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Ohi K.,Osaka University | Ohi K.,Johns Hopkins University | Hashimoto R.,Osaka University | Ikeda M.,Aichi University | And 11 more authors.
Schizophrenia Bulletin | Year: 2014

Cognitive impairments are a core feature in patients with schizophrenia. These deficits could serve as effective tools for understanding the genetic architecture of schizophrenia. This study investigated whether genetic variants associated with cognitive impairments aggregate in functional gene networks related to the pathogenesis of schizophrenia. Here, genome-wide association studies (GWAS) of a range of cognitive phenotypes relevant to schizophrenia were performed in 411 healthy subjects. We attempted to replicate the GWAS data using 257 patients with schizophrenia and performed a meta-analysis of the GWAS findings and the replicated results. Because gene networks, rather than a single gene or genetic variant, may be strongly associated with the susceptibility to schizophrenia and cognitive impairments, gene-network analysis for genes in close proximity to the replicated variants was performed. We observed nominal associations between 3054 variants and cognitive phenotypes at a threshold of P < 1.0 × 10- 4. Of the 3054 variants, the associations of 191 variants were replicated in the replication samples (P <. 05). However, no variants achieved genome-wide significance in a meta-analysis (P > 5.0 × 10- 8). Additionally, 115 of 191 replicated single nucleotide polymorphisms (SNPs) have genes located within 10 kb of the SNPs (60.2%). These variants were moderately associated with cognitive phenotypes that ranged from P = 2.50 × 10- 5 to P = 9.40 × 10- 8. The genes located within 10 kb from the replicated SNPs were significantly grouped in terms of glutamate receptor activity (false discovery rate (FDR) q = 4.49 × 10- 17) and the immune system related to major histocompatibility complex class I (FDR q = 8.76 × 10- 11) networks. Our findings demonstrate that genetic variants related to cognitive trait impairment in schizophrenia are involved in the N-methyl-d-aspartate glutamate network. © 2014 The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

Sedzik J.,Institute of Chemical Technology | Sedzik J.,National Institute of Physiological science | Jastrzebski J.P.,University of Warmia and Mazury | Grandis M.,University of Genoa
Journal of Neuroscience Research | Year: 2015

Human P0 is the main myelin glycoprotein of the peripheral nervous system. It can bind six different glycans, all linked to Asn93, the unique glycosylation site. Other myelin glycoproteins, also with a single glycosylation site (PMP22 at Asn36, MOG at Asn31), bind only one glycan. The MAG has 10 glycosylation sites; the glycoprotein OMgp has 11 glycosylation sites. Aside from P0, no comprehensive data are available on other myelin glycoproteins. Here we review and analyze all published data on the physicochemical structure of the glycans linked to P0, PMP22, MOG, and MAG. Most data concern bovine P0, whose glycan moieties have an MW ranging from 1,294.56 Da (GP3) to 2,279.94 Da (GP5). The pI of glycosylated P0 protein varies from pH 9.32 to 9.46. The most charged glycan is MS2 containing three sulfate groups and one glucuronic acid; whereas the least charged one is the BA2 residue. All glycans contain one fucose and one galactose. The most mannose rich are the glycans MS2 and GP4, each of them has four mannoses; OPPE1 contains five N-acetylglucosamines and one sulfated glucuronic acid; GP4 contains one sialic acid. Furthermore, human P0 variants causing both gain and loss of glycosylation have been described and cause peripheral neuropathies with variable clinical severity. In particular, the substitution T95→M is a very common in Europe and is associated with a late-onset axonal neuropathy. Although peripheral myelin is made up largely of glycoproteins, mutations altering glycosylation have been described only in P0. This attractive avenue of research requires further study. © 2014 Wiley Periodicals, Inc.

Maddalo G.,University of Stockholm | Shariatgorji M.,University of Stockholm | Adams C.M.,Uppsala University | Adams C.M.,Karolinska Institutet | And 10 more authors.
Analytical and Bioanalytical Chemistry | Year: 2010

Complementary collision-induced/electron capture dissociation Fourier-transform ion cyclotron resonance mass spectrometry was used to fully sequence the protein P2 myelin basic protein. It is an antigenic fatty-acid-binding protein that can induce experimental autoimmune neuritis: an animal model of Guillain-Barré syndrome, a disorder similar in etiology to multiple sclerosis. Neither the primary structure of the porcine variant, nor the fatty acids bound by the protein have been well established to date. A 1.8-Å crystal structure shows but a bound ligand could not be unequivocally identified. A protocol for ligand extraction from protein crystals has been developed with subsequent gas chromatography MS analysis allowing determination that oleic, stearic, and palmitic fatty acids are associated with the protein. The results provide unique and general evidence of the utility of mass spectrometry for characterizing proteins from natural sources and generating biochemical information that may facilitate attempts to elucidate the causes for disorders such as demyelination. © 2010 Springer-Verlag.

Sannomiya T.,Tokyo Institute of Technology | Junesch J.,ETH Zurich | Hosokawa F.,JEOL Ltd. | Nagayama K.,National Institute of Physiological science | And 2 more authors.
Ultramicroscopy | Year: 2014

A new fabrication method of carbon based phase plates for phase-contrast transmission electron microscopy is presented. This method utilizes colloidal masks to produce pores as well as disks on thin carbon membranes for phase modulation. Since no serial process is involved, carbon phase plate membranes containing hundreds of pores can be mass-produced on a large scale, which allows "disposal" of contaminated or degraded phase modulating objects after use. Due to the spherical shape of the mask colloid particles, the produced pores are perfectly circular. The pore size and distribution can be easily tuned by the mask colloid size and deposition condition. By using the stencil method, disk type phase plates can also be fabricated on a pore type phase plate. Both pore and disk type phase plates were tested by measuring amorphous samples and confirmed to convert the sinus phase contrast transfer function to the cosine shape. © 2014 Elsevier B.V.

Nakano K.,University of Tsukuba | Toya M.,University of Tokyo | Toya M.,RIKEN | Yoneda A.,Japan Womens University | And 8 more authors.
Traffic | Year: 2011

Proper cell morphogenesis requires the co-ordination of cell polarity, cytoskeletal organization and vesicle trafficking. The Schizosaccharomyces pombe mutant pob1-664 has a curious lemon-like shape, the basis of which is not understood. Here, we found abundant vesicle accumulation in these cells, suggesting that Pob1 plays a role in vesicle trafficking. We identified Rho3 as a multicopy suppressor of this phenotype. Because Rho3 function is related to For3, an actin-polymerizing protein, and Sec8, a component of the exocyst complex, we analyzed their functional relationship with Pob1. Pob1 was essential for the formation of actin cables (by interacting with For3) and for the polarized localization of Sec8. Although neither For3 nor Sec8 is essential for polarized growth, their simultaneous disruption prevented tip growth and yielded a lemon-like cell morphology similar to pob1-664. Thus, Pob1 may ensure cylindrical cell shape of S. pombe by coupling actin-mediated vesicle transport and exocyst-mediated vesicle tethering during secretory vesicle targeting. © 2011 John Wiley & Sons A/S.

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