About

Ross E Jones, M.D., MPH, FAAFP, is an associate professor of community health and family medicine at the University of Florida and a board-certified UF Health family medicine physician. His focus areas include chronic disease management, preventive medicine, and community engagement. He serves as the medical director of UF Health Family Medicine and Pediatrics – Oakleaf and has a passion for population health and telemedicine. Dr. Jones earned his medical degree at the University of Florida and completed his residency in family medicine at St. Vincent’s Medical Center in Jacksonville. His professional roles include associate professor, medical director, and various leadership positions within UF Health Family Medicine and Pediatrics, as well as other healthcare organizations. His research and clinical interests are reflected in his involvement in numerous projects related to social determinants of health, telemedicine, pharmacogenetic testing, and community-based health interventions.

Research topics

• Computer Science
• Biology
• Immunology
• Biochemistry
• World Wide Web
• Computational biology
• Pharmacology
• Chemistry
• Medicine

Selected publications

• Role of SIRT3 in the regulation of Gadd45α expression and DNA repair in β-cells

  Journal of Biological Chemistry · 2025-03-26

  articleOpen access

  In previous studies, we have shown that growth arrest and DNA damage (<i>Gadd</i>) 45α is required for the repair of nitric oxide-mediated DNA damage in <b>β</b>-cells. <i>Gadd45α</i> expression is stimulated by nitric oxide and requires forkhead box protein (Fox) O1 and NAD⁺-dependent deacetylase activity. Based on inhibitor studies, we attributed this activity to Sirtuin (SIRT)1; however, the inhibitors used in this previous study also attenuate the deacetylase activity of SIRT2, 3, and 6. We now provide experimental evidence that SIRT1 is dispensable for <b>β</b>-cell expression of <i>Gadd45α</i> and that the mitochondrial localized isoform SIRT3, is required for DNA repair in <b>β</b>-cells. We show that siRNA knockdown of <i>Sirt3</i> attenuates nitric oxide-stimulated <i>Gadd45α</i> mRNA accumulation in both wildtype and <i>Sirt1</i>^−/− INS 832/13 cells as well as isolated rat islets and that SIRT3 inhibition increases FoxO1 acetylation and attenuates DNA repair in response to nitric oxide. While SIRT3 is predominantly localized to mitochondria, a small fraction is localized in the nucleus of insulin-containing cells and functions to participate in the regulation of FoxO1-dependent, nitric oxide-stimulated DNA repair.

  PublisherOA PDFDOI

• Inhibition of Sirtuin Deacylase Activity by Peroxynitrite

  Biochemistry · 2024-09-10 · 6 citations

  articleOpen access

  Sirtuins are a class of enzymes that deacylate protein lysine residues using NAD+ as a cosubstrate. Sirtuin deacylase activity has been historically regarded as protective; loss of sirtuin deacylase activity potentially increases susceptibility to aging-related disease development. However, which factors may inhibit sirtuins during aging or disease is largely unknown. Increased oxidant and inflammatory byproduct production damages cellular proteins. Previously, we and others found that sirtuin deacylase activity is inhibited by the nitric oxide (NO)-derived cysteine post-translational modification S-nitrosation. However, the comparative ability of the NO-derived oxidant peroxynitrite (ONOO–) to affect human sirtuin activity had not yet been assessed under uniform conditions. Here, we compare the ability of ONOO– (donated from SIN-1) to post-translationally modify and inhibit SIRT1, SIRT2, SIRT3, SIRT5, and SIRT6 deacylase activity. In response to SIN-1 treatment, inhibition of SIRT1, SIRT2, SIRT3, SIRT5, and SIRT6 deacylase activity correlated with increased tyrosine nitration. Mass spectrometry identified multiple novel tyrosine nitration sites in SIRT1, SIRT3, SIRT5, and SIRT6. As each sirtuin isoform has at least one tyrosine nitration site within the catalytic core, nitration may result in sirtuin inhibition. ONOO– can also react with cysteine residues, resulting in sulfenylation; however, only SIRT1 showed detectable peroxynitrite-mediated cysteine sulfenylation. While SIRT2, SIRT3, SIRT5, and SIRT6 showed no detectable sulfenylation, SIRT6 likely undergoes transient sulfenylation, quickly resolving into an intermolecular disulfide bond. These results suggest that the aging-related oxidant peroxynitrite can post-translationally modify and inhibit sirtuins, contributing to susceptibility to aging-related disease.

