Chemicals and Drugs Commons^™

Elongation Factor-P At The Crossroads Of The Host-Endosymbiont Interface, Andrei Rajkovic, Anne Witzky, William Navarre, Andrew J. Darwin, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Elongation factor P (EF-P) is an ancient bacterial translational factor that aids the ribosome in polymerizing oligo-prolines. EF-P structurally resembles tRNA and binds in-between the exit and peptidyl sites of the ribosome to accelerate the intrinsically slow reaction of peptidyl-prolyl bond formation. Recent studies have identified in separate organisms, two evolutionarily convergent EF-P post-translational modification systems (EPMS), split predominantly between gammaproteobacteria, and betaproteobacteria. In both cases EF-P receives a post-translational modification, critical for its function, on a highly conserved residue that protrudes into the peptidyl-transfer center of the ribosome. EPMSs are comprised of a gene(s) that synthesizes the precursor molecule …

Tnf-Α-Induced Micrornas Control Dystrophin Expression In Becker Muscular Dystrophy., Alyson A. Fiorillo, Christopher R. Heier, James S. Novak, Christopher B. Tully, Kristy J. Brown, Kitipong Uaesoontrachoon, Maria C. Vila, Peter P. Ngheim, Luca Bello, Joe N. Kornegay, Corrado Angelini, Terence A. Partridge, Kanneboyina Nagaraju, Eric P. Hoffman

Genomics and Precision Medicine Faculty Publications

The amount and distribution of dystrophin protein in myofibers and muscle is highly variable in Becker muscular dystrophy and in exon-skipping trials for Duchenne muscular dystrophy. Here, we investigate a molecular basis for this variability. In muscle from Becker patients sharing the same exon 45–47 in-frame deletion, dystrophin levels negatively correlate with microRNAs predicted to target dystrophin. Seven microRNAs inhibit dystrophin expression in vitro, and three are validated in vivo (miR-146b/miR-374a/miR-31). microRNAs are expressed in dystrophic myofibers and increase with age and disease severity. In exon-skipping-treated mdx mice, microRNAs are significantly higher in muscles with low …

Acidic And Basic Destruction Of Tissues, Cydney Eaton

University Honors Program

A coroner’s case I had learned about involved a man attempting to dispose of a body with acid. Shortly after exposure, the man was apprehended and the body was located. Upon investigation, police force determined the acid used to be hydrochloric acid, however, exact concentration remains unknown (Kohr, 2010). This led to the question of which easily accessible acid works best to degrade tissue. To answer this, an experiment was conducted involving pig feet and various concentrations of common acids and a single strong base. The feet were submerged in the solutions overnight and mass percent lost or gained was …

Electrochemical Characterization Of Protein Adsorption Onto Yngrt-Au And Vlgxe-Au Surfaces, Hanna Trzeciakiewicz, Jose Esteves-Villanueva, Rania Soudy, Kamaljit Kaur, Sanela Martic-Milne

Pharmacy Faculty Articles and Research

The adsorption of the proteins CD13, mucin and bovine serum albumin on VLGXE-Au and YNGRT-Au interfaces was monitored by electrochemical impedance spectroscopy in the presence of [Fe(CN)6]3−/4−. The hydrophobicity of the Au surface was tailored using specific peptides, blocking agents and diluents. The combination of blocking agents (ethanolamine or n-butylamine) and diluents (hexanethiol or 2-mercaptoethanol) was used to prepare various peptide-modified Au surfaces. Protein adsorption onto the peptide-Au surfaces modified with the combination of n-butylamine and hexanethiol produced a dramatic decrease in the charge transfer resistance, Rct, for all three proteins. In contrast, polar peptide-surfaces induced a minimal change in …

Molecular Overlap In The Regulation Of Sk Channels By Small Molecules And Phosphoinositides, Miao Zhang, Xuan-Yu Meng, Ji-Fang Zhang, Meng Cui, Diomedes E. Logothetis

Pharmacy Faculty Articles and Research

Phosphatidylinositol 4,5-bisphosphate (PIP2) directly interacts with the small-conductance Ca2+-activated K+ 2-a (SK2-a) channel/calmodulin complex, serving as a critical element in the regulation of channel activity. We report that changes of protein conformation in close proximity to the PIP2 binding site induced by a small-molecule SK channel modulator, NS309, can effectively enhance the interaction between the protein and PIP2 to potentiate channel activity. This novel modulation of PIP2 sensitivity by small-molecule drugs is likely not to be limited in its application to SK channels, representing an intriguing strategy to develop drugs controlling the activity of the large number of PIP2-dependent proteins.

