Functional Profiling of Human Commensal Metabolites in Colorectal Cancer and Pain Sensation

The gastrointestinal tract contains the largest number and greatest diversity of microbes which are referred to collectively as the gut microbiota. Alterations in microbiota dysbiosis are associated with diverse disease states, including colorectal cancer (CRC), inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). However, the causative mechanisms mediated by the gut microbiota are still to be illustrated. Particularly, the gut commensals encode ~150 times more genes than the human genome and thousands of metabolites that mostly lack functional annotations or structural identification. Therefore, the functional profiling of human commensal metabolites is promising to reveal the molecular mechanisms of the gut microbiota regulating homeostasis or disease outcomes. Through systematic forward-screening methods on a large collection of human gut commensals from divergent phylogenies, we investigated how the gut microbiota influences physiological outcomes through small molecule metabolites in CRC colorectal cancer (CRC) and pain sensation. 1) We established an electrophoresis-based pipeline to evaluate the genotoxicity of microbial small molecule metabolites causing DNA damage. Using comparative metabolomics and bioactivity-guided natural product-discovery techniques, we discovered a previously undescribed family of genotoxic metabolites—termed the indolimines—produced by the CRC-associated species Morganella morganii whose ability to exacerbate CRC independent of inflammation was confirmed in gnotobiotic mice. Through transposon-based random mutagenesis, we identified the gene aat (encoding AAT_I protein, aspartate aminotransferase fold type I) responsible for the synthesis of primary amines, precursors of indolimines. The att- M. morganii exhibited defects of genotoxicity. This project reveals the existence of a previously unexplored universe of genotoxic small molecules from the human microbiome and implies a broader role for microbiota-derived genotoxins in CRC. In addition, the cancer-promoting mechanism of M. morganii is dissected at genetic, molecular and physiological levels. The understanding about genotoxins could instruct the diagnoses or therapies of CRC in the future. 2) We established a calcium influx-based pipeline to investigate the endogenous agonists of TRPV1 ion channel derived from the gut microbiota. We found that Klebsiella species and Accidaminococcus intestini enabled to produce heat-stable, small-molecule metabolites to activate TRPV1 channel. Particularly, A. intestini was confirmed to sensitize TRPV1+ nociceptive dorsal root ganglion (DRG) neurons, suggesting the effects of commensal metabolites in pain sensation and relevant diseases like IBS. Untargeted global metabolomics and screening of human small molecule metabolite library implied that microbial-specific phospholipids might be a novel class of endogenous ligands of TRPV1. We are still working on bacteria engineering to identify the genes or gene clusters responsible for the synthesis of TRPV1 agonists. This study indicates a potential mechanism by which the gut commensals regulate visceral pain sensation and provides a new direction for IBS diagnoses or therapies. In summary, both projects underline the significance of functional profiling of the gut microbiota in dissecting causative mechanisms in human diseases, especially those with complex etiology such as cancer, pain syndromes and neurological disorders

A Study On Influential Factors of Residential Rental Prices Based On Hedonic Price Model ——Evidence From Central Urban Districts Of Chengdu

With the government\u27s efforts to regulate housing prices, the trend of excessive housing price increases has been suppressed to some extent. Meanwhile, the government introduced a policy of renting and selling have the same rights, stimulating the development of the housing leasing market, increasing the market demand for residential leasing, and having an important impact on the formation of housing rental prices. This paper analyzes the influential factors of the formation of housing rental prices in Chengdu, selects the key variables of the residential rental characteristic price index, and constructs the model of the influential factors of the characteristic price of housing rental in Chengdu. The empirical study using residential sample data from three central urban districts in Chengdu. The data analysis showed that the 12 variables of residential building characteristics, neighborhood characteristics, location characteristics, and regional characteristics affected the residential rental price to varying degrees. The conclusions of this paper provide a theoretical basis for the pricing and management of residential leasing in Chengdu

Callous-unemotional traits and child response to teacher rewards, discipline, and instructional methods in Chinese preschools: A classroom observation study

Atypical responses to teacher rewards, discipline and different forms of instructional methods have been identified as potential contributors to disruptive behavior, low school engagement, and academic underachievement in children with elevated callous-unemotional (CU) traits. To date, research on CU traits in schools has relied on interview or questionnaire methods and has predominantly been conducted in Western countries. Thus, the present study aims to investigate the relationships between CU traits and children’s responses to teacher rewards, discipline and instructional methods in the Chinese preschool context using classroom observation. Eight teachers (7 females, 1 male; M = 37.66 years) and 116 children (56% girls; M = 5.16 years) from two mainstream Chinese preschools participated in the study. Of the 116 eligible children, the behavior of 108 children from four classes were observed during classroom activities. Findings indicated that CU traits were not related to children’s responses to discipline, nor did CU traits moderate the relationship between instructional methods and children’s academic engagement. Higher CU traits predicted a greater frequency of one-to-one teacher-child interaction. Our findings offer initial insights into the potential of early school-based interventions in fostering engagement and prosocial behavior among children with CU traits. However, they also highlight the need for additional support for preschool teachers, who face the challenge of managing these high-risk children who appear to require more individual time and attention

