Life Sciences Commons^™

The Mycobacterium Tuberculosis Drugome And Its Polypharmacological Implications, Sarah L. Kinnings, Li Xie, Kingston H. Fung, Richard M. Jackson, Lei Xie, Phillip E. Bourne

Publications and Research

We report a computational approach that integrates structural bioinformatics, molecular modelling and systems biology to construct a drug-target network on a structural proteome-wide scale. The approach has been applied to the genome of Mycobacterium tuberculosis (M.tb), the causative agent of one of today’s most widely spread infectious diseases. The resulting drug-target interaction network for all structurally characterized approved drugs bound to putative M.tb receptors, we refer to as the ‘TB-drugome’. The TB-drugome reveals that approximately one-third of the drugs examined have the potential to be repositioned to treat tuberculosis and that many currently unexploited M.tb receptors may be chemically druggable …

The Terebridae And Teretoxins: Combining Phylogeny And Anatomy For Concerted Discovery Of Bioactive Compounds, Nicolas Puillandre, Mandë Holford

Publications and Research

The Conoidea superfamily, comprised of cone snails, terebrids, and turrids, is an exceptionally promising group for the discovery of natural peptide toxins. The potential of conoidean toxins has been realized with the distribution of the first Conus (cone snail) drug, Prialt (ziconotide), an analgesic used to alleviate chronic pain in HIV and cancer patients. Cone snail toxins (conotoxins) are highly variable, a consequence of a high mutation rate associated to duplication events and positive selection. As Conus and terebrids diverged in the early Paleocene, the toxins from terebrids (teretoxins) may demonstrate highly divergent and unique functionalities. Recent analyses of the …

Alternative Trans-Splicing Of Caenorhabditis Elegans Sma-9/Schnurri Generates A Short Transcript That Provides Tissue-Specific Function In Bmp Signaling, Jianghua Yin, Ling Yu, Cathy Savage-Dunn

Publications and Research

Background Transcription cofactors related to Drosophila Schnurri facilitate the transcriptional programs regulated by BMP signaling in C. elegans, Drosophila, Xenopus, and mouse. In different systems, Schnurri homologs have been shown to act as either agonists or antagonists of Smad function, and as either positive or negative regulators of transcription. How Schnurri proteins achieve this diversity of activities is not clear. The C. elegans sma-9/schnurri locus undergoes alternative splicing, including an unusual trans-splicing event that could generate two non-overlapping shorter transcripts.

Results We demonstrate here that the shorter transcripts are expressed in vivo. Furthermore, we find that one of the short …

Dna Adducts Of Decarbamoyl Mitomycin C Efficiently Kill Cells Without Wild-Type P53 Resulting From Proteasome-Mediated Degradation Of Checkpoint Protein 1, Ernest K. Boamah, Angelika Brekman, Maria Tomasz, Natura Myeka, Maria E. Figueiredo-Pereira, Senyene Hunter, Joel Meyer, Rahul C. Bhosle, Jill Bargonetti

Publications and Research

The mitomycin derivative 10-decarbamoyl mitomycin C (DMC) more rapidly activates a p53-independent cell death pathway than mitomycin C (MC). We recently documented that an increased proportion of mitosene1-β-adduct formation occurs in human cells treated with DMC in comparison to those treated with MC. Here, we compare the cellular and molecular response of human cancer cells treated with MC and DMC. We find the increase in mitosene 1-β-adduct formation correlates with a condensed nuclear morphology and increased cytotoxicity in human cancer cells with or without p53. DMC caused more DNA damage than MC in the nuclear and mitochondrial genomes. Checkpoint 1 …

Dynamics On Multiple Timescales In The Rna-Directed Rna Polymerase From The Cystovirus Φ6, Zhen Ren, Hsin Wang, Ranajeet Ghose

Publications and Research

The de novoinitiating RNA-directed RNA polymerase (RdRP), P2, forms the central machinery in the infection cycle of the bacteriophage ϕ6 by performing the dual tasks of replication and transcription of the double-stranded RNA genome in the host cell. By measurement and quantitative analysis of multiple-quantum spin-relaxation data for the δ1 positions of Ile residues that are distributed over the 3D-fold of P2, we find that the enzyme is dynamic both on the fast (ps–ns) and slow (µs–ms) timescales. The characteristics of several motional modes including those that coincide with the catalytic timescale (500–800/s) are altered in the presence of …

Morphological Changes And Immunohistochemical Expression Of Rage And Its Ligands In The Sciatic Nerve Of Hyperglycemic Pig (Sus Scrofa), Judyta K. Juranek, Alexey Aleshin, Eileen M. Rattigan, Lynne Johnson, Wu Qu, Fei Song, Radha Ananthakrishnan, Nosirudeen Quadri, Shi Du Yan, Ravichandran Ramasamy, Ann Marie Schmidt, Matthew S. Geddis

Publications and Research

The aim of our project was to study the effect of streptozotocin (STZ)—induced hyperglycemia on sciatic nerve morphology, blood plasma markers and immunohistochemical expression of RAGE (the Receptor for Advanced Glycation End-products), and its ligands—S100B and Carboxymethyl Lysine (CML)-advanced glycation endproduct (AGE) in the laboratory pig. Six months after STZ—injections, blood plasma measurements, morphometric analysis of sciatic nerve fiber density, immunofluorescent distribution of potential molecular neuropathy contributors, ELISA measurement of plasma AGE level and HPLC analysis of sciatic nerve levels of one of the pre-AGE and the glycolysis intermediate products—methyl-glyoxal (MG) were performed. The results of our study revealed that …