Celiac disease (CeD) is a complex T cell-mediated enteropathy induced by gluten. Although genome-wide association studies have identified numerous genomic regions associated with CeD, it is... Show moreCeliac disease (CeD) is a complex T cell-mediated enteropathy induced by gluten. Although genome-wide association studies have identified numerous genomic regions associated with CeD, it is difficult to accurately pinpoint which genes in these loci are most likely to cause CeD. We used four different in silico approaches-Mendelian randomization inverse variance weighting, COLOC, LD overlap, and DEPICT-to integrate information gathered from a large transcriptomics dataset. This identified 118 prioritized genes across 50 CeD-associated regions. Co-expression and pathway analysis of these genes indicated an association with adaptive and innate cytokine signaling and T cell activation pathways. Fifty-one of these genes are targets of known drug compounds or likely druggable genes, suggesting that our methods can be used to pinpoint potential therapeutic targets. In addition, we detected 172 gene combinations that were affected by our CeD-prioritized genes in trans. Notably, 41 of these trans-mediated genes appear to be under control of one master regulator, TRAF-type zinc finger domain containing 1 (TRAFD1), and were found to be involved in interferon (IFN)gamma signaling and MHC I antigen processing/presentation. Finally, we performed in vitro experiments in a human monocytic cell line that validated the role of TRAFD1 as an immune regulator acting in trans. Our strategy confirmed the role of adaptive immunity in CeD and revealed a genetic link between CeD and IFN gamma signaling as well as with MHC I antigen processing, both major players of immune activation and CeD pathogenesis. Show less
The prokaryotic chemotaxis system is arguably the best-understood signaling pathway in biology. In all previously described species, chemoreceptors organize into a hexagonal (P6 symmetry) extended... Show moreThe prokaryotic chemotaxis system is arguably the best-understood signaling pathway in biology. In all previously described species, chemoreceptors organize into a hexagonal (P6 symmetry) extended array. Here, we report an alternative symmetry (P2) of the chemotaxis apparatus that emerges from a strict linear organization of the histidine kinase CheA in Treponema denticola cells, which possesses arrays with the highest native curvature investigated thus far. Using cryo-ET, we reveal that Td chemoreceptor arrays assume an unusual arrangement of the supra-molecular protein assembly that has likely evolved to accommodate the high membrane curvature. The arrays have several atypical features, such as an extended dimerization domain of CheA and a variant CheW-CheR-like fusion protein that is critical for maintaining an ordered chemosensory apparatus. Furthermore, the previously characterized Td oxygen sensor ODP influences CheA ordering. These results suggest a greater diversity of the chemotaxis signaling system than previously thought. Show less
Zhang, C.; Hu, M.; Laclau, B.; Garnesson, T.; Yang, X.; Li, C.; Tukker, A. 2020
Around 35% of the buildings in Europe are over 50 years old and almost 75% of the building stock is energy-inefficient. A European project VEEP is developing an innovative prefabricated concrete... Show moreAround 35% of the buildings in Europe are over 50 years old and almost 75% of the building stock is energy-inefficient. A European project VEEP is developing an innovative prefabricated concrete element (PCE) system to improve the thermal performance of new buildings (PCE1) and old buildings (PCE2). This study focused on retrofitting of old buildings via over-cladding of the building envelope with PCE2. This study aims to from a building owner/consumer’s perspective to explore the life cycle economic performance of the PCE2 system at an early stage and associated cost optimization strategies under the European context. This study tries to answer four questions: 1) whether the use of the PCE2 leads to an economic advantage over a specific life cycle of an existing building. 2) what is the biggest cost stressor in the life cycle of a PCE2? 3) the potential route for further cost optimization. and 4) how would the discount rate affect the life cycle costs, especially when Europe has entered a negative rate age? A typical apartment building in the Netherlands is selected as the case study for dynamic thermal simulation, in which the heating and cooling energy demands before and after refurbishment with PCE2 will be evaluated. By employing environmental life cycle costing (LCC), the life cycle costs over 40 years and associated strategy for cost optimization will be investigated. This research not only unveils meaningful financial implications on resource-efficient building energy retrofitting in Europe but also provides insight on methodological dilemmas within the application of LCC. Show less
The transmission of antibiotic resistance in surface water has attracted much attention due to its increasing threat to human health. The role of sunlight irradiation and the effect of dissolved... Show moreThe transmission of antibiotic resistance in surface water has attracted much attention due to its increasing threat to human health. The role of sunlight irradiation and the effect of dissolved organic matter (DOM) on the transmission of antibiotic resistance are still unclear. In this study, photo-inactivation of antibiotic resistant bacteria (ARB) was investigated using antibiotic resistant E. coli (AR E. coli) that contained the tetracycline resistance gene (Tc-ARG) as a representative. The results showed that AR E. coli underwent significant photo-inactivation due to the membrane damage induced by direct irradiation and by the generated reactive oxygen species. Simulated sunlight irradiation specifically suppressed the expression of tetracycline resistance, which is attributed to the destruction of tetracycline-specific efflux pump. Tetracycline inhibited the photo-inactivation of AR E. coli due to its selective pressure on tetracycline resistant E. coli and competitive light absorption effect. Suwannee River fulvic acid (SRFA), a representative DOM, promoted the inactivation of AR E. coli and further inhibited the expression of tetracycline resistance gene due to the generation of its excited triplet state, singlet oxygen, and hydroxyl radical. The extracellular Tc-ARG also underwent fast photodegradation under light irradiation and in the presence of SRFA, which leads to the decrease of its transformation efficiency. This study provided insight into the sunlight-induced inactivation of ARB, which is of significance for understanding the transmission of tetracycline resistance in surface water. Show less
