ORCID Profile
0000-0003-0445-5048
Current Organisations
University of Oxford
,
Radboud university medical centre
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Publisher: Springer Science and Business Media LLC
Date: 10-08-2021
DOI: 10.1038/S41467-021-24954-4
Abstract: The malaria parasite Plasmodium falciparum replicates inside erythrocytes in the blood of infected humans. During each replication cycle, a small proportion of parasites commits to sexual development and differentiates into gametocytes, which are essential for parasite transmission via the mosquito vector. Detailed molecular investigation of gametocyte biology and transmission has been h ered by difficulties in generating large numbers of these highly specialised cells. Here, we engineer P. falciparum NF54 inducible gametocyte producer (iGP) lines for the routine mass production of synchronous gametocytes via conditional overexpression of the sexual commitment factor GDV1. NF54/iGP lines consistently achieve sexual commitment rates of 75% and produce viable gametocytes that are transmissible by mosquitoes. We also demonstrate that further genetic engineering of NF54/iGP parasites is a valuable tool for the targeted exploration of gametocyte biology. In summary, we believe the iGP approach developed here will greatly expedite basic and applied malaria transmission stage research.
Publisher: Elsevier BV
Date: 2021
Publisher: Cold Spring Harbor Laboratory
Date: 23-01-2021
DOI: 10.1101/2021.01.22.427784
Abstract: Plasmodium species have a single mitochondrion that is essential for their survival and has been successfully targeted by anti-malarial drugs. Most mitochondrial proteins are imported into this organelle and our picture of the Plasmodium mitochondrial proteome remains incomplete. Many data sources contain information about mitochondrial localization, including proteome and gene expression profiles, orthology to mitochondrial proteins from other species, co-evolutionary relationships, and amino acid sequences, each with different coverage and reliability. To obtain a comprehensive, prioritized list of Plasmodium falciparum mitochondrial proteins, we rigorously analyzed and integrated eight datasets using Bayesian statistics into a predictive score per protein for mitochondrial localization. At a corrected false discovery rate of 25%, we identified 445 proteins with a sensitivity of 87% and a specificity of 97%. They include proteins that have not been identified as mitochondrial in other eukaryotes but have characterized homologs in bacteria that are involved in metabolism or translation. Mitochondrial localization of seven Plasmodium berghei orthologs was confirmed by epitope labeling and co-localization with a mitochondrial marker protein. One of these belongs to a newly identified apicomplexan mitochondrial protein family that in P. falciparum has four members. With the experimentally validated mitochondrial proteins and the complete ranked P. falciparum proteome, which we have named PlasmoMitoCarta, we present a resource to study unique proteins of Plasmodium mitochondria.
Publisher: Elsevier BV
Date: 12-2019
Publisher: Hindawi Limited
Date: 04-12-2020
DOI: 10.1111/CMI.13123
Abstract: A hallmark of the biology of Plasmodium falciparum blood stage parasites is their extensive host cell remodelling, facilitated by parasite proteins that are exported into the erythrocyte. Although this area has received extensive attention, only a few exported parasite proteins have been analysed in detail, and much of this remodelling process remains unknown, particularly for gametocyte development. Recent advances to induce high rates of sexual commitment enable the production of large numbers of gametocytes. We used this approach to study the Plasmodium helical interspersed subtelomeric (PHIST) protein GEXP02, which is expressed during sexual development. We show by immunofluorescence that GEXP02 is exported to the gametocyte-infected host cell periphery. Co-immunoprecipitation revealed potential interactions between GEXP02 and components of the erythrocyte cytoskeleton as well as other exported parasite proteins. This indicates that GEXP02 targets the erythrocyte cytoskeleton and is likely involved in its remodelling. GEXP02 knock-out parasites show no obvious phenotype during gametocyte maturation, transmission through mosquitoes, and hepatocyte infection, suggesting auxiliary or redundant functions for this protein. In summary, we performed a detailed cellular and biochemical analysis of a sexual stage-specific exported parasite protein using a novel experimental approach that is broadly applicable to study the biology of P. falciparum gametocytes.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Oxford University Press (OUP)
Date: 18-03-2020
DOI: 10.1017/S1431927620000197
Abstract: Interfaces play critical roles in materials and are usually both structurally and compositionally complex microstructural features. The precise characterization of their nature in three-dimensions at the atomic scale is one of the grand challenges for microscopy and microanalysis, as this information is crucial to establish structure–property relationships. Atom probe tomography is well suited to analyzing the chemistry of interfaces at the nanoscale. However, optimizing such microanalysis of interfaces requires great care in the implementation across all aspects of the technique from specimen preparation to data analysis and ultimately the interpretation of this information. This article provides critical perspectives on key aspects pertaining to spatial resolution limits and the issues with the compositional analysis that can limit the quantification of interface measurements. Here, we use the ex le of grain boundaries in steels however, the results are applicable for the characterization of grain boundaries and transformation interfaces in a very wide range of industrially relevant engineering materials.
