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| Open AccessVariant antigen diversity in Trypanosoma vivax is not driven by recombination
Trypanosoma rely on variant surface glycoprotein (VSG) to escape host immunity, but mechanisms generating antigenic diversity of VSG are poorly understood. Here, Silva-Pereira et al. show that T. vivax has a limited antigenic repertoire compared to T. brucei and that recombination plays little role in diversifying T. vivax VSG sequences.
- Sara Silva Pereira
- , Kayo J. G. de Almeida Castilho Neto
- & Andrew P. Jackson
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Article
| Open AccessAfrican-centric TP53 variant increases iron accumulation and bacterial pathogenesis but improves response to malaria toxin
A polymorphism in human TP53 (P47S) that predominantly exists in individuals of African descent affects ferroptosis. Here, the authors show that this results in iron accumulation in macrophages leading to more productive infection by intracellular bacteria but improved anti-inflammatory response to the malarial toxin hemozoin.
- Kumar Sachin Singh
- , Julia I-Ju Leu
- & Farokh Dotiwala
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Article
| Open AccessMetabolic balancing by miR-276 shapes the mosquito reproductive cycle and Plasmodium falciparum development
Plasmodium growth is adapted to the reproductive cycle of mosquitoes, but underlying mechanisms are unclear. Here, Lampe et al. show that the blood-meal induced miR-276 balances the termination of the mosquito amino acid catabolism and egg development, providing nutrients for Plasmodium sporozoite development.
- Lena Lampe
- , Marius Jentzsch
- & Elena A. Levashina
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| Open AccessCoupling chemical mutagenesis to next generation sequencing for the identification of drug resistance mutations in Leishmania
Here, Bhattacharya et al. chemically mutagenize Leishmania and identify genes associated with resistance to miltefosine and paromomycin by next generation sequencing. The study shows that a protein kinase (CDPK1) can mediate resistance to paromomycin by affecting translation.
- Arijit Bhattacharya
- , Philippe Leprohon
- & Marc Ouellette
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Article
| Open AccessHigh-resolution micro-epidemiology of parasite spatial and temporal dynamics in a high malaria transmission setting in Kenya
Here, Nelson et al. use amplicon next-generation sequencing of two P. falciparum polymorphic gene regions to investigate the genetic similarity of parasite populations across time and space in a pediatric cohort in Kenya. They identify both micro- and macro-scale structuring of malaria parasites in this high-transmission setting, which could inform future intervention strategies.
- Cody S. Nelson
- , Kelsey M. Sumner
- & Wendy P. O’Meara
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Article
| Open AccessCombining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness
Trypanosoma brucei relies on uptake and conversion of purines from the host, which constitutes a potential drug target. Here, Hulpia et al. combine structural elements from known trypanocidal nucleoside analogues and develop a potent trypanocide with curative activity in animal models of acute and late stage sleeping sickness.
- Fabian Hulpia
- , Dorien Mabille
- & Serge Van Calenbergh
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Article
| Open AccessLeishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition
NLRP3 activation by Leishmania parasites is critical to the outcome of the disease. Here the authors show that LRV, a virus infecting Leishmania strains associated with more severe human disease, enables the parasite to suppress the inflammasome by activating type 1 interferon through TLR3, which leads to autophagy-mediated NLRP3 degradation.
- Renan V. H. de Carvalho
- , Djalma S. Lima-Junior
- & Dario S. Zamboni
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Article
| Open AccessTranscriptomics and proteomics reveal two waves of translational repression during the maturation of malaria parasite sporozoites
Here, the authors report transcriptomes and proteomes of oocyst sporozoite and salivary gland sporozoite stages in rodent-infectious Plasmodium yoelii parasites and human infectious Plasmodium falciparum parasites and define two waves of translational repression during sporozoite maturation.
- Scott E. Lindner
- , Kristian E. Swearingen
- & Stefan H. I. Kappe
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Article
| Open AccessThe global diversity of Haemonchus contortus is shaped by human intervention and climate
Based on single worm whole genome sequencing, the authors here characterise the global evolution of the gastrointestinal parasite Haemonchus contortus and identify genes that play a role in drug resistance as well as climate-driven adaptations involving an epigenetic regulator.
- G. Sallé
- , S. R. Doyle
- & J. A. Cotton
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Article
| Open AccessCis-regulatory CYP6P9b P450 variants associated with loss of insecticide-treated bed net efficacy against Anopheles funestus
Bed nets treated with insecticides have been instrumental in reducing malaria mortality, but insecticide resistance is on the rise. Here, Mugenzi et al. identify genetic variants in the P450 gene CYP6P9b of Anopheles funestus that associate with insecticide resistance and develop a PCR-based diagnostic assay to help identify pyrethroid-resistant strains.
