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author:("majumder, A.")
1.  ANTIMICROBIAL ACTIVITY OF THE MYCOTOXIN CITRININ OBTAINED FROM THE FUNGUS PENICILLIUM CITRINUM 
Ancient Science of Life  2002;21(3):191-197.
The mycotoxin Citrinin was obtained from the fungus Penicillium citrinum. It was tested for it's Minimum Inhibitory Concentration (MIC) against some gram positive strains viz. Staphylococcus aureus, Bacillus pumilus, Bacillus subtillis, Bacillus cereus, Klebsiella pneumoniae, Streptococcus pneumoniae, Lactobacillus arabinosus and gram negative strains E.Coli, Shigella dysenteriae, shigella sonnei, shigella boydii, Salmonella typhimurium, Proteus mirabilis and Vibrio cholerae. Further the zones of inhibition produced by the fungal extract against the bacterial strains were assayed and compared with those produced by the standard antibiotic ciprofloxacin.
PMCID: PMC3331043  PMID: 22557053
2.  Pharmacognostical and Phytochemical Evaluation of the leaves of Bauhinia purpurea Linn. 
Ancient Science of Life  2010;30(2):28-32.
Various pharmacognostic parameters including macroscopy, microscopy, chemomicroscopy and behaviour of powdered drug on treatment with different chemical reagents were studied on the leaves of Bauhinia purpurea Linn. (Family Caesalpinaceae). Phytochemical screening of the plant part with various solvents revealed the presence of phenolic compounds, tannins, flavonoids, phytosterols, saponins and glycosides in it.
PMCID: PMC3336273  PMID: 22557422
3.  Arsenic Contamination of Ground Water and its Health Impact on Population of District of Nadia, West Bengal, India 
Background:
The global health impact and disease burden due to chronic arsenic toxicity has not been well studied in West Bengal.
Objective:
To ascertain these, a scientific epidemiological study was carried out in a district of the state.
Materials and Methods:
Epidemiological study was carried out by house-to-house survey of arsenic affected villages in the district of Nadia. A stratified multi-stage design has been adopted for this survey for the selection of the participants. A total number of 2297 households of 37 arsenic affected villages in all the 17 blocks were surveyed in the district.
Result:
Out of 10469 participants examined, prevalence rate of arsenicosis was found to be 15.43%. Out of 0.84 million people suspected to be exposed to arsenic, 0.14 million people are estimated to be suffering from arsenicosis in the district. Highest level of arsenic in drinking water sources was found to be 1362 μg/l, and in 23% cases it was above 100 μg/l. Majority of the population living in the arsenic affected villages were of low socio-economic condition, inadequate education and were farmers or doing physical labour. Chronic lung disease was found in 207 (12.81%) subjects among cases and 69 (0.78%) in controls. Peripheral neuropathy was found in 257 (15.9%) cases and 136 (1.5%) controls.
Conclusion:
Large number of people in the district of Nadia are showing arsenical skin lesion. However, insufficient education, poverty, lack of awareness and ineffective health care support are major factors causing immense plight to severely arsenic affected people.
doi:10.4103/0970-0218.66897
PMCID: PMC2940197  PMID: 20922118
Arsenic; toxicants; arsenic and systemic manifestations; arsenic and socio-economic issues; disease burden; skin manifestations
4.  Anthelmintic activity of root bark of Carissa carandas 
Ancient Science of Life  2007;27(1):11-13.
The anthelmintic activity of the Imethanolic extract of the root bark of Carissa carandas was evaluated on adult Indian earthworm (Pheretima posthuma) using albendazole as a reference standard. The extract caused paralysis followed by the death of worm at the tested dose level. The extract at the highest tested concentration has anthelmintic activity comparable with that of standard drug albendazole.
PMCID: PMC3330840  PMID: 22557253
5.  Studies on Pharmacognostical features of Curcuma domestica Val. 
Ancient Science of Life  2007;26(4):37-41.
The microscopic and macroscopic characters of the rhizome of Curcuma domestica Val. were studied. The behavior of the powdered drug in the presence of various chemicals was also studied. Preliminary phytochemical screening on the various extracts of the rhizome was done in order to ascertain the various chemical constituents present. These studies were carried out to identify this plant for future research work.
PMCID: PMC3330885  PMID: 22557249
6.  PHARMACOGNOSTICAL STUDIES ON THE LEAVES OF Cassia tora Linn. (FAM. CAESALPINIACEAE) 
Ancient Science of Life  2005;25(2):74-78.
