Statins and Antimicrobial Effects: Simvastatin as a Potential Drug against Staphylococcus aureus Biofilm

Statins are important lipid-lowering agents with other pleiotropic effects. Several studies have explored a possible protective effect of statins to reduce the morbidity and mortality of many infectious diseases. Staphylococcus aureus is one of the main pathogens implicated in nosocomial infections; its ability to form biofilms makes treatment difficult. The present study observed the MIC of atorvastatin, pravastatin and simvastatin against S. aureus, Pseudomonas aeruginosa, Escherichia coli and Enterococcus faecalis. Simvastatin was the only agent with activity against clinical isolates and reference strains of methicilin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). Thus, the effects of simvastatin on the growth, viability and biofilm formation of S. aureus were tested. In addition, a possible synergistic effect between simvastatin and vancomycin was evaluated. Simvastatin’s MIC was 15.65 µg/mL for S. aureus 29213 and 31.25 µg/mL for the other strains of S. aureus. The effect of simvastatin was bactericidal at 4xMIC and bacteriostatic at the MIC concentration. No synergistic effect was found between simvastatin and vancomycin. However, the results obtained against S. aureus biofilms showed that, in addition to inhibiting adhesion and biofilm formation at concentrations from 1/16xMIC to 4xMIC, simvastatin was also able to act against mature biofilms, reducing cell viability and extra-polysaccharide production. In conclusion, simvastatin showed pronounced antimicrobial activity against S. aureus biofilms, reducing their formation and viability.     

Calmodulin inhibits the epidermal growth factor receptor tyrosine kinase.

We demonstrate in this report that the epidermal growth factor (EGF) receptor from rat liver can be isolated by calmodulin affinity chromatography by binding in the presence of Ca2+ and elution with a Ca(2+)-chelating agent. The bulk of the EGF receptor is not eluted by a NaCl gradient in the presence of Ca2+. We ascertained the identity of the isolated receptor by immunoblot and immunoprecipitation using a polyclonal antibody against an EGF receptor from human origin. The purified receptor is autophosphorylated in tyrosine residues in an EGF-stimulated manner, and EGF-dependent phosphorylation of serine residues was also detected. Both the EGF and the transforming growth factor-alpha stimulate the tyrosine-directed protein kinase activity of the isolated receptor with similar affinities. Furthermore, we demonstrate that calmodulin inhibits the EGF-dependent tyrosine-directed protein kinase activity associated to the receptor in a concentration-dependent manner. This inhibition is partially Ca2+ dependent and is not displaced by increasing the concentration of EGF up to an EGF/calmodulin ratio of 10 (mol/mol). In addition, calmodulin was phosphorylated in an EGF-stimulated manner in the presence of a basic protein (histone) as cofactor and in the absence, but not in the presence, of Ca2+.     

Mitochondrial ferredoxin is required for heme A synthesis in Saccharomyces cerevisiae.

Heme A is a prosthetic group of all eukaryotic and some prokaryotic cytochrome oxidases. This heme differs from heme B (protoheme) at two carbon positions of the porphyrin ring. The synthesis of heme A begins with farnesylation of the vinyl group at carbon C-2 of heme B. The heme O product of this reaction is then converted to heme A by a further oxidation of a methyl to a formyl group on C-8. In a previous study (Barros, M. H., Carlson, C. G., Glerum, D. M., and Tzagoloff, A. (2001) FEBS Lett. 492, 133-138) we proposed that the formyl group is formed by an initial hydroxylation of the C-8 methyl by a three-component monooxygenase consisting of Cox15p, ferredoxin, and ferredoxin reductase. In the present study three lines of evidence confirm a requirement of ferredoxin in heme A synthesis. 1) Temperature-conditional yah1 mutants grown under restrictive conditions display a decrease in heme A relative to heme B. 2) The incorporation of radioactive delta-aminolevulinic acid into heme A is reduced in yah1 ts but not in the wild type after the shift to the restrictive temperature; and 3) the overexpression of Cox15p in cytochrome oxidase mutants that accumulate heme O leads to an increased mitochondrial concentration of heme A. The increase in heme A is greater in mutants that overexpress Cox15p and ferredoxin. These results are consistent with a requirement of ferredoxin and indirectly of ferredoxin reductase in hydroxylation of heme O.     

