Computer-aided discovery of antimicrobial agents as potential enoyl acyl carrier protein reductase inhibitors

Purpose: To perform a virtual screening for a set of drug-like ligand library against the Staphylococcus aureus enoyl acyl carrier protein reductase, saFabI.Methods: The virtual screening was conducted based on a previously validated pharmacophoreconstrained docking. Consequently, the top list obtained was filtered using visual inspection where forty compounds were selected for experimental testing using disk-diffusion test and broth dilution method. The hits obtained were checked for their toxicity against human fibroblasts cell lines.Results: Three compounds were active against Staphylococcus aureus and other tested gram-positive bacteria. However, no significant inhibitory activity (p < 0.05) was detected against Escherichia coli or Candida albicans. The minimum inhibitory concentration (MIC) values for the most active compounds were identified using the broth dilution method; all of them exhibited inhibitory activity within micromolar range.The docking results showed that the hits obtained exhibited a small size with a nice binding mode to saFabI enzyme, forming the important interactions with the key residues. Furthermore, the best three hits demonstrated good safety profile as they did not show any significant toxicity against human fibroblast cell line.Conclusion: Overall, the newly discovered hits can act as a good starting point in the future for the development of safe and potent antibacterial agents.Keywords: Enoyl acyl carrier protein reductase, saFabI, Antibacterial agents, Docking, Constraint, Virtual screening Tropical Journal of Pharmaceutica

Implications of Synchronous IVR Radio on Syrian Refugee Health and Community Dynamics

With 1,033,513 Syrian refugees adding a strain on the Lebanese healthcare system, innovation is key to improving access to healthcare. Our previous work identified the potential for technology to improve access to antenatal care services and increase refugee agency. Using (1) paper mock ups and a mobile based prototype, (2) process mapping, (3) focus groups and interviews and (4) key informant meetings, we explored the concept of refugee led community radio shows to deliver peer-led healthcare. We observed the influence of community radio shows on Syrian refugee health education, community dynamics and community agency in relationships between healthcare providers and refugees. Refugees were positively impacted through situating the technology within the community. We highlight issues around trust, agency, understanding, sel-forganization and privacy that resulted from running the shows through mock ups and a mobile based prototype. Our findings inform future work in community run radio shows

On the Relationships between Decision Management and Performance Measurement

Decision management is of utmost importance for the achievement of strategic and operational goals in any organisational context. Therefore, decisions should be considered as first-class citizens that need to be modelled, analysed, monitored to track their performance, and redesigned if necessary. Up to now, existing literature that studies decisions in the context of business processes has focused on the analysis of the definition of decisions themselves, in terms of accuracy, certainty, consistency, covering and correctness. However, to the best of our knowledge, no prior work exists that analyses the relationship between decisions and performance measurement. This paper identifies and analyses this relationship from three different perspectives, namely: the impact of decisions on process performance, the performance measurement of decisions, and the use of performance indicators in the definition of decisions. Furthermore, we also introduce solutions for the representation of these relationships based, amongst others, on the DMN standard.Ministerio de Economía y Competitividad BELI (TIN2015-70560-R)Junta de Andalucía P12-TIC-1867Junta de Andalucía P10-TIC-590

A Biobrick Library for Cloning Custom Eukaryotic Plasmids

Researchers often require customised variations of plasmids that are not commercially available. Here we demonstrate the applicability and versatility of standard synthetic biological parts (biobricks) to build custom plasmids. For this purpose we have built a collection of 52 parts that include multiple cloning sites (MCS) and common protein tags, protein reporters and selection markers, amongst others. Importantly, most of the parts are designed in a format to allow fusions that maintain the reading frame. We illustrate the collection by building several model contructs, including concatemers of protein binding-site motifs, and a variety of plasmids for eukaryotic stable cloning and chromosomal insertion. For example, in 3 biobrick iterations, we make a cerulean-reporter plasmid for cloning fluorescent protein fusions. Furthermore, we use the collection to implement a recombinase-mediated DNA insertion (RMDI), allowing chromosomal site-directed exchange of genes. By making one recipient stable cell line, many standardised cell lines can subsequently be generated, by fluorescent fusion-gene exchange. We propose that this biobrick collection may be distributed peer-to-peer as a stand-alone library, in addition to its distribution through the Registry of Standard Biological Parts (http://partsregistry.org/)

Cost-effectiveness of intermittent preventive treatment of malaria in infants (IPTi) for averting anaemia in Gabon: a comparison between intention to treat and according to protocol analyses

ABSTRACT: BACKGROUND: In Gabon, the impact of intermittent preventive treatment of malaria in infants (IPTi) was not statistically significant on malaria reduction, but the impact on moderate anaemia was, with some differences between the intention to treat (ITT) and the according to protocol (ATP) trial analyses. Specifically, ATP was statistically significant, while ITT analysis was borderline. The main reason for the difference between ITT and ATP populations was migration. METHODS: This study estimates the cost-effectiveness of IPTi on the reduction of anaemia in Gabon, comparing results of the ITT and the ATP clinical trial analyses. Threshold analysis was conducted to identify when the intervention costs and protective efficacy of IPTi for the ATP cohort equalled the ITT cost-effectiveness ratio. RESULTS: Based on IPTi intervention costs, the cost per episode of moderate anaemia averted was US$12.88 (CI 95$11.30 (CI 95% 4.56, 26.66) using the ATP analysis. In order for the ATP results to equal the cost-effectiveness of ITT, total ATP intervention costs should rise from US$118.38 to US$134 or the protective efficacy should fall from 27% to 18.1%. The uncertainty surrounding the cost-effectiveness ratio using ITT trial results was higher than using the ATP results. CONCLUSIONS: Migration implies great challenges in the organization of health interventions that require repeat visits in Gabon. This was apparent in the study as the cost-effectiveness of IPTp-SP worsened when drop out from the prevention was taken into account. Despite such challenges, IPTi was both inexpensive and efficacious in averting cases of moderate anaemia in infant

