Chemicals and Drugs Commons^™

Characterization Of A Novel Protease In Staphylococcus Aureus, Adam L. Johnson

Theses and Dissertations

A newly discovered cysteine protease, Prp, has been shown to perform an essential, site-specific cleavage of ribosomal protein L27 in Staphylococcus aureus. In Firmicutes and related bacteria, ribosomal protein L27 is encoded with a conserved N-terminal extension that must be removed to expose residues critical for ribosome function. Uncleavable and pre-cleaved variants were unable to complement an L27 deletion in S. aureus, indicating that this N-terminal processing event is essential and likely plays an important regulatory role. The gene encoding the responsible protease (prp) has been shown to be essential, and is found in all organisms …

The Effects Of Curcumin On The Expression Of P53 And Bcl-2 Oncoproteins On The Human Breast Carcinoma Cell Line Mda-Mb 468, Angelin S. Shajan

Theses and Dissertations

We studied the effects of curcumin on the proliferation and viability of MDA-MB-468 breast cancer cells and its effects on the expression ofBcl-2 and p53 proteins in these cells. Based on previous studies, we predicted a dose-dependent increase in p53 (tumor suppressor) expression, and a decrease in Bcl-2 (anti-apoptotic oncoprotein) expression. Briefly, MDA-MB468 cells were seeded into 12-well plates at 2.0 * 104 cells/well and allowed to grow for 72 hrs. Cells were treated with curcumin at 0, 25, 50 and 100 pM in triplicate at time zero and cultured for another 24 hours. All data were obtained using a …

Target-Directed Biosynthetic Evolution: Redirecting Plant Evolution To Genomically Optimize A Plant’S Pharmacological Profile, Dustin Paul Brown

Theses and Dissertations--Neuroscience

The dissertation describes a novel method for plant drug discovery based on mutation and selection of plant cells. Despite the industry focus on chemical synthesis, plants remain a source of potent and complex bioactive metabolites. Many of these have evolved as defensive compounds targeted on key proteins in the CNS of herbivorous insects, for example the insect dopamine transporter (DAT). Because of homology with the human DAT protein some of these metabolites have high abuse potential, but others may be valuable in treating drug dependence. This dissertation redirects the evolution of a native Lobelia species toward metabolites with greater activity …

Chemoenzymatic Studies To Enhance The Chemical Space Of Natural Products, Jhong-Min Chen

Theses and Dissertations--Pharmacy

Natural products provide some of the most potent anticancer agents and offer a template for new drug design or improvement with the advantage of an enormous chemical space. The overall goal of this thesis research is to enhance the chemical space of two natural products in order to generate novel drugs with better in vivo bioactivities than the original natural products.

Polycarcin V (PV) is a gilvocarcin-type antitumor agent with similar structure and comparable bioactivity with the principle compound of this group, gilvocarcin V (GV). Modest modifications of the polyketide-derived tetracyclic core of GV had been accomplished, but the most …

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 …

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 …

Utilization Of Placebo Response In Double-Blind Psychopharmacological Studies, Contextual Perspective, Margarita Olegovna Ashirova

Antioch University Dissertations & Theses

Placebo response has been an elusive phenomenon in the fields of medicine, medical research, and psychology. Even though it has been heavily utilized as a comparator treatment in double-blind psychopharmacological studies, the reliable definition and consistent understanding of placebo response are missing. In this contextual exploration, I outlined the state of current placebo response research and variable rates of placebo response reported in double-blind studies. I identified the gap in the literature—lack of consistent understanding of placebo response—that has led to a waste of resources by the psychopharmacological research industry. Further, I compared and contrasted the current inconsistent Western medical …

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 …

Colloidal And Biological Properties Of Triscationic Amphiphiles With One Or Two Tails, John N. Marafino

Masters Theses, 2010-2019

The decline in the development of novel antimicrobials, combined with the misusage and over prescription of antibiotics, has contributed to the increasing prevalence of antimicrobial-resistant infections. Thus development of effective novel disinfectants could reduce the transmission of pathogens and decrease the risk of infection by antibiotic resistant organisms. The antimicrobial activity of amphiphiles, compounds with hydrophobic and hydrophilic regions, was first reported in 1935, and has influenced the synthesis of amphiphiles with variations in structure. In this study, three series of amphiphiles were synthesized by two subsequent Menshutkin reactions. Each amphiphile contains one or two hydrocarbon tails ranging from 8 …

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 …

Assessment Of The Effects Of Caffeine, Gallic Acid, And Epigallocatechin-3-Gallate On Cell Inhibition, Pim-3 And E. Cadherin Protein Levels In Two Lines Of Pancreatic Cancer Cells, Lena Haddad, Melissa Rowland-Goldsmith

