438 results on '"Settore BIO/13"'
Search Results
2. Modifications of Behavior and Inflammation in Mice Following Transplant with Fecal Microbiota from Children with Autism
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Ennio Avolio, Ilaria Olivito, Eleonora Rosina, Lorenzo Romano, Tommaso Angelone, Anna De Bartolo, Manuel Scimeca, Dina Bellizzi, Patrizia D'Aquila, Giuseppe Passarino, Raffaella Alò, Rosa Maria Facciolo, Claudia Bagni, Antonino De Lorenzo, and Marcello Canonaco
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Valproic Acid ,General Neuroscience ,Settore BIO/13 ,autism spectrum disorder ,Settore MED/49 ,fecal transplant ,Disease Models, Animal ,Mice ,Pregnancy ,inflammation ,microbiota ,Animals ,Humans ,Female ,Autistic Disorder ,Child ,bacteria - Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder displaying the modification of complex human behaviors, characterized by social interaction impairments, stereotypical/repetitive activities and emotional dysregulation. In this study, fecal microbiota transplant (FMT) via gavage from autistic children donors to mice, led to the colonization of ASD-like microbiota and autistic behaviors compared to the offspring of pregnant females exposed to valproic acid (VPA). Such variations seemed to be tightly associated with increased populations of Tenericutes plus a notable reduction (p 0.001) of Actinobacteria and Candidatus S. in the gastrointestinal region of FMT mice as compared to controls. Indeed altered behaviors of FMT mice was reported when evaluated in the different maze tests (light dark, novel object, three chamber tests, novel cage test). Contextually, FMT accounted for elevated expression levels of the pro-inflammatory factors IL-1β, IL-6, COX-1 and TNF-α in both brain and small intestine. Villous atrophy and inflammatory infiltration (Caspase 3 and Ki67) were increased in the small intestine of FMT and VPA mice compared to controls. Moreover, the observed FMT-dependent alterations were linked to a decrease in the methylation status. Overall, findings of the present study corroborate a key role of gut microbiota in ASD. However, further investigations are required before any possible manipulation of gut bacteria with appropriate diets or probiotics can be conducted in ASD individuals.
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- 2022
3. A 3D adipogenesis platform to study the fate of fibro/adipogenic progenitors in muscular dystrophies
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Reggio, A, De Paolis, F, Bousselmi, S, Cicciarelli, F, Bernardini, S, Rainer, A, Seliktar, D, Testa, S, Cirillo, C, Grumati, P, Cannata, S, Fuoco, C, and Gargioli, C
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Adipogenesis ,Muscular dystrophies ,Settore BIO/13 ,Tissue engineering ,β-catenin ,Fibro/adipogenic progenitors ,LY2090314 - Published
- 2023
4. Mapping genomic loci implicates genes and synaptic biology in schizophrenia
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Trubetskoy, Vassily, Panagiotaropoulou, Georgia, Awasthi, Swapnil, Braun, Alice, Kraft, Julia, Skarabis, Nora, Walter, Henrik, Ripke, Stephan, Pardiñas, Antonio F., Dennison, Charlotte A., Hall, Lynsey S., Harwood, Janet C., Richards, Alexander L., Legge, Sophie E., Lynham, Amy, Williams, Nigel M., Bray, Nicholas J., Escott-Price, Valentina, Kirov, George, Holmans, Peter A., Pocklington, Andrew J., Owen, Michael J., Walters, James T. R., O’Donovan, Michael C., Qi, Ting, Sidorenko, Julia, Wu, Yang, Zeng, Jian, Gratten, Jacob, Visscher, Peter M., Yang, Jian, Wray, Naomi R., Bigdeli, Tim B., Fanous, Ayman H., Bryois, Julien, Bergen, Sarah E., Kähler, Anna K., Magnusson, Patrik K. E., Hultman, Christina M., Sullivan, Patrick F., Chen, Chia-Yen, Atkinson, Elizabeth G., Goldstein, Jacqueline I., Howrigan, Daniel P., Martin, Alicia R., Daly, Mark J., Huang, Hailiang, Neale, Benjamin M., Ge, Tian, Lam, Max, Belliveau, Richard A., Chambert, Kimberley D., Genovese, Giulio, Lee, Phil H., Pietiläinen, Olli, McCarroll, Steven A., Moran, Jennifer L., Smoller, Jordan W., Brown, Tyler C., Feng, Guoping, Hyman, Steven E., Sheng, Morgan, Chong, Siow Ann, Subramaniam, Mythily, Lencz, Todd, Malhotra, Anil K., Watanabe, Kyoko, Frei, Oleksandr, Agartz, Ingrid, Athanasiu, Lavinia, Melle, Ingrid, Andreassen, Ole A., Steen, Nils Eiel, DeLisi, Lynn E., Mesholam-Gately, Raquelle I., Seidman, Larry J., Koopmans, Frank, Magnusson, Sigurdur, Stefánsson, Hreinn, Stefansson, Kari, Grove, Jakob, Agerbo, Esben, Als, Thomas D., Bybjerg-Grauholm, Jonas, Demontis, Ditte, Hougaard, David M., Mors, Ole, Mortensen, Preben B., Nordentoft, Merete, Børglum, Anders D., Mattheisen, Manuel, Kim, Minsoo, Gandal, Michael J., Li, Zhiqiang, Shi, Yongyong, Zhou, Wei, Qin, Shengying, Voloudakis, Georgios, Zhang, Wen, Roussos, Panos, Adams, Mark, McIntosh, Andrew, Söderman, Erik, Jönsson, Erik G., McGrath, John J., Al Eissa, Mariam, Bass, Nicholas J., Fiorentino, Alessia, O’Brien, Niamh Louise, Pimm, Jonathan, Sharp, Sally Isabel, McQuillin, Andrew, Albus, Margot, Alexander, Madeline, Alizadeh, Behrooz Z., Bruggeman, Richard, Alptekin, Köksal, Amin, Farooq, Arolt, Volker, Lencer, Rebecca, Rothermundt, Matthias, Baune, Bernhard T., Arrojo, Manuel, Azevedo, Maria Helena, Bacanu, Silviu A., Webb, Bradley T., Wormley, Brandon K., Riley, Brien P., Kendler, Kenneth S., Begemann, Martin, Mitjans, Marina, Steixner-Kumar, Agnes A., Ehrenreich, Hannelore, Bene, Judit, Benyamin, Beben, Blasi, Giuseppe, Rampino, Antonio, Torretta, Silvia, Bertolino, Alessandro, Bobes, Julio, Bonassi, Stefano, Bressan, Rodrigo Affonseca, Gadelha, Ary, Noto, Cristiano, Ota, Vanessa Kiyomi, Santoro, Marcos Leite, Belangero, Sintia Iole, Bromet, Evelyn J., Buckley, Peter F., Buckner, Randy L., Cahn, Wiepke, Kahn, René S., Cairns, Murray J., Scott, Rodney J., Tooney, Paul A., Schall, Ulrich, Calkins, Monica E., Gur, Raquel E., Gur, Ruben C., Turetsky, Bruce I., Carr, Vaughan J., Castle, David, Harvey, Carol, Catts, Stanley V., Chan, Raymond C. K., Chaumette, Boris, Kebir, Oussama, Krebs, Marie-Odile, Cheng, Wei, Cheung, Eric F. C., Cohen, David, Consoli, Angèle, Giannitelli, Marianna, Laurent-Levinson, Claudine, Cordeiro, Quirino, Costas, Javier, Curtis, Charles, Quattrone, Diego, Breen, Gerome, Collier, David A., Di Forti, Marta, Vassos, Evangelos, Mondelli, Valeria, van Amelsvoort, Therese, Murray, Robin M., Davidson, Michael, Davis, Kenneth L., Haroutunian, Vahram, Malaspina, Dolores, Reichenberg, Abraham, Siever, Larry J., Silverman, Jeremy M., Buxbaum, Joseph D., de Haan, Lieuwe, Degenhardt, Franziska, Forstner, Andreas, Nöthen, Markus M., Dickerson, Faith, Dikeos, Dimitris, Papadimitriou, George N., Dinan, Timothy, Djurovic, Srdjan, Duan, Jubao, Gejman, Pablo V., Sanders, Alan R., Ducci, Giuseppe, Dudbridge, Frank, Eriksson, Johan G., Fañanás, Lourdes, Peñas, Javier González, González-Pinto, Ana, Molto, María Dolores, Moreno, Carmen, Parellada, Mara, Sanjuan, Julio, Crepo-Facorro, Benedicto, Mata, Ignacio, Arango, Celso, Faraone, Stephen V., Frank, Josef, Streit, Fabian, Witt, Stephanie H., Rietschel, Marcella, Freimer, Nelson B., Ophoff, Roel A., Fromer, Menachem, Stahl, Eli A., Frustaci, Alessandra, Gershon, Elliot S., Giegling, Ina, Hartmann, Annette M., Konte, Bettina, Rujescu, Dan, Giusti-Rodríguez, Paola, Szatkiewicz, Jin P., Godard, Stephanie, González Peñas, Javier, Gopal, Srihari, Savitz, Adam, Li, Qingqin S., Green, Michael F., Nuechterlein, Keith H., Sugar, Catherine A., Greenwood, Tiffany A., Light, Gregory A., Swerdlow, Neal R., Braff, David, Guillin, Olivier, Campion, Dominique, Gülöksüz, Sinan, Luykx, Jurjen J., Rutten, Bart P. F., van Winkel, Ruud, Gutiérrez, Blanca, Hahn, Eric, Hakonarson, Hakon, Pellegrino, Renata, Pantelis, Christos, Hayward, Caroline, Henskens, Frans A., Kelly, Brian J., Herms, Stefan, Hoffmann, Per, Ikeda, Masashi, Iwata, Nakao, Iyegbe, Conrad, van Os, Jim, Joa, Inge, Julià, Antonio, Marsal, Sara, Kam-Thong, Tony, Rautanen, Anna, Kamatani, Yoichiro, Karachanak-Yankova, Sena, Toncheva, Draga, Keller, Matthew C., Khrunin, Andrey, Limborska, Svetlana, Slominsky, Petr, Kim, Sung-Wan, Klovins, Janis, Nikitina-Zake, Liene, Kondratiev, Nikolay, Golimbet, Vera, Kubo, Michiaki, Kučinskas, Vaidutis, Kučinskiene, Zita Ausrele, Kusumawardhani, Agung, Kuzelova-Ptackova, Hana, Landi, Stefano, Lazzeroni, Laura C., Levinson, Douglas F., Petryshen, Tracey L., Lehrer, Douglas S., Lerer, Bernard, Li, Miaoxin, Lieberman, Jeffrey, Stroup, T. Scott, Liu, Chih-Min, Hwu, Hai-Gwo, Lönnqvist, Jouko, Loughland, Carmel M., Lubinski, Jan, Bakker, Steven, Kahn, René, Macek, Milan, Mackinnon, Andrew, Maher, Brion S., Maier, Wolfgang, Atbaşoğlu, Eşref Cem, Mallet, Jacques, Marder, Stephen R., Martorell, Lourdes, Muntané, Gerard, Vilella, Elisabet, Meier, Sandra, Schulze, Thomas G., McCarley, Robert W., McDonald, Colm, Donohoe, Gary, Morris, Derek W., Periyasamy, Sathish, Mowry, Bryan J., Medeiros, Helena, Sobell, Janet L., Melegh, Bela, Metspalu, Andres, Milani, Lili, Esko, Tõnu, Michie, Patricia T., Milanova, Vihra, Molden, Espen, Molina, Esther, Morley, Christopher P., Murphy, Kieran C., Myin-Germeys, Inez, Nenadić, Igor, Nestadt, Gerald, Pulver, Ann E., O’Neill, F. Anthony, Oh, Sang-Yun, Olincy, Ann, Freedman, Robert, Paunio, Tiina, Perkins, Diana O., Pfuhlmann, Bruno, Benner, Christian, Pirinen, Matti, Palotie, Aarno, Porteous, David, Powell, John, Quested, Digby, Radant, Allen D., Tsuang, Debby W., Rapaport, Mark H., Roe, Cheryl, Liu, Chunyu, Roffman, Joshua L., Roth, Julian, Gawlik, Micha, Saker-Delye, Safaa, Salomaa, Veikko, Suvisaari, Jaana, Shi, Jianxin, Sigurdsson, Engilbert, Sim, Kang, So, Hon-Cheong, Stain, Helen J., Stögmann, Elisabeth, Zimprich, Fritz, Stone, William S., Straub, Richard E., Hyde, Thomas, Jaffe, Andrew, Weinberger, Daniel R., Strengman, Eric, Svrakic, Dragan M., Cloninger, C. Robert, Ta, Thi Minh Tam, Takahashi, Atsushi, Terao, Chikashi, Thibaut, Florence, Tosato, Sarah, Tura, Gian Battista, Üçok, Alp, Vaaler, Arne, Veijola, Juha, Waddington, John, Waterreus, Anna, Morgan, Vera A., Jablensky, Assen V., Weiser, Mark, Wu, Jing Qin, Xu, Zhida, Yolken, Robert, Zai, Clement C., Kennedy, James L., Zhu, Feng, Saka, Meram C., Ayub, Muhammad, Black, Donald W., Buccola, Nancy G., Byerley, William F., Chen, Wei J., Crespo-Facorro, Benedicto, Galletly, Cherrie, Gennarelli, Massimo, Müller-Myhsok, Bertram, Neil, Amanda L., Pato, Michele T., Pato, Carlos N., Wang, Shi-Heng, Xu, Shuhua, Adolfsson, Rolf, Bramon, Elvira, Cervilla, Jorge A., Cichon, Sven, Corvin, Aiden, Gill, Michael, Curtis, David, Domenici, Enrico, Gareeva, Anna, Khusnutdinova, Elza, Glatt, Stephen J., Hong, Kyung Sue, Knowles, James A., Lee, Jimmy, Liu, Jianjun, Malhotra, Dheeraj, Menezes, Paulo R., Nimgaonkar, Vishwajit, Paciga, Sara A., Rivera, Margarita, Schwab, Sibylle G., Serretti, Alessandro, Sham, Pak C., Clair, David St, Tsuang, Ming T., Vawter, Marquis P., Werge, Thomas, Wildenauer, Dieter B., Yu, Xin, Yue, Weihua, Verhage, Matthijs, Sahasrabudhe, Dnyanada, Toonen, Ruud F., Posthuma, Danielle, Dai, Nan, Wenwen, Qin, Wildenauer, D. B., Agiananda, Feranindhya, Amir, Nurmiati, Antoni, Ronald, Arsianti, Tiana, Asmarahadi, Asmarahadi, Diatri, H., Djatmiko, Prianto, Irmansyah, Irmansyah, Khalimah, Siti, Kusumadewi, Irmia, Kusumaningrum, Profitasari, Lukman, Petrin R., Nasrun, Martina W., Safyuni, N. S., Prasetyawan, Prasetyawan, Semen, G., Siste, Kristiana, Tobing, Heriani, Widiasih, Natalia, Wiguna, Tjhin, Wulandari, D., Evalina, None, Hananto, A. J., Ismoyo, Joni H., Marini, T. M., Henuhili, Supiyani, Reza, Muhammad, Yusnadewi, Suzy, Abyzov, Alexej, Akbarian, Schahram, van Bakel, Harm, Breen, Michael, Charney, Alex, Dracheva, Stella, Girdhar, Kiran, Hoffman, Gabriel, Jiang, Yan, Pinto, Dalila, Purcell, Shaun, Roussos, Panagiotis, Wiseman, Jennifer, Ashley-Koch, Allison, Crawford, Gregory, Reddy, Tim, Brown, Miguel, Grennan, Kay, Carlyle, Becky, Emani, Prashant, Galeev, Timur, Gerstein, Mark, Gu, Mengting, Guerra, Brittney, Gursoy, Gamze, Kitchen, Robert, Lee, Donghoon, Li, Mingfeng, Liu, Shuang, Navarro, Fabio, Pan, Xinghua, Pochareddy, Sirisha, Rozowsky, Joel, Sestan, Nenad, Sethi, Anurag, Shi, Xu, Szekely, Anna, Wang, Daifeng, Warrell, Jonathan, Weissman, Sherman, Wu, Feinan, Xu, Xuming, Coetzee, Gerard, Farnham, Peggy, Lay, Fides, Rhie, Suhn, Witt, Heather, Wood, Shannon, Yao, Lijing, Gandal, Mike, Polioudakis, Damon, Swarup, Vivek, Won, Hyejung, Giase, Gina, Jiang, Shan, Kefi, Amira, Shieh, Annie, Goes, Fernando, Zandi, Peter, Kim, Yunjung, Mattei, Eugenio, Purcaro, Michael, Pratt, Henry, Peters, Mette A., Sanders, Stephan, Weng, Zhiping, White, Kevin, Arranz, Maria J., Lewis, Cathryn, Lin, Kuang, Walshe, Muriel, Bender, Stephan, Weisbrod, Matthias, Hall, Jeremy, Lawrie, Stephen, Linszen, Don H., Achsel, Tilmann, Bagni, Claudia, Andres-Alonso, Maria, Kreutz, Michael R., Bayés, Àlex, Biederer, Thomas, Brose, Nils, Chua, John Jia En, Coba, Marcelo P., Cornelisse, L. Niels, van Weering, Jan R. T., de Jong, Arthur P. H., MacGillavry, Harold D., de Juan-Sanz, Jaime, Dieterich, Daniela C., Pielot, Rainer, Smalla, Karl-Heinz, Gundelfinger, Eckart D., Goldschmidt, Hana L., Huganir, Richard L., Hoogenraad, Casper, Imig, Cordelia, Jahn, Reinhard, Jung, Hwajin, Kim, Eunjoon, Kaeser, Pascal S., Lipstein, Noa, Malenka, Robert, McPherson, Peter S., O’Connor, Vincent, Ryan, Timothy A., Sala, Carlo, Verpelli, Chiara, Smit, August B., Südhof, Thomas C., Thomas, Paul D., Medical Research Council (UK), National Natural Science Foundation of China, Royal Society (UK), Chinese Academy of Sciences, Shanghai Science and Technology Committee, Research Council of Norway, European Commission, Fundação de Amparo à Pesquisa do Estado de São Paulo, Ministerio de Ciencia e Innovación (España), Instituto de Salud Carlos III, Comunidad de Madrid, Fundación Alicia Koplowitz, Fundación Alonso Lozano, Mental Health Research UK, Wellcome Trust, Brain and Behavior Research Foundation, NIHR Biomedical Research Centre (UK), University College London, Generalitat Valenciana, Internal medicine, Human genetics, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), Life Course Epidemiology (LCE), Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Psychiatry, Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, RS: MHeNs - R3 - Neuroscience, MUMC+: MA Psychiatrie (3), MUMC+: MA Med Staf Spec Psychiatrie (9), MUMC+: Hersen en Zenuw Centrum (3), Trubetskoy, Vassily, Pardiñas, Antonio F., Qi, Ting, Panagiotaropoulou, Georgia, Benyamin, Beben, O'Donovan, Michael C, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Adult Psychiatry, APH - Mental Health, ANS - Complex Trait Genetics, ANS - Mood, Anxiety, Psychosis, Stress & Sleep, Molecular and Cellular Neurobiology, Functional Genomics, and Complex Trait Genetics
