A Potent Kalihinol Analogue Disrupts Apicoplast Function and Vesicular Trafficking in P. falciparum Malaria.

Here we report the discovery of MED6-189, a new analogue of the kalihinol family of isocyanoterpene (ICT) natural products. MED6-189 is effective against drug-sensitive and -resistant P. falciparum strains blocking both intraerythrocytic asexual replication and sexual differentiation. This compound was also effective against P. knowlesi and P. cynomolgi. In vivo efficacy studies using a humanized mouse model of malaria confirms strong efficacy of the compound in animals with no apparent hemolytic activity or apparent toxicity. Complementary chemical biology, molecular biology, genomics and cell biological analyses revealed that MED6-189 primarily targets the parasite apicoplast and acts by inhibiting lipid biogenesis and cellular trafficking. Genetic analyses in P. falciparum revealed that a mutation in PfSec13, which encodes a component of the parasite secretory machinery, reduced susceptibility to the drug. The high potency of MED6-189 in vitro and in vivo, its broad range of efficacy, excellent therapeutic profile, and unique mode of action make it an excellent addition to the antimalarial drug pipeline.

PfMORC protein regulates chromatin accessibility and transcriptional repression in the human malaria parasite, P. falciparum.

The environmental challenges the human malaria parasite, Plasmodium falciparum, faces during its progression into its various lifecycle stages warrant the use of effective and highly regulated access to chromatin for transcriptional regulation. Microrchidia (MORC) proteins have been implicated in DNA compaction and gene silencing across plant and animal kingdoms. Accumulating evidence has shed light into the role MORC protein plays as a transcriptional switch in apicomplexan parasites. In this study, using CRISPR/Cas9 genome editing tool along with complementary molecular and genomics approaches, we demonstrate that PfMORC not only modulates chromatin structure and heterochromatin formation throughout the parasite erythrocytic cycle, but is also essential to the parasite survival. Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) experiments suggest that PfMORC binds to not only sub-telomeric regions and genes involved in antigenic variation but is also most likely a key modulator of stage transition. Protein knockdown experiments followed by chromatin conformation capture (Hi-C) studies indicate that downregulation of PfMORC induces the collapse of the parasite heterochromatin structure leading to its death. All together these findings confirm that PfMORC plays a crucial role in chromatin structure and gene regulation, validating this factor as a strong candidate for novel antimalarial strategies.

[Conservative treatment of hepatic injuries. Management and course]. / Traitement conservateur des traumatismes hépatiques. Prise en charge et évolution.

From January 1986 to June 1994, 252 cases of closed liver trauma were treated in an emergency setting. Non surgical conservative management, after a complete imaging work-up including CT scan in all cases, was applied in 142 cases (56.3%) with no hemodynamic complication. The spontaneous outcome in these cases was quite favourable in 131 (92.2%); all lesions had disappeared in 4 to 36 weeks. Complications were observed in only 6 cases: 2 intrahepatic abscesses managed with percutaneous drainage were not further complicated, 1 biliari fistula required surgical exploration, 1 intrahepatic bilioma was drained percutaneously, 1 disinsertion of the gallbladder was treated by laparoscopy and 1 operation for bleeding was required 48 hours after the trauma in 1 case. No deaths could be directly imputed to the liver trauma, 5 patients died from neurological causes. Non-surgical conservative treatment combined with strict prolonged surveillance is a reliable management option for patients with closed liver trauma.