Kevin Saliba

Looking further! The importance of embedding visual search in action

Publisher: Cambridge University Press (CUP)

Date: 2017

DOI: 10.1017/S0140525X16000273

Abstract: A unified account of visual search in complex everyday environments requires additional deliberations on the functional grounding of Hulleman & Olivers' (H& O's) functional viewing field (FVF) model. Their model can accommodate exploitation of information that is distributed across the immediate environment. Yet the differences in search between genuinely interacting in the environment and merely watching it should challenge researchers to look further.

Inhibition of Thiamine Diphosphate-Dependent Enzymes by Triazole-Based Thiamine Analogues

Publisher: American Chemical Society (ACS)

Date: 11-04-2023

DOI: 10.1021/ACSMEDCHEMLETT.3C00047

pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum

Publisher: Wiley

Date: 02-2005

DOI: 10.1111/J.1365-2958.2004.04470.X

Abstract: Efforts to control malaria worldwide have been hindered by the development and expansion of parasite populations resistant to many first-line antimalarial compounds. Two of the best-characterized determinants of drug resistance in the human malaria parasite Plasmodium falciparum are pfmdr1 and pfcrt, although the mechanisms by which resistance is mediated by these genes is still not clear. In order to determine whether mutations in pfmdr1 associated with chloroquine resistance affect the capacity of the parasite to persist when drug pressure is removed, we conducted competition experiments between P. falciparum strains in which the endogenous pfmdr1 locus was modified by allelic exchange. In the absence of selective pressure, the component of chloroquine resistance attributable to mutations at codons 1034, 1042 and 1246 in the pfmdr1 gene also gave rise to a substantial fitness cost in the intraerythrocytic asexual stage of the parasite. The loss of fitness incurred by these mutations was calculated to be 25% with respect to an otherwise genetically identical strain in which wild-type polymorphisms had been substituted at these three codons. At least part of the fitness loss may be attributed to a diminished merozoite viability. These in vitro results support recent in vivo observations that in several countries where chloroquine use has been suspended because of widespread resistance, sensitive strains are re-emerging.

University communication strategies during a pandemic - Were the messages received?

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 2011

DOI: 10.1097/PHH.0B013E3181D3CB8E

Pgh1 modulates sensitivity and resistance to multiple antimalarials in Plasmodium falciparum

Publisher: Springer Science and Business Media LLC

Date: 02-2000

DOI: 10.1038/35002615

Abstract: Throughout the latter half of this century, the development and spread of resistance to most front-line antimalarial compounds used in the prevention and treatment of the most severe form of human malaria has given cause for grave clinical concern. Polymorphisms in pfmdr1, the gene encoding the P-glycoprotein homologue 1 (Pgh1) protein of Plasmodium falciparum, have been linked to chloroquine resistance Pgh1 has also been implicated in resistance to mefloquine and halofantrine. However, conclusive evidence of a direct causal association between pfmdr1 and resistance to these antimalarials has remained elusive, and a single genetic cross has suggested that Pgh1 is not involved in resistance to chloroquine and mefloquine. Here we provide direct proof that mutations in Pgh1 can confer resistance to mefloquine, quinine and halofantrine. The same mutations influence parasite resistance towards chloroquine in a strain-specific manner and the level of sensitivity to the structurally unrelated compound, artemisinin. This has important implications for the development and efficacy of future antimalarial agents.

Provitamin B ₅ (Pantothenol) Inhibits Growth of the Intraerythrocytic Malaria Parasite

Publisher: American Society for Microbiology

Date: 02-2005

DOI: 10.1128/AAC.49.2.632-637.2005

Abstract: Pantothenic acid, a precursor of the crucial enzyme cofactor coenzyme A, is one of a relatively few nutrients for which the intraerythrocytic parasite has an absolute and acute requirement from the external medium. In some organisms the provitamin pantothenol can serve as a source of pantothenic acid however, this was not the case for the human malaria parasite Plasmodium falciparum . Instead, pantothenol inhibited the in vitro growth of P. falciparum via a mechanism that involves competition with pantothenate and which can be attributed to inhibition of the parasite's pantothenate kinase. Oral administration of pantothenol to mice infected with the murine parasite Plasmodium vinckei vinckei resulted in a significant inhibition of parasite proliferation. This study highlights the potential of the coenzyme A biosynthesis pathway in general, and pantothenate kinase in particular, as an antimalarial drug target.

Calothrixins A and B, novel pentacyclic metabolites from Calothrix cyanobacteria with potent activity against malaria parasites and human cancer cells

Publisher: Elsevier BV

Date: 11-1999

DOI: 10.1016/S0040-4020(99)00833-9

Feedback inhibition of pantothenate kinase regulates pantothenol uptake by the malaria parasite

Publisher: Elsevier BV

Date: 08-2007

DOI: 10.1074/JBC.M704610200

Exploiting the coenzyme A biosynthesis pathway for the identification of new antimalarial agents: the case for pantothenamides

Publisher: Portland Press Ltd.

Date: 08-2014

DOI: 10.1042/BST20140158

Abstract: Malaria kills more than half a million people each year. There is no vaccine, and recent reports suggest that resistance is developing to the antimalarial regimes currently recommended by the World Health Organization. New drugs are therefore needed to ensure malaria treatment options continue to be available. The intra-erythrocytic stage of the malaria parasite's life cycle is dependent on an extracellular supply of pantothenate (vitamin B5), the precursor of CoA (coenzyme A). It has been known for many years that proliferation of the parasite during this stage of its life cycle can be inhibited with pantothenate analogues. We have shown recently that pantothenamides, a class of pantothenate analogues with antibacterial activity, inhibit parasite proliferation at submicromolar concentrations and do so competitively with pantothenate. These compounds, however, are degraded, and therefore rendered inactive, by the enzyme pantetheinase (vanin), which is present in serum. In the present mini-review, we discuss the two strategies that have been put forward to overcome pantetheinase-mediated degradation of pantothenamides. The strategies effectively provide an opportunity for pantothenamides to be tested in vivo. We also put forward our ‘blueprint’ for the further development of pantothenamides (and other pantothenate analogues) as potential antimalarials.

Transport of nucleosides across the Plasmodium falciparum parasite plasma membrane has characteristics of PfENT1

Publisher: Wiley

Date: 17-03-2006

DOI: 10.1111/J.1365-2958.2006.05125.X

Abstract: Like all parasitic protozoa, the human malaria parasite Plasmodium falciparum lacks the enzymes required for de novo synthesis of purines and it is therefore reliant upon the salvage of these compounds from the external environment. P. falciparum equilibrative nucleoside transporter 1 (PfENT1) is a nucleoside transporter that has been localized to the plasma membrane of the intraerythrocytic form of the parasite. In this study we have characterized the transport of purine and pyrimidine nucleosides across the plasma membrane of 'isolated' trophozoite-stage P. falciparum parasites and compared the transport characteristics of the parasite with those of PfENT1 expressed in Xenopus oocytes. The transport of nucleosides into the parasite: (i) was, in the case of adenosine, inosine and thymidine, very fast, equilibrating within a few seconds (ii) was of low affinity [K(m) (adenosine) = 1.45 +/- 0.25 mM K(m) (thymidine) = 1.11 +/- 0.09 mM] and (iii) showed 'cross-competition' for adenosine, inosine and thymidine, but not cytidine. The kinetic characteristics of nucleoside transport in intact parasites matched very closely those of PfENT1 expressed in Xenopus oocytes [K(m) (adenosine) = 1.86 +/- 0.28 mM K(m) (thymidine) = 1.33 +/- 0.17 mM]. Furthermore, PfENT1 transported adenosine, inosine and thymidine, with a cross-competition profile the same as that seen for isolated parasites. The data are consistent with PfENT1 serving as a major route for the uptake of nucleosides across the parasite plasma membrane.

A review of medical masks and respirators for use during an influenza pandemic

Publisher: Wiley

Date: 18-08-2009

DOI: 10.1111/J.1750-2659.2009.00101.X

Further comments on the distribution of acridine orange fluorescence in P. falciparum–infected erythrocytes

Publisher: Elsevier BV

Date: 02-2002

DOI: 10.1016/S0166-6851(01)00405-4

A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites

Publisher: Cold Spring Harbor Laboratory

Date: 14-02-2022

DOI: 10.1101/2022.02.13.480284

Abstract: With the advent of resistance to existing treatments, new drugs are needed to combat apicomplexan parasites such as the causative agents of malaria ( Plasmodium species) and toxoplasmosis ( Toxoplasma gondii ). To identify new inhibitors of the mitochondrial electron transport chain (ETC) in these parasites, we developed a Seahorse XFe96 flux analyzer approach to screen compounds from the Medicines for Malaria Venture ‘Pathogen Box’ for ETC inhibition. We identified six chemically erse, on-target inhibitors of the ETC of T. gondii , five of which also target the ETC of Plasmodium falciparum . Two of the identified compounds (MMV024937 and MMV688853) represent novel ETC inhibitor chemotypes. We pinpoint the molecular targets of these inhibitors, demonstrating that all target ETC Complex III, with MMV688853 additionally targeting a kinase with a key role in parasite invasion of host cells. Most of the compounds remain effective inhibitors of parasites that are resistant to the clinically used Complex III inhibitor atovaquone. In sum, we have developed a versatile screening approach to identify and characterize new inhibitors of the ETC in apicomplexan parasites.