Student Scholar Symposium Abstracts and Posters

According to the American Cancer Society, pancreatic cancer is currently the fourth leading cause of cancer related deaths in the United States. In addition to being an exceptionally aggressive form of cancer, it is particularly difficult to treat because it is usually diagnosed in late stages after the onset of metastasis (1). Consequently, the current treatments used, including chemotherapy and radiation, have been rendered ineffective (2). As a result, focus has been placed on using dietary alternatives which are known to possess chemopreventive properties (3). Previous studies have indicated that Gallic acid (an important phytochemical in pomegranates) and Epigallocatechin-3-Gallate (the …

Studies To Characterize Heavy Metal Content And Migration From Recycled Polyethyleneterephthalate, Michael John-Ross Whitt

Master's Theses

Packaging Materials account for 31% of the world’s municipal solid waste. Agencies like the Environmental Protection Agency (EPA) and the Agency for Toxic Substances and Disease Registry (ATSDR) are pushing for the increased use of recycled thermoplastic materials. Polyethylene terephthalate (PET) is a commonly recycled thermoplastic which is used to package ready-to-eat fruits and vegetables. Most recycled polyethylene terephthalate (RPET) packaging materials contain heavy metal catalysts, the most common being antimony. The recent increased use of recycled plastic materials has been suspected as the source of increased human heavy metal exposure. In this study, cadmium, chromium, nickel, lead and antimony …

Peptide Arrays For Detecting Naphthenic Acids In Oil Sands Process Affected Water, Kamaljit Kaur, Subir Bhattacharjee, Rajesh G. Pillai, Sahar Ahmed, Sarfuddin Azmi

Pharmacy Faculty Articles and Research

Naphthenic acids (NAs) are water-soluble components of petroleum. The characterization and quantification of NAs by analytical methods have proved quite challenging, whilst the toxic effects of these water-soluble compounds on a variety of organisms adversely affecting reproduction and steroid production is becoming apparent. In this study, we report a fluorescence-based competitive binding method for rapid sensing of the presence of NAs using cellulosic peptide array strips as sensors. The peptide array was designed from sequences derived from the estrogen receptor (ER). Several of these peptides were able to detect the presence of NAs at low micromolar (∼5 mg L^{−1 …}

Hydroxamic Acid-Based Histone Deacetylase (Hdac) Inhibitors Can Mediate Neuroprotection Independent Of Hdac Inhibition, Sama Sleiman, Yan-Ling Zhang, Jennifer Gale, Manuela Basso, Giovanni Coppola, John T. Pinto, Rajiv Ratan

NYMC Faculty Publications

Histone deacetylase (HDAC) inhibition improves function and extends survival in rodent models of a host of neurological conditions, including stroke, and neurodegenerative diseases. Our understanding, however, of the contribution of individual HDAC isoforms to neuronal death is limited. In this study, we used selective chemical probes to assess the individual roles of the Class I HDAC isoforms in protecting Mus musculus primary cortical neurons from oxidative death. We demonstrated that the selective HDAC8 inhibitor PCI-34051 is a potent neuroprotective agent; and by taking advantage of both pharmacological and genetic tools, we established that HDAC8 is not critically involved in PCI-34051's …

Hdac8 And Stat3 Repress Bmf Gene Activity In Colon Cancer Cells, Y Kang, Hui Nian, P Rajendran, W Dashwood, John T. Pinto, E Ho, R Dashwood

NYMC Faculty Publications

Histone deacetylase (HDAC) inhibitors are undergoing clinical trials as anticancer agents, but some exhibit resistance mechanisms linked to anti-apoptotic Bcl-2 functions, such as BH3-only protein silencing. HDAC inhibitors that reactivate BH3-only family members might offer an improved therapeutic approach. We show here that a novel seleno-α-keto acid triggers global histone acetylation in human colon cancer cells and activates apoptosis in a p21-independent manner. Profiling of multiple survival factors identified a critical role for the BH3-only member Bcl-2-modifying factor (Bmf). On the corresponding BMF gene promoter, loss of HDAC8 was associated with signal transducer and activator of transcription 3 (STAT3)/specificity protein …

The Non-Canonical Hydroxylase Structure Of Yfcm Reveals A Metal Ion-Coordination Motif Required For Ef-P Hydroxylation, Kan Kobayashi, Assaf Katz, Andrei Rajkovic, Ryohei Ishii, Owen E. Branson, Michael A. Freitas, Ryuichiro Ishitani, Michael Ibba, Osamu Nureki

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

EF-P is a bacterial tRNA-mimic protein, which accelerates the ribosome-catalyzed polymerization of poly-prolines. In Escherichia coli, EF-P is post-translationally modified on a conserved lysine residue. The post-translational modification is performed in a two-step reaction involving the addition of a β-lysine moiety and the subsequent hydroxylation, catalyzed by PoxA and YfcM, respectively. The β-lysine moiety was previously shown to enhance the rate of poly-proline synthesis, but the role of the hydroxylation is poorly understood. We solved the crystal structure of YfcM and performed functional analyses to determine the hydroxylation mechanism. In addition, YfcM appears to be structurally distinct from any …

