Shift to Pseudomonic acid B production in P. fluorescens NCIMB10586 by mutation of mupirocin tailoring genes mupO, mupU, mupV, and macpE

Mupirocin, a polyketide-derived antibiotic from Pseudomonas fluorescens NCIMB10586, is a mixture of pseudomonic acids (PA) that target isoleucyl-tRNA synthase. The mup gene cluster encodes both type I polyketide synthases and monofunctional enzymes that should play a role during the conversion of the product of the polyketide synthase into the active antibiotic (tailoring). By in-frame deletion analysis of selected tailoring open-reading frames we show that mupQ, mupS, mupT, and mupW are essential for mupirocin production, whereas mupO, mupU, mupV, and macpE are essential for production of PA-A but not PA-B. Therefore, PA-B is not simply produced by hydroxylation of PA-A but is either a precursor of PA-A or a shunt product. In the mupW mutant, a new metabolite lacking the tetrahydropyran ring is produced, implicating mupW in oxidation of the 16-methyl group.     

Friedelin Attenuates Neuronal Dysfunction and Memory Impairment by Inhibition of the Activated JNK/NF-κB Signalling Pathway in Scopolamine-Induced Mice Model of Neurodegeneration

Oxidative stress (OS) and c-Jun N-terminal kinase (JNK) are both key indicators implicated in neuro-inflammatory signalling pathways and their respective neurodegenerative diseases. Drugs targeting these factors can be considered as suitable candidates for treatment of neuronal dysfunction and memory impairment. The present study encompasses beneficial effects of a naturally occurring triterpenoid, friedelin, against scopolamine-induced oxidative stress and neurodegenerative pathologies in mice models. The treated animals were subjected to behavioural tests i.e., Y-maze and Morris water maze (MWM) for memory dysfunction. The underlying mechanism was determined via western blotting, antioxidant enzymes and lipid profile analyses. Molecular docking studies were carried out to predict the binding modes of friedelin in the binding pocket of p-JNK protein. The results reveal that scopolamine caused oxidative stress by (1) inhibiting catalase (CAT), peroxidase enzyme (POD), superoxide dismutase (SOD), and reduced glutathione enzyme (GSH); (2) the up-regulation of thiobarbituric acid reactive substances (TBARS) in mice brain; and (3) affecting the neuronal synapse (both pre- and post-synapse) followed by associated memory dysfunction. In contrast, friedelin administration not only abolished scopolamine-induced oxidative stress, glial cell activation, and neuro-inflammation but also inhibited p-JNK and NF-κB and their downstream signaling molecules. Moreover, friedelin administration improved neuronal synapse and reversed scopolamine-induced memory impairment accompanied by the inhibition of β-secretase enzyme (BACE-1) to halt amyloidogenic pathways of amyloid-β production. In summary, all of the results show that friedelin is a potent naturally isolated neuro-therapeutic agent to reverse scopolamine-induced neuropathology, which is characteristic of Alzheimer’s disease.     

Effect of axial strain on structural and electronic properties of zig-zag type of boron nitride nanotube (BNNT): a quantum chemical study

The influence of strain on structural and electronic properties of zig-zag type of boron nitride nanotubes (BNNTs) has been studied by density functional theory calculations. The variations of HOMO–LUMO gaps, geometrical parameters, cohesive energy, radial buckling, isodensity surfaces of the HOMOs and LUMOs, electrophilicity index, chemical potential, and chemical hardness and softness have been investigated for BNNTs at different strains. Our results show that the effect of axial strain on the electronic and structural properties of zig-zag BNNTs depends on the diameter as well as the length of the nanotube.     

Switching adaptive controllers to control fractional‐order complex systems with unknown structure and input nonlinearities

This article investigates the chaos control problem for the fractional‐order chaotic systems containing unknown structure and input nonlinearities. Two types of nonlinearity in the control input are considered. In the first case, a general continuous nonlinearity input is supposed in the controller, and in the second case, the unknown dead‐zone input is included. In each case, a proper switching adaptive controller is introduced to stabilize the fractional‐order chaotic system in the presence of unknown parameters and uncertainties. The control methods are designed based on the boundedness property of the chaotic system's states, where, in the proposed methods the nonlinear/linear dynamic terms of the fractional‐order chaotic systems are assumed to be fully unknown. The analytical results of the mentioned techniques are proved by the stability analysis theorem of fractional‐order systems and the adaptive control method. In addition, as an application of the proposed methods, single input adaptive controllers are adopted for control of a class of three‐dimensional nonlinear fractional‐order chaotic systems. And finally, some numerical examples illustrate the correctness of the analytical results. © 2014 Wiley Periodicals, Inc. Complexity 21: 211–223, 2015     

