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4. A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

Author

Bowl, Michael R, Simon, Michelle M, Ingham, Neil J, Greenaway, Simon, Santos, Luis, Cater, Heather, Taylor, Sarah, Mason, Jeremy, Kurbatova, Natalja, Pearson, Selina, Bower, Lynette R, Clary, Dave A, Meziane, Hamid, Reilly, Patrick, Minowa, Osamu, Kelsey, Lois, The International Mouse Phenotyping Consortium, Tocchini-Valentini, Glauco P, Gao, Xiang, Bradley, Allan, Skarnes, William C, Moore, Mark, Beaudet, Arthur L, Justice, Monica J, Seavitt, John, Dickinson, Mary E, Wurst, Wolfgang, de Angelis, Martin Hrabe, Herault, Yann, Wakana, Shigeharu, Nutter, Lauryl MJ, Flenniken, Ann M, McKerlie, Colin, Murray, Stephen A, Svenson, Karen L, Braun, Robert E, West, David B, Lloyd, KC Kent, Adams, David J, White, Jacqui, Karp, Natasha, Flicek, Paul, Smedley, Damian, Meehan, Terrence F, Parkinson, Helen E, Teboul, Lydia M, Wells, Sara, Steel, Karen P, Mallon, Ann-Marie, and Brown, Steve DM

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Allied Health and Rehabilitation Science, Clinical Sciences, Health Sciences, Clinical Research, Hearing Loss, Human Genome, Neurosciences, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Ear, Animals, Datasets as Topic, Genetic Testing, Hearing Tests, Mice, Mice, Knockout, Phenotype, Protein Interaction Maps, International Mouse Phenotyping Consortium
Abstract

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function.The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.

Published
2017

9. Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease

Author

Pauzuolyte, Valda; https://orcid.org/0009-0009-7352-7894, Patel, Aara, Wawrzynski, James R, Ingham, Neil J; https://orcid.org/0000-0002-0916-7347, Leong, Yeh Chwan, Karda, Rajvinder, Bitner‐Glindzicz, Maria, Berger, Wolfgang; https://orcid.org/0000-0002-0370-3815, Waddington, Simon N; https://orcid.org/0000-0003-4970-4730, Steel, Karen P, Sowden, Jane C; https://orcid.org/0000-0003-0937-2479, Pauzuolyte, Valda; https://orcid.org/0009-0009-7352-7894, Patel, Aara, Wawrzynski, James R, Ingham, Neil J; https://orcid.org/0000-0002-0916-7347, Leong, Yeh Chwan, Karda, Rajvinder, Bitner‐Glindzicz, Maria, Berger, Wolfgang; https://orcid.org/0000-0002-0370-3815, Waddington, Simon N; https://orcid.org/0000-0003-4970-4730, Steel, Karen P, and Sowden, Jane C; https://orcid.org/0000-0003-0937-2479

Abstract

Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X‐linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndp$^{tm1Wbrg}$), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno‐associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease.

Published
2023

13. The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention

Author

Bryant, Dale, Pauzuolyte, Valda, Ingham, Neil J, Patel, Aara, Pagarkar, Waheeda, Anderson, Lucy A, Smith, Katie E, Moulding, Dale A, Leong, Yeh C, Jafree, Daniyal J, Long, David A, Al-Yassin, Amina, Steel, Karen P, Jagger, Daniel J, Forge, Andrew, Berger, Wolfgang; https://orcid.org/0000-0002-0370-3815, Sowden, Jane C, Bitner-Glindzicz, Maria, Bryant, Dale, Pauzuolyte, Valda, Ingham, Neil J, Patel, Aara, Pagarkar, Waheeda, Anderson, Lucy A, Smith, Katie E, Moulding, Dale A, Leong, Yeh C, Jafree, Daniyal J, Long, David A, Al-Yassin, Amina, Steel, Karen P, Jagger, Daniel J, Forge, Andrew, Berger, Wolfgang; https://orcid.org/0000-0002-0370-3815, Sowden, Jane C, and Bitner-Glindzicz, Maria

Abstract

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Published
2022

14. Mutations in MINAR2 encoding membrane integral NOTCH2-associated receptor 2 cause deafness in humans and mice

Author

Bademci, Guney, primary, Lachgar-Ruiz, María, additional, Deokar, Mangesh, additional, Zafeer, Mohammad Faraz, additional, Abad, Clemer, additional, Yildirim Baylan, Muzeyyen, additional, Ingham, Neil J., additional, Chen, Jing, additional, Sineni, Claire J., additional, Vadgama, Nirmal, additional, Karakikes, Ioannis, additional, Guo, Shengru, additional, Duman, Duygu, additional, Singh, Nitu, additional, Harlalka, Gaurav, additional, Jain, Shirish P., additional, Chioza, Barry A., additional, Walz, Katherina, additional, Steel, Karen P., additional, Nasir, Jamal, additional, and Tekin, Mustafa, additional

