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2,138 results on '"Gladyshev, Vadim N."'

2. Age-associated clonal B cells drive B cell lymphoma in mice

Author

Castro, José P., Shindyapina, Anastasia V., Barbieri, Alessandro, Ying, Kejun, Strelkova, Olga S., Paulo, João A., Tyshkovskiy, Alexander, Meinl, Rico, Kerepesi, Csaba, Petrashen, Anna P., Mariotti, Marco, Meer, Margarita V., Hu, Yan, Karamyshev, Alexander, Losyev, Grigoriy, Galhardo, Mafalda, Logarinho, Elsa, Indzhykulian, Artur A., Gygi, Steven P., Sedivy, John M., Manis, John P., and Gladyshev, Vadim N.

Published
2024
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3. Challenges and recommendations for the translation of biomarkers of aging

Author

Herzog, Chiara M. S., Goeminne, Ludger J. E., Poganik, Jesse R., Barzilai, Nir, Belsky, Daniel W., Betts-LaCroix, Joe, Chen, Brian H., Chen, Michelle, Cohen, Alan A., Cummings, Steven R., Fedichev, Peter O., Ferrucci, Luigi, Fleming, Alexander, Fortney, Kristen, Furman, David, Gorbunova, Vera, Higgins-Chen, Albert, Hood, Lee, Horvath, Steve, Justice, Jamie N., Kiel, Douglas P., Kuchel, George A., Lasky-Su, Jessica, LeBrasseur, Nathan K., Maier, Andrea B., Schilling, Birgit, Sebastiano, Vittorio, Slagboom, P. Eline, Snyder, Michael P., Verdin, Eric, Widschwendter, Martin, Zhavoronkov, Alex, Moqri, Mahdi, and Gladyshev, Vadim N.

Published
2024
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5. PRC2-AgeIndex as a universal biomarker of aging and rejuvenation

Author

Moqri, Mahdi, Cipriano, Andrea, Simpson, Daniel J., Rasouli, Sajede, Murty, Tara, de Jong, Tineke Anna, Nachun, Daniel, de Sena Brandine, Guilherme, Ying, Kejun, Tarkhov, Andrei, Aberg, Karolina A., van den Oord, Edwin, Zhou, Wanding, Smith, Andrew, Mackall, Crystal, Gladyshev, Vadim N., Horvath, Steve, Snyder, Michael P., and Sebastiano, Vittorio

Published
2024
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10. TIME-seq reduces time and cost of DNA methylation measurement for epigenetic clock construction

Author

Griffin, Patrick T., Kane, Alice E., Trapp, Alexandre, Li, Jien, Arnold, Matthew, Poganik, Jesse R., Conway, Ryan J., McNamara, Maeve S., Meer, Margarita V., Hoffman, Noah, Amorim, João A., Tian, Xiao, MacArthur, Michael R., Mitchell, Sarah J., Mueller, Amber L., Carmody, Colleen, Vera, Daniel L., Kerepesi, Csaba, Ying, Kejun, Noren Hooten, Nicole, Mitchell, James R., Evans, Michele K., Gladyshev, Vadim N., and Sinclair, David A.

Published
2024
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11. Validation of biomarkers of aging

Author

Moqri, Mahdi, Herzog, Chiara, Poganik, Jesse R., Ying, Kejun, Justice, Jamie N., Belsky, Daniel W., Higgins-Chen, Albert T., Chen, Brian H., Cohen, Alan A., Fuellen, Georg, Hägg, Sara, Marioni, Riccardo E., Widschwendter, Martin, Fortney, Kristen, Fedichev, Peter O., Zhavoronkov, Alex, Barzilai, Nir, Lasky-Su, Jessica, Kiel, Douglas P., Kennedy, Brian K., Cummings, Steven, Slagboom, P. Eline, Verdin, Eric, Maier, Andrea B., Sebastiano, Vittorio, Snyder, Michael P., Gladyshev, Vadim N., Horvath, Steve, and Ferrucci, Luigi

Published
2024
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13. Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Author

Aguado, Julio, Amarilla, Alberto A., Taherian Fard, Atefeh, Albornoz, Eduardo A., Tyshkovskiy, Alexander, Schwabenland, Marius, Chaggar, Harman K., Modhiran, Naphak, Gómez-Inclán, Cecilia, Javed, Ibrahim, Baradar, Alireza A., Liang, Benjamin, Peng, Lianli, Dharmaratne, Malindrie, Pietrogrande, Giovanni, Padmanabhan, Pranesh, Freney, Morgan E., Parry, Rhys, Sng, Julian D. J., Isaacs, Ariel, Khromykh, Alexander A., Valenzuela Nieto, Guillermo, Rojas-Fernandez, Alejandro, Davis, Thomas P., Prinz, Marco, Bengsch, Bertram, Gladyshev, Vadim N., Woodruff, Trent M., Mar, Jessica C., Watterson, Daniel, and Wolvetang, Ernst J.

