molecules to the primary (i.e. active/catalytic) and secondary (i.e. hemadsorption) binding sites of influenza neuraminidase in glycosylated and unglycosylated states. The protein-ligand atom pairs were taken from crystal structures of ligands in the primary and secondary sites of neuraminidase for each monomer, and simulations were run for the full tetramer. Keeping in mind the primary and secondary binding sites are located just beneath the glycans (Figure 1) , the size and flexibility of the glycans here shows that they have the capability to "shield" the binding sites from ligand association. (A) The glycan structures from the MD simulations show a moderate association rate inhibition to the primary binding site irrespective of ligand chosen.

abstract:
  Influenza neuraminidase is an important drug target. Glycans are present on neuraminidase, and are generally considered to inhibit antibody binding via their glycan shield. In this work we studied the effect of glycans on the binding kinetics of antiviral drugs to the influenza neuraminidase. We created all-atom in silico systems of influenza neuraminidase with experimentally-derived glycoprofiles consisting of four systems with different glycan conformations and one system without glycans. Using Brownian dynamics simulations, we observe a two- to eight-fold decrease in the rate of ligand binding to the primary binding site of neuraminidase due to the presence of glycans. These glycans are capable of covering much of the surface area of neuraminidase, and the ligand binding inhibition is derived from glycans sterically occluding the primary binding site on a neighboring monomer. Our work also indicates that drugs preferentially bind to the primary binding site (i.e. the active site) over the secondary binding site, and we propose a binding mechanism illustrating this. These results help illuminate the complex interplay between glycans and ligand binding on the influenza membrane protein neuraminidase. Statement of Significance The influenza glycoprotein neuraminidase is the target for three FDA-approved influenza drugs in the US. However, drug resistance and low drug effectiveness merits further drug development towards neuraminidase, which is hindered by our limited understanding of glycan effects on ligand binding. Generally, drug developers do not include glycans in their development pipelines. Here, we show that even though glycans can reduce drug binding towards neuraminidase, we recommend future drug development work to focus on strong binders with a long lifetime. Furthermore, we examine the binding competition between the primary and secondary binding sites on neuraminidase, leading us to propose a new, to the best of our knowledge, multivalent binding mechanism.


id: cord-259195-bmz8995u
title: AlGaN/GaN high electron mobility transistors for protein–peptide binding affinity study
author: Huang, Chih-Cheng
date: 2013-03-15
url: https://api.elsevier.com/content/article/pii/S0956566312006720
doi: 10.1016/j.bios.2012.09.066
abstract:
  Antibody-immobilized AlGaN/GaN high electron mobility transistors (HEMTs) were used to detect a short peptide consisting of 20 amino acids. One-binding-site model and two-binding-site model were used for the analysis of the electrical signals, revealing the number of binding sites on an antibody and the dissociation constants between the antibody and the short peptide. In the binding-site models, the surface coverage ratio of the short peptide on the sensor surface is relevant to the electrical signals resulted from the peptide–antibody binding on the HEMTs. Two binding sites on an antibody were observed and two dissociation constants, 4.404×10(−11) M and 1.596×10(−9) M, were extracted from the binding-site model through the analysis of the surface coverage ratio of the short peptide on the sensor surface. We have also shown that the conventional method to extract the dissociation constant from the linear regression of curve-fitting with Langmuir isotherm equation may lead to an incorrect information if the receptor has more than one binding site for the ligand. The limit of detection (LOD) of the sensor observed in the experimental result (∼10 pM of the short peptide) is very close to the LOD (around 2.7–3.4 pM) predicted from the value of the smallest dissociation constants. The sensitivity of the sensor is not only dependent on the transistors, but also highly relies on the affinity of the ligand-receptor pair. The results demonstrate that the AlGaN/GaN HEMTs cannot only be used for biosensors, but also for the biological affinity study.


id: cord-260657-yf8fvx7k
author: Bekaert, Michaël
date: 2005-01-07
url: https://www.ncbi.nlm.nih.gov/pubmed/15629717/
doi: 10.1016/j.molcel.2004.12.009
title:
  An Extended Signal Involved in Eukaryotic −1 Frameshifting Operates through Modification of the E Site tRNA

abstract:
  By using a sensitive search program based on hidden Markov models (HMM), we identified 74 viruses carrying frameshift sites among 1500 fully sequenced virus genomes. These viruses are clustered in specific families or genera. Sequence analysis of the frameshift sites identified here, along with previously characterized sites, identified a strong bias toward the two nucleotides 5′ of the shifty heptamer signal. Functional analysis in the yeast Saccharomyces cerevisiae demonstrated that high frameshifting efficiency is correlated with the presence of a Ψ39 modification in the tRNA present in the E site of the ribosome at the time of frameshifting. These results demonstrate that an extended signal is involved in eukaryotic frameshifting and suggest additional interactions between tRNAs and the ribosome during decoding.


id: cord-262318-qpztmdnw
title: In crystallo-screening for discovery of human norovirus 3C-like protease inhibitors
author: Guo, Jingxu
date: 2020-07-16
url: https://api.elsevier.com/content/article/pii/S2590152420300131
doi: 10.1016/j.yjsbx.2020.100031
abstract:
  Outbreaks of human epidemic nonbacterial gastroenteritis are mainly caused by noroviruses. Viral replication requires a 3C-like cysteine protease (3CL(pro)) which processes the 200 kDa viral polyprotein into six functional proteins. The 3CL(pro) has attracted much interest due to its potential as a target for antiviral drugs. A system for growing high-quality crystals of native Southampton norovirus 3CL(pro) (SV3CP) has been established, allowing the ligand-free crystal structure to be determined to 1.3 Å in a tetrameric state. This also allowed crystal-based fragment screening to be performed with various compound libraries, ultimately to guide drug discovery for SV3CP. A total of 19 fragments were found to bind to the protease out of the 844 which were screened. Two of the hits were located at the active site of SV3CP and showed good inhibitory activity in kinetic assays. Another 5 were found at the enzyme’s putative RNA-binding site and a further 10 were located in the symmetric central cavity of the tetramer.