Published
2022
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15. Additional file 1 of Identification and characterisation of spontaneous mutations causing deafness from a targeted knockout programme

Author

Lewis, Morag A., Ingham, Neil J., Chen, Jing, Pearson, Selina, Di Domenico, Francesca, Rekhi, Sohinder, Allen, Rochelle, Drake, Matthew, Willaert, Annelore, Rook, Victoria, Pass, Johanna, Keane, Thomas, Adams, David J., Tucker, Abigail S., White, Jacqueline K., and Steel, Karen P.

Subjects
Data_FILES
Abstract

Additional file 1.

Published
2022
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16. The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention

Author

Bryant, Dale, primary, Pauzuolyte, Valda, additional, Ingham, Neil J., additional, Patel, Aara, additional, Pagarkar, Waheeda, additional, Anderson, Lucy A., additional, Smith, Katie E., additional, Moulding, Dale A., additional, Leong, Yeh C., additional, Jafree, Daniyal J., additional, Long, David A., additional, Al-Yassin, Amina, additional, Steel, Karen P., additional, Jagger, Daniel J., additional, Forge, Andrew, additional, Berger, Wolfgang, additional, Sowden, Jane C., additional, and Bitner-Glindzicz, Maria, additional

Published
2022
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20. Mouse screen reveals multiple new genes underlying mouse and human hearing loss

Author

Ingham, Neil J, Pearson, Selina A, Vancollie, Valerie E, Rook, Victoria, Lewis, Morag A, Chen, Jing, Buniello, Annalisa, Martelletti, Elisa, Preite, Lorenzo, Lam, Chi Chung, Weiss, Felix D, Powis, Zӧe, Suwannarat, Pim, Lelliott, Christopher J, Dawson, Sally J, White, Jacqueline K, Steel, Karen P, Ingham, Neil J [0000-0002-0916-7347], Vancollie, Valerie E [0000-0003-1547-1975], Rook, Victoria [0000-0002-1225-0870], Lewis, Morag A [0000-0002-1846-8600], Buniello, Annalisa [0000-0002-4623-8642], Martelletti, Elisa [0000-0001-8038-8866], Lam, Chi Chung [0000-0003-1370-2872], Weiss, Felix D [0000-0003-0228-5081], Lelliott, Christopher J [0000-0001-8087-4530], Steel, Karen P [0000-0002-8019-5359], and Apollo - University of Cambridge Repository

Subjects
Adult, Male, QH301-705.5, Anion Transport Proteins, Electrophysiological Phenomena, Mice, Inbred C57BL, Mice, Acoustic Stimulation, Hearing, Auditory Perception, Evoked Potentials, Auditory, Brain Stem, otorhinolaryngologic diseases, Animals, Humans, Female, Biology (General), Child, Hearing Loss, Genetic Association Studies
Abstract

Adult-onset hearing loss is very common, but we know little about the underlying molecular pathogenesis impeding the development of therapies. We took a genetic approach to identify new molecules involved in hearing loss by screening a large cohort of newly generated mouse mutants using a sensitive electrophysiological test, the auditory brainstem response (ABR). We review here the findings from this screen. Thirty-eight unexpected genes associated with raised thresholds were detected from our unbiased sample of 1,211 genes tested, suggesting extreme genetic heterogeneity. A wide range of auditory pathophysiologies was found, and some mutant lines showed normal development followed by deterioration of responses, revealing new molecular pathways involved in progressive hearing loss. Several of the genes were associated with the range of hearing thresholds in the human population and one, SPNS2, was involved in childhood deafness. The new pathways required for maintenance of hearing discovered by this screen present new therapeutic opportunities.

Published
2019

21. Collateral damage: Identification and characterisation of spontaneous mutations causing deafness from a targeted knockout programme

Author

Lewis, Morag A., primary, Ingham, Neil J., additional, Chen, Jing, additional, Pearson, Selina, additional, Di Domenico, Francesca, additional, Rekhi, Sohinder, additional, Allen, Rochelle, additional, Drake, Matthew, additional, Willaert, Annelore, additional, Rook, Victoria, additional, Pass, Johanna, additional, Keane, Thomas, additional, Adams, David, additional, Tucker, Abigail S., additional, White, Jacqueline K., additional, and Steel, Karen P., additional

Published
2021
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26. Mouse screen reveals multiple new genes underlying mouse and human hearing loss

Author

Ingham, Neil J., Pearson, Selina A., Vancollie, Valerie E, Lewis, Morag Ann, Chen, Jing, Buniello, Annalisa, Martelletti, Elisa, and Steel, Karen

