129 results on '"Almeida LP"'
Search Results
2. LINFOMA PLASMABLÁSTICO: UMA SÉRIE DE CASOS
- Author
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Magalhães, MS, primary, Oliveira, VL, additional, Silva, MMS, additional, Almeida, LP, additional, Soares, TS, additional, Emídio, RE, additional, and Silva, NAHL, additional
- Published
- 2023
- Full Text
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3. ÚLCERA MUCOCUTÂNEA EPSTEIN-BARR POSITIVA: RELATO DE CASO
- Author
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Oliveira, VL, primary, Silva, NAHL, additional, Magalhães, MS, additional, Nogueira, FL, additional, Casas, PHFDCL, additional, Silva, MMS, additional, and Almeida, LP, additional
- Published
- 2023
- Full Text
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4. PANCREATITE AGUDA GRAVE COMO COMPLICAÇÃO APÓS USO DE PEG-ASPARAGINASE NO TRATAMENTO DA LLA-B
- Author
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Silva, MMS, Almeida, LP, Sousa, MJA, Silva, ML, Ramos, IG, Emídio, RE, Nogueira, FL, Vendramini, JL, and Silva, NAHL
- Published
- 2024
- Full Text
- View/download PDF
5. RELATO DE CASO DE SÍNDROME DE SWEET NA LEUCEMIA AGUDA: DESAFIOS NO DIAGNÓSTICO E TRATAMENTO
- Author
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Soares, TS, Silva, ML, Nogueira, FL, Silva, NAHL, Sousa, MJA, Almeida, LP, Silva, MMS, Kroger, EMS, Emídio, RE, and Vendramini, JL
- Published
- 2024
- Full Text
- View/download PDF
6. NEUROTOXOPLASMOSE EM PACIENTE COM LINFOMA PLASMABLÁSTICO ASSOCIADO AO VÍRUS DA IMUNMODEFICIÊNCIA HUMANA (HIV) E POSSÍVEL INFILTRAÇÃO DE SISTEMA NERVOSO CENTRAL (SNC): RELATO DE CASO
- Author
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Almeida, LP, Silva, MMS, Silva, NAHL, Sousa, MJA, Silva, ML, Casas, PHFDCL, Nunes, MB, Nogueira, FL, Soares, TS, and Nascimento, JMTPD
- Published
- 2024
- Full Text
- View/download PDF
7. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
- Author
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Klionsky, DJ, Abdel-Aziz, AK, Abdelfatah, S, Abdellatif, M, Abdoli, A, Abel, S, Abeliovich, H, Abildgaard, MH, Abudu, YP, Acevedo-Arozena, A, Adamopoulos, IE, Adeli, K, Adolph, TE, Adornetto, A, Aflaki, E, Agam, G, Agarwal, A, Aggarwal, BB, Agnello, M, Agostinis, P, Agrewala, JN, Agrotis, A, Aguilar, PV, Ahmad, ST, Ahmed, ZM, Ahumada-Castro, U, Aits, S, Aizawa, S, Akkoc, Y, Akoumianaki, T, Akpinar, HA, Al-Abd, AM, Al-Akra, L, Al-Gharaibeh, A, Alaoui-Jamali, MA, Alberti, S, Alcocer-Gomez, E, Alessandri, C, Ali, M, Al-Bari, MAA, Aliwaini, S, Alizadeh, J, Almacellas, E, Almasan, A, Alonso, A, Alonso, GD, Altan-Bonnet, N, Altieri, DC, Alves, S, da Costa, CA, Alzaharna, MM, Amadio, M, Amantini, C, Amaral, C, Ambrosio, S, Amer, AO, Ammanathan, V, An, ZY, Andersen, SU, Andrabi, SA, Andrade-Silva, M, Andres, AM, Angelini, S, Ann, D, Anozie, UC, Ansari, MY, Antas, P, Antebi, A, Anton, Z, Anwar, T, Apetoh, L, Apostolova, N, Araki, T, Araki, Y, Arasaki, K, Araujo, WL, Araya, J, Arden, C, Arevalo, MA, Arguelles, S, Arias, E, Arikkath, J, Arimoto, H, Ariosa, AR, Armstrong-James, D, Arnaune-Pelloquin, L, Aroca, A, Arroyo, DS, Arsov, I, Artero, R, Asaro, DML, Aschner, M, Ashrafizadeh, M, Ashur-Fabian, O, Atanasov, AG, Au, AK, Auberger, P, Auner, HW, Aurelian, L, Autelli, R, Avagliano, L, Avalos, Y, Aveic, S, Aveleira, CA, AvinWittenberg, T, Aydin, Y, Ayton, S, Ayyadevara, S, Azzopardi, M, Baba, M, Backer, JM, Backues, SK, Bae, DH, Bae, ON, Bae, SH, Baehrecke, EH, Baek, A, Baek, SH, Bagetta, G, Bagniewska-Zadworna, A, Bai, H, Bai, J, Bai, XY, Bai, YD, Bairagi, N, Baksi, S, Balbi, T, Baldari, CT, Balduini, W, Ballabio, A, Ballester, M, Balazadeh, S, Balzan, R, Bandopadhyay, R, Banerjee, S, Bao, Y, Baptista, MS, Baracca, A, Barbati, C, Bargiela, A, Barila, D, Barlow, PG, Barmada, SJ, Barreiro, E, Barreto, GE, Bartek, J, Bartel, B, Bartolome, A, Barve, GR, Basagoudanavar, SH, Bassham, DC, Jr, RCB, Basu, A, Batoko, H, Batten, I, Baulieu, EE, Baumgarner, BL, Bayry, J, Beale, R, Beau, I, Beaumatin, F, Bechara, LRG, Beck, GR, Beers, MF, Begun, J, Behrends, C, Behrens, GMN, Bei, R, Bejarano, E, Bel, S, Behl, C, Belaid, A, Belgareh-Touze, N, Bellarosa, C, Belleudi, F, Perez, MB, Bello-Morales, R, Beltran, JSD, Beltran, S, Benbrook, DM, Bendorius, M, Benitez, BA, Benito-Cuesta, I, Bensalem, J, Berchtold, MW, Berezowska, S, Bergamaschi, D, Bergami, M, Bergmann, A, Berliocchi, L, Berlioz-Torrent, C, Bernard, A, Berthoux, L, Besirli, CG, Besteiro, S, Betin, VM, Beyaert, R, Bezbradica, JS, Bhaskar, K, Bhatia-Kissova, I, Bhattacharya, R, Bhattacharya, S, Bhattacharyya, S, Bhuiyan, MS, Bhutia, SK, Bi, LR, Bi, XL, Biden, TJ, Bijian, K, Billes, VA, Binart, N, Bincoletto, C, Birgisdottir, AB, Bjorkoy, G, Blanco, G, Blas-Garcia, A, Blasiak, J, Blomgran, R, Blomgren, K, Blum, JS, Boada-Romero, E, Boban, M, BoeszeBattaglia, K, Boeuf, P, Boland, B, Bomont, P, Bonaldo, P, Bonam, SR, Bonfili, L, Bonifacino, JS, Boone, BA, Bootman, MD, Bordi, M, Borner, C, Bornhauser, BC, Borthakur, G, Bosch, J, Bose, S, Botana, LM, Botas, J, Boulanger, CM, Boulton, ME, Bourdenx, M, Bourgeois, B, Bourke, NM, Bousquet, G, Boya, P, Bozhkov, PV, Bozi, LHM, Bozkurt, TO, Brackney, DE, Brandts, CH, Braun, RJ, Braus, GH, Bravo-Sagua, R, Bravo-San Pedro, JM, Brest, P, Bringer, MA, Briones-Herrera, A, Broaddus, VC, Brodersen, P, Alvarez, EMC, Brodsky, JL, Brody, SL, Bronson, PG, Bronstein, JM, Brown, CN, Brown, RE, Brum, PC, Brumell, JH, Brunetti-Pierri, N, Bruno, D, Bryson-Richardson, RJ, Bucci, C, Buchrieser, C, Bueno, M, Buitrago-Molina, LE, Buraschi, S, Buch, S, Buchan, JR, Buckingham, EM, Budak, H, Budini, M, Bultynck, G, Burada, F, Burgoyne, JR, Buron, MI, Bustos, V, Buttner, S, Butturini, E, Byrd, A, Cabas, I, Cabrera-Benitez, S, Cadwell, K, Cai, JJ, Cai, L, Cai, Q, Cairo, M, Calbet, JA, Caldwell, GA, Caldwell, KA, Call, JA, Calvani, R, Calvo, AC, Barrera, MCR, Camara, NO, Camonis, JH, Camougrand, N, Campanella, M, Campbell, EM, Campbell-Valois, FX, Campello, S, Campesi, I, Campos, JC, Camuzard, O, Cancino, J, de Almeida, DC, Canesi, L, Caniggia, I, Canonico, B, Canti, C, Cao, B, Caraglia, M, Carames, B, Carchman, EH, Cardenal-Munoz, E, Cardenas, C, Cardenas, L, Cardoso, SM, Carew, JS, Carle, GF, Carleton, G, Carloni, S, Carmona-Gutierrez, D, Carneiro, LA, Carnevali, O, Carosi, JM, Carra, S, Carrier, A, Carrier, L, Carroll, B, Carter, AB, Carvalho, AN, Casanova, M, Casas, C, Casas, J, Cassioli, C, Castillo, EF, Castillo, K, Castillo-Lluva, S, Castoldi, F, Castori, M, Castro, AF, Castro-Caldas, M, Castro-Hernandez, J, Castro-Obregon, S, Catz, SD, Cavadas, C, Cavaliere, F, Cavallini, G, Cavinato, M, Cayuela, ML, Rica, PC, Cecarini, V, Cecconi, F, Cechowska-Pasko, M, Cenci, S, Ceperuelo-Mallafre, V, Cerqueira, JJ, Cerutti, JM, Cervia, D, Cetintas, VB, Cetrullo, S, Chae, HJ, Chagin, AS, Chai, CY, Chakrabarti, G, Chakrabarti, O, Chakraborty, T, Chami, M, Chamilos, G, Chan, DW, Chan, EYW, Chan, ED, Chan, HYE, Chan, HH, Chan, H, Chan, MTV, Chan, YS, Chandra, PK, Chang, CP, Chang, CM, Chang, HC, Chang, K, Chao, J, Chapman, T, Charlet-Berguerand, N, Chatterjee, S, Chaube, SK, Chaudhary, A, Chauhan, S, Chaum, E, Checler, F, Cheetham, ME, Chen, CS, Chen, GC, Chen, JF, Chen, LL, Chen, L, Chen, ML, Chen, MK, Chen, N, Chen, Q, Chen, RH, Chen, S, Chen, W, Chen, WQ, Chen, XM, Chen, XW, Chen, X, Chen, Y, Chen, YG, Chen, YY, Chen, YQ, Chen, YJ, Chen, ZS, Chen, Z, Chen, ZH, Chen, ZJ, Chen, ZX, Cheng, HH, Cheng, J, Cheng, SY, Cheng, W, Cheng, XD, Cheng, XT, Cheng, YY, Cheng, ZY, Cheong, H, Cheong, JK, Chernyak, BV, Cherry, S, Cheung, CFR, Cheung, CHA, Cheung, KH, Chevet, E, Chi, RJ, Chiang, AKS, Chiaradonna, F, Chiarelli, R, Chiariello, M, Chica, N, Chiocca, S, Chiong, M, Chiou, SH, Chiramel, AI, Chiurchiu, V, Cho, DH, Choe, SK, Choi, AMK, Choi, ME, Choudhury, KR, Chow, NS, Chu, CT, Chua, JP, Chua, JJE, Chung, H, Chung, KP, Chung, S, Chung, SH, Chung, YL, Cianfanelli, V, Ciechomska, IA, Cifuentes, M, Cinque, L, Cirak, S, Cirone, M, Clague, MJ, Clarke, R, Clementi, E, Coccia, EM, Codogno, P, Cohen, E, Cohen, MM, Colasanti, T, Colasuonno, F, Colbert, RA, Colell, A, Coll, NS, Collins, MO, Colombo, MI, Colon-Ramos, DA, Combaret, L, Comincini, S, Cominetti, MR, Consiglio, A, Conte, A, Conti, F, Contu, VR, Cookson, MR, Coombs, KM, Coppens, I, Corasaniti, MT, Corkery, DP, Cordes, N, Cortese, K, Costa, MD, Costantino, S, Costelli, P, Coto-Montes, A, Crack, PJ, Crespo, JL, Criollo, A, Crippa, V, Cristofani, R, Csizmadia, T, Cuadrado, A, Cui, B, Cui, J, Cui, YX, Cui, Y, Culetto, E, Cumino, AC, Cybulsky, AV, Czaja, MJ, Czuczwar, SJ, D'Adamo, S, D'Amelio, M, D'Arcangelo, D, D'Lugos, AC, D'Orazi, G, da Silva, JA, Dafsari, HS, Dagda, RK, Dagdas, Y, Daglia, M, Dai, X, Dai, Y, Dai, YY, Dal Col, J, Dalhaimer, P, Dalla Valle, L, Dallenga, T, Dalmasso, G, Damme, M, Dando, I, Dantuma, NP, Darling, AL, Das, H, Dasarathy, S, Dasari, SK, Dash, S, Daumke, O, Dauphinee, AN, Davies, JS, Davila, VA, Davis, RJ, Davis, T, Naidu, SD, De Amicis, F, De Bosscher, K, De Felice, F, De Franceschi, L, De Leonibus, C, Barbosa, MGD, De Meyer, GRY, De Milito, A, De Nunzio, C, De Palma, C, De Santi, M, De Virgilio, C, De Zio, D, Debnath, J, DeBosch, BJ, Decuypere, J, Deehan, MA, Deflorian, G, DeGregori, J, Dehay, B, Del Rio, G, Delaney, JR, Delbridge, LMD, Delorme-Axford, E, Delpino, MV, Demarchi, F, Dembitz, V, Demers, ND, Deng, HB, Deng, ZQ, Dengjel, J, Dent, P, Denton, D, DePamphilis, ML, Der, CJ, Deretic, V, Descoteaux, A, Devis, L, Devkota, S, Devuyst, O, Dewson, G, Dharmasivam, M, Dhiman, R, di Bernardo, D, Di Cristina, M, Di Domenico, F, Di