The leaves and seeds of Cassia tora (Family Caesalpinaceae) are used in the treatment of leprosy, ring worm, flatulence, colic, dyspepsia, constipation, cough, bronchitis and cardiac disorders in the Ayurvedic systems of medicine. The present study deals with the study of macroscopic characters of the leaves, ash values, extractive values, behavior on treatment with different chemical reagents and fluorescence characters under ultraviolet light. Preliminary phytochemical studies on different extractives of the leaves were also performed. These studies will help in the identification of the plant for further research.
PMCID: PMC3330902  PMID: 22557196
7.  EMERGENCE OF MESUA FERREA LINN. LEAF EXTRACT AS A POTENT BACTERICIDE 
Ancient Science of Life  2003;22(4):160-165.
The methanolic extract of leaves of Mesua ferrea Linn. were tested for its antibacterial potentiality against 103 various strains of bacteria including Staphylococcus aureus, Bacillus spps. Klebsiella spps., Streptococus pneumoniae, Sarcina lutea, Lactobacilus arabinosus, Escherichia coli, shigellae, salmonellae, Proteus spps., Pseudomonas spps. and the vibrios. Significant antibacterial effects were produced by the extract against Staphylococcus aureus, Bacillus sppa., lactobacilli, Escherichia coli, shigellae and salmonellae and the results were compared with standard antibiotic ciprofloxacin. Further the extract was proved to be bacterial in its action.
PMCID: PMC3331016  PMID: 22557104
8.  ANTIMICROBIAL ACTION OF THE LEAF EXTRACT OF Lagerstroemia parviflora Roxb 
Ancient Science of Life  2002;21(3):198-201.
The benzene extract of the leaves of Lagerstroemia paviflora Roxb was tested for its Minimum Inhibitory Concentration (MIC) against Gram Positive Staphylococcus aureus, Bacillus subtilis, Bacillus cereus, Klebsiella pneumoniae, Streptococcus pneumoniae, Lactobacillus arabinosus and gram negative strains E.Coli, Shigella dysenteriae, shigella sonnei, shigella boydii, Salmonella typhimurium, Proteus mirabilis and Vibrio cholerae. Further the zones of inhibition Produced by the crude extract against four selected bacterial strains were measured and compared with those produced by the standard antibiotic Ciprofloxacin against the same bacterial strains.
PMCID: PMC3331035  PMID: 22557054
9.  Antimicrobial Potency of the Leaf – Stalk Extract of Curcuma longa (LINN) 
Ancient Science of Life  2000;20(1-2):92-96.
The methanolic extract of the leaf-stalk of curcuma longa LINN, was tested for its minimum Inhibitor concentration (MIC) against Gram positive-staphylococcus aureus, Bacillus pumilus, Bacillus subtilis, klebsiella pnemoniae, bacillus cereus, streptococcus pneumoniae, Lactobacillus arabinosus and gram negative E.coli, shigella dysenteriae, shigella sonnei, shigella boydii, salmonella typhimurium, proteus mirabilis, and Vibrio cholerae strains, further, the ones of inhibition produced by the crude extract against four selected bacterial strains were measured and compared with those produced by the standard antibiotic ciprofloxacin against the same bacterial strains.
PMCID: PMC3336426  PMID: 22557005
10.  Antagonistic Effect of Small Molecule Inhibitors of Wnt/β-catenin in Multiple Myeloma 
Anticancer research  2012;32(11):4697-4707.
Background
Development and progression of multiple myeloma is dependent on the bone marrow (BM) microenvironment, and within the BM, a number of factors are secreted, including the Wnt ligands. Bone marrow stromal cells (BMSC) secrete Wnt ligands that activate Wnt signaling in multiple myeloma. The canonical Wnt pathway which is, mediated through the transcriptional effector β-catenin (β-cat) is commonly deregulated in many cancers. Cells with active β-cat-regulated transcription (CRT) are protected against apoptosis; conversely inhibition of CRT may prevent cell proliferation.
Materials and Methods
In this study, we tested the efficacy of recently described inhibitors of CRT (iCRTs; oxazole and thiazole) for their selective antagonistic effect on Wnt-β-cat response in MM cells MM1, U266, BMSC and primary BMMC obtained from patient samples (n=16).
Results
We demonstrate that iCRTs we used block Wnt/β-cat reporter activity, down regulate β-cat expression and inhibit cell proliferation in a dose dependent manner with an optimal dose closer to 15 µM. Our data further indicate that iCRTs do not influence the expression of the upstream components of the Wnt pathway DKK1 at the optimal dose, suggesting that iCRTs may specifically target β-cat in MM cells. Additionally, iCRT-treatment of MM cells co-cultured with BMSC showed an inhibitory effect on VEGF and cell migration.
