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  • 1
    Online Resource
    Online Resource
    Erratum to: Complete sequencing of expanded SAMD12 repeats by long-read sequencing and Cas9-mediated enrichment
    Oxford University Press (OUP) ; 2021
    In:  Brain Vol. 144, No. 8 ( 2021-09-04), p. e67-e67
    Details
    In: Brain, Oxford University Press (OUP), Vol. 144, No. 8 ( 2021-09-04), p. e67-e67
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awab183
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Complete sequencing of expanded SAMD12 repeats by long-read sequencing and Cas9-mediated enrichment
    Oxford University Press (OUP) ; 2021
    In:  Brain Vol. 144, No. 4 ( 2021-05-07), p. 1103-1117
    Details
    In: Brain, Oxford University Press (OUP), Vol. 144, No. 4 ( 2021-05-07), p. 1103-1117
    Abstract: A pentanucleotide TTTCA repeat insertion into a polymorphic TTTTA repeat element in SAMD12 causes benign adult familial myoclonic epilepsy. Although the precise determination of the entire SAMD12 repeat sequence is important for molecular diagnosis and research, obtaining this sequence remains challenging when using conventional genomic/genetic methods, and even short-read and long-read next-generation sequencing technologies have been insufficient. Incomplete information regarding expanded repeat sequences may hamper our understanding of the pathogenic roles played by varying numbers of repeat units, genotype–phenotype correlations, and mutational mechanisms. Here, we report a new approach for the precise determination of the entire expanded repeat sequence and present a workflow designed to improve the diagnostic rates in various repeat expansion diseases. We examined 34 clinically diagnosed benign adult familial myoclonic epilepsy patients, from 29 families using repeat-primed PCR, Southern blot, and long-read sequencing with Cas9-mediated enrichment. Two cases with questionable results from repeat-primed PCR and/or Southern blot were confirmed as pathogenic using long-read sequencing with Cas9-mediated enrichment, resulting in the identification of pathogenic SAMD12 repeat expansions in 76% of examined families (22/29). Importantly, long-read sequencing with Cas9-mediated enrichment was able to provide detailed information regarding the sizes, configurations, and compositions of the expanded repeats. The inserted TTTCA repeat size and the proportion of TTTCA sequences among the overall repeat sequences were highly variable, and a novel repeat configuration was identified. A genotype–phenotype correlation study suggested that the insertion of even short (TTTCA)14 repeats contributed to the development of benign adult familial myoclonic epilepsy. However, the sizes of the overall TTTTA and TTTCA repeat units are also likely to be involved in the pathology of benign adult familial myoclonic epilepsy. Seven unsolved SAMD12-negative cases were investigated using whole-genome long-read sequencing, and infrequent, disease-associated, repeat expansions were identified in two cases. The strategic workflow resolved two questionable SAMD12-positive cases and two previously SAMD12-negative cases, increasing the diagnostic yield from 69% (20/29 families) to 83% (24/29 families). This study indicates the significant utility of long-read sequencing technologies to explore the pathogenic contributions made by various repeat units in complex repeat expansions and to improve the overall diagnostic rate.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awab021
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    When Norepinephrine Becomes a Driver of Breathing Irregularities: How Intermittent Hypoxia Fundamentally Alters the Modulatory Response of the Respiratory Network
    Society for Neuroscience ; 2014
    In:  The Journal of Neuroscience Vol. 34, No. 1 ( 2014-01-01), p. 36-50
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 34, No. 1 ( 2014-01-01), p. 36-50
