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Saka S.K.,Sensory Medical | Saka S.K.,International Max Planck Research | Honigmann A.,Max Planck Institute for Biophysical Chemistry | Eggeling C.,Weatherall Institute of Molecular Medicine | And 3 more authors.
Nature Communications | Year: 2014

Most proteins have uneven distributions in the plasma membrane. Broadly speaking, this may be caused by mechanisms specific to each protein, or may be a consequence of a general pattern that affects the distribution of all membrane proteins. The latter hypothesis has been difficult to test in the past. Here, we introduce several approaches based on click chemistry, through which we study the distribution of membrane proteins in living cells, as well as in membrane sheets. We found that the plasma membrane proteins form multi-protein assemblies that are long lived (minutes), and in which protein diffusion is restricted. The formation of the assemblies is dependent on cholesterol. They are separated and anchored by the actin cytoskeleton. Specific proteins are preferentially located in different regions of the assemblies, from their cores to their edges. We conclude that the assemblies constitute a basic mesoscale feature of the membrane, which affects the patterning of most membrane proteins, and possibly also their activity. © 2014 Macmillan Publishers Limited.

Suzuki T.,Tohoku University | Namba K.,Sensory Medical | Mizuno N.,Tohoku University | Nakata H.,Tokyo Metropolitan Institute of Medical Science
Methods in Enzymology | Year: 2013

The formation of homo- and hetero-oligomers between various G protein-coupled receptors (GPCRs) has been demonstrated over the past decade. In most cases, GPCR heterodimerization increases the diversity of intracellular signaling. GPCR-type purinergic receptors (adenosine and P2Y receptors) are actively reported to form hetero-oligomers with each other, with GPCRs belonging to the same group (type 1, rhodopsin-like), and even with GPCRs from another group. This chapter describes common strategies to identify dimerization of purinergic receptors (coimmunoprecipitation, bioluminescence resonance energy transfer (BRET), and immunoelectron microscopy) and to assess the alteration of their pharmacology (ligand binding, intracellular cAMP, and intracellular Ca2 + assays). We have reported dimerization of purinergic receptors using these strategies in transfected human embryonic kidney 293T cells and native brain tissue. Our data suggest that homo- and hetero-oligomerization between purinergic receptors exert unique pharmacology in this receptor group. According to these discoveries, heterodimerization is likely to be employed for the "fine-tuning" of purinergic receptor signaling. © 2013 Elsevier Inc.

Masuda S.,National Mie Hospital | Usui S.,National Mie Hospital | Matsunaga T.,Sensory Medical
International Journal of Pediatric Otorhinolaryngology | Year: 2013

Objective: Radiological and genetic examination has recently advanced for diagnosis of congenital hearing loss. The aim of this study was to elucidate the prevalence of inner-ear and/or internal auditory canal malformations in children with unilateral sensorineural hearing loss (USNHL) for better management of hearing loss and genetic and lifestyle counseling. Methods: We conducted a retrospective study of charts and temporal bone computed tomography (CT) findings of 69 consecutive patients 0-15 years old with USNHL. In two cases, genetic examination was conducted. Results: Of these patients, 66.7% had inner-ear and/or internal auditory canal malformations. The prevalence of malformations in infants (age <1 year) was 84.6%, which was significantly higher than that in children 1-15 years old (55.8%; p<0.01). Almost half of the patients (32; 46.4%) had cochlear nerve canal stenosis; 13 of them had cochlear nerve canal stenosis alone, and in 19 it accompanied other malformations. Internal auditory canal malformations were observed in 22 subjects (31.8%), 14 (20.3%) had cochlear malformations, and 5 (7.2%) had vestibular/semicircular canal malformations. These anomalies were seen only in the affected ear, except in two of five patients with vestibular and/or semicircular canal malformations. Two patients (2.9%) had bilateral enlarged vestibular aqueducts. Mutations were found in SLC26A4 in one of the two patients with bilateral large vestibular aqueducts. The prevalence of a narrow internal auditory canal was significantly higher in subjects with cochlear nerve canal stenosis (50.0%) than in subjects with normal cochlear nerve canals (11.1%; p<0.01). There were no correlations between the type and number of malformations and hearing level. Conclusions: The prevalence of inner-ear and/or internal auditory canal malformations detected by high-resolution temporal bone CT in children with USNHL was very high. Radiological and genetic examination provided important information to consider the pathogenesis and management of hearing loss. Temporal bone CT should be recommended to children with USNHL early in life. SLC26A4 mutation also should be examined in cases with bilateral enlarged vestibular aqueduct. © 2012 Elsevier Ireland Ltd.