Seasonal influenza vaccination in Australian hospital health care workers: A review

Publisher: AMPCo

Date: 09-2011

DOI: 10.5694/MJA11.10067

Abstract: To review the uptake of seasonal influenza vaccination among hospital health care workers (HCWs) in Australia to date. We searched MEDLINE and EMBASE (up to September 2010) and bibliographies of relevant reports for studies examining seasonal influenza vaccination (uptake, attitudes and/or programs) among Australian hospital HCWs. Studies relating to pandemic (H1N1) 2009 influenza vaccination or other types of health care facilities were excluded. 15 articles were assessed, of which 10 met inclusion criteria. The 10 studies were conducted between 1997 and 2008 and reported vaccination rates of hospital HCWs of 16.3%-58.7%. Two of three studies documenting uptake rates of > 50% were associated with active implementation of vaccination policies or interventions. Uptake rates by occupational group ranged from 29% to 58.3% for physicians, 19% to 56.4% for nurses, 23% to 57.7% for allied health professionals, and 18% to 66.7% for ancillary or support staff. Coverage rates in hospitals that provided the vaccine free of charge to staff (with or without an informational c aign) were no higher than in other hospitals. While seasonal influenza vaccination uptake was higher in hospitals with documented intervention programs, coverage is still low and does not appear to be affected by the provision of free vaccine to staff. State or institutional policies or mandates are likely needed to increase HCW uptake of seasonal influenza vaccination.

Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity

Publisher: Elsevier BV

Date: 08-2014

DOI: 10.1016/J.BMCL.2014.06.013

Biological characterization of chemically diverse compounds targeting the Plasmodium falciparum coenzyme A synthesis pathway

Publisher: Springer Science and Business Media LLC

Date: 17-11-2016

DOI: 10.1186/S13071-016-1860-3

Uptake of an antiplasmodial protease inhibitor into Plasmodium falciparum-infected human erythrocytes via a parasite-induced pathway

Publisher: Elsevier BV

Date: 08-1998

DOI: 10.1016/S0166-6851(98)00077-2

Choline uptake into the malaria parasite is energized by the membrane potential

Publisher: Elsevier BV

Date: 07-2004

DOI: 10.1016/J.BBRC.2004.05.164

Travel risk behaviours and uptake of pre-travel health preventions by university students in Australia

Publisher: Springer Science and Business Media LLC

Date: 17-02-2012

DOI: 10.1186/1471-2334-12-43

Abstract: Forward planning and preventative measures before travelling can significantly reduce the risk of many vaccine preventable travel-related infectious diseases. Higher education students may be at an increased risk of importing infectious disease as many undertake multiple visits to regions with higher infectious disease endemicity. Little is known about the health behaviours of domestic or international university students, particularly students from low resource countries who travel to high-resource countries for education. This study aimed to assess travel-associated health risks and preventative behaviours in a s le of both domestic and international university students in Australia. In 2010, a 28 item self-administered online survey was distributed to students enrolled at the University of New South Wales, Sydney, Australia. Multiple methods of distributing links to the online survey were utilised. The survey examined the international travel history, travel intentions, infection control behaviours and self-reported vaccination history. A total of 1663 respondents completed the online survey, 22.1% were international students and 83.9% were enrolled at an undergraduate level. Half had travelled internationally in the previous 12 months, with 69% of those travelling only once during that time with no difference in travel from Australia between domestic and international students ( p = 0.8). Uptake of pre-travel health advice was low overall with 68% of respondents reporting they had not sought any advice from a health professional prior to their last international trip. Domestic students were more likely to report uptake of a range of preventative travel health measures compared to international students, including diarrhoeal medication, insect repellent, food avoidance and condoms ( P 0.0001). Overall, students reported low risk perception of travel threats and a low corresponding concern for these threats. Our study highlights the need to educate students about the risk associated with travel and improve preventative health-seeking and uptake of precautionary health measures in this highly mobile young adult population. Although immunisation is not an entry requirement to study at Universities in Australia, large tertiary institutions provide an opportunity to engage with young adults on the importance of travel health and provision of vaccines required for travel, including missed childhood vaccines.

Targeting nutrient uptake mechanisms in Plasmodium

Publisher: Bentham Science Publishers Ltd.

Date: 2007

DOI: 10.2174/138945007779315560

Abstract: The proliferation of the intraerythrocytic malaria parasite is dependent on the uptake from the blood plasma, and from the cytoplasm of the host cell, of a range of essential nutrients. These compounds are taken up into the parasitised cell via a combination of constitutively active endogenous host cell transporters and new parasite-induced permeability pathways. On entering the infected cell they are taken up by the intracellular parasite, across the parasitophorous vacuole and parasite plasma membranes, via a combination of channels and transporters, and/or via endocytosis. Once inside the parasite, nutrients are typically phosphorylated and thereby effectively trapped within the cell. The intraerythrocytic parasite has a range of subcellular membrane-bound organelles, each endowed with their own complement of transport proteins which mediate the uptake and efflux of metabolic substrates and byproducts. Proteins that mediate the uptake, intracellular trafficking and metabolism of essential nutrients in the Plasmodium-infected erythrocyte are potential antimalarial drug targets. Here we consider the nature of the pathways involved, focusing in particular on those that mediate the uptake of three important nutrients: glucose, the key energy-substrate for the parasite pantothenate (vitamin B(5)), the precursor of the important enzyme cofactor, coenzyme A and choline, the precursor of the phospholipid phosphatidylcholine.

Nothing magical: pantomimed grasping is controlled by the ventral system

Publisher: Springer Science and Business Media LLC

Date: 15-03-2017

DOI: 10.1007/S00221-016-4868-1

Pneumococcal colonisation following influenza infection

Publisher: Elsevier BV

Date: 09-2011

DOI: 10.1016/J.VACCINE.2011.04.047

Acidification of the Malaria Parasite's Digestive Vacuole by a H+-ATPase and a H+-pyrophosphatase

Publisher: Elsevier BV

Date: 02-2003

DOI: 10.1074/JBC.M208648200

Exploring heteroaromatic rings as a replacement for the labile amide of antiplasmodial pantothenamides

Publisher: Cold Spring Harbor Laboratory

Date: 05-10-2020

DOI: 10.1101/2020.10.02.324079

Abstract: The Plasmodium parasites that cause malaria are adept at developing resistance to antimalarial drugs, necessitating the search for new antiplasmodials. Although several amide analogs of pantothenate (pantothenamides) show potent antiplasmodial activity, hydrolysis by pantetheinases (or vanins) present in blood rapidly inactivates them. We report herein the facile synthesis and biological activity of a small library of pantothenamide analogs in which the labile amide group is replaced with a variety of heteroaromatic rings. Several of the new analogs display antiplasmodial activity in the nanomolar range against P. falciparum and/or P. knowlesi in the presence of pantetheinase. A previously reported triazole and an isoxazole derivative presented here were further characterized and found to possess high selectivity indices, medium or high Caco-2 permeability, and medium or low microsomal clearance in vitro . Although we show here that the two compounds fail to suppress proliferation of P. berghei in vivo , pharmacokinetic and contact time data presented provide a benchmark for the compound profile required to achieve antiplasmodial activity in mice and should facilitate lead optimization.

Coenzyme A biosynthesis: an antimicrobial drug target

Publisher: Oxford University Press (OUP)

Date: 2008

DOI: 10.1111/J.1574-6976.2007.00093.X

Abstract: Pantothenic acid, a precursor of coenzyme A (CoA), is essential for the growth of pathogenic microorganisms. Since the structure of pantothenic acid was determined, many analogues of this essential metabolite have been prepared. Several have been demonstrated to exert an antimicrobial effect against a range of microorganisms by inhibiting the utilization of pantothenic acid, validating pantothenic acid utilization as a potential novel antimicrobial drug target. This review commences with an overview of the mechanisms by which various microorganisms acquire the pantothenic acid they require for growth, and the universal CoA biosynthesis pathway by which pantothenic acid is converted into CoA. A detailed survey of studies that have investigated the inhibitory activity of analogues of pantothenic acid and other precursors of CoA follows. The potential of inhibitors of both pantothenic acid utilization and biosynthesis as novel antibacterial, antifungal and antimalarial agents is discussed, focusing on inhibitors and substrates of pantothenate kinase, the enzyme catalysing the rate-limiting step of CoA biosynthesis in many organisms. The best strategies are considered for identifying inhibitors of pantothenic acid utilization and biosynthesis that are potent and selective inhibitors of microbial growth and that may be suitable for use as chemotherapeutic agents in humans.

