Publications by authors named "Noriko Morita"

26 Publications

  • Page 1 of 1

Investigation of the hearing levels of siblings affected by a single GJB2 variant: Possibility of genetic modifiers.

Int J Pediatr Otorhinolaryngol 2021 Oct 12;149:110840. Epub 2021 Jul 12.

Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan; Medical Genetics Center, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan. Electronic address:

Objective: Variants in GJB2 can cause autosomal recessive deafness (DFNB1). There is evidence for genotype-phenotype correlations of GJB2 variants; however, several genotypes can cause varying levels of hearing loss likely attributable to differences in genetic or environmental background. As siblings share approximately 50% of their genetic background and usually have a common environmental background, analysis of phenotypes of siblings with a specific GJB2 variant may reveal factors relevant to phenotypic variation. There have been no previous analyses of differences in hearing among siblings carrying a single GJB2 genotype. Here, we investigated hearing differences between siblings with a single GJB2 variant, which can cause various levels of hearing loss.

Methods: We examined hearing levels in 16 pairs of siblings homozygous for the c.235delC variant of GJB2. Differences in hearing acuity between sibling pairs were detected by auditory evaluation.

Results: Average differences in acoustic threshold >30 dB were observed between five pairs of siblings, whereas the remaining 11 pairs had average threshold values within approximately 10 dB of one another. Hearing loss varied from moderate to profound.

Conclusion: Our results indicate that auditory acuity associated with homozygosity for GJB2 c.235delC can vary in degree; however, in approximately 70% of younger siblings, it was approximately the same as that in the first child, despite a diverse spectrum of hearing loss among different families. These results suggest that differences in genetic background may modify the phenotype associated with homozygous GJB2 c.235delC.
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http://dx.doi.org/10.1016/j.ijporl.2021.110840DOI Listing
October 2021

Neuroendocrine Carcinoma of Uterine Cervix: Stereotactic Radiotherapy for Brain Metastasis and Stereotactic Body Radiotherapy for Renal and Pancreatic Metastases.

Cureus 2020 Jun 27;12(6):e8869. Epub 2020 Jun 27.

Surgical Pathology, Aichi Medical University, Nagakute, JPN.

A case of cervical neuroendocrine carcinoma (NEC) of the uterine cervix (NECUC) was presented. After total hysterectomy with bilateral salpingo-oophorectomy and adjuvant chemotherapy, a left renal tumor and a pancreatic lesion developed and were both diagnosed on pathological examination as metastases from NEC. In addition, a brainstem metastasis causing neurologic signs developed. The brain lesion was treated by stereotactic radiotherapy (SRT) and the renal and pancreatic lesions by stereotactic body radiotherapy (SBRT). Despite control of the renal and pancreatic lesions, multiple small lung metastases developed later. Recurrence and newly developed brain metastases were treated by repeat stereotactic radiosurgery (SRS)/SRT successfully. Chemotherapy was continued and controlled the lung metastases until three and a half years after the initial operation of the uterus.
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http://dx.doi.org/10.7759/cureus.8869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386082PMC
June 2020

Differences in hearing levels between siblings with hearing loss caused by GJB2 mutations.

Auris Nasus Larynx 2020 Dec 15;47(6):938-942. Epub 2020 Jun 15.

Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan; Medical Genetics Center, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo 152-8902, Japan. Electronic address:

Objective: Hearing loss caused by GJB2 mutations is inherited in an autosomal recessive manner (DFNB1); thus siblings of an affected child have a 25% chance of also being affected. Hearing loss among subsequent siblings carrying the same GJB2 mutation is a concern for parents and a frequent topic of enquiry during genetic counseling. Evidence exists for genotype-phenotype correlations of GJB2 mutations; however, no analysis of differences in hearing among siblings, in whom the common genetic background may decrease variation, has been reported. The purpose of the present study was to investigate hearing differences between siblings with identical GJB2 mutations.

Methods: We examined the hearing levels of 12 pairs of siblings; each pair had the same pathogenic GJB2 mutations. Differences in hearing acuity between sibling pairs detected by auditory evaluation.

Results: No significant correlation was detected between the average hearing levels of first and second affected siblings. Average differences in acoustic threshold >30 dB were observed between four pairs of siblings, whereas the remaining eight pairs had average threshold values within 20 dB of one another.

Conclusion: Our results indicate that auditory acuity would be expected to approximate that found in the first child in approximately 70% of subsequent children with GJB2-mediated hearing loss, whereas 30% of subsequent siblings would have average differences of >30 dB.
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http://dx.doi.org/10.1016/j.anl.2020.05.008DOI Listing
December 2020

Deterioration in Distortion Product Otoacoustic Emissions in Auditory Neuropathy Patients With Distinct Clinical and Genetic Backgrounds.

Ear Hear 2019 Jan/Feb;40(1):184-191

Division of Hearing and Balance Research, National Institute for Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Objectives: Auditory neuropathy (AN) is a clinical disorder characterized by the absence of auditory brainstem response and presence of otoacoustic emissions. A gradual loss of otoacoustic emissions has been reported for some cases of AN. Such cases could be diagnosed as cochlear hearing loss and lead to misunderstanding of the pathology when patients first visit clinics after the loss of otoacoustic emissions. The purpose of this study was to investigate the time course of changes in distortion product otoacoustic emissions (DPOAEs) in association with patients' genetic and clinical backgrounds, including the use of hearing aids.