Cationic Cell-Penetrating Peptides Are Potent Furin Inhibitors, Bruno Ramos-Molina, Adam N. Lick, Amir Nasrolahi Shirazi, Donghoon Oh, Rakesh Tiwari, Naglaa Salem El-Sayed, Keykavous Parang, Iris Lindberg

Pharmacy Faculty Articles and Research

Cationic cell-penetrating peptides have been widely used to enhance the intracellular delivery of various types of cargoes, such as drugs and proteins. These reagents are chemically similar to the multi-basic peptides that are known to be potent proprotein convertase inhibitors. Here, we report that both HIV-1 TAT47-57 peptide and the Chariot reagent are micromolar inhibitors of furin activity in vitro. In agreement, HIV-1 TAT47-57 reduced HT1080 cell migration, thought to be mediated by proprotein convertases, by 25%. In addition, cyclic polyarginine peptides containing hydrophobic moieties which have been previously used as transfection reagents also exhibited potent furin inhibition in vitro …

Molecular Determinants Underlying Binding Specificities Of The Abl Kinase Inhibitors: Combining Alanine Scanning Of Binding Hot Spots With Network Analysis Of Residue Interactions And Coevolution, Amanda Tse, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Quantifying binding specificity and drug resistance of protein kinase inhibitors is of fundamental importance and remains highly challenging due to complex interplay of structural and thermodynamic factors. In this work, molecular simulations and computational alanine scanning are combined with the network-based approaches to characterize molecular determinants underlying binding specificities of the ABL kinase inhibitors. The proposed theoretical framework unveiled a relationship between ligand binding and inhibitor-mediated changes in the residue interaction networks. By using topological parameters, we have described the organization of the residue interaction networks and networks of coevolving residues in the ABL kinase structures. This analysis has shown …

Characterization Of The Role That Alternative Ribonucleotide Reductases Play In Restoring Replication In The Presence Of Hydroxyurea In Escherichia Coli, Michael Sadek

PSU McNair Scholars Online Journal

DNA replication is essential for cells to grow and divide. Ribonucleotide reductase is an essential enzyme that is responsible for the formation of deoxyribonucleotides that are used in DNA synthesis during replication. Hydroxyurea is a chemotherapeutic agent that is thought to work by specifically inhibiting the ribonuceotide reductase to prevent replication. However, recent studies in E. coli have shown that following an initial period of inhibition, DNA synthesis then recovers in the presence of hydroxyurea, suggesting that the mode of death and cellular response to hydroxyurea is more complex than originally proposed. The E.coli genome encodes three ribonucleotide reductases that …

Cyclic Rhamnosylated Elongation Factor P Establishes Antibiotic Resistance In Pseudomonas Aeruginosa, Andrei Rajkovic, Sarah Erickson, Anne Witzky, Owen E. Branson, Jin Seo, Philip R. Gafken, Michael A. Frietas, Julian P. Whitelegge, Kym F. Faull, William Wiley Navarre, Andrew J. Darwin, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Elongation factor P (EF-P) is a ubiquitous bacterial protein that is required for the synthesis of poly-proline motifs during translation. In Escherichia coli and Salmonella enterica, the posttranslational β-lysylation of Lys34 by the PoxA protein is critical for EF-P activity. PoxA is absent from many bacterial species such as Pseudomonas aeruginosa, prompting a search for alternative EF-P posttranslation modification pathways. Structural analyses of P. aeruginosa EF-P revealed the attachment of a single cyclic rhamnose moiety to an Arg residue at a position equivalent to that at which β-Lys is attached to E. coli EF-P. Analysis of the genomes …

