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51. The best COVID-19 predictor is recent smell loss: a cross-sectional study

Author

Gerkin, Richard, Ohla, Kathrin, Veldhuizen, Maria Geraldine, Joseph, Paule, Kelly, Christine, Bakke, Alyssa, Steele, Kimberley, Pellegrino, Robert, Pepino, Marta, Bouysset, Cédric, Soler, Graciela, Pereda-Loth, Veronica, Dibattista, Michele, Cooper, Keiland, Croijmans, Ilja, Di Pizio, Antonella, Ozdener, M. Hakan, D'Errico, Anna, Fischmeister, Florian Ph.S, Bock, María Adelaida, Domínguez, Paloma Paloma, Yanık, Hüseyin, Boesveldt, Sanne, de Groot, Jasper, Dinnella, Caterina, Freiherr, Jessica, Laktionova, Tatiana, Mariño, Sajidxa, Monteleone, Erminio, Nunez-Parra, Alexia, Abdulrahman, Olagunju, Ritchie, Marina, Thomas-Danguin, Thierry, Walsh-Messinger, Julie, Al Abri, Rashid, Alizadeh, Rafieh, Bignon, Emmanuelle, Cantone, Elena, Cecchini, Maria Paola, Chen, Jingguo, Guàrdia, Maria Dolors, Hoover, Kara, Karni, Noam, Navarro, Marta, Nolden, Alissa, Mazal, Patricia Portillo, Rowan, Nicholas, Sarabi-Jamab, Atiye, Archer, Nicholas, Chen, Ben, Di Valerio, Elizabeth, Feeney, Emma, Frasnelli, Johannes, Hannum, Mackenzie, Hopkins, Claire, Klein, Hadar, Mignot, Coralie, Mucignat, Carla, Ning, Yuping, Ozturk, Elif, Peng, Mei, Saatci, Ozlem, Sell, Elizabeth, Yan, Carol, Alfaro, Raul, Cecchetto, Cinzia, Coureaud, Gérard, Herriman, Riley, Justice, Jeb, Kaushik, Pavan Kumar, Koyama, Sachiko, Overdevest, Jonathan, Pirastu, Nicola, Ramirez, Vicente, Roberts, S. Craig, Smith, Barry, Cao, Hongyuan, Wang, Hong, Balungwe, Patrick, Baguma, Marius, Veldhuizen, Maria, Farruggia, Michael, Pizio, Antonella, Hakan Ozdener, M, Fjaeldstad, Alexander, Lin, Cailu, Sandell, Mari, Singh, Preet, Brindha, V. Evelyn, Olsson, Shannon, Saraiva, Luis, Ahuja, Gaurav, Alwashahi, Mohammed, Bhutani, Surabhi, Fornazieri, Marco, Golebiowski, Jérôme, Hwang, Liang-Dar, Öztürk, Lina, Roura, Eugeni, Spinelli, Sara, Whitcroft, Katherine, Faraji, Farhoud, Fischmeister, Florian, Heinbockel, Thomas, Hsieh, Julien, Huart, Caroline, Konstantinidis, Iordanis, Menini, Anna, Morini, Gabriella, Olofsson, Jonas, Philpott, Carl, Pierron, Denis, Shields, Vonnie, Voznessenskaya, Vera, Albayay, Javier, Altundag, Aytug, Bensafi, Moustafa, Bock, María, Calcinoni, Orietta, Fredborg, William, Laudamiel, Christophe, Lim, Juyun, Lundström, Johan, Macchi, Alberto, Meyer, Pablo, Moein, Shima, Santamaría, Enrique, Sengupta, Debarka, Rohlfs Dominguez, Paloma, Yanik, Hüseyin, Group, GCCR, Hummel, Thomas, Hayes, John, Reed, Danielle, Niv, Masha, Munger, Steven, Parma, Valentina, Arizona State University [Tempe] (ASU), Institute of Neuroscience and Medicine [Jülich] (INM-1), Mersin University, National Institutes of Health [Bethesda] (NIH), AbScent, Pennsylvania State University (Penn State), Penn State System, National Institute of Diabetes and Digestive and Kidney Diseases [Bethesda], Yale University [New Haven], Tennessee State University, University of Illinois at Urbana-Champaign [Urbana], University of Illinois System, Institut de Chimie de Nice (ICN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Buenos Aires University and GEOG (Grupo de Estudio de Olfato y Gusto), Anthropologie Moléculaire et Imagerie de Synthèse (AMIS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), University of Bari Aldo Moro (UNIBA), University of California [Irvine] (UCI), University of California, Utrecht University [Utrecht], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Monell Chemical Senses Center, Regional Hospital West Jutland [Denmark], University of Helsinki, University of Oslo (UiO), Karunya University, Tata Institute for Fundamental Research (TIFR), Research at Sidra Medicine Research Branch [Doha, Qatar], Indraprastha Institute of Information Technology [New Delhi] (IIIT-Delhi), Sultan Qaboos University (SQU), San Diego State University (SDSU), Goethe-University Frankfurt am Main, State University of Londrina = Universidade Estadual de Londrina, University of Queensland [Brisbane], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University College of London [London] (UCL), University of Graz, Howard University, Geneva University Hospital (HUG), Cliniques Universitaires Saint-Luc [Bruxelles], Aristotle University of Thessaloniki, Scuola Internazionale Superiore di Studi Avanzati / International School for Advanced Studies (SISSA / ISAS), University of Gastronomic Sciences of Pollenzo (UNISG), Stockholm University, University of East Anglia [Norwich] (UEA), Towson University [Towson, MD, United States], University of Maryland System, A.N. Severtsov Institute of Ecology and Evolution, Russian Academy of Sciences [Moscow] (RAS), Universita degli Studi di Padova, Biruni University, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospital General de Barrio Obrero [Asunción, Paraguay] (Public Hospital Barrio Obrero ), Private practice [Milan], DreamAir Llc, Oregon State University (OSU), Cancer Center Karolinska [Karolinska Institutet] (CCK), Karolinska Institutet [Stockholm], University of Insubria, Varese, Computational Biology Center (IBM T.J. Watson Research Center), IBM, Institute for Research in Fundamental Sciences [Tehran] (IPM), Instituto de Investigación Sanitaria de Navarra [Pamplona, Spain] (IdiSNA), University of Extremadura, Technische Universität Dresden = Dresden University of Technology (TU Dresden), The Hebrew University of Jerusalem (HUJ), University of Florida [Gainesville] (UF), Temple University [Philadelphia], Pennsylvania Commonwealth System of Higher Education (PCSHE), Non-byline authors (to be listed as collaborators in PubMed under the GCCR Group Author): Sanne Boesveldt, Jasper H.B. de Groot, Caterina Dinnella, Jessica Freiherr, Tatiana Laktionova, Sajidxa Mariño, Erminio Monteleone, Alexia Nunez-Parra, Olagunju Abdulrahman, Marina Ritchie, Thierry Thomas-Danguin, Julie Walsh-Messinger, Rashid Al Abri, Rafieh Alizadeh, Emmanuelle Bignon, Elena Cantone, Maria Paola Cecchini, Jingguo Chen, Maria Dolors Guàrdia, Kara C. Hoover, Noam Karni, Marta Navarro, Alissa A. Nolden, Patricia Portillo Mazal, Nicholas R. Rowan, Atiye SarabiJamab, Nicholas S. Archer, Ben Chen, Elizabeth A. Di Valerio, Emma L. Feeney, Johannes Frasnelli, Mackenzie E. Hannum, Claire Hopkins, Hadar Klein, Coralie Mignot, Carla Mucignat, Yuping Ning, Elif E. Ozturk, Mei Peng, Ozlem Saatci, Elizabeth A. Sell, Carol H. Yan, Raul Alfaro, Cinzia Cecchetto, Gérard Coureaud, Riley D. Herriman, Jeb M. Justice, Pavan Kumar Kaushik, Sachiko Koyama, Jonathan B. Overdevest, Nicola Pirastu, Vicente A. Ramirez, S. Craig Roberts, Barry C. Smith, Hongyuan Cao, Hong Wang, Patrick Balungwe Birindwa, Marius Baguma, Karl-Franzens-Universität [Graz, Autriche], Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, The Pennsylvania State University, University of Tennessee, University of Buenos Aires [Argentina], Università degli studi di Bari Aldo Moro (UNIBA), Goethe University of Frankfurt am Main, Wageningen University and Research [Wageningen] (WUR), Radboud university [Nijmegen], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), A.N. Severtsov Institute of Ecology and Evolution RAS, 119071, Russia., RespiraLibre - Centro de Otorrinolaringología, Department of Agriculture, Food, Environment and Forestry (DAGRI), University of Florence, Partenaires INRAE, Universidad de Chile = University of Chile [Santiago] (UCHILE), Federal University of Technology of Akure (FUTA), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Bourgogne Franche-Comté [COMUE] (UBFC), University of Dayton, Iran University of Medical Sciences, University of Naples Federico II, University of Verona (UNIVR), Head and Neck Surgery, Hospital of Xi'an Jiaotong University, Institute of Agrifood Research and Technology (IRTA), University of Alaska [Fairbanks] (UAF), Hadassah Hebrew University Medical Center [Jerusalem], University of Southern Queensland (USQ), University of Massachusetts, Instituto Universitario del Hospital Italiano [Buenos Aires, Argentina], Johns Hopkins University School of Medicine [Baltimore], Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), The First Affiliated Hospital of Guangzhou Medical University (GMU), University College Dublin [Dublin] (UCD), Université du Québec à Trois-Rivières (UQTR), Guy's and St Thomas' Hospitals, University of Padova [Padova, Italy], Kilis Yedi Aralik University, University of Otago [Dunedin, Nouvelle-Zélande], Sancaktepe Education and Research Hospital, Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], UC San Diego Health, University ofFlorida, Tata Institute of Fundamental Research, Indiana University [Bloomington], Indiana University System, Columbia University Irving Medical Center (CUIMC), University of Edinburgh, University of California [Merced], University of Stirling, University of London [London], Florida State University [Panama City], Université catholique de Bukavu, Leibniz-Institute for Food Systems Biology at the Technical University of Munich, Karunya Institute of Technology and Sciences, Sidra Medicine, School of Exercise and Nutritional Sciences, Howard University College of Medicine, Geneva University Hospitals, Geneva University , Geneva , Switzerland., CHU Genève, General Hospital Papageorgiou, University of Toulouse, University of Padova, Lyon Neuroscience Research center, IBM T.J. Watson Research Center, Navarrabiomed-IdiSNA, Temple University, Julien, Sabine, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Universitad de Buenos Aires = University of Buenos Aires [Argentina], Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), University of California [Irvine] (UC Irvine), University of California (UC), Karl-Franzens-Universität Graz, Universidad de Extremadura - University of Extremadura (UEX), Radboud University [Nijmegen], Università degli Studi di Firenze = University of Florence (UniFI), University of Naples Federico II = Università degli studi di Napoli Federico II, Università degli studi di Verona = University of Verona (UNIVR), Institut de Recerca i Tecnologia Agroalimentàries = Institute of Agrifood Research and Technology (IRTA), Università degli Studi di Padova = University of Padua (Unipd), University of Pennsylvania-University of Pennsylvania, School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Tata Institute of Fundamental Research [Bangalore], University of California [Merced] (UC Merced), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Sidra Medicine [Doha, Qatar], Universitá degli Studi dell’Insubria = University of Insubria [Varese] (Uninsubria), and Universitá degli Studi dell’Insubria

