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A racemic mixture of R and S enantiomers of praziquantel (PZQ) is currently the treatment of choice for schistosomiasis. Though the S enantiomer and the metabolites are presumed to contribute only a little to the activity of the drug, in-depth sideby-side studies are lacking. The aim of this study was to investigate the in vitro activities of PZQ and its main metabolites, namely, R-and S-cis-and R-and S-trans-4=-hydroxypraziquantel, against adult worms and newly transformed schistosomula (NTS). Additionally, we explored the in vivo activity and hepatic shift (i.e., the migration of the worms to the liver) produced by each PZQ enantiomer in mice. Fifty percent inhibitory concentrations of R-PZQ, S-PZQ, and R-trans-and R-cis-4=-hydroxypraziquantel of 0.02, 5.85, 4.08, and 2.42 g/ml, respectively, for adult S. mansoni were determined in vitro. S-trans-and S-cis-4=-hydroxypraziquantel were not active at 100 g/ml. These results are consistent with microcalorimetry data and studies with NTS. In vivo, single 400-mg/kg oral doses of R-PZQ and S-PZQ achieved worm burden reductions of 100 and 19%, respectively. Moreover, worms treated in vivo with S-PZQ displayed an only transient hepatic shift and returned to the mesenteric veins within 24 h. Our data confirm that R-PZQ is the main effector molecule, while S-PZQ and the metabolites do not play a significant role in the antischistosomal properties of PZQ. S chistosomiasis or bilharzia is caused by blood flukes of the genus Schistosoma and is part of the group of neglected tropical diseases affecting more than 207 million people in tropical areas (1-3).The exclusive treatment to date for schistosomiasis is praziquantel (PZQ), which was discovered in the 1970s by Merck and Bayer. PZQ is administered as a racemic mixture of R and S enantiomers in tablets of 600 mg. The recommended dosage to treat schistosomiasis is 20 mg/kg three times in 1 day, and since PZQ does not act on juvenile worms, follow-up treatment 4 to 6 weeks later is strongly advised (4). In preventive chemotherapy programs, PZQ is administered as a single 40-mg/kg dose to at-risk populations (5). PZQ undergoes significant first-pass metabolism through the liver enzyme cytochrome P450 (CYP) 3A4 and to a lesser extent through 1A2 and 2C19 (6). R-PZQ is metabolized at a much higher rate than S-PZQ. R-PZQ is transformed mainly into cis-and trans-hydroxypraziquantel (4-OH-PZQ), while S-PZQ is converted to other monohydroxylated metabolites. In rat liver microsomes, the main metabolite is cis-4-OH-PZQ (7, 8), while in humans it is trans-4-OH-PZQ (9).The difference in the antischistosomal activity of each PZQ enantiomer has been known since 1983 (10), and several studies have observed greater activity of R-PZQ than of S-PZQ in vitro and in vivo (11)(12)(13). A clinical trial with Schistosoma japonicuminfected patients also recorded a higher efficacy of R-PZQ than of racemic PZQ at the same dosage (14, 15). Additionally, treatment with R-PZQ resulted in fewer adverse events than the standard treatment (14). However, ...

The concept of the exposome was introduced over 15 years ago to reflect the important role that the environment exerts on health and disease. While originally viewed as a call-to-arms to develop more comprehensive exposure assessment methods applicable at the individual level and throughout the life course, the scope of the exposome has now expanded to include the associated biological response. In order to explore these concepts, a workshop was hosted by the Gunma University Initiative for Advanced Research (GIAR, Japan) to discuss the scope of exposomics from an international and multidisciplinary perspective. This Global Perspective is a summary of the discussions with emphasis on (1) top-down, bottom-up, and functional approaches to exposomics, (2) the need for integration and standardization of LC- and GC-based high-resolution mass spectrometry methods for untargeted exposome analyses, (3) the design of an exposomics study, (4) the requirement for open science workflows including mass spectral libraries and public databases, (5) the necessity for large investments in mass spectrometry infrastructure in order to sequence the exposome, and (6) the role of the exposome in precision medicine and nutrition to create personalized environmental exposure profiles. Recommendations are made on key issues to encourage continued advancement and cooperation in exposomics.

Data-independent acquisition mass spectrometry (DIA-MS) is essential for information-rich spectral annotations in untargeted metabolomics. However, the acquired MS2 spectra are highly complex, posing significant annotation challenges. We have developed a correlation-based deconvolution (CorrDec) method that uses ion abundance correlations in multisample studies using DIA-MS as an update of our MS-DIAL software. CorrDec is based on the assumption that peak intensities of precursor and fragment ions correlate across samples and exploits this quantitative information to deconvolute complex DIA spectra. CorrDec clearly improved deconvolution of the original MS-DIAL deconvolution method (MS2Dec) in a dilution series of chemical standards and a 224-sample urinary metabolomics study. The primary advantage of CorrDec over MS2Dec is the ability to discriminate coeluting low-abundance compounds. CorrDec requires the measurement of multiple samples to successfully deconvolute DIA spectra; however, our randomized assessment demonstrated that CorrDec can contribute to studies with as few as 10 unique samples. The presented methodology improves compound annotation and identification in multisample studies and will be useful for applications in large cohort studies.

Isothermal microcalorimetry is a label-free assay that allows monitoring of enzymatic and metabolic activities. The technique has strengths, but most instruments have a low throughput, which has limited their use for bioassays. Here, an isothermal microcalorimeter, equipped with a vessel holder similar to a 48-well plate, was used. The increased throughput of this microcalorimeter makes it valuable for biomedical and pharmaceutical applications. Our results show that the sensitivity of the instrument allows the detection of 3 × 104 bacteria per vial. Growth of P. mirabilis in Luria Broth medium was detected between 2 and 9 h with decreasing inoculum. The culture released 2.1J with a maximum thermal power of 76 μW. The growth rate calculated using calorimetric and spectrophotometric data were 0.60 and 0.57 h–1, respectively. Additional insight on protease activities of P. mirabilis matching the last peak in heat production could be gathered as well. Growth of tumor microtissues releasing a maximum thermal power of 2.1 μW was also monitored and corresponds to a diameter increase of the microtissues from ca. 100 to 428 μm. This opens new research avenues in cancer research, diagnostics, and development of new antitumor drugs. For parasitic worms, the technique allows assessment of parasite survival using motor and metabolic activities even with a single worm.

Accurate metabolite identification remains one of the primary challenges in a metabolomics study. A reliable chemical spectral library increases the confidence in annotation, and the availability of raw and annotated data in public databases facilitates the transfer of Liquid chromatography coupled to mass spectrometry (LC–MS) methods across laboratories. Here, we illustrate how the combination of MS2 spectra, accurate mass, and retention time can improve the confidence of annotation and provide techniques to create a reliable library for all ion fragmentation (AIF) data with a focus on the characterization of the retention time. The resulting spectral library incorporates information on adducts and in-source fragmentation in AIF data, while noise peaks are effectively minimized through multiple deconvolution processes. We also report the development of the Mass Spectral LIbrary MAnager (MS-LIMA) tool to accelerate library sharing and transfer across laboratories. This library construction strategy improves the confidence in annotation for AIF data in LC–MS-based metabolomics and will facilitate the sharing of retention time and mass spectral data in the metabolomics community.

Joint Global Health Trials scheme from the Wellcome Trust, Department for International Development, and Medical Research Council.

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