Thiam Chye Tan

Human natural killer cells control Plasmodium falciparum infection by eliminating infected red blood cells

Significance Study of human immune responses to malaria parasite infection has been hampered by a lack of small animal models. Although immunodeficient mice supplemented with human RBCs support human parasite infection, these animals lack a human immune system. We have overcome this obstacle by developing mice that possess both human RBCs and immune system and that support multiple cycles of Plasmodium falciparum infection. We further show that human natural killer cells preferentially interact with and kill infected RBCs in a contact-dependent manner. The small animal model reported here likely will facilitate the dissection of human immune responses to malaria parasite infection and the evaluation of therapeutics and vaccines. Immunodeficient mouse–human chimeras provide a powerful approach to study host-specific pathogens, such as Plasmodium falciparum that causes human malaria. Supplementation of immunodeficient mice with human RBCs supports infection by human Plasmodium parasites, but these mice lack the human immune system. By combining human RBC supplementation and humanized mice that are optimized for human immune cell reconstitution, we have developed RBC-supplemented, immune cell-optimized humanized (RICH) mice that support multiple cycles of P. falciparum infection. Depletion of human natural killer (NK) cells, but not macrophages, in RICH mice results in a significant increase in parasitemia. Further studies in vitro show that NK cells preferentially interact with infected RBCs (iRBCs), resulting in the activation of NK cells and the elimination of iRBCs in a contact-dependent manner. We show that the adhesion molecule lymphocyte-associated antigen 1 is required for NK cell interaction with and elimination of iRBCs. Development of RICH mice and validation of P. falciparum infection should facilitate the dissection of human immune responses to malaria parasite infection and the evaluation of therapeutics and vaccines.

Halogen-induced charge transfer polymerization of pyrrole in aqueous media

Abstract Simultaneous polymerization and doping of pyrrole have been carried out in the presence of a halogenic electron acceptor, bromine (Br 2 ) or iodine (I 2 ), in aqueous dispersion or in a two-phase solvent system. The morphology of the polypyrrole (PPY) so produced is granular and porous. The electrical conductivity of the PPY-I 2 charge transfer (CT) complex is of the order of 10 1 ohm −1 cm −1 while that of the PPY-Br 2 complex is about one order of magnitude less. Both complexes are stable in the atmosphere. The physicochemical properties of the PPY-I 2 and PPY-Br 2 CT complexes prepared under various experimental conditions are examined in detail.

Chemical synthesis and characterization of polypyrrole-chlorine complex

Simultaneous chemical polymerization and oxidation of pyrrole have been initiated by chlorine (Cl2) in various organic solvents. The polypyrrole-chlorine (PPY-Cl2) complex so produced is granular in nature and has a room-temperature direct-current (d.c.) electrical conductivity (σ) that varies from <10−7 to 0.5 S cm−1 depending on the solvent medium used for polymerization. The PPY-Cl2 complex prepared in acetonitrile has the highest conductivity and, for this sample, a plot of ln σ versus(temperature)−14 gives a straight line over the 120–300 K region. The physicochemical and thermal properties of this sample were also examined in some detail. Substantial addition of the halogen to the pyrrole ring may have occurred during polymerization. Electrochemical characterization of the complex in powder form was also carried out using a specially modified electrode.

The Polymerization and Oxidation of Pyrrole by Halogens in Organic Solvents

Abstract Simultaneous chemical polymerization and oxidation of pyrrole have been initiated by a halogenic electron acceptor, bromine or iodine, in various organic solvents. The polypyrrole (PPY)-halogen charge transfer (CT) complexes obtained from polymerization in acetonitrile are of particular interest. Both the PPY-I2 and PPY-Br2 CT complexes are granular in nature and have an electrical conductivity in the order of 1 to 10 ohm−1 cm−1. Both complexes show remarkable stability in the atmosphere and in the presence of moisture. The PPY-I2 and PPY-Br2 CT complexes in the form of thin, coarse films have also been synthesized on a SnO2 electrode by electrochemical polymerization in acetonitrile. The physicochemical properties of the PPY-I2 and PPY-Br2 CT complexes prepared by the chemical methods are characterized by means of UV-visible and IR absorption spectroscopy, thermal and chemical analysis, and electrical conductivity and density measurements.

