Chronic kidney disease (CKD)‐associated mental disorders have been attributed to the excessive accumulation of hemodialysis‐resistant indoxyl‐3‐sulfate (I3S) in the brain. I3S not only induces ...oxidative stress but is also a potent endogenous agonist of the aryl hydrocarbon receptor (AhR). Here, we investigated the role of AhR in CKD‐induced brain disorders using a 5/6 nephrectomy‐induced CKD mouse model, which showed increased I3S concentration in both blood and brain, anxiety and impaired novelty recognition, and AhR activation in the anterior cortex. GFAP+ reactive astrocytes were increased accompanied with the reduction of glutamate transporter 1 (GLT1) on perineuronal astrocytic processes (PAPs) in the anterior cingulate cortex (ACC) in CKD mice, and these alterations were attenuated in both neural lineage‐specific and astrocyte‐specific Ahr conditional knockout mice (nAhrCKO and aAhrCKO). By using chronic I3S treatment in primary astrocytes and glia‐neuron (GN) mix cultures to mimic the CKD brain microenvironment, we also found significant reduction of GLT1 expression and activity in an AhR‐dependent manner. Chronic I3S treatment induced AhR‐dependent pro‐oxidant Nox1 and AhR‐independent anti‐oxidant HO‐1 expressions. Notably, AhR mediates chronic I3S‐induced neuronal activity enhancement and synaptotoxicity in GN mix, not neuron‐enriched cortical culture. In CKD mice, neuronal activity enhancement was observed in ACC and hippocampal CA1, and these responses were abrogated by both nAhrCKO and aAhrCKO. Finally, intranasal AhR antagonist CH‐223191 administration significantly ameliorated the GLT1/PAPs reduction, increase in c‐Fos+ neurons, and memory impairment in the CKD mice. Thus, astrocytic AhR plays a crucial role in the CKD‐induced disturbance of neuron‐astrocyte interaction and mental disorders.
Main Points
CKD elevates brain I3S to activate astrocytic AhR, which mediates astrogliosis with GLT1 hypofunction and enhances neuronal activity in ACC and hippocampus.
Intranasal AhR antagonist administration ameliorates CKD‐induced brain/behavioral changes.
Abstract
Interest in bringing p- and n-type monolayer semiconducting transition metal dichalcogenides (TMD) into contact to form rectifying pn diode has thrived since it is crucial to control the ...electrical properties in two-dimensional (2D) electronic and optoelectronic devices. Usually this involves vertically stacking different TMDs with pn heterojunction or, laterally manipulating carrier density by gate biasing. Here, by utilizing a locally reversed ferroelectric polarization, we laterally manipulate the carrier density and created a WSe
2
pn homojunction on the supporting ferroelectric BiFeO
3
substrate. This non-volatile WSe
2
pn homojunction is demonstrated with optical and scanning probe methods and scanning photoelectron micro-spectroscopy. A homo-interface is a direct manifestation of our WSe
2
pn diode, which can be quantitatively understood as a clear rectifying behavior. The non-volatile confinement of carriers and associated gate-free pn homojunction can be an addition to the 2D electron–photon toolbox and pave the way to develop laterally 2D electronics and photonics.
Background
To assess the impact of treatment delay on survival of oral/oropharyngeal cancer (OSCC).
Methods
We followed 5743 OSCCs between 2004 and 2009 from a population‐based screening program and ...ascertained death until the end of 2012.
Results
The hazard ratios (HRs) of mortality from OSCC were 1.46 (1.30‐1.65) and 1.18 (1.04‐1.33) in univariable and multivariable analyses, respectively, for treatment delay longer than 6 weeks compared with that shorter than 3 weeks. The corresponding figures were 1.12 (1.01‐1.24) and 1.00 (0.91‐1.11) for treatment delay between 3 and 6 weeks. Advancing age (1.01), higher stage (stage II: 1.84, stage III: 2.97, stage IV: 6.33), cancer in tongue (1.37), or hard palate (1.63) had higher HR of mortality (P < .05). However, treatment at medical center had a lower mortality (0.83, 0.75‐0.91) than local/regional hospital.
Conclusions
Treatment delay longer than 6 weeks for OSCCs detected via a population‐based screening program had unfavorable survival.
Urinary tract infection (UTI) is one of the most common outpatient bacterial infections. In this study, we isolated and characterized an extensively-drug resistant (XDR) NDM-5-producing Escherichia ...coli EC1390 from a UTI patient by using whole-genome sequencing (WGS) in combination with phenotypic assays.
Antimicrobial susceptibility to 23 drugs was determined by disk diffusion method. The genome sequence of EC1390 was determined by Nanopore MinION MK1C platform. Conjugation assays were performed to test the transferability of EC1390 plasmids to E. coli recipient C600. Phenotypic assays, including growth curve, biofilm formation, iron acquisition ability, and cell adhesion, were performed to characterize the function of EC1390 plasmids.
