Repurposing ebselen for Treatment of Multidrug-Resistant Staphylococcal Infections

Novel antimicrobials and new approaches to developing them are urgently needed. Repurposing already-approved drugs with well-characterized toxicology and pharmacology is a novel way to reduce the time, cost, and risk associated with antibiotic innovation. Ebselen, an organoselenium compound, is known to be clinically safe and has a well-known pharmacology profile. It has shown potent bactericidal activity against multidrug-resistant clinical isolates of staphylococcus aureus, including methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA). We demonstrated that ebselen acts through inhibition of protein synthesis and subsequently inhibited toxin production in MRSA. Additionally, ebselen was remarkably active and significantly reduced established staphylococcal biofilms. The therapeutic efficacy of ebselen was evaluated in a mouse model of staphylococcal skin infections. Ebselen 1% and 2% significantly reduced the bacterial load and the levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and monocyte chemo attractant protein-1 (MCP-1) in MRSA USA300 skin lesions. Furthermore, it acts synergistically with traditional antimicrobials. This study provides evidence that ebselen has great potential for topical treatment of MRSA skin infections and lays the foundation for further analysis and development of ebselen as a potential treatment for multidrug-resistant staphylococcal infections

The role of insulin detemir in overweight type 2 diabetes management

The recent evidence-based shift towards an algorithm of early initiation and aggressive titration of insulin therapy in the management of type 2 diabetes requires the use of an effective insulin formulation that is both safe and acceptable to patients and physicians alike. The advent of the long-acting insulin analogues, insulin detemir and glargine, in the last decade has revolutionized insulin therapy in type 2 diabetes. Their unique pharmacokinetic and pharmacodynamic properties have offered tangible advantage over the conventional intermediate and long-acting insulin preparations in terms of improving glucose control as well as reducing risk of hypoglycemia and weight gain. This review focuses on the pharmacodynamic properties of the long-acting insulin analogue detemir, the outcome of studies on its relative efficacy and safety as well as its proposed place in the management of type 2 diabetes

Repurposing Celecoxib as a Topical Antimicrobial Agent

There is an urgent need for new antibiotics and alternative strategies to combat multidrug-resistant bacterial pathogens, which are a growing clinical issue. Repurposing existing approved drugs with known pharmacology and toxicology is an alternative strategy to accelerate antimicrobial research and development. In this study, we show that celecoxib, a marketed inhibitor of cyclooxygenase-2, exhibits broad-spectrum antimicrobial activity against Gram-positive pathogens from a variety of genera, including Staphylococcus, Streptococcus, Listeria, Bacillus, and Mycobacterium, but not against Gram-negative pathogens. However, celecoxib is active against all of the Gram-negative bacteria tested, including strains of, Acinetobacter, and Pseudomonas, when their intrinsic resistance is artificially compromised by outer membrane permeabilizing agents such as colistin. The effect of celecoxib on incorporation of radioactive precursors into macromolecules in Staphylococcus aureus was examined. The primary antimicrobial mechanism of action of celecoxib was the dose-dependent inhibition of RNA, DNA, and protein synthesis. Further, we demonstrate the in vivo efficacy of celecoxib in a methicillin-resistant S. aureus (MRSA) infected Caenorhabditis elegans whole animal model. Topical application of celecoxib (1 and 2%) significantly reduced the mean bacterial count in a mouse model of MRSA skin infection. Further, celecoxib decreased the levels of all inflammatory cytokines tested, including tumor necrosis factor-α, interleukin-6, interleukin-1 beta, and monocyte chemo attractant protein-1 in wounds caused by MRSA infection. Celecoxib also exhibited synergy with many conventional antimicrobials when tested against four clinical isolates of S. aureus. Collectively, these results demonstrate that celecoxib alone, or in combination with traditional antimicrobials, has a potential to use as a topical drug for the treatment of bacterial skin infections

