An impaired 20S proteasome contributes to the accumulation of oxidized proteins in multiple sclerosis and its animal model

Carbonylated (oxidized) proteins are known to accumulate in the brain of patients with multiple sclerosis (MS) and in the spinal cord of rats with acute experimental autoimmune encephalomyelitis (EAE). Yet, our knowledge regarding mechanism(s) underlying the build-up of protein carbonyls in these inflammatory demyelinating disorders is quite limited. The objectives of this dissertation were (1) to measure the changes in protein carbonylation during disease progression, and to identify the target cells and modified proteins in the cerebellum of EAE animals, prepared by active immunization of C57/BL6 mice with MOG35-55 peptide, (2) to determine if the accumulation of carbonylated proteins in the CNS of these animals is due to a defect in the degradation of the modified proteins and (3) to establish if a similar mechanism underlies the build-up of carbonylated proteins in the cerebral white matter (WM) and gray matter (GM) of MS patients. Initial studies using double immunofluorescence microscopy showed that carbonyls accumulate mostly in white matter astrocytes of EAE mice, both in the acute and chronic phase. Two-dimensional oxyblot and mass spectrometry analysis identified β-actin, β-tubulin, GFAP and HSC-71 as the major carbonylation species throughout disease. Using a pull-down/western blot method I also discovered that the proportion of carbonylated cytoskeletal proteins is elevated in chronic EAE, suggesting that as disease progresses from the inflammatory to the neurodegenerative phase there may be an inappropriate removal of these species. This idea was subsequently tested by identifying the 20S proteasome as the proteolytic system responsible for the elimination of oxidized cytoskeletal proteins in cultured astrocytes and by demonstrating that the proteasomal activities were reduced in chronic EAE. These findings were finally extended to the human disease, where I found a profound decrease in proteasomal activity both in the normal-appearing GM and WM of MS patients. Collectively, the studies presented in this dissertation demonstrate that an impaired 20S proteasome in the central nervous system of chronic EAE mice and MS patients significantly contributes to the accumulation of carbonylated (and potentially toxic) proteins. This work may provide the foundation for future studies aimed at developing new approaches to treat MS

Protein carbonylation and aggregation precede neuronal apoptosis induced by partial glutathione depletion

While the build-up of oxidized proteins within cells is believed to be toxic, there is currently no evidence linking protein carbonylation and cell death. In the present study, we show that incubation of nPC12 (neuron-like PC12) cells with 50 μM DEM (diethyl maleate) leads to a partial and transient depletion of glutathione (GSH). Concomitant with GSH disappearance there is increased accumulation of PCOs (protein carbonyls) and cell death (both by necrosis and apoptosis). Immunocytochemical studies also revealed a temporal/spatial relationship between carbonylation and cellular apoptosis. In addition, the extent of all three, PCO accumulation, protein aggregation and cell death, augments if oxidized proteins are not removed by proteasomal degradation. Furthermore, the effectiveness of the carbonyl scavengers hydralazine, histidine hydrazide and methoxylamine at preventing cell death identifies PCOs as the toxic species. Experiments using well-characterized apoptosis inhibitors place protein carbonylation downstream of the mitochondrial transition pore opening and upstream of caspase activation. While the study focused mostly on nPC12 cells, experiments in primary neuronal cultures yielded the same results. The findings are also not restricted to DEM-induced cell death, since a similar relationship between carbonylation and apoptosis was found in staurosporine- and buthionine sulfoximine-treated nPC12 cells. In sum, the above results show for the first time a causal relationship between carbonylation, protein aggregation and apoptosis of neurons undergoing oxidative damage. To the best of our knowledge, this is the first study to place direct (oxidative) protein carbonylation within the apoptotic pathway

Prognostic Value of an Inflammation-Related Index in 6,865 Chinese Patients With Postoperative Digestive Tract Cancers: The FIESTA Study