Design: DPOAE measurements from 31 patients with AN were assessed. Genetic analyses for GJB2, OTOF, and mitochondrial m.1555A> G and m.3243A> G mutations were conducted for all cases, and the analyses for CDH23 and OPA1 were conducted for the selected cases. Patients who were younger than 10 years of age at the time of AN diagnosis were designated as the pediatric AN group (22 cases), and those who were 18 years of age or older were designated as the adult AN group (9 cases). DPOAE was measured at least twice in all patients. The response rate for DPOAEs was defined and analyzed.

Results: The pediatric AN group comprised 10 patients with OTOF mutations, 1 with GJB2 mutations, 1 with OPA1 mutation, and 10 with indefinite causes. Twelve ears (27%) showed no change in DPOAE, 20 ears (46%) showed a decrease in DPOAE, and 12 ears (27%) lost DPOAE. Loss of DPOAE occurred in one ear (2%) at 0 years of age and four ears (9%) at 1 year of age. The time courses of DPOAEs in patients with OTOF mutations were divided into those with early loss and those with no change, indicating that the mechanism for deterioration of DPOAEs includes not only the OTOF mutations but also other common modifier factors. Most, but not all, AN patients who used hearing aids showed deterioration of DPOAEs after the start of using hearing aids. A few AN patients also showed deterioration of DPOAEs before using hearing aids. The adult AN group comprised 2 patients with OPA1 mutations, 2 with OTOF mutations, and 5 with indefinite causes. Four ears (22%) showed no change in DPOAE, 13 ears (72%) showed a decrease, and one ear (6%) showed a loss of DPOAE. Although the ratio of DPOAE decrease was higher in the adult AN group than in the pediatric AN group, the ratio of DPOAE loss was lower in the adult AN group. DPOAE was not lost in all four ears with OPA1 mutations and in all four ears with OTOF mutations in the adult group.

Conclusions: DPOAE was decreased or lost in approximately 70% of pediatric and about 80% of adult AN patients. Eleven percent of pediatric AN patients lost DPOAEs by 1 year of age. Genetic factors were thought to have influenced the time course of DPOAEs in the pediatric AN group. In most adult AN patients, DPOAE was rarely lost regardless of the genetic cause.
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http://dx.doi.org/10.1097/AUD.0000000000000586DOI Listing
April 2019

Effect of anthocyanin-rich bilberry extract on bone metabolism in ovariectomized rats.

Biomed Rep 2018 Feb 14;8(2):198-204. Epub 2017 Dec 14.

Department of Obstetrics and Gynecology, School of Medicine, Aichi Medical University, Nagakute, Aichi 480-1195, Japan.

Menopause is associated with increased oxidative stress, which serves a role, in part, in the pathogenesis of postmenopausal bone loss. Fruits and vegetables are rich in antioxidative nutrients and phytochemicals. Berries are a natural source of anthocyanins, and their intake may improve bone health. The aim of the present study was to determine the effect of an anthocyanin-rich bilberry extract (VME) on bone metabolism in an ovariectomized (Ovx) rat. Female Sprague-Dawley rats (12 weeks old) were randomly divided into the following four groups: Baseline, Sham, Ovx and Ovx+VME (n=8-12 rats per group). Rats in the Baseline group were sacrificed immediately, while those in the other groups were subjected to either sham operation (Sham) or bilateral Ovx (Ovx and Ovx+VME). Rats in the Ovx+VME group were administered VME daily at a dose of 500 mg/kg body weight. At 8 weeks after surgery, bone mass and bone histomorphometry were evaluated. The femur bone mineral density (BMD) in the Ovx group was significantly lower than that in the Sham group (P<0.01). Supplementation of VME in the Ovx rats did not result in an increase in BMD. Histomorphometric analyses revealed that Ovx resulted in decreased measures of bone volume and trabecular number and increased measures of osteoid volume, mineralizing surface and bone formation rates (all P<0.01), whereas VME had no significant effects on these parameters. The present findings indicate that VME did not alter bone metabolism in Ovx rats, suggesting that consumption of VME may not be helpful in preventing postmenopausal bone loss.
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http://dx.doi.org/10.3892/br.2017.1029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776409PMC
February 2018

Prevalence of TECTA mutation in patients with mid-frequency sensorineural hearing loss.

Orphanet J Rare Dis 2017 09 25;12(1):157. Epub 2017 Sep 25.

Department of Otolaryngology, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro, Tokyo, 152-8902, Japan.

Background: To date, 102 genes have been reported as responsible for non-syndromic hearing loss, some of which are associated with specific audiogram features. Four genes have been reported as causative for mid-frequency sensorineural hearing loss (MFSNHL), among which TECTA is the most frequently reported; however, the prevalence of TECTA mutations is unknown. To elucidate the prevalence of TECTA mutation in MFSNHL and clarify genotype-phenotype correlations, we analyzed the genetic and clinical features of patients with MFSNHL.

Methods: Subjects with bilateral non-syndromic hearing loss were prescreened for GJB2 and m.1555A > G and m.3243A > G mitochondrial DNA mutations, and patients with inner ear malformations were excluded. We selected MFSNHL patients whose audiograms met the U-shaped criterion proposed by the GENDEAF study group, along with those with shallow U-shaped audiograms, for TECTA analysis. All TECTA exons were analyzed by Sanger sequencing. Novel missense variants were classified as possibly pathogenic, non-pathogenic, and variants of uncertain significance, based on genetic data. To evaluate novel possibly pathogenic variants, we predicted changes in protein structure by molecular modeling.

