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Publications by ABCC from 2008-2010
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2007
Dong H, Deng Y, Chen J, Wang S, Peng S, Dai C, Fang Y, Shao J, Lou Y, Li D. An exploration of 3'-end processing signals and their tissue distribution in Oryza sativa. Gene. 2007 Mar 15; 389(2):107-13.The 3' untranslated regions of mRNAs deeply affect many properties of eukaryotic mRNA. In plants, the polyadenine control signals contained in these regions seem to be more variable than in mammals. Three cDNA libraries derived from the leaf, endosperm and stem tissues of rice were sequenced from the 3'-end. Of the 9911 transcripts analyzed, 5723 unique transcripts were identified from the leaf sequences, 2934 from the endosperm and 1254 from the stem. The signal bias in downstream sequences may lead mRNA to be differently cleaved in different rice tissues. ABCC staff did microarray data analysis for the study and prepared figures for the paper.Download
Huppi K., Volfovsky N., Mackiewicz M., Runfola T., Jones T.L., Martin S.E., Stephens R.M., and Caplen N.J. (2007). MicroRNAs and Genomic Instability. Seminars in Cancers Biology 17, 65-73This paper reviews the examples of the association between microRNA loci and regions of genomic instability in the mouse and human genomes. It discusses the possible role of altered miRNA expression on human cancer and conducts an analysis correlating the physical location of murine miRNAs with sites of genetic alteration in mouse models of cancer. The ABCC provided data for the work and assisted in the preparation of the manuscript.Download
Pontius J.U., Mullikin J.C., Smith D., Lindblad-Toh K., Gnerre S., Clamp S., Stephens R.M., Neelam B., Volfovsky N., Schäffer A., Agarwala A., Narfström K., Murphy W.J., Giger U., Roca A.L., O'hUigin C., Antunes A., Menotti-Raymond M., Yuhki N., Pecon-Slattery J., Johnson W.E., Driscoll C., and O'Brien S.J.(2007). Initial sequence and comparative analysis of cat genome. Genome Res.17(11):1675-89The paper reports a first version of the cat genomic sequence. The assembly, annotation and variation analyses were implemented using cross-references to other available mammalian genomes that help in discovery of the genetic basis of hereditary and infectious diseases. The ABCC provided figures and annotation for the assembled genome.Download
Ambrose Z, Palmer S, Boltz VF, Kearney M, Larsen K, Polacino P, Flanary L, Oswald K, Piatak M Jr, Smedley J, Shao W, Bischofberger N, Maldarelli F, Kimata JT, Mellors JW, Hu SL, Coffin JM, Lifson JD, KewalRamani VN., 2007. Suppression of viremia and evolution of human immunodeficiency virus type 1 drug resistance in a macaque model for antiretroviral therapy. J Virol. 81:12145-55This publication demonstrated that infection of macaques with RT-SHIVmne is pathogenic and responsive to suppressive ART. Antiviral resistance mechanisms in this model mimic those found in HIV-1-infected persons receiving ART targeting RT. These data suggest that this monkey model will be useful to explore the emergence and evolutionary mechanisms that underlie HIV-1 drug resistance in vivo. RT-SHIVmne infection of macaques can be used to identify persisting reservoirs of virus during suppressive ART, which is not possible with the standard SIV model. Understanding the characteristics of these reservoirs under specific conditions of therapy, particularly the differences that exist in viruses present in the tissues as opposed to those in the blood, should help elucidate better HIV-1 treatment and eradication strategies.Download
B.L. Grigorenko, A.V. Rogov, I.A. Topol, S.K. Burt, H.M. Martinez, and A.V. Nemukhin, Mechanism of the myosin catalyzed hydrolysis of ATP as rationalized by molecular modeling. PNAS, 104, No. 17, 7057-7061, 2007.QM/MM methods were used to calculate reaction path for the ATP hydrolysis in myosin. The role of water molecules and nearest residues in the active site was investigated. Calculation data and pathway analysis provided strong support for experimental hypothesis regarding specific reaction mechanism.Download
B.L. Grigorenko, A.V. Nemukhin, M.S. Shadrina, I.A. Topol, and S.K. Burt, On the mechanisms of guanosine triphosphate hydrolysis by Ras and Ras-GAP proteins as rationalized by ab initio QM/MM simulations, Proteins: Structure, Function, and Bioinformatics., 66, 456-466, 2007.GTP hydrolysis reaction path in Ras and Ras-GAP proteins was calculated by QM and QM/MM methods. Dissociative type mechanism was established. Role of Gln61 mutation was investigated that allowed to better understand its anticatalytic effect in cancer.Download
Tam Luong Nguyen, R.G. Panchal, I.A. Topol, D. Lane, T. Kenny, J.C. Burnett, A.R. Hermone, C. McGrath, S.K. Burt, R. Gussio, S. Bavari, A theoretical study of antrax lethal factor inhibition by a set of novel carbamimidolyl-aryl-vinyl-carboxamidines: A possible mechanism involving zinc-ligation by amidine. Journal of Molecular Structure: THEOCHEM, 821, 139-144, 2007. Computational study was performed to elucidate the vast amount of the antrax letal factor inhibitors and their molecular mechanism of inhibition.Calculation of pKa allowed to describe zinc ligation by a highly basic group such as amidine. Dose independnce of these inhibitors was established due to their zinc ligation.Download
Pharmacophore Modeling of Stereoselective Binding to the Human Organic Cation Transporter (hOCT1), Ruin Moaddel, S. Ravichandran, Federica Bighi, Rika Yamaguchi and Irving W. Wainer, British Journal of Pharmacology 151(8), 1305-1314, 2007hOCT1s are expressed mostly in liver, kidney and intestines and play a prominent role in the excretion of drug molecules. In this study, we focused on how chiral drug molecules selectively bind and processed in this protein. Since hOCT1 structure is not yet resolved, 3D-QSAR modeling methods were used to build models for the active site(s) of hOCT1. This new model was able to successfully explain stereoselectivity and binding of several drug molecules. Download
Interaction of Noncompetitive Inhibitors with an Immobilized _3_2 Nicotinic Acetylcholine Receptor Investigated by Affinity Chromatography and Molecular Docking, Krzysztof Jozwiak, S. Ravichandran, Jack R. Collins, Ruin Moaddel and Irving W. Wainer, Journal of Medicinal Chemistry, 50(24), 6279-6283, 2007.Nicotininc acetylcholine receptors (nAChR) are Ligand-gated ion channels present widely in peripheral and Central nervous systems (PNS/CNS). Malfunction of these channels affect brain function, neuronal development, motor and cognitive performance. In this study, we have used multiple molecular modeling approaches (QSAR/Molecular Modeling/Docking) to understand how competitive inhibitors (drugs) can bind and affect the functioning of nAChRs. The model we had built can be potentially used to screen chiral drugs to see how they bind and affect the functioning of nAChR.Download
Computational analysis of adhesion of primer ligands to dentinal Collagen: Effect of Spacer groups in ligand and amino acid residue sequence differences in collagen J. Vaidyanathan, S. Ravichandran and T. K. Vaidyanathan, Current Drug Discovery Technologies, Volume 4(3), 150-161, 2007Adhesion of primer ligands to collagen is a important first step that decides the success of dental implant restoration. In this work, we explore the effect of the varying length of spacer groups in primers (similar to drug discovery approach) and their effects on binding to collagen. We had found that there are spacers (-CH2 groups) of certain length provide optimal binding to Collagen. In addition, we had also explored the structural variants of collagen (Type-1) and how that affects the primer-collagen binding. Download
Aldose reductase studied by comparative analysis of neutron scattering, X-ray ultra-high resolution and QM electron density maps and molecular dynamics. Raul E. Cachau, Alberto D. Podjarny, Federico Ruiz, Oscar N. Ventura, Stanley K. Burt. Biophysical Journal (S):213A-213A. 2007 Combined ultra-high resolution X-ray and Neutron scattering maps reveal a dynamic proton wire extending far from the immediacy of the reaction center pointing to a catalytic mechanism actively involving distal residues Download
