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101.
Noriko Komatsu Stephanie Win Minglu Yan Nam Cong-Nhat Huynh Shinichiro Sawa Masayuki Tsukasaki Asuka Terashima Warunee Pluemsakunthai George Kollias Tomoki Nakashima Hiroshi Takayanagi 《The Journal of clinical investigation》2021,131(6)
In rheumatoid arthritis (RA), osteoclastic bone resorption causes structural joint damage as well as periarticular and systemic bone loss. Periarticular bone loss is one of the earliest indices of RA, often preceding the onset of clinical symptoms via largely unknown mechanisms. Excessive osteoclastogenesis induced by receptor activator of NF-κB ligand (RANKL) expressed by synovial fibroblasts causes joint erosion, whereas the role of RANKL expressed by lymphocytes in various types of bone damage has yet to be elucidated. In the bone marrow of arthritic mice, we found an increase in the number of RANKL-expressing plasma cells, which displayed an ability to induce osteoclastogenesis in vitro. Genetic ablation of RANKL in B-lineage cells resulted in amelioration of periarticular bone loss, but not of articular erosion or systemic bone loss, in autoimmune arthritis. We also show conclusive evidence for the critical contribution of synovial fibroblast RANKL to joint erosion in collagen-induced arthritis on the arthritogenic DBA/1J background. This study highlights the importance of plasma-cell RANKL in periarticular bone loss in arthritis and provides mechanistic insight into the early manifestation of bone lesion induced by autoimmunity. 相似文献
102.
Mari Terada Satoshi Kutsuna Tomiteru Togano Sho Saito Noriko Kinoshita Yumiko Shimanishi Tetsuya Suzuki Yusuke Miyazato Makoto Inada Takahito Nakamoto Hidetoshi Nomoto Satoshi Ide Mitsuhiro Sato Kenji Maeda Akihiro Matsunaga Masahiro Satake Keiji Matsubayashi Hirokazu Tsuno Makiko Kojima Madoka Kuramistu Kenta Tezuka Emi Ikebe Kazu Okuma Isao Hamaguchi Katsuyuki Shiratori Motohiko Sato Yuiko Kawakami Kumi Inaba Saori Igarashi Reina Yamauchi Mina Matsumura Keiko Ishimaru Bijuan Zhang Chika Kuge Maiko Ishihara Miho Gouda Keiko Tanaka Yukihito Ishizaka Norio Ohmagari 《Transfusion》2021,61(7):1998-2007
103.
Sho Saito Kayoko Hayakawa Shinya Tsuzuki Masahiro Ishikane Maki Nagashima Kazuhisa Mezaki Yuko Sugiki Taichi Tajima Nobuaki Matsunaga Satoshi Ide Noriko Kinoshita Yoshiki Kusama Yumiko Fujitomo Takato Nakamoto Yuta Toda Mitsuo Kaku Eiichi N. Kodama Norio Ohmagari 《Antimicrobial agents and chemotherapy》2021,65(3)
104.
Masayuki Sasaki Noriko Sumitomo Yuko Shimizu‐Motohashi Eri Takeshita Kenji Kurosawa Kenjiro Kosaki Kazuhiro Iwama Takeshi Mizuguchi Naomichi Matsumoto 《Developmental medicine and child neurology》2021,63(1):111-115
A heterogeneous spectrum of clinical manifestations caused by mutations in ATP1A3 have been previously described. Here we report two cases of infantile‐onset cerebellar ataxia, due to two different ATP1A3 variants. Both patients showed slowly progressive cerebellar ataxia without paroxysmal or episodic symptoms. Brain magnetic resonance imaging revealed mild cerebellar cortical atrophy in both patients. Whole exome sequencing revealed a de novo heterozygous variant in ATP1A3 in both patients. One patient had the c.460A>G (p.Met154Val) variant, while the other carried the c.1050C>A (p.Asp350Lys) variant. This phenotype was characterized by a slowly progressive cerebellar ataxia since the infantile period, which has not been previously described in association with ATP1A3 variants or in ATP1A3‐related clinical conditions. Our report contributes to extend the phenotypic spectrum of ATP1A3 mutations, showing paediatric slowly progressive cerebellar ataxia with mild cerebellar atrophy alone as an additional clinical presentation of ATP1A3‐related neurological disorders. 相似文献
105.
Lourdes Serrano Paloma Martínez-Redondo Anna Marazuela-Duque Berta N. Vazquez Scott J. Dooley Philipp Voigt David B. Beck Noriko Kane-Goldsmith Qiang Tong Rosa M. Rabanal Dolors Fondevila Purificación Mu?oz Marcus Krüger Jay A. Tischfield Alejandro Vaquero 《Genes & development》2013,27(6):639-653
The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G2/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin localization. Consistently, SirT2 depletion significantly reduces PR-Set7 chromatin levels, alters the size and number of PR-Set7 foci, and decreases the overall mitotic deposition of H4K20me1. Upon stress, the interaction between SirT2 and PR-Set7 increases along with the H4K20me1 levels, suggesting a novel mitotic checkpoint mechanism. SirT2 loss in mice induces significant defects associated with defective H4K20me1–3 levels. Accordingly, SirT2-deficient animals exhibit genomic instability and chromosomal aberrations and are prone to tumorigenesis. Our studies suggest that the dynamic cross-talk between the environment and the genome during mitosis determines the fate of the subsequent cell cycle. 相似文献
106.