Orexin Receptor Activation Generates Gamma Band Input To Cholinergic And Serotonergic Arousal System Neurons And Drives An Intrinsic Ca(2+)-Dependent Resonance In Ldt And Ppt Cholinergic Neurons, Masaru Ishibashi, Iryna Gumenchuk, Bryan Kang, Catherine Steger, Elizabeth Lynn, Nancy Molina, Leonard M. Eisenberg, Christopher S. Leonard

NYMC Faculty Publications

A hallmark of the waking state is a shift in EEG power to higher frequencies with epochs of synchronized intracortical gamma activity (30-60 Hz) - a process associated with high-level cognitive functions. The ascending arousal system, including cholinergic laterodorsal (LDT) and pedunculopontine (PPT) tegmental neurons and serotonergic dorsal raphe (DR) neurons, promotes this state. Recently, this system has been proposed as a gamma wave generator, in part, because some neurons produce high-threshold, Ca(2+)-dependent oscillations at gamma frequencies. However, it is not known whether arousal-related inputs to these neurons generate such oscillations, or whether such oscillations are ever transmitted to neuronal …

Synthesis And Characterization Of A New Peptide Prodrug Of Glucosamine With Enhanced Gut Permeability, Hamed Gilzad Kohan, Kamaljit Kaur, Fakhreddin Jamali

Pharmacy Faculty Articles and Research

The aim of this study was to synthesize a peptide prodrug of glucosamine (GlcN) with increased gut permeability through the gut peptide transporter 1 (PepT1). Glycine-Valine ester derivative of GlcN (GVG) was synthesised using solid phase synthesis followed by characterization and evaluation of its physicochemical and intestinal stability. In addition, GVG was evaluated for its ability to be biotransformed to GlcN in the liver homogenate. In vitro absorption of the new prodrug through everted rat gut was also assessed. GVG demonstrated significant and meaningful increased gut permeability as compared with GlcN. It showed favorable stability in the gut and a …

Characterization Of Ghrelin O-Acyltransferase Active Site, Leslie Patton

Renée Crown University Honors Thesis Projects - All

Ghrelin, first discovered in 1999, is a 28-amino acid peptide hormone involved in the regulation of appetite, insulin secretion and sensitivity, and many neurological effects such as learning, memory, and depression.^1-6 Ghrelin has been identified to have a unique posttranslational octanoylation carried out by the enzyme ghrelin O-acyltransferase (GOAT). This distinctive modification is a point of interest in studying GOAT whereby blocking the acylation of the ghrelin could potentially halt the activity of the peptide hormone and provide a means of treating obesity, diabetes, and other diseases affected by ghrelin levels. The duration of my project involved working …

Accidental Phosphine Gas Poisoning With Fatal Myocardial Dysfunction In Two Families, Saleem Akhtar, Arshalooz Rehman, Surraya Bano, Anwarul Haque

Department of Emergency Medicine

ABSTRACT Aluminum phosphide is commonly used as a rodenticide and insecticide and is one of the most fatal poisons. The active ingredient is Phosphine gas which inhibits cytochrome oxidase and cellular oxygen utilization. The clinical symptoms are due to multiorgan involvement including cardiac toxicity which is the most common cause of mortality. Severity of clinical manifestations depends upon the amount of the gas to which a person is exposed. There is no specific antidote available. High index of suspicion and early aggressive treatment is the key to success. We report 2 cases of aluminum phosphide toxicity in 2 families due …

Targeting Cell Cycle Proteins In Breast Cancer Cells With Sirna By Using Lipid-Substituted Polyethylenimines, Manoj Parmar, Hamidreza Montazeri Aliabadi, Parvin Mahdipoor, Cezary Kucharski, Robert Maranchuk, Judith C. Hugh, Hasan Uludag

Pharmacy Faculty Articles and Research

The cell cycle proteins are key regulators of cell cycle progression whose de-regulation is one of the causes of breast cancer. RNA interference (RNAi) is an endogenous mechanism to regulate gene expression and it could serve as the basis of regulating aberrant proteins including cell cycle proteins. Since the delivery of small interfering RNA (siRNA) is a main barrier for implementation of RNAi therapy, we explored the potential of a non-viral delivery system, 2.0 kDa polyethylenimines substituted with linoleic acid and caprylic acid, for this purpose. Using a library of siRNAs against cell cycle proteins, we identified cell division cycle …

