Existence, uniqueness and stability results of impulsive stochastic semilinear neutral functional differential equations with infinite delays

This article presents the results on existence, uniqueness and stability of mild solutions of impulsive stochastic semilinear neutral functional differential equations without a Lipschitz condition and with a Lipschitz condition. The results are obtained by using the method of successive approximations

GmMYB176 Interactome and Regulation of Isoflavonoid Biosynthesis in Soybean

MYB transcription factors are one of the largest transcription factor families characterized in plants. They are classified into four types: R1 MYB, R2R3 MYB, R3 MYB and R4 MYB. GmMYB176 is an R1MYB transcription factor that regulates Chalcone synthase (CHS8) gene expression and isoflavonoid biosynthesis in soybean. Silencing of GmMYB176 suppressed the expression of the GmCHS8 gene and reduced the accumulation of isoflavonoids in soybean hairy roots. However, overexpression of GmMYB176 does not alter either GmCHS8 gene expression or isoflavonoid levels suggesting that GmMYB176 alone is not sufficient for GmCHS8 gene regulation. I hypothesized that GmMYB176 acts cooperatively with another factor(s) for the regulation of GmCHS8 gene expression and it may also regulate other isoflavonoid biosynthetic genes in soybean. The objective of this research was to identify the GmMYB176 interactome for GmCHS8 gene regulation and elucidate the role of GmMYB176 in isoflavonoid biosynthesis in soybean. GmMYB176 interacting proteins were identified using two translational fusion baits (GmMYB176-YFP and YFP-GmMYB176) by co-immunoprecipitation, followed by liquid chromatography-tandem mass spectrometry. The interaction of selected candidates with GmMYB176 was validated in planta and their DNA binding activities determined. GmMYB176 may form a transcriptional complex with Gm04bZIP and/or Gm05bZIP for the regulation of GmCHS8 gene expression. RNA-seq and metabolomics analyses of soybean hairy roots in which GmMYB176 was either silenced or over-expressed revealed that GmMYB176 regulates multiple genes in the isoflavonoid biosynthesis pathway, affecting the production of metabolites in phenylpropanoid pathway such as phenylalanine, liquiritigenin, daidzin, genistin, glycitein, and glyceollin. The knowledge and information generated on the role of GmMYB176 in the regulation of isoflavonoid biosynthesis will allow genetic manipulation of isoflavonoid level in soybean and/or introduce isoflavonoid pathway in non-legumes

Anti-Periodic Boundary Value Problem for Impulsive Fractional Integro Differential Equations

MSC 2010: 34A37, 34B15, 26A33, 34C25, 34K37In this paper we prove the existence of solutions for fractional impulsive differential equations with antiperiodic boundary condition in Banach spaces. The results are obtained by using fractional calculus' techniques and the fixed point theorems

Mild solutions of Riemann–Liouville fractional differential equations with fractional impulses

We consider Riemann–Liouville fractional differential equations with fractional-order derivative in the impulsive conditions. We study the existence of the mild solution by applying the Laplace transform method and (a,k)-regularized resolvent operator. We use the contraction mapping principle and fixed point theorem for condensing map to prove our existence results

Design, Synthesis and Biological Evaluation of Novel Saccharin Derivatives as Anti-Tubercular Agents Targeting Glutamine Synthetase

