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4. Contributors

Author

Adhikari, Nilanjan, primary, Ahir, Gouri, additional, Al-Dossary, Hanan A., additional, Aljafary, Meneerah Abdurhman, additional, Al-Khater, Khulood Mohammed, additional, Al-Suhaimi, Ebtesam Abdullah, additional, Amin, Sk. Abdul, additional, Ashraf, Ghulam Md, additional, Assuhaimi, Reem A., additional, Balutia, Himani, additional, Bilgrami, Anwar L., additional, Campos-Iglesias, Diana, additional, Chaudhary, Sapana Sameer, additional, Choudhary, Sameer, additional, Cicaloni, V., additional, Dutt, Rohit, additional, Dutta Gupta, Sayan, additional, Elaissari, Abdelhamid, additional, Fotopoulos, I., additional, Freije, José M.P., additional, Ganeshpurkar, Ankit, additional, Garg, Vandana, additional, Gundala, Rishitha, additional, Gupta, Satya P., additional, Haddish-Berhane, Nahor, additional, Hadjipavlou-Litina, D., additional, Harish, B.S., additional, Jana, Srabanti, additional, Jha, Tarun, additional, Kumar, Deepak, additional, Kumar, Devendra, additional, Kumar, Sanjay, additional, Lavanya, R., additional, López-Otín, Carlos, additional, Madan, A.K., additional, Mahmood, Ayesha, additional, Makar, Subhajit, additional, Mandal, Tanima, additional, Nagpal, Ashima, additional, Parasrampuria, Dolly A., additional, Peperidou, A., additional, Pettini, F., additional, Poddar, Nitesh Kumar, additional, Pontiki, E., additional, Rai, Pankaj Kumar, additional, Ravinayagam, Vijaya, additional, Rawat, Sakshi, additional, Roy, Kuldeep K., additional, Saha, Priyanka, additional, Shehzad, Adeeb, additional, Shukla, Devendra, additional, Singh, Sushil Kumar, additional, Spiga, O., additional, Srivastava, Amit Kumar, additional, Tarhini, Mohamad, additional, Tonk, Rajiv Kumar, additional, Trezza, A., additional, Uppuluri, Kiran Babu, additional, Velayutham, Ravichandiran, additional, Verma, Saroj, additional, Yu, Alex, additional, and Zafar, Nadiah, additional

Published
2020
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6. Association of toll-like receptor 7 variants with life-threatening COVID-19 disease in males: Findings from a nested case-control study

Author

Fallerini, C, Daga, S, Mantovani, S, Benetti, E, Picchiotti, N, Francisci, D, Paciosi, F, Schiaroli, E, Baldassarri, M, Fava, F, Palmieri, M, Ludovisi, S, Castelli, F, Quiros-Roldan, E, Rusconi, S, Siano, M, Bandini, M, Spiga, O, Capitani, K, Furini, S, Mari, F, Renieri, A, Mondelli, M, Frullanti, E, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Mencarelli, M, Rizzo, C, Pinto, A, Sarno, L, Beligni, G, Tommasi, A, Iuso, N, Montagnani, F, Fabbiani, M, Rossetti, B, Zanelli, G, Bargagli, E, Bergantini, L, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Caldarelli, G, Spagnesi, M, Romani, D, Piacentini, P, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, D'Arminio Monforte, A, Miraglia, F, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Gabrieli, A, Riva, A, Scotton, P, Andretta, F, Panese, S, Scaggiante, R, Gatti, F, Parisi, S, Baratti, S, Antoni, M, Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Squeo, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Bosio, G, Martinelli, E, Mancarella, S, Tavecchia, L, Gori, M, Crotti, L, Parati, G, Gabbi, C, Zanella, I, Rizzi, M, Maggiolo, F, Ripamonti, D, Bachetti, T, Rovere, M, Sarzi-Braga, S, Bussotti, M, Chiariello, M, Belli, M, Dei, S, Vaghi, M, Fallerini C., Daga S., Mantovani S., Benetti E., Picchiotti N., Francisci D., Paciosi F., Schiaroli E., Baldassarri M., Fava F., Palmieri M., Ludovisi S., Castelli F., Quiros-Roldan E., Rusconi S., Siano M., Bandini M., Spiga O., Capitani K., Furini S., Mari F., Renieri A., Mondelli M. U., Frullanti E., Valentino F., Doddato G., Giliberti A., Tita R., Amitrano S., Bruttini M., Croci S., Meloni I., Mencarelli M. A., Rizzo C. L., Pinto A. M., Sarno L. D., Beligni G., Tommasi A., Iuso N., Montagnani F., Fabbiani M., Rossetti B., Zanelli G., Bargagli E., Bergantini L., D'alessandro M., Cameli P., Bennett D., Anedda F., Marcantonio S., Scolletta S., Franchi F., Mazzei M. A., Guerrini S., Conticini E., Cantarini L., Frediani B., Tacconi D., Spertilli C., Feri M., Donati A., Scala R., Guidelli L., Spargi G., Corridi M., Nencioni C., Croci L., Caldarelli G. P., Spagnesi M., Romani D., Piacentini P., Desanctis E., Cappelli S., Canaccini A., Verzuri A., Anemoli V., Ognibene A., D'Arminio Monforte A., Miraglia F. G., Girardis M., Venturelli S., Busani S., Cossarizza A., Antinori A., Vergori A., Emiliozzi A., Gabrieli A., Riva A., Scotton P. G., Andretta F., Panese S., Scaggiante R., Gatti F., Parisi S. G., Baratti S., Antoni M. D., Monica M. D., Piscopo C., Capasso M., Russo R., Andolfo I., Iolascon A., Fiorentino G., Carella M., Castori M., Merla G., Squeo G. M., Aucella F., Raggi P., Marciano C., Perna R., Bassetti M., Biagio A. D., Sanguinetti M., Masucci L., Valente S., Mandala M., Giorli A., Salerni L., Zucchi P., Parravicini P., Menatti E., Trotta T., Giannattasio F., Coiro G., Lena F., Coviello D. A., Mussini C., Bosio G., Martinelli E., Mancarella S., Tavecchia L., Gori M., Crotti L., Parati G., Gabbi C., Zanella I., Rizzi M., Maggiolo F., Ripamonti D., Bachetti T., Rovere M. T. L., Sarzi-Braga S., Bussotti M., Chiariello M., Belli M. A., Dei S., Vaghi M., Fallerini, C, Daga, S, Mantovani, S, Benetti, E, Picchiotti, N, Francisci, D, Paciosi, F, Schiaroli, E, Baldassarri, M, Fava, F, Palmieri, M, Ludovisi, S, Castelli, F, Quiros-Roldan, E, Rusconi, S, Siano, M, Bandini, M, Spiga, O, Capitani, K, Furini, S, Mari, F, Renieri, A, Mondelli, M, Frullanti, E, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Mencarelli, M, Rizzo, C, Pinto, A, Sarno, L, Beligni, G, Tommasi, A, Iuso, N, Montagnani, F, Fabbiani, M, Rossetti, B, Zanelli, G, Bargagli, E, Bergantini, L, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Caldarelli, G, Spagnesi, M, Romani, D, Piacentini, P, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, D'Arminio Monforte, A, Miraglia, F, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Gabrieli, A, Riva, A, Scotton, P, Andretta, F, Panese, S, Scaggiante, R, Gatti, F, Parisi, S, Baratti, S, Antoni, M, Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Squeo, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Bosio, G, Martinelli, E, Mancarella, S, Tavecchia, L, Gori, M, Crotti, L, Parati, G, Gabbi, C, Zanella, I, Rizzi, M, Maggiolo, F, Ripamonti, D, Bachetti, T, Rovere, M, Sarzi-Braga, S, Bussotti, M, Chiariello, M, Belli, M, Dei, S, Vaghi, M, Fallerini C., Daga S., Mantovani S., Benetti E., Picchiotti N., Francisci D., Paciosi F., Schiaroli E., Baldassarri M., Fava F., Palmieri M., Ludovisi S., Castelli F., Quiros-Roldan E., Rusconi S., Siano M., Bandini M., Spiga O., Capitani K., Furini S., Mari F., Renieri A., Mondelli M. U., Frullanti E., Valentino F., Doddato G., Giliberti A., Tita R., Amitrano S., Bruttini M., Croci S., Meloni I., Mencarelli M. A., Rizzo C. L., Pinto A. M., Sarno L. D., Beligni G., Tommasi A., Iuso N., Montagnani F., Fabbiani M., Rossetti B., Zanelli G., Bargagli E., Bergantini L., D'alessandro M., Cameli P., Bennett D., Anedda F., Marcantonio S., Scolletta S., Franchi F., Mazzei M. A., Guerrini S., Conticini E., Cantarini L., Frediani B., Tacconi D., Spertilli C., Feri M., Donati A., Scala R., Guidelli L., Spargi G., Corridi M., Nencioni C., Croci L., Caldarelli G. P., Spagnesi M., Romani D., Piacentini P., Desanctis E., Cappelli S., Canaccini A., Verzuri A., Anemoli V., Ognibene A., D'Arminio Monforte A., Miraglia F. G., Girardis M., Venturelli S., Busani S., Cossarizza A., Antinori A., Vergori A., Emiliozzi A., Gabrieli A., Riva A., Scotton P. G., Andretta F., Panese S., Scaggiante R., Gatti F., Parisi S. G., Baratti S., Antoni M. D., Monica M. D., Piscopo C., Capasso M., Russo R., Andolfo I., Iolascon A., Fiorentino G., Carella M., Castori M., Merla G., Squeo G. M., Aucella F., Raggi P., Marciano C., Perna R., Bassetti M., Biagio A. D., Sanguinetti M., Masucci L., Valente S., Mandala M., Giorli A., Salerni L., Zucchi P., Parravicini P., Menatti E., Trotta T., Giannattasio F., Coiro G., Lena F., Coviello D. A., Mussini C., Bosio G., Martinelli E., Mancarella S., Tavecchia L., Gori M., Crotti L., Parati G., Gabbi C., Zanella I., Rizzi M., Maggiolo F., Ripamonti D., Bachetti T., Rovere M. T. L., Sarzi-Braga S., Bussotti M., Chiariello M., Belli M. A., Dei S., and Vaghi M.

Abstract

Background: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients. Methods: This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (<60 y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene.