Publisher: Elsevier BV
Date: 02-2020
Publisher: Elsevier BV
Date: 12-2023
Publisher: American Chemical Society (ACS)
Date: 23-08-2022
Publisher: Elsevier BV
Date: 06-2020
Publisher: Cold Spring Harbor Laboratory
Date: 14-05-2021
DOI: 10.1101/2021.05.12.443866
Abstract: Drug resistance and a dire lack of transmission-blocking antimalarials h er malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (ACS) inhibitor to enter preclinical development. Our studies demonstrated attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound showed exceptional in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocked P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identified ACS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. MMV693183 was well adsorbed after oral administration in mice, rats and dogs. Pharmacokinetic – pharmacodynamic modelling predicted that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. In conclusion, the ACS-targeting compound MMV693183 represents a promising addition to the portfolio of antimalarials in (pre)clinical development with a novel mode of action for the treatment of malaria and blocking transmission.
Publisher: Oxford University Press (OUP)
Date: 04-2017
DOI: 10.1017/S1431927617000356
Abstract: The local electrode atom probe (LEAP) has become the primary instrument used for atom probe tomography measurements. Recent advances in detector and laser design, together with updated hit detection algorithms, have been incorporated into the latest LEAP 5000 instrument, but the implications of these changes on measurements, particularly the size and chemistry of small clusters and elemental segregations, have not been explored. In this study, we compare data sets from a variety of materials with small-scale chemical heterogeneity using both a LEAP 3000 instrument with 37% detector efficiency and a 532-nm green laser and a new LEAP 5000 instrument with a manufacturer estimated increase to 52% detector efficiency, and a 355-nm ultraviolet laser. In general, it was found that the number of atoms within small clusters or surface segregation increased in the LEAP 5000, as would be expected by the reported increase in detector efficiency from the LEAP 3000 architecture, but subtle differences in chemistry were observed which are attributed to changes in the way multiple hit detection is calculated using the LEAP 5000.
Publisher: Elsevier BV
Date: 08-2020
Publisher: Elsevier BV
Date: 10-2020
Publisher: Cold Spring Harbor Laboratory
Date: 16-12-2022
DOI: 10.1101/2022.12.16.520724
Abstract: Several haematologic diseases, including malaria, diabetes, and sickle cell anaemia, result in a reduced red blood cell deformability. This deformability can be measured using a microfluidic device with channels of varying width. Nevertheless, it is challenging to algorithmically recognise large numbers of red blood cells and quantify their deformability from image data. Deep learning has become the method of choice to handle noisy and complex image data. However, it requires a significant amount of labelled data to train the neural networks. By creating images of cells and mimicking noise and plasticity in those images, we generate synthetic data to train a network to detect and segment red blood cells from video-recordings, without the need for manually annotated labels. Using this new method, we uncover significant differences between the deformability of RBCs infected with different strains of Plasmodium falciparum , providing clues to the variation in virulence of these strains.
Publisher: Springer Science and Business Media LLC
Date: 20-04-2022
DOI: 10.1038/S41467-022-29688-5
Abstract: Drug resistance and a dire lack of transmission-blocking antimalarials h er malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission.
Publisher: Cold Spring Harbor Laboratory
Date: 05-10-2020
DOI: 10.1101/2020.10.05.326496
Abstract: Our current understanding of mitochondrial functioning is largely restricted to traditional model organisms, which only represent a fraction of eukaryotic ersity. The unusual mitochondrion of malaria parasites is a validated drug target but remains poorly understood. Here, we apply complexome profiling to map the inventory of protein complexes across the pathogenic asexual blood stages and the transmissible gametocyte stages of Plasmodium falciparum . We identify remarkably ergent composition and clade-specific additions of all respiratory chain complexes. Furthermore, we show that respiratory chain complex components and linked metabolic pathways are up to 40-fold more prevalent in gametocytes, while glycolytic enzymes are substantially reduced. Underlining this functional switch, we find that cristae are exclusively present in gametocytes. Leveraging these ergent properties and stage dynamics for drug development presents an attractive opportunity to discover novel classes of antimalarials and increase our repertoire of gametocytocidal drugs.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2021
DOI: 10.1038/S41467-021-23919-X
Abstract: Our current understanding of mitochondrial functioning is largely restricted to traditional model organisms, which only represent a fraction of eukaryotic ersity. The unusual mitochondrion of malaria parasites is a validated drug target but remains poorly understood. Here, we apply complexome profiling to map the inventory of protein complexes across the pathogenic asexual blood stages and the transmissible gametocyte stages of Plasmodium falciparum . We identify remarkably ergent composition and clade-specific additions of all respiratory chain complexes. Furthermore, we show that respiratory chain complex components and linked metabolic pathways are up to 40-fold more prevalent in gametocytes, while glycolytic enzymes are substantially reduced. Underlining this functional switch, we find that cristae are exclusively present in gametocytes. Leveraging these ergent properties and stage dynamics for drug development presents an attractive opportunity to discover novel classes of antimalarials and increase our repertoire of gametocytocidal drugs.
Publisher: American Society for Microbiology
Date: 27-10-2021
Abstract: The unique biology and medical relevance of the mitochondrion of the malaria parasite Plasmodium falciparum have made it the subject of many studies. However, we actually do not have a comprehensive assessment of which proteins reside in this organelle.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Benjamin Jenkins.