Published
2023
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18. Meeting Report: Aging Research and Drug Discovery

Author

Meron, Esther, Thaysen, Maria, Angeli, Suzanne, Antebi, Adam, Barzilai, Nir, Baur, Joseph A, Bekker-Jensen, Simon, Birkisdottir, Maria, Bischof, Evelyne, Bruening, Jens, Brunet, Anne, Buchwalter, Abigail, Cabreiro, Filipe, Cai, Shiqing, Chen, Brian H, Ermolaeva, Maria, Ewald, Collin Y, Ferrucci, Luigi, Florian, Maria Carolina, Fortney, Kristen, Freund, Adam, Georgievskaya, Anastasia, Gladyshev, Vadim N, Glass, David, Golato, Tyler, Gorbunova, Vera, Hoejimakers, Jan, Houtkooper, Riekelt H, Jager, Sibylle, Jaksch, Frank, Janssens, Georges, Jensen, Martin Borch, Kaeberlein, Matt, Karsenty, Gerard, de Keizer, Peter, Kennedy, Brian, Kirkland, James L, Kjaer, Michael, Kroemer, Guido, Lee, Kai-Fu, Lemaitre, Jean-Marc, Liaskos, David, Longo, Valter D, Lu, Yu-Xuan, MacArthur, Michael R, Maier, Andrea B, Manakanatas, Christina, Mitchell, Sarah J, Moskalev, Alexey, Niedernhofer, Laura, Ozerov, Ivan, Partridge, Linda, Passegué, Emmanuelle, Petr, Michael A, Peyer, James, Radenkovic, Dina, Rando, Thomas A, Rattan, Suresh, Riedel, Christian G, Rudolph, Lenhard, Ai, Ruixue, Serrano, Manuel, Schumacher, Björn, Sinclair, David A, Smith, Ryan, Suh, Yousin, Taub, Pam, Trapp, Alexandre, Trendelenburg, Anne-Ulrike, Valenzano, Dario Riccardo, Verburgh, Kris, Verdin, Eric, Vijg, Jan, Westendorp, Rudi GJ, Zonari, Alessandra, Bakula, Daniela, Zhavoronkov, Alex, and Scheibye-Knudsen, Morten

Subjects
Aging, aging, drug discovery, conference, AI, longevity, Biochemistry and Cell Biology, Physiology, Oncology and Carcinogenesis, Developmental Biology
Abstract

Aging is the single largest risk factor for most chronic diseases, and thus possesses large socioeconomic interest to continuously aging societies. Consequently, the field of aging research is expanding alongside a growing focus from the industry and investors in aging research. This year's 8th Annual Aging Research and Drug Discovery (ARDD) meeting was organized as a hybrid meeting from August 30th to September 3rd 2021 with more than 130 attendees participating on-site at the Ceremonial Hall at University of Copenhagen, Denmark, and 1800 engaging online. The conference comprised of presentations from 75 speakers focusing on new research in topics including mechanisms of aging and how these can be modulated as well as the use of AI and new standards of practices within aging research. This year, a longevity workshop was included to build stronger connections with the clinical community.