Subjects
Genetic deafness, Progressive hearing loss, Genetic heterogeneity, Mouse mutant screen, SPNS2, Lipids in deafness, otorhinolaryngologic diseases, Common human disease, Therapeutic opportunities, Auditory Brainstem Response, Auditory pathology, Hearing impairment
Abstract

Adult-onset hearing loss is very common but we know little about the underlying molecular pathogenesis, impeding development of therapies. We took a genetic approach to identify new molecules involved in hearing loss by screening a large cohort of newly-generated mouse mutants using a sensitive electrophysiological test, the auditory brainstem response. We review here the findings from this screen. Thirty-eight unexpected genes associated with raised thresholds were detected from our unbiased sample of 1,211 genes tested, suggesting extreme genetic heterogeneity. A wide range of auditory pathophysiologies was found, and some mutant lines showed normal development followed by deterioration of responses, revealing new molecular pathways involved in progressive hearing loss. Several of the genes were associated with the range of hearing thresholds in the human population and one, SPNS2, was involved in childhood deafness. The new pathways required for maintenance of hearing discovered by this screen present new therapeutic opportunities.

Published
2019
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30. A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

Author

Bowl, Michael R., Simon, Michelle M., Ingham, Neil J., Greenaway, Simon, Santos, Luis, Cater, Heather, Taylor, Sarah, Mason, Jeremy, Kurbatova, Natalja, Pearson, Selina, Bower, Lynette R., Clary, Dave A., Meziane, Hamid, Reilly, Patrick, Minowa, Osamu, Kelsey, Lois, Allen, Sue, Clementson-Mobbs, Sharon, Codner, Gemma, Fray, Martin, Gardiner, Wendy, Joynson, Russell, Kenyon, Janet, Loeffler, Jorik, Nell, Barbara, Parker, Andrew, Quwailid, Deen, Stewart, Michelle, Walling, Alison, Zaman, Rumana, Chen, Chao Kung, Conte, Nathalie, Matthews, Peter, Relac, Mike, Tudose, Ilinca, Warren, Jonathan, Le Marchand, Elise, El Amri, Amal, El Fertak, Leila, Ennah, Hamid, Ali-Hadji, Dalila, Ayadi, Abdel, Wattenhofer-Donze, Marie, Moulaert, David, Jacquot, Sylvie, André, Philippe, Birling, Marie Christine, Pavlovic, Guillaume, Lalanne, Valérie, Lux, Aline, Riet, Fabrice, Mittelhaeuser, Christophe, Bour, Raphael, Guimond, Alain, Bam'Hamed, Chaouki, Leblanc, Sophie, Vasseur, Laurent, Selloum, Mohammed, Sorg, Tania, Ayabe, Shinya, Furuse, Tamio, Kaneda, Hideki, Kobayashi, Kimio, Masuya, Hiroshi, Miura, Ikuo, Obata, Yuichi, Suzuki, Tomohiro, Tamura, Masaru, Tanaka, Nobuhiko, Yamada, Ikuko, Yoshiki, Atsushi, Berberovic, Zorana, Bubshait, Mohammed, Cabezas, Jorge, Carroll, Tracy, Clark, Greg, Clarke, Shannon, Creighton, Amie, Danisment, Ozge, Eskandarian, Mohammad, Feugas, Patricia, Gertsenstein, Marina, Guo, Ruolin, Hunter, Jane, Jacob, Elsa, Lan, Qing, Laurin, Valerie, Law, Napoleon, MacMaster, Sue, Miller, David, Morikawa, Lily, Newbigging, Susan, Owen, Celeste, Penton, Patricia, Pereira, Monica, Qu, Dawei, Shang, Xueyuan, Sleep, Gillian, Sohel, Khondoker, Tondat, Sandra, Wang, Yanchun, Vukobradovic, Igor, Zhu, Yingchun, Chiani, Francesco, Di