アルツハイマー病に対する新たな治療方法の可能性 : 腎不全患者における血液透析器による血中Aβの除去と認知機能への影響

藤田保健衛生大

Derivation of classical capacity of quantum channel for discrete information source

In this letter, we prove that the classical capacity of quantum channel for $M$ symmetric states is achieved by an uniform distribution on a priori probabilities. We also investigate non-symmetric cases such as a ternary amplitude shift keyed signal set and a 16-ary quadrature amplitude modulated signal set in coherent states.Comment: 9 pages, RevTeX, 3 figures(EPSF

Global Radiation-Magnetohydrodynamic Simulations of Black Hole Accretion Flow and Outflow: Unified Model of Three States

Black-hole accretion systems are known to possess several distinct modes (or spectral states), such as low/hard state, high/soft state, and so on. Since the dynamics of the corresponding flows is distinct, theoretical models were separately discussed for each state. We here propose a unified model based on our new, global, two-dimensional radiation-magnetohydrodynamic simulations. By controlling a density normalization we could for the first time reproduce three distinct modes of accretion flow and outflow with one numerical code. When the density is large (model A), a geometrically thick, very luminous disk forms, in which photon trapping takes place. When the density is moderate (model B), the accreting gas can effectively cool by emitting radiation, thus generating a thin disk, i.e., the soft-state disk. When the density is too low for radiative cooling to be important (model C), a disk becomes hot, thick, and faint; i.e., the hard-state disk. The magnetic energy is amplified within the disk up to about twice, 30%, and 20% of the gas energy in models A, B, and C, respectively. Notably, the disk outflows with helical magnetic fields, which are driven either by radiation pressure force or magnetic pressure force, are ubiquitous in any accretion modes. Finally, our simulations are consistent with the phenomenological alpha-viscosity prescription, that is, the disk viscosity is proportional to the pressure.Comment: 5 pages, 2 figures, accepted for publication in PASJ Letter

An efficient grid layout algorithm for biological networks utilizing various biological attributes

BACKGROUND: Clearly visualized biopathways provide a great help in understanding biological systems. However, manual drawing of large-scale biopathways is time consuming. We proposed a grid layout algorithm that can handle gene-regulatory networks and signal transduction pathways by considering edge-edge crossing, node-edge crossing, distance measure between nodes, and subcellular localization information from Gene Ontology. Consequently, the layout algorithm succeeded in drastically reducing these crossings in the apoptosis model. However, for larger-scale networks, we encountered three problems: (i) the initial layout is often very far from any local optimum because nodes are initially placed at random, (ii) from a biological viewpoint, human layouts still exceed automatic layouts in understanding because except subcellular localization, it does not fully utilize biological information of pathways, and (iii) it employs a local search strategy in which the neighborhood is obtained by moving one node at each step, and automatic layouts suggest that simultaneous movements of multiple nodes are necessary for better layouts, while such extension may face worsening the time complexity. RESULTS: We propose a new grid layout algorithm. To address problem (i), we devised a new force-directed algorithm whose output is suitable as the initial layout. For (ii), we considered that an appropriate alignment of nodes having the same biological attribute is one of the most important factors of the comprehension, and we defined a new score function that gives an advantage to such configurations. For solving problem (iii), we developed a search strategy that considers swapping nodes as well as moving a node, while keeping the order of the time complexity. Though a naïve implementation increases by one order, the time complexity, we solved this difficulty by devising a method that caches differences between scores of a layout and its possible updates. CONCLUSION: Layouts of the new grid layout algorithm are compared with that of the previous algorithm and human layout in an endothelial cell model, three times as large as the apoptosis model. The total cost of the result from the new grid layout algorithm is similar to that of the human layout. In addition, its convergence time is drastically reduced (40% reduction)

