The role of pfmdr1 in Plasmodium falciparum tolerance to artemether-lumefantrine in Africa

Objective Artemether-lumefantrine (AL), presently the most favoured combination therapy against uncomplicated Plasmodium falciparum malaria in Africa, has recently shown to select for the pfmdr1 86N allele. The objective of this study was to search for the selection of other mutations potentially involved in artemether-lumefantrine tolerance and/or resistance, i.e. pfmdr1 gene amplification, pfmdr1 Y184F, S1034C, N1042D, D1246Y, pfcrt S163R and PfATP6 S769N. Methods The above mentioned SNPs were analysed by PCR-restriction fragment length polymorphism and pfmdr1 gene amplification by real-time PCR based protocols in parasites from 200 children treated with AL for uncomplicated P. falciparum malaria in Zanzibar. Results A statistically significant selection of pfmdr1 184F mostly in combination with 86N was seen in reinfections after treatment. No pfmdr1 gene amplification was found. Conclusion The results suggest that different pfmdr1 alleles are involved in the development of tolerance/resistance to lumefantrine.info:eu-repo/semantics/publishedVersio

Sickle Cell MicroRNAs Inhibit the Malaria Parasite

Sickle cell hemoglobin conveys resistance to malaria. In this issue of Cell Host & Microbe, LaMonte et al. (2012) demonstrate a surprising mechanism for this innate immunity. A microRNA enriched in sickle red blood cells is translocated into the parasite, incorporated covalently into P. falciparum mRNAs and inhibits parasite growth

When Youth Dialogue: A Pedagogic Framework for Changing the Conversation About Migration

How should educators teach about one of the most complex and pressing issues of our times? This paper presents an empirically-grounded framework to help educators understand the opportunities and challenges of engaging youth around the topic of migration, including migration involving refugees. It stresses the importance of inviting youth to dialogue in ways that involve slowing down, sharing stories, and making connections. The framework emerged from a design-based research study involving an experimental online learning community and curriculum on the topic of human migration. Posts and comments involving 140 teens from seven countries were closely analyzed using a modified grounded theory approach that incorporated constructivist principles. 14 interviews with participating educators also informed the analysis. The framework proposes that youth be supported to develop (1) curiosity and engagement about individual migration stories and migration in general, (2) nuanced understanding of the complex and diverse factors that help shape historical and contemporary migration experiences, and (3) critical awareness of their own and others’ perspectives on migration and migrants. A visual representation is provided. Specific examples of student dialogue are unpacked to illustrate the framework, with discussion of the following cognitive and affective challenges: “the Three O’s” of overgeneralization, overconfidence, and othering. The paper argues that youth of all backgrounds need opportunities to learn about migration in ways that allow them to leverage their various experiences and perspectives and engage with one another in meaningful, authentic ways

Amlodipine induced gingival hyperplasia: a case report

A 55-year-old South Indian male with hypertension, benign prostate hypertrophy and old myocardial infarction was admitted with painless inflammation of gingiva. He received amlodipine 5 mg once a day, atorvastatin 10 mg once a day, aspirin 75 mg once a day and rabeprazole 20 mg once a day for past 5 months. The patient in the case presented had gingival hyperplasia as a result of managing his hypertension with amlodipine. Calcium channel blockers are one of the most widely used anti-hypertensive and are known for causing gingival hyperplasia as an adverse effect. It may develop as a result of two inflammatory and non-inflammatory pathways. The problem completely resolved when the offending drug was withdrawn and he was switched over to an angiotensin receptor blocker. The present case is interesting as it occurred with a low dose of amlodipine (5 mg) and appeared on administration for 5 months. This paper aims at drawing the attention of clinicians toward adverse effects of amlodipine along with a brief review on the management of hyperplasia without surgical interventions

Issues in history education: perspectives from England and the USA

In this article I offer a selective overview of some of the ongoing and emerging issues concerning history education in England and the USA. I also try to explain why the history teaching practices in these two countries are very different

From protease to decarboxylase: the molecular metamorphosis of phosphatidylserine decarboxylase