- Leon M. J. Mugenzi
- , Benjamin D. Menze
- & Charles S. Wondji
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Article
| Open AccessAdaptation of Plasmodium falciparum to humans involved the loss of an ape-specific erythrocyte invasion ligand
Here, Proto et al. show that human infective Plasmodium falciparum isolates contain an inactivating mutation in the erythrocyte invasion associated gene PfEBA165, while homologues of ape-infective Laverania species are intact, and that expression of intact PfEBA165 is incompatible with parasite growth in human erythrocytes.
- William R. Proto
- , Sasha V. Siegel
- & Julian C. Rayner
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Article
| Open AccessPlasmodium vivax chloroquine resistance links to pvcrt transcription in a genetic cross
Here, a cross of Plasmodium vivax malaria parasites links a chloroquine resistance (CQR) phenotype to a 76 kb region of chromosome 1 and greater expression of pvcrt, an ortholog of the Plasmodium falciparum CQR transporter gene.
- Juliana M. Sá
- , Sarah R. Kaslow
- & Thomas E. Wellems
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Article
| Open AccessLung endothelial cell antigen cross-presentation to CD8+T cells drives malaria-associated lung injury
Severe malaria can be associated with respiratory complications. Here, the authors show that malaria-associated pulmonary vascular damage is a consequence of IFNγ-activated lung endothelial cells capturing, processing, and cross-presenting malaria parasite antigen to specific CD8+ T cells induced during infection.
- Carla Claser
- , Samantha Yee Teng Nguee
- & Laurent Renia
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Article
| Open AccessA highly dynamic F-actin network regulates transport and recycling of micronemes in Toxoplasma gondii vacuoles
Replication of Toxoplasma gondii requires replication and distribution of essential organelles such as micronemes. Here, Periz et al. show that micronemes are recycled from the mother to the forming daughter cells using a highly dynamic F-actin network that supports multidirectional vesicle transport.
- Javier Periz
- , Mario Del Rosario
- & Markus Meissner
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Article
| Open AccessA lipid-binding protein mediates rhoptry discharge and invasion in Plasmodium falciparum and Toxoplasma gondii parasites
Plasmodium and Toxoplasma parasites rely on rhoptry exocytosis for invasion, but the underlying mechanism is not known. Here, Suarez et al. characterize rhoptry apical surface proteins (RASP) that localize to the rhoptry cap and bind charged lipids, and are essential for rhoptry secretion and invasion.
- Catherine Suarez
- , Gaëlle Lentini
- & Maryse Lebrun
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Article
| Open AccessA CRISPR platform for targeted in vivo screens identifies Toxoplasma gondii virulence factors in mice
Targeted CRISPR libraries expand the use of genetic screens across experimental conditions. Here, the authors develop a method for generating and analysing small scale custom CRISPR libraries and use it in the human and livestock pathogen Toxoplasma gondii to identify virulence factors in mice.
- Joanna Young
- , Caia Dominicus
- & Moritz Treeck
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Article
| Open AccessMeiotic sex in Chagas disease parasite Trypanosoma cruzi
Here, Llewellyn and colleagues present evidence of meiotic sex in Trypanosoma cruzi, the causative agent of Chagas disease. These findings have implications for the epidemiology of the disease in endemic regions and challenge existing ideas that the parasites are strictly clonal.
- Philipp Schwabl
- , Hideo Imamura
- & Martin S. Llewellyn
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Article
| Open AccessMonoallelic expression and epigenetic inheritance sustained by a Trypanosoma brucei variant surface glycoprotein exclusion complex
Monoallelic expression of variant surface glycoprotein genes (VSGs) is essential for immune evasion by Trypanosoma brucei. Here, Faria et al. show that the VEX protein complex controls VSG allelic exclusion, and that CAF‐1 sustains inheritance of the VEX‐complex in association with the active VSG.
- Joana Faria
- , Lucy Glover
- & David Horn
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Article
| Open AccessInherent biomechanical traits enable infective filariae to disseminate through collecting lymphatic vessels
Stimuli affecting migration of filaria in host tissues are unclear. Using in situ imaging, Kilarski et al. here show that universal adaptations of nematodes allow Litomosoides sigmodontis infective larvae to mechanically break into pre-collecting lymphatics and follow the direction of flow towards the lymph node.
