Pathological TDP‐43 aggregation is characteristic of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD‐TDP); however, how ...TDP‐43 aggregation and function are regulated remain poorly understood. Here, we show that O‐GlcNAc transferase OGT‐mediated O‐GlcNAcylation of TDP‐43 suppresses ALS‐associated proteinopathies and promotes TDP‐43's splicing function. Biochemical and cell‐based assays indicate that OGT's catalytic activity suppresses TDP‐43 aggregation and hyperphosphorylation, whereas abolishment of TDP‐43 O‐GlcNAcylation impairs its RNA splicing activity. We further show that TDP‐43 mutations in the O‐GlcNAcylation sites improve locomotion defects of larvae and adult flies and extend adult life spans, following TDP‐43 overexpression in Drosophila motor neurons. We finally demonstrate that O‐GlcNAcylation of TDP‐43 promotes proper splicing of many mRNAs, including STMN2, which is required for normal axonal outgrowth and regeneration. Our findings suggest that O‐GlcNAcylation might be a target for the treatment of TDP‐43‐linked pathogenesis.
SYNOPSIS
O‐GlcNAcylation of TDP‐43 suppresses TDP‐43 proteinophathies and promotes TDP‐43’s mRNA splicing activity, with potential implications for ALS/FTLD pathogenesis.
TDP‐43 can be O‐GlcNAcylated by the enzyme OGT in vitro and in vivo, and O‐GlcNAcylation of TDP‐43 suppresses protein aggregation and hyperphosphorylation.
TDP‐43 O‐GlcNAcylation affects the locomotion and longevity of Drosophila.
O‐GlcNAcylation of TDP‐43 prevents aberrant splicing of key neuron genes, such as STMN2, Dnajc5, and Sort1.
O‐GlcNAcylation of TDP‐43 suppresses TDP‐43 proteinophathies and promotes TDP‐43’s mRNA splicing activity, with potential implications for ALS/FTLD pathogenesis.
Transition metal oxides (e.g. NiO) have been considered as promising high-capacity anode in lithium ion batteries (LIBs). However, the low electronic conductivity and huge volume change during ...cycling lead to rapid capacity fading and poor rate capability. To solve those drawbacks, we design a sandwich-like dual carbon layers coated hollow structured NiO (C@NiO@NC). The NiO nanosheets are anchored on the surface of hollow carbon nanospheres and then coated with N-doped porous carbon layer, which confine them between two carbon shells. Such hierarchical architecture with high surface area increases the contact between the electrode and electrolyte, resulting in decreased Li+ diffusion pathway. Moreover, the dual carbon layers enhance the electronic conductivity of C@NiO@NC and effectively buffer the volume changes of NiO during cycling. Therefore, this sample delivers a high capacity (1189 mA h g−1 at 100 mA g−1), superior rate capability (420 mA h g−1 at ultrahigh rate of 10000 mA g−1) and outstanding cycling stability (96.1% at 1000 mA g−1 after 1000 cycles) when used as LIBs anode. The density functional theoretical calculation further proves the enhanced electronic conductivity and more energetic favorable capability of C@NiO@NC. This facile method can be extended to other transition-metal oxides with superior electrochemical performance.
•NiO hollow sphere coated by Sandwich-like dual carbon layers.•DFT reveals enhanced electrical conductivity and lower energy barriers of C@NiO@NC.•The obtained C@NiO@NC shows brilliant electrochemical performance.
The surface receptor triggering receptor expressed on myeloid cells 2 (TREM2) plays a crucial role in maintaining a multitude of microglial activities, such as survival, proliferation, migration, ...metabolism, inflammation, and phagocytosis. However, the molecular mechanisms underlying TREM2-mediated microglial activities remain largely elusive. Herein, we found that TREM2 interacted with the type I transmembrane protein TMEM59, whose expression could facilitate autophagic flux through its carboxyl-terminus. TMEM59 expression was decreased upon lipopolysaccharide treatment. While downregulation of TMEM59 promoted anti-inflammatory factor expression and attenuated lipopolysaccharide treatment-induced inflammation. Importantly, we found that overexpression of TREM2 reduced TMEM59 protein levels through promoting its degradation, whereas TMEM59 levels were elevated in Trem2-deficient microglia. Finally, impaired survival, proliferation, migration, and phagocytosis, as well as dysregulated autophagy and metabolism in Trem2-deficient microglia were attenuated upon TMEM59 silencing. Together, our findings reveal a novel function of TREM2 in mediating TMEM59 protein degradation and demonstrate the importance of TMEM59 homeostasis in maintaining TREM2-mediated microglial activities.
