Search

Your search keyword '"Wolfram S"' showing total 1,535 results
Start Over Author "Wolfram S"
1,535 results on '"Wolfram S"'

52. Additional file 1 of Secondary structure of the human mitochondrial genome affects formation of deletions

Author

Shamanskiy, Victor, Mikhailova, Alina A., Tretiakov, Evgenii O., Ushakova, Kristina, Mikhailova, Alina G., Oreshkov, Sergei, Knorre, Dmitry A., Ree, Natalia, Overdevest, Jonathan B., Lukowski, Samuel W., Gostimskaya, Irina, Yurov, Valerian, Liou, Chia-Wei, Lin, Tsu-Kung, Kunz, Wolfram S., Reymond, Alexandre, Mazunin, Ilya, Bazykin, Georgii A., Fellay, Jacques, Tanaka, Masashi, Khrapko, Konstantin, Gunbin, Konstantin, and Popadin, Konstantin

Abstract

Additional file 1. Distribution of the perfect direct repeatsand deletions from MitoBreakin the major arc.

Published
2023
Full Text
View/download PDF

53. Additional file 2 of Secondary structure of the human mitochondrial genome affects formation of deletions

Author

Shamanskiy, Victor, Mikhailova, Alina A., Tretiakov, Evgenii O., Ushakova, Kristina, Mikhailova, Alina G., Oreshkov, Sergei, Knorre, Dmitry A., Ree, Natalia, Overdevest, Jonathan B., Lukowski, Samuel W., Gostimskaya, Irina, Yurov, Valerian, Liou, Chia-Wei, Lin, Tsu-Kung, Kunz, Wolfram S., Reymond, Alexandre, Mazunin, Ilya, Bazykin, Georgii A., Fellay, Jacques, Tanaka, Masashi, Khrapko, Konstantin, Gunbin, Konstantin, and Popadin, Konstantin

Abstract

Additional file 2. The third principal component scores, associated with aging-related deletions of healthy samples from a paper [36]. The contact, marked by the pink square, is characterized by the increased scores.

Published
2023
Full Text
View/download PDF

54. Additional file 4 of Secondary structure of the human mitochondrial genome affects formation of deletions

Author

Shamanskiy, Victor, Mikhailova, Alina A., Tretiakov, Evgenii O., Ushakova, Kristina, Mikhailova, Alina G., Oreshkov, Sergei, Knorre, Dmitry A., Ree, Natalia, Overdevest, Jonathan B., Lukowski, Samuel W., Gostimskaya, Irina, Yurov, Valerian, Liou, Chia-Wei, Lin, Tsu-Kung, Kunz, Wolfram S., Reymond, Alexandre, Mazunin, Ilya, Bazykin, Georgii A., Fellay, Jacques, Tanaka, Masashi, Khrapko, Konstantin, Gunbin, Konstantin, and Popadin, Konstantin

Abstract

Additional file 4. Hi-C contact matrix of mtDNA obtained from the human olfactory epithelium autopsies. The top row represents two contact matrixes from covid patients, middle and bottom rows represent the contact matrices from controls. Solid white squares mark the potential contact zone. Dotted white rectangles mark the contacts, emphasizing the circularity of AQmtDNA.

Published
2023
Full Text
View/download PDF

55. Additional file 3 of Secondary structure of the human mitochondrial genome affects formation of deletions

Author

Shamanskiy, Victor, Mikhailova, Alina A., Tretiakov, Evgenii O., Ushakova, Kristina, Mikhailova, Alina G., Oreshkov, Sergei, Knorre, Dmitry A., Ree, Natalia, Overdevest, Jonathan B., Lukowski, Samuel W., Gostimskaya, Irina, Yurov, Valerian, Liou, Chia-Wei, Lin, Tsu-Kung, Kunz, Wolfram S., Reymond, Alexandre, Mazunin, Ilya, Bazykin, Georgii A., Fellay, Jacques, Tanaka, Masashi, Khrapko, Konstantin, Gunbin, Konstantin, and Popadin, Konstantin

Abstract

Additional file 3. Hi-C contact matrix of mtDNA obtained from the human lymphoblastoid cells. Dotted squares mark the potential contact zones. Ovals mark the contacts, emphasizing the circularity of mtDNA.

Published
2023
Full Text
View/download PDF

56. A mitochondria-specific mutational signature of aging: increased rate of A > G substitutions on the heavy strand

Author

Alina G Mikhailova, Alina A Mikhailova, Kristina Ushakova, Evgeny O Tretiakov, Dmitrii Iliushchenko, Victor Shamansky, Valeria Lobanova, Ivan Kozenkov, Bogdan Efimenko, Andrey A Yurchenko, Elena Kozenkova, Evgeny M Zdobnov, Vsevolod Makeev, Valerian Yurov, Masashi Tanaka, Irina Gostimskaya, Zoe Fleischmann, Sofia Annis, Melissa Franco, Kevin Wasko, Stepan Denisov, Wolfram S Kunz, Dmitry Knorre, Ilya Mazunin, Sergey Nikolaev, Jacques Fellay, Alexandre Reymond, Konstantin Khrapko, Konstantin Gunbin, and Konstantin Popadin

Subjects
Mammals, Aging, Nucleotides, Mutation, Genetics, mutation spectrum, Animals, DNA, Mitochondrial, Mitochondria
Abstract

The mutational spectrum of the mitochondrial DNA (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different organisms is still incomprehensible. Since mitochondria are responsible for aerobic respiration, it is expected that mtDNA mutational spectrum is affected by oxidative damage. Assuming that oxidative damage increases with age, we analyse mtDNA mutagenesis of different species in regards to their generation length. Analysing, (i) dozens of thousands of somatic mtDNA mutations in samples of different ages (ii) 70053 polymorphic synonymous mtDNA substitutions reconstructed in 424 mammalian species with different generation lengths and (iii) synonymous nucleotide content of 650 complete mitochondrial genomes of mammalian species we observed that the frequency of AH > GH substitutions (H: heavy strand notation) is twice bigger in species with high versus low generation length making their mtDNA more AH poor and GH rich. Considering that AH > GH substitutions are also sensitive to the time spent single-stranded (TSSS) during asynchronous mtDNA replication we demonstrated that AH > GH substitution rate is a function of both species-specific generation length and position-specific TSSS. We propose that AH > GH is a mitochondria-specific signature of oxidative damage associated with both aging and TSSS.

