Antiplasmodial activity of a series of 1,3,5-triazine-substituted polyamines

Polyamine biosynthesis and function has been shown to be a good drug target in some parasitic protozoa and it is proposed that the pathway might also represent a target in the malaria parasite Plasmodium falciparum. A series of 1,3,5-triazine-substituted polyamine analogues were tested for activity against Plasmodium falciparum in vitro. The series showed activity against the parasites and were generally more active against the chloroquine-resistant line K1 than the chloroquine-susceptible line NF54. Simple unbranched analogues had better activity than analogues carrying branched or cyclic central chains. Addition of multiple triazine units in general led to increased activity of the compound

Aryl Phosphoramidates of 5-Phospho Erythronohydroxamic Acid, A New Class of Potent Trypanocidal Compounds

RNAi and enzymatic studies have shown the importance of 6-phosphogluconate dehydrogenase (6-PGDH) in Trypanosoma brucei for the parasite survival and make it an attractive drug target for the development of new treatments against human African trypanosomiasis. 2,3-O-Isopropylidene-4-erythrono hydroxamate is a potent inhibitor of parasite Trypanosoma brucei 6-phosphogluconate dehydrogenase (6-PGDH), the third enzyme of the pentose phosphate pathway. However, this compound does not have trypanocidal activity due to its poor membrane permeability. Consequently, we have previously reported a prodrug approach to improve the antiparasitic activity of this inhibitor by converting the phosphate group into a less charged phosphate prodrug. The activity of prodrugs appeared to be dependent on their stability in phosphate buffer. Here we have successfully further extended the development of the aryl phosphoramidate prodrugs of 2,3-O-isopropylidene-4-erythrono hydroxamate by synthesizing a small library of phosphoramidates and evaluating their biological activity and stability in a variety of assays. Some of the compounds showed high trypanocidal activity and good correlation of activity with their stability in fresh mouse blood

Small polar hits against <i>S. aureus</i>:Screening, initial hit optimization and metabolomic studies

The global prevalence of antibacterial resistance requires new antibacterial drugs with novel chemical scaffolds and modes of action. It is also vital to design compounds with optimal physicochemical properties to permeate the bacterial cell envelope. We described an approach of combining and integrating whole cell screening and metabolomics into early antibacterial drug discovery using a library of small polar compounds. Whole cell screening of a diverse library of small polar compounds against Staphylococcus aureus gave compound 2. Hit expansion was carried out to determine structure–activity relationships. A selection of compounds from this series, together with other screened active compounds, was subjected to an initial metabolomics study to provide a metabolic fingerprint of the mode of action. It was found that compound 2 and its analogues have a different mode of action from some of the known antibacterial compounds tested. This early study highlighted the potential of whole cell screening and metabolomics in early antibacterial drug discovery. Future works will require improving potency and performing orthogonal studies to confirm the modes of action

Enhanced IL-10 production in response to hepatitis C virus proteins by peripheral blood mononuclear cells from human immunodeficiency virus-monoinfected individuals

Background: Multiple immune evasion strategies by which HCV establishes chronic infection have been proposed, including manipulation of cytokine responses. Prior infection with HIV increases the likelihood of chronic HCV infection and accelerates development of HCV-related morbidity. Therefore, we investigated in vitro cytokine responses to HCV structural and non-structural proteins in peripheral blood mononuclear cells (PBMC) from uninfected, HIV-infected, HCVinfected and HIV/HCV-coinfected individuals. Results: Intracellular flow cytometry was used to assess IL-2, IL-10, IL-12, and IFN-γ production by freshly isolated PBMC incubated for 16 hours with recombinant HCV core, non-structural protein 3 (NS3), and NS4 proteins. Anti-HCV cellular responses were assessed in HIV/HCVcoinfected individuals by 3H-thymidine proliferation assay. Exposure to HCV antigens increased IL- 10 production by PBMC, especially in uninfected and HIV-monoinfected individuals. This IL-10 response was attenuated in chronic HCV infection even with HCV/HIV-coinfection. The cells producing IL-10 in response to HCV proteins in vitro matched a PBMC subset recently shown to constitutively produce IL-10 in vivo. This subset was found at similar frequencies in uninfected, HIVinfected, HCV-infected and HIV/HCV-coinfected individuals before exposure to HCV proteins. HCV-specific T cell proliferation was detectable in only one HIV/HCV-coinfected individual who demonstrated no HCV-induced IL-10 response. Conclusion: This pattern suggests that selective induction of IL-10 in uninfected individuals and especially in HIV-monoinfected individuals plays a role in establishing chronic HCV infection and conversely, that attenuation of this response, once chronic infection is established, favours development of hepatic immunopathology

Public health benefits of strategies to reduce greenhouse-gas emissions: overview and implications for policy makers

This Series has examined the health implications of policies aimed at tackling climate change. Assessments of mitigation strategies in four domains-household energy, transport, food and agriculture, and electricity generation-suggest an important message: that actions to reduce greenhouse-gas emissions often, although not always, entail net benefits for health. In some cases, the potential benefits seem to be substantial. This evidence provides an additional and immediate rationale for reductions in greenhouse-gas emissions beyond that of climate change mitigation alone. Climate change is an increasing and evolving threat to the health of populations worldwide. At the same time, major public health burdens remain in many regions. Climate change therefore adds further urgency to the task of addressing international health priorities, such as the UN Millennium Development Goals. Recognition that mitigation strategies can have substantial benefits for both health and climate protection offers the possibility of policy choices that are potentially both more cost effective and socially attractive than are those that address these priorities independently

Choral Ensembles Holiday Concert

KSU School of Music presents Choral Ensembles Holiday Concert.https://digitalcommons.kennesaw.edu/musicprograms/1323/thumbnail.jp

Holiday Concert, Home for the Holidays

Kennesaw State University School of Music presents Holiday Concert, Home for the Holidays.https://digitalcommons.kennesaw.edu/musicprograms/1433/thumbnail.jp

Radio Astronomy

Contains table of contents for Section 4 and reports on five research projects.National Science Foundation Grant AST 92-24191MIT Lincoln Laboratory Agreement BX-4975National Aeronautics and Space Administration/Goddard Space Flight Center Grant NAS 5-31376National Aeronautics and Space Administration/Goddard Space Flight Center Grant NAG5-10MIT Leaders for Manufacturing Progra