The Png1–Rad23 complex regulates glycoprotein turnover

Misfolded proteins in the endoplasmic reticulum (ER) are destroyed by a pathway termed ER-associated protein degradation (ERAD). Glycans are often removed from glycosylated ERAD substrates in the cytosol before substrate degradation, which maintains the efficiency of the proteasome. Png1, a deglycosylating enzyme, has long been suspected, but not proven, to be crucial in this process. We demonstrate that the efficient degradation of glycosylated ricin A chain requires the Png1–Rad23 complex, suggesting that this complex couples protein deglycosylation and degradation. Rad23 is a ubiquitin (Ub) binding protein involved in the transfer of ubiquitylated substrates to the proteasome. How Rad23 achieves its substrate specificity is unknown. We show that Rad23 binds various regulators of proteolysis to facilitate the degradation of distinct substrates. We propose that the substrate specificity of Rad23 and other Ub binding proteins is determined by their interactions with various cofactors involved in specific degradation pathways

The association between continuous polypharmacy and hospitalization, emergency department visits, and death in older adults: a nationwide large cohort study

BackgroundThis study aimed to investigate the association between continuous polypharmacy and hospitalization, emergency department (ED) visits, and death.MethodsThis retrospective study utilized 6,443,896 patients aged between 65 and 84 years of National Health Insurance claims data from 2016 to 2018. Polypharmacy and excessive polypharmacy were defined as the concurrent use of 5 or more and 10 or more medications, respectively, for durations of both 90 days or more and 180 days or more within a 1-year observation period. The primary outcome measures included all-cause hospitalization, ED visits, and mortality. Multiple logistic regression models were used adjusting for patients’ general characteristics, comorbidities, and history of hospitalization or ED visits.ResultsAmong 2,693,897 patients aged 65–84 years who had used medicines for 180 days or more (2,955,755 patients taking medicines for 90 days or more), the adverse outcomes were as follows: 20.5% (20.3%) experienced hospitalization, 10.9% (10.8%) visited the ED, and 1% (1%) died, respectively. In patients who exhibited polypharmacy for more than 180 days, the adjusted odds ratio of adverse outcomes was 1.32 (95% confidence interval [CI], 1.31–1.33) for hospitalization, 1.32 (95% CI, 1.31–1.33) for ED visits, 1.63 (95% CI, 1.59–1.67) for death, and that in excessive polypharmacy patients for more than 180 days was 1.85 for hospitalization, 1.92 for ED visits, and 2.57 for death, compared to non-polypharmacy patients.ConclusionOur results suggest that polypharmacy in older adults might lead to negative health consequences. Thus, interventions to optimize polypharmacy may need to be implemented

Moyamoya disease patient mutations in the RING domain of RNF213 reduce its ubiquitin ligase activity and enhance NFκB activation and apoptosis in an AAA+ domain-dependent manner

Moyamoya disease (MMD) is a cerebrovascular disease characterized by progressive occlusion of the internal carotid arteries. Genetic studies originally identified RNF213 as an MMD susceptibility gene that encodes a large 591 kDa protein with a functional RING domain and dual AAA+ ATPase domains. As the functions of RNF213 and its relationship to MMD onset are unknown, we set out to characterize the ubiquitin ligase activity of RNF213, and the effects of MMD patient mutations on these activities and on other cellular processes. In vitro ubiquitination assays, using the RNF213 RING domain, identified Ubc13/Uev1A as a key ubiquitin conjugating enzyme that together generate K63-linked polyubiquitin chains. However, nearly all MMD patient mutations in the RING domain greatly reduced this activity. When full-length proteins were overexpressed in HEK293T cells, patient mutations that abolished the ubiquitin ligase activities conversely enhanced nuclear factor κB (NFκB) activation and induced apoptosis accompanied with Caspase-3 activation. These induced activities were dependent on the RNF213 AAA+ domain. Our results suggest that the NFκB- and apoptosis-inducing functions of RNF213 may be negatively regulated by its ubiquitin ligase activity and that disruption of this regulation could contribute towards MMD onset

Electrophysiologic Assessment of Central Auditory Processing by Auditory Brainstem Responses in Children with Autism Spectrum Disorders

In addition to aberrant features in the speech, children with Autism Spectrum Disorder (ASD) may present unusual responses to sensory stimuli, especially to auditory stimuli. We investigated the auditory ability of children with ASD by using Auditory Brainstem Responses (ABR) as they can directly judge both hearing status and the integrity of auditory brainstem pathways. One hundred twenty-one children (71: ASD; M 58/F 13, mean age; 41.8 months, 50: control group; M 41/F 9, mean age; 38 months) were induded in the study. As compared with the values in the control group, the latency of wave V, wave I-V, and wave III-V inter-peak latencies were significantly prolonged (p<0.05) in the ASD group. The findings indicate that children with ASD have a dysfunction or immaturity of the central auditory nervous system. We suggest any children with prolonged III-V inter-peak latencies, especially high functioning children should be further evaluated for central auditory processing to set up a more appropriate treatment plan

Resting-state prefrontal EEG biomarker in correlation with postoperative delirium in elderly patients