id: cord-263033-4790dhc5
title: Posttranscriptional modification of messenger RNAs in eukaryotes
author: Laptev, I. G.
date: 2015-12-11
url: https://www.ncbi.nlm.nih.gov/pubmed/32214475/
doi: 10.1134/s002689331506014x
abstract:
  Transcriptome-wide mapping of posttranscriptional modifications in eukaryotic RNA revealed tens of thousands of modification sites. Modified nucleotides include 6-methyladenosine, 5-methylcytidine, pseudouridine, inosine, etc. Many modification sites are conserved, and many are regulated. The function is known for a minor subset of modified nucleotides, while the role of their majority is still obscure. In view of the global character of mRNA modification, RNA epigenetics arose as a new field of molecular biology. The review considers posttranscriptional modification of eukaryotic mRNA, focusing on the major modified nucleotides, the role they play in the cell, the methods to detect them, and the enzymes responsible for modification.


id: cord-267326-355q6k6k
title: Geospatial distribution of viromes in tropical freshwater ecosystems
author: Gu, Xiaoqiong
date: 2018-06-15
txt: ./txt/cord-267326-355q6k6k.txt
cache: ./cache/cord-267326-355q6k6k.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/29550725/
doi: 10.1016/j.watres.2018.03.017
summary:
  This study shows that spatial factors (e.g., reservoirs/tributaries, land use) are the main drivers of the viral community structure in tropical freshwater ecosystems. However, up till now, studies of land use impacts on the virome community in freshwater ecosystems are still limited as they mainly rely on traditional methodology (culture-based method or qPCR/RT-qPCR), which focuses on limited human virus targets without considering the whole picture of the viral community in the water environment (Corsi et al., 2014; Lenaker et al., 2017) . Thus, the objectives of this study were to: 1) investigate the overall virome distribution and diversity in diverse freshwater ecosystems (reservoirs/tributaries) in a tropical environment, 2) compare the virome community based on the different land use patterns, 3) assess the extent of human-related pathogenic viruses in surface waters, especially emerging zoonotic and human-related viruses, which may have been undetected before.

abstract:
  This study seeks to understand the general distribution of virome abundance and diversity in tropical freshwater ecosystems in Singapore and the geospatial distribution of the virome under different landuse patterns. Correlations between diversity, environmental parameters and land use patterns were analyzed and significant correlations were highlighted. Overall, the majority (65.5%) of the annotated virome belonged to bacteriophages. The percentage of Caudovirales was higher in reservoirs whereas the percentages of Dicistroviridae, Microviridae and Circoviridae were higher in tributaries. Reservoirs showed a higher Shannon-index virome diversity compared to upstream tributaries. Land use (urbanized, agriculture and parkland areas) influenced the characteristics of the virome distribution pattern. Dicistroviridae and Microviridae were enriched in urbanized tributaries while Mimiviridae, Phycodnaviridae, Siphoviridae and Podoviridae were enriched in parkland reservoirs. Several sequences closely related to the emerging zoonotic virus, cyclovirus, and the human-related virus (human picobirnavirus), were also detected. In addition, the relative abundance of PMMoV (pepper mild mottle virus) sequences was significantly correlated with RT-qPCR measurements (0.588 < r < 0.879, p < 0.05). This study shows that spatial factors (e.g., reservoirs/tributaries, land use) are the main drivers of the viral community structure in tropical freshwater ecosystems.


id: cord-271514-sls3bsm0
title: Ensemble Forecast Modeling for the Design of COVID-19 Vaccine Efficacy Trials
author: Dean, Natalie E.
date: 2020-09-15
url: https://www.ncbi.nlm.nih.gov/pubmed/33012602/
doi: 10.1016/j.vaccine.2020.09.031
abstract:
  To rapidly evaluate the safety and efficacy of COVID-19 vaccine candidates, prioritizing vaccine trial sites in areas with high expected disease incidence can speed endpoint accrual and shorten trial duration. Mathematical and statistical forecast models can inform the process of site selection, integrating available data sources and facilitating comparisons across locations. We recommend the use of ensemble forecast modeling – combining projections from independent modeling groups – to guide investigators identifying suitable sites for COVID-19 vaccine efficacy trials. We describe an appropriate structure for this process, including minimum requirements, suggested output, and a user-friendly tool for displaying results. Importantly, we advise that this process be repeated regularly throughout the trial, to inform decisions about enrolling new participants at existing sites with waning incidence versus adding entirely new sites. These types of data-driven models can support the implementation of flexible efficacy trials tailored to the outbreak setting.


id: cord-274409-4ugdxbmy
title: Mutational analysis and assessment of its impact on proteins of SARS-CoV-2 genomes from India
author: Laskar, Rezwanuzzaman
date: 2020-10-19
txt: ./txt/cord-274409-4ugdxbmy.txt
cache: ./cache/cord-274409-4ugdxbmy.txt
extension: .txt
mime: text/plain
url: https://doi.org/10.1101/2020.10.19.345066
doi: 10.1101/2020.10.19.345066
summary:
  title: Mutational analysis and assessment of its impact on proteins of SARS-CoV-2 genomes from India Further, constitution of ''Disease'' mutations in genomes from asymptomatic people was mere 11% but those from deceased patients was over three folds higher at 38% indicating contribution of these mutations to the pathophysiology of the SARS-CoV-2. With a definitive possibility of India becoming the most affected country by SARS-CoV-2 in near future and the demographic burden involved, its pertinent to be analyze the accumulating variations in the genome accounting for possible changes in protein and their potential to alter the virus in any manner. Herein we extend our study using the same congregation of sequences to analyze the nature and composition of the observed mutations and their impact on proteins of SARS-CoV-2. The distribution of Disease and Neutral variants across the different genes of SARS-CoV-2 has been shown in Table 4 and Supplementary file 5.