Objectives: We sought to determine the optimal cutting points for two inflammatory biomarkers, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR), to assess their prognostic value in patients with postoperative digestive tract cancers overall and by cancer sites, and further to construct an inflammation-related index based on the two biomarkers and assess its predictive performance.Methods: Total 6,865 assessable patients with digestive tract cancers who underwent tumor resection were consecutively enrolled from Fujian Cancer Hospital between January 2000 and December 2010, including 2535/3012/1318 patients with esophageal/gastric/colorectal cancer. The latest follow-up (median: 44.9 months) ended in December 2015. Optimal cutting points were determined using survival tree analysis overall and by cancer sites.Results: Among all study patients, the optimal cutting points were 2.07 and 168.50 to define high and low NLR and PLR, respectively. High NLR (hazard ratio [HR]: 1.48, 95% confidence interval [CI]: 1.37–1.61) and high PLR (HR: 1.41, 95% CI: 1.29–1.53) were associated with a significantly increased risk for the mortality of digestive tract cancers as a whole. By cancer sites, effect-size estimates were comparable and statistically significant. Elevation over the selected optimal cutting points for both NLR and PLR was associated with 1.69-fold increased risk of cancer-specific mortality compared to patients with simultaneously low NLR and PLR among all study patients, and this association persisted by cancer sites, especially for gastric cancer.Conclusions: Our findings demonstrate that the preoperative integrated NLR and PLR, as an inflammation-related index, is a significant independent predictor for postoperative mortality in Chinese patients with digestive tract cancers both overall and by cancer sites

Accuracy of EGN model in ultra-wideband optical fiber communication systems

The efficient and accurate evaluation of the transmission performance of high-capacity optical communication systems has always attracted significant research attentions. The enhanced Gaussian noise (EGN) model is considered as an excellent solution to predict the system performance taking into account linear and nonlinear transmission impairments. Since the conventional form of the EGN model is complicated and intractable for a fast computation, the closed-form simplification has been regarded as a direction to significantly reduce the computational complexity. However, the accuracy of such a closed-form EGN model becomes a main concern in the application of ultra-wideband optical communication systems. In this work, we have investigated the accuracy of the closed-form EGN model for ultra-wideband optical fiber communication systems, where the performance of the system using electronic dispersion compensation, multi-channel nonlinearity compensation and full-field nonlinearity compensation has been evaluated in terms of symbol rate, number of channels and signal power. Our work will provide an insight on the application of the EGN model in next-generation ultra-wideband long-haul optical fiber communication networks

Interaction Between Prediabetes and the ABO Blood Types in Predicting Postsurgical Esophageal Squamous Cell Carcinoma-Specific Mortality: The FIESTA Study

Background: We aimed to investigate the interaction between prediabetes and the ABO blood types in predicting esophageal squamous cell carcinoma (ESCC)-specific mortality by analysing data from the FIESTA study on normal/prediabetic patients with ESCC.Methods: Total 1,857 normal/prediabetic patients with ESCC who underwent three-field lymphadenectomy between January 2000 and December 2010 and survived hospitalization were analyzable, with follow-up beginning in 2000 and ending in 2015.Results: At the end of the follow-up, there were 1,161 survivors and 696 non-survivors. The follow-up time ranged from 0.5 to 180 months. The cumulative survival rates in normal patients were obviously better than in prediabetic patients. The cumulative survival rates were significantly higher in normal patients than in prediabetic patients for the blood types O and A (Log-rank test P < 0.05), while no significance was detected for the blood types B and AB. Adjusted risk estimates for ESCC-specific mortality for prediabetic patients relative to normal patients were statistically significant in the blood type B− group (hazard ratio [HR]: 1.71; 95% confidence interval [CI]: 1.33–2.20; P < 0.001), but not in the blood type B+ group (HR: 1.12; 95% CI: 0.77–1.64; P = 0.5544).Conclusions: Our findings indicate that prediabetes can predict the significant risk of ESCC-specific mortality in Chinese Han patients with the blood types O and A

Effects of Crop Planting Structure Adjustment on Water Use Efficiency in the Irrigation Area of Hei River Basin

The adjustment of crop planting structure can change the process of water and material circulation, and thus affect the total amount of water and evapotranspiration in the irrigation district. To guide the allocation of water resources in the region, it is beneficial to ascertain the effects of changing the crop planting structure on water saving and farmland water productivity in the irrigation district. This paper takes Yingke Irrigation District as the background. According to the continuous observation data from 2012 to 2013, Based on the modified Soil and Water Assessment Tool (SWAT) model and taking advantage of monthly scale remote sensing EvapoTranspiration (ET) and crop growth parameters (leaf area index and shoot dry matter), we tested the simulation accuracy of the model, proposed irrigation efficiency calculation methods considering water drainage, and established the scenario analysis method for the spatial distribution of crop planting structure. Finally, we evaluated the changes in water savings in irrigation district projects and resources, the irrigation water productivity and the net income water productivity under different planting structure scenarios. The results indicate that the efficiency of irrigation has increased by 15~20%, while considering drainage, as compared with conventional irrigation efficiency. Additionally, the adjustment of crop planting structure can reduce regional evapotranspiration by 14.9%, reduce the regional irrigation volume by 30%, and increase the net income of each regional water area by 16%

