Untargeted metabolomics to understand the basis of phenotypic differences in amphotericin B-resistant Leishmania parasites
Why this work is in the frame
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Bibliographic record
Abstract
<ns4:p> <ns4:bold>Background</ns4:bold> : Protozoan <ns4:italic>Leishmania</ns4:italic> parasites are responsible for a range of clinical infections that represent a substantial challenge for global health. Amphotericin B (AmB) is increasingly used to treat <ns4:italic>Leishmania</ns4:italic> infection, so understanding the potential for resistance to this drug is an important priority. Previously we described four independently-derived AmB-resistant <ns4:italic>L. mexicana</ns4:italic> lines that exhibited resistance-associated genetic lesions resulting in altered sterol content. However, substantial phenotypic variation between these lines, including differences in virulence attributes, were not fully explained by these changes. </ns4:p> <ns4:p> <ns4:bold>Methods:</ns4:bold> To identify alterations in cellular metabolism potentially related to phenotypic differences between wild-type and AmB-resistant lines, we extracted metabolites and performed untargeted metabolomics by liquid chromatography-mass spectrometry. </ns4:p> <ns4:p> <ns4:bold>Results:</ns4:bold> We observed substantial differences in metabolite abundance between lines, arising in an apparently stochastic manner. Concerted remodeling of central carbon metabolism was not observed; however, in three lines, decreased abundance of several oligohexoses was observed. Given that the oligomannose mannogen is an important virulence factor in <ns4:italic>Leishmania</ns4:italic> , this could relate to loss of virulence in these lines. Increased abundance of the reduced forms of the oxidative stress-protective thiols trypanothione and glutathione was also observed in multiple lines. </ns4:p> <ns4:p> <ns4:bold>Conclusions:</ns4:bold> This dataset will provide a useful resource for understanding the molecular basis of drug resistance in <ns4:italic>Leishmania</ns4:italic> , and suggests a role for metabolic changes separate from the primary mechanism of drug resistance in determining the phenotypic profile of parasite lines subjected to experimental selection of resistance. </ns4:p>
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.008 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.004 | 0.010 |
| Research integrity | 0.000 | 0.003 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it