abstract:
  The ongoing global pandemic of SARS-CoV-2 implies a corresponding accumulation of mutations. Herein the mutational status of 611 genomes from India along with their impact on proteins was ascertained. After excluding gaps and ambiguous sequences, a total of 493 variable sites (152 parsimony informative and 341 singleton) were observed. The most prevalent reference nucleotide was C (209) and substituted one was T (293). NSP3 had the highest incidence of 101 sites followed by S protein (74 sites), NSP12b (43 sites) and ORF3a (31 sites). The average number of mutations per sample for males and females was 2.56 and 2.88 respectively suggesting a higher contribution of mutations from females. Non-uniform geographical distribution of mutations implied by Odisha (30 samples, 109 mutations) and Tamil Nadu (31 samples, 40 mutations) suggests that sequences in some regions are mutating faster than others. There were 281 mutations (198 ‘Neutral’ and 83 ‘Disease’) affecting amino acid sequence. NSP13 has a maximum of 14 ‘Disease’ variants followed by S protein and ORF3a with 13 each. Further, constitution of ‘Disease’ mutations in genomes from asymptomatic people was mere 11% but those from deceased patients was over three folds higher at 38% indicating contribution of these mutations to the pathophysiology of the SARS-CoV-2.


id: cord-275307-d7htyfcl
author: Gaglia, Marta Maria
date: 2015-12-08
txt: ./txt/cord-275307-d7htyfcl.txt
cache: ./cache/cord-275307-d7htyfcl.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/26646420/
doi: 10.1371/journal.ppat.1005305
summary:
  Development of a novel bioinformatics pipeline to detect highconfidence SOX cleavage sites across the transcriptome following PARE Prior analyses of individual mRNAs indicated that the KSHV RNase SOX cuts at specific locations within the RNA, in a manner dependent on the sequence surrounding the cleavage site [5] . This example shows the expected distribution for a cut site followed by exonucleolytic degradation due PARE libraries from two replicates of SOX-expressing or GFP control cells and extracted the 5'' end of each mapped read, which represents the cleavage site (S1 Table) . Indeed, the sequences flanking the set of reproducible SOX cut sites (identified with a confidence level of 99.99%) were a closer match to the motif compared to those surrounding GFP-specific fragment ends, as shown by the distribution of the log likelihood scores (Fig 6A) .

title:
  Transcriptome-Wide Cleavage Site Mapping on Cellular mRNAs Reveals Features Underlying Sequence-Specific Cleavage by the Viral Ribonuclease SOX

abstract:
  Many viruses express factors that reduce host gene expression through widespread degradation of cellular mRNA. An example of this class of proteins is the mRNA-targeting endoribonuclease SOX from the gamma-herpesvirus Kaposi’s sarcoma-associated herpesvirus (KSHV). Previous studies indicated that cleavage of messenger RNAs (mRNA) by SOX occurs at specific locations defined by the sequence of the target RNA, which is at odds with the down-regulation of a large portion of cellular transcripts. In this study, we address this paradox by using high-throughput sequencing of cleavage intermediates combined with a custom bioinformatics-based analysis pipeline to identify SOX cleavage sites across the mRNA transcriptome. These data, coupled with targeted mutagenesis, reveal that while cleavage sites are specific and reproducible, they are defined by a degenerate sequence motif containing a small number of conserved residues rather than a strong consensus sequence. This degenerate element is well represented in both human and KSHV mRNA, and its presence correlates with RNA destabilization by SOX. This represents a new endonuclease targeting strategy, in which use of a degenerate targeting element enables RNA cleavage at specific locations without restricting the range of targets. Furthermore, it shows that strong target selectivity can be achieved without a high degree of sequence specificity.


id: cord-276405-yfvu83r9
author: Brat, Gabriel A.
date: 2020-08-19
url: https://doi.org/10.1038/s41746-020-00308-0
doi: 10.1038/s41746-020-00308-0
title:
  International electronic health record-derived COVID-19 clinical course profiles: the 4CE consortium

abstract:
  We leveraged the largely untapped resource of electronic health record data to address critical clinical and epidemiological questions about Coronavirus Disease 2019 (COVID-19). To do this, we formed an international consortium (4CE) of 96 hospitals across five countries (www.covidclinical.net). Contributors utilized the Informatics for Integrating Biology and the Bedside (i2b2) or Observational Medical Outcomes Partnership (OMOP) platforms to map to a common data model. The group focused on temporal changes in key laboratory test values. Harmonized data were analyzed locally and converted to a shared aggregate form for rapid analysis and visualization of regional differences and global commonalities. Data covered 27,584 COVID-19 cases with 187,802 laboratory tests. Case counts and laboratory trajectories were concordant with existing literature. Laboratory tests at the time of diagnosis showed hospital-level differences equivalent to country-level variation across the consortium partners. Despite the limitations of decentralized data generation, we established a framework to capture the trajectory of COVID-19 disease in patients and their response to interventions.


id: cord-285910-rw2byz31
author: Stahl, Guillaume
date: 2002-04-01
url: https://www.sciencedirect.com/science/article/pii/S0968000402020649
doi: 10.1016/s0968-0004(02)02064-9
title:
  Ribosome structure: revisiting the connection between translational accuracy and unconventional decoding

abstract:
  The ribosome is a molecular machine that converts genetic information in the form of RNA, into protein. Recent structural studies reveal a complex set of interactions between the ribosome and its ligands, mRNA and tRNA, that indicate ways in which the ribosome could avoid costly translational errors. Ribosomes must decode each successive codon accurately, and structural data provide a clear indication of how ribosomes limit recruitment of the wrong tRNA (sense errors). In a triplet-based genetic code there are three potential forward reading frames, only one of which encodes the correct protein. Errors in which the ribosome reads a codon out of the normal reading frame (frameshift errors) occur less frequently than sense errors, although it is not clear from structural data how these errors are avoided. Some mRNA sequences, termed programmed-frameshift sites, cause the ribosome to change reading frame. Based on recent work on these sites, this article proposes that the ribosome uses the structure of the codon–anticodon complex formed by the peptidyl-tRNA, especially its wobble interaction, to constrain the incoming aminoacyl-tRNA to the correct reading frame.