Our results showed that EC1390 was only susceptible to tigecycline and colistin, and thus was classified as XDR E. coli. A de novo genome assembly was generated using Nanopore 73,050 reads with an N
value of 20,936 bp and an N
value of 7,624 bp. WGS analysis showed that EC1390 belonged to the O101-H10 serotype and phylogenetic group A E. coli. Moreover, EC1390 contained 2 conjugative plasmids with a replicon IncFIA (pEC1390-1 with 156,286 bp) and IncFII (pEC1390-2 with 71,840 bp), respectively. No significant difference was observed in the bacterial growth rate in LB broth and iron acquisition ability between C600, C600 containing pEC1390-1, C600 containing pEC1390-2, and C600 containing pEC1390-1 and pEC1390-2. However, the bacterial growth rate in nutrition-limited M9 broth was increased in C600 containing pEC1390-2, and the cell adhesion ability was increased in C600 containing both pEC1390-1 and pEC1390-2. Moreover, these plasmids modulated the biofilm formation under different conditions.
In summary, we characterized the genome of XDR-E. coli EC1390 and identified two plasmids contributing to the antimicrobial resistance, growth of bacteria in a nutrition-limited medium, biofilm formation, and cell adhesion.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is originally featured with a strong clustering of mutations in NOTCH3 exons 3-6 and ...leukoencephalopathy with frequent anterior temporal pole involvement. The present study aims at characterizing the genotypic and phenotypic profiles of CADASIL in Taiwan. One hundred and twelve patients with CADASIL from 95 families of Chinese descents in Taiwan were identified by Sanger sequencing of exons 2 to 24 of NOTCH3. Twenty different mutations in NOTCH3 were uncovered, including 3 novel ones, and R544C in exon 11 was the most common mutation, accounting for 70.5% of the pedigrees. Haplotype analyses were conducted in 14 families harboring NOTCH3 R544C mutation and demonstrated a common haplotype linked to NOTCH3 R544C at loci D19S929 and D19S411. Comparing with CADASIL in most Caucasian populations, CADASIL in Taiwan has several distinct features, including less frequent anterior temporal involvement, older age at symptom onset, higher incidence of intracerebral hemorrhage, and rarer occurrence of migraine. Subgroup analyses revealed that the R544C mutation is associated with lower frequency of anterior temporal involvement, later age at onset and higher frequency of cognitive dysfunction. In conclusion, the present study broadens the spectrum of NOTCH3 mutations and provides additional insights for the clinical and molecular characteristics of CADASIL patients of Han-Chinese descents.
In the evolving field of electrocatalysis, thermal treatment of nano‐electrocatalysts has become an essential strategy for performance enhancement. This review systematically investigates the impact ...of various thermal treatments on the catalytic potential of nano‐electrocatalysts. The focus encompasses an in‐depth analysis of the changes induced in structural, morphological, and compositional properties, as well as alterations in electro‐active surface area, surface chemistry, and crystal defects. By providing a comprehensive comparison of commonly used thermal techniques, such as annealing, calcination, sintering, pyrolysis, hydrothermal, and solvothermal methods, this review serves as a scientific guide for selecting the right thermal technique and favorable temperature to tailor the nano‐electrocatalysts for optimal electrocatalysis. The resultant modifications in catalytic activity are explored across key electrochemical reactions such as electrochemical (bio)sensing, catalytic degradation, oxygen reduction reaction, hydrogen evolution reaction, overall water splitting, fuel cells, and carbon dioxide reduction reaction. Through a detailed examination of the underlying mechanisms and synergistic effects, this review contributes to a fundamental understanding of the role of thermal treatments in enhancing electrocatalytic properties. The insights provided offer a roadmap for future research aimed at optimizing the electrocatalytic performance of nanomaterials, fostering the development of next‐generation sensors and energy conversion technologies.
This review examines the impact of thermal treatments on the optimization of nano‐electrocatalysts for electrochemical applications. It focuses on atomic‐level structural changes induced by heat and assesses their influence on electrocatalysis. The article also offers tailored approaches to guide researchers in selecting effective techniques and thermal settings, thereby advancing electrochemical research.
Both high-fidelity and mismatch-tolerant recombination, catalyzed by RAD51 and DMC1 recombinases, respectively, are indispensable for genomic integrity. Here, we use cryo-EM, MD simulation and ...functional analysis to elucidate the structural basis for the mismatch tolerance of DMC1. Structural analysis of DMC1 presynaptic and postsynaptic complexes suggested that the lineage-specific Loop 1 Gln244 (Met243 in RAD51) may help stabilize DNA backbone, whereas Loop 2 Pro274 and Gly275 (Val273/Asp274 in RAD51) may provide an open "triplet gate" for mismatch tolerance. In support, DMC1-Q244M displayed marked increase in DNA dynamics, leading to unobservable DNA map. MD simulation showed highly dispersive mismatched DNA ensemble in RAD51 but well-converged DNA in DMC1 and RAD51-V273P/D274G. Replacing Loop 1 or Loop 2 residues in DMC1 with RAD51 counterparts enhanced DMC1 fidelity, while reciprocal mutations in RAD51 attenuated its fidelity. Our results show that three Loop 1/Loop 2 residues jointly enact contrasting fidelities of DNA recombinases.
Objective:
To identify the causative gene in spinocerebellar ataxia (SCA) 22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21‐q23.
Methods:
We previously characterized a large ...Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all 3 families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and cosegregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions.
Results:
We identified heterozygous mutations in the voltage‐gated potassium channel Kv4.3‐encoding gene KCND3: an in‐frame 3‐nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034G>T p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified 3 mutations, c.1034G>T p.G345V, c.1013T>C p.V338E, and c.1130C>T p.T377M, in 3 Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A‐type K+ channel conductance in whole cell patch‐clamp recordings.
Interpretation:
Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration. ANN NEUROL 2012;72:859–869.
PDF