Ankyrin is the major oxidised protein in erythrocyte membranes from end-stage renal disease patients on chronic haemodialysis and oxidation is decreased by dialysis and vitamin C supplementation

Chronically haemodialysed end-stage renal disease patients are at high risk of morbidity arising from complications of dialysis, the underlying pathology that has led to renal disease and the complex pathology of chronic kidney disease. Anaemia is commonplace and its origins are multifactorial, involving reduced renal erythropoietin production, accumulation of uremic toxins and an increase in erythrocyte fragility. Oxidative damage is a common risk factor in renal disease and its co-morbidities and is known to cause erythrocyte fragility. Therefore, we have investigated the hypothesis that specific erythrocyte membrane proteins are more oxidised in end-stage renal disease patients and that vitamin C supplementation can ameliorate membrane protein oxidation. Eleven patients and 15 control subjects were recruited to the study. Patients were supplemented with 2 × 500 mg vitamin C per day for 4 weeks. Erythrocyte membrane proteins were prepared pre- and post-vitamin C supplementation for determination of protein oxidation. Total protein carbonyls were reduced by vitamin C supplementation but not by dialysis when investigated by enzyme linked immunosorbent assay. Using a western blot to detect oxidised proteins, one protein band, later identified as containing ankyrin, was found to be oxidised in patients but not controls and was reduced significantly by 60% in all patients after dialysis and by 20% after vitamin C treatment pre-dialysis. Ankyrin oxidation analysis may be useful in a stratified medicines approach as a possible marker to identify requirements for intervention in dialysis patients

Stromal Interferon-γ Signaling and Cross-Presentation Are Required to Eliminate Antigen-Loss Variants of B Cell Lymphomas in Mice

To study mechanisms of T cell-mediated rejection of B cell lymphomas, we developed a murine lymphoma model wherein three potential rejection antigens, human c-MYC, chicken ovalbumin (OVA), and GFP are expressed. After transfer into wild-type mice 60–70% of systemically growing lymphomas expressing all three antigens were rejected; lymphomas expressing only human c-MYC protein were not rejected. OVA expressing lymphomas were infiltrated by T cells, showed MHC class I and II upregulation, and lost antigen expression, indicating immune escape. In contrast to wild-type recipients, 80–100% of STAT1-, IFN-γ-, or IFN-γ receptor-deficient recipients died of lymphoma, indicating that host IFN-γ signaling is critical for rejection. Lymphomas arising in IFN-γ- and IFN-γ-receptor-deficient mice had invariably lost antigen expression, suggesting that poor overall survival of these recipients was due to inefficient elimination of antigen-negative lymphoma variants. Antigen-dependent eradication of lymphoma cells in wild-type animals was dependent on cross-presentation of antigen by cells of the tumor stroma. These findings provide first evidence for an important role of the tumor stroma in T cell-mediated control of hematologic neoplasias and highlight the importance of incorporating stroma-targeting strategies into future immunotherapeutic approaches

Delivering health interventions to women, children, and adolescents in conflict settings: what have we learned from ten country case studies?

Armed conflict disproportionately affects the morbidity, mortality, and wellbeing of women, newborns, children, and adolescents. Our study presents insights from a collection of ten country case studies aiming to assess the provision of sexual, reproductive, maternal, newborn, child, and adolescent health and nutrition interventions in ten conflict-affected settings in Afghanistan, Colombia, Democratic Republic of the Congo, Mali, Nigeria, Pakistan, Somalia, South Sudan, Syria, and Yemen. We found that despite large variations in contexts and decision making processes, antenatal care, basic emergency obstetric and newborn care, comprehensive emergency obstetric and newborn care, immunisation, treatment of common childhood illnesses, infant and young child feeding, and malnutrition treatment and screening were prioritised in these ten conflict settings. Many lifesaving women's and children's health (WCH) services, including the majority of reproductive, newborn, and adolescent health services, are not reported as being delivered in the ten conflict settings, and interventions to address stillbirths are absent. International donors remain the primary drivers of influencing the what, where, and how of implementing WCH interventions. Interpretation of WCH outcomes in conflict settings are particularly context-dependent given the myriad of complex factors that constitute conflict and their interactions. Moreover, the comprehensiveness and quality of data remain limited in conflict settings. The dynamic nature of modern conflict and the expanding role of non-state armed groups in large geographic areas pose new challenges to delivering WCH services. However, the humanitarian system is creative and pluralistic and has developed some novel solutions to bring lifesaving WCH services closer to populations using new modes of delivery. These solutions, when rigorously evaluated, can represent concrete response to current implementation challenges to modern armed conflicts