薬物動態制御因子としてのトランスポーターアダプターの役割

細胞膜裏打ちタンパク質PDZKは、これまでの加藤らの検討から、多くの薬物トランスポーターと相互作用することがin vitroで示されているが、その薬物動態制御因子としての役割は全く不明であった。本研究では、2年間に渡る研究成果を基に次の結論を得るに至った。 1.PDZK1は薬物を輸送するトランスポーターであるPEPT1、PEPT2(いずれもペプチドトランスポーター)、OCTN1、OCTN2(いずれも有機カチオン/カルニチントランスポーター)の薬物輸送能に影響を与える制御因子であること。一方で、PDZK2は少なくともOCTN2の制御因子であること。 2.PDZK1はPET1、OCTN2、有機アニオントランスポーターOATP1Aと、小陽吸収上皮細胞または腎近位尿細管刷子縁膜表面において共局在する一方、PDZK2は近位尿細管刷子縁膜直下でOCTN2と共局在すること。 3.PDZK1が小腸の細胞膜表面におけるPEPT1、OCTN2、OATP1Aの局在に必須の因子であり、PDZK1の欠損によってこれらトランスポーターの機能および局在不全が起こること。 4.低分子量GTP結合タンパク質Rab8が、PEPT1およびグルコーストランスポーターSGLT1の小腸細胞膜表面での局在に必須であり、その遺伝子欠損は栄養吸収不全を引き起こすこと。 以上の知見は薬物を輸送するトランスポーターやひいてはトランスポーターによる薬物動態の制御因子としてのアダプター分子(PDZK1、Rab8)の役割をin vivoおよびin vitroで実証した初めての例であり、複数のトランスポーターが複数のアダプターを介したネットワークとして機能することを示し、今後の医薬品開発や臨床における適正使用において薬物動態を考える上での重要な知見である。Many types of xenobiotic transporters have been identified. They generally exhibit multispecific recognition of various types of substrates, and mediate membrane permeation of therapeutic agents, thereby playing important roles in drug absorption and disposition. We have recently proposed that protein-protein interactions involving the xenobiotic transporters may affect their function, localization and expression on plasma membranes based on in vitro experimental data. So-called adaptor proteins that directly interact with the transporters include PDZ (PSD95, Dig and ZOO domain-containing proteins. This project was performed with an aim to clarify pharmacokinetic roles of such adaptor proteins in vivo. Using pdzk1 gene knockout (pdzk1^+) mice, it was found that interaction with a PDZ adaptor PDZK1 is essential for the cell-surface localization of three solute carriers, Slc15a1 (oligopeptide transporter PEPTD, S1c22a5 (carnitine/organic cation transporter OCTN2) and Slco 1a (organic ani on transporting polypeptide, OATP1A) in mouse small intestine. Electron microscopy revealed localization of PEPT1 in intracellular vesicular structures in pdzk1^+ mice. In pdzk1^+ mice, gastrointestinal absorption of cephalexin, a substrate of PEPT1 and carnitine, a substrate of OCTN2 was delayed, compared with wild mice. In addition, uptake of estrone sulfate, a substrate of OATP1A from apical membrane of small intestine was also decreased in pdzk1^+ mice. Thus, PDZK1 plays pivotal roles as a regulator of transporters, thereby affecting the absorption of substrates of those interacting transporters. Since PDZ adaptors have multiple PDZ domains in their structure, and each PDZ domain can interact with the cytosolic region of the transporters, it can be speculated that transporters are localized within networks consisting of several transporters and adaptors. We have also found that apical localization of PEPT1 and Slc5a1 (sodium/glucose cotransporter, SGLT1) was almost completely reduced in gene knockout mice for small GTP-binding protein rab8 (rab8^+). Gastrointestinal uptake across the apical membranes of glycylsarcosine, a substrate of PEPT1 and α-methylglucose, a substrate of SGLT1 was concomitantly reduced in rab8^+. Thus, our results demonstrate that rab8 is necessary for the proper localization of the two transporters and digestion of various nutrients which are the substrate of those transporters.研究課題/領域番号:18590137, 研究期間(年度):2006–2007出典：「薬物動態制御因子としてのトランスポーターアダプターの役割」研究成果報告書　課題番号18590137 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）)　　　本文データは著者版報告書より作