Conclusion
This study provides the first in vitro data evaluation of newly described iCRTs as potential Wnt-β-cat/VEGF pathway antagonists in multiple myeloma.
PMCID: PMC3983472  PMID: 23155232
Multiple myeloma; Wnt; β-catenin; transcription; VEGF and DKK1
11.  An extra-ribosomal function of ribosomal protein L13a in macrophage resolves inflammation 
Inflammation is an obligatory attempt of the immune system to protect the host from infections. However, unregulated synthesis of pro-inflammatory products can have detrimental effects. Although mechanisms that lead to inflammation are well appreciated, those that restrain it are not adequately understood. Creating macrophage-specific L13a-knockout (KO) mice here we report that depletion of ribosomal protein L13a abrogates the endogenous translation control of several chemokines in macrophages. Upon LPS-induced endotoxemia these animals displayed symptoms of severe inflammation caused by widespread infiltration of macrophages in major organs causing tissue injury and reduced survival rates. Macrophages from these KO animals show unregulated expression of several chemokines e.g. CXCL13, CCL22, CCL8 and CCR3. These macrophages failed to show L13a-dependent RNA binding complex formation on target mRNAs. In addition, increased polyribosomal abundance of these mRNAs shows a defect in translation control in the macrophages. Thus, our studies provide the first evidence of an essential extra-ribosomal function of ribosomal protein L13a in resolving physiological inflammation in a mammalian host.
doi:10.4049/jimmunol.1201933
PMCID: PMC3608820  PMID: 23460747
12.  SNVDis: A Proteome-wide Analysis Service for Evaluating nsSNVs in Protein Functional Sites and Pathways 
Genomics, proteomics & bioinformatics  2012;11(2):10.1016/j.gpb.2012.10.003.
Amino acid changes due to non-synonymous variation are included as annotations for individual proteins in UniProtKB/Swiss-Prot and RefSeq which present biological data in a protein- or gene-centric fashion. Unfortunately, proteome-wide analysis of non-synonymous single-nucleotide variations (nsSNVs) is not easy to perform because information on nsSNVs and functionally important sites are not well integrated both within and between databases and their search engines. We have developed SNVDis that allows evaluation of proteome-wide nsSNV distribution in functional sites, domains and pathways. More specifically, we have integrated human-specific data from major variation databases (UniProtKB, dbSNP and COSMIC), comprehensive sequence feature annotation from UniProtKB, Pfam, RefSeq, Conserved Domain Database (CDD) and pathway information from Protein ANalysis THrough Evolutionary Relationships (PANTHER) and mapped all of them in a uniform and comprehensive way to the human reference proteome provided by UniProtKB/Swiss-Prot. Integrated information of active sites, pathways, binding sites, domains, which are extracted from a number of different sources, provides a detailed overview of how nsSNVs are distributed over the human proteome and pathways and how they intersect with functional sites of proteins. Additionally, it is possible to find out whether there is an over- or under-representation of nsSNVs in specific domains, pathways or user-defined protein lists. The underlying datasets are updated once every three months. SNVDis is freely available at http://hive.biochemistry.gwu.edu/tool/snvdis.
doi:10.1016/j.gpb.2012.10.003
PMCID: PMC3807806  PMID: 23618375
Active site; Binding site; N-linked glycosylation; nsSNP; nsSNV; Variation
13.  A framework for organizing cancer-related variations from existing databases, publications and NGS data using a High-performance Integrated Virtual Environment (HIVE) 
Years of sequence feature curation by UniProtKB/Swiss-Prot, PIR-PSD, NCBI-CDD, RefSeq and other database biocurators has led to a rich repository of information on functional sites of genes and proteins. This information along with variation-related annotation can be used to scan human short sequence reads from next-generation sequencing (NGS) pipelines for presence of non-synonymous single-nucleotide variations (nsSNVs) that affect functional sites. This and similar workflows are becoming more important because thousands of NGS data sets are being made available through projects such as The Cancer Genome Atlas (TCGA), and researchers want to evaluate their biomarkers in genomic data. BioMuta, an integrated sequence feature database, provides a framework for automated and manual curation and integration of cancer-related sequence features so that they can be used in NGS analysis pipelines. Sequence feature information in BioMuta is collected from the Catalogue of Somatic Mutations in Cancer (COSMIC), ClinVar, UniProtKB and through biocuration of information available from publications. Additionally, nsSNVs identified through automated analysis of NGS data from TCGA are also included in the database. Because of the petabytes of data and information present in NGS primary repositories, a platform HIVE (High-performance Integrated Virtual Environment) for storing, analyzing, computing and curating NGS data and associated metadata has been developed. Using HIVE, 31 979 nsSNVs were identified in TCGA-derived NGS data from breast cancer patients. All variations identified through this process are stored in a Curated Short Read archive, and the nsSNVs from the tumor samples are included in BioMuta. Currently, BioMuta has 26 cancer types with 13 896 small-scale and 308 986 large-scale study-derived variations. Integration of variation data allows identifications of novel or common nsSNVs that can be prioritized in validation studies.