Published
2022
Full Text
View/download PDF

60. Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients

Author

McCormack, Mark, Gui, Hongsheng, Ingason, Andrés, Speed, Doug, Wright, Galen E.B., Zhang, Eunice J., Secolin, Rodrigo, Yasuda, Clarissa, Kwok, Maxwell, Wolking, Stefan, Becker, Felicitas, Rau, Sarah, Avbersek, Andreja, Heggeli, Kristin, Leu, Costin, Depondt, Chantal, Sills, Graeme J., Marson, Anthony G., Auce, Pauls, Brodie, Martin J., Francis, Ben, Johnson, Michael R., Koeleman, Bobby P.C., Striano, Pasquale, Coppola, Antonietta, Zara, Federico, Kunz, Wolfram S., Sander, Josemir W., Lerche, Holger, Klein, Karl Martin, Weckhuysen, Sarah, Krenn, Martin, Gudmundsson, Lárus J., Stefánsson, Kári, Krause, Roland, Shear, Neil, Ross, Colin J.D., Delanty, Norman, Pirmohamed, Munir, Carleton, Bruce C., Cendes, Fernando, Lopes-Cendes, Iscia, Liao, Wei-ping, OʼBrien, Terence J., Sisodiya, Sanjay M., Cherny, Stacey, Kwan, Patrick, Baum, Larry, and Cavalleri, Gianpiero L.

Published
2018
Full Text
View/download PDF

62. Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy

Author

Luca Gozzelino, Gaga Kochlamazashvili, Sara Baldassari, Albert Ian Mackintosh, Laura Licchetta, Emanuela Iovino, Yu Chi Liu, Caitlin A Bennett, Mark F Bennett, John A Damiano, Gábor Zsurka, Caterina Marconi, Tania Giangregorio, Pamela Magini, Marijn Kuijpers, Tanja Maritzen, Giuseppe Danilo Norata, Stéphanie Baulac, Laura Canafoglia, Marco Seri, Paolo Tinuper, Ingrid E Scheffer, Melanie Bahlo, Samuel F Berkovic, Michael S Hildebrand, Wolfram S Kunz, Lucio Giordano, Francesca Bisulli, Miriam Martini, Volker Haucke, Emilio Hirsch, Tommaso Pippucci, Gozzelino L., Kochlamazashvili G., Baldassari S., Mackintosh A.I., Licchetta L., Iovino E., Liu Y.-C., Bennett C.A., Bennett M.F., Damiano J.A., Zsurka G., Marconi C., Giangregorio T., Magini P., Kuijpers M., Maritzen T., Norata G.D., Baulac S., Canafoglia L., Seri M., Tinuper P., Scheffer I.E., Bahlo M., Berkovic S.F., Hildebrand M.S., Kunz W.S., Giordano L., Bisulli F., Martini M., Haucke V., Hirsch E., and Pippucci T.

Subjects
PI3K-C2B, class II PI3K, epilepsy, mTOR, variants, Animals, Humans, Lipids, Mechanistic Target of Rapamycin Complex 1, Mice, Mutation, Phosphatidylinositol 3-Kinases, Seizures, Class II Phosphatidylinositol 3-Kinases, Epilepsies, Partial, Epilepsies, Animal, Lipid, Seizure, variant, Class II Phosphatidylinositol 3-Kinase, Settore BIO/14 - Farmacologia, Neurology (clinical), Phosphatidylinositol 3-Kinase, Human, Partial
Abstract

Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated.Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy in humans. We demonstrate that patients’ variants act as loss-of-function alleles, leading to impaired synthesis of the rare signalling lipid phosphatidylinositol 3,4-bisphosphate, resulting in mTORC1 hyperactivation. In vivo, mutant Pik3c2b alleles caused dose-dependent neuronal hyperexcitability and increased seizure susceptibility, indicating haploinsufficiency as a key driver of disease. Moreover, acute mTORC1 inhibition in mutant mice prevented experimentally induced seizures, providing a potential therapeutic option for a selective group of patients with focal epilepsy.Our findings reveal an unexpected role for class II PI3K-mediated lipid signalling in regulating mTORC1-dependent neuronal excitability in mice and humans.

Published
2022

65. A mitochondria-specific mutational signature of aging: increased rate of A > G substitutions on the heavy strand

Author

Mikhailova, Alina G, primary, Mikhailova, Alina A, additional, Ushakova, Kristina, additional, Tretiakov, Evgeny O, additional, Iliushchenko, Dmitrii, additional, Shamansky, Victor, additional, Lobanova, Valeria, additional, Kozenkov, Ivan, additional, Efimenko, Bogdan, additional, Yurchenko, Andrey A, additional, Kozenkova, Elena, additional, Zdobnov, Evgeny M, additional, Makeev, Vsevolod, additional, Yurov, Valerian, additional, Tanaka, Masashi, additional, Gostimskaya, Irina, additional, Fleischmann, Zoe, additional, Annis, Sofia, additional, Franco, Melissa, additional, Wasko, Kevin, additional, Denisov, Stepan, additional, Kunz, Wolfram S, additional, Knorre, Dmitry, additional, Mazunin, Ilya, additional, Nikolaev, Sergey, additional, Fellay, Jacques, additional, Reymond, Alexandre, additional, Khrapko, Konstantin, additional, Gunbin, Konstantin, additional, and Popadin, Konstantin, additional

Published
2022
Full Text
View/download PDF

66. Defective lipid signalling caused by mutations inPIK3C2Bunderlies focal epilepsy

Author

Gozzelino, Luca, primary, Kochlamazashvili, Gaga, additional, Baldassari, Sara, additional, Mackintosh, Albert Ian, additional, Licchetta, Laura, additional, Iovino, Emanuela, additional, Liu, Yu Chi, additional, Bennett, Caitlin A, additional, Bennett, Mark F, additional, Damiano, John A, additional, Zsurka, Gábor, additional, Marconi, Caterina, additional, Giangregorio, Tania, additional, Magini, Pamela, additional, Kuijpers, Marijn, additional, Maritzen, Tanja, additional, Norata, Giuseppe Danilo, additional, Baulac, Stéphanie, additional, Canafoglia, Laura, additional, Seri, Marco, additional, Tinuper, Paolo, additional, Scheffer, Ingrid E, additional, Bahlo, Melanie, additional, Berkovic, Samuel F, additional, Hildebrand, Michael S, additional, Kunz, Wolfram S, additional, Giordano, Lucio, additional, Bisulli, Francesca, additional, Martini, Miriam, additional, Haucke, Volker, additional, Hirsch, Emilio, additional, and Pippucci, Tommaso, additional