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• Zinc-chelating BET bromodomain inhibitors equally target islet endocrine cell types

  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · 2024-04-15 · 1 citations

  articleOpen access1st author

  Inhibition of BET bromodomains is a novel potential strategy to prevent and treat diabetes mellitus. However, BET inhibitors have negative side effects. We synthesized a BET inhibitor expected to exploit the high zinc concentration in β cells to accumulate in β cells. We show our inhibitor targeted pancreatic endocrine cells; however, it was less effective in immune cells. A control inhibitor showed the opposite effect. These findings help us understand how to target specific cells in diabetes treatment.

  PublisherOA PDFDOI

• Downregulation of lysosomal trafficking in ARPE19 cells leads to decreased transfection efficiency at high passage

  bioRxiv (Cold Spring Harbor Laboratory) · 2023-07-27 · 1 citations

  preprintOpen access

  PURPOSE: ARPE19 cells are a commonly used cell culture model for the study of retinal pigment epithelial cell biology and pathologies. However, numerous studies have demonstrated that ARPE19 undergo morphologic, transcriptomic and genomic alterations over time and with increasing passage number. Herein, we explore the mechanisms underlying increased resistance to the delivery of exogenous genetic material via transfection in ARPE19 cells using mass spectrometry. METHODS: ARPE19 cells (N=5 wells/reagent) were seeded in 6-well plates at passages 24 through 30. At 70% confluency an mCherry reporter construct was delivered via transfection using Lipofectamine 3000, Lipofectamine LTX, Lipofectamine Stem, or PEI (polyethylenimine) reagents. After 72 hours, transfection efficiency was quantified by fluorescence microscopy and flow cytometry. Mass spectrometry and immunofluorescence of ARPE19 cells were performed at passages 24 and 30 to evaluate altered protein synthesis and localization between passage numbers. RESULTS: ARPE19 transfection showed a maximum transfection efficiency of 32.4% at P26 using Lipofectamine 3000 reagent. All lipofectamine based reagents demonstrated statistically significant decreases in transfection efficiency between passages 24 and 30. Mass spectrometry analysis revealed 18 differentially expressed proteins, including down-regulation of clathrin light chain B (CLTB) and legumain (LGMN) that was confirmed via immunofluorescence imaging, which indicated altered intracellular localization. CONCLUSIONS: ARPE19 cells demonstrate passage number dependent changes in lipofectamine-based transfection efficiency. Mass spectrometry and immunofluorescence indicates the observed decrease in transfection efficiency involves the dysregulation of endocytosis and intracellular endolysosomal trafficking at later passages. TRANSLATIONAL RELEVANCE: This study contributes to mounting evidence for changes in ARPE19 cell physiology with increasing passage number. This information is of value for the continued use of ARPE19 cells as a model system for RPE biology and the development of therapeutics.

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• N-terminal BET bromodomain inhibitors disrupt a BRD4-p65 interaction and reduce inducible nitric oxide synthase transcription in pancreatic β-cells