Fazio, P, Di Fonzo, A, Di Guardo, G, Di Guglielmo, GM, Di Leo, L, Di Malta, C, Di Nardo, A, Di Rienzo, M, Di Sano, F, Diallinas, G, Diao, JJ, Diaz-Araya, G, Diaz-Laviada, I, Dickinson, JM, Diederich, M, Dieude, M, Dikic, I, Ding, SP, Ding, WX, Dini, L, Dinic, M, Dinkova-Kostova, AT, Dionne, MS, Distler, JHW, Diwan, A, Dixon, IMC, Djavaheri-Mergny, M, Dobrinski, I, Dobrovinskaya, O, Dobrowolski, R, Dobson, RCJ, Emre, SD, Donadelli, M, Dong, B, Dong, XN, Dong, ZW, Ii, GWD, Dotsch, V, Dou, H, Dou, J, Dowaidar, M, Dridi, S, Drucker, L, Du, AL, Du, CG, Du, GW, Du, HN, Du, LL, du Toit, A, Duan, SB, Duan, XQ, Duarte, SP, Dubrovska, A, Dunlop, EA, Dupont, N, Duran, RV, Dwarakanath, BS, Dyshlovoy, SA, Ebrahimi-Fakhari, D, Eckhart, L, Edelstein, CL, Efferth, T, Eftekharpour, E, Eichinger, L, Eid, N, Eisenberg, T, Eissa, NT, Eissa, S, Ejarque, M, El Andaloussi, A, El-Hage, N, El-Naggar, S, Eleuteri, AM, El-Shafey, ES, Elgendy, M, Eliopoulos, AG, Elizalde, MM, Elks, PM, Elsasser, HP, Elsherbiny, ES, Emerling, BM, Emre, NCT, Eng, CH, Engedal, N, Engelbrecht, AM, Engelsen, AST, Enserink, JM, Escalante, R, Esclatine, A, Escobar-Henriques, M, Eskelinen, EL, Espert, L, Eusebio, MO, Fabrias, G, Fabrizi, C, Facchiano, A, Facchiano, F, Fadeel, B, Fader, C, Faesen, AC, Fairlie, WD, Falco, A, Falkenburger, BH, Fan, DP, Fan, J, Fan, YB, Fang, EF, Fang, YS, Fang, YQ, Fanto, M, Farfel-Becker, T, Faure, M, Fazeli, G, Fedele, AO, Feldman, AM, Feng, D, Feng, JC, Feng, LF, Feng, YB, Feng, YC, Feng, W, Araujo, TF, Ferguson, TA, Fernandez-Checa, JC, FernandezVeledo, S, Fernie, AR, Ferrante, AW, Ferraresi, A, Ferrari, MF, Ferreira, JCB, Ferro-Novick, S, Figueras, A, Filadi, R, Filigheddu, N, FilippiChiela, E, Filomeni, G, Fimia, GM, Fineschi, V, Finetti, F, Finkbeiner, S, Fisher, EA, Fisher, PB, Flamigni, F, Fliesler, SJ, Flo, TH, Florance, I, Florey, O, Florio, T, Fodor, E, Follo, C, Fon, EA, Forlino, A, Fornai, F, Fortini, P, Fracassi, A, Fraldi, A, Franco, B, Franco, R, Franconi, F, Frankel, LB, Friedman, SL, Frohlich, LF, Fruhbeck, G, Fuentes, JM, Fujiki, Y, Fujita, N, Fujiwara, Y, Fukuda, M, Fulda, S, Furic, L, Furuya, N, Fusco, C, Gack, MU, Gaffke, L, Galadari, S, Galasso, A, Galindo, MF, Kankanamalage, SG, Galluzzi, L, Galy, V, Gammoh, N, Gan, BY, Ganley, IG, Gao, F, Gao, H, Gao, MH, Gao, P, Gao, SJ, Gao, WT, Gao, XB, Garcera, A, Garcia, MN, Garcia, VE, Garcia-Del Portillo, F, Garcia-Escudero, V, GarciaGarcia, A, Garcia-Macia, M, Garcia-Moreno, D, Garcia-Ruiz, C, Garcia-Sanz, P, Garg, AD, Gargini, R, Garofalo, T, Garry, RF, Gassen, NC, Gatica, D, Ge, L, Ge, WZ, Geiss-Friedlander, R, Gelfi, C, Genschik, P, Gentle, IE, Gerbino, V, Gerhardt, C, Germain, K, Germain, M, Gewirtz, DA, Afshar, EG, Ghavami, S, Ghigo, A, Ghosh, M, Giamas, G, Giampietri, C, Giatromanolaki, A, Gibson, GE, Gibson, SB, Ginet, V, Giniger, E, Giorgi, C, Girao, H, Girardin, SE, Giridharan, M, Giuliano, S, Giulivi, C, Giuriato, S, Giustiniani, J, Gluschko, A, Goder, V, Goginashvili, A, Golab, J, Goldstone, DC, Golebiewska, A, Gomes, LR, Gomez, R, Gomez-Sanchez, R, Gomez-Puerto, MC, Gomez-Sintes, R, Gong, Q, Goni, FM, Gonzalez-Gallego, J, Gonzalez-Hernandez, T, Gonzalez-Polo, RA, Gonzalez-Reyes, JA, Gonzalez-Rodriguez, P, Goping, IS, Gorbatyuk, MS, Gorbunov, NV, Gorojod, RM, Gorski, SM, Goruppi, S, Gotor, C, Gottlieb, RA, Gozes, I, Gozuacik, D, Graef, M, Graler, MH, Granatiero, V, Grasso, D, Gray, JP, Green, DR, Greenhough, A, Gregory, SL, Griffin, EF, Grinstaff, MW, Gros, F, Grose, C, Gross, AS, Gruber, F, Grumati, P, Grune, T, Gu, XY, Guan, JL, Guardia, CM, Guda, K, Guerra, F, Guerri, C, Guha, P, Guillen, C, Gujar, S, Gukovskaya, A, Gukovsky, I, Gunst, J, Gunther, A, Guntur, AR, Guo, CY, Guo, C, Guo, HQ, Guo, LW, Guo, M, Gupta, P, Fernandez, AF, Gupta, SK, Gupta, S, Gupta, VB, Gupta, V, Gustafsson, AB, Gutterman, DD, Ranjitha, HB, Haapasalo, A, Haber, JE, Hadano, S, Hafren, AJ, Haidar, M, Hall, BS, Hallden, G, Hamacher-Brady, A, Hamann, A, Hamasaki, M, Han, WD, Hansen, M, Hanson, PI, Hao, ZJ, Harada, M, Harhaji-Trajkovic, L, Hariharan, N, Haroon, N, Harris, J, Hasegawa, T, Nagoor, NH, Haspel, JA, Haucke, V, Hawkins, WD, Hay, BA, Haynes, CM, Hayrabedyan, SB, Hays, TS, He, CC, He, Q, He, RR, He, YW, He, YY, Heakal, Y, Heberle, AM, Hejtmancik, JF, Helgason, GV, Henkel, V, Herb, M, Hergovich, A, Herman-Antosiewicz, A, Hernandez, A, Hernandez, C, Hernandez-Diaz, S, Hernandez-Gea, V, Herpin, A, Herreros, J, Hervas, JH, Hesselson, D, Hetz, C, Heussler, VT, Higuchi, Y, Hilfiker, S, Hill, JA, Hlavacek, WS, Ho, EA, Ho, IHT, Ho, PWL, Ho, S, Ho, WY, Hobbs, GA, Hochstrasser, M, Hoet, PHM, Hofius, D, Hofman, P, Hohn, A, Holmberg, CI, Hombrebueno, JR, Hong, CW, Hong, YR, Hooper, LV, Hoppe, T, Horos, R, Hoshida, Y, Hsin, IL, Hsu, HY, Hu, B, Hu, D, Hu, LF, Hu, MC, Hu, RG, Hu, W, Hu, YC, Hu, ZW, Hua, F, Hua, JL, Hua, YQ, Huan, CM, Huang, CH, Huang, CS, Huang, CX, Huang, CL, Huang, HS, Huang, K, Huang, MLH, Huang, R, Huang, S, Huang, TZ, Huang, X, Huang, YJ, Huber, TB, Hubert, V, Hubner, CA, Hughes, SM, Hughes, WE, Humbert, M, Hummer, G, Hurley, JH, Hussain, S, Hussey, PJ, Hutabarat, M, Hwang, HY, Hwang, S, Ieni, A, Ikeda, F, Imagawa, Y, Imai, Y, Imbriano, C, Imoto, M, Inman, DM, Inoki, K, Iovanna, J, Iozzo, RV, Ippolito, G, Irazoqui, JE, Iribarren, P, Ishaq, M, Ishikawa, M, Ishimwe, N, Isidoro, C, Ismail, N, Issazadeh-Navikas, S, Itakura, E, Ito, D, Ivankovic, D, Ivanova, S, Iyer, AKV, Izquierdo, JM, Izumi, M, Jaattela, M, Jabir, MS, Jackson, WT, Jacobo-Herrera, N, Jacomin, AC, Jacquin, E, Jadiya, P, Jaeschke, H, Jagannath, C, Jakobi, AJ, Jakobsson, J, Janji, B, JansenDurr, P, Jansson, PJ, Jantsch, J, Januszewski, S, Jassey, A, Jean, S, JeltschDavid, H, Jendelova, P, Jenny, A, Jensen, TE, Jessen, N, Jewell, JL, Ji, J, Jia, LJ, Jia, R, Jiang, LW, Jiang, Q, Jiang, RC, Jiang, T, Jiang, XJ, Jiang, Y, Jimenez-Sanchez, M, Jin, EJ, Jin, FY, Jin, HC, Jin, L, Jin, LQ, Jin, MY, Jin, S, Jo, EK, Joffre, C, Johansen, T, Johnson, GVW, Johnston, SA, Jokitalo, E, Jolly, MK, Joosten, LAB, Jordan, J, Joseph, B, Ju, DW, Ju, JS, Ju, JF, Juarez, E, Judith, D, Juhasz, G, Jun, Y, Jung, CH, Jung, S, Jung, YK, Jungbluth, H, Jungverdorben, J, Just, S, Kaarniranta, K, Kaasik, A, Kabuta, T, Kaganovich, D, Kahana, A, Kain, R, Kajimura, S, Kalamvoki, M, Kalia, M, Kalinowski, DS, Kaludercic, N, Kalvari, I, Kaminska, J, Kaminskyy, VO, Kanamori, H, Kanasaki, K, Kang, C, Kang, R, Kang, SS, 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Tchetina, E, Tee, AR, Tegeder, I, Teis, D, Teixeira, N, Teixeira-Clerc, F, Tekirdag, KA, Tencomnao, T, Tenreiro, S, Tepikin, AV, Testillano, PS, Tettamanti, G, Tharaux, P, Thedieck, K, Thekkinghat, AA, Thellung, S, Thinwa, JW, Thirumalaikumar, VP, Thomas, SM, Thomes, PG, Thorburn, A, Thukral, L, Thum, T, Thumm, M, Tian, L, Tichy, A, Till, A, Timmerman, V, Titorenko, VI, Todi, SV, Todorova, K, Toivonen, JM, Tomaipitinca, L, Tomar, D, Tomas-Zapico, C, Tong, BCK, Tong, C, Tong, X, Tooze, SA, Torgersen, ML, Torii, S, Torres-Lopez, L, Torriglia, A, Towers, CG, Towns, R, Toyokuni, S, Trajkovic, V, Tramontano, D, Tran, Q, Travassos, LH, Trelford, CB, Tremel, S, Trougakos, IP, Tsao, BP, Tschan, MP, Tse, HF, Tse, TF, Tsugawa, H, Tsvetkov, AS, Tumbarello, DA, Tumtas, Y, Tunon, MJ, Turcotte, S, Turk, B, Turk, V, Turner, BJ, Tuxworth, RI, Tyler, JK, Tyutereva, EV, Uchiyama, Y, UgunKlusek, A, Uhlig, HH, Ulasov, IV, Umekawa, M, Ungermann, C, Unno, R, Urbe, S, Uribe-Carretero, E, Ustun, S, Uversky, VN, Vaccari, T, Vaccaro, MI, Vahsen, BF, Vakifahmetoglu-Norberg, H, Valdor, R, Valente, MJ, Valko, A, Vallee, RB, Valverde, AM, Van den Berghe, G, van Der Veen, S, Van Kaer, L, van Loosdregt, J, van Wijk, SJL, Vandenberghe, W, Vanhorebeek, I, Vannier-Santos, MA, Vannini, N, Vanrell, MC, Vantaggiato, C, Varano, G, Varela-Nieto, I, Varga, M, Vasconcelos, MH, Vats, S, Vavvas, DG, VegaNaredo, I, Vega-Rubin-de-Celis, S, Velasco, G, Velazquez, AP, Vellai, T, Vellenga, E, Velotti, F, Verdier, M, Verginis, P, Vergne, I, Verkade, P, Verma, M, Verstreken, P, Vervliet, T, Vervoorts, J, Vessoni, AT, Victor, VM, Vidal, M, Vidoni, C, Vieira, OV, Vierstra, RD, Vigano, S, Vihinen, H, Vijayan, V, Vila, M, Vilar, M, Villalba, JM, Villalobo, A, Villarejo-Zori, B, Villarroya, F, Villarroya, J, Vincent, O, Vindis, C, Viret, C, Viscomi, MT, Visnjic, D, Vitale, I, Vocadlo, DJ, Voitsekhovskaja, OV, Volonte, C, Volta, M, Vomero, M, Von