27 results on '"Ch'ng, Jun-Hong"'
Search Results
2. Biofilm-associated infection by enterococci
- Author
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Ch’ng, Jun-Hong, Chong, Kelvin K. L., Lam, Ling Ning, Wong, Jun Jie, and Kline, Kimberly A.
- Published
- 2019
- Full Text
- View/download PDF
3. Development of drug-loaded immunoliposomes for the selective targeting and elimination of rosetting Plasmodium falciparum-infected red blood cells
- Author
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Moles, Ernest, Moll, Kirsten, Ch'ng, Jun-Hong, Parini, Paolo, Wahlgren, Mats, and Fernàndez-Busquets, Xavier
- Published
- 2016
- Full Text
- View/download PDF
4. Can we teach an old drug new tricks?
- Author
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Ch’ng, Jun-Hong, Renia, Laurent, Nosten, Francois, and Tan, Kevin S.W.
- Published
- 2012
- Full Text
- View/download PDF
5. Author Correction: Biofilm-associated infection by enterococci
- Author
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Ch’ng, Jun-Hong, Chong, Kelvin K. L., Lam, Ling Ning, Wong, Jun Jie, and Kline, Kimberly A.
- Published
- 2019
- Full Text
- View/download PDF
6. Enterococcus faecalis suppresses Staphylococcus aureus-induced NETosis and promotes bacterial survival in polymicrobial infections.
- Author
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Kao, Patrick Hsien-Neng, Ch'ng, Jun-Hong, Chong, Kelvin K L, Stocks, Claudia J, Wong, Siu Ling, and Kline, Kimberly A
- Subjects
- *
ENTEROCOCCUS faecalis , *PHAGOCYTOSIS , *ENDOCYTOSIS , *STAPHYLOCOCCUS aureus , *NEUTROPHILS - Abstract
Enter ococcus f aecalis is an opportunistic pathogen that is frequently co-isolated with other microbes in wound infections. While E. faecalis can subvert the host immune response and promote the survival of other microbes via interbacterial synergy, little is known about the impact of E. faecalis -mediated immune suppression on co-infecting microbes. We hypothesized that E. faecalis can attenuate neutr ophil-mediated r esponses in mixed-species infection to pr omote survi v al of the co-infecting species. We found that neutr ophils control E. faecalis infection via phagocytosis, ROS production, and de gr anulation of azurophilic granules, but it does not trigger neutrophil extracellular trap formation (NETosis). However, E. faecalis attenuates Staphylococcus aureus -induced NETosis in pol ymicr obial infection by interfering with citrullination of histone, suggesting E. f aecalis can activel y suppr ess NETosis in neutrophils. Residual S. aureus -induced NETs that remain during co-infection do not impact E. faecalis, further suggesting that E. faecalis possess mechanisms to evade or survive NET-associated killing mec hanisms. E. f aecalis -driven reduction of NETosis corresponds with higher S. aur eus survi v al, indicating that this immunomodulating effect could be a risk factor in promoting the virulence polymicrobial infection. These findings highlight the complexity of the immune response to polymicrobial infections and suggest that attenuated pathogen-specific imm une r esponses contribute to pathogenesis in the mammalian host. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
7. Enhanced virulence of Plasmodium falciparum in blood of diabetic patients.
- Author
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Ch'ng, Jun-Hong, Moll, Kirsten, Wyss, Katja, Hammar, Ulf, Rydén, Mikael, Kämpe, Olle, Färnert, Anna, and Wahlgren, Mats
- Subjects
- *
PEOPLE with diabetes , *TYPE 2 diabetes , *PLASMODIUM falciparum , *GLYCOSYLATED hemoglobin , *TYPE 1 diabetes , *MALARIA , *CANDIDATUS diseases , *ERYTHROCYTES - Abstract
Rising prevalence of diabetes in sub-Saharan Africa, coupled with continued malaria transmission, has resulted more patients dealing with both communicable and non-communicable diseases. We previously reported that travelers with type 2 diabetes mellitus (T2DM) infected with Plasmodium falciparum were three times more likely to develop severe malaria than non-diabetics. Here we explore the biological basis for this by testing blood from uninfected subjects with type 1 and type 2 diabetes, ex vivo, for their effects on parasite growth and rosetting (binding of infected erythrocytes to uninfected erythrocytes). Rosetting was associated with type 2 diabetes, blood glucose and erythrocyte sedimentation rate (ESR), while parasite growth was positively associated with blood glucose, glycated hemoglobin (HbA1c), body mass index (BMI), fibrinogen and triglycerides. This study establishes a link between diabetes and malaria virulence assays, potentially explaining the protective effect of good glycemic control against severe malaria in subjects with diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
8. Diverted total synthesis of falcitidin acyl tetrapeptides as new antimalarial leads
- Author
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Kotturi, Santosh R., Somanadhan, Brinda, Ch’ng, Jun-Hong, Tan, Kevin S.-W., Butler, Mark S., and Lear, Martin J.
