Imperial College London

Professor Jake Baum

Faculty of Natural SciencesDepartment of Life Sciences

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 7594 5420jake.baum Website

 
 
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Location

 

c/o Baum labSir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
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145 results found

Malpartida-Cardenas K, Baum J, Cunnington A, Georgiou P, Rodriguez-Manzano Jet al., 2022, Electricity-free nucleic acid extraction method from dried blood spots on filter paper for point-of-care diagnostics

<jats:p>Background: Nucleic acid extraction is a crucial step for molecular biology applications, being a determinant for any diagnostic test procedure. Dried blood spots (DBS) have been used for decades for serology, drug monitoring, environmental investigations, and molecular studies. Nevertheless, nucleic acid extraction from DBS remains one of the main challenges to translate them to the point-of-care (POC).Method: We have developed a fast nucleic acid extraction (NAE) method from DBS which is electricity-free and relies on cellulose filter papers (DBSFP). The performance of NAE was assessed with loop-mediated isothermal amplification (LAMP), targeting the human reference gene beta-actin. The developed method was evaluated against FTA cards and magnetic bead-based purification, using time-to-positive (min) for comparative analysis. We optimised and validated the developed method for elution (eluted disk) and disk directly in the reaction (in-situ disk), RNA and DNA detection, and whole blood stored in anticoagulants (K2EDTA and lithium heparin). Furthermore, the compatibility of DBSFP with colourimetric detection was studied to show the transferability to the POC.Results: The proposed DBSFP is based on grade 3 filter paper pre-treated with 8% (v/v) igepal surfactant, 1 min washing step with PBS 1X and elution in TE 1X buffer after 5 min incubation at room temperature, enabling NAE under 7 min. Obtained results were comparable to gold standard methods across tested matrices, targets and experimental conditions, demonstrating the versatility of the methodology. Lastly, eluted disk colourimetric detection was achieved with a sample-to-result turnaround time under 35 min.Conclusions: The developed method is a fast, electricity-free, and low-cost solution for NAE from DBSFP enabling molecular testing in virtually any POC setting.</jats:p>

Journal article

Xie SC, Metcalfe RD, Dunn E, Morton CJ, Huang S-C, Puhalovich T, Du Y, Wittlin S, Nie S, Luth MR, Ma L, Kim M-S, Pasaje CFA, Kumpornsin K, Giannangelo C, Houghton FJ, Churchyard A, Famodimu MT, Barry DC, Gillett DL, Dey S, Kosasih CC, Newman W, Niles JC, Lee MCS, Baum J, Ottilie S, Winzeler EA, Creek DJ, Williamson N, Parker MW, Brand S, Langston SP, Dick LR, Griffin MDW, Gould AE, Tilley Let al., 2022, Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy, SCIENCE, Vol: 376, Pages: 1074-+, ISSN: 0036-8075

Journal article

Najer A, Blight J, Ducker CB, Gasbarri M, Brown JC, Che J, Hogset H, Saunders C, Ojansivu M, Lu Z, Lin Y, Yeow J, Rifaie Graham O, Potter M, Tonkin R, Penders J, Doutch JJ, Georgiadou A, Barriga HMG, Holme MN, Cunnington AJ, Bugeon L, Dallman MJ, Barclay WS, Stellacci F, Baum J, Stevens MMet al., 2022, Potent virustatic polymer-lipid nanomimics block viral entry and inhibit malaria parasites in vivo, ACS Central Science, ISSN: 2374-7943

Infectious diseases continue to pose a substantial burden on global populations, requiring innovative broad-spectrum prophylactic and treatment alternatives. Here, we have designed modular synthetic polymer nanoparticles that mimic functional components of host cell membranes, yielding multivalent nanomimics that act by directly binding to varied pathogens. Nanomimic blood circulation time was prolonged by reformulating polymer–lipid hybrids. Femtomolar concentrations of the polymer nanomimics were sufficient to inhibit herpes simplex virus type 2 (HSV-2) entry into epithelial cells, while higher doses were needed against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Given their observed virustatic mode of action, the nanomimics were also tested with malaria parasite blood-stage merozoites, which lose their invasive capacity after a few minutes. Efficient inhibition of merozoite invasion of red blood cells was demonstrated both in vitro and in vivo using a preclinical rodent malaria model. We envision these nanomimics forming an adaptable platform for developing pathogen entry inhibitors and as immunomodulators, wherein nanomimic-inhibited pathogens can be secondarily targeted to sites of immune recognition.