    Abstract: Neuronal networks are endogenously modulated by aminergic and peptidergic substances. These modulatory processes are critical for maintaining normal activity and adapting networks to changes in metabolic, behavioral, and environmental conditions. However, disturbances in neuromodulation have also been associated with pathologies. Using whole animals ( in vivo ) and functional brainstem slices ( in vitro ) from mice, we demonstrate that exposure to acute intermittent hypoxia (AIH) leads to fundamental changes in the neuromodulatory response of the respiratory network located within the preBötzinger complex (preBötC), an area critical for breathing. Norepinephrine, which normally regularizes respiratory activity, renders respiratory activity irregular after AIH. Respiratory irregularities are caused both in vitro and in vivo by AIH, which increases synaptic inhibition within the preBötC when norepinephrine is endogenously or exogenously increased. These irregularities are prevented by blocking synaptic inhibition before AIH. However, regular breathing cannot be reestablished if synaptic inhibition is blocked after AIH. We conclude that subtle changes in synaptic transmission can have dramatic consequences at the network level as endogenously released neuromodulators that are normally adaptive become the drivers of irregularity. Moreover, irregularities in the preBötC result in irregularities in the motor output in vivo and in incomplete transmission of inspiratory activity to the hypoglossus motor nucleus. Our finding has basic science implications for understanding network functions in general, and it may be clinically relevant for understanding pathological disturbances associated with hypoxic episodes such as those associated with myocardial infarcts, obstructive sleep apneas, apneas of prematurity, Rett syndrome, and sudden infant death syndrome.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.3644-12.2014
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2014
    detail.hit.zdb_id: 1475274-8
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  • 4
    Online Resource
    Online Resource
    An ATP-Dependent Inwardly Rectifying Potassium Channel, K AB -2 (Kir4.1), in Cochlear Stria Vascularis of Inner Ear: Its Specific Subcellular Localization and Correlation with the Formation of Endocochlear Potential
    Society for Neuroscience ; 1997
    In:  The Journal of Neuroscience Vol. 17, No. 12 ( 1997-06-15), p. 4711-4721
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 17, No. 12 ( 1997-06-15), p. 4711-4721
    Abstract: Cochlear endolymph has a highly positive potential of approximately +80 mV. This so-called endocochlear potential (EP) is essential for hearing. Although pivotal roles of K + channels in the formation of EP have been suggested, the types and distribution of K + channels in cochlea have not been characterized. Because EP was depressed by vascular perfusion of Ba 2+ , an inhibitor of inwardly rectifying K + (Kir) channels, but not by either 4-aminopyridine or tetraethylammonium, we examined the expression of Kir channel subunits in cochlear stria vascularis, the tissue that is supposed to play the central role in the generation of positive EP. Of 11 members of the Kir channel family examined with reverse transcription-PCR, we could detect only expression of K AB -2 (Kir4.1) mRNA in stria vascularis. K AB -2 immunoreactivity was specifically localized at the basolateral membrane of marginal cells but not in either basal or intermediate cells. Developmental expression of K AB -2 in marginal cells paralleled formation of EP. Furthermore, deaf mutant mice ( viable dominant spotting ; W V /W V ) expressed no K AB -2 in their marginal cells. These results suggest that K AB -2 in marginal cells may be critically involved in the generation of positive EP.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.17-12-04711.1997
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 1997
    detail.hit.zdb_id: 1475274-8
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  • 5
    Online Resource
    Online Resource
    Identification of U11snRNA as an endogenous agonist of TLR7-mediated immune pathogenesis
    Proceedings of the National Academy of Sciences ; 2019
    In:  Proceedings of the National Academy of Sciences Vol. 116, No. 47 ( 2019-11-19), p. 23653-23661
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 116, No. 47 ( 2019-11-19), p. 23653-23661