Published
2021

7. Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

Author

Fallerini, C., Daga, S., Mantovani, S., Benetti, E., Picchiotti, N., Francisci, D., Paciosi, F., Schiaroli, E., Baldassarri, M., Fava, F., Palmieri, M., Ludovisi, S., Castelli, F., Quiros-Roldan, E., Vaghi, M., Rusconi, S., Siano, M., Bandini, M., Spiga, O., Capitani, K., Furini, S., Mari, F., Renieri, A., Mondelli, M. U., Frullanti, E., Valentino, F., Doddato, G., Giliberti, A., Tita, R., Amitrano, S., Bruttini, M., Croci, S., Meloni, I., Mencarelli, M. A., Rizzo, C. L., Pinto, A. M., Sarno, L. D., Beligni, G., Tommasi, A., Iuso, N., Montagnani, F., Fabbiani, M., Rossetti, B., Zanelli, G., Bargagli, E., Bergantini, L., D'Alessandro, M., Cameli, P., Bennett, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, F., Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Spertilli, C., Feri, M., Donati, A., Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Caldarelli, G. P., Spagnesi, M., Romani, D., Piacentini, P., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Ognibene, A., D'Arminio Monforte, A., Miraglia, F. G., Girardis, M., Venturelli, S., Busani, S., Cossarizza, A., Antinori, A., Vergori, A., Emiliozzi, A., Gabrieli, A., Riva, A., Scotton, P. G., Andretta, F., Panese, S., Scaggiante, R., Gatti, F., Parisi, S. G., Baratti, S., Antoni, M. D., Monica, M. D., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Fiorentino, G., Carella, M., Castori, M., Merla, G., Squeo, G. M., Aucella, F., Raggi, P., Marciano, C., Perna, R., Bassetti, M., Biagio, A. D., Sanguinetti, M., Masucci, L., Valente, S., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Coviello, D. A., Mussini, C., Bosio, G., Martinelli, E., Mancarella, S., Tavecchia, L., Gori, M., Crotti, L., Parati, G., Gabbi, C., Zanella, I., Rizzi, M., Maggiolo, F., Ripamonti, D., Bachetti, T., Rovere, M. T. L., Sarzi-Braga, S., Bussotti, M., Chiariello, M., Belli, M. A., Dei, S., Fallerini, C., Daga, S., Mantovani, S., Benetti, E., Picchiotti, N., Francisci, D., Paciosi, F., Schiaroli, E., Baldassarri, M., Fava, F., Palmieri, M., Ludovisi, S., Castelli, F., Quiros-Roldan, E., Vaghi, M., Rusconi, S., Siano, M., Bandini, M., Spiga, O., Capitani, K., Furini, S., Mari, F., Renieri, A., Mondelli, M. U., Frullanti, E., Valentino, F., Doddato, G., Giliberti, A., Tita, R., Amitrano, S., Bruttini, M., Croci, S., Meloni, I., Mencarelli, M. A., Rizzo, C. L., Pinto, A. M., Sarno, L. D., Beligni, G., Tommasi, A., Iuso, N., Montagnani, F., Fabbiani, M., Rossetti, B., Zanelli, G., Bargagli, E., Bergantini, L., D'Alessandro, M., Cameli, P., Bennett, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, F., Mazzei, M. A., Guerrini, S., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Spertilli, C., Feri, M., Donati, A., Scala, R., Guidelli, L., Spargi, G., Corridi, M., Nencioni, C., Croci, L., Caldarelli, G. P., Spagnesi, M., Romani, D., Piacentini, P., Desanctis, E., Cappelli, S., Canaccini, A., Verzuri, A., Anemoli, V., Ognibene, A., D'Arminio Monforte, A., Miraglia, F. G., Girardis, M., Venturelli, S., Busani, S., Cossarizza, A., Antinori, A., Vergori, A., Emiliozzi, A., Gabrieli, A., Riva, A., Scotton, P. G., Andretta, F., Panese, S., Scaggiante, R., Gatti, F., Parisi, S. G., Baratti, S., Antoni, M. D., Monica, M. D., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Fiorentino, G., Carella, M., Castori, M., Merla, G., Squeo, G. M., Aucella, F., Raggi, P., Marciano, C., Perna, R., Bassetti, M., Biagio, A. D., Sanguinetti, M., Masucci, L., Valente, S., Mandala, M., Giorli, A., Salerni, L., Zucchi, P., Parravicini, P., Menatti, E., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Coviello, D. A., Mussini, C., Bosio, G., Martinelli, E., Mancarella, S., Tavecchia, L., Gori, M., Crotti, L., Parati, G., Gabbi, C., Zanella, I., Rizzi, M., Maggiolo, F., Ripamonti, D., Bachetti, T., Rovere, M. T. L., Sarzi-Braga, S., Bussotti, M., Chiariello, M., Belli, M. A., Dei, S., Fallerini, C, Daga, S, Mantovani, S, Benetti, E, Picchiotti, N, Francisci, D, Paciosi, F, Schiaroli, E, Baldassarri, M, Fava, F, Palmieri, M, Ludovisi, S, Castelli, F, Quiros-Roldan, E, Rusconi, S, Siano, M, Bandini, M, Spiga, O, Capitani, K, Furini, S, Mari, F, Renieri, A, Mondelli, M, Frullanti, E, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Amitrano, S, Bruttini, M, Croci, S, Meloni, I, Mencarelli, M, Rizzo, C, Pinto, A, Sarno, L, Beligni, G, Tommasi, A, Iuso, N, Montagnani, F, Fabbiani, M, Rossetti, B, Zanelli, G, Bargagli, E, Bergantini, L, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Mazzei, M, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Spertilli, C, Feri, M, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Caldarelli, G, Spagnesi, M, Romani, D, Piacentini, P, Desanctis, E, Cappelli, S, Canaccini, A, Verzuri, A, Anemoli, V, Ognibene, A, D'Arminio Monforte, A, Miraglia, F, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Gabrieli, A, Riva, A, Scotton, P, Andretta, F, Panese, S, Scaggiante, R, Gatti, F, Parisi, S, Baratti, S, Antoni, M, Monica, M, Piscopo, C, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Squeo, G, Aucella, F, Raggi, P, Marciano, C, Perna, R, Bassetti, M, Biagio, A, Sanguinetti, M, Masucci, L, Valente, S, Mandala, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Coviello, D, Mussini, C, Bosio, G, Martinelli, E, Mancarella, S, Tavecchia, L, Gori, M, Crotti, L, Parati, G, Gabbi, C, Zanella, I, Rizzi, M, Maggiolo, F, Ripamonti, D, Bachetti, T, Rovere, M, Sarzi-Braga, S, Bussotti, M, Chiariello, M, Belli, M, Dei, S, and Vaghi, M

Subjects
0301 basic medicine, Male, medicine, Disease, Severity of Illness Index, genomic, 0302 clinical medicine, HEK293 Cell, Epidemiology, genetics, 030212 general & internal medicine, Biology (General), COVID, TLR7, General Neuroscience, virus diseases, General Medicine, Single Nucleotide, Middle Aged, Italy, Cohort, Medicine, COVID-19, LASSO Logistic Regression Analysis, genomics, human, Adult, Case-Control Studies, Genetic Predisposition to Disease, HEK293 Cells, Humans, SARS-CoV-2, Toll-Like Receptor 7, Polymorphism, Single Nucleotide, medicine.symptom, Case-Control Studie, Insight, Human, medicine.medical_specialty, QH301-705.5, Science, Short Report, macromolecular substances, Asymptomatic, Settore MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA, General Biochemistry, Genetics and Molecular Biology, LASSO Logistic Regression Analysi, 03 medical and health sciences, Internal medicine, Severity of illness, Polymorphism, General Immunology and Microbiology, business.industry, Case-control study, Genetics and Genomics, LASSO logistic regression analysis, Clinical trial, 030104 developmental biology, Nested case-control study, genetic, business
Abstract

Background:Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients.Methods:This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (Results:Overall, we found TLR7 deleterious variants in 2.1% of severely affected males and in none of the asymptomatic participants. The functional gene expression profile analysis demonstrated a reduction in TLR7-related gene expression in patients compared with controls demonstrating an impairment in type I and II IFN responses.Conclusions:Young males with TLR7 loss-of-function variants and severe COVID-19 represent a subset of male patients contributing to disease susceptibility in up to 2% of severe COVID-19.Funding:Funded by private donors for the Host Genetics Research Project, the Intesa San Paolo for 2020 charity fund, and the Host Genetics Initiative.Clinical trial number:NCT04549831.

Published
2021

8. Bioinformatics Approaches to Predict Mutation Effects in the Binding Site of the Proangiogenic Molecule CD93.

Author

Cicaloni, V, Karmakar, M, Frusciante, L, Pettini, F, Visibelli, A, Orlandini, M, Galvagni, F, Mongiat, M, Silk, M, Nardi, F, Ascher, D, Santucci, A, Spiga, O, Cicaloni, V, Karmakar, M, Frusciante, L, Pettini, F, Visibelli, A, Orlandini, M, Galvagni, F, Mongiat, M, Silk, M, Nardi, F, Ascher, D, Santucci, A, and Spiga, O

Abstract

The transmembrane glycoprotein CD93 has been identified as a potential new target to inhibit tumor angiogenesis. Recently, Multimerin-2 (MMRN2), a pan-endothelial extracellular matrix protein, has been identified as a ligand for CD93, but the interaction mechanism between these two proteins is yet to be studied. In this article, we aim to investigate the structural and functional effects of induced mutations on the binding domain of CD93 to MMRN2. Starting from experimental data, we assessed how specific mutations in the C-type lectin-like domain (CTLD) affect the binding interaction profile. We described a four-step workflow in order to predict the effects of variations on the inter-residue interaction network at the PPI, based on evolutionary information, complex network metrics, and energetic affinity. We showed that the application of computational approaches, combined with experimental data, allowed us to gain more in-depth molecular insights into the CD93-MMRN2 interaction, offering a platform for developing innovative therapeutics able to target these molecules and block their interaction. This comprehensive molecular insight might prove useful in drug design in cancer therapy.

Published
2022

9. HGDiscovery: An online tool providing functional and phenotypic information on novel variants of homogentisate 1,2- dioxigenase

Author

Karmakar, M, Cicaloni, V, Rodrigues, CHM, Spiga, O, Santucci, A, Ascher, DB, Karmakar, M, Cicaloni, V, Rodrigues, CHM, Spiga, O, Santucci, A, and Ascher, DB

Abstract

Alkaptonuria (AKU), a rare genetic disorder, is characterized by the accumulation of homogentisic acid (HGA) in the body. Affected individuals lack functional levels of an enzyme required to breakdown HGA. Mutations in the homogentisate 1,2-dioxygenase (HGD) gene cause AKU and they are responsible for deficient levels of functional HGD, which, in turn, leads to excess levels of HGA. Although HGA is rapidly cleared from the body by the kidneys, in the long term it starts accumulating in various tissues, especially cartilage. Over time (rarely before adulthood), it eventually changes the color of affected tissue to slate blue or black. Here we report a comprehensive mutation analysis of 111 pathogenic and 190 non-pathogenic HGD missense mutations using protein structural information. Using our comprehensive suite of graph-based signature methods, mCSM complemented with sequence-based tools, we studied the functional and molecular consequences of each mutation on protein stability, interaction and evolutionary conservation. The scores generated from the structure and sequence-based tools were used to train a supervised machine learning algorithm with 89% accuracy. The empirical classifier was used to generate the variant phenotype for novel HGD missense mutations. All this information is deployed as a user friendly freely available web server called HGDiscovery (https://biosig.lab.uq.edu.au/hgdiscovery/).