- Witold W. Kilarski
- , Coralie Martin
- & Melody A. Swartz
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Article
| Open AccessGenomic structure and diversity of Plasmodium falciparum in Southeast Asia reveal recent parasite migration patterns
Understanding genomic variation in Plasmodium falciparum parasites and inferring migration patterns can guide malaria elimination strategies. Using genome-wide data for 1722 parasites collected from 54 districts, the authors use identity-by-descent approaches to estimate regional parasite migration and spread of artemisinin drug resistance.
- Amol C. Shetty
- , Christopher G. Jacob
- & Marie A. Onyamboko
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Article
| Open AccessThe major secreted protein of the whipworm parasite tethers to matrix and inhibits interleukin-13 function
In the study, the authors identify a protein excreted by the parasite Trichuris muris, p43, which can modulate IL-13 function, a key cytokine involved in host protection. These data suggest that p43 may be a novel therapeutic target for both whipworm infections and IL13 mediated pathologies.
- Allison J. Bancroft
- , Colin W. Levy
- & Richard K. Grencis
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Article
| Open AccessAn essential contractile ring protein controls cell division in Plasmodium falciparum
Schizogony is essential for blood stage infection of Plasmodium parasites and produces several daughter cells. Here, Rudlaff et al. identify PfCINCH and interacting proteins as essential components of the basal complex required to establish daughter cell boundaries.
- Rachel M. Rudlaff
- , Stephan Kraemer
- & Jeffrey D. Dvorin
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Article
| Open AccessA defined mechanistic correlate of protection against Plasmodium falciparum malaria in non-human primates
Proof of protection against blood-stage P. falciparum malaria by a single immunological mechanism has been elusive. Here, using engineered anti-PfRH5 chimeric monoclonal antibodies in non-human primates, the authors show that high levels of merozoite-neutralizing antibodies can achieve protection.
- Alexander D. Douglas
- , G. Christian Baldeviano
- & Simon J. Draper
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Article
| Open AccessA suite of phenotypic assays to ensure pipeline diversity when prioritizing drug-like Cryptosporidium growth inhibitors
Here, the authors provide a panel of medium-throughput assays to test potential drug candidates against different life cycle stages of Cryptosporidium with the goal to support a drug development pipeline that contains compounds with diverse molecular mechanisms of action.
- Rajiv S. Jumani
- , Muhammad M. Hasan
- & Christopher D. Huston
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Article
| Open AccessThe parasitic worm product ES-62 normalises the gut microbiota bone marrow axis in inflammatory arthritis
Gastrointestinal infection with parasitic helminths can protect against mucosal diseases via impacting on the microbiome. Here the authors show that ES-62, a product secreted by a tissue-resident helminth modulates the host gut microbiome to protect against inflammatory arthritis in a mouse model.
- James Doonan
- , Anuradha Tarafdar
- & William Harnett
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Article
| Open AccessNucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma
Protein kinase A (PKA) is typically activated by cAMP. Here, Bachmaier et al. show that PKA of Trypanosoma is activated by nucleoside-related ligands, explain the ligand selectivity swap by a co-crystal structure of trypanosome PKAR, and identify potential downstream targets by phosphoproteomics.
- Sabine Bachmaier
- , Yuri Volpato Santos
- & Michael Boshart
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Article
| Open AccessMouse models of Loa loa
Here, the authors develop a mouse model of Loa loa that reflects human infections, including eosinophilia, and determine effects of ivermectin treatment.
- Nicolas P. Pionnier
- , Hanna Sjoberg
- & Joseph D. Turner
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Article
| Open AccessMolecular mechanism for the control of virulent Toxoplasma gondii infections in wild-derived mice
Toxoplasma gondii virulence in wild-derived mice is restricted by Immunity-Related GTPases (IRG). Here, the authors show specific binding of the IRG tandem protein Irgb2-b1 with the virulence effector ROP5, and provide insights into how different ROP5 isoforms and IRG alleles shape virulence among T. gondii strains.
- Mateo Murillo-León
- , Urs B. Müller
- & Tobias Steinfeldt
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Article
| Open AccessFlagellar cAMP signaling controls trypanosome progression through host tissues
Trypanosoma brucei probably relies on chemotactic signals for movement through tsetse fly tissues, but the molecular basis is unknown. Here, the authors show that flagellar cAMP signaling is required for traversal of the peritrophic matrix and that, without it, parasites are trapped in the midgut lumen.
