Membrane active chelators as novel anti-African trypanosome and anti-malarial drugs

AbstractMalaria (Plasmodium spp.) and human African trypanosomiasis (Trypanosoma brucei spp.) are vector borne, deadly parasitic diseases. While chemotherapeutic agents for both diseases are available, difficulty in disease eradication and development of drug resistance require that new therapies targeting unexplored pathways or exploiting novel modes of action be developed. Intracellular Plasmodium and extracellular Trypanosoma brucei may have unique and essential requirements for divalent metal ions, beyond that deemed physiological for the host. Membrane Active Chelators (MACs), biologically active only in a hydrophobic lipid environment, are able to bind metal ions at elevated non-physiological concentrations in the vicinity of cell membranes. A dose–response relationship study using validated viability assays revealed that two MAC drugs, DP-b99 and DP-460, were cytotoxic for these parasites in vitro. The 50% effective concentration (EC50) values for DP-b99 and DP-460 were 87μM and 39μM for Trypanosoma brucei brucei and 21μM and 28μM for erythrocytic Plasmodium falciparum, respectively. Furthermore, drug potency was maintained for at least 24h in serum containing medium at 37°C. While the exact mechanism of action of MACs against intracellular malaria and extracellular African trypanosome parasites has yet to be determined, their potential as antiparasitic agents warrants further investigation

Inhibition of Protein-protein Interactions in Mycobacterium tuberculosis

Tuberculosis is a highly contagious, infectious disease that kills about 1.8 million people annually. Current chemotherapeutic regimens are both inefficient and taxing to the patient. In addition, the disease has suboptimal treatment due to the rise of multidrug resistant strains of Mycobacterium tuberculosis (Mtb), the causative bacterial agent of tuberculosis. Therefore, we established a critical assay to identify novel drugs that interfere with specific Mtb virulence mechanisms. The mycobacterial protein fragment complementation (M-PFC) assay was developed to screen 725 compound drug panel to find candidate drugs that interfered with important virulence-causing protein interactions of Mtb. We targeted the EsxA EsxB and EsxMEsxN interactions of the type VII secretion systems of Mtb. Our screen identified 46 small molecules that inhibited both virulence interactions, exhibiting nonspecific activity against a model cell line in vitro as well as seven hits specific to one of the two cell lines. In the future, we hope to retest the seven unique positive hits to confirm their ability to inhibit specific proteinprotein interactions of Mtb

Broadening Participation in Biology Education Research: Engaging Community College Students and Faculty

Nearly half of all undergraduates are enrolled at community colleges (CCs), including the majority of U.S. students who represent groups underserved in the sciences. Yet only a small minority of studies published in discipline-based education research journals address CC biology students, faculty, courses, or authors. This marked underrepresentation of CC biology education research (BER) limits the availability of evidence that could be used to increase CC student success in biology programs. To address this issue, a diverse group of stakeholders convened at the Building Capacity for Biology Education Research at Community Colleges meeting to discuss how to increase the prevalence of CC BER and foster participation of CC faculty as BER collaborators and authors. The group identified characteristics of CCs that make them excellent environments for studying biology teaching and learning, including student diversity and institutional cultures that prioritize teaching, learning, and assessment. The group also identified constraints likely to impede BER at CCs: limited time, resources, support, and incentives, as well as misalignment between doing research and CC faculty identities as teachers. The meeting culminated with proposing strategies for faculty, administrators, journal editors, scientific societies, and funding agencies to better support CC BER

Clinically relevant atovaquone-resistant human malaria parasites fail to transmit by mosquito.

Long-acting injectable medications, such as atovaquone, offer the prospect of a "chemical vaccine" for malaria, combining drug efficacy with vaccine durability. However, selection and transmission of drug-resistant parasites is of concern. Laboratory studies have indicated that atovaquone resistance disadvantages parasites in mosquitoes, but lack of data on clinically relevant Plasmodium falciparum has hampered integration of these variable findings into drug development decisions. Here we generate atovaquone-resistant parasites that differ from wild type parent by only a Y268S mutation in cytochrome b, a modification associated with atovaquone treatment failure in humans. Relative to wild type, Y268S parasites evidence multiple defects, most marked in their development in mosquitoes, whether from Southeast Asia (Anopheles stephensi) or Africa (An. gambiae). Growth of asexual Y268S P. falciparum in human red cells is impaired, but parasite loss in the mosquito is progressive, from reduced gametocyte exflagellation, to smaller number and size of oocysts, and finally to absence of sporozoites. The Y268S mutant fails to transmit from mosquitoes to mice engrafted with human liver cells and erythrocytes. The severe-to-lethal fitness cost of clinically relevant atovaquone resistance to P. falciparum in the mosquito substantially lessens the likelihood of its transmission in the field

Integrating Cognitive and Affective Dimensions of Pain Experience into Health Professions Education

Pain is prevalent in clinical settings, and yet it is relatively under-represented in the education of most students in the health professions. Because pain includes both sensory-discriminative and affective features, teaching students about pain presents unique challenges and opportunities. The present article describes the evolution of a new blueprint for clinical excellence that, among other competencies, incorporates a need for the emotional development of clinical trainees. The framework has been applied to the development and implementation of two new courses in pain. The first course is designed to provide a comprehensive foundation of medical knowledge regarding pain, while integratively introducing students to the affective dimensions of pain. The second course is designed to enhance students’ appreciation for the protean effects of pain through use of the humanities to represent medical experience. It is concluded that, to be most effective, fostering the emotional development of trainees in the health professions necessitates the incorporation of affect-focused learning objectives, educational tasks and assessment methods