359 results on '"Sethupathy, P"'
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2. An innovative approach utilizing bimetallic Ag@Sn-oxy nanocomposite with rGO-decorated glassy carbon-modified electrode for high-performance detection of hydroquinone
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Ramanathan, Sethupathy and Perumal, Panneerselvam
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- 2024
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3. Techniques, Tricks, and Algorithms for Efficient GPU-Based Processing of Higher Order Hyperbolic PDEs
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Subramanian, Sethupathy, Balsara, Dinshaw S., Bhoriya, Deepak, and Kumar, Harish
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- 2024
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4. miR-29 is an important driver of aging-related phenotypes
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Vijay Swahari, Ayumi Nakamura, Emilie Hollville, Yu-Han Hung, Matt Kanke, C. Lisa Kurtz, Xurde M. Caravia, David Roiz-Valle, Shenghui He, Janakiraman Krishnamurthy, Sahil Kapoor, Varun Prasad, Cornelius Flowers, Matt Beck, Jeanette Baran-Gale, Norman Sharpless, Carlos López-Otín, Praveen Sethupathy, and Mohanish Deshmukh
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Biology (General) ,QH301-705.5 - Abstract
Abstract Aging is a consequence of complex molecular changes, but whether a single microRNA (miRNA) can drive aging remains unclear. A miRNA known to be upregulated during both normal and premature aging is miR-29. We find miR-29 to also be among the top miRNAs predicted to drive aging-related gene expression changes. We show that partial loss of miR-29 extends the lifespan of Zmpste24 -/- mice, an established model of progeria, indicating that miR-29 is functionally important in this accelerated aging model. To examine whether miR-29 alone is sufficient to promote aging-related phenotypes, we generated mice in which miR-29 can be conditionally overexpressed (miR-29TG). miR-29 overexpression is sufficient to drive many aging-related phenotypes and led to early lethality. Transcriptomic analysis of both young miR-29TG and old WT mice reveals shared downregulation of genes associated with extracellular matrix organization and fatty acid metabolism, and shared upregulation of genes in pathways linked to inflammation. These results highlight the functional importance of miR-29 in controlling a gene expression program that drives aging-related phenotypes.
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- 2024
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5. Modeling Magnetically Channeled Winds in 3D: I. Isothermal Simulations of a Magnetic O Supergiant
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Subramanian, Sethupathy, Balsara, Dinshaw S., ud-Doula, Asif, and Gagné, Marc
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Astrophysics - Solar and Stellar Astrophysics ,Astrophysics - High Energy Astrophysical Phenomena - Abstract
In this paper we present the first set of 3D magnetohydrodynamic (MHD) simulations performed with the riemann geomesh code. We study the dynamics of the magnetically channeled winds of magnetic massive stars in full three dimensions using a code that is uniquely suited to spherical problems. Specifically, we perform isothermal simulations of a smooth wind on a rotating star with a tilted, initially dipolar field. We compare the mass-loss, angular momentum loss, and magnetospheric dynamics of a template star (with the properties that are reminiscent of the O4 supergiant {\zeta} Pup) over a range of rotation rates, magnetic field strengths, and magnetic tilt angles. The simulations are run up to a quasi-steady state and the results are observed to be consistent with the existing literature, showing the episodic centrifugal breakout events of the mass outflow, confined by the magnetic field loops that form the closed magnetosphere of the star. The catalogued results provide perspective on how angular-momentum loss varies for different configurations of rotation rate, magnetic field strength, and large magnetic tilt angles. In agreement with previous 2D MHD studies, we find that high magnetic confinement reduces the overall mass-loss rate, and higher rotation increases the mass-loss rate. This and future studies will be used to estimate the angular-momentum evolution, spin-down time, and mass-loss evolution of magnetic massive stars as a function of magnetic field strength, rotation rate, and dipole tilt.
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- 2023
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6. miR-29 is an important driver of aging-related phenotypes
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Swahari, Vijay, Nakamura, Ayumi, Hollville, Emilie, Hung, Yu-Han, Kanke, Matt, Kurtz, C. Lisa, Caravia, Xurde M., Roiz-Valle, David, He, Shenghui, Krishnamurthy, Janakiraman, Kapoor, Sahil, Prasad, Varun, Flowers, Cornelius, Beck, Matt, Baran-Gale, Jeanette, Sharpless, Norman, López-Otín, Carlos, Sethupathy, Praveen, and Deshmukh, Mohanish
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- 2024
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7. Comparing patient education tools for chronic pain medications: Artificial intelligence chatbot versus traditional patient information leaflets
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Prakash Gondode, Sakshi Duggal, Neha Garg, Surrender Sethupathy, Omshubham Asai, and Pooja Lohakare
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ai ,artificial intelligence ,analgesia ,chatgpt ,chronic pain ,medication adherence ,patient education ,readability ,Anesthesiology ,RD78.3-87.3 - Abstract
Background and Aims: Artificial intelligence (AI) chatbots like Conversational Generative Pre-trained Transformer (ChatGPT) have recently created much buzz, especially regarding patient education. Such informed patients understand and adhere to the management and get involved in shared decision making. The accuracy and understandability of the generated educational material are prime concerns. Thus, we compared ChatGPT with traditional patient information leaflets (PILs) about chronic pain medications. Methods: Patients' frequently asked questions were generated from PILs available on the official websites of the British Pain Society (BPS) and the Faculty of Pain Medicine. Eight blinded annexures were prepared for evaluation, consisting of traditional PILs from the BPS and AI-generated patient information materials structured similar to PILs by ChatGPT. The authors performed a comparative analysis to assess materials’ readability, emotional tone, accuracy, actionability, and understandability. Readability was measured using Flesch Reading Ease (FRE), Gunning Fog Index (GFI), and Flesch-Kincaid Grade Level (FKGL). Sentiment analysis determined emotional tone. An expert panel evaluated accuracy and completeness. Actionability and understandability were assessed with the Patient Education Materials Assessment Tool. Results: Traditional PILs generally exhibited higher readability (P values < 0.05), with [mean (standard deviation)] FRE [62.25 (1.6) versus 48 (3.7)], GFI [11.85 (0.9) versus 13.65 (0.7)], and FKGL [8.33 (0.5) versus 10.23 (0.5)] but varied emotional tones, often negative, compared to more positive sentiments in ChatGPT-generated texts. Accuracy and completeness did not significantly differ between the two. Actionability and understandability scores were comparable. Conclusion: While AI chatbots offer efficient information delivery, ensuring accuracy and readability, patient-centeredness remains crucial. It is imperative to balance innovation with evidence-based practice.