Towards a consensus on datasets and evaluation metrics for developing B-cell epitope prediction tools. Jason A. Greenbaum, Pernille Haste Andersen, Martin Blythe, Huynh-Hoa Bui, Raul E. Cachau. JOURNAL OF MOLECULAR RECOGNITION J. Mol. Recognit. 2007; 20: 75-82A proposal for developing common datasets, standardized data formats, and the means with which to consolidate B-cell epitopes information including structure analysis to enhance the development of B-cell epitope prediction tools.Download
Fast pattern recognition of protein three dimensional features using a bit-pattern approach as a prescreen. Phillip Yen, Oscar N. Ventura, Stanley K. Burt and Raul E. Cachau. Biophysical Journal (S):567A-567A. 2007A very fast search engine designed primarily for embedding in complex search algorithms (i.e. functional annotation of new structures) for the unrestricted search of 3D patterns in large moleculesDownload
In-Silico Nanobio-Design. A New Frontier in Computational Biology. Raul E. Cachau, Fernando D. Gonzalez-Nilo, Oscar N. Ventura and Martin J. Fritts. Current Topics in Medicinal Chemistry, 2007, 7, 1537-1540Computer-aided methods are the natural option to speed up the development of nanobiology. Yet, the procedures for annotation and simulation of nanoparticle properties must be developed and their limitations understood before computational methods can be fully exploited. In this review we compared the state of development of nanoscale simulations in the biological sciences, identified, bottlenecks and suggest new strategies for the development of computer-aided nanobiodevice design tools.Download
New modeling strategies for the computational characterization of nanobioparticles. Raul E. Cachau, Martin J. Fritts, Igor Topol, Stanley K. Burt, Fernando D. Gonzalez-Nilo, Mark Matties. Biophysical Journal (S):162A-162A, 2007In this work we will presented our efforts at devising strategies that, from simulations of nanoparticles in simple environments, allow the computation of properties related to their behavior in more complex environments. The approach presented departs from classical extensions of QSAR type calculations to nanoparticles, relying instead in a series of sensitivity analysis techniques that probe the stability of the particle.Download
Protein crystal growth in a simulated microgravity environment. Raul E. Cachau, Akira Sanjoh. Biophysical Journal (S):163A-163A. 2007The use of protein crystals as biosensors and in nanobiotechnology demands the development of techniques for their production in a controlled and reproducible manner. we present devices that take advantage of the growth of protein crystals in semiconductor surfaces to build crystallization microchambers that can be spun without disturbing the crystal growth process. Download
Structural characterization of peptides from phage-display libraries. Raul E. Cachau, Lauren R. H. Krumpe, Toshiyuki Mori, Oscar N. Ventura, Stanley K. Burt. Biophysical Journal (S):388A-388A, 2007Phage display procedures are a useful technology for mapping epitopes and a number of other applications. Phage-displayed peptide libraries are rich in information but the value of the consensus motif is frequently overestimated, disregarding the large amount of information encoded in the sequence variability. This information can be utilized to create structural 3D models of the bound peptide. A technique to achieve this goal is presented.Download
Towards an ultra-high resolution macromolecular structural database: analysis of proton acidities and peptide bond deformations by QM calculations, neutron scattering and X-ray crystallography studies. Raul E. Cachau, Nobuo Niimura, Stanley K. Burt. Biophysical Journal (S):41A-41A, 2007A recent effort at collecting and cataloging ultra-high resolution crystallography and neutron scatering data with emphasis on hydrogen placement and resolution has resulted in the HHDB database. Based on the results catalogued on this database and our own analysis of ultra-high resolution structures we have begun the characterization of microenvironments showing the largest deviations from average geometries and occupations in crystal structures.Download
2008
Fatima N, Yi M, Ajaz S, Stephens RM, Stauffer S, Greenwald P, Munroe DJ, and Ali IU. Altered gene expression profiles define pathways in colorectal cancer cell lines affected by celecoxib. Cancer Epidemiol Biomarkers Prev. 17(11):3051-61, 2008The authors did global transcription profiling of celecoxib-treated COX-2-positive and COX-2-deficient colorectal cancer cell lines. A pathway/functional analysis of celecoxib-affected transcripts, using Gene Ontology and Biocarta Pathways and exploring biological association networks, revealed that celecoxib modulates expression of numerous genes involved in a variety of cellular processes, including metabolism, cell proliferation, apoptotic signaling, cell cycle check points, lymphocyte activation, and signaling pathways. ABCC did microarray data and pathway analysis and prepared figures and helped writing for the paper.Download
Yi M, and Stephens RM. SLEPR: a sample-level enrichment-based pathway ranking method -- seeking biological themes through pathway-level consistency. PLoS One. 3(9):e3288, 2008.The gene-level enrichment paradigm can be limited as a result of valid sample fluctuations and biological complexities. In this report, the authors described a novel method, SLEPR, which eliminates this limitation by relying on pathway-level consistencies. This new method extends existing analysis approaches and facilitates integration of different types of HTP data. This work is exclusively done by ABCC staff as a research project for the development of a novel analysis method. The method is now in general use for analysis of investigators multi-platform high-throughput biological data.Download
Jiang H, Yi M, Mu J, Zhang L, Ivens A, Klimczak LJ, Huyen Y, Stephens RM, and Su XZ Detection of genome-wide polymorphisms in the AT-rich Plasmodium falciparum genome using a high-density microarray. BMC Genomics 9:398, 2008. The authors evaluated the polymorphism detection accuracy of a high-density 'tiling' microarray with 2.56 million probes by comparing single feature polymorphisms (SFP) calls from the microarray with known SNPs among parasite isolates. Their method for accurate mSFP detection and the mSFP identified will greatly facilitate large-scale studies of genome variation in the P. falciparum parasite and provide useful resources for mapping important parasite traits. ABCC did microarray data analysis and prepared figures for the paper. The methods developed benefit the cancer community because of similarity to CGH analysis.Download
Ambs S, Prueitt RL, Yi M, Hudson RS, Howe TM, Petrocca F, Wallace TA, Liu CG, Volinia S, Calin GA, Yfantis HG, Stephens RM, and Croce CM. Genomic profiling of microRNA and messenger RNA reveals deregulated microRNA expression in prostate cancer. Cancer Res. 68(15):6162-70, 2008In order to evaluate the involvement of microRNAs in prostate cancer, the authors determined genome-wide expression of microRNAs and mRNAs in 60 primary prostate tumors and 16 nontumor prostate tissues. The mRNA analysis revealed that key components of microRNA processing and several microRNA host genes, e.g., MCM7 and C9orf5, were significantly up-regulated in prostate tumors. In summary, microRNA expression becomes altered with the development and progression of prostate cancer. ABCC did microarray data analysis and prepared figures for the paper.Download
Jiang H, Patel JJ, Yi M, Mu J, Ding J, Stephens RM, Cooper RA, Ferdig MT, and Su XZ. Genome-wide compensatory changes accompany drug- selected mutations in the Plasmodium falciparum crt gene. PLoS One, 3(6):e2484, 2008The authors investigated changes in gene expression in these parasites grown with and without CQ (chloroquine) and also conducted hybridizations of genomic DNA to identify copy number (CN) changes in parasite genes. RNA transcript levels from 45 genes were significantly altered in one or both mutants relative to the parent line, 106/1(K76). Most of the up-regulated genes are involved in invasion, cell growth and development, signal transduction, and transport activities. Further investigation of these genes may shed light on how the parasite compensates for functional changes accompanying drug resistance mutations in a gene coding for a membrane/drug transporter. ABCC did the pathway analysis and prepared figures and helped in the writing of the paper. The methods developed are applicable to the study of drug resistance to chemotherapy.Download