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Genetics of the nervous system ,Schizophrenia/genetics ,VARIANTS ,PROFILE ,Polymorphism, Single Nucleotide ,Genome-wide association studies ,Article ,DISEASE ,SDG 3 - Good Health and Well-being ,Humans ,Genetic Predisposition to Disease ,Alleles ,Genomics ,Genome-Wide Association Study ,Schizophrenia ,Polymorphism ,RISK ,ARCHITECTURE ,Science & Technology ,Multidisciplinary ,MUTATIONS ,Genetic Predisposition to Disease/genetics ,Settore BIO/13 ,Single Nucleotide ,ASSOCIATION ,Polymorphism, Single Nucleotide/genetics ,STATISTICS ,Multidisciplinary Sciences ,INDIVIDUALS ,Science & Technology - Other Topics ,Diseases of the nervous system ,ddc:500 ,Single Nucleotide/genetics ,INTEGRATION - Abstract
Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., The work at Cardiff University was additionally supported by Medical Research Council Centre grant no. MR/L010305/1 and program grant no. G0800509. S. Xu also gratefully acknowledges the support of the National Natural Science Foundation of China (NSFC) grants (31525014, 91731303, 31771388, 31961130380 and 32041008), the UK Royal Society-Newton Advanced Fellowship (NAF\R1\191094), the Key Research Program of Frontier Sciences (QYZDJ-SSW-SYS009) and the Strategic Priority Research Program (XDB38000000) of the Chinese Academy of Sciences, and the Shanghai Municipal Science and Technology Major Project (2017SHZDZX01). O. A. Andreassen was supported by the Research Council of Norway (283798, 262656, 248980, 273291, 248828, 248778, 223273); KG Jebsen Stiftelsen, South-East Norway Health Authority, EU H2020 no. 847776. B. Melegh was supported in part by the National Scientific Research Program (NKFIH) K 138669. S. V. Faraone is supported by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602805, the European Union’s Horizon 2020 research and innovation programme under grant agreements 667302 and 728018 and NIMH grants 5R01MH101519 and U01 MH109536-01. S. I. Belangero was supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo), grant numbers: 2010/08968-6; 2014/07280-1 2011/50740-5 (including R. A. Bressan). The Singapore team (J. Lee, J. Liu, K. Sim, S. A. Chong and M. Subramanian) acknowledges the National Medical Research Council Translational and Clinical Research Flagship Programme (grant no.: NMRC/TCR/003/2008). M. Macek was supported by LM2018132, CZ.02.1.01/0.0/0.0/18_046/0015515 and IP6003 –VZFNM00064203. C. Arango has been funded by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024), co-financed by ERDF Funds from the European Commission, ‘A way of making Europe’, CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program and European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking (grant agreement no 115916, project PRISM; and grant agreement no. 777394, project AIMS-2-TRIALS), Fundación Familia Alonso and Fundación Alicia Koplowitz. E. Bramon acknowledges support from the National Institute of Health Research UK (grant NIHR200756); Mental Health Research UK John Grace QC Scholarship 2018; an ESRC collaborative award 2020; BMA Margaret Temple Fellowship 2016; Medical Research Council New Investigator Award (G0901310); MRC Centenary Award (G1100583); MRC project grant G1100583; National Institute of Health Research UK post-doctoral fellowship (PDA/02/06/016); NARSAD Young Investigator awards 2005 and 2008; Wellcome Trust Research Training Fellowship; Wellcome Trust Case Control Consortium awards (085475/B/08/Z, 085475/Z/08/Z); European Commission Horizon 2020 (747429); NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and King’s College London; and NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London (UCLH BRC - Mental Health Theme). D. Molto is funded by the European Regional Development Fund (ERDF)–Valencian Community 2014–2020, Spain. E. G. Atkinson was supported by the NIMH K01MH121659.
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- 2022
5. Age-Dependent Dysregulation of APP in Neuronal and Skin Cells from Fragile X Individuals
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Giulia Cencelli, Laura Pacini, Anastasia De Luca, Ilenia Messia, Antonietta Gentile, Yunhee Kang, Veronica Nobile, Elisabetta Tabolacci, Peng Jin, Maria Giulia Farace, and Claudia Bagni
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peptide therapy ,ADAM10 ,APP processing ,Fragile X syndrome ,SAP97 ,iPSCs ,protein synthesis ,Settore BIO/13 ,General Medicine ,Settore MED/03 - GENETICA MEDICA - Abstract
Fragile X syndrome (FXS) is the most common form of monogenic intellectual disability and autism, caused by the absence of the functional fragile X messenger ribonucleoprotein 1 (FMRP). FXS features include increased and dysregulated protein synthesis, observed in both murine and human cells. Altered processing of the amyloid precursor protein (APP), consisting of an excess of soluble APPα (sAPPα), may contribute to this molecular phenotype in mice and human fibroblasts. Here we show an age-dependent dysregulation of APP processing in fibroblasts from FXS individuals, human neural precursor cells derived from induced pluripotent stem cells (iPSCs), and forebrain organoids. Moreover, FXS fibroblasts treated with a cell-permeable peptide that decreases the generation of sAPPα show restored levels of protein synthesis. Our findings suggest the possibility of using cell-based permeable peptides as a future therapeutic approach for FXS during a defined developmental window.
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- 2023
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6. Mesoangioblasts at 20: From the embryonic aorta to the patient bed
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Giulio Cossu, Rossana Tonlorenzi, Silvia Brunelli, Maurilio Sampaolesi, Graziella Messina, Emanuele Azzoni, Sara Benedetti, Stefano Biressi, Chiara Bonfanti, Laricia Bragg, Jordi Camps, Ornella Cappellari, Marco Cassano, Fabio Ciceri, Marcello Coletta, Diego Covarello, Stefania Crippa, M. Gabriella Cusella-De Angelis, Luciana De Angelis, Arianna Dellavalle, Jordi Diaz-Manera, Daniela Galli, Francesco Galli, Cesare Gargioli, Mattia F. M. Gerli, Giorgia Giacomazzi, Beatriz G. Galvez, Hidetoshi Hoshiya, Maria Guttinger, Anna Innocenzi, M. Giulia Minasi, Laura Perani, Stefano C Previtali, Mattia Quattrocelli, Martina Ragazzi, Urmas Roostalu, Giuliana Rossi, Raffaella Scardigli, Dario Sirabella, Francesco Saverio Tedesco, Yvan Torrente, Gonzalo Ugarte, Cossu, G, Tonlorenzi, R, Brunelli, S, Sampaolesi, M, Messina, G, Azzoni, E, Benedetti, S, Biressi, S, Bonfanti, C, Bragg, L, Camps, J, Cappellari, O, Cassano, M, Ciceri, F, Coletta, M, Covarello, D, Crippa, S, Cusella-De Angelis, M, De Angelis, L, Dellavalle, A, Diaz-Manera, J, Galli, D, Galli, F, Gargioli, C, Gerli, M, Giacomazzi, G, Galvez, B, Hoshiya, H, Guttinger, M, Innocenzi, A, Minasi, M, Perani, L, Previtali, S, Quattrocelli, M, Ragazzi, M, Roostalu, U, Rossi, G, Scardigli, R, Sirabella, D, Tedesco, F, Torrente, Y, and Ugarte, G
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muscular dystrophy ,Human Biology & Physiology ,FOS: Clinical medicine ,Stem Cells ,Settore BIO/13 ,Neurosciences ,Cell Biology ,mesoderm ,muscle development ,myogenic stem cells ,pericyte ,myogenic stem cell ,Genetics ,Molecular Medicine ,Microfabrication & Bioengineering ,Function and Dysfunction of the Nervous System ,Genetics (clinical) - Abstract
In 2002 we published an article describing a population of vessel-associated progenitors that we termed mesoangioblasts (MABs). During the past decade evidence had accumulated that during muscle development and regeneration things may be more complex than a simple sequence of binary choices (e.g., dorsal vs. ventral somite). LacZ expressing fibroblasts could fuse with unlabelled myoblasts but not among themselves or with other cell types. Bone marrow derived, circulating progenitors were able to participate in muscle regeneration, though in very small percentage. Searching for the embryonic origin of these progenitors, we identified them as originating at least in part from the embryonic aorta and, at later stages, from the microvasculature of skeletal muscle. While continuing to investigate origin and fate of MABs, the fact that they could be expanded in vitro (also from human muscle) and cross the vessel wall, suggested a protocol for the cell therapy of muscular dystrophies. We tested this protocol in mice and dogs before proceeding to the first clinical trial on Duchenne Muscular Dystrophy patients that showed safety but minimal efficacy. In the last years, we have worked to overcome the problem of low engraftment and tried to understand their role as auxiliary myogenic progenitors during development and regeneration. ispartof: FRONTIERS IN GENETICS vol:13 ispartof: location:Switzerland status: published
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- 2023
7. Glioblastoma stem cells express non-canonical proteins and exclusive mesenchymal-like or non-mesenchymal-like protein signatures
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Haris Babačić, Silvia Galardi, Husen M. Umer, Deborah Cardinali, Serena Pellegatta, Mats Hellström, Lene Uhrbom, Nagaprathyusha Maturi, Alessandro Michienzi, Gianluca Trevisi, Annunziato Mangiola, Janne Lehtiö, Silvia Anna Ciafrè, and Maria Pernemalm
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endocrine system ,Cancer och onkologi ,Cancer Research ,glioblastoma stem cells ,Cell- och molekylärbiologi ,fungi ,Settore BIO/13 ,mesenchymal ,proneural ,proteogenomics ,proteomics ,signature ,General Medicine ,Oncology ,Cancer and Oncology ,Genetics ,Molecular Medicine ,Cell and Molecular Biology - Abstract
Glioblastoma’s (GBM) origin, recurrence and resistance to treatment are driven by GBM cancer stem cells (GSCs). Existing transcriptomic characterisations of GBM classify the tumours to three subtypes: classical, proneural, and mesenchymal. The comprehension of how expression patterns of the GBM subtypes are reflected at global proteome level in GSCs is limited.To characterise protein expression in GSCs, we performed in-depth proteogenomic analysis of patient-derived GSCs by RNA-sequencing and mass-spectrometry proteomics. We identified and quantified over 10,000 proteins in two independent GSCs panels, and propose a GSC-associated proteomic signature (GSAPS) that defines two distinct morphological conditions; one defined by a set of proteins expressed in non-mesenchymal - proneural and classical - GSCs (GPC-like), and another expressed in mesenchymal GSCs (GM-like). The expression of GM-like protein set in GBM tissue was associated with hypoxia, necrosis, recurrence, and worse overall survival in GBM patients.In a proof-of-concept proteogenomic approach, we discovered 252 non-canonical peptides expressed in GSCs, i.e., protein sequences that are variant or derive from genome regions previously considered protein-non-coding. We report new variants of the heterogeneous ribonucleoproteins (HNRNPs), which are implicated in mRNA splicing. Furthermore, we show that per-gene mRNA-protein correlations in GSCs are moderate and vary compared to GBM tissue.