Treating Cocaine Dependency With Psychopharmacotherapy And Behavioral Therapy, Robyn Liebman

e-Research: A Journal of Undergraduate Work

Cocaine is an addictive drug that affects more than 14 million people globally, according to the United Nations. This paper is a conceptual meta-analysis of numerous studies that tested the effects of psychopharmacological therapy along with behavioral therapy in the treatment of cocaine addiction. It is hypothesized that cocaine dependent individuals treated with a combination of psychopharmacological and behavioral therapies will be less likely to use cocaine. Measurements of cocaine use throughout the experiments were generally assessed by urine screenings. Results indicate that there is more evidence that a combination of psychopharmacological and behavioral therapies will reduce cocaine use. There …

Mistranslation Of The Genetic Code, Adil Moghal, Kyle Mohler, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

During mRNA decoding at the ribosome, deviations from stringent codon identity, or “mistranslation,” are generally deleterious and infrequent. Observations of organisms that decode some codons ambiguously, and the discovery of a compensatory increase in mistranslation frequency to combat environmental stress have changed the way we view “errors” in decoding. Modern tools for the study of the frequency and phenotypic effects of mistranslation can provide quantitative and sensitive measurements of decoding errors that were previously inaccessible. Mistranslation with non‐protein amino acids, in particular, is an enticing prospect for new drug therapies and the study of molecular evolution.

Relaxed Substrate Specificity Leads To Extensive Trna Mischarging By Streptococcus Pneumoniae Class I And Class Ii Aminoacyl-Trna Synthetases, Jennifer Shepherd, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Aminoacyl-tRNA synthetases provide the first step in protein synthesis quality control by discriminating cognate from noncognate amino acid and tRNA substrates. While substrate specificity is enhanced in many instances by cis- and trans-editing pathways, it has been revealed that in organisms such as Streptococcus pneumoniae some aminoacyl-tRNA synthetases display significant tRNA mischarging activity. To investigate the extent of tRNA mischarging in this pathogen, the aminoacylation profiles of class I isoleucyl-tRNA synthetase (IleRS) and class II lysyl-tRNA synthetase (LysRS) were determined. Pneumococcal IleRS mischarged tRNA^Ile with both Val, as demonstrated in other bacteria, and Leu in a tRNA sequence-dependent …

Investigating Propargyl-Linked Antifolates In Inhibiting Bacterial And Fungal Dihydrofolate Reductase, Joshua Andrade

Honors Scholar Theses

Antimicrobial agents have been invaluable in reducing illness and death associated with bacterial infection. However, over time, bacteria have evolved resistance to all major drug classes as a result of selective pressure. The advancement of new drug compounds is therefore vital. The Anderson-Wright Lab has focused on developing potent and selective inhibitors of dihydrofolate reductase (DHFR), an enzyme key in cell proliferation and survival, in several pathogenic species. The lab has found that a set of compounds, known as propargyl-linked antifolates, are DHFR inhibitors that are both biologically effective and have strong pharmacokinetic properties.

The efficacy of novel propargyl-linked antifolates …

Translation Initiation Rate Determines The Impact Of Ribosome Stalling On Bacterial Protein Synthesis, Steven J. Hersch, Sara Elgamal, Assaf Katz, Michael Ibba, William Wiley Navarre

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Ribosome stalling during translation can be caused by a number of characterized mechanisms. However, the impact of elongation stalls on protein levels is variable, and the reasons for this are often unclear. To investigate this relationship, we examined the bacterial translation elongation factor P (EF-P), which plays a critical role in rescuing ribosomes stalled at specific amino acid sequences including polyproline motifs. In previous proteomic analyses of both Salmonella and Escherichia coli efp mutants, it was evident that not all proteins containing a polyproline motif were dependent on EF-P for efficient expression in vivo . The α- and β-subunits of …

Sma-Causing Missense Mutations In Survival Motor Neuron (Smn) Display A Wide Range Of Phenotypes When Modeled In Drosophila, Kavita Praveen, Ying Wen, Kelsey M. Gray, John J. Noto, Akash R. Patlolla, Gregory D. Van Duyne, A. Gregory Matera

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Mutations in the human survival motor neuron 1 (SMN) gene are the primary cause of spinal muscular atrophy (SMA), a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of …