Subjects
Adult, Male, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Cross-sectional study, Visual analogue scale, Anosmia, Audiology, Logistic regression, AcademicSubjects/SCI01180, Article, Odds, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Hyposmia, Humans, Medicine, [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, 030223 otorhinolaryngology, SARS-CoV-2, business.industry, [SCCO.NEUR]Cognitive science/Neuroscience, COVID-19, Middle Aged, Prognosis, Smell, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Cross-Sectional Studies, [SDV.MHEP.OS] Life Sciences [q-bio]/Human health and pathology/Sensory Organs, Smell loss, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, Original Article, Self Report, medicine.symptom, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

BackgroundCOVID-19 has heterogeneous manifestations, though one of the most common symptoms is a sudden loss of smell (anosmia or hyposmia). We investigated whether olfactory loss is a reliable predictor of COVID-19.MethodsThis preregistered, cross-sectional study used a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified singular and cumulative predictors of COVID-19 status and post-COVID-19 olfactory recovery.ResultsBoth C19+ and C19-groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both single and cumulative feature models (ROC AUC=0.72), with additional features providing negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms, such as fever or cough. Olfactory recovery within 40 days was reported for ∼50% of participants and was best predicted by time since illness onset.ConclusionsAs smell loss is the best predictor of COVID-19, we developed the ODoR-19 tool, a 0-10 scale to screen for recent olfactory loss. Numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4

Published
2020

52. Recent smell loss is the best predictor of COVID-19:a preregistered, cross-sectional study

Author

Gerkin, Richard C, Ohla, Kathrin, Veldhuizen, Maria Geraldine, Joseph, Paule V, Kelly, Christine E, Bakke, Alyssa J, Steele, Kimberley E, Farruggia, Michael C, Pellegrino, Robert, Pepino, Marta Y, Bouysset, Cédric, Soler, Graciela M, Pereda-Loth, Veronica, Dibattista, Michele, Cooper, Keiland W, Croijmans, Ilja, Di Pizio, Antonella, Ozdener, M Hakan, Fjaeldstad, Alexander W, Lin, Cailu, Sandell, Mari A, Singh, Preet B, Brindha, V Evelyn, Olsson, Shannon B, Saraiva, Luis R, Ahuja, Gaurav, Alwashahi, Mohammed K, Bhutani, Surabhi, D'Errico, Anna, Fornazieri, Marco A, Golebiowski, Jérôme, Hwang, Liang-Dar, Öztürk, Lina, Roura, Eugeni, Spinelli, Sara, Whitcroft, Katherine L, Faraji, Farhoud, Fischmeister, Florian Ph S, Heinbockel, Thomas, Hsieh, Julien W, Huart, Caroline, Konstantinidis, Iordanis, Menini, Anna, Morini, Gabriella, Olofsson, Jonas K, Philpott, Carl M, Pierron, Denis, Shields, Vonnie D C, Voznessenskaya, Vera V, and Albayay, Javier