Pietro, Chiara, Di Segni, Gianfranco, Ermakova, Olga, Ferrara, Filomena, Fruscoloni, Paolo, Gambadoro, Aalessia, Gastaldi, Serena, Golini, Elisabetta, Sala, Gina La, Mandillo, Silvia, Marazziti, Daniela, Massimi, Marzia, Matteoni, Rafaele, Orsini, Tiziana, Pasquini, Miriam, Raspa, Marcello, Rauch, Aline, Rossi, Gianfranco, Rossi, Nicoletta, Putti, Sabrina, Scavizzi, Ferdinando, Tocchini-Valentini, Giuseppe D., Beig, Joachim, Bürger, Antje, Giesert, Florian, Graw, Jochen, Kühn, Ralf, Oritz, Oskar, Schick, Joel, Seisenberger, Claudia, Amarie, Oana, Garrett, Lillian, Hölter, Sabine M., Zimprich, Annemarie, Aguilar-Pimentel, Antonio, Beckers, Johannes, Brommage, Robert, Calzada-Wack, Julia, Fuchs, Helmut, Gailus-Durner, Valérie, Lengger, Christoph, Leuchtenberger, Stefanie, Maier, Holger, Marschall, Susan, Moreth, Kristin, Neff, Frauke, Östereicher, Manuela A., Rozman, Jan, Steinkamp, Ralph, Stoeger, Claudia, Treise, Irina, Stoeger, Tobias, Yildrim, Ali Önder, Eickelberg, Oliver, Becker, Lore, Klopstock, Thomas, Ollert, Markus, Busch, Dirk H., Schmidt-Weber, Carsten, Bekeredjian, Raffi, Zimmer, Andreas, Rathkolb, Birgit, Wolf, Eckhard, Klingenspor, Martin, Tocchini-Valentini, Glauco P., Gao, Xiang, Bradley, Allan, Skarnes, William C., Moore, Mark, Beaudet, Arthur L., Justice, Monica J., Seavitt, John, Dickinson, Mary E., Wurst, Wolfgang, De Angelis, Martin Hrabe, Herault, Yann, Wakana, Shigeharu, Nutter, Lauryl M.J., Flenniken, Ann M., McKerlie, Colin, Murray, Stephen A., Svenson, Karen L., Braun, Robert E., West, David B., Lloyd, K. C.Kent, Adams, David J., White, Jacqui, Karp, Natasha, Flicek, Paul, Smedley, Damian, Meehan, Terrence F., Parkinson, Helen E., Teboul, Lydia M., Wells, Sara, Steel, Karen P., Mallon, Ann Marie, Brown, Steve D.M., Mason, Jeremy [0000-0002-2796-5123], de Angelis, Martin Hrabe [0000-0002-7898-2353], Herault, Yann [0000-0001-7049-6900], Wakana, Shigeharu [0000-0001-8532-0924], McKerlie, Colin [0000-0002-2232-0967], Lloyd, KC Kent [0000-0002-5318-4144], Flicek, Paul [0000-0002-3897-7955], Smedley, Damian [0000-0002-5836-9850], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, Cancer Research, Candidate gene, General Physics and Astronomy, Datasets as Topic, Mice, 2.1 Biological and endogenous factors, Protein Interaction Maps, Aetiology, lcsh:Science, Pediatric, Genetics, Mice, Knockout, Multidisciplinary, medicine.diagnostic_test, Hearing Tests, Ear, Phenotype, medicine.anatomical_structure, Technology Platforms, International Mouse Phenotyping Consortium, medicine.symptom, Biotechnology, Hearing Loss/epidemiology, Hearing loss, Knockout, 1.1 Normal biological development and functioning, Science, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Clinical Research, Underpinning research, medicine, otorhinolaryngologic diseases, Auditory system, Animals, Genetic Testing, IMPC, mouse, auditory dysfunction, Set (psychology), Hearing Loss, Gene, Genetic testing, Auditory dysfunction, Human Genome, General Chemistry, 030104 developmental biology, Protein Interaction Maps/genetics, lcsh:Q
Abstract