The development of a method for identifying penalty kick strategies in association football

Publisher: Informa UK Limited

Date: 10-06-2014

DOI: 10.1080/02640414.2014.926383

Abstract: Penalty takers in association football adopt either a keeper-independent or a keeper-dependent strategy, with the benefits of the keeper-independent strategy presumed to be greater. Yet, despite its relevance for research and practitioners, thus far no method for identifying penalty kick strategies has been available. To develop a validated and reliable method, Experiment 1 assessed characteristics that observers should use to distinguish the two strategies. We asked participants to rate 12 characteristics of pre-recorded clips of kicks of penalty takers that used either a keeper-independent or keeper-dependent strategy. A logistic regression model identified three variables (attention to the goalkeeper, run-up fluency and kicking technique) that in combination predicted kick strategy in 92% of the penalties. We used the model in Experiment 2 to analyse prevalence and efficacy of both the strategies for penalty kicks in penalty shoot-outs during FIFA World Cups (1986-2010) and UEFA Football Ch ionships (1984-2012). The keeper-independent strategy was used much more frequently (i.e., 78-86%) than the keeper-dependent strategy, but successes did not differ. Penalty takers should use both the strategies to be less predictable. Goalkeepers can use the developed model to improve their chances to succeed by adjusting their behaviour to penalty takers' preferred penalty kick strategy.

Hospital health care workers' understanding of and attitudes toward pandemic influenza in Beijing

Publisher: SAGE Publications

Date: 10-05-2012

DOI: 10.1177/1010539510365097

Abstract: During a pandemic, health care workers (HCWs) will be essential to the health system response. This pre-pandemic study aimed to extend previous research by assessing the views, and intended behaviors of hospital HCWs in Beijing, China, regarding pandemic influenza. We undertook a cross-sectional investigation of a s le of HCWs from 24 hospitals in Beijing, China in January 2009. The main outcome measures were intentions regarding work attendance and quarantine, antiviral use and perceived preparation. Our study found that most HCWs perceived pandemic influenza to be very serious but very few were able to correctly define it. 74% (n=1406) of respondents accepted the risk of getting pandemic influenza as part of their job and 71% (n=1350) felt that they have the necessary knowledge to provide patient care during it. We identified two issues that could undermine the best of pandemic plans – the first, a low level of confidence in antivirals as an effective intervention secondly, a high proportion of staff potentially engaging in inappropriate working behaviors

Keeping an Eye on Noisy Movements: On Different Approaches to Perceptual-Motor Skill Research and Training

Publisher: Springer Science and Business Media LLC

Date: 06-08-2016

DOI: 10.1007/S40279-016-0600-3

Abstract: Contemporary theorizing on the complementary nature of perception and action in expert performance has led to different emphases in the study of movement coordination and gaze behavior. On the one hand, coordination research has examined the role of variability in movement control, evidencing that variability facilitates in idualized adaptations during both learning and performance. On the other hand, and at odds with this principle, the majority of gaze behavior studies have tended to average data over participants and trials, proposing the importance of universal 'optimal' gaze patterns in a given task, for all performers, irrespective of stage of learning. In this article, we discuss new lines of inquiry with the aim of reconciling these two distinct approaches. We consider the role of inter- and intra-in idual variability in gaze behaviors and suggest directions for future research.

Human dihydrofolate reductase influences the sensitivity of the malaria parasite Plasmodium falciparum to ketotifen – A cautionary tale in screening transgenic parasites

Publisher: Elsevier BV

Date: 12-2016

DOI: 10.1016/J.IJPDDR.2016.09.003

A cluster randomized clinical trial comparing fit-tested and non-fit-tested N95 respirators to medical masks to prevent respiratory virus infection in health care workers

Publisher: Wiley

Date: 27-01-2011

DOI: 10.1111/J.1750-2659.2011.00198.X

Nutrient acquisition by intracellular apicomplexan parasites: staying in for dinner

Publisher: Elsevier BV

Date: 10-2001

DOI: 10.1016/S0020-7519(01)00258-2

Abstract: The intracellular forms of the apicomplexan parasites Plasmodium, Toxoplasma and Eimeria reside within a parasitophorous vacuole. The nutrients required by these intracellular parasites to support their high rate of growth and replication originate from the host cell which, in turn, takes up such compounds from the extracellular milieu. Solutes moving from the external medium to the interior of the parasite, are confronted by a series of three membranes --the host cell membrane, the parasitophorous vacuole membrane and the parasite plasma membrane. Each constitutes a potential permeability barrier which must be either crossed or bypassed. It is the mechanisms by which this occurs that are the subject of this review.

Feasibility exercise to evaluate the use of particulate respirators by emergency department staff during the 2007 influenza season

Publisher: Cambridge University Press (CUP)

Date: 07-2009

DOI: 10.1086/599254

Structure–Activity Relationships of Antiplasmodial Pantothenamide Analogues Reveal a New Way by Which Triazoles Mimic Amide Bonds

Publisher: Wiley

Date: 29-11-2018

DOI: 10.1002/CMDC.201800327

Abstract: Pantothenamides are potent growth inhibitors of the malaria parasite Plasmodium falciparum. Their clinical use is, however, hindered due to the ubiquitous presence of pantetheinases in human serum, which rapidly degrade pantothenamides into pantothenate and the corresponding amine. We previously reported that replacement of the labile amide bond with a triazole ring not only imparts stability toward pantetheinases, but also improves activity against P. falciparum. A small library of new triazole derivatives was synthesized, and their use in establishing structure-activity relationships relevant to antiplasmodial activity of this family of compounds is discussed herein. Overall it was observed that 1,4-substitution on the triazole ring and use of an unbranched, one-carbon linker between the pantoyl group and the triazole are optimal for inhibition of intraerythrocytic P. falciparum growth. Our results imply that the triazole ring may mimic the amide bond with an orientation different from what was previously suggested for this amide bioisostere.

Issues regarding the implementation of ehealth: Preparing for future influenza pandemics

Publisher: JMIR Publications Inc.

Date: 06-12-2012

DOI: 10.2196/IJMR.2357

Pantothenate utilization by plasmodium as a target for antimalarial chemotherapy

Publisher: Bentham Science Publishers Ltd.

Date: 06-2010

DOI: 10.2174/187152610791163390

Abstract: In the absence of an effective vaccine against malaria suitable for widespread deployment, the control of this lethal infectious disease relies heavily on antimalarial chemotherapies. The most virulent of the parasites that cause malaria (Plasmodium falciparum) has, however, developed resistance to all antimalarial agents in clinical use, and there is a desperate need for new antimalarial agents that target previously unexploited parasite processes. P. falciparum requires an extracellular supply of pantothenate to support its proliferation during the erythrocytic stage of its development in humans. This requirement highlights the mechanisms involved in the utilization (uptake and metabolism) of pantothenate as potential targets for chemotherapeutic attack. Here we review the evidence demonstrating pantothenate to be an essential nutrient for P. falciparum and data from studies investigating whether this parasite has the capacity to utilize exogenous supplies of the cofactor (coenzyme A CoA) for which pantothenate serves as a precursor. The results of recent studies aimed at characterising the mechanisms by which pantothenate is taken up by the P. falciparum-infected erythrocyte and intracellular parasite, and metabolised to CoA, are described. The unique properties that may be exploited to develop selective inhibitors of pantothenate utilization by P. falciparum-infected erythrocytes are highlighted. The molecular identity of P. falciparum pantothenate transporters and CoA biosynthesis enzymes remain unconfirmed. We consider the possible identities, and emphasize the importance of generating these proteins in pure, functionally active form. The tools currently available for identifying inhibitors of pantothenate utilization that may be potent antiplasmodial agents are also discussed.

Mutations in pfmdr1 Modulate the Sensitivity of Plasmodium falciparum to the Intrinsic Antiplasmodial Activity of Verapamil

Publisher: American Society for Microbiology

Date: 02-2005

DOI: 10.1128/AAC.49.2.840-842.2005

Abstract: As well as having the ability to reverse chloroquine resistance in the human malaria parasite Plasmodium falciparum , verapamil has itself an innate antiplasmodial activity. We show here that mutations in Pgh1, the product of the malaria parasite's pfmdr1 gene, influence the parasite's susceptibility to the toxic effects of verapamil.

Inhibition of Plasmodium falciparum pH regulation by small molecule indole derivatives results in rapid parasite death

Publisher: Elsevier BV

Date: 05-2010

DOI: 10.1016/J.BCP.2009.12.025

Abstract: The V-type H+ATPase is critical during the intraerythrocytic stage of the human malaria parasite Plasmodium falciparum. It is responsible for maintaining a near-neutral cytosolic pH (pH 7.3), an acidic digestive vacuole (pH 4.5-5.5) and the generation of an inside-negative plasma membrane potential (approximately -95 mV). Inhibition of this pump is therefore likely to result in profound physiological disturbances within the parasite and parasite death, as illustrated previously by the antiplasmodial activity of the potent and specific inhibitors of the V-type H+-ATPase, bafilomycin A(1) and concanamycin A. In this study we examined the antiplasmodial activity of a series of compounds previously designed, on the basis of the active structural constituents of bafilomycin A(1), to inhibit the osteoclast V-type H+-ATPase. The compounds were tested against up to 4 strains of P. falciparum with varying chloroquine sensitivities. Of the 30 novel compounds tested, 9 had sub-micromolar antiplasmodial IC(50) values, with the most active compound having an IC(50) of 160+/-20 nM. The activity of a number of these compounds was investigated in more detail. We show that these inhibitors acidify the parasite cytosol within seconds and that some inhibitors irreversibly kill the parasite within 0.5-4 h. The antiplasmodial activity of the V-type H+-ATPase inhibitors was strongly correlated with their ability to acidify the parasite cytosol (correlation coefficient 0.98). In combination studies, we show that the inhibitors act indifferently when combined with current antimalarials. Our data support the disruption of parasite pH regulation through inhibition of its V-type H+-ATPase as an antimalarial approach.