Subjects
COVID-19, Lugtesans
Abstract

BACKGROUND: COVID-19 has heterogeneous manifestations, though one of the most common symptoms is a sudden loss of smell (anosmia or hyposmia). We investigated whether olfactory loss is a reliable predictor of COVID-19.METHODS: This preregistered, cross-sectional study used a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified singular and cumulative predictors of COVID-19 status and post-COVID-19 olfactory recovery.RESULTS: Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both single and cumulative feature models (ROC AUC=0.72), with additional features providing no significant model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms, such as fever or cough. Olfactory recovery within 40 days was reported for ~50% of participants and was best predicted by time since illness onset.CONCLUSIONS: As smell loss is the best predictor of COVID-19, we developed the ODoR-19 tool, a 0-10 scale to screen for recent olfactory loss. Numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (10

Published
2020

53. Recent smell loss is the best predictor of COVID-19: a preregistered, cross-sectional study

Author

Parma, Valentina, Overdevest, Jonathan B, Peng, Mei, Saatci, Ozlem, Sell, Elizabeth A, Yan, Carol H, Alfaro, Raul, Cecchetto, Cinzia, Coureaud, Gérard, Herriman, Riley D, Justice, Jeb M, Kaushik, Pavan Kumar, Koyama, Sachiko, Pirastu, Nicola, Ning, Yuping, Ramirez, Vicente A, Roberts, S Craig, Smith, Barry C, Cao, Hongyuan, Wang, Hong, Balungwe, Patrick, Baguma, Marius, Hummel, Thomas, Hayes, John E, Reed, Danielle R, Niv, Masha Y, Munger, Steven D, Ozturk, Elif E, Gerkin, Richard C, Ohla, Kathrin, Veldhuizen, Maria Geraldine, Joseph, Paule V, Kelly, Christine E, Bakke, Alyssa J, Steele, Kimberley E, Farruggia, Michael C, Pellegrino, Robert, Pepino, Marta Y, Bouysset, Cédric, Soler, Graciela M, Pereda-Loth, Veronica, Dibattista, Michele, Cooper, Keiland W, Croijmans, Ilja, Di Pizio, Antonella, Ozdener, M Hakan, Fjaeldstad, Alexander W, Lin, Cailu, Sandell, Mari A, Singh, Preet B, Brindha, V Evelyn, Olsson, Shannon B, Saraiva, Luis R, Ahuja, Gaurav, Alwashahi, Mohammed K, Bhutani, Surabhi, D'Errico, Anna, Fornazieri, Marco A, Golebiowski, Jérôme, Hwang, Liang-Dar, Öztürk, Lina, Roura, Eugeni, Spinelli, Sara, Whitcroft, Katherine L, Faraji, Farhoud, Fischmeister, Florian Ph S, Heinbockel, Thomas, Hsieh, Julien W, Huart, Caroline, Konstantinidis, Iordanis, Menini, Anna, Morini, Gabriella, Olofsson, Jonas K, Philpott, Carl M, Pierron, Denis, Shields, Vonnie D C, Voznessenskaya, Vera V, Albayay, Javier, Altundag, Aytug, Bensafi, Moustafa, Bock, María Adelaida, Calcinoni, Orietta, Fredborg, William, Laudamiel, Christophe, Lim, Juyun, Lundström, Johan N, Macchi, Alberto, Meyer, Pablo, Moein, Shima T, Santamaría, Enrique, Sengupta, Debarka, Domínguez, Paloma Paloma, Yanık, Hüseyin, Boesveldt, Sanne, de Groot, Jasper H B, Dinnella, Caterina, Freiherr, Jessica, Laktionova, Tatiana, Mariño, Sajidxa, Monteleone, Erminio, Nunez-Parra, Alexia, Abdulrahman, Olagunju, Ritchie, Marina, Thomas-Danguin, Thierry, Walsh-Messinger, Julie, Al Abri, Rashid, Alizadeh, Rafieh, Bignon, Emmanuelle, Cantone, Elena, Cecchini, Maria Paola, Chen, Jingguo, Guàrdia, Maria Dolors, Hoover, Kara C, Karni, Noam, Navarro, Marta, Nolden, Alissa A, Mazal, Patricia Portillo, Rowan, Nicholas R, Sarabi-Jamab, Atiye, Archer, Nicholas S, Chen, Ben, Di Valerio, Elizabeth A, Feeney, Emma L, Frasnelli, Johannes, Hannum, Mackenzie, Hopkins, Claire, Klein, Hadar, Mignot, Coralie, Mucignat, Carla, UCL - (SLuc) Service d'oto-rhino-laryngologie, and UCL - SSS/IONS/NEUR - Clinical Neuroscience

Abstract

COVID-19 has heterogeneous manifestations, though one of the most common symptoms is a sudden loss of smell (anosmia or hyposmia). We investigated whether olfactory loss is a reliable predictor of COVID-19. This preregistered, cross-sectional study used a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n=4148) or negative (C19-; n=546) COVID-19 laboratory test outcome. Logistic regression models identified singular and cumulative predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean±SD, C19+: -82.5±27.2 points; C19-: -59.8±37.7). Smell loss during illness was the best predictor of COVID-19 in both single and cumulative feature models (ROC AUC=0.72), with additional features providing no significant model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms, such as fever or cough. Olfactory recovery within 40 days was reported for ~50% of participants and was best predicted by time since illness onset. As smell loss is the best predictor of COVID-19, we developed the ODoR-19 tool, a 0-10 scale to screen for recent olfactory loss. Numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (10

