Mechanism of the Exchange Reaction in HRAS from Multiscale Modeling

HRAS regulates cell growth promoting signaling processes by cycling between active (GTP-bound) and inactive (GDP-bound) states. Understanding the transition mechanism is central for the design of small molecules to inhibit the formation of RAS-driven tumors. Using a multiscale approach involving coarse-grained (CG) simulations, all-atom classical molecular dynamics (CMD; total of 3.02 µs), and steered molecular dynamics (SMD) in combination with Principal Component Analysis (PCA), we identified the structural features that determine the nucleotide (GDP) exchange reaction. We show that weakening the coupling between the SwitchI (residues 25–40) and SwitchII (residues 59–75) accelerates the opening of SwitchI; however, an open conformation of SwitchI is unstable in the absence of guanine nucleotide exchange factors (GEFs) and rises up towards the bound nucleotide to close the nucleotide pocket. Both I21 and Y32, play a crucial role in SwitchI transition. We show that an open SwitchI conformation is not necessary for GDP destabilization but is required for GDP/Mg escape from the HRAS. Further, we present the first simulation study showing displacement of GDP/Mg away from the nucleotide pocket. Both SwitchI and SwitchII, delays the escape of displaced GDP/Mg in the absence of GEF. Based on these results, a model for the mechanism of GEF in accelerating the exchange process is hypothesized.     

Catheter ablation of recurrent polymorphic tachycardia: Use of sodium channel blockade to organize the tachycardia: A case report

A 55 year old male presented with recurrent implantable cardioverter defibrillator (ICD) shocks due to polymorphic ventricular tachycardia (PMVT). He had undergone prior catheter ablation for VT three years ago. During the prior attempt he underwent voltage guided substrate ablation. With programmed ventricular extrastimulation (PVES), PMVT was repeatedly induced requiring DC shock. Intravenous procainamide was administered and PVES was repeated which induced sustained monomorphic ventricular tachycardia (MMVT). This VT had pseudo delta waves with maximum deflection index of 0.68, suggestive of epicardial origin. Activation mapping was performed epicardially. Presystolic potentials were recorded in mid anterolateral wall of left ventricular epicardial region. Radiofrequency (RF) ablation at this site terminated the VT. Post ablation there was no inducible tachycardia and patient is free of arrhythmias during 2 years of follow-up.     

Pharmaceutical perspective on bioactives from Alstonia scholaris: ethnomedicinal knowledge,phytochemistry, clinical status,patent space,and future directions

Phytochemistry Reviews - Alstonia scholaris (L.) R. Br (Apocynaceae), a tropical tree native to Indian subcontinent, Australasia, and Malay Peninsula is well documented in Traditional Chinese...     

Substrate desolvation as a governing factor in enzymatic transformations of PAHs in aqueous-acetonitrile mixtures

Conversion of hydrophobic substrates such as polyaromatic hydrocarbons (PAHs) was studied in aqueous-organic media using transformation of pyrene by cytochrome c. The experiments were conducted in pure solvents and aqueous-acetonitrile mixtures. The reaction rates dropped gradually as the solvent concentration was increased and were negligible in pure solvents. Thermodynamic calculations show that substrate desolvation was the governing factor in this reaction. The decrease in free energy of activation upon increasing the solvent concentration was found to be proportional to the substrate transfer free energy. This suggests that in order to make such reactions feasible in organic media, it will be necessary to improve the binding between the proteins and the substrates.     

Nucleus implant parameters significantly change the compressive stiffness of the human lumbar intervertebral disc

Nucleus replacement by a synthetic material is a recent trend for treatment of lower back pain. Hydrogel nucleus implants were prepared with variations in implant modulus, height, and diameter Human lumbar intervertebral discs (IVDs) were tested in compression for intact, denucleated, and implanted condition. Implantation of nucleus implants with different material and geometric parameters into a denucleated IVD significantly altered the IVD compressive stiffness. Variations in the nucleus implant parameters significantly change the compressive stiffness of the human lumbar IVD. Implant geometrical variations were more effective than those of implant modulus variations in the range examined.     