id: cord-289443-46w52de3
title: Evolutionary insights into host–pathogen interactions from mammalian sequence data
author: Sironi, Manuela
date: 2015-03-18
url: https://doi.org/10.1038/nrg3905
doi: 10.1038/nrg3905
abstract:
  Infections are one of the major selective pressures acting on humans, and host-pathogen interactions contribute to shaping the genetic diversity of both organisms. Evolutionary genomic studies take advantage of experiments that natural selection has been performing over millennia. In particular, inter-species comparative genomic analyses can highlight the genetic determinants of infection susceptibility or severity. Recent examples show how evolution-guided approaches can provide new insights into host–pathogen interactions, ultimately clarifying the basis of host range and explaining the emergence of different diseases. We describe the latest developments in comparative immunology and evolutionary genetics, showing their relevance for understanding the molecular determinants of infection susceptibility in mammals. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1038/nrg3905) contains supplementary material, which is available to authorized users.


id: cord-300117-rlpzejjt
author: Coutard, B.
date: 2020-02-10
url: https://www.sciencedirect.com/science/article/pii/S0166354220300528
doi: 10.1016/j.antiviral.2020.104742
title:
  The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade

abstract:
  In 2019, a new coronavirus (2019-nCoV) infecting Humans has emerged in Wuhan, China. Its genome has been sequenced and the genomic information promptly released. Despite a high similarity with the genome sequence of SARS-CoV and SARS-like CoVs, we identified a peculiar furin-like cleavage site in the Spike protein of the 2019-nCoV, lacking in the other SARS-like CoVs. In this article, we discuss the possible functional consequences of this cleavage site in the viral cycle, pathogenicity and its potential implication in the development of antivirals.


id: cord-304421-xpj6c0vx
author: Piñón, Josefina D.
date: 1999-10-25
url: https://www.sciencedirect.com/science/article/pii/S0042682299999543
doi: 10.1006/viro.1999.9954
title:
  Further Requirements for Cleavage by the Murine Coronavirus 3C-like Proteinase: Identification of a Cleavage Site within ORF1b

abstract:
  Abstract The coronavirus mouse hepatitis virus strain A59 (MHV-A59) encodes a 3C-like proteinase (3CLpro) that is proposed to be responsible for the majority of the processing events that take place within the replicase polyproteins pp1a and pp1ab. In this study we demonstrate that the Q939↓S940 peptide bond, located between the polymerase and Zn-finger regions of pp1ab (the POL↓Zn site), is processed by the 3CLpro, albeit inefficiently. Mutagenesis of the POL↓Zn site, as well as the previously identified HD1↓3C site in the 1a region of pp1a and pp1ab, demonstrated that the amino acid residues at the P2 and P1 positions of the cleavage site, occupied by L and Q, respectively, were important determinants of 3CLpro substrate specificity. Finally, a direct comparison of the 3CLpro-mediated cleavages at the HD1↓3C and POL↓Zn sites was made by determining the rate constants using synthetic peptides. The results show that while a larger polypeptide substrate carrying the HD1↓3C site was processed more efficiently than a polypeptide substrate carrying the POL↓Zn site, cleavage of the synthetic peptide substrates containing these two cleavage sites occurred at similar efficiencies. This indicates that the overall conformation of a large polyprotein substrate is important in the accessibility of the cleavage site to the proteinase.


id: cord-314166-79323mzd
author: Vanderford, Thomas H.
date: 2006-12-11
url: https://www.ncbi.nlm.nih.gov/pubmed/17159231/
doi: 10.1093/molbev/msl194
title:
  Adaptation of a Diverse Simian Immunodeficiency Virus Population to a New Host Is Revealed through a Systematic Approach to Identify Amino Acid Sites under Selection

abstract:
  Simian immunodeficiency viruses (SIV) have had considerable success at crossing species barriers; both human immunodeficiency virus (HIV)-1 and HIV-2 have been transmitted on multiple occasions from SIV-infected natural host species. However, the precise evolutionary and ecological mechanisms characterizing a successful cross-species transmission event remain to be elucidated. Here, in addition to expanding and clarifying our previous description of the adaptation of a diverse, naturally occurring SIVsm inoculum to a new rhesus macaque host, we present an analytical framework for understanding the selective forces driving viral adaptation to a new host. A preliminary analysis of large-scale changes in virus population structure revealed that viruses replicating in the macaques were subject to increasing levels of selection through day 70 postinfection (p.i.), whereas contemporaneous viruses in the mangabeys remained similar to the source inoculum. Three different site-by-site methods were employed to identify the amino acid sites responsible for this macaque-specific selection. Of 124 amino acid sites analyzed, 3 codons in V2, a 2–amino acid shift in an N-linked glycosylation site, and variation at 2 sites in the highly charged region were consistently evolving under either directional or diversifying selection at days 40 and 70 p.i. This strong macaque-specific selection on the V2 loop underscores the importance of this region in the adaptation of SIVsm to rhesus macaques. Due to the extreme viral diversity already extant in the naturally occurring viral inoculum, we employed a broad range of phylogenetic and numerical tools in order to distinguish the signatures of past episodes of selection in viral sequences from more recent selection pressures.


id: cord-315951-5gsbtfag
title: Coronavirus 3CL(pro )proteinase cleavage sites: Possible relevance to SARS virus pathology
author: Kiemer, Lars
date: 2004-06-06
url: https://www.ncbi.nlm.nih.gov/pubmed/15180906/
doi: 10.1186/1471-2105-5-72
abstract:
  BACKGROUND: Despite the passing of more than a year since the first outbreak of Severe Acute Respiratory Syndrome (SARS), efficient counter-measures are still few and many believe that reappearance of SARS, or a similar disease caused by a coronavirus, is not unlikely. For other virus families like the picornaviruses it is known that pathology is related to proteolytic cleavage of host proteins by viral proteinases. Furthermore, several studies indicate that virus proliferation can be arrested using specific proteinase inhibitors supporting the belief that proteinases are indeed important during infection. Prompted by this, we set out to analyse and predict cleavage by the coronavirus main proteinase using computational methods. RESULTS: We retrieved sequence data on seven fully sequenced coronaviruses and identified the main 3CL proteinase cleavage sites in polyproteins using alignments. A neural network was trained to recognise the cleavage sites in the genomes obtaining a sensitivity of 87.0% and a specificity of 99.0%. Several proteins known to be cleaved by other viruses were submitted to prediction as well as proteins suspected relevant in coronavirus pathology. Cleavage sites were predicted in proteins such as the cystic fibrosis transmembrane conductance regulator (CFTR), transcription factors CREB-RP and OCT-1, and components of the ubiquitin pathway. CONCLUSIONS: Our prediction method NetCorona predicts coronavirus cleavage sites with high specificity and several potential cleavage candidates were identified which might be important to elucidate coronavirus pathology. Furthermore, the method might assist in design of proteinase inhibitors for treatment of SARS and possible future diseases caused by coronaviruses. It is made available for public use at our website: .