Published
2022
Full Text
View/download PDF

67. Dopamine neurons encode trial-by-trial subjective reward value in an auction-like task

Author

Daniel F. Hill, Robert W. Hickman, Alaa Al-Mohammad, Arkadiusz Stasiak, and Wolfram Schultz

Subjects
Science
Abstract

Abstract The dopamine reward prediction error signal is known to be subjective but has so far only been assessed in aggregate choices. However, personal choices fluctuate across trials and thus reflect the instantaneous subjective reward value. In the well-established Becker-DeGroot-Marschak (BDM) auction-like mechanism, participants are encouraged to place bids that accurately reveal their instantaneous subjective reward value; inaccurate bidding results in suboptimal reward (“incentive compatibility”). In our experiment, male rhesus monkeys became experienced over several years to place accurate BDM bids for juice rewards without specific external constraints. Their bids for physically identical rewards varied trial by trial and increased overall for larger rewards. In these highly experienced animals, responses of midbrain dopamine neurons followed the trial-by-trial variations of bids despite constant, explicitly predicted reward amounts. Inversely, dopamine responses were similar with similar bids for different physical reward amounts. Support Vector Regression demonstrated accurate prediction of the animals’ bids by as few as twenty dopamine neurons. Thus, the phasic dopamine reward signal reflects instantaneous subjective reward value.

Published
2024
Full Text
View/download PDF

68. Young people’s trust in institutions, civic knowledge and their dispositions toward civic engagement

Author

Wolfram Schulz

Subjects
Civic and citizenship education, Youth participation, International large-scale assessments, Education (General), L7-991
Abstract

Abstract Recent years have witnessed signs of increasing political instability in democratic countries as well as growing alienation from civic institutions and processes among citizens, especially among young people. Within the context of civic and citizenship education, it is important to review such phenomena and study their extent among young people as well as the factors that have the potential of promoting different forms of citizenship engagement. Using data from the International Civic and Citizenship Education Study (ICCS) 2016 and 2009, this article provides insights into the expectations of young people to actively engage as citizens in the future and what influences these expectations, with a primary focus on the role of civic knowledge and trust in civic institutions. Results from ICCS 2009 and 2016 show that while large majorities among young people expected to vote in elections, only relatively few found it likely to be more actively involved in political action. Except for engagement in illegal protest, young people’s expected participation in general appeared to be positively related to trust. However, associations with civic knowledge were more differentiated. Trust and civic knowledge tended to have negative correlations in countries with higher levels of perceived corruption, while a different association became apparent in democracies with more transparent institutions. Civic knowledge was consistently positively related to anticipated voting while it was negatively related to expected illegal protest. More knowledgeable students were also less inclined to consider active (conventional) forms of political participation in the future.

Published
2024
Full Text
View/download PDF

69. The influence of religious attachment on intended political engagement among lower-secondary students

Author

John Ainley and Wolfram Schulz

Subjects
Education (General), L7-991
Abstract

Abstract Religious attachment has been identified as an important correlate of civic participation, civic engagement, and civil participation among adults. This study investigates two aspects of relationships between religiosity and intended political engagement among lower secondary school students in 2009 and 2016. One aspect is the extent to which religious attachment is associated with an endorsement of the influence of religion in society. This can be viewed as the converse of secularity which asks for the separation of social and political institutions from religion. A second aspect investigated is the extent to which religious attachment is associated with expected adult electoral participation and expected adult active political participation after controlling for the effects of other characteristics. While the results from this study show no strong or consistent relationships between religious background and expected political participation among lower-secondary students, findings suggest that young people’s endorsement of religious influence in society depends strongly on their religious background and in turn shows associations with expected active political participation.

Published
2024
Full Text
View/download PDF

70. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Epilepsy Patients With KCNC2 Pathogenic Variants 10.1212/WNL.0000000000200660

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, BrÃ\textonequarternger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Leijla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, Weber, Yvonne, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, BrÃ\textonequarternger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Leijla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, and Weber, Yvonne

Abstract

Background: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyse the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.Methods: Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes.Results: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy (EOAE), focal epilepsy (FE), and myoclonic-atonic epilepsy (MAE). 10/18 variants were de novo and 8/18 variants were classified as modifying variants. 8 drug responsive cases became seizure-free using valproic acid as monotherapy or in combination including severe DEE cases. Functional analysis of four variants demonstrated gain-of-function in three severely affected DEE cases and loss-of-function in one case with a milder phenotype (GGE) as the underlying pathomechanisms.Conclusion: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

Published
2022

71. A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam.

Author

Campbell, Ciarán, McCormack, Mark, Patel, Sonn, Stapleton, Caragh, Bobbili, Dheeraj Reddy, Krause, Roland, Depondt, Chantal, Sills, Graeme J., Koeleman, Bobby P., Striano, Pasquale, Zara, Federico, Sander, Josemir W., Lerche, Holger, Kunz, Wolfram S., Stefansson, Kari, Stefansson, Hreinn, Doherty, Colin P., Heinzen, Erin L., Scheffer, Ingrid E., Goldstein, David B., O'Brien, Terence, Cotter, David, Berkovic, Samuel F., Sisodiya, Sanjay M., Delanty, Norman, Cavalleri, Gianpiero L., Campbell, Ciarán, McCormack, Mark, Patel, Sonn, Stapleton, Caragh, Bobbili, Dheeraj Reddy, Krause, Roland, Depondt, Chantal, Sills, Graeme J., Koeleman, Bobby P., Striano, Pasquale, Zara, Federico, Sander, Josemir W., Lerche, Holger, Kunz, Wolfram S., Stefansson, Kari, Stefansson, Hreinn, Doherty, Colin P., Heinzen, Erin L., Scheffer, Ingrid E., Goldstein, David B., O'Brien, Terence, Cotter, David, Berkovic, Samuel F., Sisodiya, Sanjay M., Delanty, Norman, and Cavalleri, Gianpiero L.

Abstract

OBJECTIVE: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. METHODS: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). RESULTS: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. SIGNIFICANCE: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.

Published
2022

72. Novel Pathogenic Sequence Variation m.5789T > C Causes NARP Syndrome and Promotes Formation of Deletions of the Mitochondrial Genome

Author

Hippen, Marius, Zsurka, Gabor, Peeva, Viktoriya, Machts, Judith, Schwiecker, Kati, Debska-Vielhaber, Grazyna, Wiesner, Rudolf J., Vielhaber, Stefan, Kunz, Wolfram S., Hippen, Marius, Zsurka, Gabor, Peeva, Viktoriya, Machts, Judith, Schwiecker, Kati, Debska-Vielhaber, Grazyna, Wiesner, Rudolf J., Vielhaber, Stefan, and Kunz, Wolfram S.