Triazole Substitution of a Labile Amide Bond Stabilizes Pantothenamides and Improves Their Antiplasmodial Potency

Publisher: American Society for Microbiology

Date: 12-2016

DOI: 10.1128/AAC.01436-16

Abstract: The biosynthesis of coenzyme A (CoA) from pantothenate and the utilization of CoA in essential biochemical pathways represent promising antimalarial drug targets. Pantothenamides, amide derivatives of pantothenate, have potential as antimalarials, but a serum enzyme called pantetheinase degrades pantothenamides, rendering them inactive in vivo . In this study, we characterize a series of 19 compounds that mimic pantothenamides with a stable triazole group instead of the labile amide. Two of these pantothenamides are active against the intraerythrocytic stage parasite with 50% inhibitory concentrations (IC 50 s) of ∼50 nM, and three others have submicromolar IC 50 s. We show that the compounds target CoA biosynthesis and/or utilization. We investigated one of the compounds for its ability to interact with the Plasmodium falciparum pantothenate kinase, the first enzyme involved in the conversion of pantothenate to CoA, and show that the compound inhibits the phosphorylation of [ 14 C]pantothenate by the P. falciparum pantothenate kinase, but the inhibition does not correlate with antiplasmodial activity. Furthermore, the compounds are not toxic to human cells and, importantly, are not degraded by pantetheinase.

Studies with thePlasmodium falciparumhexokinase reveal that PfHT limits the rate of glucose entry into glycolysis

Publisher: Wiley

Date: 13-08-2013

DOI: 10.1016/J.FEBSLET.2013.07.052

Abstract: To characterise plasmodial glycolysis, we generated two transgenic Plasmodium falciparum lines, one expressing P. falciparum hexokinase (PfHK) tagged with GFP (3D7-PfHK(GFP)) and another overexpressing native PfHK (3D7-PfHK(+)). Contrary to previous reports, we propose that PfHK is cytosolic. The glucose analogue, 2-deoxy-d-glucose (2-DG) was nearly 2-fold less toxic to 3D7-PfHK(+) compared with control parasites, supporting PfHK as a potential drug target. Although PfHK activity was higher in 3D7-PfHK(+), they accumulated phospho-[(14)C]2-DG at the same rate as control parasites. Transgenic parasites overexpressing the parasite's glucose transporter (PfHT) accumulated phospho-[(14)C]2-DG at a higher rate, consistent with glucose transport limiting glucose entry into glycolysis.

Respiratory viruses transmission from children to adults within a household

Publisher: Elsevier BV

Date: 04-2012

DOI: 10.1016/J.VACCINE.2011.11.047

A cross-metathesis approach to novel pantothenamide derivatives

Publisher: Beilstein Institut

Date: 13-05-2016

DOI: 10.3762/BJOC.12.95

Abstract: Pantothenamides are known for their in vitro antimicrobial activity. Our group has previously reported a new stereoselective route to access derivatives modified at the geminal dimethyl moiety. This route however fails in the addition of large substituents. Here we report a new synthetic route that exploits the known allyl derivative, allowing for the installation of larger groups via cross-metathesis. The method was applied in the synthesis of a new pantothenamide with improved stability in human blood.

Analysis of Breath Specimens for Biomarkers of Plasmodium falciparum Infection

Publisher: Oxford University Press (OUP)

Date: 25-03-2015

DOI: 10.1093/INFDIS/JIV176

The Key Glycolytic Enzyme Phosphofructokinase Is Involved in Resistance to Antiplasmodial Glycosides

Publisher: American Society for Microbiology

Date: 22-12-2020

DOI: 10.1128/MBIO.02842-20

Abstract: Malaria, caused by Plasmodium parasites, continues to be a devastating global health issue, causing 405,000 deaths and 228 million cases in 2018. Understanding key metabolic processes in malaria parasites is critical to the development of new drugs to combat this major infectious disease. The Plasmodium glycolytic pathway is essential to the malaria parasite, providing energy for growth and replication and supplying important biomolecules for other essential Plasmodium anabolic pathways. Despite this overreliance on glycolysis, no current drugs target glycolysis, and there is a paucity of information on critical glycolysis targets. Our work addresses this unmet need, providing new mechanistic insights into this key pathway.

A Pantetheinase-Resistant Pantothenamide with Potent, On-Target, and Selective Antiplasmodial Activity

Publisher: American Society for Microbiology

Date: 06-2015

DOI: 10.1128/AAC.04970-14

Abstract: Pantothenamides inhibit blood-stage Plasmodium falciparum with potencies (50% inhibitory concentration [IC 50 ], ∼20 nM) similar to that of chloroquine. They target processes dependent on pantothenate, a precursor of the essential metabolic cofactor coenzyme A. However, their antiplasmodial activity is reduced due to degradation by serum pantetheinase. Minor modification of the pantothenamide structure led to the identification of α-methyl- N -phenethyl-pantothenamide, a pantothenamide resistant to degradation, with excellent antiplasmodial activity (IC 50 , 52 ± 6 nM), target specificity, and low toxicity.

A verapamil-sensitive chloroquine-associated H⁺ leak from the digestive vacuole in chloroquine-resistant malaria parasites

Publisher: The Company of Biologists

Date: 15-05-2008

DOI: 10.1242/JCS.016758

Abstract: Chloroquine resistance in the malaria parasite Plasmodium falciparum has made malaria increasingly difficult to control. Chloroquine-resistant parasites accumulate less chloroquine than their chloroquine-sensitive counterparts however, the mechanism underlying this remains unclear. The primary site of accumulation and antimalarial action of chloroquine is the internal acidic digestive vacuole of the parasite, the acidity of which is maintained by inwardly-directed H+ pumps, working against the (outward) leak of H+. In this study we have investigated the leak of H+ from the digestive vacuole of the parasite by monitoring the alkalinisation of the vacuole following inhibition of the H+-pumping V-type ATPase by concanamycin A. The rates of alkalinisation observed in three chloroquine-resistant strains were two- to fourfold higher than those measured in three chloroquine-sensitive strains. On addition of chloroquine there was a dramatic increase in the rate of alkalinisation in the chloroquine-resistant strains, whereas chloroquine caused the rate of alkalinisation to decrease in the chloroquine-sensitive strains. The chloroquine-associated increase in the rate of alkalinisation seen in chloroquine-resistant parasites was inhibited by the chloroquine-resistance reversal agent verapamil. The data are consistent with the hypothesis that in chloroquine-resistant parasites chloroquine effluxes from the digestive vacuole, in association with H+, via a verapamil-sensitive pathway.

The inhibitory effect of 2-halo derivatives of D-glucose on glycolysis and on the proliferation of the human malaria parasite Plasmodium falciparum

Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)

Date: 19-08-2008

DOI: 10.1124/JPET.108.141929

Abstract: The intraerythrocytic stage of the human malaria parasite Plasmodium falciparum relies on glycolysis for ATP generation, and because it has no energy stores, a constant supply of glucose is necessary for the parasite to grow and multiply. The 2-substituted glucose analogs 2-deoxy-D-glucose (2-DG) and 2-fluoro-2-deoxy-D-glucose (2-FG) have been previously shown to inhibit the in vitro growth of P. falciparum and have been suggested to do so by inhibiting glycosylation in the parasite. In this study, we have investigated the antiplasmodial mechanism of action of 2-DG and 2-FG and compared it with that of other 2-substituted-glucose analogs. The compounds tested inhibited parasite growth to varying degrees, with 2-FG being the most effective. The antiplasmodial activity of some, but not all, of the analogs could be altered by varying the glucose concentration in the culture medium, increasing the antiplasmodial activity of the analogs as the glucose concentration is reduced. A trend was observed between the antiplasmodial activity of these analogs and their ability to inhibit glucose accumulation, glucose phosphorylation by hexokinase, and cytosolic pH regulation within the intraerythrocytic stage of the parasite. Our data are consistent with inhibition of glycolysis being a primary mechanism by which 2-DG and 2-FG inhibit parasite growth, and they validate the early steps in glycolysis as viable drug targets.

Acceptance of a vaccine against pandemic influenza A (H1N1) virus amongst healthcare workers in Beijing, China

Publisher: Elsevier BV

Date: 02-2011

DOI: 10.1016/J.VACCINE.2010.12.077

Abstract: Due to the advent of the new influenza A (H1N1) strain in 2009, many countries introduced mass immunization programs. Healthcare workers (HCWs) were amongst the key groups targeted for the vaccine in these programs. However, experience with the seasonal influenza vaccine has shown that there are multiple barriers related to the attitudes and perceptions of the population which influence uptake. The aim of this study was to determine pandemic influenza A (H1N1) vaccination rate amongst a group of Chinese HCWs and the associated factors around acceptance. A cross-sectional investigation of HCWs (doctors, nurses and technicians) from 19 hospitals in Beijing, China was conducted in January 2010. The main outcome measures were awareness, risk perception of H1N1, preventive measures and uptake of H1N1 vaccination during the pandemic. A total of 1657 HCWs completed the survey. A quarter of the participants reported receiving the pandemic influenza A (H1N1) vaccine. Occupation (being a doctor), receiving seasonal flu vaccine and believing in the effectiveness of the vaccine were all strongly associated with accepting the pandemic influenza A (H1N1) vaccine. Over a thousand participants (61%, 1008/1657) agreed that they were 'concerned about the side effects of the swine flu vaccine', while 758 (46%) were 'concerned that the vaccine had not been tested adequately'. While studies reported high rates of willingness to receive the vaccine, in reality these did not transpire. Aside from promoting seasonal flu vaccination, authorities need to start educational c aigns much earlier in a pandemic. Programs that are simultaneously launched with the introduction of the vaccine will not be as successful, as those which have built momentum alongside the pandemic.