Published
2022

10. The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

Author

Croci, S., Venneri, M. A., Mantovani, S., Fallerini, C., Benetti, E., Picchiotti, N., Campolo, F., Imperatore, F., Palmieri, M., Daga, S., Gabbi, C., Montagnani, F., Beligni, G., Farias, T. D. J., Carriero, M. L., Di Sarno, L., Alaverdian, D., Aslaksen, S., Cubellis, M. V., Spiga, O., Baldassarri, M., Fava, F., Norman, P. J., Frullanti, E., Isidori, A. M., Amoroso, A., Mari, F., Furini, S., Mondelli, M. U., GEN-COVID multicenter study, Chiariello, M., Renieri, A., it/ gen-covid) Mirella Bruttini, Meloni I. GEN-COVID Multicenter Study (https://sites. google. com/dbm. unisi., Rossella, Tita, Sara, Amitrano, Anna Maria Pinto, Maria Antonietta Mencarelli, Caterina Lo Rizzo17, Valentina, Perticaroli1, 2, 17, Massimiliano, Fabbiani19, Barbara, Rossetti19, Giacomo, Zanelli2, Elena, Bargagli20, Laura, Bergantini20, Miriana, D’Alessandro20, Paolo, Cameli20, David, Bennett20, Federico, Anedda21, Simona, Marcantonio21, Sabino, Scolletta21, Federico, Franchi21, Maria Antonietta Mazzei22, Susanna, Guerrini22, Edoardo, Conticini23, Luca, Cantarini23, Bruno, Frediani23, Danilo, Tacconi24, Chiara, Spertilli24, Marco, Feri25, Alice, Donati25, Raffaele, Scala26, Luca, Guidelli26, Genni, Spargi27, Marta, Corridi27, Cesira, Nencioni28, Leonardo, Croci28, Gian Piero Caldarelli29, Maurizio, Spagnesi30, Paolo, Piacentini30, Maria, Bandini30, Elena, Desanctis30, Silvia, Cappelli30, Anna, Canaccini31, Agnese, Verzuri31, Valentina, Anemoli31, Agostino, Ognibene32, Alessandro, Pancrazi32, Maria, Lorubbio32, Massimo, Vaghi33, Antonella D’Arminio Monforte34, Esther, Merlini34, Federica Gaia Miraglia34, Raffaele, Bruno35, Marco, Vecchia35, Serena, Ludovisi37, Massimo, Girardis38, Sophie, Venturelli38, Marco, Sita38, Andrea, Cossarizza39, Andrea, Antinori40, Alessandra, Vergori40, Arianna, Emiliozzi40, Stefano, Rusconi41, Matteo, Siano42, Arianna, Gabrieli42, Agostino, Riva41, Daniela, Francisci4344, Elisabetta, Schiaroli4344, Francesco, Paciosi44, Pier Giorgio Scotton45, Francesca, Andretta45, Sandro, Panese45, Renzo, Scaggiante47, Francesca, Gatti48, Saverio Giuseppe Parisi48, Melania degli Antoni49, Isabella, Zanella51, Matteo Della Monica52, Carmelo, Piscopo52, Mario, Capasso53, 54, 55, Roberta, Russo53, Immacolata, Andolfo53, Achille, Iolascon53, Giuseppe, Fiorentino55, Massimo, Carella56, Marco, Castori56, Filippo, Aucella57, Pamela, Raggi58, Carmen, Marciano58, Rita, Perna58, Matteo, Bassetti59, Antonio Di Biagio59, Maurizio, Sanguinetti61, Luca, Masucci61, Serafina, Valente63, Marco, Mandalà64, Alessia, Giorli64, Lorenzo, Salerni64, Patrizia, Zucchi65, Pierpaolo, Parravicini65, Elisabetta Menatti66 Stefano Baratti45, Tullio, Trotta67, Ferdinando, Giannattasio67, Gabriella, Coiro67, Fabio, Lena68, Coviello69, Domenico A., Cristina, Mussini70, Giancarlo, Bosio71, Enrico, Martinelli71, Sandro, Mancarella72, Luisa, Tavecchia72, Mary Ann Belli72, Lia, Crotti73, 74, 75, Gianfranco, Parati73, Marco, Gori77, Maurizio, Sanarico79, Stefano, Ceri80, Pietro, Pinoli80, Francesco, Raimondi81, Filippo, Biscarini82, Alessandra, Stella82, Marco, Rizzi83, Franco, Maggiolo83, Diego, Ripamonti83, Claudia, Suardi84, Tiziana, Bachetti85, Maria Teresa La Rovere86, Simona, Sarzi-Braga87, Maurizio, Bussotti88, Katia, Capitani2, Kristina, Zguro2, Simona, Dei90, Sabrina, Ravaglia91, Rosangela, Artuso92, Antonio, Perrella93, Francesco, Bianchi2, Giuseppe, Merla53, Gabriella Maria Squeo94, Mario, Tumbarello2, Ilaria, Rancan2, Davide, Romani30, Manola, Pisani31, Stefano, Busani38, Andrea, Tommasi43, Francesco, Castelli49, Eugenia, Quiros-Roldan49, Alessandra, Guarnaccia61, Oreste De Vivo63, Gabriella, Doddato1, 2, Annarita, Giliberti1, Francesca, Ariani1, Gianluca, Lacerenza95, Elena, Andreucci92, Giulia, Gori92, Angelica, Pagliazzi92, Erika, Fiorentini92, Paola, Bergomi96, Emanuele, Catena96, Riccardo, Colombo96, Sauro, Luchi97, Giovanna, Morelli97, Paola, Petrocelli97, Sarah, Iacopini97, Sara, Modica97, Silvia, Baroni98, Francesco Vladimiro Segala99, Francesco, Menichetti100, Marco, Falcone100, Giusy, Tiseo100, Chiara, Barbieri100, Tommaso, Matucci100, Grassi, Davide, Ferri, Claudio, Marinangeli, Franco, Brancati, Francesco, Antonella, Vincenti104, Valentina, Borgo104, Lombardi, Stefania104, Mirco, Lenzi104, Massimo Antonio Di Pietro105, Francesca, Vichi105, Benedetta, Romanin105, Letizia, Attala105, Cecilia, Costa105, Andrea, Gabbuti105, Menè, Roberto106, Umberto, Zuccon107, Lucia, Vietri107, Patrizia, Casprini108, Marcello Maffezzoni109 and Marta Colaneri110, Croci, Susanna, Venneri, Mary Anna, Mantovani, Stefania, Fallerini, Chiara, Benetti, Elisa, Picchiotti, Nicola, Campolo, Federica, Imperatore, Francesco, Palmieri, Maria, Daga, Sergio, Gabbi, Chiara, Montagnani, Francesca, Beligni, Giada, Farias, Ticiana D J, Carriero, Miriam Lucia, Di Sarno, Laura, Alaverdian, Diana, Aslaksen, Sigrid, Cubellis, Maria Vittoria, Spiga, Ottavia, Baldassarri, Margherita, Fava, Francesca, Norman, Paul J, Frullanti, Elisa, Isidori, Andrea M, Amoroso, Antonio, Mari, Francesca, Furini, Simone, Mondelli, Mario U, Gen-Covid Multicenter Study, Null, Chiariello, Mario, Renieri, Alessandra, and Meloni, Ilaria

Subjects
Male, L412F, SARS-CoV-2, COVID-19, Cell Biology, Biomarker, Polymorphism, Single Nucleotide, Severity of Illness Index, Toll-Like Receptor 3, HLA, Autophagy, TLR3, HEK293 Cell, Molecular Biology, Human, Hydroxychloroquine
Abstract

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNF�� production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-��: tumor necrosis factor