Induction of Functional Human Macrophages from Bone Marrow Promonocytes by M-CSF in Humanized Mice

Engraftment of human CD34+ hematopoietic stem/progenitor cells into immunodeficient mice leads to robust reconstitution of human T and B cells but not monocytes and macrophages. To identify the cause underlying the poor monocyte and macrophage reconstitution, we analyzed human myeloid cell development in humanized mice and found that it was blocked at the promonocyte stage in the bone marrow. Expression of human M-CSF or GM-CSF by hydrodynamic injection of cytokine-encoding plasmid completely abolished the accumulation of promonocytes in the bone marrow. M-CSF promoted the development of mature monocytes and tissue-resident macrophages whereas GM-CSF did not. Moreover, correlating with an increased human macrophages at the sites of infection, M-CSF–treated humanized mice exhibited an enhanced protection against influenza virus and Mycobacterium infection. Our study identifies the precise stage at which human monocyte/macrophage development is blocked in humanized mice and reveals overlapping and distinct functions of M-CSF and GM-CSF in human monocyte and macrophage development. The improved reconstitution and functionality of monocytes/macrophages in the humanized mice following M-CSF expression provide a superior in vivo system to investigate the role of macrophages in physiological and pathological processes.

Determining optimal gestational weight gain in a multiethnic Asian population

To define the optimal gestational weight gain (GWG) for the multiethnic Singaporean population.

Predictors and adverse outcomes of inadequate or excessive gestational weight gain in an Asian population

The aim of this study was to assess maternal characteristics as predictors of inadequate or excessive gestational weight gain (GWG) and to characterize maternal and neonatal outcomes associated with inadequate or excessive GWG in Asian women.

Electrical and thermal stability of chemically synthesized conductive polypyrrole-halogen complexes

Abstract Conductive polypyrrole(PPY)-halogen complexes were obtained via the simultaneous chemical polymerization and oxidation of pyrrole by bromine (Br 2 ), iodine (I 2 ) or chlorine (Cl 2 ). The thermal stability of these complexes was studied by thermogravimetry while the electrical stability was characterized by electrical conductivity measurements at various temperatures and current loadings, as well as by cyclic voltammetry. Although the PPY-I 2 complex shows the best thermal-physical stability, the PPY-Br 2 complex has the most favourable electrical properties. The room temperature electrical conductivity of the PPY-Br 2 complex is about 33 S/cm and the complex can sustain a current density of at least 6 A/cm 2 for more than 100 h without any degradation in conductivity. The weight and electrical conductivity of the sample, however, decrease when heated above 140°C. Both the PPY-I 2 and PPY-Br 2 complexes show good stability upon repeated redox cycling in both aqueous and organic electrolytes.

Chemical synthesis and characterization of electroactive and partially soluble polyazulene

SummarySimultaneous chemical oxidation and polymerization of azulene by iodine and bromine were carried out. The polyazulene-bromine complex is electrically conductive and partially soluble in organic solvents whereas the polyazulene-iodine complex is much less conductive and insoluble. The physicochemical properties of the polyazulene-bromine complex were characterized by elemental and thermogravimetric analyses, infrared and ultraviolet-visible absorption spectroscopy, cyclic voltammetry and gel permeation chromatography. Experimental evidences suggest that the soluble fraction of the complex consists mainly of azulene oligomers.

Characterisation of liver pathogenesis, human immune responses and drug testing in a humanised mouse model of HCV infection

Objective HCV infection affects millions of people worldwide, and many patients develop chronic infection leading to liver cancers. For decades, the lack of a small animal model that can recapitulate HCV infection, its immunopathogenesis and disease progression has impeded the development of an effective vaccine and therapeutics. We aim to provide a humanised mouse model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies. Design Recently, we have established human liver cells with a matched human immune system in NOD-scid Il2rg−/− (NSG) mice (HIL mice). These mice are infected with HCV by intravenous injection, and the pathologies are investigated. Results In this study, we demonstrate that HIL mouse is capable of supporting HCV infection and can present some of the clinical symptoms found in HCV-infected patients including hepatitis, robust virus-specific human immune cell and cytokine responses as well as liver fibrosis and cirrhosis. Similar to results obtained from the analysis of patient samples, the human immune cells, particularly T cells and macrophages, play critical roles during the HCV-associated liver disease development in the HIL mice. Furthermore, our model is demonstrated to be able to reproduce the therapeutic effects of human interferon alpha 2a antiviral treatment. Conclusions The HIL mouse provides a model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies. It could also serve as a platform for antifibrosis and immune-modulatory drug testing.