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Publication Genetic diversity in new members of the reticulocyte binding protein family in Thai Plasmodium vivax isolates(Public Library of Science, 2012) Kosaisavee V.; Lek-Uthai U.; Suwanarusk R.; Grüner A.C.; Russell B.; Nosten F.; Rénia L.; Snounou G.; MICROBIOLOGY AND IMMUNOLOGYBackground: Plasmodium vivax merozoites specifically invade reticulocytes. Until recently, two reticulocyte-binding proteins (Pvrbp1 and Pvrbp2) expressed at the apical pole of the P. vivax merozoite were considered to be involved in reticulocyte recognition. The genome sequence recently obtained for the Salvador I (Sal-I) strain of P. vivax revealed additional genes in this family, and in particular Pvrbp2a, Pvrbp2b (Pvrbp2 has been renamed as Pvrbp2c) and two pseudogenes Pvrbp2d and Pvrbp3. It had been previously found that Pvrbp2c is substantially more polymorphic than Pvrbp1. The primary goal of this study was to ascertain the level of polymorphism of these new genes. Methodology/Principal Findings: The sequence of the Pvrbp2a, Pvrbp2b, Pvrbp2d and Pvrbp3 genes were obtained by amplification/cloning using DNA purified from four isolates collected from patients that acquired the infection in the four cardinal regions of Thailand (west, north, south and east). An additional seven isolates from western Thailand were analyzed for gene copy number variation. There were significant polymorphisms exhibited by these genes (compared to the reference Sal-I strain) with the ratio of mutations leading to a non-synonymous or synonymous amino acid change close to 3:1 for Pvrbp2a and Pvrbp2b. Although the degree of polymorphism exhibited by these two genes was higher than that of Pvrbp1, it did not reach the exceptional diversity noted for Pvrbp2c. It was interesting to note that variations in the copy number of Pvrbp2a and Pvrbp2b occurred in some isolates. Conclusions/Significance: The evolution of different members of the Pvrbp2 family and their relatively high degree of polymorphism suggests that the proteins encoded by these genes are important for parasite survival and are under immune selection. Our data also shows that there are highly conserved regions in rbp2a and rbp2b, which might provide suitable targets for future vaccine development against the blood stage of P. vivax. © 2012 Kosaisavee et al.Publication Colonization with ubiquitous protist Blastocystis ST1 ameliorates DSS-induced colitis and promotes beneficial microbiota and immune outcomes(Springer Science and Business Media LLC) Deng, Lei; Wojciech, Lukasz; Png, Chin Wen; Kioh, Yan Qin Dorinda; Ng, Geok Choo; Chan, Eric Chun Yong; Zhang, Yongliang; Gascoigne, Nicholas RJ; Tan, Kevin Shyong Wei; Assoc Prof Shyong Wei, Kevin Tan; MICROBIOLOGY AND IMMUNOLOGY; PHARMACYAbstractBlastocystis is a species complex that exhibits extensive genetic diversity, evidenced by its classification into several genetically distinct subtypes (ST). Although several studies have shown the relationships between a specific subtype and gut microbiota, there is no study to show the effect of the ubiquitous Blastocystis ST1 on the gut microbiota and host health. Here, we show that Blastocystis ST1 colonization increased the proportion of beneficial bacteria Alloprevotella and Akkermansia, and induced Th2 and Treg cell responses in normal healthy mice. ST1-colonized mice showed decreases in the severity of DSS-induced colitis when compared to non-colonized mice. Furthermore, mice transplanted with ST1-altered gut microbiota were refractory to dextran sulfate sodium (DSS)-induced colitis via induction of Treg cells and elevated short-chain fat acid (SCFA) production. Our results suggest that colonization with Blastocystis ST1, one of the most common subtypes in humans, exerts beneficial effects on host health through modulating the gut microbiota and adaptive immune responses.Publication Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by dimethyl fumarate(2017) Han, J; Ma, S; Gong, H; Liu, S; Lei, L; Hu, B; Xu, Y; Liu, H; Wu, D; MICROBIOLOGY AND IMMUNOLOGYAcute graft-versus-host disease (aGVHD) remains a clinical challenge and a major source of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Dimethyl fumarate (DMF), an activator of