Mizuno Y.,Sensory Medical | Yamada M.,Sensory Medical | Shigeyasu C.,Sensory Medical
Clinical Ophthalmology | Year: 2012

Background: This study was performed to estimate the annual direct cost incurred by dry eye patients, which includes expenses for treatment and drugs, as well as the cost of punctal plugs. Methods: The study group consisted of 118 dry eye patients aged 20 years or older who visited any of the 15 medical care facilities that participated in this prospective cohort dry eye study. We estimated annual direct costs from outpatient medical records and survey questionnaires obtained from patients. Results: Of the total patients enrolled, 10 were men and 108 women, and their average age was 64.1 ± 11.2 years. The number of hospital visits made by patients was 5.8 ± 3.6 per year. Among those who used ophthalmic solutions, the numbers of bottles used per year were as follows: 32.1 ± 20.8 bottles of hyaluronic acid ophthalmic solution (87 patients), 53.1 ± 42.2 bottles of artificial tears (40 patients), and 33.2 ± 23.2 bottles of over-the-counter eyedrops (15 patients). In patients with punctal plugs, 4.1 ± 3.9 plugs were used annually. The annual drug cost was 32,000 ± 21,675 Japanese yen (323 ± 219 US dollars). The clinical cost was 16,318 ± 9961 Japanese yen (165 ± 101 US dollars). The total direct costs including punctal plug treatment amounted to 52,467 ± 38,052 Japanese yen (530 ± 384 US dollars). Conclusion: Although treatment modalities for dry eye in Japan were different from those in the US and in European countries, the direct cost of dry eye patients in Japan was comparable with that reported in those countries. Considering the high prevalence of dry eye, the direct cost of this chronic condition may be significant. © 2012 Mizuno et al, publisher and licensee Dove Medical Press Ltd.

Tsunoda M.,Tsunoda Clinic | Tsunoda K.,Sensory Medical
Annals of Family Medicine | Year: 2014

Various methods are used to treat ingrown or pincer-like toenails. We developed a novel taping method to prevent topical interruption of the circulation and resulting skin conditions and evaluated it over 14.5 years. We instructed 541 patients or their guardians in the use of the technique. Ingrown toenail symptoms and abnormal nail growth were resolved and no additional therapy was required in 276 patients. The novel taping method was significantly more effective than treatments our patients had received previously. Patient-controlled taping is the first-line treatment for every ingrown or curved toenail seen in our clinic.

Yamada M.,Sensory Medical | Mizuno Y.,Sensory Medical | Shigeyasu C.,Sensory Medical
ClinicoEconomics and Outcomes Research | Year: 2012

Background: The purpose of this study was to evaluate the impact of dry eye on work productivity of office workers, especially in terms of presenteeism. Methods: A total of 396 individuals aged ≥20 years (258 men and 138 women, mean age 43.4 ± 13.0 years) were recruited through an online survey. Data from 355 responders who did not have missing values were included in the analysis. They were classified into the following four groups according to the diagnostic status and subjective symptoms of dry eye: a definite dry eye group; a marginal dry eye group; a self-reported dry eye group; and a control group. The impact of dry eye on work productivity was evaluated using the Japanese version of the Work Limitations Questionnaire. The cost of work productivity loss associated with dry eye and the economic benefits of providing treatment for dry eye were also assessed. Results: The degree of work performance loss was 5.65% in the definite dry eye group, 4.37% in the marginal dry eye group, 6.06% in the self-reported dry eye group, and 4.27% in the control group. Productivity in the self-reported dry eye group was significantly lower than that in the control group (P < 0.05). The annual cost of work productivity loss associated with dry eye was estimated to be USD 741 per person. Conclusion: Dry eye impairs work performance among office workers, which may lead to a substantial loss to industry. Management of symptoms of dry eye by providing treatment may contribute to improvement in work productivity. © 2012 Yamada et al, publisher and licensee Dove Medical Press Ltd.