Haefen, C, Vooijs, MA, Voos, W, Vucicevic, L, Wade-Martins, R, Waguri, S, Waite, KA, Wakatsuki, S, Walker, DW, Walker, MJ, Walker, SA, Walter, J, Wandosell, FG, Wang, B, Wang, CY, Wang, C, Wang, CR, Wang, CW, Wang, D, Wang, FY, Wang, F, Wang, FM, Wang, GS, Wang, H, Wang, HX, Wang, HG, Wang, JR, Wang, JG, Wang, J, Wang, JD, Wang, K, Wang, LR, Wang, LM, Wang, MH, Wang, MQ, Wang, NB, Wang, PW, Wang, PP, Wang, P, Wang, QJ, Wang, Q, Wang, QK, Wang, QA, Wang, WT, Wang, WY, Wang, XN, Wang, XJ, Wang, Y, Wang, YC, Wang, YZ, Wang, YY, Wang, YH, Wang, YP, Wang, YQ, Wang, Z, Wang, ZY, Wang, ZG, Warnes, G, Warnsmann, V, Watada, H, Watanabe, E, Watchon, M, Weaver, TE, Wegrzyn, G, Wehman, AM, Wei, HF, Wei, L, Wei, TT, Wei, YJ, Weiergraber, OH, Weihl, CC, Weindl, G, Weiskirchen, R, Wells, A, Wen, RXH, Wen, X, Werner, A, Weykopf, B, Wheatley, SP, Whitton, JL, Whitworth, AJ, Wiktorska, K, Wildenberg, ME, Wileman, T, Wilkinson, S, Willbold, D, Williams, B, Williams, RSB, Williams, RL, Williamson, PR, Wilson, RA, Winner, B, Winsor, NJ, Witkin, SS, Wodrich, H, Woehlbier, U, Wollert, T, Wong, E, Wong, JH, Wong, RW, Wong, VKW, Wong, WWL, Wu, AG, Wu, CB, Wu, J, Wu, JF, Wu, KK, Wu, M, Wu, SY, Wu, SZ, Wu, SF, Wu, WKK, Wu, XH, Wu, XQ, Wu, YW, Wu, YH, Xavier, RJ, Xia, HG, Xia, LX, Xia, ZY, Xiang, G, Xiang, J, Xiang, ML, Xiang, W, Xiao, B, Xiao, GZ, Xiao, HY, Xiao, HT, Xiao, J, Xiao, L, Xiao, S, Xiao, Y, Xie, BM, Xie, CM, Xie, M, Xie, YX, Xie, ZP, Xie, ZL, Xilouri, M, Xu, CF, Xu, E, Xu, HX, Xu, J, Xu, JR, Xu, L, Xu, WW, Xu, XL, Xue, Y, Yakhine-Diop, SMS, Yamaguchi, M, Yamaguchi, O, Yamamoto, A, Yamashina, S, Yan, SM, Yan, SJ, Yan, Z, Yanagi, Y, Yang, CB, Yang, DS, Yang, H, Yang, HT, Yang, JM, Yang, J, Yang, JY, Yang, L, Yang, M, Yang, PM, Yang, Q, Yang, S, Yang, SF, Yang, WN, Yang, WY, Yang, XY, Yang, XS, Yang, Y, Yao, HH, Yao, SG, Yao, XQ, Yao, YG, Yao, YM, Yasui, T, Yazdankhah, M, Yen, PM, Yi, C, Yin, XM, Yin, YH, Yin, ZY, Ying, MD, Ying, Z, Yip, CK, Yiu, SPT, Yoo, YH, Yoshida, K, Yoshii, SR, Yoshimori, T, Yousefi, B, Yu, BX, Yu, HY, Yu, J, Yu, L, Yu, ML, Yu, SW, Yu, VC, Yu, WH, Yu, ZP, Yu, Z, Yuan, JY, Yuan, LQ, Yuan, SL, Yuan, SSF, Yuan, YG, Yuan, ZQ, Yue, JB, Yue, ZY, Yun, J, Yung, RL, Zacks, DN, Zaffagnini, G, Zambelli, VO, Zanella, I, Zang, QS, Zanivan, S, Zappavigna, S, Zaragoza, P, Zarbalis, KS, Zarebkohan, A, Zarrouk, A, Zeitlin, SO, Zeng, JL, Zeng, JD, Zerovnik, E, Zhan, LX, Zhang, B, Zhang, DD, Zhang, HL, Zhang, H, Zhang, HH, Zhang, HF, Zhang, HY, Zhang, JB, Zhang, JH, Zhang, JP, Zhang, KLYB, Zhang, LSW, Zhang, L, Zhang, LS, Zhang, LY, Zhang, MH, Zhang, P, Zhang, S, Zhang, W, Zhang, XN, Zhang, XW, Zhang, XL, Zhang, XY, Zhang, X, Zhang, XX, Zhang, XD, Zhang, Y, Zhang, YJ, Zhang, YD, Zhang, YM, Zhang, YY, Zhang, YC, Zhang, Z, Zhang, ZG, Zhang, ZB, Zhang, ZH, Zhang, ZY, Zhang, ZL, Zhao, HB, Zhao, L, Zhao, S, Zhao, TB, Zhao, XF, Zhao, Y, Zhao, YC, Zhao, YL, Zhao, YT, Zheng, GP, Zheng, K, Zheng, L, Zheng, SZ, Zheng, XL, Zheng, Y, Zheng, ZG, Zhivotovsky, B, Zhong, Q, Zhou, A, Zhou, B, Zhou, CF, Zhou, G, Zhou, H, Zhou, HB, Zhou, J, Zhou, JY, Zhou, KL, Zhou, RJ, Zhou, XJ, Zhou, YS, Zhou, YH, Zhou, YB, Zhou, ZY, Zhou, Z, Zhu, BL, Zhu, CL, Zhu, GQ, Zhu, HN, Zhu, HX, Zhu, H, Zhu, WG, Zhu, YP, Zhu, YS, Zhuang, HX, Zhuang, XH, Zientara-Rytter, K, Zimmermann, CM, Ziviani, E, Zoladek, T, Zong, WX, Zorov, DB, Zorzano, A, Zou, WP, Zou, Z, Zou, ZZ, Zuryn, S, Zwerschke, W, Brand-Saberi, B, Dong, XC, Kenchappa, CS, Li, ZG, Lin, Y, Oshima, S, Rong, YG, Sluimer, JC, Stallings, CL, and Tong, CK
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flux ,macroautophagy ,phagophore ,stress ,vacuole ,Autophagosome ,LC3 ,lysosome ,neurodegeneration ,cancer - Abstract
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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- 2021
8. Fauna of Noctuidae (Lepidoptera: Noctuoidea) in a pasture area in Altamira, Eastern Amazon, Pará, Brazil
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Almeida, LP, Specht, A, and Teston, JA
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owlet-moths ,estrutura da comunidade ,mariposas ,Região Neotropical ,community structure ,Neotropical region ,biodiversidade ,biodiversity - Abstract
This study evaluated the nocturnal fauna of Noctuidae in a pasture area in Altamira, Pará. Samples were collected monthly for two nights at the new moon period, from August 2007 to July 2008. We collected a total of 345 specimens (N) of 66 species (S). The most abundant species were Ptichodes basilans (Guenée) (n = 87), Leucania jaliscana (Schaus), Spodoptera frugiperda (JE Smith) (n = 28) and Argidia palmipes Guenée (n = 21). For the entire period, the following indexes were found: Shannon diversity H′= 3.20 and Brillouin H = 2.94, evenness of Shannon E′= 0.76 and Brillouin E= 0.76, and Berger-Parker dominance BP= 0.252. The greatest diversity was found in the dry season. According to the estimates of species richness, it is possible that between 14 to 72 more species exist in the region. A diversidade de Noctuidae noturnos foi estudada em área de pastagem em Altamira, Pará. As coletas foram feitas com armadilha luminosa, mensalmente durante duas noites no período de lua nova, entre agosto de 2007 a julho de 2008. Foi coletado um total de 345 espécimes (N) de 66 espécies (S). As espécies mais abundantes foram Ptichodes basilans (Guenée) (n=87), Leucania jaliscana (Schaus), Spodoptera frugiperda (J.E. Smith) (n=28) e Argidia palmipes Guenée (n=21). Para todo o período de estudo foram encontrados os seguintes índices: diversidade de Shannon H′= 3,20 e de Brillouin H= 2,94, uniformidade de Shannon E′= 0,76 e Brillouin E= 0,76, e dominância Berger-Parker BP= 0,252. A estação menos chuvosa apresentou maior diversidade. As estimativas de riqueza apresentaram a possibilidade de se encontrar entre 14 a 72 espécies a mais.
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- 2014
9. Activity-regulated cytoskeleton-associated protein controls AMPAR endocytosis through a direct interaction with clathrin-adaptor protein 2
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DaSilva, LLP, Wall, MJ, de Almeida, LP, Wauters, SC, Januário, YC, Müller, J, Correa, Sonia AL, DaSilva, LLP, Wall, MJ, de Almeida, LP, Wauters, SC, Januário, YC, Müller, J, and Correa, Sonia AL
- Abstract
© 2016 DaSilva et al. The activity-regulated cytoskeleton-associated (Arc) protein controls synaptic strength by facilitating AMPA receptor (AMPAR) endocytosis. Here we demonstrate that Arc targets AMPAR to be internalized through a direct interaction with the clathrin-adaptor protein 2 (AP-2). We show that Arc overexpression in dissociated hippocampal neurons obtained from C57BL/6 mouse reduces the density of AMPAR GluA1 subunits at the cell surface and reduces the amplitude and rectification of AMPAR-mediated miniature-EPSCs (mEPSCs). Mutations of Arc, that prevent the AP-2 interaction reduce Arc-mediated endocytosis of GluA1 and abolish the reduction in AMPARmediated mEPSC amplitude and rectification. Depletion of the AP-2 subunit µ2 blocks the Arc-mediated reduction in mEPSC amplitude, an effect that is restored by reintroducing µ2. The Arc-AP-2 interaction plays an important role in homeostatic synaptic scaling as the Arc-dependent decrease in mEPSC amplitude, induced by a chronic increase in neuronal activity, is inhibited by AP-2 depletion. These data provide a mechanism to explain how activity-dependent expression of Arc decisively controls the fate of AMPAR at the cell surface and modulates synaptic strength, via the direct interaction with the endocytic clathrin adaptor AP-2.
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- 2016
10. [Untitled]
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Arnaldo Lopes Colombo, Marcelo R. S. Briones, de Almeida Lp, and Analy Salles de Azevedo Melo
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Genetics ,Phylogenetic tree ,Veterinary (miscellaneous) ,Biology ,Applied Microbiology and Biotechnology ,Microbiology ,18S ribosomal RNA ,RAPD ,Common species ,Genetic distance ,Phylogenetics ,Genotype ,Typing ,Agronomy and Crop Science - Abstract
Fast and reliable identification of different species of the genus Candida is important to define adequate therapeutic decisions, because the different species have highly variable susceptibilities to antifungal drugs; azoles and amphothericin B. Accurate statistical records on case history and epidemiological studies also depend on effective identification. To address this problem we established a RAPD method that enabled direct identification of five very common species of Candida. Initially, reference band patterns were established for C. albicans, C. tropicalis, C. parapsilosis, C. glabrata and C. krusei. One of the primers, M2, showed remarkably conserved intra-specific patterns of approximately 10 bands each, ranging in size from 2.0 to 0.1 kb. These patterns were significantly different and species-specific. Few bands were conserved between different species of Candida, which was assumed to be consistent with their phylogenetic relatedness. In addition, band patterns were constant and reproducible and DNA isolated from single colonies yielded sufficient DNA for identification. The reference band patterns were then used, in blind experiments, to identify species of Candida in 50 randomly chosen samples, including clinical isolates and ATCC strains. RAPD results were 100% consistent with results obtained by conventional diagnostic methods and were achieved in one day instead of several days taken by conventional methods. Because ideal identification methods should be consistent with phylogeny and taxonomy we tested whether RAPD could be used to calculate genetic distances. Comparison of RAPD phylogenetic trees with 18S rRNA trees showed significant differences in tree topologies which indicated that RAPD data could not accurately measure the relative distances between different species. Also, computer simulations of RAPD random patterns were used to test whether the observed degree of RAPD band pattern similarities could occur at random. These simulations suggested that the level of inter-specific band pattern similarities observed in our data could be obtained at random, while intra-specific pattern similarities could not. RAPD would be helpful to discriminate between isolates but not to quantitate the differences. We suggest that the inaccurate estimate of genetic distances from RAPD is a general limitation of the technique and not a specific problem of our identification method. Because of the repetitive character of the target sequences, genetic distances calculated from RAPD could be affected by paralogy, namely, recombination and duplication events not parallel with speciation events.