Results: Pathogenic and possibly pathogenic variants of TECTA were found in 4 (6.0%) of 67 patients with MFSNHL. In patients with U-shaped audiograms, none (0%) of 21 had pathogenic or possibly pathogenic variants. In patients with shallow U-shaped audiograms, four (8.7%) of 46 had pathogenic or possibly pathogenic variants. Two novel possibly pathogenic variants were identified and two previously reported mutations were considered as variant of unknown significance. The clinical features of patients with pathogenic and possibly pathogenic variants were consistent with those in previous studies. Pathogenic or possibly pathogenic variants were identified in 3 of 23 families (13.0%) which have the family histories compatible with autosomal dominant and 1 of 44 families (2.3%) which have the family histories compatible with sporadic or autosomal recessive.

Conclusions: TECTA mutations were identified in 6.0% of MFSNHL. These mutations were more frequent in patients with shallow U-shaped audiograms than those with U-shaped audiograms, and in families which have the family histories compatible with autosomal dominant than those with the family histories compatible with sporadic or autosomal recessive.
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http://dx.doi.org/10.1186/s13023-017-0708-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613382PMC
September 2017

Frequency and specific characteristics of the incomplete partition type III anomaly in children.

Laryngoscope 2017 07 31;127(7):1663-1669. Epub 2016 Aug 31.

Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Objectives/hypothesis: To determine the frequency of the incomplete partition type III anomaly and the genetic and clinical features associated with POU3F4 mutations in children with hearing loss.

Study Design: Retrospective case series from 2000 to 2014 at the National Hospital Organization Tokyo Medical Center and collaborating hospitals.

Methods: A total of 1,004 patients (from 938 families) who had hearing loss by 10 years of age and had undergone computed tomography scanning of their temporal bones were enrolled in this genetic, clinical, and radiological study.

Results: The incomplete partition type III anomaly was identified in six patients (0.6%), each of whom had an enlargement of the vestibular aqueduct at the end close to the vestibule. The six patients also had POU3F4 variants, and a genetic analysis revealed frameshift deletions in three patients, a missense variant in two patients of the same family, and a large deletion in one patient. Three of the six patients with POU3F4 variants were sporadic cases, and in one patient the genetic mutation occurred de novo.

Conclusions: It was indicated that POU3F4 mutations can be predicted by incomplete partition type III anomaly by radiological examination of the inner ear. All six of the patients showed mixed hearing loss, but none showed fluctuations in hearing, which may be related to the lack of vestibular aqueduct enlargement at the operculum.

Level Of Evidence: 4 Laryngoscope, 127:1663-1669, 2017.
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http://dx.doi.org/10.1002/lary.26245DOI Listing
July 2017

Quality control of photosystem II: direct imaging of the changes in the thylakoid structure and distribution of FtsH proteases in spinach chloroplasts under light stress.

Plant Cell Physiol 2014 Jul 1;55(7):1255-65. Epub 2014 Jun 1.

Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530 Japan.

Under light stress, the reaction center-binding protein D1 of PSII is photo-oxidatively damaged and removed from PSII complexes by proteases located in the chloroplast. A protease considered to be responsible for degradation of the damaged D1 protein is the metalloprotease FtsH. We showed previously that the active hexameric FtsH protease is abundant at the grana margin and the grana end membranes, and this homo-complex removes the photodamaged D1 protein in the grana. Here, we showed a change in the distribution of FtsH in spinach thylakoids during excessive illumination by transmission electron microscopy (TEM) and immunogold labeling of FtsH. The change in distribution of the protease was accompanied by structural changes to the thylakoids, which we detected using spinach leaves by TEM after chemical fixation of the samples. Quantitative analyses showed several characteristic changes in the structure of the thylakoids, including shrinkage of the grana, outward bending of the marginal portions of the thylakoids and an increase in the height of the grana stacks under excessive illumination. The increase in the height of the grana stacks may include swelling of the thylakoids and an increase in the partition gaps between the thylakoids. These data strongly suggest that excessive illumination induces partial unstacking of the thylakoids, which enables FtsH to access easily the photodamaged D1 protein. Finally three-dimensional tomography of the grana was recorded to observe the effect of light stress on the overall structure of the thylakoids.
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http://dx.doi.org/10.1093/pcp/pcu079DOI Listing
July 2014

Quality control of PSII: behavior of PSII in the highly crowded grana thylakoids under excessive light.

Plant Cell Physiol 2014 Jul 7;55(7):1206-15. Epub 2014 Mar 7.

Graduate School of Natural Science and Technology, Okayama University, Okayama, 700-8530 Japan.

The grana thylakoids of higher plant chloroplasts are crowded with PSII and the associated light-harvesting complexes (LHCIIs). They constitute supercomplexes, and often form semi-crystalline arrays in the grana. The crowded condition of the grana may be necessary for efficient trapping of excitation energy by LHCII under weak light, but it might hinder proper movement of LHCII necessary for reversible aggregation of LHCII in the energy-dependent quenching of Chl fluorescence under moderate high light. When the thylakoids are illuminated with extreme high light, the reaction center-binding D1 protein of PSII is photodamaged, and the damaged protein migrates to the grana margins for degradation and subsequent repair. In both moderate and extreme high-light conditions, fluidity of the thylakoid membrane is crucial. In this review, we first provide an overview of photoprotective processes, then discuss changes in membrane fluidity and mobility of the protein complexes in the grana under excessive light, which are closely associated with photoprotection of PSII. We hypothesize that reversible aggregation of LHCII, which is necessary to avoid light stress under moderate high light, and swift turnover of the photodamaged D1 protein under extreme high light are threatened by irreversible protein aggregation induced by reactive oxygen species in photochemical reactions.
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http://dx.doi.org/10.1093/pcp/pcu043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080270PMC
July 2014

Quality control of Photosystem II: reversible and irreversible protein aggregation decides the fate of Photosystem II under excessive illumination.