A New Cyclic Scheduling Algorithm for Flexible Manufacturing Systems

Flexible manufacturing system control is an NP-hard problem. A cyclic approach has been demonstrated to be adequate for an infinite scheduling problem because of maximal throughput reachability. However, it is not the only optimization criterion in general. In this article we consider the minimization of the work in process (WIP) as an economical and productivity factor. We propose a new cyclic scheduling algorithm giving the maximal throughput (a hard constraint) while minimizing WIP. This algorithm is based on progressive operations placing. A controlled beam search approach has been developed to determine at each step the schedule of the next operations. After presenting the main principles of the algorithm, we compare our approach to several most known cyclic scheduling algorithms using a significant existing example from the literature.     

Genome-wide methylation profiling identifies hypermethylated biomarkers in high-grade cervical intraepithelial neoplasia

Epigenetic modifications, such as aberrant DNA promoter methylation, are frequently observed in cervical cancer. Identification of hypermethylated regions allowing discrimination between normal cervical epithelium and high-grade cervical intraepithelial neoplasia (CIN2/3), or worse, may improve current cervical cancer population-based screening programs. In this study, the DNA methylome of high-grade CIN lesions was studied using genome-wide DNA methylation screening to identify potential biomarkers for early diagnosis of cervical neoplasia. Methylated DNA Immunoprecipitation (MeDIP) combined with DNA microarray was used to compare DNA methylation profiles of epithelial cells derived from high-grade CIN lesions with normal cervical epithelium. Hypermethylated differentially methylated regions (DMRs) were identified. Validation of nine selected DMRs using BSP and MSP in cervical tissue revealed methylation in 63.2–94.7% high-grade CIN and in 59.3–100% cervical carcinomas. QMSP for the two most significant high-grade CIN-specific methylation markers was conducted exploring test performance in a large series of cervical scrapings. Frequency and relative level of methylation were significantly different between normal and cancer samples. Clinical validation of both markers in cervical scrapings from patients with an abnormal cervical smear confirmed that frequency and relative level of methylation were related with increasing severity of the underlying CIN lesion and that ROC analysis was discriminative. These markers represent the COL25A1 and KATNAL2 and their observed increased methylation upon progression could intimate the regulatory role in carcinogenesis. In conclusion, our newly identified hypermethylated DMRs represent specific DNA methylation patterns in high-grade CIN lesions and are candidate biomarkers for early detection.     

Developing a Social Autopsy Tool for Dengue Mortality: A Pilot Study

BackgroundDengue fever is a public health problem in the tropical and sub-tropical world. Dengue cases have grown dramatically in recent years as well as dengue mortality. Colombia has experienced periodic dengue outbreaks with numerous dengue related-deaths, where the Santander department has been particularly affected. Although social determinants of health (SDH) shape health outcomes, including mortality, it is not yet understood how these affect dengue mortality. The aim of this pilot study was to develop and pre-test a social autopsy (SA) tool for dengue mortality.ConclusionsThe SA tool is based on the scientific literature, a validated conceptual framework, researchers’ and health professionals’ expertise, and a pilot study. It is the first time that a SA tool has been created for the dengue mortality context. Our work furthers the study on SDH and how these are applied to neglected tropical diseases, like dengue. This tool could be integrated in surveillance systems to provide complementary information on the modifiable and avoidable death-related factors and therefore, be able to formulate interventions for dengue mortality reduction.     

Carbon Sequestration of Caesalpinia platyloba S. Watt (Leguminosae) (Lott 1985) in the Tropical Deciduous Forest

Caesalpinia platyloba was evaluated as an alternative for the retention of atmospheric carbon and as a feasible and viable economic activity in terms of income for tropical deciduous forest (TDF) peasants in the carbon markets. A total of 110 trees of C. platyloba from plantations and a TDF in the Northwest of Mexico were sampled. Growth (increase in height, diameter, and volume curves) was adjusted to assess their growth. Growth of individuals (height, diameter at breast height [DBH], age, and tree crown cover) was recorded. The Schumacher model (H = β₀e^β₁•E-1), by means of the guided curve method, was used to adjust growth models. Information analysis was made through the non-linear procedure with the multivariate secant or false position (DUD) method using the SAS software. Growth and increase models revealed acceptable adjustments (pseudo R²>0.8). C. platyloba reaches >8m of height with 12cm in diameter and 550cm³ of volume, presenting the highest increase at 11 years considered as basal age. Highest significant density of wood was in good quality sites (0.80g•cm^-3), with a carbon content (average of 99.15tC•ha^-1) at the highest density of 2500 trees•ha^-1 (without thinning). Average incomes of US$483.33tC•ha^-1 are expected. The profitability values (NPW = US$81,646.65, IRR = 472%, and B/C = 0.82) for C. platyloba make its cultivation a viable and profitable activity, considering a management scheme of the income derived from wood selling and from carbon credits.