{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:42:41Z","timestamp":1768506161237,"version":"3.49.0"},"posted":{"date-parts":[[2023,3,1]]},"group-title":"Microbiology","reference-count":91,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Borrelial pathogens are vector-borne etiological agents of Lyme disease, relapsing fever, and\n                  <jats:italic>Borrelia miyamotoi<\/jats:italic>\n                  disease. These spirochetes each encode several surface-localized lipoproteins that bind to components of the human complement system. BBK32 is an example of a borrelial lipoprotein that protects the Lyme disease spirochete from complement-mediated attack. The complement inhibitory activity of BBK32 arises from an alpha helical C-terminal domain that interacts directly with the initiating protease of the classical pathway, C1r.\n                  <jats:italic>Borrelia miyamotoi<\/jats:italic>\n                  spirochetes encode BBK32 orthologs termed FbpA and FbpB, and these proteins also inhibit C1r, albeit via distinct recognition mechanisms. The C1r-inhibitory activities of a third ortholog termed FbpC, which is found exclusively in relapsing fever spirochetes, remains unknown. Here we report the crystal structure of the C-terminal domain of\n                  <jats:italic>B. hermsii<\/jats:italic>\n                  FbpC to a limiting resolution of 1.5 \u00c5. Surface plasmon resonance studies and assays of complement function demonstrate that FbpC retains potent BBK32-like anti-complement activities. Based on the structure of FbpC, we hypothesized that conformational dynamics of the complement inhibitory domains of borrelial C1r inhibitors may differ. To test this, we utilized the crystal structures of the C-terminal domains of BBK32, FbpA, FbpB, and FbpC to carry out 1 \u00b5s molecular dynamics simulations, which revealed borrelial C1r inhibitors adopt energetically favored open and closed states defined by two functionally critical regions. This study advances our understanding of how protein dynamics contribute to the function of bacterial immune evasion proteins and reveals a surprising plasticity in the structures of borrelial C1r inhibitors.\n                <\/jats:p>","DOI":"10.1101\/2023.03.01.530473","type":"posted-content","created":{"date-parts":[[2023,3,4]],"date-time":"2023-03-04T00:45:10Z","timestamp":1677890710000},"source":"Crossref","is-referenced-by-count":0,"title":["\u201cConformational dynamics of C1r inhibitor proteins from Lyme disease and relapsing fever spirochetes\u201d"],"prefix":"10.64898","author":[{"given":"Sourav","family":"Roy","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"suffix":"Jr.","given":"Charles E.","family":"Booth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra D.","family":"Powell-Pierce","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna M.","family":"Schulz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jon T.","family":"Skare","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brandon L.","family":"Garcia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023030802351363000_2023.03.01.530473v1.1","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s12088-020-00872-9","article-title":"Complement Evasion Strategies of Human Pathogenic Bacteria","volume":"60","year":"2020","journal-title":"Indian J Microbiol"},{"key":"2023030802351363000_2023.03.01.530473v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1824"},{"key":"2023030802351363000_2023.03.01.530473v1.3","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1016\/j.tim.2020.05.004","article-title":"Complement Evasion by Lyme Disease Spirochetes","volume":"28","year":"2020","journal-title":"Trends Microbiol"},{"key":"2023030802351363000_2023.03.01.530473v1.4","doi-asserted-by":"crossref","first-page":"868","DOI":"10.3389\/fmicb.2017.00868","article-title":"Evasion mechanisms used by pathogens to escape the lectin complement pathway","volume":"8","year":"2017","journal-title":"Front Microbiol"},{"key":"2023030802351363000_2023.03.01.530473v1.5","doi-asserted-by":"crossref","first-page":"281","DOI":"10.3390\/pathogens10030281","article-title":"The