Epistemic_Statements  

CORD-19:85fe4d02c970252bd374d09ceb879165c7f6e8f6 JSONTXT 8 Projects

Annnotations TAB TSV DIC JSON TextAE

Id Subject Object Predicate Lexical cue
T1 734-913 Epistemic_statement denotes Most human 27 coronaviruses commonly cause relatively mild respiratory illnesses; however two zoonotic 28 coronaviruses, SARS-CoV and MERS-CoV, can cause severe illness and death.
T2 1167-1427 Epistemic_statement denotes The 5' 350 nucleotides folds into a set of RNA 32 secondary structures which are well conserved, and reverse genetic studies indicate that these 33 structures play an important role in the discontinuous synthesis of subgenomic RNAs in the 34 betacoronaviruses.
T3 1603-1737 Epistemic_statement denotes 36 Two competing conformations near the 5' end of the 3'UTR have been shown to make up a 37 Page 3 of 50 3 potential molecular switch.
T4 1738-1908 Epistemic_statement denotes There is some evidence that an association between the 3' and 38 5'UTRs is necessary for subgenomic RNA synthesis, but the basis for this association is not yet 39 clear.
T5 1909-2067 Epistemic_statement denotes A number of host RNA proteins have been shown to bind to the 5' and 3' cis-acting 40 regions, but the significance of these in viral replication is not clear.
T6 2171-2346 Epistemic_statement denotes A genetic interaction 42 between nsp8 and nsp9 and the region of the 3'UTR that contains the putative molecular switch 43 suggests that these two proteins bind to this region.
T7 2945-2947 Epistemic_statement denotes 36
T8 2948-3064 Epistemic_statement denotes Two competing conformations near the 5' end of the 3'UTR have been shown to make up a 37 potential molecular switch.
T9 3065-3235 Epistemic_statement denotes There is some evidence that an association between the 3' and 38 5'UTRs is necessary for subgenomic RNA synthesis, but the basis for this association is not yet 39 clear.
T10 3236-3394 Epistemic_statement denotes A number of host RNA proteins have been shown to bind to the 5' and 3' cis-acting 40 regions, but the significance of these in viral replication is not clear.
T11 3498-3673 Epistemic_statement denotes A genetic interaction 42 between nsp8 and nsp9 and the region of the 3'UTR that contains the putative molecular switch 43 suggests that these two proteins bind to this region.
T12 5427-5640 Epistemic_statement denotes Nsp8 in ORF 1a contains a second RNA-154 dependent RNA polymerase (RdRp) domain that is proposed to function as a primase and 155 produce primers utilized by the primer-dependent nsp12 RdRp (Imbert et al., 2006) .
T13 7428-7501 Epistemic_statement denotes The functional significance of this stem-loop remains to be investigated.
T14 7588-7591 Epistemic_statement denotes 375
T15 7592-7741 Epistemic_statement denotes The MHV 5'UTR SL1 has been shown to be functionally and structurally bipartite by a 377 detailed mutational and biophysical study (Li et al., 2008) .
T16 8132-8135 Epistemic_statement denotes 422
T17 8136-8231 Epistemic_statement denotes Structural probing of MHV suggests that the TRS region is single stranded (Yang et al., 2015) .
T18 8482-8534 Epistemic_statement denotes 1) is remarkably similar to SLVIII, predicted by 519
T19 8535-8661 Epistemic_statement denotes Mfold for betacoronavirus (Brown et al., 2007) , but no structural or functional evidence 520 supported the SLVIII prediction.
T20 8828-9160 Epistemic_statement denotes (Brockway and Denison, 2005) to recover viable viruses containing mutations (VUSB4) in nsp1 534 that are predicted to destabilize the base of SL6 very much as did the lethal VUSB5, it is very 535 likely that the lethality of VUSB5 and VUSB6 are due to their effects on nsp1 rather than due to 536 effects on RNA secondary structure.
