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College of Medicine: Department of Biochemistry and Molecular Biology

Chris Lesher

Oleg Karaduta & Mari Davidson invited as Guest Editors

Dr. Oleg Karaduta and Dr. Mari Davidson invite contributions to a special issue of applied sciences on the Evolution of Modern Molecular Biology Applications.

Forty years ago, when relatively powerful microprocessors first became available, many young entrepreneurs were inspired to create companies, platforms, and programming tools that helped make computing available to everyone. This in turn helped spark the information revolution. Today, thanks to the increasing sophistication, speed, and power of computer modeling and other new tools, we are on the brink of another revolution — this time in bioscience.

The aim of this Special Issue, therefore, is to offer a platform for scientists working on the different aspects of Molecular Biology; fusion of classical methods with novel approaches drives human progress, and it is this belief that fuels our optimism in that direction.

We invite you to submit manuscripts addressing novel uses of classical techniques in molecular biology and possible applications of these methods in future medical and life science research for a compilation of our current knowledge into a comprehensive issue.

More information

Congratulations Dr. Taylor!

Congratulations to Erin Taylor who successfully defended her Ph.D. dissertation entitled “Immune Modulation Response to Checkpoint Inhibition in Metastatic Melanoma” on December 1st. Erin was a student in the laboratory of Dr. Alan Tackett.

November publications

Members of the Miller labMeloxicam methyl group determines enzyme specificity for thiazole bioactivation compared to sudoxicam.

Barnette DA, Schleiff MA, Datta A, Flynn N, Swamidass SJ, Miller GP. 

Toxicol Lett.

 

 

Members of the Miller labSignificance of Multiple Bioactivation Pathways for Meclofenamateas Revealed through Modeling and Reaction Kinetics.

Schleiff MA, Flynn NR, Payakachat S, Schleiff BM, Pinson AO, Province DW, Swamidass SJ, Boysen G, Miller GP. 
Drug Metab Dispos. 

 

 

Members of the Raney labIdentifying RNA Helicase Inhibitors Using Duplex Unwinding Assays.

Marecki JC, Byrd AK, Raney KD.
Methods Mol Biol. 

 

 

Urbaniak A, Piña-Oviedo S, Yuan Y, Huczyński A, Chambers TC.
European Journal of Pharmacology

Congratulations Dr. Koss!

Congratulations to Brian Koss who successfully defended his Ph.D. dissertation entitled “Epigenetic control of Cdkn2a.Arf protects tumor-infiltrating lymphocytes from exhaustion” on November 18th. Brian was a student in the laboratory of Dr. Alan Tackett and is now a post-doctoral fellow in the Center for Translational Pediatric Research as part of the Proteomics Technology Development Shared Resource under the direction of Dr. Rick Edmondson. A summary of his research is below.

 

T cell exhaustion in cancer is linked to poor clinical outcomes and evidence suggests T cell metabolic changes precede functional exhaustion. Direct competition between tumor-infiltrating lymphocytes (TILs) and cancer cells for metabolic resources often renders T cells dysfunctional. Here, we report an epigenetic mechanism contributing to the development of metabolic exhaustion in TILs. Environmental stress produces epigenome remodeling events within tumor-infiltrating lymphocytes resulting from loss of the histone methyltransferase EZH2. Using a multi-omics approach, we have defined an ARF-mediated, p53-independent mechanism by which EZH2 inhibition leads to mitochondrial dysfunction and the resultant exhaustion. Reprogramming T cells to express a gain-of-function EZH2 mutant resulted in an enhanced ability of T cells to inhibit tumor growth. Our data suggest manipulation of T cell EZH2 within the context of cellular therapies may yield lymphocytes which are able to withstand harsh tumor metabolic environments and collateral pharmacologic insults.

Mary “Allie” Schleiff student highlight

Allie is a GPIBS Ph.D. student in the Biochemistry and Molecular Biology track. She is a fourth year student in the laboratory of Dr. Grover Paul Miller.

She graduated from Henderson State University in 2017 with an Honors Bachelor of Science degree in Biochemistry and a minor in Biology, and she received a regulatory sciences certification from the UAMS Department of Environmental and Occupational Health in Spring 2020.