Abstract

Background and Objectives We report the pathogenic sequence variant m.5789T>C in the anticodon stem of the mitochondrial tRNA for cysteine as a novel cause of neuropathy, ataxia, and retinitis pigmentosa (NARP), which is usually associated with pathogenic variants in the MT-ATP6 gene. Methods To address the correlation of oxidative phosphorylation deficiency with mutation loads, we performed genotyping on single laser-dissected skeletal muscle fibers. Stability of the mitochondrial tRNA(Cys) was investigated by Northern blotting. Accompanying deletions of the mitochondrial genome were detected by long-range PCR and their breakpoints were determined by sequencing of single-molecule amplicons. Results The sequence variant m.5789T>C, originating from the patient's mother, decreases the stability of the mitochondrial tRNA for cysteine by disrupting the anticodon stem, which subsequently leads to a combined oxidative phosphorylation deficiency. In parallel, we observed a prominent cluster of low-abundance somatic deletions with breakpoints in the immediate vicinity of the m.5789T>C variant. Strikingly, all deletion-carrying mitochondrial DNA (mtDNA) species, in which the corresponding nucleotide position was not removed, harbored the mutant allele, and none carried the wild-type allele. Discussion In addition to providing evidence for the novel association of a tRNA sequence alteration with NARP syndrome, our observations support the hypothesis that single nucleotide changes can lead to increased occurrence of site-specific mtDNA deletions through the formation of an imperfect repeat. This finding might be relevant for understanding mechanisms of deletion generation in the human mitochondrial genome.

Published
2022

73. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants

Author

Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brunger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Lejla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, Weber, Yvonne, Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brunger, Tobias, Hedrich, Ulrike B. S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S., Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Lejla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S., Ragona, Francesca, Granata, Tiziana, Reif, Phillip S., Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A., Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M., Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, and Weber, Yvonne

Abstract

Background and Objectives KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants. Methods Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes. Results We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms. Discussion These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of K(V)3.2 in the regulation of brain excitability.

Published
2022

74. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.

Author

Genetica Klinische Genetica, Brain, Child Health, Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brà Nger, Tobias, Hedrich, Ulrike B S, Augustijn, Paul B, Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J, Bruria, Ben Zeev, Doyle, Michael G, Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S, Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Leijla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S, Ragona, Francesca, Granata, Tiziana, Reif, Phillip S, Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A, Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M, Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, Weber, Yvonne, Genetica Klinische Genetica, Brain, Child Health, Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brà Nger, Tobias, Hedrich, Ulrike B S, Augustijn, Paul B, Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J, Bruria, Ben Zeev, Doyle, Michael G, Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, Kunz, Wolfram S, Lerche, Holger, Licchetta, Laura, Lohmann, Ebba, Minardi, Raffaella, McDonald, Marie, Montgomery, Sarah, Mulahasanovic, Leijla, Oegema, Renske, Ortal, Barel, Papacostas, Savvas S, Ragona, Francesca, Granata, Tiziana, Reif, Phillip S, Rosenow, Felix, Rothschild, Annick, Scudieri, Paolo, Striano, Pasquale, Tinuper, Paolo, Tanteles, George A, Vetro, Annalisa, Zahnert, Felix, Goldberg, Ethan M, Zara, Federico, Lal, Dennis, May, Patrick, Muhle, Hiltrud, Helbig, Ingo, and Weber, Yvonne

Published
2022

75. Comparative effectiveness of antiepileptic drugs in patients with mesial temporal lobe epilepsy with hippocampal sclerosis

Author

Androsova, Ganna, Krause, Roland, Borghei, Mojgansadat, Wassenaar, Merel, Auce, Pauls, Avbersek, Andreja, Becker, Felicitas, Berghuis, Bianca, Campbell, Ellen, Coppola, Antonietta, Francis, Ben, Wolking, Stefan, Cavalleri, Gianpiero L., Craig, John, Delanty, Norman, Koeleman, Bobby P. C., Kunz, Wolfram S., Lerche, Holger, Marson, Anthony G., Sander, Josemir W., Sills, Graeme J., Striano, Pasquale, Zara, Federico, Sisodiya, Sanjay M., Depondt, Chantal, Brodie, Martin J., Chinthapalli, Krishna, de Haan, Gerrit‐Jan, Doherty, Colin, Gudmundsson, Lárus J., Heavin, Sinead, Ingason, Andres, Johnson, Michael, Kennedy, Clare, Krenn, Martin, McCormack, Mark, OʼBrien, Terence J., Pandolfo, Massimo, Pataraia, Ekaterina, Petrovski, Slave, Rau, Sarah, Sargsyan, Narek, Slattery, Lisa, Stefánsson, Kári, Stern, William, Tostevin, Anna, Willis, Joseph, and Zimprich, Fritz

Published
2017
Full Text
View/download PDF

76. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants

Author

Schwarz, Niklas, primary, Seiffert, Simone, additional, Pendziwiat, Manuela, additional, Rademacher, Annika Verena, additional, Brünger, Tobias, additional, Hedrich, Ulrike B.S., additional, Augustijn, Paul B., additional, Baier, Hartmut, additional, Bayat, Allan, additional, Bisulli, Francesca, additional, Buono, Russell J., additional, Bruria, Ben Zeev, additional, Doyle, Michael G., additional, Guerrini, Renzo, additional, Heimer, Gali, additional, Iacomino, Michele, additional, Kearney, Hugh, additional, Klein, Karl Martin, additional, Kousiappa, Ioanna, additional, Kunz, Wolfram S., additional, Lerche, Holger, additional, Licchetta, Laura, additional, Lohmann, Ebba, additional, Minardi, Raffaella, additional, McDonald, Marie, additional, Montgomery, Sarah, additional, Mulahasanovic, Lejla, additional, Oegema, Renske, additional, Ortal, Barel, additional, Papacostas, Savvas S., additional, Ragona, Francesca, additional, Granata, Tiziana, additional, Reif, Phillip S., additional, Rosenow, Felix, additional, Rothschild, Annick, additional, Scudieri, Paolo, additional, Striano, Pasquale, additional, Tinuper, Paolo, additional, Tanteles, George A., additional, Vetro, Annalisa, additional, Zahnert, Felix, additional, Goldberg, Ethan M., additional, Zara, Federico, additional, Lal, Dennis, additional, May, Patrick, additional, Muhle, Hiltrud, additional, Helbig, Ingo, additional, and Weber, Yvonne, additional

