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3. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14

Author

Rafehi, H, Read, J, Szmulewicz, DJ, Davies, KC, Snell, P, Fearnley, LG, Scott, L, Thomsen, M, Gillies, G, Pope, K, Bennett, MF, Munro, JE, Ngo, KJ, Chen, L, Wallis, MJ, Butler, EG, Kumar, KR, Wu, KHC, Tomlinson, SE, Tisch, S, Malhotra, A, Lee-Archer, M, Dolzhenko, E, Eberle, MA, Roberts, LJ, Fogel, BL, Bruggemann, N, Lohmann, K, Delatycki, MB, Bahlo, M, Lockhart, PJ, Rafehi, H, Read, J, Szmulewicz, DJ, Davies, KC, Snell, P, Fearnley, LG, Scott, L, Thomsen, M, Gillies, G, Pope, K, Bennett, MF, Munro, JE, Ngo, KJ, Chen, L, Wallis, MJ, Butler, EG, Kumar, KR, Wu, KHC, Tomlinson, SE, Tisch, S, Malhotra, A, Lee-Archer, M, Dolzhenko, E, Eberle, MA, Roberts, LJ, Fogel, BL, Bruggemann, N, Lohmann, K, Delatycki, MB, Bahlo, M, and Lockhart, PJ

Abstract

Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified an intronic (GAA) repeat expansion in fibroblast growth factor 14 (FGF14). Genetic analysis of 95 Australian individuals with adult-onset ataxia identified four (4.2%) with (GAA)>300 and a further nine individuals with (GAA)>250. PCR and long-read sequence analysis revealed these were pure (GAA) repeats. In comparison, no control subjects had (GAA)>300 and only 2/311 control individuals (0.6%) had a pure (GAA)>250. In a German validation cohort, 9/104 (8.7%) of affected individuals had (GAA)>335 and a further six had (GAA)>250, whereas 10/190 (5.3%) control subjects had (GAA)>250 but none were (GAA)>335. The combined data suggest (GAA)>335 are disease causing and fully penetrant (p = 6.0 × 10-8, OR = 72 [95% CI = 4.3-1,227]), while (GAA)>250 is likely pathogenic with reduced penetrance. Affected individuals had an adult-onset, slowly progressive cerebellar ataxia with variable features including vestibular impairment, hyper-reflexia, and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2 = 0.44, p = 0.00045, slope = -0.12) and identification of a shared haplotype in a minority of individuals suggests that the expansion can be inherited or generated de novo during meiotic division. This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansions via model-free, genome-wide analysis and identifies SCA50/ATX-FGF14 as a frequent cause of adult-onset ataxia.