- Published
- 2022
8. In vivo restoration of dystrophin expression in mdx mice using intra-muscular and intra-arterial injections of hydrogel microsphere carriers of exon skipping antisense oligonucleotides
- Author
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Shani Attias Cohen, Orit Bar-Am, Claudia Fuoco, Galit Saar, Cesare Gargioli, and Dror Seliktar
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Cancer Research ,Polymers ,Immunology ,Settore BIO/13 ,Hydrogels ,Exons ,Cell Biology ,Oligonucleotides, Antisense ,Microspheres ,Dystrophin ,Mice ,Cellular and Molecular Neuroscience ,Injections, Intra-Arterial ,Mice, Inbred mdx ,Animals - Abstract
Duchenne muscular dystrophy (DMD) is a genetic disease caused by a mutation in the X-linked Dytrophin gene preventing the expression of the functional protein. Exon skipping therapy using antisense oligonucleotides (AONs) is a promising therapeutic strategy for DMD. While benefits of AON therapy have been demonstrated, some challenges remain before this strategy can be applied more comprehensively to DMD patients. These include instability of AONs due to low nuclease resistance and poor tissue uptake. Delivery systems have been examined to improve the availability and stability of oligonucleotide drugs, including polymeric carriers. Previously, we showed the potential of a hydrogel-based polymeric carrier in the form of injectable PEG-fibrinogen (PF) microspheres for delivery of chemically modified 2′-O-methyl phosphorothioate (2OMePs) AONs. The PF microspheres proved to be cytocompatible and provided sustained release of the AONs for several weeks, causing increased cellular uptake in mdx dystrophic mouse cells. Here, we further investigated this delivery strategy by examining in vivo efficacy of this approach. The 2OMePS/PEI polyplexes loaded in PF microspheres were delivered by intramuscular (IM) or intra-femoral (IF) injections. We examined the carrier biodegradation profiles, AON uptake efficiency, dystrophin restoration, and muscle histopathology. Both administration routes enhanced dystrophin restoration and improved the histopathology of the mdx mice muscles. The IF administration of the microspheres improved the efficacy of the 2OMePS AONs over the IM administration. This was demonstrated by a higher exon skipping percentage and a smaller percentage of centered nucleus fibers (CNF) found in H&E-stained muscles. The restoration of dystrophin expression found for both IM and IF treatments revealed a reduced dystrophic phenotype of the treated muscles. The study concludes that injectable PF microspheres can be used as a carrier system to improve the overall therapeutic outcomes of exon skipping-based therapy for treating DMD.
- Published
- 2022
9. Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity
- Author
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Adam C. O’Neill, Fatma Uzbas, Giulia Antognolli, Florencia Merino, Kalina Draganova, Alex Jäck, Sirui Zhang, Giorgia Pedini, Julia P. Schessner, Kimberly Cramer, Aloys Schepers, Fabian Metzger, Miriam Esgleas, Pawel Smialowski, Renzo Guerrini, Sven Falk, Regina Feederle, Saskia Freytag, Zefeng Wang, Melanie Bahlo, Ralf Jungmann, Claudia Bagni, Georg H. H. Borner, Stephen P. Robertson, Stefanie M. Hauck, and Magdalena Götz
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Centrosome ,Neurons ,Multidisciplinary ,Proteome ,Neurogenesis ,Induced Pluripotent Stem Cells ,Settore BIO/13 ,Brain ,Microtubules ,Alternative Splicing ,Mice ,Neural Stem Cells ,Periventricular Nodular Heterotopia ,Animals ,Humans ,Protein Interaction Maps ,RNA Splicing Factors ,Transcription Factors - Abstract
The centrosome provides an intracellular anchor for the cytoskeleton, regulating cell division, cell migration, and cilia formation. We used spatial proteomics to elucidate protein interaction networks at the centrosome of human induced pluripotent stem cell–derived neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell type–specific, with protein hubs involved in RNA dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant pre-mRNA-processing factor 6 (PRPF6) reproduced the periventricular misplacement in the developing mouse brain, highlighting missplicing of transcripts of a microtubule-associated kinase with centrosomal location as essential for the phenotype. Collectively, cell type–specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes.
- Published
- 2022
10. Epigenetic switch controls social actions
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Giorgia Pedini and Claudia Bagni
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Epigenomics ,Autism Spectrum Disorder ,General Neuroscience ,Settore BIO/13 ,Mutation ,Humans ,Epigenesis, Genetic - Abstract
Mutations in epigenetic factors are associated with autism spectrum disorder (ASD). In this issue of Neuron, Yan et al. (2022) show that the antagonism of ASH1L and PRC2 switches the equilibrium of histone methylation at the ephrin receptor A7 locus, causing decreased EphA7 expression, deficits in synaptic pruning, and ASD-like behaviors.
- Published
- 2022
11. Cardiac Regeneration: the Heart of the Issue
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Vittorio Manzari, Paolo Di Nardo, and Felicia Carotenuto
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Current cell ,medicine.medical_treatment ,Immunology ,Biomaterial-based technologies ,030204 cardiovascular system & hematology ,Cardiac regeneration ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Myocardial infarction ,Settore MED/50 ,Intensive care medicine ,Cardiac infarction ,Heart transplantation ,3D bioprinting ,Transplantation ,Hepatology ,Myocardial tissue ,business.industry ,Settore BIO/13 ,Cardiac cell therapy ,medicine.disease ,Settore MED/46 ,030104 developmental biology ,Nephrology ,Cardiac repair ,Surgery ,business ,Ex vivo - Abstract
Purpose of Review The regenerative capacity of the heart is insufficient to compensate for the pathological loss of cardiomyocytes during a large injury, such as a myocardial infarction. Therapeutic options for patients after cardiac infarction are limited: treatment with drugs that only treat the symptoms or extraordinary measures, such as heart transplantation. Cell therapies offer a promising strategy for cardiac regeneration. In this brief review, the major issues in these areas are discussed, and possible directions for future research are indicated. Recent Findings Cardiac regeneration can be obtained by at least two strategies: the first is direct to generate an ex vivo functional myocardial tissue that replaces damaged tissue; the second approach aims to stimulate endogenous mechanisms of cardiac repair. However, current cell therapies are still hampered by poor translation into actual clinical applications. Summary In this scenario, recent advancements in cell biology and biomaterial-based technologies can play a key role to design effective therapeutic approaches.
- Published
- 2021
12. A white paper on a neurodevelopmental framework for drug discovery in autism and other neurodevelopmental disorders
- Author
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Anett Kaale, Tony Charman, Covadonga M. Díaz-Caneja, Claudia Bagni, Matthew W. State, Stefan Leucht, Declan G. Murphy, F. de Andres-Trelles, Spyridon Siafis, Jan K. Buitelaar, Oscar Marín, Emily Simonoff, C. Arango, Daniel Umbricht, J Cusak, Randi J Hagerman, Gahan Pandina, M. Parellada, Sébastien Jacquemont, Eva Loth, P P Wang, and Baltazar Gomez-Mancilla
- Subjects
Autism ,Psychological intervention ,03 medical and health sciences ,0302 clinical medicine ,White paper ,Clinical trials ,Multidisciplinary approach ,130 000 Cognitive Neurology & Memory ,medicine ,Genetics ,Humans ,Pharmacology (medical) ,Autistic Disorder ,Child ,Biological Psychiatry ,Pharmacology ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Drug discovery ,Neurodevelopmental disorders ,Settore BIO/13 ,medicine.disease ,030227 psychiatry ,ddc ,Clinical trial ,Neuropsychopharmacology ,Psychiatry and Mental health ,Neurology ,Drug development ,Engineering ethics ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
Contains fulltext : 235396.pdf (Publisher’s version ) (Open Access) In the last decade there has been a revolution in terms of genetic findings in neurodevelopmental disorders (NDDs), with many discoveries critical for understanding their aetiology and pathophysiology. Clinical trials in single-gene disorders such as fragile X syndrome highlight the challenges of investigating new drug targets in NDDs. Incorporating a developmental perspective into the process of drug development for NDDs could help to overcome some of the current difficulties in identifying and testing new treatments. This paper provides a summary of the proceedings of the 'New Frontiers Meeting' on neurodevelopmental disorders organised by the European College of Neuropsychopharmacology in conjunction with the Innovative Medicines Initiative-sponsored AIMS-2-TRIALS consortium. It brought together experts in developmental genetics, autism, NDDs, and clinical trials from academia and industry, regulators, patient and family associations, and other stakeholders. The meeting sought to provide a platform for focused communication on scientific insights, challenges, and methodologies that might be applicable to the development of CNS treatments from a neurodevelopmental perspective. Multidisciplinary translational consortia to develop basic and clinical research in parallel could be pivotal to advance knowledge in the field. Although implementation of clinical trials for NDDs in paediatric populations is widely acknowledged as essential, safety concerns should guide each aspect of their design. Industry and academia should join forces to improve knowledge of the biology of brain development, identify the optimal timing of interventions, and translate these findings into new drugs, allowing for the needs of users and families, with support from regulatory agencies.
- Published
- 2021
13. Safe-Shields: Basal and Anti-UV Protection of Human Keratinocytes by Redox-Active Cerium Oxide Nanoparticles Prevents UVB-Induced Mutagenesis
- Author
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Francesca Corsi, Erika Di Meo, Daniela Lulli, Greta Deidda Tarquini, Francesco Capradossi, Emanuele Bruni, Andrea Pelliccia, Enrico Traversa, Elena Dellambra, Cristina Maria Failla, and Lina Ghibelli
- Subjects
keratinocytes ,Physiology ,Settore BIO/13 ,Clinical Biochemistry ,cerium oxide nanoparticles ,Cell Biology ,Biochemistry ,UV exposure ,SOD and catalase mimetic ,DNA damage ,mutagenesis ,UV protection ,Molecular Biology - Abstract
Cerium oxide nanoparticles (nanoceria), biocompatible multifunctional nanozymes exerting unique biomimetic activities, mimic superoxide-dismutase and catalase through a self-regenerating, energy-free redox cycle driven by Ce3+/4+ valence switch. Additional redox-independent UV-filter properties render nanoceria ideal multitask solar screens, shielding from UV exposure, simultaneously protecting tissues from UV-oxidative damage. Here, we report that nanoceria favour basal proliferation of primary normal keratinocytes, and protects them from UVB-induced DNA damage, mutagenesis, and apoptosis, minimizing cell loss and accelerating recovery with flawless cells. Similar cell-protective effects were found on irradiated noncancerous, but immortalized, p53-null HaCaT keratinocytes, with the notable exception that here, nanoceria do not accelerate basal HaCaT proliferation. Notably, nanoceria protect HaCaT from oxidative stress induced by irradiated titanium dioxide nanoparticles, a major active principle of commercial UV-shielding lotions, thus neutralizing their most critical side effects. The intriguing combination of nanoceria multiple beneficial properties opens the way for smart and safer containment measures of UV-induced skin damage and carcinogenesis.
- Published
- 2023
14. A novel extrusion-based 3D bioprinting system for skeletal muscle tissue engineering
- Author
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E Fornetti, F De Paolis, C Fuoco, S Bernardini, S M Giannitelli, A Rainer, D Seliktar, F Magdinier, J Baldi, R Biagini, S Cannata, S Testa, C Gargioli, Università degli Studi di Roma Tor Vergata [Roma], Università Campus Bio-Medico di Roma / University Campus Bio-Medico of Rome ( UCBM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and PRIN 2017: 201742SBXA_004 founded by Italian Ministry of University and Research to Cesare Gargioli.
- Subjects
Biomaterials ,3D bioprinting ,[SDV.BIO]Life Sciences [q-bio]/Biotechnology ,Settore BIO/13 ,Biomedical Engineering ,VML ,muscle reconstruction ,Bioengineering ,PEG-fibrinogen ,General Medicine ,skeletal muscle tissue engineering ,Biochemistry ,Biotechnology - Abstract
Three-dimensional (3D) bioprinting is an emerging technology, which turned out to be an optimal tool for tissue engineering approaches. To date, different printing systems have been developed. Among them, the extrusion-based approach demonstrated to be the most suitable for skeletal muscle tissue engineering, due to its ability to produce and deposit printing fibers in a parallel pattern that well mimic the native skeletal muscle tissue architecture. In tissue bioengineering, a key role is played by biomaterials, which must possess the key requisite of ‘printability’. Nevertheless, this feature is not often well correlated with cell requirements, such as motives for cellular adhesion and/or absorbability. To overcome this hurdle, several efforts have been made to obtain an effective bioink by combining two different biomaterials in order to reach a good printability besides a suitable biological activity. However, despite being efficient, this strategy reveals several outcomes limitations. We report here the development and characterization of a novel extrusion-based 3D bioprinting system, and its application for correction of volumetric muscle loss (VML) injury in a mouse model. The developed bioprinting system is based on the use of PEG-Fibrinogen, a unique biomaterial with excellent biocompatibility, well-suited for skeletal muscle tissue engineering. With this approach, we obtained highly organized 3D constructs, in which murine muscle progenitors were able to differentiate into muscle fibers arranged in aligned bundles and capable of spontaneously contracting when cultured in vitro. Furthermore, to evaluate the potential of the developed system in future regenerative medicine applications, bioprinted constructs laden with either murine or human muscle progenitors were transplanted to regenerate the Tibialis Anterior muscle of a VML murine model, one month after grafting.
- Published
- 2023
15. Androgen Deprivation Freezes Hormone-Sensitive Prostate Cancer Cells in a Reversible, Genetically Unstable Quasi-Apoptotic State, Bursting into Full Apoptosis upon Poly(ADP-ribose) Polymerase Inhibition
- Author
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Andrea Pelliccia, Francesco Capradossi, Francesca Corsi, Greta Deidda Tarquini, Emanuele Bruni, Albrecht Reichle, Francesco Torino, and Lina Ghibelli
- Subjects
hormone-sensitive prostate cancer ,Settore BIO/13 ,Organic Chemistry ,apoptosis ,androgen deprivation therapy ,General Medicine ,Catalysis ,PARP ,Computer Science Applications ,Inorganic Chemistry ,quasi-apoptotic state ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy - Abstract
Androgen deprivation therapy (ADT) is a powerful treatment for metastatic hormone-sensitive prostate cancer (mHSPC) patients, but eventually and inevitably, cancer relapses, progressing to the fatal castration-resistant (CR)PC stage. Progression implies the emergence of cells proliferating in the absence of androgen through still elusive mechanisms. We show here for the first time that ADT induces LNCaP mHSPC cells to collectively enter a metastable quasi-apoptotic state (QUAPS) consisting of partial mitochondrial permeabilization, limited BAX and caspase activation, and moderate induction of caspase-dependent dsDNA breaks; despite this, cells maintain full viability. QUAPS is destabilized by poly(ADP)-polymerase inhibition (PARPi), breaking off toward overt intrinsic apoptosis and culture extinction. Instead, QUAPS is rapidly and efficiently reverted upon androgen restoration, with mitochondria rapidly recovering integrity and cells collectively resuming normal proliferation. Notably, replication restarts before DNA repair is completed, and implies an increased micronuclei frequency, indicating that ADT promotes genetic instability. The recovered cells re-acquire insensitivity to PARPi (as untreated LNCaP), pointing to specific, context-dependent vulnerability of mHSPC cells to PARPi during ADT. Summarizing, QUAPS is an unstable, pro-mutagenic state developing as a pro-survival pathway stabilized by PARP, and constitutes a novel viewpoint explaining how ADT-treated mHSPC may progress to CRPC, indicating possible preventive countermeasures.
- Published
- 2023
16. Long Noncoding RNAs and Cancer Stem Cells: Dangerous Liaisons Managing Cancer
- Author
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Silvia Anna Ciafrè, Monia Russo, Alessandro Michienzi, and Silvia Galardi
- Subjects
cancer stem cells ,ceRNAs ,RNA-binding protein ,Settore BIO/13 ,Organic Chemistry ,lncRNAs ,General Medicine ,epigenetic regulation ,Catalysis ,Computer Science Applications ,Inorganic Chemistry ,Physical and Theoretical Chemistry ,Molecular Biology ,Spectroscopy - Abstract
Decades of research have investigated the mechanisms that lead to the origin of cancer, striving to identify tumor-initiating cells. These cells, also known as cancer stem cells, are characterized by the ability to self-renew, to give rise to differentiated tumor populations, and on a larger scale, are deemed responsible not only for tumor initiation but also for recurrent tumors, often resistant to chemotherapy and radiotherapy. Long noncoding RNAs are RNA molecules longer than 200 nt, lacking the ability to code for proteins, with recognized roles as fine regulators of gene expression. They can exert these functions through a variety of mechanisms, acting at almost all steps of gene expression, from modulation of the epigenetic state of chromatin to modulation of protein stability. In all cases, lncRNAs do not work alone, but they always interact with other RNA molecules, either coding or non-coding, or with protein factors. In this review, we summarize the latest results obtained about the involvement of lncRNAs in the initiating cells of several types of tumors, and highlight the different mechanisms through which they work, while discussing how the modulation of a lncRNA can affect several aspects of tumor onset and progression.