Published
2022
Full Text
View/download PDF

77. A new variant of the electromagnetic field theory of consciousness: approaches to empirical confirmation

Author

Wolfram Strupp

Subjects
consciousness, electromagnetic field, mind–body-problem, qualia, information, binding-problem, Neurology. Diseases of the nervous system, RC346-429
Abstract

There are various electromagnetic (EM) field theories of consciousness. They postulate an epineural EM field which, due to its binding properties, unifies the different neuronal information differences originating from various sensory and cognitive processes. Only through a real physical integration in space within this field could phenomenal consciousness arise. This would solve the binding problem mentioned in the philosophy of mind. On closer inspection, the electromagnetic interaction not only provides an explanation for the integrative property of the EM field, but also for the necessary differentiating contrasts of information. This article will take a closer look at the physical properties of a postulated EM field. It will also show how the problem of qualia in connection with emergentism could be solved by a new variant of EM field theory. If it can be clearly demonstrated that the postulated epineural EM field plays a decisive role in the origin of consciousness in addition to neuronal “wired” information processing, this also leaves less room for metaphysical assumptions that attempt to solve the binding problem. In experiments to prove the postulated epineural EM field by means of external electromagnetic manipulations, it can never be ruled out that these also have a direct effect on the “wired” neuronal signal processing. Therefore, on the way to proving the EM field theory of consciousness, an experimental method is needed that must ensure that external manipulations only affect the extensions of the EM field without directly influencing the neuronal network. A method will be discussed here that works with the shielding of EM fields instead of external electromagnetic stimuli.

Published
2024
Full Text
View/download PDF

79. A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam

Author

Ciarán, Campbell, Mark, McCormack, Sonn, Patel, Caragh, Stapleton, Dheeraj, Bobbili, Roland, Krause, Chantal, Depondt, Graeme J, Sills, Bobby P, Koeleman, Pasquale, Striano, Federico, Zara, Josemir W, Sander, Holger, Lerche, Wolfram S, Kunz, Kari, Stefansson, Hreinn, Stefansson, Colin P, Doherty, Erin L, Heinzen, Ingrid E, Scheffer, David B, Goldstein, Terence, O'Brien, David, Cotter, Samuel F, Berkovic, Sanjay M, Sisodiya, Norman, Delanty, and Gianpiero L, Cavalleri

Subjects
pharmacogenomics, adverse drug reactions, Anticonvulsants/adverse effects, Neurologie [D14] [Sciences de la santé humaine], Levetiracetam, Drug-Related Side Effects and Adverse Reactions, Genetic Predisposition to Disease/genetics, levetiracetam, Neurology [D14] [Human health sciences], Neurology, Pharmacogenetics, Levetiracetam/adverse effects, Case-Control Studies, Humans, Anticonvulsants, Genetic Predisposition to Disease, Neurology (clinical), psychosis, Prospective Studies, polygenic risk scoring, Genome-Wide Association Study
Abstract

OBJECTIVE: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. METHODS: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). RESULTS: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. SIGNIFICANCE: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.

Published
2022

80. Large Phenotypic Variation of Individuals from a Family with a Novel ASPM Mutation Associated with Microcephaly, Epilepsy, and Behavioral and Cognitive Deficits

Author

Randi von Wrede, Martin Schidlowski, Hans-Jürgen Huppertz, Theodor Rüber, Anja Ivo, Tobias Baumgartner, Kerstin Hallmann, Gábor Zsurka, Christoph Helmstaedter, Rainer Surges, and Wolfram S. Kunz

Subjects
genetics [Epilepsy], genetics [Cognition Disorders], Cognition, Biological Variation, Population, genetics [Microcephaly], diagnostic imaging [Intellectual Disability], ddc:570, Mutation, Genetics, Humans, genetics [Intellectual Disability], primary hereditary microcephaly, ASPM mutation, epilepsy, behavioral and cognitive deficits, genetics [Nerve Tissue Proteins], Genetics (clinical)
Abstract

Here, we report a consanguineous family harboring a novel homozygous frame-shift mutation in ASPM leading to a truncation of the ASPM protein after amino acid position 1830. The phenotype of the patients was associated with microcephaly, epilepsy, and behavioral and cognitive deficits. Despite the obvious genetic similarity, the affected patients show a considerable phenotypic heterogeneity regarding the degree of mental retardation, presence of epilepsy and MRI findings. Interestingly, the degree of mental retardation and the presence of epilepsy correlates well with the severity of abnormalities detected in brain MRI. On the other hand, we detected no evidence for substantial nonsense-mediated ASPM transcript decay in blood samples. This indicates that other factors than ASPM expression levels are relevant for the variability of structural changes in brain morphology seen in patients with primary hereditary microcephaly caused by ASPM mutations.

Published
2022
Full Text
View/download PDF

81. Genetic causes of rare and common epilepsies: What should the epileptologist know?

Author

Gaetan Lesca, Tobias Baumgartner, Pauline Monin, Angela De Dominicis, Wolfram S. Kunz, and Nicola Specchio

Subjects
Epilepsy, Exome Sequencing, Genetics, High-Throughput Nucleotide Sequencing, Humans, Genetic Counseling, General Medicine, Genetic Testing, Genetics (clinical)
Abstract

In past decades, the identification of genes involved in epileptic disorders has grown exponentially. The pace of gene identification in epileptic disorders began to accelerate in the late 2000s, driven by new technologies such as molecular cytogenetics and next-generation sequencing (NGS). These technologies have also been applied to genetic diagnostics, with different configurations, such as gene panels, whole-exome sequencing and whole-genome sequencing. The clinician must be aware that any technology has its limitations and complementary techniques must still be used to establish a diagnosis for specific diseases. In addition, increasing the amount of genetic information available in a larger patient sample also increases the need for rigorous interpretation steps, when taking into account the clinical, electroclinical, and when available, functional data. Local, multidisciplinary discussions have proven valuable in difficult diagnostic situations, especially in cases where precision medicine is being considered. They also serve to improve genetic counseling in complex situations. In this article, we will briefly review the genetic basis of rare and common epilepsies, the current strategies used for molecular diagnosis, including their limitations, and some pitfalls for data interpretation, in the context of etiological diagnosis and genetic counseling.