Database URL: BioMuta: http://hive.biochemistry.gwu.edu/tools/biomuta/index.php; CSR: http://hive.biochemistry.gwu.edu/dna.cgi?cmd=csr; HIVE: http://hive.biochemistry.gwu.edu
doi:10.1093/database/bau022
PMCID: PMC3965850  PMID: 24667251
14.  Structural Insights into the Ligand Binding and Releasing Mechanism of Antheraea polyphemus PBP1: Role of the C-terminal Tail 
Biochemistry  2013;52(6):1037-1044.
Pheromone-binding proteins (PBPs) in lepidopteran moths selectively transport the hydrophobic pheromone molecules across the sensillar lymph to trigger the neuronal response. Moth PBPs are known to bind ligand at physiological pH and release it at acidic pH while undergoing a conformational change. Two molecular switches are considered to play a role in this mechanism: (i) Protonation of His70 and His95 situated at one end of binding pocket, and (ii) Switch of the unstructured C-terminus at the other end of the binding pocket to a helix that enters the pocket. We have reported previously the role of the histidine-driven switch in ligand release for Antheraea polyphemus PBP1 (ApolPBP1). Here we show that the C-terminus plays a role in ligand release and binding mechanism of ApolPBP1. The C-terminus truncated mutants of ApolPBP1 (ApolPBP1ΔP129-V142 and ApolPBP1H70A/H95AΔP129-V142) exist only in the bound conformation at all pH levels, and they fail to undergo pH- or ligand- dependent conformational switch. Although these proteins could bind ligands even at acidic pH unlike the wild-type ApolPBP1, they had ~4 fold reduced affinity towards the ligand at both acidic and physiological pH than that of ApolPBP1wt and ApolPBP1H70A/H95A. Thus, apart from helping in the ligand-release at acidic pH, the C-terminus in ApolPBP1 also plays an important role in ligand binding and/or locking the ligand in the binding pocket. Our results are in stark contrast to those reported for BmorPBP and AtraPBP, where C-terminus truncated proteins had similar or increased pheromone-binding affinity at any pH.
doi:10.1021/bi301393v
PMCID: PMC3571721  PMID: 23327454
PBP; NMR; delipidation; ApolPBP1; Open conformation; close conformation
15.  Structure-based Comparative Analysis and Prediction of N-linked Glycosylation Sites in Evolutionarily Distant Eukaryotes 
The asparagine-X-serine/threonine (NXS/T) motif, where X is any amino acid except proline, is the consensus motif for N-linked glycosylation. Significant numbers of high-resolution crystal structures of glycosylated proteins allows us to carry out structural analysis of the N-linked glycosylation sites (NGS). Our analysis shows that there is enough structural information from diverse glycoproteins to allow development of rules which can be used to predict NGS. A Python-based tool was developed to investigate asparagines implicated in N-glycosylation in five species: Homo sapiens, Mus musculus, Drosophila melanogaster, Arabidopsis thaliana and Saccharomyces cerevisiae. Our analysis shows that 78% of all asparagines of NXS/T motif involved in N-glycosylation are localized in the loop/turn conformation in the human proteome. Similar distribution was revealed for all the other species examined. Comparative analysis of the occurrence of NXS/T motifs not known to be glycosylated and their reverse sequence (S/TXN) shows a similar distribution across the secondary structural elements, indicating that the NXS/T motif in itself is not biologically relevant. Based on our analysis, we have defined rules to determine NGS. Using machine learning methods based on these rules we can predict with 93% accuracy if a particular site will be glycosylated. If structural information is not available the tool uses structural prediction results resulting in 74% accuracy. The tool was used to identify glycosylation sites in 108 human proteins with structures and 2247 proteins without structures that have acquired NXS/T site/s due to non-synonymous variation. The tool, Structure Feature Analysis Tool (SFAT), is freely available to the public at http://hive.biochemistry.gwu.edu/tools/sfat.
doi:10.1016/j.gpb.2012.11.003
PMCID: PMC3914773  PMID: 23459159
N-linked glycosylation; Gain and loss of glycosylation; nsSNP; nsSNV; Variation
16.  A Targeted RNA Interference Screen Reveals Novel Epigenetic Factors That Regulate Herpesviral Gene Expression 
mBio  2014;5(1):e01086-13.