- Published
- 2014
- Full Text
- View/download PDF
9. SURGE complex of Plasmodium falciparum in the rhoptry-neck (SURFIN4.2-RON4-GLURP) contributes to merozoite invasion.
- Author
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Quintana, Maria del Pilar, Ch’ng, Jun-Hong, Zandian, Arash, Imam, Maryam, Hultenby, Kjell, Theisen, Michael, Nilsson, Peter, Qundos, Ulrika, Moll, Kirsten, Chan, Sherwin, and Wahlgren, Mats
- Subjects
- *
PLASMODIUM falciparum , *ERYTHROCYTES , *MEROZOITES , *ORGANELLES , *CELL membranes - Abstract
Plasmodium falciparum invasion into red blood cells (RBCs) is a complex process engaging proteins on the merozoite surface and those contained and sequentially released from the apical organelles (micronemes and rhoptries). Fundamental to invasion is the formation of a moving junction (MJ), a region of close apposition of the merozoite and the RBC plasma membranes, through which the merozoite draws itself before settling into a newly formed parasitophorous vacuole (PV). SURFIN4.2 was identified at the surface of the parasitized RBCs (pRBCs) but was also found apically associated with the merozoite. Using antibodies against the N-terminus of the protein we show the presence of SURFIN4.2 in the neck of the rhoptries, its secretion into the PV and shedding into the culture supernatant upon schizont rupture. Using immunoprecipitation followed by mass spectrometry we describe here a novel protein complex we have named SURGE where SURFIN4.2 forms interacts with the rhoptry neck protein 4 (RON4) and the Glutamate Rich Protein (GLURP). The N-terminal cysteine-rich–domain (CRD) of SURFIN4.2 mediates binding to the RBC membrane and its interaction with RON4 suggests its involvement in the contact between the merozoite apex and the RBC at the MJ. Supporting this suggestion, we also found that polyclonal antibodies to the extracellular domain (including the CRD) of SURFIN4.2 partially inhibit merozoite invasion. We propose that the formation of the SURGE complex participates in the establishment of parasite infection within the PV and the RBCs. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
10. Conducting Malaria Research in Developing Countries: A Right to Claim Healthcare.
- Author
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CAPPS, BENJAMIN and CH'NG JUN-HONG
- Subjects
- *
MALARIA , *CLINICAL trials , *HUMAN research subjects , *DUTY - Abstract
The article focuses on conducting clinical trials related to malaria in developing countries and presents a rights-duty framework for agreement between parties involved in clinical research. Topics discussed include imperfect obligations of providing healthcare by researchers, a trial by the Medical Research Council of Great Britain (MRC) for developing malaria vaccine, distinction between perfect and imperfect duties, moral obligations of researchers and rights of research participants.
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- 2013
- Full Text
- View/download PDF
11. CS6-03 Malaria Programmed Cell Death: Pathways and Perspectives
- Author
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Tan, Kevin S.W., Ch'ng, Jun Hong, Lear, Martin James, and Kumar, Kotturi Rajaiah Santosh
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- 2009
- Full Text
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12. Can a single “powerless” mitochondrion in the malaria parasite contribute to parasite programmed cell death in the asexual stages?