- Published
- 2023
17. Dystrophic Muscle Affects Motoneuron Axon Outgrowth and NMJ Assembly
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Ersilia Fornetti, Stefano Testa, Francesca De Paolis, Claudia Fuoco, Sergio Bernardini, Victorio Pozo Devoto, Gorazd Bernard Stokin, Sara Maria Giannitelli, Alberto Rainer, Anne Bigot, Carmine Zoccali, Jacopo Baldi, Doriana Sandonà, Roberto Rizzi, Claudia Bearzi, Giancarlo Forte, Stefano Cannata, and Cesare Gargioli
- Subjects
Mechanics of Materials ,Settore BIO/13 ,microfluidic ,NMJ modeling ,General Materials Science ,organ on a chip ,muscle dystrophy ,neural muscular junction ,Industrial and Manufacturing Engineering - Published
- 2022
18. FMRP modulates the Wnt signalling pathway in glioblastoma
- Author
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Giorgia Pedini, Mariachiara Buccarelli, Fabrizio Bianchi, Laura Pacini, Giulia Cencelli, Quintino Giorgio D’Alessandris, Maurizio Martini, Stefano Giannetti, Franceschina Sasso, Valentina Melocchi, Maria Giulia Farace, Tilmann Achsel, Luigi M. Larocca, Lucia Ricci-Vitiani, Roberto Pallini, and Claudia Bagni
- Subjects
Cancer Research ,Tumor ,Brain Neoplasms ,Settore BIO/13 ,Immunology ,Settore MED/27 - NEUROCHIRURGIA ,Cell Biology ,Cell Line ,Cellular and Molecular Neuroscience ,Fragile X Mental Retardation Protein ,Mice ,Ribonucleoproteins ,Cell Line, Tumor ,Neoplastic Stem Cells ,Animals ,Humans ,Glioblastoma ,Wnt Signaling Pathway ,beta Catenin - Abstract
Converging evidence indicates that the Fragile X Messenger Ribonucleoprotein (FMRP), which absent or mutated in Fragile X Syndrome (FXS), plays a role in many types of cancers. However, while FMRP roles in brain development and function have been extensively studied, its involvement in the biology of brain tumors remains largely unexplored. Here we show, in human glioblastoma (GBM) biopsies, that increased expression of FMRP directly correlates with a worse patient outcome. In contrast, reductions in FMRP correlate with a diminished tumor growth and proliferation of human GBM stem-like cells (GSCs) in vitro in a cell culture model and in vivo in mouse brain GSC xenografts. Consistently, increased FMRP levels promote GSC proliferation. To characterize the mechanism(s) by which FMRP regulates GSC proliferation, we performed GSC transcriptome analyses in GSCs expressing high levels of FMRP, and in these GSCs after knockdown of FMRP. We show that the WNT signalling is the most significantly enriched among the published FMRP target genes and genes involved in ASD. Consistently, we find that reductions in FMRP downregulate both the canonical WNT/β-Catenin and the non-canonical WNT-ERK1/2 signalling pathways, reducing the stability of several key transcription factors (i.e. β-Catenin, CREB and ETS1) previously implicated in the modulation of malignant features of glioma cells. Our findings support a key role for FMRP in GBM cancer progression, acting via regulation of WNT signalling.
- Published
- 2022
19. Single-walled carbon nanotubes protect photosynthetic reactions in Chlamydomonas reinhardtii against photoinhibition
- Author
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Taras K. Antal, Alena A. Volgusheva, Galina P. Kukarskikh, Evgeniy P. Lukashev, Alexander A. Bulychev, Andrea Margonelli, Silvia Orlanducci, Gabriella Leo, Luciana Cerri, Esa Tyystjärvi, and Maya D. Lambreva
- Subjects
Settore BIO/07 ,Physiology ,Photoprotection ,Photoinhibition ,Settore BIO/13 ,Genetics ,Carbon nanotubes ,Microalgae ,Non-photochemical quenching ,Plant Science ,Settore CHIM/03 ,Photosystem II - Abstract
Single-walled carbon nanotubes (SWCNTs) are among the most exploited carbon allotropes in nanosensing, bioengineering, and photobiological applications, however, the interactions of nanotubes with the photosynthetic process and structures are still poorly understood. We found that SWCNTs are not toxic to the photosynthetic apparatus of the model unicellular alga Chlamydomonas reinhardtii and demonstrate that this carbon nanomaterial can protect algal photosynthesis against photoinhibition. The results show that the inherent phytotoxicity of the nanotubes may be overcome by an intentional selection of nanomaterial characteristics. A low concentration (2 μg mL
- Published
- 2022
20. Comparison of Four Different Preparation Methods for Making Injectable Microgels for Tissue Engineering and Cell Therapy
- Author
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Raziel Hamami, Haneen Simaan-Yameen, Cesare Gargioli, and Dror Seliktar
- Subjects
Biomaterials ,Hydrogel ,Settore BIO/13 ,Biomedical Engineering ,Medicine (miscellaneous) ,Tissue engineering ,Cell Biology ,Micro-encapsulation ,Cell therapy - Published
- 2022
21. Editorial: Anakoinosis for promoting tumor tissue editing: Novel therapeutic opportunities for establishing clinically relevant tumor control by targeting tumor plasticity
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Daniel Heudobler, Lina Ghibelli, and Albrecht Reichle
- Subjects
Cancer Research ,Oncology ,homeostasis ,tumor plasticity ,Settore BIO/13 ,anakoinosis ,immunosurveillance ,differentiation ,tumor tissue editing - Published
- 2022
22. IUI and uterine lavage of in vivo–produced blastocysts for PGT purposes: is it a technically and ethically reasonable perspective? Is it actually needed?
- Author
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Daniela Zuccarello, Emanuele Licata, Catello Scarica, Danilo Cimadomo, Lucia De Santis, Laura Sosa Fernandez, Cinzia Di Pietro, Francesca Gioia Klinger, Antonio Capalbo, and Attilio Anastasi
- Subjects
0301 basic medicine ,Value (ethics) ,Opinion ,medicine.medical_specialty ,Reproductive medicine ,03 medical and health sciences ,0302 clinical medicine ,Genetics ,medicine ,Genetics (clinical) ,Genetic testing ,Ethics ,Medical education ,Settore BIO/17 ,030219 obstetrics & reproductive medicine ,Ethical issues ,medicine.diagnostic_test ,Settore BIO/13 ,Perspective (graphical) ,Obstetrics and Gynecology ,General Medicine ,Special Interest Group ,Reproductive genetics ,PGT ,Preimplantation development ,Settore MED/46 ,Blastocyst ,Uterine lavage ,030104 developmental biology ,Settore MED/03 ,Reproductive Medicine ,Psychology ,Developmental Biology - Abstract
A recent study by Munné et al. portrayed a protocol to retrieve in vivo produced blastocysts after IUI and uterine lavage for preimplantation genetic testing (PGT) purposes. The authors claimed this protocol might represent a reasonable future perspective for patients who do not want to undergo IVF, but still want to be informed about their embryos’ genetic/chromosomal defects. Although the intent of making PGT available also to patients who cannot or do not need to undergo IVF is respectable, the value of this study is undermined by severe technical and ethical issues. Munné and colleagues’ paper was discussed within the executive committee (i.e., president and vice-president of the society, director and vice-director of the scientific committee, secretariat, and counselors), the special interest group in reproductive genetics, the scientific committee, and the collegio dei probiviri of the Italian Society of Embryology, Reproduction and Research (SIERR). The points raised from this discussion are summarized in this opinion paper.
- Published
- 2020
23. Tackling Current Biomedical Challenges With Frontier Biofabrication and Organ-On-A-Chip Technologies
- Author
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Nehar Celikkin, Dario Presutti, Fabio Maiullari, Ersilia Fornetti, Tarun Agarwal, Alessia Paradiso, Marina Volpi, Wojciech Święszkowski, Claudia Bearzi, Andrea Barbetta, Yu Shrike Zhang, Cesare Gargioli, Roberto Rizzi, and Marco Costantini
- Subjects
Engineering ,Histology ,Research areas ,precision medicine ,Big data ,Biomedical Engineering ,regenerative medicine ,Bioengineering ,Review ,Organ-on-a-chip ,3D biofabrication ,organ-on-a-chip ,tissue engineering ,drug development ,Frontier ,Pace ,business.industry ,Settore BIO/13 ,Bioengineering and Biotechnology ,Precision medicine ,Data science ,business ,TP248.13-248.65 ,Biofabrication ,Biotechnology - Abstract
In the last decades, biomedical research has significantly boomed in the academia and industrial sectors, and it is expected to continue to grow at a rapid pace in the future. An in-depth analysis of such growth is not trivial, given the intrinsic multidisciplinary nature of biomedical research. Nevertheless, technological advances are among the main factors which have enabled such progress. In this review, we discuss the contribution of two state-of-the-art technologies–namely biofabrication and organ-on-a-chip–in a selection of biomedical research areas. We start by providing an overview of these technologies and their capacities in fabricating advancedin vitrotissue/organ models. We then analyze their impact on addressing a range of current biomedical challenges. Ultimately, we speculate about their future developments by integrating these technologies with other cutting-edge research fields such as artificial intelligence and big data analysis.
- Published
- 2021
24. Turning regenerative technologies into treatment to repair myocardial injuries
- Author
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Paolo Di Nardo, Giuseppe Orlando, Anna Maria Maccari, Felicia Carotenuto, Laura Teodori, Luciano Delbono, Carotenuto, F., Teodori, L., Maccari, A. M., Delbono, L., Orlando, G., and Di Nardo, P.
- Subjects
0301 basic medicine ,medicine.medical_specialty ,medicine.medical_treatment ,cell-biomaterial interaction ,Reviews ,Review ,Regenerative Medicine ,immunomodulation ,Cardiac regeneration ,03 medical and health sciences ,0302 clinical medicine ,Tissue engineering ,cardiac cell therapy ,Animals ,Humans ,Regeneration ,Medicine ,cell‐biomaterial interaction ,Clinical efficacy ,Settore MED/50 ,Intensive care medicine ,cardiac microenvironment ,cardiac regeneration ,tissue engineering ,Tissue Scaffolds ,business.industry ,Myocardium ,Settore BIO/13 ,Translational medicine ,Cardiac muscle ,Cell Biology ,Stem-cell therapy ,030104 developmental biology ,medicine.anatomical_structure ,Cellular Microenvironment ,030220 oncology & carcinogenesis ,Cardiac repair ,Molecular Medicine ,Stem cell ,business ,Stem Cell Transplantation - Abstract
Regenerative therapies including stem cell treatments hold promise to allow curing patients affected by severe cardiac muscle diseases. However, the clinical efficacy of stem cell therapy remains elusive, so far. The two key roadblocks that still need to be overcome are the poor cell engraftment into the injured myocardium and the limited knowledge of the ideal mixture of bioactive factors to be locally delivered for restoring heart function. Thus, therapeutic strategies for cardiac repair are directed to increase the retention and functional integration of transplanted cells in the damaged myocardium or to enhance the endogenous repair mechanisms through cell‐free therapies. In this context, biomaterial‐based technologies and tissue engineering approaches have the potential to dramatically impact cardiac translational medicine. This review intends to offer some consideration on the cell‐based and cell‐free cardiac therapies, their limitations and the possible future developments.
- Published
- 2019
25. Detection of antisense protein (ASP) RNA transcripts in individuals infected with human immunodeficiency virus type 1 (HIV-1)
- Author
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Brian T. Foley, A. Mancarella, E. de Crignis, Giampietro Corradin, Tilmann Achsel, Giuseppe Pantaleo, Francesco A. Procopio, Claudia Bagni, Cecilia Graziosi, and Biochemistry
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Gene Expression Regulation, Viral ,Male ,0301 basic medicine ,antisense transcription ,030106 microbiology ,HIV Infections ,RNA polymerase II ,antisense protein ,envelope ,Biology ,Virus Replication ,ASP ,Open Reading Frames ,Young Adult ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Transcription (biology) ,Virology ,Humans ,RNA, Antisense ,Viral ,Antisense ,Gene ,Regulation of gene expression ,Base Sequence ,Settore BIO/13 ,RNA ,Middle Aged ,Base Sequence/genetics ,CD4-Positive T-Lymphocytes/virology ,Gene Expression Regulation, Viral/genetics ,HIV Infections/virology ,HIV-1/genetics ,Open Reading Frames/genetics ,RNA, Antisense/genetics ,RNA, Viral/genetics ,Virus Replication/genetics ,HIV-1 ,antisense transcription, envelope ,Reverse transcriptase ,Antisense RNA ,Open reading frame ,030104 developmental biology ,Gene Expression Regulation ,RNA, Viral ,biology.protein - Abstract
The detection of antisense RNA is hampered by reverse transcription (RT) non-specific priming, due to the ability of RNA secondary structures to prime RT in the absence of specific primers. The detection of antisense RNA by conventional RT-PCR does not allow assessment of the polarity of the initial RNA template, causing the amplification of non-specific cDNAs. In this study we have developed a modified protocol for the detection of human immunodeficiency virus type 1 (HIV-1) antisense protein (ASP) RNA. Using this approach, we have identified ASP transcripts in CD4+ T cells isolated from five HIV-infected individuals, either untreated or under suppressive therapy. We show that ASP RNA can be detected in stimulated CD4+ T cells from both groups of patients, but not in unstimulated cells. We also show that in untreated patients, the patterns of expression of ASP and env are very similar, with the levels of ASP RNA being markedly lower than those of env. Treatment of cells from one viraemic patient with α-amanitin greatly reduces the rate of ASP RNA synthesis, suggesting that it is associated with RNA polymerase II, the central enzyme in the transcription of protein-coding genes. Our data represent the first nucleotide sequences obtained in patients for ASP, demonstrating that its transcription indeed occurs in those HIV-1 lineages in which the ASP open reading frame is present.
- Published
- 2019
26. Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies
- Author
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Ivano Condò
- Subjects
Inorganic Chemistry ,Rare Diseases ,Settore BIO/13 ,Organic Chemistry ,Humans ,General Medicine ,Physical and Theoretical Chemistry ,Settore MED/04 ,Molecular Biology ,Spectroscopy ,Catalysis ,Computer Science Applications - Abstract
A rare disease is defined by its low prevalence in the general population [...]
