Molecular docking studies of different phytochemicals obtained from medicinal Plants of Uttarakhand region for identification of potential inhibitors against mucormycosis causing fungal species

Mucormycosis is an insidious fungal infection caused by members of Mucorales and zygomycotic species. During the last few years, mucormycosis has become the third most common invasive fungal infection in patients with haematological malignancies and organ transplantations. The incidence of mucormycosis is particularly high in patients with immunocompromised health. It has been reported that CotH receptor proteins have a potential role in binding  Rhizopus species with the host cells. Further, CotH1, CotH2, and CotH3 are the spore-coating protein of mucormycosis, which are mostly responsible for the invasion of host cells and causing diseases. The present study aimed to predict the structure of CotH1, CotH2, and CotH3 receptors in Rhizpous delemar using homology modelling on SWISS Server and validated the model based on GMQE and QMEAN scores followed by analysis of the predicted model on Ramachandran plot. Further, molecular docking studies of the predominant 46 phytochemicals found in the medicinal plants of Uttarakhand region, India were done against these three receptors. Autodock vina results have shown that the binding energy value of Curcumin was -8.5 Kcal/mol against CotH1, and the binding energy value of Allosecurinin was  -7.6 Kcal/mol against CotH2 and binding energy value of Isoquercetin was -7.7 Kcal/mol against CotH3. Evaluation of the ADMET parameters has shown the high efficacy of these compounds. The present Insilico study suggests that Curcumin, Allosecurinine, and Isoquercetin are effective lead molecules against the receptors CotH1, CotH2, and CotH3 in the mucormycosis caused by fungal species R. delemar

The Mystery of Two Straight Lines in Bacterial Genome Statistics. Release 2007

In special coordinates (codon position--specific nucleotide frequencies) bacterial genomes form two straight lines in 9-dimensional space: one line for eubacterial genomes, another for archaeal genomes. All the 348 distinct bacterial genomes available in Genbank in April 2007, belong to these lines with high accuracy. The main challenge now is to explain the observed high accuracy. The new phenomenon of complementary symmetry for codon position--specific nucleotide frequencies is observed. The results of analysis of several codon usage models are presented. We demonstrate that the mean--field approximation, which is also known as context--free, or complete independence model, or Segre variety, can serve as a reasonable approximation to the real codon usage. The first two principal components of codon usage correlate strongly with genomic G+C content and the optimal growth temperature respectively. The variation of codon usage along the third component is related to the curvature of the mean-field approximation. First three eigenvalues in codon usage PCA explain 59.1%, 7.8% and 4.7% of variation. The eubacterial and archaeal genomes codon usage is clearly distributed along two third order curves with genomic G+C content as a parameter.Comment: Significantly extended version with new data for all the 348 distinct bacterial genomes available in Genbank in April 200

A Novel Heterocyclic Compound CE-104 Enhances Spatial Working Memory in the Radial Arm Maze in Rats and Modulates the Dopaminergic System

Various psychostimulants targeting monoamine neurotransmitter transporters (MAT) have been shown to rescue cognition in patients with neurological disorders and improve cognitive abilities in healthy subjects at low doses. Here, we examined the effects upon cognition of a chemically synthetized novel MAT inhibiting compound 2-(benzhydrylsulfinylmethyl)-4-methylthiazole (named as CE-104). The efficacy of CE-104 in blocking MAT (DAT – dopamine transporter, SERT – serotonin transporter and NET – norepinephrine transporter) was determined using in vitro neurotransmitter uptake assay. The effect of the drug at low doses (1 and 10mg/kg) on spatial memory was studied in male rats in the radial arm maze (RAM). Furthermore, the dopamine receptor and transporter complex levels of frontal cortex (FC) tissue of trained and untrained animals treated either with the drug or vehicle were quantified on blue native PAGE (BN-PAGE). The drug inhibited dopamine (IC50: 27.88µM) and norepinephrine uptake (IC50: 160.40µM), but had a negligible effect on SERT. In the RAM, both drug-dose groups improved spatial working memory during the performance phase of RAM as compared to vehicle. BN-PAGE western blot quantification of dopamine receptor and transporter complexes revealed that D1, D2, D3 and DAT complexes were modulated due to training and by drug effects. The drug’s ability to block DAT and its influence on dopamine transporter and receptor complex levels in the FC is proposed as a possible mechanism for the observed learning and memory enhancement in the RAM

Amino Acid Usage Is Asymmetrically Biased in AT- and GC-Rich Microbial Genomes.

