HSC College of Pharmacy
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The HSC College of Pharmacy is committed to developing patient-centric pharmacy professionals trained in an interprofessional environment. We advocate a team health care environment coupled with optimizing health through discovery.
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Item A Machine Learning Approach to Identify Predictors of Potentially Inappropriate Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Use in Older Adults with Osteoarthritis(MDPI, 2020-12-28) Patel, Jayeshkumar; Ladani, Amit; Sambamoorthi, Nethra; LeMasters, Traci; Dwibedi, Nilanjana; Sambamoorthi, UshaEvidence from some studies suggest that osteoarthritis (OA) patients are often prescribed non-steroidal anti-inflammatory drugs (NSAIDs) that are not in accordance with their cardiovascular (CV) or gastrointestinal (GI) risk profiles. However, no such study has been carried out in the United States. Therefore, we sought to examine the prevalence and predictors of potentially inappropriate NSAIDs use in older adults (age > 65) with OA using machine learning with real-world data from Optum De-identified Clinformatics((R)) Data Mart. We identified a retrospective cohort of eligible individuals using data from 2015 (baseline) and 2016 (follow-up). Potentially inappropriate NSAIDs use was identified using the type (COX-2 selective vs. non-selective) and length of NSAIDs use and an individual's CV and GI risk. Predictors of potentially inappropriate NSAIDs use were identified using eXtreme Gradient Boosting. Our study cohort comprised of 44,990 individuals (mean age 75.9 years). We found that 12.8% individuals had potentially inappropriate NSAIDs use, but the rate was disproportionately higher (44.5%) in individuals at low CV/high GI risk. Longer duration of NSAIDs use during baseline (AOR 1.02; 95% CI:1.02-1.02 for both non-selective and selective NSAIDs) was associated with a higher risk of potentially inappropriate NSAIDs use. Additionally, individuals with low CV/high GI (AOR 1.34; 95% CI:1.20-1.50) and high CV/low GI risk (AOR 1.61; 95% CI:1.34-1.93) were also more likely to have potentially inappropriate NSAIDs use. Heightened surveillance of older adults with OA requiring NSAIDs is warranted.Item A macrocyclic molecule with multiple antioxidative activities protects the lens from oxidative damage(Frontiers Media S.A., 2022-11-18) Zhang, Jinmin; Yu, Yu; Mekhail, Magy A.; Wu, Hongli; Green, Kayla N.Growing evidence links oxidative stress to the development of a cataract and other diseases of the eye. Treatments for lens-derived diseases are still elusive outside of the standard surgical interventions, which still carry risks today. Therefore, a potential drug molecule (OH)Py(2)N(2) was explored for the ability to target multiple components of oxidative stress in the lens to prevent cataract formation. Several pathways were identified. Here we show that the (OH)Py(2)N(2) molecule activates innate catalytic mechanisms in primary lens epithelial cells to prevent damage induced by oxidative stress. This protection was linked to the upregulation of Nuclear factor erythroid-2-related factor 2 and downstream antioxidant enzyme for glutathione-dependent glutaredoxins, based on Western Blot methods. The anti-ferroptotic potential was established by showing that (OH)Py(2)N(2) increases levels of glutathione peroxidase, decreases lipid peroxidation, and readily binds iron (II) and (III). The bioenergetics pathway, which has been shown to be negatively impacted in many diseases involving oxidative stress, was also enhanced as evidence by increased levels of Adenosine triphosphate product when the lens epithelial cells were co-incubated with (OH)Py(2)N(2). Lastly, (OH)Py(2)N(2) was also found to prevent oxidative stress-induced lens opacity in an ex vivo organ culture model. Overall, these results show that there are multiple pathways that the (OH)Py(2)N(2) has the ability to impact to promote natural mechanisms within cells to protect against chronic oxidative stress in the eye.Item A Method for Real-Time Assessment of Mitochondrial Respiration Using Murine Corneal Biopsy(Association for Research in Vision and Ophthalmology, 