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- 1998
11. Levantamento soroepidemiológico de leptospirose em trabalhadores do serviço de saneamento ambiental em localidade urbana da região sul do Brasil
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Luís Fernando da Silva Martins, Claudiomar Soares Brod, de Almeida Lp, and Germano Pm
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Serotype ,Veterinary medicine ,Sanitation ,business.industry ,Public Health, Environmental and Occupational Health ,Water supply ,medicine.disease ,Leptospirosis ,Agglutination (biology) ,Geography ,Direct agglutination test ,medicine ,Drainage ,business - Abstract
A pesquisa de aglutininas anti-Leptospira, pela técnica de soroaglutinação microscópica, em soros de trabalhadores dos serviços de águas, bueiros e galerias, esgotos, coleta de lixo e limpeza pública, do Município de Pelotas, RS, Brasil, revelou 10,4% de reagentes a um ou mais sorovares; não houve diferenças significantes entre as proporções de reagentes de cada um dos setores de trabalho. Foram identificados 12 sorovares diferentes; castelonis e australis, apesar de mais freqüentes, não apresentaram diferenças estatisticamente significantes com os demais. Constatou-se que 86,9% das amostras apresentavam títulos aglutinantes compreendidos entre 100 e 400; as proporções de soros com títulos iguais a 100 e 400 foram superiores às dos títulos 800, 1.600 e 3.200 (p < 0,05).
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- 1994
12. Fauna of Noctuidae (Lepidoptera: Noctuoidea) in a pasture area in Altamira, Eastern Amazon, Pará, Brazil
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Almeida, LP, primary, Specht, A, additional, and Teston, JA, additional
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- 2014
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13. Mannose and Lactobionic Acid in Nasal Vaccination: Enhancing Antigen Delivery via C-Type Lectin Receptors.
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Colaço M, Cruz MT, Almeida LP, and Borges O
- Abstract
Background/objectives: Nasal vaccines are a promising strategy for enhancing mucosal immune responses and preventing diseases at mucosal sites by stimulating the secretion of secretory IgA, which is crucial for early pathogen neutralization. However, designing effective nasal vaccines is challenging due to the complex immunological mechanisms in the nasal mucosa, which must balance protection and tolerance against constant exposure to inhaled pathogens. The nasal route also presents unique formulation and delivery hurdles, such as the mucous layer hindering antigen penetration and immune cell access., Methods: This review focuses on cutting-edge approaches to enhance nasal vaccine delivery, particularly those targeting C-type lectin receptors (CLRs) like the mannose receptor and macrophage galactose-type lectin (MGL) receptor. It elucidates the roles of these receptors in antigen recognition and uptake by antigen-presenting cells (APCs), providing insights into optimizing vaccine delivery., Results: While a comprehensive examination of targeted glycoconjugate vaccine development is outside the scope of this study, we provide key examples of glycan-based ligands, such as lactobionic acid and mannose, which can selectively target CLRs in the nasal mucosa., Conclusions: With the rise of new viral infections, this review aims to facilitate the design of innovative vaccines and equip researchers, clinicians, and vaccine developers with the knowledge to enhance immune defenses against respiratory pathogens, ultimately protecting public health.
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- 2024
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14. Development of DRIP - drought representation index for CMIP climate model performance, application to Southeast Brazil.
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Almeida LP, Formiga-Johnsson RM, Souza Filho FA, Estácio ÁBS, Porto VC, Nauditt A, and Ribbe L
- Abstract
With the escalating impacts of drought events driven by climate change, reducing the uncertainty of drought projections becomes critical for enhancing risk management and adaptation strategies. This study aimed to develop an index for assessing the performance of CMIP6 Global Climate Models in simulating meteorological drought scenarios across regional hydrological systems, intended to provide more reliable information for management purposes. Named the 'Drought Representation Index for CMIP Climate Model Performance' (DRIP), this index evaluates CMIP models' performance to represent drought severity, duration, and return period. DRIP was used to select CMIP models and create an ensemble of the best-performing models (E-DRIP) to improve the reliability of drought projections. E-DRIP was then compared with a general ensemble of available CMIP6 models (E-CMIP). We applied this method in Southeast Brazil, a region known for its climate uncertainties and low predictability; specifically, it was implemented within the Paraíba do Sul River Basin, a nationally strategic watershed in a highly populated and industrialized area, which has recently faced unprecedented drought-related water crises. Results showed that DRIP effectively assessed the individual performance of CMIP models, which exhibited considerable variability, and identified the top-performing models for a multi-model ensemble. Additionally, the E-DRIP ensemble significantly reduced uncertainties in drought projections, achieving an average reduction of 63 % in the study area compared to E-CMIP. Furthermore, the proposed method enables evaluations across any standardized drought index scale, reference period, or threshold, and can be readily adapted to other hydrological systems., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rosa Maria Formiga-Johnsson reports financial support was provided by National Council for Scientific and Technological Development. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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15. Brain-targeted drug delivery - nanovesicles directed to specific brain cells by brain-targeting ligands.
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Moreira R, Nóbrega C, de Almeida LP, and Mendonça L
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- Humans, Animals, Ligands, Neurodegenerative Diseases drug therapy, Neurodegenerative Diseases metabolism, Neurons metabolism, Peptides chemistry, Blood-Brain Barrier metabolism, Brain metabolism, Drug Delivery Systems methods, Nanoparticles chemistry
- Abstract
Neurodegenerative diseases are characterized by extensive loss of function or death of brain cells, hampering the life quality of patients. Brain-targeted drug delivery is challenging, with a low success rate this far. Therefore, the application of targeting ligands in drug vehicles, such as lipid-based and polymeric nanoparticles, holds the promise to overcome the blood-brain barrier (BBB) and direct therapies to the brain, in addition to protect their cargo from degradation and metabolization. In this review, we discuss the barriers to brain delivery and the different types of brain-targeting ligands currently in use in brain-targeted nanoparticles, such as peptides, proteins, aptamers, small molecules, and antibodies. Moreover, we present a detailed review of the different targeting ligands used to direct nanoparticles to specific brain cells, like neurons (C4-3 aptamer, neurotensin, Tet-1, RVG, and IKRG peptides), astrocytes (Aquaporin-4, D4, and Bradykinin B2 antibodies), oligodendrocytes (NG-2 antibody and the biotinylated DNA aptamer conjugated to a streptavidin core Myaptavin-3064), microglia (CD11b antibody), neural stem cells (QTRFLLH, VPTQSSG, and NFL-TBS.40-63 peptides), and to endothelial cells of the BBB (transferrin and insulin proteins, and choline). Reports demonstrated enhanced brain-targeted delivery with improved transport to the specific cell type targeted with the conjugation of these ligands to nanoparticles. Hence, this strategy allows the implementation of high-precision medicine, with reduced side effects or unwanted therapy clearance from the body. Nevertheless, the accumulation of some of these nanoparticles in peripheral organs has been reported indicating that there are still factors to be improved to achieve higher levels of brain targeting. This review is a collection of studies exploring targeting ligands for the delivery of nanoparticles to the brain and we highlight the advantages and limitations of this type of approach in precision therapies., (© 2024. The Author(s).)
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- 2024
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16. Isolation of Adeno-associated Viral Vectors Through a Single-step and Semi-automated Heparin Affinity Chromatography Protocol.
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Lopes MM, Lopes SM, Baganha R, Henriques C, Silva AC, Lobo DD, Cortes L, de Almeida LP, and Nobre RJ
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- Humans, HEK293 Cells, Dependovirus genetics, Dependovirus isolation & purification, Dependovirus chemistry, Chromatography, Affinity methods, Heparin chemistry, Genetic Vectors chemistry, Genetic Vectors genetics
- Abstract
Adeno-associated virus (AAV) has become an increasingly valuable vector for in vivo gene delivery and is currently undergoing human clinical trials. However, the commonly used methods to purify AAVs make use of cesium chloride or iodixanol density gradient ultracentrifugation. Despite their advantages, these methods are time-consuming, have limited scalability, and often result in vectors with low purity. To overcome these constraints, researchers are turning their attention to chromatography techniques. Here, we present an optimized heparin-based affinity chromatography protocol that serves as a universal capture step for the purification of AAVs. This method relies on the intrinsic affinity of AAV serotype 2 (AAV2) for heparan sulfate proteoglycans. Specifically, the protocol entails the co-transfection of plasmids encoding the desired AAV capsid proteins with those of AAV2, yielding mosaic AAV vectors that combine the properties of both parental serotypes. Briefly, after the lysis of producer cells, a mixture containing AAV particles is directly purified following an optimized single-step heparin affinity chromatography protocol using a standard fast protein liquid chromatography (FPLC) system. Purified AAV particles are subsequently concentrated and subjected to comprehensive characterization in terms of purity and biological activity. This protocol offers a simplified and scalable approach that can be performed without the need for ultracentrifugation and gradients, yielding clean and high viral titers.
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- 2024
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17. The IFIH1-A946T risk variant promotes diabetes in a sex-dependent manner.
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Stock AJ, Gonzalez Paredes P, de Almeida LP, Kosanke SD, Chetlur S, Budde H, Wakenight P, Zwingman TA, Rosen ABI, Allenspach EJ, Millen KJ, Buckner JH, Rawlings DJ, and Gorman JA
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- Female, Animals, Mice, Interferon-Induced Helicase, IFIH1 genetics, DEAD-box RNA Helicases metabolism, CD8-Positive T-Lymphocytes metabolism, Genetic Predisposition to Disease, Mice, Inbred NOD, Interferons genetics, Diabetes Mellitus, Type 1, Autoimmune Diseases genetics
- Abstract
Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet β-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 ( IFIH1 ), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 ( IFIH1
A946T ) and confers an increased risk for several autoimmune diseases, including T1D. We hypothesized that the IFIH1A946T risk variant, ( IFIH1R ) would promote T1D pathogenesis by stimulating type I interferon (IFN I) signaling leading to immune cell alterations. To test this, we developed Ifih1R knock-in mice on the non-obese diabetic (NOD) mouse background, a spontaneous T1D model. Our results revealed a modest increase in diabetes incidence and insulitis in Ifih1R compared to non-risk Ifih1 ( Ifih1NR ) mice and a significant acceleration of diabetes onset in Ifih1R females. Ifih1R mice exhibited a significantly enhanced interferon stimulated gene (ISG) signature compared to Ifih1NR , indicative of increased IFN I signaling. Ifih1R mice exhibited an increased frequency of plasma cells as well as tissue-dependent changes in the frequency and activation of CD8+ T cells. Our results indicate that IFIH1R may contribute to T1D pathogenesis by altering the frequency and activation of immune cells. These findings advance our knowledge on the connection between the rs1990760 variant and T1D. Further, these data are the first to demonstrate effects of Ifih1R in NOD mice, which will be important to consider for the development of therapeutics for T1D., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Stock, Gonzalez Paredes, de Almeida, Kosanke, Chetlur, Budde, Wakenight, Zwingman, Rosen, Allenspach, Millen, Buckner, Rawlings and Gorman.)- Published
- 2024
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18. Graft-derived neurons and bystander effects are maintained for six months after human iPSC-derived NESC transplantation in mice's cerebella.
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Mendonça LS, Henriques D, Fernandes V, Moreira R, Brás J, Duarte S, Schwamborn JC, and de Almeida LP
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- Mice, Animals, Humans, Bystander Effect, Neurons metabolism, Cerebellum metabolism, Induced Pluripotent Stem Cells metabolism, Machado-Joseph Disease metabolism
- Abstract
Machado-Joseph disease (MJD) is a neurodegenerative disorder characterized by widespread neuronal death affecting the cerebellum. Cell therapy can trigger neuronal replacement and neuroprotection through bystander effects providing a therapeutic option for neurodegenerative diseases. Here, human control (CNT) and MJD iPSC-derived neuroepithelial stem cells (NESC) were established and tested for their therapeutic potential. Cells' neuroectodermal phenotype was demonstrated. Brain organoids obtained from the Control NESC showed higher mRNA levels of genes related to stem cells' bystander effects, such as BDNF, NEUROD1, and NOTCH1, as compared with organoids produced from MJD NESC, suggesting that Control NESC have a higher therapeutic potential. Graft-derived glia and neurons, such as cells positive for markers of cerebellar neurons, were detected six months after NESC transplantation in mice cerebella. The graft-derived neurons established excitatory and inhibitory synapses in the host cerebella, although CNT neurons exhibited higher excitatory synapse numbers compared with MJD neurons. Cell grafts, mainly CNT NESC, sustained the bystander effects through modulation of inflammatory interleukins (IL1B and IL10), neurotrophic factors (NGF), and neurogenesis-related proteins (Msi1 and NeuroD1), for six months in the mice cerebella. Altogether this study demonstrates the long-lasting therapeutic potential of human iPSC-derived NESC in the cerebellum., (© 2024. The Author(s).)
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- 2024
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19. Stage-Dependent Biomarker Changes in Spinocerebellar Ataxia Type 3.
- Author
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Faber J, Berger M, Wilke C, Hubener-Schmid J, Schaprian T, Santana MM, Grobe-Einsler M, Onder D, Koyak B, Giunti P, Garcia-Moreno H, Gonzalez-Robles C, Lima M, Raposo M, Melo ARV, de Almeida LP, Silva P, Pinto MM, van de Warrenburg BP, van Gaalen J, de Vries J, Oz G, Joers JM, Synofzik M, Schols L, Riess O, Infante J, Manrique L, Timmann D, Thieme A, Jacobi H, Reetz K, Dogan I, Onyike C, Povazan M, Schmahmann J, Ratai EM, Schmid M, and Klockgether T
- Subjects
- Humans, Cross-Sectional Studies, Ataxia, Biomarkers, Machado-Joseph Disease genetics, Cerebellar Ataxia
- Abstract
Spinocerebellar ataxia type 3/Machado-Joseph disease is the most common autosomal dominant ataxia. In view of the development of targeted therapies, knowledge of early biomarker changes is needed. We analyzed cross-sectional data of 292 spinocerebellar ataxia type 3/Machado-Joseph disease mutation carriers. Blood concentrations of mutant ATXN3 were high before and after ataxia onset, whereas neurofilament light deviated from normal 13.3 years before onset. Pons and cerebellar white matter volumes decreased and deviated from normal 2.2 years and 0.6 years before ataxia onset. We propose a staging model of spinocerebellar ataxia type 3/Machado-Joseph disease that includes a biomarker stage characterized by objective indicators of neurodegeneration before ataxia onset. ANN NEUROL 2024;95:400-406., (© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
- Published
- 2024
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20. Phosphoproteome Microarray Analysis of Extracellular Particles as a Tool to Explore Novel Biomarker Candidates for Alzheimer's Disease.
