Discovery of 1,3,4-oxadiazoles with slow-action activity against Plasmodium falciparum malaria parasites.

To achieve malaria eradication, new preventative agents that act differently to front-line treatment drugs are needed. To identify potential chemoprevention starting points we screened a sub-set of the CSIRO Australia Compound Collection for compounds with slow-action in vitro activity against Plasmodium falciparum. This work identified N,N-dialkyl-5-alkylsulfonyl-1,3,4-oxadiazol-2-amines as a new antiplasmodial chemotype (e.

Activity of alkoxyamide-based histone deacetylase inhibitors against Plasmodium falciparum malaria parasites.

There are more than 240 million cases of malaria and 600,000 associated deaths each year, most due to infection with Plasmodium falciparum parasites. While malaria treatment options exist, new drugs with novel modes of action are needed to address malaria parasite drug resistance. Protein lysine deacetylases (termed HDACs) are important epigenetic regulatory enzymes and prospective therapeutic targets for malaria.

Thymidine Kinase-Independent Click Chemistry DNADetect Probes for DNA Proliferation Assessment in Malaria Parasites.

Metabolic chemical probes are small-molecule reagents that utilize naturally occurring biosynthetic enzymes for incorporation into biomolecules of interest. These reagents can be used to label, detect, and track important biological processes within living cells including protein synthesis, protein glycosylation, and nucleic acid proliferation. A limitation of current chemical probes, which have largely focused on mammalian cells, is that they often cannot be applied to other organisms due to metabolic differences.

Isolation and In Vitro and In Vivo Activity of Secondary Metabolites from Baker against Malaria Parasites.

Chemical investigation of the antimalarial medicinal plant led to the isolation of five new diterpenoids, including ajugarins VII-X (-) and teuvincenone K (), along with four known compounds, namely, 12,16-epoxy-6,11,14,17-tetrahydroxy-17(15 → 16)--5,8,11,13,15-abietapentaen-7-one (), methyl pheophorbide A (), loliolide (), and acacetin (). The chemical structures of the new compounds were elucidated using NMR spectroscopy, mass spectrometry, circular dichroism, as well as density functional theory calculations. All compounds were evaluated for activity against 3D7 malaria parasites with methyl pheophorbide A () showing the strongest activity (IC 4.

Two birds in the hand: Concurrent and switching cognitive flexibility in preschoolers.

Cognitive flexibility, the ability to think of something in more than one way, has been studied in preschoolers from two different approaches. Within executive function research, most studies operationalize cognitive flexibility using sequential tasks in which children must think of a specific stimulus first in one way and then in another way (switching cognitive flexibility). In contrast, Piagetian multiplicative classification tasks also require cognitive flexibility by asking children to consider multiple dimensions of a single stimulus at the same time.

QSAR Classification Models for Prediction of Hydroxamate Histone Deacetylase Inhibitor Activity against Malaria Parasites.

Malaria, caused by parasites, results in >400,000 deaths annually. There is no effective vaccine, and new drugs with novel modes of action are needed because of increasing parasite resistance to current antimalarials. Histone deacetylases (HDACs) are epigenetic regulatory enzymes that catalyze post-translational protein deacetylation and are promising malaria drug targets.

Empathetic Concern in Emerging Adolescents: The Role of Theory of Mind and Gender Roles.

The current study examined the roles of gender, and gender-role orientation in young adolescents' empathetic concern. In addition, this study aimed to explore the contribution of Theory of Mind in participants' empathetic concern. Finally, this study examined whether gender and gender-role orientation were implicated in emerging adolescents' Theory of Mind understanding.

Histone deacetylase inhibitor AR-42 and achiral analogues kill malaria parasites in vitro and in mice.

Malaria is caused by infection with Plasmodium parasites and results in significant health and economic impacts. Malaria eradication is hampered by parasite resistance to current drugs and the lack of a widely effective vaccine. Compounds that target epigenetic regulatory proteins, such as histone deacetylases (HDACs), may lead to new therapeutic agents with a different mechanism of action, thereby avoiding resistance mechanisms to current antimalarial drugs.

