Effect of Physical Changes in Aging on Driving Performance

The growing population of older drivers has led to societal demands for the development of technologies better suited to the characteristics of older people. One effective way of addressing this situation is to examine closely the structure that causes the performance of older drivers and then use that information to develop technologies. As the first step toward understanding that structure in this research, an attempt was made to identify significant elements of the structure from a human factors standpoint in order to pursue this approach efficiently. A questionnaire survey, an observation of driving behavior and an interview survey were conducted with older drivers. The most significant perspectives on driving were extracted from the results. Tests were then conducted with a driving simulator to verify those perspectives. Based on the surveys and tests, two significant characteristics were identified concerning the influence of aging on driving behavior. One concerns the disintegration of the stimulus-perception-cognition-response system and the other concerns the transition in attention

時間依存的阻害を考慮した薬物トランスポーターOATPの関与する薬物相互作用予測

13301甲第5081号博士（創薬科学）金沢大学博士論文要旨Abstract 要約Outline 以下に掲載：1. Journal of Pharmaceutical Sciences 105(7) pp.2231-2239 2016. ELSEVIER. 共著者：Taguchi T, Masuo Y, Kogi T, Nakamichi N, Kato Y 2. Drug Metabolism and Pharmacokinetics 34(6) pp.372-379 2019. ELSEVIER. 共著者：Taguchi T, Masuo Y, Sakai Y, Kato

Linking the beneficial effects of current therapeutic approaches in diabetes to the vascular endothelin system

The rising epidemic of diabetes worldwide is of significant concern. Although the ultimate objective is to prevent the development and find a cure for the disease, prevention and treatment of diabetic complications is very important. Vascular complications in diabetes, or diabetic vasculopathy, include macro- and microvascular dysfunction and represent the principal cause of morbidity and mortality in diabetic patients. Endothelial dysfunction plays a pivotal role in the development and progression of diabetic vasculopathy. Endothelin-1 (ET-1), an endothelial cell-derived peptide, is a potent vasoconstrictor with mitogenic, pro-oxidative and pro-inflammatory properties that are particularly relevant to the pathophysiology of diabetic vasculopathy. Overproduction of ET-1 is reported in patients and animal models of diabetes and the functional effects of ET-1 and its receptors are also greatly altered in diabetic conditions. The current therapeutic approaches in diabetes include glucose lowering, sensitization to insulin, reduction of fatty acids and vasculoprotective therapies. However, whether and how these therapeutic approaches affect the ET-1 system remain poorly understood. Accordingly, in the present review, we will focus on experimental and clinical evidence that indicates a role for ET-1 in diabetic vasculopathy and on the effects of current therapeutic approaches in diabetes on the vascular ET-1 system

Activation of neurogenesis in the hippocampus is a novel therapeutic target for Alzheimer's disease

Highlights: Targeting single mechanisms of physiological (aging) and pathological (neurodegeneration) loss of function in the brain may not be sufficient. Cell–cell interactions between transplanted adult stem cells and resident cells via gap junctions have the potential to support the aging or diseased brain. These cell–cell interactions can also increase hippocampal neurogenesis. This may be a novel therapeutic strategy for Alzheimer's disease and other neurodegenerative diseases that could be applied alongside any established treatments

Functional expression of carnitine/organic cation transporter OCTN1 in mouse brain neurons: Possible involvement in neuronal differentiation

The aim of the present study is to clarify the functional expression and physiological role in brain neurons of carnitine/organic cation transporter OCTN1/SLC22A4, which accepts the naturally occurring antioxidant ergothioneine (ERGO) as a substrate in vivo. After intracerebroventricular administration, the distribution of [ 3H]ERGO in several brain regions of octn1 -/- mice was much lower than that in wild-type mice, whereas extracellular marker [ 14C]mannitol exhibited similar distribution in the two strains. The [ 3H]ERGO distribution in wild-type mice was well correlated with the amount of ERGO derived from food intake and the OCTN1 mRNA level in each brain region. Immunohistochemical analysis revealed colocalization of OCTN1 with neuronal cell markers microtubule-associated protein 2 (MAP2) and βIII-tubulin in mouse brain and primary cultured cortical neurons, respectively. Moreover, cultured cortical neurons exhibited time-dependent and saturable uptake of [ 3H]ERGO. These results demonstrate that OCTN1 is functionally expressed in brain neurons. The addition of ERGO simultaneously with serum to culture medium of cortical neurons attenuated mRNA and protein expressions of MAP2, βIII-tubulin and synapse formation marker synapsin I, and induced those of sex determining region Y-box 2 (Sox2), which is required to maintain the properties of undifferentiated neural stem cells. In neuronal model Neuro2a cells, knockdown of OCTN1 by siRNA reduced the uptake of [ 3H]ERGO with concomitant up-regulation of oxidative stress marker HO-1 and Sox2, and down-regulation of neurite outgrowth marker GAP43. Interestingly, the siRNA knockdown decreased the number of differentiated Neuro2a cells showing long neurites, but increased the total number of cells. Thus, OCTN1 is involved in cellular differentiation, but inhibits their proliferation, possibly via the regulation of cellular oxidative stress. This is the first evidence that OCTN1 plays a role in neuronal differentiation and proliferation, which are required for brain development. Crown Copyright © 2012

