The Social Media Marketing Map (Part 1): A Tool to Empower the Digital Leaders of Extension

To date, Extension still lacks a strong social media presence. By now the majority of Extension professionals understand the importance of social media in advertising their programs, but don\u27t know where to start. The Social Media Marketing Map (SMMM) provides guidance, helping busy Extension professionals design and implement a social media strategy to engage audiences and connect them to online or face-to-face Extension events

Triaging informative cis-regulatory elements for the combinatorial control of temporal gene expression during Plasmodium falciparum intraerythrocytic development

Background: Over 2700 genes are subject to stage-specific regulation during the intraerythrocytic development of the human malaria parasite Plasmodium falciparum. Bioinformatic analyses have identified a large number of over-represented motifs in the 5′ flanking regions of these genes that may act as cis-acting factors in the promoter-based control of temporal expression. Triaging these lists to provide candidates most likely to play a role in regulating temporal expression is challenging, but important if we are to effectively design in vitro studies to validate this role. Methods: We report here the application of a repeated search of variations of 5′ flanking sequences from P. falciparum using the Finding Informative Regulatory Elements (FIRE) algorithm. Results: Our approach repeatedly found a short-list of high scoring DNA motifs, for which cognate specific transcription factors were available, that appear to be typically associated with upregulation of mRNA accumulation during the first half of intraerythrocytic development. Conclusions: We propose these cis-trans interactions may provide a combinatorial promoter-based control of gene expression to complement more global mechanisms of gene regulation that can account for temporal control during the second half of intraerythrocytic development

A validated bioluminescence-based assay for the rapid determination of the initial rate of kill for discovery antimalarials

Objectives: A future treatment for uncomplicated malaria will contain at least one component that exerts a rapid rate of kill (RoK). We describe here the validation and application of a simple, robust and rapid bioluminescence-based assay for the determination of the initial RoK in intraerythrocytic asexual stages of Plasmodium falciparum. Methods: A modification to the concentration-response bioluminescence (here termed bioluminescence relative rate of kill, BRRoK) assay, utilizing exposure to fold-IC50 concentrations (0.33x to 9x), is used to monitor the immediate cytocidal effect of 372 open source compounds for antimalarial drug discovery available through the Medicine for Malaria Venture’s Malaria Box. Results: Antimalarial drugs that exert a rapid cytocidal effect produce a concentration dependent loss of bioluminescence signal that correlates with available in vitro and in vivo estimates of parasite clearance time and parasite reduction ratio. Following the measurement of IC50 for the Malaria Box compounds in Dd2luc30 , the BRRoK assay was used to identify and rank 372 compounds for their initial cytocidal activity. Fifty three compounds in the Malaria Box show an initial relative RoK greater than that of chloroquine, with 17 of these with an initial relative RoK greater than that of dihydroartemisinin. Conclusion: The BRRoK assay provides a rapid assay format for the estimation of a key pharmacodynamic property of antimalarial drug action. The simplicity and robustness of the assay suggests it would be readily scalable for high throughput screening and a critical decision-making tool for antimalarial drug development

Deciphering the Ubiquitin-Mediated Pathway in Apicomplexan Parasites: A Potential Strategy to Interfere with Parasite Virulence

Reversible modification of proteins through the attachment of ubiquitin or ubiquitin-like modifiers is an essential post-translational regulatory mechanism in eukaryotes. The conjugation of ubiquitin or ubiquitin-like proteins has been demonstrated to play roles in growth, adaptation and homeostasis in all eukaryotes, with perturbation of ubiquitin-mediated systems associated with the pathogenesis of many human diseases, including cancer and neurodegenerative disorders

Alpha-Synuclein Oligomers Interact with Metal Ions to Induce Oxidative Stress and Neuronal Death in Parkinson's Disease

Protein aggregation and oxidative stress are both key pathogenic processes in Parkinson's disease, although the mechanism by which misfolded proteins induce oxidative stress and neuronal death remains unknown. In this study, we describe how aggregation of alpha-synuclein (α-S) from its monomeric form to its soluble oligomeric state results in aberrant free radical production and neuronal toxicity

A well-conserved Plasmodium falciparum var gene shows an unusual stage-specific transcript pattern