brilliance of Borrelia: Mechanisms of host immune evasion by Lyme disease-causing spirochetes","volume":"10","year":"2021","journal-title":"Pathogens"},{"key":"2023030802351363000_2023.03.01.530473v1.6","first-page":"3389","article-title":"Hijacking Factor H for Complement Immune Evasion","volume":"10","year":"2021","journal-title":"Front Immunol"},{"key":"2023030802351363000_2023.03.01.530473v1.7","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.00328"},{"key":"2023030802351363000_2023.03.01.530473v1.8","doi-asserted-by":"crossref","first-page":"267","DOI":"10.3390\/pathogens12020267","article-title":"Borrelia miyamotoi: A Comprehensive Review","volume":"12","year":"2023","journal-title":"Pathogens"},{"key":"2023030802351363000_2023.03.01.530473v1.9","doi-asserted-by":"publisher","DOI":"10.21775\/9781913652616.13"},{"key":"2023030802351363000_2023.03.01.530473v1.10","doi-asserted-by":"publisher","DOI":"10.21775\/9781913652616.14"},{"key":"2023030802351363000_2023.03.01.530473v1.11","doi-asserted-by":"crossref","first-page":"12","DOI":"10.3390\/vetsci3020012","article-title":"Travelling between two worlds: Complement as a Gatekeeper for an expanded host range of Lyme disease spirochetes","volume":"3","year":"2016","journal-title":"Vet Sci"},{"key":"2023030802351363000_2023.03.01.530473v1.12","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ttbdis.2012.10.039","article-title":"Complement regulator-acquiring surface proteins of Borrelia burgdorferi: Structure, function and regulation of gene expression","volume":"4","year":"2013","journal-title":"Ticks Tick Borne Dis"},{"key":"2023030802351363000_2023.03.01.530473v1.13","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.ijmm.2008.02.003","article-title":"BhCRASP-1 of the relapsing fever spirochete Borrelia hermsii is a factor H- and plasminogen-binding protein","volume":"298","year":"2008","journal-title":"International Journal of Medical Microbiology"},{"key":"2023030802351363000_2023.03.01.530473v1.14","doi-asserted-by":"crossref","first-page":"7292","DOI":"10.4049\/jimmunol.178.11.7292","article-title":"Dual Binding Specificity of a Borrelia hermsii \u2013 Associated Complement Regulator-Acquiring Surface Protein for Factor H and Plasminogen Discloses a Putative Virulence Factor of Relapsing Fever Spirochetes","volume":"178","year":"2007","journal-title":"The Journal of Immunology"},{"key":"2023030802351363000_2023.03.01.530473v1.15","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00089-10"},{"key":"2023030802351363000_2023.03.01.530473v1.16","doi-asserted-by":"publisher","DOI":"10.1128\/JB.186.9.2612-2618.2004"},{"key":"2023030802351363000_2023.03.01.530473v1.17","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.3389\/fimmu.2020.01560","article-title":"Immune Evasion Strategies of Relapsing Fever Spirochetes","volume":"11","year":"2020","journal-title":"Front Immunol"},{"key":"2023030802351363000_2023.03.01.530473v1.18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0000698"},{"key":"2023030802351363000_2023.03.01.530473v1.19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0004858"},{"key":"2023030802351363000_2023.03.01.530473v1.20","doi-asserted-by":"crossref","first-page":"886733","DOI":"10.3389\/fimmu.2022.886733","article-title":"Borrelia miyamotoi FbpA and FbpB Are Immunomodulatory Outer Surface Lipoproteins With Distinct Structures and Functions","volume":"13","year":"2022","journal-title":"Front Immunol"},{"key":"2023030802351363000_2023.03.01.530473v1.21","doi-asserted-by":"crossref","first-page":"4964","DOI":"10.1038\/s41598-021-84533-x","article-title":"Interaction between Borrelia miyamotoi variable major proteins Vlp15\/16 and Vlp18 with plasminogen and complement","volume":"11","year":"2021","journal-title":"Sci Rep"},{"key":"2023030802351363000_2023.03.01.530473v1.22","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41598-017-00412-4","article-title":"Immune evasion of Borrelia miyamotoi: CbiA, a novel outer surface protein exhibiting complement binding and inactivating