Zheng et al. show that levels of histone methyltransferases EHMT1/2, and of the histone methylation H3K9me2, are elevated in prefrontal cortex of a familial Alzheimer's disease (FAD) mouse model and ...human postmortem tissue. Inhibition of EHMT1/2 rescues cognitive deficits by relieving H3K9me2-mediated repression of glutamate receptor transcription in FAD mice.
Abstract
Epigenetic dysregulation, which leads to the alteration of gene expression in the brain, is suggested as one of the key pathophysiological bases of ageing and neurodegeneration. Here we found that, in the late-stage familial Alzheimer's disease (FAD) mouse model, repressive histone H3 dimethylation at lysine 9 (H3K9me2) and euchromatic histone methyltransferases EHMT1 and EHMT2 were significantly elevated in the prefrontal cortex, a key cognitive region affected in Alzheimer's disease. Elevated levels of H3K9me2 were also detected in the prefrontal cortex region of post-mortem tissues from human patients with Alzheimer's disease. Concomitantly, H3K9me2 at glutamate receptors was increased in prefrontal cortex of aged FAD mice, which was linked to the diminished transcription, expression and function of AMPA and NMDA receptors. Treatment of FAD mice with specific EHMT1/2 inhibitors reversed histone hyper-methylation and led to the recovery of glutamate receptor expression and excitatory synaptic function in prefrontal cortex and hippocampus. Chromatin immunoprecipitation-sequencing (ChIP-seq) data indicated that FAD mice exhibited genome-wide increase of H3K9me2 enrichment at genes involved in neuronal signalling (including glutamate receptors), which was reversed by EHMT1/2 inhibition. Moreover, the impaired recognition memory, working memory, and spatial memory in aged FAD mice were rescued by the treatment with EHMT1/2 inhibitors. These results suggest that disrupted epigenetic regulation of glutamate receptor transcription underlies the synaptic and cognitive deficits in Alzheimer's disease, and targeting histone methylation enzymes may represent a novel therapeutic strategy for this prevalent neurodegenerative disorder.
We report a double-ceramic-layer (DCL) thermal barrier coating (TBC) with high-entropy rare-earth zirconate (HE-REZ) as the top layer and yttria stabilized zirconia (YSZ) as the inner layer sprayed ...on Ni-based superalloy by atmospheric plasma spraying. La2Zr2O7 (LZ) was selected as a reference for the HE-REZ. Thermal cycling test results demonstrate that the HE-REZ/YSZ DCL coating exhibited obviously improved thermal stability when compared to the LZ/YSZ DCL coating. The reasons for the improvement of the thermal shock resistance are considered to be the anti-sinterability of the HE-REZ ceramics during the thermal cycling test attributed to the sluggish diffusion effect and as well as the better match in the coefficient of thermal expansion of HE-REZ coating with the YSZ inner layer. In addition, the HE-REZ coating maintains fluorite structure after thermal cycling test. This study makes one step forward in the development and application of high-entropy rare-earth zirconate ceramic thermal barrier coatings.
Histone methylation plays important roles in mediating the onset and progression of various cancers, and lysine-specific demethylase 5B (KDM5B), as a histone demethylase, is reported to be an ...oncogene in hepatocellular carcinoma (HCC). However, the mechanism underlying its tumorigenesis remains undefined. Hence, we explored the regulatory role of KDM5B in HCC cells, aiming to identify novel therapeutic targets for HCC. Gene Expression Omnibus database and StarBase were used to predict important regulatory pathways related to HCC. Then, the expression of KDM5B and microRNA-448 (miR-448) in HCC tissues was detected by RT-qPCR and Western blot analysis. The correlation between KDM5B and miR-448 expression was analysed by Pearson's correlation coefficient and ChIP experiments, and the targeting of YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) by miR-448 was examined by luciferase assay. Additionally, the effect of KDM5B on the proliferation, migration, invasion and apoptosis as well as tumorigenicity of transfected cells was assessed using ectopic expression and depletion experiments. KDM5B was highly expressed in HCC cells and was inversely related to miR-448 expression. KDM5B demethylated H3K4me3 on the miR-448 promoter and thereby inhibited the expression of miR-448, which in turn targeted YTHDF3 and integrin subunit alpha 6 (ITGA6) to promote the malignant phenotype of HCC. Moreover, KDM5B accelerated HCC progression in nude mice via the miR-448/YTHDF3/ITGA6 axis. Our study uncovered that KDM5B regulates the YTHDF3/ITGA6 axis by inhibiting the expression of miR-448 to promote the occurrence of HCC.
Effects of Zn addition on the microstructure and tensile properties of as-extruded Mg-8Al-2Sn (AT82) alloy were investigated in the present work. All the extruded AT82 alloys exhibited a fully ...dynamically recrystallized (DRXed) microstructure, while the grains were slightly refined with Zn addition. Moreover, second phase particles (Mg2Sn and Mg17Al12) increased significantly in amount with increasing Zn content. It was found the ultimate tensile strength (UTS) and yield strength (YS) gradually increased with increasing Zn content from 0 to 1.5wt%, meanwhile the elongation maintained unchanged at a high level, i.e. ~17–19%. In particular, the as-extruded AT82-1.0Zn alloy exhibited both a high strength and high ductility at room temperature, e.g. UTS of ~357MPa and elongation of ~19%. The superior combination of strength and ductility is mainly benefited from the enhanced work-hardening ability resulted from Zn solid solutes and the presence of more well-dispersed fine particles in AT82-1.0Zn alloy.