A-803467, A Tetrodotoxin-Resistant Sodium Channel Blocker, Modulates Abcg2-Mediated Mdr In Vitro And In Vivo, Nagaraju Anreddy, Atish Patel, Yun-Kai Zhang, Yi-Jun Wang, Suneet Shukla, Rishil J. Kathawala, Priyank Kumar

Touro College of Pharmacy (New York) Publications and Research

ATP-binding cassette subfamily G member 2 (ABCG2) is a member of the ABC transporter superfamily proteins, which has been implicated in the development of multidrug resistance (MDR) in cancer, apart from its physiological role to remove toxic substances out of the cells. The diverse range of substrates of ABCG2 includes many antineoplastic agents such as topotecan, doxorubicin and mitoxantrone. ABCG2 expression has been reported to be significantly increased in some solid tumors and hematologic malignancies, correlated to poor clinical outcomes. In addition, ABCG2 expression is a distinguishing feature of cancer stem cells, whereby this membrane transporter facilitates resistance to the …

Kaposi Sarcoma Herpesvirus Induces Ho-1 During De Novo Infection Of Endothelial Cells Via Viral Mirna-Dependent And -Independent Mechanisms, Sara Botto, Jennifer Totonchy, Jean K. Gustin, Ashlee V. Moses

Pharmacy Faculty Articles and Research

Kaposi sarcoma (KS) herpesvirus (KSHV) infection of endothelial cells (EC) is associated with strong induction of heme oxygenase-1 (HO-1), a stress-inducible host gene that encodes the rate-limiting enzyme responsible for heme catabolism. KS is an angioproliferative tumor characterized by the proliferation of KSHV-infected spindle cells, and HO-1 is highly expressed in such cells. HO-1 converts the pro-oxidant, proinflammatory heme molecule into metabolites with antioxidant, antiinflammatory, and proliferative activities. Previously published work has shown that KSHV-infected EC in vitro proliferate in response to free heme in a HO-1-dependent manner, thus implicating virus-enhanced HO-1 activity in KS tumorigenesis. The present study investigated …

Possible Effects Of Nanosecond Pulsed Electric Fields On Proteins, Stephen J. Beebe

Bioelectrics Publications

No abstract provided.

Elucidation Of A Novel Pathway In Staphylococcus Aureus: The Essential Site-Specific Processing Of Ribosomal Protein L27, Erin A. Wall

Theses and Dissertations

Ribosomal protein L27 is a component of the eubacterial large ribosomal subunit that has been shown to play a critical role in substrate stabilization during protein synthesis. This function is mediated by the L27 N-terminus, which protrudes into the peptidyl transferase center where it interacts with both A-site and P-site tRNAs as well as with 23S rRNA. We observed that L27 in S. aureus and other Firmicutes is encoded with a short N-terminal extension that is not present in most Gram-negative organisms, and is absent from mature ribosomes. The extension contains a conserved cleavage motif; nine N-terminal amino acids are …

Design, Synthesis, Antiviral Activity, And Pre-Formulation Development Of Poly-Larginine- Fatty Acyl Derivatives Of Nucleoside Reverse Transcriptase Inhibitors, Bhanu P. Pemmaraju, Swapnil Malekar, Hitesh K. Agarwal, Rakesh Tiwari, Donghoon Oh, Gustavo F. Doncel, David R. Worthen, Keykavous Parang

Pharmacy Faculty Articles and Research

The objective of this work was to design conjugates of anti-HIV nucleosides conjugated with fatty acids and cell-penetrating poly-L-arginine (polyArg) peptides. Three conjugates of polyArg cell-penetrating peptides with fatty acyl derivatives of alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC) were synthesized. In general, the compounds exhibited anti-HIV activity against X4 and R5 cell-free virus with EC50 values of 1.5–16.6 μM. FLT-CO-(CH2)12-CO-(Arg)7 exhibited EC50 values of 2.9 μM and 3.1 μM against X4 and R5 cell-free virus, respectively. The FLT conjugate was selected for further preformulation studies by determination of solution state degradation and lipid solubility. The compound was found to …