    Abstract: The activation of innate immune receptors by pathogen-associated molecular patterns (PAMPs) is central to host defense against infections. On the other hand, these receptors are also activated by immunogenic damage-associated molecular patterns (DAMPs), typically released from dying cells, and the activation can evoke chronic inflammatory or autoimmune disorders. One of the best known receptors involved in the immune pathogenesis is Toll-like receptor 7 (TLR7), which recognizes RNA with single-stranded structure. However, the causative DAMP RNA(s) in the pathogenesis has yet to be identified. Here, we first developed a chemical compound, termed KN69, that suppresses autoimmunity in several established mouse models. A subsequent search for KN69-binding partners led to the identification of U11 small nuclear RNA (U11snRNA) as a candidate DAMP RNA involved in TLR7-induced autoimmunity. We then showed that U11snRNA robustly activated the TLR7 pathway in vitro and induced arthritis disease in vivo. We also found a correlation between high serum level of U11snRNA and autoimmune diseases in human subjects and established mouse models. Finally, by revealing the structural basis for U11snRNA’s ability to activate TLR7, we developed more potent TLR7 agonists and TLR7 antagonists, which may offer new therapeutic approaches for autoimmunity or other immune-driven diseases. Thus, our study has revealed a hitherto unknown immune function of U11snRNA, providing insight into TLR7-mediated autoimmunity and its potential for further therapeutic applications.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1915326116
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2019
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome
    Oxford University Press (OUP) ; 2022
    In:  Brain Vol. 145, No. 3 ( 2022-04-29), p. 1139-1150
    Details
    In: Brain, Oxford University Press (OUP), Vol. 145, No. 3 ( 2022-04-29), p. 1139-1150
    Abstract: Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) is a late-onset, slow-progressing multisystem neurodegenerative disorder. Biallelic AAGGG repeat expansion in RFC1 has been identified as causative of this disease, and repeat conformation heterogeneity (ACAGG repeat) was also recently implied. To molecularly characterize this disease in Japanese patients with adult-onset ataxia, we accumulated and screened 212 candidate families by an integrated approach consisting of flanking PCR, repeat-primed PCR, Southern blotting and long-read sequencing using Sequel II, GridION or PromethION. We identified 16 patients from 11 families, of whom seven had ACAGG expansions [(ACAGG)exp/(ACAGG)exp] (ACAGG homozygotes), two had ACAGG and AAGGG expansions [(ACAGG)exp/(AAGGG)exp] (ACAGG/AAGGG compound heterozygotes) and seven had AAGGG expansions [(AAGGG)exp/(AAGGG)exp] (AAGGG homozygotes). The overall detection rate was 5.2% (11/212 families including one family having two expansion genotypes). Long-read sequencers revealed the entire sequence of both AAGGG and ACAGG repeat expansions at the nucleotide level of resolution. Clinical assessment and neuropathology results suggested that patients with ACAGG expansions have similar clinical features to previously reported patients with homozygous AAGGG expansions, although motor neuron involvement was more notable in patients with ACAGG expansions (even if one allele was involved). Furthermore, a later age of onset and slower clinical progression were implied in patients with ACAGG/AAGGG compound heterozygous expansions compared with either ACAGG or AAGGG homozygotes in our very limited cohort. Our study clearly shows the occurrence of repeat conformation heterogeneity, with possible different impacts on the affected nervous systems. The difference in disease onset and progression between compound heterozygotes and homozygotes might also be suspected but with very limited certainty due to the small sample number of cases in our study. Studies of additional patients are needed to confirm this.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awab363
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Mitochondrial gene in the nuclear genome induces reproductive barrier in rice
    Proceedings of the National Academy of Sciences ; 2010
    In:  Proceedings of the National Academy of Sciences Vol. 107, No. 4 ( 2010-01-26), p. 1494-1499
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 4 ( 2010-01-26), p. 1494-1499
    Abstract: Hybrid incompatibility in F 1 hybrids or later generations is often observed as sterility or inviability. This incompatibility acts as postzygotic reproductive isolation, which results in the irreversible divergence of species. Here, we show that the reciprocal loss of duplicated genes encoding mitochondrial ribosomal protein L27 causes hybrid pollen sterility in F 1 hybrids of the cultivated rice Oryza sativa and its wild relative O . glumaepatula . Functional analysis revealed that this gene is essential for the later stage of pollen development, and distribution analysis suggests that the gene duplication occurred before the divergence of the AA genome species. On the basis of these results, we discuss the possible contribution of the “founder effect” in establishing this reproductive barrier.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0908283107