- Published
- 2022
27. MEOX2 Regulates the Growth and Survival of Glioblastoma Stem Cells by Modulating Genes of the Glycolytic Pathway and Response to Hypoxia
- Author
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Carla Proserpio, Silvia Galardi, Maria Giovanna Desimio, Alessandro Michienzi, Margherita Doria, Antonella Minutolo, Claudia Matteucci, and Silvia Anna Ciafrè
- Subjects
Cancer Research ,sphere formation ,MEOX2 ,glioblastoma stem cells ,Oncology ,glycolytic enzymes ,Settore BIO/13 - Abstract
The most widely accepted hypothesis for the development of glioblastoma suggests that glioblastoma stem-like cells (GSCs) are crucially involved in tumor initiation and recurrence as well as in the occurrence of chemo- and radio-resistance. Mesenchyme homeobox 2 (MEOX2) is a transcription factor overexpressed in glioblastoma, whose expression is negatively correlated with patient survival. Starting from our observation that MEOX2 expression is strongly enhanced in six GSC lines, we performed shRNA-mediated knock-down experiments in two different GSC lines and found that MEOX2 depletion resulted in the inhibition of cell growth and sphere-forming ability and an increase in apoptotic cell death. By a deep transcriptome analysis, we identified a core group of genes modulated in response to MEOX2 knock-down. Among these genes, the repressed ones are largely enriched in genes involved in the hypoxic response and glycolytic pathway, two strictly related pathways that contribute to the resistance of high-grade gliomas to therapies. An in silico study of the regulatory regions of genes differentially expressed by MEOX2 knock-down revealed that they mainly consisted of GC-rich regions enriched for Sp1 and Klf4 binding motifs, two main regulators of metabolism in glioblastoma. Our results show, for the first time, the involvement of MEOX2 in the regulation of genes of GSC metabolism, which is essential for the survival and growth of these cells.
- Published
- 2022
28. Maintenance mechanisms of circuit-integrated axons
- Author
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Claudia Bagni, Vittoria Mariano, Nuria Domínguez-Iturza, and Lukas J. Neukomm
- Subjects
0301 basic medicine ,MITOCHONDRIAL DYSFUNCTION ,ALPHA-SYNUCLEIN ,media_common.quotation_subject ,LOCAL TRANSLATION ,Biology ,03 medical and health sciences ,Animals ,Axons ,Biological Transport ,Humans ,Mitochondria ,Neurodegenerative Diseases ,Neurodevelopmental Disorders ,Neuroglia ,0302 clinical medicine ,Function (engineering) ,media_common ,Science & Technology ,Life span ,General Neuroscience ,Settore BIO/13 ,Neurosciences ,MULTIPLE-SCLEROSIS ,NERVOUS-SYSTEM ,DROSOPHILA MODEL ,BETA-ACTIN ,030104 developmental biology ,MYELIN-ASSOCIATED GLYCOPROTEIN ,Neurosciences & Neurology ,MESSENGER-RNA ,Life Sciences & Biomedicine ,WHITE-MATTER ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Adult, circuit-integrated neurons must be maintained and supported for the life span of their host. The attenuation of either maintenance or plasticity leads to impaired circuit function and ultimately to neurodegenerative disorders. Over the last few years, significant discoveries of molecular mechanisms were made that mediate the formation and maintenance of axons. Here, we highlight intrinsic and extrinsic mechanisms that ensure the health and survival of axons. We also briefly discuss examples of mutations associated with impaired axonal maintenance identified in specific neurological conditions. A better understanding of these mechanisms will therefore help to define targets for therapeutic interventions. ispartof: CURRENT OPINION IN NEUROBIOLOGY vol:53 pages:162-173 ispartof: location:England status: published
- Published
- 2018
29. Adenosine A2A receptor inhibition reduces synaptic and cognitive hippocampal alterations in Fmr1 KO mice
- Author
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Claudia Bagni, Zaira Boussadia, Antonella Borreca, Fabrizio Vincenzi, Giorgia Pedini, Katia Varani, Antonella Ferrante, Cinzia Mallozzi, Patrizia Popoli, Monica Armida, Antonella Pèzzola, Laura Pacini, and Alberto Martire
- Subjects
0301 basic medicine ,Agonist ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Adenosine ,Dendritic spine ,medicine.drug_class ,Fragile X Mental Retardation Protein ,Fragile X Syndrome ,Adenosine A2A receptor ,NO ,lcsh:RC321-571 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Receptor ,lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry ,Biological Psychiatry ,Settore BIO/13 ,Istradefylline ,FMR1 ,Psychiatry and Mental health ,030104 developmental biology ,Endocrinology ,chemistry ,Metabotropic glutamate receptor ,Excitatory postsynaptic potential ,030217 neurology & neurosurgery - Abstract
In fragile X syndrome (FXS) the lack of the fragile X mental retardation protein (FMRP) leads to exacerbated signaling through the metabotropic glutamate receptors 5 (mGlu5Rs). The adenosine A2A receptors (A2ARs), modulators of neuronal damage, could play a role in FXS. A synaptic colocalization and a strong permissive interaction between A2A and mGlu5 receptors in the hippocampus have been previously reported, suggesting that blocking A2ARs might normalize the mGlu5R-mediated effects of FXS. To study the cross-talk between A2A and mGlu5 receptors in the absence of FMRP, we performed extracellular electrophysiology experiments in hippocampal slices of Fmr1 KO mouse. The depression of field excitatory postsynaptic potential (fEPSPs) slope induced by the mGlu5R agonist CHPG was completely blocked by the A2AR antagonist ZM241385 and strongly potentiated by the A2AR agonist CGS21680, suggesting that the functional synergistic coupling between the two receptors could be increased in FXS. To verify if chronic A2AR blockade could reverse the FXS phenotypes, we treated the Fmr1 KO mice with istradefylline, an A2AR antagonist. We found that hippocampal DHPG-induced long-term depression (LTD), which is abnormally increased in FXS mice, was restored to the WT level. Furthermore, istradefylline corrected aberrant dendritic spine density, specific behavioral alterations, and overactive mTOR, TrkB, and STEP signaling in Fmr1 KO mice. Finally, we identified A2AR mRNA as a target of FMRP. Our results show that the pharmacological blockade of A2ARs partially restores some of the phenotypes of Fmr1 KO mice, both by reducing mGlu5R functioning and by acting on other A2AR-related downstream targets.
- Published
- 2021
30. Absence of RNA-binding protein FXR2P prevents prolonged phase of kainate-induced seizures
- Author
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Adrian C Lo, Denise Gastaldo, Andrea Buzzi, Muna L Hilal, Nicholas Rajan, Ludovic Telley, Michele Simonato, Tilmann Achsel, and Claudia Bagni
- Subjects
Kainic acid ,ERK signaling, FXR2P, glutamatergic synapses, kainic acid, status epilepticus, Seizures ,ERK signaling ,FXR2P ,glutamatergic synapses ,kainic acid ,status epilepticus ,Immunoprecipitation ,RNA-binding protein ,Kainate receptor ,Status epilepticus ,Biochemistry ,Hippocampus ,Article ,NO ,Transcriptome ,03 medical and health sciences ,chemistry.chemical_compound ,Glutamatergic ,Epilepsy ,Mice ,0302 clinical medicine ,Seizures ,Genetics ,medicine ,Animals ,Molecular Biology of Disease ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Kainic Acid ,Settore BIO/13 ,RNA-Binding Proteins ,Articles ,medicine.disease ,RNA Biology ,Cell biology ,Mice, Inbred C57BL ,chemistry ,medicine.symptom ,030217 neurology & neurosurgery ,Neuroscience - Abstract
Status epilepticus (SE) is a condition in which seizures are not self‐terminating and thereby pose a serious threat to the patient's life. The molecular mechanisms underlying SE are likely heterogeneous and not well understood. Here, we reveal a role for the RNA‐binding protein Fragile X‐Related Protein 2 (FXR2P) in SE. Fxr2 KO mice display reduced sensitivity specifically to kainic acid‐induced SE. Immunoprecipitation of FXR2P coupled to next‐generation sequencing of associated mRNAs shows that FXR2P targets are enriched in genes that encode glutamatergic post‐synaptic components. Of note, the FXR2P target transcriptome has a significant overlap with epilepsy and SE risk genes. In addition, Fxr2 KO mice fail to show sustained ERK1/2 phosphorylation induced by KA and present reduced burst activity in the hippocampus. Taken together, our findings show that the absence of FXR2P decreases the expression of glutamatergic proteins, and this decrease might prevent self‐sustained seizures., Loss of RNA binding protein FXR2P reduces components of glutamatergic synapses and prevents the transition of kainate‐induced seizures to the self‐sustained status epilepticus.
- Published
- 2021
31. Skeletal Muscle Subpopulation Rearrangements upon Rhabdomyosarcoma Development through Single-Cell Mass Cytometry
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Giulio Giuliani, Francesca Sacco, Claudia Fuoco, Luisa Castagnoli, Gianni Cesareni, Graziana Palmieri, Alessandro Palma, Federica Riccio, Luca Pasquini, Lucia Lisa Petrilli, Cesare Gargioli, Simone Vumbaca, and Monika Faron
- Subjects
0301 basic medicine ,mass cytometry ,Cell type ,lcsh:Medicine ,embryonal rhabdomyosarcoma ,Article ,03 medical and health sciences ,0302 clinical medicine ,CyTOF ,Embryonal rhabdomyosarcoma ,Mass cytometry ,Mesenchymal cells ,Muscle populations ,Single cell ,Skeletal muscle ,Stem cells ,Tumor heterogeneity ,stem cells ,tumor heterogeneity ,medicine ,Progenitor cell ,skeletal muscle ,Rhabdomyosarcoma ,neoplasms ,mesenchymal cells ,business.industry ,Mesenchymal stem cell ,lcsh:R ,Settore BIO/13 ,General Medicine ,medicine.disease ,muscle populations ,single cell ,030104 developmental biology ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,Stem cell ,business - Abstract
The embryonal rhabdomyosarcoma (eRMS) is a soft tissue sarcoma commonly affecting the head and neck, the extremities and the genitourinary tract. To contribute to revealing the cell types that may originate this tumor, we exploited mass cytometry, a single-cell technique that, by using heavy-metal-tagged antibodies, allows the accurate monitoring of the changes occurring in the mononuclear cell composition of skeletal muscle tissue during tumor development. To this end, we compared cell populations of healthy muscles with those from spatiotemporal-induced eRMS tumors in a mouse model (LSL-KrasG12D/+, Tp53Fl/Fl) that can be used to develop rhabdomyosarcoma by means of infection with an adenovirus vector expressing Cre (Ad-Cre) recombinase. By monitoring different time points after tumor induction, we were able to analyze tumor progression and composition, identifying fibro/adipogenic progenitors (FAPs) as the cell type that, in this model system, had a pivotal role in tumor development. In vitro studies highlighted that both FAPs and satellite cells (SCs), upon infection with the Ad-Cre, acquired the potential to develop rhabdomyosarcomas when transplanted into immunocompromised mice. However, only infected FAPs had an antigen profile that was similar to embryonal rhabdomyosarcoma cells. Overall, our analysis supports the involvement of FAPs in eRMS development.
- Published
- 2021
32. Photocurable Biopolymers for Coaxial Bioprinting
- Author
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Cesare Gargioli, Alberto Rainer, Marco Costantini, Dror Seliktar, Andrea Barbetta, and Wojciech Swieszkowski
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Coaxial bioprinting Photocurable polymers Alginate Bioink formulation ,0303 health sciences ,3D bioprinting ,Materials science ,Settore BIO/13 ,Nanotechnology ,02 engineering and technology ,021001 nanoscience & nanotechnology ,Methacrylate ,Regenerative medicine ,Gelatin methacrylate ,law.invention ,03 medical and health sciences ,Tissue engineering ,law ,Coaxial ,0210 nano-technology ,030304 developmental biology - Abstract
Thanks to their unique advantages, additive manufacturing technologies are revolutionizing almost all sectors of the industrial and academic worlds, including tissue engineering and regenerative medicine. In particular, 3D bioprinting is rapidly emerging as a first-choice approach for the fabrication-in one step-of advanced cell-laden hydrogel constructs to be used for in vitro and in vivo studies. This technique consists in the precise deposition layer-by-layer of sub-millimetric hydrogel strands in which living cells are embedded. A key factor of this process consists in the proper formulation of the hydrogel precursor solution, the so-called bioink. Ideal bioinks should be able, on the one side, to support cell growth and differentiation and, on the other, to allow the high-resolution deposition of cell-laden hydrogel strands. The latter feature requires the extruded solution to instantaneously undergo a sol-gel transition to avoid its collapse after deposition.To address this challenge, researchers are recently focusing their attention on the synthesis of several derivatives of natural biopolymers to enhance their printability. Here, we present an approach for the synthesis of photocurable derivatives of natural biopolymers-namely, gelatin methacrylate, hyaluronic acid methacrylate, chondroitin sulfate methacrylate, and PEGylated fibrinogen-that can be used to formulate tailored innovative bioinks for coaxial-based 3D bioprinting applications.
- Published
- 2021
33. Biofabricating murine and human myo-substitutes for rapid volumetric muscle loss restoration
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Ersilia Fornetti, Cesare Gargioli, Shoji Takeuchi, Wojciech Święszkowski, Stefano Testa, Jacopo Baldi, Libero Vitiello, Piotr Garstecki, Bert Blaauw, Marco Costantini, Stefano Cannata, Luisa Castagnoli, Roberto Biagini, Minghao Nie, Gianni Cesareni, Carles Sánchez Riera, Claudia Fuoco, Carmine Zoccali, Dror Seliktar, Sergio Bernardini, and Alberto Rainer
- Subjects
0301 basic medicine ,Medicine (General) ,muscle ,Cellular differentiation ,Methods & Resources ,QH426-470 ,Biology ,Muscle mass ,Article ,03 medical and health sciences ,Mice ,R5-920 ,0302 clinical medicine ,Tissue engineering ,Muscular Diseases ,In vivo ,stem cells ,Genetics ,medicine ,Animals ,Humans ,skeletal muscle ,Muscle, Skeletal ,Musculoskeletal System ,bioprinting ,tissue engineering ,VML ,animals ,cell differentiation ,humans ,mice ,skeletal ,muscular diseases ,Muscle loss ,Tissue Engineering ,Settore BIO/13 ,Skeletal muscle ,Cell Differentiation ,Articles ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Molecular Medicine ,Stem cell ,030217 neurology & neurosurgery ,Biofabrication - Abstract
The importance of skeletal muscle tissue is undoubted being the controller of several vital functions including respiration and all voluntary locomotion activities. However, its regenerative capability is limited and significant tissue loss often leads to a chronic pathologic condition known as volumetric muscle loss. Here, we propose a biofabrication approach to rapidly restore skeletal muscle mass, 3D histoarchitecture, and functionality. By recapitulating muscle anisotropic organization at the microscale level, we demonstrate to efficiently guide cell differentiation and myobundle formation both in vitro and in vivo. Of note, upon implantation, the biofabricated myo‐substitutes support the formation of new blood vessels and neuromuscular junctions—pivotal aspects for cell survival and muscle contractile functionalities—together with an advanced muscle mass and force recovery. Altogether, these data represent a solid base for further testing the myo‐substitutes in large animal size and a promising platform to be eventually translated into clinical scenarios., The regenerative capability of skeletal muscle tissue is limited and significant tissue loss often leads to a chronic pathologic condition known as volumetric muscle loss. By exploiting the potentials of our biofabrication approach, one can manufacture advanced cell‐laden myo‐substitutes that ultimately may restore the functionalities of severely damaged skeletal muscles in vivo.
