Microbial mediated arsenic biotransformation in wetlands

Arsenic (As) is a pervasive environmental toxin and carcinogenic metalloid. It ranks at the top of the US priority List of Hazardous Substances and causes worldwide human health problems. Wetlands, including natural and artificial ecosystems (i.e. paddy soils) are highly susceptible to As enrichment; acting not only as repositories for water but a host of other elemental/chemical moieties. While macro-scale processes (physical and geological) supply As to wetlands, it is the micro-scale biogeochemistry that regulates the fluxes of As and other trace elements from the semi-terrestrial to neighboring plant/aquatic/atmospheric compartments. Among these fine-scale events, microbial mediated As biotransformations contribute most to the element’s changing forms, acting as the ‘switch’ in defining a wetland as either a source or sink of As. Much of our understanding of these important microbial catalyzed reactions follows relatively recent scientific discoveries. Here we document some of these key advances, with focuses on the implications that wetlands and their microbial mediated transformation pathways have on the global As cycle, the chemistries of microbial mediated As oxidation, reduction and methylation, and future research priorities areas

Molecular Evidence of Bartonella melophagi in Ticks in Border Areas of Xinjiang, China

Bartonella are gram-negative intracellular bacteria; certain species of Bartonella can cause diseases in mammals and humans. Ticks play a major role in the transmission of Bartonella. Xinjiang is the largest province in China according to land area and has one-third of the tick species in China; the infection rate of Bartonella in ticks in the Xinjiang border areas has not been studied in detail. Therefore, this study investigated tick infections by Bartonella in Xinjiang border areas, and the purpose of the study was to fill in gaps in information regarding the genetic diversity of tick infections by Bartonella in Xinjiang. We tested 1,549 tick samples from domestic animals (sheep and cattle) for Bartonella using ribC-PCR. Positive samples from the ribC-PCR assay for Bartonella spp. were further subjected to PCR assays targeting the ITS, rpoB and gltA genes followed by phylogenetic analyses. Bartonella DNA was detected in 2.19% (34/1,549) of tick samples, and the ITS, rpoB and gltA genes of ribC gene-positive samples were amplified to identify nine samples of Bartonella melophagi. In this study, molecular analysis was used to assess the presence and genetic diversity of B. melophagi in ticks collected from sheep and cattle from Xinjiang, China. This study provides new information on the presence and identity of B. melophagi in ticks from sheep and cattle

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction  = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Investigation of new pantothenate derivatives to combat the antimicrobial crisis