Published
2022

11. ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population

Author

Benetti, E., Tita, R., Spiga, O., Ciolfi, A., Birolo, G., Bruselles, A., Doddato, G., Giliberti, A., Marconi, C., Musacchia, F., Pippucci, T., Torella, A., Trezza, A., Valentino, F., Baldassarri, M., Brusco, A., Asselta, R., Bruttini, M., Furini, S., Seri, M., Nigro, V., Matullo, G., Tartaglia, M., Mari, F., Frullanti, E., Fallerini, C., Daga, S., Croci, S., Amitrano, S., Fava, F., Montagnani, F., Di Sarno, L., Tommasi, A., Palmieri, M., Emiliozzi, A., Fabbiani, M., Rossetti, B., Zanelli, G., Bergantini, L., D’Alessandro, M., Cameli, P., Bennet, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, F., Mazzei, M. A., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Feri, M., Scala, R., Spargi, G., Corridi, M., Nencioni, C., Caldarelli, G. P., Spagnesi, M., Piacentini, P., Bandini, M., Desanctis, E., Canaccini, A., Spertilli, C., Donati, A., Guidelli, L., Croci, L., Verzuri, A., Anemoli, V., Ognibene, A., Vaghi, M., D’Arminio Monforte, A., Merlini, E., Mondelli, M. U., Mantovani, S., Ludovisi, S., Girardis, M., Venturelli, S., Sita, M., Cossarizza, A., Antinori, A., Vergori, A., Rusconi, S., Siano, M., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Scotton, P. G., Andretta, F., Panese, S., Scaggiante, R., Parisi, S. G., Castelli, F., Quiros-Roldan, M. E., Magro, P., Minardi, C., Castelli, D., Polesini, I., Della Monica, M., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Carella, M., Castori, M., Merla, G., Aucella, F., Raggi, P., Marciano, C., Perna, R., Bassetti, M., Di Biagio, A., Sanguinetti, M., Masucci, L., Gabbi, C., Valente, S., Guerrini, S., Meloni, I., Mencarelli, M. A., Rizzo, C. L., Bargagli, E., Mandalà, M., Giorli, A., Salerni, L., Fiorentino, G., Zucchi, P., Parravicini, P., Menatti, E., Baratti, S., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Coviello, D. A., Mussini, C., Renieri, A., Pinto, A. M., GEN-COVID Multicenter Study, Benetti, E., Tita, R., Spiga, O., Ciolfi, A., Birolo, G., Bruselles, A., Doddato, G., Giliberti, A., Marconi, C., Musacchia, F., Pippucci, T., Torella, A., Trezza, A., Valentino, F., Baldassarri, M., Brusco, A., Asselta, R., Bruttini, M., Furini, S., Seri, M., Nigro, V., Matullo, G., Tartaglia, M., Mari, F., Frullanti, E., Fallerini, C., Daga, S., Croci, S., Amitrano, S., Fava, F., Montagnani, F., Di Sarno, L., Tommasi, A., Palmieri, M., Emiliozzi, A., Fabbiani, M., Rossetti, B., Zanelli, G., Bergantini, L., D'Alessandro, M., Cameli, P., Bennet, D., Anedda, F., Marcantonio, S., Scolletta, S., Franchi, F., Mazzei, M. A., Conticini, E., Cantarini, L., Frediani, B., Tacconi, D., Feri, M., Scala, R., Spargi, G., Corridi, M., Nencioni, C., Caldarelli, G. P., Spagnesi, M., Piacentini, P., Bandini, M., Desanctis, E., Canaccini, A., Spertilli, C., Donati, A., Guidelli, L., Croci, L., Verzuri, A., Anemoli, V., Ognibene, A., Vaghi, M., D'Arminio Monforte, A., Merlini, E., Mondelli, M. U., Mantovani, S., Ludovisi, S., Girardis, M., Venturelli, S., Sita, M., Cossarizza, A., Antinori, A., Vergori, A., Rusconi, S., Siano, M., Gabrieli, A., Riva, A., Francisci, D., Schiaroli, E., Scotton, P. G., Andretta, F., Panese, S., Scaggiante, R., Parisi, S. G., Castelli, F., Quiros-Roldan, M. E., Magro, P., Minardi, C., Castelli, D., Polesini, I., Della Monica, M., Piscopo, C., Capasso, M., Russo, R., Andolfo, I., Iolascon, A., Carella, M., Castori, M., Merla, G., Aucella, F., Raggi, P., Marciano, C., Perna, R., Bassetti, M., Di Biagio, A., Sanguinetti, M., Masucci, L., Gabbi, C., Valente, S., Guerrini, S., Meloni, I., Mencarelli, M. A., Rizzo, C. L., Bargagli, E., Mandala, M., Giorli, A., Salerni, L., Fiorentino, G., Zucchi, P., Parravicini, P., Menatti, E., Baratti, S., Trotta, T., Giannattasio, F., Coiro, G., Lena, F., Coviello, D. A., Mussini, C., Renieri, A., Pinto, A. M., Benetti E., Tita R., Spiga O., Ciolfi A., Birolo G., Bruselles A., Doddato G., Giliberti A., Marconi C., Musacchia F., Pippucci T., Torella A., Trezza A., Valentino F., Baldassarri M., Brusco A., Asselta R., Bruttini M., Furini S., Seri M., Nigro V., Matullo G., Tartaglia M., Mari F., Frullanti E., Fallerini C., Daga S., Croci S., Amitrano S., Fava F., Montagnani F., Di Sarno L., Tommasi A., Palmieri M., Emiliozzi A., Fabbiani M., Rossetti B., Zanelli G., Bergantini L., D'Alessandro M., Cameli P., Bennet D., Anedda F., Marcantonio S., Scolletta S., Franchi F., Mazzei M.A., Conticini E., Cantarini L., Frediani B., Tacconi D., Feri M., Scala R., Spargi G., Corridi M., Nencioni C., Caldarelli G.P., Spagnesi M., Piacentini P., Bandini M., Desanctis E., Canaccini A., Spertilli C., Donati A., Guidelli L., Croci L., Verzuri A., Anemoli V., Ognibene A., Vaghi M., D'Arminio Monforte A., Merlini E., Mondelli M.U., Mantovani S., Ludovisi S., Girardis M., Venturelli S., Sita M., Cossarizza A., Antinori A., Vergori A., Rusconi S., Siano M., Gabrieli A., Riva A., Francisci D., Schiaroli E., Scotton P.G., Andretta F., Panese S., Scaggiante R., Parisi S.G., Castelli F., Quiros-Roldan M.E., Magro P., Minardi C., Castelli D., Polesini I., Della Monica M., Piscopo C., Capasso M., Russo R., Andolfo I., Iolascon A., Carella M., Castori M., Merla G., Aucella F., Raggi P., Marciano C., Perna R., Bassetti M., Di Biagio A., Sanguinetti M., Masucci L., Gabbi C., Valente S., Guerrini S., Meloni I., Mencarelli M.A., Rizzo C.L., Bargagli E., Mandala M., Giorli A., Salerni L., Fiorentino G., Zucchi P., Parravicini P., Menatti E., Baratti S., Trotta T., Giannattasio F., Coiro G., Lena F., Coviello D.A., Mussini C., Renieri A., Pinto A.M., Elisa, F., Chiara, F., Sergio, D., Susanna, C., Sara, A., and Francesca, F.

Subjects
Male, inter individual variability, medicine.disease_cause, Whole Exome Sequencing, genetic background, angiotensin converting enzyme 2, Cohort Studies, 0302 clinical medicine, Databases, Genetic, Missense mutation, Genetics(clinical), Viral, Internalization, Frameshift Mutation, Genetics (clinical), Exome sequencing, media_common, Coronavirus, Genetics, 0303 health sciences, Mutation, Protein Stability, Aged, Angiotensin-Converting Enzyme 2, Betacoronavirus, COVID-19, Coronavirus Infections, Female, Genetic Predisposition to Disease, Humans, Italy, Middle Aged, Molecular Dynamics Simulation, Mutation, Missense, Pandemics, Peptidyl-Dipeptidase A, Pneumonia, Viral, SARS-CoV-2, Spike Glycoprotein, Coronavirus, Spike Glycoprotein, 030220 oncology & carcinogenesis, Human, media_common.quotation_subject, Biology, Article, Frameshift mutation, 03 medical and health sciences, Databases, Genetic, Genome assembly algorithms, Exome Sequencing, medicine, Allele, Gene, 030304 developmental biology, Betacoronaviru, Pandemic, Coronavirus Infection, Pneumonia, Viral infection, Cohort Studie, Missense, Spike Glycoprotein, Coronaviru
Abstract

In December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries. It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for interindividual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome sequencing data of 6930 Italian control individuals from five different centers looking forACE2variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), and p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison ofACE2WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (Pvalue

Published
2020

13. 2-hydroxy-4-(3,5,7-trihydroxy-4-oxo-4H-chromen-2-yl)phenyl(E)-3-(4-hydroxy-3-methoxyphenyl)acrylate: synthesis, in silico analysis and in vitro pharmacological evaluation

Author

Brizzi, A., Trezza, A., Spiga, O., Maramai, S., Scorzelli, F., Saponara, S., and Fusi, F.

Subjects
CaV1.2 channel, docking simulation, ferulic acid, quercetin, ester-based derivatives, KCa1.1 channel, CaV1.2 channel, patchclamp, docking simulation, homology modeling, homology modeling, patchclamp, ester-based derivatives, KCa1.1 channel, ferulic acid, quercetin
Published
2021

17. Functional, electrophysiological and molecular docking analysis of the modulation of Cav 1.2 channels in rat vascular myocytes by murrayafoline A

Author

Saponara, S, Durante, M, Spiga, O, Mugnai, P, Sgaragli, G, Huong, TT, Khanh, PN, Son, NT, Cuong, NM, and Fusi, F

Subjects
Male, Calcium Channels, L-Type, Dose-Response Relationship, Drug, Cav1.2 channel, Myocytes, Smooth Muscle, Carbazoles, patch-clamp, Research Papers, Muscle, Smooth, Vascular, Protein Structure, Secondary, Electrophysiological Phenomena, Protein Structure, Tertiary, Rats, Molecular Docking Simulation, Alkaloids, Organ Culture Techniques, vascular smooth muscle, docking, Animals, Endothelium, Vascular, murrayafoline A, Rats, Wistar, Cav1.2 channel, murrayafoline A, patch-clamp, vascular smooth muscle, docking
Abstract

The carbazole alkaloid murrayafoline A (MuA) enhances contractility and the Ca(2+) currents carried by the Cav 1.2 channels [ICa1.2 ] of rat cardiomyocytes. As only few drugs stimulate ICa1.2 , this study was designed to analyse the effects of MuA on vascular Cav 1.2 channels.Vascular activity was assessed on rat aorta rings mounted in organ baths. Cav 1.2 Ba(2+) current [IBa1.2 ] was recorded in single rat aorta and tail artery myocytes by the patch-clamp technique. Docking at a 3D model of the rat, α1c central pore subunit of the Cav 1.2 channel was simulated in silico.In rat aorta rings MuA, at concentrations ≤14.2 μM, increased 30 mM K(+) -induced tone and shifted the concentration-response curve to K(+) to the left. Conversely, at concentrations14.2 μM, it relaxed high K(+) depolarized rings and antagonized Bay K 8644-induced contraction. In single myocytes, MuA stimulated IBa1.2 in a concentration-dependent, bell-shaped manner; stimulation was stable, incompletely reversible upon drug washout and accompanied by a leftward shift of the voltage-dependent activation curve. MuA docked at the α1C subunit central pore differently from nifedipine and Bay K 8644, although apparently interacting with the same amino acids of the pocket. Neither Bay K 8644-induced stimulation nor nifedipine-induced block of IBa1.2 was modified by MuA.Murrayafoline A is a naturally occurring vasoactive agent able to modulate Cav 1.2 channels and dock at the α1C subunit central pore in a manner that differed from that of dihydropyridines.

Published
2016

18. Computational approach from gene to structure analysis of the human ABCA4 transporter involved in genetic retinal diseases

Author

Trezza, A., Bernini, A., Langella, A., Ascher, D. B., Pires, D. E. V., Sodi, A., Passerini, I., Pelo, E., Rizzo, Stanislao, Niccolai, N., Spiga, O., Rizzo S. (ORCID:0000-0001-6302-063X), Trezza, A., Bernini, A., Langella, A., Ascher, D. B., Pires, D. E. V., Sodi, A., Passerini, I., Pelo, E., Rizzo, Stanislao, Niccolai, N., Spiga, O., and Rizzo S. (ORCID:0000-0001-6302-063X)

Abstract

PURPOSE. The aim of this article is to report the investigation of the structural features of ABCA4, a protein associated with a genetic retinal disease. A new database collecting knowledge of ABCA4 structure may facilitate predictions about the possible functional consequences of gene mutations observed in clinical practice. METHODS. In order to correlate structural and functional effects of the observed mutations, the structure of mouse P-glycoprotein was used as a template for homology modeling. The obtained structural information and genetic data are the basis of our relational database (ABCA4Database). RESULTS. Sequence variability among all ABCA4-deposited entries was calculated and reported as Shannon entropy score at the residue level. The three-dimensional model of ABCA4 structure was used to locate the spatial distribution of the observed variable regions. Our predictions from structural in silico tools were able to accurately link the functional effects of mutations to phenotype. The development of the ABCA4Database gathers all the available genetic and structural information, yielding a global view of the molecular basis of some retinal diseases. CONCLUSIONS. ABCA4 modeled structure provides a molecular basis on which to analyze protein sequence mutations related to genetic retinal disease in order to predict the risk of retinal disease across all possible ABCA4 mutations. Additionally, our ABCA4 predicted structure is a good starting point for the creation of a new data analysis model, appropriate for precision medicine, in order to develop a deeper knowledge network of the disease and to improve the management of patients.