Published
2023

4. Using global team science to identify genetic parkinson's disease worldwide

Author

Vollstedt, E, Kasten, M, Klein, C, Aasly, J, Adler, C, Ahmad-Annuar, A, Albanese, A, Alcalay, R, Al-Mubarak, B, Alvarez, V, Andree-Munoz, B, Annesi, G, Appel-Cresswell, S, Arkadir, D, Armasu, S, Barber, T, Bardien, S, Barkhuizen, M, Barrett, M, Basak, A, Beach, T, Benitez, B, Berg, D, Bhatia, K, Binkofski, F, Blauwendraat, C, Bonifati, V, Borges, V, Bozi, M, Brice, A, Brighina, L, Brockmann, K, Brucke, T, Bruggemann, N, Camacho, M, Cardoso, F, Belin, A, Carr, J, Chan, P, Chang-Castello, J, Chase, B, Chen-Plotkin, A, Ju Chung, S, Cilia, R, Clarimon, J, Clark, L, Cornejo-Olivas, M, Corvol, J, Cosentino, C, Cras, P, Crosiers, D, Damasio, J, Das, P, de Carvalho Aguiar, P, De Michele, G, De Rosa, A, Dieguez, E, Dorszewska, J, Erer, S, Ertan, S, Farrer, M, Fedotova, E, Ferese, R, Ferrarese, C, Ferraz, H, Fiala, O, Foroud, T, Friedman, A, Frigerio, R, Funayama, M, Gambardella, S, Garraux, G, Gatto, E, Genc, G, Giladi, N, Goldwurm, S, Gomez-Esteban, J, Gomez-Garre, P, Gorostidi, A, Grosset, D, Hanagasi, H, Hardy, J, Hassan, A, Hattori, N, Hauser, R, Hedera, P, Hentati, F, Hertz, J, Holton, J, Houlden, H, Hutz, M, Ikeuchi, T, Illarioshkin, S, Inca-Martinez, M, Infante, J, Jankovic, J, Jeon, B, Jesus, S, Jimenez-Del-Rio, M, Kaasinen, V, Kataoka, H, Kawakami, H, Kim, Y, Klivenyi, P, Koks, S, Konig, I, Kostic, V, Koziorowski, D, Kruger, R, Krygowska-Wajs, A, Kulisevsky, J, Lai, D, Lang, A, Ledoux, M, Lesage, S, Lim, S, Lin, C, Lohmann, K, Lopera, F, Lopez, G, Lu, C, Lynch, T, Machaczka, M, Madoev, H, Magalhaes, M, Majamaa, K, Maraganore, D, Marder, K, Markopoulou, K, Martikainen, M, Mata, I, Mazzetti, P, Mellick, G, Menendez-Gonzalez, M, Micheli, F, Mirelman, A, Mir, P, Morino, H, Morris, H, Munhoz, R, Naito, A, Olszewska, D, Ozelius, L, Padmanabhan, S, Paisan-Ruiz, C, Payami, H, Peluso, S, Petkovic, S, Petrucci, S, Pezzoli, G, Pimentel, M, Pirker, W, Pramstaller, P, Pulkes, T, Puschmann, A, Quattrone, A, Raggio, V, Ransmayr, G, Rieder, C, Riess, O, Rodriguez-Porcel, F, Rogaeva, E, Ross, O, Ruiz-Martinez, J, Sammler, E, San Luciano, M, Satake, W, Saunders-Pullman, R, Sazci, A, Scherzer, C, Schrag, A, Schumacher-Schuh, A, Sharma, M, Sidransky, E, Singleton, A, Petersen, M, Smolders, S, Spitz, M, Stefanis, L, Struhal, W, Sue, C, Swan, M, Swanberg, M, Taba, P, Taipa, R, Tan, M, Tan, A, Tan, E, Tang, B, Tayebi, N, Thaler, A, Thomas, A, Toda, T, Toft, M, Torres, L, Tumas, V, Valente, E, Van Broeckhoven, C, Vecsei, L, Velez-Pardo, C, Vidailhet, M, Warner, T, Williams-Gray, C, Winkelmann, J, Woitalla, D, Wood, N, Wszolek, Z, Wu, R, Wu, Y, Xie, T, Yoshino, H, Zhang, B, Zimprich, A, Vollstedt E. -J., Kasten M., Klein C., Aasly J., Adler C., Ahmad-Annuar A., Albanese A., Alcalay R. N., Al-Mubarak B., Alvarez V., Andree-Munoz B., Annesi G., Appel-Cresswell S., Arkadir D., Armasu S., Barber T. R., Bardien S., Barkhuizen M., Barrett M. J., Basak A. N., Beach T., Benitez B. A., Berg D., Bhatia K., Binkofski F., Blauwendraat C., Bonifati V., Borges V., Bozi M., Brice A., Brighina L., Brockmann K., Brucke T., Bruggemann N., Camacho M., Cardoso F., Belin A. C., Carr J., Chan P., Chang-Castello J., Chase B., Chen-Plotkin A., Ju Chung S., Cilia R., Clarimon J., Clark L., Cornejo-Olivas M., Corvol J. -C., Cosentino C., Cras P., Crosiers D., Damasio J., Das P., de Carvalho Aguiar P., De Michele G., De Rosa A., Dieguez E., Dorszewska J., Erer S., Ertan S., Farrer M., Fedotova E., Ferese R., Ferrarese C., Ferraz H., Fiala O., Foroud T., Friedman A., Frigerio R., Funayama M., Gambardella S., Garraux G., Gatto E. M., Genc G., Giladi N., Goldwurm S., Gomez-Esteban J. C., Gomez-Garre P., Gorostidi A., Grosset D., Hanagasi H., Hardy J., Hassan A., Hattori N., Hauser R. A., Hedera P., Hentati F., Hertz J. M., Holton J. L., Houlden H., Hutz M. H., Ikeuchi T., Illarioshkin S., Inca-Martinez M., Infante J., Jankovic J., Jeon B. S., Jesus S., Jimenez-Del-Rio M., Kaasinen V., Kataoka H., Kawakami H., Kim Y. J., Klivenyi P., Koks S., Konig I. R., Kostic V., Koziorowski D., Kruger R., Krygowska-Wajs A., Kulisevsky J., Lai D., Lang A., LeDoux M., Lesage S., Lim S. -Y., Lin C. -H., Lohmann K., Lopera F., Lopez G., Lu C. -S., Lynch T., Machaczka M., Madoev H., Magalhaes M., Majamaa K., Maraganore D., Marder K., Markopoulou K., Martikainen M. H., Mata I., Mazzetti P., Mellick G., Menendez-Gonzalez M., Micheli F., Mirelman A., Mir P., Morino H., Morris H., Munhoz R. P., Naito A., Olszewska D. A., Ozelius L. J., Padmanabhan S., Paisan-Ruiz C., Payami H., Peluso S., Petkovic S., Petrucci S., Pezzoli G., Pimentel M., Pirker W., Pramstaller P. P., Pulkes T., Puschmann A., Quattrone A., Raggio V., Ransmayr G., Rieder C., Riess O., Rodriguez-Porcel F., Rogaeva E., Ross O. A., Ruiz-Martinez J., Sammler E., San Luciano M., Satake W., Saunders-Pullman R., Sazci A., Scherzer C., Schrag A., Schumacher-Schuh A., Sharma M., Sidransky E., Singleton A. B., Petersen M. S., Smolders S., Spitz M., Stefanis L., Struhal W., Sue C. M., Swan M., Swanberg M., Taba P., Taipa R., Tan M., Tan A. H., Tan E. -K., Tang B., Tayebi N., Thaler A., Thomas A., Toda T., Toft M., Torres L., Tumas V., Valente E. M., Van Broeckhoven C., Vecsei L., Velez-Pardo C., Vidailhet M., Warner T. T., Williams-Gray C. H., Winkelmann J., Woitalla D., Wood N. W., Wszolek Z. K., Wu R. -M., Wu Y. -R., Xie T., Yoshino H., Zhang B., Zimprich A., Vollstedt, E, Kasten, M, Klein, C, Aasly, J, Adler, C, Ahmad-Annuar, A, Albanese, A, Alcalay, R, Al-Mubarak, B, Alvarez, V, Andree-Munoz, B, Annesi, G, Appel-Cresswell, S, Arkadir, D, Armasu, S, Barber, T, Bardien, S, Barkhuizen, M, Barrett, M, Basak, A, Beach, T, Benitez, B, Berg, D, Bhatia, K, Binkofski, F, Blauwendraat, C, Bonifati, V, Borges, V, Bozi, M, Brice, A, Brighina, L, Brockmann, K, Brucke, T, Bruggemann, N, Camacho, M, Cardoso, F, Belin, A, Carr, J, Chan, P, Chang-Castello, J, Chase, B, Chen-Plotkin, A, Ju Chung, S, Cilia, R, Clarimon, J, Clark, L, Cornejo-Olivas, M, Corvol, J, Cosentino, C, Cras, P, Crosiers, D, Damasio, J, Das, P, de Carvalho Aguiar, P, De Michele, G, De Rosa, A, Dieguez, E, Dorszewska, J, Erer, S, Ertan, S, Farrer, M, Fedotova, E, Ferese, R, Ferrarese, C, Ferraz, H, Fiala, O, Foroud, T, Friedman, A, Frigerio, R, Funayama, M, Gambardella, S, Garraux, G, Gatto, E, Genc, G, Giladi, N, Goldwurm, S, Gomez-Esteban, J, Gomez-Garre, P, Gorostidi, A, Grosset, D, Hanagasi, H, Hardy, J, Hassan, A, Hattori, N, Hauser, R, Hedera, P, Hentati, F, Hertz, J, Holton, J, Houlden, H, Hutz, M, Ikeuchi, T, Illarioshkin, S, Inca-Martinez, M, Infante, J, Jankovic, J, Jeon, B, Jesus, S, Jimenez-Del-Rio, M, Kaasinen, V, Kataoka, H, Kawakami, H, Kim, Y, Klivenyi, P, Koks, S, Konig, I, Kostic, V, Koziorowski, D, Kruger, R, Krygowska-Wajs, A, Kulisevsky, J, Lai, D, Lang, A, Ledoux, M, Lesage, S, Lim, S, Lin, C, Lohmann, K, Lopera, F, Lopez, G, Lu, C, Lynch, T, Machaczka, M, Madoev, H, Magalhaes, M, Majamaa, K, Maraganore, D, Marder, K, Markopoulou, K, Martikainen, M, Mata, I, Mazzetti, P, Mellick, G, Menendez-Gonzalez, M, Micheli, F, Mirelman, A, Mir, P, Morino, H, Morris, H, Munhoz, R, Naito, A, Olszewska, D, Ozelius, L, Padmanabhan, S, Paisan-Ruiz, C, Payami, H, Peluso, S, Petkovic, S, Petrucci, S, Pezzoli, G, Pimentel, M, Pirker, W, Pramstaller, P, Pulkes, T, Puschmann, A, Quattrone, A, Raggio, V, Ransmayr, G, Rieder, C, Riess, O, Rodriguez-Porcel, F, Rogaeva, E, Ross, O, Ruiz-Martinez, J, Sammler, E, San Luciano, M, Satake, W, Saunders-Pullman, R, Sazci, A, Scherzer, C, Schrag, A, Schumacher-Schuh, A, Sharma, M, Sidransky, E, Singleton, A, Petersen, M, Smolders, S, Spitz, M, Stefanis, L, Struhal, W, Sue, C, Swan, M, Swanberg, M, Taba, P, Taipa, R, Tan, M, Tan, A, Tan, E, Tang, B, Tayebi, N, Thaler, A, Thomas, A, Toda, T, Toft, M, Torres, L, Tumas, V, Valente, E, Van Broeckhoven, C, Vecsei, L, Velez-Pardo, C, Vidailhet, M, Warner, T, Williams-Gray, C, Winkelmann, J, Woitalla, D, Wood, N, Wszolek, Z, Wu, R, Wu, Y, Xie, T, Yoshino, H, Zhang, B, Zimprich, A, Vollstedt E. -J., Kasten M., Klein C., Aasly J., Adler C., Ahmad-Annuar A., Albanese A., Alcalay R. N., Al-Mubarak B., Alvarez V., Andree-Munoz B., Annesi G., Appel-Cresswell S., Arkadir D., Armasu S., Barber T. R., Bardien S., Barkhuizen M., Barrett M. J., Basak A. N., Beach T., Benitez B. A., Berg D., Bhatia K., Binkofski F., Blauwendraat C., Bonifati V., Borges V., Bozi M., Brice A., Brighina L., Brockmann K., Brucke T., Bruggemann N., Camacho M., Cardoso F., Belin A. C., Carr J., Chan P., Chang-Castello J., Chase B., Chen-Plotkin A., Ju Chung S., Cilia R., Clarimon J., Clark L., Cornejo-Olivas M., Corvol J. -C., Cosentino C., Cras P., Crosiers D., Damasio J., Das P., de Carvalho Aguiar P., De Michele G., De Rosa A., Dieguez E., Dorszewska J., Erer S., Ertan S., Farrer M., Fedotova E., Ferese R., Ferrarese C., Ferraz H., Fiala O., Foroud T., Friedman A., Frigerio R., Funayama M., Gambardella S., Garraux G., Gatto E. M., Genc G., Giladi N., Goldwurm S., Gomez-Esteban J. C., Gomez-Garre P., Gorostidi A., Grosset D., Hanagasi H., Hardy J., Hassan A., Hattori N., Hauser R. A., Hedera P., Hentati F., Hertz J. M., Holton J. L., Houlden H., Hutz M. H., Ikeuchi T., Illarioshkin S., Inca-Martinez M., Infante J., Jankovic J., Jeon B. S., Jesus S., Jimenez-Del-Rio M., Kaasinen V., Kataoka H., Kawakami H., Kim Y. J., Klivenyi P., Koks S., Konig I. R., Kostic V., Koziorowski D., Kruger R., Krygowska-Wajs A., Kulisevsky J., Lai D., Lang A., LeDoux M., Lesage S., Lim S. -Y., Lin C. -H., Lohmann K., Lopera F., Lopez G., Lu C. -S., Lynch T., Machaczka M., Madoev H., Magalhaes M., Majamaa K., Maraganore D., Marder K., Markopoulou K., Martikainen M. H., Mata I., Mazzetti P., Mellick G., Menendez-Gonzalez M., Micheli F., Mirelman A., Mir P., Morino H., Morris H., Munhoz R. P., Naito A., Olszewska D. A., Ozelius L. J., Padmanabhan S., Paisan-Ruiz C., Payami H., Peluso S., Petkovic S., Petrucci S., Pezzoli G., Pimentel M., Pirker W., Pramstaller P. P., Pulkes T., Puschmann A., Quattrone A., Raggio V., Ransmayr G., Rieder C., Riess O., Rodriguez-Porcel F., Rogaeva E., Ross O. A., Ruiz-Martinez J., Sammler E., San Luciano M., Satake W., Saunders-Pullman R., Sazci A., Scherzer C., Schrag A., Schumacher-Schuh A., Sharma M., Sidransky E., Singleton A. B., Petersen M. S., Smolders S., Spitz M., Stefanis L., Struhal W., Sue C. M., Swan M., Swanberg M., Taba P., Taipa R., Tan M., Tan A. H., Tan E. -K., Tang B., Tayebi N., Thaler A., Thomas A., Toda T., Toft M., Torres L., Tumas V., Valente E. M., Van Broeckhoven C., Vecsei L., Velez-Pardo C., Vidailhet M., Warner T. T., Williams-Gray C. H., Winkelmann J., Woitalla D., Wood N. W., Wszolek Z. K., Wu R. -M., Wu Y. -R., Xie T., Yoshino H., Zhang B., and Zimprich A.