Ef-P Dependent Pauses Integrate Proximal And Distal Signals During Translation, Sara Elgamal, Assaf Katz, Steven J. Hersch, David Newsom, Peter White, William Wiley Navarre, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Elongation factor P (EF-P) is required for the efficient synthesis of proteins with stretches of consecutive prolines and other motifs that would otherwise lead to ribosome pausing. However, previous reports also demonstrated that levels of most diprolyl-containing proteins are not altered by the deletion of efp. To define the particular sequences that trigger ribosome stalling at diprolyl (PPX) motifs, we used ribosome profiling to monitor global ribosome occupancy in Escherichia coli strains lacking EF-P. Only 2.8% of PPX motifs caused significant ribosomal pausing in the Δefp strain, with up to a 45-fold increase in ribosome density observed at …

Submonomer Synthesis And Structure-Activity Relationship Studies Of Azapeptide Inhibitors Of The Insulin Receptor Tyrosine Kinase, Lathamol A. Kurian

Seton Hall University Dissertations and Theses (ETDs)

Azapeptides are a class of peptide mimics (peptidomimetics), which have served as valuable tools for the development of peptide based therapeutic agents. The therapeutic promise of azapeptides has been correlated to its primary sequence modification which translates into bio-active secondary structures that improves the pharmacological properties of the native peptide sequence. More specifically, azapeptides contain a semicarbazide within the peptide backbone which restricts the peptide bond torsion angles (φ, ψ) into pre-organized b-turn secondary structures. Thus, azapeptides have been shown to stabilize bio-active b-turn secondary structures responsible for high affinity and selective binding to a target …

Effects Of Pde4 Pathway Inhibition In Rat Experimental Stroke, Fan Yang, Rachita K. Sumbria, Dong Xue, Chuanhui Yu, Dan He, Shuo Liu, Annlia Paganini-Hill, Mark J. Fisher

Pharmacy Faculty Articles and Research

PURPOSE: The first genomewide association study indicated that variations in the phosphodiesterase 4D (PDE4D) gene confer risk for ischemic stroke. However, inconsistencies among the studies designed to replicate the findings indicated the need for further investigation to elucidate the role of the PDE4 pathway in stroke pathogenesis. Hence, we studied the effect of global inhibition of the PDE4 pathway in two rat experimental stroke models, using the PDE4 inhibitor rolipram. Further, the specific role of the PDE4D isoform in ischemic stroke pathogenesis was studied using PDE4D knockout rats in experimental stroke. METHODS: Rats were subjected to either the …

Tissue Engineering: Applications In Developmental Toxicology, Stephanie N. Thiede, Nimisha Bajaj, Kevin Buno, Sherry L. Voytik-Harbin

The Summer Undergraduate Research Fellowship (SURF) Symposium

In vivo toxicology assays are expensive, low-throughput, and often not predictive of a human response. Three-dimensional in vitro human cell-based tissue systems incorporating cell-cell and cell-matrix interactions have promise to provide high-throughput, physiologically-relevant information on the mechanism of the toxin and a more accurate assessment of the toxicity of a chemical before progression to human trials. Quantification of the disruption of vasculogenesis, the de novo formation of blood vessels from endothelial progenitor cells, can serve as an appropriate indicator of developmental toxicity since vasculogenesis is critical to the early development of the circulatory system. The current routinely used in vitro …

The Effect Of Docosahexaenoic Acid (Dha)-Containing Phosphatidylcholine (Pc) On Liquid-Ordered And Liquid-Disordered Coexistence, Yongwen Gu

Dissertations and Theses

Plasma membranes are essential to both the structure and function of mammalian cells. The first unifying paradigm of membrane structure, the Fluid Mosaic Model, is no longer considered adequate to describe the many non-homogeneous lipid structures that have been observed in both natural and model membranes over the past approximately thirty years. The field of membrane biophysics now appreciates that the complex mixture of different lipid species found in natural membranes produces a range of dynamic, laterally segregated, non-homogeneous structures which exist on time scales ranging from microseconds to minutes.

When sphingomyelin (SM), POPC and cholesterol are all present in …

Evaluation Of Pre-Harvest Screening For Antibiotics And Flunixin Meglumine In Cattle, Shuna A. Jones

School of Veterinary and Biomedical Sciences: Dissertations, Theses, and Student Research

Many antibiotics and medications used in the treatment of animals have a withdrawal time; residues are a concern for the meat industry. The most recently published 2009 USDA-FSIS Residue Program Data Report listed 135,389 Inspector-in-Charge-Generated (IICG) residue samples from 43,142,500 beef and dairy cattle inspected that year at harvest. Of these samples, 1,306 contained violative antibiotic residues and 327 violative flunixin meglumine residues. Two classes of antimicrobials comprised over half of the documented violative antimicrobial residues (beta-lactams that include ceftiofur and sulfa drugs that include sulfadimethoxine). While the violative residue rate seems small, violative residues are unacceptable. Management of carcasses …