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- 2024
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8. Techniques, Tricks and Algorithms for Efficient GPU-Based Processing of Higher Order Hyperbolic PDEs
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Subramanian, Sethupathy, Balsara, Dinshaw S., Bhoriya, Deepak, and Kumar, Harish
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Mathematics - Numerical Analysis ,65M08, 65M22, 76M12, 35Q35, 35Q61, 35Q68, 35Q85, 76W05, 68Q85 - Abstract
GPU computing is expected to play an integral part in all modern Exascale supercomputers. It is also expected that higher order Godunov schemes will make up about a significant fraction of the application mix on such supercomputers. It is, therefore, very important to prepare the community of users of higher order schemes for hyperbolic PDEs for this emerging opportunity. We focus on three broad and high-impact areas where higher order Godunov schemes are used. The first area is computational fluid dynamics (CFD). The second is computational magnetohydrodynamics (MHD) which has an involution constraint that has to be mimetically preserved. The third is computational electrodynamics (CED) which has involution constraints and also extremely stiff source terms. Together, these three diverse uses of higher order Godunov methodology, cover many of the most important applications areas. In all three cases, we show that the optimal use of algorithms, techniques and tricks, along with the use of OpenACC, yields superlative speedups on GPUs! As a bonus, we find a most remarkable and desirable result: some higher order schemes, with their larger operations count per zone, show better speedup than lower order schemes on GPUs. In other words, the GPU is an optimal stratagem for overcoming the higher computational complexities of higher order schemes! Several avenues for future improvement have also been identified. A scalability study is presented for a real-world application using GPUs and comparable numbers of high-end multicore CPUs. It is found that GPUs offer a substantial performance benefit over comparable number of CPUs, especially when all the methods designed in this paper are used., Comment: 49 pages
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- 2022
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9. The Source Stabilized Galerkin Formulation for Linear Moving Conductor Problems with Edge Elements
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Bhowmick, Sujata and Subramanian, Sethupathy
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Mathematics - Numerical Analysis - Abstract
The phenomenon of linear motion of conductor in a magnetic field is commonly found in electric machineries such as, electromagnetic brakes, linear induction motor, electromagnetic flowmeter etc. The design and analysis of the same requires an accurate evaluation of induced currents and the associated reaction magnetic fields. The finite element method is a generally employed numerical technique for this purpose. However, it needs stabilization techniques to provide an accurate solution. In this work, such a stabilization technique is developed for the edge elements. The stability and hence the accuracy is brought in by a suitable representation of the source term. The stability and accuracy of the proposed scheme is first shown analytically and then demonstrated with the help of 2D and 3D simulations. The proposed scheme is parameter-free and it would require a graded regular mesh along the direction of motion.
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- 2022
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10. A Stable Weighted Residual Finite Element Formulation for the Simulation of Linear Moving Conductor Problems
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Subramanian, Sethupathy and Bhowmick, Sujata
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Mathematics - Numerical Analysis - Abstract
The finite element method is one of the widely employed numerical techniques in electrical engineering for the study of electric and magnetic fields. When applied to the moving conductor problems, the finite element method is known to have numerical oscillations in the solution. To resolve this, the upwinding techniques, which are developed for the transport equation are borrowed and directly employed for the magnetic induction equation. In this work, an alternative weighted residual formulation is explored for the simulation of the linear moving conductor problems. The formulation is parameter-free and the stability of the formulation is analytically studied for the 1D version of the moving conductor problem. Then the rate of convergence and the accuracy are illustrated with the help of several test cases in 1D as well as 2D. Subsequently, the stability of the formulation is demonstrated with a 3D moving conductor simulation.
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- 2022
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11. FlavorDB2: An Updated Database of Flavor Molecules
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Grover, Nishant, Goel, Mansi, Batra, Devansh, Garg, Neelansh, Tuwani, Rudraksh, Sethupathy, Apuroop, and Bagler, Ganesh
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Quantitative Biology - Quantitative Methods - Abstract
Flavor is expressed through interaction of molecules via gustatory and olfactory mechanisms. Knowing the utility of flavor molecules in food and fragrances, it is valuable to add a comprehensive repository of flavor compounds characterizing their flavor profile, chemical properties, regulatory status, consumption statistics, taste/aroma threshold values, reported uses in food categories, and synthesis. FlavorDB2 (https://cosylab.iiitd.edu.in/flavordb2/) is an updated database of flavor molecules with an user-friendly interface. This repository simplifies the search for flavor molecules, their attributes and offers a range of applications including food pairing. FlavorDB2 serves as a standard repository of flavor compounds., Comment: 5 pages, 2 figures
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- 2022
12. Efficacy and Safety of Low Dose Midazolam and Ketamine for Sedation During Invasive Procedures in Pediatric Hemato-Oncology
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Sethupathy, Abinaya, Gunasekaran, Vinod, Chelliah, Suresh, Pachamuthu, Meganathan, and Duraisamy, Senguttuvan
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- 2024
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13. Arch Bar Removal—How to Do It? A Short Note
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Sailesh Kumar, R., Venugopalan, V., Raghu, K., and Raja Sethupathy Cheeman, S.
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- 2023
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14. Integrative genome-scale analyses reveal post-transcriptional signatures of early human small intestinal development in a directed differentiation organoid model
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Yu-Han Hung, Meghan Capeling, Jonathan W. Villanueva, Matt Kanke, Michael T. Shanahan, Sha Huang, Rebecca Cubitt, Vera D. Rinaldi, John C. Schimenti, Jason R. Spence, and Praveen Sethupathy
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Micro-RNA ,Post-transcriptional regulation ,Intestine ,Development ,Functional genomics ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background MicroRNAs (miRNAs) are important post-transcriptional gene regulators controlling cellular lineage specification and differentiation during embryonic development, including the gastrointestinal system. However, miRNA-mediated regulatory mechanisms involved in early embryonic development of human small intestine (SI) remains underexplored. To explore candidate roles for miRNAs in prenatal SI lineage specification in humans, we used a multi-omic analysis strategy in a directed differentiation model that programs human pluripotent stem cells toward the SI lineage. Results We leveraged small RNA-seq to define the changing miRNA landscape, and integrated chromatin run-on sequencing (ChRO-seq) and RNA-seq to define genes subject to significant post-transcriptional regulation across the different stages of differentiation. Small RNA-seq profiling revealed temporal dynamics of miRNA signatures across different developmental events of the model, including definitive endoderm formation, SI lineage specification and SI regional patterning. Our multi-omic, integrative analyses showed further that the elevation of miR-182 and reduction of miR-375 are key events during SI lineage specification. We demonstrated that loss of miR-182 leads to an increase in the foregut master marker SOX2. We also used single-cell analyses in murine adult intestinal crypts to support a life-long role for miR-375 in the regulation of Zfp36l2. Finally, we uncovered opposing roles of SMAD4 and WNT signaling in regulating miR-375 expression during SI lineage specification. Beyond the mechanisms highlighted in this study, we also present a web-based application for exploration of post-transcriptional regulation and miRNA-mediated control in the context of early human SI development. Conclusion The present study uncovers a novel facet of miRNAs in regulating prenatal SI development. We leveraged multi-omic, systems biology approaches to discover candidate miRNA regulators associated with early SI developmental events in a human organoid model. In this study, we highlighted miRNA-mediated post-transcriptional regulation relevant to the event of SI lineage specification. The candidate miRNA regulators that we identified for the other stages of SI development also warrant detailed characterization in the future.
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- 2023
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15. miRNA-214-3p stimulates carcinogen-induced mammary epithelial cell apoptosis in mammary cancer-resistant species
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Rebecca M. Harman, Sanjna P. Das, Matt Kanke, Praveen Sethupathy, and Gerlinde R. Van de Walle
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Biology (General) ,QH301-705.5 - Abstract
Abstract Mammary cancer incidence varies greatly across species and underlying mechanisms remain elusive. We previously showed that mammosphere-derived epithelial cells from species with low mammary cancer incidence, such as horses, respond to carcinogen 7, 12-Dimethylbenz(a)anthracene-induced DNA damage by undergoing apoptosis, a postulated anti-cancer mechanism. Additionally, we found that miR-214-3p expression in mammosphere-derived epithelial cells is lower in mammary cancer-resistant as compared to mammary cancer-susceptible species. Here we show that increasing miR-214 expression and decreasing expression of its target gene nuclear factor kappa B subunit 1 in mammosphere-derived epithelial cells from horses abolishes 7,12-Dimethylbenz(a)anthracene-induced apoptosis. A direct interaction of miR-214-3p with another target gene, unc-5 netrin receptor A, is also demonstrated. We propose that relatively low levels of miR-214 in mammosphere-derived epithelial cells from mammals with low mammary cancer incidence, allow for constitutive gene nuclear factor kappa B subunit 1 expression and apoptosis in response to 7, 12-Dimethylbenz(a)anthracene. Better understanding of the mechanisms regulating cellular responses to carcinogens improves our overall understanding of mammary cancer resistance mechanisms.