Front Plant Sci 2013 29;4:433. Epub 2013 Oct 29.

Graduate School of Natural Science and Technology, Okayama University Okayama, Japan.

In response to excessive light, the thylakoid membranes of higher plant chloroplasts show dynamic changes including the degradation and reassembly of proteins, a change in the distribution of proteins, and large-scale structural changes such as unstacking of the grana. Here, we examined the aggregation of light-harvesting chlorophyll-protein complexes and Photosystem II core subunits of spinach thylakoid membranes under light stress with 77K chlorophyll fluorescence; aggregation of these proteins was found to proceed with increasing light intensity. Measurement of changes in the fluidity of thylakoid membranes with fluorescence polarization of diphenylhexatriene showed that membrane fluidity increased at a light intensity of 500-1,000 μmol photons m(-) (2) s(-) (1), and decreased at very high light intensity (1,500 μmol photons m(-) (2) s(-) (1)). The aggregation of light-harvesting complexes at moderately high light intensity is known to be reversible, while that of Photosystem II core subunits at extremely high light intensity is irreversible. It is likely that the reversibility of protein aggregation is closely related to membrane fluidity: increases in fluidity should stimulate reversible protein aggregation, whereas irreversible protein aggregation might decrease membrane fluidity. When spinach leaves were pre-illuminated with moderately high light intensity, the qE component of non-photochemical quenching and the optimum quantum yield of Photosystem II increased, indicating that Photosystem II/light-harvesting complexes rearranged in the thylakoid membranes to optimize Photosystem II activity. Transmission electron microscopy revealed that the thylakoids underwent partial unstacking under these light stress conditions. Thus, protein aggregation is involved in thylakoid dynamics and regulates photochemical reactions, thereby deciding the fate of Photosystem II.
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http://dx.doi.org/10.3389/fpls.2013.00433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810940PMC
November 2013

GJB2-associated hearing loss undetected by hearing screening of newborns.

Gene 2013 Dec 6;532(1):41-5. Epub 2013 Sep 6.

Department of Otolaryngology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan; Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

The hearing loss caused by GJB2 mutations is usually congenital in onset, moderate to profound in degree, and non-progressive. The objective of this study was to study genotype/phenotype correlations and to document 14 children with biallelic GJB2 mutations who passed newborn hearing screening (NHS). Genetic testing for GJB2 mutations by direct sequencing was performed on 924 individuals (810 families) with hearing loss, and 204 patients (175 families) were found to carry biallelic GJB2 mutations. NHS results were obtained through medical records. A total of 18 pathological mutations were identified, which were subclassified as eight inactivating and 10 non-inactivating mutations. p.I128M and p.H73Y were identified as novel missense GJB2 mutations. Of the 14 children with biallelic GJB2 mutations who passed NHS, eight were compound heterozygotes and 3 were homozygous for the c.235delC mutation in GJB2, and the other three combinations of non-c.235delC mutations identified were p.Y136X-p.G45E/p.V37I heterozygous, c.512ins4/p.R143W heterozygous, and p.V37I/p.R143W heterozygous. These 14 cases demonstrate that the current NHS does not identify all infants with biallelic GJB2 mutations. They suggest that the frequency of non-penetrance at birth is approximately 6.9% or higher in DFNB1 patients and provide further evidence that GJB2 hearing loss may not always be congenital in onset.
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http://dx.doi.org/10.1016/j.gene.2013.08.094DOI Listing
December 2013

Quality control of photosystem II: lipid peroxidation accelerates photoinhibition under excessive illumination.

PLoS One 2012 27;7(12):e52100. Epub 2012 Dec 27.

Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan.

Environmental stresses lower the efficiency of photosynthesis and sometimes cause irreversible damage to plant functions. When spinach thylakoids and Photosystem II membranes were illuminated with excessive visible light (100-1,000 µmol photons m(-1) s(-1)) for 10 min at either 20°C or 30°C, the optimum quantum yield of Photosystem II decreased as the light intensity and temperature increased. Reactive oxygen species and endogenous cationic radicals produced through a photochemical reaction at and/or near the reaction center have been implicated in the damage to the D1 protein. Here we present evidence that lipid peroxidation induced by the illumination is involved in the damage to the D1 protein and the subunits of the light-harvesting complex of Photosystem II. This is reasoned from the results that considerable lipid peroxidation occurred in the thylakoids in the light, and that lipoxygenase externally added in the dark induced inhibition of Photosystem II activity in the thylakoids, production of singlet oxygen, which was monitored by electron paramagnetic resonance spin trapping, and damage to the D1 protein, in parallel with lipid peroxidation. Modification of the subunits of the light-harvesting complex of Photosystem II by malondialdehyde as well as oxidation of the subunits was also observed. We suggest that mainly singlet oxygen formed through lipid peroxidation under light stress participates in damaging the Photosystem II subunits.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0052100PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3531424PMC
July 2013

Genetic analysis of PAX3 for diagnosis of Waardenburg syndrome type I.

