Genetic manipulation of cell line derived reticulocytes enables dissection of host malaria invasion requirements

Investigatingthe role host erythrocyteproteins play in malaria infection is hampered by the genetic intractability of this anucleate cell. Here we report that reticulocytes derived through in vitro differentiation of an enucleation-competent immortalized erythroblast cell line (BEL-A) support both successful invasion and intracellular development of the malaria parasite Plasmodium falciparum. Using CRISPR-mediated gene knockout and subsequent complementation, we validate an essential role for the erythrocyte receptor basigin in P. falciparum invasion and, for the first time, demonstrate rescueby receptor re-expression.Successful invasion of reticulocytes complemented with a truncated mutant excludes a functional role for the basigincytoplasmic domain during invasion. Contrastingly, knockout of cyclophilin B, reported to participate in invasion and interact with basigin, did not impactinvasive susceptibility of reticulocytes.These data establish the use of reticulocytes derived from immortalized erythroblasts as a powerful model system to explore hypotheses regarding host receptor requirements for P. falciparum invasion

The Novel bis-1,2,4-Triazine MIPS-0004373 Demonstrates Rapid and Potent Activity against All Blood Stages of the Malaria Parasite

Novel bis-1,2,4-triazine compounds with potent in vitro activity against Plasmodium falciparum parasites were recently identified. The bis-1,2,4-triazines represent a unique antimalarial pharmacophore and are proposed to act by a novel but as-yet-unknown mechanism of action. This study investigated the activity of the bis-1,2,4-triazine MIPS-0004373 across the mammalian life cycle stages of the parasite and profiled the kinetics of activity against blood and transmission stage parasites in vitro and in vivo. MIPS-0004373 demonstrated rapid and potent activity against P. falciparum, with excellent in vitro activity against all asexual blood stages. Prolonged in vitro drug exposure failed to generate stable resistance de novo, suggesting a low propensity for the emergence of resistance. Excellent activity was observed against sexually committed ring stage parasites, but activity against mature gametocytes was limited to inhibiting male gametogenesis. Assessment of liver stage activity demonstrated good activity in an in vitro P. berghei model but no activity against Plasmodium cynomolgi hypnozoites or liver schizonts. The bis-1,2,4-triazine MIPS-0004373 efficiently cleared an established P. berghei infection in vivo, with efficacy similar to that of artesunate and chloroquine and a recrudescence profile comparable to that of chloroquine. This study demonstrates the suitability of bis-1,2,4-triazines for further development toward a novel treatment for acute malaria

Direct association with the vascular basement membrane is a frequent feature of myelinating oligodendrocytes in the neocortex

Abstract Background Oligodendrocyte lineage cells interact with the vasculature in the gray matter. Physical and functional interactions between blood vessels and oligodendrocyte precursor cells play an essential role in both the developing and adult brain. Oligodendrocyte precursor cells have been shown to migrate along the vasculature and subsequently detach from it during their differentiation to oligodendrocytes. However, the association of mature oligodendrocytes with blood vessels has been noted since the discovery of this glial cell type almost a century ago, but this interaction remains poorly explored. Results Here, we systematically investigated the extent of mature oligodendrocyte interaction with the vasculature in mouse brain. We found that ~ 17% of oligodendrocytes were in contact with blood vessels in the neocortex, the hippocampal CA1 region and the cerebellar cortex. Contacts were made mainly with capillaries and sparsely with larger arterioles or venules. By combining light and serial electron microscopy, we demonstrated that oligodendrocytes are in direct contact with the vascular basement membrane, raising the possibility of direct signaling pathways and metabolite exchange with endothelial cells. During experimental remyelination in the adult, oligodendrocytes were regenerated and associated with blood vessels in the same proportion compared to control cortex, suggesting a homeostatic regulation of the vasculature-associated oligodendrocyte population. Conclusions Based on their frequent and close association with blood vessels, we propose that vasculature-associated oligodendrocytes should be considered as an integral part of the brain vasculature microenvironment. This particular location could underlie specific functions of vasculature-associated oligodendrocytes, while contributing to the vulnerability of mature oligodendrocytes in neurological diseases

Visiones de fin de siglo

La presente publicación concentra los trabajos presentados por investigadores nacionales y extranjeros en el "Il Encuentro Internacional de Historia. El siglo XX en Bolivia y América Latina. Visiones de fin de siglo", que se realizó en la ciudad de Cochabamba entre el 27 y el 31 de julio de 1998. El encuentro fue organizado por la "Coordinadora de Historia. Investigadores Asociados" y contó con el auspicio del Centro Cultural Portales con sede en esa ciudad, así como con el apoyo de las siguientes instituciones: Facultad de Humanidades de la Universidad Mayor de San Andrés de La Paz, Plural Editores, Anden Silver Corporation, Embajada de México, Lloyl Aéreo Boliviano, Compañía Industrial de Tabacos S.A., Banco Mercantil y La Estrella. La Coordinadora de Historia, que reúne a más de 20 historiadores/as bolivianos/as, desarrolló en 1994 un encuentro similar sobre el siglo XIX en la ciudad de Sucre. Las actas del mismo, al que asistieron renombrados historiadores de Europa, Estados Unidos, Latinoamérica y Bolivia, ya han sido publicadas. En esta oportunidad, 48 expositores abordaron las siguientes temáticas planteadas por los organizadores del Congreso: - Archivos documentales bolivianos del siglo XX. - Proyectos y modelos de sociedad en Bolivia. - Estructuras y practicas políticas en Bolivia y America Latina. - Proyectos, estructuras y modelos económicos en Bolivia y América Latina. - Movimientos, actores y estructuras sociales en Bolivia y America Latina. - Culturas hegemónicas y contraculturas en Bolivia y America Latina. Diez de ellos, Horacio Cerruti, Francisco Zapata, Antonio García de Léon, Antonio Mitre, Melvin Burke, H.C.F, Mansilla, Janvier Sanjinés, Jorge Lazarte, René Antonio Mayorga y Gonzalo Sánchez de Lozada, estuvieron encargados de desarrollar "ponencias magistrales", las que se caracterizaron por intentar visiones más globales o de síntesis sobre las temáticas generales trabajadas en cada una de las jornadas. El encuentro sobre el siglo XX, tuvo la particularidad de reunir a especialistas nacionales extranjeros de distintas disciplinas de las ciencias sociales y humanas como historiadores, sociólogos, antropólogos, economistas y literatos, con el objetivo de lograr el intercambio de visiones y perspectivas de análisis bajo una óptica multirdisciplinaria. Ello permitió romper barreras entre las disciplinas que muchas veces son resultado de prejuicos y celos y desarrollar un rico y creativo débale que muy pocas yeces se realiza en nuestro medio