- Author
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Soares Martins T, Pelech S, Ferreira M, Pinho B, Leandro K, de Almeida LP, Breitling B, Hansen N, Esselmann H, Wiltfang J, da Cruz E Silva OAB, and Henriques AG
- Subjects
- Humans, tau Proteins metabolism, Proteome, Pilot Projects, Amyloid beta-Peptides metabolism, Biomarkers, Neurofibrillary Tangles metabolism, Alzheimer Disease metabolism
- Abstract
Phosphorylation plays a key role in Alzheimer's disease (AD) pathogenesis, impacting distinct processes such as amyloid-beta (Aβ) peptide production and tau phosphorylation. Impaired phosphorylation events contribute to senile plaques and neurofibrillary tangles' formation, two major histopathological hallmarks of AD. Blood-derived extracellular particles (bdEP) can represent a disease-related source of phosphobiomarker candidates, and hence, in this pilot study, bdEP of Control and AD cases were analyzed by a targeted phosphoproteomics approach using a high-density microarray that featured at least 1145 pan-specific and 913 phosphosite-specific antibodies. This approach, innovatively applied to bdEP, allowed the identification of 150 proteins whose expression levels and/or phosphorylation patterns were significantly altered across AD cases. Gene Ontology enrichment and Reactome pathway analysis unraveled potentially relevant molecular targets and disease-associated pathways, and protein-protein interaction networks were constructed to highlight key targets. The discriminatory value of both the total proteome and the phosphoproteome was evaluated by univariate and multivariate approaches. This pilot experiment supports that bdEP are enriched in phosphotargets relevant in an AD context, holding value as peripheral biomarker candidates for disease diagnosis.
- Published
- 2024
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21. Visualization and Quantification of Rapid Chromosome Movements at Early Stages of Mouse Meiosis.
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de Almeida LP, Lee CY, Carbajal A, de Castro RO, and Pezza RJ
- Subjects
- Animals, Mice, Male, Time-Lapse Imaging methods, Telomere genetics, Telomere metabolism, Seminiferous Tubules cytology, Seminiferous Tubules metabolism, Chromosomes genetics, Meiosis
- Abstract
Telomere-led rapid chromosome movements (RPMs) are a conserved characteristic of chromosome dynamics in meiosis. RPMs have been suggested to influence critical meiotic functions such as DNA repair and the association of the homologous chromosomes. Here, we describe a method using 3D time-lapse fluorescence imaging to monitor RPMs in Hoechst-stained mouse seminiferous tubules explants. We supplement visualization with customized quantitative motion analysis and in silico simulation. The ability to carry out live imaging, combined with quantitative image analysis, offers a sensitive tool to investigate the regulation of RPMs, chromosome reorganizations that precede dynamic mid-prophase events, and their contribution to faithful transmission of genetic information., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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22. FTIR Spectroscopy and Blood-Derived Extracellular Vesicles Duo in Alzheimer's Disease.
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Soares Martins T, Ferreira M, Magalhães S, Leandro K, Almeida LP, Vogelgsang J, Breitling B, Hansen N, Esselmann H, Wiltfang J, da Cruz E Silva OAB, Nunes A, and Henriques AG
- Subjects
- Humans, Spectroscopy, Fourier Transform Infrared, Lipids, Carbohydrates, Alzheimer Disease metabolism, Extracellular Vesicles metabolism, Nucleic Acids metabolism
- Abstract
Background: Alzheimer's disease (AD) diagnosis is difficult, and new accurate tools based on peripheral biofluids are urgently needed. Extracellular vesicles (EVs) emerged as a valuable source of biomarker profiles for AD, since their cargo is disease-specific and these can be easily isolated from easily accessible biofluids, as blood. Fourier Transform Infrared (FTIR) spectroscopy can be employed to analyze EVs and obtain the spectroscopic profiles from different regions of the spectra, simultaneously characterizing carbohydrates, nucleic acids, proteins, and lipids., Objective: The aim of this study was to identify blood-derived EVs (bdEVs) spectroscopic signatures with AD discriminatory potential., Methods: Herein, FTIR spectra of bdEVs from two biofluids (serum and plasma) and distinct sets of Controls and AD cases were acquired, and EVs' spectra analyzed., Results: Analysis of bdEVs second derivative peaks area revealed differences between Controls and AD cases in distinct spectra regions, assigned to carbohydrates and nucleic acids, amides, and lipids., Conclusions: EVs' spectroscopic profiles presented AD discriminatory value, supporting the use of bdEVs combined with FTIR as a screening or complementary tool for AD diagnosis.
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- 2024
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23. Correction to: The frequency of non‑motor symptoms in SCA3 and their association with disease severity and lifestyle factors.
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Hengel H, Martus P, Faber J, Giunti P, Garcia-Moreno H, Solanky N, Klockgether T, Reetz K, van de Warrenburg BP, Santana MM, Silva P, Cunha I, de Almeida LP, Timmann D, Infante J, de Vries J, Lima M, Pires P, Bushara K, Jacobi H, Onyike C, Schmahmann JD, Hübener-Schmid J, Synofzik M, and Schöls L
- Published
- 2024
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24. Ghrelin delays premature aging in Hutchinson-Gilford progeria syndrome.
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Ferreira-Marques M, Carvalho A, Franco AC, Leal A, Botelho M, Carmo-Silva S, Águas R, Cortes L, Lucas V, Real AC, López-Otín C, Nissan X, de Almeida LP, Cavadas C, and Aveleira CA
- Subjects
- Adolescent, Child, Humans, Mice, Animals, Ghrelin pharmacology, Quality of Life, Skin metabolism, Lamin Type A genetics, Lamin Type A metabolism, Aging, Progeria drug therapy, Progeria genetics, Progeria metabolism, Aging, Premature drug therapy, Aging, Premature genetics
- Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal genetic condition that arises from a single nucleotide alteration in the LMNA gene, leading to the production of a defective lamin A protein known as progerin. The accumulation of progerin accelerates the onset of a dramatic premature aging phenotype in children with HGPS, characterized by low body weight, lipodystrophy, metabolic dysfunction, skin, and musculoskeletal age-related dysfunctions. In most cases, these children die of age-related cardiovascular dysfunction by their early teenage years. The absence of effective treatments for HGPS underscores the critical need to explore novel safe therapeutic strategies. In this study, we show that treatment with the hormone ghrelin increases autophagy, decreases progerin levels, and alleviates other cellular hallmarks of premature aging in human HGPS fibroblasts. Additionally, using a HGPS mouse model (Lmna
G609G/G609G mice), we demonstrate that ghrelin administration effectively rescues molecular and histopathological progeroid features, prevents progressive weight loss in later stages, reverses the lipodystrophic phenotype, and extends lifespan of these short-lived mice. Therefore, our findings uncover the potential of modulating ghrelin signaling offers new treatment targets and translational approaches that may improve outcomes and enhance the quality of life for patients with HGPS and other age-related pathologies., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)- Published
- 2023
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25. Campomanesia xanthocarpa (Myrtaceae: Myrtoideae) seedlings reveal morpho-physiological plasticity under shade conditions.
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Almeida SMZ, Almeida LP, Giacobbo CL, Galon L, Perboni AT, Sant'Anna-Santos BF, Bermeo P, and Danner MA
- Subjects
- Chlorophyll, Photosynthesis physiology, Plant Leaves physiology, Seedlings physiology, Myrtaceae
- Abstract
Plants exposed to different light intensities generate physiological, morphological, and anatomical changes conducting to plasticity. Thus, this characteristic establishes the ability of plants to present phenotypic adjustments by the same genotype under different environmental conditions. The objective of this study was to verify the morphophysiological alterations in Campomanesia xanthocarpa (Mart.) O. Berg (guabiroba) seedlings cultivated in different shading levels. The seedlings were grown for 21 months under full sun or 30%, 50%, and 80% under shading. Growth, photosynthetic pigments, gas exchange rate, chlorophyll fluorescence, and leaf anatomy were evaluated. In all the treatments subjected to shading, plasticity mechanisms involved structural and physiological changes such as an increase in leaf area and chlorophyll content (total and Chl a), reduction in leaf thickness, and increased gas exchange and quantum yield of photosystem II. The guabiroba seedlings can be cultivated in full sun or different shading environments; even under high shading intensity (80%), the plants showed vigor similar to those produced in a sunny environment. These results confirmed our hypothesis about guabiroba acclimation capacity to shading, noteworthy information for nurseries, orchards, agroforestry systems, or forest restoration in a wide range of light environments.
- Published
- 2023
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26. Selective, broad-spectrum antiviral photodynamic disinfection with dicationic imidazolyl chlorin photosensitizers.
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Arnaut ZA, Pinto SMA, Aroso RT, Amorim AS, Lobo CS, Schaberle FA, Pereira D, Núñez J, Nunes SCC, Pais AACC, Rodrigues-Santos P, de Almeida LP, Pereira MM, and Arnaut LG
- Subjects
- Humans, Photosensitizing Agents chemistry, Disinfection, Pandemics, HEK293 Cells, Prospective Studies, SARS-CoV-2, Antiviral Agents pharmacology, Photochemotherapy methods, Anti-Infective Agents
- Abstract
The COVID-19 pandemic exposes our vulnerability to viruses that acquire the ability to infect our cells. Classical disinfection methods are limited by toxicity. Existing medicines performed poorly against SARS-CoV-2 because of their specificity to targets in different organisms. We address the challenge of mitigating known and prospective viral infections with a new photosensitizer for antimicrobial photodynamic therapy (aPDT). Photodynamic inactivation is based on local oxidative stress, which is particularly damaging to enveloped viruses. We synthesized a cationic imidazolyl chlorin that reduced by > 99.999% of the percentage inhibition of amplification of SARS-CoV-2 collected from patients at 0.2 µM concentration and 4 J cm
-2 . Similar results were obtained in the prevention of infection of human ACE2-expressing HEK293T cells by a pseudotyped lentiviral vector exhibiting the S protein of SARS-CoV-2 at its surface. No toxicity to human epidermal keratinocytes (HaCaT) cells was found under similar conditions. aPDT with this chlorin offers fast and safe broad-spectrum photodisinfection and can be repeated with low risk of resistance., (© 2023. The Author(s).)- Published
- 2023
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27. Correlation between MOVA3D, a Monocular Movement Analysis System, and Qualisys Track Manager (QTM) during Lower Limb Movements in Healthy Adults: A Preliminary Study.
- Author
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Almeida LP, Guenka LC, Felipe DO, Ishii RP, Campos PS, and Burke TN
- Subjects
- Male, Humans, Adult, Female, Young Adult, Middle Aged, Posture, Motion, Lower Extremity, Movement, Augmented Reality
- Abstract
New technologies based on virtual reality and augmented reality offer promising perspectives in an attempt to increase the assessment of human kinematics. The aim of this work was to develop a markerless 3D motion analysis capture system (MOVA3D) and to test it versus Qualisys Track Manager (QTM). A digital camera was used to capture the data, and proprietary software capable of automatically inferring the joint centers in 3D and performing the angular kinematic calculations of interest was developed for such analysis. In the experiment, 10 subjects (22 to 50 years old), 5 men and 5 women, with a body mass index between 18.5 and 29.9 kg/m
2 , performed squatting, hip flexion, and abduction movements, and both systems measured the hip abduction/adduction angle and hip flexion/extension, simultaneously. The mean value of the difference between the QTM system and the MOVA3D system for all frames for each joint angle was analyzed with Pearson's correlation coefficient (r). The MOVA3D system reached good (above 0.75) or excellent (above 0.90) correlations in 6 out of 8 variables. The average error remained below 12° in only 20 out of 24 variables analyzed. The MOVA3D system is therefore promising for use in telerehabilitation or other applications where this level of error is acceptable. Future studies should continue to validate the MOVA3D as updated versions of their software are developed.- Published
- 2023
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28. A Novel Genetic Variant in MBD5 Associated with Severe Epilepsy and Intellectual Disability: Potential Implications on Neural Primary Cilia.
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Martins M, Oliveira AR, Martins S, Vieira JP, Perdigão P, Fernandes AR, de Almeida LP, Palma PJ, Sequeira DB, Santos JMM, Duque F, Oliveira G, Cardoso AL, Peça J, and Seabra CM
- Subjects
- Child, Humans, Cilia genetics, Seizures, DNA-Binding Proteins genetics, Intellectual Disability genetics, Epilepsy genetics, Neurodevelopmental Disorders
- Abstract
Disruptions in the MBD5 gene have been linked with an array of clinical features such as global developmental delay, intellectual disability, autistic-like symptoms, and seizures, through unclear mechanisms. MBD5 haploinsufficiency has been associated with the disruption of primary cilium-related processes during early cortical development, and this has been reported in many neurodevelopmental disorders. In this study, we describe the clinical history of a 12-year-old child harboring a novel MBD5 rare variant and presenting psychomotor delay and seizures. To investigate the impact of MBD5 haploinsufficiency on neural primary cilia, we established a novel patient-derived cell line and used CRISPR-Cas9 technology to create an isogenic control. The patient-derived neural progenitor cells revealed a decrease in the length of primary cilia and in the total number of ciliated cells. This study paves the way to understanding the impact of MBD5 haploinsufficiency in brain development through its potential impact on neural primary cilia.