Intensity enhancement of photoluminescence in Tb3+/Eu3+ co-doped Ca14Zn6Al10O35 phosphor for WLEDs

This article focuses on the effect of monovalent cation doping on the optical properties of rare earth (RE = Eu³⁺, Tb³⁺) co-doped Ca₁₄Zn₆Al₁₀O₃₅ which has been synthesized by a low temperature combustion method. Crystalline phase of the Ca₁₄Zn₆Al₁₀O₃₅ phosphor was examined and confirmed by X-ray diffraction measurement. Under near-ultraviolet light excitation Eu³⁺-doped Ca₁₄Zn₆Al₁₀O₃₅ phosphor exhibit characterization of Eu³⁺ emission bands that are located at a maximum wavelength (λ_max) of approximately 470 nm and other peaks centred at 593 nm and 615 nm, respectively. With Tb³⁺-doped Ca₁₄Zn₆Al₁₀O₃₅ phosphor showing a green emission band centred at 544 nm under near-ultraviolet range. Furthermore, we studied the energy transfer process in Eu³⁺/Tb³⁺pair and enhancement in photoluminescence (PL) intensity with doping different charge compensation. Here we obtained the optimum PL emission intensity of the phosphor in broad and intense visible spectral range which may be significant for the fabrication of white light emitting diodes (WLEDs).     

Modeling <Emphasis Type="Italic">Euglena</Emphasis> sp. growth under different conditions using an artificial neural network

Microalgae are considered as the future source of biofuels because of their high biomass productivity and neutral lipid content as triacylglycerides (TAG). Microalgae have high photosynthetic efficiency and the possibility of being cultivated in different wastewaters. The isolation of potential microalgae followed by the optimization of cultivation conditions is prerequisite for successful cultivation and accumulation of high lipid content. In the present work, a three-layer artificial neural network (ANN) model is developed to predict the essential parameters (such as pH, temperature, light intensity, photoperiod, and medium composition) based on 156 sets of laboratory experiments for achieving maximum biomass from Euglena sp. The independent parameters (viz., temperature, light intensity, photoperiod and number of days at fixed pH, and media composition) were fed as input to the ANN, and biomass yield was investigated. The comparison of the simulated environmental conditions using the ANN model and experimental results are found to have an excellent correlation coefficient of about 0.97 for the model variables used in this study. The model results established that artificial neural network design may be judiciously employed for optimization of different environmental conditions for this isolated microalga.     

Assessment of Crop Damage by Protected Wild Mammalian Herbivores on the Western Boundary of Tadoba-Andhari Tiger Reserve (TATR), Central India

Crop raiding by wild herbivores close to an area of protected wildlife is a serious problem that can potentially undermine conservation efforts. Since there is orders of magnitude difference between farmers’ perception of damage and the compensation given by the government, an objective and realistic estimate of damage was found essential. We employed four different approaches to estimate the extent of and patterns in crop damage by wild herbivores along the western boundary of Tadoba-Andhari Tiger Reserve in the state of Maharashtra, central India. These approaches highlight different aspects of the problem but converge on an estimated damage of over 50% for the fields adjacent to the forest, gradually reducing in intensity with distance. We found that the visual damage assessment method currently employed by the government for paying compensation to farmers was uncorrelated to and grossly underestimated actual damage. The findings necessitate a radical rethinking of policies to assess, mitigate as well as compensate for crop damage caused by protected wildlife species.     

Early selective strategies for higher yielding bio-economic Indian ginseng based on genotypic study through metabolic and molecular markers

Applying biotechnological tools to the selection of higher-yielding bioeconomic crops is a promising and remarkable means of reducing the burden on production on a global scale. In the present study, 25 germplasms of Indian ginseng (Withania somnifera (L.) Dunal) were examined for their genetic diversity by using morphological, biochemical, and molecular markers for twenty plant growth traits. The properties of plant growth differed significantly in the maximum genotypes of Indian ginseng, the markers of randomly amplified polymorphic DNA (RAPD), and inter simple sequence repeat (ISSR) showed considerable diversity between the genotypes. The combined unweighted pair group technique with arithmetic mean (UPGMA) dendrogram of morphological, biochemical, and molecular markers grouped all 25 genotypes into two main clusters at 0.61 coefficient value. In addition to this, secondary metabolite profiling by high-performance liquid chromatography (HPLC), there were high variations for withanolide B (WL-B), withanoside-V (WS-V), wedelolactone (WDL), withanoside-IV (WS-IV), and withaferin A (WF-A) content between different genotypes. For the total alkaloid and withanolide concentration in the roots and leaves, high heritability with an increased genetic gain was observed, indicating that selection based on these traits could be an effective method in breeding programs. Furthermore, the path coefficient analysis showed a direct positive impact of the total root fiber, WL-B (leaves), WF-A (leaves), WS-IV (roots), WDL (roots), and the total alkaloid content on the dry root yield. High content of WDL, a high-quality bioactive withanolide, was also described for the first time in the genotype UWS23. These properties can further be exploited to improve the dry root yield in W. somnifera genotypes. The outcomes of the present study also provide an essential foundation for the selection of high-yielding bioeconomic varieties that could be utilized to improve Ashwagandha breeding programs.