Journal article

Bullen HE, Sanders PR, Dans MG, Jonsdottir TK, Riglar DT, Looker O, Palmer CS, Kouskousis B, Charnaud SC, Triglia T, Gabriela M, Schneider MP, Chan J-A, de Koning-Ward TF, Baum J, Kazura JW, Beeson JG, Cowman AF, Gilson PR, Crabb BSet al., 2022, The Plasmodium falciparum parasitophorous vacuole protein P113 interacts with the parasite protein export machinery and maintains normal vacuole architecture, MOLECULAR MICROBIOLOGY, Vol: 117, Pages: 1245-1262, ISSN: 0950-382X

Journal article

de Vries LE, Jansen PAM, Barcelo C, Munro J, Verhoef JMJ, Pasaje CFA, Rubiano K, Striepen J, Abla N, Berning L, Bolscher JM, Demarta-Gatsi C, Henderson RWM, Huijs T, Koolen KMJ, Tumwebaze PK, Yeo T, Aguiar ACC, Angulo-Barturen I, Churchyard A, Baum J, Fernandez BC, Fuchs A, Gamo F-J, Guido RVC, Jimenez-Diaz MB, Pereira DB, Rochford R, Roesch C, Sanz LM, Trevitt G, Witkowski B, Wittlin S, Cooper RA, Rosenthal PJ, Sauerwein RW, Schalkwijk J, Hermkens PHH, Bonnert R, Campo B, Fidock DA, Llinas M, Niles JC, Kooij TWA, Dechering KJet al., 2022, Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183, NATURE COMMUNICATIONS, Vol: 13

Journal article

Yahiya S, Jordan S, Smith HX, Gaboriau DCA, Famodimu MT, Dahalan FA, Churchyard A, Ashdown GW, Baum Jet al., 2022, Live-cell fluorescence imaging of microgametogenesis in the human malaria parasite Plasmodium falciparum, PLOS PATHOGENS, Vol: 18, ISSN: 1553-7366

Journal article

Davidson M, Andradi-Brown C, Yahiya S, Chmielewski J, O'Donnell A, Gurung P, Jeninga M, Prommana P, Andrew D, Petter M, Uthaipibill C, Boyle M, Ashdown G, Dvorin J, Reece S, Wilson D, Cunningham K, Ando DM, Dimon M, Baum Jet al., 2022, Automated detection and staging of malaria parasites from cytological smears using convolutional neural networks, Biological Imaging, Vol: 1, Pages: 1-13, ISSN: 2633-903X

Microscopic examination of blood smears remains the gold standard for laboratory inspection and diagnosis of malaria. Smear inspection is, however, time consuming and dependent on trained microscopists with results varying in accuracy. We sought to develop an automated image analysis method to improve accuracy and standardisation of smear inspection that retains capacity for expert confirmation and image archiving. Here we present a machine-learning method that achieves red blood cell (RBC) detection, differentiation between infected/uninfected cells and parasite life stage categorisation from unprocessed, heterogeneous smear images. Based on a pre-trained Faster Region-Based Convolutional Neural Networks (R-CNN) model for RBC detection, our model performs accurately, with average precision of 0.99 at an intersection-over-union threshold of 0.5. Application of a residual neural network (ResNet)-50 model to infected cells also performs accurately, with an area under the receiver operating characteristic curve of 0.98. Lastly, combining our method with a regression model successfully recapitulates intra-erythrocytic developmental cycle with accurate lifecycle stage categorisation. Combined with a mobile-friendly web-based interface, called PlasmoCount, our method permits rapid navigation through and review of results for quality assurance. By standardising assessment of Giemsa smears, our method markedly improves inspection reproducibility and presents a realistic route to both routine lab but also future field-based automated malaria diagnosis.

Journal article

Ellis KM, Lucantoni L, Chavchich M, Abraham M, De Paoli A, Luth MR, Zeeman A-M, Delves MJ, Teran FS-R, Straschil U, Baum J, Kocken CHM, Ralph SA, Winzeler EA, Avery VM, Edstein MD, Baell JB, Creek DJet al., 2021, The Novel bis-1,2,4-Triazine MIPS-0004373 Demonstrates Rapid and Potent Activity against All Blood Stages of the Malaria Parasite, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 65, ISSN: 0066-4804