Published
2019

6. Using global team science to identify genetic parkinson's disease worldwide

Author

Vollstedt, E. -J., Kasten, M., Klein, C., Aasly, J., Adler, C., Ahmad-Annuar, A., Albanese, Alberto, Alcalay, R. N., Al-Mubarak, B., Alvarez, V., Andree-Munoz, B., Annesi, G., Appel-Cresswell, S., Arkadir, D., Armasu, S., Barber, T. R., Bardien, S., Barkhuizen, M., Barrett, M. J., Basak, A. N., Beach, T., Benitez, B. A., Berg, D., Bhatia, K., Binkofski, F., Blauwendraat, C., Bonifati, V., Borges, V., Bozi, M., Brice, A., Brighina, L., Brockmann, K., Brucke, T., Bruggemann, N., Camacho, M., Cardoso, F., Belin, A. C., Carr, J., Chan, P., Chang-Castello, J., Chase, B., Chen-Plotkin, A., Ju Chung, S., Cilia, R., Clarimon, J., Clark, L., Cornejo-Olivas, M., Corvol, J. -C., Cosentino, C., Cras, P., Crosiers, D., Damasio, J., Das, P., de Carvalho Aguiar, P., De Michele, G., De Rosa, A., Dieguez, E., Dorszewska, J., Erer, S., Ertan, S., Farrer, M., Fedotova, E., Ferese, R., Ferrarese, C., Ferraz, H., Fiala, O., Foroud, T., Friedman, A., Frigerio, R., Funayama, M., Gambardella, S., Garraux, G., Gatto, E. M., Genc, G., Giladi, N., Goldwurm, S., Gomez-Esteban, J. C., Gomez-Garre, P., Gorostidi, A., Grosset, D., Hanagasi, H., Hardy, J., Hassan, A., Hattori, N., Hauser, R. A., Hedera, P., Hentati, F., Hertz, J. M., Holton, J. L., Houlden, H., Hutz, M. H., Ikeuchi, T., Illarioshkin, S., Inca-Martinez, M., Infante, J., Jankovic, J., Jeon, B. S., Jesus, S., Jimenez-Del-Rio, M., Kaasinen, V., Kataoka, H., Kawakami, H., Kim, Y. J., Klivenyi, P., Koks, S., Konig, I. R., Kostic, V., Koziorowski, D., Kruger, R., Krygowska-Wajs, A., Kulisevsky, J., Lai, D., Lang, A., Ledoux, M., Lesage, S., Lim, S. -Y., Lin, C. -H., Lohmann, K., Lopera, F., Lopez, G., Lu, C. -S., Lynch, T., Machaczka, M., Madoev, H., Magalhaes, M., Majamaa, K., Maraganore, D., Marder, K., Markopoulou, K., Martikainen, M. H., Mata, I., Mazzetti, P., Mellick, G., Menendez-Gonzalez, M., Micheli, F., Mirelman, A., Mir, P., Morino, H., Morris, H., Munhoz, R. P., Naito, A., Olszewska, D. A., Ozelius, L. J., Padmanabhan, S., Paisan-Ruiz, C., Payami, H., Peluso, S., Petkovic, S., Petrucci, S., Pezzoli, G., Pimentel, M., Pirker, W., Pramstaller, P. P., Pulkes, T., Puschmann, A., Quattrone, A., Raggio, V., Ransmayr, G., Rieder, C., Riess, O., Rodriguez-Porcel, F., Rogaeva, E., Ross, O. A., Ruiz-Martinez, J., Sammler, E., San Luciano, M., Satake, W., Saunders-Pullman, R., Sazci, A., Scherzer, C., Schrag, A., Schumacher-Schuh, A., Sharma, M., Sidransky, E., Singleton, A. B., Petersen, M. S., Smolders, S., Spitz, M., Stefanis, L., Struhal, W., Sue, C. M., Swan, M., Swanberg, M., Taba, P., Taipa, R., Tan, M., Tan, A. H., Tan, E. -K., Tang, B., Tayebi, N., Thaler, A., Thomas, A., Toda, T., Toft, M., Torres, L., Tumas, V., Valente, E. M., Van Broeckhoven, C., Vecsei, L., Velez-Pardo, C., Vidailhet, M., Warner, T. T., Williams-Gray, C. H., Winkelmann, J., Woitalla, D., Wood, N. W., Wszolek, Z. K., Wu, R. -M., Wu, Y. -R., Xie, T., Yoshino, H., Zhang, B., Zimprich, A., Albanese A. (ORCID:0000-0002-5864-0006), Vollstedt, E. -J., Kasten, M., Klein, C., Aasly, J., Adler, C., Ahmad-Annuar, A., Albanese, Alberto, Alcalay, R. N., Al-Mubarak, B., Alvarez, V., Andree-Munoz, B., Annesi, G., Appel-Cresswell, S., Arkadir, D., Armasu, S., Barber, T. R., Bardien, S., Barkhuizen, M., Barrett, M. J., Basak, A. N., Beach, T., Benitez, B. A., Berg, D., Bhatia, K., Binkofski, F., Blauwendraat, C., Bonifati, V., Borges, V., Bozi, M., Brice, A., Brighina, L., Brockmann, K., Brucke, T., Bruggemann, N., Camacho, M., Cardoso, F., Belin, A. C., Carr, J., Chan, P., Chang-Castello, J., Chase, B., Chen-Plotkin, A., Ju Chung, S., Cilia, R., Clarimon, J., Clark, L., Cornejo-Olivas, M., Corvol, J. -C., Cosentino, C., Cras, P., Crosiers, D., Damasio, J., Das, P., de Carvalho Aguiar, P., De Michele, G., De Rosa, A., Dieguez, E., Dorszewska, J., Erer, S., Ertan, S., Farrer, M., Fedotova, E., Ferese, R., Ferrarese, C., Ferraz, H., Fiala, O., Foroud, T., Friedman, A., Frigerio, R., Funayama, M., Gambardella, S., Garraux, G., Gatto, E. M., Genc, G., Giladi, N., Goldwurm, S., Gomez-Esteban, J. C., Gomez-Garre, P., Gorostidi, A., Grosset, D., Hanagasi, H., Hardy, J., Hassan, A., Hattori, N., Hauser, R. A., Hedera, P., Hentati, F., Hertz, J. M., Holton, J. L., Houlden, H., Hutz, M. H., Ikeuchi, T., Illarioshkin, S., Inca-Martinez, M., Infante, J., Jankovic, J., Jeon, B. S., Jesus, S., Jimenez-Del-Rio, M., Kaasinen, V., Kataoka, H., Kawakami, H., Kim, Y. J., Klivenyi, P., Koks, S., Konig, I. R., Kostic, V., Koziorowski, D., Kruger, R., Krygowska-Wajs, A., Kulisevsky, J., Lai, D., Lang, A., Ledoux, M., Lesage, S., Lim, S. -Y., Lin, C. -H., Lohmann, K., Lopera, F., Lopez, G., Lu, C. -S., Lynch, T., Machaczka, M., Madoev, H., Magalhaes, M., Majamaa, K., Maraganore, D., Marder, K., Markopoulou, K., Martikainen, M. H., Mata, I., Mazzetti, P., Mellick, G., Menendez-Gonzalez, M., Micheli, F., Mirelman, A., Mir, P., Morino, H., Morris, H., Munhoz, R. P., Naito, A., Olszewska, D. A., Ozelius, L. J., Padmanabhan, S., Paisan-Ruiz, C., Payami, H., Peluso, S., Petkovic, S., Petrucci, S., Pezzoli, G., Pimentel, M., Pirker, W., Pramstaller, P. P., Pulkes, T., Puschmann, A., Quattrone, A., Raggio, V., Ransmayr, G., Rieder, C., Riess, O., Rodriguez-Porcel, F., Rogaeva, E., Ross, O. A., Ruiz-Martinez, J., Sammler, E., San Luciano, M., Satake, W., Saunders-Pullman, R., Sazci, A., Scherzer, C., Schrag, A., Schumacher-Schuh, A., Sharma, M., Sidransky, E., Singleton, A. B., Petersen, M. S., Smolders, S., Spitz, M., Stefanis, L., Struhal, W., Sue, C. M., Swan, M., Swanberg, M., Taba, P., Taipa, R., Tan, M., Tan, A. H., Tan, E. -K., Tang, B., Tayebi, N., Thaler, A., Thomas, A., Toda, T., Toft, M., Torres, L., Tumas, V., Valente, E. M., Van Broeckhoven, C., Vecsei, L., Velez-Pardo, C., Vidailhet, M., Warner, T. T., Williams-Gray, C. H., Winkelmann, J., Woitalla, D., Wood, N. W., Wszolek, Z. K., Wu, R. -M., Wu, Y. -R., Xie, T., Yoshino, H., Zhang, B., Zimprich, A., and Albanese A. (ORCID:0000-0002-5864-0006)