Band gap engineering of a semiconductor in a straightforward and efficient manner is highly desirable, but it remains technically challenging. Herein, we demonstrate a powerful nanoparticle occlusion ...strategy that enables the band gap of silver phosphate (Ag3PO4) crystals to be readily tailored. Specifically, a series of diblock copolymer nanoparticles of varying morphologies is prepared by polymerization-induced self-assembly (PISA) and subsequently used as a particulate additive during the crystallization of Ag3PO4. Remarkably, these copolymer nanoparticles can be efficiently occluded within Ag3PO4 single crystals, forming organic/inorganic nanocomposite semiconductors whose optical band gap is tunable, depending on the extent of copolymer occlusion. Furthermore, these copolymer nanoparticles can act as “Trojan horses” to incorporate Pd nanoparticles into Ag3PO4, leading to an enhanced photocatalytic degradation of tetracycline under visible-light irradiation. This study provides a brand-new strategy to regulate the band gap of semiconductors, and in principle, it could enable the rational preparation of a wide range of nanocomposite semiconductor materials with controlled properties.
Summary
To assess the impact of sanitation of a living environment on gut microbiota and development of the immune system, we raised BALB/c mice under three distinct environmental conditions: a ...specific pathogen‐free animal room (SPF), a general animal room (XZ) and a farmhouse (JD). All other variables like diet, age, genetic background, physiological status and original gut microbiota were controlled for in the three groups. Using high‐throughput sequencing of the 16S rRNA gene, we found that each mouse group had a specific structure of the gut microbial community. Groups JD and XZ harboured a significantly more diverse and richer gut microbiota than did group SPF. Bacteroidetes were significantly more abundant in groups XZ and JD than in group SPF, whereas Firmicutes showed the inverse pattern. Total serum immunoglobulin E (IgE) levels were significantly lower in groups XZ and JD than in group SPF. There were no significant differences in gut microbiota diversity and serum IgE concentration between groups JD and XZ, but we found higher abundance of dominant genera in the gut microflora of group JD. We conclude that exposure to soil, house dust and decaying plant material enhances gut microbial diversity and innate immunity. Our results seem to provide new evidence supporting the hygiene hypothesis.
This study aimed to explore the risk factors, metabolic characteristics, and potential biomarkers of mild cognitive impairment in type 2 diabetes mellitus (T2DM-MCI) and to provide potential evidence ...for the diagnosis, prevention, and treatment of mild cognitive impairment (MCI) in patients with type 2 diabetes mellitus (T2DM).
A total of 103 patients with T2DM were recruited from the Endocrinology Department of The Second Affiliated Hospital of Dalian Medical University for inclusion in the study. The Montreal Cognitive Assessment (MoCA) was utilized to evaluate the cognitive functioning of all patients. Among them, 50 patients were categorized into the T2DM-MCI group (MoCA score < 26 points), while 53 subjects were classified into the T2DM without cognitive impairment (T2DM-NCI) group (MoCA score ≥ 26 points). Serum samples were collected from the subjects, and metabolomics profiling data were generated by Ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS). These groups were analyzed to investigate the differences in expression of small molecule metabolites, metabolic pathways, and potential specific biomarkers.