- Published
- 2023
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29. Stage-dependent biomarker changes in spinocerebellar ataxia type 3.
- Author
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Faber J, Berger M, Carlo W, Hübener-Schmid J, Schaprian T, Santana MM, Grobe-Einsler M, Onder D, Koyak B, Giunti P, Garcia-Moreno H, Gonzalez-Robles C, Lima M, Raposo M, Melo ARV, de Almeida LP, Silva P, Pinto MM, van de Warrenburg BP, van Gaalen J, de Vries J, Jeroen, Oz G, Joers JM, Synofzik M, Schöls L, Riess O, Infante J, Manrique L, Timmann D, Thieme A, Jacobi H, Reetz K, Dogan I, Onyike C, Povazan M, Schmahmann J, Ratai EM, Schmid M, and Klockgether T
- Abstract
Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3) is the most common autosomal dominant ataxia. In view of the development of targeted therapies for SCA3, precise knowledge of stage-dependent fluid and MRI biomarker changes is needed. We analyzed cross-sectional data of 292 SCA3 mutation carriers including 57 pre-ataxic individuals, and 108 healthy controls from the European Spinocerebellar ataxia type 3/Machado-Joseph Disease Initiative (ESMI) cohort. Blood concentrations of mutant ATXN3 and neurofilament light (NfL) were determined, and volumes of pons, cerebellar white matter (CWM) and cerebellar grey matter (CGM) were measured on MRI. Mutant ATXN3 concentrations were high before and after ataxia onset, while NfL continuously increased and deviated from normal 11.9 years before onset. Pons and CWM volumes decreased, but the deviation from normal was only 2.0 years (pons) and 0.3 years (CWM) before ataxia onset. We propose a staging model of SCA3 that includes an initial asymptomatic carrier stage followed by the biomarker stage defined by absence of ataxia, but a significant rise of NfL. The biomarker stage leads into the ataxia stage, defined by manifest ataxia. The present analysis provides a robust framework for further studies aiming at elaboration and differentiation of the staging model of SCA3., Competing Interests: GO consults for IXICO Technologies Limited, which provides neuroimaging services and digital biomarker analytics to biopharmaceutical firms conducting clinical trials for SCAs, and receives research support from Biogen, which develops therapeutics for SCAs. MS has received consultancy honoraria from Janssen, Ionis, Orphazyme, Servier, Reata, GenOrph, and AviadoBio, all unrelated to the present manuscript. LS received consultancy honoraria from Vico Therapeutics and Novartis unrelated to the present manuscript. LPA research group has private funding from PTC Therapeutics, Uniqure, Wave life Sciences, Servier, Blade Therapeutics and Hoffmann-La Roche AG outside the submitted work.
- Published
- 2023
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30. A standardised protocol for blood and cerebrospinal fluid collection and processing for biomarker research in ataxia.
- Author
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Santana MM, Gaspar LS, Pinto MM, Silva P, Adão D, Pereira D, Ribeiro JA, Cunha I, Huebener-Schmid J, Raposo M, Ferreira AF, Faber J, Kuhs S, Garcia-Moreno H, Reetz K, Thieme A, Infante J, van de Warrenburg BPC, Giunti P, Riess O, Schöls L, Lima M, Klockgether T, Januário C, and de Almeida LP
- Subjects
- Humans, Biomarkers, Machado-Joseph Disease, Spinocerebellar Ataxias, Cerebellar Ataxia, Spinocerebellar Degenerations
- Abstract
The European Spinocerebellar Ataxia Type 3/Machado-Joseph Disease Initiative (ESMI) is a consortium established with the ambition to set up the largest European longitudinal trial-ready cohort of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease (SCA3/MJD), the most common autosomal dominantly inherited ataxia worldwide. A major focus of ESMI has been the identification of SCA3/MJD biomarkers to enable future interventional studies. As biosample collection and processing variables significantly impact the outcomes of biomarkers studies, biosampling procedures standardisation was done previously to study visit initiation. Here, we describe the ESMI consensus biosampling protocol, developed within the scope of ESMI, that ultimately might be translated to other neurodegenerative disorders, particularly ataxias, being the first step to protocol harmonisation in the field., (© 2023 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)
- Published
- 2023
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31. Isolation of Extracellular Vesicles from Human Follicular Fluid: Size-Exclusion Chromatography versus Ultracentrifugation.
- Author
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Soares M, Pinto MM, Nobre RJ, de Almeida LP, da Graça Rasteiro M, Almeida-Santos T, Ramalho-Santos J, and Sousa AP
- Subjects
- Humans, Female, Ultracentrifugation methods, Proteins metabolism, Chromatography, Gel, Follicular Fluid, Extracellular Vesicles metabolism
- Abstract
Follicular fluid (FF) is the microenvironment where a growing oocyte develops. Intrafollicular communication ensures oocyte competence and is carried out through paracrine signaling, the exchange of molecules via gap junctions, and the trafficking of extracellular vesicles (EVs). The study of FF-derived EVs is important for both translational and fundamental research in the female reproductive field. This study aimed to compare the efficacy and purity of two EV isolation methods: size-exclusion chromatography (SEC) and ultracentrifugation (UC). EVs isolated using SEC and UC were compared regarding their size and concentration using dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA); protein contamination was assessed with microBCA; specific EV markers were detected with Western blot, and EV morphology was studied with transmission electron microscopy (TEM). Our results show that although both techniques isolated small EVs, a significantly increased yield in particle number was clear with UC compared with SEC. On the other hand, SEC generated purer EVs with fewer protein contaminants and aggregates. In conclusion, the selection of the most suited approach to isolate EVs must be conducted considering the degree of recovery, purity, and downstream application of the isolated EVs.
- Published
- 2023
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32. The frequency of non-motor symptoms in SCA3 and their association with disease severity and lifestyle factors.
- Author
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Hengel H, Martus P, Faber J, Giunit P, Garcia-Moreno H, Solanky N, Klockgether T, Reetz K, van de Warrenburg BP, Santana MM, Silva P, Cunha I, de Almeida LP, Timmann D, Infante J, de Vries J, Lima M, Pires P, Bushara K, Jacobi H, Onyike C, Schmahmann JD, Hübener-Schmid J, Synofzik M, and Schöls L
- Subjects
- Humans, Prospective Studies, Cross-Sectional Studies, Activities of Daily Living, Patient Acuity, Life Style, Restless Legs Syndrome epidemiology
- Abstract
Background: Non-motor symptoms (NMS) are a substantial burden for patients with SCA3. There are limited data on their frequency, and their relation with disease severity and activities of daily living is not clear. In addition, lifestyle may either influence or be affected by the occurrence of NMS., Objective: To characterize NMS in SCA3 and investigate possible associations with disease severity and lifestyle factors., Methods: In a prospective cohort study, we performed a cross-sectional analysis of NMS in 227 SCA3 patients, 42 pre-ataxic mutation carriers, and 112 controls and tested for associations with SARA score, activities of daily living, and the lifestyle factors alcohol consumption, smoking and physical activity., Results: Sleep disturbance, restless legs syndrome, mild cognitive impairment, depression, bladder dysfunction and pallhypesthesia were frequent among SCA3 patients, while mainly absent in pre-ataxic mutation carriers. Except for restless legs syndrome, NMS correlated significantly with disease severity and activities of daily living. Alcohol abstinence was associated with bladder dysfunction. Patients with higher physical activity showed less cognitive impairment and fewer depressive symptoms, but these differences were not significant., Conclusion: This study revealed a clear association between disease severity and NMS, likely driven by the progression of the widespread neurodegenerative process. Associations between lifestyle and NMS can probably be attributed to the influence of NMS on lifestyle., (© 2022. The Author(s).)
- Published
- 2023
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33. Extracellular communication between brain cells through functional transfer of Cre mRNA.
- Author
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Rufino-Ramos D, Leandro K, Perdigão PRL, O'Brien K, Pinto MM, Santana MM, van Solinge TS, Mahjoum S, Breakefield XO, Breyne K, and de Almeida LP
- Abstract
In the central nervous system (CNS), the crosstalk between neural cells is mediated by extracellular mechanisms, including brain-derived extracellular vesicles (bdEVs). To study endogenous communication across the brain and periphery, we explored Cre-mediated DNA recombination to permanently record the functional uptake of bdEVs cargo overtime. To elucidate functional cargo transfer within the brain at physiological levels, we promoted the continuous secretion of physiological levels of neural bdEVs containing Cre mRNA from a localized region in the brain by in situ lentiviral transduction of the striatum of Flox-tdTomato Ai9 mice reporter of Cre activity. Our approach efficiently detected in vivo transfer of functional events mediated by physiological levels of endogenous bdEVs throughout the brain. Remarkably, a spatial gradient of persistent tdTomato expression was observed along the whole brain exhibiting an increment of more than 10-fold over 4 months. Moreover, bdEVs containing Cre mRNA were detected in the bloodstream and extracted from brain tissue to further confirm their functional delivery of Cre mRNA in a novel and highly sensitive Nanoluc reporter system. Overall, we report a sensitive method to track bdEVs transfer at physiological levels which will shed light on the role of bdEVs in neural communication within the brain and beyond., Competing Interests: Competing interests: The authors declare no competing interests.
- Published
- 2023
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34. Osteosarcoma-Derived Exosomes as Potential PET Imaging Nanocarriers for Lung Metastasis.
- Author
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Almeida SFF, Fonseca A, Sereno J, Ferreira HRS, Lapo-Pais M, Martins-Marques T, Rodrigues T, Oliveira RC, Miranda C, Almeida LP, Girão H, Falcão A, Abrunhosa AJ, and Gomes CM
- Subjects
- Humans, Positron-Emission Tomography, Lung Neoplasms diagnostic imaging
- Abstract
Lung metastases represent the most adverse clinical factor and rank as the leading cause of osteosarcoma-related death. Nearly 80% of patients present lung micrometastasis at diagnosis not detected with current clinical tools. Herein, an exosome (EX)-based imaging tool is developed for lung micrometastasis by positron emission tomography (PET) using osteosarcoma-derived EXs as natural nanocarriers of the positron-emitter copper-64 (
64 Cu). Exosomes are isolated from metastatic osteosarcoma cells and functionalized with the macrocyclic chelator NODAGA for complexation with64 Cu. Surface functionalization has no effect on the physicochemical properties of EXs, or affinity for donor cells and endows them with favorable pharmacokinetics for in vivo studies. Whole-body PET/magnetic resonance imaging (MRI) images in xenografted models show a specific accumulation of64 Cu-NODAGA-EXs in metastatic lesions as small as 2-3 mm or in a primary tumor, demonstrating the exquisite tropism of EXs for homotypic donor cells. The targetability for lung metastasis is also observed by optical imaging using indocyanine green (ICG)-labeled EXs and D-luciferin-loaded EXs. These findings show that tumor-derived EXs hold great potential as targeted imaging agents for the noninvasive detection of small lung metastasis by PET. This represents a step forward in the biomedical application of EXs in imaging diagnosis with increased translational potential., (© 2022 The Authors. Small published by Wiley-VCH GmbH.)- Published
- 2022
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35. SIRT1 activation and its circadian clock control: a promising approach against (frailty in) neurodegenerative disorders.
- Author
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Ribeiro RFN, Pereira D, de Almeida LP, Silva MMC, and Cavadas C
- Subjects
- Humans, Aged, Sirtuin 1 genetics, Circadian Rhythm, Circadian Clocks genetics, Frailty, Neurodegenerative Diseases, Alzheimer Disease
- Abstract
With the increase in life expectancy, the incidence of neurodegenerative disorders and their impact worldwide has been increasing in recent years. Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, have complex and varied mechanisms of pathogenesis. Importantly, they share the common feature of disrupted circadian rhythms. This hallmark is believed to underlie the symptoms of such diseases and even potentially contribute to their onset. In addition, the association of physical frailty with dementia and neurodegenerative disorders has been demonstrated. In fact, frail persons are 8 times more likely to have some form of dementia and population studies report a significant prevalence for frailty in older patients with AD and PD. SIRT1 regulates the acetylation status of clock components and controls circadian amplitude of clock genes. However, the mechanisms responsible for this circadian clock control have been the subject of contradictory findings. Importantly, the activation of SIRT1 has been shown to have very relevant therapeutic potential against neurodegeneration. Nevertheless, few studies have attempted to connect the therapeutic reestablishing of SIRT1 as an approach against circadian disruption in neurodegenerative diseases. In this review, we address: circadian rhythms as an important early biomarker of neurodegenerative disorders; mechanisms for SIRT1 activation and the novel sirtuin-activating compounds (STACs); SIRT1 circadian paradox and subsequent studies in an unprecedented way in the literature; the beneficial role of SIRT1 activation in neurodegeneration; innovative proposals of how circadian-based interventions (e.g., SIRT1 activators) may become an important therapeutic approach against neurodegenerative disorders and how non-pharmacologic interventions (e.g., Mediterranean-style diet) might help in the prevention and/or treatment of these high-burden disorders, while tackling frailty and enhancing robustness., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
- Published
- 2022
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36. Editorial: Gene therapy 2.0: Biotechnology for circuit engineering and complex therapeutic approaches.
