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A self-purifying microfluidic system for identifying drugs acting against adult schistosomes.

ABSTRACT: The discovery of novel antihelmintic molecules to combat the development and spread of schistosomiasis, a disease caused by several Schistosoma flatworm species, mobilizes significant research efforts worldwide. With a limited number of biochemical assays for measuring the viability of adult worms, the antischistosomicidal activity of molecules is usually evaluated by a microscopic observation of worm mobility and/or integrity upon drug exposure. Even if these phenotypical assays enable multiple parameters analysis, they are often conducted during several days and need to be associated with image-based analysis to minimized subjectivity. We describe here a self-purifying microfluidic system enabling the selection of healthy adult worms and the identification of molecules acting instantly on the parasite. The worms are assayed in a dynamic environment that eliminates unhealthy worms that cannot attach firmly to the chip walls prior to being exposed to the drug. The detachment of the worms is also used as second step readout for identifying active compounds. We have validated this new fluidic screening approach using the two major antihelmintic drugs, praziquantel and artemisinin. The reported dynamic system is simple to produce and to parallelize. Importantly, it enables a quick and sensitive detection of antischistosomal compounds in no more than one hour.

SUBMITTER: Girod V

PROVIDER: S-EPMC9709518 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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A self-purifying microfluidic system for identifying drugs acting against adult schistosomes.

Girod Vincent V Houssier Robin R Sahmer Karin K Ghoris Marie-José MJ Caby Stéphanie S Melnyk Oleg O Dissous Colette C Senez Vincent V Vicogne Jérôme J

Royal Society open science 20221130 11

The discovery of novel antihelmintic molecules to combat the development and spread of schistosomiasis, a disease caused by several <i>Schistosoma</i> flatworm species, mobilizes significant research efforts worldwide. With a limited number of biochemical assays for measuring the viability of adult worms, the antischistosomicidal activity of molecules is usually evaluated by a microscopic observation of worm mobility and/or integrity upon drug exposure. Even if these phenotypical assays enable m ...[more]

PMID: 36465675

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Project description:BackgroundPositive selection pressure acting on protein-coding sequences is usually inferred when the rate of nonsynonymous substitution is greater than the synonymous rate. However, purifying selection acting directly on the nucleotide sequence can lower the synonymous substitution rate. This could result in false inference of positive selection because when synonymous changes at some sites are under purifying selection, the average synonymous rate is an underestimate of the neutral rate of evolution. Even though HIV-1 coding sequences contain a number of regions that function at the nucleotide level, and are thus likely to be affected by purifying selection, studies of positive selection assume that synonymous substitutions can be used to estimate the neutral rate of evolution.ResultsWe modelled site-to-site variation in the synonymous substitution rate across coding regions of the HIV-1 genome. Synonymous substitution rates were found to vary significantly within and between genes. Surprisingly, regions of the genome that encode proteins in more than one frame had significantly higher synonymous substitution rates than regions coding in a single frame. We found evidence of strong purifying selection pressure affecting synonymous mutations in fourteen regions with known functions. These included an exonic splicing enhancer, the rev-responsive element, the poly-purine tract and a transcription factor binding site. A further five highly conserved regions were located within known functional domains. We also found four conserved regions located in env and vpu which have not been characterized previously.ConclusionWe provide the coordinates of genomic regions with markedly lower synonymous substitution rates, which are putatively under the influence of strong purifying selection pressure at the nucleotide level as well as regions encoding proteins in more than one frame. These regions should be excluded from studies of positive selection acting on HIV-1 coding regions.

Dataset Information

A self-purifying microfluidic system for identifying drugs acting against adult schistosomes.

Publications

A self-purifying microfluidic system for identifying drugs acting against adult schistosomes.

Similar Datasets

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