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- 2023
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16. On Overcoming the Transverse Boundary Error of the SU/PG Scheme for Moving Conductor Problems
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Subramanian, Sethupathy, Kumar, Udaya, and Bhowmick, Sujata
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Mathematics - Numerical Analysis - Abstract
Conductor moving in magnetic field is quite common in electrical equipment. The numerical simulation of such problem is vital in their design and analysis of electrical equipment. The Galerkin finite element method (GFEM) is a commonly employed simulation tool, nonetheless, due to its inherent numerical instability at higher velocities, the GFEM requires upwinding techniques to handle moving conductor problems. The Streamline Upwinding/Petrov-Galerkin (SU/PG) scheme is a widely acknowledged upwinding technique, despite its error-peaking at the transverse boundary. This error at the transverse-boundary, is found to be leading to non-physical solutions. Several remedies have been suggested in the allied fluid dynamics literature, which employs non-linear, iterative techniques. The present work attempts to address this issue, by retaining the computational efficiency of the GFEM. By suitable analysis, it is shown that the source of the problem can be attributed to the Coulomb's gauge. Therefore, to solve the problem, the Coulomb's gauge is taken out from the formulation and the associated weak form is derived. The effectiveness of this technique is demonstrated with pertinent numerical results., Comment: 8 pages, 15 figures
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- 2021
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17. Integrative genome-scale analyses reveal post-transcriptional signatures of early human small intestinal development in a directed differentiation organoid model
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Hung, Yu-Han, Capeling, Meghan, Villanueva, Jonathan W., Kanke, Matt, Shanahan, Michael T., Huang, Sha, Cubitt, Rebecca, Rinaldi, Vera D., Schimenti, John C., Spence, Jason R., and Sethupathy, Praveen
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- 2023
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18. miRNA-214-3p stimulates carcinogen-induced mammary epithelial cell apoptosis in mammary cancer-resistant species
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Harman, Rebecca M., Das, Sanjna P., Kanke, Matt, Sethupathy, Praveen, and Van de Walle, Gerlinde R.
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- 2023
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19. Publisher Correction: A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans
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Zhang, Wencheng, Wang, Xicheng, Lanzoni, Giacomo, Wauthier, Eliane, Simpson, Sean, Ezzell, Jennifer Ashley, Allen, Amanda, Suitt, Carolyn, Krolik, Jonah, Jhirad, Alexander, Dominguez-Bendala, Juan, Cardinale, Vincenzo, Alvaro, Domenico, Overi, Diletta, Gaudio, Eugenio, Sethupathy, Praveen, Carpino, Guido, Adin, Christopher, Piedrahita, Jorge A, Mathews, Kyle, He, Zhiying, and Reid, Lola McAdams
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- 2023
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20. A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans
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Zhang, Wencheng, Wang, Xicheng, Lanzoni, Giacomo, Wauthier, Eliane, Simpson, Sean, Ezzell, Jennifer Ashley, Allen, Amanda, Suitt, Carolyn, Krolik, Jonah, Jhirad, Alexander, Dominguez-Bendala, Juan, Cardinale, Vincenzo, Alvaro, Domenico, Overi, Diletta, Gaudio, Eugenio, Sethupathy, Praveen, Carpino, Guido, Adin, Christopher, Piedrahita, Jorge A, Mathews, Kyle, He, Zhiying, and Reid, Lola McAdams
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- 2023
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21. DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma.
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Rosanna K Ma, Pei-Yin Tsai, Alaa R Farghli, Alexandria Shumway, Matt Kanke, John D Gordan, Taranjit S Gujral, Khashayar Vakili, Manabu Nukaya, Leila Noetzli, Sean Ronnekleiv-Kelly, Wendy Broom, Joeva Barrow, and Praveen Sethupathy
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Genetics ,QH426-470 - Abstract
Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long noncoding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo disease models. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, which indicates mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease.
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- 2024
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22. A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans
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Wencheng Zhang, Xicheng Wang, Giacomo Lanzoni, Eliane Wauthier, Sean Simpson, Jennifer Ashley Ezzell, Amanda Allen, Carolyn Suitt, Jonah Krolik, Alexander Jhirad, Juan Dominguez-Bendala, Vincenzo Cardinale, Domenico Alvaro, Diletta Overi, Eugenio Gaudio, Praveen Sethupathy, Guido Carpino, Christopher Adin, Jorge A Piedrahita, Kyle Mathews, Zhiying He, and Lola McAdams Reid
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Medicine - Abstract
Abstract A network of co-hepato/pancreatic stem/progenitors exists in pigs and humans in Brunner’s Glands in the submucosa of the duodenum, in peribiliary glands (PBGs) of intrahepatic and extrahepatic biliary trees, and in pancreatic duct glands (PDGs) of intrapancreatic biliary trees, collectively supporting hepatic and pancreatic regeneration postnatally. The network is found in humans postnatally throughout life and, so far, has been demonstrated in pigs postnatally at least through to young adulthood. These stem/progenitors in vivo in pigs are in highest numbers in Brunner’s Glands and in PDGs nearest the duodenum, and in humans are in Brunner’s Glands and in PBGs in the hepato/pancreatic common duct, a duct missing postnatally in pigs. Elsewhere in PDGs in pigs and in all PDGs in humans are only committed unipotent or bipotent progenitors. Stem/progenitors have genetic signatures in liver/pancreas-related RNA-seq data based on correlation, hierarchical clustering, differential gene expression and principal component analyses (PCA). Gene expression includes representative traits of pluripotency genes (SOX2, OCT4), endodermal transcription factors (e.g. SOX9, SOX17, PDX1), other stem cell traits (e.g. NCAM, CD44, sodium iodide symporter or NIS), and proliferation biomarkers (Ki67). Hepato/pancreatic multipotentiality was demonstrated by the stem/progenitors’ responses under distinct ex vivo conditions or in vivo when patch grafted as organoids onto the liver versus the pancreas. Therefore, pigs are logical hosts for translational/preclinical studies for cell therapies with these stem/progenitors for hepatic and pancreatic dysfunctions.