properties","volume":"7","year":"2017","journal-title":"Sci Rep"},{"key":"2023030802351363000_2023.03.01.530473v1.23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00012"},{"key":"2023030802351363000_2023.03.01.530473v1.24","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.69.6.4129-4133.2001"},{"key":"2023030802351363000_2023.03.01.530473v1.25","doi-asserted-by":"crossref","first-page":"5344","DOI":"10.4049\/jimmunol.164.10.5344","article-title":"Arthropod- and Host-Specific Borrelia burgdorferi bbk32 Expression and the Inhibition of Spirochete Transmission","volume":"164","year":"2000","journal-title":"The Journal of Immunology"},{"key":"2023030802351363000_2023.03.01.530473v1.26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.578419"},{"key":"2023030802351363000_2023.03.01.530473v1.27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M401691200"},{"key":"2023030802351363000_2023.03.01.530473v1.28","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2005.05042.x"},{"key":"2023030802351363000_2023.03.01.530473v1.29","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2011.07801.x"},{"key":"2023030802351363000_2023.03.01.530473v1.30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005404"},{"key":"2023030802351363000_2023.03.01.530473v1.31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007659"},{"key":"2023030802351363000_2023.03.01.530473v1.32","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.4049\/jimmunol.2100815","article-title":"A Structural Basis for Inhibition of the Complement Initiator Protease C1r by Lyme Disease Spirochetes","volume":"207","year":"2021","journal-title":"The Journal of Immunology"},{"key":"2023030802351363000_2023.03.01.530473v1.33","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01582-14"},{"key":"2023030802351363000_2023.03.01.530473v1.34","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0063437"},{"key":"2023030802351363000_2023.03.01.530473v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/S41586-021-03819-2"},{"key":"2023030802351363000_2023.03.01.530473v1.36","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1179\/0308018815Z.000000000120","article-title":"Structural biology: A century-long journey into an unseen world","volume":"40","year":"2015","journal-title":"Interdisciplinary Science Reviews"},{"key":"2023030802351363000_2023.03.01.530473v1.37","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.61.5.2192-2195.1993"},{"key":"2023030802351363000_2023.03.01.530473v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.08.011"},{"key":"2023030802351363000_2023.03.01.530473v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2010.09.008"},{"key":"2023030802351363000_2023.03.01.530473v1.40","doi-asserted-by":"publisher","DOI":"10.1063\/1.4934504"},{"key":"2023030802351363000_2023.03.01.530473v1.41","doi-asserted-by":"crossref","first-page":"e0189270","DOI":"10.1371\/journal.pone.0189270","article-title":"Molecular dynamics simulation unveils the conformational flexibility of the interdomain linker in the bacterial transcriptional regulator GabR from Bacillus subtilis bound to pyridoxal 5\u2019-phosphate","volume":"12","year":"2017","journal-title":"PLoS One"},{"key":"2023030802351363000_2023.03.01.530473v1.42","first-page":"231","article-title":"Methods of protein structure comparison","volume":"857","year":"2012","journal-title":"Methods in Molecular Biology"},{"key":"2023030802351363000_2023.03.01.530473v1.43","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0119264"},{"key":"2023030802351363000_2023.03.01.530473v1.44","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.15.4995"},{"key":"2023030802351363000_2023.03.01.530473v1.45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.80.21.6571"},{"key":"2023030802351363000_2023.03.01.530473v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/296776a0"},{"key":"2023030802351363000_2023.03.01.530473v1.47","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.80.12.3696"},{"key":"2023030802351363000_2023.03.01.530473v1.48","doi-asserted-by":"publisher","DOI":"10.1002\/bip.360230610"},{