Kumamoto University

About: Kumamoto University is a education organization based out in Kumamoto, Kumamoto, Japan. It is known for research contribution in the topics: Cancer & Population. The organization has 19602 authors who have published 35513 publications receiving 901260 citations. The organization is also known as: Kumamoto Daigaku.

Increased Expression of Integrin αvβ5 Induces the Myofibroblastic Differentiation of Dermal Fibroblasts

Abstract: The biological effect of cytokines is mainly determined by the cytokine-receptor interaction, which is modulated by the concentration and the activity of cytokines and/or their receptors. Because αv-containing integrins can bind to and/or activate latent TGF-β, these integrins have been thought to be involved in the pathogenesis of fibrotic disorders. Our recent observations that αvβ5 is up-regulated in scleroderma fibroblasts and that the transient overexpression of αvβ5 increases the human α2(I) collagen gene expression in normal fibroblasts suggest the involvement of αvβ5 in the self-activation system in scleroderma fibroblasts. In this study, we established stable transfectants with αvβ5 using normal dermal fibroblasts and demonstrated that such cells differentiated into myofibroblasts by the stimulation of autocrine TGF-β. This observation is explained by 1) αvβ5 recruiting latent TGF-β1 on the cell surface, 2) endogenous active TGF-β localizing on the cell surface, and 3) αvβ5 interacting with TGF-β receptors. Furthermore, blockade of αvβ5 reversed the myofibroblastic phenotype in scleroderma fibroblasts. These data identify a novel mechanism for the establishment of autocrine TGF-β signaling in dermal fibroblasts by the up-regulation of αvβ5 and suggest the possibility of regulating fibrotic disorders, especially scleroderma, by targeting this integrin.

Nav1.1 haploinsufficiency in excitatory neurons ameliorates seizure-associated sudden death in a mouse model of Dravet syndrome

Abstract: Dravet syndrome is a severe epileptic encephalopathy mainly caused by heterozygous mutations in the SCN1A gene encoding a voltage-gated sodium channel Nav1.1. We previously reported dense localization of Nav1.1 in parvalbumin (PV)-positive inhibitory interneurons in mice and abnormal firing of those neurons in Nav1.1-deficient mice. In the present study, we investigated the physiologic consequence of selective Nav1.1 deletion in mouse global inhibitory neurons, forebrain excitatory neurons or PV cells, using vesicular GABA transporter (VGAT)-Cre, empty spiracles homolog 1 (Emx1)-Cre or PV-Cre recombinase drivers. We show that selective Nav1.1 deletion using VGAT-Cre causes epileptic seizures and premature death that are unexpectedly more severe than those observed in constitutive Nav1.1-deficient mice. Nav1.1 deletion using Emx1-Cre does not cause any noticeable abnormalities in mice; however, the severe lethality observed with VGAT-Cre-driven Nav1.1 deletion is rescued by additional Nav1.1 deletion using Emx1-Cre. In addition to predominant expression in PV interneurons, we detected Nav1.1 in subpopulations of excitatory neurons, including entorhino-hippocampal projection neurons, a subpopulation of neocortical layer V excitatory neurons, and thalamo-cortical projection neurons. We further show that even minimal selective Nav1.1 deletion, using PV-Cre, is sufficient to cause spontaneous epileptic seizures and ataxia in mice. Overall, our results indicate that functional impairment of PV inhibitory neurons with Nav1.1 haploinsufficiency contributes to the epileptic pathology of Dravet syndrome, and show for the first time that Nav1.1 haploinsufficiency in excitatory neurons has an ameliorating effect on the pathology.

A novel maternally expressed gene, ATP10C, encodes a putative aminophospholipid translocase associated with Angelman syndrome.

Abstract: Lack of a maternal contribution to the genome at the imprinted domain on proximal chromosome 15 causes Angelman syndrome (AS) associated with neurobehavioral anomalies that include severe mental retardation, ataxia and epilepsy. Although AS patients have infrequent mutations in the gene encoding an E6-AP ubiquitin ligase required for long-term synaptic potentiation (LTP), most cases are attributed to de novo maternal deletions of 15q11-q13. We report here that a novel maternally expressed gene, ATP10C, maps within the most common interval of deletion and that ATP10C expression is virtually absent from AS patients with imprinting mutations, as well as from patients with maternal deletions of 15q11-q13.

Mutation Analysis of Patients with Hermansky-Pudlak Syndrome: A Frameshift Hot Spot in the HPS Gene and Apparent Locus Heterogeneity

Abstract: Hermansky-Pudlak syndrome (HPS) is a rare, autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles-melanosomes, platelet-dense granules, and lysosomes. As reported elsewhere, we mapped the human HPS gene to chromosome segment 10q23, positionally cloned the gene, and identified three pathologic mutations of the gene, in patients from Puerto Rico, Japan, and Europe. Here, we describe mutation analysis of 44 unrelated Puerto Rican and 24 unrelated non-Puerto Rican HPS patients. A 16-bp frameshift duplication, the result of an apparent founder effect, is nearly ubiquitous among Puerto Rican patients. A frameshift at codon 322 may be the most frequent HPS mutation in Europeans. We also describe six novel HPS mutations: a 5' splice-junction mutation of IVS5, three frameshifts, a nonsense mutation, and a one-codon in-frame deletion. These mutations define an apparent frameshift hot spot at codons 321-322. Overall, however, we detected mutations in the HPS gene in only about half of non-Puerto Rican patients, and we present evidence that suggests locus heterogeneity for HPS.

Detection of hepatocellular carcinoma arising in cirrhotic livers: comparison of gadolinium- and ferumoxides-enhanced MR imaging.

Abstract: We prospectively compared the detectability of hepatocellular carcinoma (HCC) arising in cirrhotic livers using dynamic gadolinium-enhanced fast low-angle shot (FLASH), ferumoxides-enhanced T2-weighted turbo spin-echo, and ferumoxides-enhanced T2*-weighted FLASH MR imagingFifty-three patients with HCC (32 men and 21 women) who were 33-86 years old (mean, 63 years old) were enrolled in a prospective MR study to assess hepatic lesions using both gadopentetate dimeglumine and ferumoxides Dynamic gadolinium-enhanced imaging was obtained before and 30, 60, and 180 sec after rapid bolus injection of gadopentetate dimeglumine (01 mmol/kg) Ferumoxides-enhanced T2-weighted turbo spin-echo imaging and ferumoxides-enhanced T2*-weighted FLASH imaging were performed between 30 min and 2 hr after iv infusion of ferumoxides (10 micromol/kg) Images were analyzed qualitatively and quantitatively A receiver operating characteristic curve study was performed to compare the diagnostic value of gadolinium-enhanced ima