Journal article

Xie SC, Metcalfe RD, Mizutani H, Puhalovich T, Hanssen E, Morton CJ, Du Y, Dogovski C, Huang S-C, Ciavarri J, Hales P, Griffin RJ, Cohen LH, Chuang B-C, Wittlin S, Deni I, Yeo T, Ward KE, Barry DC, Liu B, Gillett DL, Crespo-Fernandez BF, Ottilie S, Mittal N, Churchyard A, Ferguson D, Aguiar ACC, Guido RVC, Baum J, Hanson KK, Winzeler EA, Gamo F-J, Fidock DA, Baud D, Parker MW, Brand S, Dick LR, Griffin MDW, Gould AE, Tilley Let al., 2021, Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 118, ISSN: 0027-8424

Journal article

Yahiya S, Jordan S, Smith HX, Gaboriau DCA, Famodimu MT, Dahalan FA, Churchyard A, Ashdown GW, Baum Jet al., 2021, 4D live-cell imaging of microgametogenesis in the human malaria parasite <i>Plasmodium falciparum</i>

<jats:title>ABSTRACT</jats:title><jats:p>Formation of gametes in the malaria parasite occurs in the midgut of the mosquito and is critical to onward parasite transmission. Transformation of the male gametocyte into microgametes, called microgametogenesis, is an explosive cellular event and one of the fastest eukaryotic DNA replication events known. The transformation of one microgametocyte into eight flagellated microgametes requires reorganisation of the parasite cytoskeleton, replication of the 22.9 Mb genome, axoneme formation and host erythrocyte egress, all of which occur simultaneously in &lt;20 minutes. Whilst high-resolution imaging has been a powerful tool for defining stages of microgametogenesis, it has largely been limited to fixed parasite samples, given the speed of the process and parasite photosensitivity. Here, we have developed a live-cell fluorescence imaging workflow that captures the explosive dynamics of microgametogenesis in full. Using the most virulent human malaria parasite, <jats:italic>Plasmodium falciparum</jats:italic>, our live-cell approach combines three-dimensional imaging through time (4D imaging) and covers early microgametocyte development through to microgamete release. Combining live-cell stains for DNA, tubulin and the host erythrocyte membrane, 4D imaging enables definition of the positioning of newly replicated and segregated DNA. It also shows the microtubular cytoskeleton, location of newly formed basal bodies and elongation of axonemes, as well as behaviour of the erythrocyte membrane, including its specific perforation prior to microgamete egress. 4D imaging was additionally undertaken in the presence of known transmission-blocking inhibitors and the untested proteasomal inhibitor bortezomib. Here, for the first time we find that bortezomib inhibition results in a clear block of DNA replication, full axoneme nucleation and elongation. These data not only define a framework for understand

Journal article

Blight J, Sala K, Atcheson E, Kramer H, El-Turabi A, Coelho Real E, Dahalan F, Bettenbourt P, Dickinson-Craig E, Alves E, Salman A, Janse C, Ashcroft F, Hill A, Reyes-Sandoval A, Blagborough A, Baum Jet al., 2021, Dissection-independent production of a Plasmodium sporozoites from whole mosquitoes, Life Science Alliance, Vol: 4, ISSN: 2575-1077

Progress towards a protective vaccine against malaria remains slow. To date, only limited protection has been routinely achieved following immunisation with either whole-parasite (sporozoite) or subunit-based vaccines. One major roadblock to vaccine progress, and to pre-erythrocytic parasite biology in general, is the continued reliance on manual salivary gland dissection for sporozoite isolation from infected mosquitoes. Here, we report development of a multi-step method, based on batch processing of homogenised whole mosquitoes, slurry, and density-gradient filtration, which combined with free-flow electrophoresis rapidly produces a pure, infective sporozoite inoculum. Human-infective Plasmodium falciparum and rodent-infective Plasmodium berghei sporozoites produced in this way are two- to threefold more infective than salivary gland dissection sporozoites in in vitro hepatocyte infection assays. In an in vivo rodent malaria model, the same P. berghei sporozoites confer sterile protection from mosquito-bite challenge when immunisation is delivered intravenously or 60–70% protection when delivered intramuscularly. By improving purity, infectivity, and immunogenicity, this method represents a key advancement in capacity to produce research-grade sporozoites, which should impact delivery of a whole-parasite based malaria vaccine at scale in the future.