ABSTRACT
Herpes simplex virus (HSV) utilizes and subverts host chromatin mechanisms to express its lytic gene products in mammalian cells. The host cell attempts to silence the incoming viral genome by epigenetic mechanisms, but the viral VP16 and ICP0 proteins promote active chromatin on the viral genome by recruiting other host epigenetic factors. However, the dependence on VP16 and ICP0 differs in different cell lines, implying cell type-dependent functional contributions of epigenetic factors for HSV gene expression. In this study, we performed a targeted RNA interference (RNAi) screen for cellular chromatin factors that are involved in regulation of herpes simplex virus (HSV) gene expression in U2OS osteosarcoma cells, a cell line that complements ICP0 mutant and VP16 mutant virus replication. In this screen, we found the same general classes of chromatin factors that regulate HSV gene expression in U2OS cells as in other cell types, including histone demethylases (HDMs), histone deacetylases (HDACs), histone acetyltransferases (HATs), and chromatin-remodeling factors, but the specific factors within these classes are different from those identified previously for other cell types. For example, KDM3A and KDM1A (LSD1) both demethylate mono- and dimethylated H3K9, but KDM3A emerged in our screen of U2OS cells. Further, small interfering RNA (siRNA) and inhibitor studies support the idea that KDM1A is more critical in HeLa cells, as observed previously, while KDM3A is more critical in U2OS cells. These results argue that different cellular chromatin factors are critical in different cell lines to carry out the positive and negative epigenetic effects exerted on the HSV genome.
IMPORTANCE
Upon entry into the host cell nucleus, the herpes simplex virus genome is subjected to host epigenetic silencing mechanisms. Viral proteins recruit cellular epigenetic activator proteins to reverse and counter the cellular silencing mechanisms. Some of the host silencing and activator functions involved in HSV gene expression have been identified, but there have been indications that the host cell factors may vary in different cell types. In this study, we performed a screen of chromatin factors involved in HSV gene regulation in osteosarcoma cells, and we found that the chromatin factors that are critical for HSV gene expression in these cells are different from those for previously studied cell types. These results argue that the specific chromatin factors operative in different cell lines and cell types may differ. This has implications for epigenetic drugs that are under development.
doi:10.1128/mBio.01086-13
PMCID: PMC3950524  PMID: 24496796
17.  Insights into the Mechanism of Ribosomal Incorporation of Mammalian L13a Protein during Ribosome Biogenesis 
Molecular and Cellular Biology  2013;33(15):2829-2842.
In contrast to prokaryotes, the precise mechanism of incorporation of ribosomal proteins into ribosomes in eukaryotes is not well understood. For the majority of eukaryotic ribosomal proteins, residues critical for rRNA binding, a key step in the hierarchical assembly of ribosomes, have not been well defined. In this study, we used the mammalian ribosomal protein L13a as a model to investigate the mechanism(s) underlying eukaryotic ribosomal protein incorporation into ribosomes. This work identified the arginine residue at position 68 of L13a as being essential for L13a binding to rRNA and incorporation into ribosomes. We also demonstrated that incorporation of L13a takes place during maturation of the 90S preribosome in the nucleolus, but that translocation of L13a into the nucleolus is not sufficient for its incorporation into ribosomes. Incorporation of L13a into the 90S preribosome was required for rRNA methylation within the 90S complex. However, mutations abolishing ribosomal incorporation of L13a did not affect its ability to be phosphorylated or its extraribosomal function in GAIT element-mediated translational silencing. These results provide new insights into the mechanism of ribosomal incorporation of L13a and will be useful in guiding future studies aimed at fully deciphering mammalian ribosome biogenesis.
doi:10.1128/MCB.00250-13
PMCID: PMC3719678  PMID: 23689135
18.  Ixora coccinea Enhances Cutaneous Wound Healing by Upregulating the Expression of Collagen and Basic Fibroblast Growth Factor 
ISRN Pharmacology  2014;2014:751824.