Prueitt RL, Yi M, Hudson RS, Wallace TA, Howe TM, Yfantis HG, Lee DH, Stephens RM, Liu CG, Calin GA, Croce CM, and Ambs S. Expression of microRNAs and protein-coding genes associated with perineural invasion in prostate cancer. Prostate 68(11):1152-64, 2008In order to evaluate the involvement of both microRNAs and protein-coding genes in Perineural invasion (PNI), this study determined genome-wide expression patterns with a custom microRNA microarray and Affymetrix GeneChips in 50 prostate adenocarcinomas with PNI and 7 without it. Their findings suggest that alterations in microRNA expression, mitochondrial function, and cell metabolism occur at the transition from a noninvasive prostate tumor to a tumor with PNI. ABCC did microarray data analysis and prepared figures for the paper.Download
Wallace TA, Prueitt RL, Yi M, Howe TM, Gillespie JW, Yfantis HG, Stephens RM, Caporaso NE, Loffredo CA, and Ambs S. Tumor immunobiological differences in prostate cancer between African-American and European-American men. Cancer Res. 68(3):927-36, 2008The incidence and mortality rates of prostate cancer are significantly higher in African-American men when compared with European-American men. The author tested the hypothesis that differences in tumor biology contribute to this survival health disparity. Using microarray technology, the gene expression profiles of prostate tumors indicate prominent differences in tumor immunobiology between African-American and European-American men. The profiles portray the existence of a distinct tumor microenvironment in these two patient groups. ABCC did microarray data and pathway analysis and prepared figures for the paper.Download
Nyswaner KM, Checkley MA, Yi M, Stephens RM, and Garfinkel DJ. Chromatin-associated genes protect the yeast genome from Ty1 insertional mutagenesis. Genetics 178(1):197-214, 2008The authors have screened a collection of 4739 deletion mutants to identify chromosomal genes that increase Ty1 mobility (Ty1 restriction genes). Bioinformatic analyses encompassing additional Ty1 and Ty3 screens indicate that 264 unique genes involved in a variety of biological processes affect Ty mobility in yeast. These results indicate that multiple pathways restrict Ty1 mobility and histone modifications may protect coding regions from insertional mutagenesis. ABCC did pathway analysis and prepared figures for the paper.Download
Boersma BJ, Reimers M, Yi M, Ludwig JA, Luke BT, Stephens RM, Yfantis HG, Lee DH, Weinstein JN, and Ambs S. A stromal gene signature associated with inflammatory breast cancer. Int J Cancer 122(6):1324-32, 2008.The authors tested the hypotheses that the gene expression signature of tumor stroma is a distinctive feature of inflammatory breast cancer (IBC). They used laser capture microdissection to obtain enriched populations of tumor epithelial cells and adjacent stromal cells from 15 patients with IBC and 35 patients with invasive, noninflammatory breast cancer (non-IBC). In a pathway analysis, the genes differentially expressed between IBC and non-IBC tumors clustered in distinct pathways. They identified multiple pathways related to the endoplasmic stress response that could be functionally significant in IBC. ABCC did microarray data and pathway analysis and prepared figures and helped in the writing of the paper.Download
Dongqing Wang, Xianmin Xia, Ying Liu, Alexis Oetting, Robert L Walker, Yuelin Zhu, Paul Meltzer, Philip A. Cole, Yun-Bo Shi, and Paul M. Yen. Negative Regulation of TSH_ Target Gene by Thyroid Hormone Involves Histone Acetylation and Corepressor Complex Dissociation. Molecular Endocrinology. Doi: 10.1210/me.2008-0389The authors studied the negative regulation of TSHalpha target gene by thyroid hormone and showed that it involves histone acetylation and corepressor complex dissociation. ABCC staff did microarray data analysis for the study and prepared figures for the paper.Download
Yuelin Zhu, Sean Davis, Robert Stephens, Paul S Meltzer, Yidong Chen. GEOmetadb: powerful alternative search engine for the Gene Expression Omnibus (GEO). Bioinformatics. 2008 Dec 1;24(23):2798-800The authors have developed GEOmetadb in an attempt to make querying the GEO metadata both easier and more powerful. A powerful, flexible web search interface with several convenient utilities provides query capabilities not available via NCBI tools. In addition, a Bioconductor package, GEOmetadb that utilizes a SQLite export of the entire GEOmetadb database is also available, rendering the entire GEO database accessible with full power of SQL-based queries from within R. ABCC staffs designed and developed the GEOmetadb web application and R/Bioconducotr packageDownload
Huppi K., Volfovsky N., Runfola T., Jones T.L., Mackiewicz M., Martin S.E., Mushinski J.F., Stephens R.M., and Caplen N.J.(2008). The Identification of Novel MicroRNAs in a Genomically Unstable Region of Human Chromosome 8q24 . Mol Cancer Res. 6(2):212-21The paper reports computational prediction and experimental validation of 6 microRNAs in the gnomically unstable region downstream of the c-MYC oncogene. Virtually all of the miRNA precursor transcripts are expressed at higher levels in late-stage B cells (including plasmacytoma and vBL cell lines) compared with immature B cells, suggesting possible roles in lymphoid development and/or lymphoma. In addition, lentiviral vector-mediated over expression of the miR-1204 precursor (human and mouse) in a mouse pre-B-cell line increased expression of Myc. High levels of expression of the hsa-miR-1204 precursor is also seen in several epithelial cancer cell lines with MYC/PVT1 coamplification, suggesting a potentially broad role for these miRNAs in tumorigenesis. The ABCC provided the miRNA predictions.Download
Akagi K., Li J., Stephens R.M., Volfovsky N. and Symer D.E.(2008). Many mouse strain dimorphisms are due to recent L1 retrotransposition . Genome Research 18:869-880This publication presents computational method for identification and analyses of the genomic polymorphism in numerous mouse strains. The authors focused on L1 transposones insertions and deletions and demonstrated that many genes' structures and expression are altered directly by polymorphic L1 retrotransposons, including Drosha, Parp8, Scn1a, Arhgap15, and others, including novel genes. Recent endogenous L1 retrotransposition has diversified genomic structures and transcripts extensively, distinguishing mouse lineages and driving a major portion of natural genetic variation.Download
Kearney M, Palmer S, Maldarelli F, Shao W, Polis MA, Mican J, Rock-Kress D, Margolick JB, Coffin JM, Mellors JW., 2008. Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase. AIDS, 22:497-501This publication shows that HIV-1 variants that are polymorphic at drug resistance sites pre-exist frequently as minor species in antiretroviral naive individuals. Standard genotype techniques have grossly underestimated their frequency.Download
Mechanic LE, Luke BT, Goodman JE, Chanock SJ, Harris CC. Polymorphism Interaction Analysis (PIA): a method for investigating complex gene-gene interactions. BMC Bioinformatics 2008, 9:146.This paper highlights the capabilities of PIA v2.0 and demonstrates that it is superior to other methods in identifying gene-gene interactions in GWAS analyses.Download
Issaq HJ, Nativ O, Waybright T, Luke B, Veenstra TD, Issaq EJ, Kravstov A, Mullerad M. Detection of bladder cancer in human urine by metabolomic profiling using high performance liquid chromatography/mass spectrometry. J Urol. 2008 Jun;179(6):2422-6.Applied my BioMarker Discovery Kit (BMDK) software to analyze the mass spectra of urine from healthy patients and patients with bladder cancer.Download
