The bovine papillomavirus E5 protein and the PDGF β receptor: It takes two to tango

AbstractThe extremely hydrophobic, 44-amino acid bovine papillomavirus (BPV) E5 protein is the smallest known oncoprotein, which orchestrates cell transformation by causing ligand-independent activation of a cellular receptor tyrosine kinase, the platelet-derived growth factor β receptor (PDGFβR). The E5 protein forms a dimer in transformed cells and is essentially an isolated membrane-spanning segment that binds directly to the transmembrane domain of the PDGFβR, inducing receptor dimerization, autophosphorylation, and sustained mitogenic signaling. There are few sequence constraints for activity as long as the overall hydrophobicity of the E5 protein and its ability to dimerize are preserved. Nevertheless, the E5 protein is highly specific for the PDGFβR and does not activate other cellular proteins. Genetic screens of thousands of small, artificial hydrophobic proteins with randomized transmembrane domains inserted into an E5 scaffold identified proteins with diverse transmembrane sequences that activate the PDGFβR, including some activators as small as 32-amino acids. Analysis of these novel proteins has provided new insight into the requirements for PDGFβR activation and specific transmembrane recognition in general. These results suggest that small, transmembrane proteins can be constructed and selected that specifically bind to other cellular or viral transmembrane target proteins. By using this approach, we have isolated a 44-amino acid artificial transmembrane protein that appears to activate the human erythropoietin receptor. Studies of the tiny, hydrophobic BPV E5 protein have not only revealed a novel mechanism of viral oncogenesis, but have also suggested that it may be possible to develop artificial small proteins that specifically modulate much larger target proteins by acting within cellular or viral membranes

Training the next generation of Africa’s doctors: why medical schools should embrace the team-based learning pedagogy

Abstract Background As far back as 1995, the Cape Town Declaration on training Africa’s future doctor recognized the need for medical schools to adopt active-learning strategies in order to nurture holistic development of the doctor. However, medical education in Africa remains largely stuck with traditional pedagogies that emphasize the ‘hard skills’ such as knowledge and clinical acumen while doing little to develop ‘soft skills’ such as effective communication, teamwork, critical thinking or life-long learning skills. Body of abstract By reviewing literature on Africa’s epidemiologic and demographic transitions, we establish the need for increasing the output of well-trained doctors in order to match the continent’s complex current and future healthcare needs. Challenges that bedevil African medical education such as outdated curricula, limited educational infrastructure and chronic resource constraints are presented and discussed. Furthermore, increased student enrollments, a trend observed at many schools, coupled with chronic faculty shortages have inadvertently presented specific barriers against the success of small-group active-learning strategies such as Problem-Based and Case-Based Learning. We argue that Team-Based Learning (TBL) offers a robust alternative for delivering holistic medical education in the current setting. TBL is instructor-driven and embodies key attributes that foster development of both ‘hard’ and ‘soft’ skills. We elaborate on advantages that TBL is likely to bring to the African medical education landscape, including increased learner enthusiasm and creativity, accountability, peer mentorship, deep learning and better knowledge retention. As with all new pedagogical methods, challenges anticipated during initial implementation of TBL are discussed followed by the limited pilot experiences with TBL in Africa. Conclusion For its ability to enable a student-centered, active learning experience delivered at minimum cost, we encourage individual instructors and African medical schools at large, to adopt TBL as a complementary strategy towards realizing the goal of training Africa’s fit-for-purpose doctor. </jats:sec

Innovation spread: lessons from HIV

Efficient spreading of evidence-based innovations among complex health systems remains an elusive goal despite extensive study in the social sciences. Biology provides a model of successful spread in viruses, which have evolved to spread with maximum efficiency using minimal resources. Here we explore the molecular mechanisms of human immunodeficiency virus (HIV) spread and identify five steps that are also common to a recent example of spread in complex health systems: reduction in door-to-balloon times for patients with ST-segment elevation myocardial infarction (STEMI). We then describe a new model we have developed, called AIDED, which is based on mixed-methods research but informed by the conceptual framework of HIV spread among cells. The AIDED model contains five components: Assess, Innovate, Develop, Engage and Devolve, and can describe any one of the following: the spread of HIV among cells, the spread of practices to reduce door-to-balloon time for patients with STEMI and the spread of certain family health innovations in low- and middle-income countries. We suggest that by looking to the biological sciences for a model of spread that has been honed by evolution, we may have identified fundamental steps that are necessary and sufficient for efficient, low-cost spread of health innovations among complex health systems

Endothelial Cells Promote Human Immunodeficiency Virus Replication in Nondividing Memory T Cells via Nef-, Vpr-, and T-Cell Receptor-Dependent Activation of NFAT