Acta Otolaryngol 2013 Apr 20;133(4):345-51. Epub 2012 Nov 20.

Department of Otolaryngology, Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Tokyo Medical Center, Japan.

Conclusion: PAX3 genetic analysis increased the diagnostic accuracy for Waardenburg syndrome type I (WS1). Analysis of the three-dimensional (3D) structure of PAX3 helped verify the pathogenicity of a missense mutation, and multiple ligation-dependent probe amplification (MLPA) analysis of PAX3 increased the sensitivity of genetic diagnosis in patients with WS1.

Objectives: Clinical diagnosis of WS1 is often difficult in individual patients with isolated, mild, or non-specific symptoms. The objective of the present study was to facilitate the accurate diagnosis of WS1 through genetic analysis of PAX3 and to expand the spectrum of known PAX3 mutations.

Methods: In two Japanese families with WS1, we conducted a clinical evaluation of symptoms and genetic analysis, which involved direct sequencing, MLPA analysis, quantitative PCR of PAX3, and analysis of the predicted 3D structure of PAX3. The normal-hearing control group comprised 92 subjects who had normal hearing according to pure tone audiometry.

Results: In one family, direct sequencing of PAX3 identified a heterozygous mutation, p.I59F. Analysis of PAX3 3D structures indicated that this mutation distorted the DNA-binding site of PAX3. In the other family, MLPA analysis and subsequent quantitative PCR detected a large, heterozygous deletion spanning 1759-2554 kb that eliminated 12-18 genes including a whole PAX3 gene.
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http://dx.doi.org/10.3109/00016489.2012.744470DOI Listing
April 2013

Assay of photoinhibition and heat inhibition of photosystem II in higher plants.

Methods Mol Biol 2011 ;684:201-15

Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan.

When thylakoids of higher plant chloroplasts are exposed to excessive light or moderate heat stress, photosystem II reaction center-binding protein D1 is damaged. The photodamage of the D1 protein is caused by reactive oxygen species, mostly singlet oxygen, and also by endogenous cationic radicals generated by the photochemical reactions of photosystem II. Moreover, it was shown recently that the damage to the D1 protein by moderate heat stress is due to reactive oxygen species produced by lipid peroxidation near photosystem II. To maintain photosystem II activity, the oxidatively damaged D1 protein must be replaced by a newly synthesized copy, and thus degradation and removal of the photo- or heat-damaged D1 protein are essential for maintaining the viability of photosystem II. In this chapter, we describe the methods for assaying photoinhibition and heat inhibition of photosystem II in higher plant materials.
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http://dx.doi.org/10.1007/978-1-60761-925-3_17DOI Listing
January 2011

Quality control of photosystem II: FtsH hexamers are localized near photosystem II at grana for the swift repair of damage.

J Biol Chem 2010 Dec 4;285(53):41972-81. Epub 2010 Oct 4.

Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.

The reaction center-binding D1 protein of Photosystem II is oxidatively damaged by excessive visible light or moderate heat stress. The metalloprotease FtsH has been suggested as responsible for the degradation of the D1 protein. We have analyzed the distribution and subunit structures of FtsH in spinach thylakoids and various membrane fractions derived from the thylakoids using clear native polyacrylamide gel electrophoresis and Western blot analysis. FtsH was found not only in the stroma thylakoids but also in the Photosystem II-enriched grana membranes. Monomeric, dimeric, and hexameric FtsH proteases were present as major subunit structures in thylakoids, whereas only hexameric FtsH proteases were detected in Triton X-100-solubilized Photosystem II membranes. Importantly, among the membrane fractions examined, hexameric FtsH proteases were most abundant in the Photosystem II membranes. In accordance with this finding, D1 degradation took place in the Photosystem II membranes under light stress. Sucrose density gradient centrifugation analysis of thylakoids and the Photosystem II membranes solubilized with n-dodecyl-β-d-maltoside and a chemical cross-linking study of thylakoids showed localization of FtsH near the Photosystem II light-harvesting chlorophyll-protein supercomplexes in the grana. These results suggest that part of the FtsH hexamers are juxtapositioned to PSII complexes in the grana in darkness, carrying out immediate degradation of the photodamaged D1 protein under light stress.
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http://dx.doi.org/10.1074/jbc.M110.117432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3009923PMC
December 2010

Quality control of photosystem II: Thylakoid unstacking is necessary to avoid further damage to the D1 protein and to facilitate D1 degradation under light stress in spinach thylakoids.

J Biol Chem 2009 Sep 17;284(37):25343-52. Epub 2009 Jul 17.

Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.

Photosystem II is vulnerable to light damage. The reaction center-binding D1 protein is impaired during excessive illumination and is degraded and removed from photosystem II. Using isolated spinach thylakoids, we investigated the relationship between light-induced unstacking of thylakoids and damage to the D1 protein. Under light stress, thylakoids were expected to become unstacked so that the photodamaged photosystem II complexes in the grana and the proteases could move on the thylakoids for repair. Excessive light induced irreversible unstacking of thylakoids. By comparing the effects of light stress on stacked and unstacked thylakoids, photoinhibition of photosystem II was found to be more prominent in stacked thylakoids than in unstacked thylakoids. In accordance with this finding, EPR spin trapping measurements demonstrated higher production of hydroxyl radicals in stacked thylakoids than in unstacked thylakoids. We propose that unstacking of thylakoids has a crucial role in avoiding further damage to the D1 protein and facilitating degradation of the photodamaged D1 protein under light stress.
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http://dx.doi.org/10.1074/jbc.M109.007740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2757236PMC
September 2009

Quality control of photosystem II: impact of light and heat stresses.

