Mitochondrial hypermetabolism precedes impaired autophagy and synaptic disorganization in App knock-in Alzheimer mouse models.

Accumulation of amyloid β-peptide (Aβ) is a driver of Alzheimer's disease (AD). Amyloid precursor protein (App) knock-in mouse models recapitulate AD-associated Aβ pathology, allowing elucidation of downstream effects of Aβ accumulation and their temporal appearance upon disease progression. Here we have investigated the sequential onset of AD-like pathologies in AppNL-F and AppNL-G-F knock-in mice by time-course transcriptome analysis of hippocampus, a region severely affected in AD. Strikingly, energy metabolism emerged as one of the most significantly altered pathways already at an early stage of pathology. Functional experiments in isolated mitochondria from hippocampus of both AppNL-F and AppNL-G-F mice confirmed an upregulation of oxidative phosphorylation driven by the activity of mitochondrial complexes I, IV and V, associated with higher susceptibility to oxidative damage and Ca2+-overload. Upon increasing pathologies, the brain shifts to a state of hypometabolism with reduced abundancy of mitochondria in presynaptic terminals. These late-stage mice also displayed enlarged presynaptic areas associated with abnormal accumulation of synaptic vesicles and autophagosomes, the latter ultimately leading to local autophagy impairment in the synapses. In summary, we report that Aβ-induced pathways in App knock-in mouse models recapitulate key pathologies observed in AD brain, and our data herein adds a comprehensive understanding of the pathologies including dysregulated metabolism and synapses and their timewise appearance to find new therapeutic approaches for AD

Identification of Candidate Genes Associated with Charcot-Marie-Tooth Disease by Network and Pathway Analysis

Charcot-Marie-Tooth Disease (CMT) is the most common clinical genetic disease of the peripheral nervous system. Although many studies have focused on elucidating the pathogenesis of CMT, few focuses on achieving a systematic analysis of biology to decode the underlying pathological molecular mechanisms and the mechanism of its disease remains to be elucidated. So our study may provide further useful insights into the molecular mechanisms of CMT based on a systematic bioinformatics analysis. In the current study, by reviewing the literatures deposited in PUBMED, we identified 100 genes genetically related to CMT. Then, the functional features of the CMT-related genes were examined by R software and KOBAS, and the selected biological process crosstalk was visualized with the software Cytoscape. Moreover, CMT specific molecular network analysis was conducted by the Molecular Complex Detection (MCODE) Algorithm. The biological function enrichment analysis suggested that myelin sheath, axon, peripheral nervous system, mitochondrial function, various metabolic processes, and autophagy played important roles in CMT development. Aminoacyl-tRNA biosynthesis, metabolic pathways, and vasopressin-regulated water reabsorption were significantly enriched in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway network, suggesting that these pathways may play key roles in CMT occurrence and development. According to the crosstalk, the biological processes could be roughly divided into a correlative module and two separate modules. MCODE clusters showed that in top 3 clusters, 13 of CMT-related genes were included in the network and 30 candidate genes were discovered which might be potentially related to CMT. The study may help to update the new understanding of the pathogenesis of CMT and expand the potential genes of CMT for further exploration

Research on the Hydrophilic Modified of LDPE for the New Biological Suspended Filler

Urban sewage is one of the main pollution sources of the city, which pollute soil, deteriorate the water quality and increase the water shortages and urban load. LDPE is low cost and widely used as the basic material of wastewater treatment, but LDPE’s hydrophilic is not good enough to meet the need of suspended filler in wastewater treatment. In this paper the hydrophilic modified of LDPE for the new biological suspended filler was studied and the preparation and processing technique based on LDPE was researched. The hydrophilic and mechanic performance of the hydrophilic modified materials was tested. Results shown that the new type of hydrophilic modified materials has good hydrophilic and meets the demand of urban sewage treatment. The research on the new suspended filler materials has great meaning in solving the problem of urban sewage and recycling

Comparative analysis of chemical compositions and antioxidant activities of different pomelo varieties from China

China, the largest pomelo producer, has many famous pomelo varieties. However, there has been limited research on the comparative of chemical compositions and antioxidant activities among different pomelo varieties from China. In the work, five pomelo varieties and one grapefruit variety from China were studied by investigating their chemical composition and antioxidant activity. Volatiles in dichloromethane extract of pomelo peels were measured using gas chromatography - mass spectrometry. Shatianyu pomelo contained 27 volatile compounds, was the most abundant in volatiles. Total protein, phenols, and flavonoid were determined by spectrophotometry. Changshanhuyou grapefruit contained more phenols and flavonoids, while Shatianyu pomelo contained more protein. The amount of vitamin C, sugars, and organic acids were evaluated using liquid chromatography. Shatianyu pomelo had the highest amount of vitamin C and sugars, and the lower amount of organic acids. Guanximiyu pomelo had the highest amount of organic acids. Shatianyu pomelo and Changshanhuyou grapefruit possessed the higher antioxidant activities as compared to other four pomelo varieties. The antioxidant activities of pomelo pulp had no obvious correlation with the amount of total phenols, total falconoid, and vitamin C. This study is helpful to understand the nutritional value and health function of six Chinese famous pomelo varieties

A Human Brain Model Mimicking Umbilical Cord Mesenchymal Stem Cells for the Treatment of Hypoxic-Ischemic Brain Injury

We used an in vitro model of the human brain immune microenvironment to simulate hypoxic-ischemic brain injury (HIBI) and treatment with human umbilical cord mesenchymal stem cells (hUMSCs) to address the transformation barriers of gene differences between animals and humans in preclinical research. A co-culture system, termed hNAME, consisted of human hippocampal neurons (N), astrocytes (A), microglia (M), and brain microvascular endothelial cells (E). Flow cytometry measured the apoptosis rates of neurons and endothelial cells. hNAME-neurons and endothelial cells experienced more severe damage than monolayer cells, particularly after 48 h and 24 h of reoxygenation (OGD48/R24). Western blotting identified neuroinflammatory response markers, including HIF-1α, C1q, C3, TNF-α, and iNOS. Inflammatory factors originated from the glial chamber rather than the neurons and vascular endothelial chambers. A gradual increase in the release of inflammatory factors was observed as the OGD and reoxygenation times increased, peaking at OGD48/R24. The hNAME value was confirmed in human umbilical cord mesenchymal stem cells (hUMSCs). Treatment with hUMSCs resulted in a notable decrease in the severity of neuronal and endothelial cell damage in hNAME. The hNAME is an ideal in vitro model for simulating the immune microenvironment of the human brain because of the interactions between neurons, vessels, astrocytes, and microglia