- Sebastian Shaw
- , Stephanie F. DeMarco
- & Kent L. Hill
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Article
| Open AccessDual RNA-seq identifies human mucosal immunity protein Mucin-13 as a hallmark of Plasmodium exoerythrocytic infection
Host-parasite interactions during the exoerythrocytic stage of Plasmodium infection remains poorly understood. Using dual RNA-Seq, the authors show that human mucosal immunity protein mucin-13 is upregulated during Plasmodium hepatic-stage infection and marks infected cells independent of tested Plasmodium species.
- Gregory M. LaMonte
- , Pamela Orjuela-Sanchez
- & Elizabeth A. Winzeler
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Article
| Open AccessAlveolar proteins stabilize cortical microtubules in Toxoplasma gondii
Cortical microtubules of Toxoplasma gondii are exceptionally stable, but it isn’t known how they are anchored along membranes. Here, Harding et al. show that GAPM proteins localize to the inner membrane complex and are essential for maintaining the structural stability of parasites.
- Clare R. Harding
- , Matthew Gow
- & Sebastian Lourido
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Article
| Open AccessPlasmodium vivax transcriptomes reveal stage-specific chloroquine response and differential regulation of male and female gametocytes
Plasmodium vivax biology is not well understood, due to a lack of in vitro culture systems and difficulties associated with studying clinical blood samples. Here, Kim et al. use gene expression profiles from P. vivax infected patient blood and show stage-specific chloroquine response and differential regulation of male and female gametocytes.
- Adam Kim
- , Jean Popovici
- & David Serre
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Article
| Open AccessEfficient oral vaccination by bioengineering virus-like particles with protozoan surface proteins
Giardia lamblia express a dense coat of variant-specific surface proteins (VSPs) on trophozoites that protects the parasite inside the host´s intestine. Here the authors show that stability and immunomodulatory properties of VSPs can be exploited to both protect and adjuvant vaccine antigens for oral administration.
- Marianela C. Serradell
- , Lucía L. Rupil
- & Hugo D. Luján
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Article
| Open AccessPentatricopeptide repeat poly(A) binding protein KPAF4 stabilizes mitochondrial mRNAs in Trypanosoma brucei
Polyadenylation stabilizes edited mitochondrial mRNAs in Trypanosoma brucei, but the involved poly(A) binding protein is unknown. Here, Mesitov et al. show that a pentatricopeptide repeat factor KPAF4 binds to A-tail and prevents exonucleolytic degradation as well as translation of incompletely edited mRNAs.
- Mikhail V. Mesitov
- , Tian Yu
- & Inna Aphasizheva
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Article
| Open AccessA tRNA half modulates translation as stress response in Trypanosoma brucei
Trypanosoma brucei mainly relies on translational regulation to adjust gene expression, but details are unclear. Here the authors show that, under stress conditions, tRNAThr half level increases, associates with ribosomes and polysomes, and stimulates protein synthesis by facilitating mRNA loading.
- Roger Fricker
- , Rebecca Brogli
- & Norbert Polacek
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Article
| Open AccessHighly modified and immunoactive N-glycans of the canine heartworm
The glycome of parasites can have immunomodulatory properties or help to avoid immune surveillance, but details are unknown. Here, Martini et al. characterize the N-glycome of the canine heartworm, reveal an unprecedented complexity, particularly in anionic N-glycans, and determine recognition by components of the immune system.
- Francesca Martini
- , Barbara Eckmair
- & Katharina Paschinger
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Article
| Open AccessThe origins of malaria artemisinin resistance defined by a genetic and transcriptomic background
Mechanisms underlying increasing artemisinin resistance of Plasmodium in Southeast Asia remain unclear. Here, Zhu et al. integrate TWAS, GWAS and eQTL analyses for 773 P. falciparum isolates and identify genetic and transcriptomic backgrounds to artemisinin resistance.
- Lei Zhu
- , Jaishree Tripathi
- & Ye Htut
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Article
| Open AccessInflammasome activation negatively regulates MyD88-IRF7 type I IFN signaling and anti-malaria immunity
The inflammasome is an essential component of inflammatory processes and the host response to infection. Here the authors show that inflammasome activation modulates MyD88-IRF7 type I IFN signalling and anti-malaria immunity.
- Xiao Yu
- , Yang Du
- & Rong-Fu Wang
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Article
| Open AccessAdrenal hormones mediate disease tolerance in malaria
Disease tolerance mechanisms counter the negative effects of infection without decreasing the pathogen load. Here, the authors show that in mouse models of malaria, such disease tolerance can be conferred by adrenal hormones, by preventing excessive inflammation and hypoglycemia.