Published
2022

82. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Epilepsy Patients With KCNC2 Pathogenic Variants

Author

Niklas, Schwarz, Simone, Seiffert, Msc, Manuela, Pendziwiat, Annika Verena Rademacher, Tobias, Br¨unger, Phd, Hedrich, Ulrike B. S., Augustijn, Paul B., Hartmut, Baier, Allan, Bayat, Francesca, Bisulli, Phd, Md, Buono, Russell J., Ben Zeev Bruria, Doyle, Michael G., Guerrini, Renzo, Gali, Heimer, Iacomino, Michele, Hugh, Kearney, Karl Martin Klein, Ioanna, Kousiappa, Kunz, Wolfram S., Holger, Lerche, Laura, Licchetta, Ebba, Lohmann, Raffaella, Minardi, Marie, Mcdonald, Sarah, Montgomery, Lejla, Mulahasanovic, Renske, Oegema, Barel, Ortal, Papacostas, Savvas S., Francesca, Ragona, Tiziana, Granata, Reif, Phillip S., Felix, Rosenow, Annick, Rothschild, Scudieri, Paolo, Striano, Pasquale, Paolo, Tinuper, Tanteles, George A., Annalisa, Vetro, Felix, Zahnert, Goldberg, Ethan M., Zara, Federico, Dennis, Lal, Patrick, May, Hiltrud, Muhle, Ingo, Helbig, and and Yvonne Weber

Subjects
Neurology (clinical)
Abstract

Background:KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyse the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants.Methods:Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes.Results:We identified novel KCNC2 variants in 18 patients with various forms of epilepsy including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy (EOAE), focal epilepsy (FE), and myoclonic-atonic epilepsy (MAE). 10/18 variants were de novo and 8/18 variants were classified as modifying variants. 8 drug responsive cases became seizure-free using valproic acid as monotherapy or in combination including severe DEE cases. Functional analysis of four variants demonstrated gain-of-function in three severely affected DEE cases and loss-of-function in one case with a milder phenotype (GGE) as the underlying pathomechanisms.Conclusion:These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.

Published
2022

83. Permeabilized cell and skinned fiber techniques in studies of mitochondrial function in vivo

Author

Saks, Valdur A., Veksler, Vladimir I., Kuznetsov, Andrei V., Kay, Laurence, Sikk, Peeter, Tiivel, Toomas, Tranqui, Leone, Olivares, Jose, Winkler, Kirstin, Wiedemann, Falk, Kunz, Wolfram S., Dhalla, Naranjan S., editor, Saks, Valdur A., editor, Ventura-Clapier, Renée, editor, Leverve, Xavier, editor, Rossi, André, editor, and Rigoulet, Michel, editor

Published
1998
Full Text
View/download PDF

87. Distinct gene-set burden patterns underlie common generalized and focal epilepsies

Author

Mahmoud Koko, Roland Krause, Thomas Sander, Dheeraj Reddy Bobbili, Michael Nothnagel, Patrick May, Holger Lerche, Yen-Chen Anne Feng, Daniel P Howrigan, Liam E Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L Heinzen, Ryan S Dhindsa, Kate E Stanley, Gianpiero L Cavalleri, Hakon Hakonarson, Ingo Helbig, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M Sisodiya, Patrick Cossette, Chris Cotsapas, Peter DeJonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G Marson, Randy Stewart, Chantal Depondt, Dennis J Dlugos, Ingrid E Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M Regan, Susannah T Bellows, Costin Leu, Caitlin A Bennett, Esther M C Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J O'Brien, Marian Todaro, Hannah Stamberger, Danielle M Andrade, Tara R Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S Papacostas, Ioanna Kousiappa, George A Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S Reif, Susanne Knake, Wolfram S Kunz, Gábor Zsurka, Christian E Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas vanBaalen, Sarah vonSpiczak, Ulrich Stephani, Zaid Afawi, Amos D Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R Lemke, Ilona Krey, Yvonne G Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F Maisch, Bernhard J Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I Rees, Seo-Kyung Chung, William O Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R Johnson, Pauls Auce, Graeme J Sills, Larry W Baum, Pak C Sham, Stacey S Cherny, Colin H T Lui, Nina Barišić, Norman Delanty, Colin P Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G Sadleir, Chontelle King, Emily Mountier, Hande S Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R Shiedley, Catherine Shain, Russell J Buono, Thomas N Ferraro, Michael R Sperling, Warren Lo, Michael Privitera, Jacqueline A French, Steven Schachter, Ruben I Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L Helbig, Colin A Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T Pato, Carlos N Pato, Evelyn J Bromet, Celia Barreto Carvalho, Eric D Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S Lehrer, Dolores Malaspina, Stephen R Marder, Helena Medeiros, Christopher P Morley, Diana O Perkins, Janet L Sobell, Peter F Buckley, Fabio Macciardi, Mark H Rapaport, James A Knowles, Genomic Psychiatry Cohort, Ayman H Fanous, Steven A McCarroll, Namrata Gupta, Stacey B Gabriel, Mark J Daly, Eric S Lander, Daniel H Lowenstein, David B Goldstein, Samuel F Berkovic, Benjamin M Neale, Epi25 Collaborative, Koko M., Krause R., Sander T., Bobbili D.R., Nothnagel M., May P., Lerche H., Bisulli F., Tinuper P., Pippucci T., Abbott, Liam E., Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Tashman, Katherine, Korinthenberg, Rudolf, Brockmann, Knut, Kurlemann, Gerhard, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Cerrato, Felecia, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Singh, Tarjinder, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišic, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, Heyne, Henrike, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Byrnes, Andrea, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Churchhouse, Claire, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Watts, Nick, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, Hande S., Arslan, Mutluay, Yapici, Zuhal, Yis, Uluc, Solomonson, Matthew, Topaloglu, Pinar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Asli, Bebek, Nerses, Ugur-Iseri, Sibel, Baykan, Betül, Salman, Baris, Haryanyan, Garen, Yücesan, Emrah, Lal, Dennis, Kesim, Yesim, Özkara, Çigdem, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Buono, Russell J., Ferraro, Thomas N., Sperling, Michael R., Lo, Warren, Privitera, Michael, Heinzen, Erin L., French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Dhindsa, Ryan S., Piras, Federica, Gili, Tommaso, Ciullo, Valentina, Reif, Andreas, McQuillin, Andrew, Bass, Nick, McIntosh, Andrew, Blackwood, Douglas, Johnstone, Mandy, Palotie, Aarno, Stanley, Kate E., Pato, Michele T., Pato, Carlos N., Bromet, Evelyn J., Carvalho, Celia Barreto, Achtyes, Eric D., Azevedo, Maria Helena, Kotov, Roman, Lehrer, Douglas S., Malaspina, Dolores, Marder, Stephen R., Cavalleri, Gianpiero L., Medeiros, Helena, Morley, Christopher P., Perkins, Diana O., Sobell, Janet L., Buckley, Peter F., Macciardi, Fabio, Rapaport, Mark H., Knowles, James A., Cohort, Genomic Psychiatry, Fanous, Ayman H., Hakonarson, Hakon, McCarroll, Steven A., Gupta, Namrata, Gabriel, Stacey B., Daly, Mark J., Lander, Eric S., Lowenstein, Daniel H., Goldstein, David B., Lerche, Holger, Berkovic, Samuel F., Neale, Benjamin M., Helbig, Ingo, Krause, Roland, May, Patrick, Weckhuysen, Sarah, Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Cossette, Patrick, Cotsapas, Chris, DeJonghe, Peter, Dixon-Salazar, Tracy, Guerrini, Renzo, Kwan, Patrick, Marson, Anthony G., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther M. C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O'Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Šterbová, Katalin, Vlcková, Markéta, Sedlácková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Feng, Yen-Chen Anne, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Howrigan, Daniel P., Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, DFG Research Unit FOR-2715 (Germany), FNR (Luxembourg), NHGRI (US), NHLBI (US), DAAD (Germany). [sponsor], and Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center]