Chemical and genetic validation of thiamine utilization as an antimalarial drug target

Publisher: Springer Science and Business Media LLC

Date: 27-06-2013

DOI: 10.1038/NCOMMS3060

Abstract: Thiamine is metabolized into an essential cofactor for several enzymes. Here we show that oxythiamine, a thiamine analog, inhibits proliferation of the malaria parasite Plasmodium falciparum in vitro via a thiamine-related pathway and significantly reduces parasite growth in a mouse malaria model. Overexpression of thiamine pyrophosphokinase (the enzyme that converts thiamine into its active form, thiamine pyrophosphate) hypersensitizes parasites to oxythiamine by up to 1,700-fold, consistent with oxythiamine being a substrate for thiamine pyrophosphokinase and its conversion into an antimetabolite. We show that parasites overexpressing the thiamine pyrophosphate-dependent enzymes oxoglutarate dehydrogenase and pyruvate dehydrogenase are up to 15-fold more resistant to oxythiamine, consistent with the antimetabolite inactivating thiamine pyrophosphate-dependent enzymes. Our studies therefore validate thiamine utilization as an antimalarial drug target and demonstrate that a single antimalarial can simultaneously target several enzymes located within distinct organelles.

Response to Martin-Moreno et al. (2014) Surgical mask or no mask for health workers not a defensible position for Ebola

Publisher: Elsevier BV

Date: 12-2014

DOI: 10.1016/J.IJNURSTU.2014.10.004

A polymorphic drug pump in the malaria parasite

Publisher: Wiley

Date: 20-10-2008

DOI: 10.1111/J.1365-2958.2008.06451.X

Abstract: The human malaria parasite, Plasmodium falciparum, has long been known to have a homologue of the human 'multidrug resistance' P-glycoprotein. P-glycoprotein is an ABC transporter that pumps drugs from multidrug-resistant cancer cells. The malaria parasite's P-glycoprotein homologue, Pgh1, is known to influence the sensitivity of malaria parasites to a erse range of antimalarial drugs, but the mechanism by which it does so has remained obscure. In a new paper, Sanchez et al. report the successful functional expression of Pgh1 in Xenopus laevis oocytes and provide the first direct demonstration of the ability of Pgh1 to transport drugs. The work provides important new insights into the mechanism by which Pgh1 influences malaria parasite drug sensitivity.

Transport of lactate and pyruvate in the intraerythrocytic malaria parasite, Plasmodium falciparum

Publisher: Portland Press Ltd.

Date: 24-04-2001

DOI: 10.1042/BJ3550733

Abstract: The mature, intraerythrocytic form of the human malaria parasite, Plasmodium falciparum, is reliant on glycolysis for its energetic requirements. It produces large quantities of lactic acid, which have to be removed from the parasite's cytosol to maintain the cell's integrity and metabolic viability. Here we show that the monocarboxylates lactate and pyruvate are both transported across the parasite's plasma membrane via a H+/monocarboxylate symport process that is saturable and inhibited by the bioflavonoid phloretin. The results provide direct evidence for the presence at the parasite surface of a H+-coupled monocarboxylate transporter with features in common with members of the MCT (monocarboxylate transporter) family of higher eukaryotes.

H+-coupled Pantothenate Transport in the Intracellular Malaria Parasite

Publisher: Elsevier BV

Date: 05-2001

DOI: 10.1074/JBC.M010942200

A qualitative study investigating knowledge and attitudes regarding human papillomavirus (HPV) and the HPV vaccine among parents of immunosuppressed children

Publisher: Elsevier BV

Date: 11-2012

DOI: 10.1016/J.VACCINE.2012.09.066

Abstract: Barriers influencing the willingness of parents to vaccinate immunocompetent children include a lack of knowledge about human papillomavirus (HPV) and low perception of risk regarding their child's acquisition of HPV infection. However, it cannot be assumed that the facilitators and barriers of HPV vaccination are the same for parents/guardians of children who are immunocompromised, or who have chronic medical conditions. This study aimed to document the knowledge and attitudes of parents/guardians of immunosuppressed children and adolescents towards HPV infection and the vaccine. A study using qualitative methods which incorporated 27 semi-structured interviews was undertaken with parents/guardians of immunosuppressed children vaccinated against HPV at three hospitals in two states of Australia. Thematic analysis revealed that while participants acknowledged that they had heard of HPV, they did not have a strong sense of what it actually was. The level of concern held about their child acquiring an HPV infection (prior to vaccination) ranged from 'not at all' to 'extremely'. Some believed that their child was at increased risk of developing a severe HPV-related illness because of their underlying condition. The participants supported their child receiving the HPV vaccine, as they did not want to take a risk with a disease that may cause their child to return to hospital for treatment. The majority had little apprehension about the use of the HPV vaccine but expressed some concern that potential adverse effects would be more severe for immunosuppressed children. However, they stressed their belief in the safety of the vaccine and their trust in the child's health team. Our study results show that parents of children with impaired immunity would benefit from further information about the safety of the vaccine and about the important role of the vaccine for boys as well as girls.

Trends in hospitalizations for diagnosed congenital cytomegalovirus in infants and children in Australia

Publisher: Springer Science and Business Media LLC

Date: 26-01-2009

DOI: 10.1186/1471-2431-9-7

Clotrimazole inhibits the growth of Plasmodium falciparum in vitro

Publisher: Oxford University Press (OUP)

Date: 11-1998

DOI: 10.1016/S0035-9203(98)90805-7

Electrophysiological studies of malaria parasite-infected erythrocytes: Current status

Publisher: Elsevier BV

Date: 04-2007

DOI: 10.1016/J.IJPARA.2006.12.013

Editorial – Molecular Approaches to Malaria 2012 (MAM 2012)

Publisher: Elsevier BV

Date: 05-2012

DOI: 10.1016/J.IJPARA.2012.05.001

A novel heteromeric pantothenate kinase complex in apicomplexan parasites

Publisher: Cold Spring Harbor Laboratory

Date: 16-03-2021

DOI: 10.1101/2021.03.16.435557

Abstract: Coenzyme A is synthesised from pantothenate via five enzyme-mediated steps. The first step is catalysed by pantothenate kinase (PanK). All PanKs characterised to date form homodimers. Many organisms express multiple PanKs. In some cases, these PanKs are not functionally redundant, and some appear to be non-functional. Here, we investigate the PanKs in two pathogenic apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii . Each of these organisms express two PanK homologues (PanK1 and PanK2). We demonstrate that Pf PanK1 and Pf PanK2 associate, forming a single, functional PanK complex that includes the multi-functional protein, Pf 14-3-3I. Similarly, we demonstrate that Tg PanK1 and Tg PanK2 form a single complex that possesses PanK activity. Both Tg PanK1 and Tg PanK2 are essential for T. gondii proliferation, specifically due to their PanK activity. Our study constitutes the first ex les of heteromeric PanK complexes in nature and provides an explanation for the presence of multiple PanKs within certain organisms.

The Membrane Physiology of the ‘Malaria-Infected’ Red Cell

Publisher: Springer Berlin Heidelberg

Date: 2003

DOI: 10.1007/978-3-662-05181-8_24

Hexose Transport in Asexual Stages of Plasmodium falciparum and Kinetoplastidae

Publisher: Elsevier BV

Date: 12-2000

DOI: 10.1016/S0169-4758(00)01762-2

Abstract: The hexose sugar, glucose, is a vital energy source for most organisms and an essential nutrient for asexual stages of Plasmodium falciparum. Kinetoplastid organisms (e.g. Trypanosoma and Leishmania spp) also require glucose at certain critical stages of their life cycles. Although phylogenetically unrelated, these organisms share many common challenges during the mammalian stages of a parasitic life cycle, and possess hexose uptake mechanisms that are amenable to study using similar methods. Defining hexose permeation pathways into parasites might expose an Achilles' heel at which both antidisease and antiparasite measures can be aimed. Understanding the mode of entry of glucose also presents a good general model for substrate acquisition in multicompartment systems. In this review, Sanjeev Krishna and colleagues summarize current understanding of hexose transport processes in P. falciparum and provide a comparison with data obtained from kinetoplastids.