Published
2020

54. More Than Smell-COVID-19 Is Associated With Severe Impairment of Smell, Taste, and Chemesthesis.

Author

UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service d'oto-rhino-laryngologie, Parma, Valentina, Ohla, Kathrin, Veldhuizen, Maria G, Niv, Masha Y, Kelly, Christine E, Bakke, Alyssa J, Cooper, Keiland W, Bouysset, Cédric, Pirastu, Nicola, Dibattista, Michele, Kaur, Rishemjit, Liuzza, Marco Tullio, Pepino, Marta Y, Schöpf, Veronika, Pereda-Loth, Veronica, Olsson, Shannon B, Gerkin, Richard C, Rohlfs Domínguez, Paloma, Albayay, Javier, Farruggia, Michael C, Bhutani, Surabhi, Fjaeldstad, Alexander W, Kumar, Ritesh, Menini, Anna, Bensafi, Moustafa, Sandell, Mari, Konstantinidis, Iordanis, Di Pizio, Antonella, Genovese, Federica, Öztürk, Lina, Thomas-Danguin, Thierry, Frasnelli, Johannes, Boesveldt, Sanne, Saatci, Özlem, Saraiva, Luis R, Lin, Cailu, Golebiowski, Jérôme, Hwang, Liang-Dar, Ozdener, Mehmet Hakan, Guàrdia, Maria Dolors, Laudamiel, Christophe, Ritchie, Marina, Havlícek, Jan, Pierron, Denis, Roura, Eugeni, Navarro, Marta, Nolden, Alissa A, Lim, Juyun, Whitcroft, Katherine L, Colquitt, Lauren R, Ferdenzi, Camille, Brindha, Evelyn V, Altundag, Aytug, Macchi, Alberto, Nunez-Parra, Alexia, Patel, Zara M, Fiorucci, Sébastien, Philpott, Carl M, Smith, Barry C, Lundström, Johan N, Mucignat, Carla, Parker, Jane K, van den Brink, Mirjam, Schmuker, Michael, Fischmeister, Florian Ph S, Heinbockel, Thomas, Shields, Vonnie D C, Faraji, Farhoud, Santamaría, Enrique, Fredborg, William E A, Morini, Gabriella, Olofsson, Jonas K, Jalessi, Maryam, Karni, Noam, D'Errico, Anna, Alizadeh, Rafieh, Pellegrino, Robert, Meyer, Pablo, Huart, Caroline, Chen, Ben, Soler, Graciela M, Alwashahi, Mohammed K, Welge-Lüssen, Antje, Freiherr, Jessica, de Groot, Jasper H B, Klein, Hadar, Okamoto, Masako, Singh, Preet Bano, Hsieh, Julien W, GCCR Group Author, Reed, Danielle R, Hummel, Thomas, Munger, Steven D, Hayes, John E, UCL - SSS/IONS - Institute of NeuroScience, UCL - SSS/IONS/NEUR - Clinical Neuroscience, UCL - (SLuc) Service d'oto-rhino-laryngologie, Parma, Valentina, Ohla, Kathrin, Veldhuizen, Maria G, Niv, Masha Y, Kelly, Christine E, Bakke, Alyssa J, Cooper, Keiland W, Bouysset, Cédric, Pirastu, Nicola, Dibattista, Michele, Kaur, Rishemjit, Liuzza, Marco Tullio, Pepino, Marta Y, Schöpf, Veronika, Pereda-Loth, Veronica, Olsson, Shannon B, Gerkin, Richard C, Rohlfs Domínguez, Paloma, Albayay, Javier, Farruggia, Michael C, Bhutani, Surabhi, Fjaeldstad, Alexander W, Kumar, Ritesh, Menini, Anna, Bensafi, Moustafa, Sandell, Mari, Konstantinidis, Iordanis, Di Pizio, Antonella, Genovese, Federica, Öztürk, Lina, Thomas-Danguin, Thierry, Frasnelli, Johannes, Boesveldt, Sanne, Saatci, Özlem, Saraiva, Luis R, Lin, Cailu, Golebiowski, Jérôme, Hwang, Liang-Dar, Ozdener, Mehmet Hakan, Guàrdia, Maria Dolors, Laudamiel, Christophe, Ritchie, Marina, Havlícek, Jan, Pierron, Denis, Roura, Eugeni, Navarro, Marta, Nolden, Alissa A, Lim, Juyun, Whitcroft, Katherine L, Colquitt, Lauren R, Ferdenzi, Camille, Brindha, Evelyn V, Altundag, Aytug, Macchi, Alberto, Nunez-Parra, Alexia, Patel, Zara M, Fiorucci, Sébastien, Philpott, Carl M, Smith, Barry C, Lundström, Johan N, Mucignat, Carla, Parker, Jane K, van den Brink, Mirjam, Schmuker, Michael, Fischmeister, Florian Ph S, Heinbockel, Thomas, Shields, Vonnie D C, Faraji, Farhoud, Santamaría, Enrique, Fredborg, William E A, Morini, Gabriella, Olofsson, Jonas K, Jalessi, Maryam, Karni, Noam, D'Errico, Anna, Alizadeh, Rafieh, Pellegrino, Robert, Meyer, Pablo, Huart, Caroline, Chen, Ben, Soler, Graciela M, Alwashahi, Mohammed K, Welge-Lüssen, Antje, Freiherr, Jessica, de Groot, Jasper H B, Klein, Hadar, Okamoto, Masako, Singh, Preet Bano, Hsieh, Julien W, GCCR Group Author, Reed, Danielle R, Hummel, Thomas, Munger, Steven D, and Hayes, John E

Abstract

Recent anecdotal and scientific reports have provided evidence of a link between COVID-19 and chemosensory impairments, such as anosmia. However, these reports have downplayed or failed to distinguish potential effects on taste, ignored chemesthesis, and generally lacked quantitative measurements. Here, we report the development, implementation, and initial results of a multilingual, international questionnaire to assess self-reported quantity and quality of perception in 3 distinct chemosensory modalities (smell, taste, and chemesthesis) before and during COVID-19. In the first 11 days after questionnaire launch, 4039 participants (2913 women, 1118 men, and 8 others, aged 19-79) reported a COVID-19 diagnosis either via laboratory tests or clinical assessment. Importantly, smell, taste, and chemesthetic function were each significantly reduced compared to their status before the disease. Difference scores (maximum possible change ±100) revealed a mean reduction of smell (-79.7 ± 28.7, mean ± standard deviation), taste (-69.0 ± 32.6), and chemesthetic (-37.3 ± 36.2) function during COVID-19. Qualitative changes in olfactory ability (parosmia and phantosmia) were relatively rare and correlated with smell loss. Importantly, perceived nasal obstruction did not account for smell loss. Furthermore, chemosensory impairments were similar between participants in the laboratory test and clinical assessment groups. These results show that COVID-19-associated chemosensory impairment is not limited to smell but also affects taste and chemesthesis. The multimodal impact of COVID-19 and the lack of perceived nasal obstruction suggest that severe acute respiratory syndrome coronavirus strain 2 (SARS-CoV-2) infection may disrupt sensory-neural mechanisms.

Published
2020

55. Bitter Sensing TAS2R50 Mediates the trans-Resveratrol-Induced Anti-inflammatory Effect on Interleukin 6 Release in HGF-1 Cells in Culture

Author

Tiroch, Johanna, primary, Sterneder, Sonja, additional, Di Pizio, Antonella, additional, Lieder, Barbara, additional, Hoelz, Kathrin, additional, Holik, Ann-Katrin, additional, Pignitter, Marc, additional, Behrens, Maik, additional, Somoza, Mark, additional, Ley, Jakob P., additional, and Somoza, Veronika, additional

Published
2021
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59. COVID-19 and the Chemical Senses: Supporting Players Take Center Stage

Author

Cooper, Keiland W., primary, Brann, David H., additional, Farruggia, Michael C., additional, Bhutani, Surabhi, additional, Pellegrino, Robert, additional, Tsukahara, Tatsuya, additional, Weinreb, Caleb, additional, Joseph, Paule V., additional, Larson, Eric D., additional, Parma, Valentina, additional, Albers, Mark W., additional, Barlow, Linda A., additional, Datta, Sandeep Robert, additional, and Di Pizio, Antonella, additional

Published
2020
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60. Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy

Author

Laghezza, Antonio, primary, Piemontese, Luca, additional, Brunetti, Leonardo, additional, Caradonna, Alessia, additional, Agamennone, Mariangela, additional, Di Pizio, Antonella, additional, Pochetti, Giorgio, additional, Montanari, Roberta, additional, Capelli, Davide, additional, Tauro, Marilena, additional, Loiodice, Fulvio, additional, and Tortorella, Paolo, additional