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function., The full extent of the genetic basis for hearing impairment is unknown. Here, as part of the International Mouse Phenotyping Consortium, the authors perform a hearing loss screen in 3006 mouse knockout strains and identify 52 new candidate genes for genetic hearing loss.

Published
2017
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34. ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells

Author

Morozko, Eva L., primary, Nishio, Ayako, additional, Ingham, Neil J., additional, Chandra, Rashmi, additional, Fitzgerald, Tracy, additional, Martelletti, Elisa, additional, Borck, Guntram, additional, Wilson, Elizabeth, additional, Riordan, Gavin P., additional, Wangemann, Philine, additional, Forge, Andrew, additional, Steel, Karen P., additional, Liddle, Rodger A., additional, Friedman, Thomas B., additional, and Belyantseva, Inna A., additional

Published
2014
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35. Enhancement of forward suppression begins in the ventral cochlear nucleus

Author

Ingham, Neil J., Itatani, Naoya, Bleeck, Stefan, Winter, Ian M., Winter, Ian [0000-0002-1801-5281], and Apollo - University of Cambridge Repository

Subjects
Research Report, CN, cochlear nucleus, Auditory Pathways, Acoustics and Ultrasonics, AN, auditory nerve, Action Potentials, Choice Behavior, 0302 clinical medicine, PEST, parameter estimation by sequential testing, PL, primary-like, 10. No inequality, Auditory, Neurons, 0303 health sciences, Signal Processing, Computer-Assisted, ON, onset, VCN, ventral cochlear nucleus, Ch, chopper, DCN, dorsal cochlear nucleus, IC, inferior colliculus, ICc, central nucleus of the inferior colliculus, Brainstem, CS, chopper-sustained, Algorithms, Cochlear Nucleus, PN, primary-like with notch, OL, onset-L, Neuroscience(all), Guinea Pigs, OC, onset-chopper, Clinical Neurology, OS, onset- sustained, 03 medical and health sciences, S, sustained, AC, auditory cortex, PSTH, peri-stimulus time histogram, Arts and Humanities (miscellaneous), OI, onset-I, Animals, Cochlear Nerve, Molecular Biology, 030304 developmental biology, GoS, growth of suppression, CF, characteristic frequency, Context, CV, coefficient of variation, Auditory Threshold, P, pauser, Guinea pig, ISI, inter-spike interval, Inferior Colliculi, BF, best frequency, CT, chopper-transient, Masking, Acoustic Stimulation, Microelectrodes, 030217 neurology & neurosurgery, Developmental Biology
Abstract

A neuron׳s response to a sound can be suppressed by the presentation of a preceding sound. It has been suggested that this suppression is a direct correlate of the psychophysical phenomenon of forward masking, however, forward suppression, as measured in the responses of the auditory nerve, was insufficient to account for behavioural performance. In contrast the neural suppression seen in the inferior colliculus and auditory cortex was much closer to psychophysical performance. In anaesthetised guinea-pigs, using a physiological two-interval forced-choice threshold tracking algorithm to estimate suppressed (masked) thresholds, we examine whether the enhancement of suppression can occur at an earlier stage of the auditory pathway, the ventral cochlear nucleus (VCN). We also compare these responses with the responses from the central nucleus of the inferior colliculus (ICc) using the same preparation. In both nuclei, onset-type neurons showed the greatest amounts of suppression (16.9–33.5 dB) and, in the VCN, these recovered with the fastest time constants (14.1–19.9 ms). Neurons with sustained discharge demonstrated reduced masking (8.9–12.1 dB) and recovery time constants of 27.2–55.6 ms. In the VCN the decrease in growth of suppression with increasing suppressor level was largest for chopper units and smallest for onset-type units. The threshold elevations recorded for most unit types are insufficient to account for the magnitude of forward masking as measured behaviourally, however, onset responders, in both the cochlear nucleus and inferior colliculus demonstrate a wide dynamic range of suppression, similar to that observed in human psychophysics., Highlights • A two-interval forced choice procedure was used to measure suppressed thresholds. • The time course of recovery from suppression was fastest for onset units. • Growth of suppression with increased suppressor level was greatest for onset units. • Suppression in onset units was greater than that seen in auditory nerve fibres.

Published
2014
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36. Deficiency for the Ubiquitin Ligase UBE3B in a Blepharophimosis-Ptosis-Intellectual-Disability Syndrome

Author

Basel-Vanagaite, Lina, Dallapiccola, Bruno, Ramirez-Solis, Ramiro, Segref, Alexandra, Thiele, Holger, Edwards, Andrew, Arends, Mark J., Miro, Xavier, White, Jacqueline K., Desir, Julie, Abramowicz, Marc, Dentici, Maria Lisa, Lepri, Francesca, Hofmann, Kay, Har-Zahav, Adi, Ryder, Edward, Karp, Natasha A., Estabel, Jeanne, Gerdin, Anna-Karin B., Podrini, Christine, Ingham, Neil J., Altmueller, Janine, Nuernberg, Gudrun, Frommolt, Peter, Abdelhak, Sonia, Pasmanik-Chor, Metsada, Konen, Osnat, Kelley, Richard I., Shohat, Mordechai, Nuernberg, Peter, Flint, Jonathan, Steel, Karen P., Hoppe, Thorsten, Kubisch, Christian, Adams, David J., Borck, Guntram, Basel-Vanagaite, Lina, Dallapiccola, Bruno, Ramirez-Solis, Ramiro, Segref, Alexandra, Thiele, Holger, Edwards, Andrew, Arends, Mark J., Miro, Xavier, White, Jacqueline K., Desir, Julie, Abramowicz, Marc, Dentici, Maria Lisa, Lepri, Francesca, Hofmann, Kay, Har-Zahav, Adi, Ryder, Edward, Karp, Natasha A., Estabel, Jeanne, Gerdin, Anna-Karin B., Podrini, Christine, Ingham, Neil J., Altmueller, Janine, Nuernberg, Gudrun, Frommolt, Peter, Abdelhak, Sonia, Pasmanik-Chor, Metsada, Konen, Osnat, Kelley, Richard I., Shohat, Mordechai, Nuernberg, Peter, Flint, Jonathan, Steel, Karen P., Hoppe, Thorsten, Kubisch, Christian, Adams, David J., and Borck, Guntram