  Frontiers in Endocrinology · 2022-09-13 · 14 citations

  articleOpen access

  Chronic inflammation of pancreatic islets is a key driver of β-cell damage that can lead to autoreactivity and the eventual onset of autoimmune diabetes (T1D). In the islet, elevated levels of proinflammatory cytokines induce the transcription of the inducible nitric oxide synthase (iNOS) gene, NOS2 , ultimately resulting in increased nitric oxide (NO). Excessive or prolonged exposure to NO causes β-cell dysfunction and failure associated with defects in mitochondrial respiration. Recent studies showed that inhibition of the bromodomain and extraterminal domain (BET) family of proteins, a druggable class of epigenetic reader proteins, prevents the onset and progression of T1D in the non-obese diabetic mouse model. We hypothesized that BET proteins co-activate transcription of cytokine-induced inflammatory gene targets in β-cells and that selective, chemotherapeutic inhibition of BET bromodomains could reduce such transcription. Here, we investigated the ability of BET bromodomain small molecule inhibitors to reduce the β-cell response to the proinflammatory cytokine interleukin 1 beta (IL-1β). BET bromodomain inhibition attenuated IL-1β-induced transcription of the inflammatory mediator NOS2 and consequent iNOS protein and NO production. Reduced NOS2 transcription is consistent with inhibition of NF-κB facilitated by disrupting the interaction of a single BET family member, BRD4, with the NF-κB subunit, p65. Using recently reported selective inhibitors of the first and second BET bromodomains, inhibition of only the first bromodomain was necessary to reduce the interaction of BRD4 with p65 in β-cells. Moreover, inhibition of the first bromodomain was sufficient to mitigate IL-1β-driven decreases in mitochondrial oxygen consumption rates and β-cell viability. By identifying a role for the interaction between BRD4 and p65 in controlling the response of β-cells to proinflammatory cytokines, we provide mechanistic information on how BET bromodomain inhibition can decrease inflammation. These studies also support the potential therapeutic application of more selective BET bromodomain inhibitors in attenuating β-cell inflammation.

  PublisherOA PDFDOI

• Zinc‐Chelating BET Bromodomain Inhibitors Selectively Accumulate and Affect Gene Expression in Pancreatic β‐Cells

  The FASEB Journal · 2022-05-01

  article1st authorCorresponding

  The islets of Langerhans are a heterogeneous mixture of endocrine (hormone‐secreting) cells in the mammalian pancreas. Of particular interest are the β‐cells responsible for maintaining glucose homeostasis by secreting insulin in response to increased blood glucose. Type 1 diabetes (T1D) is characterized by autoimmune‐mediated destruction of β‐cells, resulting in an inability to produce and release insulin in response to changing glucose levels and subsequent reliance on daily insulin injections. There is currently no cure for T1D. The bromodomain and extra‐terminal domain (BET) family of proteins, comprised of BRD2, BRD3, BRD4 and BRDT, are a druggable family of proteins that can be targeted by pan‐BET bromodomain inhibitors (BETi), including the small molecule (+)‐JQ1. Recent studies have shown that targeting the BET family of proteins with BETi may prevent and treat T1D. However, the systemic use of current generation BETi is associated with off‐target, adverse effects including fatigue, gastrointestinal toxicity and memory loss. Since any treatment for T1D would be widely used in a pediatric patient population, avoiding off‐target effects is imperative. Here, we propose to ameliorate the off‐target effects of BET bromodomain inhibition by targeting BETi directly to pancreatic β‐cells. To achieve this, we exploited the high concentration of Zn 2+ ions (~20 mM) present in β‐cells relative to other cells in the body. We report the synthesis of a novel, zinc‐chelating analogue of (+)‐JQ1, [(+)‐JQ1‐DPA], in which the BETi (+)‐JQ1 was conjugated, via an ethylenediamine linker, to dipicolyl amine (DPA). DPA chelates Zn 2+ and thus enables (+)‐JQ1 to accumulate in β‐cells. As control compounds we also synthesized (+)‐JQ1‐DBA, a non‐zinc‐chelating analogue of (+)‐JQ1‐DPA, in which (+)‐JQ1 was conjugated to dibenzyl amine (DBA) and (‐)‐JQ1‐DPA, a zinc‐chelating compound that is inactive as a BETi. Molecular modeling and biophysical assays showed that (+)‐JQ1‐DPA and (+)‐JQ1‐DBA, but not (‐)‐JQ1‐DPA, retain binding to both bromodomains of BRD4 in vitro . Cellular assays demonstrated that (+)‐JQ1‐DPA retains efficacy; in particular, (+)‐JQ1‐DPA, attenuated the expression of NF‐ĸB target genes in β‐cells stimulated with the pro‐inflammatory cytokine, IL‐1β, a model for β‐cell destruction. Finally, using islets isolated from the INS1 Cre ; ROSA26 mTmG mouse, an established mouse model that expresses enhanced green fluorescent protein in insulin‐positive cells and mTomato in insulin‐negative cells, we demonstrated that (+)‐JQ1‐DPA affects gene transcription in pancreatic β‐cells but not in other pancreatic cell types. In conclusion, we have synthesized a zinc‐chelating analogue of (+)‐JQ1 that is selectively active in pancreatic β‐cells over other islet cell types, including macrophages and α‐cells.

