Acm1 is a negative regulator of the Cdh1-dependent anaphase-promoting complex/cyclosome in budding yeast

Cdh1 is a coactivator of the anaphase-promoting complex/cyclosome (APC/C) and contributes to mitotic exit and G(1) maintenance by facilitating the polyubiquitination and subsequent proteolysis of specific substrates. Here, we report that budding yeast Cdh1 is a component of a cell cycle-regulated complex that includes the 14-3-3 homologs Bmh1 and Bmh2 and a previously uncharacterized protein, which we name Acm1 (Apc/c(Cdh1) modulator 1). Association of Cdh1 with Bmh1 and Bmh2 requires Acm1, and the Acm1 protein is cell cycle regulated, appearing late in G(1) and disappearing in late M. In acm1 Delta strains, Cdh1 localization to the bud neck and association with two substrates, Clb2 and Hsl1, were strongly enhanced. Several lines of evidence suggest that Acm1 can suppress APC/C-Cdh1-mediated proteolysis of mitotic cyclins. First, overexpression of Acm1 fully restored viability to cells expressing toxic levels of Cdh1 or a constitutively active Cdh1 mutant lacking inhibitory phosphorylation sites. Second, overexpression of Acm1 was toxic in sic1 Delta cells. Third, ACM1 deletion exacerbated a low-penetrance elongated-bud phenotype caused by modest overexpression of Cdh1. This bud elongation was independent of the morphogenesis checkpoint, and the combination of acm1 Delta and hsl1 Delta resulted in a dramatic enhancement of bud elongation and G(2)/M delay. Effects on bud elongation were attenuated when Cdh1 was replaced with a mutant lacking the C-terminal IR dipeptide, suggesting that APC/C-dependent proteolysis is required for this phenotype. We propose that Acm1 and Bmh1/Bmh2 constitute a specialized inhibitor of APC/C-Cdh1

Mental illness in patients with end-stage kidney disease in South Korea: a nationwide cohort study

Background The limited literature on mental illness in end-stage kidney disease (ESKD) patients suggests that this disease is common and burdensome but underrecognized in clinical practice. This study aimed to analyze the prevalence of mental illness in ESKD patients. Methods We assessed the prevalence and patterns of mental illnesses in a nationwide cohort of patients diagnosed with ESKD between January 1, 2008, and December 31, 2017. The risk of mental illness was evaluated using a multivariable Cox proportional hazards model. Results A total of 70,079 patients met all study inclusion criteria. A total of 28.3% of patients had mental illness, and the specific distribution was as follows: depression, 16.8%; anxiety, 20.0%; somatoform/conversion disorder, 0.9%; stress reaction/adjustment disorder, 2.5%; and substance abuse disorder, 0.6%. The frequency of mental illness was highest in patients on hemodialysis (HD), followed by patients on peritoneal dialysis (PD) and kidney transplant (KT) patients. The peak rate of mental illness in HD and PD patients was reached 1 to 2 years after renal replacement therapy initiation, but the peak rate of most mental illnesses in KT patients occurred before surgery. The prevalence of depression was 2.19 times higher in HD patients and 1.97 times higher in PD patients than in KT patients. Conclusion ESKD patients are at high risk of mental illness, and the prevalence of mental illness is highest in HD patients. Since the onset of mental illness occurs around the initiation of renal replacement therapy, clinicians need to pay attention to mental illness when treating ESKD patients

X-ray crystal structure, UV–Vis and NMR spectroscopic, and molecular docking studies of pyribencarb isomers

The crystal structures of the pyribencarb E and Z stereoisomers were determined using single-crystal X-ray crystallography. The isomers were confirmed a single data respectively by crystal analysis, LC-UVD mass spectrometry, and NMR spectroscopy. Pyribencarb E crystallizes in triclinic P−1 and the Z isomer in monoclinic P21/c, with the crystal structures showing comparable packing motifs. Moreover, molecular docking was carried out with cytochrome bc1, revealing binding energies in the ranges of −24.9 to −17.6 and −21.6 to −14.7kcal/mol for the E and Z isomers, respectively. Through a combined experimental and theoretical approach, this study contributes to our understanding of pesticides. Graphical Abstrac

Toxicometabolomics of lindane in adult zebrafish (Danio rerio) using GC-MS/MS and LC-Orbitrap-MS/MS

