Plasmodium falciparum is the most lethal of human‐infective malaria parasites. A hallmark of P. falciparum malaria is extensive remodeling of host erythrocytes by the parasite, which facilitates the ...development of virulence properties such as host cell adhesion to the endothelial lining of the microvasculature. Host remodeling is mediated by a large complement of parasite proteins exported to the erythrocyte; among them is a single heat shock protein (Hsp)70‐class protein chaperone, P. falciparum Hsp70‐x (PfHsp70‐x). PfHsp70‐x was previously shown to assist the development of virulent cytoadherence characteristics. Here, we show that PfHsp70‐x also supports parasite growth under elevated temperature conditions that simulate febrile episodes, especially at the beginning of the parasite life cycle when most of host cell remodeling takes place. Biochemical and biophysical analyses of PfHsp70‐x, including crystallographic structures of its catalytic domain and the J‐domain of its stimulatory Hsp40 cochaperone, suggest that PfHsp70‐x is highly similar to human Hsp70 chaperones endogenous to the erythrocyte. Nevertheless, our results indicate that selective inhibition of PfHsp70‐x function using small molecules may be possible and highlight specific sites of its catalytic domain as potentially of high interest. We discuss the likely roles of PfHsp70‐x and human chaperones in P. falciparum biology and how specific inhibitors may assist us in disentangling their relative contributions.—Day, J., Passecker, A., Beck, H.‐P., Vakonakis, I. The Plasmodium falciparum Hsp70‐x chaperone assists the heat stress response of the malaria parasite. FASEB J. 33, 14611‐14624 (2019). www.fasebj.org
The asexual intraerythrocytic development of
, causing the most severe form of human malaria, is marked by extensive host cell remodeling. Throughout the processes of invasion, intracellular ...development, and egress, the erythrocyte membrane skeleton is remodeled by the parasite as required for each specific developmental stage. The remodeling is facilitated by a plethora of exported parasite proteins, and the erythrocyte membrane skeleton is the interface of most of the observed interactions between the parasite and host cell proteins. Host cell remodeling has been extensively described and there is a vast body of information on protein export or the description of parasite-induced structures such as Maurer's clefts or knobs on the host cell surface. Here we specifically review the molecular level of each host cell-remodeling step at each stage of the intraerythrocytic development of
We describe key events, such as invasion, knob formation, and egress, and identify the interactions between exported parasite proteins and the host cell cytoskeleton. We discuss each remodeling step with respect to time and specific requirement of the developing parasite to explain host cell remodeling in a stage-specific manner. Thus, we highlight the interaction with the host membrane skeleton as a key event in parasite survival.
Plasmodium falciparum , the causative agent of malaria, completely remodels the infected human erythrocyte to acquire nutrients and to evade the immune system. For this process, the parasite exports ...more than 10% of all its proteins into the host cell cytosol, including the major virulence factor Pf EMP1 (P. falciparum erythrocyte surface protein 1). This unusual protein trafficking system involves long-known parasite-derived membranous structures in the host cell cytosol, called Maurer’s clefts. However, the genesis, role, and function of Maurer’s clefts remain elusive. Similarly unclear is how proteins are sorted and how they are transported to and from these structures. Recent years have seen a large increase of knowledge but, as yet, no functional model has been established. In this perspective we review the most important findings and conclude with potential possibilities to shed light into the enigma of Maurer’s clefts. Understanding the mechanism and function of these structures, as well as their involvement in protein export in P. falciparum , might lead to innovative control strategies and might give us a handle with which to help to eliminate this deadly parasite.
Autonomous microgrid is known to lack appropriate inertia and damping for grid stabilization. Due to this, virtual synchronous machine (VISMA) has been introduced to provide necessary ancillary ...services through control of power converters. In a multi‐VISMA (n‐VISMA) microgrid, relative rotor angle stability of the power system is dependent on the active power balance after small perturbation. Thus, the use of relevant analytical models are essential issues for microgrid stability analysis. This paper presents a comprehensive small‐signal stability analysis to study inherent electromechanical oscillations in the virtual rotors. The subsystems of the microgrid consisting of VISMA, network, load and the outer power control were all modelled in Synchronous Reference Frame. The small‐signal model (SSM) was tested on IEEE‐9 bus system with VISMA replacing electromechanical synchronous machines on the network. To validate the developed numerical analytics, dynamic responses of the SSM are compared with those of the non‐linear (NL) system dynamics and the results reveal that the developed linearized SSM is sufficient to accurately characterize behaviour of the VISMA microgrid when operated in autonomous mode. Eigenvalues analysis and parameter sensitivities of the critical modes were investigated. Oscillatory participations of the VISMAs and steady state stability limit of the microgrid have also been investigated.
With the growing penetration level of inverter‐based power sources into the grid, the impact of low‐inertia, damping and deployment of new controls has raised several questions concerning system stability. As such, it is imperative to develop relevant analytical models that can suitably describe the control architecture for system stability studies. A small‐signal model was developed to study the inherent electromechanical oscillations in the system. Eigenvalues analysis and parametric sensitivities of the critical modes were investigated. Stability limit of the microgrid was also studied.