Nrf2, has been shown to have anti-inflammatory and immunomodulatory properties without significant immunosuppression. We therefore hypothesized that DMF could be potentially harnessed for the treatment of aGVHD with retention of graft-versus-tumor effect. In this study,we showed that DMF significantly inhibited alloreactive T cell responses in vitro in mixed lymphocyte reaction assay. Administration of DMF significantly alleviated the severity, histological damage, and the overall mortality of aGVHD in an MHC-mismatched aGVHD model. DMF administration reduced the activation and effector function of donor T cells in vitro and in vivo. In addition, DMF treatment upregulated antioxidant enzymes heme oxygenase-1 and glutathione S-transferase-a1 expressions. Furthermore, DMF treatment markedly increased the frequencies of Treg cells. Depletion of CD25+ cells in DMF recipients aggravated aGVHD mortality compared with IgG control recipients. DMF could promote Treg cell differentiation in a dose dependent manner by upregulating TGF-? expression in vitro. Most importantly, DMF administration preserved graft-versus-leukemia effect after bone marrow transplantation. In conclusion, our findings demonstrated DMF as a promising agent for the prevention of aGVHD after allo-HSCT. © 2017 Han, Ma, Gong, Liu, Lei, Hu, Xu, Liu and Wu.Publication Developmental transcriptome of resting cell formation in Mycobacterium smegmatis(BioMed Central Ltd., 2016) Wu M.-L.; Gengenbacher M.; Chung J.C.S.; Chen S.L.; Mollenkopf H.-J.; Kaufmann S.H.E.; Dick T.; MEDICINE; MICROBIOLOGY AND IMMUNOLOGYPublication CD151, a novel host factor of nuclear export signaling in influenza virus infection(MOSBY-ELSEVIER, 2018-05-01) Qiao, Yongkang; Yan, Yan; Sen Tan, Kai; Tan, Sheryl SL; Seet, Ju Ee; Arumugam, Thiruma Valavan; Chow, Vincent TK; Wang, De Yun; Thai, Tran; Assoc Prof Thai Tran; PHYSIOLOGY; MICROBIOLOGY AND IMMUNOLOGY; OTOLARYNGOLOGY; PATHOLOGYBackground: Despite advances in our understanding of the mechanisms of influenza A virus (IAV) infection, the crucial virus-host interactions during the viral replication cycle still remain incomplete. Tetraspanin CD151 is highly expressed in the human respiratory tract, but its pathological role in IAV infection is unknown. Objectives: We sought to characterize the functional role and mechanisms of action of CD151 in IAV infection of the upper and lower respiratory tracts with H1N1 and H3N2 strains. Methods: We used CD151-null mice in an in vivo model of IAV infection and clinical donor samples of in vitro–differentiated human nasal epithelial cells cultured at air-liquid interface. Results: As compared with wild-type infected mice, CD151-null infected mice exhibited a significant reduction in virus titer and improvement in survival that is associated with pronounced host antiviral response and inflammasome activation together with accelerated lung repair. Interestingly, we show that CD151 complexes newly synthesized viral proteins with host nuclear export proteins and stabilizes microtubule complexes, which are key processes necessary for the polarized trafficking of viral progeny to the host plasma membrane for assembly. Conclusions: Our results provide new mechanistic insights into our understanding of IAV infection. We show that CD151 is a critical novel host factor of nuclear export signaling whereby the IAV nuclear export uses it to complement its own nuclear export proteins (a site not targeted by current therapy), making this regulation unique, and holds promise for the development of novel alternative/complementary strategies to reduce IAV severity.Publication Cellular and molecular responses of Dunaliella tertiolecta by expression of a plant medium chain length fatty acid specific acyl-ACP thioesterase(Frontiers Media S.A., 2018) Lin H.; Shen H.; Lee Y.K.; MICROBIOLOGY AND IMMUNOLOGYMetabolic engineering of microalgae to accumulate high levels of medium chain length fatty acids (MCFAs) has met with limited success. Traditional approaches employ single introduction of MCFA specific acyl-ACP thioesterases (TEs), but our current research in transgenic Dunaliella tertiolecta line has highlighted that, there is no single rate-limiting approach that can effectively increase MCFA levels. Here, we