Lindane is a broad-spectrum persistent organochlorine pesticide that has been used to control pests for many years. In this study, its toxic mechanisms in adult zebrafish were investigated using targeted metabolomics with GC-MS/MS and non-targeted metabolomics with LC-Orbitrap-MS/MS. Zebrafish was exposed to lindane in water for 48 h in three groups: control, low exposure (1/10 LC50) and high exposure (LC50). In the zebrafish exposed to low concentration of lindane, 2.24–3.98 mg/kg of lindane were determined, while 35.67–56.46 mg/kg were observed in the zebrafish exposed to high concentration. A total of 118 metabolites were identified from 394 metabolites on GC-MS/MS and 45 metabolites were selected as biomarkers. A total of 62 metabolites were identified on LC-Orbitrap-MS/MS and 7 metabolites were selected as biomarkers. Three groups were well separated on partial least squares-discriminant analysis (PLS-DA), and a total of 52 metabolites in both the targeted and non-targeted metabolites were selected as biomarkers through VIP and ANOVA tests to construct a heatmap. Five metabolic pathways such as the pentose phosphate pathway (PPP), histidine metabolism, phenylalanine metabolism, alanine/aspartate/glutamate metabolism, and phenylalanine/tyrosine/tryptophan biosynthesis, were observed to show toxicologically significant alterations. Oxidative stress was also confirmed through MDA and ROS assays. Such perturbations of the metabolic pathways of zebrafish caused by the exposure to lindane resulted in significant toxicological effects

AMP-activated protein kinase-α1 as an activating kinase of TGF-β-activated kinase 1 has a key role in inflammatory signals

Although previous studies have proposed plausible mechanisms of the activation of transforming growth factor-β-activated kinase 1 (TAK1) in inflammatory signals, including Toll-like receptors (TLRs), its activating kinase still remains to be unclear. In the present study, we have provided evidences that AMP-activated protein kinase (AMPK)-α1 has a pivotal role for activating TAK1, and thereby regulate NF-κB-dependent gene expressions in inflammatory signaling mediated by TLR4 and TNF-α stimulation. AMPK-α1 specifically interacts with TAK1 and reciprocally regulates their kinase activities. Upon the stimulation of lipopolysaccharide, AMPK-α1-knockdown (AMPK-$\alpha 1^{KD}$) or TAK1-knockdown human monocytic THP-1 cells exhibit a dramatic reduction in the TAK1 or AMPK-α1 kinase activity, respectively, and subsequent suppressions of its downstream signaling cascades, which further leads to inhibitions of NF-κB and thereby productions of proinflammatory cytokines, such as TNF-α, IL-1β, and IL-6. Importantly, the microarray analysis of AMPK-$\alpha 1^{KD}$ cells revealed a dramatic reduction in the NF-κB-dependent genes induced by TLR4 and TNF-α stimulation, and the observation was in significant correlation with the results of quantitative real-time PCR. Moreover, AMPK-$\alpha 1^{KD}$ cells are highly sensitive to the TNF-α-induced apoptosis, which is accompanied with dramatic reductions in the NF-κB-dependent and anti-apoptotic genes. As a result, our data demonstrate that AMPK-α1 as an activating kinase of TAK1 has a key role in mediating inflammatory signals triggered by TLR4 and TNF-α

MYC and BCL2 overexpression is associated with a higher class of Memorial Sloan-Kettering Cancer Center prognostic model and poor clinical outcome in primary diffuse large B-cell lymphoma of the central nervous system

Table S1. Correlation of BCL6 expression and clinicopathological variables; Table S2. MYC translocation and copy number change in MYC positive cases. (DOCX 24 kb

