網羅的アラニンスキャンニングを用いたSTAT1変異の機能喪失または機能獲得の評価

広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

コベネフィットガタ カイハツ ノ カノウセイ ソーラー クッカー オ レイ トシテ

The purpose of this study is to explore and assess the results, effects and influences of the co-benefitsdevelopment approach to intended project beneficiaries in developing countries. The co-benefitsapproach aims to address the needs of communities in under-developed countries while amelioratingthe effects of climate change.For this study, I visited the remote villages in Ladakh in the Himalayan region of India on two occasionsto survey a sample of residents and beneficiaries. In addition, this research took into accountsecondary data from several previous studies.Recently, actors in international development have increasingly focused on co-benefit approaches.While several studies have been made on estimating the benefits of climate change mitigation, often littleis known on how each project following this approach assists the poorest people and addresses theirsocio-economic development needs.Additionally, problems can be seen to occur in the field when international development agenciesattempt to transfer environmentally-friendly technology to developed countries. Thus, this thesis analyzesthe development-related benefits for local people and identifies the factors to which attentionshould be paid. In this case, the research uses a case study of solar cookers, which have been providedto villagers as a co-benefit cooking tool.The study and its analysis are based on the findings of field research on the solar cooker projectundertaken by Japanese NGO JULAY LADAKH.In response to the results of this study, suggestions and proposals have been offered as to whatshould be paid attention to in the shift to co-benefit environmentally-friendly technology.While the project analyzed in this case study was judged a success by partner organizations, therewere many factors relating to the end results. So, when a similar kind of co-benefit project is planned,international cooperation agencies should research the needs and situation of the recipients on a caseby-case basis.In general, what seems to be lacking in many such co-benefit development projects is a considerationof the needs of intended beneficiaries and appropriateness of technology, rather than simply theclimate benefits of the intended usage.The study also attempts to predict the influence of the success or otherwise of such co-benefit projectsimplemented at the local level on the policy and decision-making processes among governmentand other stakeholders, especially as they relates to the achievement of the twin goals of climatechangemitigation and sustainable socio-economic development on a region-wide or nation-wide level

Cbl-b ケッソン ニ ヨル マクロファージ ノ カッセイカ オ カイシタ タイトウノウ イジョウ

Obesity is a major cause of insulin resistance and is considered a chronic low-grade inflammatory disease. Substantial evidence has accumulated in recent years that chronic infiltration and activation of macrophages in white adipose tissue underlie the obesity-related component of these insulin resistant states. In the present study, we examined the role of Cbl-b, ubiquitin ligase, in insulin action. Elderly Cbl-b-deficient mice（Cbl-b－/－mice）developed glucose intolerance and peripheral insulin resistance. Deficiency of Cbl-b gene was associated with infiltration of macrophages into the WAT and expression of cytokines, such as tumor necrosis factor-α, interleukin-6 and monocyte chemoattractant protein-1. Furthermore, Vav1, a key factor in macrophage activation, was highly phosphorylated in peritoneal Cbl-b－/－macrophages, compared with wild type macrophages, suggesting that Cbl-b deficiency induces macrophage activation. Our results suggest that Cbl-b is a negative regulator of macrophage activation, and that macrophage activation by Cbl-b deficiency, at least in part, contributes to the peripheral insulin resistance and glucose intolerance

Polyphenols prevent clinorotation-induced expression of atrogenes in mouse C2C12 skeletal myotubes

Oxidative stress is a key factor in stimulating the expression of atrogenes, which are muscle atrophy-related ubiquitin ligases, in skeletal muscle, and it induces muscle atrophy during unloading. However, the effects of antioxidative nutrients on atrogene expression have not been demonstrated. We report on the inhibitory effects of polyphenols, such as epicatechin (EC), epicatechin gallate (ECg) and epigallocatechin gallate (EGCg) and quercetin, on atrogene expression up-regulated by three dimensional (3D)-clinorotation or glucocorticoid. These treatments markedly elevated the expression of atrogenes, including atrogin-1 and MuRF-1, in mouse C2C12 myoblasts and myotubes. Interestingly, EC, ECg, EGCg and quercetin significantly decreased the expression of atrogin-1 and MuRF-1 up-regulated by 3D-clinorotation, whereas they hardly affected atrogene expression induced by dexamethasone. ERK signaling is a well known MAPK pathway to mediate oxidative stress. Therefore, we also investigated the effect of these polyphenols on phosphorylation of ERK in C2C12 myotubes. As expected, EC, ECg, EGCg, and quercetin significantly suppressed phosphorylation of ERK, corresponding to the up-regulation of atrogenes induced by 3D-clinorotation. These results suggest that antioxidative nutrients, such as catechins and quercetin, suppress atrogene expression in skeletal muscle cells, possibly through the inhibition of ERK signaling. Thus, catechins and quercetin may prevent unloading-mediated muscle atrophy

