The synthesis of potential antimalarials. Derivatives of pantoyltaurine

The general hypothesis as to the mode of action of chemotherapeutic agents, which has been formulated by Fildes, Woods, McIlwain, and others (2), offers a rational and useful guide to the design of new drugs. Thus, bacteriostasis is pictured as caused by the blocking of reactions essential to growth by an inhibiting substance which has a structure similar to that of one of the normal enzymes or metabolites essential to the growth of the organism

The structure of a new metabolic derivative of quinine

The isolation and crystallization of a product obtained by the in vitro action of rabbit liver on quinine (I) have recently been described by Kelsey, Geiling, Oldham, and Dearborn (1). The work reported here was undertaken with the object of obtaining information, as rapidly as possible, as to the possible structure of this product, which might prove useful in other malarial investigations. Thus no attempt has been made to obtain or present a rigid proof of structure of the metabolic product, which, for convenience, will be referred to as QDP (quinine-derived product). Evidence will be presented which suggests that QDP is levorotatory 2’-hydroxy-6’-methoxy-3-vinylruban-9-ol (II), according to the notation introduced by Rabe (2)

Phytohormones: Structure and physiological activity. I

In plants, growth in length by cell elongation is conditioned by certain substances elaborated in the plant and effective in minute amounts, thus having the nature of hormones. A number of simple tests have been worked out which allow of a qualitative and quantitative determination of the growth-promoting properties of various substances. With the aid of these biological tests the native growth substances or auxins have been isolated and a variety of other substances have been shown to possess growth activity. At first sight the large number of substances which are active do not appear to fall within any general classification. Upon further investigation, however, it becomes clear that there are certain common structural characteristics, and an analysis of these provides a first step in attacking the fundamental problem of the relations between chemical structure and physiological activity. This relation has in recent years been attacked in a number of other fields, usually involving physiological processes in animals. On the other hand, it would appear that plants offer an exceptionally favorable field for study in that their structures--- and possibly their physiological processes-are somewhat less complicated. Thus, it has been found possible to differentiate between some of the steps in the chain of reactions which lead to cell elongation, so that now it becomes possible to determine the exact structure required in a substance for the regulation of each of these steps

High-throughput Plasmodium falciparum hrp2 and hrp3 gene deletion typing by digital PCR to monitor malaria rapid diagnostic test efficacy

Most rapid diagnostic tests for Plasmodium falciparum malaria target the Histidine-Rich Proteins 2 and 3 (HRP2, HRP3). Deletions of the hrp2 and hrp3 genes result in false negative tests and are a threat for malaria control. A novel assay for molecular surveillance of hrp2/hrp3 deletions was developed based on droplet digital PCR (ddPCR). The assay quantifies hrp2, hrp3, and a control gene with very high accuracy. The theoretical limit of detection was 0.33 parasites/microL. The deletion was reliably detected in mixed infections with wild-type and hrp2-deleted parasites at a density of >100 parasites/reaction. For a side-by-side comparison with the conventional nested PCR (nPCR) assay, 248 samples were screened in triplicate by ddPCR and nPCR. No deletions were observed by ddPCR, while by nPCR hrp2 deletion was observed in 8% of samples. The ddPCR assay was applied to screen 830 samples from Kenya, Zanzibar/Tanzania, Ghana, Ethiopia, Brazil, and Ecuador. Pronounced differences in the prevalence of deletions were observed among sites, with more hrp3 than hrp2 deletions. In conclusion, the novel ddPCR assay minimizes the risk of false-negative results (i.e. hrp2 deletion observed when the sample is wild type), increases sensitivity, and greatly reduces the number of reactions that need to be run