Translocation of residual ethoprophos and tricyclazole from soil to spinach

The dissipation of ethoprophos and tricyclazole in soil and their translocation tendency to spinach were investigated. Prior to field trials, the analytical method for the determination of these pesticide residues was optimized and validated on soil and spinach. The field trial was conducted under greenhouse conditions for two different pretreatment periods with the pesticides. After treating with pesticides 30 (PBI-30) and 60 days (PBI-60) before seeding, soil samples were collected on different days for the dissipation study of soil. Spinach samples were harvested from the soil, and 50% and 100% mature spinach samples were collected. The initial amounts of ethoprophos residue in the PBI-60 and PBI-30 soils were 0.21 and 2.74 mg/kg, respectively, and these both decreased to less than 0.01 mg/kg on the day of spinach harvest. Similar initial residues of tricyclazole were observed in the PBI-60 (0.87 mg/kg) and PBI-30 soils (0.84 mg/kg), and these decreased to 0.44 and 0.34 mg/kg, respectively. The half-lives of ethoprophos in the soils were calculated as 7.6 and 4.8 days, respectively, while relatively long half-lives of 36.5 and 77.0 days were calculated for tricyclazole. According to the pesticide residue amounts in the spinach, the translocation rate from the soil to the spinach was determined. In the case of ethoprophos, the residual amount was already rapidly degraded in the soil, and the translocation rate could not be confirmed. On the other hand, for tricyclazole, it was confirmed that 1.19 to 1.61% of the residual amount in soil was transferred to spinach. According to these results, safe management guidelines for tricyclazole in soil were suggested considering the maximum residue limit on spinach.This work was supported by the Rural Development Administration (PJ0152772020)

Donepezil Regulates LPS and Aβ-Stimulated Neuroinflammation through MAPK/NLRP3 Inflammasome/STAT3 Signaling

The acetylcholinesterase inhibitors donepezil and rivastigmine have been used as therapeutic drugs for Alzheimer’s disease (AD), but their effects on LPS-and Aβ-induced neuroinflam-matory responses and the underlying molecular pathways have not been studied in detail in vitro and in vivo. In the present study, we found that 10 or 50 μM donepezil significantly decreased the LPS-induced increases in the mRNA levels of a number of proinflammatory cytokines in BV2 mi-croglial cells, whereas 50 μM rivastigmine significantly diminished only LPS-stimulated IL-6 mRNA levels. In subsequent experiments in primary astrocytes, donepezil suppressed only LPS-stimulated iNOS mRNA levels. To identify the molecular mechanisms by which donepezil regulates LPS-induced neuroinflammation, we examined whether donepezil alters LPS-stimulated proin-flammatory responses by modulating LPS-induced downstream signaling and the NLRP3 inflam-masome. Importantly, we found that donepezil suppressed LPS-induced AKT/MAPK signaling, the NLRP3 inflammasome, and transcription factor NF-kB/STAT3 phosphorylation to reduce neuroin-flammatory responses. In LPS-treated wild-type mice, a model of neuroinflammatory disease, donepezil significantly attenuated LPS-induced microglial activation, microglial density/morphol-ogy, and proinflammatory cytokine COX-2 and IL-6 levels. In a mouse model of AD (5xFAD mice), donepezil significantly reduced Aβ-induced microglial and astrocytic activation, density, and mor-phology. Taken together, our findings indicate that donepezil significantly downregulates LPS-and Aβ-evoked neuroinflammatory responses in vitro and in vivo and may be a therapeutic agent for neuroinflammation-associated diseases such as AD. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.1

Evaluating indoor positioning systems in a shopping mall : the lessons learned from the IPIN 2018 competition

The Indoor Positioning and Indoor Navigation (IPIN) conference holds an annual competition in which indoor localization systems from different research groups worldwide are evaluated empirically. The objective of this competition is to establish a systematic evaluation methodology with rigorous metrics both for real-time (on-site) and post-processing (off-site) situations, in a realistic environment unfamiliar to the prototype developers. For the IPIN 2018 conference, this competition was held on September 22nd, 2018, in Atlantis, a large shopping mall in Nantes (France). Four competition tracks (two on-site and two off-site) were designed. They consisted of several 1 km routes traversing several floors of the mall. Along these paths, 180 points were topographically surveyed with a 10 cm accuracy, to serve as ground truth landmarks, combining theodolite measurements, differential global navigation satellite system (GNSS) and 3D scanner systems. 34 teams effectively competed. The accuracy score corresponds to the third quartile (75th percentile) of an error metric that combines the horizontal positioning error and the floor detection. The best results for the on-site tracks showed an accuracy score of 11.70 m (Track 1) and 5.50 m (Track 2), while the best results for the off-site tracks showed an accuracy score of 0.90 m (Track 3) and 1.30 m (Track 4). These results showed that it is possible to obtain high accuracy indoor positioning solutions in large, realistic environments using wearable light-weight sensors without deploying any beacon. This paper describes the organization work of the tracks, analyzes the methodology used to quantify the results, reviews the lessons learned from the competition and discusses its future