Pancreatic β-Cell Death, Regeneration and Insulin Secretion: Roles of Poly(ADP-Ribose) Polymerase and Cyclic ADP-Ribose

In the early 1980s, we proposed a unifying model for β-cell damage (The OKAMOTO model), in which poly(ADP-ribose) synthetase/ polymerase (PARP) activation plays an essential role in the consumption of NAD+, which leads to energy depletion and necrotic cell death. In 1984, we demonstrated that the administration of PARP inhibitors to 90% depancreatized rats induces islet regeneration. From the regenerating islet-derived cDNA library we isolated Reg (Regenerating Gene) and demonstrated that Reg protein induces βcell replication via the Reg receptor and ameliorates experimental diabetes. More recently, we showed that the combined addition of IL-6 and dexamethasone induces the Reg gene expression in β-cells and that PARP inhibitors enhance the expression. In 1993, we found that cyclic ADP-ribose (cADPR), a product synthesized from NAD+, is a second messenger for intracellular Ca+ mobilization for insulin secretion by glucose, and proposed a novel mechanism of insulin secretion, the CD38-cADPR signal system

Minimal dilatations of pseudo-Anosovs generated by the magic 3-manifold and their asymptotic behavior

This paper concerns the set $\hat{\mathcal{M}}$ of pseudo-Anosovs which occur as monodromies of fibrations on manifolds obtained from the magic 3-manifold $N$ by Dehn filling three cusps with a mild restriction. We prove that for each $g$ (resp. $g \not\equiv 0 \pmod{6}$), the minimum among dilatations of elements (resp. elements with orientable invariant foliations) of $\hat{\mathcal{M}}$ defined on a closed surface $\varSigma_g$ of genus $g$ is achieved by the monodromy of some $\varSigma_g$-bundle over the circle obtained from $N(\tfrac{3}{-2})$ or $N(\tfrac{1}{-2})$ by Dehn filling two cusps. These minimizers are the same ones identified by Hironaka, Aaber-Dunfiled, Kin-Takasawa independently. In the case $g \equiv 6 \pmod{12}$ we find a new family of pseudo-Anosovs defined on $\varSigma_g$ with orientable invariant foliations obtained from N(-6) or N(4) by Dehn filling two cusps. We prove that if $\delta_g^+$ is the minimal dilatation of pseudo-Anosovs with orientable invariant foliations defined on $\varSigma_g$, then $$\limsup_{\substack{g \equiv 6 \pmod{12} g \to \infty}} g \log \delta^+_g \le 2 \log \delta(D_5) \approx 1.0870,$$ where $\delta(D_n)$ is the minimal dilatation of pseudo-Anosovs on an $n$-punctured disk. We also study monodromies of fibrations on N(1). We prove that if $\delta_{1,n}$ is the minimal dilatation of pseudo-Anosovs on a genus 1 surface with $n$ punctures, then $$\limsup_{n \to \infty} n \log \delta_{1,n} \le 2 \log \delta(D_4) \approx 1.6628.$$Comment: 46 pages, 14 figures; version 3: Major change in Section 2.1, and minor correction

A computational model based on corticospinal functional MRI revealed asymmetrically organized motor corticospinal networks in humans

新規MRI技術で利き手の神経制御メカニズムを解明 --手指運動中の脳・脊髄機能結合パターンの左右差を世界で初めて計測--. 京都大学プレスリリース. 2022-08-08.Evolution of the direct, monosynaptic connection from the primary motor cortex to the spinal cord parallels acquisition of hand dexterity and lateralization of hand preference. In non-human mammals, the indirect, multi-synaptic connections between the bilateral primary motor cortices and the spinal cord also participates in controlling dexterous hand movement. However, it remains unknown how the direct and indirect corticospinal pathways work in concert to control unilateral hand movement with lateralized preference in humans. Here we demonstrated the asymmetric functional organization of the two corticospinal networks, by combining network modelling and simultaneous functional magnetic resonance imaging techniques of the brain and the spinal cord. Moreover, we also found that the degree of the involvement of the two corticospinal networks paralleled lateralization of hand preference. The present results pointed to the functionally lateralized motor nervous system that underlies the behavioral asymmetry of handedness in humans

間欺的低酸素はヒト神経細胞においてGATA転写因子を介してPOMCとCARTのmRNAを増加させる

Sleep apnea syndrome (SAS) is characterized by intermittent hypoxia (IH) during sleep. SAS and obesity are strongly related to each other. Here, we investigated the effect of IH on the expression of major appetite regulatory genes in human neuronal cells. We exposed NB-1, SH-SY5Y, and SK-N-SH human neuronal cells to IH (64 cycles of 5 min hypoxia and 10 min normoxia), normoxia, or sustained hypoxia for 24 h and measured the mRNA levels of proopiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript (CART), galanin, galanin-like peptide, ghrelin, pyroglutamylated RFamide peptide, agouti-related peptide, neuropeptide Y, and melanocortin 4 receptor by real-time RT-PCR. IH significantly increased the mRNA levels of POMC and CART in all the neuronal cells. Deletion analysis revealed that the -705 to -686 promoter region of POMC and the -950 to -929 region of CART were essential for the IH-induced promoter activity. As possible GATA factor binding sequences were found in the two regions, we performed real-time RT-PCR to determine which GATA family members were expressed and found that GATA2 and GATA3 mRNAs were predominantly expressed. Therefore, we introduced siRNAs against GATA2 and GATA3 into NB-1 cells and found that GATA2 and GATA3 siRNAs abolished the IH-induced up-regulation of both POMC and CART mRNAs. These results indicate that IH stress up-regulates the mRNA levels of anorexigenic peptides, POMC and CART, in human neuronal cells via GATA2 and GATA3. IH can have an anorexigenic effect on SAS patients through the transcriptional activation of POMC and CART in the central nervous system.博士（医学）・甲第685号・平成30年6月27日© 2017 Elsevier Ltd. All rights reserved