- Author
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Quintino L, de Almeida LP, and Lundberg C
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2022
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37. Establishment and characterization of human pluripotent stem cells-derived brain organoids to model cerebellar diseases.
- Author
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Brás J, Henriques D, Moreira R, Santana MM, Silva-Pedrosa R, Adão D, Braz S, Álvaro AR, de Almeida LP, and Mendonça LS
- Subjects
- Animals, Brain metabolism, Humans, Organoids metabolism, Induced Pluripotent Stem Cells, Machado-Joseph Disease metabolism, Neurodegenerative Diseases metabolism
- Abstract
The establishment of robust human brain organoids to model cerebellar diseases is essential to study new therapeutic strategies for cerebellum-associated disorders. Machado-Joseph disease (MJD) is a cerebellar hereditary neurodegenerative disease, without therapeutic options able to prevent the disease progression. In the present work, control and MJD induced-pluripotent stem cells were used to establish human brain organoids. These organoids were characterized regarding brain development, cell type composition, and MJD-associated neuropathology markers, to evaluate their value for cerebellar diseases modeling. Our data indicate that the organoids recapitulated, to some extent, aspects of brain development, such as astroglia emerging after neurons and the presence of ventricular-like zones surrounded by glia and neurons that are found only in primate brains. Moreover, the brain organoids presented markers of neural progenitors proliferation, neuronal differentiation, inhibitory and excitatory synapses, and firing neurons. The established brain organoids also exhibited markers of cerebellar neurons progenitors and mature cerebellar neurons. Finally, MJD brain organoids showed higher ventricular-like zone numbers, an indication of lower maturation, and an increased number of ataxin-3-positive aggregates, compared with control organoids. Altogether, our data indicate that the established organoids recapitulate important characteristics of human brain development and exhibit cerebellar features, constituting a resourceful tool for testing therapeutic approaches for cerebellar diseases., (© 2022. The Author(s).)
- Published
- 2022
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38. Photodynamic disinfection of SARS-CoV-2 clinical samples using a methylene blue formulation.
- Author
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Lobo CS, Rodrigues-Santos P, Pereira D, Núñez J, Trêpa JCD, Sousa DL, Lourenço JV, Coelho MF, de Almeida LP, da Cunha JS, and Arnaut LG
- Subjects
- Disinfection methods, HEK293 Cells, Humans, Methylene Blue pharmacology, SARS-CoV-2, COVID-19 Drug Treatment
- Abstract
The amplitude of the coronavirus disease 2019 (COVID-19) pandemic motivated global efforts to find therapeutics that avert severe forms of this illness. The urgency of the medical needs privileged repositioning of approved medicines. Methylene blue (MB) has been in clinical use for a century and proved especially useful as a photosensitizer for photodynamic disinfection (PDI). We describe the use of MB to photo-inactivate SARS-CoV-2 in samples collected from COVID-19 patients. One minute of treatment can reduce the percentage inhibition of amplification by 99.99% under conditions of low cytotoxicity. We employed a pseudotyped lentiviral vector (LVs) encoding the luciferase reporter gene and exhibiting the S protein of SARS-CoV-2 at its surface, to infect human ACE2-expressing HEK293T cells. Pre-treatment of LVs with MB-PDI prevented infection at low micromolar MB concentrations and 1 min of illumination. These results reveal the potential of MB-PDI to reduce viral loads in the nasal cavity and oropharynx in the early stages of COVID-19, which may be employed to curb the transmission and severity of the disease., (© 2022. The Author(s), under exclusive licence to European Photochemistry Association, European Society for Photobiology.)
- Published
- 2022
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39. Exogenous loading of extracellular vesicles, virus-like particles, and lentiviral vectors with supercharged proteins.
- Author
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Breyne K, Ughetto S, Rufino-Ramos D, Mahjoum S, Grandell EA, de Almeida LP, and Breakefield XO
- Subjects
- Animals, Drug Delivery Systems, Mice, Plasmids, Transgenes, DNA genetics, Extracellular Vesicles metabolism
- Abstract
Cell membrane-based biovesicles (BVs) are important candidate drug delivery vehicles and comprise extracellular vesicles, virus-like particles, and lentiviral vectors. Here, we introduce a non-enzymatic assembly of purified BVs, supercharged proteins, and plasmid DNA called pDNA-scBVs. This multicomponent vehicle results from the interaction of negative sugar moieties on BVs and supercharged proteins that contain positively charged amino acids on their surface to enhance their affinity for pDNA. pDNA-scBVs were demonstrated to mediate floxed reporter activation in culture by delivering a Cre transgene. We introduced pDNA-scBVs containing both a CRE-encoding plasmid and a BV-packaged floxed reporter into the brains of Ai9 mice. Successful delivery of both payloads by pDNA-scBVs was confirmed with reporter signal in the striatal brain region. Overall, we developed a more efficient method to load isolated BVs with cargo that functionally modified recipient cells. Augmenting the natural properties of BVs opens avenues for adoptive extracellular interventions using therapeutic loaded cargo., (© 2022. The Author(s).)
- Published
- 2022
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40. Cerebellar morphometric and spectroscopic biomarkers for Machado-Joseph Disease.
- Author
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Miranda CO, Nobre RJ, Paiva VH, Duarte JV, Castelhano J, Petrella LI, Sereno J, Santana M, Afonso S, Januário C, Castelo-Branco M, and de Almeida LP
- Subjects
- Animals, Biomarkers, Cerebellum diagnostic imaging, Cerebellum pathology, Glutamic Acid, Humans, Mice, Mice, Transgenic, Taurine, Machado-Joseph Disease pathology
- Abstract
Machado-Joseph disease (MJD) or Spinocerebellar ataxia type 3 (SCA3) is the most common form of dominant SCA worldwide. Magnetic Resonance Imaging (MRI) and Proton Magnetic Resonance Spectroscopy (
1 H-MRS) provide promising non-invasive diagnostic and follow-up tools, also serving to evaluate therapies efficacy. However, pre-clinical studies showing relationship between MRI-MRS based biomarkers and functional performance are missing, which hampers an efficient clinical translation of therapeutics. This study assessed motor behaviour, neurochemical profiles, and morphometry of the cerebellum of MJD transgenic mice and patients aiming at establishing magnetic-resonance-based biomarkers.1 H-MRS and structural MRI measurements of MJD transgenic mice were performed with a 9.4 Tesla scanner, correlated with motor performance on rotarod and compared with data collected from human patients. We found decreased cerebellar white and grey matter and enlargement of the fourth ventricle in both MJD mice and human patients as compared to controls. N-acetylaspartate (NAA), NAA + N-acetylaspartylglutamate (NAA + NAAG), Glutamate, and Taurine, were significantly decreased in MJD mouse cerebellum regardless of age, whereas myo-Inositol (Ins) was increased at early time-points. Lower neurochemical ratios levels (NAA/Ins and NAA/total Choline), previously correlated with worse clinical status in SCAs, were also observed in MJD mice cerebella. NAA, NAA + NAAG, Glutamate, and Taurine were also positively correlated with MJD mice motor performance. Importantly, these1 H-MRS results were largely analogous to those found for MJD in human studies and in our pilot data in human patients. We have established a magnetic resonance-based biomarker approach to monitor novel therapies in preclinical studies and human clinical trials., (© 2022. The Author(s).)- Published
- 2022
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41. Cartilaginous choristoma on the lateral surface of the tongue: a case report.
- Author
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Bruzinga FFB, Costa BRM, Almeida LP, Souza MP, Horta MCR, and Grossman SMC
- Subjects
- Aged, Cartilage, Diagnosis, Differential, Female, Humans, Tongue, Choristoma diagnosis, Choristoma surgery, Tongue Diseases diagnosis, Tongue Diseases surgery
- Abstract
A cartilaginous choristoma is a nonneoplastic nodular growth of histologically normal cartilage in an abnormal site. This report describes a case of a cartilaginous choristoma on the lateral surface of the tongue in a 65-year-old woman. The entire lesion was excised, and histologic examination revealed mature cartilaginous tissue surrounded by dense connective tissue. Choristomas are rare findings in the oral cavity, easily confused with proliferative processes or soft tissue neoplasms. Nevertheless, choristomas may be part of the differential diagnosis for lesions similar to the one described in this case report., Competing Interests: The authors report no conflict of interest pertaining to any of the products or companies discussed in this article.
- Published
- 2022
42. Highly Porous Composite Scaffolds Endowed with Antibacterial Activity for Multifunctional Grafts in Bone Repair.
- Author
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Neto AS, Pereira P, Fonseca AC, Dias C, Almeida MC, Barros I, Miranda CO, de Almeida LP, Morais PV, Coelho JFJ, and Ferreira JMF
- Abstract
The present study deals with the development of multifunctional biphasic calcium phosphate (BCP) scaffolds coated with biopolymers-poly(ε-caprolactone) (PCL) or poly(ester urea) (PEU)-loaded with an antibiotic drug, Rifampicin (RFP). The amounts of RFP incorporated into the PCL and PEU-coated scaffolds were 0.55 ± 0.04 and 0.45 ± 0.02 wt%, respectively. The in vitro drug release profiles in phosphate buffered saline over 6 days were characterized by a burst release within the first 8h, followed by a sustained release. The Korsmeyer-Peppas model showed that RFP release was controlled by polymer-specific non-Fickian diffusion. A faster burst release (67.33 ± 1.48%) was observed for the PCL-coated samples, in comparison to that measured (47.23 ± 0.31%) for the PEU-coated samples. The growth inhibitory activity against Escherichia coli and Staphylococcus aureus was evaluated. Although the RFP-loaded scaffolds were effective in reducing bacterial growth for both strains, their effectiveness depends on the particular bacterial strain, as well as on the type of polymer coating, since it rules the drug release behavior. The low antibacterial activity demonstrated by the BCP-PEU-RFP scaffold against E. coli could be a consequence of the lower amount of RFP that is released from this scaffold, when compared with BCP-PCL-RFP. In vitro studies showed excellent cytocompatibility, adherence, and proliferation of human mesenchymal stem cells on the BCP-PEU-RFP scaffold surface. The fabricated highly porous scaffolds that could act as an antibiotic delivery system have great potential for applications in bone regeneration and tissue engineering, while preventing bacterial infections.
- Published
- 2021
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- View/download PDF
43. Autophagy in Spinocerebellar ataxia type 2, a dysregulated pathway, and a target for therapy.
- Author
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Marcelo A, Afonso IT, Afonso-Reis R, Brito DVC, Costa RG, Rosa A, Alves-Cruzeiro J, Ferreira B, Henriques C, Nobre RJ, Matos CA, de Almeida LP, and Nóbrega C
- Subjects
- Animals, Disease Models, Animal, Female, Humans, Male, Mice, Transfection, Autophagy genetics, Spinocerebellar Ataxias genetics, Spinocerebellar Ataxias therapy
- Abstract
Spinocerebellar ataxia type 2 (SCA2) is an incurable and genetic neurodegenerative disorder. The disease is characterized by progressive degeneration of several brain regions, resulting in severe motor and non-motor clinical manifestations. The mutation causing SCA2 disease is an abnormal expansion of CAG trinucleotide repeats in the ATXN2 gene, leading to a toxic expanded polyglutamine segment in the translated ataxin-2 protein. While the genetic cause is well established, the exact mechanisms behind neuronal death induced by mutant ataxin-2 are not yet completely understood. Thus, the goal of this study is to investigate the role of autophagy in SCA2 pathogenesis and investigate its suitability as a target for therapeutic intervention. For that, we developed and characterized a new striatal lentiviral mouse model that resembled several neuropathological hallmarks observed in SCA2 disease, including formation of aggregates, neuronal marker loss, cell death and neuroinflammation. In this new model, we analyzed autophagic markers, which were also analyzed in a SCA2 cellular model and in human post-mortem brain samples. Our results showed altered levels of SQSTM1 and LC3B in cells and tissues expressing mutant ataxin-2. Moreover, an abnormal accumulation of these markers was detected in SCA2 patients' striatum and cerebellum. Importantly, the molecular activation of autophagy, using the compound cordycepin, mitigated the phenotypic alterations observed in disease models. Overall, our study suggests an important role for autophagy in the context of SCA2 pathology, proposing that targeting this pathway could be a potential target to treat SCA2 patients., (© 2021. The Author(s).)
- Published
- 2021
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44. The Parkinson's-disease-associated mutation LRRK2-G2019S alters dopaminergic differentiation dynamics via NR2F1.
