Live research / global_health
Investigating the molecular mechanisms and epidemiological spread of artemisinin-resistant Plasmodium falciparum in East Africa, with focus on PfKelch13 C580Y and related mutations. Cathedral is using protein structure analysis, literature ingestion, open questions, and distributed contribution to organize work on an underserved global health threat.
Progress summary
Project initialized with seven field-level ghost questions, a tiered task decomposition, and a protein viewer path for PfKelch13 resistance mutations.
Start here / no biology credential required
Cathedral does not claim one person can solve resistance from a browser. It makes the research legible, separates safe beginner work from specialist judgment, keeps every claim attached to evidence, and routes the hard decisions to biologists, clinicians, epidemiologists, and monitored agents.
1 / Orient
Read the ELI5 concept layer for malaria, ACT treatment, K13, and delayed parasite clearance.
2 / Search
Choose an open question and pull live PubMed, Europe PMC, Semantic Scholar, Crossref, and arXiv evidence.
3 / Contribute
Audit study location, mutation, regimen, outcome, and source passage in a structured evidence table.
4 / Validate
Send disputed interpretations and proposed interventions to domain experts; agents handle repeatable surveillance.
Structural biology
Wildtype structures load from AlphaFold DB. Resistance mutants are folded with ESMFold and rendered inline so molecular hypotheses can sit beside the literature.
Ghost nodes
Sub-optimal dosing and incomplete treatment courses may drive resistance. It remains open whether dispensing patterns can predict future hotspots before clinical failure is observed.
Open canonical question record
The C580Y mutation accounts for the majority of validated artemisinin resistance cases globally. Other K13 mutations also confer resistance but are less prevalent; the structural and biochemical reason C580Y is so successful remains unresolved.
Open canonical question record
Artemisinin requires activation by heme to become toxic to the parasite. K13 mutations appear to reduce activation, but the complete pathway connecting K13 function to heme release remains disputed.
Open canonical question record
If K13 mutations carry high fitness cost, resistance may recede without sustained drug pressure. If low cost, it may persist; current data is contradictory across studies.
Open canonical question record
Some treatment failure cases show no K13 mutation, suggesting alternative resistance mechanisms may exist but are not yet characterized.
Open canonical question record
Uganda has high confirmed K13 mutation prevalence despite Tanzania having comparable ACT usage and similar regional conditions. The epidemiological and genomic asymmetry is not fully explained.
Open canonical question record
Existing drug combinations might overcome K13-mediated resistance faster than new drug development. Comprehensive computational screening remains incomplete.
Open canonical question record
Daily progress log
2026-07-06
Initialized Cathedral's public artemisinin-resistance research project, seeded open questions, and prepared protein-structure tooling for PfKelch13.
Blocked: Live field data from MalariaGEN and WWARN still needs source-specific adapter validation before we treat it as production evidence.
PubMed/NCBI / Semantic Scholar / UniProt / AlphaFold DB / ESMFold
Problem decomposition
Tier 1
Collect public reports from clinics, WHO updates, and local health notes. Tag country, district, date, treatment regimen, and whether K13 genotype is reported.
Tier 1
Produce short Swahili and English summaries explaining what resistance is, what it is not, and why completing ACT treatment matters.
Tier 2
Search PubMed, Semantic Scholar, and Crossref for K13/C580Y studies in Uganda, Tanzania, Rwanda, and Ethiopia. Extract year, sample size, mutations, clearance phenotype, and location.
Tier 2
Create an evidence matrix separating delayed parasite clearance, treatment failure, K13 genotype, and ACT partner-drug failure.
Tier 3
Use AlphaFold DB for wildtype and ESMFold for mutants. Compare mutation sites, structural confidence, and candidate interaction surfaces.
Tier 3
Link K13 prevalence data to country, year, and lineage where available. Identify whether spread is imported, locally selected, or both.
Tier 4
Prioritize existing drug combinations that could suppress K13-mediated partial resistance without waiting for new compounds.
Tier 4
Specify experiments that distinguish reduced artemisinin activation, altered endocytosis, stress response survival, and fitness-cost models.