Reduced expression of somatostatin in GABAergic interneurons derived from induced pluripotent stem cells of patients with parkin mutations

Abstract Parkinson’s disease (PD) is associated with both motor and non-motor symptoms, including constipation, sensory neuropathy, depression, dementia and sleep disorder. Somatostatin (SST) is considered to be a modulator of GABAergic inhibitory transmission, and its levels are reduced in cerebrospinal fluid of PD patients. In the present study, we evaluated the changes in the expression of SST in GABAergic neurons derived from induced pluripotent stem cells (iPSCs) of PD patients. Neural cells were co-treated with the Wnt antagonist IWP-2 and Shh during neurosphere formation to induce GABA-positive forebrain interneurons. Quantitative analyses showed no significant differences, but slight decreases, in the potency of differentiation into GABAergic neurons derived from iPSCs between healthy control and patients with PARK2 mutations, who have been classified as a type of early-onset familial PD due to mutations in the parkin gene. Under this condition, the mRNA level of SST in GABAergic interneurons derived from iPSCs of PARK2-specific PD patients significantly decreased as neural maturation progressed. We also found that SST-positive GABAergic neurons were clearly reduced in GABAergic neurons derived from iPSCs of patients with PARK2 mutations. These findings suggest that the reduction in the expression level of SST in GABAergic interneurons of PD may, at least partly, lead to complex PD-induced symptoms

Hemosiderin-Laden Macrophages in Bronchoalveolar Lavage: Predictive Role for Acute Exacerbation of Idiopathic Interstitial Pneumonias

Background. Hemosiderin-laden macrophages (HLMs) have been identified in the bronchoalveolar lavage fluid (BALF) of patients with idiopathic pulmonary fibrosis (IPF). This retrospective study examined the ability of HLMs in BALF to predict the acute exacerbation (AE) of chronic idiopathic interstitial pneumonias (IIPs). Methods. Two hundred and twenty-one patients with IIP diagnosed by bronchoscopy were enrolled in the study (IPF, n = 87; IIPs other than IPF, n = 134). Giemsa stain was used to detect HLMs in BALF specimens. Prussian blue stain was used to quantify HLMs in BALF, and a hemosiderin score (HS) was given to the specimens containing HLMs. Results. Twenty-four patients had a positive HS (range: 7‒132). The receiver-operating characteristic curve analysis identified the cutoff HS value for predicting the AE of IIPs to be 61.5. Seven cases had a higher HS (≥61.5) and 214 had a lower HS. AE occurred significantly earlier in the higher HS group (4/7 cases) than in the lower HS group (41/214 cases) during a median observation period of 1239 days (log-rank test, p = 0.026). Multivariate Cox proportional hazard regression analysis showed that a higher HS was a significant predictor of AE in addition to IPF, percent predicted forced vital capacity, and modified Medical Research Council score. The C-statistics for the prediction of AE did not significantly improve by all the above parameters with HS as compared without HS. Conclusions. A higher HS was a significant predictor of AE in IIPs but did not significantly improve the predictive ability of other parameters

Current Perspectives on Neonatal Screening for Propionic Acidemia in Japan: An Unexpectedly High Incidence of Patients with Mild Disease Caused by a Common PCCB Variant

Propionic acidemia (PA) is a disorder of organic acid metabolism which typically presents with acute encephalopathy-like symptoms associated with metabolic acidosis and hyperammonemia during the neonatal period. The estimated incidence of symptomatic PA in Japan is 1/400,000. The introduction of neonatal screening using tandem mass spectrometry has revealed a far higher disease frequency of approximately 1/45,000 live births due to a prevalent variant of c.1304T>C (p.Y435C) in PCCB, which codes β-subunit of propionyl-CoA carboxylase. Our questionnaire-based follow-up study reveals that most of these patients remain asymptomatic. However, reports on symptomatic patients exhibiting cardiac complications such as cardiomyopathy and QT prolongation have been increasing. Moreover, there were even cases in which these cardiac complications were the only symptoms related to PA. A currently ongoing study is investigating the risk of cardiac complications in patients with neonatal screening-detected PA caused by this common variant