2023-08-29) Liang, Wentao; Huang, Li; Yuan, Tian; Cheng, Rui; Takahashi, Yusuke; Moiseyev, Gennadiy P.; Karamichos, Dimitrios; Ma, Jian-XingPURPOSE: To develop and optimize a method to monitor real-time mitochondrial function by measuring the oxygen consumption rate (OCR) in murine corneal biopsy punches with a Seahorse extracellular flux analyzer. METHODS: Murine corneal biopsies were obtained using a biopsy punch immediately after euthanasia. The corneal metabolic profile was assessed using a Seahorse XFe96 pro analyzer, and mitochondrial respiration was analyzed with specific settings. RESULTS: Real-time adenosine triphosphate rate assay showed that mitochondrial oxidative phosphorylation is a major source of adenosine triphosphate production in ex vivo live murine corneal biopsies. Euthanasia methods (carbon dioxide asphyxiation vs. overdosing on anesthetic drugs) did not affect corneal OCR values. Mouse corneal biopsy punches in 1.5-mm diameter generated higher and more reproducible OCR values than those in 1.0-mm diameter. The biopsy punches from the central and off-central cornea did not show significant differences in OCR values. There was no difference in OCR reading by the tissue orientations (the epithelium side up vs. the endothelium side up). No significant differences were found in corneal OCR levels between sexes, strains (C57BL/6J vs. BALB/cJ), or ages (4, 8, and 32 weeks). Using this method, we showed that the wound healing process in the mouse cornea affected mitochondrial activity. CONCLUSIONS: The present study validated a new strategy to measure real-time mitochondrial function in fresh mouse corneal tissues. This procedure should be helpful for studies of the ex vivo live corneal metabolism in response to genetic manipulations, disease conditions, or pharmacological treatments in mouse models.Item A Multi-Level Analysis of Individual and Neighborhood Factors Associated with Patient Portal Use among Adult Emergency Department Patients with Multimorbidity(MDPI, 2023-01-22) Wang, Hao; Shen, Chan; Barbaro, Michael; Ho, Amy F.; Pathak, Mona; Dunn, Cita; Sambamoorthi, UshaBACKGROUND: Patient portals tethered to electronic health records (EHR) have become vital to patient engagement and better disease management, specifically among adults with multimorbidity. We determined individual and neighborhood factors associated with patient portal use (MyChart) among adult patients with multimorbidity seen in an Emergency Department (ED). METHODS: This study adopted a cross-sectional study design and used a linked database of EHR from a single ED site to patients' neighborhood characteristics (i.e., zip code level) from the American Community Survey. The study population included all adults (age > 18 years), with at least one visit to an ED and multimorbidity between 1 January 2019 to 31 December 2020 (N = 40,544). Patient and neighborhood characteristics were compared among patients with and without MyChart use. Random-intercept multi-level logistic regressions were used to analyze the associations of patient and neighborhood factors with MyChart use. RESULTS: Only 19% (N = 7757) of adults with multimorbidity used the patient portal. In the fully adjusted multi-level model, at the patient level, having a primary care physician (AOR = 5.55, 95% CI 5.07-6.07, p < 0.001) and health insurance coverage (AOR = 2.41, 95% CI 2.23-2.61, p < 0.001) were associated with MyChart use. At the neighborhood level, 4.73% of the variation in MyChart use was due to differences in neighborhood factors. However, significant heterogeneity existed in patient portal use when neighborhood characteristics were included in the model. CONCLUSIONS: Among ED patients with multimorbidity, one in five adults used patient portals. Patient-level factors, such as having primary care physicians and insurance, may promote patient portal use.Item A novel 3D culture model of fungal keratitis to explore host-pathogen interactions within the stromal environment(Elsevier Ltd., 2021-04-15) Brown, Marina E.; Montgomery, Micaela L.; Kamath, Manali M.; Nicholas, Sarah; Liu, Yutao; Karamichos, Dimitrios; Fuller, Kevin K.Fungal keratitis (FK) pathology is driven by both fungal growth and inflammation within