The var multicopy gene family encodes Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variant antigens, which, through their ability to adhere to a variety of host receptors, are thought to be important virulence factors. The predominant expression of a single cytoadherent PfEMP1 type on an infected red blood cell, and the switching between different PfEMP1 types to evade host protective antibody responses, are processes thought to be controlled at the transcriptional level. Contradictory data have been published on the timing of var gene transcription. Reverse transcription-polymerase chain reaction (RT-PCR) data suggested that transcription of the predominant var gene occurs in the later (pigmented trophozoite) stages, whereas Northern blot data indicated such transcripts only in early (ring) stages. We investigated this discrepancy by Northern blot, with probes covering a diverse var gene repertoire. We confirm that almost all var transcript types were detected only in ring stages. However, one type, the well-conserved varCSA transcript, was present constitutively in different laboratory parasites and does not appear to undergo antigenic variation. Although varCSA has been shown to encode a chondroitin sulphate A (CSA)-binding PfEMP1, we find that the presence of full-length varCSA transcripts does not correlate with the CSA-binding phenotype

The relative rate of kill of the MMV Malaria Box compounds provide links to the mode of antimalarial action and highlight scaffolds of medicinal chemistry interest

Objectives: Rapid rate-of-kill (RoK) is a key parameter in the target candidate profile 1 (TCP1) for the next-generation antimalarial drugs for uncomplicated malaria, termed Single Encounter Radical Cure and Prophylaxis (SERCaP). TCP1 aims to rapidly eliminate the initial parasite burden, ideally as fast as artesunate, but minimally as fast as chloroquine. Here we explore whether the relative RoK of the Medicine for Malaria Venture (MMV) Malaria Box compounds are linked to their mode of action (MoA) and identify scaffolds of medicinal chemistry interest. Methods: We used a Bioluminescence Relative RoK (BRRoK) assay over 6 and 48h, with exposure to equipotent-IC50 concentrations, to compare the cytocidal effects of Malaria Box compounds to benchmark antimalarials. Results: BRRoK assay data demonstrate the following relative RoK from fast to slow: inhibitors of 31 PfATP4 > parasite hemoglobin catabolism > DHFR-TS > DHODH > bc1 complex. Core scaffold clustering analyses reveal intrinsic rapid cytocidal action for diamino-glycerols and 2- (aminomethyl)phenol, but slow action for 2-phenylbenzimidazoles, 8-hydroxyquinolines, and triazolopyrimidines. Conclusions: This study provides proof of principle that a compound’s RoK is related to its MoA and that the target’s intrinsic RoK is also modified by factors affecting a drug’s access to it. Our findings highlight that as we use medicinal chemistry to improve potency, we can also improve the RoK for some scaffolds. Our BRRoK assay provides the necessary throughput for drug discovery and a critical decision-making tool to support development campaigns. Finally, two scaffolds, diamino-glycerols and 2-phenylbenzimidazoles, exhibit fast cytocidal action, inviting medicinal chemistry improvements towards TCP1 candidates

Reactive and Additive Modifications of Styrenic Polymers with Phosphorus Containing Compounds and Their Effects on Fire Retardance

Polystyrene, despite its high flammability, is widely used as a thermal insulation material for buildings, for food packaging, in electrical and automotive industries, etc. A number of modification routes have been explored to improve the fire retardance and boost the thermal stability of commercially important styrene-based polymeric products. The earlier strategies mostly involved the use of halogenated fire retardants. Nowadays, these compounds are considered to be persistent pollutants that are hazardous to public and environmental health. Many well-known halogen-based fire retardants, regardless of their chemical structures and modes of action, have been withdrawn from built environments in the European Union, USA, and Canada. This had triggered a growing research interest in, and an industrial demand for, halogen-free alternatives, which not only will reduce the flammability but also address toxicity and bioaccumulation issues. Among the possible options, phosphorus-containing compounds have received greater attention due to their excellent fire-retarding efficiencies and environmentally friendly attributes. Numerous reports were also published on reactive and additive modifications of polystyrene in different forms, particularly in the last decade; hence, the current article aims to provide a critical review of these publications. The authors mainly intend to focus on the chemistries of phosphorous compounds, with the P atom being in different chemical environments, used either as reactive, or additive, fire retardants in styrene-based materials. The chemical pathways and possible mechanisms behind the fire retardance are discussed in this review