Subjects
Exome sequencing, Male, Medicine (General), Neurology [D14] [Human health sciences], Gene-set, Genome-wide association study, Disease, Biology, Epileptogenesis, General Biochemistry, Genetics and Molecular Biology, Whole Exome Sequencing, Epilepsy, R5-920, medicine, Missense mutation, Humans, Exome, Genetic Predisposition to Disease, Gene, Genetic association, Ultra-rare variant, Genetics, Neurologie [D14] [Sciences de la santé humaine], Burden analysis, Genetic Variation, General Medicine, medicine.disease, Ultra-rare variants, Gene-sets, Case-Control Studies, Medicine, epilepsy, Epilepsy, Generalized, Female, Genetics & genetic processes [F10] [Life sciences], Epilepsies, Partial, Human medicine, Burden analysi, Génétique & processus génétiques [F10] [Sciences du vivant], Case-Control Studie, Research Paper, Genome-Wide Association Study, Human
Abstract

EBioMedicine 72, 103588 (2021). doi:10.1016/j.ebiom.2021.103588, Published by Elsevier, Amsterdam [u.a.]

Published
2021
Full Text
View/download PDF

90. Large Phenotypic Variation of Individuals from a Family with a Novel ASPM Mutation Associated with Microcephaly, Epilepsy, and Behavioral and Cognitive Deficits

Author

Wrede, Randi von, primary, Schidlowski, Martin, additional, Huppertz, Hans-Jürgen, additional, Rüber, Theodor, additional, Ivo, Anja, additional, Baumgartner, Tobias, additional, Hallmann, Kerstin, additional, Zsurka, Gábor, additional, Helmstaedter, Christoph, additional, Surges, Rainer, additional, and Kunz, Wolfram S., additional

Published
2022
Full Text
View/download PDF

91. Mitochondrial Retinopathy

Author

Birtel, Johannes, primary, von Landenberg, Christina, additional, Gliem, Martin, additional, Gliem, Carla, additional, Reimann, Jens, additional, Kunz, Wolfram S., additional, Herrmann, Philipp, additional, Betz, Christian, additional, Caswell, Richard, additional, Nesbitt, Victoria, additional, Kornblum, Cornelia, additional, and Charbel Issa, Peter, additional

Published
2022
Full Text
View/download PDF

92. Large Phenotypic Variation of Individuals from a Family with a Novel

Author

Randi, von Wrede, Martin, Schidlowski, Hans-Jürgen, Huppertz, Theodor, Rüber, Anja, Ivo, Tobias, Baumgartner, Kerstin, Hallmann, Gábor, Zsurka, Christoph, Helmstaedter, Rainer, Surges, and Wolfram S, Kunz

Subjects
Cognition, Epilepsy, Biological Variation, Population, Intellectual Disability, Mutation, Microcephaly, Humans, Nerve Tissue Proteins, Cognition Disorders
Abstract

Here, we report a consanguineous family harboring a novel homozygous frame-shift mutation in

Published
2021

93. Novel Pathogenic Sequence Variation m.5789TC Causes NARP Syndrome and Promotes Formation of Deletions of the Mitochondrial Genome

Author

Marius Hippen, Gábor Zsurka, Viktoriya Peeva, Judith Machts, Kati Schwiecker, Grazyna Debska-Vielhaber, Rudolf J. Wiesner, Stefan Vielhaber, and Wolfram S. Kunz

Subjects
Neurology (clinical), Genetics (clinical)
Abstract

Background and ObjectivesWe report the pathogenic sequence variant m.5789T>C in the anticodon stem of the mitochondrial tRNA for cysteine as a novel cause of neuropathy, ataxia, and retinitis pigmentosa (NARP), which is usually associated with pathogenic variants in the MT-ATP6 gene.MethodsTo address the correlation of oxidative phosphorylation deficiency with mutation loads, we performed genotyping on single laser-dissected skeletal muscle fibers. Stability of the mitochondrial tRNACys was investigated by Northern blotting. Accompanying deletions of the mitochondrial genome were detected by long-range PCR and their breakpoints were determined by sequencing of single-molecule amplicons.ResultsThe sequence variant m.5789T>C, originating from the patient's mother, decreases the stability of the mitochondrial tRNA for cysteine by disrupting the anticodon stem, which subsequently leads to a combined oxidative phosphorylation deficiency. In parallel, we observed a prominent cluster of low-abundance somatic deletions with breakpoints in the immediate vicinity of the m.5789T>C variant. Strikingly, all deletion-carrying mitochondrial DNA (mtDNA) species, in which the corresponding nucleotide position was not removed, harbored the mutant allele, and none carried the wild-type allele.DiscussionIn addition to providing evidence for the novel association of a tRNA sequence alteration with NARP syndrome, our observations support the hypothesis that single nucleotide changes can lead to increased occurrence of site-specific mtDNA deletions through the formation of an imperfect repeat. This finding might be relevant for understanding mechanisms of deletion generation in the human mitochondrial genome.