Ashktorab H, Tsang S, Luke B, Sun Z, Adam-Campbell L, Kwagyan J, Poirier R, Akter S, Akhgar A, Smoot D, Munroe DJ, Ali IU. Protective effect of Cox-2 allelic variants on risk of colorectal adenoma development in African Americans. Anticancer Res. 2008 Sep-Oct;28(5B):3119-23.Used personally-developed epidemeologic software to examine the odds ratio, risk ratio, and relative risk of individuals with different genotypes and haplotypes.Download
Luke BT, Collins JR. Examining the significance of fingerprint-based classifiers. BMC Bioinformatics. 2008 Dec 17;9(1):545.Showed that a decision tree and a medoid classification algorithm produced very good classification models using data that contained no biological information.Download
A.V. Nemukhin, I.A. Topol, B.L. Grigorenko, A.P. Savitsky, J.R. Collins, Conformation dependence of pKa's of the chromophores from the purple asFP595 and yellow zFP538 fluorescent proteins. Journal of Molecular Structure: THEOCHEM, 863, 39-43, 2008.Quantum based calculations of the solution pKa values were performed for selected protonation sites of the denaturated asFP595 and zFP538 chromophores in the trans- and cis-conformations in order to add in the interpretation of photophysical properties of these proteins. The results show that the pKa's of the protonation sites of the chromophore from asFP595 noticeably depend on the isomer conformation (cis or trans), while those of zFP538 are much less sensitive to isomerization.Download
B.L. Grigorenko, M.S. Shadrina, I.A. Topol, J.R. Collins, A.V. Nemukhin, Mechanism of the chemical step for the guanosine triphosphate (GTP) hydrolysis catalyzed by elongation factor Tu. Biochimica et Biophysica Acta, 1784, 1908-1917, 2008.Molecular modeling tools including molecular dynamics simulations and the QM-MMcalculations were applied for estimates of reaction energy profiles for two possible arrangements of switch II regions of elongation factor EF-Tu. Role of different arrangements of the active site residues and their influence on the reaction rate was investigated.Download
Exploring Enantiospecific Ligand-Protein Interactions Using Cellular Membrane Affinity Chromatography: Chiral Recognition as a Dynamic Process, K. Jozwiak, R. Moaddel, S. Ravichandran, A. Plazinska, J. Kozak, S. Patel, R. Yamaguchi, I. Wainer J. of Chromatography B, 875(1), 200-207, 2008Enantioselective binding results from two systems, nicotininc acetylcholine receptor (nAChR) and human Organic Cation Transporter-1 (hOCT1) were used as examples to explain that chiral recognition is a multi-step dynamic process. Conformational modifications during binding were found to be important and cannot be ignored (as in the case of static point-based models). Download
Neurocalcin-delta Modulation of ROS-GC1, A New Model of Ca2+ Signaling, V. Venkataraman, T. Duda, S. Ravichandran and R. K. Sharma, Biochemistry, 47(25), 6590-6601, 2008ROS-GC1 (Rod-Outer-Segment-membrane-Guanylate-Cyclase) is an enzyme expressed mostly in retina and plays an important role in phototransduction (regulating light adaptation). Retinal diseases (type 1 Leber's congenital amaurosis (LCA1) and cone-rod dystrophy type 6 (CORD6) ) have been identified with the mutations in the gene that codes for ROS-GC1. In this work using experiments and molecular modeling simulations, we were able to define a new model for the Ca2+ signaling of ROS-GC1.Download
Quantum model of catalysis based on a mobile proton revealed by subatomic x-ray and neutron diffraction studies of h-aldose reductase. Matthew P. Blakeley, Federico Ruiz, Raul Cachau et al. PNAS 105(6),1844-1848, 2008We present results of combined studies of the enzyme human aldose reductase (h-AR, 36 kDa) using single-crystal x-ray data (0.66 Å, 100K; 0.80 Å, 15K; 1.75 Å, 293K), neutron Laue data (2.2 Å, 293K), and quantum mechanical modeling. These complementary techniques unveil the internal organization and mobility of the hydrogen bond network that defines the properties of the catalytic engine, explaining how this promiscuous enzyme overcomes the simultaneous requirements of efficiency and promiscuity offering a general mechanistic view for this class of enzymes.Download
Darrabie, M.D., Cachau, R.E., Santacruz-Toloza L.K. and Jacobs D.O. Doxorubicin Decreases Creatine Transport In Hl-1 Cardiac Myocytes Expressing The Human Creatine Transporter, Biophysical Journal 94: 440, 2008We demonstrate that doxorubicin diminishes creatine transport in a dose- and time-dependent manner establishing for the first time that a decrease in creatine transport contributes to the myocardial energy metabolism derangements observed in doxorubicin-associated heart failure.Not Available
Recent Developments Towards A Centralized Repository For Structural Nanobiology Data. Cachau, R.E. and Gonzalez-Nilo F.D. Biophysical Journal, 94: 1628, 2008We are in the process of building a nanobioinformatics service dedicated to the collection, curation, and correlation of structural, physico-chemical, biological, and biomedical data: the Collaboratory for Structural Nanobiology (http://nanobiology.ncifcrf.gov/). In this presentation we discuss the lessons learned from an early prototype of a nanoparticle repository.Not Available
Emerging Chemistry Information from Ultra-High Resolution Structures. Cachau R.E. eCheminfo, Philadelphia, October 2008Ultra-high resolution macromolecular crystallography is a non-incremental improvement over previous macromolecular analysis techniques helping identify missing chemistries in macromolecular structures and in-situ reactivity analysisNot Available
Structural Analysis of Nanoparticles Functional Building Blocks and Nanoscale Periodic Patterns, Keller, N., McRae, I. and Cachau, R.E. Biophysical Journal, 94: 1630, 2008We are in the process of building a nanobioinformatics service dedicated to the collection, curation, and correlation of structural, physico-chemical, biological, and biomedical data: the Collaboratory for Structural Nanobiology (http://nanobiology.ncifcrf.gov/). IN this presentation we discuss the early results of the application of our fast 3D pattern search engine to the nanoparticles structure data deposited in our early prototype of a nanoparticle repository.Not Available
2009
Saydam O, Shen Y, Würdinger T, Senol O, Boke E, James MF, Tannous BA, Stemmer-Rachamimov AO, Yi M, Stephens RM, Fraefel C, Gusella JF, Krichevsky AM, and Breakefield XO. Downregulated microRNA-200a in meningiomas promotes tumor growth by reducing E-cadherin and activating the Wnt/beta-catenin signaling pathway. Mol Cell Biol. 29(21):5923-40, 2009.This study defines a typical human meningioma microRNA (miRNA) profile and characterizes the effects of one downregulated miRNA, miR-200a, on tumor growth. It reveals a previously unrecognized signaling cascade involved in meningioma tumor development and highlights a novel molecular interaction between miR-200a and Wnt signaling, thereby providing insights into novel therapies for meningiomas. ABCC did microarray data analysis and prepared figures for the paper.Download
Yi M, Mudunuri U, Che A, and Stephens RM. Seeking unique and common biological themes in multiple gene lists or datasets: pathway pattern extraction pipeline for pathway-level comparative analysis. BMC Bioinformatics 10:200, 2009.This publication introduces a new Pathway Pattern Extraction Pipeline (PPEP), which extends the existing WPS application by providing a new pathway-level comparative analysis scheme. To facilitate comparing and correlating results from different studies and sources, PPEP contains new interfaces that allow evaluation of pathway-level enrichment patterns across multiple gene lists. This analysis pipeline helps to explore the commonality or uniqueness of these lists at the level of pathways and provides a new pathway-level analysis scheme for integrative and comparative analysis of data derived from different but relevant systems. This work is exclusively done by ABCC staff as a research project for development of the novel analysis method.Download
Su XZ, Jiang H, Yi M, Mu J, and Stephens RM. Large-scale genotyping and genetic mapping in Plasmodium parasites. Korean J Parasitol. 47(2):83-91, 2009.The authors discussed some recent advances in genetic mapping and genomic studies of malaria parasites, focusing on the use of high-throughput arrays for the detection of SNP and CNV in the P. falciparum genome. Strategies for genetic mapping of malaria traits are also discussed. ABCC did microarray data analysis and prepared figures for the paper. The methods developed for the segmentation analysis are directly applicable to arrayCGH data analysis from cancer samples.Download