- Author
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Ch'ng, Jun-Hong, Yeo, Su-Ping, and Shyong-Wei Tan, Kevin
- Subjects
- *
MITOCHONDRIAL membranes , *APOPTOSIS , *CHLOROQUINE , *PROTEOLYTIC enzymes , *PLASMODIUM , *MALARIA , *ARTEMISININ - Abstract
Abstract: The protozoan pathogens responsible for malaria are from the Plasmodium genus, with Plasmodium falciparum and Plasmodium vivax accounting for almost all clinical infections. With recent estimates of mortality exceeding 800,000 annually, malaria continues to take a terrible toll on lives and the early promises of medicine to eradicate the disease have yet to approach realization, in part due to the spread of drug resistant parasites. Recent reports of artemisinin-resistance have prompted renewed efforts to identify novel therapeutic options, and one such pathway being considered for antimalarial exploit is the parasite''s programmed cell death (PCD) pathway. In this mini-review, we will discuss the roles of the plasmodium mitochondria in cell death and as a target of antimalarial compounds, taking into account recent data suggesting that PCD pathways involving the mitochondria may be attractive antimalarial targets. [Copyright &y& Elsevier]
- Published
- 2013
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13. Epitopes of anti-RIFIN antibodies and characterization of rif-expressing Plasmodium falciparum parasites by RNA sequencing.
- Author
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Ch'ng, Jun-Hong, Sirel, Madle, Zandian, Arash, del Pilar Quintana, Maria, Chun Leung Chan, Sherwin, Moll, Kirsten, Tellgren-Roth, Asa, Nilsson, IngMarie, Nilsson, Peter, Qundos, Ulrika, and Wahlgren, Mats
- Abstract
Variable surface antigens of Plasmodium falciparum have been a major research focus since they facilitate parasite sequestration and give rise to deadly malaria complications. Coupled with its potential use as a vaccine candidate, the recent suggestion that the repetitive interspersed families of polypeptides (RIFINs) mediate blood group A rosetting and influence blood group distribution has raised the research profile of these adhesins. Nevertheless, detailed investigations into the functions of this highly diverse multigene family remain hampered by the limited number of validated reagents. In this study, we assess the specificities of three promising polyclonal anti-RIFIN antibodies that were IgG-purified from sera of immunized animals. Their epitope regions were mapped using a 175,000-peptide microarray holding overlapping peptides of the P. falciparum variable surface antigens. Through immunoblotting and immunofluorescence imaging, we show that different antibodies give varying results in different applications/assays. Finally, we authenticate the antibody-based detection of RIFINs in two previously uncharacterized non-rosetting parasite lines by identifying the dominant rif transcripts using RNA sequencing. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
14. Rosette-Disrupting Effect of an Anti-Plasmodial Compound for the Potential Treatment of Plasmodium falciparum Malaria Complications.
- Author
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Ch'ng, Jun-Hong, Moll, Kirsten, Quintana, Maria del Pilar, Chan, Sherwin Chun Leung, Masters, Ellen, Moles, Ernest, Liu, Jianping, Eriksson, Anders B., and Wahlgren, Mats
- Published
- 2016
- Full Text
- View/download PDF
15. ChemInform Abstract: Diverted Total Synthesis of Falcitidin Acyl Tetrapeptides as New Antimalarial Leads.
- Author
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Kotturi, Santosh R., Somanadhan, Brinda, Ch'ng, Jun‐Hong, Tan, Kevin S.‐W., Butler, Mark S., and Lear, Martin J.
- Published
- 2014
- Full Text
- View/download PDF
16. Heme cross-feeding can augment Staphylococcus aureus and Enterococcus faecalis dual species biofilms.
- Author
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Ch'ng JH, Muthu M, Chong KKL, Wong JJ, Tan CAZ, Koh ZJS, Lopez D, Matysik A, Nair ZJ, Barkham T, Wang Y, and Kline KA
- Subjects
- Biofilms, Heme, Virulence, Enterococcus faecalis genetics, Staphylococcus aureus genetics
- Abstract
The contribution of biofilms to virulence and as a barrier to treatment is well-established for Staphylococcus aureus and Enterococcus faecalis, both nosocomial pathogens frequently isolated from biofilm-associated infections. Despite frequent co-isolation, their interactions in biofilms have not been well-characterized. We report that in combination, these two species can give rise to augmented biofilms biomass that is dependent on the activation of E. faecalis aerobic respiration. In E. faecalis, respiration requires both exogenous heme to activate the cydAB-encoded heme-dependent cytochrome bd, and the availability of O
2 . We determined that the ABC transporter encoded by cydDC contributes to heme import. In dual species biofilms, S. aureus provides the heme to activate E. faecalis respiration. S. aureus mutants deficient in heme biosynthesis were unable to augment biofilms whereas heme alone is sufficient to augment E. faecalis mono-species biofilms. Our results demonstrate that S. aureus-derived heme, likely in the form of released hemoproteins, promotes E. faecalis biofilm formation, and that E. faecalis gelatinase activity facilitates heme extraction from hemoproteins. This interspecies interaction and metabolic cross-feeding may explain the frequent co-occurrence of these microbes in biofilm-associated infections., (© 2022. The Author(s).)- Published