Repurposing clinical molecule ebselen to combat drug resistant pathogens

Without a doubt, our current antimicrobials are losing the battle in the fight against newly-emerged multidrug-resistant pathogens. There is a pressing, unmet need for novel antimicrobials and novel approaches to develop them; however, it is becoming increasingly difficult and costly to develop new antimicrobials. One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug. Ebselen, an organoselenium clinical molecule, possesses potent antimicrobial activity against clinical multidrug-resistant Gram-positive pathogens, including Staphylococcus, Streptococcus, and Enterococcus, but not against Gram-negative pathogens. Moreover, the activity of ebselen against Gram-positive pathogens exceeded those activities determined for vancomycin and linezolid, drugs of choice for treatment of Enterococcus and Staphylococcus infections. The minimum inhibitory concentrations of ebselen at which 90% of clinical isolates of Enterococcus and Staphylococcus were inhibited (MIC90) were found to be 0.5 and 0.25 mg/L, respectively. Ebselen showed significant clearance of intracellular methicillinresistant S. aureus (MRSA) in comparison to vancomycin and linezolid. We demonstrated that ebselen inhibits the bacterial translation process without affecting mitochondrial biogenesis. Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model. Finally, ebselen showed synergistic activities with conventional antimicrobials against MRSA. Taken together, our results demonstrate that ebselen, with its potent antimicrobial activity and safety profiles, can be potentially used to treat multidrug resistant Gram-positive bacterial infections alone or in combination with other antibiotics and should be further clinically evaluated. © 2015 Thangamani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Design and implementation of PSO/ABC tunned PID controller for Buck converters

In the recent years, Buck converters have been widely involved in a variety of the everyday applications such as smartphones and PCs. Buck converters can provide better and steadier performance when integrating a control system in the design. Therefore, it is interesting to work on this integration and gain the required efficiency in term of the gained voltage. In this paper, PID controller is adopted to control the output voltage of the Buck converter. An optimization is achieved on the performance of the Buck converter using two bio-inspired algorithms namely, Particle Swarm Optimization (PSO) and Artificial Bee Colony (ABC). The voltage controlled Buck converter system is simulated using MATLAB environment to validate the proposed PID controller system. In this study, the voltage regulation process of Buck converter is investigated based on many working disturbances such as the change in the supply voltage, reference voltage, and load resistance in order to verify the robustness of the proposed PID controller. Finally, the feedabck voltage control system of the Buck converter is implemented experimentaly in real-time to validatde the simulated PID controller

Merging parallel-plate and levitation actuators to enable linearity and tunability in electrostatic MEMS

In this study, a linear electrostatic MEMS actuator is introduced. The system consists of a MEMS cantilever beam with combined parallel-plate and electrostatic levitation forces. By using these two forcing methods simultaneously, the static response and natural frequency can be made to vary linearly with the voltage. The static response shows a linear increase of 90 nm/V and is maintained for more than 12μm of the tip displacement. The natural frequency shows a linear increase of 16 Hz/V and is maintained throughout a 2.9 kHz shift in the natural frequency. This wide range of linear displacement and frequency tunability is extremely useful for MEMS sensors and actuators, which suffer from the inherent nonlinearity of electrostatic forces. A theoretical model of the system is derived and validated with experimental data. Static response, natural frequency, and frequency response calculations are performed. Merging these two mechanisms enables high oscillation branches for a wide range of frequencies with potential applications in MEMS filters, oscillators, and sensors

Effects of Genotype, Season and Nutrition on Sunflower Yield and Hollow Seededness in Gezira (Sudan)