id: cord-316968-rowoylge
title: Using maximum likelihood method to detect adaptive evolution of HCV envelope protein-coding genes
author: Zhang, Wenjuan
date: 2006
url: https://www.ncbi.nlm.nih.gov/pubmed/32214724/
doi: 10.1007/s11434-006-2118-9
abstract:
  Nonsynonymous-synonymous substitution rate ratio (d (N)/d (S)) is an important measure for evaluating selective pressure based on the protein-coding sequences. Maximum likelihood (ML) method with codon-substitution models is a powerful statistic tool for detecting amino acid sites under positive selection and adaptive evolution. We analyzed the hepatitis C virus (HCV) envelope protein-coding sequences from 18 general geno/subtypes worldwide, and found 4 amino acid sites under positive selection. Since these sites are located in different immune epitopes, it is reasonable to anticipate that our study would have potential values in biomedicine. It also suggests that the ML method is an effective way to detect adaptive evolution in virus proteins with relatively high genetic diversity.


id: cord-317061-0bx704ao
author: Wu, Andong
date: 2015-10-02
txt: ./txt/cord-317061-0bx704ao.txt
cache: ./cache/cord-317061-0bx704ao.txt
extension: .txt
mime: text/plain
url: https://api.elsevier.com/content/article/pii/S0168170215002178
doi: 10.1016/j.virusres.2015.05.018
summary:
  The nsp5 of the newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) was identified as 3CLpro and its canonical cleavage sites (between nsps) were predicted based on sequence alignment, but the cleavability of these cleavage sites remains to be experimentally confirmed and putative non-canonical cleavage sites (inside one nsp) within the pp1a/1ab awaits further analysis. Some cleavage sites have been identified and confirmed by previous studies, including three cleavage sites of PLpros of human coronavirus 229E (HCoV 229E), mouse hepatitis virus (MHV), SARS-CoV, MERS-CoV and infectious bronchitis virus (IBV), whose cleavages release the first 3 non-structural proteins (Bonilla et al., 1995; Kilianski et al., 2013; Lim and Liu, 1998; Ziebuhr et al., 2007) . In order to set up a more moderate and balanced criteria for protease cleavage site identification, we compared six scanning conditions with different stringency to systematically predict the 3CLpro cleavage sites on pp1a/1ab of five coronaviruses including MERS-CoV. To rapidly evaluate the proteolysis activity of MERS-CoV 3CLpro toward the predicted cleavage sites of different substrates, a sensitive luciferase-based biosensor assay was adopted.

title:
  Prediction and biochemical analysis of putative cleavage sites of the 3C-like protease of Middle East respiratory syndrome coronavirus

abstract:
  Coronavirus 3C-like protease (3CLpro) is responsible for the cleavage of coronaviral polyprotein 1a/1ab (pp1a/1ab) to produce the mature non-structural proteins (nsps) of nsp4–16. The nsp5 of the newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) was identified as 3CLpro and its canonical cleavage sites (between nsps) were predicted based on sequence alignment, but the cleavability of these cleavage sites remains to be experimentally confirmed and putative non-canonical cleavage sites (inside one nsp) within the pp1a/1ab awaits further analysis. Here, we proposed a method for predicting coronaviral 3CLpro cleavage sites which balances the prediction accuracy and false positive outcomes. By applying this method to MERS-CoV, the 11 canonical cleavage sites were readily identified and verified by the biochemical assays. The Michaelis constant of the canonical cleavage sites of MERS-CoV showed that the substrate specificity of MERS-CoV 3CLpro is relatively conserved. Interestingly, nine putative non-canonical cleavage sites were predicted and three of them could be cleaved by MERS-CoV nsp5. These results pave the way for identification and functional characterization of new nsp products of coronaviruses.


id: cord-321150-ev6acl7b
title: Improved Algorithmic Complexity for the 3SEQ Recombination Detection Algorithm
author: Lam, Ha Minh
date: 2017-10-03
url: https://doi.org/10.1093/molbev/msx263
doi: 10.1093/molbev/msx263
abstract:
  Identifying recombinant sequences in an era of large genomic databases is challenging as it requires an efficient algorithm to identify candidate recombinants and parents, as well as appropriate statistical methods to correct for the large number of comparisons performed. In 2007, a computation was introduced for an exact nonparametric mosaicism statistic that gave high-precision P values for putative recombinants. This exact computation meant that multiple-comparisons corrected P values also had high precision, which is crucial when performing millions or billions of tests in large databases. Here, we introduce an improvement to the algorithmic complexity of this computation from O(mn(3)) to O(mn(2)), where m and n are the numbers of recombination-informative sites in the candidate recombinant. This new computation allows for recombination analysis to be performed in alignments with thousands of polymorphic sites. Benchmark runs are presented on viral genome sequence alignments, new features are introduced, and applications outside recombination analysis are discussed.