explore the accumulation of MCFAs in D. tertiolecta after transgenic expression of myristic acid biased TE (C14TE). We observe that the MCFA levels were negatively correlated to the fatty acid (FA) synthesis genes, ketoacyl-ACP synthase II (KASII), stearoyl-CoA-9-desaturase (Δ9D), and oleoyl-CoA-12-desaturase (Δ12D). To further examine the molecular mechanism of MCFA accumulation in microalgae, we investigate the transcriptomic dynamics of the MCFA producing strain of D. tertiolecta. At the transcript level, enhanced MCFA accumulation primarily involved up-regulation of photosynthetic genes and down-regulation of genes from central carbon metabolic processes, resulting in an overall decrease in carbon precursors for FA synthesis. We additionally observe that MCFA specific peroxisomal ?-oxidation gene (ACX3) was greatly enhanced to prevent excessive build-up of unusual MCFA levels. Besides, long chain acyl-CoA synthetase gene (LACS) was down-regulated, likely in attempt to control fatty acyl supply flux to FA synthesis cycle. This article provides a spatial regulation model of unusual FA accumulation in microalgae and a platform for additional metabolic engineering targeting pathways from FA synthesis, FA transport, and peroxisomal β-oxidation to achieve microalgae oils with higher levels of MCFAs. © 2018 Lin, Shen and Lee.Publication Potential relevance of salivary legumain for the clinical diagnostic of hand, foot, and mouth disease(Wiley, 2023-11-01) Tan, YW; Teo, FMS; Ler, SG; Alli-Shaik, A; Nyo, M; Chong, CY; Tan, NWH; Wang, RYL; Gunaratne, J; Chu, JJH; Dr Yan Ling Ng; MICROBIOLOGY AND IMMUNOLOGY; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); MECHANOBIOLOGY INSTITUTE; CANCER SCIENCE INSTITUTE OF SINGAPOREThe fight against hand, foot, and mouth disease (HFMD) remains an arduous challenge without existing point-of-care (POC) diagnostic platforms for accurate diagnosis and prompt case quarantine. Hence, the purpose of this salivary biomarker discovery study is to set the fundamentals for the realization of POC diagnostics for HFMD. Whole salivary proteome profiling was performed on the saliva obtained from children with HFMD and healthy children, using a reductive dimethylation chemical labeling method coupled with high-resolution mass spectrometry-based quantitative proteomics technology. We identified 19 upregulated (fold change = 1.5–5.8) and 51 downregulated proteins (fold change = 0.1–0.6) in the saliva samples of HFMD patients in comparison to that of healthy volunteers. Four upregulated protein candidates were selected for dot blot-based validation assay, based on novelty as biomarkers and exclusions in oral diseases and cancers. Salivary legumain was validated in the Singapore (n = 43 healthy, 28 HFMD cases) and Taiwan (n = 60 healthy, 47 HFMD cases) cohorts with an area under the receiver operating characteristic curve of 0.7583 and 0.8028, respectively. This study demonstrates the feasibility of a broad-spectrum HFMD POC diagnostic test based on legumain, a virus-specific host systemic signature, in saliva.Publication The vestigial esterase domain of haemagglutinin of H5N1 avian influenza A virus: Antigenicity and contribution to viral pathogenesis(MDPI AG, 2018) Zheng Z.; Paul S.S.; Mo X.; Yuan Y.-R.A.; Tan Y.-J.; MICROBIOLOGY AND IMMUNOLOGY; BIOLOGICAL SCIENCESInitial attempts to develop monoclonal antibodies as therapeutics to resolve influenza infections focused mainly on searching for antibodies with the potential to neutralise the virus in vitro with classical haemagglutination inhibition and microneutralisation assays. This led to the identification of many antibodies that bind to the head domain of haemagglutinin (HA), which generally have potent neutralisation capabilities that block viral entry or viral membrane fusion. However, this class of antibodies has a narrow breadth of protection in that they are usually strain-specific. This led to the emphasis on stalk-targeting antibodies, which are able to bind a broad range of viral targets that span across different influenza subtypes. Recently, a third class of antibodies targeting the vestigial esterase (VE) domain have been characterised. In this review, we describe the key features of neutralising VE-targeting