A field experiment was conducted to study the effects of genotype, season and nutrition on sunflower seed yield and hollow seededness in Gezira. Five sunflower cultivars (Damazin-l, Hungarian-A, Rodio, Hysun-25 and Hysun-33), two nitrogen levels (0 and 129 kgN/ha) and two levels of phosphorus  (0 and 129 kg P205/ha) were used over two seasons (autumn and winter 2000) in a randomized complete block design with four replications. Data on 14 characters were collected. results showed that the percentage of empty seeds, self-compatibility 1000-seed weight and seed yield were significantly affected by and its interaction with season. The means of these characters were relatively higher in winter than in autumn season except for the empty seeds. The application of high doses of fertilizer had no significant effect on the percentage of empty seeds, and consequently lie phenomenon of empty seeds could be attributed mainly to genetical  and seasonal effects. The genotypes mean seed yields ranged from 1127 to 1899 kg/ha, with Hysun-33 giving the highest yield. Simple  and genotypic correlation analyses emphasized that seed yield was and positively correlated with days to flowering, harvest index , head diameter, seed number/head, self-compatibility, number filled seeds/head and percent seed set. Both analyses showed negative coefficients between seed yield and empty seeds. The percentage of empty seeds was positively and significantly correlated with plant height and number of heads/plant. The path analysis indicated that head diameter, percentage of seed set, days to flowering and seed weight  were the most important traits related to seed yield where as percentage of seed set, harvest index, and days to maturity were the  most important traits contributing to high degree of self-compatibility in sunflow

Farmers' perceptions of climate change and its impact on gum Talha (Acacia seyal var. seyal) production in Bahar Alarab locality, East Darfur State, Sudan

Acacia seyal var. seyal is an essential source of income to farmers in the Bahar Alarab locality in Sudan. Farmers’ perceptions of current climate conditions and their subsequent repercussions on Gum Talha (Acacia seyal var. seyal) production remains poorly investigated and understood. To fill this gap, a survey was carried out within six villages at Bahar Alarab locality in East Darfur State, Sudan, and a total of 391 randomly selected farmers were included in the study. Moreover, rainfall and temperature data over 30 years (1988 – 2020) were analysed. The results revealed that climate change signs were perceived by farmers based on the size of gum production (27.4%), early falling of leaves (26.1%), decline in production (24.3%), and persistent insect attack (22.3%). Moreover, farmers also reported increases (65%) and decreases (19%) in temperature. In contrast, 46.5% of farmers reported that rainfall deficiency was a decreasing factor of production. Accordingly, 69% of respondents perceived an increase in temperature, whereas 49.4% reported a decrease in rainfall frequency. Additionally, the results showed that there was long-term variability in temperature over the past three decades. The results of multinomial logistic regression highlighted that household size is an important factor contributing to the increasing trend of temperature. In addition, the growth and productivity of acacia trees were found to be determinants of farmers’ perception of temperature and precipitation change over the past 30 years. The study suggests a tailored policy that could reduce climate-induced impacts on gum Talha productivity and increase farmers’ gain to avoid poverty in this locality

Conserved miRNAs are candidate post-transcriptional regulators of developmental arrest in free-living and parasitic nematodes

Animal development is complex yet surprisingly robust. Animals may develop alternative phenotypes conditional on environmental changes. Under unfavorableconditions C. elegans larvae enter the dauer stage, a developmentally arrested, long-lived, and stress-resistant state. Dauer larvae of free-living nematodes and infective larvae of parasitic nematodes share many traits including a conserved endocrine signaling module (DAF/DAF-12), which is essential for the formation of dauer and infective larvae. We speculated that conserved post-transcriptional regulatory mechanism might also be involved in executing the dauer and infective larvae fate. We used an unbiased sequencing strategy to characterize the miRNA gene complement in C. elegans, P.pacificus, and S. ratti. Our study raised the number of described miRNA genes to 257 for C. elegans, tripled the known gene set for P. pacificus to 362 miRNAs and is the first to describe miRNAs in a Strongyloides parasite. Moreover, we found a limited core set of 24 conserved miRNA families in all three species. Interestingly, our estimated expression fold changes between dauer vs. non-dauer stages and infective larvae vs. free-living stages reveal that despite the speed of miRNA gene set evolution in nematodes, homologous gene families with conserved 'dauer-infective' expression signatures are present. These findings suggest that common post-transcriptional regulatory mechanisms are at work and that the same miRNA families play important roles in developmental arrest as well as long-term survival in free-living and parasitic nematodes