Published
2022

19. Molecular damage in aging

Author

Gladyshev, Vadim N, Kritchevsky, Stephen B, Clarke, Steven G, Cuervo, Ana Maria, Fiehn, Oliver, de Magalhães, João Pedro, Mau, Theresa, Maes, Michal, Moritz, Robert L, Niedernhofer, Laura J, Van Schaftingen, Emile, Tranah, Gregory J, Walsh, Kenneth, Yura, Yoshimitsu, Zhang, Bohan, and Cummings, Steven R

Subjects
Aging, Genetics, Underpinning research, 1.1 Normal biological development and functioning, Humans, DNA Damage, Organelles, DNA, Models, Biological
Abstract

Cellular metabolism generates molecular damage affecting all levels of biological organization. Accumulation of this damage over time is thought to play a central role in the aging process, but damage manifests in diverse molecular forms complicating its assessment. Insufficient attention has been paid to date to the role of molecular damage in aging-related phenotypes, particularly in humans, in part because of the difficulty in measuring its various forms. Recently, omics approaches have been developed that begin to address this challenge, because they are able to assess a sizeable proportion of age-related damage at the level of small molecules, proteins, RNA, DNA, organelles and cells. This review describes the concept of molecular damage in aging and discusses its diverse aspects from theoretical models to experimental approaches. Measurement of multiple types of damage enables studies of the role of damage in human aging outcomes and lays a foundation for testing interventions to reduce the burden of molecular damage, opening new approaches to slowing aging and reducing its consequences.

Published
2021

24. Biomarkers of aging for the identification and evaluation of longevity interventions

Author

Moqri, Mahdi, Herzog, Chiara, Poganik, Jesse R., Justice, Jamie, Belsky, Daniel W., Higgins-Chen, Albert, Moskalev, Alexey, Fuellen, Georg, Cohen, Alan A., Bautmans, Ivan, Widschwendter, Martin, Ding, Jingzhong, Fleming, Alexander, Mannick, Joan, Han, Jing-Dong Jackie, Zhavoronkov, Alex, Barzilai, Nir, Kaeberlein, Matt, Cummings, Steven, Kennedy, Brian K., Ferrucci, Luigi, Horvath, Steve, Verdin, Eric, Maier, Andrea B., Snyder, Michael P., Sebastiano, Vittorio, and Gladyshev, Vadim N.

Published
2023
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26. ARDD 2020: from aging mechanisms to interventions

Author

Mkrtchyan, Garik V, Abdelmohsen, Kotb, Andreux, Pénélope, Bagdonaite, Ieva, Barzilai, Nir, Brunak, Søren, Cabreiro, Filipe, de Cabo, Rafael, Campisi, Judith, Cuervo, Ana Maria, Demaria, Marco, Ewald, Collin Y, Fang, Evandro Fei, Faragher, Richard, Ferrucci, Luigi, Freund, Adam, Silva-García, Carlos G, Georgievskaya, Anastasia, Gladyshev, Vadim N, Glass, David J, Gorbunova, Vera, de Grey, Aubrey, He, Wei-Wu, Hoeijmakers, Jan, Hoffmann, Eva, Horvath, Steve, Houtkooper, Riekelt H, Jensen, Majken K, Jensen, Martin Borch, Kane, Alice, Kassem, Moustapha, de Keizer, Peter, Kennedy, Brian, Karsenty, Gerard, Lamming, Dudley W, Lee, Kai-Fu, MacAulay, Nanna, Mamoshina, Polina, Mellon, Jim, Molenaars, Marte, Moskalev, Alexey, Mund, Andreas, Niedernhofer, Laura, Osborne, Brenna, Pak, Heidi H, Parkhitko, Andrey, Raimundo, Nuno, Rando, Thomas A, Rasmussen, Lene Juel, Reis, Carolina, Riedel, Christian G, Franco-Romero, Anais, Schumacher, Björn, Sinclair, David A, Suh, Yousin, Taub, Pam R, Toiber, Debra, Treebak, Jonas T, Valenzano, Dario Riccardo, Verdin, Eric, Vijg, Jan, Young, Sergey, Zhang, Lei, Bakula, Daniela, Zhavoronkov, Alex, and Scheibye-Knudsen, Morten

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Clinical Sciences, Biological Sciences, Aging, Good Health and Well Being, Artificial Intelligence, Biomedical Research, Cellular Senescence, Congresses as Topic, Drug Discovery, Humans, Life Style, Longevity, Pharmaceutical Preparations, aging, interventions, drug discovery, artificial intelligence, Biochemistry and cell biology, Clinical sciences
Abstract

Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7th Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8th ARDD meeting that is scheduled for the 31st of August to 3rd of September, 2021, at Columbia University, USA.