Abstract

Ubiquitination plays a crucial role in neurodevelopment as exemplified by Angelman syndrome, which is caused by genetic alterations of the ubiquitin ligase-encoding UBE3A gene. Although the function of UBE3A has been widely studied, little is known about its paralog UBE3B. By using exome and capillary sequencing, we here identify biallelic UBE3B mutations in four patients from three unrelated families presenting an autosomal-recessive blepharophimosis-ptosis-intellectual-disability syndrome characterized by developmental delay, growth retardation with a small head circumference, facial dysmorphisms, and low cholesterol levels. UBE3B encodes an uncharacterized E3 ubiquitin ligase. The identified UBE3B variants include one frameshift and two splice-site mutations as well as a missense substitution affecting the highly conserved HECT domain. Disruption of mouse Ube3b leads to reduced viability and recapitulates key aspects of the human disorder, such as reduced weight and brain size and a downregulation of cholesterol synthesis. We establish that the probable Caenorhabditis elegans ortholog of UBE3B, oxi-1, functions in the ubiquitin/proteasome system in vivo and is especially required under oxidative stress conditions. Our data reveal the pleiotropic effects of UBE3B deficiency and reinforce the physiological importance of ubiquitination in neuronal development and function in mammals.

Published
2012

37. Genome-wide Generation and Systematic Phenotyping of Knockout Mice Reveals New Roles for Many Genes

Author

White, Jacqueline K., primary, Gerdin, Anna-Karin, additional, Karp, Natasha A., additional, Ryder, Ed, additional, Buljan, Marija, additional, Bussell, James N., additional, Salisbury, Jennifer, additional, Clare, Simon, additional, Ingham, Neil J., additional, Podrini, Christine, additional, Houghton, Richard, additional, Estabel, Jeanne, additional, Bottomley, Joanna R., additional, Melvin, David G., additional, Sunter, David, additional, Adams, Niels C., additional, Tannahill, David, additional, Logan, Darren W., additional, MacArthur, Daniel G., additional, Flint, Jonathan, additional, Mahajan, Vinit B., additional, Tsang, Stephen H., additional, Smyth, Ian, additional, Watt, Fiona M., additional, Skarnes, William C., additional, Dougan, Gordon, additional, Adams, David J., additional, Ramirez-Solis, Ramiro, additional, Bradley, Allan, additional, Steel, Karen P., additional, Baker, Lauren, additional, Barnes, Caroline, additional, Beveridge, Ryan, additional, Cambridge, Emma, additional, Carragher, Damian, additional, Chana, Prabhjoat, additional, Clarke, Kay, additional, Hooks, Yvette, additional, Igosheva, Natalia, additional, Ismail, Ozama, additional, Jackson, Hannah, additional, Kane, Leanne, additional, Lacey, Rosalind, additional, Lafont, David Tino, additional, Lucas, Mark, additional, Maguire, Simon, additional, McGill, Katherine, additional, McIntyre, Rebecca E., additional, Messager, Sophie, additional, Mottram, Lynda, additional, Mulderrig, Lee, additional, Pearson, Selina, additional, Protheroe, Hayley J., additional, Roberson, Laura-Anne, additional, Salsbury, Grace, additional, Sanderson, Mark, additional, Sanger, Daniel, additional, Shannon, Carl, additional, Thompson, Paul C., additional, Tuck, Elizabeth, additional, Vancollie, Valerie E., additional, Brackenbury, Lisa, additional, Bushell, Wendy, additional, Cook, Ross, additional, Dalvi, Priya, additional, Gleeson, Diane, additional, Habib, Bishoy, additional, Hardy, Matt, additional, Liakath-Ali, Kifayathullah, additional, Miklejewska, Evelina, additional, Price, Stacey, additional, Sethi, Debarati, additional, Trenchard, Elizabeth, additional, von Schiller, Dominique, additional, Vyas, Sapna, additional, West, Anthony P., additional, Woodward, John, additional, Wynn, Elizabeth, additional, Evans, Arthur, additional, Gannon, David, additional, Griffiths, Mark, additional, Holroyd, Simon, additional, Iyer, Vivek, additional, Kipp, Christian, additional, Lewis, Morag, additional, Li, Wei, additional, Oakley, Darren, additional, Richardson, David, additional, Smedley, Damian, additional, Agu, Chukwuma, additional, Bryant, Jackie, additional, Delaney, Liz, additional, Gueorguieva, Nadia I., additional, Tharagonnet, Helen, additional, Townsend, Anne J., additional, Biggs, Daniel, additional, Brown, Ellen, additional, Collinson, Adam, additional, Dumeau, Charles-Etienne, additional, Grau, Evelyn, additional, Harrison, Sarah, additional, Harrison, James, additional, Ingle, Catherine E., additional, Kundi, Helen, additional, Madich, Alla, additional, Mayhew, Danielle, additional, Metcalf, Tom, additional, Newman, Stuart, additional, Pass, Johanna, additional, Pearson, Laila, additional, Reynolds, Helen, additional, Sinclair, Caroline, additional, Wardle-Jones, Hannah, additional, Woods, Michael, additional, Alexander, Liam, additional, Brown, Terry, additional, Flack, Francesca, additional, Frost, Carole, additional, Griggs, Nicola, additional, Hrnciarova, Silvia, additional, Kirton, Andrea, additional, McDermott, Jordan, additional, Rogerson, Claire, additional, White, Gemma, additional, Zielezinski, Pawel, additional, DiTommaso, Tia, additional, Edwards, Andrew, additional, Heath, Emma, additional, Mahajan, Mary Ann, additional, and Yalcin, Binnaz, additional