- Leen Vandermosten
- , Thao-Thy Pham
- & Philippe E. Van den Steen
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Article
| Open AccessEpistasis studies reveal redundancy among calcium-dependent protein kinases in motility and invasion of malaria parasites
Despite functional optimisation during evolution of parasitism, most members of a calcium dependent protein kinase (CDPK) family show genetic redundancy in Plasmodium. Here, the authors screen 294 genetic interactions among protein kinases in Plasmodium and show how some CDPKs functionally interact to control motility and host cell invasion.
- Hanwei Fang
- , Ana Rita Gomes
- & Mathieu Brochet
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Article
| Open AccessA high throughput screen for next-generation leads targeting malaria parasite transmission
Sexual forms of malaria parasites are responsible for transmission to the mosquito. Anti-malarial drug resistance remains a serious problem and requires advent of new drug therapies. Here, the authors present a high-throughput screen of potential antimalarial compounds, identifying seventeen drug-like molecules specifically targeting transmission.
- Michael J. Delves
- , Celia Miguel-Blanco
- & Jake Baum
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Article
| Open AccessNon-competitive resource exploitation within mosquito shapes within-host malaria infectivity and virulence
The evolution of within-host malaria virulence has been studied, but the vector’s contribution isn’t well understood. Here, Costa et al. show that non-competitive parasitic resource exploitation within-vector, in particular lipid trafficking, restricts within-host infectivity and virulence of the parasite.
- G. Costa
- , M. Gildenhard
- & E. A. Levashina
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Article
| Open AccessEmerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine
Increasing resistance of Plasmodium falciparum strains to piperaquine (PPQ) in Southeast Asia is of concern and resistance mechanisms are incompletely understood. Here, Ross et al. show that mutations in the P. falciparum chloroquine resistance transporter are rapidly increasing in prevalence in Cambodia and confer resistance to PPQ.
- Leila S. Ross
- , Satish K. Dhingra
- & David A. Fidock
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Article
| Open AccessA mosquito salivary gland protein partially inhibits Plasmodium sporozoite cell traversal and transmission
Mosquito saliva can affect transmission of Plasmodium to mammalian hosts, but active saliva components or mechanisms are poorly understood. Here, the authors identify a mosquito saliva protein that binds Plasmodium sporozoites and inhibits cell traversal in vitro and sporozoite speed in mice.
- Tyler R. Schleicher
- , Jing Yang
- & Erol Fikrig
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Article
| Open AccessCryopreservation of infectious Cryptosporidium parvum oocysts
Research on Cryptosporidium parasites, a major cause of acute infant diarrhea, is hampered by the short shelf life of oocysts, thus requiring routine propagation in laboratory animals. Here, the authors report a method to cryopreserve viable and infectious Cryptosporidium oocysts by ultra-fast cooling.
- Justyna J. Jaskiewicz
- , Rebecca D. Sandlin
- & Saul Tzipori
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Article
| Open AccessGenome-wide real-time in vivo transcriptional dynamics during Plasmodium falciparum blood-stage development
Transcriptomic analysis often doesn’t differentiate between newly synthesized and stabilized mRNAs. Using rapid 4-thiouracil incorporation, Painter et al. here define genome-wide active transcription throughout Plasmodium blood-stage developmental stages and identify associated regulatory DNA sequence motifs.
- Heather J. Painter
- , Neo Christopher Chung
- & Manuel Llinás
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Article
| Open AccessGenomic analysis of a pre-elimination Malaysian Plasmodium vivax population reveals selective pressures and changing transmission dynamics
Plasmodium vivax incidence in Malaysia has declined markedly over the last decade, despite evidence of chloroquine resistance. Here, Auburn et al. compare population structure of P. vivax in Malaysia to regions with intermediate and high transmission and identify genetic regions under putative selection.
- Sarah Auburn
- , Ernest D. Benavente
- & Ric N. Price
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Article
| Open AccessChanges in genome organization of parasite-specific gene families during the Plasmodium transmission stages
The development of malaria parasites is controlled by coordinated changes in gene expression. Here, the authors show that the three-dimensional genome structure of human malaria parasites is strongly connected with transcriptional activity of specific gene families throughout the life cycles of Plasmodium falciparum and Plasmodium vivax parasites.
- Evelien M. Bunnik
- , Kate B. Cook
- & Karine G. Le Roch
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Article
| Open AccessTransporter gene acquisition and innovation in the evolution of Microsporidia intracellular parasites
Microsporidia are obligate intracellular parasites that infect both humans and animals. Here, Dean et al. perform ancient gene reconstruction and functional assays to investigate the evolution and functional diversification of nucleotide transporters which are key to the parasite's intracellular lifestyle.
- P. Dean
- , K. M. Sendra
- & T. M. Embley