Published
2020

27. A comparative genomics multitool for scientific discovery and conservation

Author

Genereux, Diane P, Serres, Aitor, Armstrong, Joel, Johnson, Jeremy, Marinescu, Voichita D, Murén, Eva, Juan, David, Bejerano, Gill, Casewell, Nicholas R, Chemnick, Leona G, Damas, Joana, Di Palma, Federica, Diekhans, Mark, Fiddes, Ian T, Garber, Manuel, Gladyshev, Vadim N, Goodman, Linda, Haerty, Wilfried, Houck, Marlys L, Hubley, Robert, Kivioja, Teemu, Koepfli, Klaus-Peter, Kuderna, Lukas FK, Lander, Eric S, Meadows, Jennifer RS, Murphy, William J, Nash, Will, Noh, Hyun Ji, Nweeia, Martin, Pfenning, Andreas R, Pollard, Katherine S, Ray, David A, Shapiro, Beth, Smit, Arian FA, Springer, Mark S, Steiner, Cynthia C, Swofford, Ross, Taipale, Jussi, Teeling, Emma C, Turner-Maier, Jason, Alfoldi, Jessica, Birren, Bruce, Ryder, Oliver A, Lewin, Harris A, Paten, Benedict, Marques-Bonet, Tomas, Lindblad-Toh, Kerstin, and Karlsson, Elinor K

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Ecology, Evolutionary Biology, Genetics, Human Genome, Biotechnology, Generic health relevance, Life on Land, Animals, Biodiversity, Biomedical Research, Conservation of Natural Resources, Eutheria, Evolution, Molecular, Extinction, Biological, Genetic Speciation, Genetic Variation, Genomics, Humans, Infections, Knowledge Discovery, Loss of Heterozygosity, Neoplasms, Phylogeny, Risk Assessment, Selection, Genetic, Sequence Alignment, Species Specificity, Venoms, Zoonomia Consortium, General Science & Technology
Abstract

The Zoonomia Project is investigating the genomics of shared and specialized traits in eutherian mammals. Here we provide genome assemblies for 131 species, of which all but 9 are previously uncharacterized, and describe a whole-genome alignment of 240 species of considerable phylogenetic diversity, comprising representatives from more than 80% of mammalian families. We find that regions of reduced genetic diversity are more abundant in species at a high risk of extinction, discern signals of evolutionary selection at high resolution and provide insights from individual reference genomes. By prioritizing phylogenetic diversity and making data available quickly and without restriction, the Zoonomia Project aims to support biological discovery, medical research and the conservation of biodiversity.

Published
2020

28. Mitigating age-related somatic mutation burden

Author

Vijg, Jan, Schumacher, Björn, Abakir, Abdulkadir, Antonov, Michael, Bradley, Chris, Cagan, Alex, Church, George, Gladyshev, Vadim N., Gorbunova, Vera, Maslov, Alexander Y., Reik, Wolf, Sharifi, Samim, Suh, Yousin, and Walsh, Kenneth

Published
2023
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30. Biological age is increased by stress and restored upon recovery

Author

Poganik, Jesse R., Zhang, Bohan, Baht, Gurpreet S., Tyshkovskiy, Alexander, Deik, Amy, Kerepesi, Csaba, Yim, Sun Hee, Lu, Ake T., Haghani, Amin, Gong, Tong, Hedman, Anna M., Andolf, Ellika, Pershagen, Göran, Almqvist, Catarina, Clish, Clary B., Horvath, Steve, White, James P., and Gladyshev, Vadim N.

Published
2023
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32. Loss of epigenetic information as a cause of mammalian aging

Author

Yang, Jae-Hyun, Hayano, Motoshi, Griffin, Patrick T., Amorim, João A., Bonkowski, Michael S., Apostolides, John K., Salfati, Elias L., Blanchette, Marco, Munding, Elizabeth M., Bhakta, Mital, Chew, Yap Ching, Guo, Wei, Yang, Xiaojing, Maybury-Lewis, Sun, Tian, Xiao, Ross, Jaime M., Coppotelli, Giuseppe, Meer, Margarita V., Rogers-Hammond, Ryan, Vera, Daniel L., Lu, Yuancheng Ryan, Pippin, Jeffrey W., Creswell, Michael L., Dou, Zhixun, Xu, Caiyue, Mitchell, Sarah J., Das, Abhirup, O’Connell, Brendan L., Thakur, Sachin, Kane, Alice E., Su, Qiao, Mohri, Yasuaki, Nishimura, Emi K., Schaevitz, Laura, Garg, Neha, Balta, Ana-Maria, Rego, Meghan A., Gregory-Ksander, Meredith, Jakobs, Tatjana C., Zhong, Lei, Wakimoto, Hiroko, El Andari, Jihad, Grimm, Dirk, Mostoslavsky, Raul, Wagers, Amy J., Tsubota, Kazuo, Bonasera, Stephen J., Palmeira, Carlos M., Seidman, Jonathan G., Seidman, Christine E., Wolf, Norman S., Kreiling, Jill A., Sedivy, John M., Murphy, George F., Green, Richard E., Garcia, Benjamin A., Berger, Shelley L., Oberdoerffer, Philipp, Shankland, Stuart J., Gladyshev, Vadim N., Ksander, Bruce R., Pfenning, Andreas R., Rajman, Luis A., and Sinclair, David A.