the corneal stroma. Standard in vitro infection models involving co-culture of the pathogen and the corneal cells in tissue culture medium are sufficient to probe host responses to the fungus; however, they lack the physiological structure and nutrient composition of the stroma to accurately study fungal invasiveness and metabolic processes. We therefore sought to develop a culture model of FK that would allow for both host and fungal cell biology to be evaluated in parallel. Towards this end, we employed a previously described system in which primary human cornea fibroblasts (HCFs) are cultured on transwell membranes, whereupon they secrete a three-dimensional (3D) collagen matrix that resembles the human stroma. We demonstrated that two common mold agents of FK, Fusarium petroliphilum and Aspergillus fumigatus, penetrated into these constructs and caused a disruption of the collagen matrix that is characteristic of infection. HCF morphology appeared altered in the presence of fungus and electron microscopy revealed a clear internalization of fungal spores into these cells. Consistent with this apparent phagocyte-like activity of the HCFs, mRNA and protein levels for several pro-inflammatory cytokines/chemokines (including TNFalpha, IL-1beta, IL-6, and IL-8) were significantly upregulated compared to uninfected samples. We similarly found an upregulation of several HCF metalloproteases (MMPs), which are enzymes that breakdown collagen during wound healing and may further activate pro-inflammatory signaling molecules. Finally, several fungal collagenase genes were upregulated during growth in the constructs relative to growth in tissue culture media alone, suggesting a fungal metabolic shift towards protein catabolism. Taken together, our results indicate that this 3D-stromal model provides a physiologically relevant system to study host and fungal cell pathobiology during FK.Item Ablation of Sphingosine Kinase 1 Protects Cornea from Neovascularization in a Mouse Corneal Injury Model(MDPI, 2022-09-24) Wilkerson, Joseph L.; Basu, Sandip K.; Stiles, Megan A.; Prislovsky, Amanda; Grambergs, Richard C.; Nicholas, Sarah E.; Karamichos, Dimitrios; Allegood, Jeremy C.; Proia, Richard L.; Mandal, NawajesThe purpose of this study was to investigate the role of sphingosine kinase 1 (SphK1), which generates sphingosine-1-phosphate (S1P), in corneal neovascularization (NV). Wild-type (WT) and Sphk1 knockout (Sphk1(-/-)) mice received corneal alkali-burn treatment to induce corneal NV by placing a 2 mm round piece of Whatman No. 1 filter paper soaked in 1N NaOH on the center of the cornea for 20 s. Corneal sphingolipid species were extracted and identified using liquid chromatography/mass spectrometry (LC/MS). The total number of tip cells and those positive for ethynyl deoxy uridine (EdU) were quantified. Immunocytochemistry was done to examine whether pericytes were present on newly forming blood vessels. Cytokine signaling and angiogenic markers were compared between the two groups using multiplex assays. Data were analyzed using appropriate statistical tests. Here, we show that ablation of SphK1 can significantly reduce NV invasion in the cornea following injury. Corneal sphingolipid analysis showed that total levels of ceramides, monohexosyl ceramides (HexCer), and sphingomyelin were significantly elevated in Sphk(-/-) corneas compared to WT corneas, with a comparable level of sphingosine among the two genotypes. The numbers of total and proliferating endothelial tip cells were also lower in the Sphk1(-/-) corneas following injury. This study underscores the role of S1P in post-injury corneal NV and raises further questions about the roles played by ceramide, HexCer, and sphingomyelin in regulating corneal NV. Further studies are needed to unravel the role played by bioactive sphingolipids in maintenance of corneal transparency and clear vision.Item Allostery: An Overview of Its History, Concepts, Methods, and Applications(PLOS, 2016-06-02) Liu, Jin; Nussinov, RuthThe concept of allostery has evolved in the past century. In this Editorial, we briefly overview the history of allostery, from the pre-allostery nomenclature era starting with the Bohr effect (1904) to the birth of