Background: Phosphatidylserine decarboxylase (PSD) undergoes an autoendoproteolytic cleavage but the mechanism has not been defined. Results: PSD proenzyme processing occurs by a canonical serine protease mechanism catalyzed by a conserved aspartate-histidine-serine triad. Conclusion: PSD proenzyme executes a proteolytic reaction in cis that creates the active site of the decarboxylase. Significance: The mechanism of autoendoproteolyic processing of PSDs across phyla has been elucidated

Variant merozoite protein expression is associated with erythrocyte invasion phenotypes in Plasmodium falciparum isolates from Tanzania

[No abstract available

Altered drug susceptibility during host adaptation of a <i>Plasmodium falciparum</i> strain in a non-human primate model

Infections with Plasmodium falciparum, the most pathogenic of the Plasmodium species affecting man, have been reduced in part due to artemisinin-based combination therapies. However, artemisinin resistant parasites have recently emerged in South-East Asia. Novel intervention strategies are therefore urgently needed to maintain the current momentum for control and elimination of this disease. In the present study we characterize the phenotypic and genetic properties of the multi drug resistant (MDR) P. falciparum Thai C2A parasite strain in the non-human Aotus primate model, and across multiple passages. Aotus infections with C2A failed to clear upon oral artesunate and mefloquine treatment alone or in combination, and ex vivo drug assays demonstrated reduction in drug susceptibility profiles in later Aotus passages. Further analysis revealed mutations in the pfcrt and pfdhfr loci and increased parasite multiplication rate (PMR) across passages, despite elevated pfmdr1 copy number. Altogether our experiments suggest alterations in parasite population structure and increased fitness during Aotus adaptation. We also present data of early treatment failures with an oral artemisinin combination therapy in a pre-artemisinin resistant P. falciparum Thai isolate in this animal model

Structure and non-essential function of glycerol kinase in <i>Plasmodium</i> <i>falciparum</i> blood stages

Malaria pathology is caused by multiplication of asexual parasites within erythrocytes, whereas mosquito transmission of malaria is mediated by sexual precursor cells (gametocytes). Microarray analysis identified glycerol kinase (GK) as the second most highly upregulated gene in Plasmodium falciparum gametocytes with no expression detectable in asexual blood stage parasites. Phosphorylation of glycerol by GK is the rate-limiting step in glycerol utilization. Deletion of this gene from P. falciparum had no effect on asexual parasite growth, but surprisingly also had no effect on gametocyte development or exflagellation, suggesting that these life cycle stages do not utilize host-derived glycerol as a carbon source. Kinetic studies of purified PfGK showed that the enzyme is not regulated by fructose 1,6 bisphosphate. The high-resolution crystal structure of P. falciparum GK, the first of a eukaryotic GK, reveals two domains embracing a capacious ligand-binding groove. In the complexes of PfGK with glycerol and ADP, we observed closed and open forms of the active site respectively. The 27° domain opening is larger than in orthologous systems and exposes an extensive surface with potential for exploitation in selective inhibitor design should the enzyme prove to be essential in vivo either in the human or in the mosquito

Reticulocyte binding protein homologues are key adhesins during erythrocyte invasion by Plasmodium falciparum

The Apicomplexan parasite responsible for the most virulent form of malaria, Plasmodium falciparum, invades human erythrocytes through multiple ligand–receptor interactions. The P. falciparum reticulocyte-binding protein homologue (PfRh or PfRBL) family have been implicated in the invasion process but their exact role is unknown. PfRh1 and PfRh4, members of this protein family, bind to red blood cells and function in merozoite invasion during which they undergo a series of proteolytic cleavage events before and during entry into the host cell. The ectodomain of PfRh1 and PfRh4 are processed to produce fragments consistent with cleavage in the transmembrane domain and released into the supernatant, at about the time of invasion, in a manner consistent with rhomboid protease cleavage. Processing of both PfRh1 and PfRh4, and by extrapolation all membrane-bound members of this protein family, is important for function and release of these proteins on the merozoite surface and they along with EBA-175 are important components of the tight junction, the transient structure that links the erythrocyte via receptor–ligand interactions to the actin–myosin motor in the invading merozoite