Validation of N-myristoyltransferase as an antimalarial drug target using an integrated chemical biology approach

Malaria is an infectious disease caused by parasites of the genus Plasmodium, which leads to approximately one million deaths per annum worldwide. Chemical validation of new antimalarial targets is urgently required in view of rising resistance to current drugs. One such putative target is the enzyme N-myristoyltransferase, which catalyses the attachment of the fatty acid myristate to protein substrates (N-myristoylation). Here, we report an integrated chemical biology approach to explore protein myristoylation in the major human parasite P. falciparum, combining chemical proteomic tools for identification of the myristoylated and glycosylphosphatidylinositol-anchored proteome with selective small-molecule N-myristoyltransferase inhibitors. We demonstrate that N-myristoyltransferase is an essential and chemically tractable target in malaria parasites both in vitro and in vivo, and show that selective inhibition of N-myristoylation leads to catastrophic and irreversible failure to assemble the inner membrane complex, a critical subcellular organelle in the parasite life cycle. Our studies provide the basis for the development of new antimalarials targeting N-myristoyltransferase

A novel member of the let-7 microRNA family is associated with developmental transitions in filarial nematode parasites

Background: Filarial nematodes are important pathogens in the tropics transmitted to humans via the bite of blood sucking arthropod vectors. The molecular mechanisms underpinning survival and differentiation of these parasites following transmission are poorly understood. microRNAs are small non-coding RNA molecules that regulate target mRNAs and we set out to investigate whether they play a role in the infection event. Results: microRNAs differentially expressed during the early post-infective stages of Brugia pahangi L3 were identified by microarray analysis. One of these, bpa-miR-5364, was selected for further study as it is upregulated ~12-fold at 24 hours post-infection, is specific to clade III nematodes, and is a novel member of the let-7 family, which are known to have key developmental functions in the free-living nematode Caenorhabditis elegans. Predicted mRNA targets of bpa-miR-5364 were identified using bioinformatics and comparative genomics approaches that relied on the conservation of miR-5364 binding sites in the orthologous mRNAs of other filarial nematodes. Finally, we confirmed the interaction between bpa-miR-5364 and three of its predicted targets using a dual luciferase assay. Conclusions: These data provide new insight into the molecular mechanisms underpinning the transmission of third stage larvae of filarial nematodes from vector to mammal. This study is the first to identify parasitic nematode mRNAs that are verified targets of specific microRNAs and demonstrates that post-transcriptional control of gene expression via stage-specific expression of microRNAs may be important in the success of filarial infection

Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study

The drug-induced liver injury network (DILIN) is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study

Towards an explanatory taxonomy of adolescent delinquents: Identifying several social-psychological profiles

Abstract Taxonomic structure is examined in two large samples of delinquent youth in a domain of socio-psychological and personality factors. This paper offers a partial empirical test of the overlapping theoretical taxonomies of Moffitt (Pshycol Rev 100:674-701, 1993), Lykken (The antisocial personalities, 1995) an

The Effect of Bullying and Victimization on Cognitive Empathy Development During the Transition to Middle School.

Background Interventions aimed at reducing bullying behavior commonly target the development of empathy. Yet, few longitudinal studies have investigated how empathy levels vary with bullying and victimization over time, especially during the transition to middle school. Objective To that end, the purpose of the present study was to: (1) examine the naturally-occurring changes in cognitive empathy during the transition from elementary to middle school, and (2) explore the effect of bullying and victimization involvement on changes in cognitive empathy over time, and specifically during this school transition. Methods Latent growth curve modeling was used to examine growth trajectories in empathy over time and the effects of bullying involvement on this growth among a sample of 431 students (52 % female, 52 % Latino, 10.18 years old at baseline), using data collected during the spring semester of the 4th grade, the fall and spring semesters of 5th grade, and the spring semester of 6th grade. Results Cognitive empathy decreased over time, and a linear trajectory was the best fitting shape for these data. Bullying and victimization were both associated with lower levels of cognitive empathy throughout the study. However, the effect of victimization was small and it became non-significant when both were added to the model. Several notable participant-related differences were found