Association of Aβ with Ceramide-Enriched Astrosomes Mediates Aβ Neurotoxicity

Amyloid-β (Aβ) associates with extracellular vesicles termed exosomes. It is not clear whether and how exosomes modulate Aβ neurotoxicity in Alzheimer\u27s disease (AD). We show here that brain tissue and serum from the transgenic mouse model of familial AD (5xFAD) and serum from AD patients contains ceramide-enriched and astrocyte-derived exosomes (termed astrosomes) that are associated with Aβ. In Neuro-2a cells, primary cultured neurons, and human induced pluripotent stem cell-derived neurons, Aβ-associated astrosomes from 5xFAD mice and AD patient serum were specifically transported to mitochondria, induced mitochondrial clustering, and upregulated the fission protein Drp-1 at a concentration corresponding to 5 femtomoles Aβ/L of medium. Aβ-associated astrosomes, but not wild type or control human serum exosomes, mediated binding of Aβ to voltage-dependent anion channel 1 (VDAC1) and subsequently, activated caspases. Aβ-associated astrosomes induced neurite fragmentation and neuronal cell death, suggesting that association with astrosomes substantially enhances Aβ neurotoxicity in AD and may comprise a novel target for therapy

Novel Function of Ceramide for Regulation of Mitochondrial ATP Release in Astrocytes

We reported that amyloid β peptide (Aβ42) activated neutral SMase 2 (nSMase2), thereby increasing the concentration of the sphingolipid ceramide in astrocytes. Here, we show that Aβ42 induced mitochondrial fragmentation in wild-type astrocytes, but not in nSMase2-deficient cells or astrocytes treated with fumonisin B1 (FB1), an inhibitor of ceramide synthases. Unexpectedly, ceramide depletion was concurrent with rapid movements of mitochondria, indicating an unknown function of ceramide for mitochondria. Using immunocytochemistry and super-resolution microscopy, we detected ceramide-enriched and mitochondria-associated membranes (CEMAMs) that were codistributed with microtubules. Interaction of ceramide with tubulin was confirmed by cross-linking to N-[9-(3-pent-4-ynyl-3-H-diazirine-3-yl)-nonanoyl]-D-erythro-sphingosine (pacFACer), a bifunctional ceramide analog, and binding of tubulin to ceramide-linked agarose beads. Ceramide-associated tubulin (CAT) translocated from the perinuclear region to peripheral CEMAMs and mitochondria, which was prevented in nSMase2-deficient or FB1-treated astrocytes. Proximity ligation and coimmunoprecipitation assays showed that ceramide depletion reduced association of tubulin with voltage-dependent anion channel 1 (VDAC1), an interaction known to block mitochondrial ADP/ATP transport. Ceramide-depleted astrocytes contained higher levels of ATP, suggesting that ceramide-induced CAT formation leads to VDAC1 closure, thereby reducing mitochondrial ATP release, and potentially motility and resistance to Aβ42. Our data also indicate that inhibiting ceramide generation may protect mitochondria in Alzheimer’s disease

Increased Liver Tumor Formation in Neutral Sphingomyelinase-2-Deficient Mice

Sphingolipids are key signaling lipids in cancer. Genome-wide studies have identified neutral SMase-2 (nSMase2), an enzyme generating ceramide from SM, as a potential repressor for hepatocellular carcinoma. However, little is known about the sphingolipids regulated by nSMase2 and their roles in liver tumor development. We discovered growth of spontaneous liver tumors in 27.3% (9 of 33) of aged male nSMase2-deficient (fro/fro) mice. Lipidomics analysis showed a marked increase of SM in the tumor. Unexpectedly, tumor tissues presented with more than a 7-fold increase of C16-ceramide, concurrent with upregulation of ceramide synthase 5. The fro/fro liver tumor, but not adjacent tissue, exhibited substantial accumulation of lipid droplets, suggesting that nSMase2 deficiency is associated with tumor growth and increased neutral lipid generation in the tumor. Tumor tissue expressed significantly increased levels of CD133 and EpCAM mRNA, two markers of liver cancer stem-like cells (CSCs) and higher levels of phosphorylated signal transducer and activator of transcription 3, an essential regulator of stemness. CD133(+) cells showed strong labeling for SM and ceramide. In conclusion, these results suggest that SMase-2 deficiency plays a role in the survival or proliferation of CSCs, leading to spontaneous tumors, which is associated with tumor-specific effects on lipid homeostasis

Genomic epidemiology of dengue in Shantou, China, 2019

ObjectivesDengue has been endemic in Southeast Asian countries for decades. There are few reports tracing the dynamics of dengue in real time. In this study, we generated hundreds of pathogen genomes to understand the genomic epidemiology of an outbreak in a hyper-endemic area of dengue.MethodsWe leveraged whole-genome short-read sequencing (PE150) to generate genomes of the dengue virus and investigated the genomic epidemiology of a dengue virus transmission in a mesoscale outbreak in Shantou, China, in 2019.ResultsThe outbreak was sustained from July to December 2019. The total accumulated number of laboratory-confirmed cases was 944. No gender bias or fatalities were recorded. Cambodia and Singapore were the main sources of imported dengue cases (74.07%, n = 20). A total of 284 dengue virus strains were isolated, including 259 DENV-1, 24 DENV-2, and 1 DENV-3 isolates. We generated the entire genome of 252 DENV isolates (229 DENV-1, 22 DENV-2, and 1 DENV-3), which represented 26.7% of the total cases. Combined epidemiological and phylogenetic analyses indicated multiple independent introductions. The internal transmission evaluations and transmission network reconstruction supported the inference of phylodynamic analysis, with high Bayes factor support in BSSVS analysis. Two expansion founders and transmission chains were detected in CCH and LG of Shantou.ConclusionsWe observed the instant effects of genomic epidemiology in monitoring the dynamics of DENV and highlighted its prospects for real-time tracing of outbreaks of other novel agents in the future