Antimicrobial resistance has been an increasing public health threat in the world, due to the rapid evolution and gene transfers by microbes. Various efforts have been taken to combat antimicrobial resistance, spanning from a drive to identify unexploited antimicrobial targets to a renewed push for novel antimicrobial agents. Coenzyme A (CoA) is an essential cofactor for all living organisms. It is generally biosynthesized in five universal enzymatic steps. Although this five-step pathway is conserved in various organisms, the involved enzymes differ significantly between organisms. Therefore, focusing on the CoA biosynthetic pathway, this thesis exploits three strategies that have potential to overcome antimicrobial resistance. The first strategy used is to revisit an old, unexploited class of antimicrobials: pantothenamides, which are secondary or tertiary amides of pantothenic acid. This class of compounds exerts antimicrobial activity via a new mode of action, interfering the CoA-related pathway. Despite their interesting antimicrobial activity, their clinical use is however hindered due to their instability in human serum. To address the instability issue of pantothenamides, in chapter 2, a cross-metathesis approach to install larger groups at the geminal dimethyl position of pantothenamides was successfully developed, and was demonstrated to be an effective way to impart stability to pantothenamides in human serum. In chapter 3 and 4, a pantothenamide analogue which has the labile amide bond replaced with a stable triazole ring, was used to design a series of new pantothenamide derivatives. Overall, three new nanomolar antiplasmodial heteroaromatic pantothenamide analogues were discovered. The results also revealed a new way by which triazoles mimic amide bonds.The second strategy seeks novel antimicrobial targets. Pantothenate kinase (PanK), which catalyzes the phosphorylation of pantothenate to 4’-phosphopantothenate, is the first enzyme in the CoA biosynthetic pathway. It can be classified into three types (type I, II and III). Several inhibitors and alternative substrates have been reported for type I and II, whereas only weak inhibitors have been reported for type III. To design better inhibitors and substrates for not only type I and II PanK but also type III PanK, a small series of pantothenate analogues were synthesized in chapter 5. They were exploited as probes to compare the ligand preference of the three types of bacterial PanK. Overall, several new inhibitors and substrates were identified for each type of bacterial PanK. The third strategy involves reactivating old antibiotics. Effectiveness of aminoglycosides can be reduced towards bacteria after being acetylated by an aminoglycoside acetyltransferase. As an aminoglycoside potentiator, P-1b can effectively restore the effectiveness of aminoglycosides towards resistant bacteria. P-1b was suggested to exert its potentiating effect after being transformed by the CoA biosynthetic pathway to a CoA derivative which inhibits the acetyltransferase in resistant bacteria. To better understand the mechanism of action of P-1b, a series of in cellulo studies was performed and reported in chapter 6. The results revealed a new acetyltransferase inhibitor, and suggested that P-1b may be transformed into more than one acetyltransferase inhibitors in bacteria.La résistance aux antimicrobiennes est devenue une menace majeure à la santé publique mondiale, due à l’évolution rapide des microbes et aux transferts de gènes qu’ils effectuent. Des efforts variés ont été effectués pour combattre la résistance bactérienne, allant d’une volonté d’identifier des cibles antibactériennes inexploitées à un effort renouvelé pour le développement de nouveaux agents antibactériens. Le coenzyme A (CoA) est un cofacteur essentiel à tout organisme vivant. Il est généralement biosynthétisé par cinq étapes enzymatiques universelles. Bien que cette cascade de cinq étapes soit conservée, les enzymes impliquées diffèrent de manière significative d’un organisme à l’autre. En conséquence, en se concentrant sur le chemin de biosynthèse du CoA, cette thèse exploite trois stratégies présentant un potentiel pour vaincre la résistance microbienne.La première stratégie utilisée consiste à revisiter une ancienne classe d’antimicrobiennes non exploitée, des amines secondaires et tertiaires de l’acide pantothénique. Cette classe de composés exerce une activité antimicrobienne par un nouveau mode d’action qui interfère avec la voie de synthèse du CoA. En dépit de leur activité antibactérienne intéressante, leur utilisation clinique est empêchée par leur instabilité dans le sérum humain. Afin de remédier à ce problème d’instabilité des pantothénamides, une approche reposant sur la métathèse croisée a été développée avec succès, dans le chapitre 2, qui installe des groupes encombrants à la position diméthyl géminale des pantothénamides, et qui a fait montre d’efficacité dans la stabilisation de pantothénamides dans le sérum humain. Dans les chapitres 3 et 4, un analogue de pantothénamide, dans lequel la liaison amide labile a été remplacée par un cycle triazole stable, a été utilisé pour concevoir une série de nouveaux pantothénamides. Dans l’ensemble, trois nouveaux analogues hétéroaromatiques de pantothénamides possédant une activité anti-plasmodiale au niveau nanomolaire ont été découverts. Les résultats ont également révélé une nouvelle façon qu’ont les triazoles de mimer les liaisons amides.La deuxième stratégie identifie de nouvelles cibles antimicrobiennes. La pantothénate kinase (PanK), qui catalyse la phosphorylation du pantothénate en 4’-phosphopantothénate, est la première enzyme du chemin biosynthétique du CoA. Elle peut être classifiée en trois types (types I, II et III). Plusieurs inhibiteurs et substrats alternatifs ont été reportés pour les types I et II, tandis que seulement de faibles inhibiteurs ont été reportés pour le type III. Afin de concevoir de meilleurs inhibiteurs et substrats pour les PanK, non seulement de type I et II mais également III, une courte série d’analogues du pantothénate ont été synthétisées dans le chapitre 5. Ils ont été utilisés en tant que sondes pour comparer les ligands préférentiels des trois types de PanK. Dans l’ensemble, plusieurs nouveaux inhibiteurs et substrats ont été identifiés pour chaque type de PanK. La troisième stratégie implique la réactivation de vieux antibiotiques. L’efficacité des aminoglycosides contre les bactéries peut être réduite par leur acétylation par une aminoglycoside transférase. En tant que potentiateur d’aminoglycoside, P-1b peut rendre leur efficacité aux aminoglycosides à l’encontre des bactéries résistantes. Il a été suggéré que P-1b exerce une action de potentiation après avoir été transformé par le chemin de synthèse du CoA en un dérivé de CoA qui inhibe l’acétyltransférase des bactéries résistantes. Dans le but de mieux comprendre le mécanisme d’action de P-1b, une série d’études in cellulo ont été effectuées et rapportées dans le chapitre 6. Les résultats ont révélé un nouvel inhibiteur d’acétyltransférase et ont suggéré que P-1b est possiblement transformé en plus d’une forme d’inhibiteur d’acétyltransférase au sein des bactéries