allostery by Monod and Jacob (1961). We describe the evolution of the allostery concept, from a conformational change in a two-state model (1965, 1966) to dynamic allostery in the ensemble model (1999); from multi-subunit (1965) proteins to all proteins (2004). We highlight the current available methods to study allostery and their applications in studies of conformational mechanisms, disease, and allosteric drug discovery. We outline the challenges and future directions that we foresee. Altogether, this Editorial narrates the history of this fundamental concept in the life sciences, its significance, methodologies to detect and predict it, and its application in a broad range of living systems.Item Arginine Supplementation Promotes Extracellular Matrix and Metabolic Changes in Keratoconus(MDPI, 2021-08-13) McKay, Tina B.; Priyadarsini, Shrestha; Rowsey, Tyler; Karamichos, DimitriosKeratoconus (KC) is a common corneal ectatic disease that affects 1:500-1:2000 people worldwide and is associated with a progressive thinning of the corneal stroma that may lead to severe astigmatism and visual deficits. Riboflavin-mediated collagen crosslinking currently remains the only approved treatment to halt progressive corneal thinning associated with KC by improving the biomechanical properties of the stroma. Treatments designed to increase collagen deposition by resident corneal stromal keratocytes remain elusive. In this study, we evaluated the effects of arginine supplementation on steady-state levels of arginine and arginine-related metabolites (e.g., ornithine, proline, hydroxyproline, spermidine, and putrescine) and collagen protein expression by primary human corneal fibroblasts isolated from KC and non-KC (healthy) corneas and cultured in an established 3D in vitro model. We identified lower cytoplasmic arginine and spermidine levels in KC-derived constructs compared to healthy controls, which corresponded with overall higher gene expression of arginase. Arginine supplementation led to a robust increase in cytoplasmic arginine, ornithine, and spermidine levels in controls only and a significant increase in collagen type I secretion in KC-derived constructs. Further studies evaluating safety and efficacy of arginine supplementation are required to elucidate the potential therapeutic applications of modulating collagen deposition in the context of KC.Item Association of multimorbidity with the use of health information technology(Sage Publications, 2023-05-01) Manning, Sydney E.; Wang, Hao; Dwibedi, Nilanjana; Shen, Chan; Wiener, R. Constance; Findley, Patricia A.; Mitra, Sophie; Sambamoorthi, UshaOBJECTIVE: To examine the association of multimorbidity with health information technology use among adults in the USA. METHODS: We used cross-sectional study design and data from the Health Information National Trends Survey 5 Cycle 4. Health information technology use was measured with ten variables comprising access, recent use, and healthcare management. Unadjusted and adjusted logistic and multinomial logistic regressions were used to model the associations of multimorbidity with health information technology use. RESULTS: Among adults with multimorbidity, health information technology use for specific purposes ranged from 37.8% for helping make medical decisions to 51.7% for communicating with healthcare providers. In multivariable regressions, individuals with multimorbidity were more likely to report general use of health information technology (adjusted odds ratios = 1.48, 95% confidence intervals = 1.01-2.15) and more likely to use health information technology to check test results (adjusted odds ratios = 1.85, 95% confidence intervals = 1.33-2.58) compared to adults with only one chronic condition, however, there were no significant differences in other forms of health information technology use. We also observed interactive associations of multimorbidity and age on various components of health information technology use. Compared to younger adults with multimorbidity, older adults (>/= 65 years of age) with multimorbidity were less likely to use almost all aspects of health information technology. CONCLUSION: Health information technology use disparities by age and