Chloroquine resistance and the pH of the malaria parasite's digestive vacuole

Publisher: Elsevier BV

Date: 12-2001

DOI: 10.1054/DRUP.2002.0234

Transport and Metabolism of the Essential Vitamin Pantothenic Acid in Human Erythrocytes Infected with the Malaria Parasite Plasmodium falciparum

Publisher: Elsevier BV

Date: 04-1998

DOI: 10.1074/JBC.273.17.10190

Examining the knowledge, attitudes and practices of domestic and international university students towards seasonal and pandemic influenza

Publisher: Springer Science and Business Media LLC

Date: 26-04-2012

DOI: 10.1186/1471-2458-12-307

Uncertainty, risk analysis and change for Ebola personal protective equipment guidelines

Publisher: Elsevier BV

Date: 05-2015

DOI: 10.1016/J.IJNURSTU.2014.12.001

Common dietary flavonoids inhibit the growth of the intraerythrocytic malaria parasite

Publisher: Springer Science and Business Media LLC

Date: 2008

DOI: 10.1186/1756-0500-1-26

Purine uptake in Plasmodium: transport versus metabolism

Publisher: Elsevier BV

Date: 06-2009

DOI: 10.1016/J.PT.2009.03.006

Abstract: In a recent paper, Quashie et al. have proposed that purine uptake into the intraerythrocytic malaria parasite involves four different plasma membrane transporters - two high affinity and two low affinity. They equate one of the two high-affinity transporters with PfNT1, a transporter reported previously to be a low-affinity system. Here, we offer an alternative interpretation of their data, suggesting that the conclusions drawn by Quashie et al. take insufficient account of metabolism.

Annual influenza vaccination: Coverage and attitudes of primary care staff in Australia

Publisher: Wiley

Date: 12-10-2011

DOI: 10.1111/J.1750-2659.2010.00158.X

Thiamine analogues as inhibitors of pyruvate dehydrogenase and discovery of a thiamine analogue with non-thiamine related antiplasmodial activity

Publisher: Royal Society of Chemistry (RSC)

Date: 2022

DOI: 10.1039/D2MD00085G

Abstract: A series of derivatives of a triazole analogue of thiamine has been synthesised.

A Class of Pantothenic Acid Analogs Inhibits Plasmodium falciparum Pantothenate Kinase and Represses the Proliferation of Malaria Parasites

Publisher: American Society for Microbiology

Date: 11-2005

DOI: 10.1128/AAC.49.11.4649-4657.2005

Abstract: The growth and proliferation of the human malaria parasite Plasmodium falciparum are dependent on the parasite's ability to obtain essential nutrients. One nutrient for which the parasite has an absolute requirement is the water-soluble vitamin pantothenic acid (vitamin B 5 ). In this study, a series of pantothenic acid analogs which retain the 2,4-dihydroxy-3,3-dimethylbutyramide core of pantothenic acid but deviate in structure from one another and from pantothenic acid in the nature of the substituent attached to the amide nitrogen were synthesized using an efficient single-step synthetic route. Eight of 10 analogs tested inhibited the proliferation of intraerythrocytic P. falciparum parasites in vitro, doing so with 50% inhibitory concentrations between 15 and 200 μM. The compounds were generally selective, inhibiting the proliferation of a human cell line (the Jurkat cell line) only at concentrations severalfold higher than those required for inhibition of parasite growth. It was demonstrated that compounds in this series inhibited the phosphorylation of pantothenic acid by pantothenate kinase, the first step in the parasite's biosynthesis of the essential enzyme cofactor coenzyme A, doing so competitively, with K i values in the nanomolar range.

A novel heteromeric pantothenate kinase complex in apicomplexan parasites

Publisher: Public Library of Science (PLoS)

Date: 29-07-2021

DOI: 10.1371/JOURNAL.PPAT.1009797

Abstract: Coenzyme A is synthesised from pantothenate via five enzyme-mediated steps. The first step is catalysed by pantothenate kinase (PanK). All PanKs characterised to date form homodimers. Many organisms express multiple PanKs. In some cases, these PanKs are not functionally redundant, and some appear to be non-functional. Here, we investigate the PanKs in two pathogenic apicomplexan parasites, Plasmodium falciparum and Toxoplasma gondii . Each of these organisms express two PanK homologues (PanK1 and PanK2). We demonstrate that Pf PanK1 and Pf PanK2 associate, forming a single, functional PanK complex that includes the multi-functional protein, Pf 14-3-3I. Similarly, we demonstrate that Tg PanK1 and Tg PanK2 form a single complex that possesses PanK activity. Both Tg PanK1 and Tg PanK2 are essential for T . gondii proliferation, specifically due to their PanK activity. Our study constitutes the first ex les of heteromeric PanK complexes in nature and provides an explanation for the presence of multiple PanKs within certain organisms.

Pantothenamides Are Potent, On-Target Inhibitors of Plasmodium falciparum Growth When Serum Pantetheinase Is Inactivated

Publisher: Public Library of Science (PLoS)

Date: 06-02-2013

DOI: 10.1371/JOURNAL.PONE.0054974

Loss of pH Control in Plasmodium falciparum Parasites Subjected to Oxidative Stress

Publisher: Public Library of Science (PLoS)

Date: 11-03-2013

DOI: 10.1371/JOURNAL.PONE.0058933

The Human Malaria ParasitePlasmodium falciparumIs Not Dependent on Host Coenzyme A Biosynthesis

Publisher: Elsevier BV

Date: 09-2009

DOI: 10.1074/JBC.M109.025312

Overcoming synthetic challenges in targeting coenzyme A biosynthesis with the antimicrobial natural product CJ-15,801

Publisher: Royal Society of Chemistry (RSC)

Date: 2019

DOI: 10.1039/C9MD00312F

Abstract: Presenting an optimised synthesis of the fungus-derived antibiotic CJ-15,801 which shows selective activity against Staphylococcus aureus and Plasmodium falciparum .

Exploring Heteroaromatic Rings as a Replacement for the Labile Amide of Antiplasmodial Pantothenamides

Publisher: American Chemical Society (ACS)

Date: 04-2021

DOI: 10.1021/ACS.JMEDCHEM.0C01755

A screen of drug-like molecules identifies chemically diverse electron transport chain inhibitors in apicomplexan parasites

Publisher: Public Library of Science (PLoS)

Date: 20-07-2023

DOI: 10.1371/JOURNAL.PPAT.1011517

Abstract: Apicomplexans are widespread parasites of humans and other animals, and include the causative agents of malaria ( Plasmodium species) and toxoplasmosis ( Toxoplasma gondii ). Existing anti-apicomplexan therapies are beset with issues around drug resistance and toxicity, and new treatment options are needed. The mitochondrial electron transport chain (ETC) is one of the few processes that has been validated as a drug target in apicomplexans. To identify new inhibitors of the apicomplexan ETC, we developed a Seahorse XFe96 flux analyzer approach to screen the 400 compounds contained within the Medicines for Malaria Venture ‘Pathogen Box’ for ETC inhibition. We identified six chemically erse, on-target inhibitors of the ETC in T . gondii , at least four of which also target the ETC of Plasmodium falciparum . Two of the identified compounds (MMV024937 and MMV688853) represent novel ETC inhibitor chemotypes. MMV688853 belongs to a compound class, the aminopyrazole carboxamides, that were shown previously to target a kinase with a key role in parasite invasion of host cells. Our data therefore reveal that MMV688853 has dual targets in apicomplexans. We further developed our approach to pinpoint the molecular targets of these inhibitors, demonstrating that all target Complex III of the ETC, with MMV688853 targeting the ubiquinone reduction (Q i ) site of the complex. Most of the compounds we identified remain effective inhibitors of parasites that are resistant to Complex III inhibitors that are in clinical use or development, indicating that they could be used in treating drug resistant parasites. In sum, we have developed a versatile, scalable approach to screen for compounds that target the ETC in apicomplexan parasites, and used this to identify and characterize novel inhibitors.

Distribution of acridine orange fluorescence in Plasmodium falciparum-infected erythrocytes and its implications for the evaluation of digestive vacuole pH

Publisher: Elsevier BV

Date: 02-2002

DOI: 10.1016/S0166-6851(01)00403-0

A Randomized Clinical Trial of Three Options for N95 Respirators and Medical Masks in Health Workers

Publisher: American Thoracic Society

Date: 05-2013

DOI: 10.1164/RCCM.201207-1164OC

Coenzyme A Biosynthesis

Publisher: Springer New York

Date: 2015

DOI: 10.1007/978-1-4614-8757-9_42-1

Inhibition of hexose transport and abrogation of pH homeostasis in the intraerythrocytic malaria parasite by an O-3-hexose derivative

Publisher: Wiley

Date: 22-06-2004

DOI: 10.1016/J.FEBSLET.2004.06.032

The use of oseltamivir during an influenza B outbreak in a chronic care hospital

Publisher: Wiley

Date: 2009

DOI: 10.1111/J.1750-2659.2008.00063.X

CJ-15,801, a fungal natural product, inhibits the intraerythrocytic stage of Plasmodium falciparum in vitro via an effect on pantothenic acid utilisation

Publisher: Elsevier BV

Date: 05-2005

DOI: 10.1016/J.MOLBIOPARA.2005.02.003

Structure-activity analysis of CJ-15,801 analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation

Publisher: Elsevier BV

Date: 2018

DOI: 10.1016/J.EJMECH.2017.08.050

Abstract: Survival of the human malaria parasite Plasmodium falciparum is dependent on pantothenate (vitamin B

The pH of the digestive vacuole ofPlasmodium falciparumis not associated with chloroquine resistance

Publisher: The Company of Biologists

Date: 15-03-2006

DOI: 10.1242/JCS.02795

Abstract: Chloroquine resistance in the human malaria parasite, Plasmodium falciparum, arises from decreased accumulation of the drug in the `digestive vacuole' of the parasite, an acidic compartment in which chloroquine exerts its primary toxic effect. It has been proposed that changes in the pH of the digestive vacuole might underlie the decreased accumulation of chloroquine by chloroquine-resistant parasites. In this study we have investigated the digestive vacuole pH of a chloroquine-sensitive and a chloroquine-resistant strain of P. falciparum, using a range of dextran-linked pH-sensitive fluorescent dyes. The estimated digestive vacuole pH varied with the concentration and pKa of the dye, ranging from ∼3.7-6.5. However, at low dye concentrations the estimated digestive vacuole pH of both the chloroquine-resistant and chloroquine-sensitive strains converged in the range 4.5-4.9. The results suggest that there is no significant difference in digestive vacuole pH of chloroquine-sensitive and chloroquine-resistant parasites, and that digestive vacuole pH does not play a primary role in chloroquine resistance.