Published
2023
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33. DNA methylation markers to assess biological age

Author

Podolskiy, Dmitriy I. and Gladyshev, Vadim N.

Subjects
Quantitative Biology - Genomics
Abstract

Among the different biomarkers of aging based on omics and clinical data, DNA methylation clocks stand apart providing unmatched accuracy in assessing the biological age of both humans and animal models of aging. Here, we discuss robustness of DNA methylation clocks and bounds on their out-of-sample performance and review computational strategies for development of the clocks., Comment: 15 pages, 5 figures, to be published as Chapter 13 in "Biomarkers of aging", ed. A. Moskalev, Springer, 2019

Published
2018

34. DNA methylation aging clocks: challenges and recommendations

Author

Bell, Christopher G, Lowe, Robert, Adams, Peter D, Baccarelli, Andrea A, Beck, Stephan, Bell, Jordana T, Christensen, Brock C, Gladyshev, Vadim N, Heijmans, Bastiaan T, Horvath, Steve, Ideker, Trey, Issa, Jean-Pierre J, Kelsey, Karl T, Marioni, Riccardo E, Reik, Wolf, Relton, Caroline L, Schalkwyk, Leonard C, Teschendorff, Andrew E, Wagner, Wolfgang, Zhang, Kang, and Rakyan, Vardhman K

Subjects
Biological Sciences, Genetics, Human Genome, Aging, Generic health relevance, Animals, Biological Clocks, DNA Methylation, Epigenesis, Genetic, Genome, Human, Genome-Wide Association Study, Humans, Environmental Sciences, Information and Computing Sciences, Bioinformatics
Abstract

Epigenetic clocks comprise a set of CpG sites whose DNA methylation levels measure subject age. These clocks are acknowledged as a highly accurate molecular correlate of chronological age in humans and other vertebrates. Also, extensive research is aimed at their potential to quantify biological aging rates and test longevity or rejuvenating interventions. Here, we discuss key challenges to understand clock mechanisms and biomarker utility. This requires dissecting the drivers and regulators of age-related changes in single-cell, tissue- and disease-specific models, as well as exploring other epigenomic marks, longitudinal and diverse population studies, and non-human models. We also highlight important ethical issues in forensic age determination and predicting the trajectory of biological aging in an individual.

Published
2019

40. Development and Optimization of a Redox Enzyme-Based Fluorescence Biosensor for the Identification of MsrB1 Inhibitors.

Author

Shim, Hyun Bo, Lee, Hyunjeong, Cho, Hwa Yeon, Jo, Young Ho, Tarrago, Lionel, Kim, Hyunggee, Gladyshev, Vadim N., and Lee, Byung Cheon

Subjects
METHIONINE sulfoxide reductase, FLUORESCENT proteins, HIGH throughput screening (Drug development), KNOCKOUT mice, PHENYL compounds
Abstract