multimorbidity were observed. Education and interventions are needed to promote health information technology use among older adults in general and specifically among older adults with multimorbidity.Item Broader Implications of Modeling and Simulation (M&S) Tools in Pharmacotherapeutic Decisions: A Cautionary Optimism(Frontiers Media S.A., 2020-04-29) Chaturvedula, Ayyappa; Palasik, Brittany N.; Cho, Hae Jin; Goyal, NavinItem Cadmium-Induced Kidney Injury: Oxidative Damage as a Unifying Mechanism(MDPI, 2021-10-23) Yan, Liang-Jun; Allen, Daniel C.Cadmium is a nonessential metal that has heavily polluted the environment due to human activities. It can be absorbed into the human body via the gastrointestinal tract, respiratory tract, and the skin, and can cause chronic damage to the kidneys. The main site where cadmium accumulates and causes damage within the nephrons is the proximal tubule. This accumulation can induce dysfunction of the mitochondrial electron transport chain, leading to electron leakage and production of reactive oxygen species (ROS). Cadmium may also impair the function of NADPH oxidase, resulting in another source of ROS. These ROS together can cause oxidative damage to DNA, proteins, and lipids, triggering epithelial cell death and a decline in kidney function. In this article, we also reviewed evidence that the antioxidant power of plant extracts, herbal medicines, and pharmacological agents could ameliorate cadmium-induced kidney injury. Finally, a model of cadmium-induced kidney injury, centering on the notion that oxidative damage is a unifying mechanism of cadmium renal toxicity, is also presented. Given that cadmium exposure is inevitable, further studies using animal models are warranted for a detailed understanding of the mechanism underlying cadmium induced ROS production, and for the identification of more therapeutic targets.Item Cas9-catalyzed DNA Cleavage Generates Staggered Ends: Evidence from Molecular Dynamics Simulations(Springer Nature, 2016-11-22) Zuo, Zhicheng; Liu, JinThe CRISPR-associated endonuclease Cas9 from Streptococcus pyogenes (spCas9) along with a single guide RNA (sgRNA) has emerged as a versatile toolbox for genome editing. Despite recent advances in the mechanism studies on spCas9-sgRNA-mediated double-stranded DNA (dsDNA) recognition and cleavage, it is still unclear how the catalytic Mg(2+) ions induce the conformation changes toward the catalytic active state. It also remains controversial whether Cas9 generates blunt-ended or staggered-ended breaks with overhangs in the DNA. To investigate these issues, here we performed the first all-atom molecular dynamics simulations of the spCas9-sgRNA-dsDNA system with and without Mg(2+) bound. The simulation results showed that binding of two Mg(2+) ions at the RuvC domain active site could lead to structurally and energetically favorable coordination ready for the non-target DNA strand cleavage. Importantly, we demonstrated with our simulations that Cas9-catalyzed DNA cleavage produces 1-bp staggered ends rather than generally assumed blunt ends.Item Cellular Contractility Profiles of Human Diabetic Corneal Stromal Cells(Hindawi, 2021-06-04) Lam, Thi N.; Nicholas, S. E.; Choi, Alexander; Ma, Jian-Xing; Karamichos, DimitriosDiabetic keratopathy is a corneal complication of diabetes mellitus (DM). Patients with diabetic keratopathy are prone to developing corneal haze, scarring, recurrent erosions, and significant wound healing defects/delays. The purpose of this study was to determine the contractility profiles in the diabetic human corneal stromal cells and characterize their molecular signatures. Primary human corneal fibroblasts from healthy, Type 1 DM (T1DM), and Type 2 DM (T2DM) donors were cultured using an established 3D collagen gel model. We tracked, measured, and quantified the contractile footprint over 9 days and quantified the modulation of specific corneal/diabetes markers in the conditional media and cell lysates using western blot analysis. Human corneal fibroblasts (HCFs) exhibited delayed and decreased contractility compared to that from T1DMs and T2DMs. Compared to HCFs, T2DMs demonstrated an initial downregulation of collagen I (day 3), followed by a