Journal article

Okaniwa M, Shibata A, Ochida A, Akao Y, White KL, Shackleford DM, Duffy S, Lucantoni L, Dey S, Striepen J, Yeo T, Mok S, Aguiar ACC, Sturm A, Crespo B, Sanz LM, Churchyard A, Baum J, Pereira DB, Guido RVC, Dechering KJ, Wittlin S, Uhlemann A-C, Fidock DA, Niles JC, Avery VM, Charman SA, Laleu Bet al., 2021, Repositioning and characterization of 1-(Pyridin-4-yl)pyrrolidin-2-one derivatives as plasmodium cytoplasmic prolyl-tRNA synthetase inhibitors, ACS Infectious Diseases, Vol: 7, Pages: 1680-1689, ISSN: 2373-8227

Prolyl-tRNA synthetase (PRS) is a clinically validated antimalarial target. Screening of a set of PRS ATP-site binders, initially designed for human indications, led to identification of 1-(pyridin-4-yl)pyrrolidin-2-one derivatives representing a novel antimalarial scaffold. Evidence designates cytoplasmic PRS as the drug target. The frontrunner 1 and its active enantiomer 1- S exhibited low-double-digit nanomolar activity against resistant Plasmodium falciparum (Pf) laboratory strains and development of liver schizonts. No cross-resistance with strains resistant to other known antimalarials was noted. In addition, a similar level of growth inhibition was observed against clinical field isolates of Pf and P. vivax. The slow killing profile and the relative high propensity to develop resistance in vitro (minimum inoculum resistance of 8 × 105 parasites at a selection pressure of 3 × IC50) constitute unfavorable features for treatment of malaria. However, potent blood stage and antischizontal activity are compelling for causal prophylaxis which does not require fast onset of action. Achieving sufficient on-target selectivity appears to be particularly challenging and should be the primary focus during the next steps of optimization of this chemical series. Encouraging preliminary off-target profile and oral efficacy in a humanized murine model of Pf malaria allowed us to conclude that 1-(pyridin-4-yl)pyrrolidin-2-one derivatives represent a promising starting point for the identification of novel antimalarial prophylactic agents that selectively target Plasmodium PRS.

Journal article

Real E, Howick VM, Dahalan FA, Witmer K, Cudini J, Andradi-Brown C, Blight J, Davidson MS, Dogga SK, Reid AJ, Baum J, Lawniczak MKNet al., 2021, A single-cell atlas of Plasmodium falciparum transmission through the mosquito, NATURE COMMUNICATIONS, Vol: 12

Journal article

Haase S, miller D, Cherkaoui D, Jordan S, Gulbis J, Baum Jet al., 2021, Identification and characterisation of a phospholipid scramblase in the malaria parasite Plasmodium falciparum, Molecular and Biochemical Parasitology, Vol: 243, Pages: 1-15, ISSN: 0166-6851

Recent studies highlight the emerging role of lipids as important messengers in malaria parasite biology. In an attempt to identify interacting proteins and regulators of these dynamic and versatile molecules, we hypothesised the involvement of phospholipid translocases and their substrates in the infection of the host erythrocyte by the malaria parasite Plasmodium spp. Here, using a data base searching approach of the Plasmodium Genomics Resources (www.plasmodb.org), we have identified a putative phospholipid (PL) scramblase in P. falciparum (PfPLSCR) that is conserved across the genus and in closely related unicellular algae. By reconstituting recombinant PfPLSCR into liposomes, we demonstrate metal ion dependent PL translocase activity and substrate preference, confirming PfPLSCR as a bona fide scramblase. We show that PfPLSCR is expressed during asexual and sexual parasite development, localising to different membranous compartments of the parasite throughout the intra-erythrocytic life cycle. Two different gene knockout approaches, however, suggest that PfPLSCR is not essential for erythrocyte invasion and asexual parasite development, pointing towards a possible role in other stages of the parasite life cycle.

Journal article

Lawong A, Gahalawat S, Okombo J, Striepen J, Yeo T, Mok S, Deni I, Bridgford JL, Niederstrasser H, Zhou A, Posner B, Wittlin S, Gamo FJ, Crespo B, Churchyard A, Baum J, Mittal N, Winzeler E, Laleu B, Palmer MJ, Charman SA, Fidock DA, Ready JM, Phillips MAet al., 2021, Novel antimalarial tetrazoles and amides active against the hemoglobin degradation pathway in plasmodium falciparum., Journal of Medicinal Chemistry, Vol: 64, Pages: 2739-2761, ISSN: 0022-2623

Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified a novel tetrazole-based series that shows fast-kill kinetics and a relatively low propensity to develop high-level resistance. Preliminary structure-activity relationships were established including identification of a subseries of related amides with antiplasmodial activity. Assaying parasites with resistance to antimalarials led us to test whether the series had a similar mechanism of action to chloroquine (CQ). Treatment of synchronized Plasmodium falciparum parasites with active analogues revealed a pattern of intracellular inhibition of hemozoin (Hz) formation reminiscent of CQ's action. Drug selections yielded only modest resistance that was associated with amplification of the multidrug resistance gene 1 (pfmdr1). Thus, we have identified a novel chemical series that targets the historically druggable heme polymerization pathway and that can form the basis of future optimization efforts to develop a new malaria treatment.