Regulation Of Ghrelin: A Possible Treatment Option For Obesity And Diabetes, Sarah Picciotto

The Science Journal of the Lander College of Arts and Sciences

Obesity is a mounting problem in America today. One major concern about obesity is that it is a risk factor for type 2 diabetes, a disease that impairs insulin sensitivity and secretion. This interferes with blood glucose levels and can cause hyperglycemia, which is when there is too much circulating glucose in the blood. Ghrelin, an amino acid peptide responsible for appetite stimulation and energy balance, plays a direct role in insulin secretion and glucose metabolism. In many experiments, elevated ghrelin levels are associated with decreased insulin secretion from pancreatic islet cells. Although ghrelin concentration is decreased in obese individuals …

Drug Interactions With Glutaredoxin Orthologues, Kahlilah R. Napper, Thomas C. Leeper, Ram Khattri, Daniel Morris, Caroline Davis

Williams Honors College, Honors Research Projects

Glutaredoxin, an enzymatic protein, is an important component of cell viability and function. It catalyzes reactions involved in DNA synthesis and innate immunity [1,4]. Glutaredoxin is also essential in antibiotic resistance in pathogenic bacterial species. Pseudomonas aeruginosa in particular is responsible for infecting the lung tissue of its human hosts, resulting in the development of pneumonia and cystic fibrosis [3]. Because glutaredoxin is pertinent in cell proliferation of eukaryotic and bacterial cells alike, medicinal fragments that take advantage of the subtle differences in protein structure of the orthologous proteins can be synthesized and enhanced to bind bacterial glutaredoxins, without inhibiting …

Sharp Rna Recognition Motif Optimizations, Extensions, And Mutations For Use In 2d And 3d Nmr Experiments, Shaun M. Christie

Williams Honors College, Honors Research Projects

SMRT/HDAC Associated Repressor Protein interacts with the long noncoding RNA, produced by SRA, by binding at the RRMs. Three projects were done to prepare the truncated proteins for use in 2D and 3D NMR experiments. The first focuses on RRM 3 and its optimization during the purification process. The second focuses on RRM 2-4, which was found to be missing two alpha helices that may be important for protein stability. These helices can also interact with RRM 3 as well due to the tight association of RRMs 3 and 4. The two step PCR extension of RRM 2-4 was assumed …

Polymer Interactions With Nucleic Acids Under Various Physiological Conditions, Matthew S. Obrzut

Williams Honors College, Honors Research Projects

The goal of this project is to improve our understanding of nucleic acid interactions with cationic polymers with the theory that the polymers could protect the nucleic acids from degradation caused by biological enzymes. We seek to understand what the limitations of the cationic polymers are which, in this case, is mainly polymer-DNA compatibility. This experiment utilized peptide-dextran hybrid polymers with differing functionalizations to condense anionic nucleic acids into nanometer-sized polyplexes. Techniques of dynamic light scattering and zeta-potential were utilized to determine the particle sizes and surface charges of polyplexes.

In this experiment, dextran with a molecular weight of 20 …

Human Anatomy And Physiology Preparatory Course (1st Edition), Carlos Liachovitzky

Open Educational Resources

The overall purpose of this preparatory course textbook is to help students familiarize with some terms and some basic concepts they will find later in the Human Anatomy and Physiology I course.

The organization and functioning of the human organism generally is discussed in terms of different levels of increasing complexity, from the smallest building blocks to the entire body. This Anatomy and Physiology preparatory course covers the foundations on the chemical level, and a basic introduction to cellular level, organ level, and organ system levels. There is also an introduction to homeostasis at the beginning.