Background. Ixora coccinea L. (Rubiaceae) has been documented for traditional use in hypertension, menstrual irregularities, sprain, chronic ulcer, and skin diseases. In the present study, I. coccinea was subjected to in vitro and in vivo wound healing investigation. Methods. Petroleum ether, chloroform, methanol, and water sequential I. coccinea leaves extracts were evaluated for in vitro antioxidant, antimicrobial, and fibroblast proliferation activities. The promising I. coccinea methanol extract (IxME) was screened for in vivo wound healing activity in Wistar rat using circular excision model. Wound contraction measurement, hydroxyproline quantification, and western blot for collagen type III (COL3A1), basic fibroblast growth factor (bFGF), and Smad-2, -3, -4, and -7 was performed with 7-day postoperative wound granulation tissue. Gentamicin sulfate (0.01% w/w) hydrogel was used as reference standard. Results. IxME showed the potent antimicrobial, antioxidant activities, with significant fibroblast proliferation inducing activity, as compared to all other extracts. In vivo study confirmed the wound healing accelerating potential of IxME, as evidenced by faster wound contraction, higher hydroxyproline content, and improved histopathology of granulation tissue. Western blot analysis revealed that the topical application of I. coccinea methanol extract stimulates the fibroblast growth factor and Smad mediated collagen production in wound tissue.
doi:10.1155/2014/751824
PMCID: PMC3928818  PMID: 24624303
19.  Non-synonymous variations in cancer and their effects on the human proteome: workflow for NGS data biocuration and proteome-wide analysis of TCGA data 
BMC Bioinformatics  2014;15:28.
Background
Next-generation sequencing (NGS) technologies have resulted in petabytes of scattered data, decentralized in archives, databases and sometimes in isolated hard-disks which are inaccessible for browsing and analysis. It is expected that curated secondary databases will help organize some of this Big Data thereby allowing users better navigate, search and compute on it.
Results
To address the above challenge, we have implemented a NGS biocuration workflow and are analyzing short read sequences and associated metadata from cancer patients to better understand the human variome. Curation of variation and other related information from control (normal tissue) and case (tumor) samples will provide comprehensive background information that can be used in genomic medicine research and application studies. Our approach includes a CloudBioLinux Virtual Machine which is used upstream of an integrated High-performance Integrated Virtual Environment (HIVE) that encapsulates Curated Short Read archive (CSR) and a proteome-wide variation effect analysis tool (SNVDis). As a proof-of-concept, we have curated and analyzed control and case breast cancer datasets from the NCI cancer genomics program - The Cancer Genome Atlas (TCGA). Our efforts include reviewing and recording in CSR available clinical information on patients, mapping of the reads to the reference followed by identification of non-synonymous Single Nucleotide Variations (nsSNVs) and integrating the data with tools that allow analysis of effect nsSNVs on the human proteome. Furthermore, we have also developed a novel phylogenetic analysis algorithm that uses SNV positions and can be used to classify the patient population. The workflow described here lays the foundation for analysis of short read sequence data to identify rare and novel SNVs that are not present in dbSNP and therefore provides a more comprehensive understanding of the human variome. Variation results for single genes as well as the entire study are available from the CSR website (http://hive.biochemistry.gwu.edu/dna.cgi?cmd=csr).
Conclusions
Availability of thousands of sequenced samples from patients provides a rich repository of sequence information that can be utilized to identify individual level SNVs and their effect on the human proteome beyond what the dbSNP database provides.
doi:10.1186/1471-2105-15-28
PMCID: PMC3916084  PMID: 24467687
SRA; TCGA; nsSNV; SNV; SNP; Next-gen; NGS; Phylogenetics; Cancer
20.  Telomestatin Impairs Glioma Stem Cell Survival and Growth through the Disruption of Telomeric G-Quadruplex and Inhibition of the Proto-oncogene, c-Myb 
Purpose
Glioma stem cells (GSC) are a critical therapeutic target of glioblastoma multiforme (GBM).
Experimental Design
The effects of a G-quadruplex ligand, telomestatin, were evaluated using patient-derived GSCs, non-stem tumor cells (non-GSC), and normal fetal neural precursors in vitro and in vivo. The molecular targets of telomestatin were determined by immunofluorescence in situ hybridization (iFISH) and cDNA microarray. The data were then validated by in vitro and in vivo functional assays, as well as by immunohistochemistry against 90 clinical samples.