  PublisherDOI

• Molecular docking‐guided synthesis of NSAID–glucosamine bioconjugates and their evaluation as COX‐1/COX‐2 inhibitors with potentially reduced gastric toxicity

  Chemical Biology & Drug Design · 2021 · 12 citations

  1st authorCorresponding
  • Chemistry
  • Pharmacology
  • Biochemistry

  Non-steroidal anti-inflammatory drugs (NSAIDs) are a powerful class of inhibitors targeting two isoforms of the family of cyclooxygenase enzymes (COX-1 and COX-2). While NSAIDs are widely used in the management of pain, in particular as a treatment for osteo- and rheumatoid arthritis, their long-term use has been associated with numerous on- and off-target effects. As the carboxylic acid moiety present in common NSAIDs is responsible for some of their adverse effects, but is not required for their anti-inflammatory activity, we sought to mask this group through direct coupling to glucosamine, which is thought to prevent cartilage degradation. We report herein the conjugation of commonly prescribed NSAIDs to glucosamine hydrochloride and the use of molecular docking to show that addition of the carbohydrate moiety to the parent NSAID can enhance binding in the active site of COX-2. In a preliminary, in vitro screening assay, the diclofenac-glucosamine bioconjugate exhibited 10-fold greater activity toward COX-2, making it an ideal candidate for future in vivo studies. Furthermore, in an intriguing result, we observed that the mefenamic acid-glucosamine bioconjugate displayed enhanced activity toward COX-1 rather than COX-2.

  PublisherOA PDFDOI

• SurfaceGenie: a web-based application for prioritizing cell-type-specific marker candidates

  Bioinformatics · 2020 · 77 citations

  • Computer Science
  • Computer Science
  • World Wide Web

  MOTIVATION: Cell-type-specific surface proteins can be exploited as valuable markers for a range of applications including immunophenotyping live cells, targeted drug delivery and in vivo imaging. Despite their utility and relevance, the unique combination of molecules present at the cell surface are not yet described for most cell types. A significant challenge in analyzing 'omic' discovery datasets is the selection of candidate markers that are most applicable for downstream applications. RESULTS: Here, we developed GenieScore, a prioritization metric that integrates a consensus-based prediction of cell surface localization with user-input data to rank-order candidate cell-type-specific surface markers. In this report, we demonstrate the utility of GenieScore for analyzing human and rodent data from proteomic and transcriptomic experiments in the areas of cancer, stem cell and islet biology. We also demonstrate that permutations of GenieScore, termed IsoGenieScore and OmniGenieScore, can efficiently prioritize co-expressed and intracellular cell-type-specific markers, respectively. AVAILABILITY AND IMPLEMENTATION: Calculation of GenieScores and lookup of SPC scores is made freely accessible via the SurfaceGenie web application: www.cellsurfer.net/surfacegenie. CONTACT: Rebekah.gundry@unmc.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

