HEXA-018, a Novel Inducer of Autophagy, Rescues TDP-43 Toxicity in Neuronal Cells

The autophagy-lysosomal pathway is an essential cellular mechanism that degrades aggregated proteins and damaged cellular components to maintain cellular homeostasis. Here, we identified HEXA-018, a novel compound containing a catechol derivative structure, as a novel inducer of autophagy. HEXA-018 increased the LC3-I/II ratio, which indicates activation of autophagy. Consistent with this result, HEXA-018 effectively increased the numbers of autophagosomes and autolysosomes in neuronal cells. We also found that the activation of autophagy by HEXA-018 is mediated by the AMPK-ULK1 pathway in an mTOR-independent manner. We further showed that ubiquitin proteasome system impairment- or oxidative stress-induced neurotoxicity was significantly reduced by HEXA-018 treatment. Moreover, oxidative stress-induced mitochondrial dysfunction was strongly ameliorated by HEXA-018 treatment. In addition, we investigated the efficacy of HEXA-018 in models of TDP-43 proteinopathy. HEXA-018 treatment mitigated TDP-43 toxicity in cultured neuronal cell lines and Drosophila. Our data indicate that HEXA-018 could be a new drug candidate for TDP-43-associated neurodegenerative diseases.1

Comparison of carnivore, omnivore, and herbivore mammalian genomes with a new leopard assembly.

BACKGROUND: There are three main dietary groups in mammals: carnivores, omnivores, and herbivores. Currently, there is limited comparative genomics insight into the evolution of dietary specializations in mammals. Due to recent advances in sequencing technologies, we were able to perform in-depth whole genome analyses of representatives of these three dietary groups. RESULTS: We investigated the evolution of carnivory by comparing 18 representative genomes from across Mammalia with carnivorous, omnivorous, and herbivorous dietary specializations, focusing on Felidae (domestic cat, tiger, lion, cheetah, and leopard), Hominidae, and Bovidae genomes. We generated a new high-quality leopard genome assembly, as well as two wild Amur leopard whole genomes. In addition to a clear contraction in gene families for starch and sucrose metabolism, the carnivore genomes showed evidence of shared evolutionary adaptations in genes associated with diet, muscle strength, agility, and other traits responsible for successful hunting and meat consumption. Additionally, an analysis of highly conserved regions at the family level revealed molecular signatures of dietary adaptation in each of Felidae, Hominidae, and Bovidae. However, unlike carnivores, omnivores and herbivores showed fewer shared adaptive signatures, indicating that carnivores are under strong selective pressure related to diet. Finally, felids showed recent reductions in genetic diversity associated with decreased population sizes, which may be due to the inflexible nature of their strict diet, highlighting their vulnerability and critical conservation status. CONCLUSIONS: Our study provides a large-scale family level comparative genomic analysis to address genomic changes associated with dietary specialization. Our genomic analyses also provide useful resources for diet-related genetic and health research

Sublimation-Induced Gas-Reacting Process for High-Energy-Density Ni-Rich Electrode Materials

Ni-rich layered electrode materials have attracted great attention as a promising cathode candidate for high-energy-density lithium-ion batteries because of their high capacity and relatively low cost. However, they have been suffering from severe capacity fading for cycles, which can originate from several factors such as the phase transition at the end of charge and disintegration of the particles. Herein, a simple and novel sublimation-induced gas-reacting (SIGR) process has been developed by using elemental sulfur to conformally coat Ni-rich layered materials. The sublimated gas-phase S can react with detrimental residual Li compounds on the surface of the particles. As a result, the reacted layer of LixSyOz phases forms on the outside of the secondary particles and simultaneously in the boundaries between primary particles inside the secondary particles. Compared to other reported surface modification processes, the SIGR-treated Ni-rich materials show substantially increased capacity retention and superior voltage retention by protecting the surface from the electrolyte and mitigating disintegration of the secondary particles. The SIGR process is a simple and scalable solid-state reaction at low temperature to improve the cycling stability of high-capacity Ni-rich electrode materials.11Nsciescopu

Quantitative Electromyographic Analysis of Reaction Time to External Auditory Stimuli in Drug-Naïve Parkinson’s Disease

Evaluation of motor symptoms in Parkinson’s disease (PD) is still based on clinical rating scales by clinicians. Reaction time (RT) is the time interval between a specific stimulus and the start of muscle response. The aim of this study was to identify the characteristics of RT responses in PD patients using electromyography (EMG) and to elucidate the relationship between RT and clinical features of PD. The EMG activity of 31 PD patients was recorded during isometric muscle contraction. RT was defined as the time latency between an auditory beep and responsive EMG activity. PD patients demonstrated significant delays in both initiation and termination of muscle contraction compared with controls. Cardinal motor symptoms of PD were closely correlated with RT. RT was longer in more-affected side and in more-advanced PD stages. Frontal cognitive function, which is indicative of motor programming and movement regulation and perseveration, was also closely related with RT. In conclusion, greater RT is the characteristic motor features of PD and it could be used as a sensitive tool for motor function assessment in PD patients. Further investigations are required to clarify the clinical impact of the RT on the activity of daily living of patients with PD