Sun, M.; Wu, H.; He, M.; Jia, Y.; Wang, L.; Liu, T.; ... ; Wang, M. 2020
The transition of the energy system from fossil fuel towards renewable energy (RE) is rising sharply, which provides a cleaner energy source to the urban smart grid system. However, owing to the... Show moreThe transition of the energy system from fossil fuel towards renewable energy (RE) is rising sharply, which provides a cleaner energy source to the urban smart grid system. However, owing to the volatility and intermittency of RE, it is challenging to design an accurate and reliable short-term load forecasting model. Recently, machine learning (ML) based forecasting models have been applied for short-term load forecasting whereas most of them ignore the importance of characteristics mining, parameters fine-tuning, and forecasting stability. To dissolve the above issues, a short-term load forecasting model is proposed that incorporates thorough data mining and multi-step rolling forecasting. To alleviate the chaos of short-term load, a de-noising method based on decomposition and reconstruction is used. Then, a phase space reconstruction (PSR) method is employed to dynamically determine the train-test ratios and neurons settings of the artificial neural network (ANN). Further, a multi-objective grasshopper optimization algorithm (MOGOA) is applied to optimize the parameters of ANNs. Case studies are conducted in the urban smart grid systems of Victoria and New South Wales in Australia. Simulation results show that the proposed model can forecast short-term load well with various measurement metrics. Multiple criterion and statistical evaluation also show the good performance of the proposed forecasting model in terms of accuracy and stability. To conclude, the proposed model achieves high accuracy and robustness, which will provide references to RE transitions and smart grid optimization, and offer guidance to sustainable city development. Show less
Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results... Show moreLeukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1 , PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease. Show less
This dissertation offers a narrative perspective of the power dynamics between the Buddha and his disciples. It selects multiple narratives revolving around figures from the early monastic... Show moreThis dissertation offers a narrative perspective of the power dynamics between the Buddha and his disciples. It selects multiple narratives revolving around figures from the early monastic community as represented by Śāriputra, Devadatta, Ānanda, and Kāśyapa, who attempt to compete with, challenge, or succeed the Buddha. My treatment of the Devadatta narratives in their historical development and ideological complexities reveals that the Devadatta narrative itself is a body of multilayered, ever-changing and self-reflective rhetoric, whose pivotal function is to cope with the potential problems substantialized by Devadatta’s challenges to the Buddha. All of the vibrant stories I analyze here, which are wide-ranging in terms of geography and chronology, are open windows into the Buddhist self-understanding of fundamental theological questions concerning the nature and significance of the buddha and the identity of being a Buddhist, as well as practical issues such as how to maintain their authority and accommodate their updated needs in an age without a buddha. Seeking its methodological basis in philology, history, and literary theory, this dissertation sheds light on the dynamic interplay between narratives and ideologies and enhances our understanding of the significance of narrative in reflecting and stimulating new ideologies and constructing histories of early Buddhism. Show less
Ulcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation... Show moreUlcerative colitis is a chronic, relapsing inflammatory condition of the gastrointestinal tract with a complex genetic and environmental etiology. In an effort to identify genetic variation underlying ulcerative colitis risk, we present two distinct genome-wide association studies of ulcerative colitis and their joint analysis with a previously published scan(1), comprising, in aggregate, 2,693 individuals with ulcerative colitis and 6,791 control subjects. Fifty-nine SNPs from 14 independent loci attained an association significance of P < 10(-5). Seven of these loci exceeded genome-wide significance (P < 5 x 10(-8)). After testing an independent cohort of 2,009 cases of ulcerative colitis and 1,580 controls, we identified 13 loci that were significantly associated with ulcerative colitis (P < 5 x 10(-8)), including the immunoglobulin receptor gene FCGR2A, 5p15, 2p16 and ORMDL3 (orosomucoid1-like 3). We confirmed association with 14 previously identified ulcerative colitis susceptibility loci, and an analysis of acknowledged Crohn's disease loci showed that roughly half of the known Crohn's disease associations are shared with ulcerative colitis. These data implicate approximately 30 loci in ulcerative colitis, thereby providing insight into disease pathogenesis. Show less
