Vaccinia-Related Kinase 2 Mediates Accumulation of Polyglutamine Aggregates via Negative Regulation of the Chaperonin TRiC

Misfolding of proteins containing abnormal expansions of polyglutamine (polyQ) repeats is associated with cytotoxicity in several neurodegenerative disorders, including Huntington's disease. Recently, the eukaryotic chaperonin TRiC hetero-oligomeric complex has been shown to play an important role in protecting cells against the accumulation of misfolded polyQ protein aggregates. It is essential to elucidate how TRiC function is regulated to better understand the pathological mechanism of polyQ aggregation. Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not. Interestingly, VRK2-mediated downregulation of TRiC increased aggregate formation of a polyQ-expanded huntingtin fragment. This effect was ameliorated by rescue of TRiC protein levels. Notably, small interference RNA-mediated knockdown of VRK2 enhanced TRiC protein stability and decreased polyQ aggregation. The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.open118Ysciescopu

Dissociation Between the Growing Opioid Demands and Drug Policy Directions Among the U.S. Older Adults with Degenerative Joint Diseases

We aim to examine temporal trends of orthopedic operations and opioid-related hospital stays among seniors in the nation and states of Oregon and Washington where marijuana legalization was accepted earlier than any others. As aging society advances in the United States (U.S.), orthopedic operations and opioid-related hospital stays among seniors increase in the nation. A serial cross-sectional cohort study using the healthcare cost and utilization project fast stats from 2006 through 2015 measured annual rate per 100,000 populations of orthopedic operations by age groups (45–64 vs 65 and older) as well as annual rate per 100,000 populations of opioid-related hospital stays among 65 and older in the nation, Oregon and Washington states from 2008 through 2017. Orthopedic operations (knee arthroplasty, total or partial hip replacement, spinal fusion or laminectomy) and opioid-related hospital stays were measured. The compound annual growth rate (CAGR) was used to quantify temporal trends of orthopedic operations by age groups as well as opioid-related hospital stays and was tested by Rao–Scott correction of χ2 for categorical variables. The CAGR (4.06%) of orthopedic operations among age 65 and older increased (P...) (See full abstract in article

Frequency Coordination Between Adjacent Carriers Of Two CDMA Operators

Frequency coordination is the process that assigns frequency bands to neighboring or coexisting systems to minimize interference. This interference is caused by unwanted signals from adjacent frequency bands. Especially, interference is maximized by the spatial near-far problem which occurs in case two different cellular systems serve. This critical case happens when different cellular operators using the adjacent carriers do not collocate their base stations (BS). In this paper, we investigate the frequency coordination when two CDMA operators using adjacent CDMA carriers don\u27t collocate their BS. In order to lessen the unwanted interference, we put the guard band which separates adjacent carriers. This paper presents the simulation and laboratory test results to analyze the guard bandwidth requirement. For guard band simulation, we derive theoretical interference prediction models which calculate the quantity of unwanted interference. Additionally, this paper confirms the accuracy of the theoretical models with a series of laboratory test. The results in this paper assert the necessity for the guard band and discover the relation between the amount of that and the service quality

Effect of Crystallization Modes in TIPS-Pentacene/Insulating Polymer Blends on the Gas Sensing Properties of Organic Field-Effect Transistors

Blending organic semiconductors with insulating polymers has been known to be an effective way to overcome the disadvantages of single-component organic semiconductors for high-performance organic field-effect transistors (OFETs). We show that when a solution processable organic semiconductor (6,13-bis(triisopropylsilylethynyl)pentacene, TIPS-pentacene) is blended with an insulating polymer (PS), morphological and structural characteristics of the blend films could be significantly influenced by the processing conditions like the spin coating time. Although vertical phase-separated structures (TIPS-pentacene-top/PS-bottom) were formed on the substrate regardless of the spin coating time, the spin time governed the growth mode of the TIPS-pentacene molecules that phase-separated and crystallized on the insulating polymer. Excess residual solvent in samples spun for a short duration induces a convective flow in the drying droplet, thereby leading to one-dimensional (1D) growth mode of TIPS-pentacene crystals. In contrast, after an appropriate spin-coating time, an optimum amount of the residual solvent in the film led to two-dimensional (2D) growth mode of TIPS-pentacene crystals. The 2D spherulites of TIPS-pentacene are extremely advantageous for improving the field-effect mobility of FETs compared to needle-like 1D structures, because of the high surface coverage of crystals with a unique continuous film structure. In addition, the porous structure observed in the 2D crystalline film allows gas molecules to easily penetrate into the channel region, thereby improving the gas sensing properties