Journal article

Varghese S, Rahmani R, Drew DR, Beeson JG, Baum J, Smith BJ, Baell Jet al., 2021, Structure activity studies of truncated latrunculin analogues with anti-malarial activity, ChemMedChem, Vol: 16, Pages: 679-693, ISSN: 0014-827X

Malarial parasites employ actin dynamics for motility, and any disruption to these dynamics renders the parasites unable to effectively establish infection. Therefore, actin presents a potential target for malarial drug discovery, and naturally occurring actin inhibitors such as latrunculins are a promising starting point. However, the limited availability of the natural product and the laborious route for synthesis of latrunculins have hindered their potential development as drug candidates. In this regard, we recently described novel truncated latrunculins, with superior actin binding potency and selectivity towards P. falciparum actin than the canonical latrunculin B. In this paper, we further explore the truncated latrunculin core to summarize the SAR for inhibition of malaria motility. This study helps further understand the binding pattern of these analogues in order to develop them as drug candidates for malaria.

Journal article

Robert-Paganin J, Moussaoui D, Robblee JP, Auguin D, Blake TCA, Krementsova E, Baum J, Trybus KM, Houdusse Aet al., 2021, Deciphering the Function and the Regulation of Plasmodium falciparum Myosin A, 65th Annual Meeting of the Biophysical-Society (BPS), Publisher: CELL PRESS, Pages: 344A-344A, ISSN: 0006-3495

Conference paper

Benns HJ, Storch M, Falco J, Fisher FR, Alves E, Wincott CJ, Baum J, Baldwin GS, Weerapana E, Tate EW, Child MAet al., 2021, Prioritization of antimicrobial targets by CRISPR-based oligo recombineering

<jats:title>Summary</jats:title><jats:p>Nucleophilic amino acids are important in covalent drug development yet underutilized as antimicrobial targets. Over recent years, several chemoproteomic technologies have been developed to mine chemically-accessible residues via their intrinsic reactivity toward electrophilic probes. However, these approaches cannot discern which reactive sites contribute to protein function and should therefore be prioritized for drug discovery. To address this, we have developed a CRISPR-based Oligo Recombineering (CORe) platform to systematically prioritize reactive amino acids according to their contribution to protein function. Our approach directly couples protein sequence and function with biological fitness. Here, we profile the reactivity of &gt;1,000 cysteines on ~700 proteins in the eukaryotic pathogen <jats:italic>Toxoplasma gondii</jats:italic> and prioritize functional sites using CORe. We competitively compared the fitness effect of 370 codon switches at 74 cysteines and identify functional sites in a diverse range of proteins. In our proof of concept, CORe performed &gt;800 times faster than a standard genetic workflow. Reactive cysteines decorating the ribosome were found to be critical for parasite growth, with subsequent target-based screening validating the apicomplexan translation machinery as a target for covalent ligand development. CORe is system-agnostic, and supports expedient identification, functional prioritization, and rational targeting of reactive sites in a wide range of organisms and diseases.</jats:p>

Journal article

Miguel-Blanco C, Murithi JM, Benavente ED, Angrisano F, Sala KA, van Schalkwyk DA, Vanaerschot M, Schwach F, Fuchter MJ, Billker O, Sutherland CJ, Campino SG, Clark TG, Blagborough AM, Fidock DA, Herreros E, Gamo FJ, Baum J, Delves MJet al., 2021, The antimalarial efficacy and mechanism of resistance of the novel chemotype DDD01034957, Scientific Reports, Vol: 11, ISSN: 2045-2322

New antimalarial therapeutics are needed to ensure that malaria cases continue to be driven down, as both emerging parasite resistance to frontline chemotherapies and mosquito resistance to current insecticides threaten control programmes. Plasmodium, the apicomplexan parasite responsible for malaria, causes disease pathology through repeated cycles of invasion and replication within host erythrocytes (the asexual cycle). Antimalarial drugs primarily target this cycle, seeking to reduce parasite burden within the host as fast as possible and to supress recrudescence for as long as possible. Intense phenotypic drug screening efforts have identified a number of promising new antimalarial molecules. Particularly important is the identification of compounds with new modes of action within the parasite to combat existing drug resistance and suitable for formulation of efficacious combination therapies. Here we detail the antimalarial properties of DDD01034957-a novel antimalarial molecule which is fast-acting and potent against drug resistant strains in vitro, shows activity in vivo, and possesses a resistance mechanism linked to the membrane transporter PfABCI3. These data support further medicinal chemistry lead-optimization of DDD01034957 as a novel antimalarial chemical class and provide new insights to further reduce in vivo metabolic clearance.