Glutamine synthetase I is a vital enzyme present in the cell wall of Mycobacterium tuberculosis H37Rv. It belongs to the Ligase family was chosen after the review of literature. • A database of 500 molecules with high prospects of inhibiting the target Glutamine synthetase I were carefully chosen by making changes to the known hit molecules, here the saccharin nucleus was chosen. • The designed molecules were docked against the target chosen using AutoDock 4® TOOLS 1.5.6 software. • Seven molecules (AMA-1, AMA-2, AMA-3, AMA-4, AMA-5, AMA-6 and AMA-7) with good docking score [lower binding energy] and interactions were shortlisted for synthesis. • The selected molecules were subjected to toxicity prediction assessment by OSIRIS® property explorer developed by Acetilon Pharmaceuticals limited which is available online. The results are color coded as green color which predicts the drug likeness and possibly better activity. • The reaction condition were optimized, synthesized and labelled as BOB, CIN, NIB, OHB, PHB. • The characterization of the synthesized compounds was done using TLC, Melting point Infra-red, Mass spectrometric methods [LC-MS] and Nuclear Magnetic Resonance [H1 NMR] spectroscopy methods. • All the Synthesized compounds exhibited molecular ion peak (M+) of varying intensities. • The final pure compounds were screened for Anti-mycobacterial activity by in vitro method called Microplate Alamar Blue Assay [MABA]. • The synthesized compounds showed sensitivity [Minimum inhibitory concentration] at 12.5mcg/ml. The standard drugs Isoniazide, Ethambutol, Pyrazinamide, rifampicin and and Streptomycin exhibited anti-mycobacterial activity at 1.6mcg/ml, 1.6mcg/ml, 3.125mcg/ml, 0.8mcg/ml and 0.8mcg/ml concentrations respectively. This indicates that the synthesized compounds are as Potent as the standard drugs. • Based on the MABA report, Acute Oral Toxicity study were performed and observed that the administration of the synthesized molecules by oral route upto 2000mg/kg/b.w is safe. CONCLUSION: The current research work concludes that, • Glutamine Synthetase I is one of the critical enzymes essential for the growth and survival of Mycobacterium tuberculosis. • Molecules designed to inhibit the target enzyme, showed better in vitro antitubercular activity in Microplate Alamar Blue Assay (MABA). There is a correlation between the in silico molecular docking scores and In vitro antitubercular activity results. • The compounds AMA-3, AMA-4 & AMA-5 have the docking scores of -8.59, -8.68 & -8.05 Kcal/mol and were able to inhibit the growth of the organism even at the concentration of 12.5μg/ml. The Anti-tubercular activity of the compounds was found to be less superior than the Standard Anti-tubercular agents. • The molecules were also docked against the other critical enzymes of Mycobacterium tuberculosis. The obtained docking scores showed that the molecules were able to inhibit multiple enzymes which are necessary for the survival of the organism. • Therefore, further refinement of the molecular structure of the synthesized compounds will expected to yield promising drug candidates against the deadly disease

Genomic aberrations in normal tissue adjacent to HER2-amplified breast cancers: field cancerization or contaminating tumor cells?

Field cancerization effects as well as isolated tumor cell foci extending well beyond the invasive tumor margin have been described previously to account for local recurrence rates following breast conserving surgery despite adequate surgical margins and breast radiotherapy. To look for evidence of possible tumor cell contamination or field cancerization by genetic effects, a pilot study (Study 1: 12 sample pairs) followed by a verification study (Study 2: 20 sample pairs) were performed on DNA extracted from HER2-positive breast tumors and matching normal adjacent mammary tissue samples excised 1-3 cm beyond the invasive tumor margin. High-resolution molecular inversion probe (MIP) arrays were used to compare genomic copy number variations, including increased HER2 gene copies, between the paired samples; as well, a detailed histologic and immunohistochemical (IHC) re-evaluation of all Study 2 samples was performed blinded to the genomic results to characterize the adjacent normal tissue composition bracketing the DNA-extracted samples. Overall, 14/32 (44 %) sample pairs from both studies produced genome-wide evidence of genetic aberrations including HER2 copy number gains within the adjacent normal tissue samples. The observed single-parental origin of monoallelic HER2 amplicon haplotypes shared by informative tumor-normal pairs, as well as commonly gained loci elsewhere on 17q, suggested the presence of contaminating tumor cells in the genomically aberrant normal samples. Histologic and IHC analyses identified occult 25-200 μm tumor cell clusters overexpressing HER2 scattered in more than half, but not all, of the genomically aberrant normal samples re-evaluated, but in none of the genomically normal samples. These genomic and microscopic findings support the conclusion that tumor cell contamination rather than genetic field cancerization represents the likeliest cause of local clinical recurrence rates following breast conserving surgery, and mandate caution in assuming the genomic normalcy of histologically benign appearing peritumor breast tissue