Davé UP, Akagi K, Tripathi R, Cleveland SM, Thompson MA, Yi M, Stephens R, Downing JR, Jenkins NA, and Copeland NG. Murine leukemias with retroviral insertions at Lmo2 are predictive of the leukemias induced in SCID-X1 patients following retroviral gene therapy. PLoS Genet. 5(5):e1000491, 2009. This study showed that the genes and signaling pathways deregulated in murine leukemias with retroviral insertions at Lmo2 are similar to those deregulated in human leukemias with high LMO2 expression and are highly predictive of the leukemias induced in SCID-X1 patients. The highly concordant nature of the genetic events giving rise to mouse and human leukemias with mutations at Lmo2 are an encouraging sign to those wanting to use mice to model human cancer and may help in designing safer methods for retroviral gene therapy. ABCC did microarray data analysis and prepared figures for the paper.Download
Fatima N, Chelius D, Luke BT, Yi M, Zhang T, Stauffer S, Stephens R, Lynch P, Miller K, Guszczynski T, Boring D, Greenwald P, and Ali IU. Label-free global serum proteomic profiling reveals novel celecoxib-modulated proteins in familial adenomatous polyposis patients. Cancer Genomics Proteomics 6(1):41-9, 2009 To identify as yet poorly defined molecular determinants of celecoxib efficacy, a multidimensional serum fractionation approach was used coupled with nanospray tandem mass spectrometry to perform label-free global proteomic profiling of serum samples from the FAP/celecoxib prevention trial. Thus, using a shotgun procedure to rapidly identify important celecoxib-modulated proteins, this pilot study has uncovered novel systemic changes some of which are highly relevant for carcinogenesis and vascular biology. ABCC did data and pathway data analysis and prepared figures for the paper.Download
Martin DN, Boersma BJ, Yi M, Reimers M, Howe TM, Yfantis HG, Tsai YC, Williams EH, Lee DH, Stephens RM, Weissman AM, and Ambs S. Differences in the tumor microenvironment between African-American and European-American breast cancer patients. PLoS One 4(2):e4531, 2009.To identify the biological processes in tumors that are different by race/ethnicity, Gene Ontology and disease association analyses were performed.: The gene expression profiles of breast tumors indicate that differences in tumor biology may exist between African-American and European-American patients beyond the knowledge of current markers. Notably, pathways related to tumor angiogenesis and chemotaxis could be functionally different in these two patient groups. ABCC did microarray data and pathway analysis and prepared figures for the paper.Download
Mudunuri U, Che A, Yi M, and Stephens RM. bioDBnet: the biological database network. Bioinformatics 25(4):555-6 2009. The publication introduced bioDBnet, an online web resource that provides interconnected access to many types of biological databases. It has integrated many of the most commonly used biological databases and in its current state has 153 database identifiers (nodes) covering all aspects of biology including genes, proteins, pathways and other biological concepts. This work is exclusively done by ABCC staff as a research project for development of a database integration method that also eases the database update burden.Download
Simunovic F, Yi M, Wang Y, Macey L, Brown LT, Krichevsky AM, Andersen SL, Stephens RM, Benes FM, Sonntag KC. Gene expression profiling of substantia nigra dopamine neurons: further insights into Parkinson's disease pathology. Brain 132(Pt 7):1795-809, 2009This study has used laser microdissection to isolate single DA neurons from the substantia nigra pars compacta of controls and subjects with idiopathic Parkinson's disease matched for age and postmortem interval followed by microarrays to analyse gene expression profiles. The authors found prominent down-regulation of members of the PARK gene family and dysregulation of multiple genes associated with programmed cell death and survival. ABCC did microarray data and pathway analysis and prepared figures and helped writing for the paper. Although not directly associated with cancer, many of the same signalling pathways are revealed in neuroblastoma and other tumors of neuronal origin.Download
Yi M, and Stephens RM. Pathway Analysis: Pathway Signatures and Classification. Chapter 7 in book "Statistics and Informatics in Molecular Cancer Research", June, 2009. Oxford University Press.In recent years, pathway analysis has emerged as a category of promising analysis methods for analyzing high throughput (HTP) data. This chapter will focus specifically on pathway-based analysis of HTP data. The authors provide a brief overview of pathway analysis concepts and methodologies. They also describe the evolution from gene signatures to pathway signatures focusing on the recent development of applications of pathways to the classification of a phenotype of interest using HTP data. This work is exclusively done by ABCC staff as invited by the book's editor for summarizing the current advances in pathway analysis and highlighting the pathway analysis methods developed by ABCC staff.Not Available
Su DM, Zhang Q, Wang X, He P, Zhu YJ, Zhao J, Rennert OM, Su YA. Two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy. Mol Cancer Ther May 2009 8:1292-1304The authors studied two types of human malignant melanoma cell lines revealed by expression patterns of mitochondrial and survival-apoptosis genes: implications for malignant melanoma therapy. The results showed the presence of two types of malignant melanoma, each with a specific set of dysregulated survival-apoptosis genes. ABCC staff did cDNA array analysis for the study.Download
Toyama R, Chen X, Jhawar N, Aamar E, Epstein J, Reany N, Alon S, Gothilf Y, Klein DC, Dawid IB. Transcriptome analysis of the zebrafish pineal gland. Dev Dyn. 2009 Jul; 238(7):1813-26.The zebrafish pineal gland (epiphysis) is a site of melatonin production, contains photoreceptor cells, and functions as a circadian clock pace maker. Here, we have used microarray technology to study the zebrafish pineal transcriptome. Analysis of gene expression at three larval and two adult stages revealed a highly dynamic transcriptional profile, revealing many genes that are highly expressed in the zebrafish pineal gland. Statistical analysis of the data based on Gene Ontology annotation indicates that many transcription factors are highly expressed during larval stages, whereas genes dedicated to phototransduction are preferentially expressed in the adult. Furthermore, several genes were identified that exhibit day/night differences in expression. ABCC staff did microarray data analysis for the study and prepared figures for the paper.Download
Wei JS, Johansson P, Chen QR, Song YK, Durinck S, Wen X, Cheuk AT, Smith MA, Houghton P, Morton C, Khan J. microRNA profiling identifies cancer-specific and prognostic signatures in pediatric malignancies.Clin Cancer Res. 2009 Sep 1;15(17):5560-8. Epub 2009 Aug 25.The authors performed parallel microRNA and mRNA expression profiling on 57 tumor xenografts and cell lines representing 10 different pediatric solid tumors using microarrays. Exploration of the expression of microRNAs in relationship with their host genes showed that the expression for 43 of 68 (63%) microRNAs located inside known coding genes was significantly correlated with that of their host genes. The high expression of the OncomiR-1 host gene MIRHG1 correlates with poor outcome for patients with neuroblastoma, indicating important oncogenic functions of this microRNA cluster in neuroblastoma biology. The ABCC yellow-task staff did the microarray data analysis and help interpretation of the data.Download