- Published
- 2021
34. The RNA editing enzyme ADAR2 restricts L1 mobility
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Silvia Galardi, Sofian Alwardat, Loredana Frassinelli, Alessandro Michienzi, Marco Tripodi, Elisa Orecchini, Margherita Doria, Silvia Anna Ciafrè, and Carmine Mancone
- Subjects
RNA editing ,Adenosine Deaminase ,Retrotransposon ,Biology ,LINE-1 ,medicine ,ADAR2 ,Humans ,Molecular Biology ,chemistry.chemical_classification ,Settore BIO/13 ,double-stranded RNA (dsRNA) ,retrotransposons ,RNA-Binding Proteins ,RNA ,Cell Biology ,Adenosine ,HEK293 Cells ,Long Interspersed Nucleotide Elements ,Enzyme ,Biochemistry ,chemistry ,HeLa Cells ,Research Article ,Research Paper ,medicine.drug - Abstract
Adenosine deaminases acting on RNA (ADARs) are enzymes that convert adenosines to inosines in double-stranded RNAs (RNA editing A-to-I). ADAR1 and ADAR2 were previously reported as HIV-1 proviral factors. The aim of this study was to investigate the composition of the ADAR2 ribonucleoprotein complex during HIV-1 expression. By using a dual-tag affinity purification procedure in cells expressing HIV-1 followed by mass spectrometry analysis, we identified 10 non-ribosomal ADAR2-interacting factors. A significant fraction of these proteins was previously found associated to the Long INterspersed Element 1 (LINE1 or L1) ribonucleoparticles and to regulate the life cycle of L1 retrotransposons. Considering that we previously demonstrated that ADAR1 is an inhibitor of LINE-1 retrotransposon activity, we investigated whether also ADAR2 played a similar function. To reach this goal, we performed specific cell culture retrotransposition assays in cells overexpressing or ablated for ADAR2. These experiments unveil a novel function of ADAR2 as suppressor of L1 retrotransposition. Furthermore, we showed that ADAR2 binds the basal L1 RNP complex. Overall, these data support the role of ADAR2 as regulator of L1 life cycle.
- Published
- 2021
35. Fragile X mental retardation protein in intrahepatic cholangiocarcinoma: regulating the cancer cell behavior plasticity at the leading edge
- Author
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Matías A. Avila, Giuseppe Perrone, Leticia Colyn, Claudia Bagni, Rocco Simone Flammia, Maite G. Fernandez-Barrena, Maria Francesconi, Laura D’Andrea, Sergio Morini, Maria Zingariello, Daniela Righi, M. Ujue Latasa, Francesca Zalfa, Francesco Pantano, Giorgia Pedini, Mario Falchi, Rosa Alba Rana, and Simone Carotti
- Subjects
0301 basic medicine ,Male ,Cancer Research ,congenital, hereditary, and neonatal diseases and abnormalities ,tumor ,Cell ,Mice, Nude ,RNA-binding protein ,Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Genetics ,medicine ,Gene silencing ,Animals ,Humans ,Neoplasm Metastasis ,Molecular Biology ,cell plasticity ,Settore BIO/13 ,Cell migration ,cell line ,cortactin ,Xenograft Model Antitumor Assays ,nervous system diseases ,030104 developmental biology ,medicine.anatomical_structure ,Mechanisms of disease ,Bile Duct Neoplasms ,cholangiocarcinoma ,fragile x mental retardation protein ,030220 oncology & carcinogenesis ,Invadopodia ,Cancer cell ,Podosomes ,Cancer research ,biology.protein ,Pseudopodia ,Liver cancer ,Cortactin - Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy of the intrahepatic biliary tract with a very poor prognosis. Although some clinicopathological parameters can be prognostic factors for iCCA, the molecular prognostic markers and potential mechanisms of iCCA have not been well investigated. Here, we report that the Fragile X mental retardation protein (FMRP), a RNA binding protein functionally absent in patients with the Fragile X syndrome (FXS) and also involved in several types of cancers, is overexpressed in human iCCA and its expression is significantly increased in iCCA metastatic tissues. The silencing of FMRP in metastatic iCCA cell lines affects cell migration and invasion, suggesting a role of FMRP in iCCA progression. Moreover, we show evidence that FMRP is localized at the invasive front of human iCCA neoplastic nests and in pseudopodia and invadopodia protrusions of migrating and invading iCCA cancer cells. Here FMRP binds several mRNAs encoding key proteins involved in the formation and/or function of these protrusions. In particular, we find that FMRP binds to and regulates the expression of Cortactin, a critical regulator of invadopodia formation. Altogether, our findings suggest that FMRP could promote cell invasiveness modulating membrane plasticity and invadopodia formation at the leading edges of invading iCCA cells.
- Published
- 2021
36. The war after war: Volumetric muscle loss incidence, implication, current therapies and emerging reconstructive strategies, a comprehensive review
- Author
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Claudia Fuoco, Tommaso Sciarra, Francesco Rizzo, Cesare Gargioli, Stefano Testa, Carles Sanchez-Riera, Stefano Cannata, Ersilia Fornetti, and Mario Ciccotti
- Subjects
0301 basic medicine ,Reconstructive therapies ,medicine.medical_specialty ,QH301-705.5 ,Medicine (miscellaneous) ,Prosthesis ,Review ,Permanent disability ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,medicine ,Void volume ,Muscle injury ,Biology (General) ,Wasting ,Process (anatomy) ,Muscle loss ,business.industry ,Settore BIO/13 ,VML ,Conservative treatment ,030104 developmental biology ,medicine.anatomical_structure ,Chronic disability ,War muscle injuries ,War ,medicine.symptom ,business ,030217 neurology & neurosurgery ,Reinnervation ,Surgical ablation - Abstract
Volumetric muscle loss (VML) is the massive wasting of skeletal muscle tissue due to traumatic events or surgical ablation. This pathological condition exceeds the physiological healing process carried out by the muscle itself, which owns remarkable capacity to restore damages but only when limited in dimensions. Upon VML occurring, the affected area is severely compromised, heavily influencing the affected a person’s quality of life. Overall, this condition is often associated with chronic disability, which makes the return to duty of highly specialized professional figures (e.g., military personnel or athletes) almost impossible. The actual treatment for VML is based on surgical conservative treatment followed by physical exercise; nevertheless, the results, in terms of either lost mass and/or functionality recovery, are still poor. On the other hand, the efforts of the scientific community are focusing on reconstructive therapy aiming at muscular tissue void volume replenishment by exploiting biomimetic matrix or artificial tissue implantation. Reconstructing strategies represent a valid option to build new muscular tissue not only to recover damaged muscles, but also to better socket prosthesis in terms of anchorage surfaces and reinnervation substrates for reconstructed mass.
- Published
- 2021
37. Expression and possible roles of extracellular signal-related kinases 1-2 (ERK1-2) in mouse primordial germ cell development
- Author
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Maria Sorrenti, Serena Marcozzi, Saveria Iona, Francesca Gioia Klinger, Massimo De Felici, and Valerio Rossi
- Subjects
Male ,Cell ,Oogenesis ,Mice ,0302 clinical medicine ,Ovarian Follicle ,Cell Movement ,Gene expression ,Extracellular signal-regulated kinases (ERKs) ,Enzyme Inhibitors ,Meiotic Prophase I ,Mitogen-Activated Protein Kinase 1 ,0303 health sciences ,Microscopy, Confocal ,Mitogen-Activated Protein Kinase 3 ,030219 obstetrics & reproductive medicine ,Settore BIO/17 ,Kinase ,Cell Cycle ,Settore BIO/13 ,Days post coitum ,Cell Differentiation ,Cell biology ,Meiosis ,medicine.anatomical_structure ,embryonic structures ,Phosphorylation ,Female ,Original Article ,endocrine system ,Motility ,Mice, Transgenic ,In Vitro Techniques ,Biology ,03 medical and health sciences ,Nitriles ,Butadienes ,medicine ,Extracellular ,Animals ,Primordial germ cells ,Cell Proliferation ,DNA Primers ,030304 developmental biology ,urogenital system ,Gene Expression Profiling ,Ovary ,fungi ,Germ Cells ,Microscopy, Fluorescence ,Oocytes ,Animal Science and Zoology - Abstract
In the present work, we described the expression and activity of extracellular signal-related kinases 1-2 (ERK1-2) in mouse primordial germ cells (PGCs) from 8.5–14.5 days post coitum (dpc) and investigated whether these kinases play a role in regulating the various processes of PGC development. Using immunofluorescence and immunoblotting to detect the active phosphorylated form of ERK1-2 (p-ERK1-2), we found that the kinases were present in most proliferating 8.5–10.5 dpc PGCs, low in 11.5 dpc PGCs, and progressively increasing between 12.5–14.5 dpc both in female and male PGCs. In vitro culture experiments showed that inhibiting activation of ERK1-2 with the MEK-specific inhibitor U0126 significantly reduced the growth of 8.5 dpc PGCs in culture but had little effect on 11.5–12.5 dpc PGCs. Moreover, we found that the inhibitor did not affect the adhesion of 11.5 dpc PGCs, but it significantly reduced their motility features onto a cell monolayer. Further, while the ability of female PGCs to begin meiosis was not significantly affected by U0126, their progression through meiotic prophase I was slowed down. Notably, the activity of ERK1-2 was necessary for maintaining the correct expression of oocyte-specific genes crucial for germ cells survival and the formation of primordial follicles.
- Published
- 2020
38. Modelling Learning and Memory in Drosophila to Understand Intellectual Disabilities
- Author
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Claudia Bagni, Tilmann Achsel, Vittoria Mariano, and Alexandros K. Kanellopoulos
- Subjects
0301 basic medicine ,cognition ,Down syndrome ,Computational biology ,drosophila melanogaster ,03 medical and health sciences ,0302 clinical medicine ,Memory ,Intellectual Disability ,Intellectual disability ,medicine ,Animals ,genetics ,Drosophila ,biology ,General Neuroscience ,neurodevelopmental disorders ,Settore BIO/13 ,fungi ,Cognition ,Experimental validation ,biology.organism_classification ,medicine.disease ,030104 developmental biology ,Drosophila melanogaster ,Neurodevelopmental Disorders ,Autism ,intellectual disabilities ,learning and memory ,030217 neurology & neurosurgery ,Social behavior - Abstract
Neurodevelopmental disorders (NDDs) include a large number of conditions such as Fragile X syndrome, autism spectrum disorders and Down syndrome, among others. They are characterized by limitations in adaptive and social behaviors, as well as intellectual disability (ID). Whole-exome and whole-genome sequencing studies have highlighted a large number of NDD/ID risk genes. To dissect the genetic causes and underlying biological pathways, in vivo experimental validation of the effects of these mutations is needed. The fruit fly, Drosophila melanogaster, is an ideal model to study NDDs, with highly tractable genetics, combined with simple behavioral and circuit assays, permitting rapid medium-throughput screening of NDD/ID risk genes. Here, we review studies where the use of well-established assays to study mechanisms of learning and memory in Drosophila has permitted insights into molecular mechanisms underlying IDs. We discuss how technologies in the fly model, combined with a high degree of molecular and physiological conservation between flies and mammals, highlight the Drosophila system as an ideal model to study neurodevelopmental disorders, from genetics to behavior. ispartof: NEUROSCIENCE vol:445 pages:12-30 ispartof: location:United States status: published
- Published
- 2020
39. Injectable hydrogel microspheres for sustained gene delivery of antisense oligonucleotides to restore the expression of dystrophin protein in duchenne muscular dystrophy
- Author
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Shani Attias Cohen, Haneen Simaan-Yameen, Claudia Fuoco, Cesare Gargioli, and Dror Seliktar
- Subjects
Polymers and Plastics ,Settore BIO/13 ,Organic Chemistry ,Materials Chemistry ,General Physics and Astronomy - Published
- 2022
40. Skeletal Muscle-Derived Human Mesenchymal Stem Cells: Influence of Different Culture Conditions on Proliferative and Myogenic Capabilities
- Author
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Claudia Fuoco, Cesare Gargioli, Maria Laura Foddai, Ersilia Fornetti, Federica Riccio, Carles Sánchez Riera, Stefano Cannata, Sergio Bernardini, Jacopo Baldi, Stefano Testa, and Marco Costantini
- Subjects
0301 basic medicine ,Settore BIO/06 ,Physiology ,Myogenic contraction ,Population ,Cell ,myogenic differentiation ,Biology ,lcsh:Physiology ,03 medical and health sciences ,0302 clinical medicine ,Tissue engineering ,Physiology (medical) ,medicine ,skeletal muscle ,education ,Process (anatomy) ,030304 developmental biology ,human serum ,mesenchymal stem cells ,platelet-rich plasma ,0303 health sciences ,education.field_of_study ,lcsh:QP1-981 ,Settore BIO/13 ,Mesenchymal stem cell ,Skeletal muscle ,Brief Research Report ,3. Good health ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,Platelet-rich plasma ,Stem cell ,030217 neurology & neurosurgery - Abstract
Skeletal muscle tissue is characterized by restrained self-regenerative capabilities, being ineffective in relation to trauma extension both in time span (e.g., chronic diseases) and in size (e.g., large trauma). For these reasons, tissue engineering and/or cellular therapies represent a valuable solution in the cases where the physiological healing process failed. Satellite cells, the putative skeletal muscle stem cells, have been the first solution explored to remedy the insufficient self-regeneration capacity. Nevertheless, some limitation related to donor age, muscle condition, expansion hitch, and myogenic potentiality maintenance have limited their use as therapeutic tool. To overcome this hindrance, different stem cells population with myogenic capabilities have been investigated to evaluate their real potentiality for therapeutic approaches, but, as of today, the perfect cell candidate has not been identified yet. In this work, we analyze the characteristics of skeletal muscle-derived human Mesenchymal Stem Cells (hMSCs), showing the maintenance/increment of myogenic activity upon differential culture conditions. In particular, we investigate the influence of a commercial enriched growth medium (Cyto-Grow), and of a medium enriched with either human-derived serum (H.S.) or human Platelet-rich Plasma (PrP), in order to set up a culture protocol useful for employing this cell population in clinical therapeutic strategies. The presented results reveal that both the enriched medium (Cyto-Grow) and the human-derived supplements (H.S. and PrP) have remarkable effects on hMSCs proliferation and myogenic differentiation compared to standard condition, uncovering the real possibility to exploit these human derivatives to ameliorate stem cells yield and efficacy.
- Published
- 2020
41. miR-378-3p maintains the size of mouse primordial follicle pool by regulating cell autophagy and apoptosis
- Author
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Xiao-Feng Sun, Wei Shen, Jing Liu, Xiao-Wen Sun, Massimo De Felici, and Francesca Gioia Klinger
- Subjects
Male ,Cancer Research ,Immunology ,Cell ,Apoptosis ,Biology ,Article ,Mice ,Cellular and Molecular Neuroscience ,Ovarian Follicle ,Pregnancy ,In vivo ,Autophagy ,medicine ,Animals ,lcsh:QH573-671 ,Gene knockdown ,Settore BIO/17 ,lcsh:Cytology ,Settore BIO/13 ,Mitophagy ,Days post coitum ,Cell Biology ,In vitro ,Cell biology ,MicroRNAs ,medicine.anatomical_structure ,Infertility ,miRNAs ,Female ,Folliculogenesis - Abstract
Primordial follicle pool provides all available oocytes throughout the whole reproductive life span. Abnormal regulation in primordial follicle assembly leads to abnormal size of primordial follicle pool, even causes infertility. Here, miR-378-3p was proved to regulate mouse primordial follicle assembly both in vivo and in vitro. The expression of miR-378-3p significantly increased in mice ovaries from 17.5 dpc (days post coitum) up to 3 dpp (day post partum) compared with the expression of 16.5 dpc ovaries, which suggested that miR-378-3p was involved in primordial follicle assembly. To uncover the underlying mechanism, newborn mice ovaries were cultured in vitro in the presence of rapamycin and 3-methyladenine, which showed that the expression of miR-378-3p changed together with the percentage of primordial follicle. Moreover, during the normal process of primordial follicle assembly between 17.6 dpc and 3 dpp, autophagy is activated, while, apoptosis is inhibited. The in vivo results showed that newborn mice starved for 1.5 days showing the increased miR-378-3p, activated autophagy and inhibited apoptosis in the ovaries, had more percentage of primordial follicles. Over-expression of miR-378-3p using miR-378-3p agomir caused increased percentage of primordial follicle, increased level of autophagy, and decreased level of apoptosis. Knockdown of miR-378-3p by miR-378-3p antiagomir had the opposite results. Using pmirGLO Dual-Luciferase miRNA Target Expression system, we confirmed both PDK1 and Caspase9 were targets of miR-378-3p, which suggested that miR-378-3p activated autophagy by targeting PDK1 and inhibited apoptosis by targeting Caspase9. MiR-378-3p could be used as a biomarker of diseases caused by abnormal size of primordial follicle pool for diagnosis, prevention, or therapy.