Context matters-consensus molecular subtypes of colorectal cancer as biomarkers for clinical trials

The Colorectal Cancer Subtyping Consortium identified four gene expression consensus molecular subtypes, CMS1 (immune), CMS2 (canonical), CMS3 (metabolic), and CMS4 (mesenchymal), using multiple microarray or RNA-sequencing datasets of primary tumor samples mainly from early stage colon cancer patients. Consequently, rectal tumors and stage IV tumors (possibly reflective of more aggressive disease) were underrepresented, and no chemo-and/or radiotherapy pretreated samples or metastatic lesions were included. In view of their possible effect on gene expression and consequently subtype classification, sample source and treatments received by the patients before collection must be carefully considered when applying the classifier to new datasets. Recently, several correlative analyses of clinical trials demonstrated the applicability of this classification to the metastatic setting, confirmed the prognostic value of CMS subtypes after relapse and hinted at differential sensitivity to treatments. Here, we discuss why contexts and equivocal factors need to be taken into account when analyzing clinical trial data, including potential selection biases, type of platform, and type of algorithm used for subtype prediction. This perspective article facilitates both our clinical and research understanding of the application of this classifier to expedite subtype-based clinical trials

MCAM: A Database to Accelerate the Identification of Functional Cell Adhesion Molecules

In the post-genomic era, computational identification of cell adhesion molecules (CAMs) becomes important in defining new targets for diagnosis and treatment of various diseases including cancer. Lack of a comprehensive CAM-specific database restricts our ability to identify and characterize novel CAMs. Therefore, we developed a comprehensive mammalian cell adhesion molecule (MCAM) database. The current version is an interactive Web-based database, which provides the resources needed to search mouse, human and rat-specific CAMs and their sequence information and characteristics such as gene functions and virtual gene expression patterns in normal and tumor tissues as well as cell lines. Moreover, the MCAM database can be used for various bioinformatics and biological analyses including identifying CAMs involved in cell-cell interactions and homing of lymphocytes, hematopoietic stem cells and malignant cells to specific organs using data from high-throughput experiments. Furthermore, the database can also be used for training and testing existing transmembrane (TM) topology prediction methods specifically for CAM sequences. The database is freely available online at http://app1.unmc.edu/mcam

GmMYB176 Regulates Multiple Steps in Isoflavonoid Biosynthesis in Soybean

Isoflavonoids are a group of plant natural compounds synthesized almost exclusively by legumes, and are abundant in soybean seeds and roots. They play important roles in plant-microbial interactions and the induction of nod gene expression in Rhizobia that form nitrogen-fixing nodules on soybean roots. Isoflavonoids also contribute to the positive health effects associated with soybean consumption by humans and animals. An R1 MYB transcription factor GmMYB176 regulates isoflavonoid biosynthesis by activating chalcone synthase (CHS) 8 gene expression in soybean. Using a combination of transcriptomic and metabolomic analyses of GmMYB176-RNAi silenced (GmMYB176-Si), GmMYB176-overexpressed (GmMYB176-OE), and control soybean hairy roots, we identified a total of 33 differentially expressed genes (DEGs) and 995 differentially produced metabolite features (DPMF) in GmMYB176-Si hairy roots, and 5727 DEGs and 149 DPMFs in GmMYB176-OE hairy roots. By a targeted approach, 25 isoflavonoid biosynthetic genes and 6 metabolites were identified as differentially regulated in GmMYB176-OE and GmMYB176-Si soybean hairy roots. Taken together, our results demonstrate the complexity of isoflavonoid biosynthesis in soybean roots and suggest that a coordinated expression of pathway genes, substrate flux and product threshold level may contribute to the dynamic of the pathway regulation