MsrB1 is a thiol-dependent enzyme that reduces protein methionine-R-sulfoxide and regulates inflammatory response in macrophages. Therefore, MsrB1 could be a promising therapeutic target for the control of inflammation. To identify MsrB1 inhibitors, we construct a redox protein-based fluorescence biosensor composed of MsrB1, a circularly permutated fluorescent protein, and the thioredoxin1 in a single polypeptide chain. This protein-based biosensor, named RIYsense, efficiently measures protein methionine sulfoxide reduction by ratiometric fluorescence increase. We used it for high-throughput screening of potential MsrB1 inhibitors among 6868 compounds. A total of 192 compounds were selected based on their ability to reduce relative fluorescence intensity by more than 50% compared to the control. Then, we used molecular docking simulations of the compound on MsrB1, affinity assays, and MsrB1 activity measurement to identify compounds with reliable and strong inhibitory effects. Two compounds were selected as MsrB1 inhibitors: 4-[5-(4-ethylphenyl)-3-(4-hydroxyphenyl)-3,4-dihydropyrazol-2-yl]benzenesulfonamide and 6-chloro-10-(4-ethylphenyl)pyrimido[4,5-b]quinoline-2,4-dione. They are heterocyclic, polyaromatic compounds with a substituted phenyl moiety interacting with the MsrB1 active site, as revealed by docking simulation. These compounds were found to decrease the expression of anti-inflammatory cytokines such as IL-10 and IL-1rn, leading to auricular skin swelling and increased thickness in an ear edema model, effectively mimicking the effects observed in MsrB1 knockout mice. In summary, using a novel redox protein-based fluorescence biosensor, we identified potential MsrB1 inhibitors that can regulate the inflammatory response, particularly by influencing the expression of anti-inflammatory cytokines. These compounds are promising tools for understanding MsrB1's role during inflammation and eventually controlling inflammation in therapeutic approaches. [ABSTRACT FROM AUTHOR]

Published
2024
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41. Aging and drug discovery

Author

Bakula, Daniela, Aliper, Alexander M, Mamoshina, Polina, Petr, Michael A, Teklu, Amanuel, Baur, Joseph A, Campisi, Judith, Ewald, Collin Y, Georgievskaya, Anastasia, Gladyshev, Vadim N, Kovalchuk, Olga, Lamming, Dudley W, Luijsterburg, Martijn S, Martín-Montalvo, Alejandro, Maudsley, Stuart, Mkrtchyan, Garik V, Moskalev, Alexey, Olshansky, S Jay, Ozerov, Ivan V, Pickett, Alexander, Ristow, Michael, Zhavoronkov, Alex, and Scheibye-Knudsen, Morten

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Clinical Sciences, Biological Sciences, Aging, 5.1 Pharmaceuticals, 5.9 Resources and infrastructure (treatment development), Generic health relevance, Good Health and Well Being, aging, drug discovery, Biochemistry and cell biology, Clinical sciences
Abstract

Multiple interventions in the aging process have been discovered to extend the healthspan of model organisms. Both industry and academia are therefore exploring possible transformative molecules that target aging and age-associated diseases. In this overview, we summarize the presented talks and discussion points of the 5th Annual Aging and Drug Discovery Forum 2018 in Basel, Switzerland. Here academia and industry came together, to discuss the latest progress and issues in aging research. The meeting covered talks about the mechanistic cause of aging, how longevity signatures may be highly conserved, emerging biomarkers of aging, possible interventions in the aging process and the use of artificial intelligence for aging research and drug discovery. Importantly, a consensus is emerging both in industry and academia, that molecules able to intervene in the aging process may contain the potential to transform both societies and healthcare.

Published
2018

42. NEDD9 targets COL3A1 to promote endothelial fibrosis and pulmonary arterial hypertension

Author

Samokhin, Andriy O, Stephens, Thomas, Wertheim, Bradley M, Wang, Rui-Sheng, Vargas, Sara O, Yung, Lai-Ming, Cao, Minwei, Brown, Marcel, Arons, Elena, Dieffenbach, Paul B, Fewell, Jason G, Matar, Majed, Bowman, Frederick P, Haley, Kathleen J, Alba, George A, Marino, Stefano M, Kumar, Rahul, Rosas, Ivan O, Waxman, Aaron B, Oldham, William M, Khanna, Dinesh, Graham, Brian B, Seo, Sachiko, Gladyshev, Vadim N, Yu, Paul B, Fredenburgh, Laura E, Loscalzo, Joseph, Leopold, Jane A, and Maron, Bradley A

Subjects
Rare Diseases, Lung, 2.1 Biological and endogenous factors, Aetiology, Cardiovascular, Adaptor Proteins, Signal Transducing, Animals, Collagen Type III, Endothelial Cells, Female, Fibrosis, Humans, Hypertension, Pulmonary, Male, Phosphoproteins, Protein Binding, Pulmonary Artery, Rats, Rats, Sprague-Dawley, Smad3 Protein, Systems Biology, Biological Sciences, Medical and Health Sciences
Abstract