Amit Mishra Megha Maheshwari Deepak Chhangani Noriko Fujimori-Tonou Fumito Endo Ajay Prakash Joshi Nihar Ranjan Jana Koji Yamanaka 《Neurobiology of aging》2013
Protein aggregation and ordered fibrillar amyloid deposition inside and outside of the central nervous system cells is the common pathologic hallmark of most aging-related neurodegenerative disorders. Dominant mutations in the gene encoding superoxide dismutase 1 (SOD1) protein are linked to familial amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by progressive degeneration of motor neurons, leading to muscle paralysis and death. The major histochemical hallmark in the remaining motor neurons of ALS is the intracellular accumulation of ubiquitinated inclusions consisting of insoluble aberrant protein aggregates. However, the molecular pathomechanisms underlying the process have been elusive. Here for the first time, we report that E6-AP, a homologous to E6-AP C terminus-type E3 ubiquitin ligase depleted in ALS mouse models before neurodegeneration. E6-AP coimmunoprecipitates with the SOD1 protein and is predominantly mislocalized in mutant SOD1-containing inclusion bodies. Overexpression of E6-AP increases the ubiquitination and facilitates degradation of SOD1 proteins. Finally, we show that the overexpression of E6-AP suppresses the aggregation and cell death mediated by mutated SOD1 proteins and cellular protective effect is more prominent when E6-AP is overexpressed along with Hsp70. These data suggest that enhancing the activity of E6-AP ubiquitin ligase might be a viable therapeutic strategy to eliminate mutant SOD1-mediated toxicity in ALS. 相似文献
107.
Kanako Iwasaki Tomoyuki Fujiyama Shinya Nakata Minjeong Park Chika Miyoshi Noriko Hotta-Hirashima Aya Ikkyu Miyo Kakizaki Fumihiro Sugiyama Seiya Mizuno Manabu Abe Kenji Sakimura Satoru Takahashi Hiromasa Funato Masashi Yanagisawa 《The Journal of neuroscience》2021,41(12):2733
Sleep is regulated in a homeostatic manner. Sleep deprivation increases sleep need, which is compensated mainly by increased EEG δ power during non-rapid eye movement sleep (NREMS) and, to a lesser extent, by increased sleep amount. Although genetic factors determine the constitutive level of sleep need and sleep amount in mice and humans, the molecular entity behind sleep need remains unknown. Recently, we found that a gain-of-function Sleepy (Slp) mutation in the salt-inducible kinase 3 (Sik3) gene, which produces the mutant SIK3(SLP) protein, leads to an increase in NREMS EEG δ power and sleep amount. Since Sik3Slp mice express SIK3(SLP) in various types of cells in the brain as well as multiple peripheral tissues from the embryonic stage, the cell type and developmental stage responsible for the sleep phenotype in Sik3Slp mice remain to be elucidated. Here, we generated two mouse lines, synapsin1CreERT2 and Sik3ex13flox mice, which enable inducible Cre-mediated, conditional expression of SIK3(SLP) in neurons on tamoxifen administration. Administration of tamoxifen to synapsin1CreERT2 mice during late infancy resulted in higher recombination efficiency than administration during adolescence. SIK3(SLP) expression after late infancy increased NREMS and NREMS δ power in male synapsin1CreERT2; Sik3ex13flox/+ mice. The expression of SIK3(SLP) after adolescence led to a higher NREMS δ power without a significant change in NREMS amounts. Thus, neuron-specific expression of SIK3(SLP) after late infancy is sufficient to increase sleep.SIGNIFICANCE STATEMENT The propensity to accumulate sleep need during wakefulness and to dissipate it during sleep underlies the homeostatic regulation of sleep. However, little is known about the developmental stage and cell types involved in determining the homeostatic regulation of sleep. Here, we show that Sik3Slp allele induction in mature neurons in late infancy is sufficient to increase non-rapid eye movement sleep amount and non-rapid eye movement sleep δ power. SIK3 signaling in neurons constitutes an intracellular mechanism to increase sleep. 相似文献
108.
109.
110.
Naturally arising CD25+CD4+ regulatory T cells play key roles in the maintenance of immunologic self-tolerance and negative control of various immune responses. The majority, if not all, of them are produced by the normal thymus as a functionally distinct T-cell subpopulation, and their generation is in part developmentally controlled. Genetic abnormality in the development and function of this population can indeed be a cause of autoimmune disease, immunopathology, and allergy in humans. This regulatory population can be exploited to prevent and treat autoimmune disease by strengthening and reestablishing immunologic self-tolerance. 相似文献