Abstract

Talks on rare diseases in the field of neurology often start with a statement like this: “About 80% of all rare diseases have a neurologic manifestation and about 80% of those are genetic in origin.” Although these numbers probably represent more of an estimate than well-documented evidence, rapidly advancing and cost-effective sequencing technologies have led to the quickly growing identification of patients with hereditary neurological diseases. Although the importance of genetics for diagnosis and genetic counseling is undisputed, the recent development of first genetargeted therapies entering clinical trial1,2 is adding an important new layer to the (re-)consideration of genetic testing in neurology. However, establishing accurate genotype– phenotype and genotype–treatment relationships requires large sample sizes. Systematic reviews can serve as instruments to combine information from several small samples, but unfortunately, this is often complicated by inconsistent and incomplete reporting of clinical and genetic data across studies. Thus, large multicenter approaches are necessary to systematically and uniformly characterize patients with genetic neurologic conditions and to eventually establish sizable clinical trial-ready cohorts.

Published
2019

7. Modeling soil processes: key challenges and new perspectives

Author

Vereecken, H., Schnepf, A., Hopmans, J.W., Javaux, M., Or, D., Roose, T., Vanderborght, J., Young, M., Amelung, W., Aitkenhead, M., Allison, S.D., Assouline, S., Baveye, P., Berli, M., Bruggemann, N., Finke, P., Flury, M., Gaiser, T., Govers, G., Ghezzehei, T., Hallett, P., Hendricks Franssen, H.J., Heppell, J., Horn, R., Huisman, J.A., Jacques, D., Jonard, F., Kollet, S., Lafolie, F., Lamorski, K., Leitner, D., McBratney, A., Minasny, B., Montzka, C., Nowak, W., Pachepsky, Y., Padarian, J., Romano, N., Roth, K., Rothfuss, Y., Rowe, E.C., Schwen, A., Simunek, J., Van Dam, J., van der Zee, S.E.A.T.M., Vogel, H.j., Vrugt, J.A., Wohling, T., and Young, I.M.

Abstract

The remarkable complexity of soil and its importance to a wide range of ecosystem services presents 133 major challenges to the modeling of soil processes. Although major progress in soil models has 134 occurred in the last decades, models of soil processes remain disjointed between disciplines or 135 ecosystem services, with considerable uncertainty remaining in the quality of predictions and several 136 challenges that remain yet to be addressed. Firstly, there is a need to improve exchange of knowledge 137 and experience amongst the different disciplines in soil science and to reach out to other Earth science 138 communities. Secondly, the community needs to develop a new generation of soil models based on a 139 systemic approach comprising relevant physical, chemical, and biological processes to address critical 140 knowledge gaps in our understanding of soil processes and their interactions. Overcoming these 141 challenges will facilitate exchanges between soil modeling and climate, plant, and social science 142 modeling communities. It will allow us to contribute to preserve and improve our assessment of 143 ecosystem services and advance our understanding of climate-change feedback mechanisms, amongst 144 others, thereby facilitating and strengthening communication among scientific disciplines and society. 145 In this paper we review the role of modeling soil processes in quantifying key soil processes that shape 146 ecosystem services with focus on provisioning and regulating services. We then identify key 147 challenges in modeling soil processes including the systematic incorporation of heterogeneity and 148 uncertainty, the integration of data and models, and strategies for effective integration of knowledge 149 on physical, chemical and biological soil processes. We discuss how the soil modeling community 150 could best interface with modern modeling activities in other disciplines such as climate, ecology, and 151 plant research and how to weave novel observation and measurement techniques into soil models. We 152 propose to establish an international soil modeling consortium to coherently advance soil modeling 153 activities and foster communication with other Earth science disciplines. Such a consortium should 154 promote soil modeling platforms and data repository for model development, calibration and inter-155 comparison essential for addressing contemporary challenges.

Published
2016

8. N2O source partitioning in soils using N-15 site preference values corrected for the N2O reduction effect

Author

Wu, D., Koster, J. R., Cardenas, L. M., Bruggemann, N., Lewicka-Szczebak, D., and Bol, R.

Subjects
Chemistry, Analytical, Biochemical Research Methods, Spectroscopy
Abstract

RationaleThe aim of this study was to determine the impact of isotope fractionation associated with N2O reduction during soil denitrification on N2O site preference (SP) values and hence quantify the potential bias on SP-based N2O source partitioning. MethodsThe N2O SP values (n=431) were derived from six soil incubation studies in N-2-free atmosphere, and determined by isotope ratio mass spectrometry (IRMS). The N-2 and N2O concentrations were measured directly by gas chromatography. Net isotope effects (NIE) during N2O reduction to N-2 were compensated for using three different approaches: a closed-system model, an open-system model and a dynamic apparent NIE function. The resulting SP values were used for N2O source partitioning based on a two end-member isotopic mass balance. ResultsThe average SP0 value, i.e. the average SP values of N2O prior to N2O reduction, was recalculated with the closed-system model, resulting in -2.6 (+/- 9.5), while the open-system model and the dynamic apparent NIE model gave average SP0 values of 2.9 parts per thousand (+/- 6.3) and 1.7 parts per thousand (+/- 6.3), respectively. The average source contribution of N2O from nitrification/fungal denitrification was 18.7% (+/- 21.0) according to the closed-system model, while the open-system model and the dynamic apparent NIE function resulted in values of 31.0% (+/- 14.0) and 28.3% (+/- 14.0), respectively. ConclusionsUsing a closed-system model with a fixed SP isotope effect may significantly overestimate the N2O reduction effect on SP values, especially when N2O reduction rates are high. This is probably due to soil inhomogeneity and can be compensated for by the application of a dynamic apparent NIE function, which takes the variable reduction rates in soil micropores into account. Copyright (c) 2016 John Wiley & Sons, Ltd.