The effects of influent and operational conditions on nitrogen removal in an upflow microaerobic sludge blanket system: a model-based evaluation

Recently, upflow microaerobic sludge blanket (UMSB) system has been developed to remove ammonium and organic matter simultaneously. This study aims to establish influent and operational conditions promoting anammox-based nitrogen removal process in the UMSB reactor by using a modified Activated Sludge Model. Experiments were performed on a laboratory-scale UMSB reactor treated piggery wastewater for over two years. With the experimentally determined model parameters, the established model well simulated the UMSB reactor performance. The maximum anammox growth rate was calibrated to be 0.41 d at 35 °C. Further simulations showed that UMSB reactor operated with high influent organics or nitrogen loading rates at temperature above 15 °C can achieve efficient nitrogen removal (>70%). The nitrogen loading over 0.6 kg N/(m·d)) significantly favors anammox activity. UMSB could also be a promising system for nitrogen removal from low-strength ammonium wastewater with fluctuated COD influence. These results provide support to UMSB design and operational optimization

Bioaugmentation with Mixed Hydrogen-Producing Acetogen Cultures Enhances Methane Production in Molasses Wastewater Treatment

Hydrogen-producing acetogens (HPA) have a transitional role in anaerobic wastewater treatment. Thus, bioaugmentation with HPA cultures can enhance the chemical oxygen demand (COD) removal efficiency and CH4 yield of anaerobic wastewater treatment. Cultures with high degradation capacities for propionic acid and butyric acid were obtained through continuous subculture in enrichment medium and were designated as Z08 and Z12. Bioaugmentation with Z08 and Z12 increased CH4 production by glucose removal to 1.58. Bioaugmentation with Z08 and Z12 increased the COD removal rate in molasses wastewater from 71.60% to 85.84%. The specific H2 and CH4 yields from COD removal increased by factors of 1.54 and 1.63, respectively. Results show that bioaugmentation with HPA-dominated cultures can improve CH4 production from COD removal. Furthermore, hydrogen-producing acetogenesis was identified as the rate-limiting step in anaerobic wastewater treatment

Recommendation Algorithm for Multi-Task Learning with Directed Graph Convolutional Networks

As an important branch of machine learning, recommendation algorithms have attracted the attention of many experts and scholars. The current recommendation algorithms all more or less have problems such as cold start and single recommended items. In order to overcome these problems and improve the accuracy of personalized recommendation algorithms, this paper proposes a recommendation for multi-task learning based on directed graph convolutional network (referred to as MTL-DGCNR) and applies it to recommended areas for e-commerce. First, the user’s micro-behavior is constructed and converted into directed graph structure data for model embedding. It can fully consider the embedding of first-order proximity nodes and second-order proximity nodes, which can effectively enhance the transformation ability of features. Secondly, this model adopts the multi-task learning method, and uses knowledge graph embedding to effectively deal with the one-to-many or many-to-many relationship between users and commodities. Finally, it is verified by experiments that MTL-DGCNR has a higher interpretability and accuracy in the field of e-commerce recommendation than other recommendation models. The ranking evaluation experiments, various training methods comparison experiments, and controlling parameter experiments are designed from multiple perspectives to verify the rationality of MTL-DGCNR

Consolidated bioprocessing for butyric acid production from rice straw with undefined mixed culture

Lignocellulosic biomass is a renewable source with great potential for biofuels and bioproducts. However, the cost of cellulolytic enzymes limits the utilization of the low-cost bioresource. This study aimed to develop a consolidated bioprocessing without the need of supplementary cellulase for butyric acid production from lignocellulosic biomass. A stirred-tank reactor with a working volume of 21 L was constructed and operated in batch and semi-continuous fermentation modes with a cellulolytic butyrate-producing microbial community. The semi-continuous fermentation with intermittent discharging of the culture broth and replenishment with fresh medium achieved the highest butyric acid productivity of 2.69 g/(L•d). In semi-continuous operation mode, the butyric acid and total carboxylic acid concentrations of 16.2 and 28.9 g/L, respectively, were achieved. Over the 21-day fermentation period, their cumulative yields reached 1189 and 2048 g, respectively, corresponding to 41% and 74% of the maximum theoretical yields based on the amount of NaOH pretreated rice straw fed in. This study demonstrated that an undefined mixed culture-based consolidated bioprocessing for butyric acid production can completely eliminate the cost of supplementary cellulolytic enzymes