Current status and challenges in drug discovery against the globally important zoonotic cryptosporidiosis

The zoonotic cryptosporidiosis is globally distributed,one of the major diarrheal diseases in humans and animals.Cryptosporidium oocysts are also one of the major environmental concerns,making it a pathogen that fits well into the One Health concept.Despite its importance,fully effective drugs are not yet available.Anti-cryptosporidial drug discovery has historically faced many unusual challenges attributed to unique parasite biology and technical burdens.While significant progresses have been made recently,anti-cryptosporidial drug discovery still faces a major obstacle:identification of systemic drugs that can be absorbed by patients experiencing watery diarrhea and effectively pass through electron-dense(ED)band at the parasite-host cell interface to act on the epicellular parasite.There may be a need to develop an in vitro assay to effectively screen hits/leads for their capability to cross ED band.In the meantime,non-systemic drugs with strong mucoadhesive properties for extended gastrointestinal exposure may represent another direction in developing anti-cryptosporidial therapeutics.For developing both systemic and non-systemic drugs,a non-ruminant animal model exhibiting diarrheal symptoms suitable for routine evaluation of drug absorption and anti-cryptosporidial efficacy may be very helpful.

Origin of the low formation energy of oxygen vacancies in CeO_(2)

Oxygen vacancies play a crucial role in determining the catalytic properties of Ce-based catalysts,especially in oxidation reactions.The design of catalytic activity requires keen insight into oxygen vacancy formation mechanisms.In this work,we investigate the origin of oxygen vacancies in CeO_(2)from the perspective of electron density via high-energy synchrotron powder x-ray diffraction.Multipole refinement results indicate that there is no obvious hybridization between bonded Ce and O atoms in CeO_(2).Subsequent quantitative topological analysis of the experimental total electron density reveals the closed-shell interaction behavior of the Ce-O bond.The results of first-principles calculation indicate that the oxygen vacancy formation energy of CeO_(2)is the lowest among three commonly used redox catalysts.These findings indicate the relatively weak bond strength of the Ce-O bond,which induces a low oxygen vacancy formation energy for CeO_(2)and thus promotes CeO_(2)as a superior catalyst for oxidation reactions.This work provides a new direction for design of functional metal oxides with high oxygen vacancy concentrations.