Structural Modification of Pantothenamides Counteracts Degradation by Pantetheinase and Improves Antiplasmodial Activity

Publisher: American Chemical Society (ACS)

Date: 21-06-2013

DOI: 10.1021/ML400180D

Do they accept compulsory vaccination?. Awareness, attitudes and behaviour of hospital health care workers following a new vaccination directive

Publisher: Elsevier BV

Date: 05-2009

DOI: 10.1016/J.VACCINE.2009.03.038

Abstract: Achieving high vaccination rates among health care workers (HCW) is an ongoing challenge. In 2007, the state of New South Wales, Australia instituted a policy directive with compulsory provisions for health care workers to be vaccinated. This study sought to identify staff awareness and attitudes in the early phase of implementation. It involved a self-completed paper-based or electronic survey of HCWs in two tertiary-referral teaching hospitals in Sydney, Australia in 2007. A total of 894/1200 completed the paper survey, whilst a further 185 completed it online. Of the 1079 respondents, 60% (646/1079) were aware of the policy directive but only 10% (63/646) described the specific requirements. Seventy-eight per cent supported the policy 13% neither supported nor opposed it and 4% opposed it. This survey provides an early, broad indication of the level of understanding and the attitudes of the HCWs towards the new directive.

Awareness, attitudes and behavior of hospital healthcare workers towards a mandatory vaccination directive: Two years on

Publisher: Elsevier BV

Date: 05-2011

DOI: 10.1016/J.VACCINE.2011.03.050

Abstract: In 2007, the state of New South Wales, Australia instituted a policy directive with compulsory provisions for health care workers to be vaccinated. This study sought to identify staff awareness and attitudes two years after it was implemented. It involved a self administered paper-based questionnaire of HCWs in two tertiary-referral teaching hospitals in Sydney, Australia in 2009. In the early phase, general awareness of the policy was incomplete and detailed knowledge was poor. However, support levels were high. Two years later, while the respondents indicated that they were aware that there was a policy in place, very few of the respondents were able to accurately describe its requirements. Regardless of the level of knowledge, support for the policy was still high (83% vs. 91%, respectively). Despite the high levels of general support for the vaccine policy directive in NSW, this study indicates that including influenza vaccination into the policy could be challenging.

Attitudes amongst Australian hospital healthcare workers towards seasonal influenza and vaccination

Publisher: Wiley

Date: 09-12-2010

DOI: 10.1111/J.1750-2659.2009.00112.X

Ischaemic heart disease, influenza and influenza vaccination: a prospective case control study

Publisher: BMJ

Date: 21-08-2013

DOI: 10.1136/HEARTJNL-2013-304320

Na⁺-dependent pH Regulation by the Amitochondriate Protozoan Parasite Giardia intestinalis

Publisher: Elsevier BV

Date: 08-2001

DOI: 10.1074/JBC.M102728200

Why do I need it? I am not at risk! Public perceptions towards the pandemic (H1N1) 2009 vaccine

Publisher: Springer Science and Business Media LLC

Date: 19-04-2010

DOI: 10.1186/1471-2334-10-99

Neurophysiological Studies May Provide a Misleading Picture of How Perceptual-Motor Interactions are Coordinated

Publisher: SAGE Publications

Date: 2013

DOI: 10.1068/I0569IC

Abstract: Neurophysiological measurement techniques like fMRI and TMS are increasingly being used to examine the perceptual-motor processes underpinning the ability to anticipate the actions of others. Crucially, these techniques invariably restrict the experimental task that can be used and consequently limit the degree to which the findings can be generalised. These limitations are discussed based on a recent paper by Tomeo et al. (2012) who sought to examine responses to fooling actions by using TMS on participants who passively observed spliced video clips where bodily information was, and was not, linked to the action outcome. We outline two particular concerns with this approach. First, spliced video clips that show physically impossible actions are unlikely to simulate a “fooling” action. Second, it is difficult to make meaningful inferences about perceptual-motor expertise from experiments where participants cannot move. Taken together, we argue that wider generalisations based on these findings may provide a misunderstanding of the phenomenon such a study is designed to explore.

Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues

Publisher: Public Library of Science (PLoS)

Date: 03-04-2018

DOI: 10.1371/JOURNAL.PPAT.1006918

A Novel On-Field Training Intervention Improves Novice Goalkeeper Penalty Kick Performance

Publisher: Human Kinetics

Date: 06-2017

DOI: 10.1123/TSP.2015-0148

Purine nucleobase transport in the intraerythrocytic malaria parasite

Publisher: Elsevier BV

Date: 02-2008

DOI: 10.1016/J.IJPARA.2007.07.005

Abstract: Hypoxanthine, a nucleobase, serves as the major source of the essential purine group for the intraerythrocytic malaria parasite. In this study we have measured the uptake of hypoxanthine, and that of the related purine nucleobase adenine, by mature blood-stage Plasmodium falciparum parasites isolated from their host cells by saponin-permeabilisation of the erythrocyte and parasitophorous vacuole membranes. The uptake of both [3H]hypoxanthine and [3H]adenine was comprised of at least two components in each case there was a rapid equilibration of the radiolabel between the intra- and extracellular solutions via a low-affinity transport mechanism, and an accumulation of radiolabel (such that the estimated intracellular concentration exceeded the extracellular concentration) via a higher-affinity process. The uptake of [3H]adenine was studied in more detail. The rapid, low-affinity equilibration of [3H]adenine between the intra-and extracellular solution was independent of the energy status of the parasite whereas the higher-affinity accumulation of the radiolabel was ATP-dependent. A kinetic analysis of adenine uptake revealed that the low-affinity (equilibrative) process had a Km of approximately 1.2mM, similar to the value of 0.82 mM estimated here (using the Xenopus laevis oocyte expression system) for the Km for the transport of adenine by PfENT1, a parasite-encoded member of the 'equilibrative nucleoside/nucleobase transporter' family. The results indicate that nucleobases enter the intraerythrocytic parasite via a rapid, equilibrative process that has kinetic characteristics similar to those of PfENT1.

University life and pandemic influenza: Attitudes and intended behaviour of staff and students towards pandemic (H1N1) 2009

Publisher: Springer Science and Business Media LLC

Date: 14-03-2010

DOI: 10.1186/1471-2458-10-130

Abstract: In a pandemic young adults are more likely to be infected, increasing the potential for Universities to be explosive disease outbreak centres. Outbreak management is essential to reduce the impact in both the institution and the surrounding community. Through the use of an online survey, we aimed to measure the perceptions and responses of staff and students towards pandemic (H1N1) 2009 at a major university in Sydney, Australia. The survey was available online from 29 June to 30 September 2009. The s le included academic staff, general staff and students of the University. A total of 2882 surveys were completed. Nearly all respondents (99.6%, 2870/2882) were aware of the Australian pandemic situation and 64.2% (1851/2882) reported either "no anxiety" or "disinterest." Asian-born respondents were significantly (p 0.001) more likely to believe that the pandemic was serious compared to respondents from other regions. 75.9% (2188/2882) of respondents had not made any lifestyle changes as a result of the pandemic. Most respondents had not adopted any specific behaviour change, and only 20.8% (600/2882) had adopted the simplest health behaviour, i.e. hand hygiene. Adoption of a specific behaviour change was linked to anxiety and Asian origin. Students were more likely to attend the university if unwell compared with staff members. Positive responses from students strongly indicate the potential for expanding online teaching and learning resources for continuing education in disaster settings. Willingness to receive the pandemic vaccine was associated with seasonal influenza vaccination uptake over the previous 3 years. Responses to a pandemic are subject to change in its pre-, early and mid-outbreak stages. Lessons for these institutions in preparation for a second wave and future disease outbreaks include the need to promote positive public health behaviours amongst young people and students.