- 2022
- Full Text
- View/download PDF
17. Measuring Rosetting Inhibition in Plasmodium falciparum Parasites Using a Flow Cytometry-Based Assay.
- Author
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Quintana MDP and Ch'ng JH
- Subjects
- Animals, Child, Child, Preschool, Erythrocytes metabolism, Flow Cytometry, Humans, Plasmodium falciparum physiology, Rosette Formation, Malaria, Falciparum parasitology, Parasites
- Abstract
Rosetting is the ability of Plasmodium falciparum-infected erythrocytes (IEs) to bind to host receptors on the surface of uninfected erythrocytes (uE) leading to the formation of a cluster of cells with a central IE surrounded by uE. It is a hallmark event during the pathogenesis of P. falciparum malaria, the most severe species causing malaria, which affects mostly young children in Africa. There are no current treatments effectively targeting and disrupting parasite rosette formation. Here, we detail a high-throughput, flow cytometry based assay that allows testing and identification of potential rosetting-inhibitory compounds that could be used in combination with anti-plasmodial drugs to reduce malaria morbidity and mortality., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2022
- Full Text
- View/download PDF
18. Author Correction: Biofilm-associated infection by enterococci.
- Author
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Ch'ng JH, Chong KKL, Lam LN, Wong JJ, and Kline KA
- Abstract
In the section on initial attachment and in Figure 1 it was erroneously indicated that enterococcal surface protein (Esp) binds collagen and fibrinogen. The text and figure were changed to remove this binding interaction both online and in the pdf. The authors apologize for any confusion caused.
- Published
- 2019
- Full Text
- View/download PDF
19. Biofilm-associated infection by enterococci.
- Author
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Ch'ng JH, Chong KKL, Lam LN, Wong JJ, and Kline KA
- Subjects
- Anti-Bacterial Agents pharmacology, Drug Resistance, Multiple, Bacterial, Gram-Positive Bacterial Infections drug therapy, Gram-Positive Bacterial Infections microbiology, Humans, Urinary Tract Infections drug therapy, Urinary Tract Infections microbiology, Biofilms growth & development, Enterococcus physiology, Host Microbial Interactions
- Abstract
Enterococci are ubiquitous members of the human gut microbiota and frequent causes of biofilm-associated opportunistic infections. Enterococci cause 25% of all catheter-associated urinary tract infections, are frequently isolated in wounds and are increasingly found in infective endocarditis, and all of these infections are associated with biofilms. Enterococcal biofilms are intrinsically tolerant to antimicrobials and thus are a serious impediment for treating infections. In this Review, we describe the spatiotemporal development of enterococcal biofilms and the factors that promote or inhibit biofilm formation. We discuss how the environment, including the host and other co-colonizing microorganisms, affects biofilm development. Finally, we provide an overview of current and future interventions to limit enterococcal biofilm-associated infections. Overall, enterococcal biofilms remain a pressing clinical problem, and there is an urgent need to better understand their development and persistence and to identify novel treatments.