Results
Telomestatin impaired the maintenance of GSC stem cell state by inducing apoptosis in vitro and in vivo. The migration potential of GSCs was also impaired by telomestatin treatment. In contrast, both normal neural precursors and non-GSCs were relatively resistant to telomestatin. Treatment of GSC-derived mouse intracranial tumors reduced tumor sizes in vivo without a noticeable cell death in normal brains. iFISH revealed both telomeric and non-telomeric DNA damage by telomestatin in GSCs but not in non-GSCs. cDNA microarray identified a proto-oncogene, c-Myb, as a novel molecular target of telomestatin in GSCs, and pharmacodynamic analysis in telomestatin-treated tumor-bearing mouse brains showed a reduction of c-Myb in tumors in vivo. Knockdown of c-Myb phenocopied telomestatin-treated GSCs both in vitro and in vivo, and restoring c-Myb by overexpression partially rescued the phenotype. Finally, c-Myb expression was markedly elevated in surgical specimens of GBMs compared with normal tissues.
Conclusions
These data indicate that telomestatin potently eradicates GSCs through telomere disruption and c-Myb inhibition, and this study suggests a novel GSC-directed therapeutic strategy for GBMs.
doi:10.1158/1078-0432.CCR-11-1795
PMCID: PMC3896097  PMID: 22230766
21.  Changes in the pharmacokinetic of sildenafil citrate in rats with Streptozotocin-induced diabetic nephropathy 
Aim
The present investigates deals with the change in the pharmacokinetic of Sildenafil citrate (SIL) in disease condition like diabetic nephropathy (DN).
Method
Diabetes was induced in rats by administering Streptozotocin i.e. STZ (60 mg/kg, IP) saline solution. Assessment of diabetes was done by GOD-POD method and conformation of DN was done by assessing the level of Creatinine, Blood Urea Nitrogen (BUN) and Albuminurea. After the conformation of DN single dose of drug SIL (2.5 mg/kg, p.o.) were given orally and Pharmacokinetic Parameters like [AUC o-t (ug.h/ml), AUC 0-∞, Cmax, Tmax, Kel, Clast] were estimated in the plasma by the help of HPLC-UV.
Result
There was significant increase (p < 0.01) in the Pharmacokinetic parameters of SIL in DN rat (AUC0-t, AUC0-∞, Cmax, Tmax and T1/2) compare to normal control rat and significant increase Kel in the DN rat compare to control rat.
Conclusion
The study concluded that there was significant (p < 0.01) increase in the bioavailability of SIL in DN.
doi:10.1186/2251-6581-13-8
PMCID: PMC3922855  PMID: 24398037
Diabetic nephropathy; Streptozotocin; Sildenafil citrate
22.  Formulation and Evaluation of Fixed-Dose Combination of Bilayer Gastroretentive Matrix Tablet Containing Atorvastatin as Fast-Release and Atenolol as Sustained-Release 
BioMed Research International  2014;2014:396106.
The objective of the present study was to develop bilayer tablets of atorvastatin and atenolol that are characterized by initial fast-release of atorvastatin in the stomach and comply with the release requirements of sustained-release of atenolol. An amorphous, solvent evaporation inclusion complex of atorvastatin with β-cyclodextrin, present in 1 : 3 (drug/cyclodextrin) molar ratio, was employed in the fast-release layer to enhance the dissolution of atorvastatin. Xanthan gum and guar gum were integrated in the sustained-release layer. Bilayer tablets composed of sustained-release layer (10% w/w of xanthan gum and guar gum) and fast-release layer [1 : 3 (drug/cyclodextrin)] showed the desired release profile. The atorvastatin contained in the fast-release layer showed an initial fast-release of more than 60% of its drug content within 2 h, followed by sustained release of the atenolol for a period of 12 h. The pharmacokinetic study illustrated that the fast absorption and increased oral bioavailability of atorvastatin as well as therapeutic concentration of atenolol in blood were made available through adoption of formulation strategy of bilayer tablets. It can be concluded that the bilayer tablets of atorvastatin and atenolol can be successfully employed for the treatment of hypertension and hypercholesterolemia together through oral administration of single tablet.
doi:10.1155/2014/396106
PMCID: PMC3909979  PMID: 24527446
23.  Role of Folic Acid on Symptoms of Chronic Arsenic Toxicity 
Background:
Chronic arsenic toxicity (Arsenicosis) due to drinking of arsenic contaminated ground water is a global problem. However, its treatment is unsatisfactory. Methylation of arsenic facilitates its urinary excretion. Persons with relatively lower proportion of urinary dimethyl arsenic acid (DMA) are found to have at greater risk of developing symptoms of arsenicosis including its complications. The biochemical pathway responsible for methylation of arsenic is a folate-dependent pathway. Studies in rodents and humans suggest that folate nutritional status influences the metabolism of arsenic.