T21 9348-9730 Epistemic_statement denotes This is consistent with functional studies of SL6 which demonstrate that SL6 is not 540 essential for MHV replication (Yang et al., 2015) , in contrast to structural elements that are 541 entirely within the 5'UTR (SL1, SL2, SL4) or to the trifurcuated SL5 stem-loop which extends 542 from the 5'UTR into the nsp1 coding sequence, which are lethal or result in viruses that are 543
T22 9731-9856 Epistemic_statement denotes The coronavirus 3'UTR consists of 300 to 500 nts plus a poly(A) tail, depending upon the 547 particular coronavirus examined.
T23 10316-10524 Epistemic_statement denotes The poly(A) tail has been 559 identified as an important cis-acting signal required for BCoV DI RNA replication, although as 560 little as five As sufficed to initiate replication (Spagnolo and Hogue, 2000) .
T24 10885-11163 Epistemic_statement denotes This bulged stem-loop is predicted to be conserved amongst the 570 betacoronaviruses and the pairing, but not the primary sequence, of the four covariant base pairs, 571 is critical for the function of the secondary structure (Goebel et al., 2004b; Hsue and Masters, 572 1997) .
T25 11164-11345 Epistemic_statement denotes 3' to the 68 nts bulged stem-loop is a hairpin stem-loop which can form a 54 nts hairpin-573 type pseudoknot, which is required for BCoV DI RNA replication (Williams et al., 1999) .
T26 11346-11561 Epistemic_statement denotes The 574 pseudoknot is phylogenetically conserved among coronaviruses, both in location and in shape 575 but only partially in nucleotide sequence, indicating that it may function as a regulatory control 576 element.
T27 11562-11779 Epistemic_statement denotes Computer assisted inspection of the MERS-CoV sequence indicated it is present in this 577 newly recognized betacoronavirus as well, although in this virus the pseudoknot may contain a 578 non-canonical base pair (Fig.
T28 11799-12015 Epistemic_statement denotes (Goebel et al., 2004a) demonstrated that in MHV and BCoV, the bulged stem-loop and pseudoknot are in part mutually exclusive structures 580 because they partially overlap and cannot be formed simultaneously (see Fig.
T29 12021-12036 Epistemic_statement denotes The authors 581
T30 12037-12320 Epistemic_statement denotes proposed that the bulged stem-loop and pseudoknot are the components of a molecular switch 582 which has the potential to regulate a transition occurring during viral RNA synthesis, and 583 supported this hypothesis by a series of reverse genetic experiments (Goebel et al., 2004a) .
T31 12321-12606 Epistemic_statement denotes performed a series of biophysical studies demonstrating that the pseudoknotted conformation is 597 much less stable than the double-hairpin conformation, but suggest that stacking of the 598 pseudoknot with the S3 helix can stabilize the pseudoknotted conformation allowing it to form.
T32 12607-12610 Epistemic_statement denotes 599
T33 12611-12789 Epistemic_statement denotes Consistent with the biophysical studies, a reverse genetic study of this three helix junction region 600 suggested that S3 is essential for viral replication (Liu et al., 2013) .
T34 12790-12913 Epistemic_statement denotes However, mutations 601 disrupting the S4 helix of the triple helix junction, or deleting most of the L3 loop are tolerated.
T35 12914-13016 Epistemic_statement denotes For the alphacoronaviruses, although the pseudoknot is conserved the bulged stem loop 603 (BSL in Fig.
T36 13230-13371 Epistemic_statement denotes Although a nearby pseudoknot is present in gammacoronavirus, 606 its functional importance has not been established (Williams et al., 1999) .
T37 13698-13907 Epistemic_statement denotes It should be noted that majority of this work has been performed with 624 they recognize are likely to be conserved, it is possible that there might be some differences 626 amongst the four coronavirus genera.
T38 13908-14188 Epistemic_statement denotes 627 Two viral proteins have been shown to bind to the coronavirus 5'UTR, the N protein and 628 nsp1 ( Table 1) The MHV NTD forms a high affinity (K obs ≈8 x 10 7 M -1 ) 1:1 complex with a TRS-containing 643 RNA (5'-gAAUCUAAAC) and its complement (cTRS) (Grossoehme et al., 2009) .
