Inhibition of REV-ERBs stimulates microglial amyloid-beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer\u27s disease

A promising new therapeutic target for the treatment of Alzheimer\u27s disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary A

Ammonium Inhibits Chromomethylase 3-Mediated Methylation of the Arabidopsis Nitrate Reductase Gene NIA2

Gene methylation is an important mechanism regulating gene expression and genome stability. Our previous work showed that methylation of the nitrate reductase (NR) gene NIA2 was dependent on chromomethylase 3 (CMT3). Here, we show that CMT3-mediated NIA2 methylation is regulated by ammonium in Arabidopsis thaliana. CHG sequences (where H can be A, T, or C) were methylated in NIA2 but not in NIA1, and ammonium [(NH4)2SO4] treatment completely blocked CHG methylation in NIA2. By contrast, ammonium had no effect on CMT3 methylation, indicating that ammonium negatively regulates CMT3-mediated NIA2 methylation without affecting CMT3 methylation. Ammonium upregulated NIA2 mRNA expression, which was consistent with the repression of NIA2 methylation by ammonium. Ammonium treatment also reduced the overall genome methylation level of wild-type Arabidopsis. Moreover, CMT3 bound to specific promoter and intragenic regions of NIA2. These combined results indicate that ammonium inhibits CMT3-mediated methylation of NIA2 and that of other target genes, and CMT3 selectively binds to target DNA sequences for methylation

Development of an Evaluation Methodology for Loss of Large Area induced from Extreme Events with malicious origin

Event of loss of large area (LOLA) induced from extreme external event at multi-units nuclear installation has been emerged a new challenges in the realm of nuclear safety and regulation after Fukushima Dai-Ichi accident. The relevant information and experience on evaluation methodology and regulatory requirements are rarely available and negative to share due to the security sensitivity. Most of countries has been prepared their own regulatory requirements and methodologies to evaluate impact of LOLA at nuclear power plant. In Korea, newly amended the Nuclear Safety Acts requires to assess LOLA in terms of EDMG (Extended Damage Mitigation Guideline). Korea Institute of Nuclear Safety (KINS) has performed a pilot research project to develop the methodology and regulatory review guidance on LOLA at multi-units nuclear power plant since 2014. Through this research, we proposed a methodology to identify the strategies for preventive and mitigation of the consequences of LOLA utilizing PSA techniques or its results. The proposed methodology is comprised of 8 steps including policy consideration, threat evaluation, identification of damage path sets, SSCs capacity evaluation and identification of mitigation measures and strategies. The consequence of LOLA due to malevolent aircraft crash may significantly susceptible with analysis assumptions including type of aircraft, amount of residual fuel, and hittable angle and so on, which cannot be shared overtly. This paper introduces a evaluation methodology for LOLA using PSA technique and its results. Also we provide a case study to evaluate hittable access angle using flight simulator for two types of aircrafts and to identify potential path sets leading to core damage by affected SSCs within damaged area

Mobile resistome of human gut and pathogen drives anthropogenic bloom of antibiotic resistance

BACKGROUND:The impact of human activities on the environmental resistome has been documented in many studies, but there remains the controversial question of whether the increased antibiotic resistance observed in anthropogenically impacted environments is just a result of contamination by resistant fecal microbes or is mediated by indigenous environmental organisms. Here, to determine exactly how anthropogenic influences shape the environmental resistome, we resolved the microbiome, resistome, and mobilome of the planktonic microbial communities along a single river, the Han, which spans a gradient of human activities. RESULTS:The bloom of antibiotic resistance genes (ARGs) was evident in the downstream regions and distinct successional dynamics of the river resistome occurred across the spatial continuum. We identified a number of widespread ARG sequences shared between the river, human gut, and pathogenic bacteria. These human-related ARGs were largely associated with mobile genetic elements rather than particular gut taxa and mainly responsible for anthropogenically driven bloom of the downstream river resistome. Furthermore, both sequence- and phenotype-based analyses revealed environmental relatives of clinically important proteobacteria as major carriers of these ARGs. CONCLUSIONS:Our results demonstrate a more nuanced view of the impact of anthropogenic activities on the river resistome: fecal contamination is present and allows the transmission of ARGs to the environmental resistome, but these mobile genes rather than resistant fecal bacteria proliferate in environmental relatives of their original hosts. Video abstract