"key":"2023030802351363000_2023.03.01.530473v1.49","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(85)90230-X"},{"key":"2023030802351363000_2023.03.01.530473v1.50","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.23.8982"},{"key":"2023030802351363000_2023.03.01.530473v1.51","doi-asserted-by":"publisher","DOI":"10.2142\/biophysico.16.0_322"},{"key":"2023030802351363000_2023.03.01.530473v1.52","doi-asserted-by":"publisher","DOI":"10.1110\/ps.04882105"},{"key":"2023030802351363000_2023.03.01.530473v1.53","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/prot.340110305","article-title":"Collective motions in proteins: A covariance analysis of atomic fluctuations in molecular dynamics and normal mode simulations","volume":"11","year":"1991","journal-title":"Proteins: Structure, Function, and Bioinformatics"},{"key":"2023030802351363000_2023.03.01.530473v1.54","doi-asserted-by":"crossref","unstructured":"54. McCammon, J. A. , and Harvey, S. C. (1987) Dynamics of Proteins and Nucleic Acids, Cambridge University Press, 10.1017\/cbo9781139167864","DOI":"10.1017\/CBO9781139167864"},{"key":"2023030802351363000_2023.03.01.530473v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsb.2006.10.022"},{"key":"2023030802351363000_2023.03.01.530473v1.56","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.csbj.2017.01.001","article-title":"Detection of Side Chain Rearrangements Mediating the Motions of Transmembrane Helices in Molecular Dynamics Simulations of G Protein-Coupled Receptors","volume":"15","year":"2017","journal-title":"Comput Struct Biotechnol J"},{"key":"2023030802351363000_2023.03.01.530473v1.57","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.22175"},{"key":"2023030802351363000_2023.03.01.530473v1.58","doi-asserted-by":"publisher","DOI":"10.1021\/ja806846q"},{"key":"2023030802351363000_2023.03.01.530473v1.59","first-page":"618","article-title":"Immune Evasion by Staphylococcus aureus","volume":"7","year":"2019","journal-title":"Microbiol Spectr"},{"key":"2023030802351363000_2023.03.01.530473v1.60","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2016.02004"},{"key":"2023030802351363000_2023.03.01.530473v1.61","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20170132"},{"key":"2023030802351363000_2023.03.01.530473v1.62","doi-asserted-by":"publisher","DOI":"10.1128\/jb.00658-16"},{"key":"2023030802351363000_2023.03.01.530473v1.63","first-page":"1069","article-title":"AlphaFold2 models indicate that protein sequence determines both structure and dynamics","volume":"12","year":"2022","journal-title":"Sci Rep"},{"key":"2023030802351363000_2023.03.01.530473v1.64","doi-asserted-by":"publisher","DOI":"10.1021\/jm0341913"},{"key":"2023030802351363000_2023.03.01.530473v1.65","doi-asserted-by":"crossref","unstructured":"Dror, R. O. , Mildorf, T. J. , Hilger, D. , Manglik, A. , Borhani, D. W. , Arlow, D. H. , Philippsen, A. , Villanueva, N. , Yang, Z. , Lerch, M. T. , Hubbell, W. L. , Kobilka, B. K. , Sunahara, R. K. , and Shaw, D. E . (2015) Structural basis for nucleotide exchange in heterotrimeric G proteins. Science ( 1979 ). 348, 1361\u20131365","DOI":"10.1126\/science.aaa5264"},{"key":"2023030802351363000_2023.03.01.530473v1.66","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1109071108"},{"key":"2023030802351363000_2023.03.01.530473v1.67","doi-asserted-by":"crossref","first-page":"2984","DOI":"10.1016\/j.febslet.2013.06.056","article-title":"Structure of an atypical periplasmic adaptor from a multidrug efflux pump of the spirochete Borrelia burgdorferi","volume":"587","year":"2013","journal-title":"FEBS Lett"},{"key":"2023030802351363000_2023.03.01.530473v1.68","doi-asserted-by":"crossref","first-page":"7200","DOI":"10.1021\/acs.jpclett.9b02978","article-title":"Molecular Bases of DNA Packaging in Bacteria Revealed by All-Atom Molecular Dynamics Simulations: The Case of Histone-Like Proteins in Borrelia burgdorferi","volume":"10","year":"2019","journal-title":"Journal of Physical Chemistry