Comparison between the T2DM-MCI group and T2DM-NCI group revealed significant differences in years of education, history of insulin application, insulin resistance index, insulin-like growth factor-binding protein-3 (IGFBP-3), and creatinine levels. Further binary logistic regression analysis of the variables indicated that low educational level and low serum IGFBP-3 were independent risk factor for T2DM-MCI. Metabolomics analysis revealed that differential expression of 10 metabolites between the T2DM-MCI group and T2DM-NCI group (
< 0.05 and FDR<0.05, VIP>1.5). Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis revealed that fatty acid degradation was the most significant pathway. Receiver operating characteristic (ROC) analysis shows that lysophosphatidylcholine (LPC) 18:0 exhibited greater diagnostic efficiency.
This study revealed that a shorter duration of education and lower serum IGFBP-3 levels are independent risk factors for T2DM-MCI. Serum metabolites were found to be altered in both T2DM-MCI and T2DM-NCI groups. T2DM patients with or without MCI can be distinguished by LPC 18:0. Abnormal lipid metabolism plays a significant role in the development of MCI in T2DM patients.
Elevated LDL-C/HDL-C ratio has been shown to be a marker of lipid metabolism as well as a good predictor of coronary artery disease (CAD). Thus, the aim of this study was to investigate whether the ...LDL-C/HDL-C ratio is useful for detecting cardiovascular disease (CVD) risk factors in general healthy Uygur adults in Xinjiang. A total of 4047 Uygur subjects aged ≥35 years were selected from the Cardiovascular Risk Survey (CRS) study which was carried out from October 2007 to March 2010. Anthropometric data, blood pressure, lipid profile and fasting glucose were measured in all participants. The prevalence, sensitivity, specificity and distance on the receiver operating characteristic (ROC) curve of each LDL-C/HDL-C ratio were calculated. The prevalence of high LDL-C and low HDL-C cholesterol was high and positively correlated with higher LDL-C/HDL-C ratio in the Uygur population. In both men and women, we detected a slight apparent trend of high prevalence of hypertension and hypercholesterolemia with higher LDL-C/HDL-C ratio. Our study also demonstrated that the discriminatory power of the LDL-C/HDL-C ratio for CVD risk factors was slightly stronger in men than in women. Analysis of the shortest distance in the ROC curves for hypertension, dyslipidemia, diabetes, or ≥two of these risk factors suggested a LDL-C/HDL-C ratio cutoff of 2.5 for both men and women. The results of this study showed that a LDL-C/HDL-C ratio cut-off of 2.5 might be used as the predictive marker to detect CVD risk factors among Uygur adults in Xinjiang.
To explore the effect of cytosolic phospholipase A2α (cPLA2α) on hepatocellular carcinoma (HCC) cell adhesion and the underlying mechanisms.
Cell adhesion, detachment, and hanging-drop assays were ...utilized to examine the effect of cPLA2α on the cell-matrix and cell-cell adhesion. Downstream substrates and effectors of cPLA2α were screened
a phospho-antibody microarray. Associated signaling pathways were identified by the functional annotation tool DAVID. Candidate proteins were verified using Western blot and colocalization was investigated
immunofluorescence. Western blot and immunohistochemistry were used to detect protein expression in HCC tissues. Prognosis evaluation was conducted using Kaplan-Meier and Cox-proportional hazards regression analyses.
Our findings showed that cPLA2α knockdown decreases cell-matrix adhesion but increases cell-cell adhesion in HepG2 cells. Microarray analysis revealed that phosphorylation of multiple proteins at specific sites were regulated by cPLA2α. These phosphorylated proteins were involved in various biological processes. In addition, our results indicated that the focal adhesion pathway was highly enriched in the cPLA2α-relevant signaling pathway. Furthermore, cPLA2α was found to elevate phosphorylation levels of FAK and paxillin, two crucial components of focal adhesion. Moreover, localization of p-FAK to focal adhesions in the plasma membrane was significantly reduced with the downregulation of cPLA2α. Clinically, cPLA2α expression was positively correlated with p-FAK levels. Additionally, high expression of both cPLA2α and p-FAK predicted the worst prognoses for HCC patients.
Our study indicated that cPLA2α may promote cell-matrix adhesion
the FAK/paxillin pathway, which partly explains the malignant cPLA2α phenotype seen in HCC.
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