A Potential Involvement of Anandamide in the Modulation of HO/NOS Systems: Women,Menopause, and “Medical Cannabinoids”

Endocannabinoids and their receptors are present in the cardiovascular system; however, their actions under different pathological conditions remain controversial. The aim of our study was to examine the effects of anandamide (AEA) on heme oxygenase (HO) and nitric oxide synthase (NOS) systems in an estrogen-depleted rat model. Sham-operated (SO) and surgically induced estrogen-deficient (OVX) female Wistar rats were used. During a two-week period, a group of OVX rats received 0.1 mg/kg estrogen (E₂) per os, while AEA-induced alterations were analyzed after two weeks of AEA treatment at the dose of 1.0 mg/kg. At the end of the experiment, cardiac activity and expression of HO and NOS enzymes, content of cannabinoid 1 receptor, as well as concentrations of transient potential vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP) were measured. Our results show that estrogen withdrawal caused a significant decrease in both NOS and HO systems, and a similar tendency was observed regarding the TRPV1/CGRP pathway. Two weeks of either AEA or E₂ treatment restored the adverse changes; however, the combined administration of these two molecules did not result in a further improvement. In light of the potential relationship between AEA and HO/NOS systems, AEA-induced upregulation of HO/NOS enzymes may be a therapeutic strategy in estrogen-deficient conditions.     

Multienzymatic immobilization of laccases on polymeric microspheres: A strategy to expand the maximum catalytic efficiency

Laccase enzymes of were covalently coimmobilized on poly(glycidyl methacrylate) microspheres. The objective of this work was to create a biocatalyst that works efficiently in a wide range of pH. The coimmobilization was performed using two different strategies to compare the most efficient. The results showed that by correctly selecting the enzymes and concentrations involved in the commobilization, it is possible to obtain a biocatalyst that works efficiently at a wide pH range (2.0–7.0). The maximum activity values reached per gram of support for the obtained biocatalyst were 41.90 U (pH 3.0), 40.89 U (pH 4.0), and 39.54 U (pH 6.0). Moreover, the thermal, storage, and mechanical stabilities were improved compared to the free and single-immobilized laccases. It was concluded that enzymatic coimmobilization is an excellent alternative to obtain a robust biocatalyst that works in a wide pH range, with potential environmental and industrial applications.     

Co‐immobilized Whole Cells with ω‐Transaminase and Ketoreductase Activities for Continuous‐Flow Cascade Reactions

An improved sol–gel process involving the use of hollow silica microspheres as a supporting additive was applied for the co‐immobilization of whole cells of Escherichia coli with Chromobacterium violaceum ω‐transaminase activity and Lodderomyces elongisporus with ketoreductase activity. The co‐immobilized cells with two different biocatalytic activities could perform a cascade of reactions to convert racemic 4‐phenylbutan‐2‐amine or heptan‐2‐amine into a nearly equimolar mixture of the corresponding enantiomerically pure R amine and S alcohol even in continuous‐flow mode. The novel co‐immobilized whole‐cell system proved to be an easy‐to‐store and durable biocatalyst.     

Dual Escherichia coli DNA Gyrase A and B Inhibitors with Antibacterial Activity

The emergence of multidrug-resistant bacteria is a global health threat necessitating the discovery of new antibacterials and novel strategies for fighting bacterial infections. We report first-in-class DNA gyrase B (GyrB) inhibitor/ciprofloxacin hybrids that display antibacterial activity against Escherichia coli. Whereas DNA gyrase ATPase inhibition experiments, DNA gyrase supercoiling assays, and in vitro antibacterial assays suggest binding of the hybrids to the E. coli GyrA and GyrB subunits, an interaction with the GyrA fluoroquinolone-binding site seems to be solely responsible for their antibacterial activity. Our results provide a foundation for a new concept of facilitating entry of nonpermeating GyrB inhibitors into bacteria by conjugation with ciprofloxacin, a highly permeable GyrA inhibitor. A hybrid molecule containing GyrA and GyrB inhibitor parts entering the bacterial cell would then elicit a strong antibacterial effect by inhibition of both the GyrA and GyrB subunits of DNA gyrase and potentially slow bacterial resistance development.     

Syndecan-3 as a Novel Biomarker in Alzheimer’s Disease

Early diagnosis of Alzheimer’s disease (AD) is of paramount importance in preserving the patient’s mental and physical health in a fairly manageable condition for a longer period. Reliable AD detection requires novel biomarkers indicating central nervous system (CNS) degeneration in the periphery. Members of the syndecan family of transmembrane proteoglycans are emerging new targets in inflammatory and neurodegenerative disorders. Reviewing the growing scientific evidence on the involvement of syndecans in the pathomechanism of AD, we analyzed the expression of the neuronal syndecan, syndecan-3 (SDC3), in experimental models of neurodegeneration. Initial in vitro studies showed that prolonged treatment of tumor necrosis factor-alpha (TNF-α) increases SDC3 expression in model neuronal and brain microvascular endothelial cell lines. In vivo studies revealed elevated concentrations of TNF-α in the blood and brain of APPSWE-Tau transgenic mice, along with increased SDC3 concentration in the brain and the liver. Primary brain endothelial cells and peripheral blood monocytes isolated from APPSWE-Tau mice exhibited increased SDC3 expression than wild-type controls. SDC3 expression of blood-derived monocytes showed a positive correlation with amyloid plaque load in the brain, demonstrating that SDC3 on monocytes is a good indicator of amyloid pathology in the brain. Given the well-established role of blood tests, the SDC3 expression of monocytes could serve as a novel biomarker for early AD detection.     

Fetal phonocardiography--past and future possibilities

The paper presents an overview of the 15 year long development of fetal phonocardiography including the works on the applied signal processing methods for identification of sound components. Based on the improvements achieved on this field, the paper shows that beyond the traditional CTG test the phonocardiography may be successfully applied for long-term fetal measurements and home monitoring. In addition, by indication of heart murmurs based on a comprehensive analysis of the recorded heart sound congenital heart defects can also be detected together with additional features in the third trimester. This makes an early widespread screening possible combined with the prescribed CTG test even at home using a telemedicine system.     

Exploration–exploitation tradeoff using variance estimates in multi-armed bandits

Algorithms based on upper confidence bounds for balancing exploration and exploitation are gaining popularity since they are easy to implement, efficient and effective. This paper considers a variant of the basic algorithm for the stochastic, multi-armed bandit problem that takes into account the empirical variance of the different arms. In earlier experimental works, such algorithms were found to outperform the competing algorithms. We provide the first analysis of the expected regret for such algorithms. As expected, our results show that the algorithm that uses the variance estimates has a major advantage over its alternatives that do not use such estimates provided that the variances of the payoffs of the suboptimal arms are low. We also prove that the regret concentrates only at a polynomial rate. This holds for all the upper confidence bound based algorithms and for all bandit problems except those special ones where with probability one the payoff obtained by pulling the optimal arm is larger than the expected payoff for the second best arm. Hence, although upper confidence bound bandit algorithms achieve logarithmic expected regret rates, they might not be suitable for a risk-averse decision maker. We illustrate some of the results by computer simulations.