Published
2013
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38. A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains

Author

Simon, Michelle M, primary, Greenaway, Simon, additional, White, Jacqueline K, additional, Fuchs, Helmut, additional, Gailus-Durner, Valérie, additional, Wells, Sara, additional, Sorg, Tania, additional, Wong, Kim, additional, Bedu, Elodie, additional, Cartwright, Elizabeth J, additional, Dacquin, Romain, additional, Djebali, Sophia, additional, Estabel, Jeanne, additional, Graw, Jochen, additional, Ingham, Neil J, additional, Jackson, Ian J, additional, Lengeling, Andreas, additional, Mandillo, Silvia, additional, Marvel, Jacqueline, additional, Meziane, Hamid, additional, Preitner, Frédéric, additional, Puk, Oliver, additional, Roux, Michel, additional, Adams, David J, additional, Atkins, Sarah, additional, Ayadi, Abdel, additional, Becker, Lore, additional, Blake, Andrew, additional, Brooker, Debra, additional, Cater, Heather, additional, Champy, Marie-France, additional, Combe, Roy, additional, Danecek, Petr, additional, di Fenza, Armida, additional, Gates, Hilary, additional, Gerdin, Anna-Karin, additional, Golini, Elisabetta, additional, Hancock, John M, additional, Hans, Wolfgang, additional, Hölter, Sabine M, additional, Hough, Tertius, additional, Jurdic, Pierre, additional, Keane, Thomas M, additional, Morgan, Hugh, additional, Müller, Werner, additional, Neff, Frauke, additional, Nicholson, George, additional, Pasche, Bastian, additional, Roberson, Laura-Anne, additional, Rozman, Jan, additional, Sanderson, Mark, additional, Santos, Luis, additional, Selloum, Mohammed, additional, Shannon, Carl, additional, Southwell, Anne, additional, Tocchini-Valentini, Glauco P, additional, Vancollie, Valerie E, additional, Westerberg, Henrik, additional, Wurst, Wolfgang, additional, Zi, Min, additional, Yalcin, Binnaz, additional, Ramirez-Solis, Ramiro, additional, Steel, Karen P, additional, Mallon, Ann-Marie, additional, de Angelis, Martin, additional, Herault, Yann, additional, and Brown, Steve DM, additional

Published
2013
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39. Deficiency for the Ubiquitin Ligase UBE3B in a Blepharophimosis-Ptosis-Intellectual-Disability Syndrome

Author

Basel-Vanagaite, Lina, primary, Dallapiccola, Bruno, additional, Ramirez-Solis, Ramiro, additional, Segref, Alexandra, additional, Thiele, Holger, additional, Edwards, Andrew, additional, Arends, Mark J., additional, Miró, Xavier, additional, White, Jacqueline K., additional, Désir, Julie, additional, Abramowicz, Marc, additional, Dentici, Maria Lisa, additional, Lepri, Francesca, additional, Hofmann, Kay, additional, Har-Zahav, Adi, additional, Ryder, Edward, additional, Karp, Natasha A., additional, Estabel, Jeanne, additional, Gerdin, Anna-Karin B., additional, Podrini, Christine, additional, Ingham, Neil J., additional, Altmüller, Janine, additional, Nürnberg, Gudrun, additional, Frommolt, Peter, additional, Abdelhak, Sonia, additional, Pasmanik-Chor, Metsada, additional, Konen, Osnat, additional, Kelley, Richard I., additional, Shohat, Mordechai, additional, Nürnberg, Peter, additional, Flint, Jonathan, additional, Steel, Karen P., additional, Hoppe, Thorsten, additional, Kubisch, Christian, additional, Adams, David J., additional, and Borck, Guntram, additional