id: cord-322129-uyswj4ow
title: Comparative ACE2 variation and primate COVID-19 risk
author: Melin, Amanda D.
date: 2020-10-27
url: https://www.ncbi.nlm.nih.gov/pubmed/33110195/
doi: 10.1038/s42003-020-01370-w
abstract:
  The emergence of SARS-CoV-2 has caused over a million human deaths and massive global disruption. The viral infection may also represent a threat to our closest living relatives, nonhuman primates. The contact surface of the host cell receptor, ACE2, displays amino acid residues that are critical for virus recognition, and variations at these critical residues modulate infection susceptibility. Infection studies have shown that some primate species develop COVID-19-like symptoms; however, the susceptibility of most primates is unknown. Here, we show that all apes and African and Asian monkeys (catarrhines), exhibit the same set of twelve key amino acid residues as human ACE2. Monkeys in the Americas, and some tarsiers, lemurs and lorisoids, differ at critical contact residues, and protein modeling predicts that these differences should greatly reduce SARS-CoV-2 binding affinity. Other lemurs are predicted to be closer to catarrhines in their susceptibility. Our study suggests that apes and African and Asian monkeys, and some lemurs, are likely to be highly susceptible to SARS-CoV-2. Urgent actions have been undertaken to limit the exposure of great apes to humans, and similar efforts may be necessary for many other primate species.


id: cord-327069-vjlisnui
title: Standardization of Laboratory Methods for the PERCH Study
author: Driscoll, Amanda J.
date: 2017-06-15
url: https://www.ncbi.nlm.nih.gov/pubmed/28575358/
doi: 10.1093/cid/cix081
abstract:
  The Pneumonia Etiology Research for Child Health study was conducted across 7 diverse research sites and relied on standardized clinical and laboratory methods for the accurate and meaningful interpretation of pneumonia etiology data. Blood, respiratory specimens, and urine were collected from children aged 1–59 months hospitalized with severe or very severe pneumonia and community controls of the same age without severe pneumonia and were tested with an extensive array of laboratory diagnostic tests. A standardized testing algorithm and standard operating procedures were applied across all study sites. Site laboratories received uniform training, equipment, and reagents for core testing methods. Standardization was further assured by routine teleconferences, in-person meetings, site monitoring visits, and internal and external quality assurance testing. Targeted confirmatory testing and testing by specialized assays were done at a central reference laboratory.


id: cord-328681-jf2mj16z
title: Statistical methods for detecting molecular adaptation
author: Yang, Ziheng
date: 2000-12-01
url: https://api.elsevier.com/content/article/pii/S0169534700019947
doi: 10.1016/s0169-5347(00)01994-7
abstract:
  The past few years have seen the development of powerful statistical methods for detecting adaptive molecular evolution. These methods compare synonymous and nonsynonymous substitution rates in protein-coding genes, and regard a nonsynonymous rate elevated above the synonymous rate as evidence for darwinian selection. Numerous cases of molecular adaptation are being identified in various systems from viruses to humans. Although previous analyses averaging rates over sites and time have little power, recent methods designed to detect positive selection at individual sites and lineages have been successful. Here, we summarize recent statistical methods for detecting molecular adaptation, and discuss their limitations and possible improvements.


id: cord-332165-31tbc31x
title: The Symmetry of Viral Sialic Acid Binding Sites—Implications for Antiviral Strategies
author: Rustmeier, Nils H.
date: 2019-10-14
url: https://www.ncbi.nlm.nih.gov/pubmed/31615155/
doi: 10.3390/v11100947
abstract:
  Virus infections are initiated by the attachment of the viral particle to protein or carbohydrate receptors on the host cell. Sialic acid-bearing glycan structures are prominently displayed at the cell surface, and, consequently, these structures can function as receptors for a large number of diverse viruses. Structural biology research has helped to establish the molecular bases for many virus–sialic acid interactions. Due to the icosahedral 532 point group symmetry that underlies many viral capsids, the receptor binding sites are frequently arranged in a highly symmetric fashion and linked by five-fold, three-fold, or two-fold rotation axes. For the inhibition of viral attachment, one emerging strategy is based on developing multivalent sialic acid-based inhibitors that can simultaneously engage several of these binding sites, thus binding viral capsids with high avidity. In this review, we will evaluate the structures of non-enveloped virus capsid proteins bound to sialylated glycan receptors and discuss the potential of these structures for the development of potent antiviral attachment inhibitors.


id: cord-332855-u0amf1oh
author: Parsons, Lisa M.
date: 2019-03-22
url: https://doi.org/10.1074/jbc.ra119.007532
doi: 10.1074/jbc.ra119.007532
title:
  Glycosylation of the viral attachment protein of avian coronavirus is essential for host cell and receptor binding

abstract:
  Avian coronaviruses, including infectious bronchitis virus (IBV), are important respiratory pathogens of poultry. The heavily glycosylated IBV spike protein is responsible for binding to host tissues. Glycosylation sites in the spike protein are highly conserved across viral genotypes, suggesting an important role for this modification in the virus life cycle. Here, we analyzed the N-glycosylation of the receptor-binding domain (RBD) of IBV strain M41 spike protein and assessed the role of this modification in host receptor binding. Ten single Asn–to–Ala substitutions at the predicted N-glycosylation sites of the M41–RBD were evaluated along with two control Val–to–Ala substitutions. CD analysis revealed that the secondary structure of all variants was retained compared with the unmodified M41–RBD construct. Six of the 10 glycosylation variants lost binding to chicken trachea tissue and an ELISA-presented α2,3-linked sialic acid oligosaccharide ligand. LC/MS(E) glycomics analysis revealed that glycosylation sites have specific proportions of N-glycan subtypes. Overall, the glycosylation patterns of most variant RBDs were highly similar to those of the unmodified M41–RBD construct. In silico docking experiments with the recently published cryo-EM structure of the M41 IBV spike protein and our glycosylation results revealed a potential ligand receptor site that is ringed by four glycosylation sites that dramatically impact ligand binding. Combined with the results of previous array studies, the glycosylation and mutational analyses presented here suggest a unique glycosylation-dependent binding modality for the M41 spike protein.


id: cord-332948-h297ukuu
author: Olotu, Fisayo A.
date: 2020-10-16
url: https://api.elsevier.com/content/article/pii/S2352914820306018
doi: 10.1016/j.imu.2020.100451
title:
  Leaving no stone unturned: Allosteric targeting of SARS-CoV-2 Spike protein at putative druggable sites disrupts human angiotensin-converting enzyme interactions at the receptor binding domain.