Published
2017

19. On the mechanisms of protein surface accessibility

Author

NICCOLAI N, SPIGA O, BERNINI A, SCARSELLI M, CIUTTI A, FIASCHI I, MOLINARI H, TEMUSSI, PIERO ANDREA, Niccolai, N, Spiga, O, Bernini, A, Scarselli, M, Ciutti, A, Fiaschi, I, Molinari, H, and Temussi, PIERO ANDREA

Published
2003

20. The surface accessibility of α-bungarotoxin monitored by a novel paramagnetic probe

Author

Bernini, A, Venditti, V, Spiga, O, Prischi, F, Botta, M, Tong, AP-L, Wong, W-T, and Niccolai, N

Subjects
q-bio.BM
Abstract

The surface accessibility of {alpha}-bungarotoxin has been investigated by using Gd2L7, a newly designed paramagnetic NMR probe. Signal attenuations induced by Gd2L7 on {alpha}-bungarotoxin C{alpha}H peaks of 1H-13C HSQC spectra have been analyzed and compared with the ones previously obtained in the presence of GdDTPA-BMA. In spite of the different molecular size and shape, for the two probes a common pathway of approach to the {alpha}-bungarotoxin surface can be observed with an equally enhanced access of both GdDTPA-BMA and Gd2L7 towards the protein surface side where the binding site is located. Molecular dynamics simulations suggest that protein backbone flexibility and surface hydration contribute to the observed preferential approach of both gadolinium complexes specifically to the part of the {alpha}-bungarotoxin surface which is involved in the interaction with its physiological target, the nicotinic acetylcholine receptor.

Published
2011

24. Hydration studies on the archaeal protein Sso7d using NMR measurements and MD simulations

Author

Bernini, A, Spiga, O, Consonni, R, Arosio, I, Fusi, P, Cirri, S, Guagliardi, A, Niccolai, N, Niccolai, N., FUSI, PAOLA ALESSANDRA, Bernini, A, Spiga, O, Consonni, R, Arosio, I, Fusi, P, Cirri, S, Guagliardi, A, Niccolai, N, Niccolai, N., and FUSI, PAOLA ALESSANDRA

Abstract

Background: How proteins approach surrounding molecules is fundamental to our understanding of the specific interactions that occur at the surface of proteins. The enhanced surface accessibility of small molecules such as organic solvents and paramagnetic probes to protein binding sites has been observed; however, the molecular basis of this finding has not been fully established. Recently, it has been suggested that hydration dynamics play a predominant role in controlling the distribution of hot spots on surface of proteins. Results: In the present study, the hydration of the archaeal multifunctional protein Sso7d from Solfolobus solfataricus was investigated using a combination of computational and experimental data derived from molecular dynamics simulations and ePHOGSY NMR spectroscopy. Conclusions: We obtained a convergent protein hydration landscape that indicated how the shape and stability of the Sso7d hydration shell could modulate the function of the protein. The DNA binding domain overlaps with the protein region involved in chaperon activity and this domain is hydrated only in a very small central region. This localized hydration seems to favor intermolecular approaches from a large variety of ligands. Conversely, high water density was found in surface regions of the protein where the ATP binding site is located, suggesting that surface water molecules play a role in protecting the protein from unspecific interactions. © 2011 Bernini et al; licensee BioMed Central Ltd.

Published
2011

25. NMR studies on the surface accessibility of the archaeal protein Sso7d by using TEMPOL and Gd(III)(DTPA-BMA) as paramagnetic probes

Author

Bernini, A, Venditti, V, Spiga, O, Ciutti, A, Prischi, F, Consonni, R, Zetta, L, Arosio, I, Fusi, P, Guagliardi, A, Niccolai, N, Niccolai, N., FUSI, PAOLA ALESSANDRA, Bernini, A, Venditti, V, Spiga, O, Ciutti, A, Prischi, F, Consonni, R, Zetta, L, Arosio, I, Fusi, P, Guagliardi, A, Niccolai, N, Niccolai, N., and FUSI, PAOLA ALESSANDRA

Abstract

Understanding how proteins are approached by surrounding molecules is fundamental to increase our knowledge of life at atomic resolution. Here, the surface accessibility of a multifunctional small protein, the archaeal protein Sso7d from Sulfolobus solfataricus, has been investigated by using TEMPOL and Gd(III)(DTPA-BMA) as paramagnetic probes. The DNA binding domain of Sso7d appears very accessible both to TEMPOL and Gd(III)(DTPA-BMA). Differences in paramagnetic attenuation profiles of (1)H-(15)N HSQC protein backbone amide correlations, observed in the presence of the latter paramagnetic probes, are consistent with the hydrogen bond acceptor capability of the N-oxyl moiety of TEMPOL to surface exposed Sso7d amide groups. By using the gadolinium complex as a paramagnetic probe a better agreement between Sso7d structural features and attenuation profile is achieved. It is interesting to note that the protein P-loop region, in spite of the high surface exposure predicted by the available protein structures, is not approached by TEMPOL and only partially by Gd(III)(DTPA-BMA).

Published
2008

26. In vitro and in silico analysis of the vascular effects of asymmetrical N, N-bis(alkanol)amine aryl esters, novel multidrug resistance-reverting agents.

Author

Fusi, F., Durante, M., Spiga, O., Trezza, A., Frosini, M., Floriddia, E., Teodori, E., Dei, S., and Saponara, S.

Abstract

Asymmetrical N, N-bis(alkanol)amine aryl esters (FRA77, GDE6, and GDE19) are potent multidrug resistance (MDR) reversers. Their structures loosely remind that of the Ca antagonist verapamil. Therefore, the aim of this study was to investigate their vascular activity in vitro. Their effects on the mechanical activity of fresh and cultured rat aorta rings on Ca1.2 channel current ( I ) of A7r5 cells and their cytotoxicity on A7r5 and EA.hy926 cells were analyzed. Docking at the rat α subunit of the Ca1.2 channel was simulated in silico. Compounds tested were cytotoxic at concentrations >1 μM (FRA77, GDE6, GDE19) and >10 μM (verapamil) in EA.hy926 cells, or >10 μM (FRA77, GDE6, GDE19) and at 100 μM (verapamil) in A7r5 cells. In fresh rings, the three compounds partly antagonized phenylephrine and 60 mM K (K60)-induced contraction at concentrations ≥1 and ≥3 μM, respectively. On the contrary, verapamil fully relaxed rings pre-contracted with both agents. In cultured rings, 10 μM GDE6, GDE19, FRA77, and verapamil significantly reduced the contractile response to both phenylephrine and K60. Similarly to verapamil, the three compounds docked at the α subunit, interacting with the same amino acids residues. FRA77, GDE6, and GDE19 inhibited I with IC values 1 order of magnitude higher than that of verapamil. FRA77-, GDE6-, and GDE19-induced vascular effects occurred at concentrations that are at least 1 order of magnitude higher than those effectively reverting MDR. Though an unambiguous divergence between MDR reverting and vascular activity is of overwhelming importance, these findings consistently contribute to the design and synthesis of novel and potent chemosensitizers. [ABSTRACT FROM AUTHOR]

Published
2016
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27. Mycobacterium tuberculosis chaperonin 10 is secreted in the macrophage phagosome: Is secretion due to dissociation and adoption of a partially helical structure at the membrane?

Author

Fossati, G, Izzo, G, Rizzi, E, Gancia, E, Modena, D, Moras, M, Niccolai, N, Giannozzi, E, Spiga, O, Bono, L, Marone, P, Leone, B, Mangili, F, Harding, S, Errington, N, Walters, C, Henderson, B, Roberts, M, Coates, A, Casetta, B, Mascagni, P, Moras, ML, Leone, BE, Roberts MM, Coates AR, Fossati, G, Izzo, G, Rizzi, E, Gancia, E, Modena, D, Moras, M, Niccolai, N, Giannozzi, E, Spiga, O, Bono, L, Marone, P, Leone, B, Mangili, F, Harding, S, Errington, N, Walters, C, Henderson, B, Roberts, M, Coates, A, Casetta, B, Mascagni, P, Moras, ML, Leone, BE, Roberts MM, and Coates AR

Abstract

To confirm that Mycobacterium tuberculosis chaperonin 10 (Cpn10) is secreted outside the live bacillus, infected macrophages were examined by electron microscopy. This revealed that the mycobacterial protein accumulates both in the wall of the bacterium and in the matrix of the phagosomes in which ingested mycobacteria survive within infected macrophages. To understand the structural implications underlying this secretion, a structural study of M. tuberculosis Cpn10 was performed under conditions that are generally believed to mimic the membrane environment. It was found that in buffer-organic solvent mixtures, the mycobacterial protein forms two main species, namely, a partially helical monomer that prevails in dilute solutions at room temperature and a dimer that folds into a beta-sheet-dominated structure and prevails in either concentrated protein solutions at room temperature or in dilute solutions at low temperature. A partially helical monomer was also found and was completely associated with negatively charged detergents in a micelle-bound state. Remarkably, zwitterionic lipids had no effect on the protein structure. By using N- and C-truncated forms of the protein, the C- and N-terminal sequences were identified as possessing an amphiphilic helical character and as selectively associating with acidic detergent micelles. When the study was extended to other chaperonins, it was found that human Cpn10 is also monomeric and partially helical in dilute organic solvent-buffer mixtures. In contrast, Escherichia coli Cpn10 is mostly dimeric and predominately beta-sheet in both dilute and concentrated solutions. Interestingly, human Cpn10 also crosses biological membranes, whereas the E. coli homologue is strictly cytosolic. These results suggest that dissociation to partially helical monomers and interaction with acidic lipids may be two important steps in the mechanism of secretion of M. tuberculosis Cpn10 to the external environment

Published
2003

35. Une nouvelle méthode d'étude cinétique de formation des hydrates de TBPB et de CO2 basée sur l'ATD

Author

Clain, P., Véronique Osswald, Spiga, O., Anthony Delahaye, Laurence Fournaison, Pôle Universitaire Léonard de Vinci (PULV), Génie des procédés frigorifiques (UR GPAN), and Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)

Subjects
[SDE]Environmental Sciences
Abstract

International audience; Clathrate hydrates are crystalline compounds which can be used as phase change material (PCM) for thermal energy storage. Moreover hydrate slurries could be a good solution for industrial issues of cold distribution at various temperature levels. In fact, hydrates formed from tetra-n-butylphosphonium bromide (TBPB) + water mixtures have equilibrium conditions required for air-conditioning applications, with melting temperature at 281 K at atmospheric pressure. Moreover, their flowing conditions are also suitable. Hydrates are also able to trap molecules of carbon dioxide resulting in mixed hydrates when combined with TBPB salt. The present work investigates kinetics studies of CO2 hydrates and TBPB hydrates for various conditions of salt concentrations (15 %wt, 25 %wt and 37 %wt) and for a range of subcooling temperature between 3 and 8 K. A calorimetric method is used to determine the rate of hydrate formation thanks to a Differential Thermal Analysis (DTA). In a first time, the calorimetry method has been validated by evaluating the kinetic formation rate of CO2 hydrates then it was applied to TBPB hydrates. The results showed that the kinetic formation rate is faster when the driving force increases for each initial salt concentration. Finally, two empirical kinetics models have been tested for describing the experimental result, Avrami-Erofeev and Nakamura, and a better agreement is observed with Nakamura model.