Published
2020
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67. Allostery in Its Many Disguises: From Theory to Applications

Author

Wodak, Shoshana J., Paci, Emanuele, Dokholyan, Nikolay V., Berezovsky, Igor N., Horovitz, Amnon, Li, Jing, Hilser, Vincent J., Behar, Ivet, Karanicolas, John, Stock, Gerhard, Hamm, Peter, Stote, Roland H., Eberhardt, Jerome, Chebaro, Yassmine, Dejaegere, Annick, Cecchini, Marco, Changeux, Jean-Pierre, Bolhuis, Peter G., Vreede, Jocelyne, Faccioli, Pietro, Orioli, Simone, Ravasio, Riccardo, Yen, Le, Brito, Carolina, Wyart, Matthieu, Gkeka, Paraskevi, Rivalta, Ivan, Palermo, Giulia, Mccammon, J. Andrew, Panecka-Hofman, Joanna, Wade, Rebecca C., Di Pizio, Antonella, Niv, Masha Y., Nussinov, Ruth, Tsai, Chung-Jung, Jang, Hyunbum, Padhorny, Dzmitry, Kozakov, Dima, Mcleish, Tom, Wodak, Shoshana J., Paci, Emanuele, Dokholyan, Nikolay V., Berezovsky, Igor N., Horovitz, Amnon, Li, Jing, Hilser, Vincent J., Behar, Ivet, Karanicolas, John, Stock, Gerhard, Hamm, Peter, Stote, Roland H., Eberhardt, Jerome, Chebaro, Yassmine, Dejaegere, Annick, Cecchini, Marco, Changeux, Jean-Pierre, Bolhuis, Peter G., Vreede, Jocelyne, Faccioli, Pietro, Orioli, Simone, Ravasio, Riccardo, Yen, Le, Brito, Carolina, Wyart, Matthieu, Gkeka, Paraskevi, Rivalta, Ivan, Palermo, Giulia, Mccammon, J. Andrew, Panecka-Hofman, Joanna, Wade, Rebecca C., Di Pizio, Antonella, Niv, Masha Y., Nussinov, Ruth, Tsai, Chung-Jung, Jang, Hyunbum, Padhorny, Dzmitry, Kozakov, Dima, and Mcleish, Tom

Abstract

Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, andmetabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM(Center Europeen de Calcul Atomique et Moleculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts.

Published
2019
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68. Allostery in Its Many Disguises: From Theory to Applications

Author

Wodak, S, Paci, E, Dokholyan, N, Berezovsky, I, Horovitz, A, Li, J, Hilser, V, Bahar, I, Karanicolas, J, Stock, G, Hamm, P, Stote, R, Eberhardt, J, Chebaro, Y, Dejaegere, A, Cecchini, M, Changeux, J, Bolhuis, P, Vreede, J, Faccioli, P, Orioli, S, Ravasio, R, Yan, L, Brito, C, Wyart, M, Gkeka, P, Rivalta, I, Palermo, G, Mccammon, J, Panecka-Hofman, J, Wade, R, Di Pizio, A, Niv, M, Nussinov, R, Tsai, C, Jang, H, Padhorny, D, Kozakov, D, Mcleish, T, Wodak, Shoshana J, Paci, Emanuele, Dokholyan, Nikolay V, Berezovsky, Igor N, Horovitz, Amnon, Li, Jing, Hilser, Vincent J, Bahar, Ivet, Karanicolas, John, Stock, Gerhard, Hamm, Peter, Stote, Roland H, Eberhardt, Jerome, Chebaro, Yassmine, Dejaegere, Annick, Cecchini, Marco, Changeux, Jean-Pierre, Bolhuis, Peter G, Vreede, Jocelyne, Faccioli, Pietro, Orioli, Simone, Ravasio, Riccardo, Yan, Le, Brito, Carolina, Wyart, Matthieu, Gkeka, Paraskevi, Rivalta, Ivan, Palermo, Giulia, McCammon, J Andrew, Panecka-Hofman, Joanna, Wade, Rebecca C, Di Pizio, Antonella, Niv, Masha Y, Nussinov, Ruth, Tsai, Chung-Jung, Jang, Hyunbum, Padhorny, Dzmitry, Kozakov, Dima, McLeish, Tom, Wodak, S, Paci, E, Dokholyan, N, Berezovsky, I, Horovitz, A, Li, J, Hilser, V, Bahar, I, Karanicolas, J, Stock, G, Hamm, P, Stote, R, Eberhardt, J, Chebaro, Y, Dejaegere, A, Cecchini, M, Changeux, J, Bolhuis, P, Vreede, J, Faccioli, P, Orioli, S, Ravasio, R, Yan, L, Brito, C, Wyart, M, Gkeka, P, Rivalta, I, Palermo, G, Mccammon, J, Panecka-Hofman, J, Wade, R, Di Pizio, A, Niv, M, Nussinov, R, Tsai, C, Jang, H, Padhorny, D, Kozakov, D, Mcleish, T, Wodak, Shoshana J, Paci, Emanuele, Dokholyan, Nikolay V, Berezovsky, Igor N, Horovitz, Amnon, Li, Jing, Hilser, Vincent J, Bahar, Ivet, Karanicolas, John, Stock, Gerhard, Hamm, Peter, Stote, Roland H, Eberhardt, Jerome, Chebaro, Yassmine, Dejaegere, Annick, Cecchini, Marco, Changeux, Jean-Pierre, Bolhuis, Peter G, Vreede, Jocelyne, Faccioli, Pietro, Orioli, Simone, Ravasio, Riccardo, Yan, Le, Brito, Carolina, Wyart, Matthieu, Gkeka, Paraskevi, Rivalta, Ivan, Palermo, Giulia, McCammon, J Andrew, Panecka-Hofman, Joanna, Wade, Rebecca C, Di Pizio, Antonella, Niv, Masha Y, Nussinov, Ruth, Tsai, Chung-Jung, Jang, Hyunbum, Padhorny, Dzmitry, Kozakov, Dima, and McLeish, Tom

Abstract

Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromolecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts.

