Role of S5b/PSMD5 in Proteasome Inhibition Caused by TNF-α/NFκB in Higher Eukaryotes

SummaryThe ubiquitin-proteasome system is essential for maintaining protein homeostasis. However, proteasome dysregulation in chronic diseases is poorly understood. Through genome-wide cell-based screening using 5,500 cDNAs, a signaling pathway leading to NFκB activation was selected as an inhibitor of 26S proteasome. TNF-α increased S5b (HGNC symbol PSMD5; hereafter S5b/PSMD5) expression via NFκB, and the surplus S5b/PSMD5 directly inhibited 26S proteasome assembly and activity. Downregulation of S5b/PSMD5 abolished TNF-α-induced proteasome inhibition. TNF-α enhanced the interaction of S5b/PSMD5 with S7/PSMC2 in nonproteasome complexes, and interference of this interaction rescued TNF-α-induced proteasome inhibition. Transgenic mice expressing S5b/PSMD5 exhibited a reduced life span and premature onset of aging-related phenotypes, including reduced proteasome activity in their tissues. Conversely, S5b/PSMD5 deficiency in Drosophila melanogaster ameliorated the tau rough eye phenotype, enhanced proteasome activity, and extended the life span of tau flies. These results reveal the critical role of S5b/PSMD5 in negative regulation of proteasome by TNF-α/NFκB and provide insights into proteasome inhibition in human disease

Short-Term Effects of Combined Serial Casting and Botulinum Toxin Injection for Spastic Equinus in Ambulatory Children with Cerebral Palsy

PURPOSE: The purpose of this paper is to test the hypothesis that combination therapy of serial cast and botulinum toxin type A (BTX-A) injection can further enhance the effects of a BTX-A injection in ambulant children with cerebral palsy (CP) who have an equinus foot. MATERIALS AND METHODS: Children in group A (30 legs of 21 children) received a serial casting application after an injection of BTX-A, and children in group B (25 legs of 17 children) received only a BTX-A injection. Assessments were performed before the intervention and 1 month after the intervention. RESULTS: After the intervention, there were significant improvements in tone, dynamic spasticity, and passive range of motion (ROM) in both groups. However, the changes were greater in group A than in group B. Dimension D (standing) in Gross Motor Function Measure (GMFM)-66 was significantly improved in group A but not in group B. On the other hand, there were no significant changes in dimension E (walking, running, jumping) in GMFM-66 in either group. CONCLUSION: The results of our study suggest that a serial casting application after BTX-A injection can enhance the benefits of BTX-A injection in children with cerebral palsy.ope

iPSC Modeling of Presenilin1 Mutation in Alzheimer's Disease with Cerebellar Ataxia.

Disease modeling of Alzheimer's disease (AD) has been hampered by the lack of suitable cellular models while animal models are mainly based on the overexpression of AD-related genes which often results in an overemphasis of certain pathways and is also confounded by aging. In this study, we therefore developed and used induced pluripotent stem cell (iPSC) lines from a middle-aged AD patient with a known presenilin 1 (PSEN1) mutation (Glu120Lys; PS1-E120K) and as a control, an elderly normal subject. Using this approach, we demonstrated that the extracellular accumulation of Aβ was dramatically increased in PS1-E120K iPSC-derived neurons compared with the control iPSC line. PS1-E120K iPSC-derived neurons also exhibited high levels of phosphorylated tau, as well as mitochondrial abnormalities and defective autophagy. Given that the effect of aging is lost with iPSC generation, these abnormal cellular features are therefore indicative of PSEN1-associated AD pathogenesis rather than primary changes associated with aging. Taken together, this iPSC-based approach of AD modeling can now be used to better understand AD pathogenesis as well as a tool for drug discovery.This work was supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C2746) and a grant (2016-0588) from the Asan Institute for Life Sciences

Gene Expression Profiles in Genetically Different Mice Infected with Toxoplasma gondii: ALDH1A2, BEX2, EGR2, CCL3 and PLAU