significant upregulation by day 9. Collagen V was significantly upregulated in both T1DMs and T2DMs based on basal secretion, when compared to HCFs. Cell lysates were upregulated in the myofibroblast-associated marker, alpha-smooth muscle actin, in T2DMs on day 9, corresponding to the significant increase in contractility rate observed at the same time point. Furthermore, our data demonstrated a significant upregulation in IGF-1 expression in T2DMs, when compared to HCFs and T1DMs, at day 9. T1DMs demonstrated significant downregulation of IGF-1 expression, when compared to HCFs. Overall, both T1DMs and T2DMs exhibited increased contractility associated with fibrotic phenotypes. These findings, and future studies, may contribute to better understanding of the pathobiology of diabetic keratopathy and ultimately the development of new therapeutic approaches.Item Characterization of Tear Immunoglobulins in a Small-Cohort of Keratoconus Patients(Springer Nature, 2020-06-10) McKay, Tina B.; Serjersen, Henrik; Hjortdal, Jesper; Zieske, James D.; Karamichos, DimitriosKeratoconus (KC) is classically considered a non-inflammatory condition caused by central corneal thinning that leads to astigmatism and reduced visual acuity. Previous studies have identified increased systemic levels of pro-inflammatory factors, including interleukin-6, tumor necrosis factor-alpha, and matrix metalloproteinase-9, suggesting that KC may have an inflammatory component in at least a subset of patients. In this study, we evaluated the levels of different immunoglobulins (light and heavy chains) based on Ig alpha, Ig lambda, Ig kappa, Ig micro, and Ig heavy chain subunits in non-KC tears (n = 7 control individuals) and KC tears (n = 7 KC patients) using tandem-liquid chromatography mass spectrometry. The most abundant Ig heavy chains detected in both control individuals and KC patients were Ig alpha-1 and Ig alpha-2 likely correlating to the higher IgA levels reported in human tears. We identified significant differences in immunoglobulin kappa-chain V-II levels in KC patients compared to control individuals with no significant difference in Ig kappa/Ig lambda ratios or heavy chain levels. Our study supports previous findings suggesting that KC possesses a systemic component that may contribute to the KC pathology. Further studies are required to define causality and establish a role for systemic immune system-dependent factors and pro-inflammatory processes in KC development or progression.Item Chromobacterium spp. mediate their anti-Plasmodium activity through secretion of the histone deacetylase inhibitor romidepsin(Springer Nature, 2018-04-18) Saraiva, Raul G.; Huitt-Roehl, Callie R.; Tripathi, Abhai; Cheng, Yi-Qiang; Bosch, Jurgen; Townsend, Craig A.; Dimopoulos, GeorgeThe Chromobacterium sp. Panama bacterium has in vivo and in vitro anti-Plasmodium properties. To assess the nature of the Chromobacterium-produced anti-Plasmodium factors, chemical partition was conducted by bioassay-guided fractionation where different fractions were assayed for activity against asexual stages of P. falciparum. The isolated compounds were further partitioned by reversed-phase FPLC followed by size-exclusion chromatography; high resolution UPLC and ESI/MS data were then collected and revealed that the most active fraction contained a cyclic depsipeptide, which was identified as romidepsin. A pure sample of this FDA-approved HDAC inhibitor allowed us to independently verify this finding, and establish that romidepsin also has potent effect against mosquito stages of the parasite's life cycle. Genomic comparisons between C. sp. Panama and multiple species within the Chromobacterium genus further demonstrated a correlation between presence of the gene cluster responsible for romidepsin production and effective antiplasmodial activity. A romidepsin-null Chromobacterium spp. mutant loses its anti-Plasmodium properties by losing the ability to inhibit P. falciparum HDAC activity, and romidepsin is active against resistant parasites to commonly deployed antimalarials. This independent mode of action substantiates exploring a chromobacteria-based approach for malaria transmission-blocking.Item Chronic Inhibition of Mitochondrial