12 research outputs found
Suppression of circulating IgD+CD27+ memory B cells in infants living in a malaria-endemic region of Kenya
Background: Plasmodium falciparum infection leads to alterations in B cell subset distribution. During infancy,
development of peripheral B cell subsets is also occurring. However, it is unknown if infants living a malaria
endemic region have alterations in B cell subsets that is independent of an age effect.
Methods: To evaluate the impact of exposure to P. falciparum on B cell development in infants, flow cytometry
was used to analyse the distribution and phenotypic characteristic of B cell subsets in infant cohorts prospectively
followed at 12, 18 and 24 months from two geographically proximate regions in western Kenya with divergent
malaria exposure i.e. Kisumu (malaria-endemic, n = 24) and Nandi (unstable malaria transmission, n = 21).
Results: There was significantly higher frequency and absolute cell numbers of CD19+ B cells in Kisumu relative to
Nandi at 12(p = 0.0440), 18(p = 0.0210) and 24 months (p = 0.0493). No differences were observed between the
infants from the two sites in frequencies of naĂŻve B cells (IgD+CD27-) or classical memory B cells (IgD-CD27+).
However, immature transitional B cells (CD19+CD10+CD34-) were higher in Kisumu relative to Nandi at all three
ages. In contrast, the levels of non-class switched memory B cells (CD19+IgD+CD27+) were significantly lower
overall in Kisumu relative to Nandi at significantly at 12 (p = 0.0144), 18 (p = 0.0013) and 24 months (p = 0.0129).
Conclusions: These data suggest that infants living in malaria endemic regions have altered B cell subset
distribution. Further studies are needed to understand the functional significance of these changes and long-term
impact on ability of these infants to develop antibody responses to P. falciparum and heterologous infections
Business Ethics: The Promise of Neuroscience
Recent advances in cognitive neuroscience research portend well for furthering understanding of many of the fundamental questions in the field of business ethics, both normative and empirical. This article provides an overview of neuroscience methodology and brain structures, and explores the areas in which neuroscience research has contributed findings of value to business ethics, as well as suggesting areas for future research. Neuroscience research is especially capable of providing insight into individual reactions to ethical issues, while also raising challenging normative questions about the nature of moral responsibility, autonomy, intent, and free will. This article also provides a brief summary of the papers included in this special issue, attesting to the richness of scholarly inquiry linking neuroscience and business ethics. We conclude that neuroscience offers considerable promise to the field of business ethics, but we caution against overpromise
UCT943, a next generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria
The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite lifecycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activity than MMV048 and was more potent against resistant P. falciparum and P. vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in P. berghei and humanized P. falciparum NOD-scid IL-2RÎłnull mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vitro intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next generation Plasmodium PI4K inhibitor, the combined preclinical data suggest that UCT943 has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent and block the transmission of malaria
UCT943, a next generation plasmodium falciparum PI4K inhibitor preclinical candidate for the treatment of malaria
The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel drug target for malaria, to enter clinical development. In an effort to identify the next generation of PI4K inhibitors, the series was optimized to improve properties such as solubility and antiplasmodial potency across the parasite lifecycle, leading to the 2-aminopyrazine UCT943. The compound displayed higher asexual blood stage, transmission-blocking, and liver stage activity than MMV048 and was more potent against resistant P. falciparum and P. vivax clinical isolates. Excellent in vitro antiplasmodial activity translated into high efficacy in P. berghei and humanized P. falciparum NOD-scid IL-2RÎłnull mouse models. The high passive permeability and high aqueous solubility of UCT943, combined with low to moderate in vitro intrinsic clearance, resulted in sustained exposure and high bioavailability in preclinical species. In addition, the predicted human dose for a curative single administration using monkey and dog pharmacokinetics was low, ranging from 50 to 80 mg. As a next generation Plasmodium PI4K inhibitor, the combined preclinical data suggest that UCT943 has the potential to form part of a single-exposure radical cure and prophylaxis (SERCaP) to treat, prevent and block the transmission of malaria
Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase
As part of the global effort toward malaria eradication, phenotypic whole-cell screening revealed the 2-aminopyridine class of small molecules as a good starting point to develop new antimalarial drugs. Stemming from this series, we found that the derivative, MMV390048, lacked cross-resistance with current drugs used to treat malaria. This compound was efficacious against all Plasmodium life cycle stages, apart from late hypnozoites in the liver. Efficacy was shown in the humanized Plasmodium falciparum mouse model, and modest reductions in mouse-to-mouse transmission were achieved in the Plasmodium berghei mouse model. Experiments in monkeys revealed the ability of MMV390048 to be used for full chemoprotection. Although MMV390048 was not able to eliminate liver hypnozoites, it delayed relapse in a Plasmodium cynomolgi monkey model. Both genomic and chemoproteomic studies identified a kinase of the Plasmodium parasite, phosphatidylinositol 4-kinase, as the molecular target of MMV390048. The ability of MMV390048 to block all life cycle stages of the malaria parasite suggests that this compound should be further developed and may contribute to malaria control and eradication as part of a single-dose combination treatment