Research Interest Statement

My research focuses on a subset of structurally similar non-steroidal anti-inflammatory drugs (NSAIDs) known as diphenylamine NSAIDs. Diphenylamine NSAIDs are taken more than 15 million times each year in the United States, but roughly 15% of all people administered diphenylamine NSAIDs have a clinically observable case of hepatotoxicity from the compounds. Previous studies identified that diphenylamine hepatotoxicity is dependent upon metabolic bioactivation and varied depending upon minor structural modifications to the diphenylamine structural scaffold, but little work exists to identify the specific mechanisms by which diphenylamines cause hepatotoxicity. I used computational tools to identify potential diphenylamine metabolic bioactivations in seven marketed or withdrawn diphenylamine drugs and experimentally validate these computational results. Thus far, I have discovered that diphenylamine NSAIDs are preferentially bioactivated into quinone-species metabolites in variable amounts and by a variety of cytochrome P450 enzymes dependent upon minor structural modifications to the diphenylamine scaffold. I hope that results from this work can help direct future development of diphenylamine-containing drugs in the future and help identify and stratify patients at-risk following diphenylamine NSAID dosage to promote more personalized patient care.

Something Notable About Time as a Graduate Student

I am so grateful that I was trained as a fresh graduate student by Dr. Dusty Barnette. I was always dropping things, breaking things, and having the same information repeated to me over and over again and Dusty never batted an eye, scolded me, or made me feel like a burden. Specifically, I’m appreciative to him for always getting the tall things off the high shelves for me!

Career Goals

My dream job would be in a contract research organization conducting preclinical and clinical studies for pharmaceutical clients. Once I obtain my PhD, I intend to take a post-doctoral position through the Center for Drug Evaluation and Research (CDER) to enhance my regulatory experience and make myself more marketable!

Experiment or Technique You Would Most Like to Do

Nuclear magnetic resonance is a major technique used frequently in regulatory science and in the pharmaceutical industry, but my only exposure to it was for a week or so as an undergraduate in my Analytical Chemistry course. I was overwhelmed and scared of it then and I still am, though I want to change that!

Fun Fact

Cleaning is legitimately one of my favorite hobbies, so most laboratories stress me out a bit – ha. If I wasn’t working in science, I would want to be a professional home organizer.

Publications

  1. Schleiff, M., Payakachat, S., Schleiff, B., Pinson, A., Flynn, N., Province, D., Boysen, G., Swamidass, S. J., Miller, G. P. “Significance of Multiple Bioactivation Pathways for Meclofenamate as Revealed through Modeling and Reaction Kinetics.”
    • Publication – Accepted, Drug Metabolism and Disposition.
  2. Barnette, D., Schleiff, M., Datta, A., Flynn, N., Swamidass, S. J., Miller, G. P. “Meloxicam Methyl Group Determines Enzyme Specificity for Thiazole Bioactivation Compared to Sudoxicam.”
    • Publication – Accepted, Toxicology Letters.
  3. Pinson, A., Pouncey, D., Schleiff, M., Fantegrossi, W., Prather, P., Radominska-Pandya, A., Boysen, G., Miller, G. P. “Significance of Competing Metabolic Pathways for Synthetic Cannabinoid 5F-APINACA as Revealed through Novel Reaction Kinetics.”
    • Publication – Published, Molecules. DOI: 3390/molecules25204820
  4. Schleiff, M., Russell, L., Gonzalez, E., Bart, A., Broccatelli, F., Humphreys, G., Scott, E., Segall, M., Prasad, B., Hartman, J., Lauschke, V., Nwabufo, C., Takahashi, R., Durmus, S., Nichols, C., Martin, I., and Taub, M., Sodhi, J. “Advances in the Study of Drug Metabolism – Symposium Report of the 12th Meeting of the International Society for the Study of Xenobiotics (ISSX).”
  • Publication – May 2020, Drug Metabolism Reviews. DOI: 1080/03602532.2020.1765793

Grants

I am partially supported by a training grant through the Pharmacology, Toxicology, and Experimental Therapeutics Department in the UAMS Graduate School entitled, “Systems Pharmacology and Toxicology” (T32GM106999).

Awards

  • 2020 Third Place Bhuvan Award for Excellence in Biochemistry Graduate Research – University of Arkansas for Medical Sciences Student Research Day
  • 2020 Top 30 Finalist with Honorarium – Sternfels Prize in Drug Safety Discoveries
  • 2020 Pfizer Society of Toxicology National Conference Student Travel Award – Society of Toxicology Computational Toxicology Specialty Section
  • 2019 First Place Oral Presentation – University of Arkansas for Medical Sciences Graduate Student Association Research Symposium
  • 2019 South Central Chapter Society of Toxicology Regional Conference Travel Award
  • Graduate Student Achievement Award for Selection to the Drug Metabolism Reviews Editorial Board – University of Arkansas for Medical Sciences Fall Research Award Ceremony
  • Graduate Student Achievement Award for Selection to the International Society for the Study of Xenobiotics New Investigator Group – University of Arkansas for Medical Sciences Fall Research Award Ceremony
  • 2019 Outstanding Graduate Student Poster Presentation – Drug Discovery and Development Colloquium
  • 2019 Invited Speaker with Honorarium – Drug Metabolism and Pharmacokinetics Symposium hosted by Genentech
  • 2018 MC-Bios Computational Biology Conference Travel Award – Midsouth Computational Biology and Bioinformatics Society

Five UAMS Researchers Receive Seed Funding for New Projects

By Benjamin Waldrum

Five UAMS scientists were awarded $15,000 each to fund research projects in the coming year, thanks to an endowment created by generous donors nearly four decades ago.