Journal article

Witmer K, Dahalan F, Delves M, Yahiya S, Watson O, Straschil U, Chiwcharoen D, Sorboon B, Pukrittayakamee S, Pearson R, Howick V, Lawniczak M, White N, Dondorp A, Okell L, Chotivanich K, Ruecker A, Baum Jet al., 2021, Transmission of artemisinin-resistant malaria parasites to mosquitoes under antimalarial drug pressure, Antimicrobial Agents and Chemotherapy, Vol: 65, Pages: 1-17, ISSN: 0066-4804

Resistance to artemisinin-based combination therapy (ACT) in the Plasmodium falciparum parasite is threatening to reverse recent gains in reducing global deaths from malaria. Whilst resistance manifests as delayed parasite clearance in patients the phenotype can only spread geographically via the sexual stages and mosquito transmission. In addition to their asexual killing properties, artemisinin and its derivatives sterilise sexual male gametocytes. Whether resistant parasites overcome this sterilising effect has not, however, been fully tested. Here, we analysed P. falciparum clinical isolates from the Greater Mekong Subregion, each demonstrating delayed clinical clearance and known resistance-associated polymorphisms in Kelch13 (PfK13var). As well as demonstrating reduced asexual sensitivity to drug, certain PfK13var isolates demonstrated a marked reduction in sensitivity to artemisinin in an in vitro male gamete formation assay. Importantly, this same reduction in sensitivity was observed when the most resistant isolate was tested directly in mosquito feeds. These results indicate that, under artemisinin drug pressure, whilst sensitive parasites are blocked, resistant parasites continue transmission. This selective advantage for resistance transmission could favour acquisition of additional host-specificity or polymorphisms affecting partner drug sensitivity in mixed infections. Favoured resistance transmission under ACT coverage could have profound implications for the spread of multidrug resistant malaria beyond Southeast Asia.

Journal article

Qian WW, Xia C, Venugopalan S, Narayanaswamy A, Dimon M, Ashdown GW, Baum J, Peng J, Ando DMet al., 2020, Batch equalization with a generative adversarial network, Bioinformatics, Vol: 36, Pages: I875-I883, ISSN: 1367-4803

MotivationAdvances in automation and imaging have made it possible to capture a large image dataset that spans multiple experimental batches of data. However, accurate biological comparison across the batches is challenged by batch-to-batch variation (i.e. batch effect) due to uncontrollable experimental noise (e.g. varying stain intensity or cell density). Previous approaches to minimize the batch effect have commonly focused on normalizing the low-dimensional image measurements such as an embedding generated by a neural network. However, normalization of the embedding could suffer from over-correction and alter true biological features (e.g. cell size) due to our limited ability to interpret the effect of the normalization on the embedding space. Although techniques like flat-field correction can be applied to normalize the image values directly, they are limited transformations that handle only simple artifacts due to batch effect.ResultsWe present a neural network-based batch equalization method that can transfer images from one batch to another while preserving the biological phenotype. The equalization method is trained as a generative adversarial network (GAN), using the StarGAN architecture that has shown considerable ability in style transfer. After incorporating new objectives that disentangle batch effect from biological features, we show that the equalized images have less batch information and preserve the biological information. We also demonstrate that the same model training parameters can generalize to two dramatically different types of cells, indicating this approach could be broadly applicable.Availability and implementationhttps://github.com/tensorflow/gan/tree/master/tensorflow_gan/examples/starganSupplementary informationSupplementary data are available at Bioinformatics online.