Published
2019

72. Author Correction: RGS7 is recurrently mutated in melanoma and promotes migration and invasion of human cancer cells

Author

Qutob, Nouar, primary, Masuho, Ikuo, additional, Alon, Michal, additional, Emmanuel, Rafi, additional, Cohen, Isadora, additional, Di Pizio, Antonella, additional, Madore, Jason, additional, Elkahloun, Abdel, additional, Ziv, Tamar, additional, Levy, Ronen, additional, Gartner, Jared J., additional, Hill, Victoria K., additional, Lin, Jimmy C., additional, Hevroni, Yael, additional, Greenberg, Polina, additional, Brodezki, Alexandra, additional, Rosenberg, Steven A., additional, Kosloff, Mickey, additional, Hayward, Nicholas K., additional, Admon, Arie, additional, Niv, Masha Y., additional, Scolyer, Richard A., additional, Martemyanov, Kirill A., additional, and Samuels, Yardena, additional

Published
2019
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80. RGS7 is recurrently mutated in melanoma and promotes migration and invasion of human cancer cells

Author

Qutob, Nouar, primary, Masuho, Ikuo, additional, Alon, Michal, additional, Emmanuel, Rafi, additional, Cohen, Isadora, additional, Di Pizio, Antonella, additional, Madore, Jason, additional, Elkahloun, Abdel, additional, Ziv, Tamar, additional, Levy, Ronen, additional, Gartner, Jared J., additional, Hill, Victoria K., additional, Lin, Jimmy C., additional, Hevroni, Yael, additional, Greenberg, Polina, additional, Brodezki, Alexandra, additional, Rosenberg, Steven A., additional, Kosloff, Mickey, additional, Hayward, Nicholas K., additional, Admon, Arie, additional, Niv, Masha Y., additional, Scolyer, Richard A., additional, Martemyanov, Kirill A., additional, and Samuels, Yardena, additional

Published
2018
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83. In SilicoInvestigation of Bitter Hop-Derived Compounds and Their Cognate Bitter Taste Receptors

Author

Dunkel, Andreas, Hofmann, Thomas, and Di Pizio, Antonella

Abstract

The typical bitter taste of beer is caused by adding hops (Humulus lupulusL.) during the wort boiling process. The bitter taste of hop-derived compounds was found to be mediated by three bitter taste receptors: TAS2R1, TAS2R14, and TAS2R40. In this work, structural bioinformatics analyses were used to characterize the binding modes of trans-isocohumulone, trans-isohumulone, trans-isoadhumulone, cis-isocohumulone, cis-isohumulone, cis-isoadhumulone, cohumulone, humulone, adhumulone, and 8-prenylnaringenin into the orthosteric binding site of their cognate receptors. A conserved asparagine in transmembrane 3 was found to be essential for the recognition of hop-derived compounds, whereas the surrounding residues in the binding site of the three receptors encode the ligand specificity. Hop-derived compounds are renowned bioactive molecules and are considered as potential hit molecules for drug discovery to treat metabolic diseases. A chemoinformatics analysis revealed that hop-derived compounds cluster in a different region of the chemical space compared to known bitter food-derived compounds, pinpointing hop-derived compounds as a very peculiar class of bitter compounds.

Published
2020
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84. Bitterless guaifenesin prodrugs—design, synthesis, characterization, in vitro kinetics, and bitterness studies.

Author

Thawabteh, Amin, Lelario, Filomena, Scrano, Laura, Bufo, Sabino A., Nowak, Stefanie, Behrens, Maik, Di Pizio, Antonella, Niv, Masha Y., and Karaman, Rafik

Subjects
PRODRUGS, DRUG design, GUAIFENESIN, PHARMACOKINETICS, MOLECULAR orbitals, DRUG synthesis
Abstract

A respected number of drugs suffer from bitter taste which results in patient incompliance. With the aim of solving the bitterness of guaifenesin, dimethyl maleate, maleate, glutarate, succinate, and dimethyl succinate prodrugs were designed and synthesized. Molecular orbital methods were utilized for the design of the ester prodrugs. The density functional theory (DFT) calculations revealed that the hydrolysis efficiency of the synthesized prodrugs is significantly sensitive to the pattern of substitution on C=C bond and distance between the nucleophile and the electrophile. The hydrolysis of the prodrugs was largely affected by the pH of the medium. The experimental t1/2 for the hydrolysis of guaifenesin dimaleate ester prodrugs in 1N HCl was the least and for guaifenesin dimethyl succinate was the highest. Functional heterologous expression of TAS2R14, a broadly tuned bitter taste receptor responding to guaifenesin, and experiments using these prodrugs revealed that, while some of the prodrugs still activated the receptor similarly or even stronger than the parent substance, succinate derivatization resulted in the complete loss of receptor responses. The predicted binding modes of guaifenesin and its prodrugs to the TAS2R14 homology model suggest that the decreased activity of the succinate derivatives may be caused by a clash with Phe247. A number of novel bitterless ester guaifenesin prodrugs were designed, synthesized, and characterized. The prodrugs have shown sufficient stability at neutral pH values and rapid release under low pH conditions (stomach). Using bitter taste receptor assays, it was confirmed that the most promiscuous human bitter taste receptor responsible for the bitter perception of many drugs, the TAS2R14, is not activated by some of the prodrugs. We conclude that our approach could be used to mask the bitterness of other similar drugs. [ABSTRACT FROM AUTHOR]

Published
2019
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86. Catechol-based matrix metalloproteinase inhibitors with additional antioxidative activity

Author

Tauro, Marilena, primary, Laghezza, Antonio, additional, Loiodice, Fulvio, additional, Piemontese, Luca, additional, Caradonna, Alessia, additional, Capelli, Davide, additional, Montanari, Roberta, additional, Pochetti, Giorgio, additional, Di Pizio, Antonella, additional, Agamennone, Mariangela, additional, Campestre, Cristina, additional, and Tortorella, Paolo, additional

Published
2016
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88. Recurrent inactivating RASA2 mutations in melanoma

Author

Arafeh, Rand, primary, Qutob, Nouar, additional, Emmanuel, Rafi, additional, Keren-Paz, Alona, additional, Madore, Jason, additional, Elkahloun, Abdel, additional, Wilmott, James S, additional, Gartner, Jared J, additional, Di Pizio, Antonella, additional, Winograd-Katz, Sabina, additional, Sindiri, Sivasish, additional, Rotkopf, Ron, additional, Dutton-Regester, Ken, additional, Johansson, Peter, additional, Pritchard, Antonia L, additional, Waddell, Nicola, additional, Hill, Victoria K, additional, Lin, Jimmy C, additional, Hevroni, Yael, additional, Rosenberg, Steven A, additional, Khan, Javed, additional, Ben-Dor, Shifra, additional, Niv, Masha Y, additional, Ulitsky, Igor, additional, Mann, Graham J, additional, Scolyer, Richard A, additional, Hayward, Nicholas K, additional, and Samuels, Yardena, additional

Published
2015
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93. Amino Acid Derivatives as New Zinc Binding Groups for the Design of Selective Matrix Metalloproteinase Inhibitors

Author

Giustiniano, Mariateresa, primary, Tortorella, Paolo, additional, Agamennone, Mariangela, additional, Di Pizio, Antonella, additional, Rossello, Armando, additional, Nuti, Elisa, additional, Gomez-Monterrey, Isabel, additional, Novellino, Ettore, additional, Campiglia, Pietro, additional, Vernieri, Ermelinda, additional, Sala, Marina, additional, Bertamino, Alessia, additional, and Carotenuto, Alfonso, additional

Published
2013
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95. Non-Zinc-Binding Inhibitors of MMP-13: GRID-Based Approaches to Rationalize the Binding Process

Author

Di Pizio, Antonella, Agamennone, Mariangela, and Tortorella, Paolo

Abstract

Matrix metalloproteinases (MMPs) are zinc enzymes responsible for the degradation of the extracellular matrix. With this function, MMPs are involved in many physiological processes, but also in many pathological states. MMP-13 is implicated in the degradation of type II collagen, the main structural protein of articular cartilage, contributing to the development of osteoarthritis and inflammatory diseases. In the last years, a new generation of potent and selective MMP inhibitors (MMPIs) has been identified and classified as non-zinc-binding inhibitors (NZBIs). Several MMP-13 NZBIs have been developed and crystallographically determined in complex with the enzyme. Here, we provide a detailed review of the current knowledge about this class of MMP-13 inhibitors and, by using computational procedures, we highlight the molecular determinants that are needed for the binding process. In particular, FLAP, a program based on GRID molecular interaction fields, was used to analyze the ligand-protein interactions: molecular shape and hydrogen bond acceptor groups strongly influence the binding according to the ligand-based modeling, while the aromatic interactions are better identified by the structure-based study. The complementary results can be combined in a high performance model, showing the effectiveness of molecular interaction field based approaches to search for novel MMP-13 NZBIs.