T39 14189-14473 Epistemic_statement denotes A recent 644 study showed that the NTD-TRS interaction involves N residues R125, Y127, and Y190 and 645 anchors the adenosine-rich region in the 3' end of the TRS RNA to the β-platform of N and that 646 this interaction is critical for efficient sgRNA synthesis (Keane et al., 2012) .
T40 14474-14634 Epistemic_statement denotes This same study 647 also showed that the IBV and SARS-CoV N protein NTD shows limited binding specificity for their cognate TRS sequences (Keane et al., 2012) .
T41 14635-14816 Epistemic_statement denotes Thus it is not clear that the specific binding of 649 N protein to the TRS over and above its general RNA binding activity plays a role in sgRNA 650 synthesis for all coronaviruses.
T42 14817-14918 Epistemic_statement denotes The second viral protein that has been shown to bind to the 651 5'UTR is nsp1 (Gustin et al., 2009 ).
T43 14919-15155 Epistemic_statement denotes The BCoV nsp1 protein has been determined to bind to 652 three cis-acting stem loops in the 5'UTR, including SLIII, which corresponds to SL4b in our 653 model and to regulate viral RNA translation and replication (Gustin et al., 2009) .
T44 15156-15238 Epistemic_statement denotes It is likely that 654 the closely related MHV nsp1 protein has a similar function.
T45 15239-15444 Epistemic_statement denotes 655 A number of host proteins have been shown to bind to the 5'UTR as well (Table 1) subgenomic RNAs, suggesting that hnRNP A1 is not required for MHV discontinuous 669 transcription or genome replication.
T46 15445-15847 Epistemic_statement denotes However, it has been shown that multiple other type 670 hnRNPs, including hnRNP A2/B1, hnRNP A/B, and hnRNP A3, bind to the negative strand complement of the MHV leader TRS (Shi et al., 2003) and that overexpression of hnRNP A/B 672 resulted in a 4-5 fold enhancement of viral RNA synthesis, suggesting that these proteins might 673 also facilitate RNA synthesis and be able to substitute for hnRNP A1.
T47 16054-16057 Epistemic_statement denotes 676
T48 16058-16530 Epistemic_statement denotes The L-TRS sequence has been shown to be necessary but sufficient for SYNCRIP binding and RNase protection/gel mobility shift and UV cross-linking assays and a conserved 11 nts UGAAUGAAGUU sequence spanning position 26-36 in the 3'UTR (note that in this 695 numbering system position 1 is the first nt upstream of the poly(A) tail) was necessary for 696 protein binding activity and for efficient DI RNA replication (Yu and Leibowitz, 1995a ; Yu and 697 Leibowitz, 1995b) .
T49 17019-17172 Epistemic_statement denotes PTB has been shown to bind to a negative-strand RNA 703 complementary to the MHV 3'UTR at position 53 to 149 and less strongly at positions 270-307 704 .
T50 18142-18636 Epistemic_statement denotes Although this is an attractive model, 738 the fact that a deletion encompassing the high affinity hnRNP A1 binding site in the 3'UTR is 739 able to replicate and direct normal synthesis of subgenomic mRNAs makes the PTB-hnRNP A1 740 association less likely to have a crucial role in leader-body rejoining (Goebel et al., 2007) , 741 although the possibility that other members of the hnRNP family could substitute for hnRNP A1 742 remains a possibility (see section 5 for a discussion of this).
T51 19145-19474 Epistemic_statement denotes In 748 unpublished work P. Liu and Leibowitz identified a potential base pairing between nucleotides 8-749 24 in the MHV 5' UTR SL1 and two discontinuous sequences in the 3'UTR, nts 1-6 and 218-228 750 (note that the 3'UTR sequences are numbered with position 1 corresponding to the first 751 nucleotide 5' of the poly (A) tail).
T52 19651-19779 Epistemic_statement denotes Thus the precise mechanism by which the 5' and 3'UTRs associate during viral 754 replication remains to be functionally defined.