Journal article

Blake T, Haase S, Baum J, 2020, Actomyosin forces and the energetics of red blood cell invasion by the malaria parasite Plasmodium falciparum, PLoS Pathogens, Vol: 16, ISSN: 1553-7366

All symptoms of malaria disease are associated with the asexual blood stages of development, involving cycles of red blood cell (RBC) invasion and egress by the Plasmodium spp. merozoite. Merozoite invasion is rapid and is actively powered by a parasite actomyosin motor. The current accepted model for actomyosin force generation envisages arrays of parasite myosins, pushing against short actin filaments connected to the external milieu that drive the merozoite forwards into the RBC. In Plasmodium falciparum, the most virulent human malaria species, Myosin A (PfMyoA) is critical for parasite replication. However, the precise function of PfMyoA in invasion, its regulation, the role of other myosins and overall energetics of invasion remain unclear. Here, we developed a conditional mutagenesis strategy combined with live video microscopy to probe PfMyoA function and that of the auxiliary motor PfMyoB in invasion. By imaging conditional mutants with increasing defects in force production, based on disruption to a key PfMyoA phospho-regulation site, the absence of the PfMyoA essential light chain, or complete motor absence, we define three distinct stages of incomplete RBC invasion. These three defects reveal three energetic barriers to successful entry: RBC deformation (pre-entry), mid-invasion initiation, and completion of internalisation, each requiring an active parasite motor. In defining distinct energetic barriers to invasion, these data illuminate the mechanical challenges faced in this remarkable process of protozoan parasitism, highlighting distinct myosin functions and identifying potential targets for preventing malaria pathogenesis.

Journal article

Eagon S, Hammill JT, Sigal M, Ahn KJ, Tryhorn JE, Koch G, Belanger B, Chaplan CA, Loop L, Kashtanova AS, Yniguez K, Lazaro H, Wilkinson SP, Rice AL, Falade MO, Takahashi R, Kim K, Cheung A, DiBernardo C, Kimball JJ, Winzeler EA, Eribez K, Mittal N, Gamo F-J, Crespo B, Churchyard A, Garcia-Barbazan I, Baum J, Anderson MO, Laleu B, Guy RKet al., 2020, Synthesis and Structure-Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4-b]pyridines, JOURNAL OF MEDICINAL CHEMISTRY, Vol: 63, Pages: 11902-11919, ISSN: 0022-2623

Journal article

Moussaoui D, Robblee JP, Auguin D, Krementsova EB, Haase S, Blake TCA, Baum J, Robert-Paganin J, Trybus KM, Houdusse Aet al., 2020, Full-length Plasmodium falciparum myosin A and essential light chain PfELC structures provide new anti-malarial targets, ELIFE, Vol: 9, ISSN: 2050-084X

Journal article

Real E, Howick VM, Dahalan F, Witmer K, Cudini J, Andradi-Brown C, Blight J, Davidson MS, Dogga SK, Reid AJ, Baum J, Lawniczak MKNet al., 2020, A single-cell atlas of <i>Plasmodium falciparum</i> transmission through the mosquito

<jats:title>Abstract</jats:title><jats:p>Malaria parasites have a complex life cycle featuring diverse developmental strategies, each uniquely adapted to navigate specific host environments. Here we use single-cell transcriptomics to illuminate gene usage across the transmission cycle of the most virulent agent of human malaria – <jats:italic>Plasmodium falciparum</jats:italic>. We reveal developmental trajectories associated with the colonisation of the mosquito midgut and salivary glands and elucidate the transcriptional signatures of each transmissible stage. Additionally, we identify both conserved and nonconserved gene usage between human and rodent parasites, which point to both essential mechanisms in malaria transmission and species-specific adaptations potentially linked to host tropism. Together, the data presented here, which are made freely available via an interactive website, establish the most complete atlas of the <jats:italic>P. falciparum</jats:italic> transcriptional journey to date.</jats:p><jats:sec><jats:title>One sentence summary</jats:title><jats:p>Single-cell transcriptomics of <jats:italic>P. falciparum</jats:italic> transmission stages highlights developmental trajectories and gene usage.</jats:p></jats:sec>

Journal article

Ashdown G, Gaboriau D, Baum J, 2020, A machine learning approach to define antimalarial drug action from heterogeneous cell-based screens, Science Advances, Vol: 6, ISSN: 2375-2548

Drug resistance threatens the effective prevention and treatment of an ever-increasing range ofhuman infections. This highlights an urgent need for new and improved drugs with novelmechanisms of action to avoid cross-resistance. Current cell-based drug screens are,however, restricted to binary live/dead readouts with no provision for mechanism of actionprediction. Machine learning methods are increasingly being used to improve informationextraction from imaging data. Such methods, however, work poorly with heterogeneouscellular phenotypes and generally require time-consuming human-led training. We havedeveloped a semi-supervised machine learning approach, combining human- and machinelabelled training data from mixed human malaria parasite cultures. Designed for highthroughput and high-resolution screening, our semi-supervised approach is robust to naturalparasite morphological heterogeneity and correctly orders parasite developmental stages. Ourapproach also reproducibly detects and clusters drug-induced morphological outliers bymechanism of action, demonstrating the potential power of machine learning for acceleratingcell-based drug discovery.