abstract:
  The systematic entry of SARS-CoV-2 into host cells, as mediated by its Spike (S) protein, is highly essential for pathogenicity in humans. Hence, targeting the viral entry mechanisms remains a major strategy for COVID-19 treatment. Although recent efforts have focused on the direct inhibition of S-protein receptor-binding domain (RBD) interactions with human angiotensin-converting enzyme 2 (hACE2), allosteric targeting remains an unexplored possibility. Therefore, in this study, for the first time, we employed an integrative meta-analytical approach to investigate the allosteric inhibitory mechanisms of SARS-CoV-2 S-protein and its association with hACE2. Findings revealed two druggable sites (Sites 1 and 2) located at the N-terminal domain (NTD) and S2 regions of the protein. Two high-affinity binders; ZINC3939013 (Fosaprepitant – Site 1) and ZINC27990463 (Lomitapide – Site 2) were discovered via site-directed high-throughput screening against a library of ∼1500 FDA approved drugs. Interestingly, we observed that allosteric binding of both compounds perturbed the prefusion S-protein conformations, which in turn, resulted in unprecedented hACE2 displacement from the RBD. Estimated ΔG(binds) for both compounds were highly favorable due to high-affinity interactions at the target sites. In addition, Site 1 residues; R190, H207, K206 and K187, I101, R102, I119, F192, L226, V126 and W104 were identified for their crucial involvement in the binding and stability of ZINC3939013. Likewise, energy contributions of Q957, N953, Q954, L303, Y313, Q314, L858, V952, N953, and A956 corroborated their importance to ZINC27990463 binding at the predicted Site 2. We believe these findings would pave way for the structure-based discovery of allosteric SARS-CoV-2 S-protein inhibitors for COVID-19 treatment.


id: cord-336034-13u8njtt
author: Scott, Shannon D
date: 2009-10-13
url: https://www.ncbi.nlm.nih.gov/pubmed/19828086/
doi: 10.1186/1748-5908-4-65
title:
  Barriers and supports to implementation of MDI/spacer use in nine Canadian pediatric emergency departments: a qualitative study

abstract:
  BACKGROUND: Despite recent research supporting the use of metered dose inhalers with spacer devices (MDI/spacers) in pediatric emergency departments (PEDs) for acute exacerbations of asthma, uptake of this practice has been slow. The objectives of this study were to determine the barriers and supports to implementing MDI/spacer research and to identify factors associated with early and late adoption of MDI/spacers in Canadian PEDs. METHODS: Using a comparative case study design, we classified nine tertiary care pediatric hospital PEDs based on their stage of implementation. Data were collected using focus group interviews with physicians, registered nurses (RNs), and respiratory therapists (RTs), and individual interviews with both patient care and medical directors at each site. Initial coding was based on the Ottawa Model of Research Use (OMRU) categories of elements known to influence the uptake of innovations. RESULTS: One hundred and fifty healthcare professionals from nine different healthcare institutions participated in this study. Lack of leadership in the form of a research champion, a lack of consensus about the benefits of MDI/spacers among staff, perceived resistance from patients/parents, and perceived increased cost and workload associated with MDI/spacer use were the most prevalent barriers to the adoption of the MDI/spacer. Common strategies used by early-adopting sites included the active participation of all professional groups in the adoption process in addition to a well-planned and executed educational component for staff, patients, and families. Early adopter sites were also more likely to have the MDI/spacer included in a clinical protocol/pathway. CONCLUSION: Potential barriers and supports to implementation have been identified that will help EDs adopt MDI/spacer use. Future interventions intended to increase MDI/spacer use in PEDs will need to be sensitive to the barriers identified in this study.


id: cord-338980-pygykil7
author: Rahaman, Jordon
date: 2016-11-09
url: https://doi.org/10.1093/gbe/evw246
doi: 10.1093/gbe/evw246
title:
  Avoiding Regions Symptomatic of Conformational and Functional Flexibility to Identify Antiviral Targets in Current and Future Coronaviruses

abstract:
  Within the last 15 years, two related coronaviruses (Severe Acute Respiratory Syndrome [SARS]-CoV and Middle East Respiratory Syndrome [MERS]-CoV) expanded their host range to include humans, with increased virulence in their new host. Coronaviruses were recently found to have little intrinsic disorder compared with many other virus families. Because intrinsically disordered regions have been proposed to be important for rewiring interactions between virus and host, we investigated the conservation of intrinsic disorder and secondary structure in coronaviruses in an evolutionary context. We found that regions of intrinsic disorder are rarely conserved among different coronavirus protein families, with the primary exception of the nucleocapsid. Also, secondary structure predictions are only conserved across 50–80% of sites for most protein families, with the implication that 20–50% of sites do not have conserved secondary structure prediction. Furthermore, nonconserved structure sites are significantly less constrained in sequence divergence than either sites conserved in the secondary structure or sites conserved in loop. Avoiding regions symptomatic of conformational flexibility such as disordered sites and sites with nonconserved secondary structure to identify potential broad-specificity antiviral targets, only one sequence motif (five residues or longer) remains from the >10,000 starting sites across all coronaviruses in this study. The identified sequence motif is found within the nonstructural protein (NSP) 12 and constitutes an antiviral target potentially effective against the present day and future coronaviruses. On shorter evolutionary timescales, the SARS and MERS clades have more sequence motifs fulfilling the criteria applied. Interestingly, many motifs map to NSP12 making this a prime target for coronavirus antivirals.


id: cord-341968-uc8i9h0m
title: The Proteolytic Regulation of Virus Cell Entry by Furin and Other Proprotein Convertases
author: Izaguirre, Gonzalo
date: 2019-09-09
url: https://doi.org/10.3390/v11090837
doi: 10.3390/v11090837
abstract:
  A wide variety of viruses exploit furin and other proprotein convertases (PCs) of the constitutive protein secretion pathway in order to regulate their cell entry mechanism and infectivity. Surface proteins of enveloped, as well as non-enveloped, viruses become processed by these proteases intracellularly during morphogenesis or extracellularly after egress and during entry in order to produce mature virions activated for infection. Although viruses also take advantage of other proteases, it is when some viruses become reactive with PCs that they may develop high pathogenicity. Besides reacting with furin, some viruses may also react with the PCs of the other specificity group constituted by PC4/PC5/PACE4/PC7. The targeting of PCs for inhibition may result in a useful strategy to treat infections with some highly pathogenic viruses. A wide variety of PC inhibitors have been developed and tested for their antiviral activity in cell-based assays.