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- 2023
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23. Cellulose nanofibril/polylysine-based 3D composite antibacterial scaffold for wound healing applications
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Biranje, Santosh Shivaji, Shi, Yifei, Sun, Jianzhong, Cheng, Lu, Jiao, Haixin, Lu, Xuechu, Sethupathy, Sivasamy, Wang, Qianqian, Adivarekar, Ravindra V., and Liu, Jun
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- 2023
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24. Spatial mapping of the total transcriptome by in situ polyadenylation
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McKellar, David W., Mantri, Madhav, Hinchman, Meleana M., Parker, John S. L., Sethupathy, Praveen, Cosgrove, Benjamin D., and De Vlaminck, Iwijn
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- 2023
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25. Online Lifelong Generalized Zero-Shot Learning
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Gautam, Chandan, Parameswaran, Sethupathy, Mishra, Ashish, and Sundaram, Suresh
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Computer Science - Computer Vision and Pattern Recognition ,Computer Science - Artificial Intelligence - Abstract
Methods proposed in the literature for zero-shot learning (ZSL) are typically suitable for offline learning and cannot continually learn from sequential streaming data. The sequential data comes in the form of tasks during training. Recently, a few attempts have been made to handle this issue and develop continual ZSL (CZSL) methods. However, these CZSL methods require clear task-boundary information between the tasks during training, which is not practically possible. This paper proposes a task-free (i.e., task-agnostic) CZSL method, which does not require any task information during continual learning. The proposed task-free CZSL method employs a variational autoencoder (VAE) for performing ZSL. To develop the CZSL method, we combine the concept of experience replay with knowledge distillation and regularization. Here, knowledge distillation is performed using the training sample's dark knowledge, which essentially helps overcome the catastrophic forgetting issue. Further, it is enabled for task-free learning using short-term memory. Finally, a classifier is trained on the synthetic features generated at the latent space of the VAE. Moreover, the experiments are conducted in a challenging and practical ZSL setup, i.e., generalized ZSL (GZSL). These experiments are conducted for two kinds of single-head continual learning settings: (i) mild setting-: task-boundary is known only during training but not during testing; (ii) strict setting-: task-boundary is not known at training, as well as testing. Experimental results on five benchmark datasets exhibit the validity of the approach for CZSL.
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- 2021
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26. Generative Replay-based Continual Zero-Shot Learning
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Gautam, Chandan, Parameswaran, Sethupathy, Mishra, Ashish, and Sundaram, Suresh
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Computer Science - Computer Vision and Pattern Recognition ,Computer Science - Machine Learning - Abstract
Zero-shot learning is a new paradigm to classify objects from classes that are not available at training time. Zero-shot learning (ZSL) methods have attracted considerable attention in recent years because of their ability to classify unseen/novel class examples. Most of the existing approaches on ZSL works when all the samples from seen classes are available to train the model, which does not suit real life. In this paper, we tackle this hindrance by developing a generative replay-based continual ZSL (GRCZSL). The proposed method endows traditional ZSL to learn from streaming data and acquire new knowledge without forgetting the previous tasks' gained experience. We handle catastrophic forgetting in GRCZSL by replaying the synthetic samples of seen classes, which have appeared in the earlier tasks. These synthetic samples are synthesized using the trained conditional variational autoencoder (VAE) over the immediate past task. Moreover, we only require the current and immediate previous VAE at any time for training and testing. The proposed GRZSL method is developed for a single-head setting of continual learning, simulating a real-world problem setting. In this setting, task identity is given during training but unavailable during testing. GRCZSL performance is evaluated on five benchmark datasets for the generalized setup of ZSL with fixed and dynamic (incremental class) settings of continual learning. The existing class setting presented recently in the literature is not suitable for a class-incremental setting. Therefore, this paper proposes a new setting to address this issue. Experimental results show that the proposed method significantly outperforms the baseline and the state-of-the-art method and makes it more suitable for real-world applications.
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- 2021
27. Generalized Continual Zero-Shot Learning
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Gautam, Chandan, Parameswaran, Sethupathy, Mishra, Ashish, and Sundaram, Suresh
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Computer Science - Computer Vision and Pattern Recognition - Abstract
Recently, zero-shot learning (ZSL) emerged as an exciting topic and attracted a lot of attention. ZSL aims to classify unseen classes by transferring the knowledge from seen classes to unseen classes based on the class description. Despite showing promising performance, ZSL approaches assume that the training samples from all seen classes are available during the training, which is practically not feasible. To address this issue, we propose a more generalized and practical setup for ZSL, i.e., continual ZSL (CZSL), where classes arrive sequentially in the form of a task and it actively learns from the changing environment by leveraging the past experience. Further, to enhance the reliability, we develop CZSL for a single head continual learning setting where task identity is revealed during the training process but not during the testing. To avoid catastrophic forgetting and intransigence, we use knowledge distillation and storing and replay the few samples from previous tasks using a small episodic memory. We develop baselines and evaluate generalized CZSL on five ZSL benchmark datasets for two different settings of continual learning: with and without class incremental. Moreover, CZSL is developed for two types of variational autoencoders, which generates two types of features for classification: (i) generated features at output space and (ii) generated discriminative features at the latent space. The experimental results clearly indicate the single head CZSL is more generalizable and suitable for practical applications., Comment: Zero-shot Learning, Continual Learning, Incremental Learning
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- 2020
28. Genetic architecture modulates diet-induced hepatic mRNA and miRNA expression profiles in Diversity Outbred mice
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Que, Excel, James, Kristen L, Coffey, Alisha R, Smallwood, Tangi L, Albright, Jody, Huda, M Nazmul, Pomp, Daniel, Sethupathy, Praveen, and Bennett, Brian J
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Biological Sciences ,Genetics ,Biotechnology ,Human Genome ,Nutrition ,2.1 Biological and endogenous factors ,Aetiology ,Generic health relevance ,Animals ,Diet ,Genotype ,Hybridization ,Genetic ,Liver ,Mice ,MicroRNAs ,Multifactorial Inheritance ,Quantitative Trait Loci ,RNA ,Messenger ,Transcriptome ,quantitative trait loci ,multiparental models ,eQTL ,mirQTL ,High-fat diet ,High-protein diet ,High-fat diet ,High-protein diet ,Developmental Biology ,Biochemistry and cell biology - Abstract
Genetic approaches in model organisms have consistently demonstrated that molecular traits such as gene expression are under genetic regulation, similar to clinical traits. The resulting expression quantitative trait loci (eQTL) have revolutionized our understanding of genetic regulation and identified numerous candidate genes for clinically relevant traits. More recently, these analyses have been extended to other molecular traits such as protein abundance, metabolite levels, and miRNA expression. Here, we performed global hepatic eQTL and microRNA expression quantitative trait loci (mirQTL) analysis in a population of Diversity Outbred mice fed two different diets. We identified several key features of eQTL and mirQTL, namely differences in the mode of genetic regulation (cis or trans) between mRNA and miRNA. Approximately 50% of mirQTL are regulated by a trans-acting factor, compared to ∼25% of eQTL. We note differences in the heritability of mRNA and miRNA expression and variance explained by each eQTL or mirQTL. In general, cis-acting variants affecting mRNA or miRNA expression explain more phenotypic variance than trans-acting variants. Finally, we investigated the effect of diet on the genetic architecture of eQTL and mirQTL, highlighting the critical effects of environment on both eQTL and mirQTL. Overall, these data underscore the complex genetic regulation of two well-characterized RNA classes (mRNA and miRNA) that have critical roles in the regulation of clinical traits and disease susceptibility.
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- 2021
29. Efficient WENO-Based Prolongation Strategies for Divergence-Preserving Vector Fields
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Balsara, Dinshaw S., Samantaray, Saurav, and Subramanian, Sethupathy
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- 2023
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30. Comparative Analysis of microRNAs that Stratify in vitro Mammary stem and Progenitor Activity Reveals Functionality of Human miR-92b-3p
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Miller, James L., Kanke, Matt, Rauner, Gat, Bakhle, Kimaya M., Sethupathy, Praveen, and Van de Walle, Gerlinde R.
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- 2022
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31. Efficient, Divergence-Free, High Order MHD on 3D Spherical Meshes with Optimal Geodesic Meshing
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Balsara, Dinshaw S., Florinski, Vladimir, Garain, Sudip, Subramanian, Sethupathy, and Gurski, Katharine F.