Published
2012
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41. The Novel Mouse Mutation Oblivion Inactivates the PMCA2 Pump and Causes Progressive Hearing Loss

Author

Spiden, Sarah L., primary, Bortolozzi, Mario, additional, Di Leva, Francesca, additional, de Angelis, Martin Hrabé, additional, Fuchs, Helmut, additional, Lim, Dmitry, additional, Ortolano, Saida, additional, Ingham, Neil J., additional, Brini, Marisa, additional, Carafoli, Ernesto, additional, Mammano, Fabio, additional, and Steel, Karen P., additional

Published
2008
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45. The Effect of Reverberation on the Temporal Representation of the F0 of Frequency Swept Harmonic Complexes in the Ventral Cochlear Nucleus.

Author

Kollmeier, Birger, Klump, Georg, Hohmann, Volker, Langemann, Ulrike, Mauermann, Manfred, Uppenkamp, Stefan, Verhey, Jesko, Sayles, Mark, Schouten, Bert, Ingham, Neil J., and Winter, Ian M.

Abstract

When listening in an enclosed space, part of the sound has travelled to the listener directly from its source. In addition the listener receives multiple delayed and attenuated copies of the sound as it is reflected from the room's surfaces, an effect referred to as reverberation. This series of reflections has a filtering effect, introducing distortion in both the spectral and temporal domains. Spectral transitions are smeared in time and the introduction of slowly decaying "tails" effectively applies a low-pass filter to the temporal envelope. Since each reflection is added back to the original "direct" sound with random phase, envelope periodicity tends to be disrupted. [ABSTRACT FROM AUTHOR]

Published
2007
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49. GABAergic Inhibition Controls Neural Gain in Inferior Colliculus Neurons Sensitive to Interaural Time Differences.

Author

Ingham, Neil J. and McAlpine, David

Subjects
*GUINEA pigs, *NEURONS, *GABA, *AMINO acid neurotransmitters, *AMINOBUTYRIC acid
Abstract

We investigated the role of GABAergic inhibition on the responses of inferior colliculus (IC) neurons sensitive to interaural time differences (ITDs) in anesthetized guinea pigs. Responses to static and dynamic ITDs were obtained before, during, and after recovery from ionotophoretic application of GABA, or antagonists to the GABAA receptor gabazine and bicuculline. For most neurons, a linear relationship was observed between discharge rates evoked by a particular ITD during drug application and control discharge rates. Blocking GABAergic inhibition, or adding exogenous GABA, scaled IC discharge rates in a multiplicative (divisive) and/or additive (subtractive) manner. When the influence of iontophoresed GABA antagonists or exogenous GABA on discharge rates was accounted for, GABAergic inhibition was found to have no effect on the ITD tuning properties of IC neurons. The tuning sharpness of ITD functions, the ITD that evoked 50% response magnitude, and the relative symmetry of ITD functions around their peak response were unaffected by blockade of inhibition or addition of tonic inhibition. However, the ability of neurons to discriminate between ITDs by virtue of differences in their discharge rate was altered by blocking or adding GABA. We propose that inhibition in the IC is involved in the control of the neural gain of the output of IC neurons rather than the regulation of ITD tuning. This gain control appears to arise from a combination of additive and multiplicative processes, and may involve mechanisms such as shunting inhibition or changes in the efficacy of inhibitory and excitatory inputs. [ABSTRACT FROM AUTHOR]

Published
2005
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50. Hair Cell Loss in the Aged Guinea Pig Cochlea.

Author

Ingham, Neil J., Comis, Spiro D., and Withington, Deborah J.

Subjects
*HAIR cells, *AUDITORY pathways, *EAR aging, *GUINEA pigs
Abstract

The various effects of ageing on the auditory system, collectively termed presbycusis, are being studied across a wide range of animal species, including humans. One contributing factor to presbycusis is thought to be losses of the sensory hair cells in the cochlea. In this study, hair cell counts were obtained from cochleas of pigmented guinea pigs (Cavia porcellus) at ages ranging from 11 days to 4 years 7 months, using scanning electron microscopy to visualize the organ of Corti. Representative samples of the basal, middle and apical turn of the cochlea were photographed for analysis. Hair cell loss was observed, even in young animals. However, the loss was greater in the aged animals, but was not distributed evenly throughout the length of the cochlea. No significant loss of hair cells was seen in the basal (high frequency) or middle turn of the cochlea of the aged animals. In the apical (low frequency) turn, there was a significant loss of hair cells in all rows of outer hair cells (up to around 20%), and was most severe in the third row. There was no loss of apical inner hair cells in the aged animals. [ABSTRACT FROM AUTHOR]

Published
1999
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