Published
2016

10. Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene

Author

Lohmann, K., Wilcox, R.A., Winkler, S., Ramirez, A., Rakovic, A., Park, J.S., Arns, B., Lohnau, T., Groen, J., Kasten, M., Bruggemann, N., Hagenah, J., Schmidt, A., Kaiser, F.J., Kumar, K.R., Zschiedrich, K., Alvarez-Fischer, D., Altenmuller, E., Ferbert, A., Lang, A.E., Munchau, A., Kostic, V., Simonyan, K., Agzarian, M., Ozelius, L.J., Langeveld, A.P.M., Sue, C.M., Tijssen, M.A.J., Klein, C., and Other departments

Subjects
Family Health, Male, PRIMARY TORSION DYSTONIA, Voice Disorders, Genetic Linkage, DNA Mutational Analysis, Dystonia Musculorum Deformans, Magnetic Resonance Imaging, Severity of Illness Index, Article, Imaging, Three-Dimensional, Tubulin, BETA-TUBULIN ISOTYPES, Mutation, otorhinolaryngologic diseases, LINKAGE, Humans, Female, Genetic Predisposition to Disease, NUCLEAR-ENVELOPE, Chromosomes, Human, Pair 19, Follow-Up Studies
Abstract

Objective A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family. Methods Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of TUBB4 mRNA were determined by quantitative real-time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients. Results The disease-causing gene was mapped to a 23cM region on chromosome 19p13.3-p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the TUBB4 (tubulin beta-4; Arg2Gly) gene as the likely cause of disease. Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls. Interpretation A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia. Ann Neurol 2013;73:537-545

Published
2013

11. Short- and long-term outcome of chronic pallidal neurostimulation in monogenic isolated dystonia

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Bruggemann, N., Kuhn, A., Schneider, S. A., Kamm, C., Wolters, A., Krause, P., Moro, E., Steigerwald, F., Wittstock, M., Tronnier, V., Lozano, A. M., Hamani, C., Poon, Y. Y., Zittel, S., Wachter, T., Deuschl, G., Krüger, Rejko, Kupsch, A., Munchau, A., Lohmann, K., Volkmann, J., Klein, C., Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Bruggemann, N., Kuhn, A., Schneider, S. A., Kamm, C., Wolters, A., Krause, P., Moro, E., Steigerwald, F., Wittstock, M., Tronnier, V., Lozano, A. M., Hamani, C., Poon, Y. Y., Zittel, S., Wachter, T., Deuschl, G., Krüger, Rejko, Kupsch, A., Munchau, A., Lohmann, K., Volkmann, J., and Klein, C.

Abstract

OBJECTIVES: Deep brain stimulation of the internal pallidum (GPi-DBS) is an established therapeutic option in treatment-refractory dystonia, and the identification of factors predicting surgical outcome is needed to optimize patient selection. METHODS: In this retrospective multicenter study, GPi-DBS outcome of 8 patients with DYT6, 9 with DYT1, and 38 with isolated dystonia without known monogenic cause (non-DYT) was assessed at early (1-16 months) and late (22-92 months) follow-up using Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores. RESULTS: At early follow-up, mean reduction of dystonia severity was greater in patients with DYT1 (BFMDRS score: -60%) and non-DYT dystonia (-52%) than in patients with DYT6 dystonia (-32%; p = 0.046). Accordingly, the rate of responders was considerably lower in the latter group (57% vs >90%; p = 0.017). At late follow-up, however, GPi-DBS resulted in comparable improvement in all 3 groups (DYT6, -42%; DYT1, -44; non-DYT, -61%). Additional DBS of the same or another brain target was performed in 3 of 8 patients with DYT6 dystonia with varying results. Regardless of the genotype, patients with a shorter duration from onset of dystonia to surgery had better control of dystonia postoperatively. CONCLUSIONS: Long-term GPi-DBS is effective in patients with DYT6, DYT1, and non-DYT dystonia. However, the effect of DBS appears to be less predictable in patients with DYT6, suggesting that pre-DBS genetic testing and counseling for known dystonia gene mutations may be indicated. GPi-DBS should probably be considered earlier in the disease course. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that long-term GPi-DBS improves dystonia in patients with DYT1, DYT6, and non-DYT dystonia.

Published
2015

13. Neural network treatement of 3 years long NO measurement in temperate and tropical climates

Author

Dupont, R., Butterbach-Bahl, K., Bruggemann, N., Delon, Claire, Serça, Dominique, Laboratoire d'aérologie (LAERO), Centre National de la Recherche Scientifique (CNRS)-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées

Subjects
[PHYS.PHYS.PHYS-AO-PH]Physics [physics]/Physics [physics]/Atmospheric and Oceanic Physics [physics.ao-ph]
Abstract

Avril 2007.; The nitrogen monoxide (NO) is essential in atmospheric chemistry and especially in the troposphere, although this gas is in low concentration in the atmosphere (approximately 1 ppb). Indeed, it quickly reacts to obtain nitrogen dioxide (NO2) and to form tropospheric ozone, the major atmospheric oxidant. Nowadays, the increase of NOx concentration in the atmosphere is considered to be 0.25% per year (Davidson, 1997). This rise is essentially due to the anthropologic pressure, in which changing in land occupation takes place. Globally, soil NO emission could represent nearly 40% of total NOx emission, an amount comparable to fossil fuel combustions. However, uncertainties are large since results are ranging between 5.5 and 21 TgN per year. NO emission variation laws with soil humidity, soil temperature and other environmental parameters are well known, but those results present a high level of temporal and geographical variation. In order to generalise those complex phenomena evolution laws, a neural network have been developed. By introducing as inputs different meteorological parameters (temperature, humidity….) and soil characteristics (texture, N total, organic mater….), the neural network generates general temperate and tropical parameterisation laws that gives calculated NO fluxes in output. The goal of this study is to present 2 parameterization results on temperate and tropical forest soil NO emissions. The temperate parameterization of South-Eastern Germany forest (Hoëglwald, 1995-1997) use air and soil temperatures, soil humidity and humus pH as input data to generate soil NO fluxes in output. Fluxes are well represented by Neural Network in high and low frequencies (R2=0.76) and present good overall estimation of NO measurement (relative error < 1%). In tropical condition (Queensland, Australia), NO emission parameterization is performed from soil temperatures and humidity. It still leads to good high and low frequencies NO emission representation (R2=0.69) with a relative error < 1%. Then, temperate (1995-1997) parameterization is used to estimate (2002-2003) NO fluxes. This occurs well high and low frequency representations, but problems to evaluate magnitude of unknown meteorological situation fluxes. The final application of the neural network is not to be used as a prediction tool. Generated parameterizations are introduced on chemical model like Meso-NH to represent soil NO emissions and their impact on tropospheric chemistry, especially in tropospheric ozone production and destruction cycle.

Published
2007

14. Short- and long-term outcome of chronic pallidal neurostimulation in monogenic isolated dystonia

Author

Bruggemann, N., primary, Kuhn, A., additional, Schneider, S. A., additional, Kamm, C., additional, Wolters, A., additional, Krause, P., additional, Moro, E., additional, Steigerwald, F., additional, Wittstock, M., additional, Tronnier, V., additional, Lozano, A. M., additional, Hamani, C., additional, Poon, Y.-Y., additional, Zittel, S., additional, Wachter, T., additional, Deuschl, G., additional, Kruger, R., additional, Kupsch, A., additional, Munchau, A., additional, Lohmann, K., additional, Volkmann, J., additional, and Klein, C., additional

Published
2015
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15. Depression and quality of life in monogenic compared to idiopathic, early-onset Parkinson's disease.