Identification of glycosylation genes and glycosylated amino acids of flagellin in Pseudomonas syringae pv. tabaci

A glycosylation island is a genetic region required for glycosylation. The glycosylation island of flagellin in Pseudomonas syringae pv. tabaci 6605 consists of three orfs: orf1, orf2 and orf3. Orf1 and orf2 encode putative glycosyltransferases, and their deletion mutants, Delta orf1 and Delta orf2, exhibit deficient flagellin glycosylation or produce partially glycosylated flagellin respectively. Digestion of glycosylated flagellin from wild-type bacteria and non-glycosylated flagellin from Delta orf1 mutant using aspartic N-peptidase and subsequent HPLC analysis revealed candidate glycosylated amino acids. By generation of site-directed Ser/Ala-substituted mutants, all glycosylated amino acid residues were identified at positions 143, 164, 176, 183, 193 and 201. Matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry (MS) analysis revealed that each glycan was about 540 Da. While all glycosylation-defective mutants retained swimming ability, swarming ability was reduced in the Delta orf1, Delta orf2 and Ser/Ala-substituted mutants. All glycosylation mutants were also found to be impaired in the ability to adhere to a polystyrene surface and in the ability to cause disease in tobacco. Based on the predicted tertiary structure of flagellin, S176 and S183 are expected to be located on most external surface of the flagellum. Thus the effect of Ala-substitution of these serines is stronger than that of other serines. These results suggest that glycosylation of flagellin in P. syringae pv. tabaci 6605 is required for bacterial virulence. It is also possible that glycosylation of flagellin may mask elicitor function of flagellin molecule

Postmortem Quantitative Analysis of Prion Seeding Activity in the Digestive System

Human prion diseases are neurodegenerative disorders caused by prion protein. Although infectivity was historically detected only in the central nervous system and lymphoreticular tissues of patients with sporadic Creutzfeldt-Jakob disease, recent reports suggest that the seeding activity of Creutzfeldt-Jakob disease prions accumulates in various non-neuronal organs including the liver, kidney, and skin. Therefore, we reanalyzed autopsy samples collected from patients with sporadic and genetic human prion diseases and found that seeding activity exists in almost all digestive organs. Unexpectedly, activity in the esophagus reached a level of prion seeding activity close to that in the central nervous system in some CJD patients, indicating that the safety of endoscopic examinations should be reconsidered

Trapping of CDC42 C-terminal variants in the Golgi drives pyrin inflammasome hyperactivation

CDC42-C末端異常症に於ける炎症病態を解明 --ゴルジ体への異常蓄積がパイリンインフラマソーム形成を過剰促進--. 京都大学プレスリリース. 2022-05-02.Mutations in the C-terminal region of the CDC42 gene cause severe neonatal-onset autoinflammation. Effectiveness of IL-1β–blocking therapy indicates that the pathology involves abnormal inflammasome activation; however, the mechanism underlying autoinflammation remains to be elucidated. Using induced-pluripotent stem cells established from patients carrying CDC42[R186C], we found that patient-derived cells secreted larger amounts of IL-1β in response to pyrin-activating stimuli. Aberrant palmitoylation and localization of CDC42[R186C] protein to the Golgi apparatus promoted pyrin inflammasome assembly downstream of pyrin dephosphorylation. Aberrant subcellular localization was the common pathological feature shared by CDC42 C-terminal variants with inflammatory phenotypes, including CDC42[*192C*24] that also localizes to the Golgi apparatus. Furthermore, the level of pyrin inflammasome overactivation paralleled that of mutant protein accumulation in the Golgi apparatus, but not that of the mutant GTPase activity. These results reveal an unexpected association between CDC42 subcellular localization and pyrin inflammasome activation that could pave the way for elucidating the mechanism of pyrin inflammasome formation