- Published
- 2019
- Full Text
- View/download PDF
20. SURGE complex of Plasmodium falciparum in the rhoptry-neck (SURFIN4.2-RON4-GLURP) contributes to merozoite invasion.
- Author
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Quintana MDP, Ch'ng JH, Zandian A, Imam M, Hultenby K, Theisen M, Nilsson P, Qundos U, Moll K, Chan S, and Wahlgren M
- Subjects
- Animals, Erythrocytes metabolism, Humans, Malaria, Falciparum metabolism, Membrane Proteins genetics, Membrane Proteins immunology, Multiprotein Complexes genetics, Multiprotein Complexes metabolism, Plasmodium falciparum isolation & purification, Protozoan Proteins genetics, Rabbits, Erythrocytes parasitology, Malaria, Falciparum parasitology, Membrane Proteins metabolism, Merozoites pathogenicity, Plasmodium falciparum pathogenicity, Protozoan Proteins metabolism
- Abstract
Plasmodium falciparum invasion into red blood cells (RBCs) is a complex process engaging proteins on the merozoite surface and those contained and sequentially released from the apical organelles (micronemes and rhoptries). Fundamental to invasion is the formation of a moving junction (MJ), a region of close apposition of the merozoite and the RBC plasma membranes, through which the merozoite draws itself before settling into a newly formed parasitophorous vacuole (PV). SURFIN4.2 was identified at the surface of the parasitized RBCs (pRBCs) but was also found apically associated with the merozoite. Using antibodies against the N-terminus of the protein we show the presence of SURFIN4.2 in the neck of the rhoptries, its secretion into the PV and shedding into the culture supernatant upon schizont rupture. Using immunoprecipitation followed by mass spectrometry we describe here a novel protein complex we have named SURGE where SURFIN4.2 forms interacts with the rhoptry neck protein 4 (RON4) and the Glutamate Rich Protein (GLURP). The N-terminal cysteine-rich-domain (CRD) of SURFIN4.2 mediates binding to the RBC membrane and its interaction with RON4 suggests its involvement in the contact between the merozoite apex and the RBC at the MJ. Supporting this suggestion, we also found that polyclonal antibodies to the extracellular domain (including the CRD) of SURFIN4.2 partially inhibit merozoite invasion. We propose that the formation of the SURGE complex participates in the establishment of parasite infection within the PV and the RBCs., Competing Interests: Mats Wahlgren is a co-founder and board member at Modus Therapeutics (known before as Dilaforette), a company developing drugs for the treatment of severe malaria. This however does not alter our adherence to PLOS ONE policies on sharing data and materials included in this manuscript since none of the data is directly related to the company’s activities. All the other authors declare that they have no competing interests.
- Published
- 2018
- Full Text
- View/download PDF
21. Antibodies in children with malaria to PfEMP1, RIFIN and SURFIN expressed at the Plasmodium falciparum parasitized red blood cell surface.
- Author
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Quintana MDP, Ch'ng JH, Moll K, Zandian A, Nilsson P, Idris ZM, Saiwaew S, Qundos U, and Wahlgren M
- Subjects
- ABO Blood-Group System analysis, Child, Child, Preschool, Erythrocytes parasitology, Humans, Infant, Malaria, Falciparum parasitology, Opsonin Proteins blood, Phagocytosis, Rosette Formation, Antibodies, Protozoan blood, Malaria, Falciparum immunology, Membrane Proteins immunology, Protozoan Proteins immunology
- Abstract
Naturally acquired antibodies to proteins expressed on the Plasmodium falciparum parasitized red blood cell (pRBC) surface steer the course of a malaria infection by reducing sequestration and stimulating phagocytosis of pRBC. Here we have studied a selection of proteins representing three different parasite gene families employing a well-characterized parasite with a severe malaria phenotype (FCR3S1.2). The presence of naturally acquired antibodies, impact on rosetting rate, surface reactivity and opsonization for phagocytosis in relation to different blood groups of the ABO system were assessed in a set of sera from children with mild or complicated malaria from an endemic area. We show that the naturally acquired immune responses, developed during malaria natural infection, have limited access to the pRBCs inside a blood group A rosette. The data also indicate that SURFIN
4.2 may have a function at the pRBC surface, particularly during rosette formation, this role however needs to be further validated. Our results also indicate epitopes differentially recognized by rosette-disrupting antibodies on a peptide array. Antibodies towards parasite-derived proteins such as PfEMP1, RIFIN and SURFIN in combination with host factors, essentially the ABO blood group of a malaria patient, are suggested to determine the outcome of a malaria infection.- Published