Volfovsky N. Oleksyk T.K.,Cruz KC,Truelove A.L. ,Stephens R.M. and Smith M.W.(2009). Genome and gene alterations by insertions and deletions in the evolution of human and chimpanzee chromosome 22. BMC Genomics 10:51This paper reports 6,279 indels of 10 bp or greater in a ~33 Mb alignment between human and chimpanzee chromosome 22. After the exclusion of the indels within in repetitive DNA, 1,429 or 23% of the indels remained. Many of these indels (683 of 1,429) were in proximity of known human genes. Coding sequences and splice sites contained significantly fewer of these indels than expected from random expectations, suggesting that selection is a factor in limiting their persistence. A subset of indels from coding regions was experimentally validated and their impacts were predicted based on direct sequencing in several human populations as well as chimpanzees, bonobos, gorillas, and two subspecies of orangutans. The ABCC provided the bioinformatic analysis in the manuscript.Download
Shao W, Kearney M, Maldarelli F, Mellors JW, Stephens RM, Lifson JD, KewalRamani VN, Ambrose Z, Coffin JM, Palmer SE, 2009. RT-SHIV subpopulation dynamics in infected macaques during anti-HIV therapy. Retrovirology, 6: 101This study quantitatively describes virus evolution and population dynamics patterns in an animal model. The fact that wild type subpopulations remained as dominant subpopulations during ART treatment suggests that the presence or absence of at least some known drug resistant mutations may not greatly affect virus replication capacity in vivo. Additionally, the emergence and prevalence of V75L indicates that this mutation may provide the virus a selective advantage, perhaps escaping the host immure system surveillance. The new method presented here make it possile to observe the relative competitiveness and adaption of different viral variants and provided a valuable tool for studying HIV subpopulation emergence, persistence, and decline during ART.Download
Kearney M, Maldarelli F, Shao W, Margolick JB, Daar ES, Mellors JW, Rao V, Coffin JM, Palmer S, 2009. Human immunodeficiency virus type 1 population genetics and adaptation in newly infected individuals. J Virol. 83:2715-27This publication shows that acute subtype B HIV-1 infection usually results from transmission or outgrowth of single viral variants carrying mutations in CTL epitopes that were selected prior to transmission either in the donor or in a previous donor and that reversion of these mutations can be very slow. These results have important implications for vaccine strategies because they imply that some HLA alleles could be compromised in newly acquired HIV infections.Download
Cer RZ, Stephens R, Mudunuri U, Lebeda FJ. Mining the botulinum research literature. The Botulinum Journal. 2009 1(3):278-280 The paper describes the 'Batch Search' tool developed for the BotDB website. Batch Search was developed using botXminer. It allows searches with multiple terms at the same time. The matrix batch search allows for searches with every combination from two search term lists. The results in both cases are presented in a tabular format with summations across the rows and columnsDownload
Cer RZ, Mudunuri U, Stephens R, Lebeda FJ. IC50-to-Ki: a web-based tool for converting IC50 to Ki values for inhibitors of enzyme activity and ligand binding. Nucleic Acids Res. 2009 Jul 1; 37(Web Server issue):W441-5The IC50-to-Ki converter estimates Ki values from experimentally determined IC50 values. The calculations are available for both enzyme inhibitor reactions and protein-ligand systems. The application, formulas, background and inhibitor information is all available through the BotDB websiteDownload
Mudunuri U, Che A, Yi M, Stephens RM bioDBnet: the biological database network. Bioinformatics. 2009 Feb 15; 25(4):555-6bioDBnet was developed by integrating all the public databases available at ABCC. The current version has 170 biological identifiers covering all aspects of biology including genes, proteins, pathways. bioDBnet allows for conversions between these identifiers and also generates extensive reports with every possible annotation.Download
Naheed Fatima, Dirk Chelius, Brian T. Luke, Ming Yi, Terry Zhang, Stacey Stauffer, Robert Stephens, Patrick Lynch, Ken Miller, Tad Guszczynski, Daniel Boring, Peter Greenwald, Iqbal Unnisa Ali. Label-free Global Serum Proteomic Profiling Reveals Novel Celecoxib-modulated Proteins in Familial Adenomatous Polyposis Patients. Cancer Genomics & Proteomics 2009;6:41-50.Used BMDK to identify a putative biomarker which identifies FAP patients that will not benefit from treatment with celecoxib.Download
Ye X, Luke B, Andresson T, Blonder J. 18O Stable Isotopic Labeling in MS-based Proteomics. Briefings in Functional Genomics and Proteomics. 2009;2:136-144.I developed software that accurately measures protein ratios in isotopically labeled LC/MS/MS experiments. This software is the only available program that retains the proper physics of the experiment.Download
M. Kaszmarek, R. E. Cachau, I.A. Topol, K.S. Kasprzak, A. Ghio, and K. Salnikow, Metal ion-Stimulated iron oxidation in hydroxylases facilitates stabilization of HIF-1a protein. Toxicological Sciences, 107, No. 2, 394-403, 2009.On the basis of molecular modeling we showed that HIF-1a stabilization in human lung epithelial cells could be reached following exposure to various metal and metalloid ions, including those that cannot substitute for iron in the hydroxylases. Modeling allowed to identify a tridentate coordination of ascorbic acid (AA) with the enzyme-bound iron, which explains the specific demand for AA as the iron reductant.Download
J. R. Collins, I.A. Topol, A.V. Nemukhin, A.P. Savitsky, Computational modeling structure and spectra of biological chromophores. Progress in Biomedical Optics and Imaging, Proceedings of SPIE, BiOS , vol. 10, No.31, 2009.Modern quantum chemical approaches were applied for high level calculations of the structures of the chromophore binding pockets and to estimate spectral bands corresponding to the S0-S1 optical transitionsin fluorescent proteins. A special attention is paid to evaluate effects of point mutations in the vicinity of the chromophore group. Theoretical data provide important information on the chromophore properties aiming to interpret the resultsof experimental studies of fluorescent proteins.Download
I. Topol, J. Collins, I. Polyakov, B. Grigorenko, A. Nemukhin, On photoabsorption of the neutral form of the green fluorescent protein chromophore, Biophys. Chem., 145, 1-6, 2009.Theoretical studies of the photoabsorption band corresponding to the vertical electronic transition S0-S1 between first two singlet states were performed for the model chromophore from the green fluorescent protein (GFP) in its neutral form. Evidences were provided that the protein matrix in GFP accounts for a fairly large shift of about 40 nm in the S0-S1 absorption band as compared to the gas phase.Download
The Structural Conservation of Interferon Gamma Among Vertebrates, Ram Savan, S. Ravichandran, Jack R. Collins, Masahiro Sakai and Howard A. Young, Cytokine and Growth Factor Reviews, 20(2), 115-124 2009Interferon Gammas (IFN-g) are cytokine proteins that play an important role in immune functions and cellular communications. In this study, we analyzed the evolutionary trace of IFN-g and its function across organisms by using a novel sequence/structure based combined approach. For instance, to understand the role of IFN-g in lower vertebrates, which lacks structural data, we mapped the mammalian 3D structural information on to its 1D-protein sequence and used that information to carry out a manually curated sequence comparison to that of invertebrates. The study revealed several interesting results. An important one being the identification of structural and functional conservation of IFN-g implying the presence of a natural killer like response or even an adaptive T_H{I} immune response in lower vertebrates.Download
