Using Online Program Development to Foster Curricular Change and Innovation

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153766/1/jddj002203372011753tb05047x.pd

Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage; Plasmodium falciparum; and; Cryptosporidium parvum; in cell-culture studies. Target deconvolution in; P. falciparum; has shown that cladosporin inhibits lysyl-tRNA synthetase (; Pf; KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both; Pf; KRS1 and; C. parvum; KRS (; Cp; KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED; 90; = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between; Pf; KRS1 and; Cp; KRS. This series of compounds inhibit; Cp; KRS and; C. parvum; and; Cryptosporidium hominis; in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for; Pf; KRS1 and; Cp; KRS vs. (human); Hs; KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis

We make the road by walking it: Critical consciousness, structuration, and social change.

This study explores the development of critical consciousness among masters-level students within a social work school undergoing a curriculum change effort focused on social justice goals. The process of structuration (practice theory) guided the study, it emphasized the role of organizational structures, norms and group processes on students' interpretive schemas. Through several action research cycles, the author worked closely with faculty leaders and student participants (n=132) to triangulate multiple qualitative methods and analyses that emphasized how students created meaning vis-a-vis specific materials, interactions, structures, and curricula, and how these facilitated and/or created barrier to their learning. Analysis demonstrated four dimensions of learning necessary for students' critical consciousness: (1) an awareness of positionality; (2) the capacity to skillfully engage with conflict and dialogue; (3) critical-structural thinking; and (4) an identity as a change agent, including an awareness of their strengths, sources of power and capacity to influence change. Overall, students of color began the learning process with greater structural understanding and awareness of their identities than their white peers; thus, these groups proceeded differently through the learning process. In general, students of color progressed further within most dimensions of critical consciousness than their white peers. Examples of structures, norms, and group interactions that facilitated critical consciousness include: an emphasis on social justice values and goals; opportunities for intergroup dialogue; and, assignments illustrating the complexity of social inequalities. Barriers to critical consciousness (i.e. highly structured curriculum and anti-dialogic classroom norms) impeded students' need to connect knowledge with practice, and dialogue, reflect-on, and integrate their learning. During two action research cycles, the author worked with students to create an integrative portfolio-based learning process that increased significantly their capacity to identify their dreams and aspirations, and connect these to specific course assignments, learning goals, and professional practices. The author proposes a conceptual model that illustrates critical consciousness, structuration, and social change. She concludes: curricula in higher education need to emphasize dialogue, integrative learning, and knowledge of how to change complex systems. Additionally, higher education research needs to consider the role of organizational context and students' positionalities on issues of learning and development.Ph.D.Curriculum developmentEducationSocial SciencesSocial structureSocial workUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125594/2/3208310.pd

Evaluation of Rapidly Disintegrating Vaginal Tablets of Tenofovir, Emtricitabine and Their Combination for HIV-1 Prevention

Vaginal tablets are being developed as an alternative to gels as an inexpensive, discreet dosage form for the administration of microbicides. This work describes the pharmacokinetic (PK) evaluation of rapidly disintegrating vaginal tablets containing tenofovir (TFV, 10 mg), emtricitabine (FTC, 10 mg), and the combination of TFV and FTC (10 mg each) under in vitro and in vivo conditions, and in direct comparison to the clinical TFV 1% gel, a microbicide product in Phase III clinical testing. The PK of TFV and FTC from tablets were also evaluated in female rabbits following intravaginal administration. Direct comparison of a single dose of TFV tablets (intact or predissolved at 10 mg/mL) and TFV 1% gel showed no differences in the vaginal PK of TFV between groups; however systemic bioavailability of TFV was significantly higher from the gel. When rabbits were dosed either once or daily for seven days with intact tablets of TFV, FTC, or the combination of TFV/FTC, vaginal and systemic concentrations of TFV and FTC were unaffected by co-formulation. Moreover, plasma PK parameters were similar following a single dose or seven once-daily doses. Tissue concentrations of TFV and FTC in the cranial vagina 4 h after administration ranged between 104 and 105 ng/g. Concentrations of TFV-diphospate (TFV-DP, the active metabolite) were also high (over 103 ng/g or about 3000 to 6000 fmol/mg) in the cranial vagina 4 h after administration and similar to those measured following administration of TFV 1% gel. These data demonstrate that rapidly disintegrating vaginal tablets may be a suitable topical microbicide dosage form providing similar vaginal TFV PK to that of TFV 1% gel. The data also support co-administration of FTC with TFV in a single vaginal tablet to create a combination microbicide in a simple and inexpensive dosage form

Griffithsin carrageenan fast dissolving inserts prevent SHIV HSV-2 and HPV infections in vivo

Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) strategies with proven in vivo efficacy rely on antiretroviral drugs, creating the potential for drug resistance and complicated treatment options in individuals who become infected. Moreover, on-demand products are currently missing from the PrEP development portfolio. Griffithsin (GRFT) is a non-antiretroviral HIV entry inhibitor derived from red algae with an excellent safety profile and potent activity in vitro. When combined with carrageenan (CG), GRFT has strong activity against herpes simplex virus-2 (HSV-2) and human papillomavirus (HPV) in vitro and in vivo. Here, we report that GRFT/CG in a freeze-dried fast dissolving insert (FDI) formulation for on-demand use protects rhesus macaques from a high dose vaginal SHIV SF162P3 challenge 4 h after FDI insertion. Furthermore, the GRFT/CG FDI also protects mice vaginally against HSV-2 and HPV pseudovirus. As a safe, potent, broad-spectrum, on-demand non-antiretroviral product, the GRFT/CG FDI warrants clinical development

"God made the soil, but we made it fertile”: Gender, knowledge and practice in the formation and use of African Dark Earths in Liberia and Sierra Leone.

This paper describes West African farming practices and knowledge that lead to the formation of carbon-rich high-fertility African Dark Earths (AfDE) – human-made soils analogous to Amazonian terra preta, yet subject to continuing production and use. Gender relations and women’s roles are central to how these soils are produced and used. Through social and ecological field studies in Liberia and Sierra Leone we detail how AfDE formation and associated knowledge is gender-differentiated, the central roles of women’s deposition of charred organic materials from cooking, oil palm processing and potash production in producing AfDE, and the gendered dynamics of AfDE use and distribution in the landscape. Different species are cultivated in AfDE compared to non-anthropogenic soils, and AfDE are differentially valued by women and men for horticultural and tree crops. The spatial distribution of AfDE across the landscape reflects shifting household, marriage and settlement practices. Gender relations, subjectivities and interdependencies and the ecology of soils and landscapes mutually shape one another. National policymakers and NGOs planning or managing agricultural carbon projects in West Africa should attend to the knowledge and practices of Loma and Mende women and men who have made and cultivated carbon-rich anthropogenic soils in the region for generations