- 2018
- Full Text
- View/download PDF
22. Regulation of PfEMP1-VAR2CSA translation by a Plasmodium translation-enhancing factor.
- Author
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Chan S, Frasch A, Mandava CS, Ch'ng JH, Quintana MDP, Vesterlund M, Ghorbal M, Joannin N, Franzén O, Lopez-Rubio JJ, Barbieri S, Lanzavecchia A, Sanyal S, and Wahlgren M
- Subjects
- Calpain metabolism, Chondroitin Sulfates, Erythrocytes metabolism, Erythrocytes parasitology, Female, Humans, Malaria, Falciparum parasitology, Open Reading Frames, Placenta metabolism, Plasmodium metabolism, Plasmodium falciparum metabolism, Pregnancy, Pregnancy Complications, Parasitic parasitology, Protein Biosynthesis, Proteolysis, Protozoan Proteins genetics, Antigens, Protozoan genetics, Gene Expression Regulation, Plasmodium falciparum genetics, Protozoan Proteins metabolism
- Abstract
Pregnancy-associated malaria commonly involves the binding of Plasmodium falciparum-infected erythrocytes to placental chondroitin sulfate A (CSA) through the PfEMP1-VAR2CSA protein. VAR2CSA is translationally repressed by an upstream open reading frame. In this study, we report that the P. falciparum translation enhancing factor (PTEF) relieves upstream open reading frame repression and thereby facilitates VAR2CSA translation. VAR2CSA protein levels in var2csa-transcribing parasites are dependent on the expression level of PTEF, and the alleviation of upstream open reading frame repression requires the proteolytic processing of PTEF by PfCalpain. Cleavage generates a C-terminal domain that contains a sterile-alpha-motif-like domain. The C-terminal domain is permissive to cytoplasmic shuttling and interacts with ribosomes to facilitate translational derepression of the var2csa coding sequence. It also enhances translation in a heterologous translation system and thus represents the first non-canonical translation enhancing factor to be found in a protozoan. Our results implicate PTEF in regulating placental CSA binding of infected erythrocytes.
- Published
- 2017
- Full Text
- View/download PDF
23. Frequent GU wobble pairings reduce translation efficiency in Plasmodium falciparum.
- Author
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Chan S, Ch'ng JH, Wahlgren M, and Thutkawkorapin J
- Subjects
- Asparagine genetics, Base Composition, Evolution, Molecular, Exons, Gene Expression Regulation, Genes, Reporter, Repetitive Sequences, Nucleic Acid, Selection, Genetic, Anticodon, Base Pairing, Codon, Plasmodium falciparum genetics, Protein Biosynthesis
- Abstract
Plasmodium falciparum genome has 81% A+T content. This nucleotide bias leads to extreme codon usage bias and culminates in frequent insertion of asparagine homorepeats in the proteome. Using recodonized GFP sequences, we show that codons decoded via G:U wobble pairing are suboptimal codons that are negatively associated to protein translation efficiency. Despite this, one third of all codons in the genome are GU wobble codons, suggesting that codon usage in P. falciparum has not been driven to maximize translation efficiency, but may have evolved as translational regulatory mechanism. Particularly, asparagine homorepeats are generally encoded by locally clustered GU wobble AAT codons, we demonstrated that this GU wobble-rich codon context is the determining factor that causes reduction of protein level. Moreover, insertion of clustered AAT codons also causes destabilization of the transcripts. Interestingly, more frequent asparagine homorepeats insertion is seen in single-exon genes, suggesting transcripts of these genes may have been programmed for rapid mRNA decay to compensate for the inefficiency of mRNA surveillance regulation on intronless genes. To our knowledge, this is the first study that addresses P. falciparum codon usage in vitro and provides new insights on translational regulation and genome evolution of this parasite.
- Published
- 2017
- Full Text
- View/download PDF
24. Microbial hara-kiri : Exploiting lysosomal cell death in malaria parasites.
- Author
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Ch'ng JH, Ursing J, and Tan KS
- Abstract
The antimalarial drug chloroquine (CQ) has been sidelined in the fight against falciparum malaria due to wide-spread CQ resistance. Replacement drugs like sulfadoxine, pyrimethamine and mefloquine have also since been surpassed with the evolution of multi-drug resistant parasites. Even the currently recommended artemisinin-based combination therapies show signs of compromise due to the recent spread of artemisinin delayed-clearance parasites. Though there have been promising breakthroughs in the pursuit of new effective antimalarials, the development and strategic deployment of such novel chemical entities takes time. We therefore argue that there is a crucial need to re-examine the usefulness of 'outdated' drugs like chloroquine, and explore if they might be effective alternative therapies in the interim. We suggest that a novel parasite cell death (pCD) pathway may be exploited through the reformulation of CQ to address this need., Competing Interests: Conflict of interest: The authors declare no conflict of interest.
- Published
- 2015
- Full Text
- View/download PDF
25. A high-content phenotypic screen reveals the disruptive potency of quinacrine and 3',4'-dichlorobenzamil on the digestive vacuole of Plasmodium falciparum.