Author

Kasten, M., Kertelge, L., Tadic, V., Bruggemann, N., Schmidt, A., Vegt, J.P.M. van der, Siebner, H., Buhmann, C., Lencer, R., Kumar, K.R., Lohmann, K., Hagenah, J., Klein, C., Kasten, M., Kertelge, L., Tadic, V., Bruggemann, N., Schmidt, A., Vegt, J.P.M. van der, Siebner, H., Buhmann, C., Lencer, R., Kumar, K.R., Lohmann, K., Hagenah, J., and Klein, C.

Abstract

1 mei 2012, Item does not contain fulltext, Quality of life (QoL) is decreased in PD and is linked with depression and anxiety. However, little is known about QoL in monogenic PD. Subjects with mutations in PD genes were recruited from ongoing family and genetic studies (manifesting carriers, n = 23; nonmanifesting carriers, n = 19). For comparison purposes, we included patients with idiopathic PD (IPD; n = 128; early onset, n = 38; late onset, n = 90), healthy controls (n = 127), and data on depressive symptoms of 144 patients with major depression (treated controls). Depression affected 31% of early-onset PD cases, 21% of late-onset cases, and 44% of manifesting carriers of mutations in PD genes, but was rare in the nonmanifesting carriers (7%) and healthy controls (5%). Subjects with Parkinson-associated depression reported fewer feelings of guilt or self-doubt than treated controls, but the occurrence of suicidal ideation was associated with severity of depression only. Social phobia (P = 0.018) and agoraphobia (P = 0.059) were more common in manifesting carriers than in any other group. QoL was decreased in the Parkinson groups, particularly in the early-onset cases (P < 0.001), and QoL correlated with depression in all analyses. In our study, monogenic and IPD cases were comparable in QoL and depression characteristics. The QoL and, possibly, overall prognosis of all PD patients can be improved by appropriate attention and treatment for depression, sleep impairments, and anxiety, even if the treatment of the motor problems cannot be further optimized.

Published
2012

16. Motor pathway excitability in ATP13A2 mutation carriers: a transcranial magnetic stimulation study.

Author

Zittel, S., Kroeger, J., Vegt, J.P.M. van der, Siebner, H.R., Bruggemann, N., Ramirez, A., Behrens, M.I., Gerloff, C., Baumer, T., Klein, C., Munchau, A., Zittel, S., Kroeger, J., Vegt, J.P.M. van der, Siebner, H.R., Bruggemann, N., Ramirez, A., Behrens, M.I., Gerloff, C., Baumer, T., Klein, C., and Munchau, A.

Abstract

1 juni 2012, Item does not contain fulltext, OBJECTIVE: To describe excitability of motor pathways in Kufor-Rakeb syndrome (PARK9), an autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration caused by a mutation in the ATP13A2 gene, using transcranial magnetic stimulation (TMS). METHODS: Five members of a Chilean family with an ATP13A2 mutation (one affected mutation carrier (MC) with a compound heterozygous mutation, 4 asymptomatic MC with a single heterozygous mutation) and 11 healthy subjects without mutations were studied. We measured motor evoked potentials (MEP), the contralateral silent period (cSP), short interval intracortical inhibition (SICI), intracortical facilitation (ICF), short latency afferent inhibition (SAI) as markers of intracortical intrahemispheric inhibition/facilitation and the ipsilateral silent period (iSP) and paired-pulse interhemispheric inhibition (IHI) to probe interhemispheric motor interactions. RESULTS: CSP duration was increased in the symptomatic ATP13A2 MC. The iSP measurements revealed increased interhemispheric inhibition in both the compound heterozygous and the heterozygous MC. CONCLUSION: A compound heterozygous mutation in the ATP13A2 gene is associated with increased intracortical inhibition. In addition, some aspects of interhemispheric inhibition are increased in the presence of a single ATP13A2 mutation.

Published
2012

17. Land atmosphere exchange of reactive nitrogen

Author

Fuzzi, S., Maione, M., Skiba, U., Nemitz, E., Sutton, M.A., Vesala, T., Ambus, P., Hensen, A., Bruggemann, N., Neftel, A., Horvath, L., Freibauer, A., Cellier, P., Magliulo, E., Seufert, G., Laurila, T., Zechmeister-Boltenstern, S., Fuzzi, S., Maione, M., Skiba, U., Nemitz, E., Sutton, M.A., Vesala, T., Ambus, P., Hensen, A., Bruggemann, N., Neftel, A., Horvath, L., Freibauer, A., Cellier, P., Magliulo, E., Seufert, G., Laurila, T., and Zechmeister-Boltenstern, S.

Published
2009

18. Biosphere–atmosphere exchange of reactive nitrogen and greenhouse gases at the NitroEurope core flux measurement sites: Measurement strategy and first data sets

Author

Skiba, U., Drewer, J., Tang, Y.S., van Dijk, N., Helfter, C., Nemitz, E., Famulari, D., Cape, J.N., Jones, S.K., Twigg, M., Pihlatie, M., Vesala, T., Larsen, K.S., Carter, M.S., Ambus, P., Ibrom, A., Beier, C., Hensen, A., Frumau, A., Erisman, J.W., Bruggemann, N., Gasche, R., Butterbach-Bahl, K., Neftel, A., Spirig, C., Horvath, L., Freibauer, A., Cellier, P., Laville, P., Loubet, B., Magliulo, E., Bertolini, T., Seufert, G., Andersson, M., Manca, G., Laurila, T., Aurela, M., Lohila, A., Zechmeister-Boltenstern, S., Kitzler, B., Schaufler, G., Siemens, J., Kindler, R., Flechard, C., Sutton, M.A., Skiba, U., Drewer, J., Tang, Y.S., van Dijk, N., Helfter, C., Nemitz, E., Famulari, D., Cape, J.N., Jones, S.K., Twigg, M., Pihlatie, M., Vesala, T., Larsen, K.S., Carter, M.S., Ambus, P., Ibrom, A., Beier, C., Hensen, A., Frumau, A., Erisman, J.W., Bruggemann, N., Gasche, R., Butterbach-Bahl, K., Neftel, A., Spirig, C., Horvath, L., Freibauer, A., Cellier, P., Laville, P., Loubet, B., Magliulo, E., Bertolini, T., Seufert, G., Andersson, M., Manca, G., Laurila, T., Aurela, M., Lohila, A., Zechmeister-Boltenstern, S., Kitzler, B., Schaufler, G., Siemens, J., Kindler, R., Flechard, C., and Sutton, M.A.

Abstract

The NitroEurope project aims to improve understanding of the nitrogen (N) cycle at the continental scale and quantify the major fluxes of reactive N by a combination of reactive N measurements and modelling activities. As part of the overall measurement strategy, a network of 13 flux ‘super sites’ (Level-3) has been established, covering European forest, arable, grassland and wetland sites, with the objective of quantifying the N budget at a high spatial resolution and temporal frequency for 4.5 years, and to estimate greenhouse gas budgets (N2O, CH4 and CO2). These sites are supported by a network of low-cost flux measurements (Level-2, 9 sites) and a network to infer reactive N fluxes at 58 sites (Level-1), for comparison with carbon (C) flux measurements. Measurements at the Level-3 sites include high resolution N2O, NO (also CH4, CO2) fluxes, wet and dry N deposition, leaching of N and C and N transformations in plant, litter and soil. Results for the first 11 months (1.8.2006 to 30.6.2007) suggest that the grasslands are the largest source of N2O, that forests are the largest source of NO and sink of CH4 and that N deposition rates influence NO and N2O fluxes in nonagricultural ecosystems. The NO and N2O emission ratio is influenced by soil type and precipitation. First budgets of reactive N entering and leaving the ecosystem and of net greenhouse gas exchange are outlined. Further information on rates of denitrification to N2 and biological N2 fixation is required to complete the N budgets for some sites. The quantitative roles played by CO2, N2O and CH4 in defining net greenhouse gas exchange differ widely between ecosystems depending on the interactions of climate, soil type, land use and management.