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Physics - Computational Physics ,Astrophysics - Instrumentation and Methods for Astrophysics - Abstract
There is a great need in several areas of astrophysics and space-physics to carry out high order of accuracy, divergence-free MHD simulations on spherical meshes. This requires us to pay careful attention to the interplay between mesh quality and numerical algorithms. Methods have been designed that fundamentally integrate high order isoparametric mappings with the other high accuracy algorithms that are needed for divergence-free MHD simulations on geodesic meshes. The goal of this paper is to document such algorithms that are implemented in the geodesic mesh version of the RIEMANN code. The fluid variables are reconstructed using a special kind of WENO-AO algorithm that integrates the mesh geometry into the reconstruction process from the ground-up. A novel divergence-free reconstruction strategy for the magnetic field that performs efficiently at all orders, even on isoparametrically mapped meshes, is then presented. The MHD equations are evolved in space and time using a novel ADER predictor algorithm that is efficiently adapted to the isoparametrically mapped geometry. The application of one-dimensional and multidimensional Riemann solvers at suitable locations on the mesh then provides the corrector step. The corrector step for the magnetic field uses a Yee-type staggering of magnetic fields. This results in a scheme with divergence-free update for the magnetic field. The use of ADER enables a one-step update which only requires one messaging operation per complete timestep. This is very beneficial for parallel processing. Several accuracy tests are presented as are stringent test problems. PetaScale performance is also demonstrated on the largest available supercomputers., Comment: Accepted for publication in MNRAS
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- 2019
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32. Comprehensive microRNA analysis across genome-edited colorectal cancer organoid models reveals miR-24 as a candidate regulator of cell survival
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Jonathan W. Villanueva, Lawrence Kwong, Teng Han, Salvador Alonso Martinez, Michael T. Shanahan, Matt Kanke, Lukas E. Dow, Charles G. Danko, and Praveen Sethupathy
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Colorectal cancer ,MicroRNA ,Organoid ,CRISPR/Cas9 ,Tumor heterogeneity ,Precision medicine ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Somatic mutations drive colorectal cancer (CRC) by disrupting gene regulatory mechanisms. Distinct combinations of mutations can result in unique changes to regulatory mechanisms leading to variability in the efficacy of therapeutics. MicroRNAs are important regulators of gene expression, and their activity can be altered by oncogenic mutations. However, it is unknown how distinct combinations of CRC-risk mutations differentially affect microRNAs. Here, using genetically-modified mouse intestinal organoid (enteroid) models, we identify 12 different modules of microRNA expression patterns across different combinations of mutations common in CRC. We also show that miR-24-3p is aberrantly upregulated in genetically-modified mouse enteroids irrespective of mutational context. Furthermore, we identify an enrichment of miR-24-3p predicted targets in downregulated gene lists from various mutational contexts compared to WT. In follow-up experiments, we demonstrate that miR-24-3p promotes CRC cell survival in multiple cell contexts. Our novel characterization of genotype-specific patterns of miRNA expression offer insight into the mechanisms that drive inter-tumor heterogeneity and highlight candidate microRNA therapeutic targets for the advancement of precision medicine for CRC.
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- 2022
- Full Text
- View/download PDF
33. Nano-Agrochemicals as Substitutes for Pesticides: Prospects and Risks
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Shehbaz Ali, Naveed Ahmad, Mudasir A. Dar, Sehrish Manan, Abida Rani, Suliman Mohammed Suliman Alghanem, Khalid Ali Khan, Sivasamy Sethupathy, Noureddine Elboughdiri, Yasser S. Mostafa, Saad A. Alamri, Mohamed Hashem, Muhammad Shahid, and Daochen Zhu
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agriculture ,nanomaterials ,herbicides ,pesticides ,plant disease ,Botany ,QK1-989 - Abstract
This review delves into the mesmerizing technology of nano-agrochemicals, specifically pesticides and herbicides, and their potential to aid in the achievement of UN SDG 17, which aims to reduce hunger and poverty globally. The global market for conventional pesticides and herbicides is expected to reach USD 82.9 billion by 2027, growing 2.7% annually, with North America, Europe, and the Asia–Pacific region being the biggest markets. However, the extensive use of chemical pesticides has proven adverse effects on human health as well as the ecosystem. Therefore, the efficacy, mechanisms, and environmental impacts of conventional pesticides require sustainable alternatives for effective pest management. Undoubtedly, nano-agrochemicals have the potential to completely transform agriculture by increasing crop yields with reduced environmental contamination. The present review discusses the effectiveness and environmental impact of nanopesticides as promising strategies for sustainable agriculture. It provides a concise overview of green nano-agrochemical synthesis and agricultural applications, and the efficacy of nano-agrochemicals against pests including insects and weeds. Nano-agrochemical pesticides are investigated due to their unique size and exceptional performance advantages over conventional ones. Here, we have focused on the environmental risks and current state of nano-agrochemicals, emphasizing the need for further investigations. The review also draws the attention of agriculturists and stakeholders to the current trends of nanomaterial use in agriculture especially for reducing plant diseases and pests. A discussion of the pros and cons of nano-agrochemicals is paramount for their application in sustainable agriculture.
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- 2023
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34. Ectoine Globally Hypomethylates DNA in Skin Cells and Suppresses Cancer Proliferation
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Majjid A. Qaria, Chunyan Xu, Ran Hu, Roua A. Alsubki, Mohamed Yassin Ali, Sethupathy Sivasamy, Kotb A. Attia, and Daochen Zhu
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ectoine ,epigenetic modifications ,DNA hypomethylation ,skin cells ,tumorigenicity ,cell proliferation ,Biology (General) ,QH301-705.5 - Abstract
Epigenetic modifications, mainly aberrant DNA methylation, have been shown to silence the expression of genes involved in epigenetic diseases, including cancer suppression genes. Almost all conventional cancer therapeutic agents, such as the DNA hypomethylation drug 5-aza-2-deoxycytidine, have insurmountable side effects. To investigate the role of the well-known DNA protectant (ectoine) in skin cell DNA methylation and cancer cell proliferation, comprehensive methylome sequence analysis, 5-methyl cytosine (5mC) analysis, proliferation and tumorigenicity assays, and DNA epigenetic modifications-related gene analysis were performed. The results showed that extended ectoine treatment globally hypomethylated DNA in skin cells, especially in the CpG island (CGIs) element, and 5mC percentage was significantly reduced. Moreover, ectoine mildly inhibited skin cell proliferation and did not induce tumorigenicity in HaCaT cells injected into athymic nude mice. HaCaT cells treated with ectoine for 24 weeks modulated the mRNA expression levels of Dnmt1, Dnmt3a, Dnmt3b, Dnmt3l, Hdac1, Hdac2, Kdm3a, Mettl3, Mettl14, Snrpn, and Mest. Overall, ectoine mildly demethylates DNA in skin cells, modulates the expression of epigenetic modification-related genes, and reduces cell proliferation. This evidence suggests that ectoine is a potential anti-aging agent that prevents DNA hypermethylation and subsequently activates cancer-suppressing genes.