Dihydrolipoamide Dehydrogenase (DLDH) as an Approach to Managing Diabetic Oxidative Stress(MDPI, 2019-02-02) Yang, Xiaojuan; Song, Jing; Yan, Liang-JunMitochondrial dihydrolipoamide dehydrogenase (DLDH) is a redox enzyme involved in decarboxylation of pyruvate to form acetyl-CoA during the cascade of glucose metabolism and mitochondrial adenine triphosphate (ATP) production. Depending on physiological or pathophysiological conditions, DLDH can either enhance or attenuate the production of reactive oxygen species (ROS) and reactive nitrogen species. Recent research in our laboratory has demonstrated that inhibition of DLDH induced antioxidative responses and could serve as a protective approach against oxidative stress in stroke injury. In this perspective article, we postulated that chronic inhibition of DLDH could also attenuate oxidative stress in type 2 diabetes. We discussed DLDH-involving mitochondrial metabolic pathways and metabolic intermediates that could accumulate upon DLDH inhibition and their corresponding roles in abrogating oxidative stress in diabetes. We also discussed a couple of DLDH inhibitors that could be tested in animal models of type 2 diabetes. It is our belief that DLDH inhibition could be a novel approach to fighting type 2 diabetes.Item Collagen Crosslinking for Keratoconus: Cellular Signaling Mechanisms(MDPI, 2023-05-16) Karamichos, Dimitrios; Nicholas, Sarah E.; Khan, Asher; Riaz, Kamran M.Collagen crosslinking (CXL) is a widely used treatment to halt the progression of keratoconus (KC). Unfortunately, a significant number of patients with progressive KC will not qualify for CXL, including those with corneas thinner than 400 microm. The present study aimed to investigate the molecular effects of CXL using in vitro models, mirroring the normal, as well as thinner corneal stroma seen in KCs. Primary human corneal stromal cells were isolated from healthy (HCFs) and keratoconus (HKCs) donors. Cells were cultured and stimulated with stable Vitamin C resulting in 3D self-assembled extracellular matrix (ECM), cell-embedded, constructs. CXL was performed on (a) thin ECM with CXL performed at week 2 and (b) normal ECM with CXL performed at week 4. Constructs without CXL served as controls. All constructs were processed for protein analysis. The results showed modulation of Wnt signaling, following CXL treatment, as measured by the protein levels of Wnt7b and Wnt10a, correlated to the expression of alpha-smooth muscle actin (SMA). Further, the expression of a recently identified KC biomarker candidate, prolactin-induced protein (PIP), was positively impacted by CXL in HKCs. CXL-driven upregulation of PGC-1 and the downregulation of SRC and Cyclin D1 in HKCs were also noted. Although the cellular/molecular impacts of CXL are largely understudied, our studies provide an approximation to the complex mechanisms of KC and CXL. Further studies are warranted to determine factors influencing CXL outcomes.Item Community perspectives on AI/ML and health equity: AIM-AHEAD nationwide stakeholder listening sessions(PLOS, 2023-06-30) Vishwanatha, Jamboor K.; Christian, Allison; Sambamoorthi, Usha; Thompson, Erika L.; Stinson, Katie; Syed, Toufeeq A.Artificial intelligence and machine learning (AI/ML) tools have the potential to improve health equity. However, many historically underrepresented communities have not been engaged in AI/ML training, research, and infrastructure development. Therefore, AIM-AHEAD (Artificial Intelligence/Machine Learning Consortium to Advance Health Equity and Researcher Diversity) seeks to increase participation and engagement of researchers and communities through mutually beneficial partnerships. The purpose of this paper is to summarize feedback from listening sessions conducted by the AIM-AHEAD Coordinating Center in February 2022, titled the "AIM-AHEAD Community Building Convention (ACBC)." A total of six listening sessions were held over three days. A total of 977 people registered with AIM-AHEAD to attend ACBC and 557 individuals attended the listening sessions across stakeholder groups. Facilitators led the conversation based on a series of guiding questions, and responses were captured through voice and chat via the Slido