Doctor of Philosophy

dissertationHeparan sulfate (HS) chains play roles in numerous biological processes as they bind to various signaling molecules including fibroblast growth factors (FGFs). This graduate research aims at investigating the structural requirements and the biogenesis pathways of FGF8-binding HS motifs. In the first part, the importance of HS multivalency in regulating FGF8 and FGF receptor (FGFR) interactions in vivo was examined. A library of mono-, bis- or trisxylosides was injected into zebrafish embryos to stimulate the production of monomeric, dimeric or trimeric glycosaminoglycan (GAG) chains that are connected covalently, and thereby mimic naturally occurring proteoglycans. Upon their injection, bis- and trisxylosides caused an elongation phenotype whereas mono-xylosides did not. In situ hybridization and other experiments showed that FGF8/FGFR signaling was specifically hyperactivated in elongated embryos. Based on our findings, we propose a molecular model in which two covalently linked GAG chains interact with two FGF8 molecules and their cognate FGFRs and induce FGFR dimerization that leads to the elongation phenotype. This proposed molecular model was reaffirmed by the results of experiments testing syndecan-1 constructs containing zero, one, two or three HS side chains, in which multivalency again demonstrated its essential role in activating FGF8 signaling

Spatiotemporal evolution of SARS-CoV-2 Alpha and Delta variants during large nationwide outbreak of COVID-19, Vietnam, 2021

We analyzed 1,303 SARS-CoV-2 whole-genome sequences from Vietnam, and found the Alpha and Delta variants were responsible for a large nationwide outbreak of COVID-19 in 2021. The Delta variant was confined to the AY.57 lineage and caused >1.7 million infections and >32,000 deaths. Viral transmission was strongly affected by nonpharmaceutical interventions

Erratum: Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017

Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

Investigating the mechanism of the assembly of FGF1-binding heparan sulfate motifs

AbstractHeparan sulfate (HS) chains play crucial biological roles by binding to various signaling molecules including fibroblast growth factors (FGFs). Distinct sulfation patterns of HS chains are required for their binding to FGFs/FGF receptors (FGFRs). These sulfation patterns are putatively regulated by biosynthetic enzyme complexes, called GAGOSOMES, in the Golgi. While the structural requirements of HS–FGF interactions have been described previously, it is still unclear how the FGF-binding motif is assembled in vivo. In this study, we generated HS structures using biosynthetic enzymes in a sequential or concurrent manner to elucidate the potential mechanism by which the FGF1-binding HS motif is assembled. Our results indicate that the HS chains form ternary complexes with FGF1/FGFR when enzymes carry out modifications in a specific manner

In vitro antiviral activities of ethanol and aqueous extracts of Vietnamese traditional medicinal plants against Porcine Epidemic Diarrhea virus: a coronavirus family member

peer reviewe

Notes on culturable endophytic microorganisms isolated from 14 medicinal plants in Vietnam: a diversity analysis to predict the host-microbe correlations

Endophytes can generate a cornucopia of marvelous bioactive secondary metabolites useful for mankind but their biodiversity and associations with host plants are still elusive. In this study, we explored the culturable endophytic microorganisms associated with 14 medicinal plants that are of high socio-economic value and/or reportedly endemic to northern Vietnam. Specifically, we isolated the endophytic microorganisms by applying surface sterilization methods and identified them based on morphological and rDNA sequence analyses. Agglomerative Hierarchical Clustering (AHC) and Principal Component Analysis (PCA) were used to analyze the correlations between the taxonomic affiliations of the culturable endophytes and the characteristics of their hosts. Most of the culturable endophytes obtained were bacteria (80), and few of those were actinomycetes (15) and fungi (8). Many of them are reported to be endophytes of medicinal plants for the first time. A number of plants (5) are also reported for the first time to contain microbial endophytes, while some plants with powerful pharmaceutical potential harbor unique endophytes. Furthermore, our results reveal a strikingly close relation between the compositions of bacterial and fungal isolates from plants having anti-bacterial activity and those from plants having anti-inflammatory activity, or between the compositions of the microbial endophytic isolates from plants having anti-cancer activity and those from plants having antioxidant activity. Altogether, the results provide new findings which can be inspiring for further in-depth studies to explore and exploit the relationships between medicinal plants and their associated endophytes in northern Vietnam and world-wide.3. Good health and well-bein

Chemoenzymatically Prepared Heparan Sulfate Containing Rare 2‑O-Sulfonated Glucuronic Acid Residues

The structural diversity of natural sulfated glycosaminoglycans (GAGs) presents major promise for discovery of chemical biology tools or therapeutic agents. Yet, few GAGs have been identified so far to exhibit this promise. We reasoned that a simple approach to identify such GAGs is to explore sequences containing rare residues, for example, 2-O-sulfonated glucuronic acid (GlcA<i>p</i>2S). Genetic algorithm-based computational docking and filtering suggested that GlcA<i>p</i>2S containing heparan sulfate (HS) may exhibit highly selective recognition of antithrombin, a key plasma clot regulator. HS containing only GlcA<i>p</i>2S and 2-N-sulfonated glucosamine residues, labeled as HS_2S2S, was chemoenzymatically synthesized in just two steps and was found to preferentially bind antithrombin over heparin cofactor II, a closely related serpin. Likewise, HS_2S2S directly inhibited thrombin but not factor Xa, a closely related protease. The results show that a HS containing rare GlcA<i>p</i>2S residues exhibits the unusual property of selective antithrombin activation and direct thrombin inhibition. More importantly, HS_2S2S is also the first molecule to activate antithrombin nearly as well as the heparin pentasaccharide although being completely devoid of the critical 3-<i>O</i>-sulfonate group. Thus, this work shows that novel functions and mechanisms may be uncovered by studying rare GAG residues/sequences