Photosynth Res 2008 Oct-Dec;98(1-3):589-608. Epub 2008 Oct 21.

Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.

Photosystem II is vulnerable to various abiotic stresses such as strong visible light and heat. Under both stresses, the damage seems to be triggered by reactive oxygen species, and the most critical damage occurs in the reaction center-binding D1 protein. Recent progress has been made in identifying the protease involved in the degradation of the photo- or heat-damaged D1 protein, the ATP-dependent metalloprotease FtsH. Another important result has been the discovery that the damaged D1 protein aggregates with nearby polypeptides such as the D2 protein and the antenna chlorophyll-binding protein CP43. The degradation and aggregation of the D1 protein occur simultaneously, but the relationship between the two is not known. We suggest that phosphorylation and dephosphorylation of the D1 protein, as well as the binding of the extrinsic PsbO protein to Photosystem II, play regulatory roles in directing the damaged D1 protein to the two alternative pathways.
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http://dx.doi.org/10.1007/s11120-008-9372-4DOI Listing
March 2009

Quality control of photosystem II: reactive oxygen species are responsible for the damage to photosystem II under moderate heat stress.

J Biol Chem 2008 Oct 29;283(42):28380-91. Epub 2008 Jul 29.

Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.

Moderate heat stress (40 degrees C for 30 min) on spinach thylakoid membranes induced cleavage of the reaction center-binding D1 protein of photosystem II, aggregation of the D1 protein with the neighboring polypeptides D2 and CP43, and release of three extrinsic proteins, PsbO, -P, and -Q. These heat-induced events were suppressed under anaerobic conditions or by the addition of sodium ascorbate, a general scavenger of reactive oxygen species. In accordance with this, singlet oxygen and hydroxyl radicals were detected in spinach photosystem II membranes incubated at 40 degrees C for 30 min with electron paramagnetic resonance spin-trapping spectroscopy. The moderate heat stress also induced significant lipid peroxidation under aerobic conditions. We suggest that the reactive oxygen species are generated by heat-induced inactivation of a water-oxidizing manganese complex and through lipid peroxidation. Although occurring in the dark, the damages caused by the moderate heat stress to photosystem II are quite similar to those induced by excessive illumination where reactive oxygen species are involved.
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http://dx.doi.org/10.1074/jbc.M710465200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661399PMC
October 2008

Quality control of Photosystem II: cleavage and aggregation of heat-damaged D1 protein in spinach thylakoids.

Biochim Biophys Acta 2007 Jun 10;1767(6):838-46. Epub 2007 May 10.

Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.

Moderate heat stress (40 degrees C, 30 min) on spinach thylakoids induced cleavage of the D1 protein, producing an N-terminal 23-kDa fragment, a C-terminal 9-kDa fragment, and aggregation of the D1 protein. A homologue of Arabidopsis FtsH2 protease, which is responsible for degradation of the damaged D1 protein, was abundant in the stroma thylakoids. Two processes occurred in the thylakoids in response to heat stress: dephosphorylation of the D1 protein in the stroma thylakoids, and aggregation of the phosphorylated D1 protein in the grana. Heat stress also induced the release of the extrinsic PsbO, P and Q proteins from Photosystem II, which affected D1 degradation and aggregation significantly. The cleavage and aggregation of the D1 protein appear to be two alternative processes influenced by protein phosphorylation/dephosphorylation, distribution of FtsH, and intactness of the thylakoids.
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http://dx.doi.org/10.1016/j.bbabio.2007.05.001DOI Listing
June 2007

Quality control of photosystem II. Cleavage of reaction center D1 protein in spinach thylakoids by FtsH protease under moderate heat stress.

J Biol Chem 2006 Aug 30;281(31):21660-21669. Epub 2006 May 30.

Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530. Electronic address:

When spinach thylakoids were subjected to moderate heat stress (40 degrees C for 30 min), oxygen evolution was inhibited, and cleavage of the reaction center-binding protein D1 of photosystem II took place, producing 23-kDa N-terminal fragments. The D1 cleavage was greatly facilitated by the addition of 0.15 mM ZnCl2 and 1 mM ATP and was completely inhibited by 1 mM EDTA, indicating the participation of an ATP-dependent metalloprotease(s) in the D1 cleavage. Herbicides 3-(3,4-dichlorophenyl)-1,1-dimethyl urea, bromoxynil, and ioxynil, all of which bind to the Q(B) site, inhibited the D1 cleavage, suggesting that the DE-loop of the D1 protein is the heat-sensitive cleavage site. We solubilized the protease by treating the thylakoids with 2 M KSCN and detected a protease activity in the supernatant by gelatin activity gel electrophoresis in the 70-80-kDa region. The antibodies against tobacco FtsH and Arabidopsis FtsH2 reacted with a 70-80-kDa band of the KSCN-solubilized fraction, which suggests the presence of FtsH in the fraction. In accordance with this finding, we identified the homolog to Arabidopsis FtsH8 in the 70-80-kDa region by matrix-assisted laser desorption ionization time-of-flight mass analysis of the thylakoids. The KSCN-solubilized fraction was successively reconstituted with thylakoids to show heat-induced cleavage of the D1 protein and production of the D1 fragment. These results strongly suggest that an FtsH protease(s) is involved in the primary cleavage of the D1 protein under moderate heat stress.
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http://dx.doi.org/10.1074/jbc.M602896200DOI Listing
August 2006

Quality control of Photosystem II: an FtsH protease plays an essential role in the turnover of the reaction center D1 protein in Synechocystis PCC 6803 under heat stress as well as light stress conditions.