Prevalence of potentially inappropriate medications based on the STOPPFrail criteria in frail older patients with limited life expectancy: a cross-sectional study

Background The recently developed Screening Tool of Older Persons' Prescriptions in Frail adults with a limited life expectancy (STOPPFrail) criteria can be helpful for screening medications (PIMs), but it is yet to be widely used in clinical practice. Herein, we aimed to investigate the prevalence of PIMs based on the STOPPFrail criteria (STOPPFrail-PIM) among frail older adults with limited life expectancy admitted to the geriatric center. Methods This was a retrospective cross-sectional study conducted in the geriatric center at an academic tertiary care hospital in Korea. We evaluated frail older adults with limited life expectancy who received comprehensive geriatric assessment (CGA) admitted between 1 January, 2019 and 30 June, 2020. Frail older adults with limited life expectancy were identified by geriatricians with retrospective records and the prevalence of STOPPFrail-PIMs was analysed by trained pharmacists. Descriptive analysis, t-test, and chi-square test were conducted using IBM SPSS software version 25.0. Results Among 504 older adults who underwent CGA after admission, 171 frail older adults with limited life expectancy were identified by geriatricians and included in the study. An average of 11.3 +/- 4.7 medications were administered regularly to each patient before admission. Overall, 97.1% (166/171) had at least one STOPPFrail-PIM, and the mean number of STOPPFrail-PIM was 4.2 +/- 2.8. Drugs without clear clinical indication (A2) were the most frequent pre-admission STOPPFrail-PIM, followed by lipid-lowering therapies (B1) and neuroleptic antipsychotics (D1). The number of STOPPFrail-PIM was significantly lower at discharge than that at admission, with the decrease being the highest for A2 at 94.7%. Conclusions Most frail older adults with limited life expectancy had at least one STOPPFrail-PIM at admission, and the rate of STOPPFrail-PIM decreased significantly at discharge after the geriatric multidisciplinary team care. Further studies are needed to investigate the association between the use of STOPPFrail-PIM and adverse consequences in frail older adults.N

Surface albedo from the geostationary Communication, Ocean and Meteorological Satellite (COMS)/Meteorological Imager (MI) observation system

The surface albedo is an essential climate variable that is considered in many applications used for predicting climate and understanding the mechanisms of climate change. In this study, surface albedo was estimated using a bidirectional reflectance distribution function model based on Communication, Ocean and Meteorological Satellite/Meteorological Imager data. Geostationary orbiting satellite data are suitable for a level 2 product like albedo, which requires a synthetic process to estimate. The authors modified established methods to consider the geometry of the solar-surface-sensor of COMS/MI. Of note, the viewing zenith angle term was removed from the kernel integration used for estimating spectral albedo. Finally, the spectral (narrow) albedo was converted into the broadband albedo with shortwave length (approximately 0.3–2.5 μm). This study determined conversion coefficients using only one spectral albedo of visible channel. The estimated albedo had a relatively high correlation with Satellite Pour l’Observation de la Terre/Vegetation and low unweighted error values specific for land types or times. The validation results show that estimated albedo has a root mean square error of 0.0134 at Jeju flux site that indicates accuracy similar to that of other satellite-based products

Neuritin Attenuates Cognitive Function Impairments in Tg2576 Mouse Model of Alzheimer's Disease

<div><p>Neuritin, also known as CPG15, is a neurotrophic factor that was initially discovered in a screen to identify genes involved in activity-dependent synaptic plasticity. Neuritin plays multiple roles in the process of neural development and synaptic plasticity, although its binding receptor(s) and downstream signaling effectors remain unclear. In this study, we found that the cortical and hippocampal expression of neuritin is reduced in the brains of Alzheimer's disease (AD) patients and demonstrated that viral-mediated expression of neuritin in the dentate gyrus of 13-month-old Tg2576 mice, an AD animal model, attenuated a deficit in learning and memory as assessed by a Morris water maze test. We also found that neuritin restored the reduction in dendritic spine density and the maturity of individual spines in primary hippocampal neuron cultures prepared from Tg2576 mice. It was also shown that viral-mediated expression of neuritin in the dentate gyrus of 7-week-old Sprague-Dawley rats increased neurogenesis in the hippocampus. Taken together, our results demonstrate that neuritin restores the reduction in dendritic spine density and the maturity of individual spines in primary hippocampal neurons from Tg2576 neurons, and also attenuates cognitive function deficits in Tg2576 mouse model of AD, suggesting that neuritin possesses a therapeutic potential for AD.</p></div

Neuritin increases synaptophysin expression in rat primary neuron cultures.

<p>Primary cultured cortical neurons were transfected at DIV 10 with EGFP or neuritin subcloned in a flag-IRES-EGFP vector by employing a calcium phosphate method. 3 days after transfection, the cells were lysed and Western blotting analysis was performed with an anti-synaptophysin antibody. β-actin was used as a loading control. Densitometric analysis was also performed. Neuritin transfection significantly increased synaptophysin expression levels by approximately 3.6-fold (*<i>p</i><0.05, Student's <i>t</i>-test). The data are presented as the mean ±SEM (n = 5 dishes from 5 independent cultures for each group).</p