Journal article

Wang X, Wilkinson MD, Lin X, Ren R, Willison KR, Ivanov AP, Baum J, Edel JBet al., 2020, Correction: Single-molecule nanopore sensing of actin dynamics and drug binding, Chemical Science, Vol: 11, Pages: 8036-8038, ISSN: 2041-6520

Correction for ‘Single-molecule nanopore sensing of actin dynamics and drug binding’ by Xiaoyi Wang et al., Chem. Sci., 2020, 11, 970–979, DOI: 10.1039/C9SC05710B.

Journal article

Moussaoui D, Robblee JP, Auguin D, Krementsova EB, Haase S, Blake TCA, Baum J, Robert-Paganin J, Trybus KM, Houdusse Aet al., 2020, Structure of Full Length Plasmodium Myosin A and its light chain PfELC, dual targets against malaria parasite pathogenesis

<jats:title>Abstract</jats:title><jats:p>Parasites from the genus <jats:italic>Plasmodium</jats:italic> are the causative agents of malaria. The mobility, infectivity and ultimately pathogenesis of this parasite relies on a macromolecular complex, called the glideosome. At the core of the glideosome is an essential and divergent Myosin A motor (PfMyoA), a first order drug target against malaria. Here we present the full-length structure of PfMyoA in two states of its motor cycle. We report novel interactions that are essential for motor priming and the mode of recognition of its two light chains (PfELC and MTIP) by two degenerate IQ motifs. Kinetic and motility assays using PfMyoA variants, along with molecular dynamics, demonstrate how specific priming and atypical sequence adaptations tune the motor’s mechano-chemical properties. Supported by evidence for an essential role of the PfELC in malaria pathogenesis, these structures provide a blueprint for the design of future antimalarials targeting both the glideosome motor and its regulatory elements.</jats:p><jats:sec><jats:title>Highlights</jats:title><jats:list list-type="bullet"><jats:list-item><jats:p>The first structures of the full length PfMyoA motor in two states of its motor cycle.</jats:p></jats:list-item><jats:list-item><jats:p>A unique priming of the PfMyoA lever arm results from specific lever arm/motor domain interactions, which allows for a larger powerstroke to enhance speed.</jats:p></jats:list-item><jats:list-item><jats:p>Sequence adaptations within the motor domain and degenerate IQ motifs in the lever arm dictate PfMyoA motor properties.</jats:p></jats:list-item><jats:list-item><jats:p>PfELC is essential for blood cell invasion and is a weak link in the assembly of a fully functional motor, providing a second novel target for antimalarial

Journal article

Baum J, Pasvol G, Carter R, 2020, From 1950s malaria to COVID-19, NATURE, Vol: 582, Pages: 488-488, ISSN: 0028-0836

Journal article

Blake TCA, Haase S, Baum J, 2020, Actomyosin forces and the energetics of red blood cell invasion by the malaria parasite<i>Plasmodium falciparum</i>

<jats:title>Summary</jats:title><jats:p>All symptoms of malaria disease are associated with the asexual blood stages of development, involving cycles of red blood cell (RBC) invasion and egress by the<jats:italic>Plasmodium</jats:italic>spp. merozoite. Merozoite invasion is rapid and is actively powered by a parasite actomyosin motor. The current accepted model for actomyosin force generation envisages arrays of parasite myosins, pushing against short actin filaments connected to the external milieu that drive the merozoite forwards into the RBC. In<jats:italic>Plasmodium falciparum</jats:italic>, the most virulent human malaria species, Myosin A (PfMyoA) is critical for parasite replication. However, the precise function of PfMyoA in invasion, its regulation, the role of other myosins and overall energetics of invasion remain unclear. Here, we developed a conditional mutagenesis strategy combined with live video microscopy to probe PfMyoA function and that of the auxiliary motor PfMyoB in invasion. By imaging conditional mutants with increasing defects in force production, based on disruption to a key PfMyoA phospho-regulation site, the absence of the PfMyoA essential light chain, or complete motor absence, we define three distinct stages of incomplete RBC invasion. These three defects reveal three energetic barriers to successful entry: RBC deformation (pre-entry), mid-invasion initiation, and completion of internalisation, each requiring an active parasite motor. In defining distinct energetic barriers to invasion, these data illuminate the mechanical challenges faced in this remarkable process of protozoan parasitism, highlighting distinct myosin functions and identifying potential targets for preventing malaria pathogenesis.</jats:p>

Journal article

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