36. Targeting neuronal calcium channels and GSK3β for Alzheimer's disease with naturally-inspired Diels-Alder adducts

Author

Alessandra Bisi, Alessandra Feoli, Alfonso Trezza, Lucia Viejo, Francesco Formaggio, Manuela Bartolini, Federica Belluti, Silvia Gobbi, Ottavia Spiga, Marco Caprini, Cristobal de los Rios, Sabrina Castellano, Angela Rampa, Bisi A., Feoli A., Trezza A., Viejo L., Formaggio F., Bartolini M., Belluti F., Gobbi S., Spiga O., Caprini M., de los Rios C., Castellano S., and Rampa A.

Subjects
Neurons, Glycogen Synthase Kinase 3 beta, Ca, GSK-3β, Organic Chemistry, Alzheimer’s disease, Ca(2+) channels, Diels-Alder adducts, Docking simulation, Molecular dynamics simulation, 2+, channel, Alzheimer's disease, Biochemistry, Molecular Docking Simulation, Alzheimer Disease, Drug Discovery, Diels-Alder adduct, Humans, Calcium Channels, Molecular Biology
Abstract

The complexity of neurodegenerative diseases, among which Alzheimer's disease plays a pivotal role, poses one of the tough therapeutic challenges of present time. In this perspective, a multitarget approach appears as a promising strategy to simultaneously interfere with different defective pathways. In this paper, a structural simplification plan was performed on our previously reported multipotent polycyclic compounds, in order to obtain a simpler pharmacophoric central core with improved pharmacokinetic properties, while maintaining the modulating activity on neuronal calcium channels and glycogen synthase kinase 3-beta (GSK-3β), as validated targets to combat Alzheimer's disease. The molecular pruning approach applied here led to tetrahydroisoindole-dione (1), tetrahydromethanoisoindole-dione (2) and tetrahydroepoxyisoindole-dione (3) structures, easily affordable by Diels-Alder cycloaddition. Preliminary data indicated structure 3 as the most appropriate, thus a SAR study was performed by introducing different substituents, selected on the basis of the commercial availability of the furan derivatives required for the synthetic procedure. The results indicated compound 10 as a promising, structurally atypical, safe and BBB-penetrating Cav modulator, inhibiting both L- and N-calcium channels, likely responsible for the Ca2+ overload observed in Alzheimer's disease. In a multitarget perspective, compound 11 appeared as an effective prototype, endowed with improved Cav inhibitory activity, with respect to the reference drug nifedipine, and encouraging modulating activity on GSK-3β.

Published
2022

37. Multifaceted activity of polyciclic MDR revertant agents in drug-resistant leukemic cells: Role of the spacer

Author

Federica Belluti, Angela Rampa, Concettina Cappadone, Giovanna Farruggia, Silvia Gobbi, Giovanna Picone, Emil Malucelli, Alessandra Bisi, Dario Valenti, Ottavia Spiga, Jessica Caciolla, Alfonso Trezza, Stefano Iotti, Caciolla J., Picone G., Farruggia G., Valenti D., Rampa A., Malucelli E., Belluti F., Trezza A., Spiga O., Iotti S., Gobbi S., Cappadone C., and Bisi A.

Subjects
Bridged-Ring Compounds, MDR modulator, Revertant, Triazole, Succinimides, Antineoplastic Agents, Apoptosis, Drug resistance, P-glycoprotein, 01 natural sciences, Biochemistry, Antineoplastic Agent, Small Molecule Libraries, chemistry.chemical_compound, Structure-Activity Relationship, Small Molecule Librarie, Cell Line, Tumor, Drug Discovery, Potency, Moiety, Humans, ATP Binding Cassette Transporter, Subfamily B, Member 1, Molecular Biology, Cell Proliferation, Anthracenes, biology, Molecular Structure, 010405 organic chemistry, Chemistry, Organic Chemistry, Collateral sensitivity, Apoptosi, HL60 cell, In vitro, Drug Resistance, Multiple, 0104 chemical sciences, Molecular Docking Simulation, 010404 medicinal & biomolecular chemistry, Bridged-Ring Compound, Anticancer, Docking (molecular), Drug Resistance, Neoplasm, Anthracene, biology.protein, Drug Screening Assays, Antitumor, Human, Protein Binding
Abstract

A small library of derivatives carrying a polycyclic scaffold recently identified by us as a new privileged structure in medicinal chemistry was designed and synthesized, aiming at obtaining potent MDR reverting agents also endowed with antitumor properties. In particular, as a follow-up of our previous studies, attention was focused on the role of the spacer connecting the polycyclic core with a properly selected nitrogen-containing group. A relevant increase in reverting potency was observed, going from the previously employed but-2-ynyl- to a pent-3-ynylamino moiety, as in compounds 3d and 3e, while the introduction of a triazole ring proved to differently impact on the activity of the compounds. The docking results supported the data obtained by biological tests, showing, for the most active compounds, the ability to establish specific bonds with P-glycoprotein. Moreover, a multifaceted anticancer profile and dual in vitro activity was observed for all compounds, showing both revertant and antitumor effects on leukemic cells. In this respect, 3c emerged as a "triple-target" agent, endowed with a relevant reverting potency, a considerable antiproliferative activity and a collateral sensitivity profile.

Published
2020

38. MD and NMR studies of α-bungarotoxin surface accessibility

Author

Ottavia Spiga, Andrea Bernini, Filippo Prischi, Alfonso De Simone, Vincenzo Venditti, Neri Niccolai, Venditti, V., Bernini, A., De Simone, A., Spiga, O., Prischi, F., and Niccolai, N.

Subjects
Models, Molecular, Magnetic Resonance Spectroscopy, Surface Properties, Molecular Conformation, Biophysics, Protein hydration, Biochemistry, Paramagnetism, Molecular recognition, Molecule, Computer Simulation, Surface accessibility, Molecular Biology, biology, Chemistry, Intermolecular force, α-Bungarotoxin, Active site, Paramagnetic probe, Cell Biology, Bungarotoxins, NMR, Solvent, Crystallography, Solvation shell, Structural biology, Protein binding site, biology.protein, Protein hot spot, Gd(III)DTPA-BMA
Abstract

Protein surface accessibility represents a dimension of structural biology which has not been discussed in details so far, in spite of its fundamental role in controlling the molecular recognition process. In the present report the surface accessibility of α-bungarotoxin, a small and well characterized protein, has been investigated by analyzing its interaction with solvent and paramagnetic molecules in an integrated way. The presence of strong hydration sites, identified by a combined analysis of MD simulation and NMR results, seems to prevent the access of Gd(III)DTPA-BMA to the protein surface. On the contrary, the limited hydration of the α-bungarotoxin active site favors frequent encounters between the paramagnetic probe and the protein in the latter region. All the data obtained here for α-bungarotoxin suggest that shape and stability of the solvation shell control its surface accessibility and, hence, intermolecular interactions in a way which could be common to many other proteins. © 2007 Elsevier Inc. All rights reserved.

Published
2007
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39. NMR Studies of Protein Surface Accessibility

Author

Henriette Molinari, Arianna Ciutti, Andrea Bernini, Daniela Di Maro, Claudio Dalvit, Maria Scarselli, Neri Niccolai, Piero Andrea Temussi, Gennaro Esposito, Luisa Bracci, Ottavia Spiga, Niccolai, N, Ciutti, A, Spiga, O, Scarselli, M, Bernini, A, Bracci, L, DI MARO, D, Dalvit, C, Molinari, H, Esposito, G, and Temussi, PIERO ANDREA

Subjects
Magnetic Resonance Spectroscopy, nuclear magnetic resonance, protein accessibility, paramagnetic perturbation, Chemistry, Mutant, Cell Biology, Biochemistry, Bovine Pancreatic Trypsin Inhibitor, NMR spectra database, Crystallography, Aprotinin, Structural biology, Biophysics, Peptides, Surface protein, Molecular Biology
Abstract

Characterization of protein surface accessibility represents a new frontier of structural biology. A surface accessibility investigation for two structurally well-defined proteins, tendamistat and bovine pancreatic trypsin inhibitor, is performed here by a combined analysis of water-protein Overhauser effects and paramagnetic perturbation profiles induced by the soluble spin-label 4-hydroxy-2,2,6,6-tetramethyl-piperidine-1-oxyl on NMR spectra. This approach seems to be reliable not only for distinguishing between buried and exposed residues but also for finding molecular locations where a network of more ordered waters covers the protein surface. From the presented set of data, an overall picture of the surface accessibility of the two proteins can be inferred. Detailed knowledge of protein accessibility can form the basis for successful design of mutants with increased activity and/or greater specificity.

Published
2001
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40. NMR studies on the surface accessibility of the archaeal protein Sso7d by using TEMPOL and Gd(III)(DTPA-BMA) as paramagnetic probes

Author

Annamaria Guagliardi, Filippo Prischi, Vincenzo Venditti, Roberto Consonni, Arianna Ciutti, Lucia Zetta, Neri Niccolai, Ivana Arosio, Andrea Bernini, Paola Fusi, Ottavia Spiga, Bernini, A, Venditti, V, Spiga, O, Ciutti, A, Prischi, F, Consonni, R, Zetta, L, Arosio, I, Fusi, P, Guagliardi, A, Niccolai, N, Dipartimento di Biologia Molecolare, Università degli Studi di Siena = University of Siena (UNISI), Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Dipartimento di Biologia Strutturale e Funzionale, and Università degli studi di Napoli Federico II

Subjects
Amide, Gadolinium DTPA, Models, Molecular, Gadolinium, Surface Propertie, 01 natural sciences, Biochemistry, chemistry.chemical_compound, Nuclear magnetic resonance, Protein structure, Surface accessibility, Protein NMR, Paramagnetic probes, TEMPOL, Gd(III)(DTPA-BMA), Peptide bond, Moiety, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Spin Label, Chemistry, Hydrogen bond, BIO/10 - BIOCHIMICA, DNA-Binding Proteins, Physical Sciences, cardiovascular system, Proton, Protons, Heteronuclear single quantum coherence spectroscopy, circulatory and respiratory physiology, Surface Properties, Archaeal Proteins, DNA-Binding Protein, Biophysics, chemistry.chemical_element, 010402 general chemistry, Cyclic N-Oxides, 03 medical and health sciences, Archaeal Protein, Molecule, Amino Acid Sequence, Nuclear Magnetic Resonance, Biomolecular, 030304 developmental biology, Nitrogen Isotopes, Organic Chemistry, Hydrogen Bonding, Amides, 0104 chemical sciences, Crystallography, Cyclic N-Oxide, Spin Labels
Abstract

Understanding how proteins are approached by surrounding molecules is fundamental to increase our knowledge of life at atomic resolution. Here, the surface accessibility of a multifunctional small protein, the archaeal protein Sso7d from Sulfolobus solfataricus , has been investigated by using TEMPOL and Gd(III)(DTPA-BMA) as paramagnetic probes. The DNA binding domain of Sso7d appears very accessible both to TEMPOL and Gd(III)(DTPA-BMA). Differences in paramagnetic attenuation profiles of 1 H– 15 N HSQC protein backbone amide correlations, observed in the presence of the latter paramagnetic probes, are consistent with the hydrogen bond acceptor capability of the N -oxyl moiety of TEMPOL to surface exposed Sso7d amide groups. By using the gadolinium complex as a paramagnetic probe a better agreement between Sso7d structural features and attenuation profile is achieved. It is interesting to note that the protein P-loop region, in spite of the high surface exposure predicted by the available protein structures, is not approached by TEMPOL and only partially by Gd(III)(DTPA-BMA).