Methods:
The present study compares the effect of giving folic acid on 32 arsenicosis patients during a 6-month period and comparing the results with clinical effect of taking only arsenic-free safe water on 45 age and sex-matched arsenic-affected people for the same period.
Results:
There was significant improvement of arsenical skin lesion score of both patients treated with folic acid (2.96 ± 1.46 to 1.90 ± 0.90, P < 0.001) and arsenic free safe water (2.91 ± 1.26 to 1.62 ± 1.05, P < 0.001) for a period of 6 months. Significant improvement in systemic disease score was also observed from the baseline systemic score in folic acid treated group (4.78 ± 3.43 to 1.00 ± 1.56, P < 0.001) and the group treated with arsenic-free water (1.87 ± 2.11 to 0.82 ± 1.62, P < 0.001). However, there was a significant increased improvement of systematic disease score in the folic acid treated group compared to the control group taking arsenic free water (P < 0.001).
Conclusions:
This study provides evidence that folic acid treatment in arsenicosis cases could help in reducing clinical symptoms of arsenicosis.
PMCID: PMC3915479  PMID: 24554997
Arsenicosis; folic acid; nutritional deficiency; treatment of arsenicosis
24.  Crystal Structure and Mode of Helicase Binding of the C-Terminal Domain of Primase from Helicobacter pylori 
Journal of Bacteriology  2013;195(12):2826-2838.
To better understand the poor conservation of the helicase binding domain of primases (DnaGs) among the eubacteria, we determined the crystal structure of the Helicobacter pylori DnaG C-terminal domain (HpDnaG-CTD) at 1.78 Å. The structure has a globular subdomain connected to a helical hairpin. Structural comparison has revealed that globular subdomains, despite the variation in number of helices, have broadly similar arrangements across the species, whereas helical hairpins show different orientations. Further, to study the helicase-primase interaction in H. pylori, a complex was modeled using the HpDnaG-CTD and HpDnaB-NTD (helicase) crystal structures using the Bacillus stearothermophilus BstDnaB-BstDnaG-CTD (helicase-primase) complex structure as a template. By using this model, a nonconserved critical residue Phe534 on helicase binding interface of DnaG-CTD was identified. Mutation guided by molecular dynamics, biophysical, and biochemical studies validated our model. We further concluded that species-specific helicase-primase interactions are influenced by electrostatic surface potentials apart from the critical hydrophobic surface residues.
doi:10.1128/JB.00091-13
PMCID: PMC3697261  PMID: 23585534
25.  Isolation and Characterization of Antidermatophytic Bioactive Molecules from Piper longum L. Leaves 
Indian Journal of Microbiology  2012;52(4):624-629.
Piper longum L. (Piperaceae) commonly known as “long pepper” is a well known medicinal plant in ayurveda. Different parts of this plant, such as root, seed, fruit, whole plant etc. are used traditionally in various ailments. Here we have investigated the antidermatophytic activity of sequentially extracted petroleum ether, chloroform, methanol and water extracts from P. longum leaf against Trichophytonmentagrophytes, T. rubrum, T. tonsurans, Microsporum fulvum and M. gypseum. Better activity of chloroform and methanol extracts was observed. The chloroform extract was selected for further study and the MIC value was recorded as 5.0 mg ml−1 against the test organisms. In the chloroform extract, tannins and phenolic compounds were detected. Further activity-guided fractionation of chloroform extract by silica gel column chromatography yielded nine major fractions. Among these, fraction-1, 4, 5 and 7 showed higher antidermatophytic activity. Fraction-4 on further purification by repeated column chromatography yielded a potential antidermatophytic fraction showing MIC value of 0.625 mg ml−1 against T. mentagrophytes and T. rubrum as determined by broth microdilution method. The major compounds were identified as 1,2-benzenedicarboxylic acid, bis(2-ethylhexyl) ester (C24H38O4] (41.45 %), 2,2-dimethoxybutane (C6H14O2] (13.6 %) and β-myrcene (C10H16) (6.75 %) based on GC–MS data.
doi:10.1007/s12088-012-0303-x
PMCID: PMC3516648  PMID: 24293721
Piper longum; Activity-guided fractionation; Antidermatophytic bioactive molecules

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