Activation of PERK Signaling Attenuates Aβ-Mediated ER Stress

Alzheimer's disease (AD) is characterized by the deposition of aggregated beta-amyloid (Aβ), which triggers a cellular stress response called the unfolded protein response (UPR). The UPR signaling pathway is a cellular defense system for dealing with the accumulation of misfolded proteins but switches to apoptosis when endoplasmic reticulum (ER) stress is prolonged. ER stress is involved in neurodegenerative diseases including AD, but the molecular mechanisms of ER stress-mediated Aβ neurotoxicity still remain unknown. Here, we show that treatment of Aβ triggers the UPR in the SK-N-SH human neuroblastoma cells. Aβ mediated UPR pathway accompanies the activation of protective pathways such as Grp78/Bip and PERK-eIF2α pathway, as well as the apoptotic pathways of the UPR such as CHOP and caspase-4. Knockdown of PERK enhances Aβ neurotoxicity through reducing the activation of eIF2α and Grp8/Bip in neurons. Salubrinal, an activator of the eIF2α pathway, significantly increased the Grp78/Bip ER chaperone resulted in attenuating caspase-4 dependent apoptosis in Aβ treated neurons. These results indicate that PERK-eIF2α pathway is a potential target for therapeutic applications in neurodegenerative diseases including AD

Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine

Despite growing interest and a recent surge in papers, the role of autophagy in glucose and lipid metabolism is unclear. We produced mice with skeletal muscle–specific deletion of Atg7 (encoding autophagy-related 7). Unexpectedly, these mice showed decreased fat mass and were protected from diet-induced obesity and insulin resistance; this phenotype was accompanied by increased fatty acid oxidation and browning of white adipose tissue (WAT) owing to induction of fibroblast growth factor 21 (Fgf21). Mitochondrial dysfunction induced by autophagy deficiency increased Fgf21 expression through induction of Atf4, a master regulator of the integrated stress response. Mitochondrial respiratory chain inhibitors also induced Fgf21 in an Atf4-dependent manner. We also observed induction of Fgf21, resistance to diet-induced obesity and amelioration of insulin resistance in mice with autophagy deficiency in the liver, another insulin target tissue. These findings suggest that autophagy deficiency and subsequent mitochondrial dysfunction promote Fgf21 expression, a hormone we consequently term a 'mitokine', and together these processes promote protection from diet-induced obesity and insulin resistance

The Effects of Immobilization Stress on the Synthesis and the Catabolism of Dopamine and Norepinephrine in the Rat Hypothalamus

Immobilization stress was adopted as a prototype stress model for studying the effects of stress on dopaminergic and noradrenergic neuronal activity in the rat hypothalamus. Norepinephrine content was significantly increased after 4 hours of immobilization stress. Also, the turnover rates of both dopamine and norepinephrine were found to be significantly increased after the stress, providing the evidence of increased synthesis rates of both neurotransmitters. These findings were consistent with the increase in plasma corticosterone and catecholamine levels. The activities of tyrosine hydroxylase and dopamine-j1-hydroxylase, the synthesizing enzymes for catecholamines, were significantly increased after the stress, while that of monoamine oxidase, the catabolizing enzyme, did not change to a significant degree at all. Kinetic analysis of tyrosine hydroxylase, the rate-limiting step in catecholamine biosynthesis, revealed that Vmax was significantly increased after the stress without significant change of Km. These findings suggest that dopamine and norepinephrine may playa significant role in mediating stress responses by increasing their neuronal activities