Published
2008
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41. Mycobacterium tuberculosis chaperonin 10 is secreted in the macrophage phagosome: Is secretion due to dissociation and adoption of a partially helical structure at the membrane?

Author

Elena Giannozzi, Francesca Mangili, Emanuela Gancia, Neri Niccolai, Paolo Mascagni, Anthony R.M. Coates, Emanuele Rizzi, Gianluca Fossati, Maria Luisa Moras, Michael M. Roberts, Brian Henderson, Gaetano Izzo, Daniela Modena, L. Bono, Christopher Walters, Eugenio Biagio Leone, Ottavia Spiga, Stephen E. Harding, Neil Errington, Piero Marone, Bruno Casetta, Fossati, G, Izzo, G, Rizzi, E, Gancia, E, Modena, D, Moras, M, Niccolai, N, Giannozzi, E, Spiga, O, Bono, L, Marone, P, Leone, B, Mangili, F, Harding, S, Errington, N, Walters, C, Henderson, B, Roberts, M, Coates, A, Casetta, B, and Mascagni, P

Subjects
Circular dichroism, Magnetic Resonance Spectroscopy, Biology, Microbiology, Mass Spectrometry, Protein Structure, Secondary, Chaperonin, Cell Line, Cell membrane, Mice, Structure-Activity Relationship, Protein structure, Structural Biology, Phagosomes, medicine, Chaperonin 10, Animals, Humans, Animals, Cell Line, Cell Membrane/metabolism, Chaperonin 10/chemistry, Chaperonin 10/genetics, Chaperonin 10/metabolism, Circular Dichroism Humans, Macrophages/metabolism, Macrophages/microbiology, Magnetic Resonance Spectroscopy, Mass Spectrometry/methods, Mice, Microscopy Electron, Mycobacterium tuberculosis/metabolism, Mycobacterium tuberculosis/pathogenicity, Peptides/chemical synthesis, Peptides/chemistry, Phagosomes/metabolism, Phagosomes/microbiology, Protein Structure, Secondary Rabbits, Solvents, Structure-Activity Relationship, Molecular Biology, Protein secondary structure, Phagosome, Circular Dichroism, Macrophages, Cell Membrane, Biological membrane, GroES, Mycobacterium tuberculosis, Microscopy, Electron, medicine.anatomical_structure, Biochemistry, MED/07 - MICROBIOLOGIA E MICROBIOLOGIA CLINICA, Solvents, Rabbits, Peptides
Abstract

To confirm thatMycobacterium tuberculosischaperonin 10 (Cpn10) is secreted outside the live bacillus, infected macrophages were examined by electron microscopy. This revealed that the mycobacterial protein accumulates both in the wall of the bacterium and in the matrix of the phagosomes in which ingested mycobacteria survive within infected macrophages. To understand the structural implications underlying this secretion, a structural study ofM.tuberculosisCpn10 was performed under conditions that are generally believed to mimic the membrane environment. It was found that in buffer-organic solvent mixtures, the mycobacterial protein forms two main species, namely, a partially helical monomer that prevails in dilute solutions at room temperature and a dimer that folds into a β-sheet-dominated structure and prevails in either concentrated protein solutions at room temperature or in dilute solutions at low temperature. A partially helical monomer was also found and was completely associated with negatively charged detergents in a micelle-bound state. Remarkably, zwitterionic lipids had no effect on the protein structure. By using N- and C-truncated forms of the protein, the C- and N-terminal sequences were identified as possessing an amphiphilic helical character and as selectively associating with acidic detergent micelles. When the study was extended to other chaperonins, it was found that human Cpn10 is also monomeric and partially helical in dilute organic solvent-buffer mixtures. In contrast,Escherichia coliCpn10 is mostly dimeric and predominately β-sheet in both dilute and concentrated solutions. Interestingly, human Cpn10 also crosses biological membranes, whereas theE.colihomologue is strictly cytosolic. These results suggest that dissociation to partially helical monomers and interaction with acidic lipids may be two important steps in the mechanism of secretion ofM.tuberculosisCpn10 to the external environment.

Published
2003

42. Hydration studies on the archaeal protein Sso7d using NMR measurements and MD simulations

Author

Ivana Arosio, Ottavia Spiga, Andrea Bernini, Neri Niccolai, Paola Fusi, Simone Cirri, Roberto Consonni, Annamaria Guagliardi, Bernini, A, Spiga, O, Consonni, R, Arosio, I, Fusi, P, Cirri, S, Guagliardi, Annamaria, Niccolai, N., Guagliardi, A, and Niccolai, N

Subjects
Magnetic Resonance Spectroscopy, Archaeal Proteins, Plasma protein binding, Molecular Dynamics Simulation, Paramagnetism, Molecular dynamics, Structural Biology, Sso7d, NMR, archaebacteria, SURFACE ACCESSIBILITY, Molecule, CRYSTAL-STRUCTURES, Databases, Protein, lcsh:QH301-705.5, TEMPOL, Chemistry, Water, Hydrogen Bonding, DNA, Small molecule, Protein Structure, Tertiary, DNA-Binding Proteins, Crystallography, lcsh:Biology (General), Biophysics, SULFOLOBUS-SOLFATARICUS, Protein Binding, Research Article
Abstract

Background How proteins approach surrounding molecules is fundamental to our understanding of the specific interactions that occur at the surface of proteins. The enhanced surface accessibility of small molecules such as organic solvents and paramagnetic probes to protein binding sites has been observed; however, the molecular basis of this finding has not been fully established. Recently, it has been suggested that hydration dynamics play a predominant role in controlling the distribution of hot spots on surface of proteins. Results In the present study, the hydration of the archaeal multifunctional protein Sso7d from Solfolobus solfataricus was investigated using a combination of computational and experimental data derived from molecular dynamics simulations and ePHOGSY NMR spectroscopy. Conclusions We obtained a convergent protein hydration landscape that indicated how the shape and stability of the Sso7d hydration shell could modulate the function of the protein. The DNA binding domain overlaps with the protein region involved in chaperon activity and this domain is hydrated only in a very small central region. This localized hydration seems to favor intermolecular approaches from a large variety of ligands. Conversely, high water density was found in surface regions of the protein where the ATP binding site is located, suggesting that surface water molecules play a role in protecting the protein from unspecific interactions.

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43. Predicting therapy dropout in chronic pain management: a machine learning approach to cannabis treatment.

Author

Visibelli A, Finetti R, Roncaglia B, Poli P, Spiga O, and Santucci A

Abstract

Introduction: Chronic pain affects approximately 30% of the global population, posing a significant public health challenge. Despite their widespread use, traditional pharmacological treatments, such as opioids and NSAIDs, often fail to deliver adequate, long-term relief while exposing patients to risks of addiction and adverse side effects. Given these limitations, medical cannabis has emerged as a promising therapeutic alternative with both analgesic and anti-inflammatory properties. However, its clinical efficacy is hindered by high interindividual variability in treatment response and elevated dropout rates., Methods: A comprehensive dataset integrating genetic, clinical, and pharmacological information was compiled from 542 Caucasian patients undergoing cannabis-based treatment for chronic pain. A machine learning (ML) model was developed and validated to predict therapy dropout. To identify the most influential factors driving dropout, SHapley Additive exPlanations (SHAP) analysis was performed., Results: The random forest classifier demonstrated robust performance, achieving a mean accuracy of 80% and a maximum of 86%, with an AUC of 0.86. SHAP analysis revealed that high final VAS scores and elevated THC dosages were the most significant predictors of dropout, both strongly correlated with an increased likelihood of discontinuation. In contrast, baseline therapeutic benefits, CBD dosages, and the CC genotype of the rs1049353 polymorphism in the CNR1 gene were associated with improved adherence., Discussion: Our findings highlight the potential of ML and pharmacogenetics to personalize cannabis-based therapies, improving adherence and enabling more precise management of chronic pain. This research paves the way for the development of tailored therapeutic strategies that maximize the benefits of medical cannabis while minimizing its side effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Visibelli, Finetti, Roncaglia, Poli, Spiga and Santucci.)

Published
2025
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44. SHASI-ML: a machine learning-based approach for immunogenicity prediction in Salmonella vaccine development.

Author

Spiga O, Visibelli A, Pettini F, Roncaglia B, and Santucci A

Subjects
Vaccine Development, Algorithms, Immunogenicity, Vaccine, Antigens, Bacterial immunology, Proteome immunology, Humans, Machine Learning, Salmonella Vaccines immunology, Bacterial Proteins immunology, Bacterial Proteins genetics, Computational Biology methods, Salmonella typhimurium immunology, Salmonella typhimurium genetics, Salmonella Infections prevention & control, Salmonella Infections immunology, Salmonella Infections microbiology
Abstract

Introduction: Accurate prediction of immunogenic proteins is crucial for vaccine development and understanding host-pathogen interactions in bacterial diseases, particularly for Salmonella infections which remain a significant global health challenge., Methods: We developed SHASI-ML, a machine learning-based framework for predicting immunogenic proteins in Salmonella species. The model was trained and validated using a curated dataset of experimentally verified immunogenic and non-immunogenic proteins. Three distinct feature groups were extracted from protein sequences: global properties, sequence-derived features, and structural information. The Extreme Gradient Boosting (XGBoost) algorithm was employed for model development and optimization., Results: SHASI-ML demonstrated robust performance in identifying bacterial immunogens, achieving 89.3% precision and 91.2% specificity. When applied to the Salmonella enterica serovar Typhimurium proteome, the model identified 292 novel immunogenic protein candidates. Global properties emerged as the most influential feature group in prediction accuracy, followed by structural and sequence information. The model showed superior recall and F1-scores compared to existing computational approaches., Discussion: These findings establish SHASI-ML as an efficient computational tool for prioritizing immunogenic candidates in Salmonella vaccine development. By streamlining the identification of vaccine candidates early in the development process, this approach significantly reduces experimental burden and associated costs. The methodology can be applied to guide and optimize both research and industrial-scale production of Salmonella vaccines, potentially accelerating the development of more effective immunization strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Spiga, Visibelli, Pettini, Roncaglia and Santucci.)

