A PfRH5-Based Vaccine Is Efficacious against Heterologous Strain Blood-Stage Plasmodium falciparum Infection in Aotus Monkeys

SummaryAntigenic diversity has posed a critical barrier to vaccine development against the pathogenic blood-stage infection of the human malaria parasite Plasmodium falciparum. To date, only strain-specific protection has been reported by trials of such vaccines in nonhuman primates. We recently showed that P. falciparum reticulocyte binding protein homolog 5 (PfRH5), a merozoite adhesin required for erythrocyte invasion, is highly susceptible to vaccine-inducible strain-transcending parasite-neutralizing antibody. In vivo efficacy of PfRH5-based vaccines has not previously been evaluated. Here, we demonstrate that PfRH5-based vaccines can protect Aotus monkeys against a virulent vaccine-heterologous P. falciparum challenge and show that such protection can be achieved by a human-compatible vaccine formulation. Protection was associated with anti-PfRH5 antibody concentration and in vitro parasite-neutralizing activity, supporting the use of this in vitro assay to predict the in vivo efficacy of future vaccine candidates. These data suggest that PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans

Synthesis of Silyloxy Dienes by Silylene Transfer to Divinyl Ketones: Application to the Asymmetric Synthesis of Substituted Cyclohexanes

Silver-catalyzed silylene transfer to divinyl ketones provided 2-silyloxy-1,3-dienes with control of stereochemistry and regioselectivity. The products participated in Diels–Alder reactions with electron-deficient alkenes and imines to form six-membered-ring products diastereoselectively. Cycloaddition reactions with alkenes bearing chiral auxiliaries provided access to chiral, nonracemic cyclohexenes. The methodology, therefore, represents a synthesis of diastereomerically and enantiomerically pure products in a single flask. The highly substituted cyclohexene products could be functionalized stereoselectively to provide cyclohexanols after oxidation of the carbon–silicon bond

Synthesis of Silyloxy Dienes by Silylene Transfer to Divinyl Ketones: Application to the Asymmetric Synthesis of Substituted Cyclohexanes

Silver-catalyzed silylene transfer to divinyl ketones provided 2-silyloxy-1,3-dienes with control of stereochemistry and regioselectivity. The products participated in Diels–Alder reactions with electron-deficient alkenes and imines to form six-membered-ring products diastereoselectively. Cycloaddition reactions with alkenes bearing chiral auxiliaries provided access to chiral, nonracemic cyclohexenes. The methodology, therefore, represents a synthesis of diastereomerically and enantiomerically pure products in a single flask. The highly substituted cyclohexene products could be functionalized stereoselectively to provide cyclohexanols after oxidation of the carbon–silicon bond

Synthesis of Silyloxy Dienes by Silylene Transfer to Divinyl Ketones: Application to the Asymmetric Synthesis of Substituted Cyclohexanes

Silver-catalyzed silylene transfer to divinyl ketones provided 2-silyloxy-1,3-dienes with control of stereochemistry and regioselectivity. The products participated in Diels–Alder reactions with electron-deficient alkenes and imines to form six-membered-ring products diastereoselectively. Cycloaddition reactions with alkenes bearing chiral auxiliaries provided access to chiral, nonracemic cyclohexenes. The methodology, therefore, represents a synthesis of diastereomerically and enantiomerically pure products in a single flask. The highly substituted cyclohexene products could be functionalized stereoselectively to provide cyclohexanols after oxidation of the carbon–silicon bond

Nivel de conocimientos sobre emergencias médicas en estudiantes de medicina de universidades peruanas Level of knowledge in medical emergencies among medical students of peruvian universities

Objetivos. Evaluar el nivel de conocimientos de los estudiantes de medicina de once universidades peruanas sobre emergencias médicas. Materiales y métodos. Estudio transversal analítico, multicéntrico desarrollado entre 2007- 2008. Se utilizó un cuestionario de respuesta nominal autoaplicado con preguntas socio-educativas y diez de opción múltiple sobre emergencias médicas. Se obtuvo una muestra no probabilística de los matriculados en universidades participantes. Se obtuvieron el chi-cuadrado, los OR crudos y ajustados, con intervalos de confianza al 95% y análisis multivariado posterior. Resultados. Participaron 2109 estudiantes de medicina, la edad promedio fue 21 años (rango: 15-32), el 51% de género masculino. El 53% habían realizado un curso previo relacionado con emergencias médicas. El 60,4% desaprobó el cuestionario, la nota promedio fue 4,95 sobre 10 puntos posibles y 5,9% obtuvieron de 8-10 puntos. Se encontró una fuerte asociación entre la universidad de procedencia (OR: 0,45, IC95% 0,38-0,54), la etapa académica (OR: 1,55, IC95% 1,28-1,87), cuándo recibieron un curso del tema (OR: 0,62, IC95% 0,50-0,77) y el género (OR: 1,38, IC95% 1,15-1,65). Conclusiones. El nivel de conocimiento sobre emergencias médicas de los estudiantes de las once universidades evaluadas no es bueno, se sugiere evaluar y mejorar la formación práctica que brindan las universidades en temas de manejo de emergencias médicas.<br>Objectives. The aim of this study was to evaluate the knowledge about medical emergencies of medical students from eleven Peruvian universities. Materials and methods. Multicenter, cross-sectional study, conducted between 2007- 2008. We used a nominal response, self-administered questionnaire with socio-educational questions and ten multiple choice questions on medical emergencies. We obtained a nonrandom sample of participants enrolled in universities. We obtained the chi2, crude and adjusted ORs with 95% confidence intervals and ulterior multivariate analysis. Results. 2,109 medical students participated, the average age was 21 years (range: 15-32), 51% were males. 53% had taken a previous course related to medical emergencies. 60.4% failed the questionnaire, the average score was 4.95 over a maximum of 10 points and 5.9% obtained between 8-10 points. We found a strong association between the university of origin (OR: 0.45, 95% CI 0.38 to 0.54), the academic stage (OR: 1.55, 95% CI 1.28 to 1.87), when they received the course about subject (OR: 0.62, 95% CI 0.50-0.77) and gender (OR: 1.38, 95% CI 1.15 to 1.65). Conclusions. Knowledge of medical emergencies in the students of the eleven evaluated universities is not good, and we suggest the need of evaluating and improving the practical training offered by universities on issues regarding the management of medical emergencies