Postoperative delirium (POD) is associated with adverse outcomes in elderly patients after surgery. Electroencephalography (EEG) can be used to develop a potential biomarker for degenerative cerebral dysfunctions, including mild cognitive impairment and dementia. This study aimed to explore the relationship between preoperative EEG and POD. We included 257 patients aged &gt;70 years who underwent spinal surgery. We measured the median dominant frequency (MDF), which is a resting-state EEG biomarker involving intrinsic alpha oscillations that reflect an idle cortical state, from the prefrontal regions. Additionally, the mini-mental state examination and Montreal cognitive assessment (MoCA) were performed before surgery as well as 5 days after surgery. For long-term cognitive function follow up, the telephone interview for cognitive status™ (TICS) was performed 1 month and 1 year after surgery. Fifty-two (20.2%) patients were diagnosed with POD. A multivariable logistic regression analysis that included age, MoCA score, Charlson comorbidity index score, Mini Nutritional Assessment, and the MDF as variables revealed that the MDF had a significant odds ratio of 0.48 (95% confidence interval 0.27–0.85). Among the patients with POD, the postoperative neurocognitive disorders could last up to 1 year. Low MDF on preoperative EEG was associated with POD in elderly patients undergoing surgery. EEG could be a novel potential tool for identifying patients at a high risk of POD

Cross-National Differences in Victimization : Disentangling the Impact of Composition and Context

Varying rates of criminal victimization across countries are assumed to be the outcome of countrylevel structural constraints that determine the supply ofmotivated o¡enders, as well as the differential composition within countries of suitable targets and capable guardianship. However, previous empirical tests of these ‘compositional’ and ‘contextual’ explanations of cross-national di¡erences have been performed upon macro-level crime data due to the unavailability of comparable individual-level data across countries. This limitation has had two important consequences for cross-national crime research. First, micro-/meso-level mechanisms underlying cross-national differences cannot be truly inferred from macro-level data. Secondly, the e¡ects of contextual measures (e.g. income inequality) on crime are uncontrolled for compositional heterogeneity. In this paper, these limitations are overcome by analysing individual-level victimization data across 18 countries from the International CrimeVictims Survey. Results from multi-level analyses on theft and violent victimization indicate that the national level of income inequality is positively related to risk, independent of compositional (i.e. micro- and meso-level) di¡erences. Furthermore, crossnational variation in victimization rates is not only shaped by di¡erences in national context, but also by varying composition. More speci¢cally, countries had higher crime rates the more they consisted of urban residents and regions with lowaverage social cohesion.

The JCMT BISTRO Survey: multiwavelength polarimetry of bright regions in NGC 2071 in the far-infrared/submillimetre range, with POL-2 and HAWC+

Polarized dust emission is a key tracer in the study of interstellar medium and of star formation. The observed polarization, however, is a product of magnetic field structure, dust grain properties, and grain alignment efficiency, as well as their variations in the line of sight, making it difficult to interpret polarization unambiguously. The comparison of polarimetry at multiple wavelengths is a possible way of mitigating this problem. We use data from HAWC+ /SOFIA and from SCUBA-2/POL-2 (from the BISTRO survey) to analyse the NGC 2071 molecular cloud at 154, 214, and 850 μm. The polarization angle changes significantly with wavelength over part of NGC 2071, suggesting a change in magnetic field morphology on the line of sight as each wavelength best traces different dust populations. Other possible explanations are the existence of more than one polarization mechanism in the cloud or scattering from very large grains. The observed change of polarization fraction with wavelength, and the 214-to-154 μm polarization ratio in particular, are difficult to reproduce with current dust models under the assumption of uniform alignment efficiency. We also show that the standard procedure of using monochromatic intensity as a proxy for column density may produce spurious results at HAWC+wavelengths. Using both long-wavelength (POL-2, 850 μm) and short-wavelength (HAWC+, ≲200μm) polarimetry is key in obtaining these results. This study clearly shows the importance of multi-wavelength polarimetry at submillimetre bands to understand the dust properties of molecular clouds and the relationship between magnetic field and star formation

The JCMT BISTRO Survey: A Spiral Magnetic Field in a Hub-filament Structure, Monoceros R2

We present and analyze observations of polarized dust emission at 850 μm toward the central 1 7 1 pc hub-filament structure of Monoceros R2 (Mon R2). The data are obtained with SCUBA-2/POL-2 on the James Clerk Maxwell Telescope (JCMT) as part of the B-fields in Star-forming Region Observations survey. The orientations of the magnetic field follow the spiral structure of Mon R2, which are well described by an axisymmetric magnetic field model. We estimate the turbulent component of the magnetic field using the angle difference between our observations and the best-fit model of the underlying large-scale mean magnetic field. This estimate is used to calculate the magnetic field strength using the Davis–Chandrasekhar–Fermi method, for which we also obtain the distribution of volume density and velocity dispersion using a column density map derived from Herschel data and the C18O (J = 3 - 2) data taken with HARP on the JCMT, respectively. We make maps of magnetic field strengths and mass-to-flux ratios, finding that magnetic field strengths vary from 0.02 to 3.64 mG with a mean value of 1.0 \ub1 0.06 mG, and the mean critical mass-to-flux ratio is 0.47 \ub1 0.02. Additionally, the mean Alfv\ue9n Mach number is 0.35 \ub1 0.01. This suggests that, in Mon R2, the magnetic fields provide resistance against large-scale gravitational collapse, and the magnetic pressure exceeds the turbulent pressure. We also investigate the properties of each filament in Mon R2. Most of the filaments are aligned along the magnetic field direction and are magnetically subcritical