Published
2025
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45. Integrated Clinomics and Molecular Dynamics Simulation Approaches Reveal the SAA1.1 Allele as a Biomarker in Alkaptonuria Disease Severity.

Author

Trezza A, Roncaglia B, Visibelli A, Barletta R, Peruzzi L, Marzocchi B, Braconi D, Spiga O, and Santucci A

Subjects
Humans, Severity of Illness Index, Inflammation genetics, Inflammation metabolism, Serum Amyloid A Protein genetics, Serum Amyloid A Protein metabolism, Alkaptonuria genetics, Alkaptonuria metabolism, Molecular Dynamics Simulation, Biomarkers metabolism, Alleles
Abstract

Alkaptonuria (AKU) is a rare metabolic disorder characterized by the accumulation of homogentisic acid (HGA), leading to progressive ochronosis and joint degeneration. While much is known about HGA's role in tissue damage, the molecular mechanisms underlying acute inflammation in AKU remain poorly understood. Serum amyloid A (SAA) proteins are key mediators of the inflammatory response, yet their potential as biomarkers for inflammation in AKU has not been explored. This study investigated the role of the SAA1.1 allele as a biomarker for the severity of acute inflammation in AKU. Data from the ApreciseKUre Precision Medicine Ecosystem were analyzed to assess the relationship between SAA1 allelic variants and inflammatory markers. Molecular dynamics simulations compared the structural dynamics of SAA1.1 and SAA1.2 isoforms, with standard modeling and analysis pipelines employed. Using a clinomics approach, we showed that AKU patients expressing the SAA1.1 allele have significantly higher acute inflammation-related markers. Extensive molecular dynamics simulations revealed that the SAA1.1 isoform lent high structural instability of the C-terminal domain, accelerating the formation of amyloid fibrils and exacerbating the inflammatory condition. These findings would identify the SAA1.1 allele as a novel genetic biomarker for the progression of secondary amyloidosis in AKU and its severity. Furthermore, new molecular insights into the inflammatory mechanisms of AKU were provided, suggesting potential therapeutic approaches aimed at stabilizing SAA1.1 protein and preventing amyloid fibril formation, with significant implications in AKU and precision medicine strategies for SAA-related diseases.

Published
2025
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46. Exploring the chemical space around chrysin to develop novel vascular Ca V 1.2 channel blockers, promising vasorelaxant agents.

Author

Falbo F, Carullo G, Panti A, Spiga O, Gianibbi B, Ahmed A, Campiani G, Ramunno A, Aiello F, and Fusi F

Subjects
Animals, Structure-Activity Relationship, Rats, Humans, Male, Molecular Structure, Calcium Channels, L-Type metabolism, Calcium Channels, L-Type drug effects, Calcium Channel Blockers pharmacology, Calcium Channel Blockers chemical synthesis, Calcium Channel Blockers chemistry, Flavonoids pharmacology, Flavonoids chemistry, Flavonoids chemical synthesis, Vasodilator Agents pharmacology, Vasodilator Agents chemical synthesis, Vasodilator Agents chemistry, Molecular Docking Simulation
Abstract

The flavonoid chrysin is an effective vascular Ca V 1.2 channel blocker. The aim of this study was to explore the chemical space around chrysin to identify the structural features that can be modified to develop novel and more effective blockers. Four derivatives (Chrysin 1-4) were synthesised and a functional, electrophysiology and molecular docking approach was pursued to assess their binding mode to Ca V 1.2 channels and their activity in vascular preparations. Methylation of the 5- and 7-OH of the chrysin backbone caused a marked reduction of the Ca 2+ antagonistic potency and efficacy. However, C-8 derivatives showed biophysical features similar to those of the parent compound and, like nicardipine, bound with high affinity to and stabilised the Ca V 1.2 channel in its inactivated state. The vasorelaxant effects of the four derivatives appeared vessel-specific, addressing the molecules' derivatization towards different targets. In conclusion, the scaffold of chrysin may be considered a valuable starting point for the development of innovative vascular Ca V 1.2 channel blockers., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Published
2024
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47. Exploring the Antioxidant and Anti-Inflammatory Potential of Saffron ( Crocus sativus ) Tepals Extract within the Circular Bioeconomy.

Author

Frusciante L, Geminiani M, Shabab B, Olmastroni T, Scavello G, Rossi M, Mastroeni P, Nyong'a CN, Salvini L, Lamponi S, Parisi ML, Sinicropi A, Costa L, Spiga O, Trezza A, and Santucci A

Abstract

Repurposing saffron ( Crocus sativus ) waste presents a sustainable strategy for generating high-value products within the bioeconomy framework. Typically, flower components are discarded after stigma harvest, resulting in significant waste-350 kg of tepals per kilogram of stigmas. This research employed a comprehensive approach, integrating bioactivity studies (in vitro and in silico) with Life Cycle Assessment (LCA) evaluations, to extract and assess bioactive compounds from C. sativus tepals sourced in Tuscany, Italy. Phytochemical characterization using UPLC-MS/MS revealed a high abundance and variety of flavonoids in the hydro-ethanolic extract (CST). The antioxidant capacity was validated through various assays, and the ability to mitigate H 2 O 2 -induced oxidative stress and enhance fermentation was demonstrated in Saccharomyces cerevisiae . This study reports that C. sativus tepals extract reduces oxidative stress and boosts ethanol fermentation in yeast, paving the way for applications in the food and biofuels sectors. Further validation in RAW 264.7 macrophages confirmed CST's significant anti-inflammatory effects, indicating its potential for pharmaceutical, cosmeceutical, and nutraceutical applications. In silico studies identified potential targets involved in antioxidant and anti-inflammatory processes, shedding light on possible interaction mechanisms with Kaempferol 3-O-sophoroside (KOS-3), the predominant compound in the extract. The integration of LCA studies highlighted the environmental benefits of this approach. Overall, this research underscores the value of using waste-derived extracts through "green" methodologies, offering a model that may provide significant advantages for further evaluations compared to traditional methodologies and supporting the circular bioeconomy.

Published
2024
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48. The Personalized Inherited Signature Predisposing to Non-Small-Cell Lung Cancer in Non-Smokers.

Author

Serio VB, Rosati D, Maffeo D, Rina A, Ghisalberti M, Bellan C, Spiga O, Mari F, Palmieri M, and Frullanti E

Abstract

Lung cancer (LC) continues to be an important public health problem, being the most common form of cancer and a major cause of cancer deaths worldwide. Despite the great bulk of research to identify genetic susceptibility genes by genome-wide association studies, only few loci associated to nicotine dependence have been consistently replicated. Our previously published study in few phenotypically discordant sib-pairs identified a combination of germline truncating mutations in known cancer susceptibility genes in never-smoker early-onset LC patients, which does not present in their healthy sib. These results firstly demonstrated the presence of an oligogenic combination of disrupted cancer-predisposing genes in non-smokers patients, giving experimental support to a model of a "private genetic epidemiology". Here, we used a combination of whole-exome and RNA sequencing coupled with a discordant sib's model in a novel cohort of pairs of never-smokers early-onset LC patients and in their healthy sibs used as controls. We selected rare germline variants predicted as deleterious by CADD and SVM bioinformatics tools and absent in the healthy sib. Overall, we identified an average of 200 variants per patient, about 10 of which in cancer-predisposing genes. In most of them, RNA sequencing data reinforced the pathogenic role of the identified variants showing: (i) downregulation in LC tissue (indicating a "second hit" in tumor suppressor genes); (ii) upregulation in cancer tissue (likely oncogene); and (iii) downregulation in both normal and cancer tissue (indicating transcript instability). The combination of the two techniques demonstrates that each patient has an average of six (with a range from four to eight) private mutations with a functional effect in tumor-predisposing genes. The presence of a unique combination of disrupting events in the affected subjects may explain the absence of the familial clustering of non-small-cell lung cancer. In conclusion, these findings indicate that each patient has his/her own "predisposing signature" to cancer development and suggest the use of personalized therapeutic strategies in lung cancer.

Published
2024
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49. Three-Dimensional Quantitative Structure-Activity Relationship Study of Transient Receptor Potential Vanilloid 1 Channel Antagonists Reveals Potential for Drug Design Purposes.

Author

Gianibbi B, Visibelli A, Spinsanti G, and Spiga O

Subjects
Humans, Models, Molecular, Ligands, Quantitative Structure-Activity Relationship, TRPV Cation Channels antagonists & inhibitors, TRPV Cation Channels metabolism, Drug Design
Abstract

Transient receptor potential vanilloid 1 (TRPV1) was reported to be a putative target for recovery from chronic pain, producing analgesic effects after its inhibition. A series of drug candidates were previously developed, without the ability to ameliorate the therapeutic outcome. Starting from previously designed compounds, derived from the hybridization of antagonist SB-705498 and partial agonist MDR-652, we performed a virtual screening on a pharmacophore model built by exploiting the Cryo-EM 3D structure of a nanomolar antagonist in complex with the human TRPV1 channel. The pharmacophore model was described by three pharmacophoric features, taking advantage of both the bioactive pose of the antagonist and the receptor exclusion spheres. The results of the screening were implemented inside a 3D-QSAR model, correlating with the negative decadic logarithm of the inhibition rate of the ligands. After the validation of the obtained 3D-QSAR model, we designed a new series of compounds by introducing key modifications on the original scaffold. Again, we determined the compounds' binding poses after alignment to the pharmacophoric model, and we predicted their inhibition rates with the validated 3D-QSAR model. The obtained values resulted in being even more promising than parent compounds, demonstrating that ongoing research still leaves much room for improvement.

Published
2024
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50. Molecular Origins of the Mendelian Rare Diseases Reviewed by Orpha.net: A Structural Bioinformatics Investigation.

Author

Visibelli A, Finetti R, Niccolai N, Spiga O, and Santucci A

Subjects
Humans, Mutation, Missense, Databases, Genetic, Proteins chemistry, Proteins genetics, Models, Molecular, Amino Acid Substitution, Protein Conformation, Computational Biology methods, Rare Diseases genetics
Abstract

The study of rare diseases is important not only for the individuals affected but also for the advancement of medical knowledge and a deeper understanding of human biology and genetics. The wide repertoire of structural information now available from reliable and accurate prediction methods provides the opportunity to investigate the molecular origins of most of the rare diseases reviewed in the Orpha.net database. Thus, it has been possible to analyze the topology of the pathogenic missense variants found in the 2515 proteins involved in Mendelian rare diseases (MRDs), which form the database for our structural bioinformatics study. The amino acid substitutions responsible for MRDs showed different mutation site distributions at different three-dimensional protein depths. We then highlighted the depth-dependent effects of pathogenic variants for the 20,061 pathogenic variants that are present in our database. The results of this structural bioinformatics investigation are relevant, as they provide additional clues to mitigate the damage caused by MRD.

Published
2024
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