p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response

Autophagy contributes to the selective degradation of liquid droplets, including the P-Granule, Ape1-complex and p62/SQSTM1-body, although the molecular mechanisms and physiological relevance of selective degradation remain unclear. In this report, we describe the properties of endogenous p62-bodies, the effect of autophagosome biogenesis on these bodies, and the in vivo significance of their turnover. p62-bodies are low-liquidity gels containing ubiquitin and core autophagy-related proteins. Multiple autophagosomes form on the p62-gels, and the interaction of autophagosome-localizing Atg8-proteins with p62 directs autophagosome formation toward the p62-gel. Keap1 also reversibly translocates to the p62-gels in a p62-binding dependent fashion to activate the transcription factor Nrf2. Mice deficient for Atg8-interaction-dependent selective autophagy show that impaired turnover of p62-gels leads to Nrf2 hyperactivation in vivo. These results indicate that p62-gels are not simple substrates for autophagy but serve as platforms for both autophagosome formation and anti-oxidative stress. Liquid-liquid phase separation of p62/SQSTM1 has been previously described, although the significance in vivo remains unclear. Here the authors show p62 droplets contain ubiquitin, autophagy-related proteins and Keap1 to serve as platform of not only autophagosome formation but also Nrf2 activation.Peer reviewe

Glutamatergic neurometabolite levels in the caudate are associated with the ability of rhythm production

IntroductionGlutamatergic neurometabolites play important roles in the basal ganglia, a hub of the brain networks involved in musical rhythm processing. We aimed to investigate the relationship between rhythm processing abilities and glutamatergic neurometabolites in the caudate.MethodsWe aquired Glutamatergic function in healthy individuals employing proton magnetic resonance spectroscopy. We targeted the right caudate and the dorsal anterior cingulate cortex (dACC) as a control region. Rhythm processing ability was assessed by the Harvard Beat Assessment Test (H-BAT).ResultsWe found negative correlations between the production part of the Beat Saliency Test in the H-BAT and glutamate and glutamine levels in the caudate (r = −0.693, p = 0.002) whereas there was no such association in the dACC.ConclusionThese results suggest that higher glutamatergic neurometabolite levels in the caudate may contribute to rhythm processing, especially the ability to produce meter in music precisely

High Energy Particle Measurements during Long Discharge in LHD

The spatial resolved energy spectra can be observed during a long discharge of NBI plasma bycontinuously scanning the neutral particle analyzer. In these discharges, the plasmas are initiated by the ECH heating, after that NBI#2 (Co-injection) sustains the plasma during 40-60 seconds. The scanned pitch angle is from 44 degrees to 74 degrees. The injected neutral beam (hydrogen) energy of NBI#2 is only 130 keV because the original ion source polarity is negative. The shape of spectra is almost similar from 44 degrees to 53 degrees. However the spectra from 55 degrees are strongly varied. It reflects the injection pitch angle of the beam according to the simulation (53 degrees ot R* = 3.75 m in simulation). The beam keeps the pitch angle at incidence until the beam energy becomes to the energy, which the pitch angle scattering is occurred by the energy loss due to the electron collision. The low flux region can be observed around 10-15 keV, which is 15 times of the electron temperature. The energy region may be equal to the energy at which the pitch angle scattering is occurred. At the energy, the particle is scattered by the collision with the plasma ions and some of particles may run away from the plasma because they have a possibility to enter the loss cone. According to the simulation, the loss cone can be expected at the 10 keV with the small angular dependence. The depth of the loss cone is deep at the small pitch angle. The hollow in the spectrum may be concluded to be the loss cone as the tendency is almost agreed with the experimental result

Impurity emission characteristics of long pulse discharges in Large Helical Device

Line spectra from intrinsic impurity ions have been monitored during the three kinds of long-pulse discharges (ICH, ECH, NBI). Constant emission from the iron impurity shows no preferential accumulation of iron ion during the long-pulse operations. Stable Doppler ion temperature has been also measured from Fe XX, C V and C III spectra

Twenty-Seven Years of Phase III Trials for Patients with Extensive Disease Small-Cell Lung Cancer: Disappointing Results