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- 2023
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35. Candidate master microRNA regulator of arsenic-induced pancreatic beta cell impairment revealed by multi-omics analysis
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Todero, Jenna E., Koch-Laskowski, Kieran, Shi, Qing, Kanke, Matt, Hung, Yu-Han, Beck, Rowan, Styblo, Miroslav, and Sethupathy, Praveen
- Published
- 2022
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36. Microbial diversity and community structure in deep-sea sediments of South Indian Ocean
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Zhu, Daochen, Sethupathy, Sivasamy, Gao, Lu, Nawaz, Muhammad Zohaib, Zhang, Weimin, Jiang, Jianxiong, and Sun, Jianzhong
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- 2022
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37. A framework for fibrolamellar carcinoma research and clinical trials
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Dinh, Timothy A., Utria, Alan F., Barry, Kevin C., Ma, Rosanna, Abou-Alfa, Ghassan K., Gordan, John D., Jaffee, Elizabeth M., Scott, John D., Zucman-Rossi, Jessica, O’Neill, Allison F., Furth, Mark E., and Sethupathy, Praveen
- Published
- 2022
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38. Templated synthesis and assembly with sustainable cellulose nanomaterial for functional nanostructure
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Wang, Qianqian, Zhou, Rui, Liu, Simeng, Sethupathy, Sivasamy, Liu, Jun, Sun, Jianzhong, Zou, Lihua, and Zhu, Qianqian
- Published
- 2022
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39. Acute suppression of insulin resistance-associated hepatic miR-29 in vivo improves glycemic control in adult mice
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Hung, Yu-Han, Kanke, Matt, Kurtz, C Lisa, Cubitt, Rebecca, Bunaciu, Rodica P, Miao, Ji, Zhou, Liye, Graham, James L, Hussain, M Mahmood, Havel, Peter, Biddinger, Sudha, White, Phillip J, and Sethupathy, Praveen
- Subjects
Diabetes ,Liver Disease ,Genetics ,Nutrition ,Digestive Diseases ,Obesity ,Biotechnology ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Animals ,Base Sequence ,Blood Glucose ,DNA Methyltransferase 3A ,Diabetes Mellitus ,Type 2 ,HEK293 Cells ,Humans ,Insulin Resistance ,Liver ,Macaca mulatta ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Obese ,MicroRNAs ,Oligonucleotides ,Rats ,Rats ,Zucker ,Enho ,insulin resistance ,liver ,microRNA-29 ,UCD-T2DM ,Medical Physiology ,Biochemistry & Molecular Biology - Abstract
MicroRNAs (miRNAs) are important posttranscriptional regulators of metabolism and energy homeostasis. Dysregulation of certain miRNAs in the liver has been shown to contribute to the pathogenesis of Type 2 diabetes (T2D), in part by impairing hepatic insulin sensitivity. By small RNA-sequencing analysis, we identified seven hepatic miRNAs (including miR-29b) that are consistently aberrantly expressed across five different rodent models of metabolic dysfunction that share the feature of insulin resistance (IR). We also showed that hepatic miR-29b exhibits persistent dysregulation during disease progression in a rat model of diabetes, UCD-T2DM. Furthermore, we observed that hepatic levels of miR-29 family members are attenuated by interventions known to improve IR in rodent and rhesus macaque models. To examine the function of the miR-29 family in modulating insulin sensitivity, we used locked nucleic acid (LNA) technology and demonstrated that acute in vivo suppression of the miR-29 family in adult mice leads to significant reduction of fasting blood glucose (in both chow-fed lean and high-fat diet-fed obese mice) and improvement in insulin sensitivity (in chow-fed lean mice). We carried out whole transcriptome studies and uncovered candidate mechanisms, including regulation of DNA methyltransferase 3a (Dnmt3a) and the hormone-encoding gene Energy homeostasis associated (Enho). In sum, we showed that IR/T2D is linked to dysregulation of hepatic miR-29b across numerous models and that acute suppression of the miR-29 family in adult mice leads to improved glycemic control. Future studies should investigate the therapeutic utility of miR-29 suppression in different metabolic disease states.Enho; insulin resistance; liver; microRNA-29 (miR-29); UCD-T2DM.
- Published
- 2019
40. TGR5 Protects Against Colitis in Mice, but Vertical Sleeve Gastrectomy Increases Colitis Severity.
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Garibay, Darline, Zaborska, Karolina, Shanahan, Michael, Zheng, Qiaonan, Kelly, Katie, Montrose, David, Dannenberg, Andrew, Miller, Andrew, Sethupathy, Praveen, and Cummings, Bethany
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Colitis ,TGR5 ,VSG ,Animals ,Bariatric Surgery ,Colitis ,Colon ,Disease Models ,Animal ,Gastrectomy ,Inflammatory Bowel Diseases ,Male ,Mice ,Mice ,Inbred C57BL ,Obesity ,Receptors ,G-Protein-Coupled ,Signal Transduction - Abstract
BACKGROUND AND AIMS: Bariatric surgery, such as vertical sleeve gastrectomy (VSG), is the most effective long-term treatment for obesity. However, there are conflicting reports on the effect of bariatric surgery on inflammatory bowel disease (IBD). Bariatric surgery increases bile acid concentrations, which can decrease inflammation by signaling through the bile acid receptor, TGR5. TGR5 signaling protects against chemically induced colitis in mice. VSG increases circulating bile acid concentrations to increase TGR5 signaling, which contributes to improved metabolic regulation after VSG. Therefore, we investigated the effect of VSG on chemically induced colitis development and the role of TGR5 in this context. METHODS: VSG or sham surgery was performed in high fat diet-fed male Tgr5+/+ and Tgr5-/- littermates. Sham-operated mice were food restricted to match their body weight to VSG-operated mice. Colitis was induced with 2.5% dextran sodium sulfate (DSS) in water post-operatively. Body weight, energy intake, fecal scoring, colon histopathology, colonic markers of inflammation, goblet cell counts, and colonic microRNA-21 levels were assessed. RESULTS: VSG decreased body weight independently of genotype. Consistent with previous work, genetic ablation of TGR5 increased the severity of DSS-induced colitis. Notably, despite the effect of VSG to decrease body weight and increase TGR5 signaling, VSG increased the severity of DSS-induced colitis. VSG-induced increases in colitis were associated with increased colonic expression of TNF-α, IL-6, MCP-1, and microRNA-21. CONCLUSIONS: While our data demonstrate that TGR5 protects against colitis, they also demonstrate that VSG potentiates chemically induced colitis in mice. These data suggest that individuals undergoing VSG may be at increased risk for developing colitis; however, further study is needed.