Inducing RNAi by feeding

RNA interference (RNAi) is a technique that deliberately introducing dsRNA sequences identical to the sequence of a gene, then the result of the silence of the gene can be observed. RNAi can be activated in C. elegans, a roundworm commonly studied by researchers, by feeding worms bacteria expressing dsRNA. In this project, two RNAi strain of E. coli, dqy-11 and bli-1, will be introduced to C. elegans. Each RNAi “feeding strain” of bacteria contains a plasmid with a piece of DNA containing sequence from the gene it is designed to silence. The dsRNA eaten by the worms will turn down the gene and the results can be examined by any changes of the phenotypes

DINS : a distributed scheme for sensor fusion over fading channels

In this paper, we consider the problem of distributed sensor fusion in relay-assisted sensor networks with time-varying asymmetric communications over fading channels. A Distributed INnovation based Scheme (DINS) is proposed by fusing both the local measurements and the information received from neighboring nodes. We present a hybrid TDMA scheme for efficient implementation of DINS and the design of parameters of DINS to bring the effects of fading under a satisfactory level. With an appropriate design, it is shown that our algorithm is able to produce estimates with desired asymptotic properties of unbiasedness and consistency. Simulation results are provided to demonstrate the performance of DINS.Published versio

Challenges and potential of PD-1/PD-L1 checkpoint blockade immunotherapy for glioblastoma

Abstract PD-1/PD-L1 checkpoint blockades have achieved significant progress in several kinds of tumours. Pembrolizumab, which targets PD-1, has been approved as a first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with positive PD-L1 expression. However, PD-1/PD-L1 checkpoint blockades have not achieved breakthroughs in treating glioblastoma because glioblastoma has a low immunogenic response and an immunosuppressive microenvironment caused by the precise crosstalk between cytokines and immune cells. A phase III clinical trial, Checkmate 143, reported that nivolumab, which targets PD-1, did not demonstrate survival benefits compared with bavacizumab in recurrent glioblastoma patients. Thus, the combination of a PD-1/PD-L1 checkpoint blockade with RT, TMZ, antibodies targeting other inhibitory or stimulatory molecules, targeted therapy, and vaccines may be an appealing solution aimed at achieving optimal clinical benefit. There are many ongoing clinical trials exploring the efficacy of various approaches based on PD-1/PD-L1 checkpoint blockades in primary or recurrent glioblastoma patients. Many challenges need to be overcome, including the identification of discrepancies between different genomic subtypes in their response to PD-1/PD-L1 checkpoint blockades, the selection of PD-1/PD-L1 checkpoint blockades for primary versus recurrent glioblastoma, and the identification of the optimal combination and sequence of combination therapy. In this review, we describe the immunosuppressive molecular characteristics of the tumour microenvironment (TME), candidate biomarkers of PD-1/PD-L1 checkpoint blockades, ongoing clinical trials and challenges of PD-1/PD-L1 checkpoint blockades in glioblastoma

A cross-metathesis approach to novel pantothenamide derivatives

Pantothenamides are known for their in vitro antimicrobial activity. Our group has previously reported a new stereoselective route to access derivatives modified at the geminal dimethyl moiety. This route however fails in the addition of large substituents. Here we report a new synthetic route that exploits the known allyl derivative, allowing for the installation of larger groups via cross-metathesis. The method was applied in the synthesis of a new pantothenamide with improved stability in human blood