Computer Simulated Screening of Dentin Bonding Primer Monomers through Analysis of their Chemical Functions and their Spatial 3-D Alignment, J. Vaidyanathan, T. K. Vaidyanathan, and S.Ravichandran, Journal of Biomedical Materials Research Part B: Applied Biomaterials 88(2):447-57, 2009In dental applications, primer molecules (small molecules) usually bind to the pre-treated dentin collagen and provide a basis for further interactions (resins or monomers) and protection. Primer binding has many potential applications ranging from dentistry to tissue engineering (prosthesis, skin grafting, cosmetics etc.). Here we have used pharmacophore modeling methods using well-known primers to model the potential binding modes to the active site(s) of collagen. The top-ranked models were further used as templates to search for potential primer molecules in MayBridge 2004 database. The top ranked conformations from previous docking studies were used to validate the new pharmacophore models developed in this work. Surprisingly, we found consistent representative conformations from the direct (docking) and in-direct (pharmacophore) modeling for this system indicating that pharmacophore modeling could be effectively used as a screening approach to scan for novel primer molecules. Download
Scientific Computing and Applications in Informatics. Xinlian Liu and S. Ravichandran. The Journal of Computing Sciences and Colleges, 24(3),83, 2009As we enter into the post-genomic era, we are confronted with huge volumes of genetic data. In this tutorial, we presented a pragmatic approach of teaching scientific computing and applications in small colleges with limited resources.Download
Regioselective epoxide ring-opening using boron trifluoride diethyl etherate: DFT study of an alternative mechanism to explain the formation of syn-fluorohydrins. Mendez PS, Cachau RE, Seoane G, et al. JOURNAL OF MOLECULAR STRUCTURE-THEOCHEM 904: 21-27, 2009We have investigated the ring-opening reaction of epoxides under BF3.OEt2 catalysis in the context of our research on the oligomerization of chiral cyclohexadiendiols derived from biotransformation of halobenzenes as an alternative pathway for the design of antitumor tropolone analogs.Download
The Collaboratory for Structural Nanobiology. Gonzalez-Ibanez, A.M., Gonzalez-Nilo F.D. and Cachau R.E. Biophysical Society 53 Annual Meeting, February 25-March 05, 2009We are in the process of building a nanobioinformatics service dedicated to the collection, curation, and correlation of structural, physico-chemical, biological, and biomedical data: the Collaboratory for Structural Nanobiology (http://nanobiology.ncifcrf.gov/). In this presentation we discuss the lessons learned from an early prototype in the context of the requests put forward by first meeting on enabling standards for nanotechnology development, NIST, October, 2008Download
Nanotechnology Working Group Report, Nathan A. Baker, Raul Cachau, Elaine Freund, Marty Fritts, Sharon Gaheen, Stacey Harper, Juli Klemm, David Paik, Dennis Thomas. CaBIG (on-line July 2009)The Nano WG report aid caBIG and NCI coordinate and prioritize nano related activities through a series of inter-group and inter-agency activitiesNot Available
The Collaboratory for Structural Nanobiology. An interactive space for 3D annotation of nanobioparticles. Cachau R.E. and Gonzalez-Nilo F.D. International Dendrimer Symposium IDS: 6. Stockholm- Sweden. June 14-18, 2009We are in the process of building a nanobioinformatics service dedicated to the collection, curation, and correlation of structural, physico-chemical, biological, and biomedical data: the Collaboratory for Structural Nanobiology ( http://nanobiology.ncifcrf.gov/). In this presentation we discuss the implementation of new technologies for the graphic representation of 3D information archived in the collaboratory for structural nanobiology.Not Available
2010
Simunovic F, Yi M, Wang Y, Stephens RM, and Sonntag KC. Evidence for gender-specific transcriptional profiles of nigral dopamine neurons in Parkinson disease.PLoS One.5(1):e8856, 2010To study the molecular aspects underlying gender-specificity in PD, the authors determined the gene expression profiles of male and female dopamine (DA) neurons in sporadic PD by analyzing Affymetrix-based microarray data. The observed differences in expression profiles suggests a disease bias of the male gender. Validation of gene expression by qRT-PCR supported the microarray results, but also pointed to several caveats involved in data interpretation. ABCC did microarray data and pathway analysis and contributed to the writing in the results and the discussion sections significantly. Although not directly involved in cancer, this manuscript tests analysis of the small and highly variable data sets that are frequently encountered in rare cancers.Download
O Saydam, O Senol, T Würdinger, A Mizrak, G Baris Ozdener, AO Stemmer-Rachamimov, M Yi, RM Stephens, AM Krichevsky and XO Breakefield. Low microRNA-7 in schwannoma tumors stimulates growth through upregulation of three oncogenic signaling pathways. Submitted to Cancer ResearchThe authors carried out high-throughput miRNA expression profiling of human vestibular schwannomas using an array representing 407 known miRNAs in order to explore the role of miRNAs in tumor growth. This is the first study that supported a "tumor suppressor" function for miR-7 in these tumors by targeting major oncogenic pathways. Moreover, the result also suggests that miR-7 may serve as a potential therapeutic molecule for schwannomas. ABCC did microarray data analysis and prepared figures for the paper.Not Available
Peng Li, Shannon Burke, Juexuan Wang, Xiongfeng Chen, Mariaestela Ortiz, Song-Choon Lee and Pentao Liu, Bcl11b Deficient T Cells Lose T Cell Identity and Differentiate into Potent Killer Cells. Science. 2010, in pressT cells develop in the thymus and are critical for adaptive immunity. Natural killer (NK) lymphocytes constitute an essential component of the innate immune system in tumor surveillance and defense against microbes and viruses. This study shows that the transcription factor Bcl11b was expressed in all T cell compartments, and was indispensable for T cell lineage development. When Bcl11b was deleted, T cells from all developmental stages acquired NK cell properties and concomitantly lost or decreased T cell-associated gene expression. These Induced T-to-Natural-Killer (ITNK) cells, which were morphologically and genetically similar to conventional NK cells, killed tumor cells in vitro and effectively prevented tumor metastasis in vivo. Therefore ITNKs may represent a new cell source for cell-based therapies. ABCC staff did microarray data analysis for the study and prepared figures for the paper.Not Available
Potrykus K, Murphy H, Chen X, Epstein JA, Cashel M. Imprecise transcription termination within Escherichia coli greA leader gives rise to an array of short transcripts, GraL. Nucleic Acids Res. 2010 Mar 1; 38(5):1636-51.The study reports that greA expression is driven by two strong, overlapping P1 and P2 promoters. The P1 promoter is sigma(70)-dependent and P2 is sigma(E)-dependent. Two-thirds of transcripts terminate within the leader region and the remaining third comprises greA mRNA. The abundance of individual chains within each cluster displays a characteristic pattern, which can be differentially altered by oligonucleotide probes. Multiple termination sites are particularly sensitive to changes at the bottom of the stem. Evolutionarily conserved GraL stem structures and fitness assays suggest a biological function for the RNA clusters themselves. ABCC staff did microarray data analysis for the study and prepared figures for the paper.Download
Xiang Guo, Young Song, Qingrong Chen, Jun Wei, and Javed Khan. Neuroblastoma tumors of different stage and MYCNamplification status demonstrate distinct alternative splicing patterns. (submitted to BMC Genomics)The author used exon array profiling to investigate global alternative splicing pattern of 47 neuroblastoma samples in stage 1 and stage 4 with normal or amplified MYCN copy number (stage 1-, 4- and 4+). The results demonstrated a significant role of alternative splicing in high stage neuroblastoma, and suggested a MYCN-associated splicing regulation pathway in stage 4+ tumors. The ABCC yellow-task staff is the first author and made the major contribution from the data analysis to manuscript preparation. Not Available
