Tackling resistance: Emerging antimalarials and new parasite targets in the era of elimination [version 1; referees: 2 approved]

Malaria remains a significant contributor to global human mortality, and roughly half the world’s population is at risk for infection with Plasmodium spp. parasites. Aggressive control measures have reduced the global prevalence of malaria significantly over the past decade. However, resistance to available antimalarials continues to spread, including resistance to the widely used artemisinin-based combination therapies. Novel antimalarial compounds and therapeutic targets are greatly needed. This review will briefly discuss several promising current antimalarial development projects, including artefenomel, ferroquine, cipargamin, SJ733, KAF156, MMV048, and tafenoquine. In addition, we describe recent large-scale genetic and resistance screens that have been instrumental in target discovery. Finally, we highlight new antimalarial targets, which include essential transporters and proteases. These emerging antimalarial compounds and therapeutic targets have the potential to overcome multi-drug resistance in ongoing efforts toward malaria elimination

Utilization of the Fundamental Attribution Error with Increased Immune System Inflammation

Immune system inflammation is associated with sickness behavior, depressive mood, and alteration of decision-making processes. Because of these cognitive effects, inflammation may also lead to increased use of heuristics, for example the Fundamental Attribution Error (FAE). In the current research, inflammation was experimentally increased using the influenza vaccine, with participants receiving either the vaccine or a placebo injection and completing a measure that tests for the FAE. There were no significant differences between the two conditions regarding the number of personal, situational, or overall attributions made by the participants in the measure that would indicate use of the FAE. However, exploratory correlational analyses found that participants who were more concerned about COVID-19 were more likely to make personal attributions, which are indicative of the FAE. Future research should be conducted to establish a stronger link between inflammation and heuristic use

A study of methods of measuring exchangeable aluminum and their correlation with root damage from aluminum toxicity

Although it is known that aluminum ions are toxic to plants, very little is known about the quantity of exchangeable aluminum needed to produce damage. The purpose of this study was to evaluate three common measures of exchangeable aluminum and to correlate the amounts measured with plant root damage. Exchangeable aluminum was measured by titration of the whole soil, fluoride titration and colorimetric determination. All three determinations were found adequate for pre-diction of aluminum damage. There is a correlation between pH and exchangeable aluminum, but it is not adequate for prediction purposes. It was found that root damage was likely if more than two meq/100g of exchangeable aluminum were present and the pH was less than five. The existence of organic matter-aluminum complexes in the soils studied was not shown

Natural history of Plasmodium odocoilei malaria infection in farmed white-tailed deer

ABSTRACT White-tailed deer (Odocoileus virginianus), an ecologically and economically important species, are the most widely distributed large animals in North America. A recent study indicated that up to 25% of all white-tailed deer may be infected with Plasmodium odocoilei, a malaria parasite belonging to the distinct clade of ungulate-infecting Plasmodium spp. Because the clinical impact of P. odocoilei on deer health and survival is unknown, we undertook a retrospective longitudinal study of farmed Floridian O. virginianus fawns. We found that a substantial proportion (21%) of fawns acquire malaria infection during the first 8 months of life. Some animals naturally clear P. odocoilei infection, while other animals remain persistently positive. Importantly, we found that animals that acquire malaria parasites very early in life have poor survival compared to animals that remain uninfected. Our report thus provides the first evidence of a clinically significant impact of malaria infection in young deer. IMPORTANCE Malaria parasites of the genus Plasmodium are known to infect a variety of vertebrate hosts, including ungulates (hoofed mammals). A recent study found that up to a quarter of white-tailed deer (Odocoileus virginianus) in North America are infected with the parasite Plasmodium odocoilei. In addition to occupying an important ecological niche, white-tailed deer are popular game animals and deer farming represents a rapidly growing industry. However, the effect of P. odocoilei infection in this ecologically and economically important ungulate species is unknown. Our work is significant because (i) we identified a high prevalence of P. odocoilei in farmed deer and (ii) we found evidence for both cleared and persistent infection, as well as an association with decreased survival of young fawns

Protein prenylation and Hsp40 in thermotolerance of Plasmodium falciparum malaria parasites

During its complex life cycle, the malaria parasite survives dramatic environmental stresses, including large temperature shifts. Protein prenylation is required during asexual replication of Plasmodium falciparum, and the canonical heat shock protein 40 protein (HSP40; PF3D7_1437900) is posttranslationally modified with a 15-carbon farnesyl isoprenyl group. In other organisms, farnesylation of Hsp40 orthologs controls their localization and function in resisting environmental stress. In this work, we find that plastidial isopentenyl pyrophosphate (IPP) synthesis and protein farnesylation are required for malaria parasite survival after cold and heat shock. Furthermore, loss of HSP40 farnesylation alters its membrane attachment and interaction with proteins in essential pathways in the parasite. Together, this work reveals that farnesylation is essential for parasite survival during temperature stress. Farnesylation of HSP40 may promote thermotolerance by guiding distinct chaperone-client protein interactions

Isoprenoid biosynthesis inhibition disrupts Rab5 localization and food vacuolar integrity in Plasmodium falciparum

The antimalarial agent fosmidomycin is a validated inhibitor of the nonmevalonate isoprenoid biosynthesis (methylerythritol 4-phosphate [MEP]) pathway in the malaria parasite, Plasmodium falciparum. Since multiple classes of prenyltransferase inhibitors kill P. falciparum, we hypothesized that protein prenylation was one of the essential functions of this pathway. We found that MEP pathway inhibition with fosmidomycin reduces protein prenylation, confirming that de novo isoprenoid biosynthesis produces the isoprenyl substrates for protein prenylation. One important group of prenylated proteins is small GTPases, such as Rab family members, which mediate cellular vesicular trafficking. We have found that Rab5 proteins dramatically mislocalize upon fosmidomycin treatment, consistent with a loss of protein prenylation. Fosmidomycin treatment caused marked defects in food vacuolar morphology and integrity, consistent with a defect in Rab-mediated vesicular trafficking. These results provide insights to the biological functions of isoprenoids in malaria parasites and may assist the rational selection of secondary agents that will be useful in combination therapy with new isoprenoid biosynthesis inhibitors

Silylethynylated Heteroacenes and Electronic Devices Made Therewith

Novel silylethynylated heteroacenes and electronic devices made with those compounds are disclosed