Search

Near the northern border of Sumatra, the right-lateral strike–slip Sumatran fault zone splits into two branches and extends into the offshore, as revealed by seismic sounding surveys. However, due to its strike–slip faulting characteristics, the Sumatran fault zone's activity is rarely believed to cause tsunami hazards in this region. According to two reprocessed reflection seismic profiles, the extended Sumatran fault zone is strongly associated with chaotic facies, indicating that large submarine landslides have been triggered. Coastal steep slopes and new subsurface characteristics of submarine landslide deposits were mapped using recently acquired high-resolution shallow bathymetry data. Slope stability analysis revealed some targets with steep morphology to be close to failure. In an extreme hypothetical case, an earthquake of Mw 7 or more occurred, and the strong ground shaking triggered a submarine landslide off the northern shore of Sumatra. Based on a simulation of tsunami wave propagation in shallow water, the results of this study indicate that a potential tsunami hazard from several submarine landslide sources triggered by the strike–slip fault system can generate a tsunami as high as 4–8 m at several locations along the northern coast of Aceh. The landslide tsunami hazard assessment and early warning systems in this study area can be improved on the basis of this proposed scenario.

Abstract We recently characterized the potent antiplasmodial activity of the aggregated protein dye YAT2150, whose presumed mode of action is the inhibition of protein aggregation in the malaria parasite. Using single-dose and ramping methods, assays were done to select Plasmodium falciparum parasites resistant to YAT2150 concentrations ranging from 3× to 0.25× the in vitro IC50 of the compound (in the two-digit nM range) and performed a cross-resistance assessment in P. falciparum lines harboring mutations that make them resistant to a variety of antimalarial drugs. Resistant parasites did not emerge in vitro after 60 days of incubation, which postulates YAT2150 as an ‘irresistible’ antimalarial. The lyophilized compound is stable for at least one year stored at 25 °C. Tests performed in clinical isolates indicated that YAT2150 had also strong activity against Plasmodium vivax (IC50 between 4 and 36 nM) and Leishmania infantum (1.27 and 1.11 µM), placing it as a unique compound with perspectives of becoming the first drug to be used against both malaria and leishmaniasis.

Artemisinin-based combination therapy (ACT) is the mainstay of effective treatment of Plasmodium falciparum malaria. However, the long-term utility of ACTs is imperiled by widespread partial artemisinin resistance in Southeast Asia and its recent emergence in parts of East Africa. This underscores the need to identify chemotypes with new modes of action (MoAs) to circumvent resistance to ACTs. In this study, we characterized the asexual blood stage antiplasmodial activity and resistance mechanisms of LDT-623, a 4-aminoquinoline (4-AQ). We also detected LDT-623 activity against multiple stages (liver schizonts, stage IV-V gametocytes, and ookinetes) of Plasmodium's life cycle, a feature unlike other 4-AQs such as chloroquine (CQ) and piperaquine (PPQ). Using heme fractionation profiling and drug uptake studies in PfCRT-containing proteoliposomes, we observed inhibition of hemozoin formation and PfCRT-mediated transport, which constitute characteristic features of 4-AQs' MoA. We also found minimal cross-resistance to LDT-623 in a panel of mutant pfcrt or pfmdr1 lines, but not the PfCRT F145I mutant that is highly resistant to PPQ resistance yet is very unfit. No P. falciparum parasites were recovered in an in vitro resistance selection study, suggesting a high barrier for resistance to emerge. Finally, a competitive growth assay comprising >50 barcoded parasite lines with mutated resistance mediators or major drug targets found no evidence of cross-resistance. Our findings support further exploration of this promising 4-AQ.

Abstract Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

Abstract We report an analysis of the propensity of the antimalarial agent cabamiquine, a Plasmodium-specific eukaryotic elongation factor 2 inhibitor, to select for resistant Plasmodium falciparum parasites. Through in vitro studies of laboratory strains and clinical isolates, a humanized mouse model, and volunteer infection studies, we identified resistance-associated mutations at 11 amino acid positions. Of these, six (55%) were present in more than one infection model, indicating translatability across models. Mathematical modelling suggested that resistant mutants were likely pre-existent at the time of drug exposure across studies. Here, we estimated a wide range of frequencies of resistant mutants across the different infection models, much of which can be attributed to stochastic differences resulting from experimental design choices. Structural modelling implicates binding of cabamiquine to a shallow mRNA binding site adjacent to two of the most frequently identified resistance mutations.

Background: The prevalence of thyroid disease has seen a rapid increase in recent times, primarily attributed to the fast pace of lifestyles that often result in poor dietary choices, work-life imbalances, social stress, genetic mutations, and improved diagnostic capabilities. However, the precise contribution of these factors to thyroid disease remains a subject of controversy. Consequently, there is a pressing need to gain a comprehensive understanding of the related associations in order to potentially mitigate the associated morbidity and mortality rates. Methods: This study employed association rule mining techniques to reveal hidden correlations among complex and diverse epidemiological connections pertaining to thyroid disease associations. We proposed a framework which incorporates text mining and association rule mining algorithms with exceptionality measurement to simultaneously identify common and exception risk factors correlated with the disease through real-life digital health records. Two distinctive datasets were analyzed through two algorithms, and mutual factors were retained for interpretation. Results: The results confirmed that age, gender, and history of thyroid disease are risk factors positively related to subsequent thyroid cancer. Furthermore, it was observed that the absence of underlying chronic disease conditions, such as diabetes, hypertension, or obesity, are associated with reduced likelihood of being diagnosed with thyroid cancer. Conclusions: Collectively, the proposed framework demonstrates its sound feasibility and should be further recommended for different disease in-depth knowledge discovery.

Since its inception, the Actiotope Model of Giftedness (AMG) has provided researchers with a useful model to explain the development of exceptionality. Rather than a focus on the individual, the model postulates that exceptionality is the outcome of a system that includes complex interactions between an individual’s current level of talent and their internal and external environment. To date, however, the statistical techniques that have been used to investigate the model, including linear regression and structural equation modeling, are unable to fully operationalize the systemic nature of these interactions. In order to fully realize the predictive potential and application of the AMG, we outline the use of artificial neural networks (ANNs) to model the complex interactions and suggest that such networks can provide additional insights into the development of exceptionality. In addition to supporting continued research into the AMG, the use of ANNs has the potential to provide educators with evidence-based strategies to support student learning at both an individual and whole-school level.

Imidazolopiperazines (IZPs) are a class of compounds under clinical development for malaria, but their mechanism of action is unclear. Here, the authors show that IZPs inhibit the parasite’s secretory pathway, affecting protein trafficking and export.