Hatou S.,Sensory Medical | Hatou S.,Keio University
Cornea | Year: 2011

Na-and K-dependent ATPase (Na +,K +-ATPase) in the basolateral membrane of corneal endothelial cells plays an important role in the pump function of the corneal endothelium. We investigated the role of dexamethasone in the regulation of Na,K-ATPase activity and pump function in these cells. Mouse corneal endothelial cells were exposed to dexamethasone or insulin. ATPase activity was evaluated by spectrophotometric measurement, and pump function was measured using an Ussing chamber. Western blotting and immunocytochemistry were performed to measure the expression of the Na,K-ATPase ±1-subunit. Dexamethasone increased Na,K-ATPase activity and the pump function of endothelial cells. Western blot analysis indicated that dexamethasone increased the expression of the Na,K-ATPase ±1-subunit but decreased the ratio of active to inactive Na,K-ATPase ±1-subunit. Insulin increased Na,K-ATPase activity and pump function of cultured corneal endothelial cells. These effects were transient and blocked by protein kinase C inhibitors and inhibitors of protein phosphatases 1 (PP1) and 2A (PP2A). Western blot analysis indicated that insulin decreased the amount of inactive Na,K-ATPase ±1-subunit, but the expression of total Na,K-ATPase ±1-subunit was unchanged. Immunocytochemistry showed that insulin increased cell surface expression of the Na,K-ATPase ±1-subunit. Our results suggest that dexamethasone and insulin stimulate Na +,K +-ATPase activity in mouse corneal endothelial cells. The effect of dexamethasone activation in these cells was mediated by Na,K-ATPase synthesis and an increased enzymatic activity because of dephosphorylation of Na,K-ATPase ±1-subunits. The effect of insulin is mediated by the protein kinase C, PP1, and/or PP2A pathways. © 2011 by Lippincott Williams & Wilkins.

For the past 10 years, number of evidence has shown that activation of complement cascade has been associated with age-related macular degeneration (AMD). The genome wide association study in American population with dominantly dry-type AMD has revealed strong association with single nucleotide polymorphism (SNP) of complement genes. Protein composition of drusen, a deposit observed in sub-retinal space between Bruch's membrane and retinal pigment epithelial (RPE), contains active complement molecules in human and monkey. These evidences have leaded us to consider the possibility of suppressing complement cascade in the retina to delay or reverse the onset of AMD. To test is hypothesis we used the C3 inhibitor Compstatin on primate model with early-onset macular degeneration which develop drusen in less than 2 years after birth. Our preliminary result showed drusen disappearance after 6 months of intravitreal injection. © Springer Science+Business Media, LLC 2010.

Wen S.,Sensory Medical | Schroeter A.,Sensory Medical | Klocker N.,Sensory Medical
Archives of Biochemistry and Biophysics | Year: 2013

Hepatic encephalopathy (HE)1 is a common neuropsychiatric complication of both acute and chronic liver disease. Clinical symptoms may include motor disturbances and cognitive dysfunction. Available animal models of HE mimic the deficits in cognitive performance including the impaired ability to learn and memorize information. This review explores the question how HE might affect cognitive functions at molecular levels. Both acute and chronic models of HE constrain the plasticity of glutamatergic neurotransmission. Thus, long-lasting activity-dependent changes in synaptic efficiency, known as long-term potentiation (LTP) and long-term depression (LTD) are significantly impeded. We discuss molecules and signal transduction pathways of LTP and LTD that are targeted by experimental HE, with a focus on ionotropic glutamate receptors of the AMPA-subtype. Finally, a novel strategy of functional proteomic analysis is presented, which, if applied differentially, may provide molecular insight into disease-related dysfunction of membrane protein complexes, i.e. disturbed ionotropic glutamate receptor signaling in HE. © 2013 Elsevier Inc. All rights reserved.

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