Published
2009

19. Factors controlling regional differences in forest soil emission of nitrogen oxides (NO and N2O)

Author

Pilegaard, K., Skiba, U., Ambus, P., Beier, C., Bruggemann, N., Butterbach-Bahl, K., Dick, J., Dorsey, J., Duyzer, J., Gallagher, M., Gasche, R., Horvath, L., Kitzler, B., Leip, A., Pihlatie, M. K., Rosenkranz, P., Seufert, G., Vesala, T., Westrate, H., Zechmeister-Boltenstern, S., Pilegaard, K., Skiba, U., Ambus, P., Beier, C., Bruggemann, N., Butterbach-Bahl, K., Dick, J., Dorsey, J., Duyzer, J., Gallagher, M., Gasche, R., Horvath, L., Kitzler, B., Leip, A., Pihlatie, M. K., Rosenkranz, P., Seufert, G., Vesala, T., Westrate, H., and Zechmeister-Boltenstern, S.

Abstract

Soil emissions of NO and N2O were measured continuously at high frequency for more than one year at 15 European forest sites as part of the EU-funded project NOFRETETE. The locations represent different forest types (coniferous/deciduous) and different nitrogen loads. Geographically they range from Finland in the north to Italy in the south and from Hungary in the east to Scotland in the west. The highest NO emissions were observed from coniferous forests, whereas the lowest NO emissions were observed from deciduous forests. The NO emissions from coniferous forests were highly correlated with N-deposition. The site with the highest average annual emission (82 μg NO-N m−2 h−1) was a spruce forest in South-Germany (Höglwald) receiving an annual N-deposition of 2.9 g m−2. NO emissions close to the detection limit were observed from a pine forest in Finland where the N-deposition was 0.2 g N m−2 a−1. No significant correlation between N2O emission and N-deposition was found. The highest average annual N2O emission (20 μg N2O-N m−2 h−1) was found in an oak forest in the Mátra mountains (Hungary) receiving an annual N-deposition of 1.6 g m−2. N2O emission was significantly negatively correlated with the C/N ratio. The difference in N-oxide emissions from soils of coniferous and deciduous forests may partly be explained by differences in N-deposition rates and partly by differences in characteristics of the litter layer and soil. NO was mainly derived from nitrification whereas N2O was mainly derived from denitrification. In general, soil moisture is lower at coniferous sites (at least during spring time) and the litter layer of coniferous forests is thick and well aerated favouring nitrification and thus release of NO. Conversely, the higher rates of denitrification in deciduous forests due to a compact and moist litter layer lead to N2O production and NO consumption in the soil. The two factors soil moisture and soil temperature are often explaining most of the temporal

Published
2006

20. Inventories of N2O and NO emissions from European forest soils

Author

Kesik, M., Ambus, P., Baritz, R., Bruggemann, N., Butterbach-Bahl, K., Damm, M., Duyser, J., Horvath, L., Kiese, R., Kitzler, B., Leip, A., Li, C., Pihlatie, M., Pilegaard, K., Seufert, S., Simpson, D., Skiba, U., Smiatek, G., Vesala, T., Zechmeister-Boltenstern, S., Kesik, M., Ambus, P., Baritz, R., Bruggemann, N., Butterbach-Bahl, K., Damm, M., Duyser, J., Horvath, L., Kiese, R., Kitzler, B., Leip, A., Li, C., Pihlatie, M., Pilegaard, K., Seufert, S., Simpson, D., Skiba, U., Smiatek, G., Vesala, T., and Zechmeister-Boltenstern, S.

Abstract

Forest soils are a significant source for the primary and secondary greenhouse gases N2O and NO. However, current estimates are still uncertain due to the still limited number of field measurements and the herein observed pronounced variability of N trace gas fluxes in space and time, which are due to the variation of environmental factors such as soil and vegetation properties or meteorological conditions. To overcome these problems we further developed a process-oriented model, the PnET-N-DNDC model, which simulates the N trace gas exchange on the basis of the processes involved in production, consumption and emission of N trace gases. This model was validated against field observations of N trace gas fluxes from 19 sites obtained within the EU project NOFRETETE, and shown to perform well for N2O (r2=0.68, slope=0.76) and NO (r2=0.78, slope=0.73). For the calculation of a European-wide emission inventory we linked the model to a detailed, regionally and temporally resolved database, comprising climatic properties (daily resolution), and soil parameters, and information on forest areas and types for the years 1990, 1995 and 2000. Our calculations show that N trace gas fluxes from forest soils may vary substantial from year to year and that distinct regional patterns can be observed. Our central estimate of NO emissions from forest soils in the EU amounts to 98.4, 84.9 and 99.2 kt N yr−1, using meteorology from 1990, 1995 and year 2000, respectively. This is <1.0% of pyrogenic NOx emissions. For N2O emissions the central estimates were 86.8, 77.6 and 81.6 kt N yr−1, respectively, which is approx. 14.5% of the source strength coming from agricultural soils. An extensive sensitivity analysis was conducted which showed a range in emissions from 44.4 to 254.0 kt N yr−1 for NO and 50.7 to 96.9 kt N yr−1 for N2O, for year 2000 meteorology. The results show that process-oriented models coupled to a GIS are useful tools for the calculation of regional, national, or global i

Published
2005

26. Etiology of musician's dystonia: Familial or environmental?

Author

Schmidt, A., primary, Jabusch, H. -C., additional, Altenmuller, E., additional, Hagenah, J., additional, Bruggemann, N., additional, Lohmann, K., additional, Enders, L., additional, Kramer, P. L., additional, Saunders-Pullman, R., additional, Bressman, S. B., additional, Munchau, A., additional, and Klein, C., additional

Published
2009
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31. Emission of Biogenic Volatile Organic Compounds: An Overview of Field, Laboratory and Modelling Studies Performed during the 'Tropospheric Research Program' (TFS) 1997-2000.

Author

Schnitzler, J. P., Bauknecht, N., Bruggemann, N., Einig, W., Forkel, R., Hampp, R., Heiden, A.C., Heizmann, U., Hoffmann, T., Holzke, C., Jaeger, L., Klauer, M., Komenda, M., Koppmann, R., Kreuzwieser, J., Mayer, H., Rennenberg, H., Smiatek, G., and Steinbrecher, R.

Subjects
VOLATILE organic compounds
Abstract

Summarizes emission results of biogenic volatile organic compounds (BVOC) achieved within the frame of the national German Tropospheric Research Programme (TFS) between 1997 and 2000. Use of measured BVOC emission rates in the determination of daily and seasonal variation of BVOC emission; BVOC dependence on important meteorological and plant physiological parameters; BVOC emission inventory of Germany.

Published
2002
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32. Process-based modelling of isoprene emission by oak leaves.

Author

ZIMMER, W., BRUGGEMANN, N., EMEIS, S., GIERSCH, C., LEHNING, A., STEINBRECHER, R., and SCHNITZLER, J-P.

Subjects
*OAK, *LEAVES, *ISOPRENE
Abstract

The emission rate of the volatile reactive compound isoprene, emitted predominantly by trees, must be known before the level of photo-oxidants produced during summer smog can be predicted reliably. The emission is dependent on plant species and local conditions, and these dependencies must be quantified to be included in any empirical algorithm for the calculation of isoprene production. Experimental measurements of isoprene emission rates are expensive, however, and existing data are scarce and fragmentary. To overcome these difficulties, it is promising to develop a numerical model capable of precisely calculating the isoprene emission by trees for diverse ecosystems, even under changing environmental conditions. A basic processbased biochemical isoprene emission model (BIM) has therefore been developed, which describes the enzymatic reactions in leaf chloroplasts leading to the formation of isoprene under varying environmental conditions (e.g. light intensity, temperature). Concentrations of the precursors of isoprene formation, 3-phosphoglyceric acid and glyceraldehyde 3-phosphate, are provided by a published light fleck photosynthesis model. Specific leaf and enzyme parameters were determined for the pedunculate oak (Quercus robur L.), so that the BIM is capable of calculating oak-specific isoprene emission rates as influenced by the leaf temperature and light intensity. High correlation was observed between isoprene emission rates calculated by the BIM and the diurnal isoprene emission rates of leaves measured under controlled environmental conditions. The BIM was even capable of describing changes in isoprene emission caused by midday depression of net photosynthesis. [ABSTRACT FROM AUTHOR]

Published
2000
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34. RNAi-mediated suppression of isoprene emission in poplar transiently impacts phenolic metabolism under high temperature and high light intensities: a transcriptomic and metabolomic analysis

