Neural stem cells transplantation in cortex in a mouse model of Alzheimer's disease

Objective. The goal of this study was to elucidate the effect of neurospheres (NS) on dementia in the mouse model of nucleus basalis of Meynert (NBM) lesion. Methods. Mouse embryonic stem cell (ES) derived neurospheres were transplanted into the frontal association cortex and barrel field of S1 cortex of C57BL/6mice 4weeks after including a lesion of NBM by ibotenic acid, while other healthy mice that received ES cells served as control. Behavioral tests by 8-armradial maze were conducted 8 weeks after transplantation, and double staining of choline acetyltransferase (ChAT), serotonin, amyloid-βprotein (AP) and green fluorescent protein(GFP)12 weeks after transplantation.We found that the neurospheres transplanted into the mouse cortex survived and produced many ChAT-positive neurons and a few serotoninpositive neurons in and around the grafts. The working memory error decreased significantly in the mice grafted with neurospheres. In contrast, the ES cells developed into teratomas in all of the control mice and expressed no neurons, and the working memory deteriorated remarkably. Conclusions. Transplantation of neurospheres, but not ES cells, into the prefrontal and parietal cortices, dramatically alleviated the cholinergic deficits and recent memory disruption in the NBM lesioned mice

pH-resistant Inhibitor of Mitochondrial ADP/ATP Carrier

Bongkrekic acid (BKA), isolated from Burkholderia cocovenenans, is known to specifically inhibit the mitochondrial ADP/ATP carrier. However, the manner of its interaction with the carrier remains elusive. In the present study, we tested the inhibitory effects of 17 bongkrekic acid analogues, derived from the intermediates obtained during its total synthesis, on the mitochondrial ATP/ATP carrier. Rough screening of these chemicals, done by measuring their inhibitory effects on the mitochondrial ATP synthesis, revealed that 4 of them, KH-1, 7, 16, and 17, had moderate inhibitory effects. Further characterization of the actions of these 4 analogues on mitochondrial function showed that KH-16 had moderate; KH-1 and KH-17, weak; and KH-7, negligible side effects of both permeabilization of the mitochondrial inner membrane and inhibition of the electron transport, indicating that only KH-7 had a specific inhibitory effect on the mitochondrial ADP/ATP carrier. Although the parental bongkrekic acid showed a strong pH dependency of its action, the inhibitory effect of KH-7 was almost insensitive to the pH of the reaction medium, indicating the importance of the 3 carboxyl groups of BKA for its pH- dependent action. A direct inhibitory effect of KH-7 on the mitochondrial ADP/ATP carrier was also clearly demonstrated

Environmental Dependence of Artifact CD Peaks of Chiral Schiff Base 3d-4f Complexes in Soft Mater PMMA Matrix

Four chiral Schiff base binuclear 3d-4f complexes (NdNi, NdCu, GdNi, and GdCu) have been prepared and characterized by means of electronic and CD spectra, IR spectra, magnetic measurements, and X-ray crystallography (NdNi). A so-called artifact peak of solid state CD spectra, which was characteristic of oriented molecules without free molecular rotation, appeared at about 470 nm. Magnetic data of the complexes in the solid state (powder) and in PMMA cast films or solutions indicated that only GdCu preserved molecular structures in various matrixes of soft maters. For the first time, we have used the changes of intensity of artifact CD peaks to detect properties of environmental (media solid state (KBr pellets), PMMA cast films, concentration dependence of PMMA in acetone solutions, and pure acetone solution) for chiral 3d-4f complexes (GdCu). Rigid matrix keeping anisotropic orientation exhibited a decrease in the intensity of the artifact CD peak toward negative values. The present results suggest that solid state artifact CD peaks can be affected by environmental viscosity of a soft mater matrix

Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: implications for HIV-1 restriction