- Author
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Lee YQ, Goh AS, Ch'ng JH, Nosten FH, Preiser PR, Pervaiz S, Yadav SK, and Tan KS
- Subjects
- Amiloride pharmacology, Amiloride analogs & derivatives, Antimalarials pharmacology, Plasmodium falciparum drug effects, Quinacrine pharmacology, Vacuoles drug effects
- Abstract
Plasmodium falciparum is the etiological agent of malignant malaria and has been shown to exhibit features resembling programmed cell death. This is triggered upon treatment with low micromolar doses of chloroquine or other lysosomotrophic compounds and is associated with leakage of the digestive vacuole contents. In order to exploit this cell death pathway, we developed a high-content screening method to select compounds that can disrupt the parasite vacuole, as measured by the leakage of intravacuolar Ca(2+). This assay uses the ImageStream 100, an imaging-capable flow cytometer, to assess the distribution of the fluorescent calcium probe Fluo-4. We obtained two hits from a small library of 25 test compounds, quinacrine and 3',4'-dichlorobenzamil. The ability of these compounds to permeabilize the digestive vacuole in laboratory strains and clinical isolates was validated by confocal microscopy. The hits could induce programmed cell death features in both chloroquine-sensitive and -resistant laboratory strains. Quinacrine was effective at inhibiting field isolates in a 48-h reinvasion assay regardless of artemisinin clearance status. We therefore present as proof of concept a phenotypic screening method with the potential to provide mechanistic insights to the activity of antimalarial drugs.
- Published
- 2014
- Full Text
- View/download PDF
26. A whole cell pathway screen reveals seven novel chemosensitizers to combat chloroquine resistant malaria.
- Author
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Ch'ng JH, Mok S, Bozdech Z, Lear MJ, Boudhar A, Russell B, Nosten F, and Tan KS
- Subjects
- Animals, Drug Evaluation, Preclinical methods, Drug Resistance, Malaria parasitology, Parasites drug effects, Plasmodium falciparum drug effects, Antimalarials pharmacology, Chloroquine pharmacology, Malaria drug therapy
- Abstract
Due to the widespread prevalence of resistant parasites, chloroquine (CQ) was removed from front-line antimalarial chemotherapy in the 1990s despite its initial promise of disease eradication. Since then, resistance-conferring mutations have been identified in transporters such as the PfCRT, that allow for the efflux of CQ from its primary site of action, the parasite digestive vacuole. Chemosensitizing/chemoreversing compounds interfere with the function of these transporters thereby sensitizing parasites to CQ once again. However, compounds identified thus far have disappointing in vivo efficacy and screening for alternative candidates is required to revive this strategy. In this study, we propose a simple and direct means to rapidly screen for such compounds using a fluorescent-tagged CQ molecule. When this screen was applied to a small library, seven novel chemosensitizers (octoclothepin, methiothepin, metergoline, loperamide, chlorprothixene, L-703,606 and mibefradil) were quickly elucidated, including two which showed greater potency than the classical chemosensitizers verapamil and desipramine.
- Published
- 2013
- Full Text
- View/download PDF
27. Can we teach an old drug new tricks?
- Author
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Ch'ng JH, Renia L, Nosten F, and Tan KS
- Subjects
- Animals, Antimalarials adverse effects, Chloroquine adverse effects, Dose-Response Relationship, Drug, Humans, Malaria, Falciparum parasitology, Antimalarials pharmacology, Chloroquine pharmacology, Drug Resistance, Malaria, Falciparum drug therapy, Plasmodium falciparum drug effects, Plasmodium falciparum metabolism
- Abstract
Although resistance to chloroquine (CQ) has relegated it from modern chemotherapeutic strategies to treat Plasmodium falciparum malaria, new evidence suggests that higher doses of the drug may exert a different killing mechanism and offers this drug a new lease of life. Whereas the established antimalarial mechanisms of CQ are usually associated with nanomolar levels of the drug, micromolar levels of CQ trigger a distinct cell death pathway involving the permeabilization of the digestive vacuole of the parasite and a release of hydrolytic enzymes. In this paper, we propose that this pathway is a promising antimalarial strategy and suggest that revising the CQ treatment regimen may elevate blood drug levels to trigger this pathway without increasing the incidence of adverse reactions., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
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