- Published
- 2020
42. LifeTime and improving European healthcare through cell-based interceptive medicine
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Rajewsky, N., Almouzni, G., Gorski, S., Aerts, S., Amit, I., Bertero, M., Bock, C., Bredenoord, A., Cavalli, G., Chiocca, S., Clevers, H., Strooper, B., Eggert, A., Ellenberg, J., Fernández, X., Figlerowicz, M., Gasser, S., Hubner, N., Kjems, J., Knoblich, J., Krabbe, G., Lichter, P., Linnarsson, S., Marine, J., Marioni, J., Marti-Renom, M., Netea, M., Nickel, D., Nollmann, M., Novak, H., Parkinson, H., Piccolo, S., Pinheiro, I., Pombo, A., Popp, C., Reik, W., Roman-Roman, S., Rosenstiel, P., Schultze, J., Stegle, O., Tanay, A., Testa, G., Thanos, D., Theis, F., Torres-Padilla, M., Valencia, A., Vallot, C., van Oudenaarden, A., Vidal, M., Voet, T., Alberi, L., Alexander, S., Alexandrov, T., Arenas, E., Bagni, C., Balderas, R., Bandelli, A., Becher, B., Becker, M., Beerenwinkel, N., Benkirame, M., Beyer, M., Bickmore, W., Biessen, E., Blomberg, N., Blumcke, I., Bodenmiller, B., Borroni, B., Boumpas, D., Bourgeron, T., Bowers, S., Braeken, D., Brooksbank, C., Brose, N., Bruining, H., Bury, J., Caporale, N., Cattoretti, G., Chabane, N., Chneiweiss, H., Cook, S., Curatolo, P., de Jonge, M., Deplancke, B., de Witte, P., Dimmeler, S., Draganski, B., Drews, A., Dumbrava, C., Engelhardt, S., Gasser, T., Giamarellos-Bourboulis, E., Graff, C., Grün, D., Gut, I., Hansson, O., Henshall, D., Herland, A., Heutink, P., Heymans, S., Heyn, H., Huch, M., Huitinga, I., Jackowiak, P., Jongsma, K., Journot, L., Junker, J., Katz, S., Kehren, J., Kempa, S., Kirchhof, P., Klein, C., Koralewska, N., Korbel, J., Kühnemund, M., Lamond, A., Lauwers, E., Le Ber, I., Leinonen, V., Tobon, A., Lundberg, E., Lunkes, A., Maatz, H., Mann, M., Marelli, L., Matser, V., Matthews, P., Mechta-Grigoriou, F., Menon, R., Nielsen, A., Pagani, M., Pasterkamp, R., Pitkänen, A., Popescu, V., Pottier, C., Puisieux, A., Rademakers, R., Reiling, D., Reiner, O., Remondini, D., Ritchie, C., Rohrer, J., Saliba, A., Sanchez-Valle, R., Santosuosso, A., Sauter, A., Scheltema, R., Scheltens, P., Schiller, H., Schneider, A., Seibler, P., Sheehan-Rooney, K., Shields, D., Sleegers, K., Smit, A., Smith, K., Smolders, I., Synofzik, M., Tam, W., Teichmann, S., Thom, M., Turco, M., van Beusekom, H., Vandenberghe, R., den Hoecke, S., de Poel, I., van der Ven, A., van der Zee, J., van Lunzen, J., van Minnebruggen, G., Paesschen, W., van Swieten, J., van Vught, R., Verhage, M., Verstreken, P., Villa, C., Vogel, J., von Kalle, C., Walter, J., Weckhuysen, S., Weichert, W., Wood, L., Ziegler, A., Zipp, F., HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., Medical Research Council (MRC), UK DRI Ltd, TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany., Barcelona Supercomputing Center, LifeTime Community Working Groups, Cardiology, Neurology, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Human genetics, Rajewsky N., Almouzni G., Gorski S.A., Aerts S., Amit I., Bertero M.G., Bock C., Bredenoord A.L., Cavalli G., Chiocca S., Clevers H., De Strooper B., Eggert A., Ellenberg J., Fernandez X.M., Figlerowicz M., Gasser S.M., Hubner N., Kjems J., Knoblich J.A., Krabbe G., Lichter P., Linnarsson S., Marine J.-C., Marioni J.C., Marti-Renom M.A., Netea M.G., Nickel D., Nollmann M., Novak H.R., Parkinson H., Piccolo S., Pinheiro I., Pombo A., Popp C., Reik W., Roman-Roman S., Rosenstiel P., Schultze J.L., Stegle O., Tanay A., Testa G., Thanos D., Theis F.J., Torres-Padilla M.-E., Valencia A., Vallot C., van Oudenaarden A., Vidal M., Voet T., Alberi L., Alexander S., Alexandrov T., Arenas E., Bagni C., Balderas R., Bandelli A., Becher B., Becker M., Beerenwinkel N., Benkirame M., Beyer M., Bickmore W., Biessen E.E.A.L., Blomberg N., Blumcke I., Bodenmiller B., Borroni B., Boumpas D.T., Bourgeron T., Bowers S., Braeken D., Brooksbank C., Brose N., Bruining H., Bury J., Caporale N., Cattoretti G., Chabane N., Chneiweiss H., Cook S.A., Curatolo P., de Jonge M.I., Deplancke B., de Witte P., Dimmeler S., Draganski B., Drews A., Dumbrava C., Engelhardt S., Gasser T., Giamarellos-Bourboulis E.J., Graff C., Grun D., Gut I., Hansson O., Henshall D.C., Herland A., Heutink P., Heymans S.R.B., Heyn H., Huch M., Huitinga I., Jackowiak P., Jongsma K.R., Journot L., Junker J.P., Katz S., Kehren J., Kempa S., Kirchhof P., Klein C., Koralewska N., Korbel J.O., Kuhnemund M., Lamond A.I., Lauwers E., Le Ber I., Leinonen V., Tobon A.L., Lundberg E., Lunkes A., Maatz H., Mann M., Marelli L., Matser V., Matthews P.M., Mechta-Grigoriou F., Menon R., Nielsen A.F., Pagani M., Pasterkamp R.J., Pitkanen A., Popescu V., Pottier C., Puisieux A., Rademakers R., Reiling D., Reiner O., Remondini D., Ritchie C., Rohrer J.D., Saliba A.-E., Sanchez-Valle R., Santosuosso A., Sauter A., Scheltema R.A., Scheltens P., Schiller H.B., Schneider A., Seibler P., Sheehan-Rooney K., Shields D., Sleegers K., Smit A.B., Smith K.G.C., Smolders I., Synofzik M., Tam W.L., Teichmann S., Thom M., Turco M.Y., van Beusekom H.M.M., Vandenberghe R., Van den Hoecke S., Van de Poel I., van der Ven A., van der Zee J., van Lunzen J., van Minnebruggen G., Van Paesschen W., van Swieten J., van Vught R., Verhage M., Verstreken P., Villa C.E., Vogel J., von Kalle C., Walter J., Weckhuysen S., Weichert W., Wood L., Ziegler A.-G., Zipp F., Center for Neurogenomics and Cognitive Research, Functional Genomics, Rajewsky, N, Almouzni, G, Gorski, S, Aerts, S, Amit, I, Bertero, M, Bock, C, Bredenoord, A, Cavalli, G, Chiocca, S, Clevers, H, De Strooper, B, Eggert, A, Ellenberg, J, Fernández, X, Figlerowicz, M, Gasser, S, Hubner, N, Kjems, J, Knoblich, J, Krabbe, G, Lichter, P, Linnarsson, S, Marine, J, Marioni, J, Marti-Renom, M, Netea, M, Nickel, D, Nollmann, M, Novak, H, Parkinson, H, Piccolo, S, Pinheiro, I, Pombo, A, Popp, C, Reik, W, Roman-Roman, S, Rosenstiel, P, Schultze, J, Stegle, O, Tanay, A, Testa, G, Thanos, D, Theis, F, Torres-Padilla, M, Valencia, A, Vallot, C, van Oudenaarden, A, Vidal, M, Voet, T, Cattoretti, G, Alliance for Modulation in Epilepsy, Pharmaceutical and Pharmacological Sciences, Experimental Pharmacology, RS: Carim - H02 Cardiomyopathy, MUMC+: MA Med Staf Spec Cardiologie (9), and Cardiologie
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0301 basic medicine ,Male ,Artificial intelligence ,Legislation, Medical ,[SDV]Life Sciences [q-bio] ,Molecular datasets ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Cell- and Tissue-Based Therapy ,Diseases ,LifeTime Community Working Groups ,Disease ,Biomarkers ,Systems biology ,Health data ,Pharmacology, Toxicology and Pharmaceutics(all) ,0302 clinical medicine ,Conjunts de dades ,ethics [Delivery of Health Care] ,Health care ,Pathology ,Medicine ,European healthcare ,BRAIN ,Single-cell multi-omics ,GENE-EXPRESSION ,Multidisciplinary ,methods [Medicine] ,Education, Medical ,Settore BIO/13 ,Intel.ligència artificial ,3. Good health ,ALZHEIMERS-DISEASE ,Europe ,Health ,Management system ,Perspective ,Female ,ddc:500 ,Single-Cell Analysis ,Biomarkers, Diseases, Systems biology ,Complex diseases ,Informàtica::Aplicacions de la informàtica::Bioinformàtica [Àrees temàtiques de la UPC] ,medicine.medical_specialty ,General Science & Technology ,Cells ,MEDLINE ,cell-based interceptive medicine ,LifeTime Initiative ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,Clinical datasets ,Artificial Intelligence ,REVEALS ,LifeTime Community ,standards [Medicine] ,Humans ,OMICS ,RECONSTRUCTION ,Intensive care medicine ,trends [Medicine] ,trends [Delivery of Health Care] ,business.industry ,Disease progression ,standards [Delivery of Health Care] ,methods [Delivery of Health Care] ,030104 developmental biology ,lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4] ,single cell, personalized therapy, machine learning, bioinformatics, systems biology, disease, cell-based interceptive medicine ,Early Diagnosis ,Cardiovascular and Metabolic Diseases ,Human medicine ,business ,Delivery of Health Care ,030217 neurology & neurosurgery ,Cell based - Abstract
Here we describe the LifeTime Initiative, which aims to track, understand and target human cells during the onset and progression of complex diseases, and to analyse their response to therapy at single-cell resolution. This mission will be implemented through the development, integration and application of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during the progression from health to disease. The analysis of large molecular and clinical datasets will identify molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. The timely detection and interception of disease embedded in an ethical and patient-centred vision will be achieved through interactions across academia, hospitals, patient associations, health data management systems and industry. The application of this strategy to key medical challenges in cancer, neurological and neuropsychiatric disorders, and infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade., The LifeTime initiative is an ambitious, multidisciplinary programme that aims to improve healthcare by tracking individual human cells during disease processes and responses to treatment in order to develop and implement cell-based interceptive medicine in Europe.
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- 2020
43. Spatial control of nucleoporin condensation by fragile X‐related proteins
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Inès Jmel Boyer, Stephane Schmucker, Katerina Jerabkova, Hervé Moine, Alessandro Berto, Laurent Guerard, Claudia Bagni, Jean-Louis Mandel, Laura Pacini, Charlotte Kleiss, Yannick Schwab, Paolo Ronchi, Sébastien Jacquemont, Arantxa Agote-Arán, Izabela Sumara, 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 Jacques Monod (IJM (UMR_7592)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), 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 Paris Cité (UPCité), and MOINE, Herve
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Protein family ,[SDV]Life Sciences [q-bio] ,Dynein ,FXR1 ,Biology ,fmrp ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,nucleoporins ,annulate lamellae ,expression ,phase separation Subject Category Membrane & Trafficking ,medicine ,Membrane & Intracellular Transport ,Nuclear pore ,fragile X syndrome ,membrane ,Molecular Biology ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,0303 health sciences ,dynein ,General Immunology and Microbiology ,maturation ,nuclear-pore complex ,General Neuroscience ,Settore BIO/13 ,diffusion ,Articles ,medicine.disease ,phase-separation ,3. Good health ,Cell biology ,[SDV] Life Sciences [q-bio] ,Fragile X syndrome ,Cytoplasm ,transport ,Interphase ,progression ,Nucleoporin ,phase separation ,030217 neurology & neurosurgery - Abstract
Nucleoporins (Nups) build highly organized nuclear pore complexes (NPCs) at the nuclear envelope (NE). Several Nups assemble into a sieve‐like hydrogel within the central channel of the NPCs. In the cytoplasm, the soluble Nups exist, but how their assembly is restricted to the NE is currently unknown. Here, we show that fragile X‐related protein 1 (FXR1) can interact with several Nups and facilitate their localization to the NE during interphase through a microtubule‐dependent mechanism. Downregulation of FXR1 or closely related orthologs FXR2 and fragile X mental retardation protein (FMRP) leads to the accumulation of cytoplasmic Nup condensates. Likewise, models of fragile X syndrome (FXS), characterized by a loss of FMRP, accumulate Nup granules. The Nup granule‐containing cells show defects in protein export, nuclear morphology and cell cycle progression. Our results reveal an unexpected role for the FXR protein family in the spatial regulation of nucleoporin condensation., Fragile X‐related proteins and dynein inhibit ectopic phase separation of nucleoporins in the cytoplasm and facilitate their localization to the nuclear envelope during G1 phase of the cell cycle.