Xlf-Dependent Nonhomologous End Joining Of Complex Dna Double-Strand Breaks With Proximal Thymine Glycol And Screening For Xrcc4-Xlf Interaction Inhibitors, Mohammed Al Mohaini

Theses and Dissertations

DNA double-strand breaks induced by ionizing radiation are often accompanied by ancillary oxidative base damage that may prevent or delay their repair. In order to better define the features that make some DSBs repair-resistant, XLF-dependent nonhomologous end joining of blunt-ended DSB substrates having the oxidatively modified nonplanar base thymine glycol (Tg) at the first (Tg1) , second (Tg2), third (Tg3) or fifth (Tg5) positions from one 3’ terminus was examined in human whole-cell extracts. Tg at the third position had little effect on end-joining even when present on both ends of the break. However, Tg as the terminal or penultimate …

A Dynamic Programming Algorithm For Finding The Optimal Placement Of A Secondary Structure Topology In Cryo-Em Data, Abhishek Biswas, Desh Ranjan, Mohammad Zubair, Jing He

Computer Science Faculty Publications

The determination of secondary structure topology is a critical step in deriving the atomic structures from the protein density maps obtained from electron cryomicroscopy technique. This step often relies on matching the secondary structure traces detected from the protein density map to the secondary structure sequence segments predicted from the amino acid sequence. Due to inaccuracies in both sources of information, a pool of possible secondary structure positions needs to be sampled. One way to approach the problem is to first derive a small number of possible topologies using existing matching algorithms, and then find the optimal placement for each …

Mechanisms, Potential Therapies, And The Role Of Tgf-Β In The Formation Of Scars, Isaac Traube

The Science Journal of the Lander College of Arts and Sciences

Scarring is the inevitable outcome of wound healing. This review looks at some of the underlying mechanisms of this complex process with the aim of identifying targets for therapeutic manipulation that could result in reduced scarring or even scarless wound repair. Fetal wounds are shown to heal without scars primarily due to low levels of TGF-β1 and TGF-β2 and high levels of TGF-β3 as compared to adult wounds which heal with scars. Abnormal excessive scarring in keloid and hypertrophic scars are also attributed to TGF-β. Clinical manipulation of TGF-β ratios showed promise as a therapeutic means of controlling scar formation. …

Transfer Rna Comes Of Age, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

"The year the journal RNA was founded was slated by some in scientific publishing to be the year that one particular type of RNA's run in the spotlight would end. In 1995 I had recently started as a post-doc with Dieter Söll at Yale when he came into the lab to solemnly inform us all that an editor at a certain (S)cience journal had just told him “we won't be publishing any more tRNA papers.” For a post-doc who had migrated across the Atlantic for the sole purpose of furthering his career by working on tRNA this was not great …

A Microrna-1280/Jag2 Network Comprises A Novel Biological Target In High-Risk Medulloblastoma, Fengfei Wang, Marc Remke, Tze-Chen Hsieh, Lizi Wu, Cynthia Hawkins, Joseph M. Wu, Erxi Wu

NYMC Faculty Publications

Over-expression of PDGF receptors (PDGFRs) has been previously implicated in high-risk medulloblastoma (MB) pathogenesis. However, the exact biological functions of PDGFRα and PDGFRβ signaling in MB biology remain poorly understood. Here, we report the subgroup specific expression of PDGFRα and PDGFRβ and their associated biological pathways in MB tumors. c-MYC, a downstream target of PDGFRβ but not PDGFRα, is involved in PDGFRβ signaling associated with cell proliferation, cell death, and invasion. Concurrent inhibition of PDGFRβ and c-MYC blocks MB cell proliferation and migration synergistically. Integrated analysis of miRNA and miRNA targets regulated by both PDGFRβ and c-MYC reveals that increased …

Effect Of Hydrogen Peroxide On The Biosynthesis Of Heme And Proteins: Potential Implications For The Partitioning Of Glu-TrnaGlu Between These Pathways, Carolina Farah, Gloria Levicán, Michael Ibba, Omar Orellana

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Glutamyl-tRNA (Glu-tRNA^Glu) is the common substrate for both protein translation and heme biosynthesis via the C5 pathway. Under normal conditions, an adequate supply of this aminoacyl-tRNA is available to both pathways. However, under certain circumstances, Glu-tRNA^Glu can become scarce, resulting in competition between the two pathways for this aminoacyl-tRNA. In Acidithiobacillus ferrooxidans, glutamyl-tRNA synthetase 1 (GluRS1) is the main enzyme that synthesizes Glu-tRNA^Glu. Previous studies have shown that GluRS1 is inactivated in vitro by hydrogen peroxide (H₂O₂). This raises the question as to whether H₂O₂ negatively affects …