- Published
- 2019
41. Fructose-induced hypertriglyceridemia in rhesus macaques is attenuated with fish oil or ApoC3 RNA interference[S]
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Butler, Andrew A, Price, Candice A, Graham, James L, Stanhope, Kimber L, King, Sarah, Hung, Yu-Han, Sethupathy, Praveen, Wong, So, Hamilton, James, Krauss, Ronald M, Bremer, Andrew A, and Havel, Peter J
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Aging ,Obesity ,Prevention ,Nutrition ,Genetics ,Diabetes ,2.1 Biological and endogenous factors ,Aetiology ,Metabolic and endocrine ,Animals ,Apolipoprotein C-III ,Dietary Supplements ,Fish Oils ,Fructose ,Hypertriglyceridemia ,Macaca mulatta ,Male ,RNA Interference ,diet effects ,lipid metabolism ,nutrition ,carbohydrate ,nonhuman primate models ,apolipoproteins ,ribonucleic acid interference ,lipogenic enzymes ,acetyl-coenzyme A carboxylase ,apolipoprotein C3 ,diet effects/lipid metabolism ,nutrition/carbohydrate ,Medical Biochemistry and Metabolomics ,Biochemistry & Molecular Biology ,Biochemistry and cell biology ,Medical biochemistry and metabolomics - Abstract
Dyslipidemia and insulin resistance are significant adverse outcomes of consuming high-sugar diets. Conversely, dietary fish oil (FO) reduces plasma lipids. Diet-induced dyslipidemia in a rhesus model better approximates the pathophysiology of human metabolic syndrome (MetS) than rodent models. Here, we investigated relationships between metabolic parameters and hypertriglyceridemia in rhesus macaques consuming a high-fructose diet (n = 59) and determined the effects of FO supplementation or RNA interference (RNAi) on plasma ApoC3 and triglyceride (TG) concentrations. Fructose supplementation increased body weight, fasting insulin, leptin, TGs, and large VLDL particles and reduced adiponectin concentrations (all P < 0.001). In multiple regression analyses, increased plasma ApoC3 was the most consistent and significant variable related to diet-induced hypertriglyceridemia. FO supplementation, which attenuated increases of plasma TG and ApoC3 concentrations, reversed fructose-induced shifts of lipoprotein particle size toward IDL and VLDL, a likely mechanism contributing to beneficial metabolic effects, and reduced hepatic expression of genes regulated by the SREBP pathway, particularly acetyl-CoA carboxylase. Furthermore, RNAi-mediated ApoC3 inhibition lowered plasma TG concentrations in animals with diet-induced hypertriglyceridemia. In summary, ApoC3 is an important independent correlate of TG-rich lipoprotein concentrations in rhesus macaques consuming a high-fructose diet. ApoC3 is a promising therapeutic target for hypertriglyceridemia in patients with MetS and diabetes.
- Published
- 2019
42. Outcomes of ST Segment Elevation Myocardial Infarction without Standard Modifiable Cardiovascular Risk Factors – Newer Insights from a Prospective Registry in India
- Author
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Gnanaraj Justin Paul, Sabarish Sankaran, Karthikaa Saminathan, Mohamed Iliyas, Suryakanth Sethupathy, Sivasubramaniam Saravanan, Salai Sudhan Prabhu, Sijoy Kurian, Sandeep Srinivas, Polavarappu Anurag, Kumaran Srinivasan, Elavarasi Manimegalai, Swaminathan Nagarajan, Rajasekar Ramesh, PM Nageswaran, Venkatesan Sangareddi, and Ravishankar Govindarajulu
- Subjects
myocardial infarction ,atherosclerosis ,risk factors ,outcome ,mortality ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 ,Public aspects of medicine ,RA1-1270 - Abstract
Objectives: Patients with ST elevation myocardial infarction (STEMI) without standard modifiable cardiovascular risk factors (SMuRFs; dyslipidaemia, hypertension, diabetes mellitus and smoking) are reported to have a worse clinical outcome compared to those with SMuRFs. However, robust prospective data and low-and middle-income country perspective are lacking. We aimed to study the patients with first STEMI and assess the influence of SMuRFs on clinical outcomes by comparing the patients with and without SMuRFs. Methods: We included all consecutive STEMI patients without prior coronary artery disease enrolled in the Madras Medical College STEMI Registry from September 2018 to October 2019. We collected baseline clinical characteristics, revascularisation strategies and clinical outcome. We analysed suboptimal self-reported sleep duration as a 5th extended SMuRF (eSMuRF). Primary outcome was in-hospital mortality. Secondary outcomes included in-hospital complications and one-year all-cause mortality. Results: Among 2,379 patients, 605 patients (25.4%) were SMuRF-less. More women were SMuRF-less than men (27.1% vs 22.1%; P = 0.012). SMuRF-less patients were older (57.44 ± 13.95 vs 55.68 ± 11.74; P < 0.001), more often former tobacco users (10.4% vs 5.0%; P < 0.001), with more anterior wall MI (62.6% vs 52.1%; P = 0.032). The primary outcome [in-hospital mortality (10.7% vs 11.3%; P = 0.72)] and secondary outcomes [in-hospital complications (29.1% vs 31.7%; P = 0.23) and one-year all-cause mortality (22.3% vs 22.7%; P = 0.85)] were similar in both groups. Addition of suboptimal self-reported sleep duration as a 5th eSMuRF yielded similar results. Conclusions: 25% of first STEMI patients were SMuRF-less. Clinical outcomes of patients without SMuRFs were similar to those with SMuRFs. Suboptimal sleep duration did not account for the risk associated with the SMuRF-less status.
- Published
- 2023
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43. Oncogenic PKA signaling increases c-MYC protein expression through multiple targetable mechanisms
- Author
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Gary KL Chan, Samantha Maisel, Yeonjoo C Hwang, Bryan C Pascual, Rebecca RB Wolber, Phuong Vu, Krushna C Patra, Mehdi Bouhaddou, Heidi L Kenerson, Huat C Lim, Donald Long, Raymond S Yeung, Praveen Sethupathy, Danielle L Swaney, Nevan J Krogan, Rigney E Turnham, Kimberly J Riehle, John D Scott, Nabeel Bardeesy, and John D Gordan
- Subjects
protein kinase A ,kinase proteomics ,MYC ,fibrolamellar liver cancer ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Genetic alterations that activate protein kinase A (PKA) are found in many tumor types. Yet, their downstream oncogenic signaling mechanisms are poorly understood. We used global phosphoproteomics and kinase activity profiling to map conserved signaling outputs driven by a range of genetic changes that activate PKA in human cancer. Two signaling networks were identified downstream of PKA: RAS/MAPK components and an Aurora Kinase A (AURKA)/glycogen synthase kinase (GSK3) sub-network with activity toward MYC oncoproteins. Findings were validated in two PKA-dependent cancer models: a novel, patient-derived fibrolamellar carcinoma (FLC) line that expresses a DNAJ-PKAc fusion and a PKA-addicted melanoma model with a mutant type I PKA regulatory subunit. We identify PKA signals that can influence both de novo translation and stability of the proto-oncogene c-MYC. However, the primary mechanism of PKA effects on MYC in our cell models was translation and could be blocked with the eIF4A inhibitor zotatifin. This compound dramatically reduced c-MYC expression and inhibited FLC cell line growth in vitro. Thus, targeting PKA effects on translation is a potential treatment strategy for FLC and other PKA-driven cancers.
- Published
- 2023
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44. Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes
- Author
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Xu, Guanlan, Grimes, Tiffany D., Grayson, Truman B., Chen, Junqin, Thielen, Lance A., Tse, Hubert M., Li, Peng, Kanke, Matt, Lin, Tai-Tu, Schepmoes, Athena A., Swensen, Adam C., Petyuk, Vladislav A., Ovalle, Fernando, Sethupathy, Praveen, Qian, Wei-Jun, and Shalev, Anath
- Published
- 2022
- Full Text
- View/download PDF
45. Comprehensive microRNA analysis across genome-edited colorectal cancer organoid models reveals miR-24 as a candidate regulator of cell survival
- Author
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Villanueva, Jonathan W., Kwong, Lawrence, Han, Teng, Martinez, Salvador Alonso, Shanahan, Michael T., Kanke, Matt, Dow, Lukas E., Danko, Charles G., and Sethupathy, Praveen
- Published
- 2022
- Full Text
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46. Exploratory study reveals far reaching systemic and cellular effects of verapamil treatment in subjects with type 1 diabetes
- Author
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Guanlan Xu, Tiffany D. Grimes, Truman B. Grayson, Junqin Chen, Lance A. Thielen, Hubert M. Tse, Peng Li, Matt Kanke, Tai-Tu Lin, Athena A. Schepmoes, Adam C. Swensen, Vladislav A. Petyuk, Fernando Ovalle, Praveen Sethupathy, Wei-Jun Qian, and Anath Shalev
- Subjects
Science - Abstract
Oral verapamil lowers inflammatory markers and daily insulin needs in subjects with type 1 diabetes and helps preserve pancreatic beta cell function for at least two years. In this context, serum chromogranin A provides a promising therapy marker.