Tissue Sampling Methods and Standards for Vertebrate Genomics

The recent rise in speed and efficiency of new sequencing technologies have facilitated high-throughput sequencing, assembly and analyses of genomes, advancing ongoing efforts to analyze genetic sequences across major vertebrate groups. Standardized procedures in acquiring high quality DNA and RNA and establishing cell lines from target species will facilitate these initiatives. We provide a legal and methodological guide according to four standards of acquiring and storing tissue for the Genome 10K Project and similar initiatives as follows: four-star (banked tissue/cell cultures, RNA from multiple types of tissue for transcriptomes, and sufficient flash-frozen tissue for 1 mg of DNA, all from a single individual);three-star (RNA as above and frozen tissue for 1 mg of DNA); two-star (frozen tissue for at least 700 μg of DNA); and one-star (ethanol-preserved tissue for 700 μg of DNA or less of mixed quality). At a minimum, all tissues collected for the Genome 10K and other genomic projects should consider each species’ natural history and follow institutional and legal requirements. Associated documentation should detail as much information as possible about provenance to ensure representative sampling and subsequent sequencing. Hopefully, the procedures outlined here will not only encourage success in the Genome 10K Project but also inspire the adaptation of standards by other genomic projects, including those involving other biota

Investigating differences in village-level heterogeneity of malaria infection and household risk factors in Papua New Guinea

Malaria risk is highly heterogeneous. Understanding village and household-level spatial heterogeneity of malaria risk can support a transition to spatially targeted interventions for malaria elimination. This analysis uses data from cross-sectional prevalence surveys conducted in 2014 and 2016 in two villages (Megiar and Mirap) in Papua New Guinea. Generalised additive modelling was used to characterise spatial heterogeneity of malaria risk and investigate the contribution of individual, household and environmental-level risk factors. Following a period of declining malaria prevalence, the prevalence of P. falciparum increased from 11.4 to 19.1% in Megiar and 12.3 to 28.3% in Mirap between 2014 and 2016, with focal hotspots observed in these villages in 2014 and expanding in 2016. Prevalence of P. vivax was similar in both years (20.6% and 18.3% in Megiar, 22.1% and 23.4% in Mirap) and spatial risk heterogeneity was less apparent compared to P. falciparum. Within-village hotspots varied by Plasmodium species across time and between villages. In Megiar, the adjusted odds ratio (AOR) of infection could be partially explained by household factors that increase risk of vector exposure, such as collecting outdoor surface water as a main source of water. In Mirap, increased AOR overlapped with proximity to densely vegetated areas of the village. The identification of household and environmental factors associated with increased spatial risk may serve as useful indicators of transmission hotspots and inform the development of tailored approaches for malaria control

Persistence of Plasmodium falciparum parasitemia after artemisinin combination therapy: evidence from a randomized trial in Uganda

Artemisinin resistance is rapidly spreading in Southeast Asia. The efficacy of artemisinin-combination therapy (ACT) continues to be excellent across Africa. We performed parasite transcriptional profiling and genotyping on samples from an antimalarial treatment trial in Uganda. We used qRT-PCR and genotyping to characterize residual circulating parasite populations after treatment with either ACT or ACT-primaquine. Transcripts suggestive of circulating ring stage parasites were present after treatment at a prevalence of >25% until at least 14 days post initiation of treatment. Greater than 98% of all ring stage parasites were cleared within the first 3 days, but subsequently persisted at low concentrations until day 14 after treatment. Genotyping demonstrated a significant decrease in multiplicity of infection within the first 2 days in both ACT and ACT-primaquine arms. However, multiple clone infections persisted until day 14 post treatment. Our data suggest the presence of genetically diverse persisting parasite populations after ACT treatment. Although we did not demonstrate clinical treatment failures after ACT and the viability and transmissibility of persisting ring stage parasites remain to be shown, these findings are of relevance for the interpretation of parasite clearance transmission dynamics and for monitoring drug effects in Plasmodium falciparum parasites

Chromosomal-level assembly of the Asian Seabass genome using long sequence reads and multi-layered scaffolding

We report here the ~670 Mb genome assembly of the Asian seabass (Lates calcarifer), a tropical marine teleost. We used long-read sequencing augmented by transcriptomics, optical and genetic mapping along with shared synteny from closely related fish species to derive a chromosome-level assembly with a contig N50 size over 1 Mb and scaffold N50 size over 25 Mb that span ~90% of the genome. The population structure of L. calcarifer species complex was analyzed by re-sequencing 61 individuals representing various regions across the species' native range. SNP analyses identified high levels of genetic diversity and confirmed earlier indications of a population stratification comprising three clades with signs of admixture apparent in the South-East Asian population. The quality of the Asian seabass genome assembly far exceeds that of any other fish species, and will serve as a new standard for fish genomics