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Porter, Meghan R.,Kochi, Akiko,Karty, Jonathan A.,Lim, Mi Hee,Zaleski, Jeffrey M. Royal Society of Chemistry 2015 Chemical Science Vol.6 No.2
<▼1><P>We demonstrate that ligand–metal–Aβ interaction with subsequent radical generation is a relatively rapid mechanism for influencing Aβ structural integrity and thus, the aggregation pathway.</P></▼1><▼2><P>Current approaches toward modulation of metal-induced Aβ aggregation pathways involve the development of small molecules that bind metal ions, such as Cu(<SMALL>II</SMALL>) and Zn(<SMALL>II</SMALL>), and interact with Aβ. For this effort, we present the enediyne-containing ligand (<I>Z</I>)-<I>N</I>,<I>N</I>′-bis[1-pyridin-2-yl-meth(<I>E</I>)-ylidene]oct-4-ene-2,6-diyne-1,8-diamine (<B>PyED</B>), which upon chelation of Cu(<SMALL>II</SMALL>) and Zn(<SMALL>II</SMALL>) undergoes Bergman-cyclization to yield diradical formation. The ability of this chelation-triggered diradical to modulate Aβ aggregation is evaluated relative to the non-radical generating control pyridine-2-ylmethyl-(2-{[(pyridine-2-ylmethylene)-amino]-methyl}-benzyl)-amine (<B>PyBD</B>). Variable-pH, ligand UV-vis titrations reveal p<I>K</I><SUB>a</SUB> = 3.81(2) for <B>PyBD</B>, indicating it exists mainly in the neutral form at experimental pH. Lipinski's rule parameters and evaluation of blood–brain barrier (BBB) penetration potential by the PAMPA–BBB assay suggest that <B>PyED</B> may be CNS+ and penetrate the BBB. Both <B>PyED</B> and <B>PyBD</B> bind Zn(<SMALL>II</SMALL>) and Cu(<SMALL>II</SMALL>) as illustrated by bathochromic shifts of their UV-vis features. Speciation diagrams indicate that Cu(<SMALL>II</SMALL>)–<B>PyBD</B> is the major species at pH 6.6 with a nanomolar <I>K</I><SUB>d</SUB>, suggesting the ligand may be capable of interacting with Cu(<SMALL>II</SMALL>)–Aβ species. In the presence of Aβ<SUB>40/42</SUB> under hyperthermic conditions (43 °C), the radical-generating <B>PyED</B> demonstrates markedly enhanced activity (2–24 h) toward the modulation of Aβ species as determined by gel electrophoresis. Correspondingly, transmission electron microscopy images of these samples show distinct morphological changes to the fibril structure that are most prominent for Cu(<SMALL>II</SMALL>)–Aβ cases. The loss of CO<SUB>2</SUB> from the metal binding region of Aβ in MALDI-TOF mass spectra further suggests that metal–ligand–Aβ interaction with subsequent radical formation may play a role in the aggregation pathway modulation.</P></▼2>
Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis
Okada, Y.,Suzuki, A.,Ikari, K.,Terao, C.,Kochi, Y.,Ohmura, K.,Higasa, K.,Akiyama, M.,Ashikawa, K.,Kanai, M.,Hirata, J.,Suita, N.,Teo, Y.Y.,Xu, H.,Bae, S.C.,Takahashi, A.,Momozawa, Y.,Matsuda, K.,Momoh University of Chicago Press [etc.] 2016 American journal of human genetics Vol.99 No.2
<P>Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n=7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p=1.4 x 10(-) 9), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping.</P>