Published
2021

94. A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies

Author

Christine, Strippel, Marisol, Herrera-Rivero, Mareike, Wendorff, Anja K, Tietz, Frauke, Degenhardt, Anika, Witten, Christina, Schroeter, Christopher, Nelke, Kristin S, Golombeck, Marie, Madlener, Theodor, Rüber, Leon, Ernst, Attila, Racz, Tobias, Baumgartner, Guido, Widman, Kathrin, Doppler, Franziska, Thaler, Kai, Siebenbrodt, Andre, Dik, Constanze, Kerin, Saskia, Räuber, Marco, Gallus, Stjepana, Kovac, Oliver M, Grauer, Alexander, Grimm, Harald, Prüss, Jonathan, Wickel, Christian, Geis, Jan, Lewerenz, Norbert, Goebels, Marius, Ringelstein, Til, Menge, Björn, Tackenberg, Christoph, Kellinghaus, Christian G, Bien, Andrea, Kraft, Uwe, Zettl, Fatme Seval, Ismail, Ilya, Ayzenberg, Christian, Urbanek, Kurt-Wolfram, Sühs, Simone C, Tauber, Sigrid, Mues, Peter, Körtvélyessy, Robert, Markewitz, Asterios, Paliantonis, Christian E, Elger, Rainer, Surges, Claudia, Sommer, Tania, Kümpfel, Catharina C, Gross, Holger, Lerche, Jörg, Wellmer, Carlos M, Quesada, Florian, Then Bergh, Klaus-Peter, Wandinger, Albert J, Becker, Wolfram S, Kunz, Gerd, Meyer Zu Hörste, Michael P, Malter, Felix, Rosenow, Heinz, Wiendl, Gregor, Kuhlenbäumer, Frank, Leypoldt, Wolfgang, Lieb, Andre, Franke, Sven G, Meuth, Monika, Stoll, and Nico, Melzer

Subjects
Neurology (clinical)
Abstract

Brain : a journal of neurology (2022). doi:10.1093/brain/awac119, Published by Oxford Univ. Press, Oxford

Published
2021
Full Text
View/download PDF

96. Outcome of an Accelerated Treatment Algorithm for Patients Developing Diarrhea as a Complication of Ipilimumab-Based Cancer Immunotherapy in a Community Practice

Author

Clarice Ho and Wolfram Samlowski

Subjects
checkpoint inhibitors, diarrhea, inflammatory colitis, infliximab, glucocorticosteroids, ipilimumab, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Immune-mediated diarrhea represents a serious complication of checkpoint inhibitor therapy, especially following ipilimumab-based treatment. Efficient diagnosis and control of diarrhea remains an ongoing challenge. We developed an accelerated management paradigm for patients with ipilimumab-induced diarrhea. Patients who developed significant diarrhea (>five loose stools/day) were presumed to be developing immune colitis. Therapy was interrupted and patients were treated with a methylprednisolone dose pack. If diarrhea was not completely resolved, high-dose steroids and infliximab were promptly added. Only non-responding patients underwent further evaluation for infection or other causes of diarrhea. A total of 242 patients were treated with ipilimumab-based regimens. Forty-six developed significant diarrhea (19%) and thirty-four (74.4%) had a rapid resolution of diarrhea following glucocorticosteroid and infliximab treatment. The median time to resolution of diarrhea was only 8.5 ± 16.4 days. Accelerated treatment for presumed immune-mediated diarrhea resulted in the rapid control of symptoms in the majority of patients. There were no intestinal complications or deaths. Immunosuppressive therapy for diarrhea did not appear to decrease the remission rate or survival. After the control of diarrhea, most patients were able to continue their planned immunotherapy. Further testing in 11/46 patients with unresponsive diarrhea revealed additional diagnoses, allowing their treatment to be adjusted.

Published
2024
Full Text
View/download PDF

97. Non-linear relationships between daily temperature extremes and US agricultural yields uncovered by global gridded meteorological datasets

Author

Dylan Hogan and Wolfram Schlenker

Subjects
Science
Abstract

Abstract Global agricultural commodity markets are highly integrated among major producers. Prices are driven by aggregate supply rather than what happens in individual countries in isolation. Estimating the effects of weather-induced shocks on production, trade patterns and prices hence requires a globally representative weather data set. Recently, two data sets that provide daily or hourly records, GMFD and ERA5-Land, became available. Starting with the US, a data rich region, we formally test whether these global data sets are as good as more fine-scaled country-specific data in explaining yields and whether they estimate similar response functions. While GMFD and ERA5-Land have lower predictive skill for US corn and soybeans yields than the fine-scaled PRISM data, they still correctly uncover the underlying non-linear temperature relationship. All specifications using daily temperature extremes under any of the weather data sets outperform models that use a quadratic in average temperature. Correctly capturing the effect of daily extremes has a larger effect than the choice of weather data. In a second step, focusing on Sub Saharan Africa, a data sparse region, we confirm that GMFD and ERA5-Land have superior predictive power to CRU, a global weather data set previously employed for modeling climate effects in the region.

Published
2024
Full Text
View/download PDF

98. Multiscale and multimodal imaging for three-dimensional vascular and histomorphological organ structure analysis of the pancreas

Author

Gabriel Alexander Salg, Verena Steinle, Jonas Labode, Willi Wagner, Alexander Studier-Fischer, Johanna Reiser, Elyes Farjallah, Michelle Guettlein, Jonas Albers, Tim Hilgenfeld, Nathalia A. Giese, Wolfram Stiller, Felix Nickel, Martin Loos, Christoph W. Michalski, Hans-Ulrich Kauczor, Thilo Hackert, Christian Dullin, Philipp Mayer, and Hannes Goetz Kenngott

Subjects
Pancreas, Imaging, Synchrotron, Vascularization, Virtual histology, Computed tomography, Medicine, Science
Abstract

Abstract Exocrine and endocrine pancreas are interconnected anatomically and functionally, with vasculature facilitating bidirectional communication. Our understanding of this network remains limited, largely due to two-dimensional histology and missing combination with three-dimensional imaging. In this study, a multiscale 3D-imaging process was used to analyze a porcine pancreas. Clinical computed tomography, digital volume tomography, micro-computed tomography and Synchrotron-based propagation-based imaging were applied consecutively. Fields of view correlated inversely with attainable resolution from a whole organism level down to capillary structures with a voxel edge length of 2.0 µm. Segmented vascular networks from 3D-imaging data were correlated with tissue sections stained by immunohistochemistry and revealed highly vascularized regions to be intra-islet capillaries of islets of Langerhans. Generated 3D-datasets allowed for three-dimensional qualitative and quantitative organ and vessel structure analysis. Beyond this study, the method shows potential for application across a wide range of patho-morphology analyses and might possibly provide microstructural blueprints for biotissue engineering.

Published
2024
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results