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- 2020
44. Editorial: Tumor Systems Biology: How to Therapeutically Redirect Dysregulated Homeostasis in Tumor Systems (i.e., Anakoinosis)
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Albrecht Reichle, Daniel Heudobler, Christopher Gerner, Pan Pantziarka, Eugenio Martinelli, Ernst Holler, Francesca Corsi, and Lina Ghibelli
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Cancer Research ,tissue homeostasis ,business.industry ,Systems biology ,Settore BIO/13 ,targeted tissue engineering ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,reverse anakoinosis ,master modifiers of tumor tissues ,biomodulatory drugs ,lcsh:RC254-282 ,Cell biology ,Editorial ,Oncology ,Medicine ,chemoprevention ,anakoinosis ,business ,Homeostasis ,Tissue homeostasis ,refractory metastatic cancer - Abstract
The abstract is available here: https://uscholar.univie.ac.at/o:1241346
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- 2020
45. Stress undermines reward-guided cognitive performance through synaptic depression in the lateral habenula
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Manuel Mameli, Mauro Congiu, Anna Tchenio, Massimo Trusel, Alvaro Nuno-Perez, Arnaud L. Lalive, Mariano Soiza-Reilly, Salvatore Lecca, Denise Gastaldo, and Claudia Bagni
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0301 basic medicine ,Male ,Decision Making ,AMPA receptor ,Neurotransmission ,Synaptic Transmission ,stress ,03 medical and health sciences ,Glutamatergic ,Mice ,0302 clinical medicine ,Cognition ,Reward ,Postsynaptic potential ,Report ,Humans ,Animals ,Effects of sleep deprivation on cognitive performance ,Receptors, AMPA ,AMPA receptors ,Habenula ,Neuronal Plasticity ,General Neuroscience ,Settore BIO/13 ,Glutamate receptor ,Mice, Inbred C57BL ,030104 developmental biology ,Excitatory postsynaptic potential ,reward-guided behaviors ,Psychology ,Neuroscience ,030217 neurology & neurosurgery ,Stress, Psychological ,lateral habenula - Abstract
Summary Weighing alternatives during reward pursuit is a vital cognitive computation that, when disrupted by stress, yields aspects of neuropsychiatric disorders. To examine the neural mechanisms underlying these phenomena, we employed a behavioral task in which mice were confronted by a reward and its omission (i.e., error). The experience of error outcomes engaged neuronal dynamics within the lateral habenula (LHb), a subcortical structure that supports appetitive behaviors and is susceptible to stress. A high incidence of errors predicted low strength of habenular excitatory synapses. Accordingly, stressful experiences increased error choices while decreasing glutamatergic neurotransmission onto LHb neurons. This synaptic adaptation required a reduction in postsynaptic AMPA receptors (AMPARs), irrespective of the anatomical source of glutamate. Bidirectional control of habenular AMPAR transmission recapitulated and averted stress-driven cognitive deficits. Thus, a subcortical synaptic mechanism vulnerable to stress underlies behavioral efficiency during cognitive performance., Graphical abstract, Highlights • A specific phase during an appetitive cognitive task engages LHb neuronal dynamics • The strength of excitatory synapses in LHb neurons predicts cognitive performance • Stress triggers cognitive impairments and disrupts LHb neuronal activity • Deficits in reward-guided behaviors require a decrease in LHb AMPAR transmission, Effective evaluation of costs and benefits is fundamental for survival and vulnerable to stress. Nuno-Perez et al. show that the strength of AMPAR transmission within the mouse lateral habenula governs the incidence of non-rewarded choices in a reward-guided task. Stress weakens habenular excitatory synapses and consequently augments non-rewarded decisions.
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- 2020
46. Insights into the regulatory role of M6a epitranscriptome in glioblastoma
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Silvia Galardi, Silvia Anna Ciafrè, and Alessandro Michienzi
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Methyltransferase ,Regulator ,ALKBH5 ,FTO ,METTL14 ,METTL3 ,N6-methyladenosine ,NSUN5 ,WTAP ,YTHDF2 ,epitranscriptome ,glioblastoma ,Biology ,medicine.disease_cause ,Catalysis ,Inorganic Chemistry ,lcsh:Chemistry ,Glioma ,Gene expression ,medicine ,Physical and Theoretical Chemistry ,Molecular Biology ,lcsh:QH301-705.5 ,Spectroscopy ,Organic Chemistry ,Settore BIO/13 ,Cancer ,General Medicine ,Methylation ,medicine.disease ,Computer Science Applications ,lcsh:Biology (General) ,lcsh:QD1-999 ,Cancer research ,Stem cell ,Carcinogenesis - Abstract
N6-methyladenosine (m6A) is one of the most widespread and abundant internal messenger RNA modifications found in eukaryotes.Emerging evidence suggests that this modification is strongly linked to the activation and inhibition of cancer pathways and is associated with prognostically significant tumour subtypes. The presentreviewdescribes the dynamic nature of m6A regulator enzymes, as methyltransferases, demethylases and m6A binding proteins, and points out thevalue of the balance among these proteins in regulating gene expression, cell metabolism and cancer development. The main focus of this review is on the roles of m6A modification in glioblastoma, the most aggressive and invariably lethal brain tumour. Although the study of m6A in glioblastoma is a young one, and papers in this field can yield divergent conclusions, the results collected so far clearly demonstrate that modulation of mRNA m6A levels impacts multiple aspects of this tumour, including growth, glioma stem cells self-renewal, and tumorigenesis, suggesting that mRNA m6A modification may serve as a promising target for glioblastoma therapy. We also present recent data about another type of epitranscriptomic modification, the methylation of cytosine at a specific site of 28S rRNA, as it was recently shown to affect the biology of glioma cells, with high potential of clinical implications.
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- 2020
47. Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits
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André Fiala, Brett S. Abrahams, J. Douglas Armstrong, August B. Smit, Colin Mclean, Young Jae Woo, Claudia Bagni, Angela Giangrande, Tilmann Achsel, Marco Spinazzi, Ka Wan Li, Ulrike Pech, Patrick Callaerts, Alexandros K. Kanellopoulos, Vittoria Mariano, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Amsterdam Neuroscience - Cellular & Molecular Mechanisms, AIMMS, Molecular and Cellular Neurobiology, and Center for Neurogenomics and Cognitive Research
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Male ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Mutant ,Mitochondrion ,mitochondrial activity ,Mitochondrial Membrane Transport Proteins ,Synaptic Transmission ,Animals, Genetically Modified ,GABA ,0302 clinical medicine ,Drosophila Proteins ,Homeostasis ,BRAIN ,gamma-Aminobutyric Acid ,ComputingMilieux_MISCELLANEOUS ,GENE-EXPRESSION ,Neurons ,0303 health sciences ,Neurodevelopmental disorders ,Settore BIO/13 ,Research Highlight ,Mitochondria ,DROSOPHILA ,Drosophila melanogaster ,Schizophrenia ,GABAergic ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,Drosophila ,COMPLEX I ,Life Sciences & Biomedicine ,FRAGILE-X ,medicine.drug ,Aralar ,Biochemistry & Molecular Biology ,social group behavior ,autism ,Biology ,Neurotransmission ,Molecular neuroscience ,General Biochemistry, Genetics and Molecular Biology ,gamma-Aminobutyric acid ,Mitochondrial Proteins ,PROTEIN COMPLEXES ,CYFIP1 ,03 medical and health sciences ,mitochondrial membrane potential ,SLC25A12 (AGC1) ,medicine ,Animals ,Humans ,ddc:610 ,Social Behavior ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Aspartic Acid ,Science & Technology ,AUTISM SPECTRUM DISORDER ,Calcium-Binding Proteins ,Transporter ,Cell Biology ,medicine.disease ,DYSFUNCTION ,schizophrenia ,Glucose ,Calcium ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Social impairment is frequently associated with mitochondrial dysfunction and altered neurotransmission. Although mitochondrial function is crucial for brain homeostasis, it remains unknown whether mitochondrial disruption contributes to social behavioral deficits. Here, we show that Drosophila mutants in the homolog of the human CYFIP1, a gene linked to autism and schizophrenia, exhibit mitochondrial hyperactivity and altered group behavior. We identify the regulation of GABA availability by mitochondrial activity as a biologically relevant mechanism and demonstrate its contribution to social behavior. Specifically, increased mitochondrial activity causes gamma aminobutyric acid (GABA) sequestration in the mitochondria, reducing GABAergic signaling and resulting in social deficits. Pharmacological and genetic manipulation of mitochondrial activity or GABA signaling corrects the observed abnormalities. We identify Aralar as the mitochondrial transporter that sequesters GABA upon increased mitochondrial activity. This study increases our understanding of how mitochondria modulate neuronal homeostasis and social behavior under physiopathological conditions. ispartof: CELL vol:180 issue:6 pages:1178-+ ispartof: location:United States status: published
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- 2020
48. Lack of PKCθ Promotes Regenerative Ability of Muscle Stem Cells in Chronic Muscle Injury
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Cesare Gargioli, Piera Fiore, Valentina Saccone, Martina Sandoná, Biliana Lozanoska-Ochser, Anna Benedetti, Luca Madaro, Pier Lorenzo Puri, Marco De Bardi, and Marina Bouché
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Male ,muscle satellite cells ,Duchenne muscular dystrophy ,Duchenne Muscular Dystrophy ,mdx ,lcsh:Chemistry ,Mice ,Fibrosis ,Settore BIO/13 - BIOLOGIA APPLICATA ,Medicine ,Receptor, Notch1 ,Wasting ,lcsh:QH301-705.5 ,Spectroscopy ,Cells, Cultured ,Protein Kinase C θ ,Stem Cells ,Settore BIO/13 ,PAX7 Transcription Factor ,Cell Differentiation ,Skeletal ,General Medicine ,musculoskeletal system ,Computer Science Applications ,Muscle ,medicine.symptom ,Stem cell ,tissues ,Signal Transduction ,musculoskeletal diseases ,medicine.medical_specialty ,Inflammation ,Cardiotoxins ,Catalysis ,Article ,Inorganic Chemistry ,Downregulation and upregulation ,Internal medicine ,Animals ,Regeneration ,Physical and Theoretical Chemistry ,Progenitor cell ,Muscle, Skeletal ,Molecular Biology ,business.industry ,Organic Chemistry ,medicine.disease ,Muscular Dystrophy, Duchenne ,Endocrinology ,lcsh:Biology (General) ,lcsh:QD1-999 ,Protein Kinase C-theta ,Mice, Inbred mdx ,PAX7 ,business ,Stem Cell Transplantation - Abstract
Duchenne muscular dystrophy (DMD) is a genetic disease characterized by muscle wasting and chronic inflammation, leading to impaired satellite cells (SCs) function and exhaustion of their regenerative capacity. We previously showed that lack of PKC&theta, in mdx mice, a mouse model of DMD, reduces muscle wasting and inflammation, and improves muscle regeneration and performance at early stages of the disease. In this study, we show that muscle regeneration is boosted, and fibrosis reduced in mdx&theta, &minus, /&minus, mice, even at advanced stages of the disease. This phenotype was associated with a higher number of Pax7 positive cells in mdx&theta, muscle compared with mdx muscle, during the progression of the disease. Moreover, the expression level of Pax7 and Notch1, the pivotal regulators of SCs self-renewal, were upregulated in SCs isolated from mdx&theta, muscle compared with mdx derived SCs. Likewise, the expression of the Notch ligands Delta1 and Jagged1 was higher in mdx&theta, muscle compared with mdx. The expression level of Delta1 and Jagged1 was also higher in PKC&theta, /- muscle compared with WT muscle following acute injury. In addition, lack of PKC&theta, prolonged the survival and sustained the differentiation of transplanted myogenic progenitors. Overall, our results suggest that lack of PKC&theta, promotes muscle repair in dystrophic mice, supporting stem cells survival and maintenance through increased Delta-Notch signaling.
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- 2020
49. Toward High‐Dimensional Single‐Cell Analysis of Graphene Oxide Biological Impact: Tracking on Immune Cells by Single‐Cell Mass Cytometry
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Claudia Fuoco, Giacomo Reina, Marco Orecchioni, Valentina Bordoni, Barbara Zavan, Hazel Lin, Lucia Gemma Delogu, Alberto Bianco, Açelya Yilmazer, Davide Bedognetti, Gianni Cesareni, Martina Zoccheddu, Immunopathologie et chimie thérapeutique (ICT), Institut de biologie moléculaire et cellulaire (IBMC), and Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
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safety ,Materials science ,Nanotechnology ,02 engineering and technology ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,010402 general chemistry ,Tracking (particle physics) ,01 natural sciences ,law.invention ,Nanomaterials ,Biomaterials ,Immune system ,biocompatibility ,Single-cell analysis ,law ,Leukocytes ,Humans ,[CHIM]Chemical Sciences ,General Materials Science ,Mass cytometry ,ComputingMilieux_MISCELLANEOUS ,Graphene ,Settore BIO/13 ,Immune cells ,General Chemistry ,021001 nanoscience & nanotechnology ,Flow Cytometry ,2D materials ,0104 chemical sciences ,Nanostructures ,Proof of concept ,CyTOF ,immune cells ,Nanoparticles ,Graphite ,Single-Cell Analysis ,0210 nano-technology ,Cytometry ,Biotechnology - Abstract
Considering the potential exposure to graphene, the most investigated nanomaterial, the assessment of the impact on human health has become an urgent need. The deep understanding of nanomaterial safety is today possible by high-throughput single-cell technologies. Single-cell mass cytometry (cytometry by time-of flight, CyTOF) shows an unparalleled ability to phenotypically and functionally profile complex cellular systems, in particular related to the immune system, as recently also proved for graphene impact. The next challenge is to track the graphene distribution at the single-cell level. Therefore, graphene oxide (GO) is functionalized with AgInS2 nanocrystals (GO-In), allowing to trace GO immune-cell interactions via the indium (115 In) channel. Indium is specifically chosen to avoid overlaps with the commercial panels (>30 immune markers). As a proof of concept, the GO-In CyTOF tracking is performed at the single-cell level on blood immune subpopulations, showing the GO interaction with monocytes and B cells, therefore guiding future immune studies. The proposed approach can be applied not only to the immune safety assessment of the multitude of graphene physical and chemical parameters, but also for graphene applications in neuroscience. Moreover, this approach can be translated to other 2D emerging materials and will likely advance the understanding of their toxicology.
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- 2020
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50. Cancer stem cells from peritumoral tissue of glioblastoma multiforme: the possible missing link between tumor development and progression
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Alessio D'Alessio, Gigliola Sica, Gabriella Proietti, Barbara Fazi, Elena Binda, Angelo L. Vescovi, Annunziato Mangiola, Laura Masuelli, Cristiana Angelucci, Gina Lama, Silvia Anna Ciafrè, Roberto Bei, Angelucci, C, D'Alessio, A, Lama, G, Binda, E, Mangiola, A, Vescovi, A, Proietti, G, Masuelli, L, Bei, R, Fazi, B, Ciafre, S, and Sica, G
- Subjects
0301 basic medicine ,Proliferation and invasiveness marker ,H19 lncRNA and miR-675-5p ,proliferation and invasiveness markers ,Population ,Glioblastoma cancer stem cell ,Biology ,glioblastoma cancer stem cells ,H19 incRNA and miR-675-5p ,peritumoral cancer stem cells ,stemness markers ,oncology ,Stem cell marker ,03 medical and health sciences ,0302 clinical medicine ,SOX2 ,Cancer stem cell ,Neurosphere ,medicine ,education ,Peritumoral cancer stem cell ,Settore MED/04 - Patologia Generale ,education.field_of_study ,Kinase ,Settore BIO/13 ,Nestin ,Stemness markers ,medicine.disease ,Stemness marker ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,Settore BIO/17 - ISTOLOGIA ,Research Paper ,Glioblastoma - Abstract
In glioblastoma multiforme (GBM), cancer stem cells (CSCs) are thought to be responsible for gliomagenesis, resistance to treatment and recurrence. Unfortunately, the prognosis for GBM remains poor and recurrence frequently occurs in the peritumoral tissue within 2 cm from the tumor edge. In this area, a population of CSCs has been demonstrated which may recapitulate the tumor after surgical resection. In the present study, we aimed to characterize CSCs derived from both peritumoral tissue (PCSCs) and GBM (GCSCs) in order to deepen their significance in GBM development and progression. The stemness of PCSC/GCSC pairs obtained from four human GBM surgical specimens was investigated by comparing the expression of specific stem cell markers such as Nestin, Musashi-1 and SOX2. In addition, the growth rate, the ultrastructural features and the expression of other molecules such as c-Met, pMet and MAP kinases, involved in cell migration/invasion, maintenance of tumor stemness and/or resistance to treatments were evaluated. Since it has been recently demonstrated the involvement of the long non-coding RNAs (lncRNAs) in the progression of gliomas, the expression of H19 lncRNA, as well as of one of its two mature products miR-675-5p was evaluated in neurospheres. Our results show significant differences between GCSCs and PCSCs in terms of proliferation, ultrastructural peculiarities and, at a lower extent, stemness profile. These differences might be important in view of their potential role as a therapeutic target.
- Published
- 2018
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