Published
2016

96. The path to the G protein‐coupled receptor structural landscape: Major milestones and future directions.

Author

Kogut‐Günthel, Małgorzata M., Zara, Zeenat, Nicoli, Alessandro, Steuer, Alexandra, Lopez‐Balastegui, Marta, Selent, Jana, Karanth, Sanjai, Koehler, Melanie, Ciancetta, Antonella, Abiko, Layara Akemi, Hagn, Franz, and Di Pizio, Antonella

Subjects
*PROTEIN structure prediction, *ALLOSTERIC regulation, *SYNTHETIC proteins, *BIOPHYSICS, *ATOMIC force microscopy, *G protein coupled receptors
Abstract

G protein‐coupled receptors (GPCRs) play a crucial role in cell function by transducing signals from the extracellular environment to the inside of the cell. They mediate the effects of various stimuli, including hormones, neurotransmitters, ions, photons, food tastants and odorants, and are renowned drug targets. Advancements in structural biology techniques, including X‐ray crystallography and cryo‐electron microscopy (cryo‐EM), have driven the elucidation of an increasing number of GPCR structures. These structures reveal novel features that shed light on receptor activation, dimerization and oligomerization, dichotomy between orthosteric and allosteric modulation, and the intricate interactions underlying signal transduction, providing insights into diverse ligand‐binding modes and signalling pathways. However, a substantial portion of the GPCR repertoire and their activation states remain structurally unexplored. Future efforts should prioritize capturing the full structural diversity of GPCRs across multiple dimensions. To do so, the integration of structural biology with biophysical and computational techniques will be essential. We describe in this review the progress of nuclear magnetic resonance (NMR) to examine GPCR plasticity and conformational dynamics, of atomic force microscopy (AFM) to explore the spatial–temporal dynamics and kinetic aspects of GPCRs, and the recent breakthroughs in artificial intelligence for protein structure prediction to characterize the structures of the entire GPCRome. In summary, the journey through GPCR structural biology provided in this review illustrates how far we have come in decoding these essential proteins architecture and function. Looking ahead, integrating cutting‐edge biophysics and computational tools offers a path to navigating the GPCR structural landscape, ultimately advancing GPCR‐based applications. [ABSTRACT FROM AUTHOR]

Published
2024
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97. Relevance of G protein‐coupled receptor (GPCR) dynamics for receptor activation, signalling bias and allosteric modulation.

Author

Lopez‐Balastegui, Marta, Stepniewski, Tomasz Maciej, Kogut‐Günthel, Małgorzata M., Di Pizio, Antonella, Rosenkilde, Mette Marie, Mao, Jiafei, and Selent, Jana

Subjects
*G protein coupled receptors, *DRUG discovery, *X-ray crystallography, *DRUG design, *DRUG target
Abstract

G protein‐coupled receptors (GPCRs) are one of the major drug targets. In recent years, computational drug design for GPCRs has mainly focused on static structures obtained through X‐ray crystallography, cryogenic electron microscopy (cryo‐EM) or in silico modelling as a starting point for virtual screening campaigns. However, GPCRs are highly flexible entities with the ability to adopt different conformational states that elicit different physiological responses. Including this knowledge in the drug discovery pipeline can help to tailor novel conformation‐specific drugs with an improved therapeutic profile. In this review, we outline our current knowledge about GPCR dynamics that is relevant for receptor activation, signalling bias and allosteric modulation. Ultimately, we highlight new technological implementations such as time‐resolved X‐ray crystallography and cryo‐EM as well as computational algorithms that can contribute to a more comprehensive understanding of receptor dynamics and its relevance for GPCR functionality. [ABSTRACT FROM AUTHOR]

Published
2024
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98. Bitter Sensing TAS2R50Mediates the trans-Resveratrol-Induced Anti-inflammatory Effect on Interleukin 6 Release in HGF-1 Cells in Culture

Author

Tiroch, Johanna, Sterneder, Sonja, Di Pizio, Antonella, Lieder, Barbara, Hoelz, Kathrin, Holik, Ann-Katrin, Pignitter, Marc, Behrens, Maik, Somoza, Mark, Ley, Jakob P., and Somoza, Veronika

Abstract

Recent data have shown anti-inflammatory effects for trans-resveratrol (RSV) and rosmarinic acid (RA) in various immune-competent cell models through reduction of lipopolysaccharide (LPS)-induced interleukin 6 (IL-6) release. Because both compounds have been reported to taste bitter, we hypothesized an involvement of human bitter taste sensing receptors (TAS2Rs) on IL-6 release in LPS-treated human gingival fibroblasts (HGF-1). First, the bitter taste intensity of RSV and RA was compared in a sensory trial with 10 untrained panelists, of whom 90% rated a 50 ppm of RSV in water solution more bitter than 50 ppm of RA. A mean 19 ± 6% reduction of the RSV-induced bitter taste intensity was achieved by co-administration of 50 ppm of the bitter-masking, TAS2R43 antagonist homoeriodictyol (HED). Mechanistic experiments in a stably CRISPR-Cas9-edited TAS2R43kogastric cell model revealed involvement of TAS2R43 in the HED-evoked effect on RSV-induced proton secretion, whereas the cellular response to RSV did not depend upon TAS2R43. Next, the IL-6 modulatory effect of 100 μM RSV was studied in LPS-treated immune-competent HGF-1 cells. After 6 h of treatment, RSV reduced the LPS-induced IL-6 gene expression and protein release by −46.2 ± 12.7 and −73.9 ± 2.99%, respectively. This RSV-evoked effect was abolished by co-administration of HED. Because real-time quantitative polymerase chain reaction analyses revealed a regulation of TAS2R50in RSV with or without HED-treated HGF-1 cells, an siRNA knockdown approach of TAS2R50was applied to verify TAS2R50involvement in the RSV-induced reduction of the LPS-evoked IL-6 release in HGT-1 cells.

Published
2021
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99. The dark sides of the GPCR tree ‐ research progress on understudied GPCRs.