Impact of the Epithelial Lining Fluid Milieu on Amikacin Pharmacodynamics Against Pseudomonas aeruginosa.

Background: Even though nebulised administration of amikacin can achieve high epithelial lining fluid concentrations, this has not translated into improved patient outcomes in clinical trials. One possible reason is that the cellular and chemical composition of the epithelial lining fluid may inhibit amikacin-mediated bacterial killing.

Objective: The objective of this study was to identify whether the epithelial lining fluid components inhibit amikacin-mediated bacterial killing.

Pharmacodynamics of once- versus twice-daily dosing of nebulized amikacin in an in vitro Hollow-Fiber Infection Model against 3 clinical isolates of Pseudomonas aeruginosa.

This study aims to compare the bacterial killing of once- versus twice-daily nebulized amikacin against Pseudomonas aeruginosa and to determine the optimal duration of therapy. Three clinical P. aeruginosa isolates (amikacin MICs 2, 8, and 64 mg/L) were exposed to simulated epithelial lining fluid exposures of nebulized amikacin with dosing regimens of 400 mg and 800 mg once- or twice-daily up to 7-days using the in vitro hollow-fiber infection model.

Investigation of the in vitro and in vivo efficacy of peptoid-based HDAC inhibitors with dual-stage antiplasmodial activity.

Histone deacetylases (HDACs) have been identified as emerging antiplasmodial drug targets. In this work, we report on the synthesis, structure-activity relationships, metabolic stability and in vivo efficacy of new peptoid-based HDAC inhibitors with dual-stage antiplasmodial activity. A mini library of HDAC inhibitors was synthesized using a one-pot, multi-component protocol or submonomer pathways.

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

parasites rely heavily on glycolysis for ATP production and for precursors for essential anabolic pathways, such as the methylerythritol phosphate (MEP) pathway. Here, we show that mutations in the glycolytic enzyme, phosphofructokinase (PFK9), are associated with resistance to a primary sulfonamide glycoside (PS-3). Flux through the upper glycolysis pathway was significantly reduced in PS-3-resistant parasites, which was associated with reduced ATP levels but increased flux into the pentose phosphate pathway.

An ELISA method to assess HDAC inhibitor-induced alterations to P. falciparum histone lysine acetylation.

The prevention and treatment of malaria requires a multi-pronged approach, including the development of drugs that have novel modes of action. Histone deacetylases (HDACs), enzymes involved in post-translational protein modification, are potential new drug targets for malaria. However, the lack of recombinant P.

Pharmacodynamic Evaluation of Plasma and Epithelial Lining Fluid Exposures of Amikacin against Pseudomonas aeruginosa in a Dynamic Hollow-Fiber Infection Model.

Given that aminoglycosides, such as amikacin, may be used for multidrug-resistant infections, optimization of therapy is paramount for improved treatment outcomes. This study aims to investigate the pharmacodynamics of different simulated intravenous amikacin doses on susceptible to inform ventilator-associated pneumonia (VAP) and sepsis treatment choices. A hollow-fiber infection model with two isolates (MICs of 2 and 8 mg/liter) with an initial inoculum of ∼10 CFU/ml was used to test different amikacin dosing regimens.

Clinical Decision Making at the Bedside.

The complexity and rapidly changing environment of health care places significant pressure on nurses. How nurses make decisions within this environment has been an area of inquiry in the literature. Clinical decision making is the application of distinct thinking patterns and analysis of data at hand used to make judgements about patient care.

β-lactam antibiotic versus combined β-lactam antibiotics and single daily dosing regimens of aminoglycosides for treating serious infections: A meta-analysis.

Background: Combining aminoglycosides with β-lactam antibiotics for treating serious infections has not been associated with reduced mortality in previous meta-analyses. However, the multiple daily aminoglycoside dosing regimen principally used in most of the included studies is inconsistent with current practice.

Objective: To determine if a combination of an aminoglycoside administered as a single daily dose and a β-lactam antibiotic reduces all-cause mortality in patients compared with β-lactam antibiotic monotherapy.