- Author
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Walter J, Bolognin S, Poovathingal SK, Magni S, Gérard D, Antony PMA, Nickels SL, Salamanca L, Berger E, Smits LM, Grzyb K, Perfeito R, Hoel F, Qing X, Ohnmacht J, Bertacchi M, Jarazo J, Ignac T, Monzel AS, Gonzalez-Cano L, Krüger R, Sauter T, Studer M, de Almeida LP, Tronstad KJ, Sinkkonen L, Skupin A, and Schwamborn JC
- Subjects
- Animals, Brain pathology, COUP Transcription Factor I genetics, Cell Cycle, Cell Line, Cell Proliferation, Cell Survival, Dopaminergic Neurons pathology, Female, Humans, Induced Pluripotent Stem Cells pathology, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 genetics, Male, Mice, 129 Strain, Mice, Knockout, Mutation, Neural Stem Cells pathology, Parkinson Disease genetics, Parkinson Disease pathology, Phenotype, RNA-Seq, Signal Transduction, Single-Cell Analysis, Time Factors, Mice, Brain enzymology, COUP Transcription Factor I metabolism, Dopaminergic Neurons enzymology, Induced Pluripotent Stem Cells enzymology, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 metabolism, Neural Stem Cells enzymology, Neurogenesis, Parkinson Disease enzymology
- Abstract
Increasing evidence suggests that neurodevelopmental alterations might contribute to increase the susceptibility to develop neurodegenerative diseases. We investigate the occurrence of developmental abnormalities in dopaminergic neurons in a model of Parkinson's disease (PD). We monitor the differentiation of human patient-specific neuroepithelial stem cells (NESCs) into dopaminergic neurons. Using high-throughput image analyses and single-cell RNA sequencing, we observe that the PD-associated LRRK2-G2019S mutation alters the initial phase of neuronal differentiation by accelerating cell-cycle exit with a concomitant increase in cell death. We identify the NESC-specific core regulatory circuit and a molecular mechanism underlying the observed phenotypes. The expression of NR2F1, a key transcription factor involved in neurogenesis, decreases in LRRK2-G2019S NESCs, neurons, and midbrain organoids compared to controls. We also observe accelerated dopaminergic differentiation in vivo in NR2F1-deficient mouse embryos. This suggests a pathogenic mechanism involving the LRRK2-G2019S mutation, where the dynamics of dopaminergic differentiation are modified via NR2F1., Competing Interests: Declaration of interests J.C.S., J.J., and S.B. are shareholders of the spin-off company OrganoTherapeutics sarl. J.C.S. and J.J. are also partially paid by the company., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
45. A global analysis of extreme coastal water levels with implications for potential coastal overtopping.
- Author
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Almar R, Ranasinghe R, Bergsma EWJ, Diaz H, Melet A, Papa F, Vousdoukas M, Athanasiou P, Dada O, Almeida LP, and Kestenare E
- Abstract
Climate change and anthropogenic pressures are widely expected to exacerbate coastal hazards such as episodic coastal flooding. This study presents global-scale potential coastal overtopping estimates, which account for not only the effects of sea level rise and storm surge, but also for wave runup at exposed open coasts. Here we find that the globally aggregated annual overtopping hours have increased by almost 50% over the last two decades. A first-pass future assessment indicates that globally aggregated annual overtopping hours will accelerate faster than the global mean sea-level rise itself, with a clearly discernible increase occurring around mid-century regardless of climate scenario. Under RCP 8.5, the globally aggregated annual overtopping hours by the end of the 21
st -century is projected to be up to 50 times larger compared to present-day. As sea level continues to rise, more regions around the world are projected to become exposed to coastal overtopping.- Published
- 2021
- Full Text
- View/download PDF
46. Stress granules, RNA-binding proteins and polyglutamine diseases: too much aggregation?
- Author
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Marcelo A, Koppenol R, de Almeida LP, Matos CA, and Nóbrega C
- Subjects
- Animals, Cytoplasmic Granules metabolism, Humans, Neurodegenerative Diseases metabolism, Neurodegenerative Diseases pathology, Protein Aggregation, Pathological complications, Protein Aggregation, Pathological metabolism, Protein Aggregation, Pathological pathology, RNA-Binding Proteins metabolism, Signal Transduction physiology, Cytoplasmic Granules physiology, Neurodegenerative Diseases etiology, Peptides metabolism, RNA-Binding Proteins physiology, Stress, Physiological physiology
- Abstract
Stress granules (SGs) are membraneless cell compartments formed in response to different stress stimuli, wherein translation factors, mRNAs, RNA-binding proteins (RBPs) and other proteins coalesce together. SGs assembly is crucial for cell survival, since SGs are implicated in the regulation of translation, mRNA storage and stabilization and cell signalling, during stress. One defining feature of SGs is their dynamism, as they are quickly assembled upon stress and then rapidly dispersed after the stress source is no longer present. Recently, SGs dynamics, their components and their functions have begun to be studied in the context of human diseases. Interestingly, the regulated protein self-assembly that mediates SG formation contrasts with the pathological protein aggregation that is a feature of several neurodegenerative diseases. In particular, aberrant protein coalescence is a key feature of polyglutamine (PolyQ) diseases, a group of nine disorders that are caused by an abnormal expansion of PolyQ tract-bearing proteins, which increases the propensity of those proteins to aggregate. Available data concerning the abnormal properties of the mutant PolyQ disease-causing proteins and their involvement in stress response dysregulation strongly suggests an important role for SGs in the pathogenesis of PolyQ disorders. This review aims at discussing the evidence supporting the existence of a link between SGs functionality and PolyQ disorders, by focusing on the biology of SGs and on the way it can be altered in a PolyQ disease context.
- Published
- 2021
- Full Text
- View/download PDF
47. Mesenchymal stromal cells to fight SARS-CoV-2: Taking advantage of a pleiotropic therapy.
- Author
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Barros I, Silva A, de Almeida LP, and Miranda CO
- Subjects
- COVID-19 epidemiology, Cell- and Tissue-Based Therapy methods, Cell- and Tissue-Based Therapy trends, Humans, Multiple Organ Failure prevention & control, Multiple Organ Failure therapy, SARS-CoV-2 pathogenicity, COVID-19 therapy, Mesenchymal Stem Cell Transplantation methods, Mesenchymal Stem Cell Transplantation trends, Mesenchymal Stem Cells physiology
- Abstract
The devastating global impact of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has prompted scientists to develop novel strategies to fight Coronavirus Disease of 2019 (COVID-19), including the examination of pre-existing treatments for other viral infections in COVID-19 patients. This review provides a reasoned discussion of the possible use of Mesenchymal Stromal Cells (MSC) or their products as a treatment in SARS-CoV-2-infected patients. The main benefits and concerns of using this cellular therapy, guided by preclinical and clinical data obtained from similar pathologies will be reviewed. MSC represent a highly immunomodulatory cell population and their use may be safe according to clinical studies developed in other pathologies. Notably, four clinical trials and four case reports that have already been performed in COVID-19 patients obtained promising results. The clinical application of MSC in COVID-19 is very preliminary and further investigational studies are required to determine the efficacy of the MSC therapy. Nevertheless, these preliminary studies were important to understand the therapeutic potential of MSC in COVID-19. Based on these encouraging results, the United States Food and Drug Administration (FDA) authorized the compassionate use of MSC, but only in patients with Acute Respiratory Distress Syndrome (ARDS) and a poor prognosis. In fact, patients with severe SARS-CoV-2 can present infection and tissue damage in different organs, such as lung, heart, liver, kidney, gut and brain, affecting their function. MSC may have pleiotropic activities in COVID-19, with the capacity to fight inflammation and repair lesions in several organs., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
48. Mitochondrial and Redox Modifications in Huntington Disease Induced Pluripotent Stem Cells Rescued by CRISPR/Cas9 CAGs Targeting.
- Author
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Lopes C, Tang Y, Anjo SI, Manadas B, Onofre I, de Almeida LP, Daley GQ, Schlaeger TM, and Rego ACC
- Abstract
Mitochondrial deregulation has gained increasing support as a pathological mechanism in Huntington's disease (HD), a genetic-based neurodegenerative disorder caused by CAG expansion in the HTT gene. In this study, we thoroughly investigated mitochondrial-based mechanisms in HD patient-derived iPSC (HD-iPSC) and differentiated neural stem cells (NSC) versus control cells, as well as in cells subjected to CRISPR/Cas9-CAG repeat deletion. We analyzed mitochondrial morphology, function and biogenesis, linked to exosomal release of mitochondrial components, glycolytic flux, ATP generation and cellular redox status. Mitochondria in HD cells exhibited round shape and fragmented morphology. Functionally, HD-iPSC and HD-NSC displayed lower mitochondrial respiration, exosomal release of cytochrome c, decreased ATP/ADP, reduced PGC-1α and complex III subunit expression and activity, and were highly dependent on glycolysis, supported by pyruvate dehydrogenase (PDH) inactivation. HD-iPSC and HD-NSC mitochondria showed ATP synthase reversal and increased calcium retention. Enhanced mitochondrial reactive oxygen species (ROS) were also observed in HD-iPSC and HD-NSC, along with decreased UCP2 mRNA levels. CRISPR/Cas9-CAG repeat deletion in HD-iPSC and derived HD-NSC ameliorated mitochondrial phenotypes. Data attests for intricate metabolic and mitochondrial dysfunction linked to transcriptional deregulation as early events in HD pathogenesis, which are alleviated following CAG deletion., (Copyright © 2020 Lopes, Tang, Anjo, Manadas, Onofre, de Almeida, Daley, Schlaeger and Rego.)
- Published
- 2020
- Full Text
- View/download PDF
49. Burnout among nursing students: a mixed method study.
- Author
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Quina Galdino MJ, Brando Matos de Almeida LP, Ferreira Rigonatti da Silva L, Cremer E, Rolim Scholze A, Trevisan Martins J, and Fernandez Lourenço Haddad MDC
- Subjects
- Academic Performance psychology, Adolescent, Adult, Brazil epidemiology, Burnout, Professional diagnosis, Curriculum, Depersonalization psychology, Education, Nursing, Baccalaureate, Female, Health Surveys, Humans, Linear Models, Male, Prevalence, Qualitative Research, Workload psychology, Young Adult, Burnout, Professional epidemiology, Students, Nursing psychology
- Abstract
Objectives: Investigate the burnout syndrome among undergraduate students in nursing., Methods: Explanatory sequential mixed method study conducted at a public university in Brazil. Of the 119 nursing students, 114 consented to participate and answered a questionnaire composed of sociodemographic, academic variables, and the Maslach Burnout Inventory - Student Survey, which were analyzed by multiple linear regression. The participants of the quantitative phase with the indicative / risk of burnout were interviewed individually (n=21) to provide an in-depth understanding of the students' experiences regarding the dimensions of the syndrome, whose statements were analyzed by the Collective Subject Discourse., Results: The prevalence of burnout syndrome was 10.5% among the surveyed. The more advanced the school year, the higher were the exhaustion (p=0.003), depersonalization (p < 0.001) and low academic effectiveness (p=0.012) scores. Students with a higher workload of assignments also had higher scores of exhaustion (p=0.001), depersonalization (p < 0.001) and academic (in)effectiveness (p=0.042). Dissatisfaction with the course was related to higher exhaustion (p=0.049) and depersonalization (p=0.001). The collective speeches showed the daily demands of the course, considered as intense, producing overload and exhaustion, which produced symptoms of physical and mental illness. Thus, there was the student's distancing from the course activities, as a defensive attitude, which culminated in feelings of incompetence and frustration., Conclusions: The occurrence of burnout syndrome dimensions among nursing students was related to the activities of academic daily life. It is urgent to invest in health promotion and prevention actions of these individuals in the university context., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by the Universidad de Antioquia.)
- Published
- 2020
- Full Text
- View/download PDF
50. Restoring brain cholesterol turnover improves autophagy and has therapeutic potential in mouse models of spinocerebellar ataxia.
- Author
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Nóbrega C, Mendonça L, Marcelo A, Lamazière A, Tomé S, Despres G, Matos CA, Mechmet F, Langui D, den Dunnen W, de Almeida LP, Cartier N, and Alves S
- Subjects
- Adult, Animals, Brain pathology, Disease Models, Animal, Female, Humans, Machado-Joseph Disease pathology, Male, Mice, Transgenic, Middle Aged, Nerve Tissue Proteins metabolism, Purkinje Cells metabolism, Purkinje Cells pathology, Spinocerebellar Ataxias pathology, Autophagy physiology, Brain metabolism, Cholesterol metabolism, Machado-Joseph Disease metabolism, Spinocerebellar Ataxias metabolism
- Abstract
Spinocerebellar ataxias (SCAs) are devastating neurodegenerative disorders for which no curative or preventive therapies are available. Deregulation of brain cholesterol metabolism and impaired brain cholesterol turnover have been associated with several neurodegenerative diseases. SCA3 or Machado-Joseph disease (MJD) is the most prevalent ataxia worldwide. We show that cholesterol 24-hydroxylase (CYP46A1), the key enzyme allowing efflux of brain cholesterol and activating brain cholesterol turnover, is decreased in cerebellar extracts from SCA3 patients and SCA3 mice. We investigated whether reinstating CYP46A1 expression would improve the disease phenotype of SCA3 mouse models. We show that administration of adeno-associated viral vectors encoding CYP46A1 to a lentiviral-based SCA3 mouse model reduces mutant ataxin-3 accumulation, which is a hallmark of SCA3, and preserves neuronal markers. In a transgenic SCA3 model with a severe motor phenotype we confirm that cerebellar delivery of AAVrh10-CYP46A1 is strongly neuroprotective in adult mice with established pathology. CYP46A1 significantly decreases ataxin-3 protein aggregation, alleviates motor impairments and improves SCA3-associated neuropathology. In particular, improvement in Purkinje cell number and reduction of cerebellar atrophy are observed in AAVrh10-CYP46A1-treated mice. Conversely, we show that knocking-down CYP46A1 in normal mouse brain impairs cholesterol metabolism, induces motor deficits and produces strong neurodegeneration with impairment of the endosomal-lysosomal pathway, a phenotype closely resembling that of SCA3. Remarkably, we demonstrate for the first time both in vitro, in a SCA3 cellular model, and in vivo, in mouse brain, that CYP46A1 activates autophagy, which is impaired in SCA3, leading to decreased mutant ataxin-3 deposition. More broadly, we show that the beneficial effect of CYP46A1 is also observed with mutant ataxin-2 aggregates. Altogether, our results confirm a pivotal role for CYP46A1 and brain cholesterol metabolism in neuronal function, pointing to a key contribution of the neuronal cholesterol pathway in mechanisms mediating clearance of aggregate-prone proteins. This study identifies CYP46A1 as a relevant therapeutic target not only for SCA3 but also for other SCAs.
- Published
- 2019
- Full Text
- View/download PDF
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