The Medical Research Endowment Fund was one of the first major fundraising campaigns of the UAMS Board of Advisors. Established in 1982 to stimulate and support research programs of UAMS faculty, the fund has received financial contributions from individuals, corporations and foundations. It’s a way for donors to make an immediate impact in valuable research at the ground level.

The awards are a vital bridge between the researchers’ initial ideas and major discoveries. By providing seed funding for research, individual researchers or teams can collect preliminary data and form hypotheses before seeking major research grants.

The grant awards provide seed funding for research that has the potential to develop into scientifically significant research projects. Grants support new areas of research for junior investigators and new lines of investigation for established faculty. Awards are made annually in early fall, with funds becoming available to each investigator in January. MRE funds provide for equipment, operating expenses and consultation costs for 12 months.

The grant awardees and their projects are:

  • Alicia Byrd, Ph.D., assistant professor, Department of Biochemistry and Molecular Biology, College of Medicine; The Role of DNA Helicase B in Response to DNA Replication Stress
  • Rupak Pathak, Ph.D., assistant professor, Division of Radiation Health, Department of Pharmaceutical Sciences, College of Pharmacy; Improving Efficacy and Safety of Prostate Cancer Radiotherapy with Mevalonate Pathway Inhibitors
  • Youssef Aachoui, Ph.D., assistant professor, Department of Microbiology and Immunology, College of Medicine; Host-Pathogen Interplay Between Shigella and the Inflammasome
  • Behjatolah “BJ” Karbassi, Ph.D., assistant professor, Department of Pathology, College of Medicine; Defining Tumor-Associated Glycans on Breast Cancer Cells that are Ligands for Macrophage SR-A
  • Merideth Addicott, Ph.D., assistant professor, Department of Psychology, College of Medicine; Validating Electronic Nicotine Delivery System (END) Self-Reports Using Biochemical and Topographical Measures

Because of the generosity of donors who continue to support UAMS’ pioneering research efforts and the Medical Research Support Endowment Fund, hundreds of investigators have received funding totaling more than $3.1 million since the awards’ inception in 1982. Their return on investment has been significant, generating tens of millions of dollars in extramural funding.

October Publications

Kendrick labActivation-induced cytidine deaminase localizes to G-quadruplex motifs at mutation hotspots in lymphoma.

Xu YZ, Jenjaroenpun P, Wongsurawat T, Byrum SD, Shponka V, Tannahill D, Chavez EA, Hung SS, Steidl C, Balasubramanian S, Rimsza LM, Kendrick S.
NAR Cancer. 2020

 

Members of the Miller labSignificance of Competing Metabolic Pathways for 5F-APINACA Based on Quantitative Kinetics.

Pinson AO, Pouncey DL, Schleiff MA, Fantegrossi WE, Prather PL, Radominska-Pandya A, Boysen G, Miller GP.
Molecules. 2020

 

 

AuthorsproteiNorm – A User-Friendly Tool for Normalization and Analysis of TMT and Label-Free Protein Quantification.

Graw S, Tang J, Zafar MK, Byrd AK, Bolden C, Peterson EC, Byrum SD.
ACS Omega. 2020

 

Oleg KaradutaResistant starch slows the progression of CKD in the 5/6 nephrectomy mouse model.

Karaduta O, Glazko G, Dvanajscak Z, Arthur J, Mackintosh S, Orr L, Rahmatallah Y, Yeruva L, Tackett A, Zybailov B.
Physiol Rep. 2020

 

 

Tackett labEpigenetic Control of Cdkn2a.Arf Protects Tumor-Infiltrating Lymphocytes from Metabolic Exhaustion.

Koss B, Shields BD, Taylor EM, Storey AJ, Byrum SD, Gies AJ, Washam CL, Choudhury SR, Hyun Ahn J, Uryu H, Williams JB, Krager KJ, Chiang TC, Mackintosh SG, Edmondson RD, Aykin-Burns N, Gajewski TF, Wang GG, Tackett AJ.
Cancer Res. 2020