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Stable Respiratory Activity Requires Both P/Q-Type and N-Type Voltage-Gated Calcium Channels
    Society for Neuroscience ; 2013
    In:  The Journal of Neuroscience Vol. 33, No. 8 ( 2013-02-20), p. 3633-3645
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 33, No. 8 ( 2013-02-20), p. 3633-3645
    Abstract: P/Q-type voltage-gated calcium channels (Ca v 2.1) play critical presynaptic and postsynaptic roles throughout the nervous system and have been implicated in a variety of neurological disorders. Here we report that mice with a genetic ablation of the Ca v 2.1 pore-forming α 1A subunit (α 1A −/− ) encoded by CACNA1a (Jun et al., 1999) suffer during postnatal development from increasing breathing disturbances that lead ultimately to death. Breathing abnormalities include decreased minute ventilation and a specific loss of sighs, which was associated with lung atelectasis. Similar respiratory alterations were preserved in the isolated in vitro brainstem slice preparation containing the pre-Bötzinger complex. The loss of Ca v 2.1 was associated with an alteration in the functional dependency on N-type calcium channels (Ca v 2.2). Blocking N-type calcium channels with conotoxin GVIA had only minor effects on respiratory activity in slices from control (CT) littermates, but abolished respiratory activity in all slices from α 1A −/− mice. The amplitude of evoked EPSPs was smaller in inspiratory neurons from α 1A −/− mice compared with CTs. Conotoxin GVIA abolished all EPSPs in inspiratory neurons from α 1A −/− mice, while the EPSP amplitude was reduced by only 30% in CT mice. Moreover, neuromodulation was significantly altered as muscarine abolished respiratory network activity in α 1A −/− mice but not in CT mice. We conclude that excitatory synaptic transmission dependent on N-type and P/Q-type calcium channels is required for stable breathing and sighing. In the absence of P/Q-type calcium channels, breathing, sighing, and neuromodulation are severely compromised, leading to early mortality.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.6390-11.2013
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2013
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 9
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    Online Resource
    Loss of function at RAE2 , a previously unidentified EPFL, is required for awnlessness in cultivated Asian rice
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 32 ( 2016-08-09), p. 8969-8974
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 32 ( 2016-08-09), p. 8969-8974
    Abstract: Domestication of crops based on artificial selection has contributed numerous beneficial traits for agriculture. Wild characteristics such as red pericarp and seed shattering were lost in both Asian ( Oryza sativa ) and African ( Oryza glaberrima ) cultivated rice species as a result of human selection on common genes. Awnedness, in contrast, is a trait that has been lost in both cultivated species due to selection on different sets of genes. In a previous report, we revealed that at least three loci regulate awn development in rice; however, the molecular mechanism underlying awnlessness remains unknown. Here we isolate and characterize a previously unidentified EPIDERMAL PATTERNING FACTOR-LIKE (EPFL) family member named REGULATOR OF AWN ELONGATION 2 ( RAE2 ) and identify one of its requisite processing enzymes, SUBTILISIN-LIKE PROTEASE 1 ( SLP1 ). The RAE2 precursor is specifically cleaved by SLP1 in the rice spikelet, where the mature RAE2 peptide subsequently induces awn elongation. Analysis of RAE2 sequence diversity identified a highly variable GC-rich region harboring multiple independent mutations underlying protein-length variation that disrupt the function of the RAE2 protein and condition the awnless phenotype in Asian rice. Cultivated African rice, on the other hand, retained the functional RAE2 allele despite its awnless phenotype. Our findings illuminate the molecular function of RAE2 in awn development and shed light on the independent domestication histories of Asian and African cultivated rice.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1604849113
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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