Carriage and density of gametocytes, the transmission stages of malaria parasites, are determined for predicting the infectiousness of humans to mosquitoes. This measure is used for evaluating ...interventions that aim at reducing malaria transmission. Gametocytes need to be detected by amplification of stage-specific transcripts, which requires RNA-preserving blood sampling. For simultaneous, highly sensitive quantification of both, blood stages and gametocytes, we have compared and optimized different strategies for field and laboratory procedures in a cross sectional survey in 315 5-9 yr old children from Papua New Guinea. qRT-PCR was performed for gametocyte markers pfs25 and pvs25, Plasmodium species prevalence was determined by targeting both, 18S rRNA genes and transcripts. RNA-based parasite detection resulted in a P. falciparum positivity of 24.1%; of these 40.8% carried gametocytes. P. vivax positivity was 38.4%, with 38.0% of these carrying gametocytes. Sensitivity of DNA-based parasite detection was substantially lower with 14.1% for P. falciparum and 19.6% for P. vivax. Using the lower DNA-based prevalence of asexual stages as a denominator increased the percentage of gametocyte-positive infections to 59.1% for P. falciparum and 52.4% for P. vivax. For studies requiring highly sensitive and simultaneous quantification of sexual and asexual parasite stages, 18S rRNA transcript-based detection saves efforts and costs. RNA-based positivity is considerably higher than other methods. On the other hand, DNA-based parasite quantification is robust and permits comparison with other globally generated molecular prevalence data. Molecular monitoring of low density asexual and sexual parasitaemia will support the evaluation of effects of up-scaled antimalarial intervention programs and can also inform about small scale spatial variability in transmission intensity.
Abstract
The ongoing energy transition requires power grid extensions to connect renewable generators to consumers and to transfer power among distant areas. The process of grid extension requires a ...large investment of resources and is supposed to make grid operation more robust. Yet, counter-intuitively, increasing the capacity of existing lines or adding new lines may also reduce the overall system performance and even promote blackouts due to Braess’ paradox. Braess’ paradox was theoretically modeled but not yet proven in realistically scaled power grids. Here, we present an experimental setup demonstrating Braess’ paradox in an AC power grid and show how it constrains ongoing large-scale grid extension projects. We present a topological theory that reveals the key mechanism and predicts Braessian grid extensions from the network structure. These results offer a theoretical method to understand and practical guidelines in support of preventing unsuitable infrastructures and the systemic planning of grid extensions.
Virtual inertia control is considered as an important part of microgrids with high renewable penetration. Virtual inertia emulation based on the derivative of frequency is one of the effective ...methods for improving system inertia and maintaining frequency stability. However, in this method, the ability to provide virtual damping is usually neglected in its design, and hence, its performance might be insufficient in the system with low damping. Confronted with this issue, this paper proposes a novel design and analysis of virtual inertia control to imitate damping and inertia properties simultaneously to the microgrid, enhancing frequency performance and stability. The proposed virtual inertia control uses the derivative technique to calculate the derivative of frequency for virtual inertia emulation. Trajectory sensitivities have been performed to analyze the dynamic impacts of the virtual inertia and virtual damping variables over the system performance. Time-domain simulations are also presented to evaluate the efficiency of the virtual damping and virtual inertia in enhancing system frequency stability. Finally, the efficiency and robustness of the proposed control technique are compared with the conventional inertia control under a wide range of system operation, including the decrease in system damping and inertia and high integrations of load variation and renewable energy.
Rapid and affordable detection of analytes is critical in diagnostic technologies, but current methods are typically expensive and unsuitable for field detection. Lipidic cubic phases are optically ...isotropic, transparent lyotropic liquid crystals (LC), containing highly confined water nanochannels in‐between percolating lipid bilayers following defined space groups. Due to this nanoconfinement, the water in these systems provides a unique environment for chemical and enzymatic reactions. Here, it is shown that during the in meso peroxidase enzymatic reaction, the converted product crystallizes within the mesophase domains, generating a detectable birefringence signal and a new general assay principle is presented for the detection of an unprecedented vast class of analytes using such birefringence as sole optical output signal. By exploiting bienzymatic cascade reactions or introducing an enzyme‐linked immunosorbent assay based on birefringence (Birefringent‐ELISA), this approach is used for real‐time detection of exemplary analytes, such as glucose and cholesterol, model pathogenic microorganisms, Escherichia coli, and viruses such as Ebola and HIV. It is also shown how the same technology enables the rapid, naked‐eye screening of malaria infection via in meso detection of hemozoin crystallites. This new technology is general and readily adaptable to the rapid detection of virtually any type of analyte, such as disease biomarkers, viruses, bacteria, and parasites.
Lipidic cubic mesophases are proposed as a general tool to detect analytes of biomedical and epidemic significance by exploiting in meso enzymatic reactions. Due to nanoconfinement effects, the converted substrates crystallize, generating a detectable birefringence. By exploiting this optical signal, it is shown that enzymatic assays can be designed for simple, real‐time detection of analytes comprising biomarkers, bacteria, viruses, and parasites, illuminating new pathways toward scalable detection technologies.
Clinical trials monitoring malaria drug resistance require genotyping of recurrent Plasmodium falciparum parasites to distinguish between treatment failure and new infection occurring during the ...trial follow up period. Because trial participants usually harbour multi-clonal P. falciparum infections, deep amplicon sequencing (AmpSeq) was employed to improve sensitivity and reliability of minority clone detection. Paired samples from 32 drug trial participants were Illumina deep-sequenced for five molecular markers. Reads were analysed by custom-made software HaplotypR and trial outcomes compared to results from the previous standard genotyping method based on length-polymorphic markers. Diversity of AmpSeq markers in pre-treatment samples was comparable or higher than length-polymorphic markers. AmpSeq was highly reproducible with consistent quantification of co-infecting parasite clones within a host. Outcomes of the three best-performing markers, cpmp, cpp and ama1-D3, agreed in 26/32 (81%) of patients. Discordance between the three markers performed per sample was much lower by AmpSeq (six patients) compared to length-polymorphic markers (eleven patients). Using AmpSeq for discrimination of recrudescence and new infection in antimalarial drug trials provides highly reproducible and robust characterization of clone dynamics during trial follow-up. AmpSeq overcomes limitations inherent to length-polymorphic markers. Regulatory clinical trials of antimalarial drugs will greatly benefit from this unbiased typing method.
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