id: cord-346532-4xpnd93d
title: Allosteric Hotspots in the Main Protease of SARS-CoV-2
author: Strömich, Léonie
date: 2020-11-06
url: https://doi.org/10.1101/2020.11.06.369439
doi: 10.1101/2020.11.06.369439
abstract:
  Inhibiting the main protease of SARS-CoV-2 is of great interest in tackling the COVID-19 pandemic caused by the virus. Most efforts have been centred on inhibiting the binding site of the enzyme. However, considering allosteric sites, distant from the active or orthosteric site, broadens the search space for drug candidates and confers the advantages of allosteric drug targeting. Here, we report the allosteric communication pathways in the main protease dimer by using two novel fully atomistic graph theoretical methods: Bond-to-bond propensity analysis, which has been previously successful in identifying allosteric sites without a priori knowledge in benchmark data sets, and, Markov transient analysis, which has previously aided in finding novel drug targets in catalytic protein families. We further score the highest ranking sites against random sites in similar distances through statistical bootstrapping and identify four statistically significant putative allosteric sites as good candidates for alternative drug targeting.


id: cord-346965-0oq2n0af
title: Bridging protein local structures and protein functions
author: Liu, Zhi-Ping
date: 2008-04-18
txt: ./txt/cord-346965-0oq2n0af.txt
cache: ./cache/cord-346965-0oq2n0af.txt
extension: .txt
mime: text/plain
url: https://www.ncbi.nlm.nih.gov/pubmed/18421562/
doi: 10.1007/s00726-008-0088-8
summary:
  The characteristics between interface and noninterface portions of a protein surface, such as sequence conservation, proportions of amino acids, secondary structure, solvent accessibility and side-chain conformational entropy, are often used to distinguish the specificity of local structures relating to protein binding function. The method relies on a simplified representation of the chemical groups found in amino acid side-chains to identify functional sites from a single protein structure and a number of its sequence homologs. (2006) improved previous approaches by combining two known measures of ''functionality'' in proteins, i.e. cleft volume and residue conservation, to develop a method for identifying the location of ligand-binding pockets in proteins. (2006) applied an SVM method to predict DNA-binding sites using the features including amino acid sequence, profile of evolutionary conservation of sequence positions, and low-resolution structural information. (2006) developed a method to predict both protein-protein binding site location and interface type (obligate or non-obligate) using a Bayesian network in combination with surface patch analysis.

abstract:
  One of the major goals of molecular and evolutionary biology is to understand the functions of proteins by extracting functional information from protein sequences, structures and interactions. In this review, we summarize the repertoire of methods currently being applied and report recent progress in the field of in silico annotation of protein function based on the accumulation of vast amounts of sequence and structure data. In particular, we emphasize the newly developed structure-based methods, which are able to identify locally structural motifs and reveal their relationship with protein functions. These methods include computational tools to identify the structural motifs and reveal the strong relationship between these pre-computed local structures and protein functions. We also discuss remaining problems and possible directions for this exciting and challenging area.


id: cord-351115-dy81dtnk
title: Identification of evolutionarily stable sites across the SARS-CoV-2 proteome
author: Wang, Chen
date: 2020-10-20
url: https://doi.org/10.21203/rs.3.rs-95030/v1
doi: 10.21203/rs.3.rs-95030/v1
abstract:
  Since the first recognized case of COVID-19, more than 30 million people have been infected worldwide. Despite global efforts in drug and vaccine development to fight the disease, there is currently no vaccine or drug cure for COVID-19, though some drugs reduce severity and hasten recovery. Here we interrogate the evolutionary history of the entire SARS-CoV-2 proteome to identify functional sites that can inform the search for treatments. Combining this information with the mutations observed in the current COVID-19 outbreak, we systematically and comprehensively define evolutionarily stable sites that are useful drug targets. Several experimentally-validated effective drugs interact with these proposed target sites. In addition, the same evolutionary information can prioritize cross reactive antigens that are useful in directing multi-epitope vaccine strategies to illicit broadly neutralizing immune responses to the betacoronavirus family. Although the results are focused on SARS-CoV-2, these approaches are based upon evolutionary principles and are agnostic to organism or infective agent.


id: cord-356264-q0yqnlyl
author: Armijos-Jaramillo, Vinicio
date: 2020-03-23
url: https://doi.org/10.1101/2020.03.21.001933
doi: 10.1101/2020.03.21.001933
title:
  SARS-CoV-2, an evolutionary perspective of interaction with human ACE2 reveals undiscovered amino acids necessary for complex stability

abstract:
  The emergence of SARS-CoV-2 has resulted in more than 200,000 infections and nearly 9,000 deaths globally so far. This novel virus is thought to have originated from an animal reservoir, and acquired the ability to infect human cells using the SARS-CoV cell receptor hACE2. In the wake of a global pandemic it is essential to improve our understanding of the evolutionary dynamics surrounding the origin and spread of a novel infectious disease. One way theory predicts selection pressures should shape viral evolution is to enhance binding with host cells. We first assessed evolutionary dynamics in select betacoronavirus spike protein genes to predict where these genomic regions are under directional or purifying selection between divergent viral lineages at various scales of relatedness. With this analysis, we determine a region inside the receptor-binding domain with putative sites under positive selection interspersed among highly conserved sites, which are implicated in structural stability of the viral spike protein and its union with human receptor hACE2. Next, to gain further insights into factors associated with coronaviruses recognition of the human host receptor, we performed modeling studies of five different coronaviruses and their potential binding to hACE2. Modeling results indicate that interfering with the salt bridges at hot spot 353 could be an effective strategy for inhibiting binding, and hence for the prevention of coronavirus infections. We also propose that a glycine residue at the receptor binding domain of the spike glycoprotein can have a critical role in permitting bat variants of the coronaviruses to infect human cells.