INTRODUCTION: Genomic base composition ranges from less than 25% AT to more than 85% AT in prokaryotes. Since only a small fraction of prokaryotic genomes is not protein coding even a minor change in genomic base composition will induce profound protein changes. We examined how amino acid and codon frequencies were distributed in over 2000 microbial genomes and how these distributions were affected by base compositional changes. In addition, we wanted to know how genome-wide amino acid usage was biased in the different genomes and how changes to base composition and mutations affected this bias. To carry this out, we used a Generalized Additive Mixed-effects Model (GAMM) to explore non-linear associations and strong data dependences in closely related microbes; principal component analysis (PCA) was used to examine genomic amino acid- and codon frequencies, while the concept of relative entropy was used to analyze genomic mutation rates. RESULTS: We found that genomic amino acid frequencies carried a stronger phylogenetic signal than codon frequencies, but that this signal was weak compared to that of genomic %AT. Further, in contrast to codon usage bias (CUB), amino acid usage bias (AAUB) was differently distributed in AT- and GC-rich genomes in the sense that AT-rich genomes did not prefer specific amino acids over others to the same extent as GC-rich genomes. AAUB was also associated with relative entropy; genomes with low AAUB contained more random mutations as a consequence of relaxed purifying selection than genomes with higher AAUB. CONCLUSION: Genomic base composition has a substantial effect on both amino acid- and codon frequencies in bacterial genomes. While phylogeny influenced amino acid usage more in GC-rich genomes, AT-content was driving amino acid usage in AT-rich genomes. We found the GAMM model to be an excellent tool to analyze the genomic data used in this study

Hexammineruthenium(III) ion interactions with Z-­DNA

The structure of the complex of the hexanucleotide duplex d(CGCGCA)·d(TGCGCG) with hexammineruthenium(III) ion shows a tautomeric shift in the adenine base and a consequent disruption of the A·T base pair

Influence of Sacrificial Cathodic Protection on the Chloride Profile in Concrete

The durability of reinforced concrete structures significantly depends on the condition of the steel embedded in them. Structures exposed to chloride containing environment have reduced durability due to corrosion of the reinforcement steel. Several diffusion models have been proposed for chloride penetration. They mainly aim at predicting the initiation of corrosion of the reinforcement. They are based on diffusion conditions influenced by parameters such as relative humidity, temperature, rains etc. This work presents the influence of sacrificial cathodic protection on the chloride profile in concrete. Cathodic protection to the embedded steel in concrete was established by plugging-in a sacrificial magnesium alloy anode at the center of the slab and providing an electrical link between them. The current flowing between the magnesium anode and the embedded steel was regularly measured. The water soluble chloride content at different distances from the anode and at different times was determined after implementation of cathodic protection. The chloride content decreased at different distances from the anode, with increase in time. The diffusion of chloride occurred at a more accelerated rate due to the flow of cathodic protection current

R-Modafinil exerts weak effects on spatial memory acquisition and dentate gyrus synaptic plasticity

<div><p>Modafinil is a wake promoting drug approved for clinical use and also has cognitive enhancing properties. Its enantiomer R-Modafinil (R-MO) is not well studied in regard to cognitive enhancing properties. Hence we studied its effect in a spatial memory paradigm and its possible effects on dentate gyrus long-term potentiation (DG-LTP). Clinically relevant doses of R-MO, vehicle dimethyl sulfoxide (DMSO) or saline were administered for three days during the hole-board test and in <i>in vivo</i> DG-LTP. Synaptic levels of dopamine receptors D1R, D2R, dopamine transporter (DAT), and its phosphorylated form (ph-DAT) in DG tissue 4 h after LTP induction were quantified by western blot analysis. Monoamine reuptake and release assays were performed by using transfected HEK-293 cells. Possible neurotoxic side effects on general behaviour were also studied. R-MO at both doses significantly enhanced spatial reference memory during the last training session and during memory retrieval compared to DMSO vehicle but not when compared to saline treated rats. Similarly, R-MO rescues DG-LTP from impairing effects of DMSO. DMSO reduced memory performance and LTP magnitude when compared to saline treated groups. The synaptic DR1 levels in R-MO groups were significantly decreased compared to DMSO group but were comparable with saline treated animals. We found no effect of R-MO in neurotoxicity tests. Thus, our results support the notion that LTP-like synaptic plasticity processes could be one of the factors contributing to the cognitive enhancing effects of spatial memory traces. D1R may play an important regulatory role in these processes.</p></div

Predictive Analytics for Glaucoma Using Data From the All of Us Research Program

PurposeTo (1) use All of Us (AoU) data to validate a previously published single-center model predicting the need for surgery among individuals with glaucoma, (2) train new models using AoU data, and (3) share insights regarding this novel data source for ophthalmic research.DesignDevelopment and evaluation of machine learning models.MethodsElectronic health record data were extracted from AoU for 1,231 adults diagnosed with primary open-angle glaucoma. The single-center model was applied to AoU data for external validation. AoU data were then used to train new models for predicting the need for glaucoma surgery using multivariable logistic regression, artificial neural networks, and random forests. Five-fold cross-validation was performed. Model performance was evaluated based on area under the receiver operating characteristic curve (AUC), accuracy, precision, and recall.ResultsThe mean (standard deviation) age of the AoU cohort was 69.1 (10.5) years, with 57.3% women and 33.5% black, significantly exceeding representation in the single-center cohort (P&nbsp;=&nbsp;.04 and P &lt; .001, respectively). Of 1,231 participants, 286 (23.2%) needed glaucoma surgery. When applying the single-center model to AoU data, accuracy was 0.69 and AUC was only 0.49. Using AoU data to train new models resulted in superior performance: AUCs ranged from 0.80 (logistic regression) to 0.99 (random forests).ConclusionsModels trained with national AoU data achieved superior performance compared with using single-center data. Although AoU does not currently include ophthalmic imaging, it offers several strengths over similar big-data sources such as claims data. AoU is a promising new data source for ophthalmic research