Photochem Photobiol Sci 2005 Dec 9;4(12):983-90. Epub 2005 Sep 9.

Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.

The role of an AAA protease FtsH (slr0228) in the turnover of the D1 protein was studied under moderate heat stress conditions using wild-type cells of the cyanobacterium Synechocystis PCC 6803 and the mutant cells lacking a homologue of FtsH (slr0228). When the growth temperature of the wild-type was shifted from 30 degrees C to 40 degrees C, growth and oxygen-evolving activity were partially inhibited. Under the same heat stress, growth of the mutant was inhibited more significantly (63% inhibition after 5 days heat stress, compared with 26% inhibition with the wild-type cells) and the oxygen-evolving activity was also impaired in parallel. With heat stress at 42 degrees C, the level of the D1 protein of wild type cells was decreased, whereas that in mutant cells was not. The responses of cyanobacterial cells to heat stress observed here are quite similar to those to light stress that were reported previously. From these results, we suggest that the FtsH protease (slr0228) is responsible for both the heat-induced and light-induced degradation of the D1 protein. Notably, the amount of FtsH increased when the wild-type cells were exposed to heat stress or light stress, indicating that the up-regulation of the FtsH protease in the thylakoids is crucial for the cyanobacterial cells to cope with these abiotic stresses.
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http://dx.doi.org/10.1039/b506068kDOI Listing
December 2005

Differences in higher-level functional capacity between participants and non-participants in health checkups among the elderly.

Arch Gerontol Geriatr 2006 Mar-Apr;42(2):175-89. Epub 2005 Oct 10.

Department of Hygiene, Nara Medical University School of Medicine, Kashihara-shi, Nara 634-8521, Japan.

The present study was conducted to characterize the lifestyles and health status of non-participants and to investigate whether diminished higher-level functional capacity may cause selection bias in non-compulsory mass health screening for the elderly. Using a self-administered questionnaire for evaluating the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG Index of Competence) which consists of three sublevels, namely, instrumental self-maintenance, intellectual activity and social role, we conducted a survey of 1543 (mean age, 64.9+/-12.5 years, 677 males and 866 females) out of all the 1701 individuals over the age of 40 residing in a village where mass health screening is conducted annually. The mean TMIG Index of Competence score was the highest in Group V (composed of 434 individuals who participated in the mass health screening conducted by the village), followed, in that order, by the score in Group W (composed of 531 individuals who had undergone a health checkup organized at their workplaces or by their family physicians, but not the one conducted by the village, during the previous year) and that in Group N (composed of 578 individuals who had not undergone any health checkup during the previous year). Group N showed a significantly lower mean TMIG Index of Competence score than Groups V and W. In regard to the scores for the sublevels of the index, Group N had a significantly lower percentage of subjects, both men and women, with perfect scores than Group V for all the sublevels, and also a significantly lower percentage of subjects with a perfect score for the intellectual activity than Group W. However, there were no significant differences in the percentages of subjects habituated to exercise, drinking or smoking among the three groups. Thus, special attention may need to be paid to selection bias in mass health screenings caused by differences in the higher-level functional capacity.
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http://dx.doi.org/10.1016/j.archger.2005.06.012DOI Listing
April 2007

Quality control of photosystem II under light stress - turnover of aggregates of the D1 protein in vivo.

Photosynth Res 2005 Jun;84(1-3):29-33

Graduate School of Natural Science and Technology, Okayama University, Okayama 700-8530, Japan.

When photodamaged under excessive light, the D1 protein is digested and removed from Photosystem (PS) II to facilitate turnover of the protein. In vitro studies have shown that part of the photodamaged D1 protein forms aggregates with surrounding polypeptides before being digested by a protease(s) in the stroma [Yamamoto Y (2001) Plant Cell Physiol 42: 121-128]. The aim of this study was to examine whether light-induced aggregation of the D1 protein also occurs in vivo. The following results were obtained: (1) PS II activity in spinach leaves was significantly inhibited by weak illumination (light intensity, 20-100 microE m-2 s-1), as monitored by chlorophyll fluorescence Fv/Fm, when the leaves were kept at higher temperatures (35-40 degrees C); (2) aggregation of the D1 protein, as well as cleavage of the protein, was detected in thylakoids isolated from spinach leaves that had been subjected to heat/light stress; (3) aggregates of the D1 protein disappeared after incubation of the leaves at 25 degrees C in the dark or under illumination with weak light. Since it is dependent on the presence of oxygen, aggregation of the D1 protein is probably induced by reactive oxygen species produced in thylakoids upon illumination at elevated temperatures. Consistent with this notion, singlet oxygen production in thylakoid samples under illumination was shown to be stimulated significantly at higher temperatures.
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http://dx.doi.org/10.1007/s11120-004-7310-7DOI Listing
June 2005

[Live birth distribution by time and place from 1981 to 1998 in Japan].

Nihon Eiseigaku Zasshi 2003 Jan;57(4):674-81

Department of Hygiene, Nara Medical University, Nara, Japan.