Human endothelial cells (ECs) enhance human immunodeficiency virus (HIV) replication within CD4(+) memory T cells by 50,000-fold in a Nef-dependent manner. Here, we report that EC-mediated HIV type 1 replication is also dependent on an intact vpr gene. Moreover, we demonstrate that despite a requirement for engaging major histocompatibility complex (MHC) class II molecules and costimulators, EC-stimulated virus-producing cells (p24(high) T cells) do not proliferate, nor are they arrested in the cell cycle. Rather, they are minimally activated, sometimes expressing CD69 but not CD25, HLA-DR, VLA-1, or effector cytokines. Blocking antibodies to interleukin 2 (IL-2), IL-6, IL-7, or tumor necrosis factor do not inhibit viral replication. Cyclosporine effectively inhibits viral replication, as does disruption of the NFAT binding site in the viral long terminal repeat. Furthermore, in the presence of ECs, suboptimal T-cell receptor (TCR) stimulation with phytohemagglutinin L supports efficient viral replication, and suboptimal stimulation with toxic shock syndrome toxin 1 leads to viral replication selectively in the TCR-stimulated, Vβ2-expressing T cells. Collectively, these data indicate that ECs provide signals that promote Nef- and Vpr-dependent HIV replication in memory T cells that have been minimally activated through their TCRs. Our studies suggest a mechanism for HIV replication in vivo within the reservoir of circulating memory CD4(+) T cells that persist despite antiretroviral therapy and further suggest that maintenance of immunological memory by MHC class II-expressing ECs via TCR signaling may contribute to HIV rebound following cessation of antiretroviral therapy

Process evaluation of knowledge transfer across industries: Leveraging Coca-Cola's supply chain expertise for medicine availability in Tanzania.

Persistent gaps in the availability of essential medicines have slowed the achievement of global health targets. Despite the supply chain knowledge and expertise that ministries of health might glean from other industries, limited empirical research has examined the process of knowledge transfer from other industries into global public health. We examined a partnership designed to improve the availability of medical supplies in Tanzania by transferring knowledge from The Coca-Cola system to Tanzania's Medical Stores Department (MSD). We conducted a process evaluation including in-depth interviews with 70 participants between July 2011 and May 2014, corresponding to each phase of the partnership, with focus on challenges and strategies to address them, as well as benefits perceived by partners. Partners faced challenges in (1) identifying relevant knowledge to transfer, (2) translating operational solutions from Coca-Cola to MSD, and (3) maintaining momentum between project phases. Strategies to respond to these challenges emerged through real-time problem solving and included (1) leveraging the receptivity of MSD leadership, (2) engaging a boundary spanner to identify knowledge to transfer, (3) promoting local recognition of commonalities across industries, (4) engaging external technical experts to manage translation activities, (5) developing tools with visible benefits for MSD, (6) investing in local relationships, and (7) providing time and space for the partnership model to evolve. Benefits of the partnership perceived by MSD staff included enhanced collaboration and communication, more proactive orientations in managing operations, and greater attention to performance management. Benefits perceived by Coca-Cola staff included strengthened knowledge transfer capability and enhanced job satisfaction. Linking theoretical constructs with practical experiences from the field, we highlight the challenges, emergent strategies, and perceived benefits of a partnership across industry boundaries that may be useful to others seeking to promote the transfer of knowledge to improve global health

Exploring strategies to integrate hypertension management into community-based differentiated HIV care in sub-Saharan Africa: a scoping review protocol

Objective: To explore strategies to integrate hypertension management into community-based differentiated HIV care in sub-Saharan Africa (SSA). Introduction: Persons living with HIV (PLHIV) are at increased risk of hypertension and cardiovascular disease due to aging, chronic inflammation, and the adverse effects of antiretroviral therapy. As HIV programs in SSA strive towards HIV epidemic control, many efforts have been geared towards providing community-based differentiated services beyond health facilities. Differentiated community-based models of HIV care decongest health facilities, minimize transport costs, and improve access to critical services, and thus should be expanded to PLHIV with non-communicable diseases. However, the extent to which community-based differentiated models of HIV care have been utilized to integrate services for hypertension has not been well studied in SSA. Inclusion criteria: We will include studies published about integrating hypertension management into community-based HIV care for PLHIV in SSA without a date restriction. Case reports, case series, conference abstracts, and letters to editors will be excluded Methods: We used the Joanna Briggs Institute (JBI) Manual for Evidence Synthesis section to develop the review protocol. We will conduct a search in the following databases: MEDLINE, Embase, Web of Science, Africa-Wide Information NiPAD. We also plan to conduct an abbreviated search in Global Index Medicus and Google Scholar. We will then extract the required data from the selected articles using Covidence. The results of the scoping review will be reported following the Preferred Reporting of Systematic Reviews and Meta-analysis Scoping Review Extension

State variation in HIV/AIDS health outcomes

OBJECTIVE: Despite considerable advances in the prevention and treatment of HIV/AIDS, the burden of new infections of HIV and AIDS varies substantially across the country. Previous studies have demonstrated associations between increased healthcare spending and better HIV/AIDS outcomes; however, less is known about the association between spending on social services and public health spending and HIV/AIDS outcomes. We sought to examine the association between state-level spending on social services and public health and HIV/AIDS case rates and AIDS deaths across the United States. DESIGN: We conducted a retrospective, longitudinal study of the 50 U.S. states over 2000–2009 using a dataset of HIV/AIDS case rates and AIDS deaths per 100 000 people matched with a unique dataset of state-level spending on social services and public health per person in poverty. METHODS: We estimated multivariable regression models for each HIV/AIDS outcome as a function of the social service and public health spending 1 and 5 years earlier in the state, adjusted for the log of state GDP per capita, regional and time fixed effects, Medicaid spending as % of GDP, and socio-demographic, economic, and health resource factors. RESULTS: States with higher spending on social services and public health per person in poverty had significantly lower HIV and AIDS case rates and fewer AIDS deaths, both 1 and 5 years post expenditure (P ≤ 0.05). CONCLUSION: Our findings suggest that spending on social services and public health may provide a leverage point for state policymakers to reduce HIV/AIDS case rates and AIDS deaths in their state