Letters"},{"key":"2023030802351363000_2023.03.01.530473v1.69","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009801"},{"key":"2023030802351363000_2023.03.01.530473v1.70","doi-asserted-by":"crossref","first-page":"e0048822","DOI":"10.1128\/msystems.00488-22","article-title":"Phylogenomic Diversity Elucidates Mechanistic Insights into Lyme Borreliae-Host Association","volume":"7","year":"2022","journal-title":"mSystems"},{"key":"2023030802351363000_2023.03.01.530473v1.71","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2020.04.011"},{"key":"2023030802351363000_2023.03.01.530473v1.72","doi-asserted-by":"publisher","DOI":"10.1016\/j.pep.2005.09.003"},{"key":"2023030802351363000_2023.03.01.530473v1.73","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1007\/978-1-4939-7383-5_15","article-title":"Genetic Transformation and Complementation","volume":"1690","year":"2018","journal-title":"Methods in Molecular Biology"},{"key":"2023030802351363000_2023.03.01.530473v1.74","doi-asserted-by":"publisher","DOI":"10.1002\/jobm.3620300304"},{"key":"2023030802351363000_2023.03.01.530473v1.75","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1007\/978-1-60327-058-8_28","article-title":"Automated structure solution with the PHENIX suite","volume":"426","year":"2008","journal-title":"Methods in molecular biology"},{"key":"2023030802351363000_2023.03.01.530473v1.76","doi-asserted-by":"publisher","DOI":"10.1126\/science.1218231"},{"key":"2023030802351363000_2023.03.01.530473v1.77","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444902016657"},{"key":"2023030802351363000_2023.03.01.530473v1.78","doi-asserted-by":"publisher","DOI":"10.1107\/S1600536810002953"},{"key":"2023030802351363000_2023.03.01.530473v1.79","doi-asserted-by":"publisher","DOI":"10.1107\/S1600536810003314"},{"key":"2023030802351363000_2023.03.01.530473v1.80","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/s41592-022-01488-1","article-title":"ColabFold: making protein folding accessible to all","volume":"19","year":"2022","journal-title":"Nat Methods"},{"key":"2023030802351363000_2023.03.01.530473v1.81","doi-asserted-by":"crossref","first-page":"4016","DOI":"10.3390\/molecules25174016","article-title":"Targeting the Initiator Protease of the Classical Pathway of Complement Using Fragment-Based Drug Discovery","volume":"25","year":"2020","journal-title":"Molecules"},{"key":"2023030802351363000_2023.03.01.530473v1.82","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1993.1626"},{"key":"2023030802351363000_2023.03.01.530473v1.83","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1021\/ct900009a","article-title":"Development of OPLS-AA force field parameters for 68 unique ionic liquids","volume":"5","year":"2009","journal-title":"J Chem Theory Comput"},{"key":"2023030802351363000_2023.03.01.530473v1.84","doi-asserted-by":"publisher","DOI":"10.1016\/0010-4655(95)00042-E"},{"key":"2023030802351363000_2023.03.01.530473v1.85","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.3.CO;2-L"},{"key":"2023030802351363000_2023.03.01.530473v1.86","doi-asserted-by":"publisher","DOI":"10.1063\/1.470117"},{"key":"2023030802351363000_2023.03.01.530473v1.87","doi-asserted-by":"publisher","DOI":"10.1063\/1.448118"},{"key":"2023030802351363000_2023.03.01.530473v1.88","doi-asserted-by":"publisher","DOI":"10.1063\/1.328693"},{"key":"2023030802351363000_2023.03.01.530473v1.89","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20291"},{"key":"2023030802351363000_2023.03.01.530473v1.90","first-page":"19","article-title":"Gromacs: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1","year":"2015","journal-title":"SoftwareX"},{"key":"2023030802351363000_2023.03.01.530473v1.91","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btl461"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2023.03.01.530473","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:19:58Z","timestamp":1768450798000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2023.03.01.530473"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,1]]},"references-count":91,"URL":"https:\/\/doi.org\/10.1101\/2023.03.01.530473","relation":{},"subject":[],"published":{"date-parts":[[2023,3,1]]},"subtype":"preprint"}}