- Published
- 2022
- Full Text
- View/download PDF
47. Single-Cell Analysis Reveals Unexpected Cellular Changes and Transposon Expression Signatures in the Colonic Epithelium of Treatment-Naïve Adult Crohn’s Disease PatientsSummary
- Author
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Matt Kanke, Meaghan M. Kennedy Ng, Sean Connelly, Manvendra Singh, Matthew Schaner, Michael T. Shanahan, Elizabeth A. Wolber, Caroline Beasley, Grace Lian, Animesh Jain, Millie D. Long, Edward L. Barnes, Hans H. Herfarth, Kim L. Isaacs, Jonathon J. Hansen, Muneera Kapadia, Jose Gaston Guillem, Cedric Feschotte, Terrence S. Furey, Shehzad Z. Sheikh, and Praveen Sethupathy
- Subjects
Crohn’s Disease ,Single-Cell ,Epithelium ,Colonocyte ,Gene Expression ,ISC ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: The intestinal barrier comprises a monolayer of specialized intestinal epithelial cells (IECs) that are critical in maintaining mucosal homeostasis. Dysfunction within various IEC fractions can alter intestinal permeability in a genetically susceptible host, resulting in a chronic and debilitating condition known as Crohn’s disease (CD). Defining the molecular changes in each IEC type in CD will contribute to an improved understanding of the pathogenic processes and the identification of cell type–specific therapeutic targets. We performed, at single-cell resolution, a direct comparison of the colonic epithelial cellular and molecular landscape between treatment-naïve adult CD and non–inflammatory bowel disease control patients. Methods: Colonic epithelial-enriched, single-cell sequencing from treatment-naïve adult CD and non–inflammatory bowel disease patients was investigated to identify disease-induced differences in IEC types. Results: Our analysis showed that in CD patients there is a significant skew in the colonic epithelial cellular distribution away from canonical LGR5+ stem cells, located at the crypt bottom, and toward one specific subtype of mature colonocytes, located at the crypt top. Further analysis showed unique changes to gene expression programs in every major cell type, including a previously undescribed suppression in CD of most enteroendocrine driver genes as well as L-cell markers including GCG. We also dissect an incompletely understood SPIB+ cell cluster, revealing at least 4 subclusters that likely represent different stages of a maturational trajectory. One of these SPIB+ subclusters expresses crypt-top colonocyte markers and is up-regulated significantly in CD, whereas another subcluster strongly expresses and stains positive for lysozyme (albeit no other canonical Paneth cell marker), which surprisingly is greatly reduced in expression in CD. In addition, we also discovered transposable element markers of colonic epithelial cell types as well as transposable element families that are altered significantly in CD in a cell type–specific manner. Finally, through integration with data from genome-wide association studies, we show that genes implicated in CD risk show heretofore unknown cell type–specific patterns of aberrant expression in CD, providing unprecedented insight into the potential biological functions of these genes. Conclusions: Single-cell analysis shows a number of unexpected cellular and molecular features, including transposable element expression signatures, in the colonic epithelium of treatment-naïve adult CD.
- Published
- 2022
- Full Text
- View/download PDF
48. Unlocking the Potential of Catechyl Lignin: Molecular Regulation of Biosynthesis, Structural Organization, And Valorization.
- Author
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Uddin, Nisar, Li, Xia, Ullah, Muhammad Wajid, Sethupathy, Sivasamy, Chen, Fang, Yang, Bin, and Zhu, Daochen
- Published
- 2024
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- View/download PDF
49. Publisher Correction: A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans
- Author
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Wencheng Zhang, Xicheng Wang, Giacomo Lanzoni, Eliane Wauthier, Sean Simpson, Jennifer Ashley Ezzell, Amanda Allen, Carolyn Suitt, Jonah Krolik, Alexander Jhirad, Juan Dominguez-Bendala, Vincenzo Cardinale, Domenico Alvaro, Diletta Overi, Eugenio Gaudio, Praveen Sethupathy, Guido Carpino, Christopher Adin, Jorge A Piedrahita, Kyle Mathews, Zhiying He, and Lola McAdams Reid
- Subjects
Medicine - Published
- 2023
- Full Text
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50. Adropin: An endocrine link between the biological clock and cholesterol homeostasis
- Author
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Ghoshal, Sarbani, Stevens, Joseph R, Billon, Cyrielle, Girardet, Clemence, Sitaula, Sadichha, Leon, Arthur S, Rao, DC, Skinner, James S, Rankinen, Tuomo, Bouchard, Claude, Nuñez, Marinelle V, Stanhope, Kimber L, Howatt, Deborah A, Daugherty, Alan, Zhang, Jinsong, Schuelke, Matthew, Weiss, Edward P, Coffey, Alisha R, Bennett, Brian J, Sethupathy, Praveen, Burris, Thomas P, Havel, Peter J, and Butler, Andrew A
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Genetics ,Atherosclerosis ,Nutrition ,Digestive Diseases ,Liver Disease ,Obesity ,Prevention ,Underpinning research ,1.1 Normal biological development and functioning ,Metabolic and endocrine ,Adult ,Aged ,Animals ,Blood Proteins ,Cells ,Cultured ,Cholesterol ,LDL ,Circadian Clocks ,Female ,Glucose ,Hep G2 Cells ,Homeostasis ,Humans ,Intercellular Signaling Peptides and Proteins ,Liver ,Macaca mulatta ,Male ,Mice ,Middle Aged ,Nuclear Receptor Subfamily 1 ,Group F ,Member 1 ,Nuclear Receptor Subfamily 1 ,Group F ,Member 3 ,Peptides ,Proteins ,Cholesterol ,LDL ,Cardiovascular disease ,Adropin ,Sex ,Physiology ,Biochemistry and cell biology - Abstract
ObjectiveIdentify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function.MethodsAssociations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models.ResultsIn humans, plasma adropin concentrations are inversely related to atherogenic LDL-cholesterol (LDL-C) levels in men (n = 349), but not in women (n = 401). Analysis of hepatic Enho expression in male mice suggests control by the biological clock. Expression is rhythmic, peaking during maximal food consumption in the dark correlating with transcriptional activation by RORα/γ. The nadir in the light phase coincides with the rest phase and repression by Rev-erb. Plasma adropin concentrations in nonhuman primates (rhesus monkeys) also exhibit peaks coinciding with feeding times (07:00 h, 15:00 h). The ROR inverse agonists SR1001 and the 7-oxygenated sterols 7-β-hydroxysterol and 7-ketocholesterol, or the Rev-erb agonist SR9009, suppress ENHO expression in cultured human HepG2 cells. Consumption of high-cholesterol diets suppress expression of the adropin transcript in mouse liver. However, adropin over expression does not prevent hypercholesterolemia resulting from a high cholesterol diet and/or LDL receptor mutations.ConclusionsIn humans, associations between plasma adropin concentrations and LDL-C suggest a link with hepatic lipid metabolism. Mouse studies suggest that the relationship between adropin and cholesterol metabolism is unidirectional, and predominantly involves suppression of adropin expression by cholesterol and 7-oxygenated sterols. Sensing of fatty acids, cholesterol and oxysterols by the RORα/γ ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism. Furthermore, the nuclear receptors RORα/γ and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism.
- Published
- 2018
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