Development of Phosphodiesterase–Protein-Kinase Complexes as Novel Targets for Discovery of Inhibitors with Enhanced Specificity

Phosphodiesterases (PDEs) hydrolyze cyclic nucleotides to modulate multiple signaling events in cells. PDEs are recognized to actively associate with cyclic nucleotide receptors (protein kinases, PKs) in larger macromolecular assemblies referred to as signalosomes. Complexation of PDEs with PKs generates an expanded active site that enhances PDE activity. This facilitates signalosome-associated PDEs to preferentially catalyze active hydrolysis of cyclic nucleotides bound to PKs and aid in signal termination. PDEs are important drug targets, and current strategies for inhibitor discovery are based entirely on targeting conserved PDE catalytic domains. This often results in inhibitors with cross-reactivity amongst closely related PDEs and attendant unwanted side effects. Here, our approach targeted PDE–PK complexes as they would occur in signalosomes, thereby offering greater specificity. Our developed fluorescence polarization assay was adapted to identify inhibitors that block cyclic nucleotide pockets in PDE–PK complexes in one mode and disrupt protein-protein interactions between PDEs and PKs in a second mode. We tested this approach with three different systems—cAMP-specific PDE8–PKAR, cGMP-specific PDE5–PKG, and dual-specificity RegA–R_D complexes—and ranked inhibitors according to their inhibition potency. Targeting PDE–PK complexes offers biochemical tools for describing the exquisite specificity of cyclic nucleotide signaling networks in cells.     

Chitosan–silver nanocomposites: New functional biomaterial for health-care applications

Chitosan–silver nanocomposites (CS-HDA-AgNCs) was prepared using chitosan, biogenic silver nanocomposites, and crosslinker, hexamethylene 1,6-di(amino carboxysulfonate) (HDA). The film is flexible and transparent. Its physical, mechanical, thermal, hydrophilicity, and swelling properties were improved by HDA (2.5%). The antimicrobial activity of CS-HDA-AgNCs were not displayed any remarkable zone of inhibition but showed toxic effect in the presence of normal 3T3 fibroblasts and cancer HeLa cells. It decreases to ca. 5–7% for both cell lines. In conclusion, it can be mentioned that the CS-HDA-AgNCs, a kind of new functional biomaterial, could be useful for health-care applications.     

SMTIBEA: a hybrid multi-objective optimization algorithm for configuring large constrained software product lines

Software and Systems Modeling - A key challenge to software product line engineering is to explore a huge space of various products and to find optimal or near-optimal solutions that satisfy all...     

A novel binary gaining–sharing knowledge-based optimization algorithm for feature selection

Neural Computing and Applications - To obtain the optimal set of features in feature selection problems is the most challenging and prominent problem in machine learning. Very few human-related...     

Insights into discrepancy in power generation among glucose and malate grown Rubrivivax benzoatilyticus JA2 microbial fuel cells

In this study, Rubrivivax benzoatilyticus JA2^T (=ATCC BAA-35^T = JCM 13220^T = MTCC 7087^T), an anoxygenic photosynthetic bacterium, was subjected to altered conditions and observed for changes in power outcome in the two chambered microbial fuel cells (MFCs), the basis of which was established using metabolomic studies. This is an extension to our previous studies, which showed that, under photo heterotrophic conditions, glucose in the form of a solitary carbon resource in minimal media, caused the strain JA2 to exhibit altered growth rates, progressive loss of pigmentation and reduced cell size (3–4 μm), compared to malate grown cells (6–7 μm). When R. benzoatilyticus JA2 cells were grown in malate bio-anodes, they presented higher potentials (289.22 ± 4.6 mV or 436.22 OCV per mg dry weight) compared to glucose bioanodes (163 ± 5.5 mv or 188.98 OCV per mg dry weight). Insights from the metabolomic footprints and fingerprints have revealed differential regulation of key components in the central metabolic pathway such as fumarate, citrate and succinate, which are significantly increased in malate grown bio anodes. Strain JA2 cells when grown with malate as substrate are densely grown on the electrodes and exhibited reduced size, when observed under SEM, which contrasts with control cells grown on malate broth. The artificial selection pressure of the MFC and the different metabolic pathways followed by these bacteria are the reasons for such discrepancy in the power production by the strain JA2. These adaptations may indicate survival advantage during the electron transfer and growth in bio anodes. The study throws light on what types of effluents would be more suitable as substrates for R. benzoatilyticus JA2 microbial fuel cells.     

Editorial

Innovations in Systems and Software Engineering -     

Novel catechol-derived phosphorus-based precursors for coating applications

Polymer Bulletin - Depletion of the petroleum resources and poor flame-retardant properties of the epoxy resins drive researchers to develop an epoxy resin with good heat stability from...     

Performance investigation in modified and improved augmented power generation Kalina cycle using Python

In the generation of electricity and cogeneration, Kalina cycle is considered as one of the competitors to organic Rankine cycle. With the simplicity and identical components of the binary mixture, Kalina system makes it more prominent to get developed and implemented as well with its environmental friendly associate. This work proposes a new improved Kalina cycle system to convert the natural source from sun to useful work. The proposed system utilizes heat source suitable to medium temperature heat applications. The proposed cycle have 2 units of solar collector, favoring an additional heat recovery and higher performance. Solar hot source temperature and pressure are 190°C and 45 bar with additional flow to the turbine of 1.15 kg/s. Energy and second law analysis have considered in evaluating the performance of the proposed plant. The energy analysis shows minimum value of net power, energy efficiency and plant efficiency as 241 kW, 15.5% and 5.7. The exergy analysis defines that, to the proposed cycle, the exergy efficiency initializes at 77% with more exergy destruction at turbine with 31%. With the parametric analysis, the system is amended to have the maximum values of energy and exergy performances as 18.5%, 7.1% and 85%. The parametric study identifies the optimum value of the inlet temperature and pressure of the pump and turbine.     

Development of advanced fiber-reinforced polymer composites by polymer hybridization technique: Emphasis on cure kinetics,mechanical, and thermomechanical performance

Polymer hybridization technique, consisting of an interlayer arrangement of different polymers, acts as the most economical and promising technique in augmenting the glass fiber-reinforced polymer composite's mechanical properties. This investigation focuses on the effect of cure kinetics on the flexural behavior of glass-polymer hybrid (GPH) composite, and also elucidates the comparative analysis on the mechanical behavior of glass-epoxy (GE) composite, glass-vinyl ester (GVE) composite, and GPH composite. The optimal postcuring temperature has been found to be 200°C for GPH composite among the other postcuring temperatures conducted at 140, 170, and 230°C. Among all these abovementioned composites, highest flexural strength and interlaminar shear strength properties have been recorded by the 200°C postcured GPH composite leading to 10.87 and 18.76% increment, respectively, compared with GE composite. Furthermore, thermomechanical characterization has been done to know the viscoelastic behavior of the GPH composite postcured at different temperatures using dynamic mechanical thermal analysis. The fracture morphology of flexural tested composite samples demonstrated a combination of failure modes. Relevant information on the chemical restructuring and fracture morphology of experimented composite material using Fourier-transform infrared (FTIR) spectroscopy and Scanning electron microscopy (SEM) has also been studied.