Author

Scharf, Magdalena M., Humphrys, Laura J., Berndt, Sandra, Di Pizio, Antonella, Lehmann, Juliane, Liebscher, Ines, Nicoli, Alessandro, Niv, Masha Y., Peri, Lior, Schihada, Hannes, and Schulte, Gunnar

Abstract

A large portion of the human GPCRome is still in the dark and understudied, consisting even of entire subfamilies of GPCRs such as odorant receptors, class A and C orphans, adhesion GPCRs, Frizzleds and taste receptors. However, it is undeniable that these GPCRs bring an untapped therapeutic potential that should be explored further. Open questions on these GPCRs span diverse topics such as deorphanisation, the development of tool compounds and tools for studying these GPCRs, as well as understanding basic signalling mechanisms. This review gives an overview of the current state of knowledge for each of the diverse subfamilies of understudied receptors regarding their physiological relevance, molecular mechanisms, endogenous ligands and pharmacological tools. Furthermore, it identifies some of the largest knowledge gaps that should be addressed in the foreseeable future and lists some general strategies that might be helpful in this process. [ABSTRACT FROM AUTHOR]

Published
2024
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100. Allostery in Its Many Disguises: From Theory to Applications

Author

Yassmine Chebaro, Annick Dejaegere, Ruth Nussinov, Rebecca C. Wade, Simone Orioli, Jocelyne Vreede, Riccardo Ravasio, Paraskevi Gkeka, Jing Li, Gerhard Stock, Chung-Jung Tsai, Ivet Bahar, Emanuele Paci, Pietro Faccioli, Joanna Panecka-Hofman, John Karanicolas, Peter G. Bolhuis, Jean-Pierre Changeux, Shoshana J. Wodak, Masha Y. Niv, Antonella Di Pizio, Giulia Palermo, Roland H. Stote, Tom McLeish, Matthieu Wyart, Carolina Brito, Peter Hamm, J. Andrew McCammon, Vincent J. Hilser, Amnon Horovitz, Jerome Eberhardt, Ivan Rivalta, Nikolay V. Dokholyan, Igor N. Berezovsky, Marco Cecchini, Le Yan, Hyunbum Jang, Dima Kozakov, Dzmitry Padhorny, VIB-VUB Center for Structural Biology [Bruxelles], VIB [Belgium], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut de Chimie de Strasbourg, Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris], Collège de France (CdF), Physics Department and INFN, University of Trento [Trento], Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), Ecole Polytechnique Fédérale de Lausanne (EPFL), Laboratoire de Chimie - UMR5182 (LC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS ), Department of Biomedical Engineering [Boston], Boston University [Boston] (BU), University of Leeds, University of North Carolina at Chapel Hill, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), National University of Singapore (NUS), Weizmann Institute of Science [Rehovot, Israël], Johns Hopkins University (JHU), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Louis Pasteur - Strasbourg I-Institut de Chimie du CNRS (INC), Collège de France (CdF (institution)), Institute of Condensed Matter Physics [Lausanne], University of California [Santa Barbara] (UCSB), University of California, Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Institut de Chimie du CNRS (INC), Cancer and Inflammation Program, Leidos Biomedical Research Inc., Frederick National Laboratory, Frederick National Laboratory for Cancer Research (FNLCR), Stony Brook University [SUNY] (SBU), State University of New York (SUNY), University of York [York, UK], European Union's Horizon 2020 Research and Innovation Program under grant agreement no. 720270 (HBP SGA1)NIH grants R01GM114015, R01GM064803, and R01GM123247, grants P41GM103712 and P30DA035778Marie Curie Reintegration Grant (FP7-PEOPLE-2009-RG, no. 256533), European Project: 720270,H2020 Pilier Excellent Science,H2020-Adhoc-2014-20,HBP SGA1(2016), European Project: 256533,EC:FP7:PEOPLE,FP7-PEOPLE-2009-RG,COMPUT DRUG DESIGN(2010), Simulation of Biomolecular Systems (HIMS, FNWI), Wodak, Shoshana J, Paci, Emanuele, Dokholyan, Nikolay V, Berezovsky, Igor N, Horovitz, Amnon, Li, Jing, Hilser, Vincent J, Bahar, Ivet, Karanicolas, John, Stock, Gerhard, Hamm, Peter, Stote, Roland H, Eberhardt, Jerome, Chebaro, Yassmine, Dejaegere, Annick, Cecchini, Marco, Changeux, Jean-Pierre, Bolhuis, Peter G, Vreede, Jocelyne, Faccioli, Pietro, Orioli, Simone, Ravasio, Riccardo, Yan, Le, Brito, Carolina, Wyart, Matthieu, Gkeka, Paraskevi, Rivalta, Ivan, Palermo, Giulia, McCammon, J Andrew, Panecka-Hofman, Joanna, Wade, Rebecca C, Di Pizio, Antonella, Niv, Masha Y, Nussinov, Ruth, Tsai, Chung-Jung, Jang, Hyunbum, Padhorny, Dzmitry, Kozakov, Dima, McLeish, Tom, Wodak, S, Paci, E, Dokholyan, N, Berezovsky, I, Horovitz, A, Li, J, Hilser, V, Bahar, I, Karanicolas, J, Stock, G, Hamm, P, Stote, R, Eberhardt, J, Chebaro, Y, Dejaegere, A, Cecchini, M, Changeux, J, Bolhuis, P, Vreede, J, Faccioli, P, Orioli, S, Ravasio, R, Yan, L, Brito, C, Wyart, M, Gkeka, P, Rivalta, I, Palermo, G, Mccammon, J, Panecka-Hofman, J, Wade, R, Di Pizio, A, Niv, M, Nussinov, R, Tsai, C, Jang, H, Padhorny, D, Kozakov, D, Mcleish, T, and Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)

Subjects
Transcription, Genetic, Computer science, nuclear receptors, Biosensing Techniques, allosteric switche, Structural Biology, chemical rescue, Allostery, ComputingMilieux_MISCELLANEOUS, Cognitive science, mechanisms, 0303 health sciences, Protein function, ligand-binding, elastic network model, molecular dynamic, dynamic allostery, 030302 biochemistry & molecular biology, regulation, protein function, Biological Sciences, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, modulation, Generic Health Relevance, elastic network models, Thermodynamics, Transcription, Allosteric Site, Metabolic Networks and Pathways, signal transduction, Signal Transduction, 1.1 Normal biological development and functioning, Biophysics, allosteric drug, Molecular Dynamics Simulation, Article, 03 medical and health sciences, protein conformational changes, Genetic, Allosteric Regulation, Underpinning research, conformational-changes, Information and Computing Sciences, Animals, Humans, Molecular Biology, Elastic network models, allosteric material, 030304 developmental biology, pathway, energy landscape, Proteins, allosteric switches, molecular dynamics, protein conformational change, allosteric drugs, Conceptual framework, Gene Expression Regulation, Drug Design, network, Chemical Sciences, protein
Abstract

Allosteric regulation plays an important role in many biological processes, such as signal transduction, transcriptional regulation, and metabolism. Allostery is rooted in the fundamental physical properties of macromo-lecular systems, but its underlying mechanisms are still poorly understood. A collection of contributions to a recent interdisciplinary CECAM (Center Européen de Calcul Atomique et Moléculaire) workshop is used here to provide an overview of the progress and remaining limitations in the understanding of the mechanistic foundations of allostery gained from computational and experimental analyses of real protein systems and model systems. The main conceptual frameworks instrumental in driving the field are discussed. We illustrate the role of these frameworks in illuminating molecular mechanisms and explaining cellular processes, and describe some of their promising practical applications in engineering molecular sensors and informing drug design efforts.

Published
2019

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