Objectives: To investigate the diurnal rhythm of live births labored spontaneously, and the effects of obstetric intervention on birth time distributions.

Methods: The data of live births tabulated by time (one-hour intervals), date and birthplace throughout Japan between 1981 and 1998 were obtained with permission from the former Ministry of Health and Welfare. Together with an investigation of hourly birth numbers by place in each year, an annual transition of hourly birth rates in medical institutions and the diurnal rhythm of birth numbers in maternity homes and at home were analyzed using regression analysis.

Results: In every calendar year studied the hourly live birth numbers at hospitals showed a single-peak distribution pattern with maximum values at 13:00-15:00. The annual transition of hourly birth rates showed a 10% (birth numbers base) decrease in the 11:00-13:00 period in 1998 as compared with that in 1981, while there was a corresponding increase of 8% in the 13:00-15:00 period. Hourly birth numbers at clinics showed a double-peak distribution pattern with maximum values during the 11:00-12:00 and 14:00-15:00 periods in early 1980, while a single-peak distribution with a maximum value during the 13:00-15:00 period appeared in 1989 and has remained thereafter. Hourly birth rates (birth numbers base) increased by over 6% in the 13:00-15:00 and 17:00-20:00 periods over the past 18 years, while they decreased by 10% in the 9:00-13:00 period. The results at maternity homes were clearly different from those at hospitals and clinics. The live birth numbers totaled for the 18 years showed a double-phase distribution with a maximum value in the 6:00-7:00 period and a minimum value in the 19:00-20:00 period. The best-fit regression model for the obtained data was a sine curve with a maximum value at 6:00 (coefficient of determination 0.97). Hourly distributions of live births at home also fitted best to a since curve with the maximum value again at 6:00 (coefficient of determination 0.95).

Conclusions: The results suggested that the timing of spontaneous live births follows a circadian rhythm and that obstetric intervention affects time distributions of live births by shifting over 10% of births during the night and early morning to a working day service time (9:00-17:00).
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http://dx.doi.org/10.1265/jjh.57.674DOI Listing
January 2003

Nationwide description of live Japanese births by day of the week, hour, and location.

J Epidemiol 2002 Jul;12(4):330-5

Department of Hygiene, Nara Medical University, Kashihara, Japan.

To characterize temporal variations of live births in Japan, we analyzed data on the 1,203,147 births of 1998. In hospitals, with 20+ beds, the daily average of live births was significantly lower at weekends and national holidays (mean=1,433, SD = 100) than on weekdays (mean = 1,957, SD = 126). Hourly distributions of live births showed a single sharp peak at 1:00-2:59 pm on weekdays with a small peak at an earlier hour on Saturdays, Sundays and national holidays. The results in clinics, with no bed or less than 20 beds, were similar to those in hospitals except on Saturdays. The difference in the daily average of live births between Saturdays and weekdays was smaller in clinics than that found in hospitals, and hourly distributions on Saturdays resembled those of weekdays but not Sundays or national holidays. Maternity homes showed no differences in the mean number of daily live births over the days of the week including national holidays, and no clear peak of percentage distributions of hourly live births on each day of the week. The present study suggests that the weekly and hourly variations observed in hospitals and clinics are not due to a biological rhythm of labor, but to obstetric intervention in the timing of delivery, either through induction of labor or elective cesarean section.
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http://dx.doi.org/10.2188/jea.12.330DOI Listing
July 2002

[Effects of nutrition education for residents on intake of lipid-related nutrients].

Nihon Koshu Eisei Zasshi 2002 Apr;49(4):332-43

Department of Hygiene, Nara Medical University.

Objectives: Health education for residents is now common, but only a few studies of its effects have been made. The purpose of this study was to investigate the effects of nutrition education for residents on intake of lipid-related nutrients.

Methods: A total of 79 females (40-64 years) who underwent a health examination for residents in a town, Nara Prefecture and were found to have total serum cholesterol levels between 220 mg/dl and 300 mg/dl were divided into two groups. In the first group, nutrition education was performed during the first 24 weeks and no education was performed during the second 24 weeks as the self-control period. In the second group, no education was given during the first 24 weeks as the waiting period but was performed during the second 24 weeks. During the education period, dietary intervention for individual subjects was performed 3 times at intervals of 8 weeks by trained dietitians. The intake of nutrients was estimated by the food frequency questionnaire developed by Ueshima and Okayama, and changes in the intake of nutrients adjusted for total energy were used for evaluation of the effects of the education.

Results: In the first group of 42 subjects, three discontinued during the education period and two during the self-control period, and in the second group of the 37 subjects, six discontinued during the waiting period and three during the education period. At the end of the education period, for the total of 67 subjects (39 and 28 in the first and second groups, respectively), the total energy adjusted intake of lipid, cholesterol and saturated fatty acid were significantly lower and the PS ratio was significantly higher than in the second group during the waiting period. During the self-control period after the education, the adjusted intake of lipid-related nutrients remained unchanged in the 37 subjects of the first group who had been given the nutrition education in the first 24 weeks, and it was significantly lower at the end of the 48-week test period than at the baseline examination. The percentage of the subjects showing a desirable intake pattern of major lipid-related nutrients increased significantly after the education period.

Conclusions: These results indicate that the intake of lipid-related nutrients can be decreased by educating individual subjects about nutrition and the effects are maintained for at least 24 weeks.
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April 2002
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