Objective
Increased permeability and changes in gut microbiota contributed to the pathogenesis of Alzheimer's disease (AD). Zonulin is a key modulator that regulates intestinal barrier function. ...Peripheral platelet alterations have been involved in AD pathology. C‐type lectin‐like receptor 2 (CLEC‐2) is a receptor on the platelet surface for activation. The purpose of this study was to determine zonulin and CLEC‐2 levels in mild cognitive impairment (MCI) and AD, and investigate the relationship between zonulin and CLEC‐2.
Methods
In this study, CLEC‐2 and zonulin levels were measured using ELISA assay in 110 AD patients, 110 MCI patients, and 110 non‐demented control subjects.
Results
Increased CLEC‐2 and zonulin levels were observed in MCI and AD patients. Furthermore, AD patients had higher CLEC‐2 and zonulin levels compared with MCI patients. In addition, CLEC‐2 levels were positively correlated with zonulin levels, after adjusting confounding factors (r = .592, P < .001). Multivariate analysis revealed that increased CLEC‐2 and zonulin levels were significantly associated with reduced Mini‐Mental State Examination (MMSE) score.
Conclusions
C‐type lectin‐like receptor 2 is correlated with zonulin after adjusting confounding covariates. Moreover, increased CLEC‐2 and zonulin are the significant factors for reduced MMSE score in MCI and AD. Further studies are needed.
Three typical ceramic processing were respectively used to synthesize (Ti0.2Zr0.2Nb0.2Ta0.2W0.2)C high-entropy carbide (HEC) ceramics by spark plasma sintering. Although single-phase composition ...characterized by X-ray diffraction were obtained by the three processes, the microstructures and elemental distributions are different. The reasons for the formation of these features are preliminarily discussed. The results demonstrate that the particle sizes of the starting metallic powders was a key factor for obtaining a homogeneous distribution of each elements in the HEC. Carbide process with relatively finer starting carbide powders compared to the above metallic starting powders resulted in an HEC with homogeneous distribution of elements, but the obtained ceramics showed the lowest relative density. For oxide process, it is considered that the obviously higher reaction temperature between ZrO2 and graphite resulted in a two-phase structure of an HEC and a zirconium-rich phase, but the obtained HEC showed the highest relative density.
The first phase of molecular brain imaging of microglial activation in neuroinflammatory conditions began some 20 years ago with the introduction of 11C-(R)-PK11195, the prototype isoquinoline ligand ...for translocator protein (18 kDa) (TSPO). Investigations by positron emission tomography (PET) revealed microgliosis in numerous brain diseases, despite the rather low specific binding signal imparted by 11C-(R)-PK11195. There has since been enormous expansion of the repertoire of TSPO tracers, many with higher specific binding, albeit complicated by allelic dependence of the affinity. However, the specificity of TSPO PET for revealing microglial activation not been fully established, and it has been difficult to judge the relative merits of the competing tracers and analysis methods with respect to their sensitivity for detecting microglial activation. We therefore present a systematic comparison of 13 TSPO PET and single photon computed tomography (SPECT) tracers belonging to five structural classes, each of which has been investigated by compartmental analysis in healthy human brain relative to a metabolite-corrected arterial input. We emphasize the need to establish the non-displaceable binding component for each ligand and conclude with five recommendations for a standard approach to define the cellular distribution of TSPO signals, and to characterize the properties of candidate TSPO tracers.
Mild yet direct: A convenient and efficient method for the synthesis of various aryl ketones by palladium‐catalyzed desulfinative addition of aromatic sulfinic acid sodium salts to various nitriles ...is described (see scheme). Aromatic and aliphatic nitriles are successfully reacted with arenesulfinic acid sodium salts to form aryl ketones in good yields.
This is the first comprehensive review on inherent anisotropic features of transition metal diboride (MB2) and their implementation for tailoring the microstructure and properties of MB2-based ...Ultra-high temperature Ceramics (UHTCs). The emphasis is on the processing approaches, microstructures, and properties of self-reinforced and/or textured MB2-based composites with elongated MB2 grains. The crystal structure characteristics and grain growth behaviour of MB2 are also critically reviewed. Benefiting from the tailored microstructure, the MB2-based ceramics exhibit some improved properties. Considering the success of Si3N4 ceramics in the field of structural ceramics, it is expected that the potential MB2-based ceramic composites with abundant elongated MB2 grains, textured structures, and controlled grain boundaries would possess improved fracture toughness, thermal shock resistance, and reliable high-temperature properties, which are desired for their practical applications. Accordingly, microstructure designing and tailoring provide an important perspective for the future development of UHTCs.
Pyrrolo1,2-
indoles are structurally important scaffolds in many natural products and bioactive compounds. Herein, we report a novel synthetic method for pyrrolo1,2-
indole derivatives through ...visible-light-induced cascade dearomatizative cyclization of indoles with external nucleophiles. Moderate yields, good diastereoselectivities, and excellent regioselectivities were generally observed with the resultant indole-fused polycyclic compounds.
PDF
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