platform. A professional third-party provider transcribed the audio. Qualitative analysis included data from transcripts and chat logs. Thematic analysis was then used to identify common and unique themes across all transcripts. Six main themes arose from the sessions. Attendees felt that storytelling would be a powerful tool in communicating the impact of AI/ML in promoting health equity, trust building is vital and can be fostered through existing trusted relationships, and diverse communities should be involved every step of the way. Attendees shared a wealth of information that will guide AIM-AHEAD's future activities. The sessions highlighted the need for researchers to translate AI/ML concepts into vignettes that are digestible to the larger public, the importance of diversity, and how open-science platforms can be used to encourage multi-disciplinary collaboration. While the sessions confirmed some of the existing barriers in applying AI/ML for health equity, they also offered new insights that were captured in the six themes.Item Competitive Displacement Restores the Hyperpolarized (15)N NMR Signal in Blood Plasma(American Chemical Society, 2023-03-28) Suh, Eul H.; Kovacs, ZoltanHyperpolarized (HP) NMR can improve the sensitivity of conventional NMR experiments by several orders of magnitude, thereby making it feasible to detect the signal of low sensitivity nuclei such as (13)C and (15)N nuclei in vivo. Hyperpolarized substrates are usually administered by direct injection into the bloodstream, and interaction with serum albumin can cause rapid decay of the hyperpolarized signal due to the shortening of the spin-lattice (T(1)) relaxation time. Here we report that the (15)N T(1) of (15)N labeled, partially deuterated tris(2-pyridylmethyl)amine decreases dramatically upon binding to albumin to such an extent that no HP-(15) signal could be detected. We also demonstrate that the signal could be restored using a competitive displacer, iophenoxic acid, which binds stronger to albumin than tris(2-pyridylmethyl)amine. The methodology presented here eliminates the undesirable effect of albumin binding and should widen the range of hyperpolarized probes for in vivo studies.Item Coronavirus disease 2019 pandemic associated with anxiety and depression among Non-Hispanic whites with chronic conditions in the US(Elsevier B.V., 2022-02-22) Wang, Hao; Paul, Jenny; Ye, Ivana; Blalock, Jake; Wiener, R. Constance; Ho, Amy F.; Alanis, Naomi; Sambamoorthi, UshaOBJECTIVES: During the coronavirus 2019 (COVID-19) pandemic, increased anxiety and depression were reported, with mixed findings among individuals of different races/ethnicities. This study examines whether anxiety and depression increased during the COVID-19 pandemic compared to the pre-COVD-19 period among different racial/ethnic groups in the US. METHODS: The Health Information National Trend Surveys 5 (HINTS 5) Cycle 4 data was analyzed. We used the time when the survey was administered as the pre-COVID-19 period (before March 11, 2020, weighted N = 77,501,549) and during the COVID-19 period (on and after March 11, 2020, weighted N = 37,222,019). The Patient Health Questionnaire (PHQ) was used to measure anxiety/depression and further compared before and during COVID-19. Separate multivariable logistic regression analyses were used to determine the association of the COVID-19 pandemic with anxiety/depression after adjusting for age, sex, insurance, income, and education. RESULT: A higher percentage of Non-Hispanic whites (NHW) with chronic conditions reported anxiety (24.3% vs. 11.5%, p = 0.0021) and depression (20.7% vs. 9.3%, p = 0.0034) during COVID-19 than pre-COVID-19. The adjusted odds ratio (AOR) of anxiety and depression for NHWs with chronic conditions during the COVID-19 pandemic was 2.02 (95% confidence interval of 1.10-3.73, p = 0.025) and 2.33 (1.17-4.65, p = 0.018) compared to NHWs who participated in the survey before the COVID-19. LIMITATIONS: Limited to the NHW US population. PHQ can only be used as the initial screening tool. CONCLUSION: The COVID-19 pandemic was associated with an increased prevalence of anxiety and depression among NHW adults with chronic conditions, but not among people of color.