Role for the Plasmodium falciparum Digestive Vacuole in Chloroquine Resistance

Publisher: Elsevier BV

Date: 08-1998

DOI: 10.1016/S0006-2952(98)00140-3

Abstract: We have developed a method for the isolation of pure and intact Plasmodium falciparum digestive vacuoles capable of ATP-dependent chloroquine (CQ) accumulation in vitro. The method is rapid and reliable, and it produces a high yield of vacuoles (20%). CQ accumulation in isolated vacuoles was found to be ATP-, Mg2+-, and temperature-dependent. We then investigated the CQ-accumulating capabilities of vacuoles isolated from CQ-resistant (CQR) and CQ-sensitive (CQS) parasites. At external CQ concentrations of 100 and 250 nM, vacuoles isolated from two CQS strains (D10 and RSA3) (Vm: 380-424 fmol/10(6) vacuoles/hr) accumulated significantly more CQ (approximately 3 times) than those isolated from three (FAC8, RSA11, and RSA15) of the four CQ-resistant strains of P. falciparum tested (Vmax: 127-156 fmol/10(6) vacuoles/hr) (P < or = 0.05). We propose that the low level of CQ accumulation observed in vacuoles isolated from most of the CQ-resistant parasites tested contributes to the decreased CQ accumulation seen in these strains and, hence, to CQ resistance. Although it is often suggested that the digestive vacuole of the P. falciparum parasite is involved in the mechanism of CQ resistance, to our knowledge this is the first direct confirmation.

Purification of functional Plasmodium falciparum tubulin allows for the identification of parasite-specific microtubule inhibitors

Publisher: Elsevier BV

Date: 02-2022

DOI: 10.1016/J.CUB.2021.12.049

Abstract: Cytoskeletal proteins are essential for parasite proliferation, growth, and transmission, and therefore have the potential to serve as drug targets.

A miniaturized assay for measuring small molecule phosphorylation in the presence of complex matrices

Publisher: Elsevier BV

Date: 04-2014

DOI: 10.1016/J.AB.2013.12.010

Abstract: We describe here a simple, miniaturized radiation-based phosphorylation assay that can be used to monitor phosphorylation of a erse range of small molecule substrates in the presence of purified and crude enzyme preparations. Ba(OH)2 and ZnSO4 are used to terminate phosphoryl transfer and to precipitate selectively the phosphorylated reaction product in a single step non-phosphorylated substrate is removed by filtration prior to quantification. The key advantages over alternative radiation-based assays are that: (i) high-energy/short-lived radioactive emitters are not required (ii) high-quality data can be obtained without the need for high radioactivity concentrations and (iii) the assay is compatible with high-throughput applications.

Toward a Stable and Potent Coenzyme A-Targeting Antiplasmodial Agent: Structure–Activity Relationship Studies of N-Phenethyl-α-methyl-pantothenamide

Publisher: American Chemical Society (ACS)

Date: 06-05-2020

DOI: 10.1021/ACSINFECDIS.0C00075

A cross-sectional study of factors associated with uptake of vaccination against influenza among older residents in the postpandemic season in Beijing, China

Publisher: BMJ

Date: 11-2013

DOI: 10.1136/BMJOPEN-2013-003662

Antiplasmodial chalcones inhibit sorbitol-induced hemolysis of Plasmodium falciparum-infected erythrocytes

Publisher: American Society for Microbiology

Date: 09-2004

DOI: 10.1128/AAC.48.9.3241-3245.2004

Abstract: A series of alkoxylated and hydroxylated chalcones previously reported to have antiplasmodial activities in vitro were investigated for their effects on the new permeation pathways induced by the malaria parasite in the host erythrocyte membrane. Of 21 compounds with good antiplasmodial activities (50% inhibitory concentrations [IC 50 s], ≤20 μM), 8 members were found to inhibit sorbitol-induced lysis of parasitized erythrocytes to a significant extent (≤40% of control values) at a concentration (10 μM) that was close to their antiplasmodial IC 50 s. Qualitative structure-activity analysis suggested that activity was governed to a greater extent by a substitution on ring B than on ring A of the chalcone template. Most of the active compounds had methoxy or dimethoxy groups on ring B. Considerable variety was permitted on ring A in terms of the electron-donating or -withdrawing property. Lipophilicity did not appear to be an important determinant for activity. Although they are not exceptionally potent as inhibitors (lowest IC 50 , 1.9 μM), the chalcones compare favorably with other more potent inhibitors in terms of their selective toxicities against plasmodia and their neutral character.

Antiplasmodial Mode of Action of Pantothenamides: Pantothenate Kinase Serves as a Metabolic Activator Not as a Target

Publisher: American Chemical Society (ACS)

Date: 04-05-2017

DOI: 10.1021/ACSINFECDIS.7B00024

Abstract: N-Substituted pantothenamides (PanAms) are pantothenate analogues with up to nanomolar potency against blood-stage Plasmodium falciparum (the most virulent species responsible for malaria). Although these compounds are known to target coenzyme A (CoA) biosynthesis and/or utilization, their exact mode of action (MoA) is still unknown. Importantly, PanAms that retain the natural β-alanine moiety are more potent than other variants, consistent with the involvement of processes that are selective for pantothenate (the precursor of CoA) or its derivatives. The transport of pantothenate and its phosphorylation by P. falciparum pantothenate kinase (PfPanK, the first enzyme of CoA biosynthesis) are two such processes previously highlighted as potential targets for the PanAms' antiplasmodial action. In this study, we investigated the effect of PanAms on these processes using their radiolabeled versions (synthesized here for the first time), which made possible the direct measurement of PanAm uptake by isolated blood-stage parasites and PanAm phosphorylation by PfPanK present in parasite lysates. We found that the MoA of PanAms does not involve interference with pantothenate transport and that inhibition of PfPanK-mediated pantothenate phosphorylation does not correlate with PanAm antiplasmodial activity. Instead, PanAms that retain the β-alanine moiety were found to be metabolically activated by PfPanK in a selective manner, forming phosphorylated products that likely inhibit other steps in CoA biosynthesis or are transformed into CoA antimetabolites that can interfere with CoA utilization. These findings provide direction for the ongoing development of CoA-targeted inhibitors as antiplasmodial agents with clinical potential.

Gaze control during interceptive actions with different spatiotemporal demands.

Publisher: American Psychological Association (APA)

Date: 2017

DOI: 10.1037/XHP0000347

Abstract: It is widely accepted that the sources of information used to guide interceptive actions depend on conflicting spatiotemporal task demands. However, there is a paucity of evidence that shows how information pick-up during interceptive actions is adapted to such conflicting constraints. The present study therefore examined the effects of systematic manipulations of spatiotemporal constraints on performance, timing and gaze in an in situ interceptive action. To this end, expert futsal goalkeepers faced penalty kicks taken from 10 m and 6 m. With the more lenient spatiotemporal constraints (i.e., kicks from 10 m), the goalkeepers saved more kicks, initiated their actions later, and looked longer toward ball relative to the penalty takers' body. Furthermore, analysis of gaze patterns showed that interin idual variations in information pick-up were related to the unfolding of the penalty taker's action, revealing a less variable, funnel-like gaze pattern toward the end of the action. These findings are interpreted to reflect that changes in spatiotemporal demands induce the differential use of information for the accurate control of interceptive actions. (PsycINFO Database Record

Roseoflavin, a Natural Riboflavin Analogue, Possesses In Vitro and In Vivo Antiplasmodial Activity

Publisher: American Society for Microbiology

Date: 18-10-2022

DOI: 10.1128/AAC.00540-22

Abstract: The ability of the human malaria parasite Plasmodium falciparum to access and utilize vital nutrients is critical to its growth and proliferation. Molecules that interfere with these processes could potentially serve as antimalarials.

Purification of functional Plasmodium falciparum tubulin allows for the identification of parasite-specific microtubule inhibitors

Publisher: Cold Spring Harbor Laboratory

Date: 25-05-2021

DOI: 10.1101/2021.05.25.445550

Abstract: Cytoskeletal proteins are essential for parasite proliferation, growth, and transmission, and therefore represent promising drug targets. While αβ-tubulin, the molecular building block of microtubules, is an established drug target in a variety of cancers, we still lack substantial knowledge of the biochemistry of parasite tubulins, which would allow us to exploit the structural ergence between parasite and human tubulins. Indeed, mechanistic insights have been limited by the lack of purified, functional parasite tubulin. In this study, we isolated Plasmodium falciparum tubulin that is assembly-competent and shows specific microtubule dynamics in vitro . We further present mechanistic evidence that two compounds selectively interact with parasite over host microtubules and inhibit Plasmodium microtubule polymerization at substoichiometric compound concentrations. The ability of compounds to selectively disrupt protozoan microtubule growth without affecting human microtubules provides the exciting possibility for the targeted development of novel antimalarials.

The Aetiological Role of Human Papillomavirus in Oesophageal Squamous Cell Carcinoma: A Meta-Analysis

Publisher: Public Library of Science (PLoS)

Date: 24-07-2013

DOI: 10.1371/JOURNAL.PONE.0069238

The Influence of the Social Environment Context in Stress and Coping in Sport

Publisher: Frontiers Media SA

Date: 14-06-2016

DOI: 10.3389/FPSYG.2016.00875

University Of Cape Town

Location: South Africa

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Australian National University

Location: Australia

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Discovery Projects - Grant ID: DP0771754

Start Date: 2007

End Date: 12-2010

Amount: $285,000.00

Funder: Australian Research Council

Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100078

Start Date: 2010

End Date: 12-2010

Amount: $600,000.00

Funder: Australian Research Council

Research Networks - Grant ID: RN0460368

Start Date: 09-2004

End Date: 08-2009

Amount: $1,500,000.00

Funder: Australian Research Council