  PublisherOA PDFDOI

• 2131-P: BET Bromodomain Inhibition Upregulates SIRT1 In Pancreatic ß-Cells

  Diabetes · 2020-06-01

  article1st authorCorresponding

  Diabetes develops as a result of both genetic and environmental influences; however, low concordance rates of type 1 diabetes between monozygotic twins and increased penetrance of type 2 diabetes during aging suggests an, as yet, poorly understood epigenetic role in diabetes development and progression. The epigenetic code, of which lysine acetylation (Kac) is a major histone post-translational modification, regulates the structure and dynamics of chromatin leading to epigenetically-controlled changes in gene accessibility toward transcription factors. Histone acetylation is regulated by histone acetyltransferases and deacetylases which write and erase sites of histone acetylation, respectively. SIRT1 is a key protein deacetylase in the control of glucose homeostasis. Decreased SIRT1 can lead to impaired insulin signaling, therefore drugs that enhance either SIRT1 expression or enzymatic activity may treat insulin resistance. Bromodomains are epigenetic readers that interpret the complex pattern of histone acetylation by binding Kac residues on histones and other nuclear proteins. Of particular interest are the bromodomain and extraterminal domain (BET) family of bromodomain-containing proteins, which have recently emerged as a potential target to treat or prevent diabetes. Interestingly, we recently found that treatment of β-cells with BET bromodomain inhibitors leads to increased SIRT1 expression levels, although the underlying mechanism was unclear. Here, we use an insulinoma β-cell line (INS832/13) and primary rat islets to determine the mechanism through which BET proteins suppress SIRT1 expression. To modulate SIRT1 and BET protein levels and activity, we used a combination of small molecules that either inhibit or degrade BET proteins, in conjunction with CRISPR/Cas9 knockout β-cell lines of both SIRT1 and the individual BET proteins. In summary, BET inhibitors may provide an indirect means to increase SIRT1 activity in β-cells and improve β-cell function in the context of diabetes. Disclosure R.A. Jones Lipinski: None. S. Wynia-Smith: None. J. Nord: None. B.C. Smith: None. Funding American Diabetes Association (1-18-IBS-068 to B.C.S.); National Institute of Diabetes and Digestive and Kidney Diseases (R01DK119359)

  PublisherDOI

• SP2: Rapid and Automatable Contaminant Removal from Peptide Samples for Proteomic Analyses

  Journal of Proteome Research · 2019-02-22 · 54 citations

  article

  Peptide cleanup is essential for the removal of contaminating substances that may be introduced during sample preparation steps in bottom-up proteomic workflows. Recent studies have described benefits of carboxylate-modified paramagnetic particles over traditional reversed-phase methods for detergent and polymer removal, but challenges with reproducibility have limited the widespread implementation of this approach among laboratories. To overcome these challenges, the current study systematically evaluated key experimental parameters regarding the use of carboxylate-modified paramagnetic particles and determined those that are critical for maximum performance and peptide recovery and those for which the protocol is tolerant to deviation. These results supported the development of a detailed, easy-to-use standard operating protocol, termed SP2, which can be applied to remove detergents and polymers from peptide samples while concentrating the sample in solvent that is directly compatible with typical LC-MS workflows. We demonstrate that SP2 can be applied to phosphopeptides and glycopeptides and that the approach is compatible with robotic liquid handling for automated sample processing. Altogether, the results of this study and accompanying detailed operating protocols for both manual and automated processing are expected to facilitate reproducible implementation of SP2 for various proteomics applications and will especially benefit core or shared resource facilities where unknown or unexpected contaminants may be particularly problematic.

  PublisherDOI

Frequent coauthors

• Alan R. Katritzky

  King Abdulaziz University

  18 shared

• C. Dennis Hall

  11 shared

• Siva S. Panda

  8 shared

• Brian C. Smith

  7 shared

• M. Carmen Galán

  University of Bristol

  7 shared

• Anh‐Tuan Tran

  Vietnam National University of Agriculture

  6 shared

• Daniel S. Sem

  Concordia University Wisconsin

  6 shared

• Nicole Rivera Rosario

  University of Florida

  6 shared

Education

• M.D.

  University of Florida