Gheeya J, Johansson P, Chen QR, Dexheimer T, Metaferia B, Song YK, Wei JS, He J, Pommier Y, Khan J. Expression profiling identifies epoxy anthraquinone derivative as a DNA topoisomerase inhibitor. Cancer Lett. 2010 (in press)To discover novel drugs for neuroblastoma treatment, the authors have previously screened a panel of drugs and identified 30 active agents against neuroblastoma cells and performed microarray gene expression analysis to monitor the impact of these agents on a neuroblastoma cell line and used the connectivity map (cMAP) to explore putative mechanism of action of unknown drugs. Their study indicates that Epoxy anthraquinone derivative may be a novel DNA topoisomerase inhibitor that can be potentially used for treatment of neuroblastoma or other cancer patients. ABCC staff contributes by tool developing, and web interface designNot Available
Akagi K., Stephens R.M., Li J., Evdokimov E. , Kuehn M.R. , Volfovsky N., and Symer D.E (2010). MouseIndelDB: a database integrating genomic indel polymorphisms that distinguish mouse strains. Nucleic Acids Res. 38:D600-6This paper reports an integrated database resource containing thousands of previously unreported mouse genomic indels. The database currently includes polymorphisms identified from our alignment of 26 million whole-genome shotgun sequence traces from four laboratory mouse strains mapped against the reference C57BL/6J genome. MouseIndelDB database has proven to be a useful resource for research in mammalian genetics, genomics, and evolutionary biology. The ABCC provided bioinformatics analysis and database functionality for the project.Download
Tolstorukov M.Y., Volfovsky N. , Stephens R.M. and Park P. (2010). Impact of chromatin structure on sequence variability in the human genome. Submitted to NSMBIn this study we compose high-confidence collection of human indels nd SNPs based on the analysis of a large set of publicly available sequencing data and investigate whether the DNA loci associated with stable nucleosome positions are protected against sequence mutations. We address how the sequence variation is reflected in the occupancy profiles of nucleosomes of different types at regulatory sequences and genome-wide. We find that indels are depleted around nucleosome positions of all considered types; SNPs, on the other hand, are enriched around the positions of bulk nucleosomes but depleted around the positions preferentially occupied by epigenetically modified nucleosomesDownload
Marshall V. ,Martro E. ,Labo N. , Ray A. ,Wang D. , Mbisa G., Bagni R.K. , Volfovsky N. , Casabona J. and Whitby D. (2010). KSHV microRNA Sequences Analyses and KS Risk in an European AIDS-KS Case Control Study. Submitted to JIDThe paper examines whether the polymorphisms in the KSHV encoded microRNAs contribute to Kaposi's sarcoma risk in a European AIDS-KS case control study. Despite high conservations of the KSHV microRNAs, polymorphisms were observed including some that have been previously reported. Some polymorphisms are shown to be critical for mature miRNA processing.Download
Michael E. Abram, Andrea L. Ferris, Wei Shao, W. Gregory Alvord, and Stephen H. Hughes. The Nature, Position and frequency of mutations made in a single-cycle of HIV-1 replication. Submitted to PLoS Pathogens.There is considerable HIV-1 variation in patients. The extent of the variation is due to the high rate of viral replication, the high viral load, and to the errors made during viral replication. The authors have developed an efficient system, based on existing technology, to analyze the mutations that arise in an HIV-1 vector in a single cycle of replication. A lacZalpha reporter gene is used to identify viral DNAs that contain mutations which are analyzed by DNA sequencing. The authors also characterized the mutations that arose in both the forward and reverse orientations of the lacZalpha reporter gene. This study suggests that the nature of the mutations depends on the strand present in viral RNA.Download
Michael R. Jordan, Mary Kearney , Sarah Palmer, Wei Shao, Frank Maldarelli, Eoin P. Coakley, Colombe Chappey, Christine Wanke, John M. Coffin. Comparison of standard PCR/cloning to single genome sequencing for analysis of HIV-1 populations. Submitted to Journal of Virological MethodsTo compare standard PCR/cloning and single genome sequencing (SGS) in their ability to reflect actual intra-patient polymorphism of HIV-1 populations, a total of 530 HIV-1 pro-pol sequences obtained by both sequencing techniques from a set of 17 ART naïve patient specimens were analyzed. Overall, the study shows that neither method was more biased than the other, and that providing an adequate number of PCR templates are analyzed, and that the bulk sequencing captures the diversity of the viral population, either method is likely to provide a similar measure of population diversity.Download
Lebeda FJ, Cer RZ, Stephens RM, Mudunuri U. Temporal characteristics of botulinum neurotoxin therapy. Expert Rev Neurother. 2010 Jan;10(1):93-103The review article discusses botulinum neurotoxins and their role as a pharmaceutical treatment for a number of symptoms. It assesses the value of combining computational mining approaches with mathematical modeling to determine the patients who would be the most responsive to such treatments. botXminer developed at ABCC was used for mining botulinum literature and narrowing the number of relevant articles.Download
Long-range enhancers on 8q24 regulate c-Myc. Sotelo J, Esposito D, Duhagon MA, Banfield K, Mehalko J, Liao H, Stephens RM, Harris TJ, Munroe DJ, Wu X. Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3001-5. Epub 2010 Jan 26.This paper reports on the functional analysis of a region on chromosome 8 that has been implicated in prostate and breast cancer and shows that despite the fact that the region is 300kb distant from c-myc, it operates as a regulatory enhancer for the myc gene.Download
J-L Zeddam, KHJ Gordon, C Lauber, Cristiano A. Felipe Alves, BT Luke, TN Hanzlik, VK Ward and AE Gorbalenya. Euprosterna elaeasa virus genome sequence and evolution of the Tetraviridae family: emergence of bipartite genomes and conservation of the VPg signal with the ds RNA Birnaviridae family Virology 2010;397;145-54.Software was developed that identifies within-gene translocations and was used to classify a virus and show the cause of genetic differences.Download
Stereoselective Binding of Chiral Ligands to Single Nucleotide Polymorphs (SNPs) of the Human Organic Cation Transporter-1 Determined Using Cellular Membrane Affinity Chromatography R.Moaddela*, F. Bighia, R. Yamaguchia,b, S. Patela,c, S. Ravichandran, I.W. Wainer, Analyt Biochem, March 3, 2010.Human Organic Cation Transporters-1 (hOCT1) are expressed in kidney, liver and intestines and are involved in the bi-directional transport of small organic cations and the metabolism of xenobiotics. Variations of Single Nucleotide Polymorphisms (SNPs) in these proteins have been associated with various disorders such as Alzheimer's disease etc. In this work, we had used our previously built pharmacophore model (Brit. J. Pharmacology, 2007) along with the experimental data (chromatography) to identify which SNPs might play an important role in the metabolism/binding of xenobiotics in hOCT1. Download
FERNANDO GONZALEZ-NILO, TOMAS PEREZ-ACLE, et al. and RAUL E. CACHAU, New challenges for Bioinformatics and Computational Chemistry in NanoBiotechnology, Biological Research (on-line version April 2010)We review the existing implementations of collaborative networks and web platforms for sharing and discussing the knowledge generated in nanobiotechnology and review the existing applications of Nanobiotechnology in life science, discussing how this application can generate new requirements for diverse scientific field such as Bioinformatics and Computational Chemistry.Download
Darrabie, M.D., Cachau, R.E., Santacruz-Toloza, L. and Jacobs, D.O. Doxorubicin decreases creatine transport in HL-1 cardiac myocytes expressing the human creatine transporter. (submitted for publication Circulation Research, Circulation Research, May 2010)We demonstrate that doxorubicin diminishes creatine transport in a dose- and time-dependent manner establishing for the first time that a decrease in creatine transport contributes to the myocardial energy metabolism derangements observed in doxorubicin-associated heart failure.Not Available