The oral-gut microbiome axis in inflammatory bowel disease: from inside to insight

Inflammatory bowel disease (IBD) is an idiopathic and persistent inflammatory illness of the bowels, leading to a substantial burden on both society and patients due to its high incidence and recurrence. The pathogenesis of IBD is multifaceted, partly attributed to the imbalance of immune responses toward the gut microbiota. There is a correlation between the severity of the disease and the imbalance in the oral microbiota, which has been discovered in recent research highlighting the role of oral microbes in the development of IBD. In addition, various oral conditions, such as angular cheilitis and periodontitis, are common extraintestinal manifestations (EIMs) of IBD and are associated with the severity of colonic inflammation. However, it is still unclear exactly how the oral microbiota contributes to the pathogenesis of IBD. This review sheds light on the probable causal involvement of oral microbiota in intestinal inflammation by providing an overview of the evidence, developments, and future directions regarding the relationship between oral microbiota and IBD. Changes in the oral microbiota can serve as markers for IBD, aiding in early diagnosis and predicting disease progression. Promising advances in probiotic-mediated oral microbiome modification and antibiotic-targeted eradication of specific oral pathogens hold potential to prevent IBD recurrence

A Two-Year Surveillance of 2009 Pandemic Influenza A (H1N1) in Guangzhou, China: From Pandemic to Seasonal Influenza?

In this two-years surveillance of 2009 pandemic influenza A (H1N1) (pH1N1) in Guangzhou, China, we reported here that the scale and duration of pH1N1 outbreaks, severe disease and fatality rates of pH1N1 patients were significantly lower or shorter in the second epidemic year (May 2010-April 2011) than those in the first epidemic year (May 2009-April 2010) (P<0.05), but similar to those of seasonal influenza (P>0.05). Similar to seasonal influenza, pre-existing chronic pulmonary diseases was a risk factor associated with fatal cases of pH1N1 influenza. Different from seasonal influenza, which occurred in spring/summer seasons annually, pH1N1 influenza mainly occurred in autumn/winter seasons in the first epidemic year, but prolonged to winter/spring season in the second epidemic year. The information suggests a tendency that the epidemics of pH1N1 influenza may probably further shift to spring/summer seasons and become a predominant subtype of seasonal influenza in coming years in Guangzhou, China

The use of multi-fidelity simulation optimisation for real-time management of a manufacturing line

Manufacturers often rely on simulation models to support decision-making for a wide range of tasks from system design to routine operations. There is scope for simulation modelling to extend further to deal with situations that look for fast responses, ideally in real time. Simulation models for manufacturing systems are usually complex and large, meaning they take a long time to run. They are not able to support real-time decision-making when working with conventional simulation optimisation procedures which require multiple replications for producing the recommendations. A multi-fidelity simulation optimisation framework is designed to address this problem. It includes a low-fidelity metamodel to guide the search using the high-fidelity simulation model, which aims to reduce the replications of the high-fidelity model needed in the optimisation. The proposed method has been tested on a well-known simulation model of an inventory system and a new model of a production line. The results from both the textbook example and the manufacturing system show that it satisfies the need for real-time optimisation and performs well. In the production line case, we aim to optimise the repair policy when multiple machines break down simultaneously. The order to repair the failed machines could affect how the system would recover and would lead to different short-term system throughput. By optimising the repair policy, the system throughput is optimised. In order to carry out the optimisation in real time, a ''hot-start'' simulation model is structured for the production line system. The state space of the metamodel for the production line is modified and reduced in order to fit the metamodel with fewer data. An adaptive sequential sampling method is developed to efficiently sample from the stochastic simulation model

Ketamine and Propofol Protect Neuron Cells from Oxygen-Glucose Deprivation-Induced Injury through SAPK/JNK Signalling Pathway

Ketamine and propofol are commonly used anaesthetic reagents. Recent research revealed that ketamine and propofol have an important role in cell survival. However, it remains unknown whether they affect the outcome of hypoxic-ischemic brain injury. To address this issue, we in this study investigated the effects of ketamine and propofol on the survival and proliferation of neuronal PC12 cells after exposure to oxygen-glucose deprivation- (OGD-) induced injury. PC12 cells were maintained under a 3-dimensional (3D) culture system to mimic a real physiological microenvironment. The cell injury was induced by 5% CO2 and 95% N2 for a different time point. MTT assay was used for the cell proliferation assay. The cell apoptosis was evaluated by annexin V and propidium iodide (PI) labeling, immunofluorescence staining, transmission electron microscopy (TEM), flow cytometry, and Western blot, respectively. Our results showed that PC12 cell apoptosis was significantly increased for up to 70% after the cells were treated with OGD for 24 hours and reduced to baseline at the 72-hour time point. However, pretreatment with ketamine and propofol significantly protected the cells from OGD-induced cell apoptosis, as evidenced by more expression of antiapoptotic Bcl-2 and lower expression of proapoptotic cleaved caspase-3, phosphor-SAPK/JNK, and phosphor-c-Jun than those of untreated control cells. Thus, we conclude that ketamine and propofol protected PC12 cells from OGD-induced cell apoptosis, at least partially through the SAPK/JNK signalling pathway