antibodies and compare them with head-and stalk-class antibodies. � 2018 by the authors. Licensee MDPI, Basel, Switzerland.Publication Integrin ?7 expression is increased in asthmatic patients and its inhibition reduces Kras protein abundance in airway smooth muscle cells(Nature Publishing Group, 2019) Teoh, C.M.; Tan, S.S.L.; Langenbach, S.Y.; Wong, A.H.; Cheong, D.H.J.; Tam, J.K.C.; New, C.S.; Tran, T.; PHYSIOLOGY; SURGERY; MICROBIOLOGY AND IMMUNOLOGYAirway smooth muscle (ASM) cells exhibit plastic phenotypic behavior marked by reversible modulation and maturation between contractile and proliferative phenotypic states. Integrins are a class of transmembrane proteins that have been implicated as novel therapeutic targets for asthma treatment. We previously showed that integrin ?7 is a novel marker of the contractile ASM phenotype suggesting that targeting this protein may offer new avenues to counter the increase in ASM cell mass that underlies airways hyperresponsiveness (AHR) in asthma. We now determine whether inhibition of integrin ?7 expression would revert ASM cells back to a proliferative phenotype to cause an increase in ASM cell mass. This would be detrimental to asthmatic patients who already exhibit increased ASM mass in their airways. Using immunohistochemical analysis of the Melbourne Epidemiological Study of Childhood Asthma (MESCA) cohort, we show for the first time that integrin ?7 expression in patients with severe asthma is increased, supporting a clinically relevant role for this protein in asthma pathophysiology. Moreover, inhibition of the laminin-integrin ?7 signaling axis results in a reduction in smooth muscle-alpha actin abundance and does not revert ASM cells back to a proliferative phenotype. We determined that integrin ?7-induced Kras isoform of p21 Ras acts as a point of convergence between contractile and proliferative ASM phenotypic states. Our study provides further support for targeting integrin ?7 for the development of novel anti-asthma therapies. © 2019, The Author(s).Publication Incorporation of an intercostal catheter into a multimodal analgesic strategy for uniportal video-assisted thoracoscopic surgery: a feasibility study(BMC, 2021-07-31) Tan, Jian Wei; Mohamed, Jameelah Sheik; Tam, John Kit Chung; Assoc Prof Kit Chung John Tam; SURGERY; MICROBIOLOGY AND IMMUNOLOGY; DUKE-NUS MEDICAL SCHOOLBackground: Well-controlled postoperative pain is essential for early recovery after uniportal video-assisted thoracoscopic surgery (UVATS). Conventional analgesia like opioids and thoracic epidural anaesthesia have been associated with hypotension and urinary retention. Intercostal catheters are a regional analgesic alternative that can be inserted during UVATS to avoid these adverse effects. This feasibility study aims to evaluate the postoperative pain scores and analgesic requirements with incorporation of an intercostal catheter into a multimodal analgesic strategy for UVATS. Methods: In this observational study, 26 consecutive patients who underwent UVATS were administered a multilevel intercostal block and oral paracetamol. All of these patients received 0.2% ropivacaine continuously at 4 ml/h via an intercostal catheter at the level of the incision. Rescue analgesia including etoricoxib, gabapentin and opioids were prescribed using a pain ladder approach. Postoperative pain scores and analgesic usage were assessed. The secondary outcomes were postoperative complications, days to ambulation and length of stay. Results: No technical difficulties were encountered during placement of the intercostal catheter. There was only one case of peri-catheter leakage. Mean pain score was 0.31 (range 0–2) on post-operative day 1 and was 0.00 by post-operative day 5. 16 patients (61.6%) required only oral rescue analgesia. The number of patients who required rescue non-opioids only increased from 1 in the first 7 months to 8 in the next 7 months. There were no cases of hypotension or urinary retention. Median time to ambulation was 1 day (range 1–2). Mean post-operative length of stay was 4.17 ± 2.50 days. Conclusions: Incorporation of an intercostal catheter into a multimodal analgesia strategy for UVATS is feasible and may provide adequate pain control with decreased opioid usage.