Convergent synthesis of carbonic anhydrase inhibiting bi-heterocyclic benzamides: Structure–activity relationship and mechanistic explorations through enzyme inhibition,kinetics, and computational studies

By using a convergent methodology, a novel series of N-arylated 4-yl-benzamides containing a bi-heterocyclic thiazole–triazole core was synthesized, and the structures of these hybrid molecules, 9a–k , were corroborated through spectral analyses. The in vitro studies of these multifunctional molecules demonstrated their potent carbonic anhydrase inhibition relative to the standard used. The kinetics mechanism was exposed by Lineweaver–Burk plots, which revealed that 9j inhibited carbonic anhydrase non-competitively by forming an enzyme-inhibitor complex. The inhibition constants K_i calculated from Dixon plots for this compound was 1.2 μM. The computational study was also persuasive with the experimental results, and these molecules disclosed good results of all scoring functions and interactions, which suggested a good binding to carbonic anhydrase. So, it was predicted from the inferred results that these molecules might be considered as promising medicinal scaffolds for various diseases related to the uncontrolled production of this enzyme.     

Efficient synthetic route toward biologically active γ-carboline derivatives

An efficient and short route was established for the synthesis of anti-bovine viral diarrhea virus agents, namely 4-methyl-γ-carboline (SK4M) 1, 3-methyl-γ-carboline (SK3M) 2, 5-methyl-γ-carboline (SK5M) 3, and a new γ-carboline derivative 4, using thermal electrocyclization reaction as a key step. The evaluation of cytotoxicity of compound 4 against human cervical cancer cell line HeLa and leukemic cell line HL-60 furnished CC₅₀ value of 19.5 and 18.8 µM respectively.     

Investigation on novel thermoplastic poly(urethane-thiourea-imide)s with enhanced chemical and heat resistance

A new generation of segmented thermoplastic poly(urethane-thiourea-imide)s (PUTIs) was synthesized via reaction of polyethylene glycol and thiourea-based prepolymer with dianhydride as chain extenders. NCO-terminated prepolymer was synthesized from a new diisocyanate, 3-(3-((4-isocyanatophenyl)carbamoyl)thioureido)phenyl-4-isocyanatophenylcarbamate (IPCT), as a hard segment and PEG forming soft segment. The starting materials and polymers were characterized by conventional methods and physical properties such as solubility, solution viscosity, molecular weight, thermal stability and thermal behavior were studied. PUTIs showed partially crystalline structures. Weight average molecular weights of PUTIs (GPC measurements) were in the range of 1,68,694-1,97,035. Moreover, thermogravimetric analysis indicated that poly(urethane-thiourea-imide)s were fairly stable above 500 °C having T₁₀ of 521-543 °C. Investigation of the results authenticated the approach of introducing thiourea (using IPCT) and imide structure in polyurethanes for the improvement of thermal stability. In comparison to typical polyurethanes, these polymers exhibited better heat resistance, chemical resistance as well as processability.     

Influence of substitution on the strength and nature of CH···N hydrogen bond in XCCH···NH3 complexes

The effect of substitution on the strength and nature of CH···N hydrogen bond in XCCH···NH₃ (X = F, Cl, Br, OH, H, Me) and NCH···NH₃ complexes were investigated by quantum chemical calculations. Ab initio calculations were performed using MP2 method with a wide range of basis sets. With tacking into account the BSSE and ZPVE, the values of BEs decrease. Replacement of the nonparticipatory hydrogen atom of HCCH by the electronegative atoms (F, Cl, and Br), lead to the BEs increases. The BE corresponding to the replacement of the nonparticipatory hydrogen atom of HCCH by the OH and CH₃ groups decreases. A far greater enhancement of the interaction energy arises from replacement of HCCH by the more acidic HCN. The natural bond orbital analysis and the Bader's quantum theory of atoms in molecules were also used to elucidate the interaction characteristics of these complexes. The electrostatic nature of H‐bond interactions is predicted from QTAIM analysis. In addition, the relationship between the isotropic and anisotropic chemical shifts of the bridging hydrogen and binding energy of complexes as well as electron density at N···H BCPs were investigated. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem, 2011