Author

Jörg-Peter Schnitzler, Andreas Kaiser, Nicolas Brüggemann, Heinz Rennenberg, Ina Zimmer, Dennis Janz, Rüdiger Hampp, Philippe Schmitt-Kopplin, Francesco Loreto, Jennifer Popko, Barbara Ehlting, Katja Behnke, Andrea Polle, Robert Hänsch, Csengele Barta, Behnke, K, Kaiser, A, Zimmer, I, Bruggemann, N, Janz, D, Polle, A, Hampp, R, Hansch, R, Popko, J, Schmitt-Kopplin, P, Ehlting, B, Rennenberg, H, Barta, C, Loreto, F, and Schnitzler, Jp

Subjects
0106 biological sciences, Hot Temperature, Light, Isoprene, H2O2, Metabolite, Environmental stress, Plant Science, 01 natural sciences, chemistry.chemical_compound, Populus x canescens, Populus xcanescens, Phenolic compounds, 0303 health sciences, Phenylpropanoid, food and beverages, General Medicine, Plants, Genetically Modified, Droughts, Populus, Biochemistry, Metabolome, Carbohydrate Metabolism, RNA Interference, Seasons, Down-Regulation, Biology, Genes, Plant, Photosynthesis, Models, Biological, Article, Life Sciences, Plant Pathology, Biochemistry, general, Plant Sciences, 03 medical and health sciences, Hemiterpenes, Metabolomics, Phenols, Stress, Physiological, Pentanes, Butadienes, Genetics, DNA Primers, 030304 developmental biology, Base Sequence, Terpenes, Gene Expression Profiling, fungi, Wild type, Hydrogen Peroxide, Metabolism, chemistry, Agronomy and Crop Science, 010606 plant biology & botany
Abstract

In plants, isoprene plays a dual role: (a) as thermo-protective agent proposed to prevent degradation of enzymes/membrane structures involved in photosynthesis, and (b) as reactive molecule reducing abiotic oxidative stress. The present work addresses the question whether suppression of isoprene emission interferes with genome wide transcription rates and metabolite fluxes in grey poplar (Populusxcanescens) throughout the growing season. Gene expression and metabolite profiles of isoprene emitting wild type plants and RNAi-mediated non-isoprene emitting poplars were compared by using poplar Affymetrix microarrays and non-targeted FT-ICR-MS (Fourier transform ion cyclotron resonance mass spectrometry). We observed a transcriptional down-regulation of genes encoding enzymes of phenylpropanoid regulatory and biosynthetic pathways, as well as distinct metabolic down-regulation of condensed tannins and anthocyanins, in non-isoprene emitting genotypes during July, when high temperature and light intensities possibly caused transient drought stress, as indicated by stomatal closure. Under these conditions leaves of non-isoprene emitting plants accumulated hydrogen peroxide (H2O2), a signaling molecule in stress response and negative regulator of anthocyanin biosynthesis. The absence of isoprene emission under high temperature and light stress resulted transiently in a new chemo(pheno)type with suppressed production of phenolic compounds. This may compromise inducible defenses and may render non-isoprene emitting poplars more susceptible to environmental stress. Electronic supplementary material The online version of this article (doi:10.1007/s11103-010-9654-z) contains supplementary material, which is available to authorized users.

Published
2010
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35. Diagnosis of coeliac disease by flow cytometry of intraepithelial lymphocytes: a new 'gold' standard?

Author

Basu K, Creasey H, Bruggemann N, Stevens J, Bloxham D, and Woodward JM

Abstract

Objective: The analysis of intraepithelial lymphocytes (IELs) by flow cytometry of duodenal biopsies-the 'IEL' lymphogram-has been proposed as a diagnostic test for coeliac disease. However, its clinical applicability has been limited due to variability in methods and definitions. This study set out to define useful parameters for the application of the IEL lymphogram to the diagnosis of coeliac disease., Design: Flow cytometry was performed on 117 sets of duodenal biopsies in 107 adult patients with active coeliac disease, long-term coeliac disease on a gluten free diet and a control group. The initial 95 samples were used for hypothesis generation for the subsequent samples comprising 12 patients with coeliac disease and 10 controls., Results: Rather than using single linear cut-offs for CD3 and T-cell receptor γδ (TCRγδ)+ve IELs, a discriminant function was identified as %CD3+ve IELs+2x(%TCRγδ+IELs)>100. This differentiated coeliac disease from control biopsies in the hypothesis generating group. These results were replicated in the validation group and found to be independent of histology in patients on long-term gluten free diet up to 12 years (combined sensitivity, 98.5%; specificity, 97.7%)., Conclusions: Flow cytometric analysis of IELs is a highly sensitive and specific adjunct to serology and histological examination for the diagnosis of coeliac disease, even in individuals with coeliac disease following a gluten free diet who exhibit normal duodenal histology., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2021
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36. Motivational tuning of fronto-subthalamic connectivity facilitates control of action impulses.

Author

Herz DM, Christensen MS, Bruggemann N, Hulme OJ, Ridderinkhof KR, Madsen KH, and Siebner HR

Subjects
Adult, Cues, Female, Frontal Lobe blood supply, Healthy Volunteers, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Neural Pathways blood supply, Neuropsychological Tests, Oxygen blood, Psychomotor Performance, Reaction Time, Subthalamus blood supply, Transcranial Magnetic Stimulation, Young Adult, Choice Behavior physiology, Frontal Lobe physiology, Motivation physiology, Neural Pathways physiology, Subthalamus physiology
Abstract

It is critical for survival to quickly respond to environmental stimuli with the most appropriate action. This task becomes most challenging when response tendencies induced by relevant and irrelevant stimulus features are in conflict, and have to be resolved in real time. Inputs from the pre-supplementary motor area (pre-SMA) and inferior frontal gyrus (IFG) to the subthalamic nucleus (STN) are thought to support this function, but the connectivity and causality of these regions in calibrating motor control has not been delineated. In this study, we combined off-line noninvasive brain stimulation and functional magnetic resonance imaging, while young healthy human participants performed a modified version of the Simon task. We show that impairing pre-SMA function by noninvasive brain stimulation improved control over impulsive response tendencies, but only when participants were explicitly rewarded for fast and accurate responses. These effects were mediated by enhanced activation and connectivity of the IFG-STN pathway. These results provide causal evidence for a pivotal role of the IFG-STN pathway during action control. Additionally, they suggest a parallel rather than hierarchical organization of the pre-SMA-STN and IFG-STN pathways, since interruption of pre-SMA function can enhance IFG-STN connectivity and improve control over inappropriate responses.

Published
2014
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37. A new ¹⁵N tracer method to determine N turnover and denitrification of Pseudomonas stutzeri.

Author

Meyer A, Bergmann J, Butterbach-Bahl K, and Bruggemann N

Subjects
Denitrification, Nitrogen Isotopes metabolism, Pseudomonas stutzeri metabolism
Abstract

Although denitrification is one of the key processes of ecosystem N turnover, the understanding of the regulation of the denitrification pathway is still limited due to the lack of feasible methods for the quantification of N₂ formation. Based on the previously developed isotope pairing method, we present a new in vitro ¹⁵N tracer method for the quantification of N₂ released from denitrification by bacterial cultures. The application of the new method was enabled by replacing the background air in the sample flasks with a gas mixture of He and O₂ with an approximately 50-fold reduced N₂ background (1.7% v/v), allowing for a direct and sensitive quantification of N₂ formation with isotope-ratio mass spectrometry after ¹⁵N-labelling on the one hand, but leaving the method relatively insensitive to intrusion of ambient N₂ on the other hand. The method was tested on bacterial cultures of Pseudomonas stutzeri grown at different oxygen levels. Additionally, NO and N₂O formation were determined with a chemoluminescence analyser and a gas chromatograph, respectively. Following labelling with ¹⁵N-ammonium and ¹⁵N-nitrate, it could be shown that P. stutzeri used ammonium preferably for biomass build-up, and nitrate preferably as electron acceptor. Between 84-107% of the total available N could be recovered. Due to the high sensitivity of the new method only low levels of ¹⁵N tracer were necessary, minimising substrate-induced effects and making this method also an appropriate tool for the use on soil cores. By that it offers a new method for studying denitrification in terrestrial ecosystems.

Published
2010
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