Toxoplasma gondii can modulate host cell gene expression; however, determining gene expression levels in intermediate hosts after T. gondii infection is not known much. We selected 5 genes (ALDH1A2, BEX2, CCL3, EGR2 and PLAU) and compared the mRNA expression levels in the spleen, liver, lung and small intestine of genetically different mice infected with T. gondii. ALDH1A2 mRNA expressions of both mouse strains were markedly increased at day 1-4 postinfection (PI) and then decreased, and its expressions in the spleen and lung were significantly higher in C57BL/6 mice than those of BALB/c mice. BEX2 and CCR3 mRNA expressions of both mouse strains were significantly increased from day 7 PI and peaked at day 15-30 PI (P<0.05), especially high in the spleen liver or small intestine of C57BL/6 mice. EGR2 and PLAU mRNA expressions of both mouse strains were significantly increased after infection, especially high in the spleen and liver. However, their expression patterns were varied depending on the tissue and mouse strain. Taken together, T. gondii-susceptible C57BL/6 mice expressed higher levels of these 5 genes than did T. gondii-resistant BALB/c mice, particularly in the spleen and liver. And ALDH1A2 and PLAU expressions were increased acutely, whereas BEX2, CCL3 and EGR2 expressions were increased lately. Thus, these demonstrate that host genetic factors exert a strong impact on the expression of these 5 genes and their expression patterns were varied depending on the gene or tissue

Silicon carbide-free graphene growth on silicon for lithium-ion battery with high volumetric energy density

Silicon is receiving discernable attention as an active material for next generation lithium-ion battery anodes because of its unparalleled gravimetric capacity. However, the large volume change of silicon over charge-discharge cycles weakens its competitiveness in the volumetric energy density and cycle life. Here we report direct graphene growth over silicon nanoparticles without silicon carbide formation. The graphene layers anchored onto the silicon surface accommodate the volume expansion of silicon via a sliding process between adjacent graphene layers. When paired with a commercial lithium cobalt oxide cathode, the silicon carbide-free graphene coating allows the full cell to reach volumetric energy densities of 972 and 700 Whl(-1) at first and 200th cycle, respectively, 1.8 and 1.5 times higher than those of current commercial lithium-ion batteries. This observation suggests that two-dimensional layered structure of graphene and its silicon carbide-free integration with silicon can serve as a prototype in advancing silicon anodes to commercially viable technology.

Combined Hepatic and Splenic Abscesses in a Patient with Ulcerative Colitis

Liver abscesses are very rare complications of ulcerative colitis, and furthermore, there has been only one case of splenic abscess in a patient with ulcerative colitis reported in the English literature. We recently encountered a patient with ulcerative colitis accompanied by both hepatic and splenic abscesses. The patient was treated with abscess drainage as well as sulfasalazine and antibiotics. Follow-up sonography of the abdomen showed complete resolution of the lesions. To our knowledge, this is the first report of combined case of multiple liver abscesses combined with splenic abscess in a patient with ulcerative colitis

Les déterminants des performances scolaires des élèves marocains

Le Maroc fait partie des pays en développement dont le niveau des acquis des élèves reste relativement faible. En dépit des efforts engagés en vue d’améliorer en partie la qualité des apprentissages, les résultats des enquêtes internationales et nationales révèlent de faibles niveaux des acquis. Dès lors, l’objectif de cet article est de revenir sur les facteurs qui influencent les performances scolaires des élèves. Nous nous intéressons plus spécifiquement aux déterminants microéconomiques de la qualité de l’éducation à travers les performances des élèves. Les études sur les déterminants des performances scolaires sont riches d’enseignement. Les premières contributions se sont focalisées sur le rôle de l’environnement familial dans l’explication de la réussite des élèves (Coleman, 1966, par exemple). D’autres, plus récemment, ont abordé les facteurs liés à l’établissement scolaire. Pour autant, les contributions récentes mettent en avant l’importance à la fois de l’environnement familial et de l’école (Hanushek, 2003). Des travaux plus récents oulignent également l’influence des pairs sur les performances scolaires. Le présent travail s’inscrit dans cette logique. Son originalité se situe à un double niveau. La première réside dans la mise en évidence de l’ensemble des facteurs explicatifs des performances des élèves et des inégalités scolaires. Malgré l’existence d’une littérature abondante sur le sujet, cette question n’a pas été abordée, à notre connaissance, dans le cas marocain. La seconde cherche à corriger les problèmes d’endogénéité dans les modèles multiniveaux. Enfin, La technique d’imputation adoptée permet de traiter de façon pertinente les valeurs manquantes dans les bases de données. Cet article est structuré en trois parties. La première aborde la littérature empirique sur les déterminants de la réussite scolaire des élèves. La deuxième partie examine le modèle utilisé et décrit la base de données du Programme national d’évaluation des acquis (PNEA). Elle examine l’approche et la méthodologie utilisée. Enfin, la troisième partie traite des résultats obtenus et nous permet de formuler les principaux enseignements pouvant être tirés de nos résultats en matière de politiques publiques