Prevalence of Trypanosoma cruzi and other Trypanosomatids in frequently-hunted wild mammals from the Peruvian Amazon

To better understand the ecology of Trypanosoma cruzi in the northeastern Peruvian Amazon, we evaluated the prevalence of T. cruzi and other trypanosomatids in four orders of wild mammals hunted and consumed by inhabitants of three remote indigenous communities in the Peruvian Amazon. Of 300 wild mammals sampled, 115 (38.3%) were infected with trypanosomatids and 15 (5.0%) with T. cruzi. The prevalence of T. cruzi within each species was as follows: large rodents (Cuniculus paca, 5.5%; Dasyprocta spp., 2.6%), edentates (Dasypus novemcinctus, 4.2%), and carnivores with higher prevalence (Nasua nasua, 18.8%). The high prevalence of T. cruzi and other trypanosomatids in frequently hunted wild mammals suggests a sizeable T. cruzi sylvatic reservoir in remote Amazonian locations

Chemically Linked Vemurafenib Inhibitors Promote an Inactive BRAF^V600E Conformation

The BRAF kinase, within the mitogen activated protein kinase (MAPK) signaling pathway, harbors activating mutations in about half of melanomas and to a significant extent in many other cancers. A single valine to glutamic acid substitution at residue 600 (BRAF^V600E) accounts for about 90% of these activating mutations. While BRAF^V600E-selective small molecule inhibitors, such as debrafenib and vemurafenib, have shown therapeutic benefit, almost all patients develop resistance. Resistance often arises through reactivation of the MAPK pathway, typically through mutation of upstream RAS, downstream MEK, or splicing variants. RAF kinases signal as homo- and heterodimers, and another complication associated with small molecule BRAF^V600E inhibition is drug-induced allosteric activation of a wild-type RAF subunit (BRAF or CRAF) of the kinase dimer, a process called “transactivation” or “paradoxical activation.” Here, we used BRAF^V600E and vemurafenib as a model system to develop chemically linked kinase inhibitors to lock RAF dimers in an inactive conformation that cannot undergo transactivation. This structure-based design effort resulted in the development of Vem-BisAmide-2, a compound containing two vemurafenib molecules connected by a bis amide linker. We show that Vem-BisAmide-2 has comparable inhibitory potency as vemurafenib to BRAF^V600E both <i>in vitro</i> and in cells but promotes an inactive dimeric BRAF^V600E conformation unable to undergo transactivation. The crystal structure of a BRAF^V600E/Vem-BisAmide-2 complex and associated biochemical studies reveal the molecular basis for how Vem-BisAmide-2 mediates selectivity for an inactive over an active dimeric BRAF^V600E conformation. These studies have implications for targeting BRAF^V600E/RAF heterodimers and other kinase dimers for therapy

Molecular epidemiology of Trypanosomatids and Trypanosoma cruzi in primates from Peru

We determined the prevalence rate and risk of infection of Trypanosoma cruzi and other trypanosomatids in Peruvian non-human primates (NHPs) in the wild (n=126) and indifferent captive conditions (n=183). Blood samples were collected on filter paper, FTA cards, or EDTA tubes and tested using a nested PCR protocol targeting the 24Sar RNA gene. Main risk factors associated with trypanosomatid and T. cruzi infection were genus and the human–animal context (wild vs captive animals). Wild NHPs had higher prevalence of both trypanosomatids (64.3 vs 27.9%, P&lt;0.001) and T. cruzi (8.7 vs 3.3%, P=0.057), compared to captive NHPs, suggesting that parasite transmission in NHPs occurs more actively in the sylvatic cycle. Interms of primate family, Pitheciidae had the highest trypanosomatid prevalence (20/22, 90.9%) and Cebidae had the highest T. cruzi prevalence (15/117, 12.8%). T. cruzi and trypanosomatids are common in Peruvian NHPs and could pose a health risk to human and animals that has not been properly studied