Soil chemistry, metabarcoding, and metabolome analyses reveal that a sugarcane—Dictyophora indusiata intercropping system can enhance soil health by reducing soil nitrogen loss

IntroductionGreater amounts of fertilizer are applied every year to meet the growing demand for food. Sugarcane is one of the important food sources for human beings.MethodsHere, we evaluated the effects of a sugarcane—Dictyophora indusiata (DI) intercropping system on soil health by conducting an experiment with three different treatments: (1) bagasse application (BAS process), (2) bagasse + DI (DIS process), and (3) the control (CK). We then analyzed soil chemistry, the diversity of soil bacteria and fungi, and the composition of metabolites to clarify the mechanism underlying the effects of this intercropping system on soil properties.Results and discussionSoil chemistry analyses revealed that the content of several soil nutrients such as nitrogen (N) and phosphorus (P) was higher in the BAS process than in the CK. In the DIS process, a large amount of soil P was consumed by DI. At the same time, the urease activity was inhibited, thus slowing down the loss of soil in the DI process, while the activity of other enzymes such as β-glucosidase and laccase was increased. It was also noticed that the content of lanthanum and calcium was higher in the BAS process than in the other treatments, and DI did not significantly alter the concentrations of these soil metal ions. Bacterial diversity was higher in the BAS process than in the other treatments, and fungal diversity was lower in the DIS process than in the other treatments. The soil metabolome analysis revealed that the abundance of carbohydrate metabolites was significantly lower in the BAS process than in the CK and the DIS process. The abundance of D(+)-talose was correlated with the content of soil nutrients. Path analysis revealed that the content of soil nutrients in the DIS process was mainly affected by fungi, bacteria, the soil metabolome, and soil enzyme activity. Our findings indicate that the sugarcane–DIS intercropping system can enhance soil health

Influence of torsional stiffness on load sharing coefficient of a power split drive system

A dynamic model of power split transmission system with face gear and cylindrical gear is established. The factors including time-varying mesh stiffness, torsional stiffness, supporting stiffness, and clearance are considered in the model. The influence of the torsional stiffness of compound gear shaft on the load sharing coefficient is analyzed. The results show that the influence of the torsional stiffness of the compound gear shaft is obvious. Because the torsional stiffness of the output gear components is larger and the torsional stiffness of the input gear is smaller, so the input stage's deformation coordination ability is strong. Therefore, with the increase of the torsional stiffness of the compound gear shaft, the load sharing coefficient of the power input stages is improved, but the load sharing coefficient of the split torque stages and power confluence stages is worse. Hence, the torsional stiffness ratio of the transmission shaft should be rationally allocated under the condition that the torsional stiffness of the compound shaft is small

Influence of crack depth on dynamic characteristics of spur gear system

BackgroundRoot crack is relatively common failure scenarios in spur gear system, and its dynamic characteristics and crack identification theory are addressed by many scholars. However, cracked spur gear identification model, especially related to its signal propagation characteristics, requires in-depth research due to the limited published works.PurposeTherefore, a bending–torsional coupling nonlinear vibration model of six degrees of freedom (DOF) is established through lumped mass method. Besides, the influence of tooth root crack on the measuring point signal is considered in the model.MethodsThe system response is solved by Runge–Kutta numerical integration method. The change of different tooth-root crack depth on the response amplitude of measuring points is studied.ResultsIt is found that with the increase of crack length, meshing stiffness of single-tooth mashing area and double-tooth meshing area are reduced. In addition, precision reduces slightly, but the overall precision calculated by 6-order ARX identification model is greater than 99.40%.ConclusionThe research provides a theoretical basis for the system testing and measuring point’s parameter identification

A new mathematical modeling method for four-stage helicopter main gearbox and dynamic response optimization

A new mathematical modeling method, namely the finite element method and the lumped mass method (LMM-FEM) mixed modeling, is applied to establish the overall multi-node dynamic model of a four-stage helicopter main gearbox. The design of structural parameters of the shaft is the critical link in the four-stage gearbox, it affects the response of multiple input and output branches; however, only the meshing pairs were frequently shown in the dynamic model in previous research. Therefore, each shaft is also treated as a single node and the shaft parameters are coupled into the dynamic equations in this method, which is more accurate for the transmission chain. The differential equations of the system are solved by the Fourier series method, and the dynamic response of each meshing element is calculated. The sensitivity analysis method and parameter optimization method are applied to obtain the key shaft parameters corresponding to each meshing element. The results show that the magnitude of dynamic response in converging meshing pair and tail output pair are higher than that of other meshing pairs, and the wall thickness has great sensitivity to rotor shaft. In addition, the sensitivity analysis method can be used to select the corresponding shaft node efficiently and choose parameters appropriately for reducing the system response