Germline mutations involving small mothers against decapentaplegic-transforming growth factor-β (SMAD-TGF-β) signaling are an important but rare cause of pulmonary arterial hypertension (PAH), which is a disease characterized, in part, by vascular fibrosis and hyperaldosteronism (ALDO). We developed and analyzed a fibrosis protein-protein network (fibrosome) in silico, which predicted that the SMAD3 target neural precursor cell expressed developmentally down-regulated 9 (NEDD9) is a critical ALDO-regulated node underpinning pathogenic vascular fibrosis. Bioinformatics and microscale thermophoresis demonstrated that oxidation of Cys18 in the SMAD3 docking region of NEDD9 impairs SMAD3-NEDD9 protein-protein interactions in vitro. This effect was reproduced by ALDO-induced oxidant stress in cultured human pulmonary artery endothelial cells (HPAECs), resulting in impaired NEDD9 proteolytic degradation, increased NEDD9 complex formation with Nk2 homeobox 5 (NKX2-5), and increased NKX2-5 binding to COL3A1 Up-regulation of NEDD9-dependent collagen III expression corresponded to changes in cell stiffness measured by atomic force microscopy. HPAEC-derived exosomal signaling targeted NEDD9 to increase collagen I/III expression in human pulmonary artery smooth muscle cells, identifying a second endothelial mechanism regulating vascular fibrosis. ALDO-NEDD9 signaling was not affected by treatment with a TGF-β ligand trap and, thus, was not contingent on TGF-β signaling. Colocalization of NEDD9 with collagen III in HPAECs was observed in fibrotic pulmonary arterioles from PAH patients. Furthermore, NEDD9 ablation or inhibition prevented fibrotic vascular remodeling and pulmonary hypertension in animal models of PAH in vivo. These data identify a critical TGF-β-independent posttranslational modification that impairs SMAD3-NEDD9 binding in HPAECs to modulate vascular fibrosis and promote PAH.

Published
2018

43. Molecular Footprints of Aquatic Adaptation Including Bone Mass Changes in Cetaceans.

Author

Zhou, Xuming, Sun, Di, Guang, Xuanmin, Ma, Siming, Fang, Xiaodong, Mariotti, Marco, Nielsen, Rasmus, Gladyshev, Vadim N, and Yang, Guang

Subjects
Bone and Bones, Animals, Cetacea, Adaptation, Physiological, cetacean, comparative genomics, aquatic adaptation, bone microanatomical structure, Adaptation, Physiological, Developmental Biology, Biochemistry and Cell Biology, Evolutionary Biology, Genetics
Abstract

Cetaceans (whales, dolphins, and porpoises) are a group of specialized mammals that evolved from terrestrial ancestors and are fully adapted to aquatic habitats. Taking advantage of the recently sequenced finless porpoise genome, we conducted comparative analyses of the genomes of seven cetaceans and related terrestrial species to provide insight into the molecular bases of adaptation of these aquatic mammals. Changes in gene sequences were identified in main lineages of cetaceans, offering an evolutionary picture of cetacean genomes that reveal new pathways that could be associated with adaptation to aquatic lifestyle. We profiled bone microanatomical structures across 28 mammals, including representatives of cetaceans, pinnipeds, and sirenians. Subsequent phylogenetic comparative analyses revealed genes (including leptin, insulin-like growth factor 1, and collagen type I alpha 2 chain) with the root-to-tip substitution rate significantly correlated with bone compactness, implicating these genes could be involved in bone mass control. Overall, this study described adjustments of the genomes of cetaceans according to lifestyle, phylogeny, and bone mass.

Published
2018

46. Epigenetic predictors of species maximum life span and other life-history traits in mammals

Author

Li, Caesar Z., primary, Haghani, Amin, additional, Yan, Qi, additional, Lu, Ake T., additional, Zhang, Joshua, additional, Fei, Zhe, additional, Ernst, Jason, additional, Yang, X. William, additional, Gladyshev, Vadim N., additional, Robeck, Todd R., additional, Chavez, Andreas S., additional, Cook, Joseph A., additional, Dunnum, Jonathan L., additional, Raj, Ken, additional, Seluanov, Andrei, additional, Gorbunova, Vera, additional, and Horvath, Steve, additional

Published
2024
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