Theory of Mind, Self-Knowledge, and Perceptions of Loneliness in Emerging Adolescents.

Theory of Mind (ToM) or the ability to understand mental states in self and others to explain behavior continues to develop in adolescence and connects to social experiences. Research shows during adolescence, ToM may influence one's ability to evaluate and judge one's self-worth and their social interactions. However, few studies examine the associations among self-knowledge, ToM, and social experiences.

Cyclization-blocked proguanil as a strategy to improve the antimalarial activity of atovaquone.

Atovaquone-proguanil (Malarone®) is used for malaria prophylaxis and treatment. While the cytochrome bc1-inhibitor atovaquone has potent activity, proguanil's action is attributed to its cyclization-metabolite, cycloguanil. Evidence suggests that proguanil has limited intrinsic activity, associated with mitochondrial-function.

Proteomic analysis of Plasmodium falciparum histone deacetylase 1 complex proteins.

Plasmodium falciparum histone deacetylases (PfHDACs) are an important class of epigenetic regulators that alter protein lysine acetylation, contributing to regulation of gene expression and normal parasite growth and development. PfHDACs are therefore under investigation as drug targets for malaria. Despite this, our understanding of the biological roles of these enzymes is only just beginning to emerge.

Structure-Activity and Structure-Toxicity Relationships of Peptoid-Based Histone Deacetylase Inhibitors with Dual-Stage Antiplasmodial Activity.

Novel malaria intervention strategies are of great importance, given the development of drug resistance in malaria-endemic countries. In this regard, histone deacetylases (HDACs) have emerged as new and promising malaria drug targets. In this work, we present the design, synthesis, and biological evaluation of 20 novel HDAC inhibitors with antiplasmodial activity.

Theory of mind and preschoolers' understanding of misdeed and politeness lies.

We told ninety-nine 4- and 5-year-olds stories in which speakers told lies and truths in two contexts: those told to deny a transgression (misdeeds) and those told to spare another's feelings (politeness). Participants identified each statement as a lie or as the truth, morally judged it as good or bad, and decided whether or not to assign punishment to the speaker. All children received measures of first- and second-order false-belief understanding.

Intrapulmonary pharmacokinetics of antibiotics used to treat nosocomial pneumonia caused by Gram-negative bacilli: A systematic review.

Background: Knowledge of antibiotic concentrations achievable in the epithelial lining fluid (ELF) will help guide antibiotic dosing for treating patients with Gram-negative bacillary ventilator-associated pneumonia (VAP).

Objective: To compare: (1) the ELF:serum penetration ratio of antibiotics in patients with pneumonia, including VAP, with that in healthy study participants; and (2) the ELF and/or tracheal aspirate antibiotic concentrations following intravenous and nebuliser delivery.

Methods: Web of Science, EMBASE and PubMed databases were searched and a systematic review undertaken.

One-pot, multi-component synthesis and structure-activity relationships of peptoid-based histone deacetylase (HDAC) inhibitors targeting malaria parasites.

Malaria drug discovery has shifted from a focus on targeting asexual blood stage parasites, to the development of drugs that can also target exo-erythrocytic forms and/or gametocytes in order to prevent malaria and/or parasite transmission. In this work, we aimed to develop parasite-selective histone deacetylase inhibitors (HDACi) with activity against the disease-causing asexual blood stages of Plasmodium malaria parasites as well as with causal prophylactic and/or transmission blocking properties. An optimized one-pot, multi-component protocol via a sequential Ugi four-component reaction and hydroxylaminolysis was used for the preparation of a panel of peptoid-based HDACi.

Activity of bromodomain protein inhibitors/binders against asexual-stage Plasmodium falciparum parasites.

Bromodomain-containing proteins (BDPs) are involved in the regulation of eukaryotic gene expression. Compounds that bind and/or inhibit BDPs are of interest as tools to better understand epigenetic regulation, and as possible drug leads for different diseases, including malaria. In this study, we assessed the activity of 42 compounds demonstrated or predicted (using virtual screening of a pharmacophore model) to bind/inhibit eukaryotic BDPs for activity against Plasmodium falciparum malaria parasites.