BACKGROUND: Few studies have formally assessed whether treatment outcomes have improved substantially over the years for patients with extensive disease small-cell lung cancer (ED-SCLC) enrolled in phase III trials. The objective of the current investigation was to determine the time trends in outcomes for the patients in those trials. METHODS AND FINDINGS: We searched for trials that were reported between January 1981 and August 2008. Phase III randomized controlled trials were eligible if they compared first-line, systemic chemotherapy for ED-SCLC. Data were evaluated by using a linear regression analysis. RESULTS: In total, 52 trials were identified that had been initiated between 1980 and 2006; these studies involved 10,262 patients with 110 chemotherapy arms. The number of randomized patients and the proportion of patients with good performance status (PS) increased over time. Cisplatin-based regimens, especially cisplatin and etoposide (PE) regimen, have increasingly been studied, whereas cyclophosphamide, doxorubicin, and vincristine-based regimens have been less investigated. Multiple regression analysis showed no significant improvement in survival over the years. Additionally, the use of a PE regimen did not affect survival, whereas the proportion of patients with good PS and the trial design of assigning prophylactic cranial irradiation were significantly associated with favorable outcome. CONCLUSIONS AND SIGNIFICANCE: The survival of patients with ED-SCLC enrolled in phase III trials did not improve significantly over the years, suggesting the need for further development of novel targets, newer agents, and comprehensive patient care

p62/SQSTM1-droplet serves as a platform for autophagosome formation and anti-oxidative stress response

Autophagy contributes to the selective degradation of liquid droplets, including the P-Granule, Ape1-complex and p62/SQSTM1-body, although the molecular mechanisms and physiological relevance of selective degradation remain unclear. In this report, we describe the properties of endogenous p62-bodies, the effect of autophagosome biogenesis on these bodies, and the in vivo significance of their turnover. p62-bodies are low-liquidity gels containing ubiquitin and core autophagy-related proteins. Multiple autophagosomes form on the p62-gels, and the interaction of autophagosome-localizing Atg8-proteins with p62 directs autophagosome formation toward the p62-gel. Keap1 also reversibly translocates to the p62-gels in a p62-binding dependent fashion to activate the transcription factor Nrf2. Mice deficient for Atg8-interaction-dependent selective autophagy show that impaired turnover of p62-gels leads to Nrf2 hyperactivation in vivo. These results indicate that p62-gels are not simple substrates for autophagy but serve as platforms for both autophagosome formation and anti-oxidative stress

Bonding of different self-adhesive resins to high-strength composite resin block treated with surface conditioning

Purpose: This study aimed to evaluate the effects of chemical conditioning and self-adhesive resins (SARs)on the bonding of mechanically conditioned high-strength composite resin block (HSCRB). Methods: Eighteen sections of HSCRB (KZR-CAD HR 3 Gammatheta, Yamakin) were treated with alumina air abrasion and randomly divided into 3 groups according to the SARs for bonding: RelyX Unicem 2 (RXU), SA Luting Plus (SAL), and G-Cem ONE (GCO). The sections were further divided into 3 subgroups according to the chemical conditioning of the adherend surfaces: no conditioning (C), universal adhesive (UA), and a mixture of γ-MPTS and 10-MDP (MM). After the surface conditioning, the sections were cemented with the SARs. Each cemented section was cut into 40 beams. Half of the beams were thermocycled (4 °C/60 °C, 10,000 cycles). The micro-tensile bond strength (μTBS) values were measured using a universal testing machine.Scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), contact angles, and surface roughness measurements were performed on the adherend surfaces of each subgroup.Results: RXU showed the highest μTBS values among the 3 SARs tested, while MM application exhibited the highest μTBS values among the 3 chemical conditioning methods tested. After thermocycling, the samples in the RXU/MM, RXU/UA, and GCO/MM groups showed no significant changes in the μTBS values,whereas the others showed a significant reduction. Conclusions: The bond strength of HSCRB was influenced by the chemical conditioning, SARs, and aging. γ-MPTS and 10-MDP application yielded higher μTBS values of mechanically treated HSCRB than the UA

Recent Results from LHD Experiment with Emphasis on Relation to Theory from Experimentalist’s View

he Large Helical Device (LHD) has been extending an operational regime of net-current free plasmas towardsthe fusion relevant condition with taking advantage of a net current-free heliotron concept and employing a superconducting coil system. Heating capability has exceeded 10 MW and the central ion and electron temperatureshave reached 7 and 10 keV, respectively. The maximum value of β and pulse length have been extended to 3.2% and 150 s, respectively. Many encouraging physical findings have been obtained. Topics from recent experiments, which should be emphasized from the aspect of theoretical approaches, are reviewed. Those are (1) Prominent features in the inward shifted configuration, i.e., mitigation of an ideal interchange mode in the configuration with magnetic hill, and confinement improvement due to suppression of both anomalous and neoclassical transport, (2) Demonstration ofbifurcation of radial electric field and associated formation of an internal transport barrier, and (3) Dynamics of magnetic islands and clarification of the role of separatrix