The human APOBEC3 proteins are DNA cytidine deaminases that impede the replication of many different transposons and viruses. The genes that encode APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G and APOBEC3H were generated through relatively recent recombination events. The resulting high degree of inter-relatedness has complicated the development of specific quantitative PCR assays for these genes despite considerable interest in understanding their expression profiles. Here, we describe a set of quantitative PCR assays that specifically measures the mRNA levels of each APOBEC3 gene. The specificity and sensitivity of each assay was validated using a full matrix of APOBEC3 cDNA templates. The assays were used to quantify the APOBEC3 repertoire in multiple human T-cell lines, bulk leukocytes and leukocyte subsets, and 20 different human tissues. The data demonstrate that multiple APOBEC3 genes are expressed constitutively in most types of cells and tissues, and that distinct APOBEC3 genes are induced upon T-cell activation and interferon treatment. These data help define the APOBEC3 repertoire relevant to HIV-1 restriction in T cells, and they suggest a general model in which multiple APOBEC3 proteins function together to provide a constitutive barrier to foreign genetic elements, which can be fortified by transcriptional induction

HIV-1 Vif: a guardian of the virus that opens up a new era in the research field of restriction factors.

The research on virion infectivity factor (Vif) protein had started in late 1980s right after HIV-1 was cloned, and the function of Vif had been a mystery for a long time. However, the research on Vif has finally lead to the identification of APOBEC3G, which opens up a new era in the research field of host restriction factors in HIV-1 infection followed by TRIM5α, Tetherin/BST-2, and SAMHD1. This suggests that continuation of basic research on fundamental questions is quite important. We still have many questions on Vif and APOBEC3 and should continue to work on these proteins in the future in order to better regulate HIV-1. We will discuss not only the history but also recent advances in Vif research

シチジン ダツ アミノカ コウソ CEM15 Apobec-3G ブンシ ノ コウソ カッセイ ワ HIV-1 ウイルス リュウシ ノ カンセンセイ セイギョ ニ ヒッス デ アル ガ ソノ コウウイルス カッセイ ノ ユイイツ ノ ケッテイ インシ デワ ナイ

京都大学0048新制・課程博士博士(医学)甲第11058号医博第2771号新制||医||875(附属図書館)22590UT51-2004-J730京都大学大学院医学研究科内科系専攻(主査)教授 速水 正憲, 教授 淀井 淳司, 教授 内山 卓学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Asymptotic Behavior of Resolvents of a Convergent Sequence of Convex Functions on Complete Geodesic Spaces

The asymptotic behavior of resolvents of a proper convex lower semicontinuous function is studied in the various settings of spaces. In this paper, we consider the asymptotic behavior of the resolvents of a sequence of functions defined in a complete geodesic space. To obtain the result, we assume the Mosco convergence of the sets of minimizers of these functions

Asymptotic Behavior of Resolvents of a Convergent Sequence of Convex Functions on Complete Geodesic Spaces

The asymptotic behavior of resolvents of a proper convex lower semicontinuous function is studied in the various settings of spaces. In this paper, we consider the asymptotic behavior of the resolvents of a sequence of functions defined in a complete geodesic space. To obtain the result, we assume the Mosco convergence of the sets of minimizers of these functions

Critical role of PP2A-B56 family protein degradation in HIV-1 Vif mediated G2 cell cycle arrest

HIV-1 Vif forms an E3 ubiquitin ligase complex with host proteins to counteract host restrictive APOBEC3, and is also known to accumulate infected cells at the G2 phase to promote viral replication. However, the underlying mechanism of how Vif induces G2 arrest is not fully understood, and more specifically, direct target molecules of G2 arrest have not been identified. Here we show that degradation of B56 family proteins (PP2A-B56), one of the regulatory subunits of protein phosphatase 2A, is critical for the Vif-induced G2 arrest. NL4-3 Vif caused degradation of PP2A-B56, and complementation of PP2A-B56 overcome the Vif-induced arrest. Supportively, knockdown of PPP2R5D, one of PP2A-B56, by siRNA itself induced cell cycle arrest of non-infected cells. We also identified Vif residues I31 and R or K33 are determinants for inducing G2 arrest, and Vif variants that did not cause G2 arrest did not induce PPP2R5D degradation, although it maintain the ability to induce APOBEC3G degradation, showing strong correlation between Vif-induced arrest and PP2A-B56 degradation. In a sequence database of HIV-1 isolates, Vif strains harboring residues that presumably induce cell cycle arrest are approximately 43%, suggesting Vif-induced G2 arrest contributes to HIV-1 infection in vivo and spread. Our data help understand the mechanism of Vif-mediated arrest, and gain insights into general cell cycle regulation